Chemotherapy of gastrointestinal cancer.
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Biomedical subjects
Publications and source records attributed to C G Moertel.
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Fifty-four patients from the surgical gastroenterology service and 22 healthy controls have been prospectively evaluated in a single-blind protocol by the LAI tube method. The LAI correctly identified 25 of 33 early colorectal patients staged as Dukes' B and C at surgery but none of the Dukes' D patients. An inverse relationship was seen between the results of the non-adherence index (NAI) and CEA levels which was most pronounced in those with advanced colorectal cancer. The majority of Dukes' B and C patients having a "false negative" LAI had a CEA level greater than 2.5 ng/ml, suggesting that more advanced disease than that seen at surgery may be present. Two of 22 normal controls gave a borderline positive NAI. Some technical problems, including the relatively short life of the tumor extracts, are discussed.
Serum carcinoembryonic antigen (CEA) tests were performed on 36 patients with histologically proved locally recurrent or residual malignant disease after resection of colorectal carcinoma but with no clinical evidence of distant metastasis. Only nine patients (25%) had abnormal CEA levels of greater than 5 ng/ml despite the fact that most patients had had symptoms of recurrence for several months. Among the nine of our patients, none had CEA values greater than 5 ng/ml, and only three had levels greater than 2.5 ng/ml (3.4, 3.8, and 4.7 ng/ml). The CEA assay is not a sensitive test for early detection of recurrence of colorectal carcinoma.
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Sixty-six patients with advanced pancreatic carcinoma were randomized to receive single agent chemotherapy with either adriamycin, methotrexate, or actinomycin-D using conventional dose, route and schedule of administration. All patients had measurable lesions which were used to objective assessment of response. For adriamycin, 2 of 25 patients (8%) evidenced a partial response (2 of 15 (13%) previously untreated patients). One of 25 patients treated with methotrexate and one of 28 received actinomycin-D responded. The duration of responses ranged from 43-64 days for those patients with no chemotherapy prior to study entry. The median survival of patients who received adriamycin as initial treatment was 12 weeks compared to 8 weeks for methotrexate and 6 weeks for actinomycin-D therapy.
One hundred and sixty-eight patients with unresectable primary liver cancer were prospectively studied by members of the Eastern Cooperative Oncology Group. These patients were randomized to receive treatment with oral 5-Fluorouracil (5FU), oral 5-Fu plus Streptozotocin, oral 5-Fu plus Methyl-CCNU or Adriamycin. The single agent treatments (oral 5-Fu and Adriamycin) were associated with less gastrointestinal toxicity than were the oral 5-Fu treatment combinations. A total of 15 partial responses were reported. Adriamycin appears to be the most active agent and responsible for 9 of the 15 responses. No response was seen in any of the 48 patients randomized to oral 5-Fu alone. The survival associated with oral 5-Fu alone was significantly shorter than the survival time associated with the remaining 3 treatment programs among both North American and South African patients. A multivariate model of survival was formulated. Covariates of prognostic significance were treatment, initial performance status and sex. South African black patients had a shorter survival time than North American black patients. Excluding oral 5-Fu from consideration, prognostic variables appeared to dominate any differences between the remaining treatments under study.
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The uptake and storage of 5-hydroxytryptamine by human platelets from normal donors and patients with the carcinoid syndrome are reported. When platelets were incubated in the presence of 3H-5-hydroxytryptamine (50 microM), an initial phase of rapid uptake was observed until 5-hydroxytryptamine levels of 1--2 microgram/10(9) cells were reached. Further accumulation occurred more slowly. Electron microscopic autoradiography of cells after 5-hydroxytryptamine uptake for 60 minutes revealed that in platelets from normal donors most of the label was localized in membranes (52%), alpha granules (27%), and cytoplasm (4%). Dense bodies were associated with 18% of the silver grains. Similar membrane (50%) and alpha-granule (27%) labeling was found with platelets from patients with carcinoid syndrome. However, more cytoplasmic labeling (10%) and less dense-body labeling (11%) were found with these cells. The results support a hypothesis of two or more sites for storage of 5-hydroxytryptamine in mammalian platelets and suggest that minimal exchange between cytoplasmic and dense-body amines occurs in carcinoid platelets.
Maytansine, an ansa macrolide, was evaluated in an early clinical trial in 40 adult patients with various solid tumors. Severe nausea and vomiting, sometimes associated with watery diarrhea and abdominal cramps, and liver function abnormalities, mainly elevation of serum glutamic--oxaloacetic transaminase levels, together constituted what we considered dose-limiting toxicity. Mild hematologic toxicity (mainly thrombocytopenia), neurotoxicity, and possibly cardiac toxicity were also noted. No antitumor effect was seen. An iv dose of 0.750 mg/m2 on days 1, 3, and 5 (total dose, 2.25 mg/m2) repeated every 4 weeks is recommended for Phase II trials.
Serial carcinoembryonic antigen (CEA) measurements were evaluated in a group of 263 patients undergoing systemic chemotherapy for metastatic colorectal carcinoma. Initial CEA levels were not found to be of value in predicting the likelihood of subsequent tumor response. Although a general relation between serial CEA measurements and clinical tumor measurements was noted, these measurements were discordant in a substantial proportion of patients. Tumor measurements as an index of response to therapy were strongly correlated with survival, whereas changes in CEA values and patient survival were not correlated at a statistically significant level. Serial CEA measurements were perhaps of some value in predicting progression of malignant disease, and were roughly comparable to serum alkaline phosphatase assay in assessing response of liver metastasis to chemotherapy. Overall, serial CEA measurements added little to the standard clinical assessment of patients with advanced colorectal carcinoma receiving chemotherapy.
Thirty-two patients with advanced carcinoma of the colon or rectum were given metronidazole orally at a dose of 500-1000 mg/m2 three times a day for 7 consecutive days every 6 weeks. The dose-limiting toxic effects consisted of severe nausea, vomiting, and major motor seizures. Mild peripheral neurotoxic effects were also noted. No objective responses were noted in any of the 32 patients treated. High-dose metronidazole would not seem to have any role in the treatment of advanced colorectal carcinoma and may cause serious neurotoxicity.
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To assess the fate and efficacy of orally ingested enzymes in pancreatic insufficiency, we administered pancreatin to six patients by two schedules--eight tablets with a standard meal or two tablets hourly--and in six normal controls, quantified duodenal enzyme activity and related inactiviation of ingested enzymes to gastric and duodenal pH; in the six patients we measured malabsorption by fecal balance studies. Postprandially, gastric pH was similar in health and pancreatic insufficiency, and below 4 after 40 minutes. Duodenal pH in pancreatic insufficiency declined to approximately 4 beyond 100 minutes--lower than in health (P less than 0.05). Approximately 22 per cent and 8 per cent of trypsin and lipase activity ingested with either schedule was delivered to the ligament of Treitz. Prandial was as effective as hourly administration in decreasing steatorrhea and perhaps more effective in abolishing azotorrhea, and since it is also more convenient, we recommend it.
Triazinate (Baker's Antifol, NSC 139105) was given to 28 patients as a single agent in the chemotherapy of advanced colerectal carcinoma. The dosage utilized was 250 mg/m2 intravenously, administered daily in three consecutive days. Patients were evaluated at three weeks, six weeks, and then monthly until progression was evident. Various immunologic determinants (i.e., DNCB sensitization, immunoglobulins, recall skin tests, lymphocyte blastogenesis, and circulating lymphocytes, T-cells and B-cells) were obtained prior to treatment and at each re-evaluation. The principal side effects were dermatitis, stomatitis, diarrhea, nausea, somnolence, and leukopenia. There was no discernable effect of Triazinate on the immunologic determinants tested. There was one complete response, and four partial responses, for an objective regression rate of 18%. This study suggests that Triazinate has a definite, though limited, effect on advanced colorectal carcinoma.
One hundred and sixteen patients with advanced and metastatic adenocarcinoma of the pancreas were randomized to treatment with combined Streptozotocin and 5-fluorouracil or combined Streptozotocin and cyclophosphamide. Toxic reactions to each regimen were qualitatively similar and consisted of nausea and vomiting during the time of treatment and subsequent leukopenia and thrombocytopenia. Renal toxicity was less frequent and only rarely severe. Among 51 eligible and evaluable patients treated with the Streptozotocin-cyclophosphamide combination, 12% showed objective response and among 42 patients treated with Streptozotocin + 5-fluorouracil, 12% showed objective response. The Streptozotocin + 5-fluorouracil-treated patients showed a slight advantage in survival. Neither regimen can be considered of substantive value to the patient with advanced pancreatic carcinoma.
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We undertook to test the recent suggestion that measurement of immunoreactive carcinoembryonic antigen (CEA) in pancreatic secretion may be useful in diagnosis of pancreatic cancer. Using duodenal intubation and a perfusion method in 57 cases, we measured the rate of pancreatic CEA secretion into the duodenum under basal saline perfusion, alone and with continuous intravenous infusion of secretin (2 clinical units per kg per hr) and of cholecystokinin-pancreozymin (CCK, 15 Crick-Harper-Raper units per kg per hr); and we compared the CEA output with secretion of trypsin, lipase, and bicarbonate under the same conditions. Subsequent laparotomy revealed pancreatic carcinoma in 25 patients, pancreatitis in 7, other intraabdominal malignancies in 6, and benign nonpancreatic disorders in 19. CEA output rates did not differentiate all pancreatic-cancer patients from other patients in any test condition. However, pancreatic enzyme outputs were abnormal with almost 90% of cancers of the pancreatic head and with 75% of cancers of the pancreatic body and tail. For detection of pancreatic cancer, enzyme and bicarbonate outputs in response to CCK are more accurate than pancreatic CEA or bicarbonate outputs in response to secretin. Since CCK-stimulated enzyme outputs can be related accurately to malabsorption (not reported here), we prefer them to bicarbonate output for assessment of pancreatic function.