Short-course FAC-M versus 1 year of CMFVP in node-positive, hormone receptor-negative breast cancer: an intergroup study.

PURPOSE: To compare 1 year of therapy with continuous cyclophosphamide, methotrexate, fluorouracil (5-FU), vincristine, and prednisone (CMFVP) with a short course of treatment with a doxorubicin-based regimen in the postsurgical adjuvant treatment of patients with hormone receptor-negative, node-positive breast cancer. PATIENTS AND METHODS: Five-hundred thirty-one eligible women with hormone receptor-negative, node-positive breast cancer were randomized to receive either 1 year of therapy with CMFVP or 20 weeks of therapy with four 5-week courses of treatment with 5-FU, doxorubicin, cyclophosphamide, and methotrexate (FAC-M). RESULTS: At a median follow-up time of 4.9 years, the two treatment arms cannot be demonstrated to be different with respect to overall survival (stratified log-rank, P = .27). The 5-year survival rate is 64% on the CMFVP arm and 61% on the FAC-M arm. CMFVP produces marginally superior disease-free survival (P = .06). The estimated 5-year disease-free survival rate is 55% for patients treated with CMFVP as opposed to 50% for patients treated with FAC-M. CONCLUSION: Neither regimen was shown to be superior in terms of overall survival. Because the disease-free survival produced by CMFVP is marginally superior to that produced by FAC-M, we do not recommend FAC-M for further investigation or for routine use. Possible implications of this study are discussed in the context of other adjuvant chemotherapy trials.

Pitfalls in quality-of-life assessment: lessons from a Southwest Oncology Group breast cancer clinical trial.

There is increasing interest in evaluating the impact of cancer treatment and medical intervention on patient quality of life (QOL). This article reports the findings of a substudy that incorporated the Functional Living Index--Cancer in an ongoing adjuvant breast cancer clinical trial sponsored by the Southwest Oncology Group. The companion study had to be terminated prior to the end of the two-armed, randomized trial because of poor reporting rates over time. Problems with missing data items also occurred. Poor reporting rates in this trial motivated several recommendations for conducting QOL assessment in the cooperative group setting: (a) build support for QOL assessment among the group's leadership, (b) involve physicians and oncology nurses in the study design, (c) identify a QOL liaison at each participating institution, and (d) aggressively monitor the quality and timeliness of data submission.

One versus 2 years of CMFVP adjuvant chemotherapy in axillary node-positive and estrogen receptor-negative patients: a Southwest Oncology Group study.

PURPOSE: To determine if prolonged adjuvant treatment (2 years v 1 year) with combination chemotherapy (cyclophosphamide, methotrexate, fluorouracil [5-FU], vincristine, and prednisone [CMFVP]) in poor-prognosis breast cancer patients (estrogen receptor [ER]-negative, stage II to IIIA) would result in improved disease-free and overall survival rates. PATIENTS AND METHODS: Four hundred forty-five women with ER-negative node-positive breast cancer were enrolled by the Southwest Oncology Group (SWOG) over a period of 5 years (1979 to 1984). Randomized assignments were made to either 1 or 2 years of adjuvant CMFVP. Doses were daily oral cyclophosphamide 60 mg/m2, intravenous (i.v.) weekly methotrexate 15 mg/m2, i.v. weekly 5-FU 400 mg/m2, i.v. weekly vincristine .625 mg/m2 for the first 10 weeks, and prednisone weeks 1 through 6 with doses decreasing from 30 mg/m2 to 10 mg/m2. RESULTS: The median follow-up duration is 8.6 years, with a maximum of 11.3 years. Treatment arms were not significantly different as regards either survival or disease-free survival rates (P = .33 and P = .24, respectively). The five-year survival rate is 57% on the 1-year arm and 62% on the 2-year arm. Patients with three or fewer nodes and premenopausal status were associated with improved survival. Compliance on the 2-year arm was poor, with only 37% completing the full 2 years of treatment. SWOG grade 3 to 4 toxicity was experienced by 47% of patients on the 1-year arm and by 52% on the 2-year arm. There were no treatment-related deaths. CONCLUSION: We conclude that 2-year adjuvant treatment with CMFVP is not an improvement over 1-year treatment. Moreover, 2 years of CMFVP is difficult to complete. However, the results are not definitely negative. A moderate improvement attributed to prolonged chemotherapy, especially among patients with four or more positive nodes, cannot be ruled out.

Predictors of survival following relapse or progression of small cell lung cancer. Southwest Oncology Group Study 8605 report and analysis of recurrent disease data base.

BACKGROUND: Survival after relapse or progression of small cell lung cancer (SCLC) is poor. The Southwest Oncology Group (SWOG) initiated a study of modulation of cyclophosphamide (Cy) resistance in this population. At study closure, the value of testing new regimens in previously treated patients was being debated nationally: Is there an independent impact of treatment over favorable prognostic factors? Thus, the authors analyzed the SWOG recurrent SCLC data base. METHODS: A 12-hour infusion of cytosine arabinoside (ara-C) was used as a potential repair inhibitor of Cy-induced DNA damage in patients with relapsed SCLC. A data base of successive SWOG studies in recurrent SCLC was formed. The independent contribution to survival of prognostic factors, type of prior chemotherapy (CT), time from diagnosis, and type of CT on relapse were then assessed. RESULTS: There were 3 partial responses observed in 67 patients, with substantial myelotoxicity. The median survival was 2.5 months, and 16% lived beyond 6 months. The multivariate analysis of the recurrent SCLC data base found that a normal lactate dehydrogenase (LDH) and second-line treatment with etoposide plus cisplatin (EP), if not initially treated with either alternating or complex multidrug regimens, were the only independent predictors of improved survival. The 2-year survival of this subset was 20%. CONCLUSIONS: The Cy/ara-C program cannot be recommended for patients with recurrent SCLC. However, EP independently contributed to improved survival in patients without complex prior CT and a normal LDH. This finding supports future trials of new approaches in certain subsets of SCLC patients with limited prior treatment.

Comparison of etoposide and cisplatin with bis-chloro-ethylnitrosourea, thiotepa, vincristine, and cyclophosphamide for salvage treatment in small cell lung cancer. A Southwest Oncology Group Study.

Small cell lung cancer patients who failed primary systemic therapy or who failed after response were randomly assigned to salvage treatment with etoposide (VP-16) and cisplatin (CDDP) or bis-chloro-ethylnitrosourea, thiotepa, vincristine, and cyclophosphamide (BTOC). Good risk patients were those who had tolerated prior chemotherapy well, those who had not had prior radiation therapy, and those who were 65 years of age or younger. Patients with a history of poor tolerance, prior radiation therapy, or those who were older than 65 years of age were classified as poor risk. Forty-five patients were randomized to the BTOC regimen and 58 to the VP-16/CDDP regimen. The overall remission rate was 13% (13 of 103 patients). Good risk patients treated with the BTOC regimen had a remission rate of 27% (three of 11 patients), which was the same rate as patients treated with the VP-16/CDDP regimen (three of 11 patients). Poor risk patients had remission rates of 9% (three of 34 patients) with the BTOC regimen and 9% (four of 47 patients) with the VP-16/CDDP regimen. The median survival time from the start of therapy was 16 weeks for all patients. BTOC good risk patients had a median survival time of 10 weeks, as compared with 14 weeks for poor risk patients. VP-16/CDDP good risk patients had a median survival time of 35 weeks, as compared with 12 weeks for poor risk patients. Although based on small numbers, the advantage in survival time for good risk patients treated with VP-16/CDDP over those treated with BTOC is statistically significant. Prior exposure to VP-16 did not influence the outcome of patients treated with VP-16/CDDP. Both regimens produced moderate toxicity, but were generally well tolerated. It was concluded that VP-16/CDDP may be a useful salvage treatment for good risk patients, despite its limited remission rate. Also, it was found that BTOC has no value for patients in this setting and that neither regimen helps patients who are poor risk.

Lack of benefit of adjunctive chemotherapy in stage I malignant melanoma: a Southwest Oncology Group Study.

In 1975, the Southwest Oncology Group initiated an adjuvant study in localized malignant melanoma testing the value of aggressive chemotherapy using carmustine, hydroxyurea, and dacarbazine versus a control arm. Median disease-free survival was 7.1 years for the control arm and 6 years for the treatment arm. Survival was identical for both arms with 65% of the patients alive at 6 years. We conclude that carmustine, hydroxyurea, and dacarbazine chemotherapy is of no value as adjuvant treatment for localized melanoma.

5-Fluorouracil and folinic acid in the treatment of metastatic colorectal cancer: a randomized comparison. A Southwest Oncology Group Study.

In order to determine the clinical applicability of the in vitro observation of enhanced cytotoxicity of 5-fluorouracil (5-FU) in the presence of excess reduced folates, the Southwest Oncology Group (SWOG) performed a randomized trial evaluating two dose schedules of 5-FU and folinic acid (FA) in 128 patients with metastatic colorectal cancer. Of 125 eligible patients, 62 were randomized to receive bolus FA (200 mg/m2 days 1 through 4) in addition to 5-FU (1,000 mg/m2 days 1 through 4) by continuous four-day infusion (infusion arm), while 63 were randomized to receive bolus FA (200 mg/m2 days 1 through 5) in addition to 5-FU (325 mg/m2 days 1 through 5) by bolus injection (bolus arm). The toxicities of the two schedules differed, with stomatitis being more severe in the infusion arm and leukopenia being more severe in the bolus arm. The response rates and survival data for the two arms are nearly identical. The median survival of patients on the infusion arm is 11.0 months and of patients on the bolus arm, 10.3 months. The infusion arm produced one complete response (CR) and 12 partial responses (PRs), for a major response rate of 21% of eligible patients. The bolus arm produced three CRs and 11 PRs, for a major response rate of 22% of eligible patients. The response rate produced is minimally superior to recent cooperative group studies of colorectal cancer, but the response rate and survival experience are within the range of experience for treatment with 5-FU alone.

Effect of alternating combination chemotherapy on survival of ambulatory patients with metastatic large-cell and adenocarcinoma of the lung. A Southwest Oncology Group Study.

Using a randomized prospective trial design, chemotherapy with 5-fluorouracil, vincristine, and mitomycin C (FOMi) was compared with cyclophosphamide, doxorubicin, and cisplatin (CAP) and with FOMi alternating with CAP (FOMi/CAP) in 452 eligible patients with metastatic large-cell undifferentiated and adenocarcinoma of the lung. Objective responses were obtained in 26%, 17%, and 22% of patients treated with FOMi, CAP, and FOMi/CAP, respectively. The median survival was similar for FOMi, CAP, and FOMi/CAP therapies (20, 24, and 23 weeks, respectively), but the overall survival (log rank test), 1-year survival, and remission duration were longer for FOMi/CAP-treated patients. Survival was significantly longer for fully ambulatory FOMi/CAP-treated patients compared with either FOMi (P = .01) or CAP (P = .04). Younger patients treated with full doses of therapy responded more often than older patients receiving reduced drug doses (26% and 11%, respectively; P = .003). A prognostic factor regression analysis of all eligible patients indicates that sex, performance status, stage, and treatment assigned were important independent variables determining survival (P less than .05). Toxicity was comparable in each treatment group.

Bisantrene hydrochloride in gastric adenocarcinoma: a Southwest Oncology Group Study.

Because "the standard" chemotherapy for advanced gastric adenocarcinoma, the FAM combination of 5-fluorouracil, adriamycin, and mitomycin, is only minimally effective, there is a clear need for other choices. Therefore, the Southwest Oncology Group tested the new adriamycin analog, bisantrene, hoping that it might be more effective than the "parent drug." Twenty-six patients with gastric adenocarcinoma were treated on a program of every-3-week 2-hour bisantrene infusions. The starting dose was 260 mg/m2 (208 if poor risk), with subsequent doses based on prior toxicity. The regimen caused sufficient toxicity (especially local phlebitis with pain and swelling) to assure an adequate test. One person (3.8% of eligible patients) experienced a clinically useful 3-month response. He had previously had progressive disease on FAM. Nevertheless, we conclude that bisantrene is not an addition to the small list of drugs useful in the management of gastric adenocarcinoma.

High dose AZQ in renal cancer. A Southwest Oncology Group phase II study.

Fifty-seven patients with renal cancer were treated with AZQ, utilizing one of three IV push schedules. Only one partial response was seen in 55 evaluable patients, and considerable myelosuppression was encountered. Gastrointestinal toxicity was more severe in those patients who had received prior treatment. At these higher doses AZQ is deemed an inactive agent in patients with renal cell carcinoma, at least when the drug is administered as a push schedule.

Treatment of non-small cell bronchogenic carcinoma with vinblastine and mitomycin: a Southwest Oncology Group Study.

Forty-five patients with stage III M1 non-small cell bronchogenic carcinoma were treated with vinblastine (1 mg/m2 by iv bolus twice a day on 2 consecutive days) plus mitomycin (10 mg/m2 on Day 1). This treatment was repeated at 3-week intervals for three courses. Consolidation therapy with doxorubicin and cisplatin at doses of 50 mg/m2 each was administered to responders every 4 weeks for two courses, with subsequent vinblastine and mitomycin maintenance therapy every 6 weeks. Eleven partial remissions (24%) were achieved, with a median duration of remission of 16 weeks (range, 8-32) and a median survival of 19 weeks. No differences were seen in median duration of remission or survival by cell type or performance status.

Phase II trial of cyclophosphamide, doxorubicin, and cisplatin (CAP) versus amsacrine in patients with transitional cell carcinoma of the urinary bladder: a Southwest Oncology Group study.

The combination of cyclophosphamide, doxorubicin, and cisplatin (CAP) was reported to be effective in patients with metastatic transitional cell cancer of the urinary bladder. This study was designed to test the effectiveness of the phase II agent amsacrine (m-AMSA) versus CAP in patients previously untreated with systemic chemotherapy, with crossover if no response occurred or at the time of progression. In 23 patients who were randomized to receive CAP, three achieved complete response, seven achieved partial response, six had stable disease, and seven had disease progression. The responses in the 22 patients who received m-AMSA were: one with complete response, three with partial response, six with stable disease, and 12 with progressive disease. The overall response rate to initial CAP therapy was 43% compared to 19% for initial m-AMSA therapy. The median duration of response to CAP was 28 weeks and to m-AMSA was 21 weeks. There were no statistically significant differences in the durations of response or survival times between the groups. The main side effects of CAP were: nausea and/or vomiting, leukopenia, anemia, thrombocytopenia, and renal toxicity. Leukopenia and anemia were the major toxic effects of m-AMSA. Our study supports the justification for testing phase II agent(s) in previously untreated patients with bladder cancer with systemic chemotherapy, provided adequate crossover to a known active single or combination of agents is built into the design of such a trial.

Phase II study of aziridinylbenzoquinone (AZQ) in patients with central nervous system malignancies: a Southwest Oncology Group Study.

AZQ, an alkylating agent with lipophilic characteristics allowing CNS penetration was studied in patients with primary CNS malignancies refractory to surgical and radiotherapeutic modalities. Responses were evaluated by three criteria: neurologic examination, performance status and CT scan of the brain. Improvement in all three parameters with stable or decreasing doses of decadron was required for a partial response. Thirty-six poor risk (prior chemotherapy) patients with Grades III and IV astrocytomas were treated with 30 mg/m2. Three patients had a partial response (14, 17, 60 weeks duration). Two patients had mixed responses (worsening of one disease parameter with improvement in another), four had stable disease and one patient had improvement in neurologic parameters with a stable CT scan. Twenty-six patients had increasing disease. Fifteen good risk patients (no prior chemotherapy) with recurrent grades III and IV astrocytomas were treated at a dose of 40 mg/m2 intravenously every three weeks. There were no objective responses in this group of patients. Three patients with nonastrocytomas were treated and no responses observed. The drug was well tolerated. Myelosuppression in the form of leukopenia and thrombocytopenia was the major toxicity. Myelosuppression required dose reductions in eight patients and discontinuation of therapy due to repeated treatment delays in two patients. AZQ at doses of 30 and 40 mg/m2 given on an intermittent bolus schedule is inactive in patients with Grades III and IV recurrent astrocytoma.

Combination chemotherapy plus levamisole in the treatment of disseminated malignant melanoma. A Southwest Oncology Group study.

Two hundred-eighty patients were randomized to receive either BCNU, hydroxyurea and imidazole carboxamide (BHD), BHD plus levamisole, or high-dose DTIC plus actinomycin D. There was no difference in response rate in the three groups (24%, 25% and 22%). Females responded better than males and, as expected, those with a better performance status responded more favorably than those with poor performance status. Patients whose primary site of melanoma was on the extremities did significantly better than those melanomas originating on the trunk or head and neck. Patients with lymphocyte counts greater than 2000/mm3 fared better than those with lymphopenia. Those responders who received high-dose DTIC plus actinomycin D had a significantly longer length of response than those receiving the immunotherapy limb. This was also true in those patients who had a prior disease-free interval of greater than 6 months before being placed in this study. Although there was no difference in survival from the start of treatment in all patients, those patients receiving high-dose DTIC plus actinomycin D and who had a prior disease-free interval of greater than 6 months, had significantly superior survival when compared to the immunotherapy limb. It is concluded that the addition of Levamisole to BHD does not improve response rate and may in certain subsets be detrimental to disease-free response and survival. High-dose DTIC plus actinomycin D is equally effective to BHD.

Methyl-glyoxal bis guanyl hydrazone (methyl-GAG, MGBG) in advanced breast cancer. A Phase II trial of the Southwest Oncology Group.

The Southwest Oncology Group has evaluated methyl-GAG on a weekly schedule among patients with metastatic breast cancer. Among 72 fully and partial evaluable patients, one complete and four partial responses were seen. Toxicity was similar to other trials with this compound except for thrombocytopenia which was more frequent and severe and probably related to tumor infiltrating marrow. In addition, one patient experienced recall dermatitis following methyl-GAG. This toxicity has not been previously reported with this compound. Methyl-GAG has minimal activity at this dose and schedule among heavily pretreated patients with breast cancer.