Adjuvant Cytotoxic and Endocrine Therapy in Pre- and Postmenopausal Patients With Breast Cancer and One to Nine Infiltrated Nodes

Abstract

The present randomized phase III trial was designed to detect a 15% benefit in relapse-free survival (RFS) or overall survival (OS) from the incorporation of adjuvant tamoxifen to the combination of CNF [cyclophosphamide, 500 mg/m2; mitoxantrone (Novantrone), 10 mg/m2; fluorouracil, 500 mg/m2 chemotherapy and ovarian ablation in premenopausal patients with node-positive breast cancer and conversely from the incorporation of CNF chemotherapy to adjuvant tamoxifen in node-positive postmenopausal patients. From April 1992 until March 1998, 456 patients with operable breast cancer and one to nine infiltrated axillary nodes entered the study. Premenopausal patients were treated with six cycles of CNF chemotherapy followed by ovarian ablation with monthly injections of triptoreline 3.75 mg for 1 year (Group A, 84 patients) or the same treatment followed by 5 years of tamoxifen (Group B, 92 patients). Postmenopausal patients received 5 years of tamoxifen (Group C, 145 patients) or 6 cycles of CNF followed by 5 years of tamoxifen (Group D, 135 patients). Adjuvant radiation was administered to all patients with partial mastectomy. After a median follow-up period of 5 years, 125 patients (27%) relapsed and 79 (17%) died. The 5-year actuarial RFS for premenopausal patients was 65% in Group A and 68% in Group B (p = 0.86) and for postmenopausal patients 70% in Group C and 67% in Group D (p = 0.36). Also, the respective OS rates were 77% and 80% (p = 0.68) for premenopausal and 84% and 78% (p = 0.10) for postmenopausal patients. Severe toxicities were infrequently seen, with the exception of leukopenia (18%), among the 311 patients treated with CNF. In conclusion, the present study failed to demonstrate a 15% difference in RFS in favor of node-positive premenopausal patients treated with an additional 5 years of tamoxifen after CNF adjuvant chemotherapy and ovarian ablation. Similarly, six cycles of CNF preceding 5 years of tamoxifen did not translate to a 15% RFS benefit in node-positive postmenopausal patients.

Breast cancer follow-up strategies in randomized phase III adjuvant clinical trials: a systematic review

“…Among the 66 papers describing follow-up methodology, minimal and intensive approaches were equally represented, each being followed by 33 (50%) trials. Only 6 papers report the use of tumor markers measurement (carcinoembryonic antigen and carbohydrate antigen 15–3) during follow-up [ 46 , 48 , 57 , 75 , 82 , 88 ] and none includes the use of computed tomography scans, positron emission tomography scanning and magnetic resonance imaging.…”

“…For each follow-up approach, the frequency at which the different exams are performed is highly variable, ranging from 1 to 4 times/year for history and/or physical examinations, and from 1 to 3 times/year for imaging modalities, as shown in Table 4 . Almost all RCTs showed the highest number of evaluations/year in the first 1–2 years of follow-up; 5-year follow-up and annually thereafter was chosen by almost all studies, with the following exceptions: two studies interrupted all imaging modalities at the 3rd year [ 83 , 84 ]; one study discontinued chest radiographs and bone scan at the 4th year [ 46 ] and one study ended chest radiographs at the 3rd year [ 66 ].…”

“…The frequency of follow-up is higher in the first 2–3 years after surgery and tends to decrease thereafter. Almost all RCTs, except few studies [ 46 , 83 , 84 ], continue programmed controls at least 5 years after treatment, independently from the chosen follow-up methodology. These issues are still object of debate [ 135 ], since neither the optimum frequency nor duration of follow-up has been clearly defined [ 23 , 136 , 137 ].…”