Between October 1981 and June 1983, the Eastern Cooperative Oncology Group (ECOG) conducted a prospectively randomized trial (EST 1581) of the four most active chemotherapy regimens for metastatic non-small-cell lung cancer (NSCLC). Four hundred eighty-six good performance status patients (PS 0 or 1; 81%) were randomized to receive cyclophosphamide, doxorubicin, methotrexate, and procarbazine (CAMP); mitomycin, vinblastine, and cisplatin (MVP); etoposide and cisplatin (VP-P); or vindesine and cisplatin (VDA-P). All regimens were administered in the doses and schedules originally reported. Complete response (CR) plus partial response (PR) rates for the four regimens were CAMP, 17%; MVP, 31%; VP-P, 20%; and VDA-P, 25%. The response rate for MVP was significantly higher in patients with squamous and adenocarcinoma histologies, but there was no impact on median survival (overall, 24.5 weeks). The duration of response did not differ by treatment as previously suggested for VDA-P. There were 15 CRs (CAMP, one; MVP, six; VP-P, two; VDA-P, six), and 12 patients have survived more than 2 years. Toxicity was significant with 20 treatment-related deaths. CAMP was significantly less toxic than the other regimens (P less than .001). VDA-P demonstrated significantly more life-threatening (seven) and lethal (three) episodes of nephrotoxicity (P less than .001) despite an aggressive hydration program that in itself caused significant morbidity. Analysis of the toxicity data showed, however, that most of the severe toxicity occurred in the 19% of patients who were initially PS 2, suggesting that they are not appropriate candidates for trials of new agents or combinations. None of these regimens can be recommended as a standard therapy for metastatic NSCLC.

A total of 248 analyzable patients with Stages III-IV ovarian epithelial cancer (114 with and 134 without prior chemotherapy) were randomized to one of four cisplatin (DDP)-hexamethylmelamine (HMM) regimens. In each, HMM, 200 mg/m2 was given orally daily on days 8-21 of each 21-day cycle. DDP was given i.v. on Day 1 at a dose of 37.5 mg/m2 (regimens A and B) or 75 mg/m2 (regimens C and D). In addition, since pyridoxine administration has been reported to reduce the neurotoxicity of HMM, that agent was given at a dose of 300 mg/m2 orally on Days 1-21 in regimens B and D. Randomization was stratified for performance status (0-1, 2-3) and largest tumor diameter at entry (greater than 2- less than or equal to 10 cm, greater than 10 cm) for previously untreated patients, and for performance status and time from initial diagnosis to entry on study (less than or equal to 1 year, greater than 1 year) for previously treated patients. The overall response rate (PR + CR) was 54%, with 25% of patients achieving a complete response. The 61% response rate with the higher dose DDP regimens was significantly greater than the 47% response rate with the lower dose regimens (p = 0.031). Multivariate analysis identified higher DDP dose, age less than 60 years, no prior chemotherapy, small tumor bulk and favorable tumor grade as significant prognosticators for response. The overall median response duration was 8.3 months (range 1-70 months). Prior chemotherapy, pyridoxine administration, recent diagnosis, and large tumor size were identified by multivariate analysis as factors adversely affecting response duration. Patients treated with the higher dose DDP regimens had more severe nausea, vomiting, and neurotoxicity. This study demonstrates that the combination of DDP + HMM is an effective regimen for advanced ovarian carcinoma that yields response rates comparable to other more complex regimens, and that there is a dose-response relationship for DDP in ovarian cancer. Although pyridoxine administration significantly reduced neurotoxicity, its adverse effect on response duration suggests that the agent should not be administered with DDP or HMM. The mechanism by which pyridoxine may unfavorably affect response duration deserves further investigation.

One hundred and forty-four evaluable patients with recurrent or metastatic renal cell carcinoma (RCC) were treated with vinblastine infusion (n = 35), L-alanosine (n = 36), acivicin (n = 27), or aminothiadiazole (n = 46). Observed objective response rates of 9%, 3%, 4%, and 2%, respectively indicate that noe of these agents has significant antineoplastic activity in recurrent or metastatic RCC. Multivariate analysis of survival data suggests that initial performance status, time from initial diagnosis to study entry, and the presence or absence of lung metastases are important prognostic factors for survival. After adjustment for these factors, treatment assignment was also seen to be of prognostic value. All four treatments were generally well tolerated. There were no reports of life-threatening or lethal toxicities; however, 37% of the patients experienced severe reactions to treatment, primarily myelosuppression, anemia, neuropathies, and mucositis.

Twenty-nine patients with metastatic prostate cancer progressing after hormonal therapy (orchiectomy 19, diethylstilbesterol 10) and who had never received cytotoxic therapy were treated with carboplatin. Patients had good clinical performance status (66% PS 0,1) and adequate renal (creatinine < 2.0 mg/dL) and bone marrow function. The standard dose of carboplatin administered was 400 mg/sq m. Seventeen patients received this dose and 12 either 320 mg/sq m or 250 mg/sq m based on reduced renal function or prior radiation. Five patients had bidimensionally measurable disease: one experienced a partial regression of cervical lymph node metastases of 97 days duration. Twenty-four patients had metastatic disease evaluable by clinical status, bone scan and acid phosphatase. In one patient > 50% reduction in number of abnormal areas of bone scan uptake occurred; 3 patients experienced improvement in clinical status; in no patient did an elevated prostate acid phosphatase return to normal. All patients entered on study have progressed and died: median time to progression was 94 days (6 to 625 days); median survival was 297 days (6-1152 days). The primary toxicity of carboplatin was myelosuppression. The median WBC and platelet nadirs after cycle one were 3150/cu mm and 93,000/cu mm, respectively. Dose escalations to grade 2 or greater myelosuppression were mandated. Twenty-six achieved at least grade 2 myelosuppression during carboplatin treatment. We conclude that carboplatin administered at this dose and schedule has no important activity in hormone refractory prostate cancer.

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A total of 83 patients with metastatic transitional cell carcinoma who had previously received no systemic therapy entered a randomized phase II evaluation of carboplatin and cis-dichloro-transdihydroxy-bis-isopropylamine platinum IV (CHIP), administered respectively at 400 and 270 mg./m.2 every 28 days. Among evaluable patients with measurable disease response rates were 3 of 22 (14%, 95% confidence interval 5 to 35%) for carboplatin and 4 of 25 (16%, 95% confidence interval 5 to 36%) for CHIP. Among 17 patients with evaluable but not measurable metastases (10 carboplatin and 7 CHIP recipients) there were no responses. Median survival for 64 evaluable patients was 4.8 months (5.0 months for carboplatin and 4.3 months for CHIP recipients). Independent factors prognostic for survival (p less than 0.01) were performance status (0 or 1 versus 2 or 3), liver metastases, prior radiation therapy and recent weight loss (p = 0.02). Multivariate analysis confirmed that a performance status of 2 or 3 and liver metastases were predictive of shorter survival. A total of 31% of the patients treated with carboplatin and 34% of those who received CHIP experienced severe or life-threatening myelosuppression. While the response rates with carboplatin and CHIP are modest, we believe that the characteristics of these agents indicate that they should be evaluated further.

A 45-year-old man was diagnosed with multiple myeloma, IgA-kappa, in 1975. Thirteen years later he presented with obstructive jaundice. Computed tomography (CT) showed a 6-cm mass in the head of the pancreas. Needle aspiration showed myeloma. The jaundice resolved after treatment with radiotherapy. Extraosseous involvement by myeloma is frequently found at autopsy but obstructive jaundice from myeloma of the head of the pancreas is quite rare. This atypical complication of myeloma may be related to the patient's long survival.

Evidence of increasing risk of nephrotoxicity was sought in the records of 95 patients who had received 300–826 mg/m2 cumulative doses of cis‐platinum in single doses of 50–75 mg/m2 every 3–4 weeks, with hydration and diuresis using mannitol and furosemide. The incidence of serum creatinine elevation to >1.5 mg/dl was 4.2% per patient and 0.75% per dose, no higher than the incidence observed at lower cumulative doses. Among 54 of these patients observed for at least 3 months after cessation of cis‐platinum chemotherapy, only one had later deterioration of renal function to a serum creatinine of 1.9; both kidneys had been irradiated to 1900 rad in this patient. It was concluded that cumulative, delayed or severe nephrotoxicity are not significant problems related to prolonged cis‐platinum administration at moderate doses when hydration and diuretics are routinely used.