Clinical experience with chronomodulated infusional 5-fluorouracil chemoradiotherapy for pancreatic adenocarcinoma.

PURPOSE: To evaluate retrospectively the efficacy and chronic toxicities of concurrent radiotherapy and chronomodulated infusion 5-fluorouracil (5-FU) in patients with pancreatic adenocarcinoma. METHODS AND MATERIALS: Twenty-eight patients with pancreatic adenocarcinoma were treated between January 1997 and May 2000 with 5-FU chronomodulated chemoradiotherapy. Chronomodulated delivery of chemotherapy was chosen on the basis of a lower toxicity profile in the treatment of GI malignancies. The median age was 64 years. Of the 28 patients, 12 were men and 16 were women. Eight patients had unresectable disease and 20 were treated after pancreatic resection. The median radiation dose was 50.4 Gy given in 28 fractions. The median field length and width was 10.6 cm and 10.9 cm, respectively. Concurrent chemotherapy with 5-FU was administered 5 d/wk, with a median total dose of 8.4 g/m2 (300 mg/m2/d). Chronomodulated 5-FU delivery consisted of a low basal infusion for 16 h followed by an 8-h escalating-deescalating infusion peaking at 10 pm. Survival and recurrence data were evaluated using Kaplan-Meier actuarial analysis. Toxicities were recorded using the Radiation Therapy Oncology Group grading system. RESULTS: The median follow-up for all patients was 26 months (range, 4-68 months). The median overall survival for the 20 patients treated postoperatively was 34 months, with a 3- and 5-year actuarial survival rate of 40% and 21%, respectively. If the 3 patients with carcinoma of the ampulla were removed from the data set, the mean overall survival in the resected patients was 34 months, with a 3-year and 5-year actuarial survival rate of 40% and 17%, respectively. The 8 unresectable patients had a median overall survival of 14 months, and none lived past 2 years. No patient experienced Grade 3 or 4 hematologic toxicity or weight loss. Five patients had nausea and dehydration requiring i.v. fluids; only one (4%) was hospitalized. Four patients required a dose reduction of 5-FU, one for nausea, one for a transient ischemic attack, one for an infection, and one because of myocardial infarction. Seven resected patients, four of whom had no evidence of disease, developed diabetes mellitus 1-2 years after radiotherapy. CONCLUSION: Chronomodulated 5-FU administration, based on the concept of chronotolerance, has relatively low acute toxicity. Our median survival rate was greater than that after most chemoradiotherapy programs that result in more acute toxicity. Additional study is warranted to evaluate chronomodulated radiosensitizing chemotherapy schedules in prospective trials and with attention to late effects after radiotherapy, including diabetes mellitus.

Four decades of continuing innovation with fluorouracil: current and future approaches to fluorouracil chemoradiation therapy.

PURPOSE: Chemoradiotherapy, the combination of external radiation therapy and concurrent chemotherapy, has been the basis for the oncologic management of many patients since its development in the 1960s. Fluorouracil (FU) chemoradiotherapy has demonstrated success in several organ sites with multiple dosing schedules that now guide the selection of oral analogs of FU to provide new chemoradiotherapy options. METHODS: This article reviews the metabolism and pharmacology of FU and the advantages of administration of FU by continuous infusion or bolus. The potential role and impact of the oral fluorouracil prodrugs UFT, S-1, BOF-A2, and capecitabine as replacements for intravenous administration are discussed. The results of recent chemoradiotherapy studies with FU from 2000 to 2003 are summarized in rectal, head and neck, esophageal, gastric, pancreatic, biliary, anal, and cervical cancers. RESULTS: Chemoradiotherapy with FU has the potential to widen the therapeutic window by minimizing normal tissue toxicity while maintaining effective tumor toxicity. Overall, FU chemoradiotherapy maximizes local control and, for some tumor sites (such as head and neck, pancreatic, biliary, cervical, esophageal, and gastric cancers), improves survival rates. Moreover, FU chemoradiotherapy results in improved organ preservation with excellent functional outcome in several anatomic sites including head and neck cancer, anal, and rectal cancer, with improved sphincter preservation. CONCLUSION: FU chemoradiotherapy continues to play an important role in the management of many cancer sites. During the last four decades, optimal dosing schedules have produced a therapeutic gain. The introduction of oral prodrug analogs will likely further improve the results of FU therapy in several organ systems, such as the rectum, head and neck, and esophagus.

Phase II study of gemcitabine in combination with docetaxel in patients with advanced pancreatic carcinoma (E1298). A trial of the eastern cooperative oncology group.

BACKGROUND: Responses have been observed in several studies of docetaxel as treatment for advanced pancreatic carcinoma. This trial was designed to determine if the addition of docetaxel to gemcitabine therapy produced responses in >/=25% of patients with chemonaive advanced pancreatic cancer. PATIENTS AND METHODS: This trial involved patients with biopsy-proven, advanced carcinoma of the pancreas not amenable to surgical resection. Patients received docetaxel 75 mg/m(2) i.v. over 1 h followed by gemcitabine 2,000 mg/m(2) biweekly until progression or intolerable toxicity. The primary endpoint of the trial was to determine the objective response rate with secondary endpoints of progression-free survival and overall survival. RESULTS: Out of the 32 eligible patients, 2 patients had a complete response and 2 patients had a partial response for an observed objective response rate of 12.5% (90% CI: 4.4, 26.4%). Median survival was 4.7 months. Most toxicities were hematologic, with 48% of patients experiencing grade 4 toxicity. CONCLUSIONS: The confirmed complete response rate of 6% and partial response rate of 6% is encouraging, but the toxicity of this regimen appears significant. Based upon these results, this combination of gemcitabine and docetaxel is not worthy of further study. Different schedules and dosages may be more promising.