1. Identification of localized rectal cancer (RC) patients (pts) who may NOT require preoperative (preop) chemoradiation (CRT). D. Roda 1, M. Frasson 2, E. García-Granero 2, S. Roselló 1, B. Flor 2, E. Rodríguez 1, P. Esclapez 2, S. Campos 3, S. García- Botello 2, A. Cervantes 1. Department of Hematology Medical Oncology1, Colorectal Unit, Department of Surgery2, INCLIVA, University of Valencia, Valencia, Spain. Abstract # 50936

2. Abstract Background: Preop CRT is becoming the standard of care for patients with locally advanced RC. However, since the introduction of total mesorectal excision (TME), local recurrence rates are significantly reduced and some pts can be spared from a potentially toxic overtreatment. Preop staging with magnetic resonance imaging (MRI) and/or endorectal ultrasonography (ERUS) may help in selecting pts for preop CRT. This retrospective study was designed to assess factors predicting recurrence in an institutional series of RC pts with clinical stage T2N+, T3N0/+, treated by radical surgery without preop CRT. Methods: Between Nov 1997 to Nov 2008, our multidisciplinary group staged preop 398 RC patients by ERUS and/or MRI. We selected for this analysis 154 consecutive pts, having uT2N+, uT3N0, and uT3N+ rc, who didn’t get preop CRT. Macroscopical assessment of mesorectal excision and microscopic study of all circumferential resection margins (CRM) was determined. Factors potentially related with local recurrence (LR), Disease free survival (DFS) and overall survival (OS) were studied. Results: Median follow-up was 34 months (range, 18 to 68,2 months). LR rate was 8.5%, and 5-year DFS and OS were respectively 64.5% and 75.4% for the whole group. Threatened mesorectal fascia at preop staging, defined as tumor located at < 2 mm, was seen in 19 patients and was the most powerful single factor to predict a higher risk for LR, shorter DFS and worse OS. Other factors such as preop N+ or location of the tumor did not predict the risk of LR. Conclusions: Threatening of mesorectal fascia as defined preoperative by US or MRI, was the only significant factor predicting LR as well as worse DFS and OS. RC pts clinically staged as T3N0/+ or T2N+ > 2 mm away from mesorectal fascia could be treated with TME alone with a risk of LR of less than 5%, and overtreatment with preop CRT could be avoided. Abstract # 50936

3. Background Preop CRT is becoming the standard of care for patients with locally advanced RC. However, since the introduction of total mesorectal excision (TME), local recurrence rates are significantly reduced and some pts can be spared from a potentially toxic overtreatment. Preop staging with magnetic resonance imaging (MRI) and/or endorectal ultrasonography (ERUS) may help in selecting pts for TME surgery alone.

4. This retrospective study was designed to assess factors predicting local and overall recurrence in an institutional serie of RC pts with clinical stage T2N+, T3N0/+, treated by radical TME surgery without preoperative CRT. Purpose

5. Methods: Between Nov 1997 to Nov 2008, our multidisciplinary group staged preop 398 RC patients by ERUS and/or MRI in a single institution. We selected for this analysis 154 consecutive pts, having cT2N+, cT3N0, and cT3N+ RC, who didn’t get preop CRT. TME was performed in all patients. Standard pathologic analysis was performed on all resection specimens: macroscopical assessment of mesorectal excision and microscopic study of all circumferential resection margins (CRM) was determined.

6. Factors potentially related with local recurrence (LR), disease free survival (DFS) and overall survival (OS) were studied. Statistical analysis included  2 test for prognostic variables. Univariate analysis of survival were carried out by the Kaplan-Meier Method. A Cox multivariate survival analysis was performed with factors found to be statistically significant on the univariate analysis. Methods:

7. 398 RC pts evaluated with ERUS and/or MRI 350 pts with cT2N+ or cT3 rectal cancer cT1 :4 pts cT2N0 : 20 ptsc T4 : 24 pts 160 patients treated with preoperative CRT 190 pts operated without preoperative CRT 36 pts M1 154 pts with R0 or R1 resection Figure 1- Selection of patients

8. Median Age (range) 70 (38-90) Sex Male94 (61%) Female60 (39%) Tumor Location Upper rectum17 (11%) Medium rectum55 (35,7%) Lower rectum82 (53,2%) Preop staging Only ERUS77 (50,0%) Only MRI15 (9,74%) ERUS and MRI62 (40,26%) Preop CRM Free111 (72,1%) Threatened19 (12,3%) No Evaluable24 (15,6%) Surgical Procedure Miles' procedure42 (27,3%) Sphincter saving procedure112 (72,7%) Post-op Mortality 6 (3,9%) Quality mesorectum Complete77 (50,0%) Nearly Complete26 (16,88%) Incomplete9 (5,85%) Not evaluated42 (27,27%) Post-Op Therapy CT+RT3 (2%) CT34 (22,1%) Table 1. Patients characteristics

9. Results Median follow-up was 39 months (range, 18 to 152 months). 5-year actuarial LR rate, DFS OS9.5%64.5%75.4%For the whole group, 5-year actuarial LR rate, DFS and OS were 9.5% 64.5% and 75.4% respectively. Different preoperative factors were studied as predictors of recurrence : treatened vs free fascia preoperative nodal status surgery (Miles' procedure vs sphincter saving procedure) tumor location.

10. Results Threatened mesorectal fascia at preop staging, defined as tumor located at < 2 mm, was seen in 19 patients and was the most powerful single factor to predict a higher risk for LR, shorter DFS and worse OS. (fig 1 and 2).

11. Results Crude Rate (%) Hazard Ratio 95% CIP value Preoperative CRM Threatened or not evaluable vs. free fascia LR 21 vs. 4.5 7.21.9-270.004 DFS 63.1 vs.78.3 2.81.2-6.60.015 OS 73.6 vs. 86.4 3.21.1-8.90.025 Patological CRM Affected vs. free fascia LR 28.0 vs. 3.211.903.5-41.0<0.0001 DFS 40.0 vs 80.64,812.5-9-3<0.0001 OS 52.0 vs 89.75.422.5-11.7<0.0001 Patological N N+ vs N- LR 19.5 vs 3.43.921.0-14.00.04 DFS 54.7 vs 87.54.802.4-9.6<0.0001 OS 66.5 vs 93.26.152.4-15.1<0.0001 Table 3. Univariate analysis for LR, DFS, and OS Table 3. Univariate analysis for LR, DFS and OS. Pathological CRM and nodal status were studied as predictors of recurrence. In a univariate analysis both were significant predictors of LR, DFS and OS (Table 3).

12. Results Hazar d Ratio 95% CIP value Patological CRM Affected vs. free fascia LR9.6 2.39- 38.49 0.001 DFS2,61.32-5.340.006 OS2.541.11-5.80.027 Patological N N+ vs N- LR1.60.36-7.160.53 DFS3.91.79-8.480.001 OS5.57 1.94- 15.94 0.001 However, in a multivariate Cox regression analysis, only involved CRM resulted as an independent predictor of LR, while both were independent predictors of DFS and OS (Table 4). Table 4. Multivariate analysis for LR, DFS and OS.

13. pN- (n) pN+ (n) Total (n) Overstaged (%) Undesrtaged (%) Accuracy (%) cN-431255-21,878,2 cN+44509446,8-53,2 cNx325--- Total906415428,67,860,4 Results Table 2. Preoperative N staging vs Pathologic N examination

14. Threatening of mesorectal fascia as defined preoperatively by ERUS or MRI, was the only preop significant factor predicting higher risk for LR as well as worse DFS and OS. RC pts clinically staged as T3N0/+ or T2N+ > 2 mm away from mesorectal fascia could be treated with TME alone with a risk of LR of less than 5%, and overtreatment with preop CRT could be avoided. To improve accuracy of preop staging may help in better selection of RC patients preoperative treatment. Conclusions: