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160 Background: ICARuS is a randomized phase II, multicenter trial to evaluate the relative efficacy of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with mitomycin C vs. Early Postoperative Intraperitoneal Chemotherapy (EPIC) with floxuridine (FUDR), after cytoreductive surgery (CRS), for the treatment of peritoneal metastases (PM) from colorectal (CRC) or appendiceal cancer (AC). PRODIGE7 results failed to demonstrate benefit of HIPEC therapy after complete gross resection of CRC PM, prompting termination of CRC accrual and early cohort analysis. Methods: Patients with isolated, confirmed PM were eligible for 1:1 randomization to CRS plus HIPEC with mitomycin C or CRS plus EPIC with FUDR. Patients were stratified by recent systemic chemotherapy and disease (AC vs. CRC). The trial was originally powered to evaluate 212 patients for a 20% gain in a primary endpoint of 3-year progression free survival (PFS: HR = 1.75). Results: Seventy-five CRC patients were included between 4/2013 and 12/2018 for HIPEC (N = 40) or EPIC (N = 35) treatment. Baseline characteristics were well balanced. After a median follow up of 36 months, the median PFS was 7.7 months (95% CI: 6.3-11.1) in the HIPEC arm and 8.8 months (95% CI: 7.1-21.9) in the EPIC arm, HR = 0.69 (95% CI: 0.42-1.14) p = 0.14. In the 42 left-sided primary cancers, the median PFS was 8.4 months (95% CI: 6.4-17.7) in the HIPEC arm and 12.5 months (95% CI: 8.1-NR) in the EPIC arm, HR = 0.60 (95% CI: 0.29-1.22) p = 0.14. In the 33 right-sided primary cancers, the median PFS was 6.5 months (95% CI: 5.5-14.1) in the HIPEC arm and 8 months (95% CI: 5.8-24.1) in the EPIC arm, HR = 0.80 (95% CI: 0.39-1.64) p = 0.53. PFS was significantly better in the EPIC arm among patients with BRAF wildtype (WT) tumors and patients with higher PM burden (PCI > 7). There was no difference between HIPEC and EPIC in the primary toxicity endpoint of complications grade 3 or above (23 vs. 34%, p = 0.3). Conclusions: Three-year PFS did not significantly differ between treatment arms. The lack of survival benefit of HIPEC in the entire cohort and in subset analysis is consistent with the findings of PRODIGE7. ICARuS remains open to accrual for AC. These data support further investigation of the potential benefit of EPIC with CRS in carefully selected patients with CRC PM. Clinical trial information: NCT01815359 .

14 Background: Surgical margins following rectal cancer resection impact oncologic outcomes and may reflect adequacy of care. We examined the relationship between race, ethnicity, or region of care with margin positivity following rectal cancer resection. Methods: We queried the National Cancer Database (NCDB) for patients diagnosed with stage II-IV rectal cancer between 2004-2018 who underwent surgical resection and excluded patients with missing data for race/ethnicity and radiation therapy/surgery status, and/or who had local excision only. We performed a propensity-score analysis via inverse probability of treatment weighting (IPTW) of margin positivity rate as outcome and race/ethnicity and region as predictors of interest. We controlled for age, sex, Charlson-Deyo Score, pathologic stage, pathologic grade, time from diagnosis to surgical resection, surgery type, sequence of radiation and surgery, facility type, insurance type, level of education, distance between patient and facility, and region of the United States. Results: Our query yielded 73,269 patients. Median patient age was 63 (IQR: 54-72) years and 40% were female. 81%,8%, 6%, and 5% were non-Hispanic White, non-Hispanic Black, Hispanic, and non-Hispanic Other, respectively. After IPTW adjustment, non-Hispanic Black patients had 19% higher odds of margin positivity relative to non-Hispanic White patients (OR: 1.185, 95% CI: 1.094-1.284; p

754 Background: Timing of surgery following completion of neoadjuvant therapy (NT) for locally advanced rectal cancer (LARC) has important implications for treatment response. However, it was recently reported in the GRECCAR 6 trial that delayed surgery beyond 8 weeks from completion of NT is associated with increased complications. Within a cohort of LARC patients treated with NT (CRT alone, Total NT (TNT) and chemotherapy alone) we examine perioperative complications based on time from NT to surgery. Methods: Patients with Stage II/III LARC ≤15cm from the anal verge who received NT from 06/01/09 – 03/01/15 were identified and preoperative morbidity collected on those undergoing rectal resection. Patients were grouped according to time of surgery from completion of NT (5-8 weeks – early surgery / 8-12 weeks – late surgery). Results: 798 patients were identified and 547 underwent rectal resection within 12 weeks of completing NT (440 LAR and 107 APR). Surgery was performed 5-8 following NT in 252 pts and 8-12 weeks following NT in 246 pts. 204 patients (41%) had a post-op complication: 53 (10%) Grade 3-5 complication and 83 (17%) SSI. There were no statistically significant differences in rates of all complications (44% vs 38%), grade 3-5 complications (9% vs 11%), SSI (17% vs 17%), and LOS (median 6 days vs 6 days) between the early and late surgery groups. Similar results were obtained when evaluating the subgroups by type of NT (CRT alone, chemo alone or TNT), surgical approach (open vs minimally invasive and sphincter preservation vs colostomy), post-treatment TNM stage and year of treatment (all NS). In addition, we did not observe differences in rates of downstaging responses: T downstaging (63% vs 64%), N downstaging (61% vs 54%), > 95% regression (34% vs 34%) or pCR rates (18% vs 18%) between the early and later surgery groups. Conclusions: In patients undergoing radical surgery for LARC post NT, we do not observe an effect of timing of surgery on surgical complications. Although timing of surgery is reported to influence response rates, we did not reproduce these findings, likely as a consequence of the high rate of deferral of surgery/ non-operative management in this cohort.

Purpose The purpose of this study was to describe the frequency of interventions necessary to palliate the intact primary tumor in patients who present with synchronous, stage IV colorectal cancer (CRC) and who receive up-front modern combination chemotherapy without prophylactic surgery. Patients and Methods By using a prospective institutional database, we identified 233 consecutive patients from 2000 through 2006 with synchronous metastatic CRC and an unresected primary tumor who received oxaliplatin- or irinotecan-based, triple-drug chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin; bolus fluorouracil, leucovorin, and irinotecan; or fluorouracil, leucovorin, and irinotecan) with or without bevacizumab as their initial treatment. The incidence of subsequent use of surgery, radiotherapy, and/or endoluminal stenting to manage primary tumor complications was recorded. Results Of 233 patients, 217 (93%) never required surgical palliation of their primary tumor. Sixteen patients (7%) required emergent surgery for primary tumor obstruction or perforation, 10 patients (4%) required nonoperative intervention (ie, stent or radiotherapy), and 213 (89%) never required any direct symptomatic management for their intact primary tumor. Of those 213 patients, 47 patients (20%) ultimately underwent elective colon resection at the time of metastasectomy, and eight patients (3%) underwent this resection during laparotomy for hepatic artery infusion pump placement. Use of bevacizumab, location of the primary tumor in the rectum, and metastatic disease burden were not associated with increased intervention rate. Conclusion Most patients with synchronous, stage IV CRC who receive up-front modern combination chemotherapy never require palliative surgery for their intact primary tumor. These data support the use of chemotherapy, without routine prophylactic resection, as the appropriate standard practice for patients with neither obstructed nor hemorrhaging primary colorectal tumors in the setting of metastatic disease.

Purpose After preoperative chemoradiotherapy of rectal cancer, the number of retrievable and metastatic lymph nodes is decreased. The current TNM classification is based on number and not location of lymph node metastases and may understage disease after chemoradiotherapy. The aim of this study was to examine the prognostic significance of location of involved lymph nodes in rectal cancer patients after preoperative chemoradiotherapy. Patients and Methods We prospectively examined whole-mount specimens from 121 patients with uT3-4 and/or N+ rectal cancer who received preoperative chemoradiotherapy followed by resection. Location of involved lymph nodes was compared with median number of lymph nodes involved as well as presence of distant metastasis at presentation. Results Lymph node metastases were detected in 37 patients (31%). Thirteen patients with lymph node involvement along major supplying vessels (proximal lymph node metastases) had a significantly higher rate of distant metastatic disease at time of surgery than patients without proximal lymph node involvement (P < .001); median number of lymph nodes involved was two for patients with proximal lymph node metastases and 1.5 for patients with mesorectal lymph node involvement alone. Conclusion Our data suggest that, after preoperative chemoradiotherapy, proximal lymph node involvement is associated with a high incidence of metastatic disease at time of surgery. Because the median number of involved lymph nodes is low after preoperative chemoradiotherapy, the TNM staging system may not provide an accurate assessment of metastatic disease. Therefore, the ypTNM staging system should incorporate distribution as well as number of lymph node metastases after preoperative chemoradiotherapy for rectal cancer.

Purpose Treatment of rectal cancer with neoadjuvant radiotherapy has been shown to reduce local recurrence and improve overall survival. The role of chemoradiotherapy in patients with T2, N0 and early T3, N0 rectal cancer, treated by radical surgery with total mesorectal excision, remains controversial. The aim of this study was to identify predictors of recurrence in this group of patients to enhance treatment selection. Patients and Methods One hundred patients with primary T2-3, N0 adenocarcinoma of the rectum, uniformly treated by surgery alone, were studied. The pathology slides available for 97 patients were rereviewed. Three patients with incomplete data sets were excluded. Clinical and survival data were obtained from a prospective computerized database and updated from hospital and office charts. The study end points were disease-free survival, disease-specific survival (DSS), time to pelvic recurrence (PR), and distant recurrence. Results Complete follow-up was available for all study patients. Median follow-up was 79.5 months (range, 57.7 to 105.9 months). During this time period 30 patients (31.9%) died as a result of disease and 64 patients (68.1%) remained alive and disease free. Five-year DSS was 73%. The cumulative risk for PR was 8% at 5 years and 10% at 8 years. Lymphovascular invasion, preoperative serum carcinoembryonic antigen (CEA > 5 ng/mL) level, and age older than 70 years were all associated with adverse outcome. Conclusion Patients with T2-3, N0 rectal cancers and either lymphovascular invasion or elevated CEA levels have reduced survival and a higher incidence of PR, and should be considered for future randomized trials.

3519 Background: The most common therapy for locally advanced (T3/4 or N+) rectal cancer (LARC) consists of preoperative chemoradiotherapy (chemoRT) followed by surgery and adjuvant chemotherapy. Recently, use of total neoadjuvant therapy (TNT) with preoperative chemotherapy in addition to chemoRT prior to resection has been accepted as an alternative. Methods: Of 811 consecutive patients (pts) who presented with LARC at our cancer center in 2009-2015, 320 received chemoRT with planned adjuvant chemotherapy, and 308 received TNT (induction FOLFOX/CAPOX chemotherapy followed by chemoRT). Treatment and outcome data for those two cohorts were compared. Results: Pts in the TNT cohort received greater percentages of the planned oxaliplatin and fluorouracil prescribed dose than those in the chemoRT with planned adjuvant chemotherapy cohort (p < 0·005 and p < 0·001, respectively). The complete response (CR) rate, which includes pathological CR (pCR) and clinical CR (cCR) at 6 months post-treatment, was 21% in the chemoRT with planned adjuvant chemotherapy cohort and 36% in the TNT cohort. The median follow-up was 40 months in the chemoRT with planned adjuvant chemotherapy cohort and 23 months in the TNT cohort. Fewer distant recurrences were seen in patients who had T downstaging (p < 0·001), N downstaging (p < 0·005), a cCR (p = 0·005), or a pCR (p < 0·005). There was no statistically significant difference in distant-recurrence-free survival between the two cohorts. Conclusions: Our findings provide additional support for the National Comprehensive Cancer Network (NCCN) guidelines for rectal cancer treatment, which categorizes TNT as a viable treatment strategy that facilitates superior compliance and delivery of systemic therapy. Given its high CR rate, TNT may be beneficial as part of a nonoperative treatment strategy aimed at organ preservation.

621 Background: Histology at the invasive front of colon cancer can predict malignant potential. However, the optimal histological marker is yet to be established. This study compares the various invasive front histologic markers. Methods: A single-institution prospective database was queried for consecutive patients who underwent curative resection for Stage I-III colon adenocarcinoma from 2007-14. Histologic features were reviewed by a pathologist, including poorly differentiated clusters (PDC), tumor budding (BD), perineural invasion (PN), desmoplastic reaction (DR) and Crohn’s like reaction (CLR) at the invasive front, and WHO grade of the whole tumor. PDC was defined as cancer clusters of ≥ 5 cancer cells that lack a gland-like structure, and was graded into G1 ( < 5), G2 (5-9) and G3 ( ≥ 10) by the highest number of the clusters /HPF. Clinical outcome included recurrence free survival (RFS) and peak hazard function of recurrence and death identified using the kernel-smoothing method. Predictive accuracy was measured with concordance probability estimate (CPE) for proportional hazards regression. Inter-observer agreement was assessed by weighted kappa values on diagnoses rendered by 3 pathologists on 50 randomly selected cases. Results: The study cohort consisted of 851 patients with a median follow up of 36 months. PDC, BD, PN, DR and CLR at the invasive front were significantly associated with RFS. When analyzed by stage, PDC, BD and PN were associated with RFS both in Stage II and Stage III, while the others were prognostic only in Stage III. CPE was the highest in PDC (0.642), indicating the best predictive accuracy, while it was the lowest in WHO grade (0.526). Weighted kappa was also the highest for PDC, indicating the best inter-observer agreement (PDC: 0.824, WHO grade: 0.568). The smoothed graph of the hazard function showed that the risk of recurrence was not only the highest but peaked earlier for PDC G3 (between0 and 12 months) than PDC G2 (between12 and 24 months) and G1 (no evident peak). Conclusions: Of the commonly evaluated histologic markers at the invasive front, PDC grade is the most predictive and reproducible. Further confirmatory investigations are warranted to determine if PDC can replace WHO grade.

684 Background: This study reports the evolving multimodality management of locally advanced rectal cancer (LARC) and associated outcomes at a high volume center. Methods: Patients with Stage II/III LARC

662 Background: Current therapy for locally advanced rectal cancer (LARC) consists of 6 months of perioperative therapy, either with pre-operative chemo-radiotherapy (CRT) and post operative adjuvant chemotherapy (PAC) or total neoadjuvant therapy (TNT) with induction chemotherapy (ICT) followed by CRT then surgery. The aim of our study was to report on the safety, efficacy and complete response rates comparing TNT to PAC in a larger series of LARC patients (pts) at Memorial Sloan Kettering Cancer Center (MSKCC). Methods: Pts treated at MSKCC (2009-15) were analyzed based on the intended treatment schedule (TNT or PAC). 730 LARC pts were treated with CRT, of these 320 received neoadjuvant CRT and 308 received TNT. Results: In the TNT group 205 pts (73%) underwent surgery within 26 weeks of completion of treatment, of which 38 (19%) had a pCR. Of the 78 pts who did not undergo surgery within 26 weeks, 68 (87%) had a complete clinical response (cCR). In the PAC group 293 pts (92%) underwent surgery within 26 weeks and 45 (15%) had a pCR. Of the 27 pts who did not undergo surgery within 26 weeks 22 (81%) had a cCR. The median follow up was 25 mo in the TNT group and 29 mo in the PAC group. There was no statistically significant difference in the distant metastasis free survival between the treatment regimens, despite a higher number of cT4 and cN + tumors in the TNT group. Fewer distant recurrences were seen in pts who had evidence of T downstaging (P < 0.001), N downstaging (P < 0.005), the presence of a cCR (P = 0.005) or a pCR (P < 0.005). Of the pts who received all treatment at MSKCC, comparison of dose of 5-FU and oxaliplatin between the preoperative (N = 249) and postoperative regimens (N = 101) was notable for a higher average dose received of both 5FU and oxaliplatin (p < 0.005 and p < 0.001) in the ICT group. Conclusions: These data add weight to the evidence already included in the NCCN guidelines that pre-operative chemotherapy as part of TNT is a viable treatment strategy with superior compliance and delivery of systemic therapy. Given the high complete response rate, TNT may be used as part of an organ preservation treatment strategy.

587 Background: Few markers reliably identify colorectal cancer (CRC) patients at risk of recurrence and death. SMAD4 loss occurs in 10-20% of cases and has shown promise in identifying high-risk stage II/III patients. We examined SMAD4 status and association with clinical/pathologic features in 446 stage I-IV CRC patients at Memorial Sloan Kettering (MSK). Methods: Patients undergoing curative resection were included (1981-2010). Familial polyposis syndrome patients and those with inadequate tissue were excluded. Tissue microarrays were constructed (n=364). Immunohistochemistry for SMAD4 and mismatch repair (MMR) proteins was completed. SMAD4 nuclear stain intensity was scored (scale=0-3; 0=loss). On whole sections, MMR proteins (present or absent), tumor-infiltrating lymphocytes (TILs) and peritumoral lymphocyte aggregates (PLAs) were scored (scale=0-3). Associations between clinical/pathologic features and SMAD4 loss vs. retention were analyzed. Kaplan-Meier estimates and log-rank test were used for recurrence-free and overall survival analyses (RFS and OS). Results: SMAD4 loss was noted in 13%. Median age at diagnosis was 53 years, and 51% were male. The cohort consisted of 61% hindgut tumors and 62% stage II/III patients. With up to 33 years of follow-up, the mean was 6 years. SMAD4 loss correlated with higher tumor and nodal stage, adjuvant therapy use, and lower TIL and PLA scores (pmedian) were noted to have worse OS with SMAD4 loss (p

PURPOSE: To examine the relationship between patient characteristics and the use of adjuvant pelvic radiation with and without chemotherapy among patients aged 65 years and older with stage II and III rectal cancer. PATIENTS AND METHODS: A retrospective cohort study using the Surveillance, Epidemiology, and End Results–Medicare linked database identified 1,411 patients aged 65 and older with resected stage II and III rectal cancers diagnosed between 1992 and 1996. From claims submitted to Medicare, we measured the use of pelvic radiation therapy with or without chemotherapy and pre- or postoperatively. RESULTS: Fifty-seven percent of patients received radiation, 42% received chemotherapy and radiation, and 7% had treatment delivered preoperatively. Age was the strongest determinant of treatment: 73% of patients aged 65 to 69, 66% aged 70 to 75, 52% aged 75 to 79, 39% aged 80 to 84, and 21% aged 85 to 89 received radiation. The age trend remained strong after adjusting for other factors that predict receipt of treatment and after exclusion of patients with any evident comorbidity (P < .001). Patients were more likely to receive radiation treatment if they had an abdominal perineal resection, stage III disease, or a T4 tumor. CONCLUSION: Because pelvic recurrences are a substantial cause of morbidity, further efforts are needed to ensure that elderly patients have the opportunity to make informed decisions regarding adjuvant treatment.

PURPOSE In this study, we investigated the association between matrix metalloproteinase (MMP)-9 RNA expression in primary colorectal cancer (CRC) and standard clinicopathologic variables and determined whether levels of MMP-9 RNA predict relapse and survival. PATIENTS AND METHODS Tumor and paired normal mucosa specimens from 71 primary CRC patients following resections were assessed. RNA levels were determined via Northern blot hybridization and quantitated with laser densitometry. Results were expressed as tumor/normal mucosa (T/N) fold-increase calculated after normalizing for RNA loading using 28S expression. Statistical analysis was performed using the SAS statistical package procedure. Kaplan-Meier survival curves were compared with the two-sided log-rank test. RESULTS The mean T/N MMP-9 RNA fold-increase was 9.4 +/- 1.0 (mean +/- SE) (P < .001). Overexpression of MMP-9 RNA correlated significantly with status of synchronous distant metastases (M stage) (P = .004) and Dukes' stage (P = .008). A T/N fold-increase of 5.0 was used to discriminate between high (> 5.0) and low (< or = 5.0) T/N MMP-9 expression. High T/N MMP-9 RNA expression was associated with a significantly shorter disease-free (P = .0001) and overall (P = .0002) survival duration. In univariate and multivariate analyses, T/N MMP-9 RNA level was found to be an independent prognostic factor for disease-free survival. CONCLUSION This report provides the first evidence that increased MMP-9 RNA production in primary human CRC may be a powerful, independent predictor of recurrence and outcome.

PURPOSE To determine whether p53 protein expression is similar within primary colorectal cancer (CRC) and synchronous regional and distant metastases and to assess whether p53 nuclear protein expression could predict outcome in patients with synchronous unresectable liver metastases treated by hepatic artery infusional (HAI) chemotherapy. MATERIALS AND METHODS Paraffin sections from tumor and corresponding normal mucosa representative of 50 consecutive advanced CRC cases were examined for p53 nuclear protein expression by immunohistochemistry using the monoclonal antibody PAb 1801. Patterns of p53 nuclear expression were correlated with standard clinicopathologic variables and outcome, including response to HAI and survival. In a subset analysis, the pattern of nuclear p53 immunoreactivity was compared between primary CRC and lymph node and liver metastases. RESULTS Positive nuclear immunoreactivity for p53 protein was found in 72% of cases. The pattern of p53 protein expression in lymph node and liver metastases was identical to that of the primary tumor. The median survival time was 21.0 months in patients with p53-positive tumors and 53.2 months in patients with p53-negative tumors (Wilcoxon test P = .038). Two-year survival rates were 41.7% and 78.6%, respectively (P < .01). No significant difference was found in the response rates to HAI chemotherapy between the two groups. By multivariate analysis, p53 protein status was the single best predictor of survival, with a relative risk of 6.312. CONCLUSION Our results indicate that nuclear p53 protein status in primary CRC is similar to that in metastatic sites and may be the dominant predictor of survival in patients with advanced hepatic metastases.

509 Background: Nonoperative management (NOM) of rectal cancer following a clinical complete response (cCR) to neoadjuvant therapy is a non-standard approach. We review our experience with NOM to evaluate safety and efficacy. Methods: A retrospective review of prospectively collected data between 2006 and 2014 was conducted. We compared patients completing neoadjuvant therapy for stage I to III rectal cancers who: a) achieved cCR and were treated with NOM, or b) underwent standard total mesorectal excision (TME) and achieved a pathologic complete response (pCR). Kaplan-Meier estimates and the log-rank test were used. Results: Seventy-three patients underwent NOM after cCR. From 369 rectal resections performed, 72 (20%) achieved pCR and form the comparison group. Median follow-up across both groups was 3.3 years. Rectal preservation was achieved in 56 (77%) of the patients treated with NOM. Of the 19 NOM patients with local regrowth, 18 were salvaged successfully with standard TME (n=16) or local excision (n=2), with one patient pending a salvage operation (n=1). No significant differences were noted in the number of distant recurrences between the NOM and pCR groups. Four-year disease-specific survival and overall survival between the two groups were not significantly different. Conclusions: In this highly selected group of patients with cCR to neoadjuvant treatment, NOM with surgical salvage of local tumor regrowth achieved local control in all patients. The oncologic outcome for NOM patients at 4 years was comparable to patients with pCR after rectal resection. These data continue to suggest that NOM does not compromise oncologic outcome, and that preservation of the rectum is achieved in a majority of patients. [Table: see text]

With the introduction of improved surgical techniques such as total mesorectal excision and autonomic nerve preservation during the last two decades, a corresponding decrease in local recurrence rates and increase in overall survival of patients with rectal cancer has been observed. Despite the broad implementation of these techniques, local recurrence and survival after an abdominoperineal resection (APR) have not improved to the same degree as that seen after an anterior resection. This difference has been attributed, in part, to relative smaller tissue volumes around the tumor and higher rates of cancer at circumferential resection margins (CRM) after an APR compared with an anterior resection. Because of this, a number of investigators have called for a change in the technical approach of the APR. Since the late 1990s, surgeons at the Karolinska University Hospital have used an extended posterior perineal approach with gluteus maximus flap reconstruction of the pelvic floor in patients with extensive primary or locally recurrent rectal cancer infiltrating the pelvic floor or with coccygeal or sacral involvement. In the retrospective review by West et al in this issue of Journal of Clinical Oncology, standard APR specimens are compared with those obtained with a cylindrical approach. Specifically, they compare the amount of tissue removed around potentially curable primary rectal adenocarcinomas as well as rates of CRM and intraoperative perforations. In addition, an effort is made to document the impact of such a change in surgical approach on a single surgeon’s practice. The authors must be commended for their long-standing efforts and contributions addressing the importance of surgical technique and pathologic assessment of adequacy of the resected specimen. In this article, the authors report the superiority of the cylindrical relative to the standard APR approach in terms of CRM and perforation rates. We agree with their final concluding sentence: “Use of this operation in combination with new preoperative neoadjuvant therapies should further improve results without the risk of increasing perforation rates.” However, we would add that the incorporation of a more extensive APR approach to the surgical armamentarium will necessitate further emphasis on the need for improved patient selection, given that it is not clear whether all distal rectal adenocarcinomas requiring an APR will benefit from a cylindrical approach as much as from preoperative neoadjuvant therapies. Though the authors demonstrate an apparent superiority of the cylindrical APR approach, their analysis should be interpreted with caution. It is retrospective and based on a small sample size, especially for the cylindrical group, with just 27 combined reported experiences between the two institutions. Therefore, due to the small sample size, statistically significant differences cannot be detected among patients undergoing a standard and a cylindrical APR, but it appears that there is a trend toward more preoperative therapy utilization (97% v 67%) and less stage III disease (30% v 43%) in the cylindrical group compared with the standard APR group. Would the results, therefore, have been the same if the rate of preoperative therapy had been similar between both surgical approaches? Similarly, although the authors demonstrate that a highly experienced, senior surgeon can learn and adopt the cylindrical APR approach, the data do not fully support their conclusion “that adoption of the cylindrical technique can lead to an immediate improvement in CRM positivity and perforation rates for an individual surgeon.” First, this conclusion is based on a single surgeon’s experience with only eight patients who were treated with the cylindrical approach. Second, it is unclear how many of these patients received preoperative chemoradiotherapy. Was the rate of preoperative chemoradiotherapy use similar between the standard APR and cylindrical APR groups? The data from Table 1 in West et al suggest that preoperative therapy was used much more frequently in the cylindrical than in the standard APR group. Furthermore, given that the Leeds group adopted the Karolinska approach in 2005, is it possible that—in addition to performing a cylindrical APR—they also began to use preoperative chemoradiotherapy more liberally? The Karolinska standard practice has been to use neoadjuvant radiation or chemoradiotherapy for “all patients with low rectal cancer requiring an APR.” In fact, in the published Karolinska experience, nearly 70% of patients received neoadjuvant 50 Gy of radiation. Therefore, are the reported improvements in CRM and perforation rates solely due to a more extended APR, to increased use of neoadjuvant therapies, or a combination of both? JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 21 JULY 2

3605 Background: Standard pre-op CRT and post-op chemo for LARC delays the start of optimal systemic therapy by 18-22 weeks. To more promptly address micrometastases that could lead to distant failure, and supported by evidence of excellent primary tumor response to FOLFOX, we began offering FOLFOX as initial treatment for patients (pts) with high-risk LARC. More recently, we have begun offering all planned FOLFOX prior to CRT and surgery. Methods: We obtained an IRB waiver to review records of all clinical stage II/III RC pts treated with initial FOLFOX followed by CRT and total mesorectal excision (TME) at our institution between 2007 and 2012. Of approximately 300 rectal pts treated with CMT, 61 received some or all of their planned FOLFOX as initial therapy. Results: The median age of these 61 pts was 52 years, 54% male. At diagnosis, 84% had T3N1-2 or T4N0-1 tumors and 16% had T3N0 tumors. Of these, 57 received induction FOLFOX (median 7 cycles) then received pre-op CRT, while 4 pts achieved an excellent response to chemotherapy alone, declined CRT, and went directly to TME. Twelve pts did not undergo surgery; 9 had a complete clinical response and elected to be managed non-operatively; 1 refused recommended surgery despite incomplete tumor regression, 1 had surgery deferred due to comorbidities, and 1 developed distant metastatic disease prior to planned surgery. Of the 61 patients, 19 (31%) had either a pathCR (14) or a complete clinical response (5) leading to non-operative management. Of the 49 pts who underwent TME, all had R0 resections and 23 (47%) had tumor response >90%, including 13 (27%) with pathCR. Of the 28 patients who received all 8 cycles of initial FOLFOX, 8 achieved a pathCR (29%) and 3 achieved a complete clinical responses (11%), managed non-operatively. All patients completed therapy as planned. There were no SAEs requiring delay in treatment during either FOLFOX or CMT. Conclusions: FOLFOX before CRT results in substantial tumor regression, a high rate of delivery of all planned therapy, and a substantial rate of pathCRs. Chemo and CMT before planned TME provides a favorable opportunity for consideration of non-operative management.

1555 Background: The majority of LS patients harbor germline mutations in the MLH1 or MSH2 genes. However, ~10% have MSH6 and ~

350 Background: Lynch syndrome (LS), resulting from a germline mutation in a DNA mismatch repair (MMR) gene, is associated with ~70% lifetime colorectal cancer (CRC) risk. Although LS-associated colon cancer is associated with both favorable prognosis and lack of efficacy to 5-fluorouracil, clinical features of LS-associated rectal cancer (RC) have not been characterized. Methods: Clinical genetics database review (1998–2012) identified all probands with CRC and a deleterious germline mutation in a MMR gene (MLH1, MSH2, MSH6, PMS2) diagnostic of LS. Probands without identifiable mutations or variants of unknown significance were excluded. Clinical history and pedigree was extracted from medical records and Progeny. Results: Of 119 LS patients with CRC, 16 (13.4%) had RC. Mean age at RC diagnosis was 40.6 (range, 23-56) with 31% having synchronous (n=3) or metachronous (n=2) colon cancer. All RC patients met Revised Bethesda and 63% met Amsterdam II criteria. As opposed to LS-associated colon cancer, the majority of RC patients harbored MSH2 mutations (36% colon vs 69% RC, p value 0.01). 11 tumors were analyzed for MSI or defective MMR protein expression by IHC; results were abnormal and thereby concordant with germline test results in all cases. Of 14 RC patients with clinical data, 5 proceeded directly to surgery (4 stage 0/I; 1 stage II). Nine patients received pre-op treatment for clinical stage II/III (n=7) or IV (n=2) disease, with all receiving chemoradiation and five also receiving pre-op FOLFOX. Downstaging of primary tumor occurred in 66.6% (6/9) and of lymph nodes in 77.7% (7/9) of cases. All nine patients underwent R0 resections; however, pCR was not observed in any of the cases. Notably, one patient with clinical T3N+ disease (by MRI and EUS) had upfront surgery identifying pT2N0 disease with prominent tumor infiltrating lymphocytes. Of 14 patients, mean follow-up of 4.3 years (range, 0.3-13.5), none had disease recurrence; however, one was diagnosed with a new primary colon cancer. Conclusions: Although less common than colon cancer,RC is an important component of LS and may be overrepresented in MSH2 mutation carriers. Given high risk of synchronous or metachronous cancers, appropriate surveillance for second malignancies is necessary.

526 Background: Optimal management of patients with locally advanced rectal cancer (LARC) and synchronous, resectable metastases remains controversial and treatment decisions benefit from a multidisciplinary approach. To better characterize the role of induction chemotherapy followed by chemoradiation and surgery, we evaluated patterns of distal progression and overall survival in this subset of patients. Methods: We reviewed records of 25 LARC patients with synchronous resectable metastases treated with induction chemotherapy (ICT) followed by 5-fluorouracil-based concurrent chemoradiation (CRT) at our institution between December 2006 and December 2010. Radiation was delivered using a standardized three-field technique or IMRT. The incidence and sites of failure were analyzed. Overall survival (OS) and progression-free survival (PFS) were calculated from the completion of CRT using the Kaplan-Meier method. Results: Of the 25 patients who received ICT followed by CRT, 21 (84%) underwent total mesorectal excision and metastectomy. Eleven patients (44%) had liver metastases. The median ICT duration was 2.4 months. Twenty patients (80%) received a FOLFOX-based ICT regimen and 5 patients (20%) received irinotecan-based chemotherapy. Two patients had unresectable disease, one was medically inoperable, and surgery was aborted due to intra-operative complications in one patient. Eighteen of the 21 were NED after surgery and metastatectomy (86%) with 24% pathologic complete response rate in the primary tumor; 10 (56%) received adjuvant chemotherapy. None of the patients recurred locally. Six of the 18 (33%) progressed distally, four of whom had received adjuvant chemotherapy. Four distal recurrences were in the lungs. With a median follow-up of 29.6 months, the 3-year OS was 50.4%. Median OS and PFS were 25.1 months and 13.5 months, respectively. Conclusions: ICT prior to CRT is associated with acceptable toxicity, substantial primary tumor regression, and promising clinical outcomes in patients with high-risk LARC with synchronous, resectable metastatic disease.

3583 Background: Tumor regression grade (TRG) is a measure of histopathologic response of rectal cancer to preoperative chemoradiation (CRT) and correlates with outcomes. Several TRG systems have been reported including Mandard (5, 3 tier), Dowrak/Rodel (5, 3 tier), Memorial Sloan Kettering Cancer Center (MSKCC), and American Joint Committee of Cancer (AJCC). The purpose of this study is to compare the different TRG systems and determine which one(s) best predict recurrence and survival. Methods: Review of prospective maintained database from 1998 to 2007 identified 563 patients with locally advanced rectal cancer (T3/4 and/or N1) and treated with long-course CRT followed by total mesorectal excision. TRG was determined by measuring proportion of tumor mass replaced by fibrosis. Patients were then classified into the various TRG schemes which were compared by analyzing association with recurrence and survival using concordance index (CI) and reclassification index. CI is a measure that summarizes the predictive strength of a marker. Computing and contrasting CI across several markers is a way of selecting the best prognostic marker. Results: 75% of patients were noted to have clinical stage III disease by endorectal ultrasound or rectal MRI. Following resection with median follow-up of 39.3 months, 2% developed local recurrence and 17% developed distant metastasis. The median interval time between completion of CRT and surgery is 48 days. 20% demonstarted complete pathological response. CI of the 3 tier Mandard, 3 tier Dowrak/Rodel, MSKCC and AJCC are 0.665, 0.653, 0.683, and 0.694, respectively (higher number indicates better prediction). The AJCC was significantly more accurate in predicting recurrence than the 3- tier Mandard (p=0.002), and Dowrak/Rodel (p=0.006). AJCC had a higher CI than MSKCC although it did not reach significance (p=0.068). Comparing the 3 tier systems, MSKCC was most accurate and correctly reclassified 17 % and 23 % of the patients Mandard and Dowrak/Rodel systems, respectively. Conclusions: TRG predicts recurrence and survival following combined modality therapy for rectal cancer. The TRG system that recently was proposed in the 7thAJCC staging is currently the most accurate predictor.

3563 Background: The utility of adding 18F-Fluorodeoxyglucose-Positron Emission Tomography (PET) to the pre-treatment staging of patients with locally advanced rectal cancer has not been well evaluated. Methods: Following completion of standard work-up, including physical examination, endorectal ultrasound, CT of the abdomen and pelvis, and chest CT or chest x-ray, 150 patients with primary, resectable, biopsy-proven rectal adenocarcinoma requiring neoadjuvant chemoradiation were enrolled in a prospective, single-stage, phase II study evaluating the role of PET. All patients underwent a dedicated whole-body PET prior to initiation of neoadjuvant chemoradiation. The primary endpoint of this analysis was to determine the accuracy of PET in detecting extrapelvic metastatic disease in primary rectal cancer patients considered operable on the basis of currently-standard work-up. Results: Among the 117 eligible patients found to be stage II or III by standard staging techniques, none (0%) were found by PET to have extrapelvic metastatic disease. PET yielded a false positive result in 3 patients (2.6%). PET yielded a false-negative result in 3 patients who were subsequently diagnosed with metastatic disease: 2 pre-operatively (liver, lung) and 1 intra-operatively (obturator lymph node). In 1 patient, PET did identify a previously unappreciated obturator lymph node metastasis; left pelvic sidewall dissection at the time of rectal resection confirmed metastatic adenocarcinoma in one obturator lymph node. Conclusions: Of the 117 rectal cancer patients evaluated and found to have locoregional disease by standard examination and imaging techniques, none had extrapelvic metastatic disease accurately identified by PET. PET did not improve the accuracy of pre-treatment staging. As such, consistent with current NCCN guidelines, PET does not have a role in pre-treatment staging of locally advanced rectal cancer.

3649 Background: Stage II/III rectal cancer is treated with chemotherapy (chemo) plus radiation therapy (RT) followed by surgery, and then post-op chemo. Pelvic RT reduces local recurrence, but mos...

3644 Background: The aim of this study is to characterize patterns of recurrence in locally advanced rectal cancer treated with combined modality therapy (CMT) including neoadjuvant chemoradiation ...

3657 Background: Alterations in bowel function following sphincter-preserving surgery (SPS) for rectal cancer have not been well studied, limiting our ability to effectively counsel patients regard...

3633 Background: Guidelines for the appropriate duration of imaging after a curative resection for rectal cancer are lacking. Current ASCO and NCCN guidelines conflict and are limited as the data t...

22127 Background: HNPCC increases lifetime risk of a constellation of cancers including colorectal (CRC; 80%), endometrial (EC; 43–60%), ovarian (OC; 10–12%) and ureter (5%). Despite provision of s...

3612 Introduction: Early knowledge of rectal cancer response to preoperative combined modality therapy (CMT) may provide an opportunity to identify patients with minimal response and who may benefit from alternative treatment regimens. We prospectively evaluated the novel concept of assessing rectal cancer response with fluorodeoxyglucose positron emission tomography (PET) early after the commencement of preoperative CMT. Methods: 21 prospectively accrued patients with locally advanced rectal cancer (ERUS T3–4/N1) received preoperative CMT (5040 cGy with 5-FU-based chemotherapy). Patients were imaged with a PET scan prior to and 10–12 days after (early PET) commencement of CMT. PET scans were interpreted by two Nuclear Medicine physicians using four specific parameters [(SUVmax, SUVaverage, total lesion glycolysis (TLG), and visual response score (VRS)]. Percent pathologic response was quantified using whole mount sections. Pathologic complete response (pCR) was defined as no viable tumor cells on patholo...

3568 Background: Laboratory data suggest that HMG-CoA reductase inhibitors, or statins, may have antitumor activity in colorectal cancer. We explored whether or not statins might enhance the efficacy of neoadjuvant chemoradiation in rectal cancer. Methods: Between 1996–2001, 358 patients with clinically resectable, nonmetastatic rectal cancer underwent surgery at Memorial Sloan-Kettering Cancer Center after neoadjuvant chemoradiation for either locally advanced tumors, or for low-lying tumors that would require abdominoperineal resection. We excluded 9 patients for RT dose < 45 Gy or if statin use was unknown, leaving 349 evaluable patients. Median RT dose was 50.4 Gy (range: 45–55.8 Gy), and 308 (88%) received 5-FU based chemotherapy. Medication use, comorbid illnesses, clinical stage by DRE and ultrasound, and type of chemotherapy were analyzed for associations with pathologic complete response (pCR), defined as no microscopic evidence of tumor. Fisher's exact test was used for categorical variables, Ma...

3536 Background: Accurate preoperative assessment of rectal carcinoma response to neoadjuvant CMT may guide subsequent therapy, including extent of resection. Our aim was to determine the accuracy of this clinical assessment in a prospective manner. Methods: The study group consisted of 94 prospectively accrued patients with locally advanced (bulky or endorectal ultrasound T3/T4 and/or N1) rectal carcinoma at a median distance of 6.75 cm from the anal verge (range 0–13 cm) treated with preoperative CMT (5040 cGy with 5-FU-based chemotherapy) followed by radical surgery with total mesorectal excision. The operating surgeon prospectively assessed the tumor in terms of specific parameters: mobility, morphology, and circumference of lesion prior to initiation of CMT. Under anesthesia, the same operating surgeon estimated tumor response based upon the same specific parameters and categorized the extent of response into 5 groups: 1=progression; 2= 0–29%; 3=30–59%; 4=60–89%; and 5=greater than 90% response. Perc...