) Locally advanced pancreatic and gastric cancers are usually incurable and rapidly fatal. Although there is some treatment benefit when 5-FU is added as a radiosensitizer to radiation therapy, more effective treatment is urgently needed. The feasibility of using Taxol as a radiation sensitizer in vivo to treat aggressive, locally advanced neoplasms has been intensively studied by the Clinical Oncology Group of Rhode Island (COGRI). High response rates and acceptable toxicity have been achieved for over 160 patients treated with Taxol plus concurrent radiation (Taxol/RT) in COGRI protocols for nonsmall cell lung carcinoma (NSCLC) and glioblastoma. In vitro data suggests that Taxol may be a radiation sensitizer for pancreatic cancer and the applicants preliminary clinical data suggests that Taxol/RT has substantial activity against locally advanced gastric cancer. Furthermore, this combined treatment modality has been well tolerated by the first 10 patients treated with Taxol and upper abdominal radiation. Therefore, the applicants propose to undertake a phase I study to determine the maximally tolerated dose (MTD) of Taxol in conjunction with upper abdominal radiation for locally advanced gastric and pancreatic cancer. Molecular genetic alterations that disturb cell cycle regulation in tumor cells can affect their response to chemotherapeutic agents and radiation. Taxol blocks cells at G2M, the most radiosensitive phase of the cell cycle. Many of the genes which regulate critical cell cycle checkpoints are altered in human tumors. The p53 tumor suppressor gene serves a critical role at the G1S transition, where it can either block entry into S phase or activate programmed cell death (apoptosis) in response to DNA damage. p53 gene mutations interfere with the activation of apoptosis in response to radiation and most chemotherapeutic agents. Recent evidence suggests that Taxol is unique in its ability to activate apoptosis in tumor cells with p53 mutations. The pl6 (MTS-1) gene product acts in the same pathway as p53 to inhibit cell cycle progression at G1S. pl6 is deleted and/or mutated in a significant fraction of human tumors including 50 percent of pancreatic adenocarcinomas and these changes may alter response to therapeutic interventions as well. These findings suggest that alterations in the p53 and pl6 genes may interact with Taxol/RT to modify treatment response. The applicant proposes to prospectively evaluate p53 and pl6 gene alterations in tumor tissue derived from patients treated with Taxol/RT for gastric and pancreatic carcinoma to gather preliminary data to test this hypothesis. These studies are the essential basis for a planned phase II trial to measure the therapeutic efficacy of Taxol/RT for locally advanced gastric and pancreatic adenocarcinoma and determine whether treatment response is modulated by specific genetic mutations that alter cell cycle control.
| Safran, H; Akerman, P; Cioffi, W et al. (1999) Paclitaxel and concurrent radiation therapy for locally advanced adenocarcinomas of the pancreas, stomach, and gastroesophageal junction. Semin Radiat Oncol 9:53-7 |
| Safran, H; King, T P; Choy, H et al. (1997) Paclitaxel and concurrent radiation for locally advanced pancreatic and gastric cancer: a phase I study. J Clin Oncol 15:901-7 |
| Sikov, W M; Safran, H (1997) Weekly paclitaxel as a radiation sensitizer for locally advanced gastric and pancreatic cancers: the Brown University Oncology Group experience. Front Biosci 2:e21-7 |
