Sixty-nine patients with advanced breast cancer treated with cytotoxic chemotherapy were randomized to receive concomitantly either norethisterone acetate (progestogen group) or a placebo (placebo group). Objective responses were seen in 53% of patients in the progestogen group and 61% of patients in the placebo group. The median duration of response was the same for both groups (38 weeks). Three out of ten patients in the placebo group, who received subsequently the progestogen on relapse, had a further objective regression. The overall survival in the two groups was similar, although in a sub-group of patients who had operable tumors, but a subsequent short disease-free interval, survival was significantly better in the placebo group. There was less myelosuppression in the progestogen group, who were able to receive higher doses of cytotoxic drugs. Less nausea and vomiting occurred in the progestogen group, but subjective side effects were similar. It is concluded that there is no advantage therapeutically in combining cytotoxic chemotherapy and progestogen therapy and, in some patients, better results are obtained using the two treatments sequentially.

This cooperative prospective study was designed to answer the following questions in cases with acute lymphoblastic leukemia induced to achieve complete remission with the combination of vincristine and prednisone (if by day 29 the bone marrow was not M1, daunorubicin was added to the former regimen) and who received preventive CNS therapy with 2400 rad of cobalt-60 to craniocervical region and simultaneously intrathecal methotrexate and dexamethasone: 1) Is a short intensification with cytosine-arabinoside and cyclophosphamide immediately after complete remission useful? 2) Does the use of weekly doses of 6-mercaptopurine and methotrexate have the same maintenance effect as daily 6-mercaptopurine and twice weekly methotrexate? and 3) Do further 3 month-doses of intrathecal methotrexate and dexamethasone help to decrease still more the incidence of meningeal leukemia? From October 1972 to December 1975, 473 previously untreated patients entered this study and 465 (390 children and 75 adults) are evaluated in this paper. Of them, 373 (80%) achieved complete remission (children 84% and adults 61%). Out of 109 "high risk" children (one or more of the following characteristics at diagnosis: marked organomegaly, mediastinal widening, leukocytosis above 50000/mm3 and CNS involvement) 83 (76%) and out of 281 "standard risk" children (all the others) 244 (87%) achieved complete remission. The median duration of complete remission according to different prognostic factors was as follows: "high risk" children 10 months, adults 24 months and "standard risk" children 25 months. Duration of complete remission of the "standard risk" children in relation to with or without intensification, daily or weekly maintenance and additional intrathecal therapy or none, showed no significant difference; however, those who received intensification, daily maintenance and further intrathecal therapy behaved slightly better. Median survival for all the cases of this study was as follows: adults 10 months, "high risk" children 12 months and "standard risk" children 26 months. At 36 months, 13% of "high risk" children, 25% of adults and 39% of "standard risk" children are still alive. We conclude that the variables studied in this protocol did not show significant extension of complete remission, however the sum of them seems to offer some advantage. Moreover, what appears clear is the importance of prognostic factors which must be taken into account in future studies.

Thirty-seven patients with advanced or recurrent lung cancer were randomized to cytoxan (CTX) alone, COMF (CTX, oncovin, methotrecate and 5-FU) or AMCOF (adriamycin, methotrexate, CTX, oncovin and 5-FU) after receiving radiation therapy to primary and bulky tumor sites. Median survival was 3 months for CTX, 6 months for COMF and 14 months for AMCOF. Analysis of those with cell (small cell) carcinoma showed median survival of 8.5 months. Oat cell cases treated with CTX survived 5 months (8 patients) with COMF 7.5 months (15 patients) and with AMCOF 13 months (14 patients). The median survival of those with adenocarcinoma or epidermoid carcinoma treated with CTX survived 3 months, with COMF 6 months and with AMCOF 15.5 months. Toxicity was moderate though no life-theatening toxicity developed in spite of the protocol design of escalation to achieve some degree of hematologic toxicity in all patients.

The purpose of this phase II clinical trial was to evaluate the effectiveness of triazinate and pyrazofurin in the treatment of advanced breast cancer. Although an occasional patient experienced stability of disease, neither agent, as employed in this study, was able to produce an objective antitumor effect in this group of patients with previous chemotherapeutic exposure. At the dosages used in this study, neither agent can be recommended for further treatment of advanced breast cancer.

Two hundred and twenty-seven children with recurrent acute lymphoblastic leukemia were treated with various combinations of vincristine, prednisone, cyclophosphamide and L-asparaginase in an approach to the induction of remission. The combination of L-asparaginase 1,000 mu/kg iv q.d. x 10, vincristine 2.0 mg/m2iv q.w. x 4 and prednisone 40 mg/m2 p.o.q.d. x 28 days was found to be highly effective. The incidence of remission was 73%. No significant improvement was achieved when cyclophosphamide was added to this regimen. Various combinations of cytosine arabinoside, cyclophosphamide, vincristine, prednisone, BCNU or CCNU failed to maintain remission duration for more than two or three months. Neither BCNU nor CCNU prevented the development of CNS leukemia.

A prospective randomized clinical trial of treatment with vincristine, cyclophosphamide, methotrexate and 5-fluorouracil after conventional curative treatment for stage II breast cancer is described. The results at 2 years are recorded together with details of toxicity. Future plans are discussed briefly.

To assess the clinical value of the organ culture drug prediction assay in the present study we summarize the results of two randomized trials in lung carcinoma (61 patients) and ovarian carcinoma (74 patients) comparing predicted and non-predicted or no surgical adjuvant chemotherapy. No real progress could be achieved by predicted cancer chemotherapy. The reasons of the negative results of our studies are discussed.

Fifty-seven patients referred to Roswell Park Memorial Institute between 1971-1975 with Stage III or IV epithelial ovarian cancer treated with prior radiation therapy were randomly allocated to treatment with melphalan, 5-fluorouracil (5-Fu) plus melphalan (FUME), actinomycin-D plus 5-fluorouracil plus melphalan (ACFUME), actinomycin-D, or 5-fluorouracil plus cyclophosphamide (ACFUCY). These patients receiving 5-FU plus melphalan had longer median duration of survival with better quality of life. Combination chemotherapeutic agents effected significantly. better responses (P less than 0.05) than single agent chemotherapy. The ACFUME and ACFUCY combinations resulted in higher incidence of severe and life-threatening toxicity. Patients showing complete response had maximum median duration of survival.

A total of 128 patients were randomly assigned to two induction treatment programs: Adriamycin and L-PAM versus Cytoxan, 5-Fluorouracil, and Prednisone in an effort to assess their primary capacity for objective response. The two regimens appeared quite comparable in this respect. The 100 patients who had achieved clinical benefit following initial treatment were subsequently randomly allocated to reveive either a fixed alternate treatment program involving the two drug regimens or were continued on the treatment program responsible for their initial improvement. Although those patients who received the fixed alternate treatment shcedule had a somewhat longer progression-free interval compared to the two single-treatment programs (median duration of 16 months versus 12 months, respectively), the three treatment programs including the fixed alternate treatment schedules had comparable median survivals of 21-24 months with little difference noted in survival curves at any point thus far in the analysis. There were no differences noted in survival for the fixed alternating treatment group of patients, with respect to which induction regimen had been utilized to achieve initial response. The toxicity for these treatment programs was tolerable and compatible with outpatient administration. Myelosuppression occurred in the vast majority of patients on either regimen but in both regimens was relatively platelet sparing.

A randomized therapeutic trial of three induction regimens for patients with lymphosarcoma and reticulum-cell sarcoma was conducted by the Cancer and Leukemia Group B (CALGB) (formerly Acute Leukemia Group B.) Addition of streptonigrin, but not cyclophosphamide, to the combination of vincristine and prednisone improved the complete remission rate achieved after a 42-day induction program. The duration of the subsequent remission and survival was not influenced by the induction combination assigned. Remission maintenance with cyclophosphamide was superior to maintenance with methotrexate. The results of this study are compared with others in which advantages for three or four drug treatment regimens have been reported.

Adding duborimycin to the association of vincristine + DTIC in the treatment of malignant melanoma produces therapeutic results interesting but not statistically significant and not counter-balancing the toxic side effects. This study confirms the lack of positive results of polychemotherapy in melanoma as compared to treatment by an efficacious single drug therapy (DTIC); it also emphasizes the necessity of randomized studies so that valuable comparisons may be done.

In a placebo-controlled double-blind study the prophylactic value of oral systemic treatment with the antimycotic agent miconazole was assessed in 30 highly predisposed patients receiving intensive cytostatic chemotherapy because of haematological malignancies. Patients colonized with Candida before treatment were not freed from this micro-organism by miconazole treatment. However, only 3 out of 6 initially non-colonized miconazole-treated patients became colonized during the study, against 10 out of 10 placebo-treated patients (p = 0.036). Seven out of 15 patients in the placebo group developed clinical mycosis, against only two out of 15 in the miconazole group. The miconazole-treated patients remained clinically free of mycosis for 252 out of 264 treatment days, while the placebo-treated patients remained free of mycosis for only 263 out or 338 treatment days (p = 0.0001). The results indicate that systemic miconazole treatment protects highly predisposed patients from colonization with Candida and prevents or postpones clinically established candidosis.

Two controlled double-blind studies were carried out successively on a cancerous out-patient population receiving multiple combination chemotherapy at successive treatment courses to show the anti-emetic efficiency of metopimazine compared to a placebo. The patient was taken as his own control and the treatment order was randomly selected. The first trial--consisting of sixty-seven patients, showed a weak statistically significant difference (0.05 less than p less than 0.10) between metopimazine at doses of 30 mg/day or 15 mg/day and a placebo. The second trial--comparing a higher dose of metopimazine (45 mg/day) among one hundred and sixteen patients, showed a highly statistically significant therapeutic advantage over a placebo (0.001 less than p less than 0.01).

Treatment of older acute leukemia patients has been the subject of recent debate. We treated 101 acute leukemia patients in a prospective randomized trial. Fifty-seven per cent of the population was over 50. Half were treated with a mild induction program (VAMP) and half with a vigorous program (CAT). The older patients who received vigorous treatment did better than those who received mild treatment. We suggest that patients over 50 should be regarded as a separate category in design of treatment protocols in order to further maximize the benefits of therapy.

One hundred patients with advanced, recurrent, or metastatic squamous cell carcinoma of the head and neck were treated with chemotherapy and BCG as adjuvant immunotherapy. The overall response rate was 35 per cent, and the median duration of response was seventeen weeks. BCG does not prolong duration of remission or survival time.

Thirty two patients with malignant lymphoma - mainly Hodgkin's disease - were randomized for simultaneous treatment by high doses of metenolone during MOPP chemotherapy, to reduce its hematological toxicity. The results have shown surprisingly an increased hemato-toxicity in patients receiving androgens, with significantly more marked anemia and thrombocytopenia, reducing the total doses of anti-cancer drugs. This side effect could be explained by a cycling of the hematopoietic stem-cells and call to some caution when androgens are used during cancer chemotherapy.

Fifty-six untreated patients with acute leukemia (38 acute myelogenous leukemia, 16 acute lymphoblastic leukemia, and 2 blast crisis of chronic granulocytic leukemia) were randomized on admission to one of three groups--one to receive oral anticandidal prophylaxis through the period of remission induction chemotherapy with nystatin, another to receive natamycin, and the third to receive no anticandidal prophylaxis. Neither of the first two groups show any advantage over the last and it is concluded that provided gut sterilization regimes are not employed, prophylactic oral anticandidal treatment is of no value in these patients and should be reserved until there is clinical evidence of infection.

Mitotic indices, labeling indices (LI), and tritiated thymidine incorporation into DNA of marrow cells were conducted in patients with leukemia to determine if correlations existed between kinetic measurements, clinical features, and response to chemotherapy. Higher proliferative activity was observed in chronic granulocytic leukemia (CGL) and blastic phase of CGL than in acute leukemia. In acute myelogenous leukemia there was no correlation with various clinical features studied. Those patients demonstrating greater than 60% reduction in circulating leukemia cells within 7 days had a higher initial LI than those with less than 60% reduction. Cytosine arabinoside, methotrexate, and hydroxyurea were investigated to determine their synchronizing capability; cytosine arabinoside and methotrexate were superior to hydroxyurea. In a cycle-sensitive schedule specifically designed to synchronize cells, responses occurred more frequently in patients who increased thier LI 48 hours after priming doses of cytosine arabinoside. In an intensive-chemotherapy schedule which produced more remissions than the cycle-sensitive schedule, there was no relationship between initial kinetic measurements and response. Kinetic values increased as patients achieved remissions.

A controlled clinical trial comparing two-drug and three-drug combination chemotherapy was performed in 206 patients with advanced bronchogenic carcinoma, comprised of 26.2% with epidermoid carcinoma, 30.1% with small cell anaplastic carcinoma, 27.2% with adenocarcinoma, and 15.6% with large cell carcinoma. Each drug combination consisted of agents with different modes of action and included a cell-cycle-stage nonsensitive and a cell-cycle-state-sensitive agent. The overall response rate was highest for small cell carcinoma (48.2%) and adenocarcinoma (23.6%); it was less than 10% in epidermoid and large cell carcinoma. Similarly, the overall median survival was twice as long for the first two cell types (7 months) as compared with that recorded for the other two cell types (3 1/2 months). The combination of 1 (2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), cyclophosphamide, and methotrexate was shown to be statistically superior to cyclophosphamide and methotrexate with regard to objective respones rate, duration of response, and median survival for adenocarcinoma. Responders lived significantly longer than nonresponders (254 versus 90 days for small cell anaplastic carcinoma patients and 244 versus 184 days for adenocarcinoma patients). No difference in survival or objective response rate was observed between the different treatments for the other two cell types of lung cancer.