Barry H. Kaplan

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.

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.

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.

Second-effort surgical resection for bulky ovarian cancer

Eighteen women with bulky ovarian cancer at the start of chemotherapy were brought to second laparotomy after 6 months of combination chemotherapy in an effort to resect previously unresectable tumor masses. Only one of 18 had significant resection of bulk tumor such that no gross tumor was remaining, although 8 of 15 had the residual uterus removed and 6 of 10 had resection of residual ovary or ovaries. Failure to resect tumor was due to absence of any gross tumor (33%), presence of myriad small seedlings not amenable to resection (22%), or massive residual tumor (18%). Partial resection was accomplished in 22%, but all relapsed promptly in spite of continued aggressive therapy with drugs and whole abdominal irradiation. It is concluded that 6‐month “second‐effort” surgical resection is unlikely to benefit many women with bulky ovarian cancer, and that surgical resection must be attempted early in the course of the disease if it is to be effective.

Effective chemotherapy for esophageal cancer with methotrexate, bleomycin, and cis-diamminedichloroplatinum II.

Ten patients with squamous cancer of the esophagus were treated with an outpatient regimen combining cis‐diamminedichloroplatinum (II), methotrexate and bleomycin. Nine of these had metastatic disease or recurrence after radiotherapy. Objective responses were noted in 50%, regardless of performance status or metastatic site. None of three patients with prior radiation therapy responded, however. Median duration of response was six months. Responders survived a median of eight months versus five months for nonresponders. Three patients had severe hematologic toxicity. A single patient with massive disease confined to the esophagus had an excellent response to six weeks of chemotherapy before radical irradiation. He is disease‐free after two years but is paraplegic from radiation myelitis. This chemotherapy program is an effective palliative therapy for metastatic esophageal cancer. Its safety and efficacy as part of the initial treatment of local disease should be further investigated.

Adriamycin and cis-diamminedichloroplatinum in the treatment of metastatic endometrial adenocarcinoma

Adriamycin (50 mg/m2) and cis-diamminedichloroplatinum (50 mg/m2) were administered every 21 days to treat metastatic endometrial adenocarcinoma. This regimen resulted in three responses (one complete and two partial) in nine women (33%). Most patients had moderate or severe hematologic and gastrointestinal toxicity. One patient experienced moderate neurotoxicity. This combination of drugs did not appear effective in the treatment of recurrent endometrial adenocarcinoma, but may have a role in the therapy of primary widespread disease.