Treatment of limited small-cell lung cancer with concurrent etoposide/cisplatin and radiotherapy followed by intensification with high-dose cyclophosphamide: a Southwest Oncology Group study.

Between March 1986 and May 1988, the Southwest Oncology Group enrolled 58 previously untreated patients with limited small-cell lung cancer on a treatment program that administered high-dose cyclophosphamide (150 mg/kg) as late intensification. Treatment consisted of induction chemo-radiotherapy, (weeks 1 to 11), consolidation chemotherapy (weeks 11 to 18), and intensification (week 18). Median age was 61.5 years. Eighty-nine percent of patients had a Southwest Oncology Group (SWOG) performance status of 0-1. Twenty-one patients completed all prescribed treatments. There were seven treatment-related deaths, four as a result of intensification. Fifty-six patients are available for response analysis. Thirty-two patients achieved a complete remission (CR) (57%) and fifteen achieved a partial remission (PR) (26%). Median survival for all patients is 11.1 months. Among the 21 patients who received intensification, nine remain alive in a CR with a median survival of 27 months. This sequence of treatments was not associated with a survival advantage for the group as a whole, possibly because of the toxicity of induction and consolidation treatment and the delayed administration of high-dose cyclophosphamide.

An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas.

PURPOSE AND METHODS: Doxorubicin alone or with dacarbazine (DTIC; AD) is considered the best available therapy for metastatic adult sarcomas. Ifosfamide is active in sarcomas that have failed to respond to a doxorubicin-based regimen. This study was designed to determine if ifosfamide added to doxorubicin and DTIC (ADI) significantly effects toxicity, response rate, and survival. Patients with measurable metastatic or unresectable sarcoma were randomized to receive AD or ADI. Patients with chondrosarcomas, fibrosarcomas, and other sarcomas of bone were eligible, although those with osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma, Kaposi's sarcoma, and mesothelioma were excluded, as were patients with prior chemotherapy for sarcoma or prior doxorubicin. RESULTS: Between 1987 and 1989, 340 eligible patients were randomized. Significantly more myelosuppression, a higher response rate (17% v 32%; P < .002) and longer time to progression (4 v 6 months; P < .02) were observed for patients who received ifosfamide. An overall survival advantage for the two-drug regimen (12 v 13 months; P = .04) was not significant by multivariate analysis. CONCLUSION: In all three randomized trials of doxorubicin with and without ifosfamide (Eastern Cooperative Oncology Group [ECOG], European Organization for Research and Treatment of Cancer [EORTC], and this study), the response rate was higher for the ifosfamide-containing arm, significantly so in this and the ECOG studies. An improved response rate may be particularly important for the preoperative management of high-grade, borderline resectable lesions or pulmonary metastases, particularly in younger patients. In older patients, or for low-to intermediate-grade lesions, doxorubicin and DTIC followed by ifosfamide on progression is preferred.

Multicenter clinical trial of mitoxantrone in non-Hodgkin's lymphoma and Hodgkin's disease.

In this phase II multicenter trial, the efficacy and safety of mitoxantrone (Novantrone; Lederle Laboratories, Wayne, NJ) were evaluated in the treatment of 206 patients with relapsed non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) previously treated with other agents. Sixty-nine percent of the patients had received prior therapy with doxorubicin. The patients received 14 mg/m2 of mitoxantrone every 3 weeks. Nineteen (12%) of the NHL patients and two (7%) of the HD patients had complete responses (CRs). The combined CR and partial response (PR) rates were 37% (60 of 163) for NHL patients and 36% (10 of 28) for HD patients; the median duration of response was 323 days for NHL patients and 209 days for HD patients. The median survival times were 337 days for patients with NHL and 469 days for patients with HD. The median survival time for patients with low-grade NHL was 589 days compared with 298 days for patients with intermediate-grade NHL and 167 days for patients with high-grade NHL. The median time to treatment failure was 73 days for NHL patients and 98 days for HD patients. The major toxicity was myelosuppression, which was moderate and reversible. Nausea, vomiting, and alopecia were mild. There were two cases of congestive heart failure (CHF) considered related to treatment; both patients had received prior treatment with doxorubicin. In this group of heavily pretreated patients, mitoxantrone was effective and well tolerated. Responses were seen with mitoxantrone in patients who had relapsed after prior therapy with doxorubicin and in patients who had failed to respond to prior therapy with doxorubicin. Mitoxantrone should be evaluated in less heavily pretreated patients and should be considered for incorporation into combination chemotherapeutic regimens for the treatment of malignant lymphoma.

A randomized trial of five cisplatin-containing treatments in patients with metastatic non-small-cell lung cancer: a Southwest Oncology Group study.

Six hundred eighty assessable patients with measureable stage III M1, non-small-cell lung cancer (NSCLC) were randomized to one of five treatment arms including cisplatin, etoposide (VP-16) +/- methylglyoxal bisguanylhydrazone (MGBG; PVp, PVpM); cisplatin, vinblastine (PVe); or PVe alternating with vinblastine, mitomycin (PVeMi); or fluorouracil, vincristine, mitomycin/cyclophosphamide, doxorubicin, cisplatin (FOMi/CAP). The overall response rate was 20% with 3% complete responses and 17% partial remissions. The duration of these responses was not statistically different by treatment regimen and varied from 2.7 months to 5.0 months. The overall median survival for all patients was 5.3 months and is not different by treatment. Toxicity was greater in PVpM. The similarity of results for response, duration of response, and survival does not establish the superiority of any of these platinum-based regimens for standard clinical usage.

Role of recombinant interferon alfa-2a maintenance in patients with limited-stage small-cell lung cancer responding to concurrent chemoradiation: a Southwest Oncology Group study.

PURPOSE: This study was designed to determine if recombinant interferon alfa-2a (rIFN alpha-2a) could prolong remission duration and/or survival in patients with limited-stage small-cell lung cancer (SCLC) who achieved an objective response to chemoradiotherapy. A secondary end point was to assess the toxicity of chronic IFN administration. PATIENTS AND METHODS: One hundred seventy-one of 215 eligible patients achieved an objective response and were eligible to receive rIFN alpha-2a (3 million units [MU]/m2 subcutaneously three times per week escalated to 9 MU/m2 as tolerated) or observation for 2 years. RESULTS: One hundred thirty-two of 140 registered patients were eligible. Sixty-four patients were randomized to receive IFN and 68 to observation alone. The median time from randomization to progression was 9 months on the IFN arm and 10 months on the observation arm (P = .72). The overall median survival time was 16 months on the observation arm versus 13 months on the IFN arm (P = .77). Significant toxicities occurred in the rIFN alpha-2a arm. Grade 3 or higher toxicities included malaise, fatigue, and/or lethargy (30%), leukopenia (14%), neutropenia (13%), dyspnea (13%), nausea (11%), and respiratory infection (6%). Forty-three patients discontinued treatment due to intolerable side effects. CONCLUSION: rIFN alpha-2a in the dose and schedule used in this study failed to prolong response duration or survival in patients with limited-stage SCLC who had previously responded to an induction chemoradiotherapy program. Failure may have been partly related to poor tolerance and inability to complete therapy.

Adjuvant CMFVP versus adjuvant CMFVP plus ovariectomy for premenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a Southwest Oncology Group study.

PURPOSE: To determine whether the addition of surgical ovariectomy to standard chemotherapy prolongs disease-free survival (DFS) and overall survival in premenopausal patients with estrogen receptor (ER)-positive operable breast cancer with positive axillary nodes. PATIENTS AND METHODS: Three hundred fourteen premenopausal patients with ER-positive, node-positive breast cancer were enrolled between July 1979 and July 1989. Patients were stratified according to number of involved nodes and type of primary surgery and randomized to receive either of the following: (1) cyclophosphamide 60 mg/m2/d by mouth for 1 year, methotrexate 15 mg/m2 intravenously (i.v.) weekly for 1 year, fluorouracil (5-FU) 400 mg/m2 i.v. weekly for 1 year, vincristine .625 mg/m2 i.v. weekly for the first 10 weeks, and prednisone weeks 1 to 10 with doses decreasing from 30 mg/m2 to 2.5 mg/m2 (CMFVP); or (2) bilateral ovariectomy followed by CMFVP. RESULTS: The median follow-up time is 7.7 years and the maximum 13.2 years. Treatment arms are not significantly different with respect to either survival or DFS (one-sided log-rank, P = .55 and .70, respectively). The 7-year survival rate is 71% on the CMFVP arm and 73% on CMFVP plus ovariectomy. No significant differences were observed in node or receptor level subsets. CONCLUSION: We conclude that, in this study, the addition of ovariectomy did not improve results over chemotherapy alone in the treatment of premenopausal women with node-positive, ER-positive, operable breast cancer. Our sample size was too small to detect a small improvement. The death hazards ratio of CMFVP/CMFVP plus ovariectomy was 1.22 (95% confidence interval [CI], .79 to 1.89).

Chemotherapy of drug-resistant ovarian cancer: a Southwest Oncology Group Study.

We present a final analysis, including pathology review, of a cooperative group study of drug-resistant ovarian cancer. Of 200 patients registered, 112 were eligible and evaluable, with a response rate of 26% and median survival of 7 months. Because these results are poorer than those reported in the preliminary and interim analyses of this study, we scrutinized the 88 excluded patients, most of whom failed to meet our strict pathologic criteria for a diagnosis of ovarian cancer of epithelial type, and who, as a heterogeneous group, fared better than patients who did meet the eligibility criteria. We believe this analysis provides insight into the spectrum of diseases that are frequently called ovarian cancer, but might be more properly labeled abdominal carcinomatosis.

Improved survival duration with combination chemotherapy induction for multiple myeloma: a Southwest Oncology Group Study.

Four hundred forty previously untreated patients with active multiple myeloma were entered into a randomized trial (Southwest Oncology Group [SWOG] study 7927/28) comparing vincristine, melphalan, Cytoxan (Mead Johnson & Company, Evansville, Ind), and prednisone (VMCP) alternating with vincristine, BCNU, Adriamycin (Adria Laboratories, Columbus, Ohio) and prednisone (VBAP) with or without levamisole with vincristine, Cytoxan, and prednisone (VCP) with or without levamisole for induction therapy. The treatment groups were well balanced for all of the known major prognostic factors. Patients receiving VMCP-VBAP responded (greater than or equal to 75% regression) more frequently to induction therapy, both without (54%) and with (44%) levamisole v VCP without (28%) or with (28%) levamisole (P less than .001). In addition, patients receiving VMCP-VBAP (+/- levamisole) had a survival duration determined to be significantly increased by all forms of analysis: 48 and 33 months for VMCP-VBAP without and with levamisole v 29 and 26 months for VCP without and with levamisole (P = .011 overall). Levamisole did not improve response rates or survival duration (P greater than or equal to .1), nor did it prolong remission in the maintenance phase (P = .85). Analysis of SWOG study 7704/05 (updated April 1985) confirmed improved survival for combination therapy v MP, but no benefit for levamisole. The overall findings support the use of VMCP-VBAP as an excellent treatment option for remission induction in patients with active myeloma of all stages and prognostic categories.

Combined treatment with chemotherapy and neutron irradiation for limited non-small-cell lung cancer: a Southwest Oncology Group Study.

Seventy-three patients with regional, inoperable non-small-cell lung cancer received treatment with initial chemotherapy for two cycles (vinblastine-mitomycin followed in 3 weeks by vinblastine-cisplatin), with planned subsequent neutron irradiation to the primary site and concurrent, elective whole-brain irradiation using photons, followed by two more cycles of identical chemotherapy. Histology was reported as adenocarcinoma or large cell in 75%, and 60% had Radiation Therapy Oncology Group (RTOG) stage 3 disease; the remainder had stage 4. The response rate to chemotherapy induction was 51%. There were 58 patients in a second phase of the study who were potentially eligible for treatment with a medically dedicated cyclotron having more favorable characteristics with regard to treatment planning and dose delivery (neutrons "B"). The overall response rate in this group was 79%. Chemotherapy toxicity included four fatalities (5%), with three related to mitomycin C induced bilateral pneumonitis, and an additional five patients (7%) with life-threatening events that required hospitalization. Two fatalities were attributed to combined effects of chemotherapy and radiation, and six more to chest radiation therapy, for an overall treatment-related death incidence of 12 of 73 (16%). Four of the six deaths related to chest irradiation occurred after treatment with a "physics-based" neutron generator (neutrons "A"). Among the 45 who received neutrons in the B group, two (4%) had radiation-related deaths, and another four (10%) had clinically evident radiation pneumonitis. Pretreatment performance status (PS) and response to chemotherapy, but not RTOG stage or weight loss, were significantly associated with survival. Among patients who actually received chest irradiation, only initial response to chemotherapy remained as a significant predictor of survival in univariate analysis, with a median survival of 20 months in responders v 9 months in chemotherapy nonresponders. The patterns of first relapse observed in B group patients revealed that 28% were distant, while 64% were locoregional. This represents a reversal of the usual pattern in studies of chest irradiation alone. It probably reflects elimination of brain relapse by the use of elective whole-brain irradiation, impact of systemic chemotherapy on micrometastases elsewhere, and conservative treatment volumes employed for the chest irradiation in an attempt to minimize its toxicity. Further exploration of combined modality therapy is indicated for regional non-small-cell disease, with a real potential for survival impact if the therapeutic index can be improved.

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.

Interferon versus interferon plus prednisone remission maintenance therapy for multiple myeloma: a Southwest Oncology Group Study.

PURPOSE: We evaluated the vincristine, doxorubicin, and dexamethasone (VAD) regimen alone or with chemosensitizers for remission induction and interferon (IFN) versus IFN plus prednisone (IFN/P) for remission maintenance in previously untreated multiple myeloma. PATIENTS AND METHODS: Two hundred thirty-three patients were registered for remission-induction therapy with VAD or VAD plus the chemosensitizers verapamil and quinine. Patients who achieved remission were randomized to maintenance therapy with IFNalpha 3 MU in the evening three times weekly or IFN plus 50 mg of prednisone (IFN/P) on the morning after IFN until relapse. RESULTS: Two hundred twenty-nine patients were eligible for induction. Fatal toxicities in nine patients who received VAD plus verapamil and quinine led to closure of this arm after 47 registrations. Subsequently, all patients received VAD induction. Despite the high early mortality rate on VAD plus sensitizers, overall survival by induction arm did not differ for median or 5-year survival with approximately 40% of patients surviving 5 years. Eighty-nine eligible patients who achieved remission were randomized to maintenance. Patients who received IFN/P had improved progression-free survival (median, 19 v9 months for IFN; P = .008). After 48 months, progression-free survival on IFN/P was at the thirtieth percentile, whereas it was below the tenth percentile on IFN alone. Median survival from start of maintenance was long on both arms (57 months for IFN/P v 46 months for IFN; P = .36). CONCLUSION: IFN/Pwas more effective than IFN alone. Improved relapse-free survival may be attributable to IFN/P or to the use of prednisone for maintenance. This latter alternative is currently being studied.

Combination chemotherapy using adriamycin, DTIC, cyclophosphamide, and actinomycin D for advanced soft tissue sarcomas: a randomized comparative trial. A phase III, Southwest Oncology Group Study (7613).

The term soft tissue sarcoma refers to a large variety of malignant tumors arising in extraskeletal connective tissues that connect, support, and surround discrete anatomic structures. All visceral organs also contain a connective stroma that can undergo malignant transformation. Because of the histological similarities of this group of tumors and their relative rarity, treatment prescriptions for patients that have disseminated disease are most often uniform. In this study, we asked the question whether adding a third drug (cyclophosphamide or actinomycin D) to Adriamycin (Adr [Adria Laboratories, Columbus, OH])-(3,3-dimethyl-1-triazeno)- imidazole-4-carboxamide (DTIC) would improve the response rate and/or survival. A unique feature of this cooperative group clinical trial was the mandatory pathology review of the histological material. All patients of the Southwest Oncology Group between June 1, 1976, and November 17, 1979, who had a biopsy-confirmed diagnosis of a soft tissue sarcoma with convincing clinical or biopsy-documented evidence of metastatic disease were eligible for the study. Patients were randomized to receive (1) Adr, 60 mg/m2 intravenously, day 1, and DTIC, 250 mg/m2 every 3 weeks (104 patients); (2) Adr and DTIC as in (1) and cyclophosphamide, 500 mg/m2, day 1 (112 patients); or (3) Adr and DTIC as in (1) and actinomycin D, 1.2 mg/m2, day 1, (119 patients). There was no statistically significant difference in response rates (33%, 34%, and 24%) (P = .25). Median durations of response were 31 weeks in the Adr-DTIC arm, 26 weeks in the cyclophosphamide-DTIC-Adr arm, and 23 weeks in the Adr-DTIC-Actinomycin D arm (P = .78). Median durations of survival were 37, 42, and 50 weeks, respectively. Again, no statistically significant differences were observed (P = .59). Toxicities from each of these treatment arms were formidable and were equivalent. Prognostic factor analysis showed a prognosis based on bone marrow reserve, sex, and pathology subtype favorable to patients.

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.

Adjuvant CMFVP versus melphalan for operable breast cancer with positive axillary nodes: 10-year results of a Southwest Oncology Group Study.

Four hundred forty-one women with operable breast cancer with histologically positive axillary nodes were randomized to receive either combination cyclophosphamide (60 mg/m2 orally everyday for 1 year); fluorouracil (300 mg/m2 intravenously [IV] weekly for 1 year); methotrexate (15 mg/m2 IV weekly for 1 year); vincristine (0.625 mg/m2 IV for 10 weeks); prednisone (30 mg/m2 orally days 1 to 14, 20 mg/m2 days 15 to 28, 10 mg/m2 days 29 to 42) (CMFVP) or single-agent melphalan (L-PAM) (5 mg/m2 orally every day for 5 days every 6 weeks for 2 years) chemotherapy after a modified or radical mastectomy between January 1975 and February 1978. Patients were stratified according to menopausal status and number of positive nodes (one to three, more than three nodes) before randomization. Seventy-eight patients were ineligible, most (56) because they were registered more than 42 days from surgery. Maximum duration of follow-up is 12 years, with a median of 9.8 years. The treatment arms were balanced with respect to age, menopausal status, and number of positive nodes. Among eligible patients, disease-free survival and survival were superior with CMFVP (P = .002, .005, respectively). At 10 years, 48% of patients treated with CMFVP remain alive and disease-free and 56% remain alive, compared with 35% alive and disease-free and 43% alive on the L-PAM arm. Disease-free survival and survival were significantly better with CMFVP compared with L-PAM only in premenopausal patients and patients with four or more positive nodes. Both regimens were well tolerated, although toxicity was more severe and more frequent with CMFVP. We conclude that after 10 years of follow-up, adjuvant combination chemotherapy with CMFVP is superior to single-agent L-PAM in patients with axillary node-positive primary breast cancer. The major advantage is in premenopausal women and in patients with more than three positive axillary nodes.

Combined therapies for squamous-cell carcinoma of the esophagus, a Southwest Oncology Group Study (SWOG-8037).

Conservative treatment of esophageal cancer with radiation therapy has afforded few long-term survivors. In order to improve outcome, patients with locoregional disease were treated using a combined modality approach. Patients were treated with chemotherapy consisting of a 96-hour continuous infusion of 5-fluorouracil (5-FU), 1,000 mg/m2/d, days 1 to 4 and days 29 to 32; cisplatin 75 mg/m2, day 1 and 29; and radiation 3,000 rad, days 1 to 19. In the absence of progressive disease, patients underwent esophagectomy. One hundred twenty-eight patients were registered of whom 113 were eligible and 106 were evaluable. Toxicity included gastrointestinal (GI) symptoms, mucositis, and myelosuppression. One hundred two patients completed chemoradiotherapy. Following its completion, 11 patients refused surgery, six were considered poor surgical risks, and 14 had progressive disease. Of the remaining 71 patients, 16 had unresectable disease, 13 had residual disease which was incompletely resected, 24 had disease which could be completely resected, and 18 were without disease on pathologic examination. The overall operability rate was 63% and the overall resectability rate, 49%. Surgical mortality was 11%. Eighty-nine of 113 eligible patients have died, with a median survival of 12 months and a 2-year survival of 28%. The median postsurgical survival for all 71 patients was 14 months and was 32 months for those patients attaining complete remission (CR). Combined modality therapy remains an investigational approach. Attempts should be directed at increasing response rate to initial therapy. A randomized comparison between combined modality treatment and radiation therapy is necessary to definitively determine the usefulness of this more aggressive approach.

Phase I dose-finding and pharmacokinetic study of paclitaxel and carboplatin with oral valspodar in patients with advanced solid tumors.

PURPOSE: To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic (PK) profile of paclitaxel and carboplatin when administered every 3 weeks with the oral semisynthetic cyclosporine analog valspodar (PSC 833), an inhibitor of P-glycoprotein function. PATIENTS AND METHODS: Fifty-eight patients were treated with escalating doses of paclitaxel ranging from 54 to 94.5 mg/m(2) and carboplatin area under the plasma concentration versus time curve (AUC) ranging from 6 to 9 mg.min/mL, every 21 days. The dose of valspodar was fixed at 5 mg/kg every 6 hours for a total of 12 doses from day 0 to day 3. The MTD was determined for the following two groups: (1) previously treated patients, where paclitaxel and carboplatin doses were escalated; and (2) chemotherapy-naïve patients, where paclitaxel dose was escalated and carboplatin AUC was fixed at 6 mg.min/mL. PK studies of paclitaxel and carboplatin were performed on day 1 of course 1. RESULTS: Fifty-eight patients were treated with 186 courses of paclitaxel, carboplatin, and valspodar. Neutropenia, thrombocytopenia, and hepatic transaminase elevations were DLTs. In previously treated patients, no DLTs occurred at the first dose level (paclitaxel 54 mg/m(2) and carboplatin AUC 6 mg.min/mL). However, one of 12, two of six, two of four, four of 11, and two of five patients experienced DLTs at doses of paclitaxel (mg/m(2))/carboplatin AUC (mg.min/mL) of 67.5/6, 81/6, 94.5/6, 67. 5/7.5, and 67.5/9, respectively. In chemotherapy-naïve patients, one of 17 developed DLT at paclitaxel 81 mg/m(2) and carboplatin AUC 6 mg/mL.min. There was prolongation of the terminal phase of paclitaxel elimination as evidenced by an increased time that plasma paclitaxel concentration was >/= 0.05 micromol/L, ranging from 16.6 +/- 6.7 hours to 41.5 +/- 9.8 hours for paclitaxel doses of 54.5 mg/m(2) to 94.5 mg/m(2), respectively. CONCLUSION: The recommended phase II dose in chemotherapy-naïve patients is paclitaxel 81 mg/m(2), carboplatin AUC 6 mg.min/mL, and valspodar 5 mg/kg every 6 hours. In previously treated patients, the recommended phase II dose is paclitaxel 67.5 mg/m(2), carboplatin AUC 6 mg.min/mL, and valspodar 5 mg/kg every 6 hours. The acceptable toxicity profile supports the rationale for performing disease-directed evaluations of paclitaxel, carboplatin and valspodar on the schedule evaluated in this study.

Adjuvant CMFVP versus tamoxifen versus concurrent CMFVP and tamoxifen for postmenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a Southwest Oncology Group study.

PURPOSE: To compare chemohormonal therapy, chemotherapy alone, and hormonal therapy alone in postmenopausal patients with estrogen receptor (ER)-positive operable breast cancer and positive axillary nodes with respect to survival and disease-free survival (DFS). PATIENTS AND METHODS: Eight hundred ninety-two postmenopausal women with ER-positive, node-positive breast cancer were enrolled by the Southwest Oncology Group (SWOG) from July 1979 to March 1989 and 74 by the Eastern Cooperative Oncology Group (ECOG) between June 1987 and March 1989. Patients were stratified according to number of involved nodes and type of primary surgery and randomized to receive the following: (1) tamoxifen 10 mg twice daily by mouth for 1 year; (2) cyclophosphamide 60 mg/m2/d by mouth for 1 year, methotrexate 15 mg/m2 intravenously (IV) weekly for 1 year, fluorouracil (5-FU) 400 mg/m2 IV weekly for 1 year, vincristine .625 mg/m2 IV weekly for the first 10 weeks, and prednisone during weeks 1 to 10 with doses decreasing from 30 mg/m2 to 2.5 mg/m2 (CMFVP); or (3) the combination of tamoxifen and CMFVP. RESULTS: The median follow-up duration is 6.5 years, with a maximum of 12.8 years. Treatment arms are not significantly different with respect to either survival or DFS (log-rank, 2 df, P = .82 and .23, respectively). The 5-year survival rate is 77% for the tamoxifen arm, 78% for CMFVP, and 75% for the combination. No significant differences were observed in node or receptor level subsets. Severe or worse toxicity was experienced by 56% of patients on CMFVP and 61% on CMFVP plus tamoxifen, compared with 5% on tamoxifen alone. CONCLUSION: CMFVP chemotherapy, either alone or in combination with tamoxifen, has not been shown to be superior to tamoxifen alone in the treatment of postmenopausal women with node-positive, ER-positive, operable breast cancer.

bcl-2, p53, and response to tamoxifen in estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group study.

PURPOSE: To test the hypothesis that high bcl-2 expression and accumulation of p53 protein, both of which should inhibit apoptosis, are associated with a poorer tamoxifen response and a more aggressive clinical course in estrogen receptor (ER)-positive metastatic breast cancer. METHODS: A total of 205 paraffin-embedded tumor blocks were evaluated for nuclear p53 (a marker of p53 inactivation) and cytoplasmic bcl-2 by immunohistochemistry (IHC). All patients received tamoxifen as initial therapy for metastatic disease. The study began in 1982 and follow-up duration of the 24 patients last known alive is 8 years. RESULTS: Response to tamoxifen and time to treatment failure (TTF) were not significantly associated with p53 status, although patients with higher p53 had a worse survival (P = .008; median, 36 v 20 months). Higher bcl-2 expression was associated with higher levels of ER (P = .02), better response to tamoxifen (62% v 49%; P = .07), longer TTF (median, 9 v 5 months; P = .002), and better survival (median, 40 months v 25 months; P = .009). In multivariate analyses, including ER, progesterone receptor (PgR), and p53, high bcl-2 remained significantly associated with a longer TTF (P = .007) and survival (P = .07). p53 status was a significant factor for shorter survival (P = .05), but not for TTF (P = .61). CONCLUSION: p53 status, as determined by IHC is not significantly associated with response to tamoxifen, although tumors with altered p53 protein are inherently more aggressive. Contrary to expectation, high bcl-2 identifies a relatively indolent phenotype of ER-positive metastatic breast cancer, in which patients experience a better clinical response to tamoxifen and a longer survival.

Multimodal therapy for limited small-cell lung cancer: a randomized study of induction combination chemotherapy with or without thoracic radiation in complete responders; and with wide-field versus reduced-field radiation in partial responders: a Southwest Oncology Group Study.

In 1979 we initiated a phase III study in the Southwest Oncology Group (SWOG) which was designed to determine the value of chest radiation in limited-stage small-cell lung cancer patients achieving complete response after induction chemotherapy, and to test the use of wide-field v more limited-volume radiation in patients with partial responses (PRs) and patients with stable disease (SD). The induction chemotherapy (VMV-VAC) consisted of vincristine, 2 mg intravenously (IV) every week for six doses; methotrexate, 60 mg/m2 IV days 1 and 43; VP-16, 50 mg/m2/d IV days 1 to 5 and 43 to 47; doxorubicin, 60 mg/m2 IV days 22 and 64; and cyclophosphamide, 1,000 mg/m2 IV days 22 and 64. Four hundred ninety-four patients were registered, of whom 473 were eligible. Of 466 response-evaluable patients, 153 (33%) achieved complete disease remission (CR) with chemotherapy. A total of 387 patients entered the consolidation phase of treatment after chemotherapy and response determination. CR patients were prospectively randomized to receive chest radiation, consisting of 4,800 rad administered in a split-course scheme, or to continue chemotherapy without interruption. The treatment volume was based on tumor extent before the induction chemotherapy. Maintenance chemotherapy consisted of cyclophosphamide and VP-16 administered for four cycles before a period of reinduction chemotherapy consisting of VMV-VAC as described above. Patients receiving chest radiation therapy were given the same maintenance and reinduction chemotherapy programs following completion of the chest radiation. One hundred ninety-one eligible patients achieving PR or SD status after induction chemotherapy were randomized to a preinduction treatment volume or to a postinduction reduced tumor volume, with treatment portals designed according to tumor extent before or after induction chemotherapy, respectively. After completion of the entire treatment plan, there were 218 (47%) CRs and 121 (26%) PRs. These figures represent the greatest response achieved at any point in the treatment program. The median survival for all eligible patients was 57 weeks (74 weeks for CRs). Overall survival for CR patients was not different for patients who did or did not receive chest radiation. However, patterns of tumor relapse were affected by the chest radiation, as 38 of 42 relapsing patients who did not receive radiation had intrathoracic recurrences in comparison to only 20 of 36 radiated patients.(ABSTRACT TRUNCATED AT 400 WORDS)

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.