Steven E. Vogl

A randomized trial of the four most active regimens for metastatic non-small-cell lung cancer.

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.

Cis‐platin based combination chemotherapy for advanced ovarian cancer. High overall response rate with curative potential only in women with small tumor burdens

Thirty‐eight women with advanced ovarian cancer were given monthly cycles of intravenous cyclophosphamide, Adriamycin (doxorubicin) and cis‐platin, and oral hexamethylmelamine. Of 26 with tumor which would be evaluated for response, 42% had complete remission and 50% partial remission. Median time to disease progression from entry for all 38 patients was 13 months, and median survival 23.5 months. The bulk of tumor at the time chemotherapy was begun was the only significant prognostic factor for time to disease progression and survival. Of the seven women surviving free of disease a median of three years later, five had no mass > 2 centimeters in diameter at entry. Toxicity was predominantly myelosuppression and vomiting, with mild peripheral neuropathy in 27% and no significant renal or cardiac toxicity. The response rate of 92% is much higher than that previously reported with melphalan, and the survival considerably longer. The toxicity is acceptable, given the substantial improvement in results.

Chemotherapy of advanced head and neck cancer with methotrexate, bleomycin, and cis-diamminedichloroplatinum II in an effective outpatient schedule

Thirty‐one patients with advanced cancer of the head and neck, twenty‐six of whom had failed prior irradiation, were treated with an out‐patient chemotherapy regimen combining methotrexate, bleomycin, and cis‐diamminedichloroplatinum (II). The overall response rate among evaluable patients was 61%, with 22.5% complete remission. If 6 additional patients not completing 3 weeks of treatment are included, the response rate was 51.4%. The median duration of partial remission was 3 months, but none of the complete remitters has relapsed with a follow‐up of two to twenty months (median six). Response rate was not dependent on performance status, prior irradiation, or primary site. Toxicity was mild. The remission rate and duration suggest that this regimen may be superior to single agents, and as effective as more complicated and toxic regimens using higher doses of the same drugs.

A randomized prospective comparison of methotrexate with a combination of methotrexate, bleomycin, and cisplatin in head and neck cancer

Combination chemotherapy with methotrexate, bleomycin, and cis‐diamminedichloroplatinum (II) was compared to weekly therapy with methotrexate alone in a randomized prospective trial in 163 patients with recurrent or metastatic squamous cancer of the mucous membranes of the head and neck. The combination produced responses in 48% compared to 35% for methotrexate alone, with 16% complete remissions versus 8%, respectively. The difference in overall and complete remission rates is significant (P = 0.04) using a one‐sided binary regression test. Median time to disease progression among responders was 5.8 months for the combination and 5 months for methotrexate, and median survival was 5.6 months in each group. Toxicity was similar in the two groups. Ambulatory patients, those without fixed neck nodes and those without distant metastases, responded more often. Poor performance status, distant metastases, history of heavy smoking, and adjacent organ invasion by the primary tumor were associated with shorter survival, as were weight loss, the presence of tumor in the neck, and heavy alcohol consumption. The addition of bleomycin and cisplatin to methotrexate produces more remissions, and especially complete remissions, but has not made a major impact on the course of far‐advanced head and neck cancer.

Recurrent ovarian carcinoma: Retreatment utilizing combination chemotherapy including cis-diamminedichloroplatinum in patients previously responding to this agent

Eleven women with advanced ovarian cancer treated postoperatively with combination chemotherapy (cytoxan, hexamethylmelamine, Adriamycin, and cis-platinum) had disease-free intervals of 5 to 46 months (mean: 22 months) and subsequently developed recurrent carcinoma. Each patient was then retreated with combination chemotherapy which included cis-platinum. There was a 72% response rate to retreatment (36% complete, 36% partial). These overall and complete remission rates are comparable to those of platinum-based combination chemotherapy in patients without prior treatment. Those patients who responded to retreatment had a significantly longer mean survival rate than those who did not.

Toxicity of Cis‐diamminedichloroplatinum II given in a two‐hour outpatient regimen of diuresis and hydration

A two‐hour program of hydration with 2 liters of 0.45% saline‐5% dextrose and diuresis with furosemide and mannitol was employed to administer cis‐diamminedichloroplatinum(II) on an outpatient basis; 760 courses were administered to 158 patients. The dose was 50 mg/M2 every three to four weeks, and was given in combination with other anti‐neoplastic agents in all but two patients. Only eight patients (5.13%) ever became azotemic. Of these, only three ever had serum creatinine determinations greater than 2 mg/dl, and azotemia was reversible in two months in all but one. Risk of azotemia did not increase with increasing cumulative dose. There were two anaphylactoid reactions, one sudden death, and two cases of hearing loss. Nausea and vomiting were universal, and often severe. This program of hydration and diuresis allows convenient outpatient administration of this drug with minor risk of mild nephrotoxicity.

Failure of effective initial chemotherapy to modify the course of stage IV (MO) squamous cancer of the head and neck

Twenty‐four patients with advanced squamous cancer of the head and neck without distant metastases were given combination chemotherapy including methotrexate, bleomycin and diamminedichloroplatinum before planned local treatment with irradiation or surgery. Of 22 evaluable patients, 17 had objective partial or complete remission to initial chemotherapy. However, only ten patients ever had complete clearing at any time of all tumor on clinical evaluation. Median survival was ten months, and only two patients remained alive 14 and 29 months, respectively, from entry. Toxicity was minimal with the three‐drug treatment, but the addition of mitomycin‐C at the start of chemotherapy substantially increased toxicity without improving efficacy. Subsequent surgery and radiotherapy were accomplished without unusual difficulty.

Hexamethylmelamine and Low or Moderate Dose Cisplatin With or Without Pyridoxine for Treatment of Advanced Ovarian Carcinoma: A Study of the Eastern Cooperative Oncology Group

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.

Cervical cysts: Cancer until proven otherwise?

A cystic neck mass can be either malignant or benign; 22% of patients (4/18) admitted with the tentative diagnosis of branchial cyst in a recent 2‐year period (1977‐1979) had metastatic carcinoma: epidermoid, thyroid or salivary gland. Preoperative fine needle aspiration was diagnostic in 1 instance and unhelpful in 2. Frozen section analysis of the gross specimen invariably provided the correct diagnosis. All patients with malignancies had subclinical primary disease and in 1 instance random biopsies identified its origin.

Efficacy study of intensive cis‐platin therapy in advanced non‐small cell bronchogenic carcinoma

Thirty patients with advanced non‐small cell bronchogenic carcinoma were treated with cis‐platin, 75 mg/M2 weekly for three weeks, then every three weeks. Eighteen were ambulatory, 22 had distant metastases, 14 had prior irradiation, and none had prior chemotherapy. Ten patients (33%) had objective remissions lasting a median of three months. Responders lived a median of five months, compared to three months for nonresponders. Transient mild azotemia was noted in twelve patients. Cis‐platin has definite but modest activity in non‐small cell bronchogenic carcinoma.