Gunderson, Leonard L.

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.

4009 Background: An ∼65% 5-year disease-free-survival (DFS) rate from 5-FU/mitomycin/radiation for anal carcinoma needs improvement. Methods: A phase III randomized trial compared 5-FU (1,000mg/m2 days 1–4 and 29–32) plus mitomycin (10mg/m2 days 1 and 29) and radiation (45 to 59 Gy) (Arm A) to 5-FU (1,000mg/m2 days 1–4, 29–32, 57–60 and 85–88) plus cisplatin (75mg/m2 on days 1, 29, 57 and 85) and radiation (45 to 59 Gy; start day=57) (Arm B) in anal carcinoma patients. Stratification included gender, clinical N status and tumor diameter. Primary endpoint was DFS. Statistical power was 80% with two-sided test to detect 10% DFS increase for Arm B. Results: Of 682 patients accrued, 598 were analyzable. Most unanalyzed patients’ data are early. Patient characteristics were balanced. Median age was 55 years, women predominated (69%), 27.5% had >5 cm tumor diameter and 26% had clinically N+ cancer. Preliminary 5-year estimated DFS was 56% for Arm A and 48% for Arm B (p=0.28) and 5-year estimated overall survival was 69% for both arms (p=0.24). Men(p=0.04), clinically N+ cancer (p<0.0001) and tumor diameter >5 cm (p=0.005) independently prognosticated DFS in a multivariate analysis. 5-year colostomy rate was 10% for Arm A and 20% for arm B(p=0.12). Grade 3/4 toxicity rates: non-hematologic=76% for Arm A and 75% for Arm B but hematologic=67% for Arm A and 47% for Arm B(p=0.0004). Conclusions: In Intergroup-98–11, induction 5-FU/cisplatin followed by 5-FU/cisplatin/radiation failed to improve DFS compared to the standard treatment, 5-FU/mitomycin/radiation. Supported by RTOG U10 CA21661, CCOP U10 CA37422, Stat U10 CA32115. No significant financial relationships to disclose.

Purpose This brief report describes a planned, interim, 6-patient toxicity analysis that confirms the safety of pemetrexed, carboplatin, radiation with subsequent surgery, as prescribed in the North Central Cancer Treatment Group trial N044E, in patients with locally advanced esophageal cancer. Methods Six patients with locally advanced, potentially resectable esophageal cancer received pemetrexed 500 mg/m 2 and carboplatin AUC = 6 on days 1 and 22 with 5040 centigray of concomitant radiation in 28 fractions over 5.5 weeks followed by esophagectomy as a prelude to a phase II multi-institutional trial. Results Only 1 of the 6 patients experienced a grade 4 adverse event (neutropenia). This patient also experienced a grade 3 depression. Of the remaining 5 patients, three experienced at least one grade 3 adverse event (neutropenia, nausea/vomiting, and esophagitis). There were no deaths. Incidentally, one patient manifested a complete pathologic response, three a partial pathologic response, and one stable disease. Conclusion These preliminary observations on safety suggest that this regimen can be further studied in this clinical setting.

All but the earliest cases of nonmetastatic gastric cancer represent a therapeutic challenge given the high propensity of these patients to develop locoregional and distant relapse. Neoadjuvant or adjuvant strategies that include chemoradiotherapy or chemotherapy have been associated with significant toxicity, but also improvement in patient survival. Technologic advances in the planning and delivery of radiotherapy (RT) have enabled significant progress in the accuracy and conformality of radiation treatment. Four-dimensional CT and image-guided RT improve the accuracy of radiation treatment. Three-dimensional RT and intensity-modulated RT allow increased conformality of radiation dose distribution, sparing of normal organs, and providing opportunity for dose escalation. Initial clinical experience with these technologies shows favorable tolerance and outcomes.

PURPOSE: We postulated that the pathologic evaluation of the lymph nodes of surgical specimens from patients with rectal cancer can have a substantial impact on time to relapse and survival. PATIENTS AND METHODS: We analyzed data from 1,664 patients with T3, T4, or node-positive rectal cancer treated in a national intergroup trial of adjuvant therapy with chemotherapy and radiation therapy. Associations between the number of lymph nodes found by the pathologist in the surgical specimen and the time to relapse and survival outcomes were investigated. RESULTS: Patients were divided into groups by nodal status and the corresponding quartiles of numbers of nodes examined. The number of nodes examined was significantly associated with time to relapse and survival among patients who were node-negative. For the first through fourth quartiles, the 5-year relapse rates were 0.37, 0.34, 0.26, and 0.19 (P = .003), and the 5-year survival rates were 0.68, 0.73, 0.72, and 0.82 (P = .02). No significant differences were found by quartiles among patients determined to be node-positive. We propose that observed differences are primarily related to the incorrect determination of nodal status in node-negative patients. Approximately 14 nodes need to be studied to define nodal status accurately. CONCLUSION: These results suggest that the pathologic assessment of lymph nodes in surgical specimens is often inaccurate and that examining greater number of nodes increases the likelihood of proper staging. Some patients who might benefit from adjuvant therapy are misclassified as node-negative due to incomplete sampling of lymph nodes.

327 Background: The use of preoperative therapy for pancreatic cancer remains controversial. This study reviews our experience using neoadjuvant chemotherapy and chemoradiation (CRT) followed by surgery with intraoperative electron irradiation (IOERT) for patients with borderline resectable (BR) or unresectable (UR) tumors. Methods: A retrospective review identified 48 patients (pts) with primary BR/UR pancreas adenocarcinoma treated with preop CRT with intent to proceed to curative surgery with IOERT. Seventeen patients did not undergo attempted resection and are excluded (disease progression, 12; medically inoperable, 3; declined surgery, 2). Thirty-one patients proceeded to resection attempt and are the subject of this analysis. Kaplan-Meier survival analysis was performed using log rank test for significance. Median follow up was 19 months (mo). Results: Complete resection (R0) was achieved in 11 pts, R1 in 5, and R2 or not resected (IOERT alone) in 15 patients. Twenty-six pts died (23 of disease, 2 unrelated causes, 1 uncertain). Median overall survival (OS) was 19 mo for all pts. Local progression was detected in only 5 patients (16%) while distant disease developed in 24 (77%). Resection status significantly correlated with OS; R0/R1 patients had a median survival of 23 mo vs. 10 mo for R2/unresected tumors (p = 0.002). Three-year OS was 35% vs. 0%, respectively. Survival was not influenced by tumor location, CA19-9 baseline or response, tumor size, or initial judgment of resectability (BR vs. UR). BR tumors were resectable after neoadjuvant therapy in 9 of 11 patients (R0, 8; R1, 1) while 8 of 20 initially UR tumors underwent resection (R0, 3; R1, 4; R2, 1). Conclusions: Neoadjuvant therapy combined with IOERT has the possibility to improve patient selection for surgical resection and to optimize local therapy. Although the prognosis for locally advanced pancreatic cancer remains poor, survival was superior among patients for whom R0 or R1 resection was achieved. Distant metastasis remained the dominant pattern of failure, and novel systemic agents are needed. Prospective evaluation of the impact of neoadjuvant chemotherapy, CRT, and IOERT is warranted.

367 Background: On initial publication of GI Intergroup RTOG 98-11, concurrent chemoradiation with 5FU+mitomycin (MMC) decreased colostomy failure (CF) vs induction plus concurrent 5FU+cisplatin (CDDP), but did not significantly impact disease free or overall survival (DFS, OS). The intent of the current analysis is to determine the long-term impact of treatment on survival (DFS, OS, colostomy-free [CFS]), CF and relapse (local-regional [LRF], distant [DM]) in this patient group. Methods: Stratification factors included gender, clinical node status, and primary size. DFS/OS were estimated univariately by Kaplan-Meier method and treatment arms compared by log-rank test. Time to relapse/CF were estimated by cumulative incidence method and treatment arms compared by Gray's test. Multivariate analyses were done with Cox proportional hazard models to test for treatment differences, adjusting for stratification factors. Results: Of 682 patients accrued, 649 were analyzable for outcomes. As seen in the table, 5-yr DFS and OS were statistically better for RT+5FU/MMC vs RT+5FU/CDDP (67.7 v 57.6%, p=.0.0045; 78.2 v 70.5%, p=0.021) with trends toward statistical significance for CFS, LRF, and CF (71.8 v 64.9%, p=0.053; 20 v 26.5%, 11.9 v 17.3%, p=0.092 and 0.075). Similar results were seen in multivariate analysis. Conclusions: Concurrent chemoradiation with 5FU-MMC has a statistically significant impact on DFS and OS vs induction + concurrent 5FU-CDDP and borderline significance for CFS, CF and LRF. Therefore, RT+5FU/MMC remains the preferred standard of care. Potential strategies to improve outcomes include treatment intensification and individualized molecular-based treatment. Supported by RTOG grant U10 CA21661 and CCOP grant U10 CA37422 from the National Cancer Institute (NCI). [Table: see text] No significant financial relationships to disclose.