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Two of 200 patients treated with chlorozotocin have evidenced interstitial pulmonary disease. The cumulative doses of chlorozotocin were 480 and 670 mg/m2 when symptoms developed. Pulmonary function tests in both patients showed impaired diffusion, and an alveolar-arterial gradient which worsened with exercise. Open-lung biopsy in one patient showed typical interstitial inflammation and early fibrosis, and excluded lymphangitic spread of tumor. Discontinuation of chlorozotocin resulted in either improvement or stabilization of the pulmonary disease.

An in vitro cell free assay system to measure phosphorylated products of 5-Fluorouracil is described. Total phosphorylated products and mono-, di and triphosphates of 5-Fluorouracil are measured along with the rate of fluorodeoxyuridylate generation. This assay has been applied to ten murine tumors and eight biopsy specimens from human breast adenocarcinomas. Phosphorylation patterns have been examined in murine tumors demonstrating in vivo sensitivity or resistance to 5-Fluorouracil. There are distinct differences in the patterns of phosphorylation between sensitive and resistant tumors. In a 5-Fluorouracil sensitive murine tumor, mono-, di and triphosphates are produced. In a resistant tumor only monosphophates are produced. Cell free supernatants from human breast tumors produce less total phosphorylation than murine tumors and some specimens produce only monophosphates whereas others produce mono-, di and triphosphates. Human tumors are in general more efficient producers of fluorodeoxyuridylate than murine tumors. These data suggest that resistance to 5-Fluorouracil may correlate with decreased concentration of di and triphosphates of 5-Fluorouracil in some murine tumors. Further experiences is required to demonstrate the value of this easily performed assay system in predicting clinical response to 5-Fluorouracil in man.

A consensus Development Conference was held at the National Institutes of Health from September 29-October 1, 1980, to address issues concerning the role of carcinoembryonic antigen (CEA) as a marker in the management of cancer. The panel met following formal presentations and discussions to assess the issues based on the evidence presented. These issues included: Should CEA be used in cancer screening? Is CEA helpful in cancer diagnosis? What does CEA tell about the extent and outcome of cancer? Is CEA helpful in monitoring cancer treatment? This paper constitutes the panel's findings.

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.

1-(2-Chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea (NSC 95466) is a lipid-soluble nitrosourea that is presently undergoing clinical evaluation. In this Phase I study, the toxicity of this drug was examined after administration of the drug to cancer patients on 3 successive days every 6 to 8 weeks. Clinical pharmacology was studied using 1-[chloroethyl-14C](2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea. The dose-limiting toxicity was myelosuppression. The maximal tolerated dose was 105 mg/sq m, which produced a median platelet nadir of 40,000/microliter on Day 32 and a median white blood cell count nadir of 2200/microliter on Day 42. Progressive anemia was also observed. There was no evidence of acute or chronic hepatic, renal, or pulmonary damage. One patient with a metastatic hypernephroma exhibited a partial clinical remission. Plasma disappearance of the drug following bolus administration was biphasic, with an initial half-life of 18 to 25 min and a second half-life of 9 hr. Clearance of intact drug coincided largely with the initial disappearance phase of total radioactivity. Entry of radioactivity into the cerebrospinal fluid was observed. Approximately 35% of plasma radioactivity was protein bound, the major binder being albumin. Drug excretion was predominantly renal, and biliary elimination was only minor.

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.

We have treated 11 patients having a variety of tumor types and three patients having mitomycin-C-associated thrombotic thrombocytopenic purpura (TTP) with extracorporeal plasma perfusion through filters containing immobilized protein A from Staphylococcus aureus. In performing more than 140 procedures we observed only minimal toxicity, of which fever, chills, nausea, and vomiting were the most common symptoms, occurring in 25% of the patients. Significant decrease in blood pressure and bronchospasm were rare complications. However, none of these side effects were severe enough to require therapeutic intervention. The antitumor effect of immunoperfusion was modest. In 10 adequately treated patients there was one measurable tumor reduction (40% decrease of original tumor mass). Two patients had correction of total small bowel obstruction, with return to normal food intake and restoration of normal bowel habits, lasting for 6 and 3 months; and two of the two adequately treated TTP patients had dramatic hematological improvement after four and five immunoperfusion treatments and are well at present. We found direct correlation between extent of complement activation and clinical toxicity. By temperature manipulation of the perfusion procedure we were able to control the above-mentioned side effects caused by complement activation.

Chlorozotocin is a glucose-substituted chloroethyl nitrosourea with pharmacologic properties suggesting it is a relatively nonmyelosuppressive cancer chemotherapy drug. Preclinical studies have shown that this drug possesses approximately twice the in vitro alkylating activity of the chloroethyl nitrosoureas BCNU and CCNU. In the L1210 leukemia system, chlorozotocin has curative activity at doses that result in minimal bone marrow toxicity. In vitro studies of human bond marrow stem cells have shown that chlorozotocin is relatively sparing of these cells compared to BCNU. Phase I and phase II trials in man have been performed that show that chlorozotocin's dose-limiting toxicity is thrombocytopenia at doses greater than 120 mg/m2. In the phase II trial, 16% of patients with colon cancer and 20% of patients with malignant melanoma evidenced objective regression of disease. Chlorozotocin is now undergoing phase II evaluation in combination chemotherapy trials in colon and stomach cancer.