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).

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.

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.

Late intensification with POMP chemotherapy prolongs survival in acute myelogenous leukemia--results of a Southwest Oncology Group study of rubidazone versus adriamycin for remission induction, prophylactic intrathecal therapy, late intensification, and levamisole maintenance.

Between August 1978 and September 1982, 642 patients with newly diagnosed acute myelogenous leukemia (AML) were entered onto a Southwest Oncology Group Study which addressed four questions. (i) What is the comparative utility of rubidazone versus adriamycin in remission induction? (ii) What is the role of prophylactic intrathecal therapy in AML? (iii) Does late intensification affect treatment outcome? (iv) Does maintenance with levamisole affect disease-free survival or overall survival? Among 611 evaluable patients, 329 (54%) achieved complete remission. There was no difference in the remission rate between those patients receiving rubidazone (54%) and those receiving adriamycin (54%) as part of the induction regimen. Prophylactic intrathecal therapy with cytosine arabinoside had no effect on the incidence of central nervous system disease or survival. After nine months of complete remission, patients were randomized between late intensification with POMP (mercaptopurine + vincristine + methotrexate + prednisone) or continued maintenance with OAP (vincristine + cytosine arabinoside + prednisone). T patients randomized to late intensification had better survival and disease-free survival, compared to those randomized to receive no late intensification (p = 0.027 and 0.030, respectively). At twelve months of remission, surviving patients were randomized to receive levamisole or no further treatment. There was no evidence that levamisole affected survival or disease-free survival.

cis-Diamminedichloroplatinum in the treatment of advanced epidermoid carcinoma of the penis: a Southwest Oncology Group Study.

A total of 26 patients with biopsy proved epidermoid carcinoma of the penis (Jackson stage III or IV) with measurable disease, no prior chemotherapy and adequate renal function received 50 mg. per M.2 cis-diamminedichloroplatinum intravenously on days 1 and 8 of 28-day cycles. There were 4 partial responses (15.4 per cent), with a response duration of 1 to 3 months. The median survival was 4.7 months. This agent cannot be recommended as treatment for advanced epidermoid carcinoma of the penis using this particular dose and schedule.

Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group Study.

The Southwest Oncology Group (SWOG) colorectal adjuvant study 7510 went through two phases. From 1975 to 1977, 309 patients were randomized to chemotherapy alone or the same chemotherapy plus immunotherapy. From 1977 until 1980, 317 patients were randomized among the same two therapy programs and a control group. With a minimum follow-up in either phase of greater than 7 years, data are now mature. They show no difference in relapse-free survival (RFS) nor overall survival (OS) in either the two-way phase or in the three-way phase. There is no indication, except possibly in one very small subset, that the addition of immunotherapy to chemotherapy provides an improvement in OS or in RFS. Using data from patients accrued after randomization to the control group, we fail to find evidence that either chemotherapy alone or chemoimmunotherapy improves OS or RFS when contrasted to outcomes obtained by patients on the control arm. In fact, we have significant evidence, at the P = .016 level, that chemotherapy does not improve OS by at least 50%; we also have significant evidence, at the P = .011 level, that chemoimmunotherapy will not improve OS by at least 25%. No evidence of efficacy was demonstrated for either treatment regimen, even though enough therapy was given to result in significant toxicities. Acute toxicity was at least moderate, but not fatal, in 75% of patients. Recognizable delayed toxicity included rare cases of fatal renal failure and acute leukemia.

Effect of oxygen on the clonal growth of adherent cells (CFU-F) from different compartments of mouse bone marrow.

We have used collagenase to isolate cell populations from different compartments of mouse bone marrow. Cells were obtained from the shaft of the femur, the endosteum, and compact bone. We have studied the growth-enhancing effects of physiologically low oxygen levels on fibroblast colony-forming unit (CFU-F) growth in vitro. Low oxygen levels (0.1%-10% O2) increased CFU-F formation 1.8- to 2.8-fold. However, cells from the compact bone consistently grew with much higher efficiencies (12- to 31-fold) than did cells from femoral cavity and endosteal areas. These data indicate the usefulness of enzymatic methods of isolating cells from compartments of bone and the use of low oxygen atmosphere to enhance stromal cell growth in vitro.

A phase II trial of vinblastine in patients with advanced or recurrent endometrial carcinoma. A Southwest Oncology Group Study.

Forty-one patients with advanced or recurrent endometrial carcinoma no longer amenable to control with surgery and/or radiotherapy were entered into study. Five of these were ineligible for study. One eligible patient never received any treatment, another had no baseline information recorded; these were thus inevaluable. The remaining 34 patients received continuous infusion vinblastine (1.5 mg/m2) as a 24-h infusion daily for 5 days every 3 weeks. One complete and 3 partial responses were observed among these 34 patients, for an overall objective response rate of 12%. Two of these 4 responders are deceased, and 2 remain alive with disease at 18 and 22 months, respectively. The most common toxicity noted was leukopenia in 22 patients (65%); 12 (35%) of these had severe or life-threatening leukopenia (less than 2,000 WBC/microliter). Fourteen of the 34 (41%) experienced nausea and vomiting. Other adverse effects were less common. Overall, 15 of the 34 patients (44%) experienced severe or life-threatening toxicity. In this trial, continuous infusion vinblastine was toxic and had minimal to moderate efficacy at best. These facts suggest that the drug at the dose and schedule tested has no role in the management of advanced or recurrent endometrial carcinoma.

Primary transfection as a mechanism for transformation of host cells by human tumor cells implanted in nude mice.

Establishment of cell lines in vitro from a human lung cancer xenograft in nude mice resulted in transformed mouse cell lines. The transformed mouse cell lines expressed both mouse-specific and human-specific histocompatibility antigens. Of 3 cell lines, 2 were tumorigenic in BALB/c nude mice but not in normal mice. Tumors formed by the transformed mouse cell lines were fibroblastoid and epithelioid by histology. In addition, tumors exhibited neuroepithelial differentiation by ultrastructural and immunohistochemical analysis. Phenotypically they were similar to the original patient and human xenograft tumor. These data suggest that previous reports of host cell transformation and induction of fibrosarcomas may not be true fibrosarcomas. Human DNA sequences were present in the tumorigenic cell lines, indicating that spontaneous transfection of human tumor DNA into host cells had occurred. The implication of these findings is that human genetic information has been transferred to primary mouse host fibroblasts, which resulted in a transformed as well as a differentiated phenotype.

The use of interferon in the treatment of multiple myeloma.

Almost all patients with multiple myeloma still relapse or become refractory in 2 to 3 years. Interferon (IFN) therapy has clearly influenced the levels of abnormal serum proteins in some patients. A multi-institutional phase II clinical trial used alfa-2b recombinant interferon (Intron A, Schering, Kenilworth, NJ) in 38 evaluable patients with relapsing and refractory multiple myeloma; two thirds of the patient population had received extensive prior treatment. Seven responded, of whom three continued to do so beyond 1 year--one with an ongoing complete remission. An additional 13 had at least a 25% decrease in abnormal paraproteins. Of nine patients who were initially refractory to chemotherapy, two responded to IFN. Of nine relapsing patients returned to chemotherapy following IFN therapy, six then responded. Thirty previously untreated patients with multiple myeloma were treated with IFN followed by melphalan and prednisone; of 24 evaluable patients, 18 responded with a median duration of 10+ months. Alfa-2b IFN apparently does not antagonize melphalan or prednisone, nor does it appear to worsen the response of the two drugs alone. Effectiveness of recombinant alfa-2b IFN in pretreated relapsing patients suggests additional trials are needed to study its effects in previously untreated patients. A significant number of patients who relapsed on their original chemotherapy and subsequent interferon will apparently respond to the reinstitution of chemotherapy.

Role of hypoxia in anticancer drug-induced cytotoxicity for Ehrlich ascites cells.

A review of the literature on the effect of hypoxia on in vitro drug sensitivity had suggested that there was consistently more cytotoxicity under hypoxic conditions for the drugs misonidazole and mitomycin C while there was much conflicting data for the drugs Adriamycin and bleomycin. We have examined the effect of oxygen on the cellular response of Ehrlich's ascites tumor cells to the drugs mitomycin C, misonidazole, Adriamycin, and bleomycin. Significant differences were observed when we compared the cytotoxicity of mitomycin C and misonidazole as a function of oxygen concentration. For the drugs Adriamycin and bleomycin no differential effects of oxygen were noted for a 1-h drug exposure with hypoxia while some differences were noted only for bleomycin for an 8-h drug exposure time. Because differences dependent on oxygen concentration were observed for some drugs but not others at the same experimental conditions, and as indicated by a review of the literature, it is suggested that some of the conflicting data in the literature with respect to some of these drugs may be cell-line dependent. Other variables which may also be of importance were the duration of drug exposure time in hypoxia and cell density. The observed oxygen concentration-dependent changes in cell survival for the Ehrlich cells with drugs examined could not be explained on the basis of changes in drug-induced cellular oxygen consumption.

Recombinant alfa interferon in renal cell carcinoma: a randomized trial of two routes of administration.

Ninety-seven patients with recurrent or metastatic renal cell carcinoma were randomized to receive recombinant interferon (IFN) alfa-2b (Intron A; Schering-Plough, Kenilworth, NJ) by either the subcutaneous (SC) or intravenous (IV) route. The SC dosage was 2 X 10(6) IU/m2 three times weekly, and the IV dose 30 X 10(6) IU/m2 for five consecutive days every 3 weeks. Dose escalation to a maximum of 10 X 10(6) IU/m2 SC and 50 X 10(6) IU/m2 IV was allowed for patients with minimal or absent toxicity. Five of 51 of the SC-treated patients (10%) and three of 46 of the IV-treated patients (7%) had a partial response (PR) or complete response (CR). Patients with prior nephrectomy, no prior treatment, and lack of bone metastases were most likely to respond, and a retrospective analysis of this subgroup revealed a 23% response rate. Achievement of response took from 3 weeks to 11 months, while response duration lasted from 3 to 31+ months. All responders had prior nephrectomy; six of eight had no prior chemotherapy or hormonal therapy; five had lung metastases, and none had bone metastases. Regardless of route, almost all patients developed a flu-like syndrome; however, grade 3 or greater toxicity was much more common for IV-treated patients. This trial demonstrates modest, but definite antitumor activity for recombinant interferon in advanced renal cell carcinoma. SC administration with lower dose and toxicity is as effective as treatment administered IV.

Randomized comparisons of radiotherapy and carmustine versus procarbazine versus dacarbazine for the treatment of malignant gliomas following surgery: a Southwest Oncology Group Study.

Between 1977 and 1981, the Southwest Oncology Group entered 278 patients on a randomized study (SWOG 7703) to compare the effect of three different chemotherapeutic agents given in combination with radiotherapy (6000 rads over 7 weeks) following surgery for malignant gliomas. The chemotherapy regimens were: carmustine (BCNU)--80 mg/m2 iv daily X 3 every 6 weeks; procarbazine (PCB)--100 mg/m2 orally; or dacarbazine (DTIC)--175 mg/m2 iv daily X 5 every 4 weeks. Patients were stratified according to age, and degree of resection, with no differences identified between groups. The response rates (complete plus partial) for BCNU and DTIC were significantly better than for PCB [BCNU, 39%; PCB, 13%; and DTIC, 38% (P less than 0.01)]. The response duration and survival were somewhat better in patients treated with BCNU and DTIC, but compared to patients treated with PCB, the difference was not statistically significant. Median survival times were: BCNU, 45 weeks; PCB, 31 weeks; and DTIC, 49 weeks (P greater than 0.3). There were six toxic deaths with BCNU and four with PCB, most of which were due to infection associated with leukopenia. The high toxicity and minimal benefit of chemotherapy added to radiotherapy compared to historical results with radiotherapy alone suggest that combined treatment may not be indicated for some patients.

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.