Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information

Alternate Title

Adjuvant Combination Chemotherapy in Node-Positive Breast Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	over 18	NCI	CLB-9344 E-C9344, NCCTG-943051, SWOG-9410, INT-0148

Objectives

I.  Determine whether higher doses of doxorubicin (DOX) used in an adjuvant 
regimen with cyclophosphamide (CTX) increase disease-free and overall survival 
in patients with early stage breast cancer.

II.  Determine whether paclitaxel (TAX) following 4 courses of CTX/DOX (CA) 
further improves disease-free and overall survival compared to CA alone.

III.  Determine whether TAX improves disease-free and overall survival at 3 
different doses of DOX in the CA regimen, especially whether TAX following 
standard-dose DOX/CTX is more effective than high-dose DOX/CTX without TAX.

IV.  Assess the incidence of life-threatening and lethal toxicity with 
different doses of DOX in the CA regimen, with and without subsequent TAX.

V.  Determine whether the longer duration of chemotherapy for patients 
receiving TAX is associated with a reduction in local recurrence in patients 
whose definitive treatment was lumpectomy plus radiotherapy.

VI.  Assess the differences among the treatments in actual chemotherapy 
delivered, percentage of patients who experience delays in treatment delivery 
because of neutropenia and other treatment-related toxicity, number of 
hospital days required for recovery from febrile neutropenia on each course, 
and the incidence of platelet and erythrocyte transfusions on each course.

Entry Criteria

Disease Characteristics:

Histologically confirmed adenocarcinoma of the breast with one or more 
 positive lymph nodes (T1-3, N1, M0) that is considered operable (clinical
 stage N1 eligible)

No locally advanced disease in the judgment of the investigator, e.g.:
 No fixed tumors
 No peau d'orange skin change
 No skin ulcerations
 No inflammatory disease

Patients with 10 or more histologically involved axillary nodes eligible
 only if treatment on protocol CLB-9082 or EST-2190 (bone marrow
 transplantation) is refused

Definitive resection required:
 Modified radical mastectomy or segmental mastectomy with axillary node
 dissection within 84 days prior to entry
 No evidence of gross or microscopic disease in the resection margins

 Standard radiotherapy for segmental mastectomy patients administered
  after completion of all chemotherapy

Hormone receptor status:
 Any ER or PgR status

Prior/Concurrent Therapy:

Biologic therapy:
  Not specified

Chemotherapy:
  No prior chemotherapy for current malignancy
  No prior chemotherapy that has compromised bone marrow reserves or other
   organ function

Endocrine therapy:
  Not specified

Radiotherapy:
  No prior radiotherapy for current malignancy
  No prior radiotherapy that has compromised bone marrow reserves or other
   organ function

Surgery:
  Definitive resection required (see Disease Characteristics)

Patient Characteristics:

Age:
  Over 18 

Sex:
  Women only

Menopausal status:
  Pre- and postmenopausal

Performance status:
  Zubrod 0-1

Life expectancy:
  At least 2 years

Hematopoietic:
  WBC at least 3,000/mm3
  Platelet count at least 100,000/mm3
  Hemoglobin at least 9 g/dL

Hepatic:
  Bilirubin less than 1.5 times normal

Renal:
  Creatinine less than 1.5 times normal

Cardiovascular:
  Left ventricular ejection fraction normal
  No myocardial infarction within 6 months
  No congestive heart failure
  No other uncontrolled or severe cardiovascular disease
  Arrhythmia requiring treatment allowed at the discretion of the physician

Other:
  No active bacterial, viral, or fungal infection
  No clinically defined AIDS
  No serious medical illness that would limit survival to less than 2 years
  No psychiatric condition that would prevent informed consent
  No concurrent metastatic disease from a second cancer that would interfere
   with interpretation of results
  No morbid obesity that would preclude full-dose treatment
  Not pregnant or lactating
  Effective contraception required during and for at least 2 months following
   therapy

Blood/body fluid analyses to determine eligibility and physical exams
completed within 14 days prior to registration

EKG, x-rays, and bone scans obtained within 80 days prior to registration

Expected Enrollment

About 3,000 patients will be entered over 3 years.  If accrual is insufficient 
after either 1 or 2 years, Arm II will be closed.

Outline

This is a randomized study.  Patients are stratified by participating 
institution.

Patients are randomized to one of three doses of doxorubicin and then 
randomized within each group to receive paclitaxel or not.

The first group receives cyclophosphamide and standard-dose doxorubicin.  The 
second group receives cyclophosphamide and medium-dose doxorubicin.  The third 
group receives cyclophosphamide and high-dose doxorubicin.  All groups receive 
4 courses of therapy at 3-week intervals.

Within each group, one half of the patients receive paclitaxel every 3 weeks 
for 4 weeks.

All receptor-positive patients receive oral tamoxifen daily for 5 years.

No other chemotherapy or hormonal therapy is permitted except steroids as 
antiemetics or for adrenal failure.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, 
and yearly thereafter.

Hayes DF, Thor AD, Dressler LG, et al.: HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med 357 (15): 1496-506, 2007.[PUBMED Abstract]

Hayes DF, Thor A, Dressler L, et al.: HER2 predicts benefit from adjuvant paclitaxel after AC in node-positive breast cancer: CALGB 9344. [Abstract] J Clin Oncol 24 (Suppl 18): A-510, 2006.

Sartor CI, Peterson BL, Woolf S, et al.: Effect of addition of adjuvant paclitaxel on radiotherapy delivery and locoregional control of node-positive breast cancer: cancer and leukemia group B 9344. J Clin Oncol 23 (1): 30-40, 2005.[PUBMED Abstract]

Henderson IC, Berry DA, Demetri GD, et al.: Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21 (6): 976-83, 2003.[PUBMED Abstract]

Sartor CI, Fitzgerald TJ, Laurie F, et al.: Effect of addition of adjuvant paclitaxel on radiotherapy delivery and locoregional control for node positive breast cancer in CALGB 9344. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-38, 10, 2003.

Henderson IC, Berry D, Demetri G, et al.: Improved disease-free (DFS) and overall survival (OS) from the additon of sequential paclitaxel (T) but not from the escalation of doxorubicin (A) dose level in the adjuvant chemotherapy of patients (PTS) with node-positive primary breast cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A390A, 101a, 1998.

Lamont EB, Herndon JE 2nd, Weeks JC, et al.: Measuring clinically significant chemotherapy-related toxicities using Medicare claims from Cancer and Leukemia Group B (CALGB) trial participants. Med Care 46 (3): 303-8, 2008.[PUBMED Abstract]

Muss HB, Berry DA, Cirrincione C, et al.: Toxicity of older and younger patients treated with adjuvant chemotherapy for node-positive breast cancer: the Cancer and Leukemia Group B Experience. J Clin Oncol 25 (24): 3699-704, 2007.[PUBMED Abstract]

Berry DA, Cirrincione C, Henderson IC, et al.: Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295 (14): 1658-67, 2006.[PUBMED Abstract]

Giordano SH, Duan Z, Kuo YF, et al.: Impact of a scientific presentation on community treatment patterns for primary breast cancer. J Natl Cancer Inst 98 (6): 382-8, 2006.[PUBMED Abstract]

Lamont EB, Herndon JE 2nd, Weeks JC, et al.: Measuring disease-free survival and cancer relapse using Medicare claims from CALGB breast cancer trial participants (companion to 9344). J Natl Cancer Inst 98 (18): 1335-8, 2006.[PUBMED Abstract]

Muss H, Berry D, Cirrincione C, et al.: Toxicity of older and younger patients (pts) treated (Rx) with intensive adjuvant chemotherapy (Cx) for node-positive (N+) breast cancer (BC): the CALGB experience. [Abstract] J Clin Oncol 24 (Suppl 18): A-559, 2006.

Campone M, Fumoleau P, Bourbouloux E, et al.: Taxanes in adjuvant breast cancer setting: which standard in Europe? Crit Rev Oncol Hematol 55 (3): 167-75, 2005.[PUBMED Abstract]

Lamont EB, Herndon JE 2nd, Weeks JC, et al.: Criterion validity of Medicare chemotherapy claims in Cancer and Leukemia Group B breast and lung cancer trial participants. J Natl Cancer Inst 97 (14): 1080-3, 2005.[PUBMED Abstract]

Muss HB, Woolf S, Berry D, et al.: Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer. JAMA 293 (9): 1073-81, 2005.[PUBMED Abstract]

Berry DA, Cirrincione C, Henderson IC, et al.: Effects of improvements in chemotherapy on disease-free and overall survival of estrogen-receptor negative, node-positive breast cancer: 20-year experience of the CALGB U.S. Breast Intergroup. [Abstract] Breast Cancer Res Treat 88 (Suppl 1): A-29, 2004.

Dougherty MK, Schumaker LM, Jordan VC, et al.: Estrogen receptor expression and sensitivity to paclitaxel in breast cancer. Cancer Biol Ther 3 (5): 460-7, 2004.[PUBMED Abstract]

Piccart MJ, Lohrisch C, Duchateau L, et al.: Taxanes in the adjuvant treatment of breast cancer: why not yet? J Natl Cancer Inst Monogr (30): 88-95, 2001.[PUBMED Abstract]

Annemans L, Moeremans K, Henderson I, et al.: Cost-effectiveness of the sequential addition of taxol (T) to doxorubicin plus cyclophosphamide (AC) in the adjuvant chemotherapy of patients with node-positive breast cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 19: A-1752, 2000.

Trial Contact Information

Trial Lead Organizations

Cancer and Leukemia Group B

I. Craig Henderson, MD, Protocol chair		Ph: 415-353-7070; 800-888-8664

Eastern Cooperative Oncology Group

Lori Goldstein, MD, Protocol chair		Ph: 215-728-2689; 888-369-2427 Email: lj_goldstein@fccc.edu

Southwest Oncology Group

Silvana Martino, DO, Protocol chair		Ph: 310-582-7900 Email: martinos@jwci.org

North Central Cancer Treatment Group

James Ingle, MD, Protocol chair		Ph: 507-284-3731 Email: ingle.james@mayo.edu