The effect of Levamisole on the human granulopoiesis was studied in patients randomized to receive, in addition to adjuvant chemotherapy for primary breast cancer, either no other treatment or additional unspecific immune therapy with Levamisole. The reaction of granulopoiesis to the cytostatic drugs, as characterized by changes of peripheral blood polymorphonuclear neutrophils (PMN), functional bone marrow granulocyte reserve, serial bone marrow cytology, and granulopoietic stem cells (CFU-C) in marrow and blood, was not affected by administration of Levamisole. The data support the concept that Levamisole has no direct effect on human bone marrow granulopoiesis, but that an allergic mechanism is involved in the pathogenesis of Levamisole-induced agranulocytosis. The expectation that Levamisole exerts a beneficial effect by stimulation of the granulopoiesis, as previously suggested for BCG and Corynebacterium parvum, could not be substantiated in our studies.

Patients with stage III and IV melanoma were randomly assigned to receive procarbazine (100 mg/m2, Days 1--10), vinblastine (5 mg/m2, Days 1 and 8), and actinomycin D (0.5 mg/m2, Days 1 and 8) with or without methanol-extracted residue (MER) of bacillus Calmette-Guerin (200 micrograms in five sites). In patients with measurable disease, 20% (eight of 40 patients) responded with only the combination chemotherapy while 15% (six of 39 patients) responded with the MER added. Toxicity was tolerable except for some instances of severe, gastrointestinal toxicity associated with procarbazine. MER as given in this study, failed to either increase the response rate or prolong survival.

The value of immunotherapy as an adjuvant to chemotherapy for advanced breast cancer is an unsettled question. To clarify this issue, 71 women with measurable or evaluable metastatic breast cancer were randomized to receive cyclophosphamide, 5-fluorouracil, and prednisone (CFP) with or without methanol-extracted residue of Bacillus Calmette-Guerin (MER). The total regression rates were 52% (CFP) and 39% (CFP + MER), including complete regression rates of 13% (CFP) and 65% (CFP + MER). The median duration of regressions for CFP-treated patients was 257-261 days and for CFP + MER-treated patients was 385 days. The median time to progression was 248-261 days in the CFP group and 159 days in the CFP-MER group. Projected median survival for both treatment groups is 20 months. Immunotherapy (MER) as used in this study does not appear to augment regression rates or vurvival for patients with advanced breast cancer receiving CFP.

In hope of reducing the duration of adjuvant treatment in premenopausal patients with operable breast cancer and histologically positive axillary lymph nodes, a prospective controlled study was started in September 1975. A total of 160 patients were randomized to receive 12 cycles of adjuvant CMF, while 165 were allocated to receive 6 cycles. At 3 years from radical mastectomy, the relapse-free survival was 85.4% in the 12-cycle group compared to 82.6% for the 6-cycle subset (P = 0.29). In both treatment groups, the incidence of treatment failure was directly proportional to the number of involved axillary nodes and to the clinical tumor size. Drug-induced amenorrhea as well as estrogen receptor status failed to significantly affect the results obtained. Treatment failures were more often documented in distant sites, while only 4--5% relapse was observed in local-regional areas. Overall survival was also similar for both treatment arms (86.2% vs. 85.1%, P = 0.49). Toxicity was moderate and reversible and no drug-induced neoplasms were so far observed. Present results achieved with 6 cycles of adjuvant CMF appear encouraging. However, they are still too preliminary to recommend the routine use of 6 cycles instead of the classical 12 cycles.

Sixty-three patients were randomised into two groups each receiving the same 40-h sequential chemotherapy regimen (methotrexate or 5-FU, followed by vinblastine and cyclophosphamide). In the group receiving infusions of chemotherapeutic agents at times taking into account the circadian rhythm of tumoral proliferation, the antitumoral effectiveness appeared significantly better with respect to both tumoral regressions (85% contrasting with 58% in the other group) and the duration of response and survival.

Fifty-eight patients with advanced head and neck cancer were entered into a randomised trial comparing radical radiation therapy to the primary tumour and associated lymph node areas with a combination of radiation therapy plus chemotherapy. The distribution of tumour types and stages was similar in the two treatment groups. The response rates to radiation therapy alone (50% complete plus parital response) and to radiation therapy plus chemotherapy (60% complete plus partial response) were not significantly different. However, a significant difference in survival was found between the two groups. The median duration of survival for the patients treated by means of radiation therapy alone was 18 weeks; that for the combined therapy was 36 weeks. The combination of radical radiation therapy plus intermittent high-dose chemotherapy was well tolerated and appears to be an approach that warrants further trial.

In this study 523 previously untreated patients with acute myelocytic leukemia were randomly allocated to induction therapy with daunorubicin 60 mg/M2 daily X 3, cytosine arabinoside and thioguanine 100 mg/M2 each every 12 hours until marrow hypoplasia was achieved, or a 5-day course of the three drugs with daunorubicin 100 mg/M2 given on dav 1 and cytosine arabinoside plus thioguanine each given at a dose of 100 mg/M2 every 12 hours for five days. All patients received cyclophosphamide 600 mg/M2 followed in 24 hours by hydroxyurea 500 mg/M2 every six hours for four doses monthly for maintenance therapy. Patients were randomized to receive one of three antimetabolite treatments beginning 24 hours after the last dose of hydroxyurea each month for seven days. One such treatment consisted of 6-mercaptopurine 100 mg/M2 daily, another group received 6-thioguanine at the same dose daily, and the third group received 50 mg/M2 of both antimetabolites daily. There were no significant differences in complete response rate, remission duration, or survival among the various treatment groups.

A total of 144 patients with advanced sarcomas were entered into a randomized prospective protocol with four treatment arms utilizing different combinations of chemotherapeutic agents. Of these, 120 patients (83%) were judged acceptable. Treatment 1: actinomycin-D (Act-D), 0.01 mg/kg IV, days 1--5; phenylalanine mustard (L-PAM), 4 mg PO, days 1--10 every six weeks. Treatment 2: Act-D, 0.01 mg/kg IV, days 1--5; L-PAM, 4 mg PO, days 1--10; vincristine, 1 mg IV, days 1, 8, 15, 22, 29, 36, repeat every six weeks. Treatment 3: Act-D, 0.01 mg/kg IV, days 1--5; L-PAM, 4 mg PO, DAYS 1--10; NSC-1026, 200 mg/kg IV, days 1--6. Treatment 4: Adriamycin, 0.4 mg/kg IV, days 1, 2, 3, 8, 9, 10, then 2XWK starting day 15 (max. 1,200 mg). There was a provision that upon progression of the disease in the first three treatment regimens, patients would be crossed over to Treatment 4. Responses were as follows: 1 - Partial Response (PR) 1/25; No Change (NC) 9/25 (36%). gF2 - NC 17/26 (65%). 3 - NC 13/25 (52%). 4 - Complete Response (CR) 1/41; PR 6/41; (15%); NC 27/41 (66%). Clearly Treatment 4 was the best arm, with a 17% response rate and an initial progression rate of 17%. The only other response was a partial in 1. The difference is statistically significant (H = 17.247, P = 0.0006). If the responders to Adriamycin were analyzed without crossovers, the response rate would be 22% (6/27). (H = 14.079, P = 0.003). Median times to progression were 12.5, 8.7 weeks for 1 and 2, and 5 weeks for 3 and 4. There was no significant difference in the median survival times among the four treatment arms. It appears that Adriamycin as a single drug is superior to the drug combinations and would probably be even more effective used in combination with known active agents.

Sixty-seven patients with measurable colorectal carcinoma were randomized to receive two different schedules of Methyl CCNU, 5-FU and Vincristine (MOF). The treatment schedule consisted of Methyl CCNU 150 mg/m2 po q 70 days, 5-FU 300 mg/m2 iv for 5 consecutive days q 35 days, and Vincristine 1 mg/m2 IV q 35 days. The same total dose was used in each arm; in MOF A, the Methyl CCNU was given on day 1, while in MOF B, the Methyl CCNU was divided and given over 5 consecutive days. In MOF A, there was a 10% partial response rate and a 10% minor response rate. In MOF B, the partial response rate was 12% and the minor response rate was 21%. This difference is not statistically significant, but the patients in MOF B experienced less gastrointestinal toxicity (p less than .001).

Seventy-eight advanced breast cancer patients with hormone-resistant disease or visceral metastases were randomized to receive either of two low dose regimens consisting of cyclophosphamide (C), methotrexate (M), 5-fluorouracil (F), and Adriamycin (A) as their initial chemotherapy. One group was treated with CAMF, and the other with CMF until progression, followed by A (CMF leads to A). C was given at 50 mg/m2, po, days 1-14; M at 20 mg/m2, F at 300 mg/m2, and A at 20 mg/m2, iv, days 1 and 8 of each 28-day cycle. The response rates for CAMF vs. CMF did not differ significantly (complete and partial responses-62% vs. 49%; stabilizations-23% vs. 31%). Responses by site of metasis, median times to progression and median survivals were similar for both groups. Poor and good risk partial responders had similar survivals. Twelve percent of CMF patients treated with Adriamycin at the time of progression had partial responses with an associated improved survival. Since CMF is as effective as CAMF, but has less toxicity, low dose therapy with CMF is more acceptable than CAMF as an initial chemotherapy regimen for metastatic breast cancer. Adriamycin may be reserved for subsequent regression induction.

In 163 children with acute nonlymphocytic leukemia (ANLL), a D-ZAPO induction program consisting of daunomycin, 5-azacytidine, cytosine arabinoside, prednisone, and vincristine resulted in a remission rate of 71.8%. Immunologic therapy was employed during maintenance with the aim of prolonging remission and improving survival. The administration of immunotherapy consisting of a mixture of bacillus Calmette-Guérin (BCG) and allogenic acute myelomonocytic leukemic cells injected intradermally on day 14 of each of the first three monthly cycles of 6-thioguanine for ten days, 5-azacytidine and cytosine arabinoside for four days, and vincristine for one day did not improve remission duration or survival compared to that due to chemotherapy alone. Important prognostic factors identified in this study included a remission induction rate significantly better for females than males (P = 0.04), for children between the ages of 5 and 10 years compared to those greater than this age group (P = 0.01), and a prolonged remission duration (P = 0.04), and survival (P less than 0.01) for patients with initial white blood counts of less than 20 x 10(9)/liter.

One hundred eighteen patients with metastatic carcinoid tumor were randomized to treatment with streptozotocin combined with cyclophosphamide or with 5-fluorouracil (5-FU). Commonly experienced side effects were nausea, vomiting, leukopenia, thrombocytopenia, and nephrotoxicity. Objective response rates among eligible and evaluable patients treated with the 5-FU combination was 14 of 42 (33%) and with the cyclophosphamide combination, 12 of 47 (26%). Among those patients with carcinoids primary to the small bowel the respective response rates were 44% and 37%. The overall response rates for patients with carcinoids of pulmonary or unknown origin were only 12% and 17%. There was no significant difference in patient survival between the two treatment arms. Among 11 patients who received crossover therapy with 5-FU alone there were two responders. There were no responders among eight patients treated with cyclophosphamide alone. Urinary 5HIAA excretion proved to be a useful biologic marker in these patients that correlated well with the observed measurements of tumor bulk. Median survival times from the diagnosis of unresectable malignant disease related to sites of origin of carcinoid tumor were the following: small bowel, 28.4 months; pancreas, 24.0 months; lung, 15.1 months; and unknown origin, 9.0 months. Metastatic carcinoid tumor is a malignant disease susceptible to chemotherapeutic approaches and continued investigation of the therapy of these neoplasms should be strongly encouraged.

Eighty patients with advanced ovarian adenocarcinoma were treated in a prospective, randomized trial comparing a four-drug combination--hexamethylmelamine, cyclophosphamide, methotrexate and 5-fluorouracil--with the oral alkylating agent, melphalan. Treatment with the four-drug combination was associated with a significantly increased overall response rate (75 vs. 54 per cent) (P less than 0.05), more complete remissions (33 vs. 16 per cent) and longer median survival (29 vs. 17 months) (P less than 0.02) but more severe toxicity than occurred with melphalan. Patients with minimal residual disease had a significantly higher overall response rate than patients with extensive residual disease (84 vs. 53 per cent) (P less than 0.05). Patients with advanced disease who achieved a complete remission documented by peritoneoscopy or laparotomy (or both) have a median survival that will exceed three years. The four-drug regimen is more effective than melphalan in the management of advanced ovarian adenocarcinoma.

In a randomized multi-institutional trial of the Eastern Cooperative Oncology Group, 316 patients with advanced measurable colorectal adenocarcinoma were treated with a weekly schedule of 5-fluorouracil given orally and intravenously with oral-5-fluorouracil in combination with cyclophosphamide or 6-thioguanine, or with oral Methyl CCNU administered once every eight weeks. On failure or progression, 133 protocol patients crossed-over to a secondary therapy, while 116 other patients previously treated with 5-fluorouracil off protocol were randomized to treatment with Methyl CCNU or B-2'-deoxythioguanosine. Response rates among patients who had received no prior chemotherapy were 18% to oral 5-FU, 15% to intravenous 5-FU and to MeCCNU, 12% to 5-FU and 6-thioguanine and 5% to cyclophosphamide and 5-FU, with little activity (3% response rate) in crossover or previously treated patients. Treatment with 5-FU, particularly oral 5-FU was associated with the least drug-related toxicity. Hematologic toxicity was greatest with Methyl CCNU, but was no more frequent in previously treated than in untreated patients. A tendency toward cumulative bone marrow depression was noted. 5-FU was effective only in ambulatory patients, whereas responses among non-ambulatory patients were seen only in the group treated with Methyl-CCNU.

Fifty-two untreated patients with colorectal cancer were randomized to receive 5-fluorouracil (5-FU) alternating either with methotrexate (MTX) or Baker's Antifol (BAF) with or without the immunostimulant, levamisole (Program I). Fifty-five patients who had received prior treatment were randomized to receive methyl-CCNU (Me) with MTX or BAF (Program II). Fifteen of these patients had failed to respond to initial therapy with 5-FU plus MTX or BAF and subsequently received Me plus the alternate antifol. Overall response rate for each of programs I and II was 10%. The responses were 1/11 with 5-FU-MTX plus levamisole, 2/12 with 5-FU-MTX, 1/8 with 5-FU-BAF plus levamisole, 0/8 with 5-FU-BAF, 2/20 with Me-MTX and 2/21 with Me-BAF. The median survival times (MST) for patients receiving Programs I and II were 10 and 5 months, respectively. The MST for all patients receiving MTX was significantly longer than that of patients receiving BAF Survival was not influenced by levamisole administration. Both chemotherapy programs were well tolerated. The sequential administration of 4 active agents failed to improve the results of treatment of colorectal cancer.

Adriamycin is of noteworthy efficacy in the treatment of metastatic breast cancer. Its role in combination regimens is under investigation. One hundred seventy-five women with advanced breast cancer were entered into a prospectively randomized trial comparing two five-drug regimens. Regimen CMFVP consisted of cyclophosphamide (C), methotrexate (M), 5-fluorouracil (F), vincristine (V), and prednisone (P). Regimen CAFVP was identical but substituted Adriamycin (A) for methotrexate. Twenty-seven patients were disqualified; 148 were evaluable. With CMFVP the complete response rate (CR) was 11%, and the partial response rate (PR) was 46%; with CAFVP, CR was 13% and PR was 45%. Duration of response tended to be slightly longer for patients on the Adriamycin arm. The median survival for CR and PR patients with CMFVP was 20.2 months, which was shorter (p = .07) than the 33 month median survival with CAFVP. Although statistical significance was not reached at the 5% level, the increased survival of responders on the Adriamycin regimen supports the data of other studies which suggest that first line combination chemotherapy in advanced breast cancer should include Adriamycin.

This controlled study of children with ALL was designed to test the efficacy and toxicity of one-, two-, three- and four-drug therapy during remission and whether more aggressive therapy in the first eight weeks prolongs remission in patients with features associated with a particularly poor prognosis. After inducing remission with prednisone, vincristine and asparaginase, patients received cranial irradiation and IT methotrexate and were randomized to receive: 1--methotrexate alone; 2--methotrexate plus mercaptopurine; 3--same as in group 2 plus cyclophosphamide; and 4--same as in group 3 plus arabinosyl cytosine. Patients with CNS leukemia at diagnosis received IT methotrexate weekly during the induction period and a higher dose of CNS irradiation. Patients with anterior mediastinal enlargement at diagnosis received radiotherapy to the mass during the induction period. Patients who failed to attain bone marrow remission after four weeks of therapy were given daunorubicin and prednisone for 2--4 additional weeks. Of the 282 patients entering this study between January 1972 and November 1975, 268 (95%) attained complete remission and 228 (85%) were randomized to receive continuation chemotherapy with 1, 2, 3 or 4 drugs. In Group 1 (methotrexate alone), 14 of 20 patients relapsed and 9 developed leukoencephalopathy without antecedent CNS leukemia apparently due to higher doses of intravenous methotrexate; in Groups 2, 3 and 4 the results were equivalent, but without leukoencephalopathy in initial CR. The addition of cyclophosphamide and arabinosyl cytosine increased toxicity and complications without demonstrably increasing the leukemocidal effect. In the 40 patients given additional early therapy, the modalties employed in this study did not prolong remission.

One hundred and sixty-eight patients with unresectable primary liver cancer were prospectively studied by members of the Eastern Cooperative Oncology Group. These patients were randomized to receive treatment with oral 5-Fluorouracil (5FU), oral 5-Fu plus Streptozotocin, oral 5-Fu plus Methyl-CCNU or Adriamycin. The single agent treatments (oral 5-Fu and Adriamycin) were associated with less gastrointestinal toxicity than were the oral 5-Fu treatment combinations. A total of 15 partial responses were reported. Adriamycin appears to be the most active agent and responsible for 9 of the 15 responses. No response was seen in any of the 48 patients randomized to oral 5-Fu alone. The survival associated with oral 5-Fu alone was significantly shorter than the survival time associated with the remaining 3 treatment programs among both North American and South African patients. A multivariate model of survival was formulated. Covariates of prognostic significance were treatment, initial performance status and sex. South African black patients had a shorter survival time than North American black patients. Excluding oral 5-Fu from consideration, prognostic variables appeared to dominate any differences between the remaining treatments under study.