In 126 postmenopausal women with metastatic breast cancer, four chemotherapeutic combination programs were tested. Patients were stratified and randomized to one of the four programs: (1) fluorouracil, cytoxan and prednisone (CFP): (2) fluorouracil, cytoxan and Adriamycin (CAF); (3) cytoxan and Adriamycin (CA); or (4) alternating combinations of CFP-CA. Objective response rates were 17% for 18 patients on CFP, 25% for 40 patients on CAF, 42% for 41 patients on CA and 63% for 19 patients on CFP-CA. CFP-CA provided a significantly higher response rate than either CFP or CAF. The response rate of CA was intermediate. The duration of remission and survival were similar for all four groups. When progression or relapse following remission was demonstrated, patients were rerandomized to either adrenalectomy or tamoxifen. There were no responders either in the 15 patients undergoing adrenalectomy or the 11 patients receiving tamoxifen. In a crossover study, nine adrenalectomized patients received tamoxifen and four tamoxifen-treated patients underwent adrenalectomy. None responded. It appears that response rates to hormonal modalities are reduced in patients previously treated by combination chemotherapy.

Patients who had measurable evidence of recurrent or metastatic colorectal carcinoma following surgery and radiotherapy but no prior chemotherapy were randomized to one of five combination chemotherapy programs. Four of the treatments utilized five consecutive days of fluorouracil (FU) (days 1--5 and days 36--40) plus one oral dose of semustine (ME) (day 1) every ten weeks: (A) FU + ME; (B) FU + ME + vincristine (VC) (day 1 and day 36); (C) FU + ME + dacarbazine (DC) (days 1, 2, 36, 37); (D) FU + ME + VC + DC. The fifth treatment option(E) used a weekly treatment program of FU I.V. on day 1 plus hydroxyurea (HU) P.O. on day 4. The overall response rate was 13% (60/472) and the median survival time from start of therapy for all patients was 31 weeks. The response rate and the median survival time for each combination was (A) 9/103 = 9%, 26 weeks; (B) 10/92 = 11%, 28 weeks; (C) 15/101 = 15%, 37 weeks; (D) 11/91 = 12%, 27 weeks; (E) 15/85 = 18%, 38 weeks. There is no statistical difference in response rate or survival duration among any of the treatment options. The therapies containing DC produced the only complete responses (3 patients on treatment C and 2 on D). Treatment D was also associated with the longest median response duration (Treatment D = 55 weeks). Treatment A (FU + ME) was associated with the highest incidence of life-threatening toxicity.

The effect of a synchronizing-recruiting drug schedule vs. myelotoxic therapy on remission rate and of Bacillus Calmette-Guerin on remission duration and survival of adults with acute myelogenous leukemia were studied in a prospective cooperative trial. After randomized remission induction with Arabinosyl Cytosine + vincristine + methotrexate + leucovorin (AVML), thioguanine + Ara-C + Daunorubin (TAD), or Daunorubicin + Ara-C (DA), complete remissions (CR) were consolidated with TAD or AVML. CRs were maintained with BCG vaccination (Tice strain) by the tine technique, or BCNU plus Ara-C (B/A), or no further therapy (NFT). Of 209 evaluable TAD patients, 105 (50%) achieved CR; of 187 DA, 97 (52%) achieved CR. AVML yielded only 15 CR among 59 patients (25%). The time to remission was significantly shorter with DA compared with TAD. Ninety-seven patients were randomized to maintenance therapy (35 B/A, 30 BCG, 32 NFT). There were no differences in remission duration (7, 8, 6 months) or survival (16, 22, 16 months, respectively). Manipulation of the cell cycle, as employed in this study, was not helpful. There may be a marginal effect of BCG, but our data fail to show a statistically significant benefit.

Ninety-one evaluable patients with advanced Hodgkin's disease (patients with stages IIB, IIIB, or IV disease and patients with IIIA disease who were greater than 35 years old or had mixed cellularity or lymphocyte depletion histology) received chemotherapy with MOPP and ABDV given in alternating months; radiation therapy (RT) (2000 rad in 2 weeks) was given during Month 5 of therapy to the previously untreated patients through ports that were limited to the originally bulky disease. The complete remission rates observed were: 88% in previously untreated patients, 69% in patients who had had prior RT but minimal chemotherapy, and 50% in patients who had had prior heavy chemotherapy. The actuarial relapse-free survival rates at 4 years, for patients who had complete remission, are: previously untreated, 84%; prior RT, 70%; and prior heavy chemotherapy, 30%. The total actuarial survival rates at 5 years for all 118 patients, evaluable and nonevaluable, who were entered in the study, are: previously untreated, 80%, prior RT, 57%; and prior heavy chemotherapy, 40%.

This report summarizes the results of a randomized multi-institutional clinical trial in advanced gastric carcinoma comparing four combination chemotherapy regimens: 5-FU, Adriamycin + mitomycin C (FAMi); 5-FU, Adriamycin + methyl-CCNU (FAMe); 6-FU, ICRF-159 + methyl-CCNU (FIMe); and 5-FU + methyl-CCNU (FMe). One-hundred-eight-one evaluable patients received chemotherapy. These objective tumor response rates were observed among the 59 patients with measurable indicator lesions: FAMi, 3/12 (25%); FAMe3, 3/10 (30%); FIMe, 4/19 (21%); FMe, 1/18 (6%). The survival distributions for the four treatment groups were significantly different (P less than or equal to 0.05), with these median survivals observed (in weeks from the onset of chemotherapy): FAMi, 29.6; FAMe, 34.4; FMe, 22.9; FIMe, 17.4. Two nontreatment variables were found to be significantly associated with survival when analyzed using the Cox covariate model: pretreatment performance status (P less than 0.0001), and presence or absence of measurable metastatic disease (P less than 0.001). After adjustment for the effects of these and other clinical variables, two treatment regimens were found to be associated with improved survival: FAMi therapy (P less than 0.01), and FAMe therapy (P = 0.07). Toxicity was, in general, moderate and consisted primarily of gastrointestinal side effects and myelosuppression. We conclude that the FAMi and FAMe regimens are superior to the FIMe and FMe regimens in the management of advanced gastric cancer.

From 1969 to 1979, 155 patients with advanced Hodgkin's disease were treated with a combined modality protocol (combination chemotherapy and irradiation to all sites of disease). The actuarial 10-year survival of all patients who started therapy is 78%, and the relapse-free survival is 67%. Within the group of patients with advanced disease, age greater than 40 years and/or stage IV disease with multiple extranodal sites of involvement adversely affected prognosis. Since 1978, these patients have been treated with MOPP-ABVD and irradiation, with a resulting 3-year survival of 87% compared with 58% for those treated with MVVPP in prior years. A comparison between MVVPP and MOPP, also begun in 1978, has thus far yielded no significant differences. Second malignancies have occurred in four patients apparently cured of their Hodgkin's disease: two patients with acute leukemia and two with non-Hodgkin's lymphoma. Avascular necrosis of bone has developed in nine patients. There have not been other serious long-term complications. This combined modality treatment approach appear to offer a significant survival advantage compared with treatment programs using chemotherapy alone.

Seventy-four patients with non-small cell lung cancer were treated in a prospective, randomized trial either with a four-drug combination of cisplatin, doxorubicin, cyclophosphamide, and vindesine (PACE) or with a three-drug combination of cisplatin, cyclophosphamide, and vindesine (PCE). None of these patients had received prior chemotherapy, and all had a Karnofsky performance status of at least 60. Of 68 evaluable patients, 21 (31%) had complete or partial remissions. Response rates for PACE and PCE were similar, and there was no difference in response rates for patients with adenocarcinoma or epidermoid cancer. The median duration of remission was 10 months (range, 2-26+); five patients are still in remission (median, 18+ months; range, 17+ to 26+). The median duration of survival for responding patients (complete or partial) was 18 months. Toxic effects, including mild to moderate myelosuppression, peripheral neuropathy, and nephrotoxicity, were manageable in general. The response rates and remission durations for PACE and PCE are similar to those seen with the two-drug combination of cisplatin and vindesine, and toxic effects are similar. Thus, the addition of doxorubicin and/or cyclophosphamide adds no advantage to the use of the cisplatin and vindesine combination alone.

After stratification for extent of small cell lung cancer, 109 patients were randomized to receive cycles of chemotherapy with cyclophosphamide, doxorubicin, and VP-16-213 [CAVP16 (regimen I)] or to receive CAVP16 to maximum response (minimum of three courses) and then chemotherapy with CCNU, methotrexate, vincristine, and procarbazine (COMP) alternating with CAVP16 (regimen II). A group of patients who achieved complete remission were randomized to receive whole-brain irradiation or to have observation only. Of the 44 patients with limited disease, 28 (64%) achieved a complete remission and 11 (26%) achieved a partial remission. Of the 65 patients with extensive disease, 26 (40%) achieved a complete remission and 28 (46%) achieved a partial remission. There were no significant differences between the regimens in response or survival. The projected median survival times are 14 and 10 months for limited and extensive disease, respectively. Nearly 30% of patients with limited disease will be 2-year, disease-free survivors. Twenty-nine patients were randomized to receive cranial irradiation or observation only; none of the 15 irradiated patients developed cerebral metastases, but five of 14 randomized to observation relapsed in the brain (P = 0.02). One patient died with necropsy evidence of only intracranial disease. The principal hematologic toxic effect was leukopenia. There were 31 febrile episodes (21 infectious) during neutropenia and four toxic deaths. Nonhematologic toxicity was mild. Cranial irradiation in patients who achieve complete remission delays or reduces the incidence of CNS metastases. Although alternating chemotherapy is not beneficial, combination chemotherapy with CAVP16 alone is highly effective treatment modality for small cell.

One hundred and seventy six patients (81 controls, 95 receiving treatment) have entered a prospective randomized trial of long-term oral adjuvant razoxane (ICRF-159) following removal of a colorectal cancer. The median follow-up is 34 months. The treated patients in Dukes' groups B and C have a significantly longer disease-free interval than the control patients (P = 0.01 'as randomized' and P = 0.004 'as treated'). The differences in survival for Dukes' groups B and C are not significant, although follow-up is short. In Dukes' groups B and C, however, 24 of 56 of the patients in the control group have died (43%), as against only 17 of 64 in the treatment group (27%). The treatment produces very few side-effects, is well tolerated by patients, and is taken orally.

A total of 164 patients with non-Hodgkin's lymphoma (NHL) were randomized to receive cycles of treatment every 3 weeks with either CTP, ie, cyclophosphamide (400 mg/m2/day orally X 5), teniposide (VM-26) (100 mg/m2 iv X 1), and prednisolone (60 mg/m2/day orally X 5), or COP, ie, vincristine (1.4 mg/m2 iv X 1; maximum, 2 mg) with the same cyclophosphamide and prednisolone doses listed above. Results were analyzed according to whether the patients' NHL histology was favorable (47 patients) or unfavorable (117). The great majority of patients in each group had advanced disease (stage IV in 70% and stage III in 20%). For each histologic group, the results with the two regimens were similar with respect to remission incidence and survival. In favorable-histology NHL, CTP produced 57% complete remissions (CR) and 29% partial remissions (PR), compared with 54% CR and 19% PR for COP. Survival in these patients was also similar for the two regimens, the relative death rates being 1.13 for CTP-treated patients and 0.88 for COP-treated patients (P = 0.75). In patients with unfavorable-histology NHL, CTP produced 38% CR and 28% PR, compared with 43% CR and 35% PR for COP, the relative death rates being 1.10 for CTP-treated patients and 0.90 for COP-treated patients (P = 0.49). Neurotoxicity was virtually absent in patients treated with CTP, whereas in COP-treated patients it was severe in 12% and moderate in 36%. Other toxic effects occurred with equivalent frequency in the two regimens. These results show that teniposide can replace vincristine in combination with cyclophosphamide and prednisolone in the treatment of NHL, with freedom from neurotoxicity and comparable survival and response rates.

The nausea and vomiting associated with combination chemotherapy is a serious cause of morbidity. Though widely used, metoclopramide has not previously been shown, in controlled studies, to be of benefit in reducing these side-effects. A double blind placebo-controlled randomized trial of IV and oral metoclopramide is reported, based on 117 courses of chemotherapy. Of 59 courses in which metoclopramide was given, vomiting was prevented in 28 (47%), compared with only 10 of 58 (17%) in the control group, a highly significant (P less than 0.001) improvement. The importance of adequate dosage of metoclopramide and the role of IV metoclopramide are emphasized.

The Southwest Oncology Group performed a randomized study comparing combination chemotherapy alone versus combination chemotherapy plus BCG versus DTIC plus BCG in the treatment of disseminated malignant melanoma. A 31% response rate was noted with combination chemotherapy alone, a 27% response rate with combination chemotherapy plus BCG, and an 18% response rate with DTIC plus BCG. Survival was not influenced by type of therapy, but the responders had significantly longer survival than the nonresponders. There appeared to be some significant differences in response as related to age wherein those patients between the ages of 30 and 60 years had a higher response rate to combination chemotherapy as compared to DTIC plus BCG. Those patients older than 60 years of age had a higher response rate in the BCG groups. Furthermore, in those patients older than 60 years of age who responded, their duration of response was longer if they received BCG than those who did not receive BCG. It should be emphasized that those differences noted in various age groups could occur by chance alone. These differences should be studied in the future, by appropriate pretreatment stratifications. Patients with higher peripheral lymphocyte counts had significantly better response rates and those patients with higher numbers of positive delayed hypersensitivity skin tests had significantly greater survival. A significant improvement in survival was noted in patients whose PPD converted from negative to positive during therapy.

Fifty-one adult patients with acute nonlymphocytic leukemia (excluding acute promyelocytic leukemia) were treated on the L-12 protocol. The L-12 differed from the preceding L-6 in that 2,2-anhydro-1-B-D-arabinofuranosyl-5-fluorocytosine (AAFC), replaced arabinosylcytosine (ara-C) together with 6-thioguanine (TG) for remission induction. Achievement of remission was followed by an extended 14-week multi-drug consolidation program. With this more intense regimen, an overall complete remission rate of 49% and a median remission duration of 23.7 months were achieved; these results were not significantly better than the 57% complete remission rate and 8.6 months median remission duration obtained with the L-6 regimen. Four year disease-free survival was 22% on the L-12 compared with 16% on the L-6 protocol. No relationship between prognosis and FAB classification was found on either the L-6 or the L-12 protocol.

Between 1976 and 1978 the Eastern Cooperative Oncology Group tested ten regimens in 415 patients with histologically documented, inoperable non-small cell bronchogenic carcinoma. Most patients were ambulatory (69%) and had extensive disease (69%). Patients were stratified by cell type: squamous cell carcinoma (SQ), large cell anaplastic carcinoma (LC), or adenocarcinoma (AD). Ineffective single agents (including cell types tested and percent complete and partial responses) were dactinomycin (SQ, 6%), dianhydrogalactitol (SQ, 0), ftorafur (AD and LC, 3%), and piperazinedione (AD and LC, 7%), Ineffective combination regimens included the contemporary standard regimen cyclophosphamide (CYT) plus CCNU (SQ, AD, and LC, 9%), methotrexate plus doxorubicin (ADR) plus CYT plus CCNU (MAC) (SQ and AD, 12%), and mitolactol plus ADR (AD and LC, 8%). When compared to CYT plus CCNU the following regimens demonstrated significant activity: CYT plus bleomycin plus cisplatin (SQ, 23%; P = 0.02) and ADR plus 5-FU plus cisplatin (AD and LC, 24%; P = 0.006). Mitomycin demonstrated marginal activity in squamous cell cancer (19%, P = 0.06). Neither "active" regimen improved survival although responders to any regimen had a significant prolongation of median survival (31.6 vs 15.7 weeks, P = 0.002). The MACC regimen, piperazinedione, and mitomycin were substantially more toxic than the two effective regimens, which were adequately tolerated. Ambulatory performance status, limited disease, and prior surgery were significant positive prognostic variables whereas prior radiation and pretreatment weight loss adversely affected response or survival.

Between September 1978 and March 1979 the Eastern Cooperative Oncology Group compared the CAMP (cyclophosphamide, doxorubicin, methotrexate, and procarbazine) and HAM (hexamethylmelamine, doxorubicin, and methotrexate) regimens in 154 patients with metastatic non-small cell bronchogenic carcinoma. Most patients were ambulatory (77%) and had not received prior radiotherapy (59%). HAM produced two complete responses (CR) and eight partial responses (PR) (n = 77; 2.5% CR, 10.4% PR, 13% overall response) whereas CAMP resulted in five CR and 12 PR (n = 77; 6.5% CR, 15.6% PR, 22% overall response). This difference was not statistically significant (P = 0.14 with Fisher's exact 2-sided test) nor was the difference in overall median survival (HAM, 22.1 weeks and CAMP, 19.3 weeks). Responders had a significantly improved median survival (32.5 weeks) compared to nonresponders (17.9 weeks, P = 0.018). Ambulatory performance status and lack of prior radiotherapy were positive predictors for prolonged survival.

Fifty-seven evaluable patients with advanced ovarian carcinoma were randomized to receive either a combination of hexamethylmelamine, cyclophosphamide, methotrexate and 5-fluorouracil (Hexa-CAF) or high-dose cyclophosphamide alone given intravenously intermittently. Objective responses were seen in 62% of patients receiving cyclophosphamide alone, and 36% of patients in the Hexa-CAF regimen, this difference being statistically significant (P less than 0.05). The median duration of objective response (10 months vs. 9 months) and the median survival (11 months vs. 10 months) were greater in the cyclophosphamide group, but these differences were not statistically significant. It is concluded that there is no therapeutic advantage for the Hexa-CAF protocol over the alkylating agent used alone.

Fifty-one patients with metastatic breast cancer were randomly allocated to receive either a four drug combination consisting of cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP), or a combination of vincristine, Adriamycin, and cyclophosphamide (VAC) with cross-over on relapse. Objective responses were seen in 17 of 26 patients (65%) in the CMFP group and in 14 of 25 patients (56%) in the VAC group, but this difference was not statistically significant. The median duration of response for each group was one year. The estimated median survival was greater for the CMFP group, but this was not significant. Toxicity was more severe with the VAC regimen. It is concluded that there is no therapeutic advantage of the VAC over the CMFP regimen.

Sixty-one evaluable patients with advanced squamous cell carcinoma of the cervix were treated in a randomized fashion with either doxorubicin, vincristine, and 5-FU in combination (AVF) or with cyclophosphamide (CTX). Of 31 patients treated with AVF, only three (10%) responded (one complete response and two partial responses). Of 30 patients treated with CTX, there were two (7%) with partial responses. Two patients responded to AVF after failing CTX; one patient responded to CTX after failing AVF. Neither of these regimens was predictably useful in our patient population.