Preoperative chemoradiation for adenocarcinoma of the pancreas: excessive toxicity of prophylactic hepatic irradiation.

PURPOSE: In an effort to reduce relapse in the liver and improve survival in patients with potentially resectable adenocarcinoma of the pancreatic head, we combined whole-liver irradiation with our standard preoperative chemoradiation regimen. METHODS AND MATERIALS: Eleven patients with biopsy-proven, potentially resectable adenocarcinoma of the pancreatic head were treated with 50.4 Gy of external beam irradiation to the pancreas (1.8 Gy/day, 5 days/week) and concurrent continuous infusion 5-fluorouracil (300 mg/m2 per day). The liver was treated with 23.4 Gy on Days 8 through 21 (13 fractions; 1.8 Gy/fraction). Patients, who upon restaging with radiography and computed tomography were considered to have resectable tumors, were subsequently taken to surgery. If, at surgery, tumors were resectable, pancreaticoduodenectomy was performed, and 10 Gy of intraoperative electron-beam radiation therapy was delivered to the bed of the resected pancreas. RESULTS: All 11 patients completed chemoradiation. Two treatment-related deaths occurred following chemoradiation, prompting premature termination of the study. Of seven patients taken to surgery, four underwent resection. Seven patients have died of disease, five with liver metastases. CONCLUSIONS: Prophylactic hepatic chemoradiation, as given in this study, was associated with two treatment-related deaths and a higher than expected incidence of subsequent liver metastases. Our data do not support the use of this treatment program in patients with adenocarcinoma of the pancreas.

Rapid-fractionation pre-operative chemoradiation for malignant periampullary neoplasms.

The multimodality treatment of adenocarcinoma of the pancreatic head has been shown to improve survival compared with surgery alone. The delivery of chemotherapy and radiation therapy (chemoradiation) before rather than after pancreaticoduodenectomy ensures that all patients who undergo surgery receive the other components of multimodality therapy. In an effort to reduce overall treatment time and cost, the use of rapid-fractionation preoperative chemoradiation was explored. Radiation therapy was delivered with 18-MeV photons to a total dose of 30 Gy given in 10 fractions over 2 weeks. 5-Fluorouracil was given concurrently by continuous infusion at a dose of 300 mg m-2 day-1. Four weeks after the completion of chemoradiation, patients underwent pancreaticoduodenectomy and electron-beam intraoperative radiation therapy (10 Gy). All patients completed the treatment programme without delay. The rapid-fractionation programme was delivered at nearly half the cost of standard chemoradiation and histologic evidence of tumour cell injury was present in all resected specimens. There were no perioperative anastomotic complications, and median hospital stay was 20 days. Rapid-fractionation chemoradiation warrants further study in the neoadjuvant setting.

Preoperative infusional chemoradiation therapy for stage T3 rectal cancer.

PURPOSE: To evaluate preoperative infusional chemoradiation for patients with operable rectal cancer. METHODS AND MATERIALS: Preoperative chemoradiation therapy using infusional 5-fluorouracil (5-FU), (300 mg/m2/day) together with daily irradiation (45 Gy/25 fractions/5 weeks) was administered to 77 patients with clinically Stage T3 rectal cancer. Endoscopic ultrasound confirmed the digital rectal exam in 63 patients. Surgery was performed approximately 6 weeks after the completion of chemoradiation therapy and included 25 abdominoperineal resections and 52 anal-sphincter-preserving procedures. RESULTS: Posttreatment tumor stages were T1-2, N0 in 35%, T3 N0 in 25%, and T1-3, N1 in 11%; 29% had no evidence of tumor. Local tumor control after chemoradiation was seen in 96% (74 out of 77); 2 patients had recurrent disease at the anastomosis site and were treated successfully with abdominoperineal resection. Overall, pelvic control was obtained in 99% (76 out of 77). The survival after chemoradiation was higher in patients without node involvement than in those having node involvement (p = n.s.). More patients with pathologic complete responses or only microscopic foci survived than did patients who had gross residual tumor (p = 0.07). The actuarial survival rate was 83% at 3 years; the median follow-up was 27 months, with a range of 3 to 68 months. Acute, perioperative, and late complications were not more numerous or more severe with chemoradiation therapy than with traditional radiation therapy (XRT) alone. CONCLUSIONS: Excellent treatment response allowed two-thirds of the patients to have an anal-sphincter-sparing procedure. Gross residual disease in the resected specimen indicates a poor prognosis, and therapies specifically targeting these patients may improve survival further.

5-Fluorouracil-radiation interactions in human colon adenocarcinoma cells.

PURPOSE: To determine the effect of cellular proliferation and cell cycle stage on the ability of postirradiation 5-fluorouracil (5-FU) to radiosensitize cultured human colon adenocarcinoma Clone A cells. METHODS AND MATERIALS: Cell survival curves were generated for irradiated: (a) log- and plateau-phase Clone A cells; and (b) Clone A cells separated by centrifugal elutriation into the various phases of the cell cycle; with and without postirradiation treatment with 100 micrograms/ml 5-FU. RESULTS: Postirradiation treatment with 5-FU sensitized proliferating cells to a greater degree than it sensitized cells growing in plateau phase. The beta component of cell kill in log-phase cells was increased by a factor of 1.5 with a sensitizer enhancement ratio of 1.21 at the 0.01 survival level. Plateau-phase cells showed less radiosensitization (sensitizer enhancement ratio of 1.13 at the 0.01 survival level); however, there was a mild increase in both alpha and beta kill in plateau-phase cells. Elutriated G1 cells were the most radiosensitive, independent of treatment with 5-FU. The phase of the cell cycle had little effect on the ability of fluorouracil to radiosensitize Clone A cells. CONCLUSION: Proliferating cells are more susceptible to radiosensitization with 5-FU than plateau-phase cells are, but this effect appears to be independent of the phase of the cell cycle.

Effects of successive unilateral ablations of principalis cortex upon performances of delayed alternation and delayed response by monkeys.

Monkeys were trained on delayed alternation (DA), and were then subjected to serial unilateral or simultaneous bilateral ablations of the banks of the sulcus principalis of each frontal lobe. When subjects with unilateral lesions were retrained on DA, their performances were intermediate to those of normal and bilateral animals. This interoperative training failed to protect the serially operated monkeys from losses of DA following their second-stage ablations, for they then performed as poorly as one-stage subjects and subjects prepared with serial ablations that were not given practice on the task between the two operations. Additional postoperative tests of delayed responding (DR) showed that both serially and simultaneously ablated subjects also had severe impairments of performance of DR. This result confirmed, in principle, a finding that monkeys with large unilateral ablations, if reoperated after many months for the removal of the contralateral dorsolateral perfrontal cortex, will thereafter exhibit DR deficits that are both severe and endure for a period of years. It contrasted sharply with a recent observation that DR is retained by monkeys subjected to two-stage symmetrical ablations of the principalis cortex, which suggests that recoveries of frontal-lobe functions are powerfully affected by the orders in which serial extirpations are performed.