[Adjuvant treatment of breast cancer].
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Biomedical subjects
Publications and source records attributed to A Goldhirsch.
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Among 422 patients with advanced breast cancer treated in a randomized trial we observed 60 complete responses (CR). Sixteen were achieved among 206 patients treated with endocrine therapy alone and 37 among 216 patients treated with concomitant chemotherapy and endocrine therapy. The incidence of CR in women treated with the concomitant modality was higher in those with dominant soft tissue disease, intermediate in those with osseous or pulmonary involvement, and low in patients with liver metastases. Bone was shown to be the organ most responsive to therapy among patients treated with hormonotherapy, while patients with soft tissue metastases had an unexpectedly low rate of complete remission with this modality. The probability of achieving a CR was inversely proportional to the tumor burden in the patients treated with concomitant chemotherapy and endocrine therapy. For complete responders on hormone treatment alone and for those on combined endocrine and cytotoxic therapy, both median time to progression (26 and 29 months, respectively) and survival (52 and 53 months, respectively) were similar and statistically significantly longer than in partial or minor responders. This observation leads us to the conclusion that the hormonal component is the determinant for the length of a CR.
Four hundred four women with suspected pelvic masses or histories suggesting ovarian cancer (eg, low abdominal pain) entered a prospective study designed to assess the accuracy of sonography in confirming or excluding the presence of ovarian cancer. Three hundred twelve of these patients were operated on and evaluated within three weeks after sonography. The predictive value of the sonographic evidence of malignancy was 73% (38 of 52 patients), whereas benign tumors were predicted correctly in 95.6% (177 of 185). Sonographic reassessment of masses with patterns suggesting benign disease may be an alternative to immediate surgical exploration in a selected population (ie, those with poor surgical risk). The sonographic detection of ovarian malignancy requires further improvement; as a diagnostic tool it continues to present a challenge.
The prognostic significance of histologic tumor grade has been evaluated in 1537 women entered into the Ludwig Trials I-IV of adjuvant therapy for node-positive breast cancer. Tumor grade was determined on histologic review of primary tumor sections by two central review pathologists using a modification of the Bloom and Richardson grading system. The 5-year overall survival rates (+/- SE) were: Grade 1, 86% +/- 2; Grade 2, 70% +/- 2; and Grade 3, 57% +/- 2 (P less than 0.0001). This survival difference was seen in both premenopausal (P less than 0.0001) and postmenopausal (P less than 0.0001) women. Significant differences in disease-free survival (DFS) by tumor grade were also observed (P less than 0.0001). The tumor grade determined by the 75 contributing local clinic pathologists was also highly significant for predicting DFS and overall survival. Tumor grade remained a statistically significant prognostic factor for DFS (P less than 0.0001) and overall survival (P less than 0.0001) in multivariate analyses controlling for nodal status, tumor size, estrogen receptor status, menopausal status, age, peritumoral vessel invasion, and treatment assigned. In postmenopausal patients for whom adjuvant treatment was compared with no adjuvant therapy, the prognostic significance of tumor grade was modified by the effect of treatment. The presence of vessel invasion by primary tumor cells was a stronger predictor of early recurrence than was increasing tumor grade in postmenopausal patients who received no adjuvant therapy. The higher failure rates for patients with high-grade tumors was due to a larger number of failures in regional and visceral sites. Tumor grade can be determined by any pathologist and allows for selection of a subpopulation of breast cancer patients at high risk for early mortality.
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Sixteen non-pretreated patients with locally advanced cervical cancer (FIGO Stage IIIb) were treated with two 3-week cycles of platinum, bleomycin, and methotrexate (PBM), which were followed by radiation therapy. Response to both modalities was seen in 11 patients (69%), and three patients (19%) had a progression-free survival of more than 2 years. Radiation therapy was proven to be feasible after two cycles of PBM combination chemotherapy.
Overviews are valuable investigations that require international cooperation, and can provide a useful summary of available information on a current therapeutic issue. Combining results of trials in early breast cancer is an appropriate example of such procedures. However, the advantage of bringing a large amount of information together might be overcome by the disadvantages of improper conduct and overinterpretation of the overview findings. A prospective protocol must be prepared and followed. The results must be presented in sufficient detail to allow independent conclusions to be reached. The influence of strict application of the arithmetic construct must be recognized when determining whether the conclusions about the impact of separate components of treatment are appropriate. Most importantly, the transition from scientific inquiry to the application of treatment recommendations for individual patients must still be made very cautiously. We stress the importance of the results from individual, well-conducted clinical trials for providing the critical information for guiding the choice of treatment for patients outside of trials.
Between 1978 and 1981, 463 evaluable postmenopausal patients 65 years of age or younger with operable breast cancer and metastases in axillary lymph nodes were entered in Ludwig Breast Cancer Study III (Ludwig III) and randomly allocated to receive chemoendocrine therapy with cyclophosphamide, methotrexate, 5-fluorouracil, low-dose continuous prednisone, and tamoxifen (CMFp + T) for 12 monthly cycles, or endocrine therapy alone with prednisone and tamoxifen (p + T) for 1 year, or no adjuvant treatment after mastectomy (observation). At 60 months' median follow-up, the 5-year disease-free survival (DFS) rates were 59% for CMFp + T, 41% for p + T, and 31% for observation (P less than .0001), and the 5-year overall survival (OS) rates were 71% for CMFp + T, 64% for p + T, and 59% for observation (P = .16; CMFp + T v observation, P = .07). A new quality of life-oriented endpoint was defined to assist in the selection of therapeutic approach after surgery for postmenopausal patients: the time without symptoms of disease and subjective toxic effects of treatment (TWiST). Despite the larger initial discount due to subjective toxicity with chemoendocrine therapy, by 5 years postmastectomy the net difference in average TWiST for treated patients compared with the observation group was positive and approximately equal for both adjuvant treatment programs. Adjuvant chemoendocrine therapy for postmenopausal women appears to be justified due to an emerging OS advantage and increasing TWiST gained for the treated patients.
Data on 1,601 patients with node-positive operable breast cancer who were randomized in four different prospective adjuvant therapy trials were analyzed to evaluate the role of routine bone scans and the alkaline phosphatase value at regular intervals in screening for bone involvement. Bone scan was a prerequisite for randomization and was repeated within the first 12 months in 90% (1,441) of the patients. Abnormal or doubtful scan findings had to be verified by x-ray examination. The repeated scan results were normal in 1,263 (87.8%) patients, doubtful but with no radiologic evidence of bone metastasis in 161 (11%), and abnormal (radiologically confirmed) in 17 (1.2%). After a median observation of 4 years bone metastases as the first relapse developed in 136 (8.5%) patients. This occurred in 87 of 1,263 (6.9%) of the patients with normal repeated scan results and in 18 of 161 (11.2%) of those with doubtful repeated scan findings. Based on the results of the first repeated scan, early detection of a first recurrence in bone might have been possible for 2.4% of the population. Serum alkaline phosphatase levels were also without clinical use. Bone scan in the observation of patients with operable breast cancer should be performed only as dictated by the clinical situation.
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The Ludwig Breast Cancer Study Group conducted four concomitant trials involving adjuvant chemotherapy and endocrine therapy. In Ludwig I, adjuvant combination chemotherapy was used with or without prednisone to treat premenopausal and perimenopausal women with metastases in 1-3 axillary lymph nodes. The impact of adding low-dose, continuous prednisone (7.5 mg/day) to an adjuvant, chemotherapy regimen of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) was investigated in a randomized trial of 491 premenopausal and perimenopausal patients with operable breast cancer and metastases in 1-3 axillary lymph nodes. As a consequence of lower hematologic toxicity, a significantly higher dose of CMF could be administered with added prednisone (P less than 0.0001). However, at the 4-year median follow-up, no significant improvement was observed in disease-free survival (DFS) (73% vs. 77%; P = 0.35) or overall survival (OS) (both 86%; P = 0.73). Induced amenorrhea was associated with a longer DFS for younger patients, those who received lower CMF doses, and those with tumors that were estrogen receptor (ER) positive. In Ludwig III, adjuvant therapy was administered to younger postmenopausal women in a study of chemotherapy plus endocrine therapy versus endocrine therapy alone versus mastectomy alone. In this randomized trial of 463 postmenopausal women 65 years of age or younger with axillary node metastases, treatment with the combination of CMF plus low-dose prednisone and tamoxifen (CMFp + T), was compared to endocrine therapy alone (p + T) or to no further treatment after total mastectomy and axillary clearance. At a median follow-up of 4 years, the DFS was 61% for the CMFp + T group, compared with 48% for the p + T group (P = 0.01) and 31% for the observation group (P less than 0.0001). The 4-year OS rates were not statistically different (76%, 67%, and 68%, respectively; P = 0.30). Treatment with CMFp + T reduced local, regional, and distant metastases and was equally effective in improving DFS in patients with ER-positive or ER-negative tumors. In Ludwig II, chemotherapy was given with or without oophorectomy in premenopausal and perimenopausal patients with metastases in 4 or more axillary nodes.(ABSTRACT TRUNCATED AT 400 WORDS)
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Polyneuropathy developed in 7 of 87 women who had been treated with cis-platinum for ovarian carcinoma. Distal disturbances of sensitivity were clinically prominent, the emphasis being on disturbed vibratory perception and acrognosis. No relevant signs of motor dysfunction were noticed, neither clinically nor neurophysiologically. Sural biopsies taken from two women revealed a primary axonal degeneration, mostly affecting the myelinic fibres of large diameter. In 3 cases mild reversion was seen, and in 4 cases no definite reversion, of the disturbed functions - uncertain gait and clumsiness of the hands - during the follow-up period of 6 to 30 months.
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The current situation in the treatment of metastatic breast cancer is reviewed. Overall the concurrent use of endocrine treatment and chemotherapy does not improve the therapeutic results as compared to a treatment encompassing only one modality. However, results diverge widely in different subgroups. Data emerging from various randomized trials are beginning to define subgroups of patients, who should be treated differently. Such data are discussed and their importance for future trials in the field of advanced breast cancer reviewed.