Phase III Randomized Study of Adjuvant Chemotherapy with Intensive CAF (CTX/ADR/5-FU) for Four Months vs Low-Dose CAF for Four Months vs Standard-Dose CAF for Six Months in Patients with Node-Positive Stage II Breast Cancer

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Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentClosed16 and overNCICLB-8541


I.  Determine whether there is a dose-dependent relationship between 
disease-free survival and amount of drug administered in patients with Stage 
II breast cancer treated with CAF (cyclophosphamide/adriamycin/5-fluorouracil).
II.  Determine whether low-dose CAF therapy produces disease-free survival 
results comparable to those of conventional-dose CDF therapy.
III.  Determine whether two regimens that provide an equal cumulative dose of 
CAF produce comparable disease-free survival results.
IV.  Compare high-dose, conventional-dose, and low-dose CDF with respect to 
the toxicities experienced in an ambulatory, outpatient setting.

Entry Criteria

Disease Characteristics:

See General Eligibility Criteria

Patient Characteristics:

See General Eligibility Criteria

General Eligibility Criteria:

Female patients aged 16 years and 
older with histologically confirmed Stage II adenocarcinoma of the breast, 
including clinical Stage I and II patients who are found to have 
histologically involved axillary lymph nodes, T1-2, N1, M0 (T3 tumors, i.e., 
tumors more than 5 cm in greatest dimension, are excluded), provided not more 
than 6 weeks (preferably 2 weeks) has elapsed since radical mastectomy, 
modified radical mastectomy, or segmental mastectomy (lumpectomy).  Patients 
who have had segmental mastectomy must be reviewed by a radiotherapist prior 
to randomization to confirm suitability for post-chemotherapy radiotherapy.  
Patients with unilateral multifocal disease are eligible only if they have 
been treated with mastectomy (not lumpectomy) with negative surgical margins 
and if their lesions were discreet (not diffuse).  There may have been no 
prior treatment.  ER status must be known, and determination of PR status is 
desirable.  Adequate hematologic, renal, and hepatic function must be 
demonstrated by the following laboratory values:  WBC greater than 3,500, 
platelets greater than 100,000, and hemoglobin greater than 10 g/dl; BUN less 
than 1.5 times normal and creatinine less than 1.8 mg/dl; and bilirubin less 
than 1.5 times normal.  The performance status must be 0 or 1 and the daily 
caloric intake must exceed 1,000.  There may be no previous or concomitant 
second malignancy aside from curatively treated carcinoma in situ of the 
cervix and nonmelanomatous skin cancer; patients with bilateral breast cancer 
are excluded.  Patients must be free from uncontrolled or severe 
cardiovascular disease including myocardial infarction within 6 months and 
congestive heart failure.  Active infection must be brought under control 
prior to entry, and there must be no medical illness that would preclude 
intensive chemotherapy.  Pregnancy excludes.

Expected Enrollment

Based on accrual characteristics through 01/88, a sample size of 1,450 
patients will be required to provide 900 eligible patients for initial 
analysis, excluding lumpectomy and peri- and postmenopausal ER-positive 
patients.  As of 11/89, 1,200 patients had been accrued, and it was estimated 
that one further year of accrual would be required to meet accrual goals.


Randomized study.  All patients are randomized on Arms I, II, and III.  
Treatment should begin within 2 weeks following surgery if possible, but in no 
case more than 6 weeks postoperatively.  All segmental mastectomy patients 
receive radiotherapy on Regimen A beginning 4 weeks after completion of 
adjuvant chemotherapy.  All peri- and postmenopausal patients whose tumors are 
ER-positive (at least 7 fmol/mg protein) receive tamoxifen for 5 years on 
Regimen B.  All peri- and postmenopausal ER-positive patients who had 
previously completed chemotherapy on this protocol also receive tamoxifen on 
Regimen B.
Arm I:  3-Drug Adjuvant Combination Chemotherapy.  CAF:  Cyclophosphamide, 
CTX, NSC-26271; Doxorubicin, Adriamycin, ADR, NSC-123127; 5-Fluorouracil, 
5-FU, NSC-19893.  High-dose therapy for 4 months.
Arm II:  3-Drug Adjuvant Combination Chemotherapy.  CAF.  Low-dose therapy for 
4 months.
Arm III:  3-Drug Adjuvant Combination Chemotherapy.  CAF.  Standard-dose 
therapy for 6 months.
Regimen A:  Radiotherapy.  Irradiation of the breast and chest wall using Co60 
or 4-6 MeV accelerator beams for the initial target volume and electrons for a 
boost field.
Regimen B:  Endocrine Therapy.  Tamoxifen, TMX, NSC-180973.

Published Results

Berry DA, Muss HB, Thor AD, et al.: HER-2/neu and p53 expression versus tamoxifen resistance in estrogen receptor-positive, node-positive breast cancer. J Clin Oncol 18 (20): 3471-9, 2000.[PUBMED Abstract]

Budman D, Wood W, Korzun A, et al.: Initial findings of CALGB 8541: a dose and dose intensity trial of cyclophosphamide (C), doxorubicin (A) and 5-fluorouracil (F) as adjuvant treatment of stage II, node+ female breast cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 11: A-29, 51, 1992.

DiGiovanna MP, Stern DF, Edgerton S, et al.: Influence of activation state of ErbB-2 (HER-2) on response to adjuvant cyclophosphamide, doxorubicin, and fluorouracil for stage II, node-positive breast cancer: study 8541 from the Cancer and Leukemia Group B. J Clin Oncol 26 (14): 2364-72, 2008.[PUBMED Abstract]

Dressler LG, Berry DA, Broadwater G, et al.: Comparison of HER2 status by fluorescence in situ hybridization and immunohistochemistry to predict benefit from dose escalation of adjuvant doxorubicin-based therapy in node-positive breast cancer patients. J Clin Oncol 23 (19): 4287-97, 2005.[PUBMED Abstract]

Dressler LG, Broadwater G, Berry D, et al.: A comparison of two HER2 FISH methods to measure HER2 amplification and predict clinical outcome. [Abstract] J Clin Oncol 22 (Suppl 14): A-566, 18s, 2004.

Harris LN, Broadwater G, Abu-Khalaf M, et al.: Topoisomerase II{alpha} amplification does not predict benefit from dose-intense cyclophosphamide, doxorubicin, and fluorouracil therapy in HER2-amplified early breast cancer: results of CALGB 8541/150013. J Clin Oncol 27 (21): 3430-6, 2009.[PUBMED Abstract]

Katz ML, Donohue KA, Alfano CM, et al.: Cancer surveillance behaviors and psychosocial factors among long-term survivors of breast cancer. Cancer and Leukemia Group B 79804. Cancer 115 (3): 480-8, 2009.[PUBMED Abstract]

Muss H, Berry D, Thor A, et al.: Lack of interaction of tamoxifen (T) use and ErbB-2/HER-2/Neu (H) expression in CALGB 8541: a randomized adjuvant trial of three different doses of cyclophosphamide, doxorubicin and fluorouracil (CAF) in node-positive primary breast cancer (BC). [Abstract] Proceedings of the American Society of Clinical Oncology 18: A256, 1999.

Oliveri JM, Day JM, Alfano CM, et al.: Arm/hand swelling and perceived functioning among breast cancer survivors 12 years post-diagnosis: CALGB 79804. J Cancer Surviv 2 (4): 233-42, 2008.[PUBMED Abstract]

Paskett E, Herndon J 2nd, Donohue K, et al.: Health-related quality of life in long-term breast cancer survivors: differences by adjuvant chemotherapy dose in Cancer and Leukemia Group B study 8541. Cancer 115 (5): 1109-20, 2009.[PUBMED Abstract]

Roach M 3rd, Cirrincione C, Budman D, et al.: Race and survival from breast cancer: based on Cancer and Leukemia Group B trial 8541. Cancer J Sci Am 3 (2): 107-12, 1997 Mar-Apr.[PUBMED Abstract]

Rosner GL, Hargis JB, Hollis DR, et al.: The relationship between toxicity and obesity in adjuvant therapy for breast cancer (CALGB 8541). [Abstract] Proceedings of the American Society of Clinical Oncology 14: A-142, 111, 1995.

Wood WC, Budman DR, Korzun AH, et al.: Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 330 (18): 1253-9, 1994.[PUBMED Abstract]

Related Publications

Paskett ED, Herndon JE 2nd, Day JM, et al.: Applying a conceptual model for examining health-related quality of life in long-term breast cancer survivors: CALGB study 79804. Psychooncology 17 (11): 1108-20, 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]

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.

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.

Guidi AJ, Berry DA, Broadwater G, et al.: Association of angiogenesis and disease outcome in node-positive breast cancer patients treated with adjuvant cyclophosphamide, doxorubicin, and fluorouracil: a Cancer and Leukemia Group B correlative science study from protocols 8541/8869. J Clin Oncol 20 (3): 732-42, 2002.[PUBMED Abstract]

Kornblith AB, Herndon JE 2nd, Zuckerman E, et al.: Social support as a buffer to the psychological impact of stressful life events in women with breast cancer. Cancer 91 (2): 443-54, 2001.[PUBMED Abstract]

Muss HB, Thor AD, Berry DA, et al.: c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med 330 (18): 1260-6, 1994.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Cancer and Leukemia Group B

Daniel Budman, MD, Protocol chair
Ph: 516-562-8958

Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.