Chemotherapy of advanced stages of large bowel cancer has until recently made little progress since the introduction of 5-FU 16 years ago. While survival is improved for patients who respond, 5-FU alone has made little impact on life span of the overall population of patients. Mitomycin-C and the chloroethyl nitrosourea antitumor agents, and in particular methyl-CCNU, have also demonstrated marginal activity in large bowel cancer. Two recently reported controlled clinical trials of combination chemotherapy have demonstrated response rates that are substantially better than those obtained with 5-FU alone; a 43% response rate in colorectal carcinoma has been reported using a combination of 5-FU, BCNU, vincristine, and DTIC, compared to a 25% response with 5-FU as a single agent; a 44% objective response rate with a combination of 5-FU, methyl-CCNU, and vincristine has been reported to be significantly better than 5-FU alone. 5-FU as an adjuvant following surgical resection with curative intent has not prevented tumor relapse; however, it is hoped that future studies employing more effective drug combinations will result in increased number of patients achieving disease free survival.

Thirty-three patients with renal cancer began treatment with human lymphoblastoid interferon (Wellferon) between August 1982 and February 1983. Interferon was administered as an i.m. injection at a dose of 5 X 10(6) units/sq m 3 times per week. Treatments were continued for at least 24 weeks in the absence of rapid disease progression or intolerable toxicity. Five patients demonstrated partial responses, which continued in two patients with durations of 239+ and 300+ days. Prolonged therapy was often required with a mean time to response of 99 days (22 to 190 days). Toxicity was substantial. Fever, chills, arthralgias, and myalgias occurred following most doses, but usually were well tolerated. Leukopenia and hepatic enzyme elevations were usually modest and always reversible. Dose-limiting side effects were progressive fatigue and anorexia which reversed within approximately 4 to 6 weeks after cessation of interferon therapy. There was no correlation between interferon levels, clinical toxicities, and response in this group of patients. We conclude that interferon has definite antitumor activity in renal cancer when given by this dose and schedule.

Twenty-three patients with advanced solid tumors received 9-hydroxy-2N-methyl-ellipticinium acetate at a single daily i.v. dose of 15–80 mg/m2 for 5 consecutive days, repeated every 3 weeks. One partial and one minor response were achieved in two patients with breast cancer. Dryness of the mouth was dose-related and dose-limiting. Local phlebitis was also dose-related and frequently severe at the highest dose levels. Other non-hematologic toxic effects were essentially mild to moderate and included nausea, vomiting, diarrhea, stomatitis, fever, weakness, transient renal and hepatic impairment, alopecia and chest pain. Minimal myelosuppression was encountered. It appears that 60 mg/m2/day is the maximum tolerated dose with a five-day schedule. According to our findings, this schedule does not seem to offer any advantage over the previously tested weekly administrations.

1,3,5-Triglycidyl-s-triazinetrione is a triepoxide derivative with attractive antitumor properties in mice. In this phase I trial, the drug was given as an i.v. infusion over 30 + min repeated every 2–3 weeks. The trial was initiated at a starting dose of 33 mg/m2 and doses were escalated up to 2,000 mg/m2. Local thrombophlebitis was dose-limiting and apparently dose-related. Other toxic effects were mild to moderate and consisted of nausea, vomiting, leukopenia and hair loss. More favorable formulations or schedules of administration are needed before testing this new agent in phase II trials.

Ametantrone is a new aminoanthraquinone derivative that achieves antitumor activity in a large variety of animal models. It is a dark blue dye. In this phase I study, the drug was given as a 30-min i.v. infusion repeated every 2–3 weeks. Nineteen patients were entered into the trial and received a total of 43 courses. All were adult patients with advanced solid tumors, mainly squamous cell carcinoma of the head and neck and nonsmall cell carcinoma of the lung. Sixteen had undergone prior chemotherapy; only one had not been previously treated. The trial was initiated at a starting dose of 10 g/m2 and dose levels were escalated up to 180 mg/m2. Leukopenia was dose-related, well predictable, rapidly reversible and dose-limiting. At 135 mg/m2, the median WBC nadir was 1800/mm3 (1000–4400) and the median PMN was 950/mm3 (460–2240). Among all courses, WBC nadir occurred on median day 12 (8–18) and recovery was seen on medianday 16 (10–29). Thrombocytopenia (< 100,000/mm3) was encountered in two courses. There was no evidence of cumulative myelosuppression with repeated courses. Non-hematological toxic effects were negligible and included stomatitis in one course, minor alopecia in three patients, and questionably drug-related orthostatic hypotension in three patients. Reversible blue skin discoloration was seen in five patients. All patients treated with ≧ 40 mg/m2 had dark blue urine for 2 or 3 days. Antitumor activity with response 50% could not be documented. Ametantrone appears to be very well tolerated and easy to handle. Its clinical anticancer potential remains to be determined. A dose-schedule of 135 mg/m2 q 2–3 weeks may be recommended for phase II studies in solid tumors.

Patients manifesting the syndrome of cachexia of malignancy exhibit an abnormal diabetic glucose tolerance. In our patients this has been correlated with a marked resistance to administered insulin, while insulin receptors on monocytes are normal. Lipolysis remains responsive to the effects of insulin. The oxidation of FFA, as a substrate for metabolism, has been reported to be increased, and the utilization of glucose as a metabolic fuel is reduced. Increased Cori cycle activity has been demonstrated, which produces an enhanced gluconeogenesis from lactate and amino acids; there is an expenditure of 6 ATP for the synthesis of each mole of glucose. An attempt to interrupt the Cori cycle in man, using hydrazine sulfate to inhibit the enzyme phosphoenolpyruvate carboxykinase, has not resulted in reproducible clinical benefit. However, successful treatment of the underlying tumor may produce a total reversal of the cachexia syndrome, suggesting that neoplasms have the potential to elaborate an, as yet, unidentified metabolic toxin. The use of insulin to counteract the reported abnormalities should be examined as a possible supportive measure in the total nutritional management of the cancer patient.

Nine patients with malignancy requiring chemotherapy were evaluated before, during, and in the recovery phase of their antineoplastic regimen with selected absorptive studies and jejunal biopsies. Depression of the crypt mitoses occurred without change in the indices of absorption. The mitotic indices returned to pretreatment counts on the recovery phase biopsies. Even after prolonged therapy, restudy in three of the patients failed to demonstrate clinical malabsorption. We conclude that chemotherapy-related malabsorption does not contribute to overall malnutrition of cancer patients during the first months of treatment.

Eighteen patients with advanced metastatic malignancy who had 21 pleural effusions requiring sclerosis for control were randomly allocated to intrapleural therapy with tetracycline or quinacrine. Tetracycline produced partial or complete control of the effusion in ten of 12 trials for a median duration of 6 months (range 1.5 to 22 months). Partial or complete control was obtained in nine of ten trials with quinacrine, for a median duration of 3 months (range 1 to 13 months). All complete responders who died achieved control of their effusions until their terminal admissions despite clinical evidence of overt systemic tumor progression in the intervening period. Single-dose tetracycline therapy was accompanied by less fever (p less than 0.04) and less pleuritic pain (p = 0.09) than quinacrine. Tetracycline is effective, well tolerated, easily administered, and should be considered as the initial therapy for malignant pleural effusions requiring pleural sclerosis.