During the first three years of this grant, the applicant began testing the hypothesis that the outcome for high-risk patients (pts) with local regional gastric cancer can be improved by intensive pre- and postoperative (postop) adjuvant chemotherapy, given both systemically and intraperitoneally (IP). High-risk (T3-T4) pts are identified by endoscopic ultrasound cisplatin-FU postop. The clinical trial has accrued 56 evaluable pts, and is completed. Tolerance to preop therapy has been demonstrated; the curative resection rate of 61 percent in T3/T4 pts compares favorably with that of similar T3/T4 pts seen concurrently who did not receive neoadjuvant therapy (35 percent). Postop chemotherapy has been tolerable, but IP FU-cisplatin has been cumbersome. The preliminary survival distribution curve is encouraging. On the basis of new data available from a random assignment trial in advanced disease, and in preparation for the next national Intergroup trial, the applicant plans to test a new preoperative regimen of cisplatin and fluorouracil followed by operation, followed by intraperitoneal FUdR-leucovorin (a regimen which is less toxic and easier to deliver). As part of this study, a quality of life assessment will be made both for study pts and for non-study pts undergoing surgery alone. This investigational approach will then be proposed as the experimental area of the next national intergroup trial. The applicant has compared EUS predicted tumor stage and thickness with pathologic proven TNM and tumor thickness. In contrast to its accuracy in pts not previously exposed to chemotherapy, EUS appears to be significantly less useful in predicting T and N stage in treated pts. EUS-predicted tumor thickness has only a moderate correlation with pathologically confirmed measurements, suggesting it will, be of limited use in measuring response to chemotherapy. The applicant will now evaluate laparoscopy with laparoscopic guided ultrasound to stage pts and predict outcome, when compared to EUS. Correlative laboratory studies have focused on invasion and metastases and on molecular biological studies in both chemotherapy-treated and untreated pts. Human gastric cancer cell lines have been established and characterized. Mutations of the p53 suppressor gene decreased response to chemotherapy in gastric cancer cell lines. The applicant will now correlate the presence of mutated p53 with clinical outcome in patients receiving pre and postoperative chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA056125-05
Application #
2517566
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1991-09-30
Project End
1999-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
5
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Lydiatt, W M; Davidson, B J; Schantz, S P et al. (1998) 9p21 deletion correlates with recurrence in head and neck cancer. Head Neck 20:113-8
Kelsen, D; Karpeh, M; Schwartz, G et al. (1996) Neoadjuvant therapy of high-risk gastric cancer: a phase II trial of preoperative FAMTX and postoperative intraperitoneal fluorouracil-cisplatin plus intravenous fluorouracil. J Clin Oncol 14:1818-28
Davidson, B J; Lydiatt, W M; Abate, M P et al. (1996) Cyclin D1 abnormalities and tobacco exposure in head and neck squamous cell carcinoma. Head Neck 18:512-21
Lydiatt, W M; Murty, V V; Davidson, B J et al. (1995) Homozygous deletions and loss of expression of the CDKN2 gene occur frequently in head and neck squamous cell carcinoma cell lines but infrequently in primary tumors. Genes Chromosomes Cancer 13:94-8
Murty, V V; Li, R G; Mathew, S et al. (1994) Replication error-type genetic instability at 1q42-43 in human male germ cell tumors. Cancer Res 54:3983-5
Mathew, S; Murty, V V; Bosl, G J et al. (1994) Loss of heterozygosity identifies multiple sites of allelic deletions on chromosome 1 in human male germ cell tumors. Cancer Res 54:6265-9
Mitra, A B; Murty, V V; Pratap, M et al. (1994) ERBB2 (HER2/neu) oncogene is frequently amplified in squamous cell carcinoma of the uterine cervix. Cancer Res 54:637-9
Christman, K; Saltz, L; Schwartz, G et al. (1993) Granulocyte colony-stimulating factor: effective in ameliorating fluorouracil-based myelosuppression? J Natl Cancer Inst 85:826-7
Rao, P H; Mathew, S; Lauwers, G et al. (1993) Interphase cytogenetics of gastric and esophageal adenocarcinomas. Diagn Mol Pathol 2:264-8