# Presentation: 673516

## TAXOL® (paclitaxel) for Adjuvant Treatment of Node Positive Breast CancerOncologic Drug Advisory Committee  Adjuvant Chemotherapy of Breast Cancer

- Larry Norton, M.D.
- Memorial Sloan-Kettering Cancer Center
- New York, New York

## Adjuvant Chemotherapy of Primary Breast Cancer: What We Know

- Chemotherapy Improves Disease-Free and Overall Survival
- Polychemotherapy > Monochemotherapy
- Multiple Cycles > Single Exposure
- No Major Advantage to Durations > 3 Months
- Anthracycline Combinations > CMF

## Early Breast Cancer Trialists’ Collaborative Group 

- _Comparison (N)_
- CMF *vs.* Nil (8,150)
- CMF+ *vs.* Nil (3,218)
- Anthracyclines+ *vs.* CMF (6,950)
- Longer *vs.* Shorter (6,104)

- _Recurrence_
**+24 ± 3**
**+20 ± 5**
**+12 ± 4**
**+7 ± 4**

- Early Breast Cancer Trialists’ Collaborative Group

- _Death_
**+14 ± 4**
**+15 ± 5**
**+11 ± 5**
**-1 ± 5**

- Lancet Vol. 352, 9/98

## Simulation of Impact of Chemotherapy

- Years

- Annual Odds of Recurrence:
**Nil** = 15%/Yr
**CMF** = 11.4%/Yr (Reduced by 24%)
**AC** = 10%/Yr (Reduced by 12%)

**0**

**20**

**40**

**60**

**80**

**100**

**0**

**2**

**4**

**6**

**8**

**10**

**AC**

**CMF**

**Nil**

## Adjuvant Chemotherapy of Primary Breast Cancer: What Else We Know

- Adriamycin Doses < 40mg/m2  are Inferior  to 60 mg/m2 (CALGB 8541)
- Cyclophosphamide Doses > 600 mg/m2 are not Superior (NSABP B-22)
- Chemotherapy Seems More Effective in ER- Than ER+ Disease (EBCTCG)

## Early Breast Cancer Trialists’ Collaborative Group 

- _Subgroup (N)_
- Age < 50, ER- (1398)
- Age < 50, ER+ (1115)
- Age  50, ER- (3240)
- Age  50, ER+ (6793)

- _Recurrence_
**+40 ± 7**
**+33 ± 8**
**+30 ± 5**
**+18 ± 4**

- Early Breast Cancer Trialists’ Collaborative Group

- _Death_
**+35 ± 9**
**+20 ± 10**
**+17 ± 6**
**+9 ± 5**

- Lancet Vol. 352, 9/98

## Adjuvant Chemotherapy of Primary Breast Cancer: How To Improve

- Dose-Escalate Anthracycline?
- Integrate New Agents?
- Chemotherapy?
- Biological Agents?
- Improve Drug Scheduling?
- Dose-Density, Sequential?

## Recently Approved New Drugs for the Treatment of (Advanced) Breast Cancer:

- Paclitaxel
- Docetaxel
- Capecitabine
- Trastuzumab

## Adjuvant Chemotherapy of Primary Breast Cancer: Why Paclitaxel?

- Active as First Chemotherapy for Stage IV:  52-59% Response Rates                   (M.D. Anderson, MSKCC *et al.*)
- Active after Extensive Prior Chemotherapy, Including Anthracycline-Resistant Disease:   22-30% Response Rates                             (NCI, MSKCC *et al.*)

## “Normal” Dose Intensity & Dose Escalation

- A 1&2

- “Normal” Dose Intensity & Dose Escalation

## “Normal” Dose Intensity & Dose Escalation

- A 1&2

- “Normal” Dose Intensity & Dose Escalation

## “Normal” Dose Intensity & Increased Dose Density

- B1&3

- “Normal” Dose Intensity & Increased Dose Density

## “Normal” Dose Intensity & Increased Dose Density

- “Normal” Dose Intensity & Increased Dose Density

## Alternating Therapy is Not Dose Dense

- C4&5

## Sequential Therapy is Dose Dense

- 3&6

## Stage II Breast Cancer with 4 Involved Axillary Lymph Nodes

- Bonadonna *et al*., JAMA, 1995

- Doxorubicin

- CMF

## Stage II Breast Cancer with >4 Involved Axillary Lymph Nodes

- Bonadonna *et al*., JAMA, 1995

- p = .002

**% at 10 Years**

## CALGB 9141 (Pilot)Node-Positive Stage II-IIIA (N=172)

- Doxorubicin

- Cyclophosphamide

- 2000 mg/m2

- 130/145 (89.7%)of Patients Starting Paclitaxel Completed Rx.
- 	On Paclitaxel:

- Demetri *et al.*, ASCO-1997

- 75 mg/m2

- 25% Grade IV Leukopenia
- 4% Grade IV Thrombocytopenia

- + G-CSF

## Intergroup 0148/CALGB 9344Node-Positive Stage II-IIIA

- Randomize

- 60

- 75

- 90

- Doxorubicin mg/m2

- G-CSF

- Cyclophosphamide

- 600 mg/m2

- No Further Chemotherapy

- Tamoxifen forHR(+)

- Paclitaxel 175 mg/m2

## Relationship ofCALGB 9344 (Int 0148)toCurrent U.S.Cooperative Group Trials

## NSABP B-28Node-Positive Stage II-IIIA

- No Further Chemotherapy

- Concomitant Tamoxifen x 5 Years for HR(+) _or_ Postmenopausal (Age  50)

- (Survival)

## Intergroup/CALGB 9741 Node-Positive Stage II-IIIA

- Doxorubicin (A) 60 mg/m2
- Paclitaxel (T) 175 mg/m2
- Cyclophosphamide (C) 600 mg/m2

- 3-Week Cycles

- 2-Week Cycles (w/ G-CSF)

## Intergroup/SWOG 4-9 LN+ Trial

- STAMP I or
- STAMP V

- A

- C

- A

- T

- C

- Randomize

## Intergroup/ECOG Stage II TrialHER2 (-)

- Doxorubicin  60 mg/m2

- Cyclophosphamide 600 mg/m2

- Paclitaxel

- Docetaxel

- Tamoxifen if HR(+)

## Integration of Biological Agent:Trastuzumab (Herceptin)

## NSABP Stage II TrialHER2 (+)

- Doxorubicin  60 mg/m2

- Cyclophosphamide 600 mg/m2

- Paclitaxel

- Tamoxifen if HR(+)

- Herceptin

## Intergroup/NCCTG Stage II TrialHER2 (+)

- Doxorubicin  60 mg/m2

- Cyclophosphamide 600 mg/m2

- Tamoxifen if HR(+)

- 52 wks

- 52 wks

- Paclitaxel

- Herceptin

## CALGB Stage IIIB Trial(HER2+)

- Doxorubicin  60 mg/m2

- Cyclophosphamide 600 mg/m2

- Paclitaxel 90 mg/m2

- Dexrazoxane or Not

- Herceptin or Not

- Herceptin for a Year or Not

- Surgery
- &
- RT

- Tamoxifen if HR(+)

## Summary of Advantagesof This Approach

- Integrates Paclitaxel
- Active as a Single Agent
- Active Post-Anthracycline
- Minimizes Incremental Toxicity
- Allows Integration of Biological Therapy

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