A COMPLETE GUIDE TO LUNG CANCER Copyright 2001, Howard A. Gutman
TABLE OF CONTENTS 1. What is Cancer 2. Metastasis 3. The cancer process in the Lung 4. Lung Anatomy 5. Chemotherapy 5A. Chemotherapy side effects 6. Radiation 7. Surgery 8. Treatment of Non small cell cancer, stages 1 and 2 9. Treatment of Non small cell, stages 3 and 4 10. Small Cell Lung Cancer 11. Metastasis and Anti-angiogenesis treatments 12. Gene Therapy 13. Clinical Trials 14. Other experimental therapies and overseas treatment 15. Mesothelioma 16. Omitted or other forms of lung cancer 17. Health Insurance Issues 18. Long and Short.-term Survival 19. Screening and early Detection of Lung Cancer 20. Medical malpractice claims. 21. Smoking and Cancer 22. Asbestos, silica and other occupational claims 23. Racial and Gender Influences in the Cause and Treatment of Lung Cancer 24. Research Sources. 25. What Families Members Can Do to Help. APPENDIX 1. Glossary 2. Organizations Dealing with Lung Cancer 3. Seminars and symposiums dealing with lung cancer 4. U.S. News and World Report Rating of Hospitals
__________________________________________________________________ CHAPTER 1: WHAT IS CANCER _________________________________ 1.0 WHY PATIENTS AND THEIR FAMILIES NEED A BASIC UNDERSTANDING OF LUNG CANCER This book is designed to provide a detailed, but understandable, review of lung cancer. Specifically, By understanding the basics, you can direct your questioning to the details of your condition, rather than asking for general explanations about cancer and how it develops. Some decisions may not be made by the doctor alone. In many cases, there are experimental treatments. Knowing the medical basis for the treatment may help you make the decision of whether a particular clinical trial or other treatment is for you. Understanding what certain chemotherapy drugs are trying to do, and why certain side effects develop may help you to understand and deal with them. 1.02 Organizational Scheme Chapter one begins by discussing what cancer is, how and why normal cells change to cancer cells. Chapter two discusses how tumors metastasize. Chapter three discusses lung cancer specifically, the division between small cell and non-small cell lung cancer, and the different stages and ways of categorizing cancers. By the end of chapter three, you should have a basic understanding of how your disease developed and where it stands now. Chapters four through nine discuss surgery, chemotherapy and radiation which are the primary forms of treatment, and in nine through eleven, we review treatments at different stages utilizing materials from the National Cancer Institute. This chapter discusses what cancer is and how normal cells change to cancerous ones. 1.03 The Approach of This Book As I worked on this book, a member of my family contracted cancer, and I realized firsthand the stress such a diagnosis entails. However, I have tried to discuss cancer in a analytical fashion, laying out the facts and science even where they may paint a difficult picture, believing that being educated can only help the patient and his family. This is designed to be a middle book, more detailed than a general book about cancer, easier to read than a medical text. My goal is to lay out the science of lung cancer in a thorough, comprehensive, but understandable fashion. We begin by discussing what cancer is. 1.04 Limits Hopefully this book will add to your knowledge about lung cancer and help you to work with your physician. This book is not designed to provide medical advice regarding any individual= s condition; indeed treatment alternatives may depend upon a number of individual factors. Note that I am not a physician or oncologist. Cancer research is an evolving area; some areas may have changed and conclusions might be modified. This again highlights the fact that this book is not designed to treat any patient but as a resource source for you to use under the guidance of the physician you select.
1.1 COMMON CHARACTERSTICS OF CANCERS 1.11 Abnormal Growth Cancers share three basic characteristics: unregulated growth, lack of differentiation, and the capacity to metastasize to neighboring tissues. Cancer is a malfunction which creates abnormal growth of cells in an area of the body: {Cancer}manifests itself as a population of cells that have lost their normal controls of growth and differentiation and are proliferating. In the first instance, these cells, derived initially from a normal cell, form a primary tumor (literally a swelling).... {This} primary tumor comprises a population of cells which are said to be growth transformed- that is they have acquired a set of mutations to a set of genes which allow them to divide repeatedly in a way that normal cells cannot. Vile, Cancer Metastasis: From Mechanisms to Therapies 24 (Wiley & Sons 1995). 1.12 Cell Division is a Normal Process Cell division and replacement is a normal process in the body. Cells in some parts of our body are constantly growing like fingernails and hair. Other areas are not growing bigger, but the cells within them are multiplying. Thus, while one characteristic of cancer cells is their ability to multiply, normal cells do that too: A Cells do all kind of things, including divide into more cells: one cell can divide into two cells, each "offspring cell" can divide into two cells, and so on. Cell division occurs at various times and for various reasons: cells divide during the growth and development of the embryo and the fetus, for example, and when there is a need to repair an injury in the body, such as a scraped knee. Cells also divide in cancer- cancer occurs when they divide out of control A (2) 1.13 Why Cell Growth is Necessary Cell growth is needed because almost all parts of the body are subjected to daily wear and tear that kills or damages cells. Growth is needed to replace or replenish cells and sometimes to perform specific functions. For example, cells in our immune system grow to kill certain germs. As a child grows to an adult and increases in size, there is clearly cell growth and duplication. Cell growth and duplication are normal and necessary functions in our body. While normal tissue enjoys a careful balance where cell growth and duplication occurs when cells die or for other specific reasons, cancerous tissue may simply grow. Unregulated growth means a tumor grows without regard to the needs of the tissue or the normal controls for that cell or gene. One text explains: A In the first stage, a normal cell undergoes an initial genetic change which partly releases it from the normally very stringent controls imposed upon its growth potential; the daughter cells accumulate further genetic mutations which accentuate this loss of normal growth regulation, until a population of tumor cells emerge which no longer respond to normal signals preventing cell division and growth. The cells of the primary tumor are, therefore, said to be growth transformed. The genetic mutations which accumulate in these primary tumor cells are to members of two classes of cellular genes, the proto-oncogenes and the tumor suppressor genes. These genes control the ability of cells to pass through the cell cycle and, hence, their ability to divide or, alternatively to stop dividing and to undergo {differentiation] @ (1) Cancer is generally not unique behavior of a cell, but normal behavior expressed to an extreme or in an incorrect context. Division and duplication of cells, movement of cells to damaged areas, and are all characteristics of normal cells. Even metastasis, movement of cells to other organs may occur with healing of wounds, the developement of a fetus, or attacking bacteria. 1.14 Understanding the term Unregulated Growth To call the growth of cancer cells completely unregulated or unpredictable is somewhat inaccurate. Tumors share certain characteristics and we can to some extent predict how they will behave. Some types of tumors grow rapidly, like small cell cancer, while others grow slowly. 1.15 Classifying Tumors Based Upon Growth Characteristics We categorize different types of lung tumors based primarily upon their growth characteristics. There are two main categories of lung cancer small cell and non-small cell. Small cell tumors grow rapidly but are susceptible to chemotherapy while non-small cell tumors grow more slowly. Chapters 3-5 explains the categorization scheme for lung cancer. 1.16 Differentiation Normal cells are differentiated, that is constructed or organized for a specific purpose. As a cell changes, it loses some of its distinctive characteristics, i.e., its differentiation. Cancer cells are classified from well-differentiated to poorly differentiated, with the degree of differentiation one indicator of how the cell has changed. Under a microscope, a pathologist can look at the cell, determine and categorize its differentiation. Tumor cells are labeled from well-differentiated, meaning relatively limited changes have occurred to poorly differentiated, meaning significant changes have occurred. The extent of differentiation is one factor in evaluating the status of the patient, but has not become a critical factor. Instead the extent of metastasis, or movement to other tissues, has become the chief factor in determining the status of the tumor and the treatment which will be administered. 1.17 Metastasis Probably the most serious danger in cancer development is the tendency of cancerous cells to metastasize, that is, invade neighboring structures, and transmit the cellular malfunctions to those cells: A Whereas a benign tumor will expand in size as a consequence of cell division, it will not invade surrounding tissues nor will it shed cells that are capable of initiating tumor foci elsewhere in the body. A malignant tumor will, however, actively invade and destroy surrounding tissue and also give rise to cells which often spread to produce foci of tumor growth at distant sites. Vile, Cancer Metastasis: From Mechanisms to Therapies 101-102. (Wiley & Sons 1995). 1.171 Analogies to Normal Cellular Behavior Metastasis is not strange or unique behavior, but essentially cells misusing certain inherent traits. Imagine if someone= s leg suffered a serious burn or injury. The body would likely repair the leg by replenishing cells and repairing damaged sources of blood supply. With a cancer, the body believes the area is damaged, so it connects with neighboring sources of blood and nourishment to replenish the damaged area. In truth, many cancers do reflect damage to DNA, but the remedy the body creates simply spreads the cancer, rather than repair the damage. Metastasis, the movement of cancer cells to normal organs and structures seems strange. Yet analogies to the behavior of normal cells are seen: A It is also important to remember that expression of invasion promoter genes is not a purely pathological phenomenon seen only in cancer. Certain normal cell types demonstrate different elements of the phenotype as part of their usual functions. Thus, leukocytes resemble metastatic cells in many ways since they must leave the bone marrow and move, via the circulation to specific sites elsewhere in the body where they must penetrate to sites of infection and inflammation. Similarly, embryonic cells must move between developing tissues in a way that can be likened to tumor cell invasion.... Therefore, expression of the invasive phenotype by cancer cells should be thought of more as the activation of normal cellular programmes in an inappropriate cellular context, than as the expression of completely novel phenotypes. In this way, it may be possible to understand how and why the genes of invasion are expressed so aberrantly in tumor cells and, therefore, to generate more mechanism-based and effective treatments.@ Vile, Cancer Metastasis: From Mechanisms to Therapies 24 (Wiley & Sons 1995). 1.173 Summary of the Metastatic Process Here is a short summary of the metastasic process: 1) Cancer cells located in an organ such as the lung manage to break down the barrier confining them to that organ. A Local invasion by tumor cells involves the activation of genetic programs which allow them to pass away from the confines of the primary tumor mass, through any surrounding tissues and eventually to reach of blood or lymph vessel.@ Vile, id. 2) The tumor cells then move to an adjoining lymph node or blood vessel, with the tumor establishing a source of blood supply in that new location. 3) The tumor cells manage to penetrate the protective barrier of another organ, called the basement membrame. Cells move into the new organ, and establish a source of blood supply for future growth. The process by which tumors establish new sources of blood supply is called angiogeneses, and a major source of cancer research is the creation of anti-angiogenesis drugs to frustrate this process. 1.174 Tumors Are Categorized Based Upon the Extent of Metastasis Cancers are categorized based upon the extent of metastasis (as well as growth). Non small cell lung cancers (the largest type of lung cancer) are classified from stage 1 to stage 4. Stage 1 tumors are limited to a defined area in a single part of the lung. Stage 4 means the tumor has metastasized to another organ, with stages 2 and 3 assessing the extent of movement to adjoining or distant lymph nodes. Stage one cancers are usually treated with surgical removal of the tumor, while stage four metastatic tumors treated with chemotherapy. 1.175 Metastastic Cancer Cells Retain the Characteristics of the Original Organ One writer explains: A even though cancers enlarge, invade adjacent body parts, and travel to distant metastatic locations, they remain unchanged. The characteristics of human tumors, with rare exceptions, are fixed for the life of every tumor, regardless of where or when distant metastases of the tumor are found. In 1874, Dr. W. Moxon, an English pathologist, described rectum in liver, referring to rectal tumors that were growing in their original unchanged forms after metastasizing to the liver.... a prostrate tumor that is diagnosed early prostrate specific antigen (PSA) was detected in the blood will continue to produce PSA years later at a metastatic site.@ Dermer, The Immortal Cell 46-47 (Avery Pub. Co. 1994).
1.2 DIFFERENCES AMONG CANCERS 1.21 Cancer as a Group of Diseases While cancers share the three traits of unregulated growth, loss of differentiation, and proposenity to metastasize, the extent of each may vary. Some cancers are highly metastatic meaning they move quickly to other parts of the body, while others move slowly over years or even decades. Cancers are categorized using these three characteristics, the extent of growth, differentiation, and presence of metastasis. Most scientists believe that cancer is a group of related diseases with certain common characteristics, not one disease. Indeed, the factors which cause cancer vary. 1.22 Varying Causes of Different Cancers. Diet plays a critical role in the development of colon cancer, yet it has a limited role in lung, and perhaps no role in skin cancer. Nutrition plays a role in many cancers, but does not affect others. Given that the factors which create cancers vary, not surprisingly the tumors themselves differ. Cancers behave differently depending upon their type and the organ where they originate. Cancers are also treated differently. 1.23 Differences in Behavior of Different Cancers Cancers behave differently depending upon their type and the organ where they originate. Some cancers spread or metastasize very quickly while others are slow-moving. 1.24 Treatment Treatment is generally organ specific, a skin cancer would be treated differently than a prostrate cancer. Indeed, since there are different types of cancer in a particular organ, treatment can vary according to type. As we see later, small cell lung cancer is treated differently than other types.
1.2 GENES AND CHROMOSOMES Many patients or family members will read about gene therapy and different advances in cancer research. A basic knowledge of what genes and chromosomes are will help you understand these advances and are how they can be important to you. Later chapters discusses gene therapy and treatments where scientists try to alter the messages gene send to one another. 1.21 Chromosomes Genes are part of a large structure called chromosomes in the body: A Simply put, chromosomes are the structures that hold our genes. Genes are the individual instructions that tell our bodies how to develop and keep our bodies running
healthy. In every cell of our body there are 50,000 to 100,000 genes that are located on 46 chromosomes. These 46 chromosomes occur as 23 pairs. We get one of each pair from our mother in the egg, and one of each pair from our father in the sperm.@ Chromosome Deletion Outlook, http://members.aol.com/cdousa/intro.htm. An excellent book called Understanding Cancer discussed the structure of chromosomes: The behavior of every cell in the body is controlled by a highly complex molecule called DNA (for deoxyribonucleic acid), which is situated in the cell= s nucleus and serves as the cell= s brain. The DNA is the blueprint for everything the cell does. In a human cell, the DNA is arranged in 46 sections called chromosomes,... The chromosomes can be arranged in a specific order (called karotype) according to their size and shape....{C}hromosomes contain genes that determine different things about he person: height, hair, color, eye color, and so on. Coleman, Understanding Cancer 30 (John Hopkins Press 1998). 1.22 Genes Coleman then goes on to explain these genes: the 46 chromosomes contain more than 100,000 genes. (A gene is a segment of DNA that determines the structure of a protein). Each gene occupies a specific location on a chromosome. Like the chromosomes, the genes are arranged in pairs- one gene from the mother, the other from the father. Each pair of genes is called a pair of alleles.... Id. at 30. In many instances, we can identify the location of specific genes, and there is a world-wide program to provide a genetic map of the human body. 1.23 What Do Genes Do A Through a number of biochemical steps, each gene tells a cell to make a different protein. Some genes instruct the cell to manufacture structural proteins, which serve as building blocks. Other genes tell the cell to produce hormones, growth factors or cytokins, which (as noted above) exit the cell and communicate with other cells. Still other genes tell the cell to produce regulatory proteins that control the function of other proteins or tell other genes when to turn A on@ or A off.@ Id. at 30. This is a finely-turned process. Cancer occurs when the genes are damaged, and things do not function as intended. 1.24 Cell Cycle 1.241 Why We Need to Understand Cell Cycles There are different cell cycles which are important to understand for a number of reasons. Identifying the factors which trigger transition to various stages has been a major goal of cell cycle research and with it cancer research overall. How do we stop cancer cells from replicating. If we can inhibit the process at any of its various stages, we can provide a cure or at least a hinderance. Anti-cancer drugs are frequently directed to specific points in the cell cycle. Understanding cell cycles helps you understand how various anti-cancer drugs work. A The cell cycles are coordinated by the expression and/or activation of regulatory proteins.@ Gupta, Overview of Cell Cycle and Apoptosis (cell death) 90, Pass, Lung Cancer Principles and Practice (2000). Factors existing outside the cell prompt the cell= s division. Medical research addresses cancer in two ways: we can try to change parts of the cell itself or factors which are influencing the cell= s behavior. Some simple cancers have been cured by identifying a specific factor which is influencing the cell= s behavior, and creating something, perhaps an antibody, to address it. Unfortunately, lung cancer involves a large group of different factors, and isolating the critical or most potent one has been difficult. 1.242 Cell Cycle Phases There are 4 broad phases of the cell cycle: G1, S, G2, and M. In G1 or Gap 1, the cell synthesizes proteins which will enable it to grow. S phase genes contain a factor, S-phase promoting factor, or SPF, which helps cells go from G1 to S, or synthesis. Phase 2 is S or Synthesis. Here the cell replicates its DNA so it now has 2 complete sets of DNA. This allows the cell to divide into two daughter cells, each with a complete copy of DNA. But, before the cell can do this, it needs to enter the third phase, G2:
During the G2 phase, the cell again undergoes growth and protein sythesis (it needs enough proteins for 2 cells!)...priming it to be able to divide. Once this is complete (by the way, there are many "checkpoints" along the way!), the cell finally enters the fourth and final phase of the cell cycle: the M (Mitosis) phase.@ 1.25 Chemotherapy and Cell Cycle Some chemotherapy drugs aim to address cancer at specific phases in the cell cycle.
1.3 HOW NORMAL CELLS CHANGE TO CANCER CELLS 1.31 Proto-Oncogenes and Oncogenes Cancer cells are basically good cells gone bad and we can with some precision identify those cells which can become cancers. These are genes already involved with cell division and growth which are called proto-oncogenes. A Mutations to a proto-oncogene alters its structure and activates it to produce an oncogene. The protein product of the oncogene is itself altered so that it can no longer be switched off by normal cellular signals and its expression directs the cell to divide@ Vile, Cancer Metastasis: From Mechanisms to Therapies 4-5 (Wiley & Sons 1995). A proto-oncogene is a normal gene which performs certain growth functions but when altered, can turn into a cancerous oncogene: A the beginnings of cancer lay not in a wholesale rewiring of the cell, but in a subtle alteration of a fistful of key genes among the human quote of DNA. Under normal circumstances, such genes play a vital, growth-related role in all or most tissues of the body. In some tissues, the genes may set up the rounds of simple division, helping skin cells to proliferate into a scab around a wound, or allowing the immune system to send out a host of antibodies to assail an invading pathogen.... Whatever their assigned tasks, the genes that scientists have designated oncogenes share a common characteristic: they are vulnerable to mutations. And once mutated, the genes contribute to the birth of a tumor. That= s why the genes are oncogenes; onco is from the Greek onkos meaning mass. Some scientists prefer to say protooncogene when referring to the healthy progenitor of a cancer gene, but most biologists rather imprecisely say oncogene for any gene that is prone to becomeing tumorrigenic. Nevertheless, it= s important to keep in mind that our cells possess oncogenes not because some nasty natureal or supernatural force place them there to keep our population in check, but because the body requires the genes to grow.@ Angier, Natural Obsessions 5 (Mariner Books 1999) A An oncogene is a sequence of deoxyribonucleic acid (DNA) that has been altered or mutated from its original form, the proto-oncogene. Operating as a positve growth regulator, the proto-oncogene is involved in promoting the differentiation and proliferation of normal cells. A variety of proto-oncogenes are involved in different crucial steps of cell growth, and a change in the protoB oncogene= s sequence or in the amount of protein it produces can interfere with its normal role in cellular regulation. Uncontrolled cell growth, or neoplastic transformation, can ensue, ultimately resulting in the formation of a cancerous tumor.@ www brittanica.com. It= s somewhat like an eight year old boy playing baseball in the house, a normal activity performed in the wrong context where it can do substantial harm. 1.32 How Oncogenes are Categorized We have identified a number of proto-oncogenes and oncogenes. The term oncogene derives from the Greek term onco, meaning mass, and cancer is a mass of abnormal tissue. We know from our discussion of chromosomes that genes and oncogenes can be identified with a specific location such as chromosome 17. Oncogenes are also given specific names, which are usually three letter abbreviations such as myc, erb, or P53. Sometimes a prefix will be added such as v, for virus, indicating that the oncogene is associated with a virus, or c, indicating that the oncogene is associated with a chromosome defect. 1.33 The Two Types of Oncogenes: Growth and Tumor Suppressor Genes There are two types of gene mutations which essentially combine to create a cancer. The first, is an abnormality of a gene involved with growth. An example is a gene that produces a protein that causes a growth-factor receptor on the cell's surface to be constantly on when in fact no growth factor is present. Thus the cell receives a constant message to divide. The second type of gene which turns off the cell cycle and helps control cell growth is called a tumor suppressor gene. When the tumor suppressor gene malfunctions, the signal to the gene to stop duplicating is lost. Imagine a car. A car would travel when it wasn= t supposed to if the accelerator was on ( growth-factor gene) or if the brakes were not functioning, (tumorsuppressor gene). 1.34 How Do Cells Know When to Divide: Cells divide only when they receive the proper signals from growth factors that circulate in the bloodstream or from a cell they are in direct contact with. For example, if a person loses blood, a growth factor called erythropoietin which is produced in the kidneys, circulates in the bloodstream and tells the bone marrow to manufacture more blood cells. Growth factors that come from outside the cell can transmit a message by binding to the appropriate receptor on the cell triggering a signaling system that activates a specific gene in the cell's nucleus. Other signals generated within the cell itself can use the signaling system to activate a gene.
1.4 HOW GENES ARE DAMAGED AND BECOME ONCOGENES 1.41 DNA Damage A normal gene can become damaged in different ways. A cell can become abnormal when part of a gene is lost (deleted), when part of a chromosome is rearranged and ends up in the wrong place on a chromosome (called a translocation), or when an extremely small defect occurs in the DNA, which results in an abnormal DNA blueprint and production of a defective protein. A gene may be initially defective or an outside product such as tobacco smoke may over time cause damage. In some situations, we can identify which gene has been damaged: In Burkitt lymphoma, a malignancy of immature B cells, one characteristic feature is a chromosomal translocation about 80% of the time, a translocation between the long arms of chromosomes 8 and 14 are involved; less frequently, a translocation between the long arms of chromosomes 8 and 2 or chromosomes 8 and 22. All three translocations found in Burkitt lymphoma involve a specific position on chromosome 8 (8q24) that is occupied by the cellular proto-oncogene/oncogene, c-myc. www.cancergenetics.org. 1.42 Time for Cancer to Develop Cancer does not develop overnight though some people will associate an cancer with some event or exposure that happened a few months before. Instead, as we explain in chapter two, most tumors are associated with a series of changes that may occur over a period of 10 to 15 years or even longer.
1.5 CANCER TERMINOLOGY 1.51 Primary Site The place where the first tumor is found on a patient is called the primary site and the cancer that initially forms, the primary cancer. Cancers retain characteristics based upon where they originate. Thus, a cancer which originated in the lung but metastasized to the breast would still be characterized as a lung cancer. 1.52 Complete Response and Partial Response The term complete response means elimination of the cancer, at least based upon available medical tools of measurement. It unfortunately does not preclude reappearance of the disease. The term partial response, as used by most authorities means a 50% reduction in the size of the tumor. The initial chemotherapy is called first-line chemotherapy; if the chemotherapy is needed again, that is second-line chemotherapy. Since there the cells develop some immunity to chemotherapy, there may be some different considerations with second line chemotherapy. 1.53 Lymph Nodes There are two basic ways that cancer metastasize, that is spread to other organs. The most common route is by channels that exist in every part of the body called lymph channels. Lymph channels are a fine network of vessels that carry the liquid portion of the blood from different parts of the body. Returning to the bloodstream, the lymph is filtered through lymph nodes and returns to a large lymph vessel near the heart. Given the flow of lymph to and from the lymph nodes, we can understand why the finding of cancerous cells in the lymph nodes will be critical. If the tumor has moved to a lymph node, its potential for dissemination throughout the body increases. A tumor which is detected and removed before a lymph node becomes cancerous has a far better prognosis than one which has contaminated a nearby lymph node. 1.531 Regional and Other Lymph Nodes. In staging the patient, that is ascertaining his status, doctors consider whether the lymph nodes are cancerous, and where the cancerous nodes are located. The spread of a tumor to a lymph node located near the tumor, or a regional node, is less serious than the spread to one further away, a contralateral node. If the lymph node is further from the tumor, that indicates a greater spread of the tumor. 1.54 Blood Vessels A tumor may also spread through the body through a blood vessel. There are various tests to ascertain the extent of cancer in the blood however, blood vessels cannot be individually assessed as lymph nodes usually are. A surgeon will generally obtain samples or biopsies from lymph nodes to ascertain whether the nodes are cancerous. This is important because as we will see in chapter 4, the type of treatment given depends upon lymph node status. 1.55 Carcinomas and other Forms of Cancer The most common type of cancer is a carcinoma, a cancer that arises in the cells that forms the lining of different parts of the body. Cancers in the lung, breast, prostrate, and colon are all carcinomas. Cancers that involve tissue or bone are called sarcomas. Cancers involving blood cells are known as lymphomas or leukemias. While most research is organ specific, some studies will cross organ lines. Some forms of chemotherapy for lung cancer are also used for breast or colon. Scientists are less likely to test a treatment on other types of cancer.
1.6 Reserved 1.7 CANCER AND THE IMMUNE SYSTEM Because cancer cells are basically normal cells gone wrong, they are frequently not recognized by the immune system. Sometimes there is a minor type of immune reaction, but by various mechanisms, the cancer cells manage not to be affected by it. 1.71 The Argument for An Immune Reaction. The precise role of the immune system in cancer is confusing and unclear, with some indication of an immune defense, and some of immune failure in the face of cancer. A In support of immune surveillance, lymphocytic and mononuclear infiltrates are found in many tumors, and their presence correlates with a better prognosis in certain tumor types. Tumor-infiltrating mononuclear cells have been shown in a number of studies to lyse tumor cells in vitro. (In vitro means a test of cells in a laboratory). In addition, immunological activation markers... are unregulated or induced on tumor cells in a proportion of cancers. These observations, however, have not been universal, and provide only indirect evidence for immunological responses to tumors. Early studies of chemically or irradiation-induced tumors in inbred mice revealed the presence of unique antigens in these tumors. Tumor cells which were transplanted from the host into a naive recipient (the term naive means that patient or animal was not previously exposed to the substance at issue) grew progressively. On the other hand, if the tumor was transplanted into an animal which had been exposed previously to the same tumor, then the tumor was rejected.@ Vile, Cancer Metastasis: From Mechanisms to Therapies 101-102. (Wiley & Sons 1995). 1.72 How the Immune System Fails in Attacking Cancer Vile also discusses the compelling contradictory findings: Against an effective immune surveillance mechanism is the lack of an increase in the incidence of most common cancers in patients with immunodeficiencies or on long-term immunesuppression. Immuno-depressed individuals do show an increased incidence of lymphoid malignancies and tumors associated with oncogenic viruses, but not of the more common spontaneous tumors such as cancers of the lug, breast, or colon. Similarly, no increased incidence of tumors is seen in congenitally immunodeficient nude mice. Id. At 102. 1.73 Observations About the Immune System= s Role. We can provide some general observations about cancer and the immune system: 1) The immune system has some role in attacking cancer cells, but it is frequently reduced or evaded entirely, 2) The efficiency of the immune system depends upon the type of cancer and its location. This reinforces the basic principle that cancer treatment is organ-specific. Indeed, the Food and Drug Association (FDA) does not approve A cancer drugs,@ but essentially approves drugs for treatments on specific types of cancers. This is why it is almost always incorrect to read an article about positive finding of a cancer drug on one organ and assume it will translate to success on another. 3) Since the immune system has the capacity to successfully attack various types of foreign bodies, research continues in terms of improving the performance of the immune system. This can entail ways of having specific cells like killer T cells activate against cancer cells, or somehow improve the body= s ability to recognize cancer as an abnormal event. For example, researchers have taken metastasic cells removed at surgery and then separated the lymphocytes in those cancer cells in them. Lymphocytes are components in the immune system which kill germs and foreign cells. On their own and keep by themselves in a dish, those are later capable of killing the cancer cells. Yet when they are adjacent to cancer cells in a secondary tumor inside the body, somehow they are prevented or blocked from killing those cancer cells. In other words, cancer cells as they grow and establish a metastasis can somehow... neutralize the cancer-killing abilities of the neighboring lymphocytes. @ Thus, one area of research is promoting the body= s natural defense mechanisms to eliminate these cancer cells. Buckman, What You Really Need to Know About Cancer 17 (Johns Hopkins Press 1997).
CHAPTER 2: THE PROCESS OF METASTASIS _________________________________ 2.1 METASTASIS PLAYS A CENTRAL ROLE IN LUNG CANCER TREATMENT 2.11 The Importance of Understanding Metastasis The potential for metastasis is a problem for all cancers, and in particular lung cancer. The chief cause of death in lung cancer is not the direct damage to the lung but the consequences of metastasis. Most lung tumors are detected in an advanced stage where there has been significant spread of the tumor. Thus, an understanding of how a tumor metastasizes, and ways of treating metastatic lung cancer are critical to any discussion of treatment options. 2.12 The Steps Involved in Metastasis There are four basic steps involved with metastasis: 1) Tumor cells in an organ such as the lung must separate from each over, overcoming the usual restrictions imposed by cell adhesion and cell-contact inhibition, 2) Tumor cells come to a nearby lymph node or blood vessel enabling them to use that pathway to ultimately travel to another organ 3) The tumor encroaches into the protective covering of another organ breaking down the extracellular matrix. 4)Tumor cells create a blood supply (vascularization) by inducing capillary growth into and around the tumor- a process know as angiogenesis. An adequate blood supply is essential so that the rapidly proliferating cells can obtain nutrients and oxygenation, otherwise mass necrosis (cell death) can half the growth of the cells. Tumor cells move to another organ which can sustain its growth.
2.2 HOW CANCER CELLS SEPARATE Normal cells are connected with one another. For example, cells in a person= s arm combine to help perform various tasks. However, in a cancerous tumor, one of the first steps is for cells separate from one another. A Separation of cells from the primary tumor mass must occur before long range spread can be possible. Detachment of single cells or clumps of cells may be directly related to a decreased level of cell adhesiveness in tumor populations.@ Wile, Id, at 26. A The family of cadherin molecules help cells bind to one another, maintaining a sound structure. Cadherin mollecules regulate cell adhesion, though we cannot precisely define the role of each type- This study described the expression pattern of cadherins and catenins in normal bronchial epithelium. The authors' results show that these proteins involved in cell-cell adhesion are abnormally expressed in the majority of non-small cell lung carcinomas.... These findings support the hypothesis that alterations in expression, and particularly loss of expression, of cadherins/catenins may play an important role in the development of the malignant phenotype in lung cancer, however, they also point out the complexity of this system and the need for additional study.@ Cadherin and Catenin Expression in Normal Human Bronchial Epithelium and Non-small Cell Lung Cancer, Lung Cancer, Vol. 24 (3) (1999) pp. 157-168.
2.3 HOW TUMOR PENETRATE OTHER ORGANS AND DRUGS AND DRUGS TO INHIBIT THAT PROCESS The boundary that separates one group of normal cells from the next is called the basement membrane. Under a microscope, a tumor, a group of cancer cells, can be seen be seen penetrating through the basement membrane: Cancers can produce substances that attack constituents of the glue that binds cells together (the technical term is intercellular matrix). This matrix contains many different components, such as a substance called collagen, which gives strength to many tissues. Cancers may produce a type of substance called collagenase that attacks and breaks down the substance Cancer cells can also produce other substances such as hyaluronidase, a group of substances called protease, and probably dozens of others that allow the growing cancer cells to push through normal tissue boundaries. As a result, cancers often have a very ragged, irregular, and indistinct border- a feature that is often important in distinguishing a cancer from a nonmalignant lesion, as nonmalignant areas (such as warts, benign tumors, or cysts) have a border that is clearly visible and quite distinct.).@ Buckman, What You Really Need to Know About Cancer 14 (Johns Hopkins Press 1997). Certain proteins called metalloproteinases or MMP help enable the tumor to penetrate these barriers. A Matrix metalloproteinases (MMPs) are a class of structurally related enzymes that function in the degradation of extracellular matrix proteins... Increased MMP activity is detected in a wide range of cancers and seems correlated to their invasive and metastatic potential. MMPs thus seem an attractive target for both diagnostic and therapeutic purposes.@ Dennis, Matrix Metalloproteinase inhibitors: Present achievements and Future Prospects, Invest New Drugs 1997;15(3):175-85. 2.31 Drugs to Combat MMP New drugs are being designed and tested to see if they can frustrate this process of MMP. Many have worked in a laboratory where these drugs succeed in frustrating this process with cancer tissue, and sometimes animals. However, with humans, there has been difficulty in delivering the particular drug to the tumor area in sufficient quantity to be effective. A later chapter discusses the success of MMP drugs.
2.4 ANGIONGENESIS 2.41 Tumors Cannot Grow Beyond a Certain Size Without Creating a Source of Blood Supply. Once the tumor cells have separated, entered a nearby lymph node, and penetrated a distant or nearby organ, the final step is to link to a source of blood supply and nourishment. For simplicity, we have called this the final step; some scientists would suggest that establishment of a source of blood supply occurs first, or that there are multiple parts of the process. The creation of a source of blood supply is essential to a tumor= s growth, and probably to its ability to sustain itself. Dr. Judah Folkman pioneered this area called angiogenesis research and a book about him explains: no tumor could grow beyond a tiny size until it sent out a chemical message to recruit an ample blood supply. For that chemical signal to be sent out, Folkman believed, an angiogenic switch had to be flipped- a switch that turned on the tumor= s production of a growth-producing agent such as B-FGF (basic fibroblast growth factor), or VEGF (vascular endothelial growth factor), which Folkman had long referred to as TAF. It was this angiogenic switch that made nearby blood vessels sprout and grow new branches and kick-started the rapid growth of tumors. Cook, Dr. Folkman= s War Angiogenesis and the Struggle to Defeat 2.43 Anti-angiogenesis Research There is continuing research about developing drugs to inhibit growth factors with called anti-angiogenesis drugs. A number of drugs are attempting to inhibit angiogneseis and there are over 100 clinical trials involving anti-angiogenesic drugs. Chemotherapy involves drugs used to kill cancer cells while anti-angiogeneic drugs attempt to frustrate their spread. Since the two types of drugs work differently, new research attempts to combine the two types of drugs. One theme of cancer research in the 21st century is combining different types of treatment, with each type reaching an optimal level of toxicity, where it attacks cancer cells but not does not unmanageable damage to other cells.
2.5 WHERE DOES METASTASIS OCCUR 2.51 Location and Proximity Metastasis is partly explained by geographical proximity: In some instances, this organ preference of metastasis can be explained simply in terms of the anatomical relationship of the organ with the site of the primary tumor growth. Hence, many secondary tumors will develop in those organs which provide the first capillary bed encountered by dispersing metastatic cells, since the tumor cells may be carried as aggregates which pass into a capillary whose lumen is smaller than the clump diameter. A knowledge of the circulatory anataomical associations of the primary tumor site with other organs can typically be used to predict the seeding site of about 60% of the metastases from that tumor. Metastases from colon cancer probably occur with high frequency because the liver receives the drainage of the blood supply to the large intestine. Vile, Cancer Metastasis: From Mechanisms to Therapies10-11 (Wiley 1995) (hereinafter cited as Vile, at ). 2.52 Chemical and Cellular Attractants In other instances, there are specific chemical or other attractants which lead cancer cells to particular parts of the body: Usually when tumors are located at a distant site which could not be predicted on the basis of circulatory anatomy, it is because the site expresses specific determinants which actively promote the growth of the metastatic cells. We know that different structures are harder or easier to penetrate, and some areas such as brain, bone, and liver are the subject of frequent metastasis, while others such as feet are virtually never. It may be that those structures where lymph and blood are frequently transmitted have to be receptive to other cells, allowing cancer cells to enter. Using an analogy, a burglar might be able to penetrate some houses whereas others would have sufficient protection. 2.53 Soil and Seed Hypothesis Eighty years ago, Paget proposed the A seed and soil hypothesis.@ That is, a seed (the carcinoma) will only give rise to a secondary tumor in organs that sustain its growth (the soil). That is, cancers can only successfully locate in certain organs; for others, inherent characteristics of the organ prevents or inhibits metastasis. Additionally, organs vary in their ability to resist penetration by cancer cells, A The basement membrane of different organs vary in composition and the hetrogeneity in binding of tumor cells to components of the extracellular matrix may well be another mediator in the organ preference of metastasis.@ Vile, Cancer Metastasis: From Mechanisms to Therapies 54 (1995) 2.54 Different Types of Collagens Scientists divide the collagens in the basement membranes into types and describe how tumors create collagenese to attack some of these protective barriers: Tumor cell invasion requires crossing tissue compartment barriers such as basement membranes and interstitial connective tissue. Both of these barriers have various collagen types that compose the structural scaffolding upon which other matrix components {are assembled]... Ultrastructural studies of tumor cell invasion demonstrated local dissolution of basement membrane materials and suggested that tumor cells produce a distint callegonolytic enzyme to degrade basement membranes. In support of this concept, highly metastatic tumor cells, endothelial cells, and polymorphonuclear leukocytes have been found to produce a type IV collagen-specific metalloproteinase.....Type IV collagenolytic activity correlates with metastatic activity in murine tumor models. Highly aggresive human tumors, such as carcinomas, melanomas, hepatomasa, fibrosarcomas, and reticulim cell sarcomas, all have elevated levels of type IV collagense when compared with benign control cells. (1) Thus we can theorize that bodily structures with collagen types 1-3 are less susceptible to metastasis that those with types 4 and 5.
2.6 GROWTH FACTORS 2.61 Why Cancer Patients and their Families Need to Understand Growth Factors and Related Concepts Some cancer patients may be asked to participate in clinical trial, experiment procedures testing new drugs after they have shown success in laboratory experiments on cells and tests with animals. Some of these clinical trials deal with methods of combating growth factors or cancer spread to other organs. Thus, an understanding of these terms and what the new drugs are attempting to do may help you to decide whether to utilize these new treatments. The term growth factors is frequently used, sometimes with different meanings depending upon the speaker. Sometimes, growth factor is used as a term synonymous with oncogene or proto-oncogene. Thus growth factors refers to a protein, or signal which prompts improper cell growth and replication, i.e., cancer. In some instances, growth factors are used to denote certain behavior involved with angiogenesis, the establishment of sources of blood supply by tumors. To heighten precision, scientists have identified many growth factors and attempted to define their behavior, when do they prompt cell division, why, on what types of tumors to they act. 2.611 The many different growth factors and why it is difficult to find a cure. In an ideal context, a growth factor would be identified, the reason why it acts in an abnormal fashion would be determined, a method of preventing this behavior, perhaps by administration of an outside agent would be identified, and the tumor would be cured, or at least its spread frustrated. This model has worked with other types of cancer, however, there are problems at each stage with lung. Specifically, 1) There are a number of growth factors involved with lung cancer. Determining which one is preeminent has been difficult. 2) Since there are different growth factors, it is likely that there will be different types of treatment for different types of lung cancer. However, today we divide treatments in two large categories: small cell and non-small cell. We will need to further define the cancer type and cell behavior to achieve even a partial cure. 3) Achieving a cure in the laboratory has been easier than in practice. Anti-cancer drugs like angiostatin appeared to frustrate cancer spread in the laboratory but have not done so in practice. 4) Delivering the drug to the cancer is difficult. How do we arrange so that any drug or new gene reaches the necessary areas. Thus, the cancer researcher's task is difficult and we must be careful not to attribute too much significance to small advances in the laboratory. This is why cancer testing is a five or more step process: Test the new agent in a laboratory on cancer cells, in vitro testing (check) Evaluate the test on animals, Perform initial tests to see if the new drug is tolerated by humans and does not cause significant side effects, (Phase 1 Clinical Trial) Compare the new drug with existing treatment to determine if the new treatment achieves best results. (Phase 3 Clinical Trial) Determine whether the new drug should be combined with other existing forms of treatment to achieve optimum efficiency, evaluating the new drug in different contexts. Will future researchers be able to build upon our increasing knowledge, use computers to digest and analyze information more effectively and ultimately develop a cure. In the interim, the multi-faceted nature of the task means that it is difficult to develop a quick cure so that those who report extraordinary results may not be genuine. 2.62 Tumor Angiogenesis Factor- TAF and VEGF One well-known growth factor is tumor angiogenesis factor (TAF). A The tumor secretes a substance known as tumor angiogenesis factor (TAF) which induces blood vessels to produce new capillaries that grow toward the tumor and finally connect with it.@ American Cancer Society, Informed Decisions 19 (1997). Scientists now call TAF, vascular endothelial growth factor (VEGF), indicating it creates new sources of vascular growth or blood supply, and arises in the endothelial or lining cells. One of the chief areas of medical research is finding ways of inhibiting VEGF. One could find ways of directly stopping or reducing VEGF, or inhibiting those factors which prompt VEGF. While VEGF occupies a significant role, there are a number of other growth factors involved in the cancer process. One difficulty with combating cancer is identifying the roles of these different growth factors so that substances can be developed to attack or frustrate them.
2.7 DIFFICULT TREATING METASTATIC CANCER Once a cancer has metastasized, it is more difficult to attack or cure. Let us look at some of the difficulties metastatic cancer presents. 2.71 Surgery and Metastatic Cancer Surgery is the first consideration in treating a cancer; simply remove the cancer in an operation. However, if the cancer has spread to various parts of the body, it would be difficult to remove the entire tumor. One might know where the tumor cells are located, and even if we did, operating on many different organs would be risky and time-consuming. Many lung cancer patients are older, with breathing capacity compromised by years of smoking. For such patients, lengthy procedures would create substantial risk. That is why surgery is almost never used if the cancer has metastasized to another organ (stage 4 cancer as we discuss in a later chapter). However, if the tumor has moved to a nearby lymph node but not yet reached another organ, surgery may be recommended if the patient has good pulmonary reserve (breathing capacity). 2.72 Radiation and Metastasis Radiation has some of the same problems as surgery. Radiation is designed to target specific areas of the body. If the cancer has spread, radiation may not completely successful in killing all the cancer cells. 2.73 Chemotherapy Chemotherapy is the use of drugs to kill cancer cells. Theoretically, chemotherapy could at least work in various ways. Drugs could interfere with the messages to travel that certain tumor cells receive to replicate or move, it could increase defenses in the basement membrane, or it could induce the body= s own defenses to attack the invading cancer cells. These drugs have been successful in reducing the size and spread of tumors, in mitigating pain, but they are not regarded as an overall cure, at least in most cases where the tumor has metastasized to another organ. Why? First, chemotherapy generally has only the capacity to kill a certain percentage of cancer cells. Thus, as cancer cells spread and divide creating a larger number of cells, the ability of chemotherapy to completely combat it decreases. Secondly, as chemotherapy progresses, some cancer cells unfortunately develop the ability to withstand the chemotherapy, called multi-drug resistance. Sometimes, a drug will be used, substantially reduce the size of the tumor, but lose its effectiveness after a period of time. Second-line chemotherapy involves drugs used after the first group has stopped being effective. 2.74 Anti-angiogeneic Drugs Anti-angionesis drugs are a specific type of drug to combat the process of angiogenesis. On a technical level, chemotherapy drugs are designed to kill cells while anti-angiognenic drugs try to frustrate the creation of new blood vessels. These drugs are in their infancy with numerous clinical trials attempting to find a drug which effectively stops the angiogenesis process Consider an analogy. Many believe that crime is connected with a lack of education. A city decides to try a program which provides after school assistance to junior high and high school students in subjects such as english, math, and science. After one year, crime statistics have not decreased. Do we conclude that the program is ineffective. There may be other factors at work, it may take long to demonstrate a connection. Cancer researchers face similar problems trying to isolate a single factor in a clinical trial. In the laboratory, other factors can be eliminated but in trial with humans, many variables remain. This is one reason why laboratory successes in detecting gene abnormalities do not immediately translate into successful treatments.
CHAPTER THREE: THE CANCER PROCESS IN THE LUNG _________________________________ 3.1 ONCOGENES AND HOW CANCER DEVELOPS IN THE LUNG Having a basic understanding of cellular behavior helps us understand the carcinogenic process. Recall an oncogene is a cellular component which stimulates or predisposes a cell to divide, and a tumor suppressor gene, the cell component which can stop or frustrate abnormal cellular division. Lung cancer is basically a two step process, activation of growth oncogenes, and deactivation of recessive tumor suppressor genes. Dr. Devita= s book, Cancer Principles and Practices of Oncology, explains the cancer process in the lung: 1. Exposure to a carcinogen prompts production of growth factors by bronchial cells in the lung. 2. Continued exposure leads to the development of deletions and translocation in the genes. Abnormal oncogenes develop and those replicating cells are activated or developed. Other oncogenes are also activated. 3. There are other genetic changes, such as mutation of ras family, c-raf-1 and other oncogenes, some of which could involve growth factor or growth factor receptor genes. Thus, three steps occur: growth factor is produced, continued exposure leads to changes in the DNA, and finally abnormal growth factors develop. The book, Lung Cancer by Desmond Carney describes the process of carcinogenesis, the change of normal cells to cancer cells this way: The concept of multi step carcinogenesis, which has been well described in some human carcinomas such as carcinoma of the colon, remains much more elusive in lung cancer.... Initiation is the first step when DNA in a cell is altered so that it no longer responds normally to signals for proliferation or differentiation. This can occur over a short period of time and years before cancer develops. The second step, promotion is the expansion of the initiated cell into nodules, papillomas or polyps; progression to the third and final step is the evolution of the premalignant lesion into invasive cancer. Carney, Lung Cancer 15 (Arnold Publishing Co., Great Britain, 1995) Here is another description of lung cancer development: The current hypothesis is that at least 10-20 genetic mutations are required to produce a lung cancer cell from the normal one. These mutations cause activation of oncogenes (dominant cellular factors, which stimulate or predispose a cell to divide) and deletion of tumor suppressor genes....The development of cancer is due not only to abnormal cell proliferation with loss of growth control, but also to abnormalities in the cells intrinsic cell death programme, (apotheosis). Proto-oncogenes induce cellular proliferation which activate to oncogenes. Activation may occur by point mutation, over expression, or deletion of genetic material. Oncogenes evaluated for prognostic impact in NSCLS(non small cell lung cancer) include the ras oncogeny, c-erb B-2 oncogenies, also called HER-2 and neu oncogeny and Bcl-2 oncogeny (3). These oncogenes have also been evaluated in clinical trials.... All lung cancer cells produce hormones and peptides, which can function as growth factors and generate growth loops. These include epidermal growth factor, transforming growth factor a, platelet derived growth factor, insulin-like growth factor... Inactivation of genes, that normally regulates cellular growth and thereby have a restraining effect of tumor-genesis (tumor suppressor genes) can lead to uncontrolled cell proliferation, in many cases, inactivation occurs by point mutation of one allele, and subsequently loss of an amount of the genetic material of the other. Prevention of cell division may be based on our increased understanding of the effect of growth factors in lung cancer. There are multiple and diverse simulators, meaning that blocking the action of a single growth factor is unlikely to be effective. However, inhibition of intracellular mechanisms that control multiple growth stimulating inputs offers a more realistic potential for intervention. (4) 3.21 Initiator, Promoter Carcinogenic Process Many scientists describe the cancer process as a two step process of initiation and promotion. Thus some cancer agents initiate changes in the body to alter the cells, with other agents taking these initially changed cells and transforming them into cancer cells. It is believed that since these are multiple carcinogens in cigarette smoke, it acts as both initiator and promoter. The book Lung Cancer describes the process this way: The concept of multi step carcinogenesis, which has been well described in some human carcinomas such as carcinoma of the colon, remains much more elusive in lung cancer.... Initiation is the first step when DNA in a cell is altered so that it no longer responds normally to signals for proliferation or differentiation. This can occur over a short period of time and years before cancer develops. The second step, promotion is the expansion of the initiated cell into nodules, papillomas or polyps; progression to the third and final step is the evolution of the premalignant lesion into invasive cancer. Carney, Lung Cancer 15(Arnold Publishing Co. Great Britain, 1995) 3.22 The Carcinogenic Process in a Smoker A company called Lungcheck describes the development of cancer in a smoker: 1. Columnar Cells Protect the Lung. Before you started to smoke, your air passages probably looked perfectly healthy. Tall columnar cells lining the air passages help keep the lungs clean. Some columnar cells secrete sticky mucus which coats the entire respirator tract with a protective barrier. The mucus traps the dust particles you inhale. Other columnar cells grow hair-like bristles (cilia) that sweep the mucus and trapped dirt out of the lungs and up to your throat, where you can cough it up. 2. Irritation to Columnar Cells As you start to smoke, this cleaning process begins to break down. Poisons in cigarette smoke paralyze the cilia and their sweeping motion stops. Severe irritation to the columnar cells results. 3. Production of Mucus and white Blood Cells In response to this irritation, your lung tissue produces more mucus and white blood cells in an attempt to protect itself from the poisons in cigarette smoke. 4. Columnar Cells Deteriorate and Metaplasia Develops As the irritation from smoking gets worse, patches of columnar cells begin to deteriorate and change their shape. The cilia disappear and the columnar cells transform themselves into flat, lacelike cells, a process called metaplasia. 5. The Precancerous Phase Called Dysphasia These metaplastic cells become Increasing abnormal until they reach a precancerous stage called dysplasia. Even at this stage, if you quit smoking, your lungs have a good chance to recover and heal themselves. Cancer develops after your lung suffers many years of irritation from cigarette smoke. Lungcheck was developed to detect lung cancer or even precancerous changes at an early stage. Lungcheck is a type of sputum cytology (analysis of sputum) which has a great life-saving potential by identifying cancerous changes at an early stage, but unfortunately like most early detection tools in the lung, has limited use.
3.3 HOW LUNG CANCER DEVELOPS: THE ROLE OF SPECIFIC GENES 3.31 Growth and Tumor Suppressor Genes There are again two types of gene mutations: an abnormality which causes unrestrained growth, (growth factor gene) and one which causes a tumor suppressor gene to malfunction: A Two broad categories of oncogenes exist: dominant oncogenes, whose increased expression and function produce transformation and neoplasia, and recessive oncogenes (or tumor suppressor genes), whose absent or reduced expression permits the development of neoplasia. The protein components of oncogenes are involved in key cellular processes such as growth, differentiation, and cell death, and they may be involved in the process of carcinogenesis at numerous early and late stages." 3.32 Why Only Some Cigarette Smokers Get Cancer We know that both genes are involved with the formation of cancers. This helps explain why some smokers contract cancer while others don= t. It may be that cigarette smoke causes some changes but only results in cancer when combined with an existing gene abnormality. That is why people with family histories of certain cancers are more likely to contract cancer than others. It is somewhat like destruction of buildings in a hurricane. Buildings with defects in the foundation will be damaged while others can withstand the assault. Additionally, we know that exposure to multiple carcinogens increases the risk of cancer. Thus, people who smoke and were exposed to asbestos are more likely to contract lung cancer than people exposed to only one carcinogen. It would simplify analysis to say that smoking causes a change in a dominant gene while asbestos causes a malfunctions in a tumor suppressor gene (or vice versa). However, it appears that each carcinogen can cause changes in both types of genes: A Various factors, including cigarette smoking, asbestos, and diet, have been reported t o correlate with the development of lung cancer. Of these factors, cigarette smoking is believed as the major carcinogen for lung cancer. Recent studies indicate that cigarette smoke carcinogens cause genetic damages at both oncogenes(K-ras) and tumor suppressor genes(p53) of lung cancer, and hence initiate and promote the development of lung cancer.@ Yano, Causative Agents for Lung Carcinogenesis, Nippon Rinsho, 2000 May, 58:5, 1017-22. At this stage in cancer research, we are generally unable to reverse the cell abnormalities though significant progress has been made in identify them. Clinical trials for patients with advanced cancer are experimenting with various means of correcting or mitigating gene malfunctions. 3.33 Growth Oncogenes Which Contribute to Lung Cancer We can identify specific genes involved in the developement of cancer in the lung: A Some of the well known genetic events leading to the development of lung cancer are mutations in the K-ras gene, mutations in the p53 tumor suppressor gene, abnormalities of the retinoblastoma gene (Rb) and defects of other cell cycle regulating genes (beside the Rb gene). Molecular alterations of genes responsible for the integrity and repair of the genetic material may lead to genomic instability. Mutations in several other genes can lead to a different response to internal or external signals which induce programmed cell death (apoptosis) or to the (over) expression of growth factors, ...@ Fleischacker, Molecular Genetic Characteristics of Lung Cancer... Lung Cancer, Vol. 25 (1) (1999) pp. 7-24. Generally the genes which cause lung cancer are not peculiar to lung cancer; that is, they contribute to the carcinogenic process in other areas of the body. For example, squamous cell cancer is a common type of lung cancer and there are squamous cells in other parts of the body. We examine specific types below. Some readers may wonder why it is necessary to discuss particular genes in a general book about lung cancer. Many clinical trials that patients and their families will want to evaluate aim to remedy particular genetic abnormalities, and a basic knowledge of this area can help you understand what a new drug is attempting to do. 3.34 K-Ras Gene The K-Ras Gene is a gene associated with the development and spread of lung cancer. A recent study found that 13% of Taiwanese men with adenocarcinoma had K-Ras mutations but no women had these mutations. While many Taiwanese men smoke, very few women do. Thus, the study indicates that smoking contributes to the development of adenocarcinomas (a type of lung cancer,) and creates K-Ras mutations, but that other factors also contribute to the developement lung cancer. 3.341 K-Ras and VEGF K-Ras is a proto-oncogene which means that the normal K-Ras gene performs certain functions in the body, while the mutant form contributes to cancerous behavior. The normal form is called wild-type while the abnormal form is called mutant K-Ras. Recall that vascular endothelial growth factor (VEGF) causes the creation of new blood vessels and the spread of the tumor. One study found that abnormalities of the K-Ras Gene contributed to VEGF. A Of 14 tumors with mutant K-ras genes, 7 cases (50.0%) had high VEGF expression whereas only 39 of the 167 tumors with wild-type K-ras 23.4%) had high VEGF expression.@ Konishi, The K-ras gene regulates vascular endothelial growth factor gene expression in Non-small cell Lung Cancers, Int J Oncol 2000 Mar;16(3):501-11. 3.342 K- Ras Mutations and the Early Detection of Lung Cancer In the United States, the vast majority of lung tumors are detected late, when physical pain the patient is experiencing means that the tumor has grown and spread. Ideally, lung cancer, or cellular abnormalities presaging lung cancer, could be detected early, leading to medical intervention when it is most likely to effect a cure. Sputum cytology is a means of evaluating cells in the lung by having the patient emit a deep cough and analyzing those cells in a laboratory. A 1999 article asks whether a means of evaluating K-Ras mutations could be added to conventional sputum cytology technigues to provide a method of early detection: A K-ras mutations may occur early during the development of lung cancer and in the subgroup of adenocarcinoma. Mao et al developed a very sensitive and specific PCRbased assay to examine sputum samples from a population of patients, some of whom were diagnosed with lung cancer at a later time. Using this method, the group was able to detect in 8/10 patients the identical mutation identified in the primary tumor in at least one sputum sample, 1-13 months prior to clinical diagnosis. Scott et al. established a sensitive PCR/Ligase chain reaction-based detection system and were able to detect K-ras codon 12 mutations in 84% of the specimens examined in bronchoalveolar lavage fluid (BAL) of patients at high risk for second primary cancer. Ronai et al. showed the existence of K-ras gene mutations in the sputum of patients without lung cancer. This research group also showed that mutations of the K-ras gene were much more frequent in lung tissue of cancer patients than in a non-tumor population. Ronai et al. used the enriched PCR method to detect cells with a mutated K-ras gene in the sputum of non-cancer patients, which indicates that: (i) only a minority of cells carry this mutation; and (ii) mutations in this gene might be an early event in the tumorigenesis of lung tumors. Fleischacker, Molecular Genetic Characteristics of Lung Cancer, useful as Real Tumor Markers, Lung Cancer, Vol. 25 (1) (1999) pp. 7-24. 3.35 Myc Photogene Family Scientists have identified one particular gene family, the Myc gene, as associated with abnormal cellular development and cancer in various organs. 3.36 The Retinoblastoma (RB) Gene and Small Cell Lung Cancer The retinoblastoma (RB) gene has a protein that appears to regulate the cell cycle. It is associated with a rare tumor of the eye. Most small cell lung cancers have absent or abnormal RB protein. Studies of individuals with abnormalities regarding RB genes showed they develop tumors at 10 times the normal rate. 3.37 The P-53 Tumor Suppressor Gene The P-53 gene is another gene specifically associated with the development of many cancers. P-53 is a tumor suppressor gene and alteration of the gene results in it not preventing abnormal cell development. Imagine a policeman at a busy intersection. If we taped the officer's hands behind him, he would not be able to regulate traffic or stop cars. In a sense, the P-53 gene acts like a policeman regulating cell development, and cancer results partly because the P-53 gene malfunctions. p53 protein...mediates several cellular functions: regulation of the cell division cycle, DNA repair, and programmed cell death. DNA repair, and programmed cell death. In response to various forms of genomic DNA damage... the p53 protein can arrest the cell cycle at the G1 to S transition point, thus affording time for DNA repair and preventing duplication of a mutant cell, or alternatively, failing DNA repair, p53 protein can implement programmed cell death (apoptosis). Accordingly, p53 has been dubbed the A guardian of the genome.@ Etiology of Cancer: Carcinogenesis:http:/edcenter.med.cornell.edu./CUMC_PathNotes/Neoplasia/Neoplasia_04.html. 3.371 Wild and Mutant type P-53 Genes P-53 is a protein of 53 kilodaltons and is located on chromosome 17 (p13). There are two types of P-53. First, there is normal P-53 also called wild-type P-53. This is P-53 in its normal condition, serving various tumor suppression functions outlined above. Mutant P-53 means the gene has been damaged. Not only will the gene not perform its tumor suppressor function, evidence indicates it plays a role in prompting duplication of cells. Gemba, Immunohitochemical Detection of Mutant P53 protein in Small Cell Lung Cancer: Relationship to Treatment Outcome, Lung Cancer, vol 29 (1) (2000) pp. 23-31. 3.372 P53 and Small Cell Lung Cancer A 1999 study found that 52% of small cell cancer patients had traces of P53 in bronchial specimens. Gemba, Immunohitochemical Detection of Mutant P53 protein in Small Cell Lung Cancer: Relationship to Treatment Outcome, Lung Cancer, vol 29 (1) (2000) pp. 23-31. P53 presence was unfortunately a negative factor for these patients. A The overall response rate of patients in the p53 -positive group was significantly lower than that in the P53 negative group.@ Gemba, id. 2.373 Early Diagnosis of Lung Cancer with P-53 Testing P-53 alterations appear to occur early in lung cancer: A One of the most promising future of p53-Ab concerns their detection in the sera of people with high risk for cancer such as lung cancer or workers exposed to carcinogens. As stated above p53 alteration is an early event in lung cancer, several years before the clinical diagnosis of the tumor. Recently, p53-Ab were detected in sera of two patients who were heavy smokers without diagnosed lung malignancy. Both of these patients developed invasive squamous lung cancer 5 and 15 months, respectively, after detection of serum p53-Ab. In one patient, the level of serum antibodies directed against different epitopes of p53 protein was shown to progressively increase during the 15 months of follow-up before the diagnosis. In this patient, p53 overexpression was detected in tumoral cells from bronchial biopsy specimens. Since p53 alterations represent an early genetic changes in lung carcinogenesis, it is suggested that p53-Ab detection represents a new and sensitive tool for detection of preneoplastic and microinvasive bronchial lesions in patients with a high risk of lung cancer, i.e., heavy smokers. This finding was confirm by Trivers et al. using three types of assays to detect p53-Ab. They were able to find p53-Abs before diagnosis in several patients with Chronic Obstructive Pulmonary disease. This is also supported by the recent observation that p53-Ab can be detected in the sera of workers exposed to vinyl chloride and highly susceptible to developing angiosarcoma of the liver.@ P-53 Mutation in Lung Cancer http://perso.curie.fr/Thierry.Soussi/p53_mutation_in_%20lung.html#Bronchopulmonary%20cancers
2.374 Cell Experimentation If this damage to P-53 could be repaired or new P53 delivered, then cancerous behavior could theoretically be limited. This type of treatment has worked in the laboratory dealing with cancer cells: Reintroducing a wild-type p53 gene into lung cancer cells, including bronchioalveolar lung cancer (BAC), dramatically inhibits tumor cell growth and promotes tumor cell death despite the presence of mutations in multiple other genes. Lee, Gene Therapy, 324 in Pass, Lung Cancer: Principles and Practice (2000). 3.375 Clinical Trials with P53 In a laboratory, scientists have been able to control tumor growth by introducing sufficient amounts of P-53. Clinical trials have shown modest success with humans by introducing P-53 gene retro-virus into the area of the tumor. Getting a sufficient amount in the body without creating intolerable effects continues to be the challenge. To simplify the discussion, we divided genes into two categories, dominant or growth genes, and tumor suppressor genes. However, as the above shows, the process by which tumors grow is complex and sophisticated, with the term growth an oversimplification. The tumor suppressor genes play some role in growth while the dominant genes perform related functions.
3.4 TREATMENT OPTIONS Understanding the way in which cancer develops can help us understand why certain treatment are administered. Here are the primary forms of treatment for lung cancer: 1. Surgery The purpose of surgery is to remove the cancerous cells. With removal, the capacity to metastasize is eliminated as well as the direct impact upon the organ itself. Surgery is the preferred method of treatment, but frequently the cancer has spread so that it does not make sense to undergo the risks associated with surgery only to remove part of the tumor. 2. Radiation Radiation aims to do something similar, kill the cancer cells. Sometimes the purpose of radiation can be curative, to eliminate the cancer, alone or with other forms of treatment, or palliative, that is treatment designed to reduce pain or discomfort associated with the cancer. 3. Chemotherapy Chemotherapy is the use of certain drugs to kill cancer cells or prevent them from dividing or replicating. Today, mutlti-modal chemotherapy is the standard treatment, using a group of drugs which work in different ways to kill cancer cells or inhibit their growth and duplication. 4. Gene Therapy "The approach is to treat the disease by inserting a gene that has been lost or altered, or trying to block expression of a gene whose function is to promote uncontrolled cell growth. Gene therapy can also be used to provide a new function to cells, such as producing new proteins." Alcase, The Lung Cancer Manual 6.24 (1999) available online with the Alliance for Lung Cancer Advocacy, Support and Education. 5. Anti-AngioGenesis Drugs The principal danger of lung cancer is its spread to other organs. These drugs seek to limit and inhibit the spread of cancer through various means.
CHAPTER FOUR: THE STRUCTURE OF THE LUNG AND LUNG CANCER CLASSIFICATION ________________________________________ 4.1 LUNG ANATOMY 4.10 The Left and Right Lungs The lungs are two organs located in the chest or thoracic cavity. The right lung has three sections called lobes. The left lung has two lungs and is smaller because the heart takes up more room on that side of the body. A tumor= s location might be identified as right upper lobe or left lower lobe. The lung= s basic function is breathing, taking in oxygen and getting rid of carbon dioxide gas. See What is Lung Cancer, www.educ.kent.edu. 4.11 The Trachea and the Pleura The trachea is a thin windpipe about four and a half inches long which divides into the right and left lungs. The windpipe or trachea brings air into the lungs. The lining which surrounds the lungs and helps to protect them is called the pleura, and the chest cavity is called the pleural cavity. Mesothelioma, a rare form of lung cancer, comes from asbestos entering the pleura and creating tumors in it. Pleurisy is inflammation of the pleural membrane. The pleura is divided into an outer layer called the parietal pleura and an inner layer, the visceral pleura. Between the parietal pleura and the visceral pleura is the pleural cavity which contains a lubricating fluid the body forms between the membranes to allow them to move easily on one another during breathing. On occasion, this fluid would need to be drained in a lung cancer patient. If the pleural cavity fills with air, this is called pneumothorax, and blood in the pleura is called hemothorax. 4.12 Mediastinum The mediastinum is an area between the two lungs which contains lymph nodes. Recall that lymph nodes are part of the lymph system which helps purify the blood and remove certain byproducts. A mediastonomy is a procedure where the physician looks at the mediastinal area to detect the presence of cancer in the mediastinal lymph nodes. You will see reference to mediastinal nodes in the description of stage in assessing non-small cell lung cancer. 4.13 The bronchial tree. The bronchial system is like a tree with the trunk the primary bronchus, branches, the bronchioles, and numerous small twigs, the alveoli. The trachea leads first to the primary bronchus in the right and left lungs. Some scientists refer to the bronchi as the larger airways. The right bronchus is more vertical, shorter and wider than the left and as a result, foreign objects that enter can lodge in it. Cancer in the right lung is slightly more common 55% versus 45% than in the left. ( Remember too that the right lung is a little larger than the left, with three lobes). Some patients have squamous cell carcinoma, which is a tumor involving squamous cells in the bronchus. The bronchi divide to form small bronchi called the secondary or lobal bronchi, which in turn continue to branch forming tertiary bronchi which divide into bronchioles. See What is Lung Cancer, www.educ.kent.edu Bronchospasm associated with asthma occurs when the muscles of the walls of the bronchioles go into spasm narrowing or closing off the air passageways and causing labored breathing. 4.14 Alveoli and breathing Bronchioles subdivide into microscopic branches called respiratory bronchioles, and this in turn divides into microscopic alveoli where air exchange occurs. In the alveoli, carbon dioxide from the outside is converted to oxygen, and a descriptive name for alveoli is air sacs. The lungs consist of about 300 million alveoli where the primary exchange of gas and breathing functions occur. During emphysema, the walls of the alveolar are destroyed by smoking. The author of The Chronic Bronchitis and Emphysema Handbook explains this process: Because emphysema destroys elastic fibers in the membranous walls surrounding individual air sacs these alveoli lose their ability to recoil to their original size during expiration. Then, as an alveolus remains stretched, the rest of the membrane fibers eventually break. The wall is destroyed, meaning the air sac with its neighbor. As the process continues, alveoli become larger and fewer. It is somewhat like tearing down the interior walls in a building of multi-room apartments until each apartment is one large room. The alveoli's membrane walls- which are richly supplied with capillaries, the circulatory system's tiniest vessels- are the actual gas exchange sites. Haas, The Chronic Bronchitis and Emphysema Handbook (1990) The process by which foreign substances destroy cells can cause different forms of disease. In some instances, the area will remain damaged as in emphysema while in others it appears the process of rebuilding and replacing cells creates cancer. A less common form of lung cancer is bronchio-alveolar, which affects the smaller alveiolar region of the lung. Since smoke and dust first come in contact with the primary bronchus, it would make sense that more cancers would occur there. However, since the advent of filtered cigaretes, smokers compensate by inhaling more deeply and cancer affecting the deeper airways are occuring more frequently. 4.16 Nodes One of the chief dangers of cancer is that it may spread or metastasize to other organs and we discussed lymph nodes earlier. The Lung Cancer Manual by Alcase, an advocacy group for lung cancer, notes, Because the lungs are so richly supplied with blood vessels, they serve as a convenient route for lung cancer cells to travel to other parts of the body. Most of the cancer cells that enter the bloodstream die, some survive and grow and become metastatic cancer... The lungs also have a rich supply of lymph vessels. The system of lymph vessels resembles the system of blood vessels. The purpose of the lymphatic system is to drain the clear fluid called lymph from the body tissues and bring it back into circulation. Lymph nodes filter germs and other foreign invaders, such as cancer cells. Trapped cells can create tumorous growth in the lymph nodes causing them to swell, and an enlarged lymph node in the neck region can be an indication of lung cancer. Lung cancer usually develops in a single spot but if lymph nodes are involved, it may spread to other parts of the body. Typically the lymph nodes in the hilus (hilar lymph nodes) the place where the large airways and blood vessels enter the lung from the mediastinum (towards the center of the chest) are affected first. From there, the cancer may spread to the nodes of the mediastinum and then to the nodes in the neck and /or abdomen. If the tumor cells enter the blood stream, they may migrate (metastasize) to the liver, other section of the lung, the brain, the bones, and/or the bone marrow. Alcase, Lung Cancer Manual (1998) (at the time of this printing, the lung cancer manual was available at no cost on the Alcase website). 4.161 Staging and Measuring Lymph Node Involvement The extent to which the lymph nodes are involved is an important consideration in determining the stage of disease, and the prognosis. Once there is lymph node involvement, surgery is unlikely to remove all the cancer. Thus, the staging systems below consider as a critical element the presence of cancer in the lymph nodes. A cancer located in the larger bronchi would typically move towards an adjacent hilar lymph node, then a mediastinal lymph node, and then to a node connected with another organ. 4.17 Sources of Pain A tumor that grows may obstruct a bronchus, causing shortness of breath or chest pain. Thus, two of the classic non-specific symptoms of lung cancer are shortness of breath and chest pain. A non-specific symptom is one which can indicates a number of different diseases.
4.2 TYPES OF LUNG CANCER: NON-SMALL CELL AND SMALL-CELL Lung cancer is divided into two basic types, non-small cell and small cell. About 80% of lung cancers are non-small cell. Non-small cell lung cancer (NSCLC) combines at least three types of lung cancer: squamous cell (occasionally called epidermoid carcinoma), adenocarcinoma, and large cell carcinoma. These are classified together because their treatment and prognosis are generally similar. One textbook explains: The remaining common histologic varieties of lung cancer- adenocarcinoma, squamous cell carcinoma, large cell carcinoma- behave as a group in a biologically similar fashion and respond similarly to therapeutic intervention. These tumors account for approximately 85% of all lung cancers. Aisner, Comprehensive Textbook of Thoracic Oncology (Williams & Wilkins 1996). 4.21 Squamous Cell Carcinoma Squamous cell refers first to a type of cell which lines the large bronchi, and squamous cell tumors are generally centrally located. It is generally agreed that approximately 90% of squamous cell carcinomas arise in subsegmental or larger bronchi...they have a tendency to grow centrally toward the main stem bronchus and to infiltrate the underlying bronchial cartilage, lymph nodes, and adjacent lung parenchyma. In time, this progression may lead to the formation of largenodular masses. Epithelial tissue lines body surfaces or tissues, glands, and body cavities, and squamous cell is a type of epithelial tissue. Squamous cells line the pleural cavity and squamous cell cancer can occur outside the brochi and in other parts of the body . Thus one question is whether a squamous cancer is another part of the body will act similar to a squamous cell tumor in the lung. 4.212 The Percentage of Squamous Cell Carcinomas is Decreasing Perhaps Because Smokers are Breathing Low Tar Cigarettes More Deeply Leading to Peripheral Rather Than Central Tumors While squamous cell remains the most prevalent form of lung cancer, its incidence is decreasing. One study found the percentage of squamous tumors in men decreased from 51.8% to 42.7%. Aisner, et. al., Comprehensive Textbook of Thoracic Oncology 251 (1996). With filtered cigarettes becoming more prevalent, smokers may be inhaling more deeply leading to the development of more peripheral adenocarcinomas rather than the central squamous cell carcinomas. 4.213 Squamous Cell Carcinomas and Early Diagnosis with Sputum Cytology There are important changes in squamous cells that occur long before the cancers can be seen on an x-ray. Sputum cytology is a device to detect these cancers at their earliest and most treatable stages. Sputum cytology is a test where the patient provides a deep cough and sputum, which is then analyzed in a laboratory by a pathologist. See Lungcheck.com (website by commercial entity providing detailed reports). The cytology can frequently identify early stage cancers and if sputum cytology were used more widely, many lives would be saved. 4.22 Adenocarcinoma Adenocarcinoma is the second type of lung cancer comprising the group non-small cell lung cancer. It represents about 40% of all cancers and has become the most common lung cancer among women. It generally starts near the outer edges of the lungs, and its increasing incidence is connected with the tendency of smokers to breath the lower-tar cigarettes more deeply. It is occasionally called glandular cancer. 4.221 Adenocarcinoma, Asbestosis and Silicosis While smoking remains the largest cause of adenocarcinoma, some scientists have seen an association with lung scars, and the term scar carcinomas has been used with adenocarcinoma. Where a foreign particle deposits in the lung, and collagen forms to encapsulate the particle, some have called this scar formation. For a detailed discussion of silica-related scar formation, See Castranova, Silica and Silica-Related Diseases (CRC Publications 1997). Asbestosis, silicosis, residuals of tuberculosis along with other scar formations have been linked to adenocarcinoma. Thus, an individual with asbestosis and adenocarcinoma, would likely have a legal claim. See Chapter 22. Some have questioned how closely adenocarcinoma should be associated with the various types of fibrosis or scaring in the lung: For many years, adenocarcinoma was believed to develop on the basis of scar of (a) any kind. Although we do not deny the existence of scar cancer in the lung,... We have proposed the concept that central or subpleural scars in most peripheral adenocarcinomas were formed not before, but after, the development of carcinoma, and showed the mode of development of such a scar or a fibrotic focus. 4.222 Subtypes of Adenocarcinoma There are three subtypes of adenocarcinoma: * Acinar * Papillary * Bronchioalveolar * Solid carcinoma with mucus formation Acinar is the most common subtype. 4.223 Bronchioalveolar Carcinoma Bronchioalveolar carcinoma is a type of adenocarcinoma which originates in the alveoli. Squamous cell carcinoma usually begins in the larger breathing areas, while adenocarcinomas originate in the smaller or peripheral airways, even occasionally at the microscopic level of the alveoli. 4.23 Large Cell Cancer Large cell cancer constitutes about 15% of all cancers and the term large cell refers to large, masses of tissue usually displaying signs of necrosis (cell death). Since one of the characteristics of the tumor is necrosis, it can sometimes be confused with a poorly differentiated adenocarcinoma or squamous cell carcinoma. That is, the characteristic large cell tumor has experienced significant cellular changes similar to those which change a normal cell to a poorly differentiated adenocarcinoma. However, since the treatment for adenocarcinoma, squamous cell, and large cell are generally grouped together, a physician might not be overly concerned with distinguishing cell type within the group. A subtype of large cell carcinoma is giant cell. 4.231 Categorizing Large Cell 4.25 Differences Within the Non-Small Cell Lung Cancer Category It is rare to categorize a disease based upon what it is not, but here it is accurate. Non-small cell lung cancer has these differences from small cell lung cancer: 1) it does not quickly metastasize like small cell, 2) it is not immediately responsive to chemotherapy in most cases like small cell, With that said, there are many important differences within the non-small cell group which impact treatment and prognosis. 4.251 Greater Expression of MMP Adenocarcinoma has a greater tendency to metastasize, compared with squamous cell. Most organs have a protective barrier called the extracellular matrix. During cancer, certain proteins called metalloproteinases or MMP help enable the tumor to penetrate these barriers. A Matrix metalloproteinases (MMPs) are a class of structurally related enzymes that function in the degradation of extracellular matrix proteins that constitute the pericellular connective tissue and play an important role in both normal and pathological tissue remodelling. Increased MMP activity is detected in a wide range of cancers and seems correlated to their invasive and metastatic potential. MMPs thus seem an attractive target for both diagnostic and therapeutic purposes.@ Dennis, Matrix metalloproteinase inhibitors: present achievements and future prospect, Invest New Drugs 1997;15(3):175-85. A Matrix metalloproteinases are a family of zinc-containing proteolytic enzymes that break down extracellular matrix proteins in normal physiological processes such as embryogenesis, tissue growth, and wound healing. The family includes collagenases, gelatinases, stromelysins and metalloelastase. Observational and experimental data from studies of human malignancy indicate that these proteinases are induced by the tumour in order to reconstruct adjacent normal tissue to allow neovascularisation, tumour growth and spread. Tumours have been shown to overexpress certain matrix metalloproteinases relative to normal tissue and recent studies have shown an association between high levels of expression and poor prognosis.A Brown, Matrix metalloproteinase inhibitors in the treatment of cancer, Med Oncol 1997 Mar;14(1):1-10 One study found that adenocarcinomas produced greater quantities of these MMP= s than squamous cell tumors possibly accounting for the greater tendency of aendocarcinomas to metastasize. A Compared with squamous cell carcinoma (SqCC), adenocarcinoma (AdC) more frequently overexpressed MMP-1, -11, -13, -14, and TIMP-2, and TIMP-1 and/or TIMP-2 overexpression.@ Thomas, Differential expression of matrix metalloproteinases and their inhibitors in non-small cell lung cancer, J Pathol, 2000 02, 190: 2, 150-6. Thus, we can theorize that an additional amount of MMP inhibitors, would be needed to accomplish the same result with adenocarcinomas as with squamous cell tumors. 4.252 Longer Survival with Squamous Cell One study found, A For the 71 stage II patients with a squamous histology, a 5-year survival rate of 44% was noted as opposed to 14% for patients with a large cell or adenocarcinoma.@ (1) Given that dramatic difference in survival, one could argue that it could be erroneous to group squamous cell and adenocarcinoma patients in the same clinical trial. Using this assumption about 5 year survival, if the same drug were given to two groups of patients, one squamous and adeno, results could be interpreted to show triple the effectiveness (as measured by 5 year mortality) in the first group. Additionallly, since adenocarcinomas usually produce a greater number of MMP= s, we can theorize that higher doses of MMP inhibitors may be necessary to accomplish the same result as with squamous cell. Thus, there are dangers in grouping these three types of cancer together, both for treatment and research. Future research may examine how the tumors act differently, allowing physicians to make more accurate judgments, and refine treatment based upon type. References 1. Rodrigus, The Impact of Surgical Adjuvant Thoracic Radiation for Different Stages of Non-Small Cell Lung Cancer: The Experience of a Single Institution, Lung Cancer 23 (1999) 1117.
4.3 SMALL CELL CANCER 4.31 Characteristics and Subclassifications The other type of cancer group is small cell which has sub-classifications of oat cell and mixed. Small cell acts differently than non-small cell, requires different types of treatment, has its own prognosis, and therefore is separately categorized. It usually originates in large central airways and is composed of sheets of small cells. Small cell carcinoma is a tumor of neuroendocrine origin and is very aggressive, metastazing early and often. Endocrine cells are associated with growth which probably explains why small cell cancers are aggressive. Small cell carcinoma accounts for approximately 15% to 20% of all lung cancers. Small cell is a high-grade tumor meaning it reproduces and metastasizes quickly, but is also responsive to chemotherapy. 4.32 Role of Smoking and Location in Large Airways Smoking is a clear factor in the development of small cell tumors. As with other cancers, but perhaps even more so, early detection and treatment is the key to cure. 4.33 Related Hormonal Syndromes Small cell carcinoma can cause a number of hormonal syndromes. "The tumor cells may produce ectopic adrenocorticotropic hormone (ACTH), resulting in Cushing's syndrome, another paraneoplastic hormone syndrome that commonly occurs is the syndrome of inappropriate anti-diuretic hormone (SIADH). This is caused by secretion of ADH from the tumor. 4.34 Small Cell Staging Small cell cancer is usually staged only as limited or extensive, depending on whether or not it has spread outside the chest. For non-small cell cancer, treatment will depend upon stage; stage 1 tumors are usually surgically resected. In contrast, chemotherapy is the standard treatment for small cell cancers, so most physicians do not use the stage 1-4 terminology for nonsmall cell cancer. In chapter 5, I discuss the question of how small cell cancer should be staged. Limited stage carcinomas account for 30% of all cases. Limited stage means the small cell cancer is confined to one of the regional lymph nodes. Regional lymph nodes means lymph nodes in the area where the tumor originates. 70% of small cell carcinomas are extensive meaning at the time of diagnosis, the cancer has spread to other organs, or at least beyond the regional lymph nodes. Because extensive disease is common, patients are evaluated with head CT scan, bone scan, liver scan and bone marrow biopsy to see if any metastasis is present. 4.35 Small Cell Location and Appearance Over 90% of small cell tumors are found in a central location and they typically grow around major bronchi.. The tumor typically extends also to lymph nodes and may invade vascular tissue which explains why many patients have metastases at the time of diagnosis 3.36 Role of Surgery in Small Cell Lung Cancer With non-small lung cancer, surgery is the preferred option and is invariably used for early stage lung cancers, except when the patient has other significant health problems which create risks for surgery. However, a medical article discusses surgery for small cell lung cancer patients: In the 1950's, surgical resection was still considered the preferred treatment of SCLC (small cell lung cancer) However, in a study conducted by the British Medical Research Council in the 1960's, patients were randomly assigned to receive surgery alone or radiotherapy alone; in patients with limited disease, the median survival was 199 days for those receiving surgical treatment versus 300 days for those receiving radiotherapy. One the basis of this study and the discovery of systemic chemotherapeutic agents with activity, surgical treatment for SCLC has been abandoned, and chemotherapy has been used for both limited and extensive disease. Midthun, Chemotherapy for Advanced Lung Cancer Postgraduate Medicine, vol. 101, no. 3, March 1997. Some observations: 1. Scientists determine the validity of certain treatment forms through epidemiological studies. The word epidemiological comes from epidemic and epidemiological studies investigate the patterns of disease, sometimes comparing the impact of disease between two group receiving different types of treatment. 2. Books like this are intended to provide a general overview, and you need to listen to your physician's advice regarding specific types of treatment, since statements in books and articles can be misinterpreted by patients unaware of subtle difference, for example, differences between non-small cell and small cell. Likewise, your physician should be familiar with recent studies and developments. 3. The National Cancer Institute agrees that surgery has limited utility in small cell lung cancer, but would not agree that surgery has been abandoned. See Chapter Four. One has to be careful of making quick conclusions based upon one or two studies, and you need to measure a study conclusions against our overall medical knowledge in an area. Perhaps a better way of assessing surgery and small cell cancer is to say that many small cell cancers have already had significant spread at the time of diagnosis. Where there has been such spread, that is movement to lymph nodes or other organs, surgical resection cannot accomplish the goal of completely removing the tumor. However, if we can be persuaded that the entire cancer can be removed, surgery might be appropriate. 4.37 Comparison among the Different Types The book Lung Cancer categorizes the different forms of cancer as follows: In lung cancer, we know that the histological type (type of cell) is one of the most important factors, and that SCLC is most malignant of all; squamous cell carcinoma, adenocarcinoma and large cell are intermediate in terms of malignancy; while carcinoid tumor, adenoid cystic carcinoma and mucoepidermoid carcinoma (all relatively rare) are low grade malignancies. Carney, Lung Cancer (Arnold Publishing Co., Great Britain, 1995)
4.4 CLASSIFICATION OF NON SMALL CELL LUNG CANCER BY STAGE 4.41 The American Joint Committee on Cancer (AJCC) Classification Non-small cell lung cancer patients are classified by stage which largely determines the type of treatment which is provided. To understand your disease and treatment, you should have at least a basic understanding of the staging process. The American Joint Committee on Cancer (AJCC) uses the TNM classification. with T designating the size and location of the primary tumor, N the existence of cancerous lymph nodes, and M meaning metastasis or spread to other organs. Thus a medical chart would have a notation; classification of tumor, T1NoMo. (Tumor, size 1, no lymph node involvement, and no or 0 metastasis). Tumors are classified from 0-4 based upon their size, ranging from a 0, tumor which cannot be seen on an x-ray but only identified microscopically, to a T4, a tumor, going beyond the lung tissue into another organ or structure. N or node specifies whether the tumor has entered into a lymph node and that node= s location in relation to the tumor. A tumor may first spread to an adjoining hilar lymph node, N1, and then to a contralateral lymph node, node further away from the main tumor. An overriding question is whether surgery can eliminate the tumor, and the higher the lymph node classification the less likely surgery will be performed. Lung surgery is major surgery carrying some significant risks. If the physician believes it is unlikely that the entire cancer can be removed, he may therefore believe that surgery should not be performed and that other forms of treatment should be used. M designates Metastasis or spread of the tumor to other organs. If the cancer has spread to another organ, surgery again is not likely to be a viable option since the cancer cannot be entirely removed. The physician will want to accurately "stage the patient" not only to assess surgery but to gauge what type of chemotherapy or radiation is preferred. Here is the staging terminology: PRIMARY TUMOR (T) TX or T0: Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscope T1: A tumor that is 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, and without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus)* T2: A tumor with any of the following features of size or extent: More than 3 cm in greatest dimension Involves the main bronchus, 2 cm or more distal to the carina Invades the visceral pleura associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung T3: A tumor of any size that directly invades any of the following: chest wall (including superior sulcus tumors), diaphragm, mediastinal pleura, parietal pericardium; or tumor in the main bronchus less than 2 cm distal to the carina but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung T4: A tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina; or separate tumor nodules in the same lobe; or tumor with a malignant pleural effusion ** REGIONAL LYMPH NODES (N) NX: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes including involvement by direct extension of the primary tumor N2: Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s) N3: Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s) DISTANT METASTASIS (M) MX: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis present Note: M1 includes separate tumor nodule(s) in a different lobe (ipsilateral or contralateral). Sites are specified according to the following notations: BRA = brain EYE = eye HEP = hepatic LYM = lymph nodes MAR = bone OSS = osseous OTH = other OVR = ovary PER = peritoneal PLE = pleura PUL = pulmonary SKI = skin 4.41 Metastasis, Types and Areas. The most common sites of metastatic spread are the bone, brain, liver, and adrenals. 4.411 Brain Metastasis These metastasis are discussed are Carney, Lung Cancer at page 64: The reported incidence of asymptomatic brain metastasis varies from 2.7 to 9.6 percentand the value of screening (to detect these metastases) remains controversial. Silent intracerebral metastases occurring in isolation are well described with Adeno and large cell carcinomas. This is an uncommon presentation in patients with squamous cell carcinoma... Thus in contrast to other cell types, routine pre-operative brain scans are not indicated in those patients in whom the primary tumor is of squamous cell origin. 4.412 Metastasis to Bone Carney= s book (65-66) reviews testing for bone metastasis: Fifty per cent of bone material content must be lost before changes are apparent on plain radiographs.... [Thus] plain radiograph is an insensitive method of investigating localized bone pain. Radiopharmaceutical bone scans are in contrast highly sensitive though non- specific. Bone scanning is thus only indicated in those patients who have bone pain, elevated alkaline phosphatase levels, or recent exacerbation of bone pain... MRI may be useful to assess localized areas of persistent bone pain which appear normal on bone scan and plain radiographs. 4.42 The International Staging System for Lung Cancer The International System for Staging Lung Cancer was adopted in 1997 by the American Joint Committee on Cancer and the Union International Contre le Cancer. The international staging system uses the TNM classification and then gives the patients a number, i.e., stage 1, stage 4, with the use of surgery and the patient's survival negatively related to the stage number. That is, surgery would generally be used to remove a tumor from a stage 1 patient, where it would not be employed for a stage 4 patient with metastasis since the tumor could not be completely removed Stage I is divided into two categories by the size of the tumor; IA, T1N0M0 and IB, T2N0M0. Stage II is divided into two categories by the size of the tumor and by the nodal status; IIA, T1N1M0 and IIB, T2N1M0. T3N0 was been moved from stage IIIA in the 1986 version of the staging system to stage IIB. The other change has been to clarify the classification of multiple tumor nodules. Satellite tumor nodules in the same lobe as the primary lesion that are not lymph nodes should be classified as T4 lesions. Intrapulmonary ipsilateral metastasis in a lobe other than the lobe containing the primary lesions should be classified as an M1 lesion (stage IV). Another type of staging is done by the AJCC. Their categorization using T, tumor size. N, nodes, and M, metastasis is as follows: Occult Carcinoma TXN0M0 (T x means the tumor is sufficiently small than it cannot be seen on an x-ray). Stage 1 T1or T2, N0,M0 Stage 2 T1, N1, M0 or T2, N1, M0 or T3, N0, M0 or T1N1M0, or T2, N1, M0 Stage 3A T1, N2, M0 or T2, N2, M0 or T3, N1, M0 or T3, N2, M0 Stage 3B Any T-T4, N3; Stage 4 Any TAny NM1 Here is a shorthand way of understanding the stages. ! Stage 1 The cancer is located only in the lung, and has not spread to the lymph nodes. This is the least advanced stage. The treatment recommended for Stage I lung cancer is surgical removal of the tumor which is successful for most patients. ! Stage 2 The cancer has spread to the nearby lymph nodes found in the chest near the lungs. Lymph nodes are small-bean shaped structures where cells are stored; nodes can trap cancer cells or bacteria traveling through the body. Depending on the size of the nodes as seen on a CT Scan, a physician may recommend a mediastinoscopy to examine the lymph nodes in the chest and perform a biopsy on them and to see whether the nodes are cancerous or enlarged because of inflammation associated with the cancer. If the biopsy shows no signs of cancer in the mediastinal lymph nodes, the physician may recommend surgery followed by radiation and chemotherapy directed to the cancerous lymph nodes. ! Stage 3 The cancer is found in the lymph nodes in the middle of the chest away from the lungs. Stage III lung cancer has two types. If the cancer is a single tumor, or mass, it is called Stage III-A. Most doctors will recommend beginning treatment for Stage III-A with chemotherapy, or a combination of anti-cancer drugs, and radiation. If the cancer in the chest has spread to more than one area, it is called Stage III-B. Most doctors do not recommend surgery for Stage III-B. A combination of chemotherapy and radiation is usually of the greatest benefit. ! Stage 4 is the most advanced stage of lung cancer. This is when the cancer has spread to a distant part of the body- for example, the liver, bones, brains, or some other organ. For Stage IV, most doctors are in agreement that chemotherapy is the most effective treatment and different types of chemotherapy will be tested. Because the cancer cannot be removed at this stage, surgery will not be performed, and the patients prognosis for long-term survival is not good. Patients in Stage 4 or Stage 3B are clearly candidates for clinical trials. And while the overall statistical probability for long-term survival is not favorable in Stage 5 where there is metastasis, the patient survival time will vary and there are a small number of cases with more favorable outcomes. Excerpted and modified from Cancer care, Inc. website 3.43 Small Cell Staging The above classification scheme is for non-small cell carcinoma, squamous cell, adenocarcinoma, and large cell. Unlike these nonsmall cell carcinomas, small cell carcinoma is staged only as limited or extensive, depending on whether or not it has spread outside the chest. Limited stage carcinomas account for only 30% of all cases. Limited stage is confined to one hemithorax and regional lymph nodes (including mediastinal, contralateral hilar, and ipsilateral supraclavicular). Given the prevalence of metastasis, small cell patients are usually e evaluated with head CT scan, bone scan, liver scan and bone marrow biopsy to see if there has been metastasis. Some books will use the non-small cell terminology for small cell, even though the stages have different meanings for small cell tumors. For example, surgery would be the usual treatment for stage 1 non-small cell tumors, while it would still be unusual for small cell.
4.6 CELL DIFFERENTIATION Scientists and physicians also classify lung cancer by its cell differentiation. Normal tissue is differentiated while cancerous tissue is haphazard, disorganized if you will. As one book explains: When a cell grows and develops normally, it becomes more specialized to perform a particular function in life. This process is called differentiation and it results in irreversible changes in the cell's characteristics. Differentiated cells are mature cells that perform a particular function. For example, a lung cell looks and works like other lung cells. As a cell becomes more differentiated, it becomes more restricted in what it can do.... As malignant, or cancerous cell grow and divide, they become less and less differentiated. Eventually, they can nor longer perform the functions of the tissue where they originated.... The term differentiation is also used to describe how the cells of a tumor appear in comparison to normal cells. For example, tumors that are classified as "well differentiated" still contain cells that resemble normal cells of the original tissue. Alcase, The Lung Cancer Manual 2.4 (1998) Pathologists and physicians classify tumors according to their state of differentiation: ! Well differentiated, (a cell at its earliest stage of carcinogenesis) ! Moderately differentiated (more progression in the change to cancer cells) ! Poorly differentiated (a cell seen as clearly cancerous) Within those categories, there may be subcategories, such as well to-moderately differentiated, or moderately to poor differentiated. Generally, the level of differentiation is a positive factor in survival with the more differentiated the cancer cell, the less chance of metastasis. One study found the DNA content of poorly differentiated adenocarcinoma significantly greater than that of well-differentiated adenocarcinoma. Carney, Lung Cancer (Little Brown 1995). Thus one can assume that the loss of differentiation is associated with increasing DNA mutations in the cell. However, stage rather than differentiation remains the primary factor in determining treatment. 4.61 The Importance of Classification Survival as well as the nature of treatment is related to lung cancer stage as you will see in chapter four. If a tumor is relatively small, confined to a particular location without involvement of lymph nodes, or other organs, surgery- removal of the tumor would be the preferred treatment. In contrast, if the tumor had already spread to another organs, surgery would not accomplish he desired goal since parts of the cancer would remain. Let us review what these three items means before looking at the classification. 4.62 Patient Stage Related to Survival Finally, tumor size, nodes, and metastasis are directly related to survival. Survival rates of 60-80% have been reported in TXNoMo patients. That is, patients with microscopic tumors with no lymph node involvement or metastasis. In contrast, appreciably lower survival rates apply when the cancer is much larger, lymph nodes are involved, or metastasis to other organs has occurred.
4.7 TREATMENT OVERVIEW The particular types of treatment are discussed in detail in the succeeding sections. Because the materials can be somewhat technical, you need to understand the terminology which is used in this area. 4.71 Surgical Options Surgery is the treatment of choice for non-small cell lung cancer. Ideally, a small cancerous tumor is removed with surrounding tissue and that eliminates the cancer. This is done for smaller tumors, ideally without any lymph node involvement. 4.72 Lobectomy The lungs are divided into lobes. There are generally three lobes on the right lung, two on the left lung. The left lung also has a cardiac notch to accommodate the shape of the heart. A lobectomy involves removal of the entire section of lobe of the lung. 4.73 Pneumonectomy Pneumonectomy is surgical removal of the entire lung. 4.74 Wedge Resection Wedge resection is removal of a small part of the lung. Because cancer recurrence rates were higher with wedge resection than with lobectomy in some recent studies, this treatment is not generally used.
4.8 DIAGNOSTIC TOOLS 4.81 Chest X-Ray The most widely used diagnostic tool is the chest x-ray. It is economical and easy to use. A chest x-ray could take as little as ten minutes and cost less than $100. However, it is not a reliable method of diagnosing lung cancer. Many smaller tumors whose early detection could be critical to the patient's survival are missed with the chest x-ray. 4.811. Chest X-Ray Interpretation Problems Radiologists are upon to make critical assessments based upon what are frequently almost imperceptible shadows. The chest contains tissues of different consistency, with air next to thick soft tissue and bone. Adequately producing an image which provides clear definition of all structures in the chest requires meticulous technique and attention to detail. The machine (film processor) used to develop the film should be working properly though up to 50% of x-ray film processors may have some deficiency.@ www.chest.x-ray.com. While this is a most commonly performed examination, it often is done incorrectly. Studies have shown that from 20B 40% of x-rays are incorrectly interpreted. www.chest.x-ray.com. Indeed, there is a discernible difference in skill among radiologists interpreting chest x-ray films. However, even with good equipment and skilled people, the x-ray is still inaccurate. 4.822 Chest X-Ray Misses Over 75% of Stage 1 Tumors, those at the Most Treatable Stage An important 1999 study discussed deficiencies in the chest x-ray, contrasting it with the accuracy of the CT or Cat Scan. In this study 1,000 smokers with no symptoms of disease were evaluated with CT Scan and chest x-ray. 27 of the participants were found to have lung tumors which were detected by CT Scan. However, only 7 of the 27 tumors were detected by chest x-ray! Many corporations trumpet less than 1 in 100 defects for various products and the HLA test for detecting paternity is more than 99.7% accurate. The chest x-ray in contrast was shown here to be less than 30% accurate in the patients who would benefit most by early diagnosis. Not suprisingly but quite sadly, many patients with advanced lung cancer reveal that they had a prior x-ray which failed to detect the tumor. Stage 1 or beginning stage cancers are the most treatable. The results of the chest x-ray in this study for small, stage 1 tumors was even worse. With the Ct Scan, 23 of the 27 tumors were detected at stage 1. However, the chest-ray revealed only 4 of the 23 small, stage 1 tumors. Thus A stage 1 tumors were detected six times more frequently on low-dose CT than on radiography.@ Note, that this study was done in a clinical context at a well-known hospital. The x-ray machines were presumably working correctly and the slides interpreted by capable radiologists. Even in this context, the chest-ray performed poorly. The study dealt with smokers with at least 10 pack year histories (pack years are computed by multiplying the number of years smoked by the number of packs in each year), who had no symptoms of cancer. Most of the persons detected turned out to have highly treatable cancers. Chest x-rays do detect some tumors, but primarily those at advanced stages which are more difficult to treat. It is a test of limited use, better than nothing, but not even 40 or 50% reliable in detecting small tumors. Given the unreliability of the x-ray, we hope that physicians will begin using CT Scans to test those at high risk. Certainly, where an x-ray is ambiguous or displays some abnormalities, the prudent physician should order an x-ray. Misread chest x-rays are a chief source of medical malpractice claims. The prudent physician will check his equipment and have all slides read by a qualified radiologist. While that can reduce the possibility of error, it cannot eliminate the inherent limitations of the test. 4.82 Sputum Cytology Sputum cytology is a microscopic analysis of cells from the lung. The patient does a deep cough and the liquid or sputum is analyzed by a pathologist and a report prepared. Using sputum cytology, a man named Saccamanno in a landmark study was able to detect the progression of lung cancer in a smoker. This test has the following benefits and limitations 1. The test is effective at diagnosing central squamous cell carcinomas, even at microspopic levels, imperceptible on a chest-ray and perhaps a CT Scan. Thus, it has some utility is detecting tumors at an early stage when the disease can be cured. 2. Recall that the category non-small cell lung cancer includes squamous cell cancer and adenocarcinoma. Squamous cell cancer is generally located in the larger central airways , while adenocarcinomas tend towards the smaller, peripheral airways of the lung. The nature of the test is to retrieve liquid in the lungs, and the patient is more likely to cough up liquid from the larger more central parts of the bronchial tree, than the parts of the smaller airways that produce adenocarcinoma. Thus, the test is effective at diagnosing squamous cell cancers, but less effective at detecting adenocarcinomas. While squamous cell remains the most common form of cancer, with low tar cigarette smokers inhaling more deeply, the number of adenocarcinomas in the peripheral airways is almost equal. 3. The European Cancer Institutes states, A Sputum cytological analysis is greater for squamous (93%) or small cell (89%) histotypes than for adenocarcinoma (25%) and large cell carcinoma (54%). www.sias.it/start/chap-13/chap13-2.htm Thus, sputum cytology is a good tool for detecting some lung tumors, but not others. Used with Ct Scan, the two become a reliable method of detecting lung cancer in its early stages. The test is inexpensive, running in the $100.00 range. 4.821 Recent Advances in Detection of Lung Cancer with Sputum Cytology Sputum cytology is an economical, non-invasive way of detecting lung cancer in its earliest and most treatable stage, with its primary drawback difficulty in detecting adenocarcinomas. However, a recent study indicated progress in refining sputum cytology to improve detection of adenocarcinoma: Lam and colleagues developed a computer-assisted and automated image analysis method that detects aneuploidy and nuclear abnormalities in sputum samples. Between 5000 and 10,000 cells are stained with a Feulgen thionine DNA cellular stain, analyzed with a digital camera, and then screened using computer-assisted algorithms. In a series presented at the presidential symposium, Lam reported results showing that this screening technique was 70% sensitive for stage 0/1 lesions and 80% for adenocarcinomas, with a specificity of 90%. Lynch, 9th World Conference on Lung Cancer, (2000) citing, Lam et. al, Lung Cancer Control Strategy in the New Millennium. Lung Cancer. 2000;29(Suppl 2):145. 4.83 Computerized Tomography or CT Scan Computerized tomography or CT uses a beam that rotates around the body to produce a series of pictures taken from different angles. See www. Colorado Health Net, org./cancerlung.symptoms.html. This information is then processed by computer to produce a cross-section of a specific area. CT can reveal the existence of a tumor, and specifics about its location and size. Today, CT is the best non-surgical method of detecting lung cancer and revealing its size and status. 4.831 CT Scan to Detect the Nature and Extent of Disease. Indeed, physicians go beyond using Ct as a device to detect cancer to using it to determine the extent of disease. CT is used to provide a picture of whether a tumor has infilitrated lymph nodes or other organs. One study found the CT to be 80% effective in determining whether there was cancer in lymph nodes: A meta-analysis of 42 studies published between 1980 and 1988 found (using a node size greater than 1.0 cm as abnormal) a pooled sensitivity of 83%, specificity of 81% and accuracy of 81%. The 20% false negative rate is largely due to microscopic metastases to normal sized lymph nodes and the 20% false positive rate is due to enlarged nodes from pre- or coexisting inflammatory disease.@ chestx-ray.com/StaginglungCa/Lung Cancer The Early Lung Cancer Detection survey found an even higher rate of reliability in detecting tumors themselves. 4.84 Test Specificity and Accuracy Let us review these terms which are frequently used with medical tests. A false negative occurs where the patient has a disease or characteristic and the test fails to detect that. Thus, the test is falsely or incorrectly negative; it should have been positive. Another word for false negative is accuracy. That is, what percentage of persons with a given disease are detected. If the CT is 80% accurate in detecting lymph node metastases, its accuracy or false negative rate is 80%. Specificity is the number of false positives. That is, how many tests are incorrectly read as positive. For example, a person with inflamed nodes could have a CT Scan read as positive for spread of the cancer to the node. 4.85 Bronchoscopy If Ct Scan is the most reliable non-invasive test, bronchoscopy is the most reliable minimally invasive test. While bronchoscopy should be viewed as a surgical procedure, its risks are generally minimal. The Virtual Hospital is an excellent site which describes bronchoscopy: A Bronchoscopy is the examination of the airways under direct visualization. Bronchoscopy began with the use of a candle and a rod with a polished metal disk to visualize the osopharaynx. It has evolved into a wide variety of precision optical instruments capable of visualizing the endobronchial tree to the 5th or 6th generation.... bronchoscopy is used to obtain peripheral lung samples in the presence of lung parenchymal disease such as peripheral coin lesion(s), hilar adenopathy, or diffuse or focal parenchymal infiltrates. Finally, bronchoscopy is useful in staging lung cancer, evaluating the airways in patients with normal radiographic findings and positive sputum cytology, and evaluating the airways after thoracic trauma, or if there is a suspected airway foreign body.@ Virtual Hospital, Lung Ttumors: A Multidisciplinary Database, Bronchoscopy, www.vh.org.Providers/Textbooks/LungTumors/Diagnosis/Bronchoscopy/bronchosopy.htm. 4.851. How the Patient Feels During a Bronchoscopy The website Healthgate.com discusses what a patient will experience during a bronchoscopy A The surgeon makes a small incision in the skin on the chest with a scalpel. The biopsy needle is inserted into the lung. You may feel a sharp, temporary pain when the biopsy needle touches the lung. A small amount of lung tissue is removed. Biopsy needle and syringe are removed. Adhesive bandage is applied to the biopsy site. Tissue is sent to the laboratory for analysis.@ 4.842 Reliability of the Bronchoscopy Reliability seems to depend upon the location of the tumor. A Tumors may be present in three ways in the lung, as central endoscopically visible lesions, as submucosal or extrinsic lesions, and as peripheral lung lesions. The diagnostic yield and bronscospic approach to diagnose these lesions varies among these three presentations. In endobronchial visible lesions, bronchoscopy will correctly diagnose the lesion in 94% of the cases if at least 5 samples of the lesion are obtained.... By contrast, direct forceps biopsy correctly diagnoses only 27% of patients with extrinsic airway compression or with submucosal or peribronchial disease. The low yield is most likely due to the fact that the forceps biopsy does not sample tissue deep enough. Much better diagnostic results are obtained in this situation by using transbronchial needle aspiration. In this technique, a 1 cm. needle attached to a catheter is placed through the mucosa using the bronchoscopy.... The diagnostic yield for peripheral lung lesions varies widely from 30-90% using transbronchial biopsies. In this technique, the forceps are passed through the airways distal to the directly visualized sites using fluoroscopy.@ Virtual Hospital, Lung Tumors: A Multidisciplinary Database, Bronchoscopy, www.vh.org.Providers/Textbooks/LungTumors/Diagnosis/Bronchoscopy/bronchosopy.htm. Sadly, some people have gone undiagnosed after a physician failed to detect a tumor during a bronchoscopy. The above highlights that the following: 1) Bronchoscopy is not a conclusive test. Where symptoms of lung cancer continue, and a definitive diagnosis of another disease is not made, additional diagnostic tests must be done. Our office is handling a medical malpractice claim where the physician essentially concluded treatment with a negative bronchoscopy and the patient was diagnosed with lung cancer approximately one year later. Where a patient seems to fit the profile of a lung cancer patient- significant smoking history, loss of weight, fatigue, chest pain, cough, and has other symptoms of the disease, a repeat bronchoscopy, needle biopsy, or even a thoracatomy (surgical biopsy) may be called for with a negative bronchoscopy. Timely diagnosis of lung cancer is critical. 2) Success in detecting the tumor will depend upon the tumor= s location and to some extent, the skill of the physician performing the procedure. 3) An adequate sampling is critical. Reports should clearly indicate how many samples have been taken so the extent of reliance on the bronchoscopy can be determined by other physicians. 4.85 Tools to Analyze Cancer Cells Cancer cells may be analyzed to assess their structure and DNA. 4.851 Flow Cytometry Flow Cytometry measures how many pairs of chromosomes the cells= s DNA contains. See American Cancer Society, Informed Decisions 136 (1997). If a cells has a normal number of chromosomes, it is diploid. If the cells have severely disrupted DNA, it is said to be aneuploid. 4.852 S-plase Faction, SPF SPF measures the percentage of diseased cells in the synthesis phase of cell division. If the number is high, a great percentage of cells are in the S-phase and dividing rapidly, indicating the tumor is growing quickly. American Cancer Society, Informed Decisions 136 (1997). A low SPF indicates a slow-growing tumor. Both flow cytometry and SPF show promise in providing an early indication of disease, though neither are routinely reommended for screening purposes.
4.9 SYMPTOMS OF LUNG CANCER There are five basic symptoms of lung cancer: cough, chest pain, fatigue, hemoptysis (or coughing up blood), dyspnea, difficulty breathing. Devita notes, A Symptoms of centrally located tumors include cough, wheezing, stridor, deep chest pain, hemoptysis, and dyspnea,@ Devita, Principles and Practice of Oncology (3rd Ed. 1989 note that later editions are available). 4.91 The Sad Under diagnosis of Lung Cancer As we note in a later chapter, there are potential legal claim arising from the failure of many physician to timely diagnose lung cancer. Indeed, in a country with supposedly the best medical care in the world, more people are diagnosed with advanced stage lung cancer than the more easily treatable stage 1 cancers. One would think that most lung cancers would be timely diagnosed. After all, lung cancer is the largest type of cancer for both men and women, unlike other cancers, the risk factors, smoking and exposure to dust like asbestos are easily identified, and the time of diagnosis can make a significant difference in the patient= s prognosis. Nonetheless, we can identify four reasons why lung cancers are under diagnosed: 1) chest x-rays are a difficult tool to interpret and as noted, only tumors of at least 1 cm (centimeter) can be seen on a chest x-ray. 2) Strangely at the same time they note significant difference in patient prognosis based upon stage at diagnosis, both the American Cancer Society and the National Cancer Institute have failed to advocate programs for early detection of lung cancer. Instead unduly relying on 20 and 25 year old studies whose significance have been misinterpreted, they fail to recommend the obvious, that in addition to telling smokers not to smoke, we need to encourage them to be regularly checked for signs of a progressive disease which will afflict approximately 1 in 10. Those reading this book who are heavy current or former smokers should be aggressive in seeking the maximum amount of testing and request that tests be performed regularly. While quitting reduces risks, and presumably stays the development of many cancers, former smokers still have an enhanced risk for the disease. Chapter four discusses the different options for patients depending upon the stage at which their cancer was diagnosed.
DEFINITIONS Cancer A cellular malignancy where loss of normal controls- results in unregulated growth, lack of differentiation, and ability to invade local tissues and metastasize. Chest X-Ray An x-ray of the thoracic or chest area which includes the lungs. The chest x-ray will show tumors of at least 1 centimeter. Its advantage in its ease of use and low cost, disadvantage is that small tumors can be missed and others may not be shown. Differentiation Normal cells are differentiated. As cancer progresses, cells lose their essential characteristics or differentiation. Cancer cells are categorized from well-differentiated to poorly differentiated. Lobectomy Surgical removal of one of the lobes of the lung. M or Metastasis M refers to metastasis in the TNM staging system, or movement of cancer from the lung to another organ. N (or Node) N refers to lymph node in the TNM staging system. Pneumonectomy Surgical removal of the entire lung Sputum Cytology Analysis of lung cells by having the smoker cough. Effective at detecting very small microscopic cancers. An excellent technology not used nearly enough. TNM Classification The American Joint Committee on Cancer (AJCC) has designated staging by the TNM classification. with T designating the size and location of the primary tumor, N standing for the existence of cancerous lymph nodes, and M meaning metastasis or spread to other organs. Thus a medical chart would have a notation; classification of tumor, T1NoMo. T or Tumor T is the primary tumor in the TNM staging system, and is measured from 0, undetectable on an ordinary x-ray to 4 based upon its size and spread to nearby organs or structures.
CHAPTER FIVE: CHEMOTHERAPY _________________________________ 5.0 WHAT IS CHEMOTHERAPY 5.01 A Chemo@ or Chemical Therapy The term A Chemo@ means chemical and chemotherapy is the use of particular drugs alone or in combination to treat cancer. The term anti-cancer drugs is simpler. However, anti-cancer drug is a broad term covering a number of different types of drugs which affect cancer. Chemotherapy is generally used to identify anti-cancer drugs whose primary goal is to kill cancer cells. The mechanisms by which chemotherapy drugs attempt to attack cancer are varied. Since the drugs perform different functions, it should make sense to use a number of different drugs simultaneously to attack cancer (so long as normal organs are not signficantly impaired ) and that is what is being done today. Most patients are given more than one drug. The best mix of drugs or even the optimum dose is not known for lung cancer, and clinical trials continue to investigate the success of different combinations, with these trials yielding varying and sometimes contradictory results. Clinical trials generally divide patients by stage and category and it is possible that the particular type of tumor, squamous, adeno or large cell, might play a role, or the degree of differentiation in the cell, poorly differentiated to well-differentiated. Medical abstracts summarizing the results of clinical trials are available on Medline, www.healthgate.com (Medline is the world medical literuature database). Generally, chemotherapy targets any area where cancer cells are located, in comparison to surgery and radiation which target defined areas. Chemotherapy may be used to reduce tumors, or in some cases, prevent the development of cancer in particular areas. These drugs generally destroy cancer cells by stopping them from growing or multiplying at one or more points in their life cycle. Most oncologists will recommend multi-modal chemotherapy (more than one drug), though the best mix of drugs is not known with clinical trials yielding varying results. The task is to provide a large enough dose to successfully attack the cancer while not unduly affecting the normal cells. 5.02 History of Chemotherapy An accident in World War 2 paved the way for modern chemotherapy. A U.S. navy vessel sank in Naples, Italy. When the mustard gases it was carrying exploded, the casualties who had been exposed to the poisonous gases were examined and it was found that large number of cells in their bone marrow had disappeared and their lymphatic system had atrophied. An Army biologist began testing on animals with similar substances and found he was able to inhibit lymphoid tumors in animals. These drugs were tested on humans with Hodgkin's disease and found to temporarily inhibit tumors.
5.1 THE FDA APPROVAL PROCESS The Food and Drug Administration (FDA) regulates prescription drugs. Prescription drugs must be given with a doctor= s supervision and have FDA approval for use in the United States. FDA approval comes after review of clinical trials and other data to determine the safety and effectiveness of a particular drug. For example, in a shining moment, the FDA refused to approve Thalidomide in the early 1960's believing that adequate information about its safety had not been provided. Subsequently it was found that the drug caused serious birth defects. 5.11 FDA approval is Organ and Treatment Specific. Cancer or chemotherapy drugs are not approved for all purposes. Instead the FDA limits their use to certain organs and sometimes in certain doses. For example, look at this FDA approval: A FDA today approved Taxotere for treating non-small cell lung cancer that does not respond to cisplatin-based chemotherapy.... Taxotere was approved for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior cisplatin-based chemotherapy. Most patients with non-small cell lung cancer are found to have metastatic disease (cancer which has spread to other organs) when diagnosed, and curative treatment is not possible. Two randomized controlled clinical trials demonstrated that patients treated with Taxotere had increased survival compared to patients receiving supportive care or cancer therapy consisting of either vinorelbine or ifosfamide.@ www.fda.gov. Note, that the approval denotes the type of cancer covered, the status of the patient, and the circumstances of use.
5.2 HOW DOES CHEMOTHERAPY WORK 5.21 Chemotherapy Generally Targets Rapidly Growing Cells Chemotherapy attacks all body cells to some extent, but targets rapidly dividing cells such as cancer cells. Its effect on other rapidly dividing cells such as hair follicles, cells lining the stomach, and red blood cells, accounts for at least some of its side effects. Chemotherapy affects the course of cancer by taking advantage of the cancer cell's penchant for constant reproduction. Almost all of the drugs used in chemotherapy suppress cancer by somehow altering the cells' DNA and thus their ability to reproduce. See Bruning, Coping with Chemotherapy (Ballantine Books 1993) (an excellent book written by a woman with breast cancer) . 5.22 What Does Cell-Cycle Specific Chemotherapy Mean Almost all the drugs used in chemotherapy suppress cancer by altering the cells' DNA and thus their ability to replicate or reproduce. Since DNA is most vulnerable to drug interference during the reproductive phases of the life cycle, cancer cells are more likely to be affected than are the bulk of the body's normal cells, which reproduce at a much more relaxed pace. Thus, the very characteristic that makes cancer so dangerous has in some cases helped to contribute to its undoing. Indeed, some rapidly growing cancer such as small cell cancer are particularly susceptible to chemotherapy. Chemotherapy drugs are either cell-cycle-specific (lethal to cells only during a specific reproductive phase) or "cell-cycle-nonspecific" (able to sabotage the cells no matter what phase they are in). In a sense, the inner workings of cells (cancerous and otherwise) are like gearboxes; what chemotherapy does is to throw a biochemical monkey wrench into the gearbox causing the machine to grind to a half-causing the cells to stop working, to die. 5.23 Adjuvant Therapy, Combining Chemotherapy with Other Therapy Sometimes chemotherapy is the only therapy a patient receives. One advantage of primary chemotherapy is that because the cancer cells have not yet been exposed to anticancer drugs, they may be more vulnerable. A case of primary chemotherapy could be a patient with a severe heart problem who could not tolerate surgery and chemotherapy would be the exclusive form of treatment. The disadvantage of such chemotherapy is that the drugs must destroy a larger target, since none of the cells were removed by surgery or diminished by radiation. Chemotherapy used in addition to surgery or radiation is called adjuvant therapy (adjuvant or in addition to). Chemotherapy is sometimes used after surgery and/or radiation therapy to help destroy any cancer cells that may remain. 5.25 Considerations Before Treatment Begins Because chemotherapy can be harmful to certain organs, preliminary tests are conducted. For example, cells in the bone marrow frequently divide and therefore like other rapidly dividing cells are susceptible to the effects of chemotherapy. Thus, a blood test would be conducted to determine that the patient has a healthy number of red and white blood cells and platelet. Liver, kidney, and heart would normally also be checked.
5.3 CHEMOTHERAPY TERMINOLOGY 5.31 Activity The first question that must be asked is whether the drug has some favorable impact upon a particular type of cancer. If it does, the drug is A active.@ That a drug is active does not mean it will always or usually be used. Its level of activity may be less than other drugs, or its side effects could be significant. Let use assume that we have drugs A, B, C, and D. 5.32 Partial and Complete Response There are some objective ways of categorizing activity. Most scientists call a partial response, a 50% decrease in the size of the tumor. Thus, if we have an 8 centimeter tumor, and with a particular drug, the tumor is reduced to 4 centimeters, the drug is active and the patient had a partial response. If the tumor is completely eliminated, for example, it cannot be seen on an x-ray, that is called a complete response. A complete response must unfortunately be distinuished from a cure. Chemotherapy might temporarily eliminate a tumor, only to have it later return, or it might leave microscopic traces undiscernible by x-ray or perhaps even Ct Scan.
5.4 CLASSIFYING CHEMOTHERAPY There are five basic types of chemotherapy drugs: 5.41 Alkylating Agents Alkylating agents bind with DNA, preventing the cell from dividing. Cisplatin, a widely used drug is considered an alkylating agent, though it inhibits DNA by a mechanism that is different from most drugs in this category. It is cell cycle nonspecific, meaning it is not designed for any specific cycle in the cell. 5.42 Antimetabolite Antimetabolite mimic nutrients the cells needs, tricking the cell into consuming them, so it eventually starves to death. 5.43 Plant Alkaloids Plant alkaloids, also called vinca alkaloids are cell cycle specific. They interfere with those parts of chromosomes necessary for cell division. A Vinorelbine is now the major vinca alkaloid worth consideration. Vinorelbine is a classic antitubulin agent that arrests cell mitosis in metaphase and prevents tubulin polymerization to form microtubules. It is a cell cycle-dependent antimitotic agent.@ Pritchard, Other Chemotherapeutic Agents: Do We Need Them,@ The 2nd International Breast Cancer International Research Group Conference, medscape.com Taxol, a popular drug, is a plant alkaloid and destroys a cancer cell= s ability to function and divide by preventing the cell from dissembling its fibrous skeleton of micro tubules. When the natural process is inhibited, the cell becomes choked with fibrous structures 5.44 Antitumor Antibiotics These are not the same drugs used to treat bacterial infections. Rather, these drugs cause the strands of genetic material that make up DNA to uncoil, thereby preventing the cell from reproducing. An example is doxorubicin, though this type of chemotherapy has had limited use with lung cancer. 5.45 Hormones Hormones occur naturally in the body and are involved with the normal growth process. Since some tumors may require certain hormones to grow, when the hormone is blocked, the tumor may not grow. Tamoxifen is an example of a hormone. Cuneo-Lung Cancer Study Group, M. Tonato, From Nitrogen-Mustards to cis-platinum and Beyond, www.culcase.org. The Cuneo lung cancer study group is one of the few organizations devoted solely to lung cancer and it holds an important conference on lung cancer each year.
5.5 PARTICULAR DRUGS 5.51. Taxol Taxol has been used to treat cancer for some years. It is an extract from the bark and needles of the yew tree, Taxus brevi folia. Taxol is a white powder and when prepared for use becomes a clear, colorless liquid which is given by intravenous route only. It has been used to treat the following cancers: Ovarian, Testis Metastatic breast cancer Head and neck cancer, melanoma, and lung cancer. Taxol is most commonly used in combination with other chemotherapy drugs such as: 5-FU, Adriamycin, Vinorelbine, Cytoxan and Cisplatinum .The type and extent of a cancer will determine the method and schedule of administration of this drug. This decision is made by the medical oncologist. At present, Taxol is normally given once every three weeks. The history of Taxol is supplied on a webpage entitled The Taxol Molecule: Taxol was discovered at Research Triangle Institute in 1967 when Dr. Monroe E. Wall and Mansukh C. Wani isolated the compound from the Pacific Yew Tree, taxus brevi folia and noted its antitumor activity in a broad range of rodent tumors. Interest in Taxol waned for nearly a decade. ... In 1980, scientists at Albert Einstein Medical College reported that Taxol has a unique mechanisms of action, making it the prototype for a new class of chemotherapeutic drugs. Taxol bind tubulin, thereby inhibiting cell division... RTI.org. (Research Triangle Institute) It is active as single agent therapy in non pretreated NSCLC and probably also after prior chemotherapy. Combinations with cisplatin or carboplatin have been the object of multiple phase II studies.(7). Taxol is manufactured by Bristol-Meyers Squibb. www.BMS.com. 5.511 Taxol Side effects: While its consistent effectiveness throughout many clinical trials has made it a stable of lung cancer chemotherapy, there are side effects effects associated with Taxol. Some patiients will experience nausea or loss. I discuss some ways to deal with nausea in the next chapter. Other side effects have included: Low white blood counts, low platelet count, anemia, hair loss, soreness of the mouth, difficulty swallowing , diarrhea, nerve damage, allergic reactions, fluid retention.. Taxol is metabolized in the liver and excreted into bile and dosage may be reduced for patients with liver dysfunction or liver metastasis. Some patients have considered Gemcitabine instead of Taxol to reduce these side effects, though Gemcitabine has fewer clinical trials to confirm its efficacy. Patients should relay any side effects or problems to their oncologist. 5.52.Docetaxel A recent press release touted the ability of Docetaxel to address non-small cell lung cancer, at least where prior chemotherapy had been unsuccessful: A Events SA (NYSE: AVE), announced today that Taxotere* (docetaxel) for Injection Concentrate, 75 mg/m2, was cleared for marketing by the US Food and Drug Administration (FDA) for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) after failure of prior platinumbased chemotherapy. Taxotere is the first chemotherapeutic agent to be approved by the FDA for the second-line treatment of advanced non-small-cell lung cancer.... We hope this new approval for Taxotere will enable physicians to extend the lives of non-small-cell lung cancer patients who previously had limited options once their disease had progressed..... About.Com Pharmaceutical Guide Quoting December 23, 1999 Press Release by Events Co. Note that the above is a quotation from a press release, not an impartial analysis, and it is not clear whether the FDA has approved this drug for patients without prior unsuccessful chemotherapy. From the press release, it appear further clinical trials should directly compare Taxotere with other chemotherapy drugs in patients who have not undergone chemotherapy. 5.54 Tamoxifen 5.5541 Trade Name and Manufacturer Tamoxifen is manufactured by Zeneca and has the trade name Nolvadex. It is also less commonly called Tamoxifen Citrate, Tamaxin, Tamofen, 5.5542 Mechanism of Action Some cancer cells are estrogen sensitive, and estrogen binds to these cells and stimulates them to grow and divide. Tamoxifen is an anti-estrogen which inhibits the binding of estrogen and with it the division and growth of cancer cells. Not surprisingly, Tamoxifen has been used during the last twenty years for treatment of breast cancer. (1) Tamoxifen is also known to work through other growth factors and the immune system to provide some benefit to patients whose tumors are not estrogen sensitive. It appears to exert its anti-tumor effects by competing with estradiol for estrogen receptor protein. (2) 5.543 Classification Tamoxifen is classified as a hormonal/biological response modifier or an antineoplastic. (2) 5.544 Potential Side Effects Any form of chemotherapy drug should be carefully monitored by the oncologist for potential side effects. According to one source speaking about the use of Tamoxifen for breast cancer, A adverse reactions to Tamoxifen citrate are relatively mild and rarely severe enough to require discontinuation of treatment.@ (2) 5.644A Emotional Changes Since Tamoxifen impacts a hormone which in turn interacts with mood, it can conceivably impact mood or create emotional changes 5.644B Liver Changes Tamoxifen has been associated with changes in liver enzyme levels or other liver abnormalities. Thus, the existence of liver problems may be a contraindication 5.55 Vinorelbine This drug is active or effective with non-small cell lung cancer and has been successfully combined with cisplatin. Vinorelbine has been investigated in 4 randomized trials and found to improve survival. The combination of vinorelbine to cisplatin has been compared in two randomized trials to vinorelbine alone with significant response rates improvement with survival increase in one (Le Chevalier, J Clin Oncol 12: 360; 1994) and not in the other (Depierre, Ann Oncol 5: 37; 1994). In the first one, the comparison was also performed with a third arm treatment made of cisplatin and vindesine, with a marginal effect on survival. It should be noted that both trials have obtained high quality score in our review (89 and 79,8%). 5.56 Gemcitabine It is active as single therapy in non pretreated NSCLC and has been shown in phase II randomized trials to be better tolerated than the combination cisplatin-etoposide. That is, its side effects appear to be less and is generally not associated with nausea or vomiting. Gemciabine, sometimes called Gemcar has been successfully combined with cisplatin and ifosfamide in phase II studies. Results of phase III trials are pending. 5.57 Topotecan Two studies assessing its effectiveness as single therapy in non pretreated NSCLC have shown contradictory results. Further data are required to specify the place of topotecan.
5.6 THE ERA OF MULTI-MODAL OR COMBINATION CHEMOTHERAPY From a search for the magic bullet or cure, has come a recognition that success is most likely to come from a combination of drugs, each of which has an incremental impact on cancer. While combining four drugs with 20% response rate will unfortunately not lead to an 80% response, it will yield success beyond that of any one drug. One article explains the considerations in multi-modal chemotherapy: A Four principles underlie the design of chemotherapy combinations. First, each agent in a regimen should be independently active against the tumor. Unless there is unexpected synergy, adding an agent with the same mechanism of action or inhibiting the same enzyme is unlikely to enhance the response with an additive effect, but will add to the toxicity. Secondly, each drug in the regimen should have an independent mechanism of action, preferably with each drug in the combination targeting different steps along a biochemical pathway. Third, there should be no cross resistance among the drugs in the regimen, so that if one drug selects a resistant tumor subpopulation, it is unlikely to be cross-resistant to another drug in the combination that kills through a different mechanism. Fourth, each of the drugs should have a different dose-limiting toxicity. Two drugs with the same toxicity profile given at maximum tolerated dose can produce unacceptable toxicity.@ Chemotherapy //www.pitt.edu/~super1/lecture/lec0701/l24.htm One of the presenters at the 1998 Cuneo Lung Cancer conference summarized the status of chemotherapy for late stage lung cancer patients: A During the two decades from 1970 to 1990. the results of chemotherapy for stage IV disease have been unimpressive. Cisplatin was demonstrated to have modest activity, and appeared to be synergistic with etoposide and vinca alkaloids. Numerous phase III studies compared different cisplatin combination chemotherapy regimens and failed to identify a "standard" program (2,3). Furthermore, phase III studies comparing chemotherapy to supportive care had mixed results, with others failing to demonstrate an advantage for chemotherapy in stage IV disease. Only from a recent meta-analysis a small advantage for the combinations containing cisplatin could be demonstrated (4). During the past 5 years, several new agents have been evaluated in NSCLC (Non small cell lung cancer) and demonstrated improved results compared toolder regimens. The first of these, vinorelbine, was developed in France. Le Chevalier and colleagues conducted a phase III study in 612 evaluable patients with NSCLC (5). Patients were randomized to vinorelbine plus cisplatin, vinorelbine alone, or vinorelbine + cisplatin. Objective responses were seen in 30%, 14% and 19% of patients. Furthermore, there was statistically significant improved survival with cisplatin + vinorelbine, with 35% one year survival versus 27% for cisplatin + vindesine. The Southwest Oncology Group (SWOG) in the U.S. evaluated single agent cisplatin (100 mg/m) versus the same cisplatin + vinorelbine (25 mg/m) weekly in 432 patients with NSCLC. The response rates were 10% versus 26%, and there was a statistically significant survival advantage for the vinorelbine regimen, with 16.4% versus 35.4% 1 year survival (6). The taxons (paclitaxel and docetaxel) have also demonstrated activity, with a 20-30% single agent response. In the U.S., paclitaxel achieved a 40% 1 year survival in studies by Eastern Co-operative Oncology Group (ECOG) and M.D. Anderson, ECOG subsequently performed a phase III study in 571 evaluable patients, randomizing patients to cisplatin (75 mg/m) + etoposide, versus cisplatin (75 mg/m) + paclitaxel, given as a 24 hour infusion at a dosage of 135 mg/m or 250 mg/m with G-CSF. Response rates were 12%, 27% and 32% and there was improved survival with the two paclitaxel arms (7). Gemcitabine is one of the most extensively evaluated single agents in NSCLC, with response rates of 20-30% world-wide (8). Several phase II studies have evaluated cisplatin + Gemcitabine, with 30-50% response rates and 40% 1 year survival (9). Carboplatin + paclitaxel (3 hour or 24 hour infusions) are among the most popular regimens in the U.S., based entirely upon phase II studies (10)..... Other large randomized trials comparing the new combinations are being performed in Europe. It is reasonable to expect that one of these new regimens will achieve improved survival in advanced disease and more probably when used as adjuvant therapy or combined with radiotherapy in earlier stage disease.@
Cuneo-Lung Cancer Study Group, M. Tonato, From Nitrogen-Mustards to cis-platinum and Beyond, www.culcase.org. The Cuneo lung cancer study group is one of the few organizations devoted solely to lung cancer and it holds an important conference on lung cancer each year. In another article presented at the 1999 conference entitled, A Activity of Drugs Recently Introduced in the Market for the Treatment of Non-Small Cell Lung Cancer, Sculier, et., al write, A During the last decade, chemotherapy has been shown to significantly improve survival in patients with non-small cell lung cancer (NSCLC), whatever the disease stage - loco-regionally advanced or metastatic - is. The most active A classical" cytotoxic drugs in that indication are cisplatin, mitomycin C, ifosfamide, vindesine and vinblastine , as reported in a meta-analysis that we performed in 1990 (Lung Cancer, 7: 243-252;1991). The level of evidence of survival benefit is based on multiple randomized trials testing a cisplatin-containing chemotherapy arm versus a control arm without chemotherapy. There are very few data yet available about non-cisplatin based regimens. A series of new active drugs against NSCLC has been identified during the last ten years and most of them are today commercially available, at least in some countries. They are gemcitabine ( a pyrimidine analogous antimetabolite like cytarabine), the taxons paclitaxel and docetaxel (inhibitors of the depolymerisation of the tubulin molecules of the micro tubules, blocking the cell in phase M), the camptothecin derivatives irinotecan and topotecan (topoisomerase I inhibitors), vinorelbine (a vinca-alkaloid inhibiting tubulin polymerization).
5.7 MULTI-DRUG RESISTANCE Chemotherapy works best when there are (1) small numbers of cancer cells that are (2) actively dividing. Chemotherapy is highly effective with small cell lung cancers promptly diagnosed, since this type of cancer rapidly divides. The effectiveness of chemotherapy with non-small cell lung cancer is less clear. One writer states, Whereas radical surgery or radiotherapy are potentially curative treatments for disease which is localized, chemotherapy is the only major modality with the potential to eradicate disease which has disseminated. In some less common malignancies, chemotherapy is indeed curative in a large proportion of patients. Examples of such diseases are acute leukemias, lymphomas and testicular teratoma. For the more common solid tumors, however, long-term disease eradication by chemotherapy is rarely seen. The main reason for this is the relative lack of selectivity displayed by current anticancer drugs. Their differential toxicity towards malignant cells within the body is such that they cannot be administered at dose level which may eliminate the malignant population without killing the patient. Some progress has resulted from the development of combination regimens which combine several drugs with different modes of action and nonoverlapping toxicities. Twentyman, Mechanism of Drug Resistance in Lung Cancer Cells, excerpted in Carney, Lung Cancer (Arnold Publ. Co. Great Britain 1995). In "cell kinetics" experiments it has been shown that drugs destroy a constant fraction or percentage of cells, not a constant number. So if there are 10 trillion cancer cells and 99 percent are killed, 100 billion are still left after the first treatment. After the second treatment, 1 billion cells are left, and after the third 10 million remain. The proportion of cells killed is the same, but each time a smaller number of cells is killed. The cells that are resting rather than actively reproducing escape the drugs' killing effects. In between treatments, when it is safe, the resting cells resume production and replace the ones that have been killed. Chemotherapy under the best of conditions is a matter of taking two steps forward and one step back, and it is very difficult to make enough progress to kill off every single cell. Kinetic studies have also shown that as the cancer increases in size-the more cells it contains-the number of actively reproducing cells (the "growth fraction") decreases. The higher the number you start with, the harder and longer you have to work at getting the cell population down, because not only are there more cells to kill, there are more cells that are not vulnerable. 5.71 The Development of MDR, Multi-Drug Resistance In addition to the fact that chemotherapy may not reach every cancer cell, unfortunately cancer cells develop resistance to certain drugs. Thus, while initially successful, chemotherapy is subsequently less effective at addressing recurrent cancer. One author suggests that PGP (P-glycoprotein) is produced which inhibits the ability of the drug to reach cancer cells, thus reducing A intracellular drug concentrations and hence reduced cytotoxicity.@ Twentyman, Mechanisms of Drug Resistance in Lung Cancer Cells, 214, in Carney, Lung Cancer (Arnold Pub. Co. 1995). In a laboratory, Twentyman developed cancer cells which increased their resistance to doxorubicin, a chemotherapy drug. 5.72 Assessing Resistance to Chemotherapy A contributor to the same book states, At least three different MDR (multi-drug resistance) phenotypes exist, two of which are are relatively well defined. The best known is the so-called > classical= or Pglycoprotein- related MDR phenotypes, in which resistance is due to reduction of the intracellular drug accumulation via a 170 kDa protein pump (P-glycoprotein). Jensen, et. al., New Directions in Drug Therapy of Small Cell Carcinoma based on in vitro studies, 234, in Carney, Lung Cancer (Arnold Pub. Co. 1995). 5.73 Why Dosage and Scheduling Can Be Critical Devita and Park in their book on cancer, discuss the reasons why dosage scheduling can be critical and is the subject of many clinical trials. A Rapidly growing tumors tend to be most sensitive to chemotherapy. Also, damage to normal tissues at short intervals after chemotherapy or wide-field radiation is most often observed in organs such as the bone marrow or the intestine, which are renewal tissue known to contain rapidly proliferating cells. These observations suggest that rapidly proliferating cells may be more susceptible to therapy and have led to several studies of the relationship between cytotoxicity and proliferative rate. When mammalian cells are cultured, they show a period of exponential growth when all cells are proliferating, followed by slowing of growth as cells become crowded and consume available nutrients.... Frequently this type of experiment leads to survival curves which show that rapidly proliferating cells are more sensitive to the drug. This technique and others have demonstrated that some drugs (e.g. methotrexate, cytarbine, and vinca alkaloids) exert lethal effects only against proliferating cells. Others, including anthracylines and most alkylating agents, have some activity against slowly proliferating cells but are considerably more toxic to proliferating cells. Only for alkylating drugs, including cisplatin, nitrosoureas, and bleomycin, is there little or no selectivity, and this may be cell-line dependent. Most drugs and ionizing radiation vary in their lethal effects at different phases of the cell Because most drugs have varying toxicity for cells in different phases of the cell cycle, immediately after treatment a high proportion of surviving cells will be partially synchronized in a resistant phase. Several investigators have proposed that drug treatment might be scheduled at intervals that allow the surviving tumor cells to progress to a drug sensitive phase of the cell cycle, or, conversely, such that cells in critical normal tissues are again in a drug-resistant phase. In practice, the wide heterogeneity of cell cycle parameters makes this difficult to achieve. It has been demonstrated that therapeutic outcome is markedly dependent on scheduling interval for drug treatment of experimental tumors, but it has been difficult to predict the optimum scheduling interval from knowledge of cell kinetics. Institute. For updated information visit its website(s) at www.nci.org. Devita, et. al, Principles and Practice of Oncology (Lippincott 3d ed. 1989) This tells us is that chemotherapy administrations should not be missed. Since the oncology staff has carefully constructed a regimen based upon its knowledge of the location of the cancer, its stage, and other dynamics, that schedule should not be disrupted. If an administration is missed, the doctor should be immediately informed.
5.8 HOW DRUGS ARE SELECTED The oncologist= s choice of drug depends on the type of cancer, location, stage, its impact on bodily functions, the patient= s general health, and his assessment of clinical trials or studies. Clinical trials are research studies that test new cancer treatments or refine existing ones. While some increase in survival times may be seen, most clinical trials do not show tremendous breakthroughs. Patients participate in clinical trials to make an important contribution to medical care and because other treatment options may be limited. To learn more about clinical trials, call the National Cancer Institute's Cancer Information Service and ask for the booklet What Are Clinical Trials All About? You also may want to ask about the videotape "Patient to Patient: Cancer Clinical Trials and You." The Cancer Information Service can be reached by dialing 1-800-4-CANCER (1-800-422-6237).
5.9 CHEMOTHERAPY ADMINISTRATION 5.91 Where is Chemotherapy Administered : Chemotherapy for lung cancer is generally administered in a phsyician= s office, a clinic or hospital's oncology department. When the patient first begins chemotherapy, a hospital stay might be needed to assess the medicine's effects. 5.92 How Often Will Chemotherapy be administrered.? How often the therapy is administered will vary. Chemotherapy is sometimes given in on-and-off cycles that include rest periods so that the body has a chance to re-build new cells and the patient regain its strength. 5.93 Goals of Chemotherapy Depending on the type of cancer and its stage of development, chemotherapy can be used: * To cure cancer. * To keep the cancer from spreading. * To slow the cancer's growth. * To kill cancer cells that may have spread to other parts of the body from the original tumor. To relieve symptoms that may be caused by the cancer. * Chemotherapy also help people live more comfortably by eliminating cancer cells which cause pain, discomfort or other problems. This is called palliative care, where the goal is to help the patient better function, not cure. 5.94 Methods of Administration One common way for the drug to be given is by mouth. This is more convenient and less costly than other methods. The disadvantage is that may be many instructions given with the drug, and the patients should follow these instructions explicitly and maintain careful records of when the drugs are taken. Drugs may also be injected into a vein where the cancer cells appear to be circulating. Two kinds of pumps-external and internal- may be used to control the rate of delivery of chemotherapy. External pumps remain outside the body. Some are portable and allow a person to move around while the pump is in use. Other external pumps are not portable and may restrict activity. Internal pumps are placed surgically inside the body, usually right under the skin. They contain a small reservoir (storage area) that delivers the drugs into the catheter. Internal pumps allow people to go about most of their daily activities. 5.95 Does Chemotherapy Hurt Getting chemotherapy by mouth, on the skin, or by injection generally feels the same as taking other medications by these methods. Having an IV started usually feels like drawing blood for a blood test. Some people feel a coolness or other unusual sensation in the area of the injection when the IV is started. Report such feelings to your doctor or nurse. Be sure that you also report any pain, burning, or discomfort that occurs during or after an IV treatment. Many people have little or no trouble having the IV needle in their hand or lower arm. However, if a person has a hard time for any reason, or if it be comes difficult to insert the needle into a vein for each treatment, it may be possible to use a central venous catheter or port. This avoids repeated insertion of the needle into the vein. Central venous catheters and ports cause no pain or discomfort if they are properly placed and cared for, although a person usually is aware that they are there. It is important to report any pain or discomfort with a catheter or port to your doctor or nurse. 5.96 Use of Other Medication During Chemotherapy Some medicines may interfere with the effects of your chemotherapy. That is why you should take a list of all your medications to your doctor before you start chemotherapy. Your list should include the name of each drug, how often you take it, the reason you take it, and the dosage. Remember to include over-the-counter drugs such as laxatives, cold pills, pain relievers, and vitamins. Your doctor will tell you if you should stop taking any of these medications before you start chemotherapy. After your treatments begin, be sure to check with your doctor before taking any new medicines or stopping the ones you already are taking. 5.97 Working During Chemotherapy Most people are able to continue working while they are being treated with anticancer drugs. It may be possible to schedule your treatments late in the day or right before the weekend, so they interfere with work as little as possible. If your chemotherapy makes you very tired, you might want to think about adjusting your work schedule for a while. Speak with your employer about your needs and wishes at this time. You may be able to agree on a part-time schedule, or perhaps you can do some of your work at home. Under Federal and state laws, some employers may be required to allow you to work a flexible schedule to meet your treatment needs. To find out about your on-the-job protections, check with your local American Cancer Society, a social worker, or your congressional or state representative. The National Cancer Institute's publication Facing Forward: A Guide for Cancer Survivors, also has information on work-related concerns. How Will I Know If My Chemotherapy Is Working? Your doctor and nurse will use several methods to measure how well your treatments are working. You will have frequent physical exams, blood tests, scans, and x-rays. Don't hesitate to ask the doctor about the test results and what they show about your progress. While tests and exams can tell a lot about how chemotherapy is working, side effects tell very little. (Side effects-such as nausea or hair loss-occur because chemotherapy harms some normal cells as well as cancer cells.) Sometimes people think that if they don't have side effects, the drugs aren't working, or that, if they do have side effects, the drugs are working well. But side effects vary so much from person to person, and from drug to drug, that having them or not having them usually isn't a sign of whether the treatment is effective. If you do have side effects, there is a lot you can do to help relieve them. The next section of this document describes some of the most common side effects of chemotherapy and gives you some hints for coping with them. FOOTNOTES 1. Bruning, Coping with Chemotherapy (Ballantine Books 1993) 2. Devita, et. al. Principles and Practice of Oncology (1999)
CHAPTER FIVEA: CHEMOTHERAPY SIDE EFFECTS _______________________________
5.0A MEDICAL REASONS FOR SIDE EFFECTS It is important to discuss, but not overemphasize, the significance of side effects from chemotherapy. With the emergence of new drugs, medication to reduce side effects, and refinements in dose, some of the traditional side effects have been reduced. I discuss side effects generally, but only your oncologist can give you a case-specific analysis based upon, the nature of your disease and the type of chemotherapy provided. The American Cancer Society Guide, Informed Consent (172) describes the reason for side effects: A All the tissues and organs of the body are subject to an anticancer drug= s action, which is to destroy rapidly dividing cells or prevent them from reproducing. Cancer cells, which continuously and quickly replace themselves, are obviously targets. But some health cells that also divide rapidly, such as those in the hair follicles and lining the intestinal trace, are vulnerable to the drugs as well. Consequently, temporary hair loss and nausea are common side effects. The challenge, then, for the oncologist is to balance the cancer-destroying benefits of a particular drug or combination of drugs against their toxic effects. It is sometime quite a delicate balance, but with good emotional and physical care and support the side effects can be managed in most cases and, if not fully controlled, at least made tolerable.@ The American Cancer Society Guide, Informed Consent 172 (1997). 5.1AIN ADDITION TO LENGTHENING LIFE, CHEMOTHERAPY MAY IMPROVE QUALITY OF LIFE BY REDUCING THE SYMPTOMS OF THE DISEASE. Chemotherapy causes side effects in some patients. However, it is incorrect to therefore conclude that the decision to use chemotherapy represents a tradeoff between length and quality of life. One recent study analyzes quality of life with the use of an increasingly popular chemotherapy drug for lung cancer, vinorelbine. Effects of Vinorelbine on Quality of Life and Survival of Elderly Patients with Advanced Non Small-Cell Lung Cancer, 91, No. 1 66-72 (Jan. 6, 1999) First, the study found that vinorelbine extended life among the stage 3b and 4 patients with advanced lung cancer. Survival rates at 6 months and .12 months were 55% and 32% in the chemotherapy treated group versus 41% and 14% in the group receiving best available care without chemotherapy. Indeed, the trial had to be stopped because physicians were increasingly reluctant to assign patients to the control group whose mortality rate was demonstrably higher. There is increasingly little debate that chemotherapy extends life even among advanced lung cancer patients, at 3b and 4. In the vinorelbine chemotherapy group, there was one patient with a complete remission and 14 partial responses of 50% or more reduction in tumor volume (of approximately 76 in the group). There should be little question that chemotherapy has proven to be effective even with patients whose cancer has metastasized to lymph nodes or other organs. Chemotherapy will extend life in many cases, and in a few it had the capacity to serve as a cure. Based upon this study and some others, the only realistic question is what type of chemotherapy should be prescribed. Equally important to cancer patients were the findings of quality of life. Quality of life or (Qol) can be statistically measured using a questionnaire given to patients in the clinical trial, and comparing results in the group receiving chemotherapy and the one given best supportive care. Vinorelbine-treated patients scored better on quality of life, and the study found a reduction in cancer-related symptoms such as pain and dyspnea, loss of breath. This would presumably correlate with the reduction in the size of the tumor in many cases. The study did find an increase in certain chemo-related side effects. Constipation was observed in three patients, heart arrhythmias in two, loss of hair- alopecia in three, and other side effects in approximately five. Thus there is a sad tradeoff between chemo-related side effects and those of the disease itself, but most would prefer the chemotherapy and the prospect of extending life with the drug. The study concludes, A we obtained a survival advantage that was not at the expense of a worse Qol (quality of life). It should be noted that while these results may be representative, they remain to be duplicated, since quality of life has generally not be the focus of studies of chemotherapy and lung cancer. Likewise, the results of other chemotherapy drugs such as cisplatin could be conceivably different.
5.2A NAUSEA, VOMITING, AND THE USE OF ANTI-EMETIC DRUGS Some anticancer drugs cause nausea and vomiting because they affect parts of the brain that control vomiting and/or irritate the stomach lining. The severity of these symptoms depends on several factors, including the chemotherapeutic agent(s) used, dose, schedule, and the patient's reaction. Management of nausea and vomiting caused by chemotherapy is an important part of care for cancer patients when it does occur. Although patients usually receive antiemetic drugs that help control nausea and vomiting, there is no single best approach to reducing these symptoms in all patients. Doctors must tailor antiemetic therapy to meet each individual's needs, taking into account the type of anticancer drugs being administered; the patient's general condition, age, and related factors; and, of course, the extent to which the antiemetic is helpful. Note, however, that our ability to combat nausea has improved, and do not assume that side effects encountered by a patients 10 years ago will occur with the same severity today. 5.21 Mainstream Anti-emetic Drugs The informative book, A Guide to Chemotherapy states, "Sedative/hypnotics such as Valium and almane have been used to reduce nausea in patients. Many oncologists are prescribing Ativan, an antinausea medication that also acts as an antidepressant and sleeping pill.@ 5.22 Marijuana and Nausea There has been some interest in the use of marijuana to treat a number of medical problems, including chemotherapy-induced nausea and vomiting in cancer patients. Two forms of marijuana have been used: compounds related to the active chemical constituent of marijuana taken by mouth and marijuana cigarettes. Dronabinol (Marinol), a synthetic form of the active marijuana constituent delta-9-tetrahydrocannabinol (THC), is available by prescription for use as an antiemetic. The U.S. Food and Drug Administration has approved its use for treatment of nausea and vomiting associated with cancer chemotherapy in patients who have not responded to the standard antiemetic drugs. NCI scientists feel that antiemetic drugs or combinations of antiemetic drugs have been shown to be more useful than synthetic THC as "first-line therapy" for nausea and vomiting caused by anticancer drugs. Examples include drugs called serotonin antagonists, including ondansetron (Zofran) and granisetron (Kytril), used alone or combined with dexamethasone (a steroid hormone); metoclopramide (Reglan) combined with diphenhydramine and dexamethasone; high doses of methylprednisolone (a steroid hormone) combined with droperidol (Inapsine); and prochlorperazine (Compazine). Continued research with other agents and combinations of these agents is under way to determine their usefulness in controlling chemotherapy-induced nausea and vomiting. However, NCI scientists believe that synthetic THC may be useful for some cancer patients who have chemotherapy-induced nausea and vomiting that cannot be controlled by other antiemetic agents. The expected side effects of this compound must be weighed against the possible benefits. Dronabinol often causes a "high" (loss of control or sensation of unreality), which is associated with its effectiveness; however, this sensation may be unpleasant for some individuals. The informative book, A Guide to Chemotherapy deals specifically with the side effects of chemotherapy and discusses them generally, though not specifically with reference to chemotherapy drugs for lung cancer. "Sedative/hypnotics such as Valium and Dalmane have been used to reduce nausea in patients. Many oncologist are prescribing Ativan, an antinausea medication that also acts as an antidepressant and sleeping pill."
5.3A CHEMOTHERAPY AND INFECTION Chemotherapy may increase the risk of infection: Chemotherapy and extensive radiotherapy often interfere with t he formation and maturation of blood cells (hematopoeises)... According to a Gallup poll of chemotherapy patients,nearly half had their treatment postponed at least once because their white counts were alarmingly low. White cells safeguard us again infection, partiuclarly the neutrophils, which make up 60 percent of all white cells. Their job is to intercept and destroy bacteria. A person is said to be mildly neutropenic when her absolute neutrophil count (ANC) is between 2,000 and 1,000. The ANC is determined by multiplying the percentage of neutrophils by the total white-blood-cell count. Oncologists will generally continue chemotherapy so long as the number says in the 500-1000 range, which is considered moderate netrupenia.... Most chemo regimens suppress your immune system for perhaps a week to ten days, after which time the neutrophil count starts climbing back. The other key players in fighting off disease are the lymphocytes which track down viruses. Although chemotherapy depletes thenumber of lymphocytes, says Dr. Rajagopal, the ones that remain are functional. During this period of impaired immunity, the major concern is to immediately treat any bacterial infections that develop. The GI tract, along with the skin and the respiratory tract, is a haven for bacteria. A Teeley & Bashe, The Complete Cancer Survival Guide 707-08 (Doubleday 2000) 5.31A Ways to Reduce Infection Some general precautions against infection: C Wash your hands frequently. Be sure to clean under your nails and between your fingers. Take a warm bath or shower each day and wash between folds of skin. Germs may locate inside the groin, between a woman= s breasts- anywherte than skin touches skin and is not exposed to air. C Stay anyone from anyone with a cold or disease. Do not share drinking glasses, washclothes or other items which may carry germs. C When you are done preparing food- particularly meat, poultry, and eggs, disinfect countertops and cutting boards. C Avoid small groceries and check food expiration dates. Avoid food leftover for more than a day. Check that your refridgerator and freezer are working properly. C Cook fresh vegetables. Avoid raw foods like shellfish or sushi.
5.4A CHEMOTHERAPY AND YOUR EMOTIONS Any observer must express tremendous admiration for the typical patient. Chemotherapy can bring major changes to a person's life. It can affect overall health, threaten a sense of wellbeing, disrupt day-to-day schedules, and put a strain on personal relationships. No wonder, then, that many people feel tearful, anxious, angry, or depressed at some point during their chemotherapy. These emotions are perfectly normal and understandable, but they also can be disturbing. Fortunately, there are ways to cope with these emotional "side effects," just as there are ways to cope with the physical side effects of chemotherapy. (Some time after this was written, my wife contracted a form of cancer, not of the lung. However, I realized that is far easier to talk about calmness and relaxation as an outlooker, than as a patient or family member).
5.5 SOURCES OF SUPPORT There are many sources of support you can draw on. Here are some of the most important: * Doctors and nurses. If you have questions or worries about your cancer treatment, talk with members of your health care team. Some doctors may be easily to speak with about side effects, while others may be more distant and clinical. Try to find a knowledgeable and sympathetic person at your hospital or phsyician= s office so you can discuss issues of side effects or other questions. * Counseling professionals. There are different kinds of counselors who can help you express, understand, and cope with the emotions cancer treatment can cause. Depending on your preferences and needs, you might want to talk with a psychiatrist, psychologist, or social worker. * Religious Groups Your priest, minister, or rabbi is best qualified to talk about the difficult questions you may experience during treatment. It is perfectly appropriate to reach out to your clergyman even if you have not attended services. * Friends and family members. Talking with friends or family members can help you feel a lot better. Often, they can comfort and reassure you in ways that no one else can. You may find, though, that you'll need to help them help you. At a time when you might expect that others will rush to your aid, you may have to make the first move. Some people do not understand cancer, and may withdraw from you because they're afraid of your illness. Others may worry that they will upset you by saying "the wrong thing." You can help relieve these fears by being open in talking with others about your illness, your treatment, your needs, and your feelings. By talking openly, you can correct mistaken ideas about cancer. You can also let people know that there's no single "right" thing to say, so long as their caring comes through loud and clear. Once people know they can talk with you honestly, they may be more willing and able to open up and lend their support. The National Cancer Institute's booklet Taking Time offers useful advice to help cancer patients and their families and friends communicate with one another. * Support groups. Support groups are made up of people who are going through the same kinds of experiences as you. Many people with cancer find they can share thoughts and feelings with group members that they don't feel comfortable sharing with anyone else. Support groups also can serve as an important source of practical information about living with cancer. Support can also be found in one-to-one programs that put you in touch with another person very similar to you in terms of age, sex, type of cancer, and so forth. In some programs, this person comes to visit you. In others, a "hotline" puts you in touch with someone you can talk with on the telephone. Sources for information about support programs include your hospital's social work department, the local office of your American Cancer Society, and the National Cancer Institute's Cancer Information Service. (See Resources.) On-line Support There are a variety of sources of assistance available on the Internet. One is a group which shares their experience by way of posting to a news group. For those unfamiliar with the Internet, these are groups devoted to specific subjects, on American Online, simply use the key word newsgroup. Individuals can post a question or comment on a prior posting with the posts divided by topic. For some, it is easier to talk about sensitive topics on computer in the anonymity of your own home. The occasional disadvantage is that misinformation could be communicated. However, by and large, people find these news groups to be a useful way of acquiring information and communicating your feelings. Here are some tips to help yourself while you are getting chemotherapy from the National Cancer Institute: * Try to keep your treatment goals in mind. This will help you keep a positive attitude on days when the going gets rough. Remember that eating well is very important. Your body needs food to rebuild tissues and regain strength. * Keep a journal or diary while you're in treatment. A record of your activities and thoughts can help you understand the feelings you have as you go through treatment, and highlight questions you need to ask your doctor or nurse. You also can use your journal to record the steps you take to cope with side effects and how well those steps work. That way, you'll know which methods worked best for you in case you have the same side effects again. * Set realistic goals and don't be too hard on yourself. You may not have as much energy as usual, so try to get as much rest as you can, let the "small stuff" slide, and only do the things that are most important to you. * Ask your doctor or nurse about a safe and practical exercise program. Using your body can help you feel better about yourself, help you get rid of tension or anger, and build your appetite.
5.6 RELIEVING STRESS You can use a number of methods to cope with the stresses of cancer and its treatment. Here are some techniques recommended by the National Cancer Institute. A Muscle tension and release. Lie down in a quiet room. Take a slow, deep breath. As you breathe in, tense a particular muscle or group of muscles. For example, you can squeeze your eyes shut, frown, clench your teeth, make a fist, or stiffen your arms or legs. Hold your breath and keep your muscles tense for a second or two. Then breathe out, release the tension, and let your body relax completely. Repeat the process with another muscle or muscle group. You also can try a variation of this method, called "progressive relaxation." Start with the toes of one foot and, working upward, progressively tense and relax all the muscles of one leg. Next, do the same with the other leg. Then tense and relax the rest of the muscle groups in your body, including those in your scalp. Remember to hold your breath while tensing your muscles and to breathe out when releasing the tension. * Rhythmic breathing. Get into a comfortable position and relax all your muscles. If you keep your eyes open, focus on a distant object. If you close your eyes, imagine a peaceful scene or simply clear your mind and focus on your breathing. Breathe in and out slowly and comfortably through your nose. If you like, you can keep the rhythm steady by saying to yourself, "In, one two; Out, one two." Feel yourself relax and go limp each time you breathe out. You can do this technique for just a few seconds or for up to 10 minutes. End your rhythmic breathing by counting slowly and silently to three. * Biofeedback. With training in biofeedback, you can help control body functions such as heart rate, blood pressure, and muscle tension. A machine will sense when your body shows signs of tension and will let you know in some way such as making a sound or flashing a light. The machine will also give you feedback when you relax your body. Eventually, you will be able to control your relaxation responses without having to depend on feedback from the machine. Your doctor or nurse can refer you to some one trained in teaching biofeedback. * Imagery. Imagery is a way of daydreaming that uses all your senses. It usually is done with your eyes closed. To begin, breathe slowly and feel yourself relax. Imagine a ball of healing energy- perhaps a white light-forming somewhere in your body. When you can "see" the ball of energy, imagine that as you breathe in you can blow the ball to any part of the body where you feel pain, tension, or discomfort such as nausea. When you breathe out, picture the air moving the ball away from your body, taking with it any painful or uncomfortable feelings. (Be sure to breathe naturally; don't blow.) Continue to picture the ball moving toward you and away from you each time you breathe in and out. You may see the ball getting bigger and bigger as it takes away more and more tension and discomfort. To end the imagery, count slowly to three, breathe in deeply, open your eyes, and say to yourself, "I feel alert and relaxed." . * Visualization. Visualization is a method that is similar to imagery. With visualization, you create an inner picture that represents your fight against cancer. Some people getting chemotherapy use images of rockets blasting away their cancer cells or of knights in armor battling their cancer cells. Others create an image of their white blood cells or their drugs attacking the cancer cells. Visualization and imagery may help relieve stress and increase your sense of self-control. But it is very important to remember that they cannot take the place of the medical care your doctor prescribes to treat your cancer. * Hypnosis. Hypnosis puts you in a trance-like state that can help reduce discomfort and anxiety. You can be hypnotized by a qualified person, or you can learn how to hypnotize yourself. If you are interested in learning more, ask your doctor or nurse to refer you to someone trained in the technique. * Distraction. You use distraction any time an activity takes your mind off your worries or discomforts. Try watching TV, listening to the radio, reading, going to the movies, or working with your hands by doing needlework or puzzles, building models, or painting. You may be surprised how comfortably the time passes.@
5.7A LOSS OF WEIGHT, ANOREXIA AND CACHEXIA Anorexia, the loss of appetite or desire to eat, is the most common symptom in cancer patients that may occur early in the disease or later as the cancer grows and spreads. Cachexia is a wasting condition in which the patient has weakness and a marked and progressive loss of body weight, fat, and muscle. Anorexia and cachexia frequently occur together, but cachexia may occur in patients who are eating an adequate diet but have malabsorption of nutrients. A Tumor cells deprive normal cells of nutrients. Meanwhile the body is expending extra energy as it heals from the effects of cancer surgery, radiotherapy, or chemotherapy . In order to sustain vital functions, the body retrieves nutrients stored in fatty tissue. Once all available fat has been broken down for fuel, it sets to work on muscle. Of all nutrients, protein is the one most essential for building muscle, bone, skin, and bood cells. If the body= s cells consume more protein than you take in, muscle mass rapidly wastes away, causing the emaciated look often associated with cancer.@ Teelley & Bashe, The Complete Cancer Survival Guide (Doubleday 2000). Maintenance of body weight and adequate nutritional status can help patients feel and look better, and maintain or improve their performance status. Teely recommends the following: COMPLETE PROTEINS canned tuman, skinless turkey, steak, whitemeat chicken, whole milk, hard-boiled effs, nuts, wheat germ. NUTRIONAL SUPPLMENTS with your oncologist= s approval LIGHT EXERCISE To stimulate your appetite, The author of that book, a cancer patient himself, recommends foods dense in high-quality protein. such as meat, chicken, fish, egs, and dairy products. Some patients may not easily tolerate these foods, and you will need to structure a diet which provides the necessary nutrients without creating nausea.
CHAPTER SIX: RADIATION ______________________
6.1 WHAT IS RADIATION THERAPY Here is an explanation of radiation: A Radiation therapy (RT) is the use of focused high energy electromagnetic waves (photons) or electrons to treat cancerY . These beams strike and transfer varying amounts of energy to carbon, nitrogen, and hydrogen atoms in or near the DNA chains in the nucleus of cells thereby producing breaks, deletions, or cross linkages in the DNA chains, some of which are lethal to the cell. A few cells may die within minutes after being hit, but after sustaining lethal damage most cells survive until they attempt to go through mitosis and cell division. Cells are most sensitive to RT when they are in mitosis or shortly after cell division. Tissues in which a high proportion of cells are actively multiplying tend to be more sensitive to high energy photons than are tissues where most cells divide relatively infrequently. By giving daily doses of RT large enough to kill a high proportion of the rapidly dividing cancer cells while killing only a small proportion of the more slowly dividing normal tissue cells in the area, a malignant tumor can be eradicated. The factors which determine whether or not a cancer can be eradicated by radiation therapy include the sensitivity of the tumor to RT, the volume of tumor cells to be eradicated and the tolerance of the most radiation sensitive vital tissues in the area. This latter factor is influenced by how effectively these structures can be shielded from the irradiation received by the tumor and whether the vital tissues can be sacrificed without mortality. Thus, RT is most effective when the volume of tumor cells to be treated is small, i.e. microscopic deposits of tumor cells left behind after the visible part of a tumor has been surgically excised, or when the tumor can be given a high dose of high energy photons or electrons without destroying the function of the vital structures in the areaY 6.2 BENEFITS OF RADIATION 6.21 Radiation and Small Cell Cancer A 1997 article summarizes the research, A Although chest irradiation has been used to treat SCLC for over four decades, its standard role in the management of limited-stage disease was established only during the last decade. Multiple prospective randomized trials have shown that the addition of thoracic radiation therapy to chemotherapy usually halves local failure rates, from >60% with chemotherapy alone to about 30% with chemoradiation therapy. Kumar, The role of thoracic radiotherapy in the management of limited-stage small cell lung cancer: past, present, and future, A Chest 1997 Oct;112(4 Suppl):259S-265S
6.3 TYPES OF RADIATION The primary type of radiation used for lung cancer is external beam radiation which directs radiation from a machine to the area of the tumor. Another type of radiation used with other cancers is brachytherapy, used more frequently with other types of tumors, in which a radioactive source is placed inside the body in the area of the tumor. 6.31 Hyperfractionated Radiotherapy Hyper fractionated radiotherapy is a new form of radiation which has been used in other areas. One study showed beneficial results but increased side effects: A Patients were randomly allocated in a 3:2 ratio to CHART (Continuous hyperfractionated accelerated radiotherapy) or conventional radiotherapyY . {In the Chart group]there was a 24% reduction in the relative risk of death, which is equivalent to an absolute improvement in 2-year survival of 9% from 20% to 29% (p = 0.004, 95% CI 0.63-0.92). Subgroup analyses (predefined) suggest that the largest benefit occurred in patients with squamous cell carcinomas (82% of the cases), in whom there was a 34% reduction in the relative risk of death (an absolute improvement at 2 years of 14% from 19% to 33%). During the first 3 months, severe dysphagia occurred more often in the CHART group than in the group on conventional radiotherapy (19 vs 3%). Otherwise, there were no important differences in short-term or long-term morbidityY . CHART compared with conventional radiotherapy gave a significant improvement in survival of patients with NSCLC.@ Saunders, Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee [see comments] Lancet 1997 Jul 19;350(9072):161-5 6.311 Cost Issues with Hyperfractioned Radiotherapy Some HMO may balk at the cost of this type of radiation even if there is some research showing its effectiness. See Coyle, Costs of conventional radical radiotherapy versus continuous hyperfractionated accelerated radiotherapy (CHART) Clin Oncol (R Coll Radiol) 1997;9(5):313-21 However, Chart is not an unusual or strange therapy, it has been used with other forms of cancer, and there are clinical findings indicating its effectiveness with lung cancer. Thus, it should be a decision of the physician and patient as to its use. I suspect that confronted with a vigorous well-documented presentation, most HMO= s would provide reimbursement for this treatment, even if they initiatially rejected its use, and did not approve its use for lung cancer on a routine basis. We seem to have limited side effects with radiation but also limited curative powers. The obvious question becomes can does be increased to kill more cancer cells without causing substantial destruction of normal tissue or disproportionate side effects: McGuire, 73.6 Gy and Beyond: Hyperfractionated, Accelerated Radiotherapy for Non-Small-Cell Lung Cancer. J Clin Oncol 2001 Feb 1;19(3):705-711 6.4 HOW RADIATION IS PERFORMED 6.41 Personnel Involved There are different medical professionals involved with radiation as follows: Radiation Oncologist a physician specializing in treating cancer with radiation. He makes many of the decisions as to the type and frequency of radiation. Radiation Physicist an expert in medical physics trained in planning radiation treatment. He helps determine the treatment plan and the specific of the radiation. Dosimetrist, a technician who also plans and calculates the dosage of radiation and how it will be administered, sometimes with a computer program. Radiation Technologist A specially trained technician who operates the radiation equipment. A nurse trained in radiation therapy may help patients deal with any side effects. See American Cancer Society, Informed Decisions 1997). 6.5 SIDE EFFECTS Generally there are not significant, long-lasting side effects, and one of the goals of radiation and why it requires skill is to attack the tumor without damaging normal tissue . Radiation therapy does not hurt, though some people experience a sensation of warmth or tingling. While chemotherapy kills some normal cells as well as tumorous cells, the goal of radiation is kill only cancerous cells. While one injecting a drug into the bloodstream cannot control its effect, however, when directing radiation one can, and there are fewer side effects associated with radiation than chemotherapy. 6.51 Tiredness Tiredness and lethargy are associated with radiation, though the precise cause is not known. . According to the American Cancer Society Guide, A fatigue is likely to begin early and increase using the course of treatment, peaking between the third and fifth weeks.... Why the body reacts to radiation in this way isn= t exactly understood, though there are a number of plausible explanations. It may be that the healing process drains the body= s energy. Another reason may be the buildup of toxic wastes resulting from cell destruction. An increase in the body= s metabolism may play a role, too. Furthermore, daily trips to a radiation center disrupt the normal activities of life.@ American Cancer Society, Informed Decisions (1997). 9.52 Poor Appetite It may be that changes in some cells affect hunger signals or the stress of illness reduces appetite. 9.53 Skin Problems Skin in the radiation area may undergo temporary changes such as redness, dryness, or itchiness. 9.54 Addressing Side Effects With any side effects, the physician and nurse should be informed. Doctors vary, with radiation we can have skilled physicians with limited empathy for the patient. Consider cancer support groups and speak with groups like the American Cancer Society. You should consult with your oncologist before making any changes since that could affect treatment in some way. 6.6 RADIATION FOLLOWING SURGERY There is debate about the benefits of radiation following surgery. One study found a slightly elevated mortality in patients who had undergone radiation after surgery, though investigations in this area are ongoing and we can expect clinical trials.
CHAPTER SEVEN: SURGERY AND DIAGNOSTIC PROCEDURES _______________________________
7.1 SURGICAL DIAGNOSTIC PROCEDURES 7.11 Types of Biopsies A biopsy is usually the first surgical procedure a patient will undergo. It involves taking a piece of tissue and having it analyzed by a pathologist to determine its cellular makeup. A biopsy can determine whether the cells taken are cancerous and sometimes determine the level of differentiation in the tissue. The excellent website called Oncolink reviews the different types of biopsies.. These include aspiration biopsy, needle biopsy, excisional biopsy, and incisional biopsy. The approach used depends on the type of tumor suspected, its size, location, and characteristics of growth... Aspiration Aspiration of cells and tissue fragments through a needle that has been guided to a suspected malignant tissue. Cytological analysis can provide a tentative diagnosis. Since the tumor can be missed, only a positive test is diagnostically significant. Needle Obtaining a core of tissue through a specially designed needle introduced into suspected malignant tissue. Sufficient for the diagnosis of most tumors. Differentiating benign or reparative lesions from malignancies is often difficult with soft tissue and bony sarcomas. Since the tumor can be missed, only a positive test is diagnostically significant. Incisional Removal of a small wedge of tissue from a larger tumor mass. Preferred method for diagnosing soft tissue and bony sarcomas. Excisional Excision of the entire suspected tumor tissue. Procedure of choice for small, accessible tumors when they can be done without compromising the ultimate procedure.@ http://oncolink.upenn.edu 7.12 Other Diagnostic Procedures A mediastinoscopy is a diagnostic procedure to test whether mediastinal lymph nodes are positive. For example, if multiple nodes are positive, surgery might not be recommended because it would not eliminate the cancer and open chest surgery could involve significant risk. The procedure involves inserting a crop through a small incision in the neck or check into the mediastinum where the nodes in that areas are viewed and tested. A thorascopy is a limited surgical procedure that allows the lining of the chest wall and the lungs to be examined for tumor. A thorascopy is inserted through a small incision in the chest wall. These procedures are diagnostic, they do not attempt to cure the cancer, but determine its existence and extent. 7.2 TYPES OF SURGERY 7.21 When is Surgery Performed Surgery is the preferred form of treatment for stage 1 patients, and is assessed with many stage 2 and stage 3A patients. Surgery is generally not performed upon stage 3B and Stage 4 patients. Ideally, surgery results in the removal of the entire tumor and that result becomes less possible as the tumor spreads and invades other structures. The ideal of cure and eliminating the tumor occurs in approximately 50% to 60% of stage 1 patients. Where the patient has other significant health problems, surgery may not be recommended, for example, for an 84 year old man with significant heart problems. Surgery removes the lung tumor and surrounding tissue. If the patient has severe breathing problems, he may lack sufficient pulmonary reserve to permit surgery. 7.22 Lobectomy and pneumonectomy There are two basic types of surgery to remove a lung tumor, lobectomy and pneumonectomy Lobectomy is surgical removal of one of the lobes of the lung. Less intrusive procedures like a wedge resection, removal of part of the lobe have been tried, but cancer reoccurred in greater percentages so they are not generally used. A bilbectomy is the removal of two lung lobes. A pneumonectomy is the removal of the entire lung, and would be used where the cancer may involve substantial portions of the lung. Thoracotomy is the general name for surgery to examine the lung and remove cancerous portions. Yahoo has a good brief explanation: A thoracotomy is a surgical procedure to open the chest and repair or remove lung tissue While the patient is deep asleep and pain-free (general anesthesia), an incision is made between the ribs to expose the lung. The chest cavity will be examined and diseased lung tissue will be removed (All or portions of relevant lymph nodes will be removed and undergo pathology testing to see if they are cancerous) A drainage tube is inserted to drain air, fluid and blood out of the chest cavity and the ribs and skin are closed. Hospital stay is usually 7 to 10 days. Deep breathing is important to help prevent pneumonia, infection and re-expand the lung. The chest tube remains in place until the lung has fully re-expanded. Pain is managed with medications. The patient recovers fully in 1-3 months after the operation. Http://health.yahoo.com
7.3 VIDEO-ASSISTED THROASCOPIC SURGERY Benefits In recent years, surgeons have utilized modern technology in surgery, particularly the television camera. Laparoscopic surgery, use of a laparoscopy together with a television camera has now been used for a number of years in many gall bladder removals and certain gynecological procedures. Recently, some have begun using this type of television aided surgery in lung procedures. The advantages of the camera-aided procedures are as follows: by using and moving a camera during surgery, much smaller incisions can be used. For example, with laparascopic gall bladder removal, four small incisions are used instead of the large one with traditional surgery. Thus, there is an appreciably smaller scar and shorter recovery period. With this video-assisted lung surgeries, it may not be necessary to break a rib to enter the area where the lung is located, as is done with standard surgery. Thus, we have a less intrusive surgery, reduced pain, smaller scar, and quicker recovery time. Potential Problems Using our knowledge of laparoscopic procedures, we can suggest the following drawbacks with video-assisted thorascopic surgery. In nine out of ten procedures, the result is a quicker, less intrusive surgery, with a smaller scar and quicker recovery. However, using these new procedures requires significant skill and there is a high learning curve. There is less, or at least different, visibility with a video-assisted procedure; the surgeon now relies on a television camera. Thus if there are anatomical anomalies or other problems, the surgeon could be hindered by his lack of direct visibility. If a serious problem arises, the procedure will have to converted to an open or traditional procedure, creating a small amount of added risk. We can identify two potential problems. First, a surgeon inexperienced with this type of procedure will present greater risks. With such a procedure, you want a surgeon highly experienced with this procedure, at a hospital which it is also routinely done. Secondly, given the reduced or at least different visibility and the need to convert the procedure if problems arise, use may be limited for patients with other significant health problems.
IDEAL PROFILE
PROBLEM PROFILE
DR.= S EXPERTISE
Extensive experience, over 100 surgeries of this exact type performed.
Limited experience (note that this will not be quickly revealed)
HOSPITAL
Excellent hospital with years of experience performing this particular type
New to hospital, nurses and others learning how it
RELEVANT FACTORS
works
GENERAL HEALTH
Excellent health other than the cancer
Existing health problems such as COPD chronic obstructive pulmonary disorder or heart problems, Present additional risks
STATUS OF THE TUMOR
Small stage 1 tumor
Stage 1b, 2, or 3, more complicated surgery.
7.4 HOSPITAL STAYS We have included U.S. News and World Report= s excellent rating system for cancer centers. With experience and specialization, we can expect that care at these top hospitals will be better. 7.41 Private Nurses and Problems at Night Care in ICU (intensive care units) following surgery is usually excellent, and care during days at most hospitals are usually good also. Where there is a difference tends to be at night. Few nurses and staff wish to work at night, and with limited budgets, there are frequent staffing problems at many hospitals which will not be apparent to the average patient or his family. Consider hiring a nurse or health care aid to assist in monitoring the patient during the night when problems are least likely to be detected. Unfortunately, insurance is unlikely to cover this type of expenses. Alternatively, consider having a family member sleep over or remain in the room if possible to assist the patient.
CHAPTER EIGHT: NON-SMALL CELL LUNG CANCERSTAGES 1 AND 2 _________________________________ 8.0 OVERVIEW 8.01 The Author= s Approach Chapter 4, 5, and 6 include detailed material from the National Cancer Institute (NCI) website. The National Cancer Institute is a government funded agency which compiles information and oversees various studies. It is a conservative and authoritative source. The material from NCI is generally thorough and authoritative; however, it frequently is difficult reading. My goal is to take material designed for medical professionals, organize, explain and abbreviate it so that it can be understood by the average patient or family member. To do this, I have done several things. First, each chapter begins with a brief summary. This will highlight the issues which you will be examining. Secondly, for some individual topics, I have provided a summary after each section, to give a less technical overview of what is said. Thirdly, where the material became overly technical, I have removed some portions to facilitate the reading while hopefully maintaining the important material. Fourthly, while NCI is authoritative, their views are not the only ones, though they usually provide a good start. Therefore, at the end of some sections, I have provided excerpts from articles and presentations or even my own views. Even with these steps, the material can still be challenging, though I believe a good knowledge of this will be important for the patient or family member seeking to understand the nature of treatment and any options presented. Try to read each section, consult the definitions at the end of the book, and have a medical dictionary on hand. If you become confused about different stages, review the discusssion of different stages in chapter 2. This chapter presumes you are familiar with the TNM staging system, and NCI will uses terms like T1 or T2 indicating the size and location of the primary tumor. If you are able to digest the information here, you may be able to reduce the general information which takes up time in doctor-patient conferences, better understand your condition and the treatment which is proposed, and be able to ask your physician knowledgeable questions about treatment procedures and alternatives 8.02 Treatment Overview Since the use of surgery, type of treatment, chemotherapy and radiation depends upon stage, the chapter is divided that way. Surgery is the major potential curative option for early diagnosed patients with smaller tumors and no lymph node involvement or metastasis. For others, radiation and chemotherapy provides varying results delineated below. The book, Lung Cancer by Carney (Arnold Pub. Co., Great Britain, 1995) provides a summary of treatment options at different stages ! A Stage 1 (T1 N 0 MO or T2 N0 M0) These patients have T1 or T2 carcinomas but no metastasis to lymph nodes or distant organs. They are candidates for curative resection (surgical removal of the tumor) with a very favorable prognosis. ! Stage 2 (T1 N1 M0 or T2 N1 M0) These patients have T1 or T2 carcinomas but also have pulmonary node metastasis (N1). Hilar lymphanopathy may require pneumonectomy (removal of the lung) for curative resection, and as a result, some patients with poor pulmonary reserve may not be candidates for surgery. ! Stage 3a (T3 N0 M0, T3 N1 M0 or T1-3 N2 Mo) These patients have locally advanced disease with hilar or ipsilateral mediastinal nodal metastasis, but a select few may be suitable for surgical resection. Prognosis is poor with 5 year survival less than 20 percent. ! Stage 4 (T1-4 N1-3 M1) These patients have distant metastasis and have the worst overall prognosis. Surgery is of no proven benefit, but radiotherapy or chemotherapy may provide palliative relief. A Carney, Lung Cancer (Arnold Pub. Co., Great Britain, 1995) Today, it appears that chemotherapy is clearly beneficial even in stage 3 and 4 patients. It extends life, reduces the ill effects of the cancer, and in a minority of cases can provide a cure.
8.2 OCCULT NON-SMALL CELL LUNG CANCER (Stage 0) TX, N0, M0 An occult cancer is a microscopic tumor which cannot be seen on a chest x-ray. Tumors discovered in this fashion are very early stage and curable by surgery. 8.21 Why Most Occult Tumors are Squamous Cell One text states, A 90% of occult lung cancers are squamous carcinomas, and 10% are either adenocarcinomas or large cell carcinomas.@ Martini, et. al. Treatment of Stage 1 and II Disease 339 in Aisner, Comprehensive Textbook of Thoracic Oncology (Williams & Wilkins 1996). Squamous cell tumors are usually in the main bronchus. Sputum cytology is gathering sputum from a cough. These small central tumors can sometimes be detected during an analysis of cells from a cough while deeper tumors in the smaller airways are not so easily found. The 90% figure means that of early cancers diagnosed, 90% are squamous cell, not that 90% of all tumors are squamous cell. Diagnostic tools like sputum cytology need to be used more often, so we can treat certain lung cancer in its early stage when treatment is most effective. Since sputum cytology is less effective at revealing adenocarcinomas, it is not an all-inclusive diagnostic tool. Nonetheless with a cost of less than $100.00 per administration and date of detection critical, it needs to be utilized more frequently. Tis, N0, M0 Stage 0 non-small cell lung cancer (NSCLC) is the same as carcinoma in situ of the lung. Because these tumors are by definition noninvasive and incapable of metastasizing, they should be curable with surgical resection; however, there is a high incidence of second primary cancers, many of which are unresectable. Phototherapy has been described as an alternative to surgical resection in carefully selected patients. [1-3] This investigational treatment seems to be most effective for very early central tumors that extend less than 1 centimeter within the bronchus.[2] Efficacy of this treatment modality in the management of early NSCLC remains to be proven. Treatment options: 1. Surgical resection using the least extensive technique possible (segmentectomy or wedge resection) to preserve maximum normal pulmonary tissue since these patients are at high risk for second lung cancers. 2. Endoscopic photodynamic therapy.[2,3] 8.22 Author= s Note on Photodynamic Therapy A recent article discusses photodynamic therapy and its use with Stage 0 patients: Photodynamic therapy uses a photosensitizing agent, which becomes activated when exposed to light of the appropriate wavelength (1) and produces toxic oxygen radicals, resulting in cell death....Tissue penetrations is limited to a few millimeters in this method. This fact and the relatively low power prohibit complete eradication of large obstructing airway lesions. However, successful eradication of superficial (penetration less than 5 millimeters) bronchial wall tumors has been demonstrated. Superficial tumors are usually squamous cell carcinomas that are radiographically occult. They are often detected through cytological examination of sputum. Surgical resection remains the best treatment for early-stage lung cancer. However, photodynamic therapy may be considered for some operable cancers, for cancers that are inoperable because of high surgical risk or limited pulmonary function or because they are multicentric, and for cancer in patient who refuse surgery. To be a candidate for photodynamic therapy, a patients must have a superficial stage 1 lesion (I/e. no evidence of nodal metastasis) that has a surface area estimated to be less than 3cm.Midthun, Endobronchial Techniques in Lung Cancer, Options for Nonsurgical Care. Vol. 101, No. 3, March 1997 Postgraduate Medicine Note that this photodynamic surgery is generally an option only for those patients who cannot tolerate surgery. For example, if an 84 year old man with previous heart problems and poor health were diagnosed with in-situ lung cancer, photodynamic therapy could be used. For others, given the overall good results achieved through surgery, that is the preferred form of treatment.
References: 1. Omitted 2. Furuse K, Fukuoka M, Kato H, et al.: A prospective phase II study on photodynamic therapy with photofrin II for centrally located early-stage lung cancer. Journal of Clinical Oncology 11(10): 1852-1857, 1993. 3. Edell ES, Cortese DA: Photodynamic therapy in the management of early superficial squamous cell carcinoma as an alternative to surgical resection. Chest 102(5): 1319-1322, 1992.
8.3 STAGE I NON-SMALL CELL LUNG CANCER 9.30 Surgery is the Preferred Option leading to Excellent Five Year Survival Prospects Surgery, specifically a lobectomy- removal of the affected lobe of the lung and surrounding tissue, is the preferred option. Stage 1 patients have an excellent prognosis, ranging from 55% to 85% five year survival, depending upon the study. One writer found that 80% of stage 1 operated patients never had another lung tumor. Why don= t we operate on all stage 1 patients? 9.31 Surgery and Pulmonary Reserve The main consideration in surgery is whether the patient has sufficient pulmonary reserve. That is, can his pulmonary or respiratory system tolerate the removal of substantial parts of a lung. Surgery involves removal of not only the tumor, but some surrounding tissue. For the average person, removal of a part of one lung would not present significant problems. However if a patient= s lungs have not only cancer but other disease such as emphysema, a physician may decide against surgery. Pulmonary function tests assess the patient= s breathing capacity in various contexts. 8.32 Wedge Resection Surgery Instead of Lobectomy Is Recommended Only for Stage 1 Patients with Impaired Pulmonary Function NCI states, A Patients with impaired pulmonary function may be considered for segmental or wedge resection of the primary tumor; the Lung Cancer Study Group has conducted a randomized study (LCSG-821) to compare lobectomy with limited resection for patients with stage I cancer of the lung. The results of this study show a reduction in local recurrence for patients treated with lobectomy compared with those treated with limited excision but no significant difference in overall survival.[2] Similar results have been reported from a nonrandomized comparison of anatomic segmentectomy and lobectomy.[3] A survival advantage was noted with lobectomy for patients with tumors greater than 3 centimeters, but not for those with tumors smaller than 3 centimeters. However, the rate of local/regional recurrence was significantly less after lobectomy, regardless of primary tumor size. Another study of stage I patients showed that those treated with wedge or segment resections had a local recurrence rate of 50% (31 of 62) despite having undergone complete resections.[4] Exercise testing may aid in the selection of patients with impaired pulmonary function who can tolerate lung resection.[5] The availability of video-assisted thoracoscopic wedge resection permits limited resections in patients with poor pulmonary function who are not usually considered candidates for lobectomy.[6]@ 8.33 Radiation is Used for Stage 1 Patients with Poor Pulmonary Reserve NCI states, A Patients with stage I disease for whom surgery is deemed inappropriate may be considered for radiation therapy with curative intent. In one report of patients older than 70 years of age who had resectable lesions smaller than 4 centimeters but who were medically inoperable or who refused surgery, survival at 5 years following radiation therapy with curative intent was comparable to a historical control group of patients of similar age resected with curative intent. In the two largest retrospective radiation therapy series, inoperable patients treated with definitive radiation therapy achieved 5-year survival rates of 10% and 27%. Both series found that patients with T1, N0 tumors had better outcomes, with 5-year survival rates of 60% and 32% in this subgroup..... Careful treatment planning with precise definition of target volume and avoidance of critical normal structures to the extent possible is needed for optimal results and requires the use of a simulator. Treatment options: 1. Lobectomy or segmental, wedge, or sleeve resection as appropriate. 2. Radiation therapy with curative intent (for potentially resectable patients who have medical contraindications to surgery). 3. Clinical trials of adjuvant chemotherapy following resection... 5. Endoscopic photodynamic therapy (under clinical evaluation in highly selected T1, N0, M0 patients). 4.33 Post-Operative Radiation for Stage 1 Tumors. A 1999 article in the respected journal Lung Cancer states, A There is no place for routine postoperative thoracic radiotherapy after complete resection of a stage 1 tumour@ Rodrigues, The Impact of Surgical Adjuvant Thoracic Radiation for different Stages of Non Small Cell Lung Cancer: the Experience from a Single Institution, Lung Cancer 23 (1999) 11-17.
8.3 STAGE II NON-SMALL CELL LUNG CANCER 8.31 Surgery as the Preferred Option for Stage 2 Non-Small Cell Patients NCI states, A Surgery is the treatment of choice for patients with stage II non-small cell lung cancer (NSCLC). Careful preoperative assessment of the patient's overall medical condition, especially the patient's pulmonary reserve, is critical in considering the benefits of surgery. The immediate postoperative mortality rate is age-related, but up to 5%-8% with pneumonectomy or 3%-5% with lobectomy can be expected. 8.32 Radiation for Patients for Whom Surgery is Not Recommended NCI states, A Patients with stage II disease for whom surgery is not recommended but with sufficient pulmonary reserve may be considered for radiation therapy with curative intent.[1] Among patients with excellent performance status, up to a 20% 3-year survival rate may be expected if a course of radiation therapy with curative intent can be completed. In the largest retrospective series reported to date, 152 patients with medically inoperable NSCLC treated with definitive radiation therapy achieved a 5-year overall survival rate of 10%; however, the 44 patients with T1 tumors achieved an actuarial disease-free survival rate of 60%. This retrospective study also suggested that improved disease-free survival was obtained with radiation therapy doses greater than 6,000 cGy.... 8.33 Surgery and Chemotherapy and/or Radiation for Stage 2 Non Small Cell Patients Recall that stage 2 means that the tumor has penetrating adjoining lymph nodes. Thus the potential for dissemination of the cancer is greater and the chance that surgery can remove the entire tumor less. Thus, combining surgery with some type of post-surgical treatment for eradicating any remaining tumor cells makes logical sense. However, precisely what should be done and what benefits can be realized continues to be debated. One site discusses the potential benefits of adding radiation to surgery: A Although surgery is the cornerstone for treating stage II disease, the addition of postoperative adjuvant radiation and chemotherapy may be more effective in this patient population. Postoperative radiation therapy decreases the rate of local relapse, especially in patients with squamous cell NSCLC, but long-term survival is not improved.
9.4 CHEMOTHERAPY ADDED TO RADIATION FOR STAGE 2 PATIENTS, A CONTINUING AREA OF CONTROVERSY With lymph node involvement at stage 2, the possibility of recurrence or metastasis increases. One may reason that in addition to radiating the area of the tumor to kill any cancer cells missed at surgery, why not add chemotherapy to attack any cells in that or other areas. While the approach carries with it some logic, clinical studies have not shown success, and many if not most physicians would reason that patients should not be required to deal with chemotherapy treatment if definite benefits are not shown. Here are results from one study.
39
38 months
Recurrance Rate
53
56%
Recurrence Time
30.4
26.1 months
Median Survival Time
A presentation at the 2000 World Conference on Lung Cancer summarizes the results: A This large, well-conducted, multicenter study suggests no clinical advantage at all for adding chemotherapy to radiation therapy in the management of resectable lung cancer. While newer chemotherapy agents are available, it is not clear that these drugs would change the fundamental outcome compared with the widely used platinum-based regimen used in this study. It is fair to say that the use of chemotherapy in the adjuvant setting of stage 2 or 3A NSCLC remains investigational; however, to date, these data are not encouraging.@ Burstein, Adjuvant Chemotherapy for Lung Cancer: Still No Benefit, World Conference on Lung Cancer (2000), www.medscape.com, referencing, Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ. 1995;311:899-909.Keller SM, Adak S, Wagner H, et al. A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. N Engl J Med. 2000;343:1217-1222. Others have reached similar conclusions, A Chemotherapy used alone or in combination with radiation therapy postoperatively resulted in prolonged time to disease progression and a modest improvement in survival. However, long-term survival was not affected. The precise role of adjuvant chemotherapy and/or radiation therapy in patients with stage II NSCLC remains to be determined. Investigators are also exploring the use of preoperative and postoperative paclitaxel and carboplatin chemotherapy in patients with stages Ib, IIa, IIb, and IIIa NSCLC.@ www.uspharmacist.com current Treatment of Non-Small Cell Lung Cancer, (US Pharmacist Continuing Education).@ Note that these studies deal only with prophlactic chemotherapy, that is chemotherapy designed to deal with the possibility of additional cancer cells remaining. Where a recurrence is detected, the patient= s stage would change, and chemotherapy would likely be administered as part of standard treatment. Prophylactic chemotherapy is not standard treatment for stage 2 non small cell patients, though some patients may be interested in clinical trials assessing post-operative chemotherapy. 9.34 Survival Rates for Stage 2 Non Small Cell Patients A 1999 article in the journal Lung Cancer states, A For the 98 patients with postoperative lobar or hilar node metastases, overall survival rates at 3 and 5 years of 45.2 and 37.3% were found. Fifteen (15.3% showed a local failure within the radiation field as a first failure relapse. Distant metastases as first failure were noted in 38 patients (39%) with 12/38 brain metastases.... At 5 years, a local progression free survival rate of 79% and a distant metastasis free survival rate of 52% was noted. @ Rodrigues, The Impact of Surgical Adjuvant Thoracic Radiation for different Stages of Non Small Cell Lung Cancer: the Experience from a Single Institution, Lung Cancer 23 (1999) 11-17. 8.341 Survival Rate Differences Between Adenocarcinoma and Squamous Cell The above article states, A For the 71 stage II patients with a squamous histology, a 5-year survival rate of 44% was noted as opposed to 14% for patients with a large cell or adenocarcinoma. Although the local failure was not different (the term local failure meaning reappearance of the tumor in the area of radiation or where the tumor was removed) 17% for squamous, 11% for non-squamous, the non-squamous group failed more often at distant sites. From the 27 patients, 18 developed metastases as a first failure with 8/27 (30%) brain metastases. For the squamous group, 20/71 (28% developed distant metastases, with 5/71 brain (metastases).@ Rodrigues, The Impact of Surgical Adjuvant Thoracic Radiation for different Stages of Non Small Cell Lung Cancer: the Experience from a Single Institution, Lung Cancer 23 (1999) 11-17. It can be concluded that adenocarcinoma is a quick moving tumor than squamous cell. Significant different like these may lead physicians and scientists to make distinctions in treatment within the non-small cell category. Today, for the most part, squamous cell, adenocarcinoma and large cell tumors are treated alike.
CHAPTER 9: NON-SMALL CELL LUNG CANCERSTAGES 3 AND 4 ___________________________________________________
9.1 STAGE 3 IS DIVIDED INTO 3A AND 3B One website explains how stage 3 non-small cancer came to be subdivided into two categories: Stage III lung cancer originally included patients with locally advanced disease, without distant metastases. In 1986, the International Staging System for Lung Cancer further divided this group into two subgroups C IIIA and IIIB.4 These subgroups attempted to separate patients with tumors that were potentially resectable (stage IIIA) from patients with tumors clearly beyond the scope of surgical extirpation (stage IIIB). Stage IIIA originally included tumors of any size within the lung with limited extension of the primary site to the pericardium, mediastinal pleura or fat, or chest wall and without lymph node metastases or with lymph node metastases confined to the ipsilateral mediastinal lymph nodes. Experience has demonstrated that patients with this classification form a very heterogeneous group, with a long-term survival following surgical resection that ranges from 10 to 50%. Consequently,this classification has recently been modified. www.chestnet.org/education/pccu/vol12/lesson18.html One of the main difference between stage 3 A and B non small cancer is that surgery is part of 3A treatment. Surgery in stage 1 patients is designed to remove all of the tumor. In stage 3A while that may not be the goal, it is at least to remove enough tumor to make the risks of surgery and reduction of lung capacity make sense. In stage 3B where the tumor has extended beyond the immediate area into the mediastinum and adjoining structures, it is felt tha the risk does not make sense. Since one group with different treatment plans is confusing, the division into 3A and 3B. Note that within each category are tumors with different characteristics, but the intra-category treatments are essentially the same. 9.11 TNM Grouping and Stage 3 The grouping using the TNM (tumor, node, metastatsis) is now, Stage IIIA T1-3, N2, MOT3, N1, MO, Stage IIIB T4, Any N, MO Any T, N3, MO.
9.2. CHEMOTHERAPY, RADIATION AND SURGERY ARE THE STANDARD TREATMENT WITH THE BEST MIX OF THE THREE STILL UNDER INVESTIGATION A pharmaceutical site provides a good overview of Stage 3 A treatment: A Historically, patients with stage III NSCLC (locally advanced disease) were managed with radiation therapy, but long-term survival was poor (5%B 10%). The development of active chemotherapy regimens for NSCLC has led to the use of combined modality therapy for the management of stage III disease. Surgery and radiation are effective at controlling local disease, while chemotherapy works to control distant metastatic disease. Any two of these modalities or all three could be combined to treat stage III disease. However, patients with stage IIIb disease are generally not candidates for surgical resection and will most commonly receive combination chemotherapy, plus or minus radiation therapy. Numerous trials comparing combined chemotherapy/radiation to radiation alone have been conducted in patients with stage III NSCLC. The chemotherapy regimens and radiation schedules have varied greatly among the studies, and conflicting results have emerged.... When two different meta-analyses were conducted with the data from all of the published randomized trials comparing chemotherapy/radiation with radiation alone, a small improvement in survival was reported for combined modality therapy. All of these studies utilized the older generation of chemotherapy regimens (cisplatin or cisplatin-based) in combination with radiotherapy. The improved activity of the newer combination chemotherapy regimens used in stage IV disease could lead to improved results when combined with radiation for the treatment of stage III disease. www.uspharmacist.com 9.22 Chemotherapy Before Surgery or NeoAdjuvant Surgery Chemotherapy and radiation are also, with research continuing as to what combination of these three forms of treatment will achieve the best results. Recall that Stage III A tumors involve either large T2 or 3 tumors orsituations of significant lymph node involvement. Many physicians believe in chemotherapy before surgery: Neoadjuvant chemotherapy with or without radiation therapy followed by surgery is another combined modality treatment for stage III (primarily stage IIIa) disease that is under investigation. Neoadjuvant chemotherapy is administered to patients with bulky disease prior to surgery in an attempt to decrease tumor size and increase surgical resectability. Two randomized studies have {favorably} compared chemotherapy followed by surgery with surgery alone.@ Current Treatment of Non-Small Cell Lung Cancer, U.S. Pharmacist continuing Education. A recent article discusses the purposes of neoadjuvant chemotherapy: The purpose of neoadjuvant chemotherapy is the eradication of micrometastatic disease, which is almost invariably manifest when ipsilateral mediastinal or subcarinal lymph nodes (N2) are involved. A chest computed tomography (CT) imaging study may show lymph nodes extending throughout many mediastinum regions, including the aortopulmonic window, the paratracheal region, and the precarinal and subcarinal areas.... Three randomized phase III trials reported that administering cisplatin-based chemotherapy before surgery to patients with resectable stage IIIA lung cancer improved survival results over those obtained with surgery alone or surgery plus radiotherapy. The MD Anderson investigators have recently updated the long-term follow-up of a selected high-risk population of patients with advanced but still resectable non-small cell lung cancer (NSCLC), T1-3N2M0 or T3-4N0M0.... This study shows that a preresectional chemotherapy regimen of cisplatin in combination with ifosfamide and mitomycin does improve the clinical outcome in comparison with surgery alone.@ Rosell, Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: a 7-year assessment of a randomized controlled trial Lung Cancer, Vol. 26 (1) (1999) pp. 7 - 14 9.11 T1, N2, M0 or T2, N2, M0 or T3, N1, M0 or T3, N2, M0 9.121 Immunotherapy No consistent benefit from any form of immunotherapy has been demonstrated thus far in the treatment of NSCLC. Treatment options: 1. Surgery alone in highly selected cases.[20-22] 2. Chemotherapy combined with other modalities.[4-6,12,17-19] 3. Surgery with postoperative radiation therapy.[13,15] 4. Radiation therapy alone.[1,2] Superior sulcus tumor (T3, N0 or N1, M0)
9.4 STAGE IIIB NON-SMALL CELL LUNG CANCER Chemotherapy is the primary treatment for Stage 3B and Stage 4 non small cell lung cancer. We can note the following: 6. In the 80's and early 90's, there was some debate about whether chemotherapy improved survival, and whether multiple agents helped. That debates has probably ended. Studies have demonstrated a consistent (if relatively modest) benefit to chemotherapy over other treatments, and have also shown that multi-modal chemotherapy is better than single agent. If different drugs can fight cancer and work in different ways, it would make sense that a combination would achieve better results so long as significant side effects were not created. 7. No one combination has demonstrated markedly better results throughout different clinical trials than others. Clinical trials continue to test various combinations against one other to determine rates of tumor dimunition, partial and complete response rate (partial meaning at least 50% reduction of the tumor and complete meaning no visible tumor at a certain point in time), survival rates, and side effects. To call such clinical trials A experimental@ is a little misleading. The clinical trials are generally using the same drug combinations that practitioners use, only in a defined clinical setting. 3. The term non-small cell lung cancer includes adenocarcinoma, squamous cell, and large cell cancers. While we have grouped these three types together, it is possible that each type acts a little differently. Conceivably, one drug could be better for squamous and another for large cell. The fact that people with different types of tumors are grouped together, and different ages and health has made to more difficult to distinguish which drug is most effective. 4. The platinum-drugs, cisplatin and carboplatin have been the mainstays of chemotherapy for stage 3 and 4 patients, with the above list concentrating on platinum drug combinations. Taxol and Carboplatin appear in practice to be the most frequently used combination, though the literature does not clearly indicate better results with this combination. 5. Gemcitabine and Gemcitabine combinations have been showing results roughly comparable to these platinum combinations, with Gemcibaine sometime reported to have fewer side effects- A Kosimidis showed that a nonplatinum-containing regimen was equivalent to standard carboplatin/paclitaxel for the treatment of advanced disease. The results of this study are also consistent with the recent South West Oncology Group (SWOG) and Eastern Cooperative Oncology Group (ECOG) studies presented at the American Society for Clinical Oncology (ASCO) over the past 2 years@ Kosmidis P. A randomized phase III trial of paclitaxel plus carboplatin versus paclitaxel plus gemcitabine in advanced non-small cell lung cancer (NSCLC): a preliminary analysis. Lung Cancer. 2000;29(Suppl 2):147, cited in Lynch, 9th World Conference on Lung Cancer, Presidential Symposium, (2000), www.medscape.com For patients concerned about chemotherapy side effects, this may become a valid alternative, though scientists may disagree about whether it achieves precisely the same results. There are difficult issues of medical choice which might ultimately have to be made by the patient= s themselves. Is a slightly longer projected life-span worth additional side effects. Chemotherapy presents the problem of killing cancer cells, while preserving normal cells and bodily functions. How do we eliminate the rapidly dividing cells we call cancer, but preserve the other rapidly dividing cells necessary for different life functions. 6. A review of some chemotherapy studies and drugs is included in the appendix. 9.32 Stage 3 B Patients Managed Best by Chemotherapy and Radiation NCI states, A Patients with stage IIIb non-small cell lung cancer (NSCLC) do not benefit from surgery alone and are best managed by initial chemotherapy, chemotherapy plus radiation therapy, or radiation therapy alone, depending on sites of tumor involvement and performance status. Most patients with excellent performance status should be considered for combined modality therapy. However, patients with malignant pleural effusion are rarely candidates for radiation therapy, and should generally be treated similarly to stage IV patients (see separate section of this summary on treatment of stage IV disease). Many randomized studies of unresectable patients with stage III NSCLC show that treatment with neoadjuvant or concurrent cisplatin-based chemotherapy and chest irradiation is associated with improved survival compared to treatment with radiation therapy alone.[1-5] A meta-analysis of patient data from 11 randomized clinical trials showed that cisplatin-based combinations plus radiation therapy resulted in 10% reduction in the risk of death compared with radiation therapy alone.[6] Patients with stage IIIb disease with poor performance status are candidates for chest irradiation to palliate pulmonary symptoms (e.g., cough, shortness of breath, or local chest pain). No consistent benefit from any form of immunotherapy has been demonstrated thus far.@
9.4 STAGE IV NON-SMALL CELL LUNG CANCER Chemotherapy is the primary form of treatment and serves to extend life and sometimes reduce cancer-related symptomology. While there is near agreement that chemotherapy is beneficial, the exact form of chemotherapy which should be used remains unclear, though the combination of Taxol and Carboplatin is becoming the standard treatment. Carboplatin, vinorelbine, taxol, gemcitabine and other forms of chemotherapy have displayed benefits, but the optimal mix of drugs remains unclear since clinical trials have reached varying results. Some have suggested that the nonsmall cell cancer category is too large and encompasses forms of lung cancer which might respond slightly differently to forms of chemotherapy. For example, some studies have shown that squamous cell cancer metasatizes slower than adenocarcinoma so the prognosis for squamous cell patients is a little better. Thus, if we tried the same drug in two clinical trials of non-small cell patients at the same stage but with different proportions of patients with adenocarcinoma, we could expect different results with the same drug. Perhaps future studies and evaluation will consider the percentage of adenocarcinoma patients in assessing results. The National Cancer Institute states, A Cisplatin-containing and carboplatin-containing combination chemotherapy regimens produce objective response rates (including a few complete responses) that are higher than those achieved with single-agent chemotherapy. Although toxic effects may vary, outcome is similar with most cisplatin-containing regimens; a randomized trial comparing five cisplatincontaining regimens showed no significant difference in response, duration of response, or survival.[1] Patients with good performance status and a limited number of sites of distant metastases have superior response and survival when given chemotherapy when compared to other patients.[2] A prospective randomized comparison of vinorelbine plus cisplatin versus vindesine plus cisplatin versus single agent vinorelbine has reported improved response rate (30%) and median survival (40 weeks) with the vinorelbine plus cisplatin regimen.[3] Two small phase II studies reported that paclitaxel (Taxol) has single-agent activity in stage IV patients, with response rates in the range of 21%- 24%.[4,5] Reports of paclitaxel combinations have shown relatively high response rates, significant 1 year survival, and palliation of lung cancer symptoms.[6] With the paclitaxel plus carboplatin regimen, response rates have been in the range of 27%-53% with 1-year survival rates of 32%-54%.[6,7] The combination of cisplatin and paclitaxel was shown to have a higher response rate than the combination of cisplatin and etoposide.[8] Additional clinical studies should better define the role of these newer combination chemotherapy regimens in the treatment of advanced non-small cell lung cancer.[8] Meta-analyses have shown that chemotherapy produces modest benefits in short-term survival compared to supportive care alone in patients with inoperable stages IIIb and IV disease.[911] Although these results support further evaluation of chemotherapeutic approaches for both metastatic and locally advanced non-small cell lung cancer (NSCLC), efficacy of current programs is such that no specific regimen can be regarded as standard therapy. Appropriate patients should be encouraged to participate in clinical trials. Outside of a clinical trial setting, chemotherapy should be given only to patients with good performance status and evaluable tumor lesions who desire such treatment after being fully informed of its anticipated risks and limited benefits. Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC such as tracheal, esophageal, or bronchial compression, bone or brain metastases, pain, vocal cord paralysis, hemoptysis, or superior vena cava syndrome. In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[12] Such therapeutic intervention may be critical in the prolongation of an acceptable lifestyle in an otherwise functional patient. In the rare patient with synchronous presentation of a resectable primary tumor in the lung and a single brain metastasis, surgical resection of the solitary brain lesion is indicated with resection of the primary tumor and appropriate postoperative chemotherapy and/or irradiation of the primary tumor site and with postoperative whole-brain irradiation delivered in daily fractions of 180-200 cGy to avoid long-term toxic effects to normal brain tissue. In asymptomatic patients kept under close observation, treatment may often be appropriately deferred until symptoms or signs of progressive tumor develop.@
9.8 SECOND-LINE CHEMOTHERAPY AND OTHER OPTIONS FOR STAGE FOUR PATIENTS In some circumstances, the non-small cell patient will have a tumor seemingly unresponsive to chemotherapy. What should be done? 9.81 Change of Chemotherapy Regimen As noted, there are various types of anti-cancer drugs, with no consensus of what is best, and even in what amount. If one type of chemotherapy is not successful in reducing the size of a tumor, the patient should consider a change. While we may find that some types of tumors are chemo-resistant or develop that characteristic, it may also be that some drugs work better on particular types of tumors. The term non-small cell cancer comprises squamous cell, large cell, and adenocarcinoma. It could be that certain drugs work better on certain types of non-small cell cancer, those in certain locations, or with certain cellular characteristics (poorly differentiated versus moderately differentiated). There is at least as much about lung cancer that we don= t as we do, despite millions in research. Thus, it is certainly reasonable to switch physicians, hospitals, or chemotherapy regimens where what was being done is not successful. 5.82 Experimental Programs and Clinical Trials We deal with experimental treatments and clinical trials in later chapters. However, it is perfectly appropriate for the stage 4 patient, particularly those whose tumors have not responded to chemotherapy, to consider new forms of treatment. This area is rapidly evolving with numerous drugs being tried, some with limited success. At the time of evaluation, which will likely be some period after publication, the patient and his physician must survey the literature, consider the location of clinical trials, and choose among various treatments. We can provide a brief overview here based upon some of the information available at the time this is written. Before looking at specific drugs, here are some of the considerations to evaluate. We have clinical trials stages 1, 2, and 3, and generally the higher the number, the greater chance of success.
Clinical Trial Stage
Is the treatment located near you. Obviously going to a distant hospital can create stress for the patient and family.
Location
Is there published literature indicating some success. If there are reports of initial success in clinical trials, are these evaluations from impartial third parties.
Reported Success and Objectivity of the Reporter
Reputation of the Hospital
Is the trial done by an excellent hospital or cancer center unlikely to stake its reputation on a questionable form of treatment.
Your Oncologist= s Opinion
Based upon the evaluation of your condition, does your oncologist recommend participation in this trial or protocol.
Eligibility
Some clinical trials are limited to patients with no prior chemotherapy or those without certain medical problems. (Remember the clinical trial authors generally want to create conditions for success).
Plausibility
Ultimately you have to make a decision of whether this particular experimental treatment will be successful.
9.82 Anti-AngioGenesis Drugs Angiogenesis drugs attempt to hinder the establishment of new sources of blood supply by metastatic tumors. These drugs are still experimental but the patient whose tumors has not been combatted by chemotherapy may wish to consider them. No anti-angionenic drugs has been determined by the FDA to be effective in treating non-small cell lung cancer, though clinical trials continue. 9.821 Erissa Erissa has shown promising results in some earliest clinical trials, though these results have not reached formal FDA approval. 9.831 Interferon Interferon has shown some promise in the treatment of advanced non-smallcell cancer. 9.84 Hospice. If most physicians and patients believe in maintaining a positive attitude and hope for cure, there are others who believe that all lives must inevitably come to an end and that sometime, all medical science does is prolong the patient= s agony. Whether chemotherapy has this result is debatable since some studies show that chemotherapy increases quality of life by mitigating the harmful effects of the tumor. Some patients may decide that maintaining a peaceful and dignified end, free of medical unnecessary medical intervention is the preferred course. Where an older patient has stage 4 metastatic lung cancer, where has not responded to chemotherapy, such a decision cannot be regarded as wholly unreasonable. The decisions are difficult, but perhaps the patient= s well-considered wishes must be respected in such a situation. Hospices provide end of life care, frequently doing this far better than a hospital or other facility. 9.85 Experimental Drugs A final alternative where existing chemotherapy or other treatments have not achieved positive results is to consider certain drugs awaiting FDA approval. Because these drugs are experimental, they are generally administered in a clinical trial. However, a patient may not wish to enter a clinical trial or may be ineligible for certain ones because of his physical status and the advanced stage of disease. There are several lawful ways to obtain a drug in clinical trials: A If the eligibility criteria in a study protocol are not suitable for a particular patient, it may still be possible to be treated according to the study protocol special exception (sometimes called compassionate exemption). ... Another alternative is for a physician to file a single patient or emergency directly with the FDA. www.FDA.gov.
CHAPTER TEN: SMALL CELL LUNG CANCER _________________ 10.0 AUTHOR= S OVERVIEW AND SOURCES 10.01 Small Cell Cancer Spreads and Metastasizes Quickly Small cell is a quick-moving cancer, rapidly spreading to lymph nodes and other organs. A Characterized by rapid cell division, SCLC long-term survival rates are low because patients usually have widespread disease at the time of diagnosis... Metastases usually involve the bone (35% of the cases), liver (25% of the cases) and either the brain, central nervous system, lymph nodes, subcutaneous tissue, or pleura (10% of cases).@ www.cancer.mednet.cula.edu/CancerJournal/htm/small.html. We will first look at an NCI overview of small cell and then address specific issues. NCI states, A Without treatment, small cell carcinoma of the lung has the most aggressive clinical course of any type of pulmonary tumor, with median survival from diagnosis of only 2-4 months. Compared with other types of lung cancer, small cell carcinoma has a greater tendency to be widely disseminated by the time of diagnosis, but is much more responsive to chemotherapy and irradiation. Because of the propensity for distant metastases, localized forms of treatment, such as surgical resection or radiation therapy, generally cannot produce long-term survival.[1] With incorporation of current chemotherapy regimens into the treatment program, however, survival is unequivocally prolonged, with at least a 4- to 5-fold improvement in median survival compared with patients who are given no therapy. Furthermore, about 10% of the total population of patients remain free of disease over two years from the start of therapy, the time period during which most relapses occur. However, even these patients are at risk of dying from lung cancer (both small and non-small cell types). The overall survival at 5 years is 5%-10%. At the time of diagnosis, approximately 40% of patients with small cell carcinoma will have tumor confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes. These patients are designated as having limited stage disease, and most 2-year disease-free survivors come from this group. In limited stage disease, median survival of 16-24 months with current forms of treatment can reasonably be expected. A small proportion of patients with limited stage disease may benefit from surgery with or without adjuvant chemotherapy; these patients have an even better prognosis. Patients with tumor that has spread beyond the supraclavicular areas are said to have extensive stage disease and have a worse prognosis than patients with limited stage. Median survival of 6-12 months is reported with currently available therapy, but long-term disease-free survival is rare. The pretreatment prognostic factors which consistently predict for prolonged survival include good performance status, female gender, and limited stage disease.[3,9,10] Patients with involvement of the central nervous system or liver at the time of diagnosis have a significantly worse outcome.[3,9-11] In general, patients who are confined to bed tolerate aggressive forms of treatment poorly, have increased morbidity, and rarely attain 2-year disease-free survival. However, patients with poor performance status can often derive significant palliative benefit and prolongation of survival from treatment. Regardless of stage, the current prognosis for patients with small cell lung cancer is unsatisfactory even though considerable improvements in diagnosis and therapy have been made over the past 10-15 years. Therefore, all patients with this type of cancer may appropriately be considered for inclusion in clinical trials at the time of diagnosis.@
10.1 SMALL CELL STAGING Exactly how small cell should be staged is somewhat controversial, with two different approaches representing to some extent different approaches to treatment. Recall that non-small cell cancer is divided into four stages (five if we count 3A and 3B) based on the involvement of lymph nodes and other organs. In contrast, most United States physicians divide small cell into but two categories: limited and extensive. Our National Cancer Institute explains, A Because occult or overt metastatic disease is present at diagnosis in most patients, survival is usually not affected by small differences in the amount of locoregional tumor involvement. Therefore, the detailed TNM staging system developed for lung cancer by the American Joint Committee on Cancer (AJCC) is not commonly employed in patients with small cell carcinoma. A simple 2-stage system developed by the Veterans Administration Lung Cancer Study Group is more commonly used for staging small cell lung cancer patients.@ [1] Non small cell is divided into stages because the determination of whether to perform surgery depends upon stage. If surgery is not generally recommended for small cell patients a four stage demarcation is unnecessary. One text states, A The biologic nature of small cell lung cancer causes dissemination to regional lymph nodes and/or distant metastatic sites in more than 90% of patients at the time of initial presentation.@ Small cell cancers are a quick moving or high-grade cancer which double and metastasize quickly. 10.11 Countries Which Use Four Step Staging for Small Cell A Japanese article discusses surgery and employs the four step staging of non small cell cancer. Indeed, given the difficult prognosis of small cell patients, the use of surgery must be considered The two step staging system contains an implicit bias against surgery, since surgical decisions need to utilize accurate information about tumor status that the simple two stage analysis does not provide.
10.2 CHEMOTHERAPY AS THE PRIMARY FORM OF TREATMENT IN THE U.S. In the United States, chemotherapy is the primary form of treatment for small cell lung cancer. Initial results are usually promising but the cancer frequently returns, and second line chemotherapy has less success. A text on lung cancer explains: A (Chemotherapy) regimens will result in response rates of 85-95% in limited disease and 65-85 percent in extensive disease patients. Complete responses, prerequisite for potential cure, can be achieved in about 50 per cent limited disease patients and in about a quarter of extensive disease patients. Depending on the addition of radiotherapy, in limited disease patients about a third will have disease-free survival in excess of 2 years.@ Chemotherapy of Small Cell Lung Cancer, 157, in Carney, Lung Cancer (Arnold Publ Co. 1995) 10.22 Recurrence and Drug Resistance While the initial success of chemotherapy for small cell cancer is indeed promising, the propensity for recurrence and difficulties combating that are troubling. In 1991, one doctor wrote, A Chemotherapy is the main treatment modality for small cell lung cancer. The disease is highly chemoresponsive and around 50 per cent of patients receive complete response. In the great majority of these, however, the disease recurs within a few months and is progressively chemoresistant.@ Twentyman, Mechanism of Drug Resistance in Lung Cancer Cells, included in Carney, Lung Cancer (Arnold Publ. Co. 1995). A A primary cause of treatment failure in SCLC (Small Cell Lung Cancer) is the emergence of drug-resistant cell clones during chemotherapy.@ Chemotherapy of Small Cell Lung Cancer, 158 in Carney, Lung Cancer (Arnold Publ. Co. 1995). 10.25 Cellular Classification The current classification of subtypes of small cell lung cancer are:[1] * small cell carcinoma * mixed small cell/large cell carcinoma * combined small cell carcinoma (small cell lung cancer combined with neoplastic squamous and/or glandular components) Electron microscopy, which can detect neuroendocrine granules, may help to differentiate between small cell and non-small cell cancers. Neuroendocrine carcinomas of the lung represent a spectrum of disease. At one extreme is small cell lung cancer, which has a poor prognosis. At the other extreme are bronchial carcinoid, with an excellent prognosis after surgical excision. Between these extremes is an unusual entity called well-differentiated neuroendocrine carcinoma of the lung.[4] It has been referred to as malignant carcinoid, metastasizing bronchial adenoma, pleomorphic carcinoid, non-benign carcinoid tumor, and atypical carcinoid. Like small cell lung cancer, it occurs primarily in cigarette smokers, but it metastasizes less frequently. The 5-year survival rate is greater than 50% in some series, and surgical cure appears possible in most stage I patients. Careful diagnosis is important, however, since the differential pathologic diagnosis from small cell lung cancer may be difficult. 10.32 NCI Staging A Staging procedures are important in distinguishing patients who have disease limited to their thorax from those who have distant metastases. Determining the stage of cancer by nonsurgical means allows a better assessment of prognosis and identifies sites of tumor that can be evaluated for response. Also, the choice of treatment is usually influenced by stage, particularly when chest irradiation or surgical excision is added to chemotherapy for patients with limited stage disease. Staging procedures commonly used to document distant metastases include bone marrow examination, computed tomographic or magnetic resonance imaging scans of the brain, computerized tomographic scans of the chest and the abdomen, and radio nuclide bone scans. Because occult or overt metastatic disease is present at diagnosis in most patients, survival is usually not affected by small differences in the amount of locoregional tumor involvement. Therefore, the detailed TNM staging system developed for lung cancer by the American Joint Committee on Cancer (AJCC) is not commonly employed in patients with small cell carcinoma. This international staging system is outlined in detail in the PDQ summary on non- small cell lung cancer. A simple 2-stage system developed by the Veterans Administration Lung Cancer Study Group is more commonly used for staging small cell lung cancer patients.[1] 10.33 Limited stage Limited stage small cell lung cancer means tumor confined to the hemithorax of origin, the mediastinum, and the supraclavicular nodes, which can be encompassed within a "tolerable" radiation therapy port. There is no universally accepted definition of this term, and patients with pleural effusion, massive pulmonary tumor, and contralateral supraclavicular nodes have been both included within and excluded from limited stage by various groups. 10.34 Extensive stage Extensive stage small cell lung cancer means tumor that is too widespread to be included within the definition of limited stage disease above. Patients with distant metastases (M1) are always considered to have extensive stage disease.[1,2]
10.4 LIMITED STAGE SMALL CELL LUNG CANCER 10.41 Surgery and the Stage 1 or Limited Stage Patient Even if we assume that at least 90% of small cell patients have advanced disease, that leaves a critical 10% with timely diagnosed tumors confined to part of a single lung. That subgroup has a excellent prognosis perhaps almost equivalent to stage 1 non-small cell patients. One text states, A Shields analysis of patients with small cell carcinomas in the VASOG trials also demonstrated the importance of TNM (tumor, node, metastasis) staging for tumors of this cell type. Sixty percent of patients with T1, No, Mo tumors were alive at 5 years, whereas there were almost no 5-year survivors among the patients who presented either with T2--3 tumors or with mediastinal lymph node involvement. Patients with T1 tumors with only hilar or bronchopulmonary nodes involved had an intermediate survival of approximately 30%. In fact, these survival results are similar to those of patients who have undergone complete surgical resection for non-small cell lung cancer of equivalent stage.@ Aisner, et. al., Comprehensive Textbook of Thoracic Oncology 441 (Williams & Wilkins 1996). 10.42 Excellent Japanese Results with Surgery and Stage 1 and 2 Small Cell Patients A Japanese study found good results with surgery for small cell patients. The author concluded that surgery played a substantial role in long survival for limited stage small cell lung cancer. A The 4 year survival rate of the patients in stage I was 50%, and that of those in stage II and IIIA was 50% and 37.5%.@ The authors boldly conclude, A Surgical resection for limited SCLC should be recommended in patients with stage I, II and T3NoMo or T3N1Mo disease. Ohkubo, Surgical Analysis for Small Cell Lung Cancer of the Lung , Kyobu Geka 1999 Dec; 52 (13) 1061-6. (abstract available on medline, go to healthgate.com and search for small cell lung cancer surgery). Aisner concludes, A Although there was general acceptance by the 1970's that surgical resection was inappropriate for the majority of patients with small cell lung cancer, the observations of Shields and his colleagues suggested that there might be a subpopulation of patients with small cell cancers for whom a surgical approach could be considered.@ Id. at 441. The notion that small cell treatment is comparable to non-small cell treatment would be rejected by most physicians and investigators. However, at least at early stage 1, there are signficant similarities and the same favorable prognosis. In many areas surgery is not performed upon small cell patients, even in earlier stages. The small cell patient will want to carefully review his options and assure himself that decisions are made or recommended by oncologists and surgeons of the highest caliber. If surgeon is a realistic option, this highlights the need for early detection. As I discuss later in the book, neither the American Cancer Society nor the National Cancer Institute recommend screening as a means to assure timely diagnosis and improved long term survival. 10.43 Chemotherapy and Radiation for Limited Stage Patients A It is useful to identify patients with limited- stage disease as several randomized controlled trials employing combined modality therapy (chemotherapy and thoracic irradiation in this group have demonstrated survival advantage over treatment with chemotherapy alone.@ Richardson & Ihde, Staging of Small Cell Cancer 114, in Carney, Lung Cancer (Arnold Publ Co. 1995). NCI states A In patients with small cell lung cancer, combination chemotherapy produces results that are clearly superior to single-agent treatment, and moderately intensive doses of drugs are superior to doses that produce only minimal or mild hematologic toxicity. Current programs yield overall objective response rates of 65%-90% and complete response rates of 45%-75%. Because of the frequent presence of occult metastatic disease, chemotherapy is the cornerstone of treatment of limited stage small cell lung cancer. Combinations containing two or more drugs are needed for maximal effect. Mature results of prospective randomized trials suggest that combined modality therapy produces a modest but significant improvement in survival compared with chemotherapy alone. Two meta-analyses showed an improvement in 3-year survival rates of about 5% for those receiving chemotherapy and radiation therapy compared to those receiving chemotherapy alone. Most of the benefit occurred in patients less than 65 years of age. Combined modality treatment is associated with increased morbidity and, in some trials, increased treatment-related mortality from pulmonary and hematologic toxic effects; proper administration requires close collaboration between medical and radiation oncologist.ve effect for combined modality therapy employed thoracic irradiation early in the course of treatment, concurrently with chemotherapy. 6.53 Particular Chemotherapy Drugs Used As with non-small cell, definiing combinations of drugs, maximum doses, and other variables, is a continuing process with sometimes conflicting results. By the time this is printed, there may be clinical trials which provide new information. At the end of 2000, at a conference, on research wrote, A Although clinical trials have failed to show superiority of 1 chemotherapeutic regimen over another, the original combination regimens of cyclophosphamide/doxorubicin-based chemotherapy has been replaced by combination cisplatin/etoposidebased regimens.@ Reddy, Small Cell Lung Cancer: Improving Outcomes, Presentation, American Society for Therapeutic Radiology and Oncology 42nd Annual Meeting, 2000, excerpted on www.medscape.com. 10.54 Chemotherapy and Radiation Reddy also suggests that combining chemotherapy with radiation improves results: Combined modality therapy appears to result in improved complete response rates, but with increased toxicity. There is a benefit associated with the addition of radiation therapy to multiagent chemotherapy, compared with chemotherapy alone. Recent Intergroup data published in the New England Journal of Medicine reported improved overall survival with the use of concurrent twice-daily fractionated radiotherapy and cisplatin/etoposide.[17] Patients with limited-stage SCLC (N = 417) were randomized to once-daily (45 Gy/25 fractions/5 weeks) or twice-daily (45 Gy/30 fractions/3 weeks) radiotherapy given concurrently with cycle 1 of cisplatin/etoposide. The median survival for all patients was 20 months, with a 40% 2-year survival rate. Overall survival was significantly better in the twicedaily arm compared with the standard fractionation arm (26% vs 16%, respectively). An increase in transient grade-3 esophagitis was seen in the twice-daily arm. Reddy, id at 1.
6.7 EXTENSIVE STAGE SMALL CELL LUNG CANCER NCI states, A As in limited stage small cell carcinoma, chemotherapy should be given as multiple agents in doses associated with at least moderate toxicity in order to produce the best results in extensive stage disease. Doses and schedules used in current programs yield overall response rates of 70%-85% and complete response rates of 20%-30% in extensive stage disease. Since overt disseminated disease is present, combination chemotherapy is the cornerstone of treatment of this stage of small cell lung cancer. Combinations containing two or more drugs are needed for maximal benefit. The relative effectiveness of many 2- to 4-drug combination programs appears similar, and there are a large number of potential combinations. Therefore, a representative selection of regimens that have been found to be effective by at least two independent groups has been provided. Some physicians have administered two of these or other regimens in alternating sequences, but there is no proof that this strategy yields substantial survival improvement.[1-3] Optimal duration of chemotherapy is not clearly defined, but there is no obvious improvement in survival when the duration of drug administration exceeds 6 months.[4,5] There is no clear evidence from reported data that maintenance chemotherapy will improve survival duration.[6-9] Combination chemotherapy plus chest irradiation does not appear to improve survival compared with chemotherapy alone in extensive stage small cell lung cancer. However, radiation therapy plays an extremely important role in palliation of symptoms of the primary tumor and of metastatic disease, particularly brain, epidural, and bone metastases... Patients with small cell lung cancer treated with chemotherapy with or without chest irradiation who have achieved a complete remission can be considered for administration of prophylactic cranial irradiation (PCI). Patients whose cancer can be controlled outside the brain have a 60% actuarial risk of developing central nervous system metastases within 2-3 years after starting treatment.[11,12] The majority of these patients relapse only in their brain and nearly all of those who relapse in their central nervous system die of their cranial metastases.[1214] The risk of developing central nervous system metastases can be reduced by more than 50% by the administration of PCI in doses of 2400 cGy.[12] Retrospective studies have shown that long-term survivors of small cell lung cancer (>2 years from the start of treatment) have a high incidence of central nervous system impairment.[15-17] However, prospective studies have shown that patients treated with PCI do not have detectably different neuropsychological function than patients not treated.[12] In addition, the majority of patients with small cell lung cancer have neuropsychological abnormalities present before the start of cranial irradiation and have no detectable decline in their neurological status up to 2 years after the start of their cranial irradiation.[18] Patients treated for small cell lung cancer continue to have declining neuropsychologic function after 2 years from the start of treatment.[15-17] Therefore, additional neuropsychologic testing of patients beyond 2 years from the start of treatment will be needed before concluding that PCI does not contribute to the decline in intellectual function. Many more patients with extensive stage small cell carcinoma have greatly impaired performance status at the time of diagnosis when compared to patients with limited stage disease. Such patients have a poor prognosis and tolerate aggressive chemotherapy or combined modality therapy poorly. Single-agent intravenous, oral, and low-dose biweekly regimens have been developed for these patients,[19-22] However, prospective randomized studies have shown that patients with a poor prognosis who are treated with conventional regimens live longer than those treated with the single-agent or low-dose regimens.[21-23] Treatment options: Standard: 1. Combination chemotherapy with one of the following regimens with or without PCI given to patients with complete responses: The following regimens produce similar survival outcomes: CAV: cyclophosphamide + doxorubicin + vincristine [24,25] CAE: cyclophosphamide + doxorubicin + etoposide [26] EP or EC: etoposide + cisplatin or carboplatin [27,28] ICE: ifosfamide + carboplatin + etoposide [29] 2. Radiation therapy to sites of metastatic disease unlikely to be immediately palliated by chemotherapy, especially brain, epidural, and bone metastases. 3. Identification of effective new agents is difficult in patients who have previously been treated with standard chemotherapy because response rates to agents, even of known efficacy, are known to be lower than in previously untreated patients. This situation led to the suggestion that patients with extensive disease who are medically stable be treated with new agents under evaluation, with provisions for early change to standard combination therapy if there is no response.[34] Such a strategy has been shown to be feasible, with survival comparable to survival with initial standard therapy, as long as the patients with extensive disease are carefully chosen.[35-37] A variety of other strategies have been proposed, depending on the activity of the new agent in other tumors, in preclinical small cell lung cancer models, or the activity of drug analogs.[38] Active single agents undergoing further evaluation include paclitaxel and topotecan.[39,40] Under clinical evaluation: Areas of active clinical evaluation in extensive stage small cell lung cancer include evaluation of new drug regimens, dose intensity, alternative drug schedules, and high-dose chemotherapy. A meta-analysis of long-term outcomes in extensive stage disease did not show consistent evidence for improved response rates or survival for more intense chemotherapy regimens.[41][Level of evidence: 1iiA] 10.72 Recurrent Small Cell Lung Cancer The prognosis for small cell lung carcinoma that has progressed despite chemotherapy is poor. NCI states, These patients should be considered for palliative therapy or clinical trials. Patients who are primarily resistant to chemotherapy and those who have received multiple chemotherapy regimens rarely respond to additional treatment. However, patients who have initially responded and relapsed more than 6 months following initial treatment are more likely to respond to additional chemotherapy. While no single chemotherapy regimen should be considered standard, those that have shown activity as second line treatment include oral etoposide, etoposide/cisplatin, cyclophosphamide/doxorubicin/vincristine (CAV), lomustine/methotrexate, and topotecan.[1-8] Patients with central nervous system recurrences can often obtain palliation of symptoms with radiation therapy and/or additional chemotherapy. The majority of patients treated with radiation therapy obtain objective responses and improvement following radiation therapy.[12] A retrospective review showed that 43% of patients treated with additional chemotherapy at the time of CNS relapse respond to second-line chemotherapy.[13] Treatment options: 1. Palliative radiation therapy.[11] 2. Salvage chemotherapy can provide some palliative benefit for patients previously sensitive to standard chemotherapy.[2,4-8] 3. Local palliation with endobronchial laser therapy, endobronchial stents, and/or brachytherapy.[9,10] 4. Clinical trials of phase I or phase II drugs. Refer to PDQ or to CancerNet (http://cancernet.nci.nih.gov) for information on clinical trials for patients with recurrent small cell lung cancer. Author's Note This chapter is based upon public material supplied by the National Cancer Institute. For updated information visit its website(s) at www.nci.org
10.9 PROPHYLACTIC CRANIAL RADIATION A well-known author on lung cancer notes the prevalence of metastasis to the brain with small cell lung cancer and suggests pre-diagnosis radiation to reduce the effects of metastasis. His letter in the August 12, 1999 issue of the New England Journal of Medicine entitled Prophylactic Cranial Irradiation and Small-Cell Lung Cancer says the following: A Small-cell lung cancer, the type of lung cancer most strongly associated with tobacco exposure, accounts for 20 to 25 percent of all cases of lung cancer (approximately 45,000 new cases per year in the United States). The majority of patients are treated with combination chemotherapy (etoposide and cisplatin) for four to six months, with or without concurrent thoracic irradiation. The median survival for patients who are not treated is only 6 to 12 weeks, whereas for patients treated with combination chemotherapy, the median survival is 10 to 12 months. For patients with extensive disease (disease extending beyond one hemithorax or beyond regional lymph nodes) who are treated with combination chemotherapy, the median survival is only seven to nine months. (1) Limited disease (disease confined to the lung) accounts for 30 to 40 percent of all newly diagnosed cases of small-cell lung cancer. It is now treated with combination chemotherapy and thoracic irradiation of the site of the primary tumor. With this approach, the median survival is 18 months, and up to 25 percent of patients survive for more than 2 years. The use of combination chemotherapy and concurrent thoracic irradiation of the site of the primary tumor in these patients is based on the results of meta-analyses that revealed that chemotherapy plus thoracic irradiation improved the overall two- or three-year rate of survival by 5.4 percent, as compared with chemotherapy alone. (2,3) More recent studies aimed at defining the best method of combining chemotherapy with thoracic irradiation have indicated that twice-daily thoracic irradiation given concurrently with chemotherapy results in two- and five-year survival rates of 44 percent and 22 percent, respectively. (4) These results confirm the importance of both thoracic irradiation and chemotherapy in the treatment of patients with limited small-cell lung cancer. A major cause of morbidity and mortality in patients with small-cell lung cancer is brain metastasis, which in most patients results in multiple tumors. At the time of initial diagnosis, brain metastases can be detected in up to 10 percent of patients, and 1 to 2 percent of these patients have metastases only in the brain. However, among patients who complete chemotherapy, an additional 30 to 70 percent subsequently have clinically apparent brain metastases, and even more have such metastases at autopsy. (5) Moreover, among patients who have a complete remission with chemotherapy, approximately 15 percent have brain metastases as the initial or sole manifestation of recurrence. As the length of survival after diagnosis increases, the risk of metastases to the brain increases. Thus, as chemotherapy with concurrent thoracic irradiation becomes more effective for patients with limited small-cell lung cancer, the frequency of brain metastases later in the course of the disease may continue to rise. For many years, prophylactic cranial irradiation has been used in patients with small-cell lung cancer in the belief that the treatment of microscopic or subclinical metastases would prevent or delay the onset of symptomatic brain metastases, but its efficacy for this purpose has been uncertain. Those who advocate prophylactic cranial irradiation point out that it is a safe way to reduce the overall incidence of brain metastases, even if only a small number of patients benefit. (6,7) Others argue against routine prophylactic cranial irradiation. They point out that the brain is rarely the sole site of recurrence, that radiation can be neurotoxic, and that radiation therapy does not prolong survival. (8,9) In this issue of the Journal, Auperin et al. report the results of a detailed meta-analysis of the efficacy of prophylactic cranial irradiation in 987 patients (847 patients with limited disease and 140 patients with extensive disease) who took part in seven trials and who had complete remission with chemotherapy, with or without thoracic irradiation. (10) Prophylactic cranial irradiation was associated with an absolute decrease of 25.3 percent in the cumulative incidence of brain metastasis at three years, from 58.6 percent in the control group to 33.3 percent in the treatment group. More important, prophylactic cranial irradiation was also associated with an absolute increase in overall survival of 5.4 percent at three years, from 15.3 percent in the control group to 20.7 percent in the treatment group. Prophylactic cranial irradiation was beneficial in patients with either limited or extensive disease. As previously reported in the two largest trials included in the meta-analysis, in which neuropsychological tests were performed on most but not all patients before, during, and after treatment, neurocognitive impairment was often detected at diagnosis, but no deterioration was found after prophylactic cranial irradiation. (6,7) Can we now conclude that prophylactic cranial irradiation should become standard treatment for all patients with small-cell lung cancer who are in complete remission? I think so. This study confirms that there is a small absolute survival advantage for patients who receive prophylactic cranial irradiation. Even though this advantage is small, it is important: early studies of thoracic irradiation in patients with limited-stage small-cell lung cancer revealed no significant trend toward improved survival, but when large numbers of patients were studied, the small absolute survival benefit associated with thoracic irradiation was identified. (2,3) Today, for almost all patients with limited small-cell lung cancer, thoracic irradiation is an integral part of therapy. We still do not know how best to integrate prophylactic cranial irradiation with chemotherapy in patients with small-cell lung cancer. The optimal dose of radiation, volume of tissue to be irradiated, and duration and timing of prophylactic cranial irradiation have not been determined. Also, questions remain regarding the safety and long-term neuropsychological consequences of prophylactic cranial irradiation. The study found a significant survival benefit, but it should be noted that four of the trials included in the meta-analysis had fewer than 100 patients, which suggests that there may have been some selection bias. On the basis of the data presented, it is now reasonable to include prophylactic cranial irradiation as part of the treatment of patients with limited small-cell lung cancer who are in complete remission (usually evident after three or four cycles of chemotherapy) and of patients with extensive disease who have isolated metastases and are in complete remission. To minimize the risk of neurologic damage, prophylactic cranial irradiation should not be administered concurrently with chemotherapy or to elderly patients. As treatment of the primary tumor in patients with small-cell lung cancer improves, brain metastases are likely to become an increasingly frequent manifestation of treatment failure. Thus, studies are needed to define the optimal dose and fractionation schedule for prophylactic cranial irradiation and to determine how best to integrate this therapy with chemotherapy and thoracic irradiation. D. Carney, Prophylactic Cranial Irradiation and Small-Cell Lung Cancer, The New England Journal of Medicine Vol. 341, No. 7 (August 12, 1999)
CHAPTER ELEVEN: CLINICAL TRIALS _________________________________ 11.1 WHAT IS A CLINICAL TRIAL How do we know if a particular form of treatment works? Self-reporting by doctors, hospitals or pharmaceutical companies could be subject to exaggeration or at least inaccuracy. Instead, what is needed is a scientific method of assessing the reliability of certain treatments and comparing them with what is used today. Clinical trials are designed to test new drugs, compare them with existing treatments, and determine if they provide better results, fewer side effects, or other benefits. Before a drug can be approved for use by the FDA, clinical trials must show it has some type of demonstrable positive effect.
11.2 DIFFERENT STAGES OF A CLINICAL TRIAL There are three stages in clinical trials. The stages are progressive, stage one, being a basic test to see if a drug has some effect and to establish the maximum amount which can be given without substantial side effects, stage two, to evaluate the drug and assess its success, usually based upon the maximum allowable does established in stage one, and stage 3, measuring the drug against conventional treatments being used, to see if it provides better or at least comparable benefits.
11.3 STAGE ONE TESTS Stage one is the first step to see if a particular drug or other form of therapy works, and to define a maximum allowable dosage assuming it does. For example, if interleukin has been successful with some forms of cancer, a phase one trial could be used to see if it works by reducing the size of lung tumors. Individuals entering the study would be prescribed interleukin, measurements would be made, and the study authors would attempt to ascertain whether the drug positively impacts patients. In addition to seeing if the drug has some impact, in stage one, the study authors try to define a maximum dose, that is, what amount of the drug can be prescribed without significant side effects. Using Interleukin, we may administer the drug in various doses to see what is the maximum amount which can be tolerated without substantial side effects. Note that a clinical trial can be stopped or modified if a clear pattern emerges. For example, if people given large amounts of Interleukin suffer severe effects, we may decide to reduce the amount to prevent injury. Likewise, if it becomes clear that certain doses of the drug are providing clearly beneficial results, we may change the design so that all patients receive the benefit from the drug. Typically, however, the results are not clear, and conclusions about the drug are made after a phase of the study is completed. Here is how the American Cancer Society describes stage one: A During a phase I trial-the initial investigation of a treatment= s safety and effectiveness in humans- a promising new therapy is tested to learn if it is worthy of further investigation. In the case of a new drug, this is when researchers learn about its effects by gradually increasing the dosage in a step-wise fashion and carefully analyzing the response among the participants. These are preliminary trials in which the researchers learn, for example, how well the drug is absorbed by the body, how much of it reaches the blood stream, and how it is metabolized and eliminated from the body.@ American Cancer Society, Informed Decisions 230 (1997) 11.31 Stage One is Not Designed to Assess the Success of a Drug While we want to see if a drug works in stage one, defining the extent of tumor reduction is not really our purpose. A phase 1 trial might administer a drug in different dosages with response rates depending on the dosage. We would not measure the success or failure at stage one. If we have five different dosages used at stage 1, it is difficult to tell whether the drug works. If we have 18 participants in a stage 1 trial given three different doses of a new drug and in the group given the maximum there are two persons with partial responses, it is somewhat misleading to conclude that the drug has a 33% response rate at its maximum dose. Most scientists would instead call the results in phase 1 A promising@ and proceed to realistically assess the drug at phase 2. 11.32 A Stage One Protocol Here is an example of a description of a phase 1 clinical trial: Phase I Study of Irinotecan and Gemcitabine in Patients With Unresectable or Metastatic Solid Tumors Objectives I. Determine the maximum tolerated dose (MTD) and the principal toxicities of irinotecan and gemcitabine in patients with surgically unresectable or metastatic solid tumors. II. Determine if the principal toxicities and MTD of this combination regimen are affected by drug sequencing in this patient population. III. Determine the potential for gemcitabine to alter the pharmacokinetic characteristics when administered with irinotecan in these patients. IV. Describe the influence effected by varying the administration sequence of this combination regimen in this patient population. V. Obtain preliminary data regarding efficacy of this combination regimen in these patients. Protocol Entry Criteria --Disease Characteristics-Histologically confirmed metastatic or surgically unresectable solid tumor, having received the following maximum number of prior therapies for advanced disease: Bladder cancer - no more than 1 prior therapy Breast cancer - no more than 2 prior therapies... Lung cancer - no more than 1 prior therapy (this clinical trial deals with different forms of cancer, others may be restricted to lung cancer, or even to a particular stage and type of lung cancer) Bidimensionally measurable disease outside a previously irradiated field at least 2 cm x 2 cmNo known bone metastases... Chemotherapy: No prior irinotecan, topotecan, or gemcitabine, Prior adjuvant chemotherapy allowed, if at least 1 year between last dose of adjuvant chemotherapy and recurrence of cancer The study seeks to test two chemotherapy drugs which have shown some prior success in reducing the size of tumors and what is experimental is apparently a unique combination of the two being tested. The study involves a number of different cancers. Patients with some but not extensive chemotherapy are permitted. 11.33 Participation in Phase 1 Tests Some scientists would say that it is overly simplistic to say that phase 3 tests are the safest, phase 2 second, and phase 1 the least safe. What we can say is that by phase 3, a drug has been initially tested for maximum allowable dose, shown some promise in stage 2 in reducing tumors without creating significant side effects, and is now measured against standard treatment in stage 3. No such track record is present for drugs used to phase 1 and they are at least to some extent, an unknown quantity. We are probably unsure of the drug= s efficacy, at the least we do not know the appropriate dose that should be administered. Thus, most physicians would advise caution before entering a phase I trial. While it may be initially appealing to participate in a trial involving an innovative new treatment, the practical reality is that too much remains to be done at stage 1. Only those patients with a poor prognosis who have been told that conventional treatment is unlikely to do any good and who are ineligible for stage 2 and 3 trials would want to participate in a stage 1 assessment. One can note that in a stage 1 trial, the patient will frequently get excellent care and attention from physicians intimately acquainted with the particular disease.
11.3 STAGE 2 TESTS Stage two clinical trials test treatments shown to have promise in stage 1. With hopefully a decent sample size, we now administer the maximum dose and see how the drug performs. In particular with lung cancer, we will assess partial response rate, usually defined as reduction of tumor size by one half, complete response, elimination of the tumor on x-ray or Ct Scan, and survival rate. For example, let us assume that for a drug to be used to treat non-small cell cancer, it should show at least a 20% response rate, that is, at least 20% of the patients= tumors show at least a partial response, without significant side effects, at least as compared with other forms of chemotherapy . The American Cancer Society describes stage two trials this way, A Once researchers confirm the possible value of a drug (or other treatment) and determine the safe dosage and other specifics of administering it, they focus on how effective it is people with one (a particular form of) cancer.... to gather information about how well people are responding, researchers may measure the size of tumors for shrinkage.... The study may also involve monitoring the patient= s blood for substances called tumor markers that often indicate whether their cancers are growing or shrinking.@ American Cancer Society, Informed Decisions 230 (1997) If good results are shown in stage 2, we are now ready for stage 3. We will compare the new drug with the standard treatment used, with patients randomly assigned to either group. Thus, if Interleukin works at stages one and two, we compare its success in a phase 3 trial against, for example, a cisplatin based chemotherapy. Obviously if it is no better than existing treatments, there is no reason for its usage. For example, Gemcitabine may not show significantly better response rates than Cisplatin, but its diminished side effects merit its FDA approval. The stages are progressive, stage one, being a basic test to see if a drug has some effect and to establish the maximum dosage without , if it does appear to work, stage two is designed to refine the dose and assess side-effects, and finally, stage three, measuring the drug against conventional treatments being used. Once a drug shows positive results in stage 3 it is generally ready to be marketed. Here is a description of a phase 2 clinical trial: A In a prior Cancer and Leukemia Group B (CALGB) Phase II trial of patients with advanced, previously untreated mesothelioma, diyhdro-5-azactidine (DHAC) demonstrated a 17% response rate, including 1 complete response, with only mild myelosuppression. This Phase II study (CALGB 9031) was conducted to determine the effectiveness of and toxicities that would result from adding cisplatin to DHAC administered to the same patient population. Overall, 5 objective responses were observed in 29 evaluated patients (objective response rate, 17%.... The major toxicity noted was significant chest/pericardial pain,... (s)ignificant leukopenia was observed in 29% of the patients. The addition of cisplatin to DHAC did not increase the response rate over that observed with DHAC alone in patients with mesothelioma; however, it did increase toxicity, especially leukopenia. This combination is not recommended for further studies involving mesothelioma patients.@ Samuels, et. al, Di-hydro-5-azacytidine and Cisplatin in the Treatment of Malignant Mesothelioma: a phase II study by the Cancer and Leukemia Group B, Cancer, 1998 Apr, 82:9, 1578-84. Let us review the results from this trial: 1) We can infer that there was a phase I clinical trial involving DHAC where the drug was shown to diminish tumor size (partial response) without unwarranted side effects. A phase II trial followed which showed a modest 17% response rate for use of DHAC, and in the trial various doses of DHAC were likely tried. 2) Most physicians use multi-modal chemotherapy, administering various types of anti-cancer drugs to attack the disease in different ways. Cisplatin is a well-known chemotherapy drug which has been shown to have demonstrated ability to reduce tumor size in many trials involving non-small cell lung cancer. Its efficacy in attacking mesothelioma, a rare type of lung cancer, is not known. In this phase II trial, Cisplatin was combined with DHAC, in the hope of improving response rates without creating additional side effects. If the study were successful, a phase III trial would occur, comparing DHAC and Cisplatin against the standard treatment being used, with patients randomly assigned to either group. 3) This Phase 2 trial was not successful. The response rate did not improve upon existing forms of treatment while the rate of side effects did, and the authors concluded that this combination did not warrant further investigation. 4) This appears to be part of an on-going study. The study authors will now have to determine whether the 17% response rate using DHAC alone merits a phase III trial. If other chemotherapy drugs show a response rate of more than 17%, then the drug would presumably not be FDA approved. The study authors may decide to combine DHAC with another drug, or take other action to improve the response rate. These changes would be evaluated in additional phase I or II trials and if successful, compared against the prevailing form of treatment in phase III.
11.4 STAGE THREE Assume that interleukin showed promise in stage 1 with a maximum dosage being determined, in stage 2 there were good results with that dosage, the drug is now ready for stage 3 comparison testing. In stage 3, the drug will be compared with conventional methods of treatment. 11.41 Patients are Divided by type of Cancer and Stage To accurately assess a form of treatment, the participants must be restricted to those with a particular form of disease at a particular stage. Thus non-small cell and small cell trials would almost always be done separately, and usually trials would be restricted to stage. Thus our hypothetical trial could be called, Assessment of the Effect of Interleukin with Chemotherapy versus Chemotherapy Alone in Stage 3 B non-small cell lung cancer patients. Since the study authors, (sometimes with a pharmaceutical company= s assistance) are interested in demonstrating a positive result, they will frequently restrict participation to those in otherwise good health. Thus, a clinical protocol, the summary of how and what will be done, may restrict the trial, and prohibit those with other health problems from participating. If the stage 3 trial shows a positive result, then other trials might be conducted to confirm the results and meet FDA requirements before allowing the product to be marketed tot he public. Sometimes clinical trials will display inconsistent or contradictory results, which is why a series of trial is more reliable than one. For example, an increase in survival in a 20 person clinical trial might be due to one patient doing very well for reasons which could be unrelated to the particular drug tested. A meta-analysis is combining the results of many tests to reach particular conclusions
11.5 SOURCES OF INFORMATION ABOUT PENDING CLINICAL TRIALS An excellent book is Finn, Cancer Clinical Trials (O= Reilly 1999). To learn about pending clinical trials, go on the Internet to the National Cancer Institute (NCI) site: http://CancerTrials.nci.nih.gov/. You may also call the National Cancer Institute's Cancer Information Service and ask for the booklet What Are Clinical Trials All About, or view the videotape "Patient to Patient: Cancer Clinical Trials and You." The Cancer Information Service can be reached by dialing 1-800-4-CANCER (1-800-422-6237). Where there is effective available conventional treatment, it makes sense for the patient to get it, rather than be randomly assigned a form of treatment which may or not be effective. That is why participants in clinical trials are generally limited to those for whom conventional treatment has not been proven effective. Thus, stage 3B and stage 4 lung cancer patients are eligible for clinical trials, because conventional treatment is not usually curative.
11.6 CLINICAL TRIAL TERMINOLOGY Protocol is the written outline of a clinical trial. The patients receives an informed consent document which will provide an abbreviated description, but you can request and obtain the protocol itself. Standard treatment refers to the therapy that is accepted by the medical community and has FDA approval. For example, the forms of treatment set forth in chapters four and five are generally the standard treatments. Placebo is a harmless substance given to members of the control group when the study is attempting to evaluate the benefit of adding a new drug to current treatment. American Cancer Society, Informed Decisions 230 (1997). Control group refers to the people in a clinical trial receiving the standard treatment, and not the experimental treatment. Randomization means the participants are randomly assigned to either an experimental or a control group. In a double-blind study, neither the physicians nor the participant= s know which treatments are administered to whom until the study is completed. This is done to prevent some types of conscious or unconscious bias. In a blind study, the patients are not told whether they are receiving the experimental treatment, but the doctors are informed. 11.71 Placebos are Rarely Used in Cancer Clinical Trials Cancer clinical trials typically do not use placebos unlike other trials for the following reason. These clinical trials typically test a new cancer drug or formulation in phases one and two and measure it against standard treatment in stage 3. The primary measuring point is likely to be tumor reduction and there is usually no place in this framework for the absence of treatment, i.e., a placebo.
11.8 CONSIDERATIONS IN ENTERING CLINICAL TRIALS Occasionally, you will see clinical trials for patients for whom conventual treatment works. There is one clinical trial attempting to assess the efficacy of sampling some lymph nodes versus all lymph nodes in surgical resection. Participation in such clinical trials seems to make little sense from the patient= s perspective. Instead, a clinical trial makes sense when available treatment appears may not to be sufficient. Here are some of the advantages and disadvantages of clinical trials:
ADVANTAGES ! Potentially useful for advanced stage patients for whom conventional treatment does not appear effective, ! Treatment is usually provided in fine medical institutions by specialists who are among the best in their field, ! A feeling of helping others and the medical profession towards a cure for lung cancer,
DISADVANTAGES ! Treatment can be guided by considerations in the clinical protocol. ! Historically, only a small portion of clinical trials in non-small cell lung cancer have had significant results, ! Treatment can sometimes occur in a distant medical center, rather than a local hospital, For advanced stage patients, clinical trials are clearly an option, but must be discussed with the treating oncologist. 11.81 Eligibility and Conflicts. The creators of the clinical trial seek first and foremost to establish that their drug works which is determined by looking at statistics of how the drug performs during the trial. For example, if existing chemotherapy drugs have a 25% partial response, a successful trial would show a 30% reduction. Thus, it is in the interest of the study creators to pick those patients who are most likely to fare well. If we know that those patients were severe existing health problems or generally less likely to respond to new drugs, then the study creators may want to exclude them from the trial. (Note that in a stage 3 trial at least theoretically that would not matter, because we selecting two equivalent groups.). Many trials exclude patients with prior unsuccessful chemotherapy, and those with severe health problems. It is conceivable that some of these people could benefit or at least might want to participate.
CHAPTER 12: ANTI-ANGIOGENESIS DRUGS _________________________________ 12.0 THE DIFFERENT STEPS IN METASTASIS Metastasis remains the most serious danger of lung cancer. While considerable progress has been made in understanding cancer, that has not translated to success in treating metastatic cancer.
12.1 THE BEST SOLUTION TO METASTASIS: EARLY DETECTION Since medical science has been largely ineffective in treating metastatic cancer, the best solution is early detection. Surgically removing the tumor at an early stage usually eliminates the need to address the consequences of a tumor that has spread. Sadly, despite recognizing the difficulties in treating metastatic disease, neither the National Cancer Institute nor the American Cancer Society recommend programs for early detection and diagnosis of lung cancer.
12.2 ANGIOGENESIS 12.21 What is Angiogenesis Angiogenesis is the disturbing ability of cancer cells to form new sources of blood supply to facilitate their expansion into other organs. In 1998, the National Cancer Institute provided this summary: Angiogenesis means the formation of new blood vessels. Angiogenesis is a process controlled by certain chemicals produced in the body. These chemicals stimulate cells to repair damaged blood vessels or form new ones. Other chemicals, called angiogenesis inhibitors, signal the process to stop. Angiogenesis plays an important role in the growth and spread of cancer. New blood vessels "feed" the cancer cells with oxygen and nutrients, allowing these cells to grow, invade nearby tissue, spread to other parts of the body, and form new colonies of cancer cells. Because cancer cannot grow or spread without the formation of new blood vessels, scientists are trying to find ways to stop angiogenesis. They are studying natural and synthetic angiogenesis inhibitors, also called anti-angiogenesis agents, in the hope that these chemicals will prevent the growth of cancer by blocking the formation of new blood vessels. In animal studies, angiogenesis inhibitors have successfully stopped the formation of new blood vessels, causing the cancer to shrink and die. http//cancernet.nci.nih.gov/ 12.22 Angiogenesis can be a Normal Part of Body Regeneration Angiogenesis occurs in healthy individuals, and is part of normal body functions: A Angiogenesis is the term for the growth of new blood vessels in the body. In a healthy body, angiogenesis produces blood vessels to heal wounds and restore blood flow to
tissues after injury. In females, angiogenesis occurs during the monthly reproductive cycle (to rebuild the uterus lining, to mature the egg during ovulation) and during pregnancy (to build the placenta, the circulation between mother and fetus). A healthy body controls blood vessel development through a process of stimulating or inhibiting angiogenesis. Normally, the inhibitors dominate the stimulators so angiogenesis does not occur. When the body loses control over angiogenesis, serious diseases may take over. Excessive angiogenesis is noted in cancer, but also such diseases as diabetic blindness, rheumatoid arthritis, and psoriasis. The new blood vessels feed the diseased tissues and destroy normal tissue because the diseased cells produce abnormal amounts of angiogenic stimulants or growth factors, overwhelming the natural inhibitors. These new blood vessels also allow tumor cells to escape into the circulatory system and find their way to other organs. This migration is known as tumor metastases.@ http://www.biopulse.com/anti-angiogenesis.html A recent article on Medscape, an excellent source of cancer information, says: A Angiogenesis, or neovascularization -- the formation of new capillaries from preexisting blood vessels -- is central to normal development and homeostasis. In the physiologic setting, this proliferative process occurs during embryogenesis (where the growth of new blood vessels derived from angioblasts is termed vasculogenesis), during regular cyclic menstruation, as normal hypertrophic growth of muscle tissue after heavy exercise, and is an important component of repair (nerve regeneration, dermal wound healing, bone growth). In the adult organism, angiogenesis is typically controlled and short-lived, shutting off within a week or two of initiation. However, aberrant induction of angiogenesis, leading to the uncontrolled ingrowth of capillaries, may also occur and plays a major role in the pathogenesis of tumor growth, rheumatoid arthritis, atherosclerosis, chronic inflammatory diseases, and various retinopathies. In this context, angiogenesis appears to be a critical step in the establishment, growth, and metastasis of solid tumors, mediating the transition from an avascular, quiescent state by providing the "harmless" cluster of accumulating cells with essential oxygen and nutrients.@ Gaiso, Anti-Angiogenesis, A New Anticancer Therapy, (medscape Oncology 2 (1) (1999) 12.23 Size and AngioGenesis The Lycos website dealing with lung cancer discusses tumor size and anngiogenesis: A One promising avenue of cancer research is the study of a group of compounds called angiogenesis inhibitors. These are drugs that block angiogenesis, the development of new blood vessels. Solid tumors cannot grow beyond the size of a pinhead (1 to 2 cubic millimeters) without inducing the formation of new blood vessels to supply the nutritional needs of the tumor. By blocking the development of new blood vessels, researchers are hoping to cut off the tumor's supply of oxygen and nutrients, and therefore its continued growth and spread to other parts of the body The National Cancer Institute and its participants have been gracious in placing their research on the Internet. In proceedings from an NCI conference, a speaker explains the angiogenesis process. The process that we are talking about is angiogenesis. As we all know, in order for tumors to grow beyond the size of 2 cubic millimeters in volume, they must develop a vasculature so that, as the tumor cell population grows, the malignant cells secrete angiogenic factors which stimulate nearby vasculature endothelial cells to proliferate and to form tubes and capillaries to promote the continued growth and expansion of the tumor. This new blood vessel formation also allows tumor cells to extravasate into the bloodstream,travel through the bloodstream, establish colonies again at distal sites, and grow metastatic disease and establish a vasculature once again. Teicher, Angiogenesis as a Target for CancerTherapy www.conferencecast.com/webtie/sots/lung/transcripts/teichertran.htm Thus, if this process can be eliminated, or even delayed, the prospect for long-term survival would dramatically increase. Squamous cell and adenocarcinoma are two types of non-small cell lung cancer. Squamous cell tumors frequently have areas of necrosis, or cell death. Statistically, squamous cell patients seem to survive longer than those with adenocarinoma. Thus we can survive that adenocarcinomas may produce chemicals, protein reaction to create angiogenesis more effectively than squamous cell tumors, enabling the adeno tumors to spread.
12.3 WHERE IS METASTASIS LIKELY TO OCCUR 12.31 Proximity to Nearby Organs and Blood Vessels Metastasis is partly explained by geographical proximity: In some instances, this organ preference of metastasis can be explained simply in terms of the anatomical relationship of the organ with the site of the primary tumor growth. Hence, many secondary tumors will develop in those organs which provide the first capillary bed encountered by dispersing metastatic cells, since the tumor cells may be carried as aggregates which pass into a capillary whose lumen is smaller than the clump diamater. A knowledge of the circulatory anataomical associations of the primary tumor site with other organs can typically be used to predict the seeding site of about 60% of the metastases from that tumor. Metastases from colon cancer probably occur with high frequency because the liver receives the drainage of the blood supply to the large intestine. Vile, Cancer Metastasis: From Mechanisms to Therapies10-11 (Wiley 1995) (hereinafter cited as Vile, at ). 12.32 Cellular Connections In other instances, there are specific chemical or other attractants which lead cancer cells to particular parts of the body: Usually when metasases seed at a site which could not be predicted on the basis of circulatory anatomy, it is because the site expresses specific determinants which actively promote the growth of the metastatic cells, thereby providing a favorable soil....
12.4 METASTASIS AND THE IMMUNE RESPONSE 12.41 Highly Metastatic Cancers and the Immune Response Tumors vary in their ability to circumvent individual organ= s immune defenses. Vile states: A Tumor cells must evade the immune response to achieve successful growth and metastases Target organ-associated natural mechanisms are important in the late stage of cancer progression and metastasis formation. A number of reports have shown that some metastatic cell line are more resistant to host immunity... For example the highly metastatic RAW117-H10 lymphoma cell line is more resistant to the cytotoxic activity of spleen-derived mice natural killer (NK) cells than the poorly metastatic parental RAW117-P cell line. Resident Kupffer cells in the liver also show heterogenity in their tumer-killing ability....Poorly understood mechanisms of heterogeneity in the susceptibility of tumors to organ immunity may contribute to the organ preference of metastasis.@ Vile at 60. Thus, the ability of a tumor to metastasize depends upon its cellular type and the ability of the host cells to recognize it as an invader, and successfully attack the intruding cell.
12.5 ANTI-ANGIOGENESIS DRUGS The Lycos website dealing with lung cancer discusses clinical trials with anti-angiogenesis drugs: About 20 angiogenesis inhibitors are currently being tested in human trials. Most are in early phase I or II clinical (human) studies. Three are in phase III testing and the results for one are expected by the end of 1999. (See list of Angiogenesis Inhibitors in Clinical Trials.) Phase I/II trials include a limited number of people to determine the safety, dosage, effectiveness, and side effects of a drug. In phase III trials, hundreds of people around the country are assigned at random to receive either the new treatment or the standard treatment. Background In normal tissue, new blood vessels are formed during tissue growth and repair, and the development of the fetus during pregnancy. In cancerous tissue, tumors cannot grow or spread (metastasize) without the development of new blood vessels. Blood vessels supply tissues with oxygen and nutrients necessary for survival and growth. Endothelial cells, the cells that form the walls of blood vessels, are the source of new blood vessels and have a remarkable ability to divide and migrate. The creation of new blood vessels occurs by a series of sequential steps. An endothelial cell forming the wall of an existing small blood vessel (capillary) becomes activated, secretes enzymes that degrade the extracellular matrix (the surrounding tissue), invades the matrix, and begins dividing. Eventually, strings of new endothelial cells organize into hollow tubes, creating new networks of blood vessels that make tissue growth and repair possible. 12.51 Endothelial Cell Growth The Lycos site, then discusses this cell growth: Most of the time endothelial cells lie dormant. But when needed, short bursts of blood vessel growth occur in localized parts of tissues. New capillary growth is tightly controlled by a finely tuned balance between factors that activate endothelial cell growth and those that inhibit it. About 15 proteins are known to activate endothelial cell growth and movement, including angiogenin, epidermal growth factor, estrogen, fibroblast growth factors (acidic and basic), interleukin 8, prostaglandin E1 and E2, tumor necrosis factor-, vascular endothelial growth factor (VEGF), and granulocyte colony-stimulating factor. Some of the known inhibitors of angiogenesis include angiostatin, endostatin, interferons, interleukin 1 ( and), interleukin 12, retinoic acid, and tissue inhibitor of metalloproteinase-1 and -2. (TIMP-1 and -2).@ Lycos 12.52 Growth Factors At a critical point in the growth of a tumor, the tumor sends out signals to the nearby endothelial cells to activate new blood vessel growth. Two endothelial growth factors, VEGF and basic fibroblast growth factor (bFGF), are expressed by many tumors and seem to be important in sustaining tumor growth. Angiogenesis is also related to metastasis. It is generally true that tumors with higher densities of blood vessels are more likely to metastasize and are correlated with poorer clinical outcomes. Also, the shedding of cells from the primary tumor begins only after the tumor has a full network of blood vessels. In addition,both angiogenesis and metastasis require matrix metalloproteinases, enzymes that break down the surrounding tissue (the extracellular matrix), during blood vessel and tumor invasion. Strategies Of the anti-angiogenesis drugs now in clinical trials, some were designed to target specific molecules involved in new blood vessel formation. For others, the exact mechanism of the drug is not known, but it has been shown to be anti-angiogenic by specific laboratory tests (in the test tube or in animals). In general, four strategies are being used by investigators to design anti-angiogenesis agents: Block the factors that stimulate the formation of blood vessels Use natural inhibitors of angiogenesis Block molecules that allow newly forming blood vessels to invade surrounding tissue Incapacitate newly dividing endothelial cells Standard Chemotherapy Versus Angiogenesis Inhibitors Several differences between standard chemotherapy and anti-angiogenesis therapy result from the fact that angiogenesis inhibitors target dividing endothelial cells rather than tumor cells. Anti-angiogenic drugs are not likely to cause bone marrow suppression, gastrointestinal symptoms, or hair loss -- symptoms characteristic of standard chemotherapy treatments. Also, since anti-angiogenic drugs may not necessarily kill tumors, but rather hold them in check indefinitely, the endpoint of early clinical trials may be different than for standard therapies. Rather than looking only for tumor response, it may be appropriate to evaluate increases in survival and/or time to disease progression. Drug resistance is a major problem with chemotherapy agents. This is because most cancer cells are genetically unstable, are more one to mutations and are therefore likely to produce drug resistant cells. Since angiogenic drugs target normal endothelial cells which are not genetically unstable, drug resistance may not develop. So far, resistance has not been a major problem in long-term animal studies or in clinical trials. Finally, anti-angiogenic therapy may prove useful in combination with therapy directly aimed at tumor cells. Because each therapy is aimed at a different cellular target, the hope is that the combination will prove more effective. Early trials are under way. For further information about clinical trials, refer to the National Cancer Institute's website: http://cancertrials.nci.nih.gov.@ 13.22 Drugs Used for Angiogenesis Set forth below is a chart from the National Institute of Health of angiogenesis drugs and their status as of July, 1998. The chart discusses angiogenesis generally, and does not deal specifically with lung cancer.
ANTI-ANGIONGENESIS RESEARCHDrugs that prevent new blood vessels from invading surrounding tissue: DRUG COMPANY NAME PHASE MECHANISM OF ACTION
British Biotech
Phase III
Marimastat
Annapolis, Md.
Synthetic inhibitor of matrixmetalloproteinases (MMPs)
Bay 12-9566
Bayer
Phase III
Synthetic MMP inhibitor
Phase III
Synthetic MMP inhibitor
Phase I
Synthetic MMP inhibitor
Phase I
Antibiotic derivative
West Haven, Conn. AG3340
Agouron LaJolla, Calif.
CGS27023A
Novartis East Hanover, N.J.
COL-3
Collagenex Pharmaceuticals
that inhibits MMPs
Newtown, Pa. Vitaxin
Ixsys, Inc.
Phase I
Antibody to integrin, present
LaJolla, Calif.
on endothelial cell surface
Natural inhibitors of angiogenesis: Platelet factor-4
Repligen
Phase II
Inhibits endothelial cell
Cambridge, Mass. Interleukin-12
growth
Genetics Institute
Phase I/II
Inhibits endothelial
Cambridge, Mass.
cell growth
Drugs that block factors that stimulate the formation of blood vessels: RhuMabVEGF
SU5416
Genentech
Phase II/III
Monoclonal antibody to
South San Francisco,
vascular endothelial
Calif.
growth factor (VEGF)
Sugen, Inc.
Phase I
Molecule that blocks
Redwood City, Calif.
VEGF receptor signaling
12.51 Practical Difficulties with Anti-Angiogenesis Drugs Teicher discusses some of the theoretical problems with these drugs and the important of timing in the drug administration in animal studies: We then looked at the antiangiogenic combination, starting therapy very early in the life of the tumor on day 4, when the tumor is just a seed and beginning to explode in its angiogenic activity. We are starting the angiogenic agent combination 3 days later on day 7, when the tumor is actually a fairly well-established nodule. The cytotoxic chemotherapy was administered on days 7-11. So we learned a lesson that cancer researchers learn again and again, and that is the tumor burden is very important. If we started the antiangiogenic therapy early on day 4 and treated at days 4-11 or 4-18, we obtained the greatest enhancement in tumor growth delay, but even if we had to limit the antiangiogenic therapy to the same 5-day period that we gave the cytotoxic therapy, we still had tumor growth delay of 29 days, which was better than cytotoxic chemotherapy alone. It was only when we administered the antiangiogenic therapy for the full 2-week period of days 4-18, which is really the full exponential growth phase of this tumor, that we obtained the greatest tumor response and with this therapeutic regimen. Forty to fifty percent of the animals were cured of the Lewis lung carcinoma. Cancer Therapy www.conference-cast.com/webtie/sots/lung/transcripts/teichertran.htm
12.53 Matrix metalloproteinases Inhibitors Instead of trying to kill the cancer cells, one could try to prevent metastasis or spread to other organs. Recall that cancer cells metastasize because they do not have an enclosing shell and acquire the ability to penetrate the shells or basement membranes of normal cells. Matrix metalloproteinases (MMP) such as collagenase, help break down the extracellular matrix which protects other bodily structures. Some drugs are used to inhibit MMP, and thereby to prevent tissue matrix break. We can review some of the recent information about these drugs. However, none have been shown to have proven, clear anti-cancer fighting properties in laboratory experiments and clinical studies. All have a theoretical basis for believing they could be used which are described below. Experimental data indicate that angiogenesis is crucial for growth and persistence of solid tumor and of their metastases. Another agent to display antiangiogenesis properties is suramin . Although suramin has shown, at least in vitro (in cells), to inhibit lung cancer growth (7), clinical studies in NSCLC have yielded negative results. Angiostatin, a component of plasminogen and endostatin, inhibits metastasis by inducing a balance between metastatic and primary tumor cells defined as "dormancy". Both agents are capable of inhibiting tumor growth in vivo in animal models. Although tumors re-grow when anti-angiogenic treatment is discontinued, experimental tumors, remain sensitive to a second cycle of treatment with the same agent. Different from conventional chemotherapeutic agents, no drug-resistance was observed even after multiple repeated cycles of antiangiogenic therapy (9). These agents hold considerable promise for the treatment of a number of tumor types including NSCLC. Other drugs which, in preclinical models, have been found to be angiogenesis inhibitors and that are currently entering clinical trials include TNP-470 (a synthetic fumagillin derivative), thalidomide, vitamin and squalamine. 13.21 National Cancer Institute Discussion of Anti-AngioGenesis References Paget, Distribution of Secondary Growths in Cancer of the Breast, 1889, Lancet 571-73 Vile, Cancer Metastasis: From Mechanisms to Therapies (Wiley & Sons 1995)
CHAPTER THIRTEEN: GENE THERAPIES _______________________________________________ 13.0 GENE THERAPY REMAINS EXPERIMENTAL FOR LUNG CANCER Surgery, radiation, and chemotherapy are the primary forms of treatment for lung cancer. While surgery has been successful with stage 1 tumors, chemotherapy has had limited success with stage 4 metastatic tumors. Therefore, research continues into finding new methods of tumor control and eradication. Gene therapy is a broad category of treatment which attempts to improve immune responses, correct gene abnormalities, and otherwise address the gene malfunctions which are cancer. The American Cancer Society Book, Informed Decisions says this: A Excitement has grown about a fourth approach, one that stimulates the body= s own immune system to recognize, attack, and destroy cancer cells. It= s called biological therapy or biotherapy, because the agents are made from living body cells. Biological therapy began with the discovery of immunization more than 200 years ago. In modern times, research has centered on isolating specific cells of the immune system and their chemical products and manipulating them in the laboratory to target their activity and control their effects.@ Informed Decisions, p. 192. A Introducing genetic material can directly inhibit tumor growth by replacing a damaged tumor-suppresor gene, decreasing the expression of activated or overexpressed dominant oncogenes, or by introduction of an enzymatic activity that confers sensitivity to an otherwise nontoxic drug.@ Lee, et. al., Gene Therapy 323, in Pass, Lung Cancer Principles and Practice (Lippincott 2000). We can say broadly that chemotherapy attempts to eliminate cancer cells, while gene therapy attempts to correct gene malfunction, though there is a significant overlap or question of definition. While gene or biological therapy has shown some success in treating other types of cancer, its use has been limited with lung.
13.2 OBSTACLES IN GENE THERAPY Here are some of the problems researchers have encountered. 13.21 Getting Access to All the Tumor Cells A In all of these studies, it has been difficult to deliver recombinant virus into solid tumors so as to transduce a significant fraction of the tumor cells, and the effect is limited to the injected nodule, which may be of limited clinical benefit.A Lee, et. al., Gene Therapy 325, in Pass, Lung Cancer Principles and Practice (Lippincott 2000). 13.22 Side Effects Anti-angiogenesis gene therapy attempts to frustrate the creation of new blood vessels or the use of existing channels by tumor cells. Recall that angiognesis is in other contexts a normal process used for wound healing and other functions which this therapy may frustrate.
13.3 TYPES OF DRUGS INVOLVED WITH GENE THERAPY 13.31 T Cells and Lymphocytes The most important cells of the immune system are the white blood cells known as lymphocytes. There are two main types of lymphocytes, T cells and B cells. T cells get their name from the fact that they multiply and mature inside the thymus gland in the chest. T cells include the following: C Killer T cells destroy the invader directly. C Lymphokine-producing T cells release proteins called lymphokins, such as the interferons and interleukin 2, which speed up the activity of the immune system, C Helper T cells boost the activity of B cells. C Suppressor T cells slow down the immune response to keep the system from attacking normal cells. C Memory T cells keep a record of the invader encountered, so the next time the body is exposed there will be an efficient response. As you can see, there are various types of T cells. Probably the most important are killer T cells, and much investigation has focused upon activating these killer T cells. 13.32 Interferons Interferons are proteins secreted by immune cells that A interfere@ with a virus= s ability to reproduce and proliferate. In the laboratory, low concentrations of interferon help boost the power of natural killer T cells. With some tumors, interferons can help inhibit the development of the blood vessels that tumors need to metastasize and grow, the process called angiogenesis. Thus, interferon is being investigated for use as an anti-angiogenesis. There are three main types and 17 subtypes of interferon. Drugs like Interferon may be effective with certain types or forms of cancer, but not others. For example, the FDA has found that interferon has a proven benefit in treating a certain form of leukemia, and with other forms of cancer. It is not routinely used for lung cancer, though there may be clinical trials (see chapter 18 for discussion of clinical trials) testing in use with lung cancer. Generally, drugs are approved for specific types of cancer, thus interferon may be routinely used for leukemia, but be classified as experimental for lung cancer, with use for lung cancer limited to clinical trials where there is close supervision and consent forms noting various risks. 13.31 Anti-Tumor Growth Therapy Anti-growth factor therapy can be accomplished through two different strategies. One is to hamper the binding of growth factor to their receptors. The other is to interfere with the signal that occurs after the growth factor has bound to its receptor. See Ardizoni, Drug Therapy of Non-Small Cell Lung Cancer: News from the Lab, Cuneo Lung Cancer Conference. Ardizoni explains, This latter strategy is achieved by inhibiting signal transduction molecules such as tyrosine kinase (PTK) and protein kinase C (PKC). The rationale is that the inhibition of deregulated cellular signaling pathways in malignant cells at the level of PKC or PTK, where multiple mitogenic signals converge, should lead to the inhibition of tumor growth. PKC inhibitors, in addition to reducing tumor growth, are also able to sensitize cancer cells to cytotoxic agents by reverting the MDR phenotype. A series of new drugs with anti-PTK or anti-PKC properties have been recently developed and are close to entering clinical trials in a number tumor types including lung cancer (10). Another enzyme involved in signal transduction which has been targeted for anticancer drug development is farnesyl transferase. Farnesylation is necessary for the association of ras proteins to the cell membrane and therefore for their transforming activity. A number of compounds which are able to interact with Farnesylation of H-ras and K-ras proteins have been developed.... Experiments in human tumor xenograft, including A-549 lung cancer xenografts, have shown almost 90% growth inhibition. Some of these agents are presently undergoing phase I clinical evaluation in a number of tumor types including NSCLC.@ 13.36 Distinguishing Active and Passive Immunotherapy Immunotherapy is therapy designed to trigger an immune response. Nonspecific immunotherapy is designed to trigger some type of general immune response activating a wide range of immune cells. For example, the immune response to tuberculosis also assists in fighting certain types of cancer. A Certain cancer cells contain antigens that appear foreign to your immune system. In some cases, it is possible to remove cancer cells, analyze them in the lab, and identify their antigens. Theoretically, once the antigens are know, a treatment can be designed that stimulates a specific immune response against them. This is called specific active immunotherapy. Results of this approach have been disappointing.@ American Cancer Society, Informed Decisions (1999) 13.4 P-53 GENE THERAPY 13.41 Role of the P-53 Gene P-53 is a tumor suppressor gene. Recall that cancer results from activation of growth proto-oncogenes and inhibition of tumor-suppressor genes such as P-53. Its role is critical: p53 protein...mediates several cellular functions: regulation of the cell division cycle, DNA repair, and programmed cell death. DNA repair, and programmed cell death. In response to various forms of genomic DNA damage... the p53 protein can arrest the cell cycle at the G1 to S transition point, thus affording time for DNA repair and preventing duplication of a mutant cell, or alternatively, failing DNA repair, p53 protein can implement programmed cell death (apoptosis). Accordingly, p53 has been dubbed the A guardian of the genome.@ Etiology of Cancer: Carcinogenesis:http:/edcenter.med.cornell.edu./CUMC_PathNotes/Neoplasia/Neoplasia_04.html. 13.42 Wild and Mutant type P-53 Genes P-53 is a protein of 53 kilodaltons. It is located on chromosome 17 (p13). There are two types of P-53. First, there is normal P-53 also called wild-type P-53. This is P-53 in its normal condition, serving various tumor suppression functions outlined above. Mutant P-53 means the gene has been damaged. Not only will the gene not perform its tumor suppressor function, evidence indicates it plays a role in prompting duplication of cells: A Mutant p53 loses its original function but may acquire a new potentially oncogenic activity. Conversion of p53 protein from a normal to a mutant phenotype alters its histochemical feautres; the half-life of the protein is proloned from 6-20 minutes to several hours. This increases the amount of p53 protein in affected cells,... Detection of excessive amounts of p53 protein is useful as a marker of mutation because the amount of wild-type p53 protein is too low to be detected in nonmutant cells.@ Gemba, Immunohitochemical Detection of Mutant P53 protein in Small Cell Lung Cancer: Relationship to Treatment Outcome, Lung Cancer, vol 29 (1) (2000) pp. 23-31. 13.44 With What Cancers is P-53 Damage Associated P-53 damage occurs in approximately 50% of the following cancers: breast colon, stomach, bladder, and non-small cell lung cancer. A In non-small cell lung cancer (NSCLC), most series report that 50% to 60% of tumors have identifiable mutations.@ Szak, P53 in Pass, Lung Cancer: Principles and Practice (2000). 13.45 P53 and Small Cell Lung Cancer A 1999 study found that 52% of the patient had traces of P53 in bronchial specimens. Gemba, Immunohitochemical Detection of Mutant P53 protein in Small Cell Lung Cancer: Relationship to Treatment Outcome, Lung Cancer, vol 29 (1) (2000) pp. 23-31. P53 presence was unfortunately a negative factor for these patients. A The overall response rate of patients in the p53 -positive group was significantly lower than that in the P53 negative group.@ Gemba, id. However, P53 does not seem to be correlated with other factors such as stage of disease. In another study, bronchial specimens from lung cancer patients @ were used for detection of p53 gene mutation.... 15 of 25 (60%) specimens were found to be positive. In 10 small cell lung cancer specimens, 7 were positive; in 15 non-small lung cancer specimens, 8 were positive. Clinical analysis showed no correlation between positivity and the patients' clinical data such as age, sex, smoking habit, stage of tumor at the time of diagnosis.@ 13.46 Cell Experimentation If this damage to P-53 could be repaired, then tumor spread could be limited and perhaps P-53 could again perform its function of preventing cell duplication. This type of treatment has worked in the laboratory dealing with cancer cells: Reintroducing a wild-type p53 gene into lung cancer cells, including bronchioalveolar lung cancer (BAC), dramatically inhibits tumor cell growth and promotes tumor cell death despite the presence of mutations in multiple other genes. Lee, Gene Therapy, 324 in Pass, Lung Cancer: Prinicples and Practice (2000). A In NSCLC it was initially shown that introduction of a vector containing the wt-53 (wild type) into cell lines, which {had} either a deletion or a missense mutation in p53, markedly reduced cell proliferation and tumorigenecity.@ Fredericksen, Gene Therapy for Lung Cancer, Lung Cancer, Vol. 23 (3) (1999) pp. 191-207. 13.48 Clinical Trials and Other Research on Humans 13.48.1 Presence of P53 Correlated with Survival A Presence of p53 antibodies in sera before of during/after radiation therapy can predict increased survival in patients with non-small cell lung cancer.@ P53 auto-antibodies in non-small cell lung cancer patients can predict increased life expectancy after Radiotherapy,@ Anticancer Res 1998 May-Jun;18(3B):1999-2002. Some limited, promising results have been seen in P-53 clinical trials. Here is one description: A In the protocol, tumor regression was observed in three out of seven patients. In two patients, postreatment biopsies taken 4 weeks after injection with the retrovirus (P53 wild type) showed no evidence of viable tumor.@ However, the patients involved in the trial died, with the inhibition of the tumor apparently too late. Fredericksen, Gene Therapy for Lung Cancer, Lung Cancer, Vol. 23 (3) (1999) pp. 191-207. 13.461 Problems and Hurdles to Successful Treatment It is difficult to repair the gene, the solution being studied is transferring another P-53 gene to the cancer area. Lee writes: The complexities of the three-dimensional structure of the p53 tumor-suppresor gene product and the radical changes in this structure induced by a single point mutation makes it extremely difficult to restore its function with pharmaceuticals. Thus, the basic concept of tumor suppressor gene therapy utilizing p53 is to reintroduce a functionally active copy of the defeicte genes in the cancer cell by direct gene transfer to directly induce cell death by apotosis. Lee, id at 324. Getting enough P-53 to the tumor to have significant results is difficult: A In all of these studies, it has been difficult to deliver reconbitant virus into solid tumors so as to transduce a significant fraction of the tumor cells, and the effect is limited to the injected nodule, which may be of limited real clinical benefit.@ Lee, at 324.
CHAPTER 14: LONG AND SHORT-TERM SURVIVAL _________________________________ 14.0 SURVIVAL AND THE SIGNIFICANCE OF METASTASIS Cancer overall is a serious disease, with lung cancer particularly serious. Why? First, we can say generally that the existence of cancer in the lung itself is usually not a cause of death. Instead, it is the tendency of cancer to metastasize, going through lymph nodes or blood vessels to other organs which generally causes death. The seriousness of a cancer is directly related to its propensity to metastasize. Thus, prostrate cancer usually has a good survival rate because the cancer does not easily move from the prostrate; whereas, pancreatic cancer has a high mortality because the pancreas secretes hormones which are spread throughout the body. Likewise, lung cancer, with a network of lymph nodes and blood vessels going to and from the lung does have an unfortunate tendency to metastasize. Survival with lung cancer is linked to stage which is connected with the tendency to metastasize. A stage one patient with a surgically resected tumor will generally do well, and we have five year survival rates ranging from 55% to 75%. One Japanese study found survival rates approaching 80% for stage one and stage 0 lung cancers. (microscopic tumors only visible on cellular examination). Ideally, when a stage one cancer is surgically resected, there is no more cancer, and nothing to metastasize. Many of the 30-40% of stage 1 patients who have future problems were not really stage 1 patients at all; that is, there were cancer cells within the lymph nodes which could not be seen though available diagnostic tools. As the cancer progresses, the chance of metastasis increases and the probability of long-term survival decreases. There is a direct relationship between stage and long term survival. Let us look at excerpts from American Cancer Society research with all cancers:
ALL STAGES
LOCAL
REGIONAL
DISTANT
Breast
84%
97%
76%
21%
Cervix
69
91
49
9
Lung
14
49
18
2
Pancreas
4
15
5
2
Prostrate
89
100
94
31
TYPE OF CANCER
This chart is based on cases diagnosed from 1986-1993, www.bioscience.org, American Cancer Society Surveillance Research, 1998. Survival rates today are higher, because these statistics are based on cases 7-14 years old. While the absolute numbers will be higher, the basic trend will remain constant. Where we have a stage 4 patient whose cancer has already reached another organ, the prognosis is dim., but not hopeless. With a stage 4 patient, the cancer has already spread, and the physician has the task of preventing further spread and arresting the cancer through chemotherapy, as well as treating the symptoms in the lung and the other organ.
14.1 WHAT TYPES OF SURVIVAL ASSESSMENTS PHYSICIANS CUSTOMARILY MAKE Estimations of survival time generally represent a statistical assessment, not an assessment of a particular patient. We know on an aggregate basis that because stage 3 and 4 patients larger cancer with a greater tendency to metastasis that their probability of survival is decreased. However, in most cases, the doctor cannot venture an entirely accurate prediction as to a particular patient. Thus, if there is a 5 year survival rate for stage 3 patients, the oncologist usually cannot tell whether our patient will be the lucky one for whom chemotherapy will work successfully.
14.2 PREDICTIONS ARE ACCURATE ON AN AGGREGATE, NOT INDIVIDUAL BASIS Within a statistical group are people who live longer and shorter, and the doctor usually has no accurate way of determining the patient's precise period of survival. People with advanced state 4 cancer do have remissions, albeit a small number. The term six months, frequently used, is a somewhat arbitrary number, accurately taking into account the uncertainty of prediction. Some doctors do not like to provide predictions, believing that they could in some way frustrate recovery by decreasing a patient= s will to live, and that the patient may misinterpret an opinion as fact. When a doctor interprets a pathology slide as squamous cell carcinoma, that is a fact, or something very close to it, when he ventures an estimates on survival time, that is really an opinion, albeit an educated opinion. 14.21 Examples of Issues with Small Cell Lung Cancer For example, some estimate that 50% of patients with small cell lung cancer have a complete response to chemotherapy, meaning the tumor disappears. Sadly, the cancer generally reappears. However, the physician cannot accurate predict when or if the cancer will reappear, though he can utilize established diagnostic tools to assess the current status of the cancer.
14.3 STAGE The primary factor in assessing survival is cancer stage. Many questions relating to treatment and status of particular cancers are discussed in chapter 4 (nonsmall cell) and chapter 5, small cell. The Lung Cancer Manual provides five year survival estimates as follows: ! stage IA 60% to 67% (that is, 60 to 67% of people diagnosed stage 1A NSCLC are alive five years after being diagnosed, ! stage 1B 36% to 71% ! stage 2A 34% to 55% ! stage 2B 24% to 39% ! stage 3A 13% to 23% ! stage 3B about 5% ! stage 4 about 1% Alcase, The Lung Cancer Manual 6.2 (1999) (as of the date of this publication available only on-line but at no cost on the Alcase website) With respect to small-cell cancer, the median survival time for patients with limited SCLC is 14 to 30 months. From 10% to 25^% of people diagnosed with limited stage SCLC live five years. With treatment, the median survival time for patients with extensive disease is 8 to 14 months. Only 1% and 5% of people diagnosed with extensive-stage SCLC live five years or more.@ Alcase, The Lung Cancer Manual 7.2 (1999). An informative website on lung cancer presents these survival statistics based upon patients for patients eligible for surgery:
Stage
TNM (Tumor Node Metastasis Staging)
5 Year Survival
1a
T1N0Mo
67%
1b
T2N0Mo
57%
2a
T1N1Mo
55%
2B
T2N1Mo;, T3NoMo
39%
3a
T3N1Mo;T1-3N2Mo
23%
any T,N3, MO;
3b
20 mm. Of the 42 lung cancers < or = 20 mm, 74% (31/42) were located in the well penetrated lung zones and 71% (22/31) of these were missed on CXR. 26% (11/42) were concealed by hilar vessels, mediastinum, heart or diaphragm, and all (11/11) of these were missed on CXR. 93% (39/42) of the lung cancers < or = 20 mm were adenocarcinomas and 79% (31/39) of these were missed on CXR. 7% (3/42) were epidermoid carcinomas or small cell carcinomas and 66% (2/3) of these were missed on CXR. The overall accuracy of interpretation on CXR for lung cancers was 61%, sensitivity was 23% and specificity 96%. Although there was an association between presence of lung cancer and positive reading of CXR (chi 2 test of association, p < 0.05), the percentage of positive readings was only 23%. Thus, CXR was poor at visualizing CT detectable lung cancers of < or = 20 mm diameter, which are usually of very low density, and cannot be relied upon for detection of surgically curable small lung cancer.@ Br J Radiol 2000 Feb;73(866):137-45.
Thus, chest x-ray failed to detect a number of tumors greater than 20 millimeters. More significantly, if failed in detecting smaller, surgically removable tumors, when timely diagnosis could do the most good. Perhaps, a radiologist cannot recommend a CT Scan in every cases referred to him. However, he must recognize that this is a highly imprecise test at best, and using it to base determinations may well cost the patient his life. Where there are smokers, or some type of positive finding on x-ray, Ct Scan should be recommended.
19.6 THE NEED FOR A CLEAR STANDARD AS A WELL TO REDUCE CLAIMS AND SAVE LIVES Both physicians and patients would benefit from a clear standard regarding diagnostic testing. Today, most patients are diagnosed late, after their cancers have spread, presenting serious questions about long-term survival. Since many of these patients saw physicians before they were diagnosed, we live in a litigious society and the patient= s health may have been comprosmised by the delay, inevitably claims will be brought. Compensating the patient and/or his family does not solve the basic problem. Ultiamtely it would reduce claims and benefit physicians were a clear standard enunciated. Thus, if the American Cancer Society determined that CT Scans were warranted for patient with a heavy smoking history, say 30 pack years (packs per day smoked x years smoked), that would establish a benchmark. Doctors could presceibe Ct Scans for such persons at risk, and a clear demarcation would reduce the incidence of claims. References 1. Hamer, Medical malpractice in diagnostic radiology: claims, compensation and patient injury,Radiology, 1987 Jul;164(1):263-6
CHAPTER TWENTY: HEALTH INSURANCE ISSUES ______________________________________ 20.1 A HEALTH INSURANCE POLICY IS A CONTRACT Under American law, two parties can agree to pay for a service or enter into any other contract. Under extreme circumstance, an agreement can be said to be so unfair as to be unconscionable, or be unenforceable because it involves illegal conduct or conduct which offends public policy. However, in most contract cases including those involving health insurance, the court's task is to determine what was intended, first by looking at the written agreement. A It is the duty of the courts to enforce an insurance policy as it is written, and the courts are not at liberty to rewrite policies of insurance to provide coverage where no coverage was intended. Likewise, we are not at liberty to rewrite an insurance policy simply because we do not favor its terms or because its provisions produce harsh results. In the absence of fraud, overreaching or unconscionability, the courts must give effect to an insurance policy if its language is clear and its intent certain. A Black v. Aetna Ins.. Co., 909 S.W.2d 1, 3 (Tenn. App. 1995 Thus, the first task for any patient or family member is to assemble the relevant papers and to review what the health care agreement provides. The chief areas of dispute are as follow 1) is the treatment medically necessary and therefore should the health care provider be required to pay for it, 2) may the patient choose a hospital or physician,
20.2 WHAT IS MEDICALLY NECESSARY The health care policy typically states that the provider will reimburse for what is medically necessary. 20.21 Consider and Evaluate what the HMO says, though you do not have to accept It In many cases, HMO's act unreasonably and for their own financial interests. Sometimes however, a patient may fail to understand medicine or the nature of the HMO. Initially, the HMO does not have to refer you to the physician or hospital that you would like or prefer. The very nature of the HMO is to achieve cost savings through negotiation and centralization of certain tasks. Thus, if the HMO has retained qualified hospital A to provide certain treatment, you may not simply opt for hospital B because you like it better, (or you may be called upon to pay additional costs for B) . You do have a right to select a hospital, or more accurately participate in the selection process, if the particular physician or hospital is not as well-equipped to perform a task as your own. Thus you would need to demonstrate their selection's lack of, at least lesser qualification as compared with your choice. 20.22 Some examples, Defining what is Medically Necessary Let us look at three examples of HMO problems, noting that the approach to each will be different: 1)John Smith has stage 4 lung cancer. The doctor has prescribed an FDA approved medication to relieve pain which while effective is very expensive. The HMO has delayed for several days providing the appropriate approvals. 2) After being given a negative prognosis from the treating oncologist, the Smith family decides that the approach which has the best chance of cure is an innovative approach being taken by a physician located in Los Cacos, Mexico. There are reports on the Internet and in some newspapers of success though the procedure is not FDA approved. 3) United States physician have experimented with a bone marrow transplant for terminal lung cancer patients. The FDA has allowed the procedure for limited use. The HMO refused to provide payment for the procedure. The HMO= s delay in 1 is clearly wrong and unlawful; its refusal to approve 2 is clearly correct and lawful, and it is probably wrong in 3. Regarding 1, there have been reports of HMO= s delaying pain medication for cancer patients, figuring the cost is substantial while the long term benefits are minimal. However, no patient should suffer. If you have a family member in that situation, you should contact the HMO orally, follow up with a supervisor, send a letter, send a letter by express mail, contact an attorney, have him file a complaint, file a complaint with the insurance board of your state, have the attorney seek an injunction for the care. If your family member is in pain and you even suspect delay for financial reasons, do all these steps quickly, hopefully within 72 hours. Let them know you are looking at a substantial lawsuit if proper treatment is not provided. In 2 there is little you can do, no HMO will (or perhaps should) approve an unusual procedure in a foreign land. If you decide on that course, you will be responsible for your own costs. Regarding 3, the approach may be similar to 1 with an exception. In 1, the HMO was simply delaying; here, the HMO= s position has some validity because the procedure is experimental. You can and should push the HMO, but if you go to court, you will need to gather medical studies and other information to establish that this course is the medically appropriate one.
20.3 BE ASSERTIVE Assuming the HMO is acting unreasonably, as a lawyer, one sees a somewhat strange phenomenon in how people approach the legal system. You may see a client send four letters and file a formal complaint over damage to a $121.00 dress. In a divorce, two combatants may spend hours arguing over the disposition of a piece of furniture or a lamp. Yet sometimes people with real concerns, and family members of those with cancer are strangely passive. Certainly, if you believe a particular type of treatment is necessary, you should be aggressive in demanding . . Documents your concerns in a letter. 20.31 Make Sure that Necessary Papers Have, In Fact, Been Submitted by Your Physician In some cases HMO= s delay things, but in others their requests for information or supporting documentation are ignored. Certainly it is irritating for a well-regarded oncologist to spend hours each week justifying a decision he made to a junior clerk at an HMO, but it must be done. In for example 1 above, an expensive pain-reliever, an HMO auditor may ask why a lessexpensive drug could not be substituted, and ask the doctor as a participating physician to provide information supporting his decision. Generally, the doctor must provide information reasonably requested an pertinent to the treatment decision. As a patient, you may need to check that your anger is properly directed towards the HMO, and not a doctor who neglected to supply information the HMO requested.
20.4 ITEMS TO INCLUDE IN AN HMO LETTER Assuming you believe the HMO is at fault, a letter to them should outline the following: 1) the treatment which is needed, and has been rejected, 2) the medical justification for the treatment, attaching your physician letter of explanation, and any medical studies or other data you have located, 3) a statement that the plan member will suffer severe and irreparable physical injury as a result of the delay in treatment, and noting that such injury may have already occurred because of the HMO's delay, 4) noting that you are contacting an attorney to institute legal action as a result of the HMO's willful and deliberate disregard of the patient's health and well-being, and expect to institute legal action against the responsible individuals as well as the plan itself. Consider placing particular responsibility upon the particular person who rejected the treatment. You should fight, and in most cases you will win. From an health insurer's point of view, they may want to limit certain types of health care costs, but will alter their position if the possibility of legal or other exposure exists. There have been several large verdicts against HMO's.
20.5 WHOM TO CONTACT WHEN YOU HAVE AN HMO PROBLEM If an HMO fails to authorize treatment which you believe is medically justified, you could write to the following: 1) the HMO case manager, 2) his or her supervisor, 3) the state insurance commission who deals with health care issues, 4) the central office of the health insurer, 5) members of the board of directors of the HMO, 6) your local newspaper or radio station. 7) state assemblyman or representative, 8) an Internet website dealing with this issue, Generally form letters and copies receive less attention than the original. If you want action, address your correspondence to each of the above. Letters should be direct but brief. No letter should be longer than a page, but do include some brief documentation supporting your position. 20.6 LEGAL ACTION If an HMO refuses to authorize necessary treatment, you can contact an attorney to file a lawsuit. A lawsuit or claim is initiated by filing a complaint with the court which identified the litigants, what the defendant has done wrong and why, and how the plaintiff has or will be injured by that wrong. While it is preferable to have an attorney representing you, set forth below is a form of complaint designed for use by an individual representing himself. ROBERT PATIENT SUPERIOR COURT OF NEW JERSEY ESSEX COUNTY - LAW DIVISION Plaintiff vs Civil Action INSURANCE COMPANY, COMPLAINT AND JURY DEMAND Docket No. Defendant COUNT ONE (BREACH OF CONTRACT) 1. Plaintiff resides at 43 Spring Street, Maplewood, New Jersey. Defendant is a health maintenance organization licensed by the State of New Jersey, with offices at 40 Broad Street, Newark, New Jersey. 2. Under a contract with the Defendant, Plaintiff is entitled to medical and hospital treatment with the costs of such services to be paid by the HMO. 3. Plaintiff has lung cancer. Only July 23, 1999, Plaintiff's physician recommended hospitalization to provide relief from pain associated with plaintiff's cancer. Such recommendation was reasonable and necessary for treatment of Plaintiff's condition. 4. Defendant HMO has failed to approve reimbursement to the appropriate medical and hospital providers for such treatment despite oral and written requests from Plaintiff and his physician. 5. As a result, Plaintiff has been denied medically necessary treatment. More particularly, as a result, Plaintiff has suffered substantial pain and his medical condition has deteriorated as a result of the defendant HMO'S willful and deliberate refusal to perform its contractual obligations. 6. Plaintiff believes and therefore alleges, that defendant has constructed procedures to deprive plaintiff and others of the medical treatment to which they are entitled for the purpose of reducing its costs. Furthermore, Defendant HMO has concealed and misstated its reasons for denying treatment to delay and frustrate Plaintiff and his physicians from arranging for required medical services. The above conduct violates the terms of the Plaintiff's insurance contract, insurance statutes and other applicable law. WHEREAS, Plaintiff demands judgment against Defendant for compensation damages, punitive damages, and injunction requiring Defendant to perform its contract and restraining it from further violating applicable insurance claims. JURY DEMAND Plaintiff requests a trial by jury. Dated: July 5, 2000 ___________________________________ Robert Patient 20.71 Comment on the Form Complaint This is based on New Jersey practice; practices vary from state to state. Generally, what a complaint does is explain who the Plaintiff and Defendant are where they are located, what the Defendant did wrong, how the Plaintiff was injured by the Defendant's acts, and what Plaintiff is seeking. File the complaint with the court with the necessary filing fee, get a docket number or a copy of the complaint marked "filed", and serve that complaint on the Defendant. You can ask a local process-server or subpoena service to serve or hand deliver the complaint to the HMO. You may wish to send the accompanying Letter to the Defendant Enclosed please find a copy of the complaint which I have filed with the Superior Court. I confirm that as of this date, you have not authorized the treatment which I need. If this changes, please immediately call me and my physicians. If you have any questions regarding this Complaint, you may call me directly at 973-467-8040 though I may be retaining counsel shortly.
CHAPTER 21: ASBESTOS, SILICA AND OTHER OCCUPATIONAL CLAIMS ___________________________________ 21.1 WHY SOME LUNG CANCER VICTIMS MAY BE ENTITLED TO COMPENSATION Exposure to dangerous dusts in the workplace is the second leading cause of lung cancer after smoking. These dusts include silica in its many and varied forms, asbestos, and other carcinogens. Because the cellular changes comprising cancer occur slowly, exposures to dusts of ten and 20 years before may be key in the legal assessment of a claim, and make many victims unaware of their right to compensation. 21.2 WHAT TYPES OF LEGAL CLAIMS MAY BE BROUGHT There are two basic claims, a worker's compensation claim which is usually covered by the employer worker's compensation insurance, and a claim against the manufacturer of dusts or chemicals to which the employee can demonstrate exposure. Many courts require proof that the exposure was regular and proximate.
21.3 THE LEGAL BASIS FOR THE CLAIM 21.31 Asbestos and Silica Negligence and Product Liability Claims We have two types of claims: negligence and products liability. Negligence is the failure to that care which a prudent person would have used in similar circumstances. In asbestos claims, the plaintiff argues that there was ample evidence of the dangers of asbestos which were disregarded by the manufacturer and/or distributor of the product. The manufacturer should have placed appropriate warnings, suggested regular pulmonary examinations, encapsulated the asbestos so that it would not become airborne, reduced the concentration of asbestos, or utilized available substitutes. A products liability claims suggests that the product was unsafe and is therefore responsible for any resultant injuries. Silicosis was known as a serious disease from the early 30's, and manufacturers failed to provide warnings, recommend wet methods to reduce dust, use inorganic silica instead of the more toxic crystalline silica, and recommend bi-yearly medical testing. 21.4 ASBESTOS EXPOSURE "The word asbestos refers to a group of naturally occurring mineral silicates. Although different in chemical composition and physical properties, they share characteristics of heat and chemical resistance. Asbestos has been used for multiple purposes including textiles, asbestos cement, thermal insulation, building materials, and friction products such as brake linings. There have been hundreds of commercial applications of asbestos since the expansion of this industry began in the late 1800's." Aisner, et. al., Comprehensive Textbook of Thoracic Oncology (Williams & Wilkins 1996). Asbestos is associated with lung cancer, and with asbestosis, a particular type of lung disease involving a reducing in breathing capacity. These occupations may have had significant exposure to asbestos and other dusts: ! Pipefitters, steam fitters, insulators, and boilermakers ! Construction, carpenters, plumbers, sheet metal workers, ! Maintenance men, custodians, steam fitters, ! Brake mechanics. These are the considerations a lawyer world use in evaluating a claim: * Was there substantial exposure to asbestos. For example, an insulator removing asbestos, or a brake mechanic would have substantial exposure; in contrast someone with minor bystander exposure has a tough time arguing asbestos was a causative factor in the disease, * Is there accompanying asbestosis or other asbestos disease such as pleural plagues, indicating asbestos fibers penetrated the lung * Was the plaintiff a heavy smoker so that smoking can be regarded as the causative agent, * Have there been other claims regarding the particular worksite, * Does any pathology of the lung tissue indicate the presence of asbestos fibers. If you are considering such a claim, you should consult a qualified attorney to evaluate it. The author of this book handles such claims in New Jersey as do other attorneys. 21.5 DIET AND LUNG CANCER Low fruit and vegetable intake has been associated with lung cancer. European Consensus Statement on Lung Cancer: Risk Factors and Prevention Cancer J. Clin 1998, 48, 167. However, advanced intake of products like Beta-Carotene have not been demonstrated to inhibit or hinder tumors which have already developed. 21.6 FAMILY HISTORY We know that many smokers never contract lung cancer, even after heavy exposure. It is clear that a combination of genetic malfunctions must occur for lung cancer to occur, which explains why there is a latency, or time-gap, between the first time of exposure to a carcinogenc and the date a cancer is diagnosed. A family history indicating some type of gene malfunction may predispose an individual to lung cancer. Those with such a history should particularly avoid smoking and occupational exposures, as well as arrange for frequent screenings.
CHAPTER 22: RESOURCE SOURCES _______________________________ 22.0 RESEARCH INTRODUCTION AND OVERVIEW Hopefully this book has provided substantial information about lung cancer. Here are some ways to proceed to obtain further information. You generally should proceed in the following manner in reading and research: 1) Read a general text on cancer such as American Cancer Society, Informed Decisions (1997) (Some other good books are listed below). If you are comfortable that you understand the material in that book (or this one), go to step two. Otherwise, re-read the book until you find that you have a solid understanding of the basic precepts and terminology used in discussing cancer. Keep a medical dictionary with you if you have questions. 2) Go to a specialized medical text on cancer such as Devita, Principles and Practice of Oncology. Or read articles in a medical journal such as Lung Cancer. 3) Go online to Medline (www.healthgate.com) or Oncolink and run a search on the specific type of cancer, treatment question, or other issue. 4) Try to do as much of 1-4 as possible, and then review the results with your physician. The goal is not to impress him with your knowledge or contradict his recommendations based on a short research session. Instead like the student who has diligently studies the homework, by doing so, you can better take advantage of his knowledge and ask intelligent questions that reflect your acquaintance with the subject matter.
22.1 BOOKS There are a number of excellent books on lung cancer. Medical books are available for purchase from the publishers or sometimes from an online bookseller such as Amazon. Most of the books should be available for review at a medical library General Books on Cancer 1. Buchman, What You Really Need to Know About Cancer (Johns Hopkins Press ) an excellent overview of the cancer process, but not specifically devoted to lung cancer. Read this first, and then try to specialized medical books. 2. Coleman, Understanding Cancer (Johns Hopkins Press, 1997) an excellent book which explains medical terms in easy to understand language. Read this book, and What you Really need to Know about Cancer, and try the specialized medical books. 3. American Cancer Society Informed Decisions, The Complete Book of Cancer Diagnosis, Treatment, and Recovery (Viking Press 1997) SPECIALIZED MEDICAL BOOKS ON LUNG CANCER 1. Lung Cancer Manual, by Alcase, available on-line as of this date. 2. Lung Cancer by Lippincott Medical Publishers, an excellent, but detailed examination of lung cancer, designed for medical professionals 3. Aisner, Comprehensive Textbook of Thoracic Oncology (Lippincott, 1996) A book designed for medical professionals, but tremendously useful and detailed 4. Devita, Cancer, Principles and Practice of Oncology ( The leading source of cancer overall, designed for physicians, this comprehensive text covers everything you would need to know, but the reading is not always easy. 5. Carney, Lung Cancer (1995), published in Great Britain, and distributed in the United States by Little Brown & Co. 22.2 PLACES TO GET BOOKS AND OTHER INFORMATION Many hospitals and medical schools have detailed libraries which are open to the general public for reading. Occasionally, you may need an introductory letter from your local library to use another library. Generally you cannot take out books from another library but your own library may be able to arrange to borrow the book for you. Amazon.com, and Barnes &
Noble.com have extensive lists of books including those in specialized areas available for purchase. 22.3 ON-LINE SOURCES- THE COMPREHENSIVE MEDLINE INTERNATIONAL FREE DATABASE. Information is also available on-line, through the Internet. The premier search device for information about lung cancer and other medical subjects is Medline. The service is free and available on the Internet. A number of different companies offer free Medline courtesy of the National Library of Medicine including www.healthgate.com. Medline is the search engine to use for specific information about a new form of treatment or a particular area of medicine. Medline will give a list of medical abstracts of articles from the last 20 years. Here is the description of Medline furnished by the National Library of Medicine. ! Medline is the National Library of Medicine's (NLM) premier bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the health care system, and the preclinical sciences. ! It contains bibliographic citations (e.g., authors, title, and journal reference) and author abstracts from over 3,900 biomedical journals published in the United States and 70 foreign countries during the current four years and contains over 9 million records dating back to 1966. ! Has worldwide coverage, but 88% of the citations in current MEDLINE are to English-language sources and 76% have English abstracts. ! Contains the citations that appear in Index Medicus, as well as the citations of "special list" journals. Special list journals include those indexed for the Index to Dental Literature and the International Nursing Index. Citations for MEDLINE are created by the National Library of Medicine, International MEDLARS partners, and cooperating professional organizations. ! An English abstract, if published with the article, is included in MEDLINE. ! Approximately 33,000 new citations are added each month (about 7,300 weekly; 350,000 - 400,000 yearly). 22.31 Medline Subject Headings and MeSH Vocabulary The MeSH Vocabulary is the biomedical subject headings, subheadings, and supplementary chemical terms used in indexing and searching MEDLINE as well as many other databases in the MEDLARS system. Indexers always use the most specific MeSH term(s) available to describe the subject content of an article. Lonesome Doc(r) - Obtaining the Full Text of a Medical Article Online The Lonesome Doc feature of PubMed and Internet Grateful Med allows you to place an order electronically for the full-text of articles you select from the references retrieved in your searches. Delivery is made available by a medical library in your region with which you set up an agreement for this service; a local charge may apply. " 22.33 Sample MEDLINE Record Here is what a sample Medline record dealing with heart disease would look like. TITLE: Screening for cardiac disease in patients having noncardiac surgery [comment] [see comments] AUTHOR: Fleisher LA; Eagle KA AUTHOR AFFILIATION: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. SOURCE: Ann Intern Med 1996 Apr 15;124(8):767-72 CITATION IDS: PMID: 8633839 UI: 96213860 COMMENT: Comment on: Ann Intern Med 1996 Apr 15;124(8):763-6 ABSTRACT: The preoperative evaluation of the cardiac patient having noncardiac surgery offers an opportunity to identify occult and further define known cardiovascular disease to modify both perioperative and long-term care. The baseline probability of cardiovascular disease should initially be assessed using clinical variables and identifying unstable symptoms, including unstable angina and congestive heart failure. The decision about whether to obtain noninvasive testing to further define cardiovascular status should be made on the basis of the testing's potential to modify perioperative care, the prior probability of advanced coronary disease based on clinical history, and the magnitude of the surgical procedure.
Noninvasive testing is best done in selected patients who are at moderate clinical risk. Otherwise, testing loses its predictive value because of a high incidence of false-negative and false-positive results. Quantitative imaging can also be used to identify those patients in whom coronary angiography is indicated. The value of coronary revascularization before noncardiac surgery has not been studied in a randomized prospective manner, but several cohort studies have suggested that patients who survive coronary artery bypass grafting have decreased risk during subsequent noncardiac surgery. Given the potential short-term increase in morbidity from two surgical procedures, it is prudent to reserve coronary revascularization before noncardiac surgery for those patients in whom it is associated with improved long-term survival. If coronary revascularization is reserved for these patients, then the overall evaluation should prove cost- effective from the perspective of both perioperative and long-term cardiovascular care. MAIN MESH HEADINGS: Coronary Disease/complications, Surgical Procedures, Operative ADDITIONAL MESH HEADINGS: Heart Function Tests Human Postoperative complications/prevention & control Preoperative Care, Risk Factors Support, Non-U.S. Gov. PUBLICATION TYPES: COMMENT JOURNAL ARTICLE REVIEW REVIEW, TUTORIAL 22.21 Oncolink Another good source of information on-line is Oncolink, a cancer database operated by the University of Pennsylvania. 22.3 Support and Information Groups on the Internet There is an excellent group on line where people exchange experiences about cancer and you may request information from other lung cancer survivors and persons with similar diseases. See alt.support cancer. Participants discuss treatment, family and psychological issues. America Online calls these groups news groups while the term usenet groups is occasionally used by other search devices. 22.4 MEDICAL JOURNALS DEALING WITH LUNG CANCER You can obtain relevant medical articles through your Medline search. However, you may wish to order or review the many medical journals which deal with cancer. Recognize that some of the material may be technical, but you have the opportunity to obtain detailed information on critical issues at your local medical or hospital library. The International Association for the Study of Lung Cancer prepares a journal called lung cancer which is published by Elsevier Publishing Co. There are other journals which deal generally with lung cancer. American Journal of Respiratory and Critical Care Medicine (from the American Thoracic Society Annals of Thoracic (chest) SurgeryCA Cancer Journal for Clinicians (published by the American Cancer Society) A peer-reviewed journal for physicians. An article which is peer-reviewed generally will have greater credibility and impact than one which is not. Cancer (also published by the American Cancer Society) (published detailed information about cancer cause and treatments). Cancer Control, Journal of the Moffit Cancer Center 22.5 ORGANIZATIONS DEALING WITH LUNG CANCER 22.51 International Association for the Study of Lung Cancer (IASLC) Founded in 1972, IASLC is an international organization of 1150 members in 53 countries. The purpose of the Association is to promote the study of the etiology, the epidemiology, the prevention, the diagnosis, the treatment, and all other aspects of lung cancer and to disseminate information about lung cancer to the members of the Association, to the medical community at large, and to the public. As noted, they publish a journal devoted exclusive to lung cancer, which while somewhat in nature, is wothwhile reading to learn about new development in this area. 22.52 ALCASE A group called Alcase, (Alliance Against Lung Cancer) has been active in promoting early detection programs, and increasing funding for lung cancer. They have excellent materials and are accessible on the web. 22.6 WEBSITES DEALING WITH LUNG CANCER Below is a list of sites available online. Since Webaddresses sometimes change, we have not attempted to list them; instead simply type in these keywords onto a directory like Yahoo and you should be able to locate the site and related information. . UNITED STATES ORGANIZATIONS DEVOTED TO LUNG CANCER 1. Alliance for Lung Cancer Advocacy, Support, and Education (ALCASE) - is the leading lung cancer advocacy group. Started by lung cancer survivor Peggy McCarthy, the organization is a vigorous advocate for early detection of lung cancer and prepared an including an excellent lung cancer manual, available online at www.alcase.com WORLD ORGANIZATIONS AND SITES DEVOTED TO LUNG CANCER 1. Cuneo Lung Cancer Study Group . The Group describes itself this way: In 1983, a group of chest physicians decided to devote their professional interest to the study of lung cancer. The group, who later became known as "Cuneo Lung Cancer Study Group," is still active at the "A. Carle Hospital of Chest Diseases", in the city of Cuneo, Italy. The "A. Carle" hospital, currently named "S. Croce and Carle" hospital, was then designated as Hospital of National Importance, and serves the whole Cuneo Province as 2nd Referral Institution. Among the prime acts of the Group, the creation of a clinical database for patients with carcinoma of the lung. Its website, www.culcasg.org. contains the complete text of recent studies from the group, presentations at its annual conference, and other important information. It was one of the first groups to seriously discuss, some say advocate, programs for early detection of lung cancer. 2. The International Association for the Study of Lung Cancer or IASLC prepare , the journal Lung Cancer, the only scientific journal devoted solely to lung cancer. In addition, they organize conferences on lung cancer. 1998 world lung cancer conference. European Lung Cancer Working Party contains presentations from the September, 1999 conference, recent about recent developments in chemotherapy, and comparison of the effectiveness of different chemotherapy drugs.
ONLINE DIRECTORIES OR SEARCHING TOOLS OncoLink - Lung Cancer The excellent cancer database oncolink which contains over 100,000 pages, sources, and materials. CancerLit: Thoracic Cancers (National Cancer Institute) On-line abstracts for health professionals. Sorted by month and year for Small Cell lung Cancer, Mesothelioma, Medline: The world medical databases containing over 500,000 articles about cancer and other subjects. UNITED STATES HOSPITAL WEBPAGES Lung Cancer Information from Memorial Sloan-Kettering Information about different types of cancers from one of the United States' leading cancer centers Roswell Park Cancer Institute - cancer, breast, ovarian, bone, prostate, lung, lymphoma, pediatric cancer, skin cancer, colon/rectal, cancer treatment and diagnosis, research, education. Lung Tumors: A Multi disciplinary Database - multimedia textbook illustrating the diagnosis and treatment of lung cancer. Lung Cancer Online - information and resources for patients and families. Lung Cancer Information Center - contains information for health professionals and patients on diagnosis, staging and treatment of various forms of lung cancer. PATHOLOGY, TYPES OF CANCERS Lung Tumors: A Multidisciplinary Database Lung Tumors Database from The Virtual Hospital, material on pathology. CANCER AND LUNG ORGANIZATIONS American Lung Association Cuneo Lung Cancer Study Group - Studio e la Ricerca Clinica contro il
CLINICAL TRIALS, NON-SMALL CELL LUNG CANCER PDQ Clinical Trials List: Non-small cell lung cancer (CancerNet, USA) Information for Health Professionals SCREENING AND EARLY DETECTION PROGRAMS Lung Check Inc. A commercial laboratory specializing in early lung cancer detection and prevention. The site contains excellent information about lung cancer screening and early detection programs. Lungcheck provides an inexpensive but effective way for smokers and others at risk to detect lung cancer in its early and treatable stages. SMOKING PREVENTION ISSUES Cigarette Advertising and Children - Information sheet (Cancer Society of New Zealand) . Summary of how children are affected by cigarette advertising. Early Age at Smoking Initiation and Tobacco Carcinogen DNA Damage in the Lung (Wiencke JK, Thurston SW, Kelsey KT, et al. Journal of the National Cancer Institute, Vol. 91, 614-619, 1999) Great American Smoke Out (American Cancer Society) Lung Cancer and Cigarette Smoking Web Page by Frederic W. Grannis Jr. M.D. Thoracic surgeon at leading California hospital discusses f diagnosing and treating lung cancer. Office on Smoking and Health - Tobacco Information and Prevention Sourcepage (Center for Disease Control, USA) Extensive cigarettes links. Parenting Smoke free Children (Cancer Society) Parts of the attached were excerpted from the University of New Castle page, Guide to Cancer. To go to that informative webpage, University of New Castle To obtain an updated list of lung cancer links, and simply link to the sites on-line, go to the author= s website, www lungcancerclaims.com
CHAPTER TWENTY THREE EVALUATING YOUR HOSPITAL _________________________________ 23.1 AN OVERVIEW There are contrasting views about the importance of a particular hospital. One book notes, "There are no studies that compare the quality of chemotherapy treatments across the board between cancer centers and local facilities. But there was a reassuring study that compared the results of the Eastern Cooperative Oncology Group consisting of university hospitals or major treatment centers with 100 affiliates consisting of small community hospitals and private-practice groups of physicians. The study involved ninety-seven randomized trials and 4,506 patients. The authors of the report of the study, published in May 6, 1982, issue of the New England Journal of Medicine, wrote that "over a wide spectrum of studies and sites, the survival, response, toxicity, and data quality were the same in affiliates as in major treatment centers." However, another study found that mortality rates in some forms of cancer surgery were related to the surgeons experience with that particular type of surgery. However, U.S. News and World Report along with other groups evaluate hospitals. Given the complexity of cancer treatment, it is reasonable to assume there will be some difference based upon the physician and hospital's skill, training, and experience. The ratings are included in the index. Some comments. 23.11 Leading Hospitals The two highest ranked hospitals were M.D. Anderson in Texas and Sloan Kettering in New York City. Other highly-ranked hospitals included the Mayo Clinic in Minnesota.
CHAPTER 24 SMOKING CESSATION PROGRAMS _________________________________ 24.1 WHY TALK ABOUT SMOKING One might conclude that a discussion about smoking is superfluous in a book about lung cancer, since the readers or their families have already contracted the disease. However, it would be important even for this group to quit smoking. The same disease process which created the initial tumor could theoretically create further tumors with further exposure to carcinogenic smoke. Surgery cannot be performed if breathing function is severely impaired and smoking has the capacity to further damage the lung even where it does not create tumors. Further, since smoking plays such a central role in lung cancer, one must discuss smoking and prevention to discuss the disease. Discussing lung cancer requires a discussion of its chief cause. Indeed, some with lung cancer will be the most vigorous advocates of educational programs, and will want to teach others how to avoid what they have endured.
24.2 STATISTICS ABOUT SMOKING "Smoking is a chronic condition that affects more than 46 million Americans. People who smoke are at risk of heart disease, cancer, and other smoking-related illnesses that cost more than $50 billion annually to treat, and an additional $47 billion in indirect costs from lost time at work and disability. Smoking is the single greatest preventable cause of death and illness in the United States. An estimated 420,000 people die every year from smoking-related illnesses. Studies show that over 70 percent of adult smokers would like to quit, but only half of them have ever been urged to quit by their health care provider. Smoking only with delayed diagnosis is the chief cause of lung cancer.@ 24.11 The Increase in Lung Cancer Among Women Between 1973 and 1995, lung cancer incidence in US women rose by 126% while incidence rates in men rose by only 0.9%. During this period, incidence rates for small cell carcinoma of the lung (SCLC) increased by over 160%, faster than other histologic types in women and 8 times faster than the increase for SCLC in men. Lung cancer now accounts for one of every eight new cancers in women and one of every five lung cancers is SCLC. Small cell carcinoma is diagnosed most frequently in heavy smokers and rarely in non-smokers. Osann, Small cell lung cancer in women: Risk associated with Smoking, Prior Respiratory Disease, and Occupation Lung Cancer, Vol. 28 (1) (2000) pp. 1 - 10 24.12 Particular Risk Factors Associated with Smoking A All aspects of smoking are associated in a dose-specific fashion with the risk of developing lung cancer. The risk of lung cancer increases with increasing number of cigarettes smoked per day, ranging from 2.5 for those smoking less than one pack per day to 32.8 for those smoking greater than two packs per day. Increased duration of smoking similarly carried proportionately larger risk, going from 3.5 for those smoking up to 29 years to 9.0 for those who smoked >50 years. Starting smoking at an early age also increased the risk; relative risk for those starting before 16 years being 10.3 compared to a relative risk of 6.4 for those who started smoking later.@ Khuder, Effect of cigarette smoking on major histological types of lung cancer in men, Lung Cancer, Vol. 22 (1) (1998) pp. 15-21 24.12 Types of Cancer and Smoking Khuder discusses the type of cancer in relation to smoking: We found the strongest relationship between smoking and lung cancer for small cell carcinoma. This is consistent with reports in the literature that show a stronger relationship for squamous and small cell carcinomas compared to adenocarcinoma.... In this study, the number of cigarettes smoked per day was strongly associated with both squamous cell and small cell cancer of the lung... central lesions with more exposure to tobacco smoke particles (squamous cell or small cell carcinoma) may therefore have stronger association than peripheral ones, with less exposure (adenocarcinoma and large cell carcinoma)... patients with squamous and small cell carcinomas were heavier smokers compared to patients with adenocarcinoma.@ Khuder, id. 24.3 REDUCED BUT CONTINUING RISK FOR SMOKERS THAT HAVE QUIT Quitting smoking dramatically decreases one= s odds of getting lung cancer. with the risk decreasing over time. A Cigarette smoking is strongly associated with risk for small cell carcinoma. Odds ratios are nine times higher for current smokers than former smokers A Osann, Small cell lung cancer in women: Risk associated with Smoking, Prior Respiratory Disease, and Occupation Lung Cancer, Vol. 28 (1) (2000) pp. 1 - 10 A In the 1990 study we were able to assess the effects of prolonged cessation among those who had smoked cigarettes for many years. Although efforts to change from cigarettes to other types of tobacco, or from smoking substantial numbers of cigarettes to smoking smaller numbers, seemed to confer only limited benefit stopping smoking confers substantial benefit.... Even people who stop smoking at 50 or 60 years of age avoid most of their subsequent risk of developing lung cancer, and that those who stop at 30 years of age avoid more than 90% of the risk attributable to tobacco of those who continue to smoke. In the United Kingdom widespread cessation has roughly halved the number of cases of lung cancer that would now be occurring, as by 1990 it had already almost halved the number that would have occurred in the study.@ Smoking, Smoking Cessation, and Lung Cancer in the UK since 1950: Combination of National Statistics with two case-control studies, BMJ 2000;321:323-329 ( 5 August) However, it will probably never be the same risk of a nonsmoker. The numerous genetic changes that result in lung occur over a period of roughly 15 years. Stopping smoking may eliminate some DNA damage which may contribute to lung cancer; in other circumstances the carcinogenic process may be already in place. In the Cornell study of early detection, a substantial number of lesions and pulmonary abnormalities were associated with former smokers. Thus, former smokers continue to have substantial risks of contracting lung cancer, and systems of early detection must concentrate on them as well as smokers. 24.31 The Question of Reduced Tar Cigarettes We can concretely say that quitting smoking substantially reduces, but does not eliminate lung cancer risk. The question of whether risk is similarly reduced by low tar cigarettes is more difficult. The advent of low tar cigarettes has brought with it an increase in the number of adenocarcinomas, non small cell cancers which generally arise in the peripheral lung areas. One sensible theory is that low tar smokers breath the smoke more deeply, allowing the carcinogen is reach the smaller pathways of the lung. Adenocarcinomas are generally more dangerous than squamous cell tumors, since the adeno tumors seem to metastasize more quickly with clinical trials showing a poorer prognosis for patients with adenocarcinoma. Thus, it may be that low tar cigarettes are having a minimal impact. Certainly most researchers would strongly recommend that the patient quit rather than change brand or type.
24.4 A TEN STEP PLAN FOR DECREASING SMOKING A numberof articles, books, tapes, and other materials have been compiled dealing with smoking. Below, utilizing some of these materials, and my own views, I have put forth a program for reducing the incidence of smoking. 1. Recognize that We Have Been Generally UnSuccesful to Date and that Stronger Methods are Needed to Diminish Smoking Lung cancer from smoking is been the largest avoidable cause of death in the United States. Lung cancer is responsible for the largest number of cancer death in the United States, and is responsible for more deaths among women than breast and cervical cancer combined. Substantial numbers of young people continue to become addicted to smoking. Thus, our starting point must be to recognize that however well-intentioned we have been, our efforts to severely limit smoking have generally been a failure. 2. School Anti-Smoking Programs Should Candidly and Accurately Describe the Hazards of Smoking The danger is not overly frightening a potential smoker but not adequately conveying the serious risks inherent in this habit. We need to spend less time worrying about the sensibilities of teenagers and more time starkly informing them of the hazards of smoking. Anti-smoking programs should include the elements listed below even though, or perhaps precisely because, they may scare some people. 3. Personal Testaments from Smokers with Different Types of Cancer Should be a Part of Every Program. It is sad to see someone terminally ill discuss the hazards of smoking, but it is necessary and important to vividly explain what can occur. No lawyer in a personal injury case would rely only on impersonal records; he would want to personalize the injury and give a jury a vivid sense of its impact. Whether the patient is speaking first hand, by videotape or other means, having patients will throat cancer, lung cancer, chronic obstructive pulmonary disease, and other ailments speak is a critical element of any presentation. 4. Include Slides and Pictures Vividly Showing the Hazards of Smoking Whether it be a diseased lung, x-ray of a smoker, or the photograph of a family, pictures speak louder than words. 5. Discuss the Difficulty of Curing Metastatic Disease While medical advances continue, metastatic lung cancer continues is a difficulty disease to confront. Speakers should briefly describe how cancer metastasizes and our current difficulties in curing disease once that has occured. 6. Include Statistics Some presentations include only statistics, but discussing life expectancies, the difficulties of complete cure, rates of mortality among smokers and other facts can impress the perspective smoker with the hazards of this habit. 7. Discuss the Alternatives for Quitting Beyond telling people not to smoke, a presentation should discuss the methods of quitting, and how they have worked including the difficulty of quitting.
24.3 SMOKING CESSATION GUIDELINES FROM THE NATIONAL CANCER INSTITUTE A The smoking cessation guideline challenges clinicians-physicians and other health care providers-to aggressively motivate and help their patients who smoke to quit. The guideline makes specific recommendations about how clinicians can identify smokers, repeatedly encourage them to quit, and offer treatments that have been proven to work. The guideline found three treatment elements were particularly effective, used either alone or together, in helping smokers quit. They are: ! Nicotine replacement therapy-either the prescribed nicotine patch or nicotine gum, which doubles the rate of successfully quitting. [Nicotine gum has been approved for overthe-counter (OTC) use by the FDA. The nicotine patch was approved for OTC use by the FDA in July 1996.] ! Social support-encouragement and support from the clinician. ! Skills training/problem solving-practical advice and techniques from the clinician that help people adapt to life as a non-smoker. ! Individual or group counseling programs are also helpful. The guideline panel found a direct relationship between the intensity of treatment and the likelihood for success. The guideline recommends that counseling programs, if chosen, be delivered over 4 to 7 sessions (20 to 30 minutes in length), for at least 2 weeks, but preferably for 8 weeks. No conclusions were drawn about the effectiveness of the following treatments: * Acupuncture or hypnosis. There was insufficient evidence to support the effectiveness of either of these therapies. * Clonidine, antidepressants, and anxiolytics/benzodiazepines. Lack of data and/or faulty studies offered little support for their use. The guideline panel made no recommendations regarding the use of nicotine nasal sprays and nicotine inhalers. There were limited data on these products. At the time of the panel's deliberations, the products were not licensed for prescription in the United States. [As the guideline went to press, the FDA approved the prescription use of nicotine nasal spray.] 24.31 Educational Programs * Identify smokers. Ask every patient at every visit if they smoke. * Implement a tobacco-user identification system in every clinic. * Record smoking status as a vital sign. * Encourage smokers to quit. * Ask smokers about their desire to quit and reinforce their intentions. * Give motivational messages to those who aren't ready to quit. * Help motivated smokers set a quit date. * Prescribe nicotine replacement therapy. * Offer specific, practical advice about how to deal with life as a non-smoker, particularly how to handle situations or emotional states that may cause relapse. * Encourage relapsed smokers to try to quit again.
24.5 RECOMMENDATIONS FOR SMOKERS WHO WANT TO QUIT Note again that these recommendations are excerpted from a National Cancer Institute page on smoking generally, and not directed specifically towards lung cancer patients. You should speak with your physician regarding a program to quite smoking. However, while substances like nicotine are routinely used by people trying to quit smoking, no smoker should use it without a doctor's permission since it may impact certain forms of treatment. * Talk with your doctor. Discuss nicotine replacement therapy and strategies to deal with wanting to smoke again. Do everything you can to maximize the chances for success. * Be committed. Make sure you're ready to work hard to quit * Set a quit date. Don't try to "taper off." * Build on past mistakes. If you've tried to quit before, think about what helped and what hurt. * Enlist support. Tell your family and friends you're quitting. Create a network you can turn to for help. * Learn how to avoid or cope with situations and behavior that make you want to smoke.
24.6 A GUIDE FOR HEALTH CARE Health care systems face the daily challenge of balancing quality of care and costs for every patient. Health care administrators, insurers (including managed care plans), and purchasers, can play a vital role in tackling the leading preventable cause of illness and death-smoking. The purpose of this guide is to provide tools to make smoking cessation a priority in your organization. You can help eliminate the roadblocks to developing standard procedures for assessment and treatment of tobacco use in every health care setting. The most successful smoking cessation programs are supported by institutional policies. They incorporate reimbursement practices, clinical and systems procedures, incentives for providers, and clinician education. Supporting institution-wide smoking cessation programs can yield both shortand long-term cost savings for patients. * Americans spend an estimated $50 billion annually on direct medical care for smoking-related illnesses. Lost productivity and forfeited earnings due to smoking-related disability account for another $47 billion per year. * The average cost per smoker for effective cessation treatment is $165.61. * Smoking cessation interventions are less costly than other routine medical interventions such as treatment of mild to moderate high blood pressure or high cholesterol and preventive medical practices such as periodic mammography. * Smoking cessation interventions can save on costs by reducing health risks and complications for infants and young children. 24.81 Strategies Following are five strategies that have been demonstrated to be effective in helping health care providers identify and treat tobacco users.... Screening systems that systematically identify and document smoking status result in higher rates of smoking cessation interventions by clinicians and in higher quit rates among patients who smoke. This approach increases the probability that tobacco use is consistently assessed and documented. Studies show that smoking cessation interventions involving minimal contact with health care providers-physicians, nurses, social workers, counselors, and others-even in sessions lasting as few as 3 minutes, are more effective at increasing cessation rates than no contact at all. Intensive interventions are more effective and should be used when resources permit. Health care report cards such as the Health Plan Employer Data and Information Set (HEDIS) are now mandating that managed care organizations include information documenting delivery of effective smoking cessation services. Action Implement an office-wide system that ensures that, for every patient, tobacco-use status is queried and documented. Office system change: Expand vital signs data to include tobacco use (see sample diagram below). Frequency of utilization Whenever health care staff collect the traditional vital signs data, they should query and document tobacco use Strategy 2. Provide education, resources, and feedback to promote provider intervention Smoking cessation interventions delivered by multiple types of health care providers (e.g., nurses, dentists, psychologists, social workers) markedly increase cessation rates compared with interventions where no provider intervenes (e.g., self-administered interventions). Results are consistent across diverse provider groups, with no clear advantage to any single provider type. To encourage provider interventions, health care administrators, insurers, and purchasers should provide both training and incentives, such as reimbursement for clinicians (see strategy 5). It is important to dedicate staff both to provide smoking cessation treatment and to assess the delivery of this treatment in staff performance evaluations. National data suggest that, in a given visit with a clinician, most smokers are not advised to quit smoking and are not assisted with cessation. Factors that contribute to this problem include failure to (a) include smoking assessment and cessation in the performance expectations of clinicians and (b) provide clinicians with an environment that supports systematic intervention with smokers. Without supportive systems, policies, and environmental prompts, the individual clinician cannot be counted on to assess and treat tobacco use reliably. Action * Health care systems should ensure that clinicians have the knowledge and training to treat smoking, that clinicians and patients have cessation resources, and that clinicians are given feedback about their cessation practices. * Clinical sites should communicate to staff the importance of intervening with smokers and should designate one staff person (e.g., nurse, medical assistant, or other clinician) to coordinate and deliver smoking cessation treatments. Strategies for Implementation Educate: On a regular basis, offer lectures/seminars/in-services with CME and other credit for smoking cessation treatment. Resources: Have patient self-help materials, as well as nicotine replacement "starter kits," readily available in every exam room. Provide feedback: Drawing on data from chart audits, electronic medical records, or computerized patient databases, evaluate the degree to which clinicians are identifying, documenting, and treating patients who smoke, and provide feedback to clinicians about their level of intervention. Communicate to each staff member (e.g., nurse, medical assistant, or other clinician) his or her responsibilities in the delivery of smoking cessation services. Designate a smoking cessation treatment coordinator for every clinical site. Delineate the responsibilities of the smoking cessation coordinator, including instructing patients on the effective use of cessation treatments (e.g., nicotine replacement therapy, telephone calls to and from prospective quitters, and scheduled follow-up visits, especially in the immediate post-quit period). Strategy 3. Promote hospital policies that support and provide smoking cessation services Evidence Implementing inpatient smoking cessation programs increases the rate at which hospitalized patients successfully quit. It is vital that hospitalized patients attempt to quit smoking because smoking may interfere with their recovery. Hospitalized patients may be particularly motivated to make a quit attempt for two reasons. First, the illness that resulted in their hospitalization may have been caused or exacerbated by smoking. Second, the hospital's smoke-free environment may enhance their motivation to quit. In addition, systematic, institutionalized mechanisms to identify exsmokers is a necessary first step in delivering relapse prevention messages. Furthermore, all clinicians have an important role as nonsmoking models for their patients. Action Provide smoking cessation inpatient consultation services to all smokers admitted to a hospital and to all health care personnel who smoke. Implement a system to identify and document the tobacco-use status of all hospitalized patients.Offer cessation treatment to all hospitalized patients who use tobacco. Identifya clinician(s) to deliver smoking cessation inpatient consultation services for every hospital. Reimburse providers for smoking cessation inpatient consultation services. Expand hospital formularies to include effective smoking cessation pharmaco-therapy such as the nicotine patch and nicotine gum. Ensure compliance with JCAHO regulations mandating that all sections of the hospital be entirely smoke free. Educate all hospital staff regarding nicotine withdrawal, including effective treatments such as nicotine replacement therapy and counseling. Strategy 4. Include smoking cessation treatments as paid services in all health benefits packages Evidence Smoking cessation treatments (both pharmacotherapy and counseling) are not consistently provided as paid services for subscribers of health insurance packages. The level of coverage is particularly surprising given that studies show that physician counseling against smoking is at least as cost-effective as several other preventive medical practices, including the treatment of mild or moderate hypertension or high cholesterol.
CHAPTER TWENTY SIX: RACIAL, GENDER, AND AGE FACTORS IN THE TREATMENT OF LUNG CANCER _____________________________________ 26.1 DIFFERENCES BETWEEN WOMEN AND MEN 26.11 Summary of the Recent NCI Study Investigators at the National Cancer Institute in Bethesda, Md., have published the first study that analyzes the gender differences in precancerous changes in smokers' lung tissue. This study, in the Journal of the National Cancer Institute, finds that women develop a different pattern of bronchial changes than men do; that airflow obstruction, a common means to assess those at risk of lung cancer, does not seem to be valid, especially for women; and that lung damage due to smoking persists for many years and probably for life. See Journal of National Cancer Institute, April 21, 1999. More men and women die from lung cancer than from any other type of cancer. This year an estimated 171,600 new cases of lung cancer will be diagnosed, and 158,000 people will die from this disease. Approximately 50 percent of lung cancer occurs in former smokers. Women are more susceptible to the harmful effects of tobacco-related carcinogens -- the odds ratios for major types of lung cancer are consistently higher in women than in men at every level of exposure to cigarette smoke. Furthermore, this gender difference cannot be explained by differences in baseline exposure, smoking history or body size; it is likely due to women's higher susceptibility to tobacco carcinogens. "Cancer is the result of a complex multi step process," said Gazdar, associate director of the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research. "We are actively trying to develop methods of early detection and chemoprevention -- ways to chemically reverse precancerous lesions and block cancer development -- for those at high risk." The scientists found that men had a significantly higher incidence of precancerous lesions in the large central airways than women. They also found that fewer women than men had high-grade preinvasive lesions. Because women develop more cancers in the peripheral (outer) parts of the lung than men do, Gazdar and co-workers presume that women smokers are selectively damaging these parts of the lung, while smoking damage in men targets the larger, more centrally located airways. The general lesson from this study is that methods of lung-cancer screening in high risk populations must take gender into consideration, and perhaps, different screening procedures and criteria will have to be used for men and for women. 25.12 Japanese Study Finds Increasing Incidence of Adenocarcinoma Among Women and Younger Lung Cancer Patients A Japanese study was recently completed on 790 cases of lung cancer to review the characteristics and survival rates of lung cancer patients under and over the age of 50. The study analyzed data on patients at the Tochigi Cancer Center Hospital. Jpn J Cancer Res, 1999 May, 90:5, 490-5 Of the 790 patients, 77 (9.7%) were under the age of 50 at diagnosis. The percentage of women in the younger patient group was significantly higher than that in the older patient group (39.0% vs. 27.5%; P = 0.034). Thus we have an increasing incidence of women smokers with adenocarcinoma. Tumor histology revealed a significant preponderance of adenocarcinomas (60 patients, 77.9%) and a paucity of squamous cell carcinomas (8 patients, 10.4%) in the younger age group
25.2 RACIAL DIFFERENCES IN THE TREATMENT OF LUNG CANCER 25.21 The Rate of Lung Cancer in the Afro-American community While one is reluctant to ascribe racist motives, studies indicate the following: ! The percentage of blacks contracting lung cancer is higher percentage wide than whites. This is probably due to higher exposure rates to dangerous dusts such as silica and asbestos in different occupations, higher rates of smoking, residence in cities with poorer air quality and vehicle emissions, and other risk factors, ! Blacks are unfortunately diagnosed at later stages and have higher mortality rates than whites. ! Blacks are less likely to have surgery performed, which is generally the most successful medical alternative 25.22 Racial and Economic Issues An article entitled, A The economics of surviving cancer@ contains some disturbing findings: Disadvantaged Americans are far more likely to die of the most treatable form of lung cancer than average - not because of poor health habits, but because they don't receive the proper treatment for their malignancy. Health care delivery expert Howard P. Greenwald has analyzed more than 5,000 cases of stage-1 non-small-cell lung cancer attempting to explain why cancer mortality rates are higher among racial minorities and the socially disadvantaged than among higher-income Americans and whites. His findings are detailed in "Uneven Odds: Explaining High Cancer Death Rates Among Minorities and the Poor," a paper presented March 28 at an American Cancer Society conference in New Orleans.... Greenwald found that surgery may have saved the lives of nearly one in three patients whose cancer was detected early enough for surgery. But the poorest patients were about a third less likely to receive surgery than the richest patients. Fifty percent of the patients in the bottom 10 percent of income levels received surgical treatment, whereas 72 percent of patients in the top 10 percent of income levels received it. The mortality rates were even more dramatic. Greenwald found that the poorest patients were only half as likely as the richest patients to survive. Only 22 percent of the poorest lived at least five years after diagnosis, compared to 45 percent among the richest patients. As a subset of the study group, African-American patients carried an additional burden. According to Greenwald, they had a one-in-four chance of surviving, compared to a one-in-three chance among white Americans. While 61 percent of whites received surgery, only 51 percent of African Americans did. "In the form of lung cancer studied, lack of appropriate care seems to have contributed strongly to excess mortality among the disadvantaged," Greenwald said. "It explains about 50 percent of the excess mortality in poor people and all of the excess mortality in African Americans...." Southern California Chronicle, www.usc.edu Greenwald has written extensively about socio-economic factors and cancer. He is the author of Who Survives Cancer (1992) and Social Problems in Cancer Control (1980). 25.23 What Should Be Done Afro-Americans need to take a more assertive role in their treatment, assess the quality of their hospitals and physicians, and assure themselves that they are receiving the best treatment. Given the extent of risk from lung cancer and its consequences, there needs to be an effective screening program, particularly for Afro- Americans. The message of this book is repeatedlung cancer at early stages is very treatable, the problems occur when the cancer is permitted to spread . 25.4 FAMILY HISTORY OF LUNG CANCER AND ITS ROLE A recent article was titled, Is there a genetic basis for lung cancer susceptibility? Recent Results Cancer Res, 1999, 151:, 3-12 The author states, A The major risk factor for lung cancer is exposure to tobacco smoke. Exposure to radon, heavy metals used in smelting, and asbestos also greatly increase risks for lung cancer. However, only about 11% of tobacco smokers ultimately develop lung cancer, suggesting that genetic factors may influence the risk for lung cancer among those who are exposed to carcinogens. Further support for this hypothesis is provided by several epidemiological studies and also from molecular epidemiological studies. Epidemiological studies show approximately 14-fold increased risks for lung cancer among average tobacco smokers and approximately 2.5-fold increased risks attributable to a family history of lung cancer after controlling for tobacco smoke. Segregation analyses suggest that a rare autosomal dominant gene may explain susceptibility to early-onset lung cancer, but these results explain a minority of lung cancer cases, which include a family history. Therefore, more common genetic variants or polymorphism are hypothesized to affect lung cancer risk. Environmental carcinogenesis resulting from tobacco smoke exposure is a complex process that can involve activation of procarcinogens that lead to adduct formation and subsequent failure of DNA repair, which should normally remove these abducts. Studies comparing DNA repair capacity among newly diagnosed lung cancer patients and age-matched controls indicate significant differences between the two groups. On culturing with bleomycin lymphocytes from lung cancer patients and age- and ethnicity-matched controls, the lymphocytes from lung cancer cases have been consistently observed to show higher levels of chromatic breaks than the control lymphocytes. A similar assay has been developed using benzo-[alpha]pyrene diol-epoxide (BPDE), a reactive substrate that is derived by in vitro processes from benzo[alpha]pyrene, a major carcinogen in tobacco smoke. Results from this assay show an even more significantly higher level of damaged chromatids in lung cancer patients than in controls. Poor DNA repair is independent of tobacco smoking status. The cellular processes involved in DNA repair of bleomycin and BPDE have not yet been fully elaborated. However, the consistency of findings with these two carcinogens indicates that DNA repair capacity influences risk for lung cancer among individuals.@ The study tells us that while tobacco is the primary risk factor, family history plays an important but subsidiary role. Those with a family history of lung cancer may have less of a capacity to repair smoking related DNA damage, therefore leading to increased incident of lung cancer.
CHAPTER 26: ALTERNATIVES FOR THE TERMINALLY ILL ______________________________________________________
26.1 THE PROBLEM OF TERMINOLOGY I used the term terminally ill because it is a phrase which many people use. However, it is nondescriptive and inaccurate. It can describe a variety of stages of lung cancer, lumping together patients with different prognoses. When speaking about a patient, it is far more accurate to use the TNM staging system and to discuss the specific stage of disease. Thus, not only does the phrase terminally ill frequently group patients with different stages of disease, it presupposes a degree of predictive accuracy which does not exist. If only 15% of patients with disease at a particular stage will survive 3 years, a particular patient may live longer.
CHAPTER 27: HANDLING LUNG CANCER FOR THE PATIENT AND HIS FAMILY ______________________________________________ 27.1 SOME OVERALL SUGGESTIONS Family and close friends can play a vital role in helping a cancer patient. Here are some things you can do for a family member with lung cancer: 1. Do the research. Some of the information patients will see is hard. It is frequently better for a close family member to cull through medical studies, and help locate the best physician, hospital, and form of treatment. 2. Support with Chemotherapy or Radiation If a patient is undergoing chemotherapy or radiation, make arrangements to accompany him to the physician or hospital or at least pick him up. Dealing with cancers every day, oncologists may not have time to provide the emotional support a family member can. 3. Handling Medical Bills and HMO Problems. Dealing with HMO= s can be time-consuming and exasperating. Taking this task off the patient= s mind can be a welcome relief. 4. Contact Support Groups for the Patient and Spouse
Alcase is the national lung cancer support group. Find out about support options, learn about new treatment developments, and learn from others how to deal with the disease. 26.2 RESEARCH AND DEALING WITH LUNG CANCER Some patients will want to fully understand their disease and obtaining information about it is helpful in dealing with it. Most however, they would rather not spend their time thinking about metastasis and disease process. For this group, the family member who can studiously but quietly obtain information about treatment alternatives can provide a great help. For many, simply saying your doctor recommends this particular form of chemotherapy, my research shows he is very well-qualified and this is the best choice, is sufficient.
26.3 PRACTICAL TIPS One support group put together this list of A 25 PRACTICAL TIPS TO HELP THOSE FACING A SERIOUS ILLNESS:@ 1) Don't avoid me. Be the friend...the loved one you've always been. 2) Touch me. A simple squeeze of my hand can tell me you still care. 3) Call me to tell me you're bringing my favorite dish and what time you are coming. Bring food in disposable containers, so I won't worry about returns. 4) Take care of my children for me. I need a little time to be alone with my loved one. My children may also need a little vacation away from my illness. 5) Weep with me when I weep. Laugh with me when I laugh. Don't be afraid to share this with me. 6) Take time out for a pleasure trip, but know my limitations. 7) Call for my shopping list and make a "special" delivery to my home. 8) Call me before you visit, but don't be afraid to visit. I need you. I am lonely 9) Help my family. I am sick, but they may be suffering. Offer to come stay with me to give my loved ones a break. Invite them out. Take them places. 10) Help me celebrate holidays (and life) by decorating my hospital room or home or bringing me tiny gifts of flowers or other natural treasures. 11) Be creative! Bring me a book of thoughts, taped music, a poster for my wall, cookies to share with my family and.friends...an old friend who hasn't come to visit me. 12) Let's talk about it. Maybe I need to talk about my illness. Find out by asking me : "Do you feel like talking about it?" 13) Don't always feel we have to talk. We can sit silently together. 14) Can you take me or my children somewhere I may need transportation to a treatment....to the store...to a doctor. 15) Help me feel good about my looks. Tell me I look good, considering my illness. 16) Please include me in a decision. I've been robbed of so many things. Please don't deny me a chance to make decisions in my family...in my life. 17) Talk to me of the future. Tomorrow, next week, next year. Hope is so important to me. 18) Bring me a positive attitude. It's catching! 19) What's in the news? Magazines, photos, newspapers, verbal reports, keep me from feeling the world is passing me by. 20) Could you help me with some cleaning? During my illness, my family and I still face: dirty clothes, dirty dishes, dirty house. 21) Water my flowers. 22) Just send a card to say "I care." 23) Pray for me and share your faith with me. 24) Tell me what you would like to do for me and, when I agree, please do it! 25) Tell me about support groups Iike Make Today Count, Cancerwise, and American Cancer Society so I can share with others. From the brochure "25 Tips to Help Those Facing a Serious Illness" from Saint Anthony's Hospital's Make Today Count.
DEFINITIONS Accuracy This term is used with a medical test, for example, a method to detect cancer. A test= s specificity refers to the percentage of patients whose cancers are accurately seen. Assume that a test is given to 100 people, of whom 10 have lung cancer. If the test detects 8 of the 10 with lung cancer, it has a specificity of 80%. The test might also incorrectly indicate that some people had cancer, when in fact they did not have the disease. For example, an x-ray could show a shadow which might be incorrectly interpreted as a tumor. This would be a false negative. Accuracy usually refers to the percentage of false negatives. Assume that the test misinterprets that 2 people have cancer when in fact they do not. That would be an accuracy rate of 98%, meaning that 2 of 100 were false negatives. Adjuvant therapy Adjuvant means in addition to. Adjuvant therapy typically refers to chemotherapy given after surgery. Neo-adjuvant therapy refers to chemotherapy given before surgery. AngioGenesis The process by which cancer cells connect with blood vessels and metastasize to other organs. Anti-angiogenesis A drug which inhibits the ability of cancer cells to form or connect to blood vessels. Apostastasis Cell death. Scientists study this phenomenon to try to determine what conditions cancer cells die. Cancer A cellular malignancy where loss of normal controls- results in unregulated growth, lack of differentiation, and ability to invade local tissues and metastasize. Cell-cycle-specific, A form of chemotherapy lethal to cells only during a specific phase. Chest X-Ray An x-ray of the thoracic or chest area which includes the lungs. The chest x-ray will show tumors of at least 1 centimeter. Its advantage in its ease of use and low cost, disadvantage is that small tumors can be missed and others may not be shown. Clinical Trial Control group People in a clinical trial receiving the standard treatment, and not the experimental treatment. Differentiation Normal cells are differentiated. As cancer progresses, cells lose their essential characteristics or differentiation. Cancer cells are categorized from well-differentiated to poorly differentiated. Growth Factor Hemothorax When the pleural cavity fills with blood. Lobectomy Surgical removal of one of the lobes of the lung. Lymphocytes White blood cells, the body= s mechanism to fight cancer, a type of lymphocyte is the T cell M or Metastasis M refers to metastasis in the TNM staging system, or movement of cancer from the lung to another organ. Matrix metalloproteinases refers to particular substances in cancer cells (MMP) which help break down the protective barriers which protects other bodily structures. Some drugs have been developed to inhibit MMP Neo-adjuvant therapy Adjuvant means in addition to. Adjuvant therapy is chemotherapy given after surgery. A recent refinement is to give chemotherapy in some situations before surgery, which is called neo-adjuvant therapyo NSLC A frequently used abbreviation for non-small cell lung cancer. N (or Node) N refers to lymph node in the TNM staging system. P-53 One of the most important tumor supressor genes. Abnormalities in P-53 are found in many cancers, including small and non-small cell cancer. One type of gene therapy seeks to inject normal or wild-type to restore tumor suppresion activity. P-53 (mutant type) This is P-53 which has been damaged and mutated, and is found in many tumors. Not only will the gene not perform its tumor suppressor function, evidence indicates it plays a role in prompting duplication of cells or cancerous activity. P-53 (wild-type) This is P-53 in its normal condition, serving various tumor suppression functions. Palliative Treatment designed to relieve pain or discomfort rather than achieve a cure. Pneumonectomy Surgical removal of the entire lung Pneumothorax If the pleural cavity fills with air, this is called pneumothorax. Pleura A thin membrane encasing each lung. SLC A frequently used abbreviation for small cell lung cancer. Various types of cancer are classified as small cell or non-small cell. Types of cancers within each category share similar characteristics in terms of tumor growth and metastasis. Sputum Cytology Analysis of lung cells by having the smoker cough. Effective at detecting very small microscopic cancers. An excellent technology not used nearly enough. Specificity The percentage of cancers accurately seen by a test. If ten people have tumors, and a test detects 8 of those, its specificity is 80%. Put another way, the rate of false positives is 20%. Tumor angiogenesis factor(TAF) Tumor cells need a blood supply to bring them fresh nutrients and carry away wastes. The process by which a tumor links up with the bloodstream is called angiogeneses. It is believed that the tumor secretes a substance known as or (TAF) which induces blood vessels to produce new capillaries that grow toward the tumor and finally connect with it.@ TNM Classification Tumor classification. with T designating the size and location of the primary tumor, N standing for the existence of cancerous lymph nodes, and M meaning metastasis or spread to other organs. Thus a medical chart would have a notation; classification of tumor, T1NoMo, meaning a small tumor which has not invaded lymph nodes or metastasized. T or Tumor T is the primary tumor in the TNM staging system, and is measured from 0, undetectable on an ordinary x-ray to 4 based upon its size and spread to nearby organs or structures. T Cell A type of white blood cells which activates to fight cancer. Also called killer cells.
TREATMENTS FOR LUNG CANCER CHEMOTHERAPY Name of Drug Type Side Effects Status
Nausea
FDA-approved treatment. Gradually being replaced by carboplatin to reduce side effects.
Myelosuppresion
FDA-approved treatment. Carboplatin and Taxol are probably the standard treatment today.
Platinum-based drug.
Cisplatin
Carboplatin
Platinum-based drug
FDA approved treatment, Carboplatin and Taxol are probably the standard treatment today.
Taxol (Paclitaxel)
Gemcitabine
Ifosamide
ANTI-ANGIOGENSIS AND RELATED DRUGS Name of Drug Type Side Effects Status
Iressa or ZD 1829
MMP or mallioproteasis
Marimostat
The theory is that Iressa blocks a pathway implicated in a variety of solid tumors. The pathway is triggered by an epidermal growth factor that binds to an epidermal growth factor receptor (EGFr) that sends signals within the cell via tyrosine kinase. Blocking the tyrosine kinase switches inhibits tumor growth.@
In clinical trials, newspaper reports of favorable results. Iressa or ZD 1839. See Iressa Shows Promising AntiTumor Activity and is Well Tolerated with Minimal Side Effects: Oncology News, vo. 9, no. 7, Supp 3 (July 2000). However, without reliable published data, the efficacy of the drug remains speculative.
inhibitor
Initial favorable results, but still in clinical trials. Initially showed dramatic reduction of tumors in mice, but results were not easily duplicated, Clinical trials have not shown significant results, with scientists attempting to modify the drug or its usage.
Anti-angiogenesis drug pioneered by Judah Folkman
Angiostatin
APPENDIX TWO Ask Jeeves Answer: OncoLink Conference Announcement: Perugia International Canc INDEX American Cancer Society 3, 37, 38, 95, 108, 109, 113, 119-123, 126-129, 131, 133, 134, 140, 149, 156, 157, 178, 179, 183, 186, 203, 204 Anatomy 16, 40, 156 Angiogenesis 3, 123, 124, 126, 145, 206 Anti-angiogenesis 3, 123, 124, 206 Apostasis 12 Appetite 114, 116, 120 Asbestos 18, 34, 38, 149-152, 154, 155, 157, 160, 163, 175, 176 Asbestosis 21, 157, 176 Basement membrane 3 Biological Response Modifiers 15 Blood Vessels 3, 5, 18, 123, 133, 206 Bone 2, 4, 19, 23, 26, 27, 29, 32, 62, 73, 74, 81, 83, 94, 96, 104, 136, 170, 184, 186 Bone Marrow 2, 19, 23, 26, 29, 73, 74, 94, 96, 104, 136, 170 Brain 4, 19, 26, 27, 62, 64-67, 73, 76, 80, 81, 83-85, 90-93, 111, 118, 136, 145 Bronchial Tree 16-18, 35 Bronchitis 17, 141 Cancer 1-40, 42-50, 52-87, 89-116, 118-136, 139-147, 149-157, 159-167, 170, 171, 173, 175, 176, 178-180, 182-190, 197, 199-204, 206, 207, 209 Carboplatin 61, 63, 82, 85, 86, 98, 99 Carcinoid Tumor 24, 72, 156, 157 Chemotherapy 5, 7, 8, 14, 15, 22-25, 28, 29, 40, 42, 43, 48, 50-66, 68-71, 73-79, 81-112, 114, 115, 119, 121, 125, 126, 130, 134-137, 140, 143, 144, 147, 153, 184, 187, 201, 206 Chest x-ray 32, 34, 38, 43, 140, 166 Chromosome 2 Cigarette 10, 72, 156, 159, 186 Clinical Trial 7, 48, 50, 56, 60, 62, 105, 110, 128-131, 147, 152, 153, 202 Control Group 47, 92, 110, 130, 131, 200, 202, 203 Cuneo Lung Cancer Conference 97, 124, 125 Devita 6, 8, 37, 104, 105, 108, 139, 141, 142, 178, 179, 183 Differentiation 1, 7, 9-12, 29, 30, 40, 206 DNA 2, 8-10, 12, 30, 37, 95-97, 125, 164, 186 Dominant 9, 11, 14, 164 Dosage 98, 104, 107, 118, 119, 128, 129 Dosimetrist 118, 119 Drug 15, 45, 53, 69, 74, 76, 77, 81, 83, 86, 89, 95, 96, 100-111, 119, 124-126, 128-130, 143-145, 147, 171, 196, 206 Dyspnea 37, 110, 141, 142 Emphysema 17, 34, 49, 141, 166 Endocrine 22, 156 Enzyme 3, 102, 124 European Lung Cancer Working Party 99, 184 Failure to diagnose cancer 167 Family History 34, 141, 163, 164 Fibrosis 21 Gemcitabine 98, 100 Gene therapy 14, 15, 125 Health Insurance 169, 195, 196 HMO 36, 37, 169-174, 188, 195, 203 Hormone 23, 97, 102, 111, 116, 142 Hypnosis 116, 189 IASLC 183-185 Immunotherapy 54, 58, 121, 122 Informed Consent 95, 109, 130, 146 Initiator 9, 10 Interferon 15, 123 Intracellular 9, 104 Ionizing Radiation 104 Johns Manville 154, 155 Large Cell 19, 22, 24, 29, 35, 43, 52, 72, 136 Legal 21, 36, 37, 165, 166, 171, 172, 175 Limited Disease 23, 68, 78, 90, 91 Liver 4, 19, 23, 26, 29, 70, 96, 101, 102, 136, 147 Lobectomy 31, 40, 46-49, 51, 52, 206 Loss of function 11 Lung Cancer Manual 15, 18, 19, 30, 40, 179, 183 Lymph Node 5, 18, 19, 26, 30, 31, 36, 38, 40, 42, 57, 207 Lymphocytes 4, 122, 164, 207 Mediastinum 16, 18, 19, 26, 70, 73 Medical malpractice 165, 167 Medically necessary 169, 170, 173 Metastasis 4, 5, 23, 25-27, 29, 30, 40, 42-44, 57, 58, 62, 64-66, 84, 90-92, 101, 123, 124, 133, 134, 136, 142, 145, 149, 153, 154, 186, 207 metastasis 5 MMP 123, 207 MRI 27, 34 Myc 12, 14 Nausea 108-112, 115, 116, 146 Negligence 166, 175 Neurological 77, 80, 82, 85 Node 5, 18, 19, 26, 30, 31, 36, 38, 40, 42, 43, 54, 57, 58, 207 Non-small cell cancer 68 Oncogene 8, 39 Oncolink 178, 182, 184 Oncology 6, 8, 15, 19, 20, 37-40, 43, 46, 49, 50, 52, 55-58, 60, 61, 63, 64, 66, 67, 71, 74, 78-80, 84-87, 89, 90, 97, 98, 104, 105, 108, 125, 126, 136, 139, 140, 142, 146, 150, 157, 159, 176, 178, 179, 187, 200 P53 gene 13, 125 Paclitaxel 61-63, 83, 87, 98-100, 125 Palliative 14, 43, 62, 65, 66, 70, 85, 88, 106, 136 Pathology 13, 39, 72, 135, 151, 176, 185, 186 Performance Sta us 51, 53, 54, 58, 61, 62, 65, 70, 77, 82, 116, 137, 140 Peritoneal Mesothelioma 151 Pleura 18, 20, 25, 26, 136, 149, 150, 152, 153, 207 Pleural Mesothelioma 150, 154 Pneumonectomy 31, 40, 43, 49, 51, 52, 153, 207 Prognostic Factors 39, 70, 71, 79, 84, 137 Promoter 9, 10 Prophylactic Cranial Radiation 90 Protocol 60, 129-131 Radiation 14, 25, 28, 29, 32, 42, 45, 47-49, 51-60, 62, 64-66, 69, 71, 73-81, 83, 85, 88, 90-92, 94-96, 104, 118-121, 136, 147, 152, 153, 201 Red blood cells 95 Regional Lymph Nodes 23, 26, 29, 90, 142 Scheduling 104, 105, 118 Screening 27, 42, 139-141, 160, 163, 166, 167, 181, 185, 186, 192, 197, 199-203 Side-effects 128 Smoking 10, 13, 17, 21, 22, 34, 38, 141, 150, 156, 157, 159, 160, 164, 166, 175, 176, 186, 188-199, 203, 204 Smoking cessation 188-198 Stage 5, 10, 11, 16, 19, 20, 22-25, 27-30, 35, 38, 39, 42-54, 56-61, 63, 68-78, 80- 83, 85, 87, 88, 92, 97, 98, 105, 106, 110, 128-131, 133-137, 139, 140, 143, 145, 146, 149, 151, 152, 156, 161, 170, 199-204 Stage 1 27, 28, 38, 43, 44, 128-130, 133, 135, 136, 145, 204 Stage 2 28, 43, 129, 130 Stage 3 28, 43, 128, 130, 134, 135, 145 Stage 4 27, 29, 43, 129, 134-137, 143, 170 Standard of Care 166, 168 Support groups 113, 120 Survival 23, 27, 29-31, 39, 42, 43, 45-48, 51, 53-55, 58-65, 68-84, 86, 88, 90-92, 97-99, 104, 105, 109, 110, 128, 130, 133-137, 139, 140, 143, 149, 153, 154, 160, 162, 181, 187, 199-201, 203, 204 Symptoms 19, 35, 37, 58, 61, 62, 64, 65, 81, 88, 106, 109-111, 134, 139-142, 152, 153, 166, 181, 199 Taxol 61, 63, 64, 96, 100, 101 TNM Classification 25, 27, 38, 40, 207 Tumor 3-5, 8, 9, 11-14, 16, 19, 22-28, 30-35, 37, 39, 40, 43, 45, 47, 49, 51, 53-55, 58, 62, 64, 65, 68-70, 72-77, 81, 88, 90, 93, 96, 97, 102, 105, 106, 110, 118, 119, 124-126, 129, 133, 135, 136, 141, 142, 145-147, 149, 150, 156, 157, 160, 166, 184, 185, 188, 207 White blood cells 96, 116, 122, 207 Women 13, 21, 38, 139, 159, 160, 199, 202, 204
BACK COVER A Complete Guide to Lung Cancer is a comprehensive reference for lung cancer victims and their families. Written in a detailed but understandable fashion, the book reviews chemotherapy, radiation, the different stages of lung cancer and many other critical topics. Learn why non-small cell and small cell cancer are categorized separately, how chemotherapy works, and the origin of lung cancer. Written with medical sites and clear definitions, the book provides medical information in everyday language. The appendix contains detailed ratings of over 600 hospitals across the United States.
APPENDIX 1 LUNG CANCER SUPPORT GROUPS AND ORGANIZATIONS Alliance for Lung Cancer Advocacy, Alcase Founded by a former patient, Alcase (The Alliance for Lung Cancer Advocacy) is the leading lung cancer advocacy organization in the world. Their services include: an online manual, new research developements, and other information on their website, available volunteers and referrals to support groups in most states, advocacy for screening programs, and research on lung cancer. Contact: ALCASE www.alcase.org , 1601 Lincoln Avenue, P.O. Box 849 Vancouver, WA 98666 USA Tel: (800) 298-2436 International Association for the Study of Lung Cancer (IASLC) Founded in 1972, IASLC is the leading medical group devoted to lung cancer. It publishes the respected publication called Lung Cancer. While the journal is intended for physicians, it has important information about new forms of treatment and diagnosis of the disease. Abstracts from the publication are available on-line, though full text access requires a subscription. IASLC is an international organization of 1150 members in 53 countries and holds conferences each year, where new data and findings are disseminated. . The purpose of the Association is to study the etiology, epidemiology, prevention, diagnosis, treatment, and all other aspects of lung cancer and to disseminate information about lung cancer to the members of the Association, the medical community at large, and to the public. They publish a journal devoted exclusive to lung cancer called Lung Cancer. Many important findings are included in the Lung Cancer journal and on-line access is provided to members. Cuneo Lung Cancer Study Group This Italian based group describes itself this way: In 1983, a group of chest physicians decided to devote their professional interest to the study of lung cancer. The group, who later became known as "Cuneo Lung Cancer Study Group," is still active at the "A. Carle Hospital of Chest Diseases", in the city of Cuneo, Italy. The "A. Carle" hospital, currently named "S. Croce and Carle" hospital, was then designated as Hospital of National Importance, and serves the whole Cuneo Province as 2nd Referral Institution. Among the prime acts of the Group, the creation of a clinical database for patients with carcinoma of the lung. Its website, www.culcasg.org. contains the complete text of recent studies from the group, presentations at its annual conference, and other important information. It was one of the first groups to seriously discuss, some say advocate, programs for early detection of lung cancer. To learn about the group, check their website or, write to: CuLCaSG (Associazione Cuneese per lo Studio e la Ricerca Clinica contro il Cancro del Polmone), via Romita 15, I-12011 Borgo S. Dalmazzo, Cuneo, Italy, telephone: (+39.171.441733 or +39.171.44177) asking for dr. Gianfranco Buccheri, E-mail:
[email protected] European Lung Cancer Working Party This is a group of European physicians whose focus is the diagnosis and treatment of lung cancer. Their website is limited and membership is required. However, this is another groups which can provide accurate (though technical) assessements of different forms of treatment and developement regarding chemotherapy and radiation. Cancer Care, Inc. National Office, 275 7th Ave $ New York, NY 10001 Services: 212 302 2400 $ 1 800 813 HOPE (4673)
[email protected] Administration: 212 221 3300 $ Fax: 212 719 0263. While not devoted specifically to lung cancer, this organization had taken a leading role in many areas to enlighten people about lung cancer, and bring more public resources to the problem. National Cancer Institute This United States government entity conducts research on all forms of cancer and approves clinical trials. Information about standard forms of treatment, experimental therapies, clinical trials, and virtually anything about cancer is available from either their website or their offices themselves. www.NCI.net. American Cancer Society The American Cancer Society may be the important cancer-fighting organization in the world. It has locations across the United States where volunteers provide assistance and programs are held. The American Cancer Society has played a leading role in smoking cessation programs but has lagged in the equally important area of early diagnosis of lung cancer. ACS does not simply help patients; it sets policies. Thus, if ACS embraced the idea of lung cancer screening for high-risk patients, it would likely be adopted. Other Lung Cancer Organizations Throughout The World Finish Lung Cancer Cooperative Group (FLCCG) West Japan Lung Cancer Group (WJLCG) Spanish Lung Cancer Group (SLCG) USA Soutwest Oncology Group (SWOG) Eastern Cooperative Oncology Group (ECOG)
APPENDIX TWO REFERENCES SOURCES Medical Books About Lung Cancer Pass, et al, Lung Cancer Principles and Practice (Lippincott Williams & Wilkins 2000) A superbly documented book, examining most of the important topics in lung cancer research and treatment. The book is designed for physicians but many of the topics can be understood by a patient or family member with some scientific background, a good medical dictionary, and a willingness to learn. This book presents a far more thorough and evenhanded analysis than most newspapers or periodicals. Carney, Lung Cancer A 1995 volume, like Pass= s book, designed for physicians. General Medical Texts on Cancer Devita, Cancer, Principles and Practice of Oncology, (Lippincott Williams & Wilkins) Probably the best-known medical book about cancer, well-researched and detailed, but designed for physicians. Critiques of Medical Research Methods Germer, The Immortanl Cell Why cancer Research Fails
APPENDIX 3, ONLINE INFORMATION Medline Medline is the world database of medical literature and contains abstracts of over 500,000 articles about treatment, diagnosis, chemotherapy, and a host of other issues. Medline is free and can be accessed in a number of ways including www.healthgate.com, www.medscape.com. Medline is the source cancer researchers use to review recent studies and medical literature.
Oncolink This cancer database compiled by the University of Pennsylvania contains excellent information.
Lungcanceronline.COM An excellent source, written by a lung cancer patients which is continually updates and reviews studies, medical, literature, and other materials.
APPENDIX 4 CONFERENCES AND SEMINARS ON LUNG CANCER Many of these conferences will be rather technical. Nonetheless, a family member may want to attend to learn who are the leading authorities on lung cancer and what new developements are being discussed. Some conferences will charge a fee, and others may restrict attendance, but in many cases, the public or at least interested patients or their families may attend. Some of these conferences have already occured but are listed because their findings are important and are generally accessible on the Internet. To check for further conference, look at these sites: www.docguide.com, a site which provides a list of many medical conferences throughout the world.
1998 A At the Second Cuneo Lung Cancer Conference... any possible option for the treatment of the loco-regionally-advanced non-small cell lung cancer (NSCLC) was reviewed, critically reconsidered, challenged, and compared to each other.@ The Cueno website summarizes these findings. www culcase.org
1999 2000 International Association Study of Lung Cancer IASLC, Ninth International Conference of Lung Cancer, September 11, Tokyo, Japan. Material presented at the meeting is included in the IASLC journal, Lung Cancer, 2000: 29; suppl. 1 & 2.
2001 March 15-17 First National Lung Cancer Conference 2001 Mumbai, India www.thoraciconcologyindia.com April 26, April 30, 2001 4th International Congress on Lung Cancer Date: City: Halkidiki Country: Greece Contact: FORUM International Congress Organizers, 18 Mitropoleos Street, 54624 Thessaloniki, Greece Phone: 30-3125-7128 Fax: 30-3124-3588 E-Mail:
[email protected] April 30 International Association Study of Lung Cancer IASLC, Mollecular Biology and Pharmacogenetic Research in the Treatment of Lung Cancer. E-mail
[email protected]. June 03, 2001 7th Central European Lung Cancer Conference - June 06, 2001 City: Prague Country: Czech Republic Contact: Congress Secretariat Phone: 42-022-426-1371 Fax: 42-022-426-1371 E-Mail:
[email protected] August 19 The Biology and Prevention of Lung Cancer Contact James R. Rigas, MD, Director of the Thoracic Oncology Program, Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, E-mail,
[email protected] Sept 11-15, 2000 IASLC (International Association for Lung Cancer) World conference on Lung Cancer, Tokyo, Japan. A Tokyo 2000 has been above all a Congress of Chemotherapy, {and investigation of drugs such as} gemcitabine, the taxans, vinorelbine, irinotecan, topotecan.@ . November 3-4, 1st European Conference Perspectives in Lung Cancer, Lisbon, Portugal, Contact Imedex, USA, Inco. 70 Technology Drive, Alpharetta, Georgia 30005-3969 Telephone 770-751-7332, fax, 77--751-7334, 2002 March 09, 2002 2nd World Conference on Clinical Cooperative Research for Lung Cancer Date: March 08, 2002 - City: Brussels Country: Belgium Contact: Conference Secretariat Phone: 32-2-539-0496 Fax: 32-2-534-3756 E-Mail:
[email protected] 2003 August 10-14, 2003, International Association for the Study of Lung Cancer and the British Columbia Cancer Agency presents the 10th World Conference on Lung Cancer, .Lung Cancer in the 21st Century: Genome to Clinic, Vancouver, Canada: PROTOCOLS AND CONVENTIONS 1. Indent 4 spaces TO space 5 for paragraphs 2. Main headings, 7.1, 7.2 with the associated text should be in 14 point bold, in all caps. like this
7.2 LUNG CANCER CLASSIFICATIONS. Have them begin flush with left margin. Indent next headings to pre-set tab. 3. Subheadings, 7.12 are in regular text. 4. The title of articles in footnotes should be in italics. 5. APPENDIX 1. Materials from U.S. News & World Report Vanessa 1. Check headings, etc. 2. Do spellcheck 3. Do table of contents. 4. Find out how to do index. Howard 1. Get front cover scanned by printer 2. Get blurbs for book from Diane Outcault William Nicholson Other author, 3. This important group has branches
9.1 STAGE Surgery is the preferred form of treatment for stage 1 patients, and is assessed with many stage 2 and stage 3A patients. Surgery is generally not performed upon stage 3B and Stage 4 patients. Ideally, surgery results in the removal of the entire tumor and that result becomes less possible as the tumor spreads and invades other structures. The ideal of cure and eliminating the tumor occurs in approximately 50% to 60% of stage 1 patients. Where the patient has other significant health problems, surgery may not be recommended, for example, for an 84 year old man with significant heart problems. Surgery removes the lung tumor and surrounding tissue. If the patient has severe breathing problems, he may lack sufficient pulmonary reserve to permit surgery. METASTASIS
9.0 The Different Steps In Metastasis Metastasis remains the most serious danger of lung cancer. While considerable progress has been made inunderstanding cancer, that has not translated to substantial success in treating metastatic cancer. There are at least four steps involved with metastasis: 1) A Tumor cells must separate from each over, overcoming the usual restrictions imposed by hemotypic cell adheresion and cell-contact inhibition 2) As well as the tumor expanding by sheer weight of numbers, it encroaches into the local tissue by an active process involving lysis of host cells and degradation of the extracellular matrix (ECM) proteolysis 3) Fo0llowing separate from each other and degradation of the surrounding stroma, tumor cells must then be able to move into the region coleared by the action of the proteolytic enzymes by an active process of cell motility, 4) tumor cells must also promote their own vascularization by inducing capillary growth into and around the tumor- a process know as angiogenesis. An adequate blood supply is essential so that the rapidly proliferating cells can obtain nutrients and oxygenation, otherwise mass necrosis can half the growth of the cells.... Following invasion through endothelial laywers, the cells can reach the blood in which they are distributed to distant sites for metastaic growth. (5) Thereafter local invasion by tumor cells involves the activiation of genetic programms which allow them to pass away from the confines of the primary tumor mass, through any surrounding tissues and, eventually, to reach oa blood or lymph vessel. Vile, Cancer Metastasis: From Mechanisms to Therapies 21-22 (Wiley & Sons 1995)
9.1 THE BEST SOLUTION TO METASTIS: EARLY DETECTION Since medical science has been largely ineffective in treating metastatic cancer, the best solution is early detection. Surgically removing the tumor at an early stage usually eliminates the need to address the consequences of a tumor that has spread. Sadly, neither the National Cancer Institute nor the American Cancer Society recommend programs for early detection and diagnosis of lung cancer.
CHAPTER THIRTEEN: INTERACTING WITH YOUR PHYSICIAN _______________________________________________________________ 13.1 PURPOSE OF THIS BOOK AND YOUR ROLE This book is designed to essentially to explain the basic concepts of cancer diagnosis and treatment in an understandable way. As the author, I do not profess to be more knowledgable about lung cancer than your oncologist or physician and as noted, I am a lawyer, not a physician. Likewise, a patient should not on the basis of some research into cancer believe that he understands more about cancer than his physician. On occasion, some patients have suggested treatment plans to their physician based upon reading or research. That is inappropriate and represents a misunderstanding of the relative roles. Instead, while you should read what you can, and be sagacious in selecting a qualified doctor, ultimately he rather than you will be making the determinations about how your disease should be treated. Imagine a seminar with a noted historian. You would not want to spend your time asking him about specific dates, for example, when the Declaration of Independence was signed. Instead you would want to take advantage of his knowledge and insight. Likewise, the primary purpose of this book is to help you understand some of the basics of cancer care and treatment so you can discuss the important matters with your doctor, rather than have him spend the time explaining basic concepts of cancer.
13.2 WHAT YOU WILL WANT TO KNOW Here is a checklist of items you should know and understand : 1) the type of lung cancer you have, non-small cell or small cell, 2) the cellular type, squamous cell or adenocarcinoma, for example, 3) if chemotherapy is being recommended, the type of drugs that will be given,
13.3 WHAT QUESTIONS NOT TO ASK Some may suggest that a doctor performs many roles, with treatment and diagnosis being but one. He may and should minister to the patient= s emotional as well as physical needs they would argue. However note that in a time of managed care a doctor= s time may be limited. Thus you generally would not want to spend a large amount of time dealing with questions of how bills will be paid or matters unrelated to treatment.
13.4 SECOND OPINIONS There are two basic reasons for a second opinion. First, you may want to check if there is a better-qualified or knowledgeable physician. Someone may graduate in the bottom half of her class, but do you wanted to be treated by him or her. Secondly, you may want additional information about the particular treatment and investigate alternatives. Even if your consultation does not lead to a change, it may reveal treatment alternatives and other issues to discuss with your physician. The choice of a physician is an important one, and intelligent patients obtain second opinions before and sometimes during the course of treatment. 13.41 Where do You get a Second Opinion. Some patients will want a second opinion from someone unaffiliated with the physician they are seeing. In this way, an impartial opinion can be obtained. However, there are practical difficulties. The patient usually will not have all the medical records, and to get them meaning telling the treating physician. If requests are to be requested, the direct approach is best and to explain that a second opinion is being requested. When requests are requested, some physiciains may worry that the patient is evaluating a malpractice action. The process that we are talking about is angiogenesis. As we all know, in order for tumors to grow beyond the size of 2 cubic millimeters in volume, they must develop a vasculature so that, as the tumor cell population grows, the malignant cells secrete angiogenic factors which stimulate nearby vasculature endothelial cells to proliferate and to form tubes and capillaries to promote the continued growth and expansion of the tumor. This new blood vessel formation also allows tumor cells to extravasate into the bloodstream, travel through the bloodstream, establish colonies again at distal sites, and grow metastatic disease and establish a vasculature once again. Angiogenesis means the formation of new blood vessels. Angiogenesis is a process controlled by certain chemicals produced in the body. These chemicals stimulate cells to repair damaged blood vessels or form new ones. Other chemicals, called angiogenesis inhibitors, signal the process to stop. Angiogenesis plays an important role in the growth and spread of cancer. New blood vessels "feed" the cancer cells with oxygen and nutrients, allowing these cells to grow, invade nearby tissue, spread to other parts of the body, and form new colonies of cancer cells. Because cancer cannot grow or spread without the formation of new blood vessels, scientists are trying to find ways to stop angiogenesis. They are studying natural and synthetic angiogenesis inhibitors, also called anti-angiogenesis agents, in the hope that these chemicals will prevent the growth of cancer by blocking the formation of new blood vessels. In animal studies, angiogenesis inhibitors have successfully stopped the formation of new blood vessels, causing the cancer to shrink and die. Whether angiogenesis inhibitors will be effective against cancer in humans is not yet known. Various angiogenesis inhibitors are currently being evaluated in clinical trials (research studies in humans). These studies include patients with cancers of the breast, prostate, brain, pancreas, lung, stomach, ovary, and cervix; some leukemias and lymphomas; and AIDS-related Kaposi's sarcoma Among the agents which are currently in clinical trial, that have been described under the very broad umbrella of antiangiogenic agents, I have several slide examples, and these are from the NCI database. Marimastat, these are matrix metalloprotease inhibitors. Marimastat is well into Phase III randomized trials. It is a matrix metalloprotease inhibitor. The Bayer compound, Bay 125966, also, is well into Phase III trials, the Agouron compound, AG-3340. I am sure that many people in this room have worked with these agents or are currently working with these agents: COL 3, neovastat and the Bristol-Myers compound Among agents which inhibit the proliferation of endothelial cells directly are TNP-470 which is in Phase II clinical trials, both alone and in combination with cytotoxic therapies, thalidomide, squalamine, combretastatin-4A prodrug, and endostatin. Phase I clinical trials of endostatin should start, I believe, next one to two weeks Among agents which block the signal transduction of the angiogenic signal are the VEGF antibodies in Phase II clinical trials. The two Sugen compounds, SU5416 and SU6668, these are compounds which block the VEGF receptor signaling of the KDR receptor by binding to the ATP site in this molecule. Sugen compound 5416, as you know, is given intravenously, and the Sugen compound 6668 is given orally. Also, the Novartis compounds and interferon alpha continue to be explored as a potential antiangiogenic agent. Agents which are involved in the inhibition of the integrin signaling pathway include vitexin, the human form of LM609 which is an antibody to the integrin receptor which is in Phase II clinical trials, as well as a compound from Merck which I am not familiar with, EDM 121974, which is a small molecule integrin blocking agent. From the NCI, CAI continues to be explored as an inhibitor of calcium influx. The cytokine interleukin 12 may act directly as an antiangiogenic agent, but it is its up regulation of interferon gamma that is believed to be intimately involved in the mechanism of action of that agent, and IM 862. With the Bayer compound, the biphenyl matrix metalloprotease inhibitor, a similar randomized Phase III trial in small cell lung cancer is also well under way. We then looked at the antiangiogenic combination, starting therapy very early in the life of the tumor on day 4, when the tumor is just a seed and beginning to explode in its angiogenic activity. We are starting the angiogenic agent combination 3 days later on day 7, when the tumor is actually a fairly well-established nodule. The cytotoxic chemotherapy was administered on days 7-11. So we learned a lesson that cancer researchers learn again and again, and that is the tumor burden is very important. If we started the antiangiogenic therapy early on day 4 and treated at days 4-11 or 4-18, we obtained the greatest enhancement in tumor growth delay, but even if we had to limit the antiangiogenic therapy to the same 5-day period that we gave the cytotoxic therapy, we still had tumor growth delay of 29 days, which was better than cytotoxic chemotherapy alone. It was only when we administered the antiangiogenic therapy for the full 2-week period of days 4-18, which is really the full exponential growth phase of this tumor, that we obtained the greatest tumor response and with this therapeutic regimen. Forty to fifty percent of the animals were cured of the Lewis lung carcinoma. In Burkitt lymphoma, a malignancy of immature B cells, one characteristic feature is a chromosomal translocation....about 80% of the time, a translocation between the long arms of chromosomes 8 and 14 are involved; less frequently, a translocation between the long arms of chromosomes 8 and 2 or chromosomes 8 and 22. All three translocations found in Burkitt lymphoma involve a specific position on chromosome 8 (8q24) that is occupied by the cellular proto-oncogene/oncogene, c-myc, and specific positions on chromosomes 2, 14, and 22 Double reading of radiographs increases the likelihood of detecting pulmonary disease and, accordingly, physicians have an obligation to view the radiographic examinations performed on their patients, either with the radiologist or independently. It is also essential that the radiologist be proved with the clinical findings before he interprets the radiographs, a practice which will result in significant improvement in the accuracy of radiologic reports Prim Care 1976 Mar;3(1):107-36 Conventional chest radiography (CXR) is a poor diagnostic tool for detecting lung cancers at a surgically curable stage. To determine the visibility of peripheral small lung cancers on CXR, we retrospectively examined the usefulness of CXR using a consecutive series of 44 cases detected on CT screening and later confirmed by histopathology. All cases had been detected by low dose CT during a population based screening trial for lung cancer. The control group consisted of 48 chest radiographs of normal subjects. Tumour diameters ranged from 6 mm to 45 mm, with 95% (42/44) < or = 20 mm, and 5% (2/44) > 20 mm. CXR failed to detect 77% (34/44) of all cancers, including 79% (33/42) < or = 20 mm and 50% (1/2) > 20 mm. Of the 42 lung cancers < or = 20 mm, 74% (31/42) were located in the well penetrated lung zones and 71% (22/31) of these were missed on CXR. 26% (11/42) were concealed by hilar vessels, mediastinum, heart or diaphragm, and all (11/11) of these were missed on CXR. 93% (39/42) of the lung cancers < or = 20 mm were adenocarcinomas and 79% (31/39) of these were missed on CXR. 7% (3/42) were epidermoid carcinomas or small cell carcinomas and 66% (2/3) of these were missed on CXR. The overall accuracy of interpretation on CXR for lung cancers was 61%, sensitivity was 23% and specificity 96%. Although there was an association between presence of lung cancer and positive reading of CXR (chi 2 test of association, p < 0.05), the percentage of positive readings was only 23%. Thus, CXR was poor at visualizing CT detectable lung cancers of < or = 20 mm diameter, which are usually of very low density, and cannot be relied upon for detection of surgically curable small lung cancer. Br J Radiol 2000 Feb;73(866):137-45 Medical malpractice in diagnostic radiology: claims, compensation, and patient injury Radiology, 1987 Jul;164(1):263-6 Eighteen radiologists failed to detect 27 potentially resectable bronchogenic carcinomas revealed retrospectively on serial chest radiographs... Six consultant radiologists, who were biased by knowledge that the cases were of missed bronchogenic carcinoma, were individually shown the radiographs in 22 of the cases. Each consultant missed a mean of 26% (5.8 +/- 1.7) of the lesions. At least one of the six consultants missed the lesion in 16 (73%) of the cases. Radiology 1992 Jan;182(1):115-22 To examine the effect that a concise, objective, and potentially computer-extractable history would have on diagnostic accuracy in the interpretation of chest radiographs, we designed and tested a computerized patient-history form that could be integrated realistically into the clinical environment. We performed a series of studies in which 247 posteroanterior normal (79) and abnormal (168) chest radiographs were interpreted by four board-certified radiologists, both with and without accompanying clinical histories. The radiologists recorded their confidence rating of the presence or absence of one or more of the following abnormalities: interstitial disease, nodule, and pneumothorax. Analysis of receiver operating characteristics showed that, with the exception of interpretation of one abnormality by one radiologist, there were no statistically significant differences (p less than .05) between cases interpreted with and without the history form for any of the radiologists. The results of our study suggest that knowledge of clinical history does not affect the accuracy of chest radiograph interpretations for the detection of interstitial disease, nodules, and pneumothoraces. These results may not be applicable to other clinical situations. Comment in: AJR Am J Roentgenol 1990 Sep; 155(3):653-4; Comment in: AJR Am J Roentgenol 1990 Dec; 155(6):1342-3 Tumor cells must separate from each other, overcoming the usual restrictions imposed by cell (adhesion) and cell-cell contact inhibition. As well as the tumor expanding by sheer weight of numbers, it encroaches into the local tissue by an active process involving lysis of local cells and degradation of the extracellular matrix (ECM). Following separation from each other and degradation of the surrounding stroma, tumor cells must then be able to move into the region cleared by the action of their enzymes by an active process of cell motility. Tumor cells must also promote their own vascularization by inducing capillary growth into and around the tumor by a process known as angiogenesis. Angiogenesisis is important to the primary tumor in two ways. An adequate blood supply is essential so that the rapidly proliferating cells can obtain nutrients and oxygenation, otherwise mass necroses (cell death) will halt the growth of the cells. In addition, extensive vascularization of the tumor places more tumor cells within easy access of the circulation. ... Hence, effectve angiogenesis by tumors is important both for continued local growth of the tumor and for propagation of the cells to distant sites. Therefore, local invasion by tumor cells involves the activation of genetic programs which allow them to pass away from the confines of the primary tumor mass, through any surrounding tissues and, eventually to reach a blood or lymph vessel. Initially, we note that every school should have an established anti-smoking program which many do already. However, we see the following deficiencies in educational programs: 1. Reluctance to Bring Cancer patients in to Discuss Their Pain and the Consequences of Smoking As a trial lawyer, my experience is in persuasion. No attorney would ever present a case of serious injury in a dry, clinical fashion; instead he would demonstrate that the injury affected real people in a devastating way. Likewise, with smoking, we need to bring in smokers to discuss their cancer, and the devastating impact of smoking. 2. Have Evidence Presented in a Realistic Stark Fashion Which Accurately Reflects the Hazards of Smoking. The consequences of smoking are serious, why minimize them. Films should display a throat cancer victim with a laryngectomy (voicebox removal or a lung cancer patient with metastatic cancer. These are not exaggerated risks; they are an accurate portaryal of the dangers of tobacco.
24.4 RECOMMENDATIONS FOR CLINICIANS The growth and development of new tissue in vivo requires adequate transport of nutrients to the tissue and removal of waste products. When new tissue is small (i.e. less than 1-2 mm diameter) local diffusion will provide sufficient mass transport to and from the site. Upon further growth, the requirements for mass transport exceed the capacity of diffusive flux, so a blood supply must be developed for the new tissue. The process of creating a stable blood source is known as angiogenesis and is mediated by many molecular entities defined as angiogenic factors. Angiogenesis is required in tissue engineering of replacement tissues and organs to insure the new tissue has adequate blood supply for mass transport to promote adaptation and viability of the engineered tissue in the patient. For cases of undesired tissue growth in cancerous tumors and synovial pannus formation in rheumatoid arthritis, inhibition of angiogenesis is a major clinical goal. Therefore, the discovery of molecular mediators of angiogenesis and understanding the relationships between these angiogenic factors is critical to developing successful strategies to either enhance or inhibit angiogenesis. http://www.glycotech.com/angio/angiogenesis.htm CHAPTER NINE RADIATION 9.1 WHAT IS RADIATION 9.11 How Radiation Works The Virtual Hospital explains how radiation works: Radiation therapy (RT) is the use of focused high energy electromagnetic waves (photons) or electrons to treat cancerY . These beams strike and transfer varying amounts of energy to carbon, nitrogen, and hydrogen atoms in or near the DNA chains in the nucleus of cells thereby producing breaks, deletions, or cross linkages in the DNA chains, some of which are lethal to the cell. A few cells may die within minutes after being hit, but after sustaining lethal damage most cells survive until they attempt to go through mitosis and cell division. Cells are most sensitive to RT when they are in mitosis or shortly after cell division. Tissues in which a high proportion of cells are actively multiplying tend to be more sensitive to high energy photons than are tissues where most cells divide relatively infrequently. By giving daily doses of RT large enough to kill a high proportion of the rapidly dividing cancer cells while killing only a small proportion of the more slowly dividing normal tissue cells in the area, a malignant tumor can be eradicated. The factors which determine whether or not a cancer can be eradicated by radiation therapy include the sensitivity of the tumor to RT, the volume of tumor cells to be eradicated and the tolerance of the most radiation sensitive vital tissues in the area. This latter factor is influenced by how effectively these structures can be shielded from the irradiation received by the tumor and whether the vital tissues can be sacrificed without mortality. Thus, RT is most effective when the volume of tumor cells to be treated is small, i.e. microscopic deposits of tumor cells left behind after the visible part of a tumor has been surgically excised, or when the tumor can be given a high dose of high energy photons or electrons without destroying the function of the vital structures in the areaY Virtual Hospital, 9.12 Persons Involved. Jefferson Hospital in Philadelphia provides a summary of what will occur: A Before beginning your radiation therapy, we will design a treatment plan uniquely tailored for you. This step usually requires two visits to the department before your actual treatment begins. Your first planning visit begins with a simulation, which takes about two hours. Radiation therapists, working under the supervision of your radiation oncologist, perform the simulation. At the beginning of this session, the radiation therapist will photograph you for future reference and identification. At times, you may have a positioning mold made to assist you in holding a specific posture. If so, the radiation therapist will ask you to lie on a table to make a styrofoam cast mold of your upper body. This mold will be used during treatment to be sure your body position is the same each day. We may ask you to hold on to a bar positioned above your head. This moves your arms out of the treatment field and allows us to use any angles of the radiation beam necessary for your treatment. The therapist will mark your skin and your mold with a marker, and place a few permanent freckle-size tattoo marks on your skin for indelible reference points for the treatments. If contrast is needed to visualize the planning fields, the nurse will start an intravenous (IV) line to allow us to inject contrast. A separate consent for contrast will be obtained along with an explanation of possible side effects. A CT/simulation of your chest will be done in the department. Your radiation oncologist will use the information with sophisticated computers to create a 3-dimensional image of your chest as seen from all angles.Your radiation oncologist will work with physicists and dosimetrists to plan the direction and shape of the radiation beams used to treat you. This will help assure that the entire intended treatment area is covered and the amount of radiation directed to the surrounding normal tissues is minimized. When you return for the second and final step in the treatment planning process, the radiation therapists will take beam films (port films). You will be positioned as you were during simulation under the radiation treatment machine, and X-ray images will be taken from each of the beams that will be used in your treatment. Your radiation oncologist will check that each of these is accurate in relation to the plan before your treatment begins. This second step serves as a "dry run" or check of the treatment plan. It is never used to evaluate the cancerY . Treatments are given daily, Monday through Friday, for two to seven weeks. You should allow about one hour for each treatment session. We will try to accommodate your request for a daily treatment time, which can be between 8 a.m. and 4:45 p.m. After undressing and putting on a hospital gown, you will be asked to come into the treatment room where the radiation therapist will precisely position you under the treatment machine. The machine, which produces radiation (or high-energy X-rays), is called a linear accelerator. During the actual treatment you will be alone in the room, but the therapists can see and hear you at all times through a monitoring system. You will not feel anything during the treatment but you may hear the machine turn on and off. The radiation therapists may come in and out of the room to set up each of the planned positions. The total time in the room will be 10 to 20 minutes, but the actual treatment takes only a few minutes. Once you are off the treatment table, you are not "radioactive."Your radiation oncologist oversees your entire treatment. During the course of treatment you will have weekly appointments with the attending radiation oncologist, a resident physician and a nurse to evaluate your response to treatment and any side effects. Please plan your time to allow for a longer visit on these appointment days. At these appointments, feel free to discuss your concerns and ask any questions you may have. If you would like to speak with the doctor or nurse at any time between these visits, ask the radiation therapist to contact them.@ Wasik, A Patient's Guide to External Radiation Therapy for Lung Cancer, Bodine Center for Cancer Treatment Thomas Jefferson University Hospital, www.kcc.tju.edu/RadOnc/lun.htm 9.2 THE ROLES OF RADIATI0N 9.21 Reducing Pain or Symptoms of Disease One important role of radiation is palliative, that is, to reduce pain in eminating from specific areas, increase function, A Often 5 to 10 treatments given over 12-14 days will open airways and improve pulmonary function, allow a patient's pneumonia to be brought under control with antibiotics, terminate hemoptysis, or shrink metastatic deposits in the brain allowing focal and generalized neurologic abnormalities to clear. These treatments can also slow or stop the growth of a tumor deposit in bone, and prevent a fracture or allow a fracture to heal. Properly administered radiation therapy can also reduce the size of metastases compressing the spinal cord, thereby preventing paralysis or reversing the superior vena cave compression syndrome. Virtual Hospital@ 9.22 Cure Surgical removal of the tumor is the primary curative option. Ideally, a surgeon in early stage disease can remove an entire tumor. With more advanced disease, it is difficult for radiation to eradicate a cancer which has spread to various parts. 9.23 9.3 THE INTERACTION BETWEEN RADIATION AND OTHER FORMS OF TREATMENT If the last 5 decades saw the development of chemotherapy, radiation, and other forms of treatment, this decade is concentrating on the interrelationship between treatment modalities. That is, how does chemotherapy impact radiation, will tumor subject to anti-angiogenesis drugs be easier to radiate. We are recognizing the importance of multimodal forms of treatment. and standard treatment of stage 3 and many stage 4 non-small cell patients is radiation and chemotherapy. 9.31 Chemotherapy and Radiation for Non-Small Cell Patients. One researcher discusses how to make the combination of vinorelbine, a chemotherapy drug, and radiation most effective by looking at cell cycle: In this cell line radiation produced a block in the G2/M phase of the cell cycle, with the maximum block (60% to 70%) occurring 10 hours after treatment. The greatest potentiation was seen when irradiated cells were exposed to vinorelbine after they had plateaued in the G2/M phase of the cycle. Vinorelbine given early after irradiation, when only 10% to 30% of the cells were in G2/M, produced survival ratios similar to those of controls treated with radiation alone. In A549 cells radiation induced a G1 block. In this case, vinorelbine was unable to potentiate the effects of radiation. These studies show that vinorelbine can potentiate the antitumor effects of radiation and that the potentiation is cell cycle-dependent, with the maximal effect being obtained when the cells are in the G2 phase Edelstein, Potentiation of radiation therapy by vinorelbine (Navelbine) in non-small cell lung cancer. Semin Oncol 1996 Apr;23(2 Suppl 5):41-7 Clinical trials continue to try to assess the optimal combination and timing of chemotherapy and radiation. 9.32 Chemotherapy and Radiation for Small Cell Patients A 1997 article summarizes the research, A Although chest irradiation has been used to treat SCLC for over four decades, its standard role in the management of limited-stage disease was established only during the last decade. Multiple prospective randomized trials have shown that the addition of thoracic radiation therapy to chemotherapy usually halves local failure rates, from >60% with chemotherapy alone to about 30% with chemoradiation therapy. Kumar, The role of thoracic radiotherapy in the management of limited-stage small cell lung cancer: past, present, and future, A Chest 1997 Oct;112(4 Suppl):259S-265S The notion of stabilizing disease has become almost as important as eradicating it. 9.4 RADIATION SIDE EFFECTS Radiation generally does not involve substantial side effects. A lung cancer support group describes some typical ones: A Most people begin feeling tired after one or two weeks of radiation treatment to the chest area. This feeling may slowly increase as therapy continues. It does not mean that cancer is getting worse. Resting more during treatment is advised. The fatigue usually wears off within a week after treatment is finished. A dry or sore throat and difficulty in swallowing are minor, temporary complications of radiation therapy. These problems may be noticed within a few days to two weeks after treatment has begun. These symptoms are caused by the radiation irritating the tissues in the throat and usually only last a week or two. Although eating may be difficult when these symptoms are present, a soft or liquid diet may be helpful until the discomfort subsides. Milkshakes, cream soups, or prepared liquid supplements are good choices. The skin may also be affected by radiation treatments. Skin in the treatment area may look and feel red, irritated, sunburned, or tanned. Loss of hair (only in the treated area) may occur, but it will grow back after about three months. Care for the skin should be discussed with your nurse or doctor. Ask about lotions that can be used to soothe the irritation. Months after radiation treatment is complete, some people who have received radiation to the lungs experience a slight hardening of the shoulder and chest muscles that causes aching and stiffness. Your nurse or doctor may recommend exercises to do while you are receiving the treatments to minimize the chance of this happening. Radiation therapy to the chest usually does not cause nausea, but if it does occur, your physician can provide antinausea medications. .@ www.alcase.org There are 4 broad phases of the cell cycle: G1 (and G0 ), S, G2, and M.
The G1 (Gap 1) phase is characterized by gene expression and protein synthesis. This is really the only part of the cell cycle regulated primarily by extracellular stimuli (like mitogens and adhesion). Anyway, this phase enables the cell to grow and to produce all the necessary proteins for DNA synthesis. Why is this important? Well, it primes the cell to enter the next phase: S (Synthesis) phase. During the S phase, the cell replicates its DNA...so it now has 2 complete sets of DNA. Why would the cell want 2 complete sets of DNA? This allows the cell to divide into two daughter cells, each with a complete copy of DNA. But, before the cell can do this, it needs to enter the third phase of the cell cycle: the G2 (Gap 2) phase. During the G2 phase, the cell again undergoes growth and protein sythesis (it needs enough proteins for 2 cells!)...priming it to be able to divide. Once this is complete (by the way, there are many "checkpoints" along the way!), the cell finally enters the fourth and final phase of the cell cycle: the M (Mitosis) phase. During the M phase, the cell splits apart (called cytokinesis) into two daughter cells. Now, the cycle has been completed! What do the cells do know? Well, there are two choices...it can either start the cycle again by entering G1, or it can become quiescent by entering G0 (remember me mentioning this phase earlier?) were among the first to describe the finding that K-ras mutations may occur early during the development of lung cancer and in the subgroup of adenocarcinoma. Mao et al developed a very sensitive and specific PCR-based assay to examine sputum samples from a population of patients, some of whom were diagnosed with lung cancer at a later time. Using this method, the group was able to detect in 8/10 patients the identical mutation identified in the primary tumor in at least one sputum sample, 1-13 months prior to clinical diagnosis. Scott et al. established a sensitive PCR/Ligase chain reaction-based detection system and were able to detect K-ras codon 12 mutations in 84% of the specimens examined in bronchoalveolar lavage fluid (BAL) of patients at high risk for second primary cancer. Ronai et al. showed the existence of K-ras gene mutations in the sputum of patients without lung cancer. This research group also showed that mutations of the K-ras gene were much more frequent in lung tissue of cancer patients than in a non-tumor population. Ronai et al. used the enriched PCR method to detect cells with a mutated K-ras gene in the sputum of non-cancer patients, which indicates that: (i) only a minority of cells carry this mutation; and (ii) mutations in this gene might be an early event in the tumorigenesis of lung tumors 1) Cancer cells located in an organ such as the lung manage to break down the barrier confining them to that organ. A Local invasion by tumor cells involves the activation of genetic programs which allow them to pass away from the confines of the primary tumor mass, through any surrounding tissues and eventually to reach of blood or lymph vessel.@ (1) A In summary, this study described the expression pattern of cadherins and catenins in normal bronchial epithelium. The authors' results show that these proteins involved in cell-cell adhesion are abnormally expressed in the majority of non-small cell lung carcinomas.@ 2) The tumor cells then move to an adjoining lymph node or blood vessel, and the tumor may thereafter establish a source of blood supply in the new location. 3) The tumor cells sometimes can manage to penetrate the protective barrier in another organ, called the basement membrame. Cells move into the new organ, and establish a source of blood supply for future growth. This process by which tumors establish new sources of blood supply is called angiogeneses and a major source of cancer research is the creation of anti-angiogenesis drugs to prevent or impair this process. NCI provides a more detailed look at stage 3, dividing treatment between III A and B, A Depending on clinical circumstances, the principal forms of treatment that are considered for patients with stage III non-small cell lung cancer (NSCLC) are radiation therapy, chemotherapy, surgery, and combinations of these modalities. Although the majority of these patients do not achieve a complete response to radiation therapy, there is a reproducible long-term survival benefit in 5%-10% of patients treated with standard fractionation to 6,000 cGy, and significant palliation often results. Patients with excellent performance status and those who require a thoracotomy to prove that surgically unresectable tumor is present are most likely to benefit from radiation therapy.[1] Because of the poor long-term results, these patients should be considered for clinical trials. Trials examining fractionation schedules, endobronchial laser therapy, brachytherapy, and combined modality approaches may lead to improvement in the control of this regional disease.[2] One prospective randomized clinical study showed that radiation therapy given as three daily fractions improved overall survival compared to radiation therapy given as one daily fraction.[3][Level of evidence: 1iiA] The addition of chemotherapy to radiation therapy has been reported to improve survival in prospective clinical studies that have used modern cisplatin-based chemotherapy regimens.[4-7] A meta-analysis of patient data from 11 randomized clinical trials showed that cisplatin-based combinations plus radiation therapy resulted in 10% reduction in the risk of death compared with radiation therapy alone.[8] The optimal sequencing of modalities and schedule of drug administration remains to be determined and is under study in ongoing clinical trials.[9] Patients with N2 disease apparent on chest radiograph and documented by biopsy or discovered by prethoracotomy exploration have a 5-year survival rate of only about 2%. The use of preoperative (neoadjuvant) chemotherapy has been shown to be effective in these clinical situations in two small randomized studies of a total of 120 patients with stage IIIa NSCLC.[10,11] The 58 patients randomized to three cycles of cisplatin-based chemotherapy followed by surgery had a median survival more than three times as long as patients treated with surgery but no chemotherapy in both these studies. Two additional single-arm studies have evaluated either two to four cycles of combination chemotherapy or combination chemotherapy plus chest irradiation for 211 patients with histologically confirmed N2 stage IIIa NSCLC.[12] Sixty-five percent to 75% of patients were able to have a resection of their cancer, and 27%-28% were alive at 3 years. These results are encouraging, and combined-modality therapy with neoadjuvant chemotherapy with surgery and/or chest radiation therapy should be considered for patients with good performance status who have stage IIIa NSCLC. Although most retrospective studies suggest that postoperative radiation therapy can improve local control for node-positive patients whose tumors were resected, it remains controversial whether it can improve survival.[13,14] One controlled trial in patients with completely resected stage II or III squamous cell lung cancer failed to demonstrate a survival benefit for patients who received postoperative irradiation, although local recurrences were significantly reduced.[15] A meta-analysis of 9 randomized trials evaluating postoperative radiation versus surgery alone showed no difference in overall survival with adjuvant radiation in patients with stage III disease.[16][Level of evidence: 1iiA] It will be important to determine whether these outcomes can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals. In two controlled trials with carefully staged surgically resected patients, adjuvant combination chemotherapy with cisplatin, doxorubicin, and cyclophosphamide produced modestly increased disease-free survival and a trend toward improved survival, especially in the first year after surgery.[17-19] Based on these data, participation in clinical trials evaluating adjuvant therapy after surgical resection should be encouraged. this study shows that a preresectional chemotherapy regimen of cisplatin in combination with ifosfamide and mitomycin does improve the clinical outcome in comparison with surgery alone The 5-year survival for patients with stage IIIA N2 non-small cell lung cancer is variable but tends to be less than 5% for patients treated with surgery plus radiotherapy . These results do not differ substantially from those obtained with irradiation alone . The purpose of neoadjuvant chemotherapy is the eradication of micrometastatic disease, which is almost invariably manifest when ipsilateral mediastinal or subcarinal lymph nodes (N2) are involved. A chest computed tomography (CT) imaging study may show lymph nodes extending throughout many mediastinum regions, including the aortopulmonic window, the paratracheal region, and the precarinal and subcarinal areas. A mediastinoscopic examination can then be used to confirm metastatic lymph nodes. Three randomized phase III trials reported that administering cisplatin-based chemotherapy before surgery to patients with resectable stage IIIA lung cancer improved survival results over those obtained with surgery alone or surgery plus radiotherapy . The MD Anderson investigators have recently updated the long-term follow-up of a selected high-risk population of patients with advanced but still resectable non-small cell lung cancer (NSCLC), T1-3N2M0 or T3-4N0M0 We can call the messages that are sent growth factors. There are a different growth factors with perhaps the most important, tumer angiogenesis factor, also called vascular endothelial or vaand epidermal growth factor. However, they each perform certain normal and replenishment functions in the body which malfunction with a cancer. Chemotherapy aims to kill cancer cells. A new group of drugs called anti-angiogenesis drugs, aims to frustrate angiogenesis, the creation of sources of blood supply by cancer cells. The tumor secretes a substance known as tumor angiogenesis factor (TAF) which induces blood vessels to produce new capillaries that grow toward the tumor and finally connect with it.@ American Cancer Society, Informed Decisions 19 (1997). Drugs designed to inhibit this process are called anti-angiogenesis drugs. Things to do TABLE OF CONTENTS 1.36 Clinical Trials There are a number of clinical trials dealing with proteins, growth and tumor-suppressor genes. A clinical trial is an experiment performed after a substantial amount of background work to see how a particular drug performs. For example, a scientist might try to inject tumor-suppresor genes to ascertain if the growth and duplication process could be shopped or hindered. One form of gene therapy involves injecting materials to change genes to eliminate or minimize their harmful characteristics. Gene therapy is still experimental with lung cancer, though a number of clinical trials deal with anti-angiogenesis drugs, drugs to inhibit the metastatic process. Chemotherapy is the use of drugs which is various ways try to kill the cancer cells. Chemotherapy may target those cells which duplicate and while killing cancer cells, can also impact some normal cells. The basic problem is to kill enough cancer cells while not impairing other bodily functions, with scientists continuing to refine drug dosage to achieve maximum results with minimum side effects. Today, multi-modal chemotherapy, the use of various drugs which work in different ways, in combination, has become standard. We know that using a group of drugs achieves the best results for lung cancer, though we do not know what is the optimum mix, with different clinical trial achieving varying results. Chemotherapy has some success in extending life, but generally does not provide a permanent cure for lung cancer. There are reports of partial and total remission associated with chemotherapy, and cases of cure, but it would be inaccurate to say that the average patient with advanced lung cancer would be permanently cured. Ff 1.36 Clinical Trials There are a number of clinical trials dealing with proteins, growth and tumor-suppressor genes. A clinical trial is an experiment performed after a substantial amount of background work to see how a particular drug performs. For example, a scientist might try to inject tumor-suppresor genes to ascertain if the growth and duplication process could be shopped or hindered. One form of gene therapy involves injecting materials to change genes to eliminate or minimize their harmful characteristics. Gene therapy is still experimental with lung cancer, though a number of clinical trials deal with anti-angiogenesis drugs, drugs to inhibit the metastatic process. Chemotherapy is the use of drugs which is various ways try to kill the cancer cells. Chemotherapy may target those cells which duplicate and while killing cancer cells, can also impact some normal cells. The basic problem is to kill enough cancer cells while not impairing other bodily functions, with scientists continuing to refine drug dosage to achieve maximum results with minimum side effects. Today, multi-modal chemotherapy, the use of various drugs which work in different ways, in combination, has become standard. We know that using a group of drugs achieves the best results for lung cancer, though we do not know what is the optimum mix, with different clinical trial achieving varying results. Chemotherapy has some success in extending life, but generally does not provide a permanent cure for lung cancer. There are reports of partial and total remission associated with chemotherapy, and cases of cure, but it would be inaccurate to say that the average patient with advanced lung cancer would be permanently cured. DISCLAIMER This book is intended to provide general information about lung cancer. It is not intended to and should not be used for the purpose of medical diagnosis or treatment. All information is supplied as is, and we make no warranty or guaranty regarding the correctness, or completeness of the information supplied. Please consult with your physician for any diagnosis or treatment. : From September 1993 to December 1998, 1669 individuals underwent a biannual screening program for lung carcinoma. The program included posteroanterior radiograph, sputum cytology, and low dose spiral CT at a for-profit organization: The Anti-Lung Cancer Association (ALCA). A total of 9993 examinations were carried out. The low dose spiral CT parameters used were 120 kvP, 50 mA, 10-mm collimation, and 2:1 pitch. RESULTS: Peripheral lung carcinoma was detected in 31 of 9993 examinations (0.3%). Of the 31 cases, 24 tumors (77%) were detected by low dose spiral CT but were not visible on standard chest radiography. Twenty-two of the 24 tumors were Stage IA (T1N0M0, according to staging system revised in 1997). CONCLUSIONS: Low dose spiral CT shows promise for lung carcinoma screening. The effectiveness of the technique for the detection of minute lung lesions remains to be established. Routine use of the technique will require resolution of several issues. These issues include the establishment of CT diagnostic criteria, the development of a diagnostic support system, the establishment of methods for definite diagnosis, and assessments of efficacy. The large clinical studies of lung cancer screening carried out more than 20 years ago were interpreted as evidence against screening. Those studies have been recently reassessed in the light of methodologic flaws in the randomization of subjects at risk for lung cancer. There is no evidence to support the former conclusion that screening is ineffective and the consequent official recommendation not to screen for lung cancer. The hypothesis of overdiagnosis of lung cancers diagnosed by screening is false. Clinical evidence supports the concept that the current dogma against screening for lung cancer is untrue. Indeed, the 5-year survival rate of patients with NSCLC detected in stage I and radically resected ranges from 60% to 80%. This rate is in sharp contrast to the 10% survival rate of stage I NSCLC not resected. About 90% of lung cancer cases are detected among smokers and former smokers; these well-known at-risk subjects should be offered a screening test with the goal of detecting the disease when it is in stage I. It is expected that the techniques for early detection of lung cancer will be refined and become more sensitive in the near future, so that it will be possible to detect an increasingly large proportion of lung cancers when they are truly in stage I (i.e., nonmetastatic) and curable by radical surgical resection. Low-dose helical CT scan is currently believed to represent a very useful technique for screening for lung cancer, with a higher sensitivity than chest radiograph screening. Chest radiography for lung cancer screening, however, is cheaper and ubiquitously available, and it should still be recommended if CT scan is locally unavailable. As underscored in a recent commentary in The Lancet, the existing public health policy discouraging the screening for lung cancer is in urgent need of reconsideration. Dominioni Screening for Lung Cancer Chest Surg Clin N Am 2000 Nov;10(4):729-36