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Purpose: 5-Fluorouracil (5-FU)/leucovorin, irinotecan, and nab-paclitaxel are all active agents in gastrointestinal cancers; the combination, FOLFIRABRAX, has not been previously evaluated. UDP Glucuronosyltransferase 1A1 (UGT1A1) clears SN-38, the active metabolite of irinotecan. UGT1A1*28 polymorphism reduces UGT1A1 enzymatic activity and predisposes to toxicity. We performed a trial to assess the safety and tolerability of FOLFIRABRAX with UGT1A1 genotype–guided dosing of irinotecan. Patients and Methods: Patients with previously untreated, advanced gastrointestinal cancers received FOLFIRABRAX with prophylactic pegfilgrastim every 14 days. UGT1A1 *1/*1, *1/*28, and *28/*28 patients received initial irinotecan doses of 180, 135, and 90 mg/m2, respectively. 5-FU 2,400 mg/m2 over 46 hours, leucovorin 400 mg/m2, and nab-paclitaxel 125 mg/m2 were administered. Doses were deemed tolerable if the dose-limiting toxicity (DLT) rate during cycle 1 was ≤35% in each genotype group. DLTs were monitored using a sequential procedure. Results: Fifty patients enrolled, 30 pancreatic, 9 biliary tract, 6 gastroesophageal, and 5 others. DLTs occurred in 5 of 23 (22%) *1/*1 patients, 1 of 19 (5%) *1/*28 patients, and 0 of 7 *28/*28 patients. DLTs were all grade 3: diarrhea (3 patients), nausea (2 patients), and febrile neutropenia (1 patient). The overall response rate was 31%. Response rates in pancreatic, gastroesophageal, and biliary tract cancers were 34%, 50%, and 11%, respectively. Eighteen patients (36%) received therapy for at least 24 weeks. Conclusions: FOLFIRABRAX with genotype-guided dosing of irinotecan is tolerable in patients with advanced gastrointestinal cancer and UGT1A1*1*1 or UGT1A1*1*28 genotypes. Too few *28/*28 patients were enrolled to provide conclusive results. Responses occurred across multiple tumor types.

BACKGROUND FOLFIRINOX (5-fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) is an effective but toxic therapy for pancreatic cancer. UGT1A1 (UDP glucuronosyltransferase 1A1) eliminates the active metabolite of irinotecan. Polymorphisms reduce UGT1A1 activity, leading to toxicity. The primary objective was to determine the dose-limiting toxicity (DLT) rate in cycle 1 of modified FOLFIRINOX (mFOLFIRINOX) using genotype-guided dosing of irinotecan for the most common UGT1A1 genotypes (*1/*1, *1/*28) in advanced gastrointestinal malignancies, with expansion in pancreatic and biliary tract cancers. METHOD 5-FU (2400 mg/m2 over 46 hours), leucovorin (400 mg/m2 ), oxaliplatin (85 mg/m2 ), and irinotecan were given every 14 days. Irinotecan doses of 180, 135, and 90 mg/m2 were administered for UGT1A1 genotypes *1/*1, *1/*28, and *28/*28, respectively. Prophylactic pegfilgrastim was omitted in cycle 1 for cohort 1 (tolerability by genotype), but was given in cohort 2 (tolerability by tumor type). Doses were tolerable if the upper limit of a 2-sided 80% confidence interval for DLT rate was ≤33%. RESULTS In cohort 1, DLTs (most commonly febrile neutropenia, fatigue, diarrhea) occurred in 2/15 (13%), 3/16 (19%), and 4/10 (40%) patients with *1/*1, *1/*28, and *28/*28 genotypes, respectively. In cohort 2, 6/19 (32%) pancreatic and 4/19 (21%) biliary tract cancer patients experienced DLTs (most commonly fatigue, diarrhea, nausea/vomiting). In cohort 2, upper confidence limits of DLT rates exceeded 33%. Response rates were 38% in pancreatic and 21% in biliary tract cancers. CONCLUSION On the basis of our prespecified criteria, tolerability of UGT1A1 genotype-guided mFOLFIRINOX was not established in pancreatic and biliary tract cancers. However, this regimen was effective.

Background The benefit of adding external beam radiation to adjuvant chemotherapy in patients that have undergone a margin positive resection for early stage, pancreatic ductal adenocarcinoma has not been determined definitively. Methods The National Cancer Data Base was queried to evaluate the utility of adjuvant radiation in patients with pathologic stage I–II pancreatic ductal adenocarcinoma who underwent upfront pancreatoduodenectomy with a positive margin (margin positive resection) between 2004 and 2013. Results In the study, 1,392 patients met inclusion criteria, of whom 263 (18.9%) were lymph node-negative (pathologic stages IA, IB, IIA) and 1,129 (81.1%) were node-positive (pathologic stage IIB); 938 (67.4%) patients received adjuvant radiation and chemotherapy, while 454 (32.6%) received adjuvant chemotherapy alone. Cox modeling stratified by nodal status demonstrated the benefit of radiation to be statistically significant only in node positive patients (hazard ratio 0.81, 95% confidence interval, 0.71–0.93). Node-positive patients receiving adjuvant radiation and chemotherapy had an adjusted median survival of 17.5 months vs 15.2 months for those receiving adjuvant chemotherapy alone (P = .003). In patients who had negative nodes, there was no difference in overall survival with radiation (22.5 vs 23.6 months, P = .511). Conclusion Addition of radiation to adjuvant chemotherapy after a margin positive resection confers a survival benefit albeit limited (about 2 months) in patients with node-positive pancreatic head cancer. (Surgery 2017;160:XXX-XXX.)

Background and Objectives Surgery followed by gemcitabine and/or a fluoropyrimidine is standard therapy for resectable PDAC. mFOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 Day 1, 5-FU 2400 mg/m2 × 48 h IV, peg-filgrastim 6 mg SQ day 3, every 14 days) has substantial activity in metastatic PDAC. We wished to determine the tolerability/efficacy of peri-operative mFOLFIRINOX in resectable PDAC. Methods Patients with resectable PDAC (ECOG PS 0/1) received four cycles of mFOLFIRINOX pre- and post-surgery. The primary endpoint was completion of preoperative chemotherapy plus resection. Secondary endpoints included completion of all therapy, R0 resection, treatment related toxicity, PFS, and OS. Results Twenty-one patients enrolled: median age 62 (47-78); 20/21 (95%) completed four cycles of preoperative mFOLFIRINOX; response by RECIST was 1 CR, 3 PR, 16 SD; 17/21 (81%) completed resection, 16/21 (76%) R0; 14/21 (66%) completed four cycles of postoperative mFOLFIRINOX. Grade 3 and 4 toxicity occurred in 23% and 14% patients pre-operatively, 26% and 6.0% post-operatively. Nine patients are alive with median follow-up of 27.7 (3.1-47.1) months. Conclusions PST using mFOLFIRINOX in resectable PDAC is feasible and tolerable. R0 resection rate is high and survival promising, requiring longer follow-up and larger studies for definitive assessment.

Neoadjuvant protocols for early stage pancreatic adenocarcinoma (PDAC) frequently involve external beam radiation used in combination with systemic chemotherapy. The benefit of radiation in these protocols has not been determined.We examined patients with stage I and II PDAC within the National Cancer Data Base between 2006 and 2012. Propensity score matching was used to compare patients receiving neoadjuvant chemotherapy including radiation (NCRT) to those receiving neoadjuvant chemotherapy without radiation (NCT) prior to pancreaticoduodenectomy.Prior to matching, NCRT patients had higher rates of T3 tumors (P = 0.046) and vascular abutment (P 0.001). Propensity score matching (1:1) yielded 397 patients per group. Patients treated with NCRT were more likely to have node negative resections (P 0.001) but had increased rates of 90-day mortality (P = 0.015) and demonstrated a trend towards shorter overall survival (P = 0.0502) than those receiving NCT.In early stage PDAC, the addition of radiation to NCT is often utilized with more advanced disease and is associated with higher perioperative mortality and no long-term overall survival benefit.

The absolute benefit of adjuvant external beam radiation therapy after a margin-negative resection in early stage pancreatic cancer has not been determined.We queried the National Cancer Data Base for patients with pathologic stage I-II pancreatic adenocarcinoma who underwent operative resection between 2004 and 2012. Multivariate Cox regression adjusted for age, race, comorbidities, facility type, location and volume, type of pancreatectomy, and tumor grade was used to estimate stage-specific survival.A total of 15,966 patients with stage I-II pancreatic adenocarcinoma underwent upfront operative therapy (no neoadjuvant treatment) and had a margin-negative resection during the study period. A total of 835 (5.2%) patients were pathologic stage IA, 1,539 (9.5%) were stage IB, 3,378 (20.9%) were stage IIA, and 10,214 (63.1%) were stage IIB. Chemoradiation utilization increased with increasing stage (22.8% in stage IA vs 39.6% in stage IIB, P .01). Chemoradiation was more common at low-volume centers (39.0% vs 31.7% at high-volume centers, P .01) and with younger age (43.3% of patients70 years old compared to 25.0% ≥70 years old, P .01). Treatment at a high-volume center was associated with decreased mortality (hazard ratio 0.80-0.89) across all stages. Age ≥70 years old (hazard ratio 1.18-1.29, P .01) and higher grade (hazard ratio 1.68-2.69, P .01) were associated with higher risk of mortality at all stages. Chemoradiation was associated with a benefit in median overall survival over chemotherapy alone for stage IIB disease (21.8 months vs 19.5 months, P .01). Chemoradiation was not associated with a significant benefit in median overall survival for stage IA, IB, or IIA disease (P .30).Addition of radiation to adjuvant chemotherapy after margin-negative resection of pancreatic adenocarcinoma is associated with a limited survival benefit in patients with pathologic stage IIB disease and should be weighed against its associated risks in these patient groups.

377 Background: Neoadjuvant therapy has been associated with a median overall survival (OS) of 18 – 23 months (mo) in patients (pts) with BR pancreatic ductal adenocarcinoma (PDAC). To establish reference regimens to which novel treatments can be compared in future studies, we evaluated neoadjuvant mFOLFIRINOX with or without RT in BR PDAC in a phase II National Clinical Trials Network (NCTN) trial. Methods: Pts with ECOG PS 0-1 and BR PDAC confirmed by central real-time radiographic review after pre-registration were randomized to either arm A: 8 cycles of neoadjuvant mFOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 46 hours), or arm B: 7 cycles of mFOLFIRINOX followed by stereotactic body RT (SBRT, 33-40 Gy in 5 fractions [fx]) or hypofractionated image guided RT (HIGRT, 25 Gy in 5 fx). Pts in either arm without disease progression underwent pancreatectomy, then 4 cycles of adjuvant mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 46 hours). The primary endpoint, 18-mo OS rate, of each arm was compared to a historical control of 50%. Planned interim analysis mandated closure of either arm in which 0.05). Treatment detailed in Table. The 18-mo OS rate based on Kaplan Meier estimates was 67.9% (95%CI: 54.6 – 78.0) in arm A and 47.3% (95%CI: 33.7 – 59.7) in arm B. Among pts who underwent pancreatectomy, 18-mo OS rate was 93.1% (95%CI: 84.3 – 100) and 78.9% (95%CI: 62.6 – 99.6) in arm A and B, respectively. With median follow-up of 27 and 31 mo, median OS was 31.0 (95%CI: 22.2 – NE) mo and 17.1 (95%CI: 12.8 – 24.4) mo in arm A and B, respectively. Conclusions: Neoadjuvant mFOLFIRINOX was associated with favorable OS relative to historical data in pts with BL PDAC in this phase II NCTN trial. mFOLFIRINOX with hypofractionated RT did not improve OS compared to historical data. mFOLFIRINOX represents a reference regimen in this setting and a backbone on which to add novel agents. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org Clinical trial information: NCT02839343. [Table: see text]

The value of neoadjuvant chemotherapy in the treatment of early stage pancreatic cancer is not yet clear.We evaluated patients from the National Cancer Data Base who underwent pancreaticoduodenectomy for clinical stage I and II pancreatic adenocarcinoma between 2006 and 2012.In total, 7,881 patients were identified. Of these, 27.5% received no chemotherapy, 57.4% received adjuvant chemotherapy, 10.2% received neoadjuvant chemotherapy alone, and 4.9% received perioperative chemotherapy, both preoperative and postoperative chemotherapy. Neoadjuvant chemotherapy use (neoadjuvant chemotherapy alone and perioperative chemotherapy) increased from 12.0% in 2006 to 20.2% in 2012. Patients who received chemotherapy prior to the operation (neoadjuvant chemotherapy alone and perioperative chemotherapy) had greater rates of margin negative (80.2% vs 73.0%, P .001) and node negative (58.2% vs 28.7%, P .001) resections and shorter mean durations of stay (12.0 vs 11.1 days, P = .012) than those receiving either adjuvant chemotherapy or no chemotherapy at all. There were no differences in 30-day unplanned readmissions (P = .074) and 90-day mortality (P = .227). On Cox survival analysis, adjusted for clinical variables including age and comorbid disease, patients undergoing perioperative chemotherapy, adjuvant chemotherapy, and neoadjuvant chemotherapy alone demonstrated significantly improved overall survival relative to that of patients undergoing resection alone (all P .001). Patients receiving perioperative chemotherapy demonstrated a significant overall survival advantage compared with those receiving adjuvant chemotherapy (hazard ratio 0.75; 95% confidence interval, 0.65-0.85). Neoadjuvant chemotherapy alone had a marginal overall survival benefit compared with adjuvant chemotherapy (hazard ratio 0.89; 95% confidence interval, 0.81-0.98).Early stage pancreatic cancer patients who receive perioperative chemotherapy have better overall survival than those receiving no chemotherapy, adjuvant chemotherapy, or neoadjuvant chemotherapy alone. Patterns of postoperative morbidity are similar regardless of the sequence of therapy. Neoadjuvant chemotherapy should be considered for patients presenting with early stage pancreatic cancer.

Importance Patients with locally advanced gastroesophageal adenocarcinoma (ie, stage ≥T3 and/or node positive) have high rates of recurrence despite surgery and adjunctive perioperative therapies, which also have high toxicity profiles. Evaluation of pharmacogenomically dosed perioperative gFOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, andUGT1A1genotype–directed irinotecan) to optimize efficacy while limiting toxic effects may have value. Objective To evaluate the coprimary end points of margin-negative (R0) resection rates and pathologic response grades (PRGs) of gFOLFIRINOX therapy among patients with locally advanced gastroesophageal adenocarcinoma. Design, Setting, and Participants This single-group phase 2 trial, conducted at 2 academic medical centers from February 2014 to March 2019, enrolled 36 evaluable patients with locally advanced adenocarcinoma of the esophagus, gastroesophageal junction, and gastric body. Data analysis was conducted in May 2019. Interventions Patients received biweekly gFOLFIRINOX (fluorouracil, 2400 mg/m2over 46 hours; oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2forUGT1A1genotype 6/6, 135 mg/m2forUGT1A1genotype 6/7, or 90 mg/m2forUGT1A1genotype 7/7; and prophylactic peg-filgrastim, 6 mg) for 4 cycles before and after surgery. Patients with tumors positive forERBB2also received trastuzumab (6-mg/kg loading dose, then 4 mg/kg). Main Outcomes and Measures Margin-negative resection rate and PRG. Results A total of 36 evaluable patients (27 [78%] men; median [range] age, 66 [27-85] years; 10 [28%] with gastric body cancer; 24 [67%] with intestinal-type tumors; 6 [17%] withERBB2-positive tumors; 19 [53%] withUGT1A1 genotype 6/6; 16 [44%] with genotype 6/7; and 1 [3%] with genotype 7/7) were enrolled. Of these, 35 (97%) underwent surgery; 1 patient (3%) died after completing neoadjuvant chemotherapy while awaiting surgery. Overall, R0 resection was achieved in 33 of 36 patients (92%); 2 patients (6%) with linitis plastica achieved R1 resection. Pathologic response grades 1, 2, and 3 occurred in 13 patients (36%), 9 patients (25%), and 14 patients (39%), respectively, and PRG 1 was observed in 11 of 24 intestinal-type tumors (46%). Median disease-free survival was 30.1 months (95% CI, 15.0 months to not reached), and median overall survival was not reached (95% CI, 8.3 months to not reached). There were no differences in outcomes byUGT1A1genotype group. A total of 38 patients, including 2 (5%) with antral tumors, were evaluable for toxic effects. Grade 3 or higher adverse events occurring in 5% or more of patients during the perioperative cycles included diarrhea (7 patients [18%]; 3 of 19 patients [16%] with genotype 6/6; 2 of 16 patients [13%] with genotype 6/7; 2 of 3 patients [67%] with genotype 7/7), anemia (2 patients [5%]), vomiting (2 patients [5%]), and nausea (2 patients [5%]). Conclusions and Relevance In this study, perioperative pharmacogenomically dosed gFOLFIRINOX was feasible, providing downstaging with PRG 1 in more than one-third of patients and an R0 resection rate in 92% of patients. Trial Registration ClinicalTrials.gov Identifier:NCT02366819

Background There is considerable debate about the safety and clinical equivalence of laparoscopic pancreaticoduodenectomy (LPD) and open pancreaticoduodenectomy (OPD) for pancreatic ductal adenocarcinoma (PDCA). Study Design We queried the National Cancer Data Base to identify patients undergoing LPD and OPD for PDCA between 2010 and 2011. Chi-square and Student's t -tests were used to evaluate differences between the 2 approaches. Multivariable logistic regression modeling was performed to identify patient, tumor, or facility factors associated with perioperative mortality. Results Four thousand and thirty-seven (91%) patients underwent OPD. Three hundred and eighty-four (9%) patients underwent LPD. There were no statistical differences between the 2 surgical cohorts with regard to age, race, Charlson score, tumor size, grade, stage, or treatment with neoadjuvant chemoradiotherapy. Laparoscopic pancreaticoduodenectomy demonstrated a shorter length of stay (10 ± 8 days vs 12 ± 9.7 days; p Conclusions Laparoscopic pancreaticoduodenectomy is equivalent to OPD in length of stay, margin-positive resection, lymph node count, and readmission rate. There is a higher 30-day mortality rate with LPD, but this appears driven by a surmountable learning curve for the procedure.

Background: Irinotecan is commonly used in combination with oxaliplatin as a component of FOLFIRINOX chemotherapy for several gastrointestinal malignancies. The purpose of this case report is to describe a patient who developed acute paralysis and aphasia while receiving her initial infusion of irinotecan. Case Report: A 67-year-old woman with newly diagnosed metastatic pancreatic adenocarcinoma presented for her first cycle of FOLFIRINOX chemotherapy. During her infusion of irinotecan, she developed acute onset of generalized weakness, paralysis of all extremities, and nonfluent aphasia with complete inability to communicate. This episode was self-limited and resolved within 2 h. Prior to subsequent infusions she received intravenous repletion of potassium and had no recurrence of symptoms. Discussion: In selected cases, coadministration of irinotecan and oxaliplatin may result in severe generalized weakness and aphasia, which may be triggered by underlying electrolyte disturbances. Careful monitoring and correction of potassium may help prevent this reaction.

FOLFIRINOX (FFX) was introduced to clinical practice in 2010 following publication of the PRODIGE 4/ACCORD 11 study, which compared this novel regimen to gemcitabine in metastatic pancreatic cancer. Median overall survival, progression-free survival, and objective responses were all superior with FFX and there was improved time to definitive deterioration in quality of life. Despite initial concerns over toxicity, there has been rapid uptake of this regimen, both revolutionizing management and opening the door to innovative research. As experience with FFX has accrued, many questions have arisen including the management of toxicities, the impact of frequent modifications, the optimal number of cycles, integration with other regimens and modalities, interpretation of radiologic and serologic response, utility of molecular signatures, and potential benefit in unique clinical settings such as pre- and postsurgery. This review will closely examine these issues, not only to summarize current knowledge but also to fuel scientific debate.

Purpose The risk of severe neutropenia from treatment with irinotecan is related in part to UGT1A1*28, a variant that reduces the elimination of SN-38, the active metabolite of irinotecan. We aimed to identify the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of irinotecan in patients with advanced solid tumors stratified by the *1/*1, *1/*28, and *28/*28 genotypes. Patients and Methods Sixty-eight patients received an intravenous flat dose of irinotecan every 3 weeks. Forty-six percent of the patients had the *1/*1 genotype, 41% had the *1/*28 genotype, and 13% had the *28/*28 genotype. The starting dose of irinotecan was 700 mg in patients with the *1/*1 and *1/*28 genotypes and 500 mg in patients with the *28/*28 genotype. Pharmacokinetic evaluation was performed at cycle 1. Results In patients with the *1/*1 genotype, the MTD was 850 mg (four DLTs per 16 patients), and 1,000 mg was not tolerated (two DLTs per six patients). In patients with the *1/*28 genotype, the MTD was 700 mg (five DLTs per 22 patients), and 850 mg was not tolerated (four DLTs per six patients). In patients with the *28/*28 genotype, the MTD was 400 mg (one DLT per six patients), and 500 mg was not tolerated (three DLTs per three patients). The DLTs were mainly myelosuppression and diarrhea. Irinotecan clearance followed linear kinetics. At the MTD for each genotype, dosing by genotype resulted in similar SN-38 areas under the curve (AUCs; r2 = 0.0003; P = .97), but the irinotecan AUC was correlated with the actual dose (r2 = 0.39; P < .001). Four of 48 patients with disease known to be responsive to irinotecan achieved partial response. Conclusion The UGT1A1*28 genotype can be used to individualize dosing of irinotecan. Additional studies should evaluate the effect of genotype-guided dosing on efficacy in patients receiving irinotecan.

4050 Background: Complete resection (R0) and pathologic response grade (PRG) correlate with long-term GEA outcome. FOLFIRINOX demonstrated efficacy in advanced GEA; gFOLFIRINOX improved tolerability. We evaluated R0, PRG and tolerability in this pilot P study. Methods: Gastric body (GB) + esophagogastric (EGJ) GEA patients (pts) with ≥T3Nx or TxN+ were enrolled & treated with 4 pre + 4 postoperative biweekly cycles of gFOLFIRINOX (5-FU 2400mg/m2 over 46 hrs; oxaliplatin 85mg/m2; iri: 180mg/m2 for UGT1A1 genotype 6/6, 135mg/m2 for 6/7, 90mg/m2 for 7/7) (+ trastuzumab (T) 6mg/kg then 4mg/kg for HER2+) with prophylactic peg-filgastrim. 1°endpoint R0 resection required 36 pts to assess for a 90% R0 rate (intention to treat (ITT)) with 90% power + 0.05 alpha; ≥30/36 R0 considered positive. Co-1°endpoint was PRG (Becker); 36 pts provided 85% power with 0.05 alpha for a complete (pCR G1a) rate of 16%. 2°endpoints were safety/toxicity, PET response, & R0/PRG by tumor site, histologic subtype, HER2 status, & UGT1A1 genotype. We report efficacy and toxicity data from the neoadjuvant (Neo) portion of the study; postop data & survival outcomes will be presented at the meeting. Results: 4 sites enrolled 36 ITT pts between 2/2014-8/2018; 75% male, median age 66 (range 27-85). All pts completed all 4 cycles of Neo therapy: 10% had any dose reduction of iri (16%/0%/25% by genotype 6/6, 6/7, 7/7); any G3+ toxicity occurred in 35% of pts (32% 6/6, 29% 6/7, 75% 7/7). G3+ toxicity in ≥5% of pts: diarrhea (17.5%; 6/6 21%, 6/7 11%, 7/7 25%), anemia (5%), vomiting (5%). Efficacy is shown in the Table. Of pts going to surgery, both R1 resections were GB linitus. PRG1(a+b) was achieved in 36% of ITT pts, 46% of intestinal type histology. Conclusions: Neo gFOLFIRINOX was tolerable with surrogate efficacy comparable to FLOT. Clinical trial information: NCT02366819. [Table: see text]

663 Background: Infusional-5-fluorouracil (inf-5FU), administered over 48 hours every 2 weeks, is frequently prescribed for the treatment of gastrointestinal cancers. A portable infusion device (ID) may be used for this purpose to enable treatment at home. At our institution, patients are educated by an oncology nurse as to what to expect, and how to function once they leave the infusion center. However, there is no formal process in place to report their experience and to record and analyze the results. The intended goal of this study was to accomplish this, such that the data could improve the education and experience of future patients. Methods: After verbal consent, a sequential cohort of patients, who had received 2 or more treatments with inf-5FU for gastrointestinal cancer, was invited to complete a de-identified paper questionnaire concerning their experience. Eleven specific questions suggested by the GI group were included, with an opportunity to add comments. The surveys were then collated and reviewed. Results: See table. Conclusions: While most patients felt well prepared by their medical team as to what to expect from the ID (93.1%), ≥ 25% had issues with bathing (73.6%), sleep (37.5%), exercising (30.6%), intimacy (26.4%), social interactions (25%) and anxiety (25%). These insights will be used to improve the education of future patients and a second assessment will follow. 72/72 patients approached over 6 months completed the survey with results below: [Table: see text]

Pancreatic cancer is the fourth leading cause of cancer death in the USA. However, in the last decade, there has been considerable progress in the understanding and treatment of this disease and we are starting to see an impact on survival and quality of life. Chemotherapeutic and surgical options have increased, and refinements in classification and staging to reflect both the biology of these cancers, and the critical interface between these tumors and the adjacent mesenteric and hepatic vasculature, have been proposed. Modern treatment has, of necessity, evolved into a multidisciplinary, multimodality exercise and choices regarding the type and sequencing of therapeutic modalities are now much more complex. Borderline resectable and locally advanced cancers are particularly challenging in this regard as all available modalities will usually be employed at some time during treatment, and goals of therapy will frequently need to be adjusted. Discussion of every patient in a multidisciplinary cancer conference or clinic has become essential to establishing appropriate care plans, and the composition and conduct of such meetings has been analyzed and defined. Academic productivity is also enhanced by this multidisciplinary approach, and the educational component is valuable both for experienced personnel and trainees. Future progress will add to the complexity of care for these challenging patients as molecular and genetic data become increasingly detailed, and biologics, vaccines, and immunotherapies are incorporated into treatment. Collaboration and connectivity between providers from all disciplines of care will be ever more critical to providing optimal results.

Biliary tract cancers (gallbladder cancer, intra- and extra-hepatic cholangiocarcinoma and selected periampullary cancers) accounted for 12,760 new cases of cancer in the USA in 2010. These tumors have a dismal prognosis with most patients presenting with advanced disease. Early, accurate diagnosis is essential, both for potential cure where possible and for optimal palliative therapy in all others. This review examines the currently available and emerging technologies for diagnosis and treatment of this group of diseases.

Biliary tract cancers (gallbladder cancer, intra- and extra-hepatic cholangiocarcinoma, and selected periampullary cancers) accounted for 12,760 new cases of cancer in the USA in 2010. These tumors have a dismal prognosis with most patients presenting with advanced disease. Early, accurate diagnosis is essential, both for potential cure where possible and for optimal palliative therapy in all others. This review examines the currently available and emerging technologies for diagnosis and treatment of this group of diseases. J. Surg. Oncol. 2012; 106:332–338. © 2012 Wiley Periodicals, Inc.

e16241Background: 5-FU, IRI, and NP are active in GI cancers; the combination, FOLFIRABRAX, has not been evaluated. UGT1A1 clears SN-38, the active metabolite of IRI. UGT1A1*28 polymorphism reduces...

Purpose Sonic hedgehog (SHH), an activating ligand of smoothened (SMO), is overexpressed in > 70% of pancreatic cancers (PCs). We investigated the impact of vismodegib, an SHH antagonist, plus gemcitabine (GV) or gemcitabine plus placebo (GP) in a multicenter phase Ib/randomized phase II trial and preclinical PC models. Patients and Methods Patients with PC not amenable to curative therapy who had received no prior therapy for metastatic disease and had Karnofsky performance score ≥ 80 were enrolled. Patients were randomly assigned in a one-to-one ratio to GV or GP. The primary end point was progression-free-survival (PFS). Exploratory correlative studies included serial SHH serum levels and contrast perfusion computed tomography imaging. To further investigate putative biologic mechanisms of SMO inhibition, two autochthonous pancreatic cancer models (KrasG12D; p16/p19fl/fl; Pdx1-Cre and KrasG12D; p53R270H/wt; Pdx1-Cre) were studied. Results No safety issues were identified in the phase Ib portion (n = 7), and the phase II study enrolled 106 evaluable patients (n = 53 in each arm). Median PFS was 4.0 and 2.5 months for GV and GP arms, respectively (95% CI, 2.5 to 5.3 and 1.9 to 3.8, respectively; adjusted hazard ratio, 0.81; 95% CI, 0.54 to 1.21; P = .30). Median overall survival (OS) was 6.9 and 6.1 months for GV and GP arms, respectively (95% CI, 5.8 to 8.0 and 5.0 to 8.0, respectively; adjusted hazard ratio, 1.04; 95% CI, 0.69 to 1.58; P = .84). Response rates were not significantly different. There were no significant associations between correlative markers and overall response rate, PFS, or OS. Preclinical trials revealed no significant differences with vismodegib in drug delivery, tumor growth rate, or OS in either model. Conclusion The addition of vismodegib to gemcitabine in an unselected cohort did not improve overall response rate, PFS, or OS in patients with metastatic PC. Our preclinical and clinical results revealed no statistically significant differences with respect to drug delivery or treatment efficacy using vismodegib.

427 Background: FOLFIRINOX improves survival compared with gemcitabine in advanced pancreatic cancer (PC), but with significant toxicity (Conroy, NEJM 2011). UGT1A1 clears SN-38, the active metabolite of irinotecan (IRI); UGT1A1*28 polymorphism reduces enzymatic activity and predisposes to severe IRI toxicity. We hypothesized that dosing mFOLFIRINOX based on UGT1A1 genotype would improve tolerability. The primary objective of this study (NCT01643499) was to determine whether genotype-guided dosing of IRI in mFOLFIRINOX is tolerable. A secondary objective was to describe objective response rates (ORR) in PC and biliary tract cancers (BTC). Methods: mFOLFIRINOX was given every 14 days. CT scans were obtained every 8 weeks. UGT1A1 *1/*1, *1/*28, and *28/*28 pts received initial IRI doses of 180, 135, and 90 mg/m2, respectively. 5-FU dose was 2400 mg/m2 over 46 hours (no bolus); leucovorin 400 mg/m2; oxaliplatin 85 mg/m2. In cohort 1 (tolerability cohort by genotype), prophylactic pegfilgrastim was not allowed in cycle 1 (28 days) unless clinically indicated. In cohort 2 (expansion tolerability cohort in PC and BTC), prophylactic pegfilgrastim was given. DLT during cycle 1 was defined as Grade (Gr) 3/4 neutropenia with fever; Gr 4 neutropenia lasting ≥ 5 days; Gr 4 thrombocytopenia, or Gr 3/4 non-hematologic toxicity despite optimal medical management. Doses were tolerable if the DLT rate during cycle 1 was ≤ 33% with 70-80% statistical confidence. Results: In cohort 1, DLTs were observed in 2/15 (13%) *1/*1 pts; 2/16 (13%) *1/*28 pts; 3/9 (33%) *28/*28 pts. In cohort 2, DLTs were observed in 6/19 (32%) PC pts and 4/19 (21%) BTC pts. DLTs in cohort 1 (some pts with multiple): neutropenic fever (5); Gr 3 fatigue (4); Gr 3 diarrhea (2). DLTs in cohort 2: Gr 3 fatigue (3); Gr 3 diarrhea (3); Gr 3 nausea/vomiting (2); Gr 5 sepsis without neutropenia (1); Gr 5 multi-organ failure (1); neutropenic fever (1); Gr 3 anorexia (1). To date, ORR is 13/39 (33%) in PC and 6/28 (21%) in BTC. Conclusions: mFOLFIRINOX is not tolerable in PC and BTC, even with UGT1A1 genotype-guided dosing of IRI and prophylactic pegfilgrastim. More needs to be done to improve the tolerability of this regimen. Clinical trial information: NCT01643499.

97 Background: Node positive disease (N+) is frequent (~40%) following neoadjuvant therapy (NAT) and esophagectomy, yet limited data exist regarding the efficacy of adjuvant chemotherapy (AC) in this setting. There are no randomized studies addressing this question and single-institution, retrospective studies have reported mixed findings. Methods: A retrospective analysis was conducted using the National Cancer Database. 2,258 N+ patients were identified who had received NAT (83.3% chemoradiation and 17.7% chemotherapy alone) followed by esophagectomy. Patients with either incomplete staging or treatment data were excluded, as were those who died within 90 days following esophagectomy. Multivariate logistic regression was used to test for differences in patient characteristics between those who did (AC+) or did not (AC-) receive AC. Overall survival (OS) after surgery, by AC status, was analyzed using Cox regression in a sample propensity matched on relevant demographic and clinical factors. Results: 433/2258 patients received AC (19.2%). Patients who received AC tended to be younger (OR 0.98 per 1-year increase, P = .03) and had a higher socioeconomic status (SES) (OR 1.47 for high vs. low SES, P = .01). Although there were no significant differences in comorbidity (P = .32), AC+ patients had significantly shorter hospital stays after surgery (OR 0.98 per 1-day increase, P = .03). Pathologic T classification was unrelated to the likelihood of receiving AC (P = .39), however patients with a higher pathologic N stage were more likely receive AC (OR 2.12 for pN3 vs. pN1, P < .001). Those receiving AC had demonstrably longer OS from the time of surgery than those who did not (HR 0.78, P = .004). Median OS for the entire cohort was 22.6 months, whereas the administration of AC was associated with an improvement in median OS of 6.2 months (26.3 vs. 20.1 months). Conclusions: This retrospective analysis indicates that AC is associated with a significant improvement in OS (median 6.2 months) in N+ patients following NAT and esophagectomy. Further studies are needed to clarify the optimal role of AC in this setting.

The oncologic equivalence of laparoscopic distal pancreatectomy (LDP) to open pancreatectomy (ODP) for ductal adenocarcinoma (DAC) is not established.The National Cancer Data Base was used to compare perioperative outcomes following LDP and ODP for DAC between 2010 and 2011.One hundred forty-five patients underwent LDP; 625 underwent ODP. Compared with ODP, patients undergoing LDP were older (68 ± 10.1 vs 66 ± 10.5 years, P = .027), more likely treated in academic centers (70% vs 59%, P = .01), and had shorter hospital stays (6.8 ± 4.6 vs 8.9 ± 7.5 days, P.001). Demographic data, lymph node count, 30-day unplanned readmission, and 30-day mortality were identical between groups. Multivariable regression identified a lower probability of prolonged length of stay with LDP (odds ratio .51, 95% confidence interval .327 to .785, P = .0023). There was no association between surgical approach and node count, readmission, or mortality.LDP for DAC provides shorter postoperative lengths of stay and rates of readmission and 30-day mortality similar to OPD without compromising perioperative oncologic outcomes.

Background Carbohydrate antigen (CA) 19-9 is the most common serum biomarker used in pancreatic adenocarcinoma (PC). Elevated preoperative levels have been shown to correlate with more advanced stage, greater risk of unresectability, and overall worse survival. The prognostic value of CA 19-9 nonproduction, which is present in an estimated 5% to 15% of the population, is unclear. We sought to determine whether CA 19-9 nonproduction was associated with worse survival after PC resection. Methods We retrospectively reviewed our institution's prospective pancreatic database for all PC patients with documented preoperative CA 19-9 values who underwent resection with curative intent from March 1992 to August 2009. After excluding 10 perioperative deaths, 200 patients remained for analysis. Results Mean and median follow-up was 23.3 and 16.1 months, respectively. Median survival in months for patients with preoperative CA 19-9 levels in U/mL by category was as follows: normal (5.1 to 36.9): 32, nonproduction (≤ 5): 21, mildly elevated (37 to 99.9): 35, highly elevated (100+): 16. Factors significantly associated with worse overall survival were: nonwhite race, nonproduction or highly elevated preoperative CA 19-9 (≥ 100 U/mL), estimated blood loss ≥ 1 L, tumor size (≥ 2 cm), lymph node-positivity, and advanced (3/4) histologic grade. On multivariate analysis, only CA 19-9 nonproduction or highly elevated production, estimated blood loss ≥ 1 L, advanced histologic grade, and node positivity remained significant in the final model. Conclusions CA 19-9 nonproduction is not associated with improved survival after pancreatic cancer resection, as has previously been asserted, when compared with patients with normal and elevated levels.

Importance Although consensus statements support the preoperative treatment of borderline resectable pancreatic cancer, no prospective, quality-controlled, multicenter studies of this strategy have been conducted. Existing studies are retrospective and confounded by heterogeneity in patients studied, therapeutic algorithms used, and outcomes reported. Objective To determine the feasibility of conducting studies of multimodality therapy for borderline resectable pancreatic cancer in the cooperative group setting. Design, Setting, and Participants A prospective, multicenter, single-arm trial of a multimodality treatment regimen administered within a study framework using centralized quality control with the cooperation of 14 member institutions of the National Clinical Trials Network. Twenty-nine patients with biopsy-confirmed pancreatic cancer preregistered, and 23 patients with tumors who met centrally reviewed radiographic criteria registered. Twenty-two patients initiated therapy (median age, 64 years [range, 50-76 years]; 55% female). Patients registered between May 29, 2013, and February 7, 2014. Interventions Patients received modified FOLFIRINOX treatment (85 mg/m2 of oxaliplatin, 180 mg/m2of irinotecan hydrochloride, 400 mg/m2of leucovorin calcium, and then 2400 mg/m2of 5-fluorouracil for 4 cycles) followed by 5.5 weeks of external-beam radiation (50.4 Gy delivered in 28 daily fractions) with capecitabine (825 mg/m2orally twice daily) prior to pancreatectomy. Main Outcomes and Measures Feasibility, defined by the accrual rate, the safety of the preoperative regimen, and the pancreatectomy rate. Results The accrual rate of 2.6 patients per month was superior to the anticipated rate. Although 14 of the 22 patients (64% [95% CI, 41%-83%]) had grade 3 or higher adverse events, 15 of the 22 patients (68% [95% CI, 49%-88%]) underwent pancreatectomy. Of these 15 patients, 12 (80%) required vascular resection, 14 (93%) had microscopically negative margins, 5 (33%) had specimens that had less than 5% residual cancer cells, and 2 (13%) had specimens that had pathologic complete responses. The median overall survival of all patients was 21.7 months (95% CI, 15.7 to not reached) from registration. Conclusions and Relevance The successful completion of this collaborative study demonstrates the feasibility of conducting quality-controlled trials for this disease stage in the multi-institutional setting. The data generated by this study and the logistical elements that facilitated the trial’s completion are currently being used to develop cooperative group trials with the goal of improving outcomes for this subset of patients. Trial Registration clinicaltrials.gov Identifier:NCT01821612

4103Background: Surgical resection followed by adjuvant gemcitabine or 5-FU is standard for resectable pancreatic cancer (PC). FOLFIRINOX has substantial activity in metastatic PC. The efficacy and...

312 Background: Surgical resection plus adjuvant gemcitabine or 5-FU is standard therapy for resectable PDAC. Infusional 5-FU, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) has substantial activity in metastatic PDAC. Efficacy and tolerability of peri-operative FOLFIRINOX in resectable PDAC is unknown. Methods: Patients (pts) with ECOG PS 0/1 and resectable PDAC confirmed by multidisciplinary review received 4 cycles of mFOLFIRINOX (mFFX)(oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 day 1, 5-FU 2400 mg/m2 x 48 hours, peg-filgrastim 6 mg SQ day 3) pre- and 4 cycles post- surgery. Results: 21/21 enrolled pts started therapy (median age: 63 (47-78), 81% ECOG 0). 20/21 pts completed 4 cycles of preoperative mFFX (1 withdrew for toxicity), 17/21 pts had successful surgical resection (3 had disease noted in the liver at surgery) and 14/21 completed 4 cycles of postoperative mFFX (2 pts expired prior to postoperative mFFX within 90 days of surgery -1 from an M.I. and 1 from a GI bleed; 1 pt had excessive toxicity after cycle 5). Radiographic response by RECIST following preoperative therapy was 1 CR, 3 PR, 16 SD, 0 PD. Of the 17 (81%) patients undergoing curative-intent surgery, 16/17 (94%) had R0 resections. Treatment effect was seen in 10/17 specimens with 1 pathologic CR. Doses were modified per protocol in 30% pts preoperatively (neuropathy 1; thrombocytopenia 2; neutropenia 3; diarrhea 2) and 26% postoperatively (neuropathy 3; diarrhea 3; allergic reaction 1). Grade III and IV adverse events were observed in 23% and 14% pts (overlapping) in the preoperative, and 26% and 0.06% pts in the postoperative phases. 18 pts are alive with a median follow up of 17.3 months. Conclusions: 17/21 (81%) pts completed neoadjuvant mFFX and surgical resection. 14/21 (66%) pts completed all planned therapy. Radiographic responses were rare but efficacy is suggested by the high R0 resection rate: 16/17 (94%) in pts undergoing resection, and 16/21 (76%) pts overall. Toxicity was manageable and within the expected range. 8 cycles of mFFX is a feasible and tolerable peri-operative regimen in pts with resectable PDAC and ECOG PS 0/1. Definitive assessment of efficacy will require longer follow up and larger studies. Clinical trial information: NCT01660711.

396 Background: Chemotherapy regimens used for GIM are often notably myelosuppressive and may also engender hypersplenism. This can result in platelet (plt) and/or absolute neutrophil counts (ANC) too low for the maintenance of required dose intensity or frequency. One successful approach to this problem is surgical splenectomy but this is both morbid and invasive. An alternative strategy uses super-selective embolization of the splenic arterial tree, which is performed as an outpatient, and is far better tolerated. The true efficacy of this technique is uncertain and the optimal patients (pts) for this procedure are not well defined. Methods: Between 11/2012 and 6/2015, pts with ECOG PS 0/1 currently on active therapy for GIM in our clinics, whose plts and/or ANC were consistently below threshold values for appropriate frequency or intensity of therapy, were referred to Interventional Radiology for splenic embolization. Selective catheterization of the splenic artery was achieved via a femoral approach. This was followed by super-selective catheterization of branches of the splenic artery, as distally as possible, with subsequent embolization using Embosphere particles (300-500 micron spheres). All pts received prophylactic IV antibiotics. Results: 10 pts were identified and referred and all were deemed suitable for embolization. The mean plt count prior to the procedure was 73,000 (39,000-167,000) and the mean ANC was 3.5 (1.3 – 5.3). Following one procedure in 9 pts and 2 procedures in 1 pt, the mean plt count rose to 175,000 (55,000-432,000) and the ANC to 7.2 (2.9 – 13.2) immediately, and to a maximum of 253,000 (76,000-511,000) and 9.3 (5.0 – 14.5) within one to two months.Splenic enlargement was noted in 6 pts (mean size 18.3 cm) prior to the procedure and was not present in 4 pts. Following embolization all patients were able to resume chemotherapy with previously effective doses and/or frequency. Conclusions: In our cohort of pts with GIM, splenic embolization was successful at restoring acceptable plt and/or ANC levels for the resumption of effective chemotherapy. Splenomegaly does not appear to be a prerequisite for success.

4008 Background: Infusional 5-FU, oxaliplatin, leucovorin and irinotecan (FOLFIRINOX) is effective for metastatic PDAC. The tolerability and efficacy of neoadjuvant FOLFIRINOX and CRT for BLR PDAC ...

177 Background: Adenocarcinomas of the distal esophagus, gastroesophageal junction and stomach (GEC) remain challenging cancers to treat. Unfortunately, 80-90% of newly diagnosed patients (pts) present with advanced disease where the overall median survival (mOS) is less than 1 year. Discouragingly, various common first-line metastatic regimens have similar overall response rates (ORR) (30-40%; and 47% for HER2+ with trastuzumab). Given results within other GI tumors, FOLFIRINOX was administered to pts with newly diagnosed advanced GEC. Methods: A pooled analysis from two independent ongoing clinical trials was conducted from: 1) the University of Chicago UC (NCT01643499) where pts received modified ‘mFOLFIRINOX’ with irinotecan dosing based on UGT1A1*28 genotyping; and 2) Washington University (WU) (NCT01928290) where pts received standard ‘sFOLFIRINOX’ as previously described, and HER2+ pts also received trastuzumab (sFOLFIRINOX-T). Both studies administered therapy every 14 days. Trastuzumab was administered as 6 mg/kg loading dose then 4 mg/kg every 14 days. mFOLFIRINOX used UGT1A1 genotype *1/*1, *1/*28, and *28/*28 to assign initial irinotecan doses of 180, 135, and 90 mg/m2, respectively. The mFOLFIRINOX 5-FU dose was 2400 mg/m2 over 46 hours (no bolus) with leucovorin 400 mg/m2, and oxaliplatin 85 mg/m2. Outcomes included ORR, tolerability/safety, mPFS, and mOS for both trials. Results: In the pooled analysis, 18 pts with GEC were enrolled to date (11 at WU and 7 at UC), and 16 evaluable for response. ORR was 62.5% (10/16), (HER2- 58% (7/12), HER2+ 75% (3/4)). One HER2+ pt experienced a CR. mPFS was 8 months (range 1.5-18 months), however 10/16 pts have not progressed on first-line therapy to date. There were no unexpected toxicities for any of the regimens. Conclusions: ORR and PFS with first-line FOLFIRINOX were encouraging for metastatic GEC. sFOLFIRINOX was well tolerated in these patients, and sFOLFIRINOX-T was safely administered.mFOLFIRINOX consisting of genotype-directed irinotecan dose reductions and no 5FU bolus may limit toxicity yet retain similar benefit to sFOLFIRINOX. Continued investigation of this regimen is warranted given these encouraging preliminary results. Clinical trial information: 01928290.

2570 Background: The risk of severe neutropenia from irinotecan (I) is in part related to UGT1A1*28, a polymorphism that reduces the elimination of SN-38, the active metabolite of I. We aimed to identify the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of I in advanced solid tumor patients (pts) stratified by*1/*1, *1/*28, and *28/*28 genotypes. We hypothesized that *1/*1 pts would tolerate a higher MTD than the standard 350 mg/m2 dose and that *28/*28 pts would require dose reduction. Methods: 68 pts (30 lung, 30 gastrointestinal, 8 other cancers) received q3w, flat-dose I. Genotype frequencies were 46% (*1/*1), 41% (*1/*28), and 13% (*28/*28). Pts (66% males, median age 68 years) had 0-1 PS (only one pt had PS 2). 82% were Caucasians, 13% African Americans, and 4% Hispanics. The I starting dose was 700 mg in *1/*1 and *1/*28 pts, and 500 mg in *28/*28 pts. Pharmacokinetics was obtained at cycle 1. DLT at cycle 1 was defined as grade (G) 4 neutropenia (N) for ≥4 days, G≥3N on a treatment day, G≥3 febrile N, G4 anemia or thrombocytopenia, or G≥3 non-hematological toxicity. Results: In *1/*1 pts, the MTD was 850 mg (4 DLTs/16 pts), and 1000 mg was not tolerated (2 DLTs/6). In *1/*28 pts, the MTD was 700 mg (5 DLTs/22) and 850 mg was not tolerated (4 DLTs/6). In *28/*28 pts, the MTD was 400 mg (1 DLT/6) and 500 mg was not tolerated (3 DLTs/3). DLTs were mainly G4N, G≥3 febrile N, and G3 diarrhea. I clearance followed linear kinetics. I and SN-38 AUCs were associated with decreased log10ANC nadir (r2 0.27 and 0.30, respectively, p

4022 Background: Sonic Hh (SHh), the ligand for the Hh pathway, is over-expressed in >80% of PC. V, a small molecule antagonist of the Hh signaling pathway, has activity in preclinical PC models. Methods: We conducted a multi-center, placebo-controlled, phase IB/randomized phase II trial of GV or GP. Eligible pts, KPS 80-100, had previously untreated metastatic PC, or had completed adjuvant therapy > 6 months (mo) prior. Primary endpoint: progression-free survival (PFS). Correlatives: serial SHh serum levels; serial contrast perfusion CT imaging. To allow for early stopping due to lack of efficacy, a planned interim analysis was performed after approximately 50% of the expected number of PFS events occurred. The protocol stipulated that the trial would be terminated if the probability of rejecting the null hypothesis were the trial to continue (conditional power) was 2 over 30 minutes, days (D) 1, 8, 15, Q28D. Pts, stratified by KPS (80 v 90/100), and disease status (newly-diagnosed/recurrent), were randomized to V (150 mg PO daily) or P. For pts on P, cross-over was allowed at progression. Results: 70 evaluable pts (V/P 35/35) enrolled at 12 sites 2/10-6/11. Pt characteristics: median age 63/63 (range 49-79/48-82); KPS 80: 8/8; 90: 12/14; 100: 15/13. Grade 3/4 toxicity (%pts): neutropenia 20/26; hyponatremia 3/11; fatigue 9/6; hyperglycemia 14/6; elevated alkaline phosphatase 9/11. Response (%): complete 0/3, partial 0/11, stable disease 49/31. Median PFS: 3.7/2.4 mo (95% CI: 2.4-4.6/1.9-3.7; adjusted HR 0.92 [0.52-1.64]). Upon progression/unblinding, 23 GP pts crossed over to GV. Median overall survival (OS): 6.3/5.4 mo (95% CI:4.9-7.8/4.2-8.0, adjusted HR 0.97, [0.47-2.01]). 1-year survival (%): 24/24. Laboratory and radiological correlatives will be presented. Conclusions: GV has an acceptable toxicity profile. This trial did not meet criteria for futility at this interim analysis. The study is expected to complete accrual of 112 pts in February 2012. The final analysis will be reported after 90 events. Funded by NCI N01-CM-62201.

e14642 Background: Ampullary adenocarcinoma represents 1% of GI cancers but accounts for almost 30% of Whipple operations at major centers. Prognosis falls between that of pancreatic and duodenal cancer, but demographic and prognostic factors are not well delineated. Methods: Retrospective review, with patient consent, of an IRB approved common surgical database at two academic institutions. This includes all cases operated on for ampullary adenocarcinoma between 1997 and 2009. Demographics and factors with potential relevance for prognosis by literature review were examined via Kaplan Meier and/or Cox models. Results: 74 cases were identified: 50 had conventional and 22 pylorus preserving Whipple procedures with 2 unresectable cases. Demographics: 38 males, 36 females; 64 Caucasian, 6 African American and 4 others; age 23-83, median 63.08 years. Tumor characteristics: Tis -1, T1-10, T2-22, T3-27, T4-12, Unknown-2; N0-35, N1-38, Unknown-1; pre-existing adenomas in 37 (50%). Tumor markers: CEA 2/34 and CA 19-9 16/37 tested were abnormal. Adjuvant therapy given (chemo and/or chemoRT): 33/74. Status: 34 patients alive and 41 deceased with a median follow-up of 22 months. Factors associated with poor outcome: Perineural invasion (PNI) p = 0.02; Pre-existing adenoma p = 0.001; Weight loss of 10 lbs or more p = 0.01; RBC transfusion in the OR p = 0.001. Factors not statistically prognostic: T stage, lymph nodal status, lymphovascular invasion, jaundice, CEA or CA 19-9 values and absence of adjuvant therapy. Pancreaticobiliary versus intestinal subtype was assessed by H and E staining but one third of cases were indeterminate, and while these appeared to have a worse prognosis, IHC will be performed for accurate classification and determination of significance. Conclusions: This dataset describes the demographics of patients treated for ampullary adenocarcinoma over 12 years and identifies PNI, weight loss, pre-existing adenoma and transfusion in the OR as adverse factors. These prognostic factors (and potentially histologic subtype) should be considered in patient care and future study design.

334 Background: Ampullary adenocarcinoma represents 1% of GI cancers but accounts for almost 30% of Whipple operations at major centers. Prognosis falls between that of pancreatic and duodenal cancer, but demographic and prognostic factors are not fully delineated. A better understanding of the biology of this disease is essential both for patient care and for the optimal design of future studies. Methods: Retrospective review, with patient consent, of an IRB approved comprehensive common surgical database at two academic institutions. This database included all cases operated on for ampullary adenocarcinoma between 1997 and 2009. Demographics and factors thought to have potential relevance for prognosis by literature review were examined, where available, via Kaplan Meier and/or Cox models. Results: 74 cases were identified: 50 had conventional and 22 pylorus preserving Whipple procedures with 2 unresectable cases. Demographics: 38 males, 36 females; 64 Caucasian, 6 African American and 4 others; age 23-83, median 63.08 years. Tumor characteristics: Tis -1, T1-10, T2-22, T3-27, T4-12, Unknown-2; N0-35, N1-38, Unknown-1; pre-existing adenomas in 37 (50%). Tumor markers: CEA 2/34 and CA 19-9 16/37 tested were abnormal. Adjuvant therapy given (chemo and/or chemoRT): 33/74. Status: 34 patients alive and 41 deceased with a median follow-up of 22 months. Factors associated with poor outcome: Perineural invasion (PNI) p = 0.02; Pre-existing adenoma p = 0.001; Weight loss of 10 lbs or more p = 0.01; RBC transfusion in the OR p = 0.001. Factors not statistically prognostic: T stage, lymph nodal status, lymphovascular invasion, jaundice, CEA or CA 19-9 values and absence of adjuvant therapy. Pancreaticobiliary versus intestinal subtype could not be assessed as this was rarely reported. Conclusions: This dataset describes the demographics of patients sequentially treated for ampullary adenocarcinoma over 12 years, and identifies PNI, weight loss, pre-existing adenoma and transfusion in the OR as adverse factors. These prognostic factors (and potentially histologic subtype) should be considered in patient care and future study design.