S. W. Hall

Adriamycin, BCNU, ftorafur chemotherapy of pancreatic and biliary tract cancer

Twenty‐six evaluable patients with disseminated or locally unresectable pancreatic or biliary tract carcinoma received Ftorafur (4 g/m2 iv day 1 and 22 and 2 g/m2 iv day 4 and 26), Adriamycin (60 mg/m2 IV day 1 and 45 mg/m2 iv day 22) and BCNU (150 mg/m2 iv day 1) combination chemotherapy (FAB) repeated at 6–8 week intervals. Two (29%) complete and one (14%) partial remissions were observed in 7 patients with biliary carcinoma while 5 of 19 (26%) patients with pancreatic carcinoma achieved partial remissions. Median survival for responding patients was ∼11 months (range 7–16+) with median survivals of about 6 months (p < 0.05) and about 3 months (p < 0.05) for patients with stable and progressive disease. Major drug toxicity was myelosuppression with median lowest granulocyte counts of 1,000/μl and platelet counts of 88,000/μl. Approximately 25% of patients required antibiotic therapy for fever of unknown origin or documented infections. Other tolerable drug toxicities included nausea, vomiting and mucositis. The FAB regimen appears quite promising in biliary tract cancer and has efficacy in pancreatic carcinoma that warrants further clinical trials. Because of myelotoxicity observed with this regimen we now recommend a BCNU starting dose of 100 mg/m2 instead of 150 mg/m2.

Clinical pharmacological and toxicological studies of Cis-diamminedichloroplatinum (II) by continuous intravenous infusion

Summary Pharmacological and toxicological studies of DDP were conducted in 35 patients with solid tumors, who received a priming dose of the agent at 5 mg/m 2 followed by continuous i.v. infusion at 20 mg/m 2 daily for 5 days. DDP in biological fluids was determined either colorimetrically or by atomic absorption spectrometry. Upon cessation of infusion, the average terminal plasma t½ of DDP in 7 patients was 34.7 hr; however, in a patient with oliguric renal failure, it was 96 hr. During infusion, plasma DDP concentrations varied between 0.5–4.3 mg/l. The cumulative urinary excretion of DDP was 34 per cent in 8 days. In concentrations of 1–50 mg/l DDP was 26–56 per cent bound to human plasma protein at 28°. The toxicity of DDP by i.v. infusion included nausea and vomiting in 94 per cent of the patients, but of much less severity than by other schedules. Additionally, nephrotoxicity was seen in 21 per cent of the patients, and tinnitus or audiogram abnormalities in 10 per cent; hematologic toxicity was mild. Complete remission lasting more than 4 months was seen in a patient with basal cell carcinoma. Also, of 7 patients with squamous cell carcinoma of the head and neck or cervix, 3 showed partial remission and 2 showed stabilization of their disease. Continuous i.v. infusion therefore offers the advantage of attenuating the nausea and vomiting caused by DDP.

Actinomycin‐D, levamisole chemoimmunotherapy of refractory malignant melanoma

Sixty adult patients with disseminated melanoma refractory to DTIC or Dacarbazine were given chemoimmunotherapy with intermittent high single dose Actinomycin‐D and Levamisole. Actinomycin‐D was given at a dose of 1.5‐2.0 mg/m2 intravenously every 3 to 4 weeks. Levamisole was given in a dose of 150 mg/day for two consecutive days each week (50 patients) and in a dose of 200 mg every other day (10 patients). Antitumor responses consisted of 2% complete remissions (CR), 2% partial remissions (PR), and 33% disease improvement less than PR or stabilization (S). Comparison of these patients who received Actinomycin‐D + Levamisole with those on an immediately preceding study in a similar population where Actinomycin‐D was given as a single agent revealed no difference in response rates. Patients who responded to Actinomycin‐D + Levamisole (CR + PR + S) survived significantly longer (35 weeks) than nonresponders (12 weeks, p < 0.01). Survival was not longer (p <.05) in responding patients (CR + PR + S) receiving Actinomycin‐D + Levamisole (35 weeks) compared to those responding to Actinomycin‐D alone (18 weeks, p = 0.09). Hematologic toxicity was tolerable with median lowest granulocyte counts of 1.6 × 103/μ1 and platelet counts of 134,000/μ1. Other toxic effects were predominantly nausea, vomiting, and mucositis. In those patients who received alternate day Levamisole there was greater gastrointestinal upset as well as fever, rash and central nervous system toxicity which was unacceptable.

Metabolism and Disposition of Baker's Antifolate (NSC-139105), Ftorafur (NSC-148958), and Dichlorallyl Lawsone (NSC-126771) in Man

(1978). Metabolism and Disposition of Bakers Antifolate (NSC-139105), Ftorafur (NSC-148958), and Dichlorallyl Lawsone (NSC-126771) in Man. Drug Metabolism Reviews: Vol. 8, No. 1, pp. 137-150.

Clinical pharmacology of the anticancer polypeptide neocarzinostatin.

SummaryThe clinical pharmacology of the anticancer polypeptide neocarzinostatin was studied in 16 patients with disseminated neoplasia using a radioimmunoassay technique. Patients who received 2,400–3,600 U of the drug per square meter BSA by rapid IV infusion had triphasic plasma decay curves. For eight patients with normal hepatic and renal function, neocarzinostatin mean plasma half-lives were 0.14, 0.50, and 7.7h. The mean plasma drug clearance was 32.4 ml/min/m2 and the apparent volume of distribution 19.3l/m2. Two patients with liver dysfunction had shorter terminal plasma half-lives and greater drug clearances, while two with renal disease exhibited prolonged plasma half-lives and reduced drug clearances. The mean cumulative urinary excretion of neocarzinostatin was 69.1% of the administered dose at 72 h in three patients with normal hepatic and renal function. One patient with liver disease excreted 90.4%, while a patient with renal disease excreted only 58.1% of the dose in 24 h. In one patient with marked liver disease, biliary excretion accounted for 0.1% of the administered dose in 72 h. Cerebrospinal fluid concentrations of neocarzinostatin studied in two patients showed a CSF penetration of about 16% the plasma concentration at 1–5 h; concentrations persisted for 19 h in one patient with an Omayha reservoir. Neocarzinostatin was rapidly cleared from the plasma and eliminated in the urine. Dosage reductions of 50% are recommended for patients with impaired renal function, while no reduction or escalated doses could be tolerated by patients with liver disease. The pharmacologic data suggest a continuous IV infusion may be a more toxic but perhaps more effective schedule of administration.

Clinical, toxicological, and pharmacological studies of combination chemotherapy of adenocarcinoma with Adriamycin and Baker's Antifolate

SummaryTen patients with disseminated adenocarcinoma were treated with combination chemotherapy employing Adriamycin and Bakers Antifolate (BAF). There were seven patients with lung adenocarcinoma, two of whom achieved partial remission while the remaining five had their disease stabilized. Drug toxicity to the bone marrow, gastrointestinal mucosa, and skin was dose-limiting and was greater than the known toxicities of the individual drugs. Pharmacological studies of both drugs were performed on five patients to determine whether abnormal pharmacokinetics could explain this collateral toxicity. Adriamycin plasma concentrations and disappearance seemed to be unaffected by BAF. However, BAF levels were prolonged, apparently due to an Adriamycin effect on the plasma elimination of BAF, resulting in a prolonged exposure of sensitive tissues and organs to BAF. Consequently, when BAF and Adriamycin are used in combination, appropriate dose and schedule changes must be made to avoid any potentially serious side effects.