Breast Cancer: Strategies for the 1990s 11

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Adjuvant Chemotherapy of Breast Cancer James B. Breitmeyer, MD, PhD,* and I. Craig Henderson, MD, FACPt

For many patients, carcinoma of the breast is a systemic or disseminated disease at the time of diagnosis. Recent analyses have demonstrated that a subset of patients may enjoy long-term disease-free survival after prompt and appropriate surgical management, particularly when the primary tumor is small and lymph node spread has not occurred. 82 However, the dogma of sequential lymphatic spread, which supported Halstedian management practices, has been replaced by an understanding that distant hematogenous dissemination of malignant cells may already have occurred even with the earliest detection methods available. Initial surgical management has an all-or-none effect on long-term survival: either the patient will enjoy extended disease-free survival, or she will die of disseminated breast cancer at approximately the same time as she would have if surgery had not been performed. 41 Therefore, adjuvant therapies designed to suppress or eliminate neoplastic cells outside the surgical field have become essential in the overall care of the patient with breast cancer. The rationale for adjuvant chemotherapy will be presented in this review, with a detailed discussion of which subsets of patients with breast cancer are likely to benefit most from it. It is essential to understand that not all patients are likely to benefit equally from adjuvant chemotherapy. Therefore, it also is important to obtain a clear understanding of the risks and potential short- and long-term adverse effects of adjuvant chemotherapy in order to evaluate the likely risk-benefit ratio of treatment for each individual patient. RATIONALE FOR ADJUVANT THERAPY Among the earliest indications that adjuvant therapy could be beneficial in breast cancer were studies involving ovarian ablation at the time of *Instructor in Medicine, Harvard Medical School; and Attending Physician, Breast Evaluation Center, and Research Scientist, Division of Tumor Immunology, Dana-Farber Cancer Institute, Boston, Massachusetts tAssociate Professor of Medicine, Harvard Medical School; and Medical Director, Breast Evaluation Center, Dana-Farber Cancer Institute, Boston, Massachusetts

Surgical Clinics of North America-Vo!' 70, No.5, October 1990






mastectomy. The oldest of these studies, that of the Christie Hospital in Manchester, England, randomized women who were either premenopausal or perimenopausal (within 2 years of cessation of menses) to treatment with either radical mastectomy or radical mastectomy plus ovarian ablation via radiotherapy. Ten- and fifteen-year follow-up showed a survival advantage for women treated with ovarian ablation, although this difference never reached statistical significance. 19, 20 Similar results were obtained in five other trials of adjuvant ovarian ablation. 15, 60, 70, 71, 78 However, in a trial conducted in Toronto, a statistically significant improvement in both disease-free interval and overall survival was observed in the subset of patients who were over the age of 45 but still menstruating after treatment with ovarian ablation and prednisone. 60, 61 These results provided an important early indication that adjuvant treatment could improve the outlook after mastectomy for breast cancer and formed part of the rationale for testing adjuvant chemotherapy. At the time these data were published, the benefits of ovarian ablation were considered to be too small to justify the technique for routine use. However, the patients were not selected for expression of estrogen receptors by their tumors, which we now know to be a Significant determinant of responsiveness to hormonal therapies. As a result, there is renewed interest in this approach as a front-line adjuvant therapy for certain patients, and new studies are in progress. The randomized trials that established the unequivocal benefit from adjuvant chemotherapy and have become standards for comparison were initiated in 1972 and 1973. At that time, early reports of adjuvant oophorectomy implied promise, and combination chemotherapy programs effective for metastatic breast cancer, especially the CMF program 16, 17, 22 (cyclophosphamide, methotrexate, 5-fluorouracil), were being developed. The two major randomized trials, conducted by the National Surgical Adjuvant Breast Project (NSABP) and the Instituto Nazionale dei Tumori in Milan, Italy, are summarized in Table 1. In both studies, patients with operable tumors (including some with T3 lesions) and pathologically documented involvement of axillary lymph nodes were enrolled after mastectomy. Patients were stratified according to the extent of lymph node involvement (one to three positive nodes or more than three positive nodes) and age (no more than 49 years or 50 years or older; NSABP) or menopausal status (premenopausal or postmenopausal; Milan). Patients in the NSABP trial were randomized to postsurgical treatment with placebo or L-phenylalanine mustard (L-PAM; also known as phenylalanine mustard, melphalan, or chlorambucil; 0.15 mg/kg per day orally for 5 consecutive days every 6 weeks for 17 courses; approximately 2 years' total therapy). Patients in the Milan trial were randomized after surgery to no therapy or CMF (cyclophosphamide 100 mg/M2 orally days 1 to 14, methotrexate 40 mg/M2 intravenously days 1 and 8, and 5-fluorouracil 600 mg/M2 intravenously days 1 and 8 for 12 cycles of 28 days each; total therapy approximately 1 year). The lO-year results of these two seminal studies are presented in Table 1. 9, 27 Adjuvant chemotherapy increased the proportion of patients free of breast cancer at 10 years after mastectomy. In the Milan trial, this improvement reached statistical significance (P = 0.001). In both trials, there was a trend toward an increased overall survival after chemotherapy,





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Table 1. Ten-year Results of NSABP and Milan Trials Randomizing Patients to Receive Adjuvant Chemotherapy or No Treatment After Mastectomy for Node-Positive Breast Cancer NSABP PATIENT GROUP


Recurrence-free at 10 years (%) All patients 29 Premenopausru 29 Postmenopausal 28






38 46 34

0.06 0.02 0.49

31 31 32

43 48 38

48 61 41

0.30 0.02 0.80

47 45 50

55 59 52


0.001 0.0005 0.32

Alive at 10 years (%)

All patients Premenopausal Postmenopausal

41 37 43


Adjuvant chemotherapy of breast cancer.

Many women will not be cured of breast cancer by even the best early detection and surgical techniques because of micrometastases present at diagnosis...
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