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      Well-Differentiated Pancreatic Nonfunctioning Tumors/Carcinoma

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          Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma.

          The combination of streptozocin and fluorouracil has become the standard therapy for advanced islet-cell carcinoma. However, doxorubicin has also been shown to be active against this type of tumor, as has chlorozotocin, a drug that is structurally similar to streptozocin but less frequently causes vomiting. In this multicenter trial, we randomly assigned 105 patients with advanced islet-cell carcinoma to receive one of three treatment regimens: streptozocin plus fluorouracil, streptozocin plus doxorubicin, or chlorozotocin alone. The 31 patients in whom the disease did not respond to treatment were crossed over to chlorozotocin alone or to one of the combination regimens. Streptozocin plus doxorubicin was superior to streptozocin plus fluorouracil in terms of the rate of tumor regression, measured objectively (69 percent vs. 45 percent, P = 0.05), and the length of time to tumor progression (median, 20 vs. 6.9 months; P = 0.001). Streptozocin plus doxorubicin also had a significant advantage in terms of survival (median, 2.2 vs. 1.4 years; P = 0.004) that was accentuated when we considered long-term survival (greater than 2 years). Chlorozotocin alone produced a 30 percent regression rate, with the length of time to tumor progression and the survival time equivalent to those observed with streptozocin plus fluorouracil. Crossover therapy after the failure of either chlorozotocin alone or one of the combination regimens produced an overall response rate of only 17 percent, and the responses were transient. Toxic reactions to all regimens included vomiting, which was least severe with chlorozotocin; hematologic depression; and, with long-term therapy, renal insufficiency. The combination of streptozocin and doxorubicin is superior to the current standard regimen of streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. Chlorozotocin alone is similar in efficacy to streptozocin plus fluorouracil, but it produces fewer gastrointestinal side effects than the regimens containing streptozocin. It therefore merits study as a constituent of combination drug regimens.
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            Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas.

            The role of systemic chemotherapy in the management of pancreatic endocrine carcinoma (islet cell carcinoma; PEC) is an area of considerable controversy. Response rates ranging from 6% to 69% have been reported for streptozocin-based chemotherapy. We retrospectively studied 84 patients with locally advanced or metastatic PEC who had been treated with fluorouracil, doxorubicin, and streptozocin (FAS) to determine the objective response rate, duration of progression-free survival (PFS), and duration of overall survival (OS). Eligible patients had histologic or cytologic confirmation of their tumor and measurable disease on computed tomography or magnetic resonance imaging scans. Response to treatment was evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors Committee. Sixty-one of the patients were male and 23 were female, with a median age of 54 years (range, 24 to 78 years). The response rate (RR) to FAS was 39%, with a median response duration of 9.3 months. The 2-year PFS rate was 41%, and the 2-year OS rate was 74%. The extent of liver metastatic disease correlated with a worse PFS (P = .01 by log-rank test) and a worse OS (P < .0001 by log-rank test). Analyses showed that metastatic replacement of more than 75% of the liver and prior chemotherapy were independently associated with inferior PFS. Patients with locally advanced or metastatic PEC who are treated with FAS may have a reasonable RR, and responders may experience longer PFS and OS. The volume of metastases in the liver is the most important predictor of outcome.
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              Surgical treatment of neuroendocrine metastases to the liver: a plea for resection to increase survival.

              Hepatic metastases from neuroendocrine tumors have a protracted natural history and are associated with endocrinopathies. Resection is indicated for symptom control. Previous reports have suggested improvement in survival for patients undergoing debulking procedures. The records of all consecutive patients undergoing resection of hepatic metastases from neuroendocrine tumors between 1977 and 1998 were reviewed. Tumors were classified according to histology, endocrine activity, and primary location. Patients lost to followup before 1 year were excluded. Followups were based on outpatient evaluations and were updated by correspondence. The Kaplan-Meier method was used to generate survival and recurrence curves, and the log-rank test was used for comparison. A total of 170 patients fulfilled the inclusion criteria, of whom 73 were men. Mean age (+/-SD) was 57 (+/-11.5) years. Carcinoid (n = 120) and nonfunctioning islet cell tumors (n = 18) predominated; the ileum (n = 85) and the pancreas (n = 52) were the most common primary sites. Major hepatectomy (one or more lobes) was performed in 91 patients (54%). The postoperative complication rate was 14%, and two patients died (1.2%). Operation controlled symptoms in 104 of 108 patients, but the recurrence rate at 5 years was 59%. Operation decreased 5-hydroxyindoleacetic acid levels considerably, and no patient experienced carcinoid heart disease postoperatively. Recurrence rate was 84% at 5 years. Overall survival was 61% and 35% at 5 and 10 years, respectively, with no difference between carcinoid and islet cell tumors. Hepatic resection for metastatic neuroendocrine tumors is safe and achieves symptom control in most patients. Debulking extends survival, although recurrence is expected. Hepatic resection is justified by its effects on survival and quality of life.

                Author and article information

                S. Karger AG
                February 2007
                23 February 2007
                : 84
                : 3
                : 196-211
                Departments of aSurgery and bRadiology, University of Verona, Verona, Italy; cDepartment of Internal Medicine, Charité, University of Berlin, Berlin, Germany; dDepartment of Nuclear Medicine, University of Rotterdam, Rotterdam, The Netherlands; eM. Körner, University of Bern, Institut für Pathologie, Bern, Switzerland; fDepartment of Oncology, South Florida University, Tampa, Fla., USA; gDepartment of Internal Medicine, Charité, University of Berlin, Berlin, Germany; hDepartment of Radiology, Charité Universitätsmedizin, Berlin, Germany; iDepartment of Surgery, Städtisches Klinikum Neuss, Lukas Hospital, Neuss, Germany; jDepartment of Surgery, Zürich Hospital, Zürich, Switzerland; kDepartment of Surgery, Vivantes Humboldt Hospital, Berlin, Germany; lDepartment of Endocrine Oncology, University of Uppsala, Uppsala, Sweden; mDepartment of Pathology, University of Lyon, Lyon, France
                98012 Neuroendocrinology 2006;84:196–211
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 4, References: 171, Pages: 16
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