A randomized trial comparing adjuvant fluorouracil, doxorubicin, and mitomycin with no treatment in operable gastric cancer. International Collaborative Cancer Group.

Three hundred fifteen patients with operable gastric cancer were randomized to receive fluorouracil, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and mitomycin (FAM) or no adjuvant treatment between September 1981 and July 1984. After excluding ineligible patients, 281 patients are included in this analysis. Treatment was moderately well tolerated by the majority of patients, the common side effects being nausea and vomiting (58%) and alopecia (57%). Three possible treatment-related deaths were seen, all due to cardiac failure. At median follow-up of 68 months, 164 patients have died, 73 in the treated arm and 91 in the control arm. There was no significant difference in disease-free or overall survival between the two arms of the study (P = 0.21). There is some evidence that patients with more advanced carcinoma (T3-T4) derived some benefit from treatment (P = 0.04). The interpretation of this finding must take into account that all subgroups were defined retrospectively, and this could, therefore, be a chance finding. We conclude that adjuvant chemotherapy as given in this trial is not indicated as routine treatment in operable gastric cancer, but that further evaluation in stage T3-T4 patients is warranted.

6-[Bis(2-chloroethyl)amino]-6-deoxygalactopyranose hydrochloride (C6-galactose mustard), a new alkylating agent with reduced bone marrow toxicity.

We have previously reported that chloroethyl nitrosourea and nitrogen mustard bone marrow toxicity can be selectively reduced by placement of the cytotoxic group on specific positions of a glucose molecule. We have now synthesized and evaluated a new drug in which the mustard cytotoxic group is attached to the carbon-6 position of galactose (C6-GLM). C6-GLM, administered i.p. as a single 10% lethal dose of 15.5 mg/kg, produced a 121% increase in life span (ILS) in mice bearing the ascitic P388 leukemia, compared to a 60% ILS with a 10% lethal dose of nitrogen mustard (P less than 0.01). A single p.o. dose of C6-GLM, 16 mg/kg, produced an ILS of 58%. Against i.p.-implanted B-16 melanoma, i.p. C6-GLM produced a 56% ILS compared to 30% with an equitoxic dose of nitrogen mustard (P less than 0.01). The activity of the two drugs for Ehrlich ascites was comparable, with 60% survivors with the galactose mustard. A single 10% lethal dose of C6-GLM reduced the white blood cells to 74% of control; circulating granulocytes remained at 91% of initial values. With nitrogen mustard, the nadir white blood cell count was 57% of control with an absolute granulocyte count of 70% of initial values (P less than 0.01). The toxicity of melphalan was considerably greater, with a lower and more protracted while blood cell nadir and an absolute neutrophil count nadir of 49% of control. These findings paralleled the relative decrements in bone marrow DNA synthesis produced by the three drugs. Measurement of human bone marrow granulocyte-macrophage colony-forming units, following in vitro exposure to graded concentrations of the three mustards, confirmed the bone marrow sparing properties of C6-GLM. At the highest concentration, 1 X 10(-2) mM, the latter drug produced only a 33% reduction in colonies compared to a 75% reduction with nitrogen mustard and a virtual elimination of activity of colony-forming units with melphalan. The demonstration of antitumor activity, at least equivalent to nitrogen mustard, without the necessity of significant bone marrow toxicity supports the development of C6-GLM for clinical trials in humans.

The role of chemotherapy in the management of gastric and pancreatic carcinomas.

Gastric and pancreatic carcinomas are important worldwide health problems, typically diagnosed late in the disease process when symptoms of pain and weight loss signify the presence of locally advanced or metastatic tumor. During the past decade, new regimens of combination chemotherapy have, in general, produced increased response rates for patients with advanced gastric cancer, with evidence of improved survival in several controlled trials. For patients with locally advanced gastric cancer, combined-modality therapy has resulted in long-term survival for approximately 15% of cases. The role of adjuvant therapy is now being defined in several randomized control trials of doxorubicin-based chemotherapy regimens. The position of combination chemotherapy for advanced pancreatic carcinoma is less well defined, but present data favor a regimen of streptozotocin, mitomycin-C, and 5-fluorouracil. Combined-modality therapy has resulted in modest improvements in disease-free survival for patients with locally advanced and resected tumors. The search for more effective drugs for gastrointestinal cancer represents the highest priority in the development of treatment strategies for this important group of tumors.

Current management of advanced and locally unresectable gastric carcinoma.

Gastric cancer is the most chemotherapy-responsive adenocarcinoma of the major gastrointestinal sites. For patients with advanced disease, the response rates and survival achieved with recently designed Adriamycin-based regimens represent an improvement over the past use of 5-fluourouracil alone or combined with a chloroethylnitrosourea. Effective palliative treatment can be administered in an out-patient setting without the necessity of producing severe or life-threatening toxicity. Nevertheless, response durations are finite, as is patient survival. It is essential that Phase II trials of new drugs be continued in an attempt to identify agents with greater therapeutic activity for this disease. For the locally unresectable stage, combined modality therapy incorporating palliative resection of the primary tumor, regional radiation therapy and chemotherapy, has provided long-term disease-free survival for 15--25% of all patients. The most promising aspect of current clinical investigation is the application of the Adriamycin-based drug combinations in controlled trials of surgical adjuvant therapy.

Preclinical and clinical studies on chlorozotocin, a new nitrosourea with decreased bone marrow toxicity.

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.

Cachexia of malignancy: potential role of insulin in nutritional management.

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.

Chemotherapy of large intestinal carcinoma. Current results and future prospects.

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.

Pancreatic cholera: beneficial effects of treatment with streptozotocin.

Two patients with pancreatic cholera and islet-cell carcinoma were treated with intra-arterial streptozotocin. Before therapy, they had stool volumes from 2 to 8 liters per day and required 200 to 800 mEq per day of supplemental potassium. After three to five doses of streptozotocin (1.5 per square meter), both stool volume and number and size of hepatic metastases decreased markedly. One patient has had normally formed stools for 12 months; the other had a 90 per cent reduction in stool volume for 13 months with additional therapy. Both patients' serum potassium returned to normal without need for supplementation. Jejunal adenylate cyclase activity was normal in both, and plasma vasoactive intestinal peptide was detectable in only one. After chemotherapy, these findings showed no consistent change. Pharmacologic studies suggest that arterial administration increased either tumor or hepatic extraction (or both) of streptozotocin by two times and decreased renal exposure to this nephrotoxic drug by one third.