Survival of patients with metastatic breast cancer treated with either combination or sequential chemotherapy.

One hundred twenty-one patients with metastatic adenocarcinoma of the breast were randomized to concurrent combination therapy or single-drug chemotherapy administered sequentially. Although response frequency and duration of response were significantly increased in patients receiving the combination regimen, survival was not significantly prolonged when compared to those receiving sequential treatment. For the 69 patients free of liver metastasis, median survival was comparable in both treatment arms (14.4 months sequential versus 12.8 months combination). These results indicate that a large subset of patients with metastatic breast cancer may benefit from less aggressive therapeutic regimens. Furthermore, these results illustrate that conclusions of chemotherapy trials in breast cancer based only on response frequency and duration of response represent preliminary results subject to change when final survival information becomes available.

Combination chemotherapy, glucocorticoids, and interferon alfa in the treatment of multiple myeloma: a Southwest Oncology Group study.

PURPOSE: Standard therapy for multiple myeloma consists of cytotoxic chemotherapy plus glucocorticoids. Interferon (IFN) alfa maintenance is reported to prolong chemotherapy-induced remissions and survival. This study evaluates induction chemotherapy, glucocorticoids, and interferon maintenance in myeloma. PATIENTS AND METHODS: Five hundred twenty-two previously untreated myeloma patients were randomized to three chemotherapy regimens with differing glucocorticoid intensities. Patients who achieved remission were randomized to receive IFN or observation until relapse. Patients who failed to respond to chemotherapy received IFN alfa plus dexamethasone (DEX). RESULTS: Five hundred nine patients were eligible for induction chemotherapy. Chemotherapy with higher dose-intensity glucocorticoids yielded higher response rates and improved survival (P = .02 for the three-group comparison; P < .05 for each higher glucocorticoid arm v vincristine, melphalan, cyclophosphamide, and prednisone alternating with vincristine, carmustine [BCNU], doxorubicin, and prednisone [VMCP/VBAP]). One hundred ninety-three patients who achieved remission were randomized to receive IFN alfa 3 MU three times weekly or observation. IFN was not superior to observation for relapse-free (P = .95) or overall survival (P = .39) from start of maintenance. Eighty-eight induction failures received 5 MU of IFN three times weekly plus DEX. Patients who received IFN/DEX had a median survival duration of 48 months from start of IFN/DEX. CONCLUSION: Higher-dose glucocorticoids increases frequency of response to chemotherapy and prolong survival in myeloma. IFN maintenance with the dose schedule used in this trial did not prolong relapse-free or overall survival. We cannot exclude a small effect of IFN, as most individual trials do not have sufficient statistical power. Meta-analysis of randomized trials evaluating IFN maintenance in myeloma might be of value. While IFN appeared ineffective, addition of higher-dose glucocorticoids improved outcome in myeloma.

Prognostic significance of progesterone receptor levels in estrogen receptor-positive patients with metastatic breast cancer treated with tamoxifen: results of a prospective Southwest Oncology Group study.

PURPOSE: Southwest Oncology Group (SWOG) protocol 8228 is a prospective trial designed to investigate the prognostic significance of progesterone receptor (PgR) levels in estrogen receptor (ER)-positive breast cancer patients who were treated with tamoxifen. This study was undertaken because the value of PgR measurements in advanced breast cancer had been assessed previously only in studies that were small, retrospective, or included heterogeneously treated patients. METHODS: Receptor assays were performed only in the laboratories that met strict quality control guidelines. Of the 398 patients entered, 342 patients were eligible and assessable for the study end points of objective clinical response, time to treatment failure, and overall survival. RESULTS: Multivariate analysis shows that elevated PgR levels significantly and independently correlated with increased probability of response to tamoxifen, longer time to treatment failure, and longer overall survival. Overall response rate (defined as complete response [CR], partial response [PR], or stable disease [SD] for greater than 6 months) in this trial was 54%. Response rates to tamoxifen were 43%, 53%, and 61% in subsets of patients with less than 10, 10 to 99, and more than 100 fmol/mg PgR, respectively. Exploratory subset analysis using PgR and other prognostic variables identified ER-positive patient subsets with response rates to tamoxifen ranging from 24% (premenopausal patients) to 86% (postmenopausal patients with ER greater than 38 and PgR greater than 329 fmol/mg). No groups of ER-positive patients were identified who had such a low response rate as to absolutely preclude considering the use of tamoxifen. Multivariate analysis showed the independent, statistically significant predictors were: for response to tamoxifen, menopausal status, PgR, and ER; for time to treatment failure, menopausal status, disease-free interval (DFI), PgR, and ER; and for overall survival DFI, PgR, ER, site of disease, and history of adjuvant therapy. CONCLUSION: We conclude that knowledge of PgR levels together with other clinical information can improve the pretreatment assessment of ER-positive breast cancer patients with metastatic disease.

alpha-Interferon for remission maintenance: preliminary report on the Southwest Oncology Group Study.

This preliminary report focuses on the therapeutic role of interferon in a large randomized trial evaluating combination chemotherapy induction and interferon maintenance, as compared with no maintenance therapy, in patients with newly diagnosed multiple myeloma. The trial also included an evaluation of the combination of interferon and dexamethasone therapy for patients who failed to respond to induction chemotherapy or who had achieved only a partial remission. Case accrual is completed for remission induction with 505 eligible patients registered on study, but is still open for additional maintenance registrations. As of January 1991, 161 patients have been randomized to interferon versus observation, but the therapeutic results of this aspect of the study remain coded. Toxicity of interferon maintenance was generally of a mild to moderate degree, and less severe than that of the interferon/dexamethasone combination, which was due to the addition of steroid side effects. Among 41 patients who failed to achieve remission with chemotherapy, 13 (32%) achieved at least a partial remission with interferon/dexamethasone, and only five others (12%) have had progressive disease. Of 12 partial responders on induction chemotherapy, five (42%) achieved remission (75% tumor regression) with interferon/dexamethasone. To date, more than 65% of patients receiving interferon/dexamethasone remain alive, suggesting that this regimen will be useful for patients who fail to achieve remission with induction chemotherapy.

A phase II study of high dose ARA-C and mitoxantrone for treatment of relapsed or refractory adult acute lymphoblastic leukemia.

PURPOSE: The Southwest Oncology Group performed a Phase II study to investigate the effectiveness of an induction regimen of high dose cytosine arabinoside (ara-C) with high dose mitoxantrone for treatment of relapsed or refractory adult acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Patients at least 16-years-old with ALL that was in relapse after, or was refractory to, standard induction therapy including at least vincristine and prednisone were eligible, as long as they had no prior treatment with high dose ara-C. The induction regimen included high dose ara-C (3 g/m2 by 3-h i.v. days 1-5) and mitoxantrone (80 mg/m2 by 15-30 min i.v. 12-20 h after the first dose of ara-C). The study design called for a maximum of 55 patients, with early termination if less than nine of the first 30 achieved complete remission. RESULTS: Thirty-three patients entered the study, and 31 were included in the analysis. All 31 completed one course of induction therapy. Four patients died of infection and a fifth of cardiomyopathy with possible sepsis. Seven patients achieved complete remission (23%; 95% confidence interval 10-41%). One of the seven received syngeneic bone marrow transplantation while in remission, and the other six all relapsed within 10 months. All 31 patients died within 25 months after entering the study. CONCLUSIONS: The regimen of high dose ara-C and mitoxantrone was found to be insufficiently effective to warrant further investigation.

Pseudo-Gaucher cells in the bone marrow of a patient with Hodgkin's disease.

The authors studied an 18-year-old woman with stage IIIB nodular sclerosis Hodgkin's disease whose bone marrow contained abnormal storage cells that resembled Gaucher cells by light microscopic examination ("pseudo-Gaucher" cells). Electron microscopic examination revealed that these cells differed from true Gaucher cells and resembled storage cells previously described in chronic myelogenous leukemia. The patient's peripheral blood leukocyte beta-glucosidase and serum acid phosphatase levels were elevated, ruling out the diagnosis of inherited Gaucher's disease. After treatment with six monthly cycles of systemic chemotherapy (nitrogen mustard, vincristine, procarbazine, bleomycin, doxorubicin, and prednisone), all signs of Hodgkin's disease and pseudo-Gaucher cells disappeared. Repeat leukocyte beta-glucosidase and serum acid phosphatase levels were unchanged. The present case is unique with its documentation of classical enzyme patterns for beta-glucosidase and acid phosphatase and electron microscopic features. The authors postulate that pseudo-Gaucher cells result from excessive cell breakdown with an overload of available beta-glucosidase.

The surgical resection and chemotherapy of metastatic osteogenic sarcoma of the right ventricle.

The case report of a patient with metastatic osteogenic sarcoma of the right ventricle who had had an interscapulothoracic amputation in October, 1970, and a left lower lobectomy in June, 1973, for pulmonary metastasis is presented. The patient was hospitalized in October, 1974, with signs and symptoms of right ventricular outflow obstruction and arrhythmia, and cardiac workup established the presence of a right ventricular tumor. The lesion was successfully resected using cardiopulmonary bypass, and the diagnosis of metastatic osteogenic sarcoma was confirmed. The patient did well after the operation and returned to normal activity. She was placed on adjuvant Adriamycin (doxorubicin) chemotherapy, but 6 months later died of Adriamycin toxicity.

Phase II study of diaziquone in untreated advanced gastric carcinoma. A Southwest Oncology Group Study.

Twenty-nine patients with a diagnosis of advanced adenocarcinoma of the stomach with gross unresectable or measurable residual disease and no prior therapy were entered into a study utilizing diaziquone (AZQ) in an intermittent 3-week schedule of 40 mg/m2. Of 28 eligible patients, 1 (4%) experienced a partial response, 7 (25%) had stable disease of no response, and 18 (64%) developed increasing disease. Two (7%) were unevaluable. Median survival was 3.8 months. Major toxicities were myelosuppression and gastrointestinal, 11 of which were considered to be life-threatening. AZQ used as a single intermittent agent appears to have no significant activity to warrant use in untreated advanced gastric carcinoma. However, recognizing the short plasma half-life of AZQ, significant responses by other schedules of administration are not precluded.

Chemotherapy-induced myocardial infarction in a young man with Hodgkin's disease.

A 32-year-old male with stage IIIA nodular sclerosing Hodgkin's disease and no cardiac risk factors presented with chest pain after receiving chemotherapy consisting of multiple drugs, including vinca alkaloids. He completed an uncomplicated anterior wall myocardial infarction. Coronary angiography documented the absence of significant coronary artery disease. Exercise stress testing with gated scan confirmed loss of anterior wall motion and a decreased left ventricular ejection fraction. Vascular toxicity, including, rarely, myocardial infarction, has been reported following antineoplastic regimens containing vinca alkaloids. Hypercoagulable states, cardiac invasion by tumor, and coronary artery spasm are possible etiologies. Of these, coronary artery spasm appears most likely. Management should include discontinuation of the offending drug and supportive care.

Metastatic carcinomatosis of the liver mimicking cirrhosis: case report and review of the literature.

Carcinomatous involvement of the liver mimicking cirrhosis is a rare complication of metastatic carcinoma, most frequently seen with scirrhous carcinoma of the breast. The case of a 46-year-old woman with breast carcinoma presenting with ascites, jaundice, spider angiomata, and portal hypertension is reported. On hepatic scan the liver appeared to be almost the same size as the spleen, a finding frequently seen in cirrhosis. A chemotherapeutic program was introduced, but was of no benefit, and the patient died with uncontrolled esophageal bleeding. The prominent histologic feature on autopsy was intense stromal fibrosis and intravascular tumor infiltration with compression of vessels of the portal system.

Treatment of advanced breast carcinoma with 5-fluorouracil: a randomized comparison of two routes of delivery.

Fifty-one patients with metastatic breast carcinoma were randomized to treatment with weekly 5-fluorouracil (5-FU) either by mouth or intravenously. Prior treatment included radiation therapy (75%), chemotherapy(27%), and hormonal therapy (86%). Response frequency (tumor reduction greater than or equal to 50%) in the 49 evaluable patients was 24% (6/25) for oral oral vs. 29% (7/24) for intravenous administration. Disease was stable in an additional 13% of patients treated intravenously and 20% of patients treated orally. Median survival was 9.8 months for intravenously treated patients and 12.1 months for orally treated patients (N.S.). A multivariate model of survival, to adjust for imbalance between treatment groups, also showed comparable survival in the two groups. Neither response nor survival was significantly correlated with nadir granulocyte count. Weekly oral 5-FU results in comparable response and survival to 5-FU given intravenously, consistent with a relatively low dose-response relationship for 5-FU in breast carcinoma.

Treatment of advanced gastric carcinoma with 5-fluorouracil: a randomized comparison of two routes of delivery.

Fifty-seven patients with advanced gastric carcinoma were randomized to receive 15 mg/kg/week of 5-fluorouracil by either the iv or oral route. Toxic effects of treatment included nausea and vomiting (40% with the oral route versus 35% with the iv route) and myelosuppression, with a wbc count of less than 4000/mm3 (28% with the oral route versus 32% with the iv route). The frequency of partial response was 12% (three of 25 patients) for the oral route and 16% (five of 32 patients) for the iv route. Only two of 36 patients with liver metastases responded. No advantage was seen for the oral versus the iv route of 5-fluorouracil in the treatment of advanced gastric carcinoma.

Discrepancies between flow cytometric and cytogenetic studies in the detection of aneuploidy in human solid tumors.

Parallel flow cytometric (FCM) cell DNA studies and cytogenetic studies were performed on clinical samples from twenty human solid tumors of various types and on cell lines established in tissue culture from three of these tumors. Six of twenty clinical samples (30%) showed concordance between flow cytometry and cytogenetics with respect to the presence or absence of aneuploidy. Among the fourteen cases with discrepancies between the two methods, 8 (40% of all cases) showed hypodiploidy by cytogenetics and had diploid DNA histograms. Three cases (15%) had prominent discrete peaks in the triploid to tetraploid region by cytogenetics but had only barely discernible corresponding peaks in the DNA histogram. In two cases (10%) cytogenetic studies revealed diffuse aneuploidy. Cytogenetic studies demonstrated near-tetraploidy in three samples, but only one of these was detected by FCM; all three cases exhibited other numerical chromosomal abnormalities. In one case aneuploidy was demonstrated by FCM and not by cytogenetics. Among the tumor cell lines established in culture, the DNA Index was often higher than the cytogenetic index. Overall, 13/20 or 65% of patients with solid tumors in this study had numerical chromosomal abnormalities that were not detected by flow cytometry. Eleven of these patients had distant metastases at the time of tumor sampling, and nine of these died of their disease within 1-11 months of the time of study.

Phase II trial of trimetrexate in untreated advanced gastric carcinoma. A Southwest Oncology Group study.

Twenty-three evaluable patients with advanced gastric adenocarcinoma were treated with trimetrexate at doses of 8-12 mg/m2 intravenously daily for five days, with cycles repeated every 21 days. One complete response was seen for an overall response rate of 4% (95% confidence interval 0-22%). Hematologic toxicities of grade > or = 3 were seen in 10/23 patients, and overall any grade 3 or greater toxicity was seen in 14/23 patients. Trimetrexate has minimal activity against gastric adenocarcinoma in this study, and no further investigation of this agent at this dose and schedule is recommended in this disease.

A randomized trial of two schedules of trimetrexate versus 5-fluorouracil in advanced colorectal cancer: a Southwest Oncology Group study.

Trimetrexate (TMQ), a non-classical folate antagonist, was studied in a randomized controlled trial in patients with advanced colorectal cancer and without prior chemotherapy. Patients were randomly assigned to one of three treatments: TMQ at 200 mg/m2 i.v. q 2 weeks, TMQ at 12 mg/m2 i.v. daily x 5 or 5-fluorouracil (5-FU) at 15 mg/kg i.v. weekly. Overall response rates were: 6% (four partial responses in 71 patients, 95% CI of 2-14%) for q 2 week TMQ, 0% (zero of 29, 95% CI of 0-29%) for daily x 5 TMQ and 18% (two complete and nine partial responses in 62 patients, 95% CI of 9-30%) for 5-FU. Median survival estimates were 10.3 months for the q 2 week TMQ schedule, 8.7 months for the daily x 5 TMQ schedule and 13.6 months for the 5-FU schedule. Grade < or = 3 toxicities were significantly more common with TMQ. TMQ does not appear to have significant antitumor activity against colorectal cancer.