Sixteen-week multidrug regimen versus cyclophosphamide, doxorubicin, and fluorouracil as adjuvant therapy for node-positive, receptor-negative breast cancer: an Intergroup study.
ABSTRACT The Intergroup conducted this breast cancer adjuvant trial to compare an investigational 16-week regimen with cyclophosphamide, doxorubicin, and fluorouracil (5-FU; CAF). The 16-week regimen features greater doxorubicin and 5-FU dose-intensity than CAF and improved scheduling of antimetabolites with sequential methotrexate and 5-FU, as well as infusion 5-FU.
A total of 646 node-positive, receptor-negative patients were randomly assigned to receive either the 1 6-week regimen or six cycles of CAF. Breast cancer outcomes included recurrence as well as disease-free and overall survival. Toxicity was evaluated by the Common Toxicity Criteria (CTC). Treatment-related quality of life was assessed by the Breast Chemotherapy Questionnaire (BCQ) before, during, and 4 months after treatment in 163 patients. The trial was designed to use one-sided tests of significance for power calculations, but is now reported with both one-sided and the traditional two-sided tests of significance.
At a median follow-up of 3.9 years, the estimated 4-year recurrence-free survival rate was 67.5% with the 16-week regimen versus 62.7% with CAF (P = .19, two-sided; P = .095, one-sided). The estimated 4-year survival rate was 78.1% with the 16-week regimen versus 71.4% with CAF (P = .10, two-sided; P = .05, one-sided). CAF produced significantly higher grades of leukopenia, granulocytopenia, and thrombocytopenia, as well as liver and cardiac toxicity, whereas the 16-week regimen produced significantly higher grades of anemia, nausea, stomatitis, and weight loss, as well as skin and neurotoxicity. There were three treatment-related deaths with CAF but none with the 16-week regimen. During treatment, quality of life declined significantly more with the 16-week regimen than CAF, but by 4 months posttreatment, there was no difference.
The 16-week regimen produced marginally better breast cancer outcomes than CAF with similar toxicity but a greater reduction in during-treatment quality of life. The 16-week regimen should not be used instead of a standard-dose regimen without careful consideration of the 16-week regimen's pros and cons, which include its complicated schedule. It should probably not be tested further, but its antimetabolite schedules and frequent drug administration (ie, dose density) should be considered in the development of new regimens.
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- "In a direct compar - ison , six courses of classical CMF ( 154 days ) and four courses of AC yielded similar results despite the different durations ( Fisher et al , 1990 , 2000 ) . Likewise a short but complex 16 - week regimen ( including a continuous administration of cytotoxics during the entire period of treatment ) yielded results marginally superior to those seen with six courses of cyclophosphamide , doxorubicin and 5 - fluorouracil ( CAF ) ( Fetting et al , 1998 ) . On the other hand , the US Intergroup trial of the addition of 4 cycles of paclitaxel ( Taxol 1 ) following four cycles of AC demonstrated a small but significant improvement in disease - free and overall survival using the longer , different regimen ( Henderson et al , 1998 ) . "
ABSTRACT: Cyclophosphamide, methotrexate and fluorouracil adjuvant combination chemotherapy for breast cancer is currently used for the duration of six monthly courses. We performed a joint analysis of two studies on the duration of adjuvant cyclophosphamide, methotrexate and fluorouracil in patients with node-positive breast cancer to investigate whether three courses of cyclophosphamide, methotrexate and fluorouracil might suffice. The International Breast Cancer Study Group Trial VI randomly assigned 735 pre- and perimenopausal patients to receive ‘classical’ cyclophosphamide, methotrexate and fluorouracil for three consecutive cycles, or the same chemotherapy for six consecutive cycles. The German Breast Cancer Study Group randomised 289 patients to receive either three or six cycles of i.v. cyclophosphamide, methotrexate and fluorouracil day 1, 8. Treatment effects were estimated using Cox regression analysis stratified by clinical trial without further adjustment for covariates. The 5-year disease-free survival per cents (±s.e.) were 54±2% for three cycles and 55±2% for six cycles (n=1024; risk ratio (risk ratio: CMF×3/CMF×6), 1.00; 95% confidence interval, 0.85 to 1.18; P=0.99). Use of three rather than six cycles was demonstrated to be adequate in both studies for patients at least 40-years-old with oestrogen-receptor-positive tumours (n=594; risk ratio, 0.86; 95% confidence interval, 0.68 to 1.08; P=0.19). In fact, results slightly favoured three cycles over six for this subgroup, and the 95% confidence interval excluded an adverse effect of more than 2% with respect to absolute 5-year survival. In contrast, three cycles appeared to be possibly inferior to six cycles for women less than 40-years-old (n=190; risk ratio, 1.25; 95% confidence interval, 0.87 to 1.80; P=0.22) and for women with oestrogen-receptor-negative tumours (n=302; risk ratio, 1.15; 95% confidence interval, 0.85 to 1.57; P=0.37). Thus, three initial cycles of adjuvant cyclophosphamide, methotrexate and fluorouracil chemotherapy were as effective as six cycles for older patients (40-years-old) with oestrogen-receptor-positive tumours, while six cycles of adjuvant cyclophosphamide, methotrexate and fluorouracil might still be required for other cohorts. Because endocrine therapy with tamoxifen and GnRH analogues is now available for younger women with oestrogen-receptor-positive tumours, the need for six cycles of cyclophosphamide, methotrexate and fluorouracil is unclear and requires further investigation. British Journal of Cancer (2002) 86, 1705–1714. doi:10.1038/sj.bjc.6600334 www.bjcancer.com © 2002 Cancer Research UKBritish Journal of Cancer 07/2002; 86(11):1705-14. DOI:10.1038/sj.bjc.6600334 · 4.82 Impact Factor
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ABSTRACT: A Phase II study was performed evaluating the disease free and overall survival rates associated with a dose-intensive, 16-week, doxorubicin-based adjuvant chemotherapy regimen in women with breast carcinoma and > or = 10 involved axillary lymph nodes. Eligible patients underwent staging with computed tomography and bone scanning and were treated with a 16-week, dose-intensive chemotherapy regimen, comprised of 8 2-week courses of cyclophosphamide, 100 mg/m2 orally, on Days 1-7; doxorubicin, 40 mg/m2 intravenously (i.v.), on Day 1; methotrexate, 100 mg/m2 i.v., on Day 1 with leucovorin rescue, 10 mg/m2, every 6 hours for 6 doses orally on Day 2; vincristine, 1 mg i.v. on Day 1; 5-fluorouracil (5-FU), 600 mg/m2 i.v., on Day 2 over 2 hours; and 5-FU, 300 mg/m2/day continuous i.v. on Days 8 and 9. Tamoxifen, 20 mg daily, was administered to patients with estrogen receptor positive tumors treated after October 1988. All patients were offered locoregional radiation therapy. Sixty-four women were treated on protocol. The median follow-up of 27 surviving patients was > 8 years at last follow-up. Three patients were lost to follow-up. The median time to progression was 54 months, the Kaplan-Meier estimate of event free survival at 5 years was 44% (95% confidence interval [CI], 31-56%), and the Kaplan-Meier estimate of overall survival at 5 years was 57% (95% CI, 44-69%). At 98 months the Kaplan-Meier estimate of freedom from recurrence was 31% (95% CI, 19-43%) and the Kaplan-Meier estimate of survival at 111 months was 36% (95% CI, 23-49%). Despite the use of dose-intensive, doxorubicin-based, adjuvant chemotherapy, and intensive staging prior to study entry, the results of the current study are similar to those of previous reports for standard dose chemotherapy and appear inferior to those reported for high dose therapy.Cancer 03/1999; 85(4):899-904. DOI:10.1002/(SICI)1097-0142(19990215)85:43.3.CO;2-L · 4.90 Impact Factor
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ABSTRACT: In the last three decades, there has been a gradual, though significant change in the treatment of early stage breast cancer. For almost a century, physicians advocated an "anatomical view" of the dissemination of this disease, which justified a more radical and mutilating treatment strategy. Finally in the mid-1970s, results from large randomized trials began to show that either mastectomy or lumpectomy with radiation therapy were appropriate treatment for women with early stage disease. These results suggested that breast cancer can actually be a systemic disease ("biological view") even in early stages. This hypothesis was confirmed when large randomized clinical trials demonstrated the effectiveness of adjuvant systemic therapy in controlling micrometastatic disease in women with node-positive and node negative disease. As we approach the end of this century, most patients with early stage disease will be offered some form of adjuvant systemic therapy, before or after local treatment with surgery, with or without local radiation therapy. There has been a lot of interest on the proper sequence of the therapeutic modalities, in particular with the recent publication of larger randomized trials of primary systemic therapy. This specific topic is discussed elsewhere in this issue by Singletary.Surgical Oncology 09/1999; 8(2):93-101. DOI:10.1016/S0960-7404(99)00036-5 · 2.37 Impact Factor