Randomized trial of 3 different regimens of combination chemotherapy in patients receiving simultaneously a hormonal treatment for advanced breast cancer. Combination chemotherapy for advanced breast cancer: two regimens containing adriamycin. Comparison of four-combination chemotherapy programs in metastatic breast cancer: comparison of multiple drug therapy with cytoxan, 5-FU and prednisone versus cytoxan and adriamycin, versus cytoxan, 5-FU and adriamycin, versus cytoxan, 5-FU and prednisone alternating with cytoxan and adriamycin. Differential response to chemotherapy in metastatic breast cancer in relation to estrogen receptor level. Results of a prospective randomized study. Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies. Response and survival in advanced breast cancer after two non-cross-resistant combinations. Survival of premenopausal women with metastatic breast cancer. Long-term follow-up of Eastern Cooperative Group and Cancer and Leukemia Group B studies. Combination chemotherapy for metastatic breast carcinoma. Prospective comparison of multiple drug therapy with L-phenylalanine mustard. Megestrol acetate and aminoglutethimide/hydrocortisone in sequence or in combination as second-line endocrine therapy of estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group phase III trial.
We report the results of a randomized trial carried out by the Swiss Group for Clinical Cancer Research (SAKK) and in which 230 patients with advanced breast cancer receiving concurrently a hormonal treatment (oophorectomy for pre- and tamoxifen for postmenopausal women) were randomly allocated to three different regimens of combination chemotherapy. The therapeutic results registered with the two more intensive combinations (LMP/FVP and LMFP/ADM) were similar with regard to response rates, time to progression and survival. The patients receiving the low-dose chemotherapy lmfp showed a statistically significant lower response rate (32%, P less than 0.001) and a shorter survival (P = 0.03) than the results observed in patients treated with the two other regimens. This difference was particularly pronounced, at least regarding survival, in the following subgroups: postmenopausal women, patients with a poor performance status, dominant visceral lesions, two sites of disease and a disease-free interval longer than 12 months. Patients with bony metastases as dominant lesion fared similarly with all three regimens of chemotherapy. This latter subset of advanced breast cancer patients should probably be spared too intensive cytotoxic treatment. This is, to our knowledge, the first report of a randomized trial showing an evident correlation between response rate and survival in various subgroups of patients with advanced breast cancer treated with different chemotherapeutic regimens. Forty-eight women with advanced metastatic carcinoma of the breast were treated with one of two combination chemotherapy regimens: 1) adriamycin and cyclophosphamide or 2) adriamycin, cyclophosphamide, methotrexate and 5-fluorouracil. The response rate in the two-drug treatment group was 50% and in the four-drug treatment group, 55%. The median duration of response was ten months in both treatment groups. Dramatic responses were seen in patients with visceral metastases. Patients who responded to chemotherapy had a significantly longer survival than nonresponders (p less than 0.01). The long interval between adriamycin doses (six weeks) in the four drug regimen did not adversely effect the response rate--an important finding in view of the dose-related cardiac toxicity of this agent. In 126 postmenopausal women with metastatic breast cancer, four chemotherapeutic combination programs were tested. Patients were stratified and randomized to one of the four programs: (1) fluorouracil, cytoxan and prednisone (CFP): (2) fluorouracil, cytoxan and Adriamycin (CAF); (3) cytoxan and Adriamycin (CA); or (4) alternating combinations of CFP-CA. Objective response rates were 17% for 18 patients on CFP, 25% for 40 patients on CAF, 42% for 41 patients on CA and 63% for 19 patients on CFP-CA. CFP-CA provided a significantly higher response rate than either CFP or CAF. The response rate of CA was intermediate. The duration of remission and survival were similar for all four groups. When progression or relapse following remission was demonstrated, patients were rerandomized to either adrenalectomy or tamoxifen. There were no responders either in the 15 patients undergoing adrenalectomy or the 11 patients receiving tamoxifen. In a crossover study, nine adrenalectomized patients received tamoxifen and four tamoxifen-treated patients underwent adrenalectomy. None responded. It appears that response rates to hormonal modalities are reduced in patients previously treated by combination chemotherapy. The predictive value of estrogen receptor (ER) level for response to chemotherapy was studied in 182 patients with metastatic breast cancer in a prospective study. Patients were stratified according to ER status and dominant site of disease and randomized to one of three regimens: cyclophosphamide, 5-Fluorouracil, and prednisone (CFP) versus CFP, methotrexate, and vincristine (CFPMV) versus doxorubicin and cyclophosphamide (AC). There was no significant differences in all response categories (P = 0.21), was taken as a predictor for response to chemotherapy, there was no significant difference in overall response (P = 0.61) between ER+ (62/108, 57%) and ER- patients (31/49, 63%). However, there was a significant trend toward a higher degree of response in ER- patients (more complete response [CR] nine of 49, 18%, and fewer failures six of 49, 12%) than in ER+ (less CR seven of 108, 7%, and more failures 37/108, 34%) (P = 0.006). Patients with higher measured levels of ER showed worse response (Kendall's tau C, P = 0.026). This trend for ER- patients to have better response than ER+ patients was generally consistent, regardless of the predominant site of metastases or chemotherapy regimen (P = 0.04 for CFP; P = 0.08 for CFPMV; and P = 0.20 for AC). The advantage of a better response for ER- patients was nullified by an earlier relapse which was reflected in longer duration of remission, time to treatment failure, and survival in favor of ER+ patients (12.3 months versus 7.3 months remission duration, 18.7 months versus 13.6 months survival in partial responders). These data suggest that ER- patients respond to a higher extent to chemotherapy but relapse sooner than ER+ patients, suggesting a more rapid growth for ER- tumors. In patients with ER- tumors and poorer prognosis on conventional chemotherapy, new trials of intensive consolidation after response should be considered. Endometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled.
                Patients (n=540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy.
                In the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95%confidence interval (CI) 0.41-0.99; P=0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P=0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P=0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35-0.88; P=0.01).
                Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results.
                Copyright 2010 Elsevier Ltd. All rights reserved. A prospective study with two cytotoxic combinations (cyclophosphamide, methotrexate, and fluorouracil (CMF), and adriamycin plus vincristine (AV)) was carried out in 110 patients with advanced breast cancer. There was no significant difference between the treatment groups in the response rate after primary treatment, the median duration of response, and the median survival. In both groups responders survived for longer than non-responders. Secondary treatment after crossover for progression or relapse resulted in response rates of 35% for AV and 20% for CMF. Toxicity was mainly represented by reversible haemosuppression. These results are comparable with those obtained with other multiple-drug regimens, and combination chemotherapy alone seems to have reached a plateau in its capacity to control disseminated breast cancer. In premenopausal women with metastatic breast cancer, differences in survival curves early during follow-up can be misleading. The authors therefore analyzed long-term survival in 378 patients, entered in three randomized trials, started between 1973 and 1978. Combined data from the three trials were used to increase the power for identifying prognostic variables. Cancer and Leukemia Group B (CALGB) trial 7382 randomized patients to oophorectomy plus either cyclophosphamide or combination chemotherapy or observation. Eastern Cooperative Oncology Group (ECOG) 2174 randomized patients who had not progressed 3 months after oophorectomy to combination chemotherapy or combination chemotherapy or observation. Trial ECOG 2177 randomized estrogen receptor (ER) positive or ER-unknown patients to oophorectomy plus combination chemotherapy or immediate combination chemotherapy, and ER-negative patients were directly assigned to combination chemotherapy. Hence ER-negative patients need not have been healthy enough to be randomized to oophorectomy. With only 14% of the patients still alive, median survival on the three studies was 30, 24, and 28 months. The median survival of individual treatments changed noticeably in ECOG 2174 and ECOG 2177 with long-term follow-up. At this time there are no differences in survival between randomized regimens in any of the three trials. In a multivariate model, factors associated with significantly poorer survival were visceral-dominant disease, nodal metastases, breast metastases, age younger than 45 years, ER negativity, and not receiving chemotherapy immediately after oophorectomy. This treatment difference was thus not due to imbalances in the prognostic variables used in the model, but it may be due to imbalances of unknown prognostic factors or differences in patient selection. A prospective randomized clinical trial was undertaken in 184 patients with metastatic breast carcinoma to compare single drug chemotherapy with L-phenylalanine mustard (L-PAM) and intermittent combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluourouracil (CMF). All patients had not been previously treated with cytotoxic drugs and all had objectively measurable visceral of soft tissue disease. Of the 93 patients who received CMF, 49 (53%) achieved a complete (14 patients) or partial (35 patients) regression of measurable tumor, for a median duration of 25 weeks. Eighteen of the 91 patients (20%) treated with L-PAM responded, for a median duration of 13 weeks. The toxicity was primarily hematologic, and greater in the CMF group, which also received more cycles of therapy because of the higher rate and duration of response. The overall survival of CMF-treated patients was superior to that of the single drug group. The differences were even greater when the patients were subclassified according to the presence of liver involvement or nonambulatory performance status. The superior antitumor effect of CMF over L-PAM suggests that it may be a more effective drug regimen to be used as an adjuvant to primary therapy. A phase III randomized trial was performed to determine whether combination hormonal therapy with aminoglutethimide (AG) and hydrocortisone (HC) plus megestrol acetate (MA) improved response rates, response duration, or increased survival over the sequential use of each hormone in women with estrogen receptor-positive metastatic breast cancer (MBC) who had maintained stable disease for at least 6 months or responded to tamoxifen.
                Two hundred eighty-eight postmenopausal women with progressive estrogen receptor-positive MBC were randomly selected to receive MA 40 mg four times daily (arm I), AG 250 mg four times daily with HC 40 mg daily in divided doses (arm II), versus the combination of MA plus AG given at the same dosages (arm III). Patients on arms I and II who progressed after an adequate trial were crossed over to the other treatment arm.
                Two hundred thirty-five eligible patients were evaluated for response, time to treatment failure, and survival. Response was only reported for patients with measurable disease and was not statistically different among the three arms. There were two partial responses (PRs) on MA (6%), four complete responses (CRs) and six PRs on AG (24%), and eight PRs and three CRs on MA plus AG (23%) in 32, 42, and 48 measurable patients, respectively. Median times to treatment failure were also similar at 5, 4, and 7 months. Survival was also not statistically different among the three arms at 26, 27, and 26 months for arms I, II, and III, respectively. Toxicity was greater in the two AG arms with respect to fatigue, nausea and vomiting, and rash.
                With the exception of toxicity, there is no response, time to treatment failure, or survival benefit for any one group when comparing MA, AG, or the combination at their stated doses in women with estrogen receptor-positive MBC who had previously responded to or stabilized with tamoxifen.
The addition of one or more drugs to the regimen shows a statistically significant advantage for tumour response in women with metastatic breast cancer but the results suggest no difference in survival time or time to progression. The positive effect on tumour response was also associated with increased toxicity.