Richard A. Bender

Advanced ovarian adenocarcinoma. A prospective clinical trial of melphalan (L-PAM) versus combination chemotherapy.

Abstract Eighty patients with advanced ovarian adenocarcinoma were treated in a prospective, randomized trial comparing a four-drug combination — hexamethylmelamine, cyclophosphamide, methotrexate and 5-fluorouracil — with the oral alkylating agent, melphalan. Treatment with the four-drug combination was associated with a significantly increased overall response rate (75 vs. 54 per cent) (P<0.05), more complete remissions (33 vs. 16 per cent) and longer median survival (29 vs. 17 months) (P<0.02) but more severe toxicity than occurred with melphaIan. Patients with minimal residual disease had a significantly higher overall response rate than patients with extensive residual disease (84 vs. 53 per cent) (P<0.05). Patients with advanced disease who achieved a complete remission documented by peritoneoscopy or laparotomy (or both) have a median survival that will exceed three years. The four-drug regimen is more effective than melphalan in the management of advanced ovarian adenocarcinoma. (N Engl J Med 299:...

The pharmacokinetics of [3H]‐vincristine in man

The pharmacokinetics, metabolism, and excretion of aromatically labeled tritiated vincristine (VCR) was examined in 4 patients. Clearance of radioactivity from the blood was triphasic with half‐life tV2 values of 0.85, 7.4, and 164 min. The initial phases probably represent distribution and binding to formed blood elements which exceeded 50% of the administered dose by 20 min. Excretion of radioactivity was principally fecal, with 33% recovered in the feces by 24 hr and 69% by 72 hr. Considerably less radioactivity (12%) was excreted in the urine over the 72‐hr period. Approximately 40% of fecally excreted and 46% of urinary excreted radiolabel represented metabolites, which suggests that at least 34% of the VCR dose was excreted as metabolites. Plasma metabolites represented from less than 1 % to 30% or more of radioactivity in plasma. Ultraviolet spectral analysis of all metabolites revealed preservation of the intact VCR dimer, which suggests that metabolism involves alteration of side groups.

HEXAMETHYLMELAMINE IN ALKYLATING AGENT-RESISTANT OVARIAN CARCINOMA

Twenty‐one patients with advanced ovarian cancer proven resistant to standard alkylating chemotherapy were evaluated in a prospective study of Hexamethylmelamine. All but three patients received 8 mg/kg daily with dose modifications appropriate to the degree of toxicity; the latter three patients were treated on an intermittent 14 day course of 8 mg/kg daily. Six patients (28%) experienced an objective response with a median duration of 2.5 months (range 1—5 months). The toxic effects requiring dose modification were gastrointestinal in 57%, hematologic in 62%, and neurologic in 28.5%. An average of 60.5% of the total projected dose was tolerated for a median of 44 days (range 7‐113). Twelve patients (57%) experienced severe toxicity requiring discontinuation of therapy. It is apparent from this study that Hexamethylmelamine is an active agent in ovarian cancer and is not invariably cross‐resistant to conventional alkylating agent therapy. These two characteristics make it an attractive agent for use in combination. Its toxicity in previously treated patients in the schedules used here, however, is substantial. Cancer 42:2157–2161, 1978.

Antineoplastic Drugs: Clinical Pharmacology and Therapeutic Use

The treatment of malignant disease has undergone an evolution over the past decade with the development of many new agents and combinations of agents useful in antineoplastic therapy. Such agents are somewhat unique from other classes of drugs in having a very narrow therapeutic index. Furthermore, as many of these agents only exert their effects during certain phases of the cell cycle, their action is schedule-dependent. Thus, a thorough understanding of the pharmacology of these agents and of potential drug interactions is imperative for their safe and effective use by the oncologist or cancer therapist. This review will deal with the clinical pharmacology of some of the more commonly used antineoplastic agents with emphasis on selected newer agents of proven therapeutic efficacy.

Eosinophilic meningitis complicating Hodgkin's disease. A report of a case and review of the literature.

A case of eosinophilic meningitis as a complication of Hodgkins disease is reported. Intrathecal chemotherapy with methotrexate and whole brain radiation therapy were effective in clearing the cerebrospinal abnormalities, pathologic evidence of meningeal disease, and the clinical manifestations. The differential diagnosis of eosinophilic meningitis and therapy of lymphomatous meningitis are discussed. Cancer 40:406–409, 1977.

Prospective evaluation of two tumor-associated proteins in pancreatic adenocarcinoma.

Twenty‐eight patients with biopsy‐proven, surgically staged pancreatic adenocarcinoma were prospectively studied for elevations in plasma carcinoembryonic antigen (CEA) and serum α and β subunits of human chorionic gonadotropin (hCG). At the time of presentation, the CEA was elevated in 57% of patients, the hCG‐β in 7.3%, and the hCG‐α in no one. Twenty‐five patients were placed on a treatment protocol and followed regularly until disease progression. With respect to CEA, 3 patients with initially elevated value showed at least a twofold increase in level prior to or concurrent with disease progression, and 5 patients never had an abnormal value. Finally, while hCG‐α remained normal in all patients throughout their treatment course, hCG‐β became elevated in 3 patients having been normal at the time of presentation. Thus, a total of 17.5% of patients had an elevated hCG‐β sometime during their clinical course. While the combined assays did not improve diagnostic sensitivity, an hCG‐β elevation developed 13 weeks prior to a CEA elevation and 17 weeks prior to documented disease progression in one patient. Due to the difficulty in documenting disease progression clinically in this disease, the hCG‐β may be a useful tool to monitor disease activity. Moreover, the reported elevation of hCG‐α in pancreatic islet cell tumors supports the difference in their cell of origin from hCG‐β producing solid adenocarcinomas and suggests separate genetic control governing the production of certain placental polypeptides. Cancer 43:591–595, 1979.

Advanced Ovarian Adenocarcinoma A Prospective Clinical Trial of Melphalan (L-PAM) Versus Combination Chemotherapy

Eighty patients with advanced ovarian adenocarcinoma were treated in a prospective, randomized trial comparing a four-drug combination--hexamethylmelamine, cyclophosphamide, methotrexate and 5-fluorouracil--with the oral alkylating agent, melphalan. Treatment with the four-drug combination was associated with a significantly increased overall response rate (75 vs. 54 per cent) (P less than 0.05), more complete remissions (33 vs. 16 per cent) and longer median survival (29 vs. 17 months) (P less than 0.02) but more severe toxicity than occurred with melphalan. Patients with minimal residual disease had a significantly higher overall response rate than patients with extensive residual disease (84 vs. 53 per cent) (P less than 0.05). Patients with advanced disease who achieved a complete remission documented by peritoneoscopy or laparotomy (or both) have a median survival that will exceed three years. The four-drug regimen is more effective than melphalan in the management of advanced ovarian adenocarcinoma.