Macdonald, J. S.

4515 Background: INT0116 (SWOG 9008) was a prospectively randomized phase III trial of postoperative adjuvant therapy utilizing 5-FU/leucovorin plus external beam radiation in 582 eligible cases of resected stage IB-IV(M0) stomach and gastroesophageal junction cancers. Initial results (NEJM 345: 725, 2001) showed both overall and disease free survivals improved by chemoradiation. Methods:We now report INT0116 results with >10years median follow-up. Exploratory subset outcomes are also reported. Results: INT0116 continues to show benefit for chemoradiation with hazard ratios (HR) for survival (HR=1.32, p=.004) and disease free survival (HR=1.51, p<.001) favoring chemoradiation. Subset analyses were performed for sex, race, T and N stage, D-level of surgical resection, tumor location (proximal or other), histology (intestinal or diffuse) and Maruyama index. Chemoradiation benefited all subsets with the exceptions of women and diffuse histology. In women the HR for therapy was 1.0(0.68–1.45). The HR for therapy in diffuse histology cases was 0.97(0.62–1.40). Interaction between these factors is suggested as women were significantly more likely to have diffuse histology than men (56% versus 33%). A multivariate analysis of sex and histology did not detect an effect of sex once histology was included. These data suggest that sex may not be an independent variable for lack of response to chemoradiation but that diffuse histology may be. Long term toxicities were examined. Thirty-five second tumors occurred in 31 cases. Twenty-two occurred in chemoradiation cases and 9 in surgery only cases. Second tumors represented a spectrum of types of neoplasms commonly occurring in this age group (median age 60 years). Excessive numbers of tumors known to be caused by radiation and/or chemotherapy were not noted. More tumors may have occurred in the treated patients since their death rates were less than surgery only cases. Conclusions: With >10 years median follow-up, survival remains improved in stage IB-IV (M0) gastric cancer cases treated with post-operative chemoradiaiton. All subsets benefit from this treatment with the exception of cases with diffuse histology. Women may be more likely to have diffuse histology gastric cancers. No increases in late toxic effects were noted. No significant financial relationships to disclose.

4006 Background: Lymph node (LN) metastasis is associated with decreased survival in rectal cancer. It has been suggested that at least 14 LN be evaluated for adequate staging. However, a large percentage of patients have fewer than the recommended number of LN examined. We hypothesized that LN ratio would be predictive of overall survival in rectal cancer. Methods: Data was analyzed from Intergroup 0114, a mature trial of postoperative adjuvant chemotherapy and radiation in T3/4 and/or LN positive rectal cancer. Survival was the same for all arms allowing the entire group to be considered as one. The primary endpoint evaluated was overall survival. A proportional hazards model was used to determine the relative prognostic impact of LN ratio compared to number of LN examined, number of positive LN, number of negative LN and AJCC nodal stage. LN ratio was defined as the number of positive LN divided by the total number of LN examined. Four groups were analyzed based on proportion of positive LN: =0.25, >0.25–0.50, >0.50–0.75 and >0.75. Results: 1,648 patients were evaluable. There were 251 T1/2, 1,251 T3 and 146 T4 tumors. 513 patients were N0, 743 N1 and 392 N2. Median number of LN was 9. LN ratio was predictive of 5-year overall survival with rates of 0.71, 0.56, 0.50 and 0.43 respectively when analyzed by quartile (p<0.0001). LN ratio remained significant when overall survival was analyzed by number of LN examined and grouped into <10, <15 and >15 nodes evaluated (p<0.0001 for all). LN ratio also predicted overall survival in N1 (p=0.04) and N2 (p=0.0002) disease. When comparing LN ratio (χ2=79.5, p<0.0001) to number of LN examined (χ2=4.7, p=0.03), number of positive LN (χ2=38, p<0.0001), number of negative LN (χ2=32, p<0.0001) and AJCC nodal stage (χ2=55.5, p<0.0001), LN ratio appears to be the strongest predictor of overall survival. Conclusion: LN ratio predicts overall survival in patients with resected rectal cancer. Importantly, this is true in patients who have had a small number of LN evaluated, in addition to those with a large number of LN examined. LN ratio also appears to be a stronger predictor of overall survival than other described LN prognostic factors. LN ratio may be a useful variable to stratify outcome in patients with node-positive rectal cancer. No significant financial relationships to disclose.

PURPOSE: The gastrointestinal Intergroup studied postoperative adjuvant chemotherapy and radiation therapy in patients with T3/4 and N+ rectal cancer after potentially curative surgery to try to improve chemotherapy and to determine the risk of systemic and local failure. PATIENTS AND METHODS: All patients had a potentially curative surgical resection and were treated with two cycles of chemotherapy followed by chemoradiation therapy and two additional cycles of chemotherapy. Chemotherapy regimens were bolus fluorouracil (5-FU), 5-FU and leucovorin, 5-FU and levamisole, and 5-FU, leucovorin, and levamisole. Pelvic irradiation was given to a dose of 45 Gy to the whole pelvis and a boost to 50.4 to 54 Gy. RESULTS: One thousand six hundred ninety-five patients were entered and fully assessable, with a median follow-up of 7.4 years. There was no difference in overall survival (OS) or disease-free survival (DFS) by drug regimen. DFS and OS decreased between years 5 and 7 (from 54% to 50% and 64% to 56%, respectively), although recurrence-free rates had only a small decrease. The local recurrence rate was 14% (9% in low-risk [T1 to N2+] and 18% in high-risk patients [T3N+, T4N]). Overall, 7-year survival rates were 70% and 45% for the low-risk and high-risk groups, respectively. Males had a poorer overall survival rate than females. CONCLUSION: There is no advantage to leucovorin- or levamisole-containing regimens over bolus 5-FU alone in the adjuvant treatment of rectal cancer when combined with irradiation. Local and distant recurrence rates are still high, especially in T3N+ and T4 patients, even with full adjuvant chemoradiation therapy.