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Background: Only a few studies investigated the association between proton pump inhibitor (PPI) use and pancreatic cancer, with inconsistent results. Moreover, these studies had a number of methodologic limitations. Our objective was to assess this association in a nationwide case–control study. Methods: We used the French National Health Data System (SNDS), covering 99% of the French population since 2006. Incident cases of pancreatic cancer, identified between 2014 and 2018, were matched with up to four controls on year of birth, sex, frequency of hospitalization within 8 years prior to index date, and department of residence. Associations between PPIs and pancreatic cancer were estimated using conditional logistic regression models adjusted for sociodemographic characteristics, risk factors of pancreatic cancer (including diabetes mellitus, tobacco-related diseases, and morbid obesity), and other comorbidities. Results: A total of 23,321 cases of pancreatic cancer (mean age, 69.8 years; 51.7% males) and 75,937 matched controls were included. Overall, 77.8% of cases and 75.5% of controls were PPI ever users. Ever (vs. never) PPI use was associated with an increased risk of pancreatic cancer [adjusted OR (aOR) = 1.05, 95% confidence interval (CI), 1.01–1.09]. A dose–response relationship was observed [1–30 cumulative defined daily dose (cDDD): aOR = 0.92, 95% CI, 0.87–0.97; 31–180 cDDD: aOR = 1.05, 95% CI, 1.00–1.11; 181–1,080 cDDD: aOR = 1.18, 95% CI, 1.12–1.24; >1,080 cDDD: aOR = 1.17, 95% CI, 1.10–1.23]. Conclusions: On the basis of these findings, a slight increase in the risk of pancreatic cancer associated with high cumulative doses of PPIs cannot be excluded. Impact: Given the overuse of PPIs, efforts should be continued to limit treatments to appropriate indications and durations.

Background: Neuroendocrine carcinomas (NECs) of the digestive tract are rare and aggressive tumours. In localised disease the treatment is surgery. Based on expert consensus, international guidelines recommend the administration of adjuvant chemotherapy combining etoposide and platinum derivatives, justified by the high risk of metastatic relapse. However, no clinical study has proven the benefit of neoadjuvant or adjuvant chemotherapy. Objectives: We aimed to evaluate the effect of neoadjuvant +/– adjuvant and adjuvant therapy in this indication. Methods: We performed a retrospective observational French study to evaluate overall survival (OS) and disease-free survival (DFS), prognostic factors for survival, and chemotherapy toxicity. Results: Seventy-three patients had surgical resection of a localised digestive NEC between January 1, 2000 and December 31, 2016. The majority of patients presented colorectal (35%) tumours and the median Ki-67 value was 70%. Forty-three patients received chemotherapy, either perioperative (neoadjuvant +/– adjuvant) or adjuvant. The median OS and DFS for the whole population was 24 and 9 months, respectively. The median OS and DFS for patients receiving chemotherapy was 62 and 13 months, respectively. Positive postoperative node status and Ki-67 ≥80% had a negative prognostic impact on OS and DFS. Administration of chemotherapy had a positive prognostic impact on OS and DFS. Sixteen grade 3/4 toxicities were reported without toxic death. Conclusions: Our results suggest a positive effect on survival of chemotherapy in resected digestive NECs, but further studies are needed to confirm these results.

Background Poorly differentiated neuroendocrine carcinomas (NEC) are rare diseases with a poor prognosis. Platinum-etoposide (PE) has been the recommended first-line treatment for decades. FOLFIRINEC (NCT04325425) is a national multicenter randomized phase II study which aims to challenge this standard regimen. Methods The primary objective is to compare the median progression-free survival (PFS) under mFOLFIRINOX versus PE. The secondary objectives are to evaluate the objective response rates (ORR), median overall survival (OS), safety and quality of life. The associated real-time translational study will establish a molecular profile for each patient enrolled. Main inclusion criteria are NEC of gastroenteropancreatic (GEP) or unknown origin, metastatic and RECIST 1.1 evaluable disease, tumor sample available and no contraindication to chemotherapy. Patients will be randomized 1:1 between PE every 21 days for 6–8 cycles and mFOLFIRINOX every 14 days for up to 12 cycles and stratified according to center, performance status, Ki67 and pathological subtype. This trial will randomize 218 patients (24 months of follow-up) to have 80% power to detect an improvement of the median PFS from 5 months under PE to 7.5 months under mFOLFIRINOX (HR of 0.67, α =5%, two-sided). An intermediate analysis is planned at 50% of events. Recruitment started on October 20, 2020.

Purpose Functional studies have demonstrated that some mutations of ERBB3, which encodes for human epidermal growth factor receptor (HER) 3, are oncogenic via activation of the ErbB family signaling pathway. Significant clinical activity of anti-HER2 therapies (trastuzumab plus lapatinib combination or afatinib) has been reported in patients with ERBB3-mutated cancers. This study was designed to report the rate of activating ERBB3 mutations in small bowel adenocarcinoma (SBA), a rare tumor type in which we previously reported a high rate (12%) of ERBB2-activating mutations. Materials and Methods DNA from 74 SBAs, previously characterized for ERBB2 mutations and mismatch repair status, was submitted for sequencing of ERBB3 exons 3, 6, 7, 8, and 23. Orthogonal validation by targeted next-generation sequencing was performed. Results Four of 74 SBAs (5.4%) displayed ERBB3-activating mutations, including three p.V104M mutations (c.310 G>A) in exon 3 and one p.E928G mutation (c.2783 A>G) in exon 23. No mutations were detected in exons 6, 7, and 8. ERBB3-activating mutations were associated with microsatellite instability ( P = .002) and the presence of ERBB2-activating mutations ( P = .002). Two SBAs with co-occurrence of ERBB2 and ERBB3 mutations were further analyzed by targeted next-generation sequencing. Mutant allelic frequencies suggested that both mutations were shared by the same clone rather than being harbored by mutually exclusive tumor subclones. Conclusion SBAs display a high rate of ERBB3-activating mutations, which have been shown to be targetable by anti-HER2 therapies. Strikingly, ERBB3 was frequently comutated with ERBB2, suggesting a strong oncogenic addiction of these SBAs to the HER2 pathway.

Background: Log odds of positive lymph nodes (LODDS) classification showed superiority over 8th edition N staging in predicting survival of small bowel adenocarcinoma (SBA) patients. The aim of this study was to develop and validate the Tumor, LODDS, and Metastasis (TLM) staging of SBA. Methods: Totally 1789 SBA patients from the Surveillance, Epidemiology, and End Results (SEER) database between 1988–2010, 437 patients from SEER database between 2011–2013 and 166 patients from multicenters were categorized into development, validation and test cohort, respectively. The TLM staging was developed in the development cohort using Ensemble Algorithm for Clustering Cancer Data (EACCD) method. C-index was used to assess the performance of the TLM staging in predicting cancer-specific survival (CSS) and was compared with the traditional 8th edition TNM staging. Findings: Four-category TLM staging designed for the development cohort showed higher discriminatory power than TNM staging in predicting CSS in the development cohort (0.682 vs. 0.650, P

Microsatellite instability (MSI) is a tumor phenotype linked to somatic or germline (Lynch syndrome) inactivating alterations of DNA mismatch repair genes. A broad spectrum of neoplasms exhibits MSI phenotype, mainly colorectal cancer, endometrial cancer, and gastric cancer. MSI tumors are characterized by dense immune infiltration and high load of tumor neo-antigens. Growing evidence is accumulating on the efficacy of immune checkpoint inhibition for patients treated for MSI solid tumors. We present a comprehensive overview of MSI phenotype, its biological landscape and current diagnostic methods. Then we focus on MSI as a predictive biomarker of response to immune checkpoint inhibition in the context of colorectal cancer and non-colorectal tumors.

Poorly differentiated neuroendocrine tumors are rare but their incidence is rising. High-grade neuroendocrine lung tumors, including small-cell lung cancer, are part of this group. Outside of the lung, they most often arise within the gastrointestinal tract (oesophagus, guts and pancreas) and are called neuroendocrine carcinomas. Due to their rarity, very little is known about neuroendocrine carcinomas of the pancreas and the gastrointestinal tract and few studies have been done. Therefore, most therapeutic recommendations are issued from studies on small-cell lung cancers. Histological scores have grown more accurate these past few years: poorly differentiated neuroendocrine tumors regroup various entities such as small-cells, large-cells and mix tumors, which seem to have different prognosis. They are diagnosed at a metastatic state in more than 50 % of cases. In localised disease, surgery is performed on selected patients. Adjuvant chemotherapy is administered in poorly differentiated neuroendocrine tumors of the lung and is an option in neuroendocrine carcinomas, without proof of efficacy. If not operable, radiochemotherapy is done for tumors of the lung, rectum, and eosophagus. If the disease is diagnosed at a metastatic state, chemotherapy is administered with a combination of platin salts (cisplatin or carboplatin) and etoposide. In poorly differentiated neuroendocrine tumors of the lung, prophylactic cranial irradiation is performed in localized disease if there is a good response to chemotherapy. Even if these therapies have improved the overall survival, no improvement has been made during the past four decades and the prognosis remains low.

This review reports 3 of recently published molecular classifications of the 3 main gastro-intestinal cancers: gastric, pancreatic and colorectal adenocarcinoma. In colorectal adenocarcinoma, 6 independent classifications were combined to finally hold 4 molecular sub-groups, Consensus Molecular Subtypes (CMS 1-4), linked to various clinical, molecular and survival data. CMS1 (14% MSI with immune activation); CMS2 (37%: canonical with epithelial differentiation and activation of the WNT/MYC pathway); CMS3 (13% metabolic with epithelial differentiation and RAS mutation); CMS4 (23%: mesenchymal with activation of TGFβ pathway and angiogenesis with stromal invasion). In gastric adenocarcinoma, 4 groups were established: subtype "EBV" (9%, high frequency of PIK3CA mutations, hypermetylation and amplification of JAK2, PD-L1 and PD-L2), subtype "MSI" (22%, high rate of mutation), subtype "genomically stable tumor" (20%, diffuse histology type and mutations of RAS and genes encoding integrins and adhesion proteins including CDH1) and subtype "tumors with chromosomal instability" (50%, intestinal type, aneuploidy and receptor tyrosine kinase amplification). In pancreatic adenocarcinomas, a classification in four sub-groups has been proposed, stable subtype (20%, aneuploidy), locally rearranged subtype (30%, focal event on one or two chromosoms), scattered subtype (36%, 200 structural variation events, defects in DNA maintenance). Although currently away from the care of patients, these classifications open the way to "a la carte" treatment depending on molecular biology.

Introduction Data are lacking with regard to curative resection of metastasis from small bowel adenocarcinoma (SBA). This study evaluated outcomes and prognostic factors in patients with curatively resected metastatic SBA. Methods A series of 34 patients undergoing resection of metastatic SBA from January 2009 to November 2014 at French centers were included into this cohort study. The primary endpoint was overall survival (OS). Secondary endpoints were recurrence-free survival (RFS) and prognostic factors. Univariate analyses were performed to determine prognostic risk factors. Results The sites of SBA metastases were peritoneal (29.4%), liver (26.5%), lymph nodes (11.8%), lung (2.9%), multiple (14.7%), and other (14.7%). Thirty (88.2%) patients received adjuvant or perioperative chemotherapy, mainly was oxaliplatin-based (76.5%). The median OS was 28.6 months and RFS was 18.7 months. Fourteen (41.2%) patients survived for more than 36 months. In univariate analysis, poor differentiation (P = 0.006), invaded margins (P = 0.003), and lymphatic invasion in the primary tumor (P = 0.039) were associated with decreased OS. Conclusion Overall survival of patients after resection of metastatic SBA remains poor, but long-term survivors are observed. Resection of metastatic SBA should be consider if patients are expected to be operated on with curative intent and have moderately or well-differentiated tumors.

Microsatellite instability (MSI) is a molecular indicator of defective DNA mismatch repair (dMMR) and is observed in approximately 5% of metastatic colorectal cancers (mCRC). MSI is a major predictive biomarker for the efficacy of immune checkpoint inhibitors (ICKi) amongst mCRC patients. After summarizing the literature about the efficacy of conventional cytotoxic regimens, we will highlight studies that have demonstrated the clinical activity of ICKi for patients with chemoresistant MSI/dMMR mCRC. Then we will focus on ongoing clinical trials and emerging challenges for the treatment of patients with MSI/dMMR mCRC.

Background: The prognostic roles of three common lymph node staging schemes, number of positive lymph nodes (pN), lymph node ratio (LNR) and log odds of positive lymph nodes (LODDS) in small bowel adenocarcinoma (SBA) are unclear. We assessed their prognostic ability in SBA. Methods: A total of 2128 patients diagnosed with SBA between 1988 and 2010 from the Surveillance, Epidemiology, and End Results (SEER) database and 186 patients from 15 hospitals in France and China were identified. We evaluated the prognostic ability of the schemes in both continuous and stratified patterns using R2, Harrell's C, and time-dependent receiver operating characteristic curve analyses. Findings: For continuous pattern, the LODDS had a better capacity of discrimination and higher accuracy of prognosis than pN and LNR. Similarly, the stratified LODDS classification had a better performance of discrimination and higher accuracy of prognosis than the pN and LNR classification. The multivariable model using the LODDS classification also showed superiorly predictive accuracy and discriminatory capacity to those of the 7th and, 8th TNM node and LNR classification. These results were fully validated in an independent international multicentre cohort. Interpretation: The LODDS scheme showed a better prognostic performance than the LNR or pN schemes in patients with SBA regardless of continuous or stratified pattern. The LODDS scheme could serve as an auxiliary to lymph node staging systems in future revisions of the American Joint Committee on Cancer (AJCC) manual. Fund: This work was funded by the Zhejiang Province Natural Science Fund of China. Keywords: Small bowel adenocarcinoma, Log odds of positive lymph nodes, Lymph node ratio, Number of positive lymph nodes, Prognosis, Multicentre cohort

Background Neuroendocrine tumors (NET) represent a heterogeneous group of rare tumors, some of them secreting serotonin resulting in the carcinoid syndrome (CS). CHD is an integral part of this syndrome but remains poorly understood. The GTE is conducting a national survey of patients at risk for CHD aiming at evaluating the occurrence & progression rates of CHD, the frequency & results of cardiac surgery, and patient outcomes as well as the role of clinical characteristics and biomarkers as predictive markers; 600 patients are expected over a 5-year period with a 10-year follow-up. We herein present the study status at one year. Methods Patients with a metastatic ileum or bronchial NET, or any NET with a CS or 5HIAA levels greater than at least twice the upper normal range, seen by a NET specialist and a referee cardiologist are eligible. Clinical, pathological, biological parameters and previous treatments are collected. A transthoracic echocardiography is realised at inclusion and at least every year. Results From March 2018 to March 2019, 167 patients from 8 centers were included. Median [range] time from NET diagnosis to study inclusion was 56 months [0-501]. Median age was 66 years [34-86] with a male preponderance (53%); 85% had ileum NETs, 8% lung NETs, and 7% other NETs with CS or elevated 5HIAA; 100% had metastatic disease. Most of them have been pretreated: somatostatin analogs 96%, surgery of primary tumor 81% or metastasis 34%, liver embolization 24%, peptide receptor radionuclide therapy 19%, chemotherapy 16%, targeted therapy 12%, radiofrequency ablation 6%, interferon 2%. At inclusion, 81 patients (49%) had a CS, 67% with flushing, 68% with diarrhea. CHD was documented in 22 (13%) patients, all of them had tricuspid disease and simultaneous pulmonary, mitral and/or aortic disease for respectively 13, 3 and 1 of them; 14 patients with CHD had a CS. Seven patients underwent cardiac surgery for CHD. Conclusions The first large prospective multicentric study about CHD is ongoing. Preliminary results confirm the feasibility of the study with nearly 170 patients included in one year and 13% of CHD. The inclusion of new patients and 10-year follow-up will allow a better knowledge of the current incidence, progression and prognosis of CHD. Clinical trial identification NCT03498040. Legal entity responsible for the study French Group of Endocrine Tumors (GTE). Funding IPSEN. Disclosure G. Cadiot: Advisory / Consultancy: Novartis; Advisory / Consultancy: Ipsen; Advisory / Consultancy: AAA; Advisory / Consultancy: Keocyt. P. Nazeyrollas: Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Novartis; Honoraria (self), Non-remunerated activity/ies: MSD; Honoraria (institution): Sanofi; Honoraria (institution): novo-nordisk; Travel / Accommodation / Expenses, Non-remunerated activity/ies: actelion; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Bayer; Non-remunerated activity/ies: Servier; Non-remunerated activity/ies: bms. P. Afchain: Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Ipsen. F. Delelis: Honoraria (self): Novartis; Honoraria (self): boehringer. J. Forestier: Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Honoraria (self): Servier. C. Lombard Bohas: Advisory / Consultancy: Ipsen; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AAA. All other authors have declared no conflicts of interest.

4140 Background: Small bowel adenocarcinoma (SBA) is a rare tumour. Large genomic analyses with prognostic assessments are lacking. Methods: BIONADEGE is an ancillary study of the NADEGE cohort that enrolled 347 patients (pts) with SBA from 2009 to 2012. Next generation sequencing investigates the presence of 740 hot spot somatic mutations in 46 genes involved in carcinogenesis. The MSI (MicroSatellite Instable) status was assessed using 5 microsatellites. The MMR (MisMatch Repair) status was assessed by immunochemistry (4 antibodies). Results: A total of 196 tumour samples were collected and 125 pts had conclusive results for mutation analysis. The clinical and tumours characteristics were comparable in the NADEGE and BIONADEGE cohort except for metastatic stage at diagnostic underrepresented in the BIONADEGE cohort (17.7%) due to missing tumour sample. A predisposing disease was reported in 25 (20.0%) cases (among them 14 Lynch syndromes and 7 Crohn diseases). The number of mutation observed was 0 in 9.6% pts, only 1 in 32.0%, 2 in 26.4% and ≥3 in 32.0%. The most frequent genomic alteration were KRAS (44.0%), TP53 (38.4%), PIK3CA (20.0%), APC (18.4%), SMAD4 (14.4%) and ERBB2 (7.2%). Altogether, a genomic alteration was observed in 90.3% of tumour. KRAS mutation were more frequent in synchronous metastatic tumour than in localized tumour (72.7% vs 38.2%, p = 0.003). There was no significant difference of mutation rate according to primary location for the most frequently altered gene. With caution to small sample, IDH1 mutation is more frequent and APC mutation never seen in Crohn disease. The rate of dMMR tumor was 38.6% in localized tumour and 0% in synchronous metastatic tumour. After a median follow-up of 55 months (95%CI [44-63]), M0 stage, pN0, pT1-2 were associate with better survival in univariate analysis. No significant prognostic value of genomic alteration was associated with OS. dMMR status was associate with a better prognosis for OS in pts with MMR status determined by immunohistochemistry (HR = 0.55 [0.29-1.01], p = 0.055). Conclusions: A high frequency of targetable alteration is observed in SBA. There is several specificities according to predisposing disease. No association between genomic alteration and prognostic was observed except a trend for a better prognosis associate with dMMR.

Whether the survival benefit of perioperative FOLFOX in patients with liver metastases of colorectal cancer (LMCRC) is provided by preoperative chemotherapy (CT), postoperative CT, or both remains unclear. This study aimed to evaluate, in patients with resectable LMCRC, the survival impact of preoperative and postoperative separately.Between 2000 and 2010, the 179 patients (126 men, age 61 ± 11 years) with initially resectable LMCRC, who underwent liver resection (LR) and were offered pre- and/or postoperative FOLFOX were included. Twenty-four (13%) patients did not receive CT, 27(15%) patients received only preoperative CT, 71 (40%) patients received only postoperative CT, and 57 (32%) patients received both pre- and postoperative CT.Operative morbidity and mortality rates were 19 and 0.6%, respectively. At 1, 3, and 5 years, OS and DFS rates were 97, 66, 46 and 60, 32, and 24%, respectively. Postoperative FOLFOX was an independent predictor of increased OS (HR = 0.55 [95% CI, 0.35-0.87] p = 0.01) and DFS (HR = 0.54 [0.36-0.82] p = 0.0017), whereas the synchronous onset of the metastasis and the presence of radiographically occult liver metastases were independent predictors of poorer OS. Alternatively, preoperative FOLFOX had no significant influence on OS (HR = 0.96 [0.57-1.60] p = 0.83) or DFS (HR = 1.05 [0.66-1.66] p = 0.87).The survival benefit of FOLFOX in patients with resectable LMCRC may be provided by postoperative rather than preoperative administration.

Small bowel adenocarcinomas (SBAs) are rare tumors, but their incidence is increasing. The most common primary location is the duodenum. Even though SBAs are more often sporadic, some diseases are risk factors. Early diagnosis of small bowel adenocarcinoma remains difficult, despite significant radiologic and endoscopic progress. After R0 surgical resection, the main prognostic factor is lymph node invasion. An international randomized trial (BALLAD [Benefit of Adjuvant Chemotherapy For Small Bowel Adenocarcinoma] study) will evaluate the benefit of adjuvant chemotherapy. For metastatic disease, retrospectives studies suggest that platinum-based chemotherapy is the most effective treatment. Phase II studies are ongoing to evaluate targeted therapy in metastatic SBA.

Purpose This study compared chemotherapy discontinuation with maintenance therapy with leucovorin and fluorouracil after six cycles of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) chemotherapy in the first-line treatment of metastatic colorectal cancer. Patients and Methods Two hundred two patients with untreated metastatic colorectal cancer were randomly assigned to receive six cycles of modified FOLFOX7 (mFOLFOX7) followed by simplified leucovorin plus bolus and infusional fluorouracil until progression (arm 1 or maintenance arm, n = 98) or six cycles of mFOLFOX7 before a complete stop of chemotherapy (arm 2 or chemotherapy-free interval [CFI] arm, n = 104). Reintroduction of mFOLFOX7 was scheduled after tumor progression in both arms. The primary study end point was duration of disease control (DDC). Results Median DDC was 13.1 months in patients assigned to the maintenance arm and 9.2 months in patients assigned to the CFI arm (P = .046). Median progression-free survival (PFS) and overall survival were 8.6 and 23.8 months, respectively, in the maintenance arm and 6.6 and 19.5 months, respectively, in the CFI arm. Median duration of maintenance therapy (arm 1) and CFIs (arm 2) were 4.8 months and 3.9 months, respectively. Overall response rates were 59.2% and 59.6% for the initial FOLFOX chemotherapy and 20.4% and 30.3% for FOLFOX reintroduction in arms 1 and 2, respectively. Conclusion The planned complete discontinuation of chemotherapy had a negative impact on DDC and PFS compared with the maintenance therapy strategy. These results suggest that chemotherapy discontinuation cannot be decided before therapy is initiated in patients with advanced colorectal cancer.

Purpose. GemOx was defined as a D1-D2 schedule, based on preclinical data. In order to improve convenience for patients, we evaluated a simplified D1-D1 GemOx regimen (S-GemOx) in MPA. Patients and methods. Patients (pts) with MPA were 2:1 randomly assigned for first-line treatment to S-GemOx (gemcitabine 1,000 mg/m 2, 100-minute infusion D1 immediately followed by oxaliplatin 100 mg/m 2, 120-minute infusion) or to GemOx (Gem D1 and ox D2). Treatment was repeated in each arm every 2 weeks until disease progression. Stratification was performed on center and PS. Results. Fifty-seven pts were enrolled, S-GemOx = 37 (PS 2: 22%), GemOx = 20 (PS 2: 20%). Populations were well balanced for age (64.9 vs 66.6 years); gender (57 vs 65% male), location of primary tumor (pancreas head: 49 vs 50%), and metastatic sites (liver 76 vs 85%; peritoneum 24 vs 20%; lung 16 vs 10%; lymph nodes 14 vs 15%; other 5 vs 5%). Tumor differentiation significantly differed between the 2 groups (S-GemOx: 8% poorly differentiated vs GemOx: 36%). Response rate was 27% (95% CI: 12-42) in arm S-GemOx and 10% (95% CI: 0-23) in GemOx. Median PFS was 4.0 and 2.5 months in S-GemOx and GemOx, respectively. Median OS was 7.6 and 3.2 months in S-GemOx and GemOx, respectively. Since more cycles were administered in S-GemOx (8.5 [1-29] vs 5.8 [2–12]), grade 3 oxaliplatin-induced neuropathy was higher in S-GemOx [21.6 vs 0%]). Conclusions. Activity and tolerance of S-GemOx are in the same range as compared to our previous experiences of classical GemOx in metastatic pancreatic cancer. The very bad outcome of patients randomized in GemOx arm could at least be in part explained by the high-rate of poorly differentiated tumors.

Purpose Perioperative chemotherapy with 5-fluorouracil and cisplatin, with or without epirubicin, improves overall survival in resectable gastroesophageal junction and gastric adenocarcinoma. The aim of this retrospective multicenter study was to evaluate the safety and efficacy of perioperative chemotherapy with a FOLFOX-based regimen. Patients and methods We enrolled patients with resectable gastric or gastroesophageal adenocarcinoma, who had at least 3 cycles of a pre-operative FOLFOX-based regimen. The primary end point was the feasibility of the peri-operative chemotherapy. Results We enrolled 109 patients from 2007 to 2012 in 12 centres. Their median age was 66, 67% were men and 73% had gastric tumours. The median number of chemotherapy courses was 6 with a median of 4 pre-operative cycles and 2 post-operative cycles. Twenty-three patients received at least 8 cycles of chemotherapy. In univariate analysis, the Karnofsky index at inclusion was the only factor associated with 8 cycles of chemotherapy. An R0 resection was achieved in 100 patients (95.2%). Conclusion The FOLFOX-based perioperative regimen achieves favourable results in real life practice. The optimal number of chemotherapy cycle remains to be determined. FOLFOX regimen may be used as an alternative treatment option to a cisplatin-based regimen in resectable gastroesophageal adenocarcinoma. A prospective randomized trial is needed to confirm these results.

Background Relapses of epithelial ovarian carcinoma (EOC) have a poor prognosis. Isolated lymph node relapses (ILNR) are considered of relatively good prognosis with intensive therapy. Methods This retrospective study aimed to describe incidence, characteristics, outcomes and prognostic factors of ILNR treated over 15 years. Results Twenty-seven patients (4.2%) experienced an ILNR among 640 patients. Median age was 59 years, tumour stages included stage I ( n =4), II ( n =5), III ( n =15) and IV ( n =3). After initial optimal treatment, median progression-free survival (PFS) was 26 months. Sites of relapse were retroperitoneum ( n =15), left supraclavicular ( n =7), mediastinum ( n =4), iliac ( n =4) and inguinal ( n =3). ILNR locations were unique in 63% of patients ( n =17) and multiple in 37% ( n =10). Treatment modalities were surgery in eight patients (30%), chemotherapy in 15 (55%) and radiotherapy in 5 patients (18%), alone or in combination. Seven patients without tumour-related symptoms (26%) were not treated. Median overall survival (OS) after ILNR was 26 months. Median OS from initial diagnosis was 68 months. 25% of patients had a very long survival (>100 months), independent of their initial staging or PFS. There was no difference in 2-year survival after ILNR between the groups of early relapse (before 24 months) and late relapse (after 24 months). In the seven non-treated patients, median OS was 91 months. Conclusion ILNR is a rare event in EOC. Time to relapse may not have its usual prognostic value. Immediate or delayed therapy should be discussed in case of asymptomatic ILNR.

Background: Small bowel adenocarcinoma (SBA) is a rare tumour with a poor prognosis. Molecular biology data on SBA carcinogenesis are lacking. Methods: Expression of HER2, β-catenin, p53 and mismatch repair (MMR) protein was assessed by immunohistochemistry. KRAS, V600E BRAF mutations and microsatellite instability were investigated. Results: We obtained samples from 63 SBA patients (tumour stages: I–II: 30% III: 35% IV: 32% locally advanced: 3%). HER2 overexpression (3+) was observed in 2 out of 62 patients, overexpression of p53 in 26 out of 62, abnormal expression of β-catenin in 12 out of 61, KRAS mutation in 21 out of 49, BRAF V600E mutation in 1 out of 40 patients, MMR deficiency (dMMR) in 14 out of 61 and was consistent with Lynch syndrome in 9 out of 14 patients. All of the dMMR tumours were in the duodenum or jejunum and only one was stage IV. Median overall survival (OS) was 36.6 months (95% CI, 26.9–72.2). For all patients, in univariate analysis, stages I–II (P

Small bowel adenocarcinomas are rare tumours, but their incidence is increasing. Their most common primary location is the duodenum. The few studies that have collected data regarding small bowel adenocarcinoma are not homogeneous and are widely spread over time. Even though these tumours are most often sporadic, some predisposing diseases have been identified, among which Crohn's disease and genetic syndromes. Early diagnosis of small bowel adenocarcinoma remains difficult despite significant radiological and endoscopic progress. After surgical resection the main prognostic factor is node invasion; in this case, adjuvant chemotherapy can be expected to be beneficial, although this has not been established by randomised trials. For metastatic disease, platinum-based chemotherapy seems to be the most effective treatment. Targeted therapies have not yet been evaluated in this type of cancer.

International audience; Background: Small-bowel adenocarcinoma (SBA) is a rare tumor of poor prognosis. Data on the efficacy of chemotherapy for advanced SBA are scarce. Patients and methods: All patients with advanced SBA who received frontline chemotherapy from 1996 to 2008 were eligible for this retrospective multicenter study. Results: Ninety-three consecutive patients were included. In the entire population, the median progression-free survival (PFS) and overall survival (OS) times were 6.6 and 15.1 months, respectively. Median PFS times among patients treated with LV5FU2 (n = 10), FOLFOX (n = 48) FOLFIRI (n = 19) and LV5FU2-cisplatin (n = 16) were 7.7, 6.9, 6.0 and 4.8 months, respectively, while median OS times were 13.5, 17.8, 10.6 and 9.3 months, respectively. In multivariate analysis, World Health Organization performance status (PS) (P < 0.0001) and elevated serum levels of carcinoembryonic antigen (CEA) (P = 0.02) and carbohydrate antigen 19-9 (CA 19-9) (P = 0.03) were the only variables significantly associated with poor OS. In the subgroup of patients treated with platinum-based chemotherapy, multivariate analysis showed that LV5FU2-cisplatin was associated with poorer PFS (P < 0.0001) and OS (P = 0.02) compared with FOLFOX. Conclusions: This is the largest study of chemotherapy in advanced SBA. Baseline PS and CEA and CA 19-9 levels were the main prognostic factors. FOLFOX seems to be the most effective platinum-based chemotherapy regimen.

Background According to previously reported Groupe Coordinateur Multidisciplinaire en Oncologie (GERCOR) studies in locally advanced pancreatic cancer (LAPC), concomitant chemoradiotherapy (CCRT) may be recommended for patients who do not experience disease progression after systemic induction chemotherapy (CT). To further improve patient outcome with classical fluorouracil (FU)-based CCRT, this study was designed to prospectively investigate a CCRT with FU infusion and weekly oxaliplatin after 2 months of gemcitabine and oxaliplatin (GEMOX) induction chemotherapy. Patients and Methods Nonpretreated patients with LAPC having WHO performance status (PS) of 0 to 2 received four induction cycles of GEMOX (gemcitabine 1 g/m2 on day 1 and oxaliplatin 100 mg/m2 on day 2; day 1 of a 15-day cycle). One month after cycle 4, patients who did not experience disease progression with PS 0 to 2 received 45 Gy over 5 weeks + 10 Gy (as a concomitant boost during the last 2 weeks) of radiotherapy (RT), with daily 250 mg/m2 FU as a continuous infusion and 60 mg/m2of oxaliplatin weekly. Results Of 59 patients, 50 patients (84.7%) received CCRT, whereas nine patients did not because of disease progression (seven patients), CT toxicity (one patient), or personal decision (one patient). Forty-four patients (74.5%) completed the fully planned CCRT. Median progression-free survival and overall survival durations were 7.6 and 12.2 months, respectively, for the whole population and 9.4 and 12.6 months, respectively, for patients who completed CCRT. CCRT grade 3 to 4 toxicities (National Cancer Institute Common Toxicity Criteria) were neutropenia (10.4%), thrombocytopenia (8.4%), nausea and vomiting (16.7%), and diarrhea (12.5%). Conclusion Concomitant administration of weekly oxaliplatin, continuous-infusion FU, and RT in patients with LAPC is feasible, with an acceptable acute and late safety profile. The encouraging results observed despite a nonoptimal patient selection (owing to the short induction time) indicates that further randomized evaluation to better define the specific role of oxaliplatin in CCRT is deserved.

Background Small bowel adenocarcinoma (SBA) is a rare tumor with poor prognosis. Data about molecular biology on SBA carcinogenesis are lacking. Methods We characterised a number of candidate oncogenic pathways and the immunophenotype according to the primary localisation of patients with SBA treated in 11 centers between 1996 and 2008. Tissue microarrays were constructed from tumour samples and DNAs were extracted from formalin fixed paraffin embedded samples. HER2, b catenin, TP53 and mismatch repair (MMR) protein expression were assessed by immunohistochemistry. Overexpression of TP53 was defined as more than 50% of cells with nuclear staining. Abnormal expression of b catenin was defined as a nuclear staining. KRAS mutation was investigated. Patients were enrolled in the study at all stage of the disease. Results Samples from 63 patients were obtained, ampullary tumours were excluded. The median age was 58 years. Tumour stages were I-II n = 19 (30%), III n = 22 (35%), IV n = 20 (32%) and undefined n = 2 (3%). A HER2 surexpression (3+) was observed in 2/51 (3.9%) cases both in ileum. Overexpression of TP53 was observed in 23/53 (43%). Abnormal expression of b catenin was observed in 11/52 (21%) cases. A loss of MMR proteins occurred in 7/55 (13%) cases (3 MLH1, 2 MSH2, 2 MSH6), none was stage IV. A KRAS mutation was observed in 19/48 (40%) cases that involved codon 12 in 13 (68%) cases or G > A transition in 16 (84%). Tumours with KRAS mutation were stage IV in 31% of the cases. Survival analysis will be available at the meeting. Conclusion This large study suggests that molecular phenotype of SBA is close to colon phenotype with low level of HER 2 surexpression and high level of KRAS mutation. Ileum tumours seem to have a different phenotype than proximal tumours. Duodenum n = 32 (51%) Jejunum n = 18 (28%) Ileum n = 13 (21%) Stage IV n = 20 9 (45%) 6 (30%) 5 (25%) HER2 surexpression n = 2 0 (0%) 0 (0%) 2 (100%) TP53 overexpression n = 23 12 (52%) 6 (26%) 5 (22%) Abnormal b catenin n = 11 4 (36%) 2 (18%) 5 (45%) Abnormal MMR n = 7 3 (43%) 4 (57%) 0 (0%) KRAS mutation n = 19 11 (58%) 6 (32%) 2 (10%) Disclosure All authors have declared no conflicts of interest.

e15018 Background: Perioperative 5-fluorouracile (5-FU) associated with cisplatin chemotherapy improved overall and recurrence free survival, the R0 resection rate, in resectable gastro-oesophageal...

e19523 Background: Chemotherapy (CT) toxicity recording is usually performed when patients (pts) have recovered from previous cycle side-effects (SE), and could have therefore forgetten their incid...

4024 Background: Oxaliplatin combined with fluoropyrimidines is standard adjuvant therapy in stage III colon cancer and first-line therapy in stage IV colorectal cancer. Oxaliplatin can be reintroduced either at relapse, or after maintenance or after chemotherapy holidays. In this study we defined the sensitivity to oxaliplatin reintroduction based on the oxaliplatin-free interval. Methods: Stage IV pts entered in the OPTIMOX1 and 2 studies (FOLFOX4, FOLFOX7 followed by maintenance without oxaliplatin or chemotherapy holidays) and pts having relapsed after metastases surgery and neoadjuvant or adjuvant FOLFOX for resectable stage IV were eligible if they were rechallenged with FOLFOX. Endpoints were: survival from reintroduction according to interval between the last cycle of oxaliplatin first-line and reintroduction, survival and response at reintroduction according to first FOLFOX response and PFS. Results: 330 pts were included: male 60%, colon/rectum/both 62%/35%/2%, resectable/unresectable: 14%/86%, PS 0–1 / >1: 90%/10%, sites 1/>1: 57%/43%. 23 pts had adjuvant and 22 pts had neoadjuvant chemotherapy. 58 pts (18%) had FOLFOX reintroduction before progression. PFS/OS from reintroduction according to induction FOLFOX response were 8.7/19.5 mths if CR, 4.6/15.2 mths if PR, and 3.2/9.7 mths if SD (P=.0019/.01). PFS/OS from reintroduction according to induction FOLFOX PFS were 2.9/9.3 mths if PFS [Table: see text] No significant financial relationships to disclose.

15539 Background: The most commonly used schedules for MGA are 5FU in combination with CDDP with or without Epirubicin (ECF) or Docetaxel (TCF). Irinotecan combined with 5FU (FOLFIRI regimen) was reported as active and well tolerated in a French randomized phase II study (Bouche, JCO 2004). The aim of this retrospective study was to evaluate the FOLFIRI regimen in a larger series of MGA patients (pts). Methods: Between 05/99 and 03/07, 219 pts from 13 French centers (162 males (72%), median age: 62 years, range: 25–88) were treated with at least one cycle of FOLFIRI. Primary tumour sites were 127 (58%) stomach and 92 (42%) gastroesophageal junction. The WHO status was 0 or 1 in 81% of pts and 95 (43%) pts were asymptomatic. One hundred forty two pts (65%) were treated in first- line (including 42 pts previously exposed to chemotherapy as (neo)adjuvant therapy). The 77 others pts (35%) received FOLFIRI as second- (n = 60) or later- (n=17) line for MGA. Results: Median number of chemotherapy cycles was 6 (r...

4592 Background: GEMOX was defined as a D1-D2 schedule, based on preclinical data. In order to improve convenience for patients, we evaluated a simplified D1-D1GEMOX regimen (S-GEMOX) in MPA. Methods: Patients (pts) with MPA were 2:1 randomly assigned for first-line treatment to S-GEMOX (arm A : gemcitabine 1,000mg/m2, 100 min infusion D1 immediately followed by oxaliplatin 100 mg/m2, 120 min infusion) or to GEMOX (arm B : gem D1 and ox D2). Treatment was repeated in each arm every 2 weeks until disease progression. Stratification was performed on centre and PS. Results: Fifty-seven pts were enrolled, A = 37 (PS 2 : 22%), B = 20 (PS 2 : 20%). Populations were well balanced for age (64.9 yrs vs 66.6), gender (57% male vs 65), location of primary tumor (pancreas head 49% vs 50), and metastasic sites (liver 76% vs 85; peritoneum 24% vs 20; lung 16% vs 10; lymph nodes 14% vs 15; other 5% vs 5). Tumor differentiation significantly differed among the 2 groups (A : 8% poorly differentiated vs B : 36%). Response rate was 27% (95% CI : 12–42) in arm A and 10% (95% CI : 0 - 23) in arm B. Median PFS was 4.0 and 2.5 months in arm A and B, respectively. Median OS was 7.6 and 3.2 months in arm A and B, respectively. S-GEMOX was more toxic than GEMOX for gr 3–4 neutropenia (20% vs 0%) and thrombocytopenia (16% vs 10%). Other toxicities were comparable. However, since more cycles were administered in arm A (8.5 (1–29) vs 5.8 (2–12)), gr 3 oxaliplatin- induced neuropathy was higher in arm A (21.6% vs 0%). Conclusions: S-GEMOX is active in MPA. This activity is in the same range as compared to our previous experiences of GEMOX. The very bad outcome of pts randomized in arm B could be in part explained by the high rate of poorly differentiated tumors. This study emphazises one more time the limit of studies with small sample size of pts in MPA. No significant financial relationships to disclose.

13533 Background: The BOND study demonstrated Cetuximab (Cx) activity in irinotecan-refractory metastatic colorectal cancer (IRMCCR) patients (pts). Cx was approved in Europe early 2004 for this population. The aim of this study was to survey its efficacy in a unselected population of IRMCCR treated in 4 french academic centers. Methods: Data of all IRMCCR pts who had received Cx with or without irinotecan regimen between Jan 2004 and Sept 2005 were included in this survey. Exhaustivity of treated pts was established based on pharmacy registry. Primary end-point was time to tumor progression (TTP). Secondary end-points were overall survival (OS) and tumor response (RECIST). Results: Characteristics of the 76 included IRMCCR pts were : male/female : 44/32; median age 59.5 yrs (range 23 - 79); performance status : 0–1 (59 pts) and 2–3 (17); median number of tumor sites : 2 (1 - 5). The median number of chemotherapy regimens preceeding first Cx administration was 3 (range 1 to 5). At least one local treatment of the metastases (surgical resection and/or radiofrequency ablation) was a part of the strategy before Cx for 39 pts (51.3%). EGFR status was positive in 72 pts and negative in 4. Cx was administered : alone in 4 pts, combined with FOLFIRI in 4 and with irinotecan alone in 68 (89%). 10 pts received only one infusion Cx (early clinical progression : 6; patient decision : 2; early death : 2). Median number of Cx infusions was 10 (range 1 to 60). Median TTP (intent-to-treat) was 3.3 months [IC95% : 2.2–4.6]. Median OS since first-line chemotherapy and first Cx administration were 33.6 months [IC95% : 27.7–41.1] and 7.6 months [IC95% : 5.6–9.5], respectively. Tumor response (full population) was complete response 1.3%, partial response 19.7% (overall response 21%), stable disease 25% (disease control : 46%), progression 37% and not evaluable 17%. Conclusions: This therapeutic survey in a unselected population of IRMCCR are in accordance with the results of the BOND study for TTP, OS and tumor response. (supported by ADEBIOPHARM ER48). [Table: see text]

4039 Background: According to previous GERCOR studies in LAPC, concomitant chemoradiation therapy (CCRT) is indicated for non-progressive patients (pts) after systemic chemotherapy (CT). In order to improve the results of a classical 5FU-based CCRT, this study was designed to assess the efficacy and toxicity of weekly oxaliplatin (Ox), 5FU continuous infusion (c.i.) and radiation therapy (RT) in LAPC pts. Methods: Eligibility criteria included non resectable pathologically-proven LAPC, age > 18 yrs, PS < 2, and no prior CT or RT. All patients were first treated with 4 cycles of GEMOX (gemcitabine 1000 mg/m2, 100 min IV, d1; Ox 100 mg/m2, 2h IV, d2, every 2 wk). One month after cycle 4, non-progressive pts with PS < 2 received 45 Gy (25 fractions, 5 d/wk) + 10 Gy (concomitant boost in macroscopic tumor during wks 4 & 5, six hours apart large volume irradiation), combined with 250 mg/m2/d 5FU c.i. and weekly Ox. Initial 50 mg/m2 Ox dose was increased to 60 mg/m2 in absence of unacceptable toxicity after the 3 first included pts. Results: 60 pts were included (29 F/ 31 M, age 65.8 ± 9.6 yrs, range 37 - 80). 50 pts (83%) received CCRT, while 10 did not for the following reasons: metastatic progression (7 pts), OMS>2 (1), and CT toxicity (2). 44 pts (73 %) received the full planned CCRT dose-intensity. NCI-CTC grade 3–4 toxicities during CCRT and the following month (% of pts) were : neutropenia (14%), thrombocytopenia (10%), nausea-vomiting (20%), diarrhea (12%) and neuropathy (2%). 2 toxic deaths occurred during CCRT. With a median follow up of 15 mo, median progression-free survival (PFS) and overall survival (OS) of the whole population were 7.6 mo and 13.8 mo, respectively. For pts who received CCRT, median PFS and OS were 9.4 and 13.9 mo, respectively (2.6 and 9.9 mo, respectively, for pts who did not received CCRT). Conclusion: Chemotherapy before CCRT can identify pts who might potentially benefit of CCRT. Concomitant administration of weekly Ox, continuous IV FU and RT in LAPC is feasible with an acceptable toxicity. The results in terms of PFS and OS compare favourably with a classical 5FU-based CCRT. [Table: see text]

3581 Background: Median survival in patients (pts) with MRC can reach 20 months with chemotherapy and should further improve with combined targeted therapies. CFI should be considered in order to improve quality of life of long survivors. Methods: 197 pts responders or stable with chemotherapy in a single institution benefited from CFI of at least 3 months, for any reason, in a 12 year period (1992–2005). Therapy was rechallenged in case of disease progression. Duration of CFI and overall survival (OS) were analyzed according to therapy and prognostic factors. Results: In 146 pts who had a CFI after a first-line, chemotherapy was 5FU-based in 32 pts, oxaliplatin-based in 103 pts (FOLFOX alone in 64 pts, FOLFOX followed by 5FU in 39 pts), irinotecan-based in 11 pts. In 51 pts who had a CFI after a second-line, chemotherapy was 5FU-based in 6 pts, oxaliplatin-based in 30 pts, irinotecan-based in 15 pts. There was no correlation between therapy duration before CFI and CFI duration, p=.66. Median CFI duration was 29 weeks (wks) in first line and 21 wks in second line, p=.0005. Median therapy duration and CFI were 42 and 26 wks after 5FU-based chemotherapy, 12 and 27 wks after FOLFOX and 36 and 37 wks after FOLFOX followed by 5FU, p=.001 and p=.12, respectively. In first-line, CFI lasted a median of 39 wks in 15 pts in complete response, 29 wks in 61 partial responders and 27 wks in 70 stable pts, p=.33. Among patients who had a CFI after a first-line therapy, those with good prognostic factors (PS 0, normal LDH and alkaline phosphatases [Table: see text]

3585 Background: SBA is a rare tumor with poor prognosis. Data regarding SBA molecular alterations are lacking. Methods: We searched for several candidate oncogenic alterations and characterised the immunophenotype according to the primary tumour location in pts with SBA (all stages; ampullary tumours excluded) treated in 11 centres from 1996 to 2008. Tissue microarrays were constructed from tumour samples, and DNA was extracted from formalin-fixed, paraffin-embedded samples. HER2, β-catenin, TP53, and mismatch repair (MMR) protein expression was assessed by immunohistochemistry. A molecular analysis assessed microsatellite instability, KRAS mutation and BRAFV600E mutation. Results: We obtained samples from 63 SBA pts (median age, 58 years; tumour stage: I-II, n=19 (30%); III, n=22 (35%); IV, n=20 (32%); locally advanced, n=2 (3%)). HER2 overexpression (3+) was observed in 2/62 (3%) pts. Overexpression of TP53 was observed in 26/62 (42%) pts. Abnormal expression of β-catenin was observed in 12/62 (19%) pts. MMR deficiency (dMMR) was observed in 14/61 (23%) pts, consistent with Lynch syndrome in 7/14 (50%) pts. All of the dMMR tumours were in duodenum or jejunum. Only one of dMMR tumour was stage IV. A KRAS mutation was observed in 21/49 (43%) pts. BRAFV600E mutation was observed in only 1/40 pt. Median overall survival (OS) was 36.6 months (95% confidence interval [CI], 26.9-72.2). In univariate analysis, stage I-II (p