Adjuvant Cytotoxic and Targeted Therapy [PDF]

Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer © AGO

e. V.

in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2014.1

Adjuvant Cytotoxic and Targeted Therapy

Adjuvant Cytotoxic and Targeted Therapy © AGO

e. V.

in der DGGG e.V. sowie in der DKG e.V.

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Version 2002: Möbus / Nitz



Versionen 2003–2013: Harbeck / Jackisch / Janni / Loibl / von Minckwitz / Möbus / Müller / Nitz Schneeweiss / Simon / Solomeyer / Stickeler / Thomssen

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Version 2014: Untch / von Minckwitz

Guidelines Breast Version 2014.1

www.ago-online.de

Subtype-specific General systemic Strategies © AGO

e. V.

in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2014.1

HR+/HER2- and “low risk”: 

Endocrine therapy without chemotherapy

AGO ++

HR+/HER2- and “high risk” 

Conventionally dosed AT-based chemotherapy



Dose dense & escalated in case of high tumor burden



Followed by endocrine therapy

++ + ++

HER2+ 

www.ago-online.de

Trastuzumab plus •

Sequential A/T-based regimen with concurrent T + H

•

Anthracycline-free, carboplatin-cont. regimen

•

Dose dense & escalated in case of high tumor burden

++ ++ + +

TNBC 

Conventionally dosed AT-based chemotherapy



Dose dense & escalated

In case of indication for chemotherapy, consider neoadjuvant approach

++ + ++

Adjuvant Chemotherapy without Concurrent Trastuzumab: Overview © AGO

e. V.

in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2014.1

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Anthracyclines (instead of CMF)

Oxford / AGO LoE / GR

1a A

++

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Taxanes

1a A

++



Dose-dense (node-positive disease)

1a A

++

CMF (instead of no therapy)

1a A

++

EC - T (instead of FEC – T)

1ba A

++

www.ago-online.de

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

Non-Anthracycline Containing Regimens without Trastuzumab © AGO

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Equivalent OS efficacy to  4 x A / EC:  4-6 x Pac q3w 1b  6 x CMF 1a

B A

+/+/-

B

+

Superior OS efficacy to 4 x AC : www.ago-online.de



4 x DC

1b

Taxanes Optimal Combinations and Dosages © AGO

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in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2014.1

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Regimen

Oxford / LoE / GR

AGO



EC  Pw

E90C q3w x 4  P80 qw1 x 12

1ba B

++



DAC

D75A50C q3w x 6

1b

A

++



AC  Pw

A60C q3w x 4  P80 qw1 x 12

1b

A

++



AC  D

A60C q3w x 4  D100 qw3 x 4

1b

A

++



EC  D

E90C q3w x 4  D100 qw3 x 4

1ba B

++

Recommended Taxane-Based Regimens – Standard Dose © AGO

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in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2014.1

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Combination Treatment  DAC (BCIRG 001, instead of FAC)  DC (US Oncol., instead of AC)  AD (E2179, instead of AC) Sequential Treatment (Equal Duration)  ECPw (GIM, instead of FECPw)  FEC  D (PACS 01, instead of FEC)  AC  Pw (E1199, instead of AC  P3w)  FE60C D (TACT, instead of FE60C) (TACT, instead of E  CMF)  AP  CMF (ECTO, instead of A  CMF) Sequential Treatment (Unequal Duration)  AC  P (NSABP B-28, instead of AC)  FEC  P (GEICAM 9906, instead of FEC)  AC  D (BCIRG 005, instead of DAC)  EC  D (WSG/AGO, instead of FE100C)  EC  D (ADEBAR, instead of FE120C)  A  D  CMF > AD  CMF(BIG 2-98, instead of A  C  CMF)  E  D  CMF (TAXIT 216, instead of E  CMF

Oxford / LoE / GR

AGO

1b 1b 2b

A A B

++ + +/-

1ba 1b 1b

B B A

++ + ++

2b 2b

B B

+

1b 2b 1ba 1ba 1ba 2b 2b

A B B B B B B

+ + ++ ++ +/+ +/-

In studies with adequately dosed anthracyclines, benefit from adding taxanes seems to be small. In the sequence AC-Taxane, there is no evidence of superiority of either taxane. Next to substance-specific side-effects, weekly administration was in general less toxic (LoE 2ba, B). In Germany, often EC (90/600) is used instead of AC.

Adjuvant Chemotherapy (Other Drugs) © AGO

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in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2014.1

Capecitabine containing regimen

1a

B

+/-

2b

B

+/-

(in case of HER2 neg., ER/PgR neg., TPN)

E-Cis-F www.ago-online.de

Gemcitabine containing regimen

-

Adjuvant Chemotherapy (Dose-dense and / or Dose-escalated) © AGO

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in der DGGG e.V. sowie in der DKG e.V.

Dose-dense regimen (N +) dd ACP / AC-P q2w (instead of q3w) (CALGB 9741)

1b

A

+



AC / ddP q1w x 12 (instead of P q3w)

1b

A

++



*EC / ddP q1w x 12 (instead of P q3w)

1b

B

++



EC/ddP q2w (instead of q3w)

1ba

A

+



AC/ddP q1w (instead of q2w)

1ba

A

++



ddEC q2w/ddP q1w (instead of EC q3w)

2ba

B

+



ddE120C830 q2w x 6 => P q3w x 4

1b

A

+/-



ddACPq2w = 6x TAC

1b

A

+/-

1b

A

++



Guidelines Breast Version 2014.1

www.ago-online.de

Oxford / AGO LoE / GR

Dose-dense and dose-escalated regimen (N  4+) 

dd E-P-C q2w (instead of EC-P q3w) (AGO) * Extrapolated from doxorubicin trials

Adjuvant Treatment with Trastuzumab I © AGO

e. V.

Oxford / AGO LoE / GR

in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2014.1



Node-positive disease

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Node-negative disease

1a

A

++

(whenever chemotherapy is considered as adequate) 

> 10 mm

1a

A

++



> 5–10 mm

2b

B

+



≤ 5 mm

2b

B

+/-

www.ago-online.de

Adjuvant Treatment with Trastuzumab II © AGO

Oxford / AGO LoE / GR

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in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2014.1

Start of treatment Simultaneously with taxanes  Sequentially up to 3 months after chemotherapy 

1a

A

++

1b

B

+

Duration   www.ago-online.de



For 1 year For 2 years For 0.5 years

1b A a 1b B a 1b B

++ -

2b 2b

++ ++

Dosage  

2 (4*) mg/kg every week 6 (8*) mg/kg every 3 weeks *Loading dose * Loading dose

B B

Adjuvant Trastuzumab Cardiac Monitoring for CHF © AGO

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Oxford LoE: 5

GR: D

AGO: ++

Before start of trastuzumab 

History, physical examination (edema, hepatomegaly)  Echocardiography (alternative to MUGA)

Assessment of LVEF

During trastuzumab www.ago-online.de

Regular assessment of  Heart rate increase > 15% above individual base level  Body weight increase ≥ 2 kg/week 3 monthly assessment of LVEF

Adjuvant Treatment with Trastuzumab: Schedules © AGO

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Simultaneously 

With paclitaxel / docetaxel after AC / EC



With P q1w 12 x without A in pT (< 3 cm), pN0



 

With docetaxel and carboplatin

1b A 2ba B 1b A

++ +/+

With anthracyclines With taxanes dose-dense

2b 2b

B B

+/+*

2b

B

+

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Radiotherapy concurrent with Trastuzumab

* Study participation recommended

Adjuvant Therapy with Other Targeted Agents © AGO

e. V.

Oxford / AGO LoE / GR

in der DGGG e.V. sowie in der DKG e.V. Guidelines Breast Version 2014.1

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Lapatinib 



(delayed adjuvant treatment)

Pertuzumab

5 D 1b B

-

5

-

D

www.ago-online.de

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Bevacizumab

a

1b B

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Adjuvant Cytotoxic and Targeted Therapy (2/14)

Further information: Screened data bases: Pubmed 2003 – 2013, ASCO 2006 – 2013, SABCS 2006 – 2013, ECCO (n.d.), EBCC (n.d.). Cochrane data base (20072013) Screened guidelines: Consensus on the primary therapy of early breast cancer (St. Gallen 2007, 2009, 2011, 2013): Goldhirsch A, et al. Ann Oncol. 2007 Jul;18(7):1133-44. Goldhirsch et al, Ann Oncol. 2009 Aug;20(8):1319-29. Goldhirsch et al, Ann Oncol. 2011 Aug; 22(8):1736-47. 1. Goldhirsch A, Winer EP, Coates AS et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 2013; 24: 2206–2223. - NCCN 2013: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf (Download 24. Jan 2011) - NCI: http://www.cancer.gov/cancertopics/pdq/treatment/breast/HealthProfessional/page7#Section_519 - http://www.cancer.gov/cancertopics/pdq/treatment/breast/HealthProfessional/ (Download 24. Jan 2011)

References: Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thürlimann B, Senn HJ; Panel members. Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Ann Oncol. 2009 Aug;20(8):1319-29.

Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ; Panel members. Strategies for subtypes-dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011 Aug;22(8):1736-47. Goldhirsch A, Winer EP, Coates AS et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 2013; 24:2206–2223.

Subtype-specific General Systemic Strategies (3/14)

Further information: In patients with HR+/HER2- and “low risk” the treatment of choice is endocrine therapy without chemotherapy In patients with HR+/HER2- and “high risk” the recommended treatment is conventionally dosed AT-based chemotherapy or dose dense & escalated regimens in case of high tumor burden followed by endocrine therapy In patients with HER2+ disease Trastuzumab is recommended for one year plus  Sequential A/T-based regimen with concurrent T + H  Or an anthracycline-free, carboplatin-containing regimen  Or dose dense & escalated in case of high tumor burden  In patients with TNBC the treatment contains conventionally dosed AT-based chemotherapy  Or dose dense & escalated chemotherapy In case of an indication for chemotherapy, the neoadjuvant approach should be considered

No references

Adjuvant Chemotherapy without Concurrent Trastuzumab: Overview (4/14)

Further information: CMF should be given at a dosage of C 600 mg/m2 d1+8 q4w i.v., alternatively the classical oral application can be chosen with C 100 mg/m m2 d1-14 p.o. q4w. The three-weekly administration implies an underdosing, because a dose of CMF less than 85 % of the conventional dosage leads to a reduction of the efficacy (Bonadonna 1995). Similar conclusions can be drawn from the data of a study in the metastatic setting (Engelmann 1991) and in an older metaanalysis (Hryniuk 1986). Therefore, CMF at a dosage of 600/40/600 mg/m2 q3w is regarded as not adequate. If the indication for adjuvant chemotherapy is given after evaluation of risk, potential benefits and side effects, an anthracycline-based combination chemotherapy is regarded as minimum standard treatment. As shown in a meta-analysis, there is a reduction of the relapse rate (ratio 0.89, p=0.0001) and mortality (ratio 0.84, p