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Thirteen patients with advanced small cell bronchogenic carcinoma (SCBC) received at least three weekly cycles of iv streptozotocin (STZ). There were no objective responses. Four patients progressed by the third week of therapy and an additional eight by the fourth week. Toxicity was acceptable especially in view of the extensive prior therapy. STZ is unlikely to be of benefit in combination chemotherapy regiments for SCBC.

Thirty-two patients with small cell carcinoma of the lung were given chest radiotherapy to progressive intrathoracic tumor after failing chemotherapy. Two-thirds of these patients received split-course treatment at a dose of 4000 rad in 10 fractions. Sixteen of 25 evaluable patients (64%) had an objective response, but only five responders did not progress within the port during life. Median time to local progression was 16 weeks. Two patients, one of whom was given concurrent chemotherapy, survived greater than 18 months, and one is free of disease at 31+ months. Short-term palliation of chest disease and occasional long-term survival are possible with this regimen, although most patients will die with systemic disease within several months. Small cell carcinoma of the lung is less responsive to irradiation as second-line therapy than as initial therapy, but doses of greater than or equal to 4000 rad can offer symptomatic relief in many cases and, rarely, survival beyond 18 months.

Eighteen patients with histologically documented small cell carcinoma of the lung who had failed initial combination chemotherapy regimens were treated with single-agent cisplatin in a dose of 100 mg/m2 every 3 weeks, with mannitol and fluid diuresis. Tumor regression was limited to one partial response (response rate, 6%; 95% confidence limits. 1%-27%). Significant toxic effects were gastrointestinal (severe nausea and vomiting in 12 of 14 patients) and hematologic (severe leukopenia in one patient and severe thrombocytopenia in three). The antitumor efficacy of high-dose cisplatin in heavily pretreated patients with small cell carcinoma of the lung appears to be marginal.

Thirty-five previously untreated patients with multiple myeloma were treated with a 60-week course of alternating, potentially non-cross-resistant chemotherapy combinations (melphalan and prednisone; vincristine, cyclophosphamide, doxorubicin, and prednisone; and carmustine, melphalan, and prednisone), alternating every 15 weeks in an attempt to prevent the development of drug resistance. The overall objective response rate (greater than 50% decrease in M protein) was 60% and six patients (17%) had a complete disappearance of the M protein. After 60 weeks, chemotherapy was discontinued in 17 responding or stable patients until relapse occurred from 4 to 39 months later (median, 12 months). Patients relapsing late (greater than 12 months after discontinuation of therapy) responded more frequently than those relapsing earlier to the reinstitution of the same chemotherapy program. The overall response rate and the actuarial median survival of 26 months in the 35 patients do not differ from the results reported recently with nonalternating combinations given until clinical tumor progression. The failure of this study to prolong survival by using alternating regimens may be due to (a) the likely possibility that the initial two regimens are not actually non-cross-resistant in most myeloma patients, and (b) the long interval between the alternating regimens, particularly in the face of the low response rate to the initial regimen of melphalan and prednisone.

Eighteen previously untreated patients with advanced nonresectable adenocarcinoma of the stomach were treated with a four-drug regimen consisting of 5-fluorouracil, methyl-CCNU, adriamycin, and mitomycin C. Objective responses occurred in only two patients (11%); the majority of patients had stable disease for greater than or equal to 8 weeks (61%). The median survival of 27 weeks was similar to that reported in other combination chemotherapy trials. Numerous staging and restaging procedures and strict response criteria were utilized and each was evaluated for its effectiveness in following responses. None of these parameters was useful for evaluating response of intra-abdominal tumor. We conclude that this four-drug combination is no better than previously described two-drug regimens.

Pentamethylmelamine (PMM) is a water-soluble monodemethylated derivative of hexamethylmelamine and has a similar spectrum of activity against murine tumors. Unlike hexamethylmelamine, it is suitable for parenteral administration. We conducted a phase I trial of PMM given as a weekly 1-hour iv infusion to 34 extensively pretreated patients with advanced solid tumors. Eight dose levels ranging from 80 to 1500 mg/m2 were studied. A median of three infusions (mean, 4.2; range, 1-24) were given to each patient. Severe nausea and vomiting was dose-limiting at 1500 mg/m2; it was unresponsive to antiemetics and persisted up to 48 hours. Mild to moderately depressed levels of consciousness were seen in one third of the patients at dose levels of greater than or equal to 750 mg/m2. Consistent dose-related myelosuppression was not observed. Hepatocellular toxicity manifested by elevated serum transaminases occurred sporadically, usually in patients with liver metastases, but could not be unequivocally attributed to the drug. No complete or partial tumor responses were noted. At each dose level, the pharmacokinetics of PMM disappearance from plasma were studied in one to three patients with a gas chromatograph-mass spectrometer assay which exclusively measured the unmetabolized drug. The data obtained wee consistent with a two-compartment model of drug distribution, with a mean dose-independent terminal half-life of 143 minutes (range, 43-370). Peak drug levels were directly proportional to dose. The relative lack of myelotoxicity would make PMM an attractive candidate for addition to combination regimens if antitumor activity at tolerable doses could be documented. On this schedule, the recommended dose is 100 mg/m2 for phase II trials.

Pretreatment performance status (PS)is a major prognostic factor for both treatment response and survival duration in cancer clinical trials. PS is, however, a subjective index that may be markedly influenced by acute self-limited events. The objective of this study was to develop a prognostic index, based on pretreatment laboratory results, that might serve as an alternative to PS in patients with small cell anaplastic lung cancer. Results have been analyzed in 56 newly diagnosed patients with a minimum followup of 10 months and a median followup of 21 months. Patients were divided into high and low groups for each laboratory parameter based on readings either above or below the median value. Patients with high hemoglobin or albumin levels or low serum alpha-1 globulins, gamma globulins, or LDH survived significantly longer than patients with the opposite levels. When these factors were evaluated by multivariate analysis, albumin and hemoglobin were the most influential prognostic factors for survival. After inclusion of these two laboratory parameters, PS was no longer a significant prognosticator of survival. An objective prognostic index based on pretreatment laboratory results appears feasible in patients with small cell lung cancer.

Seventeen patients with small cell carcinoma of the lung (SCCL) refractory to at least one combination chemotherapy regimen were treated with a high-dose methotrexate (HDMTX) program consisting of 1500 mg/m2 of MTX by iv infusion at a constant rate over 30 hrs following a priming dose of 50 mg/m2 of MTX iv. Administration of calcium leucovorin was begun at the end of the infusion. Treatment was repeated every 2 weeks. No complete or partial responses were observed, and the median time to tumor progression was 4 weeks. Hematologic toxicity was much more severe than anticipated, with five patients having thrombocytopenic bleeding requiring platelet transfusions. This HDMTX regimen was both ineffective and unexpectedly toxic in our heavily pretreated patients with SCCL. Literature review discloses little evidence that HDMTX programs have superior activity to standard doses of MTX in this disease.

Sixty-one protocol-eligible patients with small cell bronchogenic carcinoma received cyclic alternating combination chemotherapy with two or three non-cross-resistant drug combinations. No chest or prophylactic brain radiation therapy was used. Twenty-eight months after starting treatment, disease-free survival was 23% for patients achieving a complete response (CR) and 13% overall. Initial treatment consisted of high-dose cyclophosphamide, methotrexate, and CCNU (CMC) for 6 weeks. Patients then received vincristine, adriamycin, and procarbazine (VAP) for 6 weeks. The addition of VAP increased the CR rate from 42% to 74% in limited-disease patients and from 24% to 36% in extensive-disease patients. Half of the patients were randomized to a third combination of VO-16-213 and ifosfamide. These patients were cycled at 6-week intervals through the three drug regimens while the remaining patients were cycled between CMC and VAP. The addition of VP-16-213 and ifosfamide did not increase the CR rate or prolong survival. Only complete responders survived beyond 24 months. Sequential use of non-cross-resistant drug combinations represents one method for increasing the CR rate.