Introduction to Radiation Oncology [PDF]

Introduction to Radiation Oncology St Vincent’s Hospital Gerald Fogarty

Radiation Oncology – talk plan  

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How it works – process, fractionation, targeted therapy, tissue preservation Side effects – acute and late Intent Delivery – Teletherapy (EBRT), Brachytherapy Prostate brachytherapy Results Career

Process  

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New patient – in clinic - RO decides if RT indicated + what intent of therapy is Planning – in dept - includes preparation eg dental RV, simulation, computer planning, acceptance of plan by RO. Concurrent Treatments organised. Treatment – in dept - fractionated, development of acute effects 0-3/12, treatment rvs Followup – in clinic - why? - disease recurrence, development of late effects 6mths +

Radiation Oncology – how it works  

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DNA is the genetic material in the cell nucleus Must be functioning well for cell to divide and therefore for cancers to grow or organs to maintain themselves radiation causes damage to DNA- doesn’t work so cell eventually wears out and dies – doesn’t divide – death at cell division Oxygen fixes RT changes, works better if cells well oxygenated – fix blood count, don’t smoke

Radiation Oncology – how it works 

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ionizing radiation causes double stranded breaks in DNA Leads to immediate death or apoptosis, or death at cell division

Radiation Oncology – death at cell division

Radiation Oncology – targeted therapy 

Aim of all cancer therapy is to increase death of tumour cells, minimize damage to normal cells – maximize therapeutic ratio.  Radiation is a localized treatment unlike chemo - physically targeted  Lots of effort to ensure only physical target is treated

Radiation Oncology – biologically targeted 

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In irradiated volume – normal cells can repair - only cancer cells lack DNA radiation repair proteins – this difference is exploited in RT However, if give all dose in short time – repair capacity of normal cells swamped – leads to side effects Treatment is fractionated – give a small dose each day – normal cells repair between the fractions, cancer cells do not. Other reasons for fractionation include other “r”s – reoxygenation, redistribution, repopulation

Radiation Oncology – biologically targeted 

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Therefore radiation is good for normal tissue preservation - can select out tumour from normal tissue eg lumpectomy + RT has replaced mastectomy for early Br Ca ie RT is additional or adjuvant to surgery Women can keep breast H+N larynx preservation

Tissue preservation

Tissue preservation 6 months post rt

6 months post rt close up

Radiation Oncology – acute side effects or those which happen during treatment 

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Due to damage in normal cells that have a similar life cycle to cancer cells – but only in irradiated field! cells that are normally dividing to maintain their function – based on adult stem cell populations hierarchically organized - eg gut, mucosa, bone marrow, skin This explains side effects and timing from any cytotoxic therapy - diahorrea - 3 days, mucositis – 7 days, WCC depletion - 7 days, loss of hair 14 days

Radiation Oncology – acute side effects Worse with increased or more rapid dose, when given with chemo or poor nutrition – normal cells within the RT field unable to repair properly – need to maintain weight  Think of this as a sterile acute inflammation – coz it is! Case Study follows  Needs specialist nursing care – suddenly goes!  When treating with radical intent, we push people thru this – cruel to be kind - these cells will recover – is necc to cure the cancer, is rapidly dividing at end of XRT finishing course in certain time frame is essential – accelerated repopulation 

Acute side effects necc for cure

Close up pre rt

Axial CT scan of axilla

Lat after 27 Gy

One week after 45/15/5 - Lat

Two weeks after 45/15/5 Close Lat

Three weeks after 45/15/5 - Ant

6 weeks post 45/15/5- Lat

6 weeks post 45/15/5-Close Lat

18 weeks post 45/15/5-lat

Radiation Oncology – late side effects 

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Think of this as a sterile chronic inflammation – dominated by fibrosis – loss of gland tissue eg saliva, and elasticity – loss of rectal reservoir effect Take time to develop – 6 months to 2 yrs following RT Caused by big dose per fraction Do not get better Determine maximum doses given to certain organs - bad ones are fistula and tissue decompensation

30 years after 40 Gy in 10 fractions ( 2 weeks)

Modern Breast Rt – 5 weeks

AxD +46/23/5 Fin 99 46/25/5 Fin 05

Radiation Oncology – intent 

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Radical intent -To cure or at least control for a long time eg 60Gy in 30 # @ 5per wk 60/30/5 – push people thru acute effects Issues of late effects – therefore small daily doses for a long time to get sufficient dose – 2 Gy/d Palliative intent – life quality not quantity - patients not going to live long enough to exhibit late effects – bigger fraction sizes, overall less dose 36/12/3, shorter overall treatment times

Radiation Oncology - delivery 

Teletherapy – External Beam Radiotherapy (EBRT) – radiation beamed into patient from a distance

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Brachytherapy – radioactive sources put into or onto a tumour

Radiotherapy Physical Characteristics 

Inverse square law – intensity falls as square of distance from source Brachytherapy range

Teletherapy range

1.2 1 0.8 Intensity 0.6 0.4 0.2 0 1

2

3

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Distance from Source

5

Radiotherapy Physical Characteristics - Teletherapy external beam (EBRT)  from a source relatively distant  slow fall off in tissue  ideal for irradiating large volumes but will collect innocent normal structures in entrance and exit paths  Types SXRT, DXRT, Megavoltage – skin sparing 

Skin sparing - 6 MV Photons Skin Surface

10 cm depth

EBRT for Prostate Cancer

Position of rectum unknown

Radiotherapy Physical characteristics - Brachytherapy source is close to tumour  high dose to nearby tumour  rapid fall off  low dose to distant normal tissue  Types – appositional, interstitial, intracavity  Ultimate conformal therapy 

Seeds I 125 – 60 day half life  Low dose rate – like multiple very small fractions  Photons emitted have very little penetration – ideal for no ECE, preservation of urethra yet can get 145Gy into prostate  Similar to surgery – but gland preserved 

Interstitial Brachytherapy – Prostate seeds – Low dose rate (LDR) permanent

Seeds vs RP for low risk 

No RCT

Biochemical freedom from failure Brachytherapy vs Radical Prostatectomy in low risk patients % free of failure

100 80 60

Mt Sinai JHH*

40 20 0 0

1

3

5

10

Years

*J Urol 169, 2003

New Techs

Multileaf collimators

IMRT MLCs move during treatment delivery so modulating the dose cloud  3DCRT Vs IMRT is like Plain XR vs CT  Selected centres only  Need resources, long time on linac 30mins - rationed to few radical cases  New ways to deliver IMRT – VMAT, cyberknife, tomotherapy –VMAT in Aust  Mater Sydney is only NSW site for VMAT 

VMAT IMRT Volumetric modulated arc therapy (VMAT)  Varian trade name of “Rapid ARC” RA IMRT  IMRT can be delivered in 3.5 mins per fraction  Better dosimetry  Less motion during the fraction  Better patient comfort less time on bed  More thru put – other cases eg palliative can be treated  Mater is now site for WBRT trial 

NCF and WBRT Neurocognitive function (NCF) is maintained by hippocampus (Manda).  NCF problems post WBRT have been reported. (DeAngelis, Chang trial)  3D Conformal WBRT irradiates all the brain including both hippocampi  Hippocampi can now be avoided with IMRT 

VMAT IMRT with simultaneous integrated boost (SIB) 1 Brain metastases (BM) especially pts with 1-3 BMs tend to spare the hippocampi (1/53; 0.97% Marsh) - 8 mel pts none with mets in hipp/limbus  Brain mets are now being treated alone with either stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT). Difference is the latter is fractionated. 

VMAT IMRT with SIB 2 

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Using IMRT with mets that are amenable to SRS/SRT, the mets alone can be treated as in the usual stereotactic fashion, or the mets can be treated concurrently with WBRT using a simultaneous integrated boost (SIB) BMs are treated to a higher dose needed for macroscopic sterilisation – 60-70Gy Rest of the brain is treated to the usual dose for microscopic sterilization – 30-36Gy VMAT – can give simultaneous SRS to mult lesions – may replace dedicated SRS machines for BM treatment – also easy and quick, only mask no fixed head frame

Hippocampi can be contoured with aid of MRI coregistration

IMRT Dosimetry of WBRT with hippocampal sparing with SIB of mets

Dose Volume Histogram (DVH)

Stereotactic Body Rt (SBRT) or Stereotactic Ablative RT (SABR) With IGRT, IMRT, VMAT can really treat conformally  Can get big dose per fraction to tumour only  Needs attention to immobilization and daily IGRT 

Example-symptomatic T6 met

3D CRT – bone marrow, spinal cord in field

SBRT or SABR – sparing of BM, sp cord

Radiotherapy and Immunology

Immunology and RT 1 

Multiple compartments of the immune system play a role in tumour rejection.  Antitumour T cells are endowed with antigen specificity and memory  T cells can be excluded by tumour negative regulatory mechanisms or immune checkpoints.  Activation of these is required for tumour rejection  Antitumor T cells are reactivated by blocking these blocking mechanisms.

Immunology and RT 2 

Neoantigens generated by cancer genetic instability play a key role in effective T-cell– mediated tumor rejection.  RT targeted to a cancer can increase release of autologous neoantigens to the immune system.  Cell death induced by radiation generates danger signals and inflammatory cytokines that promotes the ability of dendritic cells to cross-present released antigens to T cells.

Immunology and RT 3 Radiation’s in-field effects extend to all compartments of the tumor microenvironment  Radiation’s out of field effects - convert the irradiated cancer into an effective in-situ personalized tumor vaccine – rejection of systemic metastases (a phenomenon known as abscopal effect) when complemented by immunotherapy 

Issues 1 

Conventional vs Stereotactic  Lymphocytes very radiosensitive – in vivo dosimeter  Conventional irradiates more tissue – ends in lymphopeania - destroys immuno helping effect?  Stereotactic –SABR – ablation increases antigen yield? Now asked by MOs for this.

Stereotactic Body Rt (SBRT) or Stereotactic Ablative RT (SABR) 

Can get big dose per fraction to tumour only  Needs careful attention to immobilization and daily image guidance  Soon to arrive at SVH

Issues 2 

Regression seen often in melanoma  Abscopal – never seen by me  Recent interest started with Postow et al. N Engl J Med. 2012;366 (10):925-931.  Ipi +RT in Mel

Future 

RT + immune therapy trials  Mech unknown – T cell trafficking between mets?  Remove primary tumour?  Has changed outlook in melanoma – how to give RT?  Will need RCTs

Thank you! Questions!