Accepted Manuscript /j.ejso Reference: YEJSO To appear in: European Journal of Surgical Oncology

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1 Accepted Manuscript Conservative surgery vs. duodeneopancreatectomy in primary duodenal Gastrointestinal Stromal Tumors (GIST): A retrospective review of 114 patients from the French Sarcoma Group (FSG) F. Duffaud, P. Meeus, J.B. Bachet, P. Cassier, T.K. Huynh, E. Boucher, O. Bouché, V. Moutardier, A. le Cesne, B. Landi, F. Marchal, J.O. Bay, F. Bertucci, J.P. Spano, E. Stoeckle, O. Collard, L. Chaigneau, N. Isambert, V. Lebrun-Ly, J. Mancini, J.Y. Blay, S. Bonvalot PII: DOI: S (14) Reference: YEJSO /j.ejso To appear in: European Journal of Surgical Oncology Received Date: 31 January 2014 Revised Date: 15 April 2014 Accepted Date: 19 April 2014 Please cite this article as: Duffaud F, Meeus P, Bachet JB, Cassier P, Huynh TK, Boucher E, Bouché O, Moutardier V, le Cesne A, Landi B, Marchal F, Bay JO, Bertucci F, Spano JP, Stoeckle E, Collard O, Chaigneau L, Isambert N, Lebrun-Ly V, Mancini J, Blay JY, Bonvalot S, Conservative surgery vs. duodeneopancreatectomy in primary duodenal Gastrointestinal Stromal Tumors (GIST): A retrospective review of 114 patients from the French Sarcoma Group (FSG), European Journal of Surgical Oncology (2014), doi: /j.ejso This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Original article Conservative surgery vs. duodeneopancreatectomy in primary duodenal Gastrointestinal Stromal Tumors (GIST): A retrospective review of 114 patients from the French Sarcoma Group (FSG) F. Duffaud 1, P. Meeus 2, J.B. Bachet 3, P. Cassier 4, T.K Huynh 1, E. Boucher 5, O. Bouché 6, V. Moutardier 7, A. le Cesne 8, B. Landi 9, F. Marchal 10, J.O Bay 11, F. Bertucci 12, J.P. Spano 13, E. Stoeckle 14, O. Collard 15, L. Chaigneau 16, N. Isambert 17, V. Lebrun-Ly 18, J. Mancini 19, J.Y. Blay 4, S. Bonvalot 20. Authors affiliations: 1: Service d Oncologie Médicale, CHU Timone, AP-HM, Marseille, and Aix-Marseille Université (AMU), Marseille, France 2 : Service de Chirurgie, Centre Léon Bérard, Lyon, France 3: Service d hépato-gastroentérologie, CHU Pitié Salpétrière, Paris, France 4. Service d Oncologie Médicale, Centre Léon Bérard, Lyon, France 5 : Service d Oncologie médicale, Centre Eugène Marquis, Rennes, France 6: Service d Oncologie digestive, CHU de Reims, France 7. Service de Chirurgie digestive, CHU Nord, Marseille, France 8 : Service d Oncologie médicale, Institut Gustave Roussy, Villejuif, France 9 : Service de Gastro-entérologie et Oncologie digestive, Hôpital Européen Georges Pompidou, Paris, France 10 : Département de Chirurgie, Institut de Cancérologie de Lorraine, Vandoeuvre les Nancy, France 11 : Service d oncologie médicale, CHU Clermont Ferrand, France 12 : Service d Oncologie médicale, Institut Paoli Calmettes, Marseille, France 13 : Service d Oncologie médicale, CHU Pitié Salpétrière, Paris, France 14 : Service d oncologie médicale, Institut Bergonié, Bordeaux, France 15 : Service d Oncologie Médicale, CLCC, Institut de Cancérologie Lucien Neuwirth, Saint- Etienne, France 16 : Service d oncologie médicale, CHU de Besançon, France 17 : Oncologie médicale, Centre G Leclerc, Dijon, France 18 : Service d Oncologie médicale, CHU Dijon, France 1

3 19: Service de Santé Publique et d Information Médicale, Unité de Biostatistiques, CHU Timone, Marseille, and Aix-Marseille Université (AMU), France 20 : Service de Chirurgie, Institut G Roussy Villejuif, France Corresponding author : Prof Florence Duffaud Service d Oncologie Médicale, Hôpital la Timone, 264 rue Saint Pierre, Marseille, France. Phone: ; Fax : fduffaud@mail.ap-hm.fr 2

4 Abstract: Background: Duodenal GISTs represent 3-5% of all GISTs with limited understanding of patient outcomes. We conducted a retrospective analysis of primary localized duodenal GISTs. Methods: Patients were identified via a survey from 16 FSG centers (n=105), and a group of 9 patients enrolled in the BFR14 trial. Data were collected from the original database and patient files, in agreement with French legislation. Results: 114 patients were included, with a median age of 57. Tumors originated mainly in D2 (33%), or D3 (24%), with a median size of 5 cm. 109 patients had resection of the primary tumor; with a Local Resection (LR, n=82), a pancreaticoduodenectomy (PD, n=23), and data were missing for 4 patients. Resections were R0 (n= 87, 79%), R1 (n= 8, 7%), R2 (n=6). Tumor characteristics were: KIT+ (n=104), CD34 + (n= 58). Miettinen risk was low (n=43), and high (n=52). Imatinib was administered preoperatively (n=12) and post-operatively (n=19). With a median follow-up of 36 months (2-250), 98 patients are alive, and 33 relapsed. The 5-year OS and EFS rates are 86.5% and 54.5%. EFS was similar for patients in the LR and the PD groups (P > 0.05). In multivariate analysis, ECOG PS, and CD34 expression are independent prognostic factors on OS. Miettinen risk and spindle cell type are independent predictive factors for relapse. Conclusions: Patients with resected duodenal GIST have a reasonably favourable prognosis. This study favours a preservation of pancreas when there are no anatomical constraints. LR exhibit similar survival and smaller morbidity then PD. Key words: duodenal GIST, local resection, pancreaticoduodenectomy, imatinib therapy 3

5 Introduction Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract (1, 2). While GISTs can arise throughout the entire GI tract, they commonly originate from the stomach (50-60%), and small bowel (30-40%) (3). Duodenal GISTs (D-GISTs) represent a rare subset with an overall frequency of 3-5%, but still represent approximately 30% of primary small bowel tumors (3). Standard treatment of localized GIST is complete surgical excision with negative margins without dissection of clinically negative lymph nodes (7-10) except in pediatric GISTs. However, the optimal surgical procedure for duodenal GISTs remains to be established (4-7). There are currently few reports addressing the surgical procedures for duodenal GISTs (11-15). Pancreaticoduodenectomy (PD) or more limited resections (LR) with pancreas preservation such as wedge or segmental resections of the duodenum are proposed according to the tumor presentation (anatomic site and size) and ECOG PS (13). Necessity to perform a systematic PD to achieve larger margins has been scarcely studied (11, 16, 17). It is now established that adjuvant Imatinib improves disease-free survival (DFS) and overall survival (OS) (18, 19). However, its potential role in the neoadjuvant setting has not been specifically explored due to the rarity of these specific localizations (20). The objective of this study was to analyse the oncological results of the type of surgery, limited resection (LR) vs. pancreaticoduodenectomy (PD) on primary non metastatic D- GISTs, and the effect of neoadjuvant Imatinib. Patients and Methods Patients with histologically proven localized D-GIST were eligible for this retrospective study. It was conducted in 16 French Sarcoma Group (FSG) institutions. We collected 114 patients with localized D-GISTs treated between June 1993 and May 2012, including 9 patients from the French BFR14 trial data base. Patients with recurrent or metastatic disease at diagnosis were excluded. Methods for data collection: A standard data file was created to retrieve information on patients characteristics, tumor clinicopathological characteristics, treatment approaches including surgical procedures and imatinib therapy (pre and/or postoperatively), and patterns of failure (local recurrence, metastasis). Follow-up information were obtained by outpatient visits. 4

6 Tumor variable: Tumor size was defined as the greatest dimension of the tumor in the surgical specimen reported by the original pathologist or the dimension at the radiological imaging in case of preoperative Imatinib treatment with a dimensional response. KIT and CD34 immunostaining were collected, as histological subtypes, mutational analysis and site of tumor origin. Tumors were classified using Miettinen classification (21), based on mitotic index, tumor size, and tumor site. Due to a limited number of cases of duodenal GISTs, tumours from the groups 3a en3b according to Miettinen classification (21) were combined in one group (very Low and Low Risk group), with a risk of relapse from 0 to 8.3%, as tumors from the groups 6a and 6b were combined in one group (High Risk group), with a risk of relapse 34%. Mutational analysis, specific site of origin of the tumor, were recorded Treatment variables: Surgery was classified as pancreaticoduodenectomy (PD) and limited resection (LR) which included duodenal wedge or segmental resection. Choice was driven according to the size and location of tumor relatively to pancreas and bile duct. Complications were graded according to Dindo scale (17). The UICC R classification was used to classify microscopic margins (18). Pre- and post-operative treatment with imatinib was given according to the decision of the Multidisciplinary Sarcoma Board of each reference center. Patients were treated within clinical trials when eligible. Tumor response was assessed every 3 to 4 months according to Response Evaluation Criteria in Solid Tumor (RECIST 1.0). Follow-up was carried out through routine visits for clinical assessment at outpatient clinic every 3 to 4 months during the first two years after surgery and roughly every 6 months thereafter. Ethics statement: This was a retrospective minimal risk review and all patients consented to use standard clinical data. Our IRB exempts such minimal risk survey studies from IRB approval, according to the French laws. The board of directors of the French Sarcoma Group approved the study. Statistical analysis: Continuous variable were expressed as median (range) and categorical variables were expressed as percentage. We retrospectively analyzed the following putative prognostic factors: gender, age at presentation, tumor size, ECOG PS (0-1 vs. 2-3), mitotic count ( 5/50 5

7 HPF, > 5/50 HPF), histological subtype, necrosis (yes/no), CD 34 positivity (yes/no), anatomical location (second portion vs. first, third and fourth portion), type of resection (PD vs. LR), margins status (R0-R1 vs. R2), tumor rupture (yes/no), Miettinen risk of relapse (High Risk vs. Low Risk), Imatinib therapy (yes/no). Fisher s exact test was used to compare percentage. The study endpoints were Event-Free survival (EFS) and Overall Survival (OS), computed from the date of diagnosis (done by preoperative biopsy or by surgery) to the date the event was recorded (local and/or regional and/or metastatic relapse) for EFS and patient s death for OS or censored at the date of the last follow-up in event-free patients. Survival curves were plotted using the Kaplan-Meier method and compared with the Log- Rank test. Median follow-up was calculated using the reverse Kaplan-Meier method. Cox proportional hazards regression analysis was used for Multivariate analysis for EFS and OS. All statistical tests were 2-sided and the threshold for statistical significance was P=0.05. Analyses were performed with SPSS software (version 17.0, SPSS Inc. IL, USA) Results Patient and disease characteristics: They are listed in Table 1. For patients diagnosed before 2000, a pathological review of the primary tumor or a metastasis with C117 immunostaining was done to confirm the diagnosis of GIST. Treatment Modalities and outcome: They are reported in Table 2 and 3. Surgery All but 5 patients had a surgery (n=109); one patient developed distant metastases during preoperative imatinib, for 3 patients duodenal tumor was considered non resectable on preoperative CT scan evaluation despite imatinib therapy, and one patient was still on preoperative Imatinib at the date of the last analysis. LR was technically possible in 82 (74%) patients, but 23 (21%) patients required PD. Surgical procedure was missing concerning 4 patients. Tumor rupture happened in 5 patients, with no detailed reason given in the data files, but all tumors were above 7 centimetres. Morbidity and mortality 6

8 There was one perioperative death due to digestive haemorrhage after PD. Twenty-one (19%) patients developed post-operative complications; 15 (18%) after LR and 6 (26%) after PD (P=0.37), with 10 Dindo (17) (grade III-V) surgical complications; one grade IIIa (infected haematoma requiring percutaneous drainage), 6 grade IIIb (4 severe digestive haemorrhages and 2 duodenal fistulae requiring surgical resections), 2 grade IV (one acute kidney insufficiency with pulmonary embolism, and one acute haemorrhagic shock), and one grade V (fatal digestive haemorrhage).. Imatinib therapy Eleven patients received preoperative imatinib at 400 mg daily before surgical resection, during a median period of 3 months (range, 2-11). Tumor response was assessed every 2 to 3 months according to RECIST 1.0. A partial response (PR) was observed in 5 patients, and a stable disease (SD) in 5, whereas one patient progressed on Imatinib. A surgical resection was possible for six patients; 3 had a LR, 3 had a LR extended to adjacent organs, resulting in 4 R0s, one R1, and one R2 resection. Five patients had no tumor resection (see above). Overall a 50% resectability rate was achieved for initially unresectable disease. Four of 6 patients with tumor resected were alive at the date of last follow-up without evidence of disease (at 2, 2.5, 3.5, and 7 years), one was lost to follow-up at 3 years, and one died at 5 months. For the 5 patients without tumor resection, 2 were alive at the date of the analysis (at 5.5 and 10 years from diagnosis), one was lost to follow up at 7 months, and 2 died at 6 months and 6 years). According to their estimated risk of relapse and according to ongoing trials during this period, 20 patients (16.6%) were treated with Imatinib post-operatively at 400 mg daily, with a median duration of 7 months (range 2-41); 5 of them received preoperative imatinib.. Clinical outcome: At the time of the analysis, the median follow-up was 36 months (range, 2-250), and 98 patients (86%) were alive. Thirty-three patients (30%) relapsed, including 30 (26%) patients who developed distant metastases, and 6 a locoregional recurrence. In the group of patients treated with imatinib (n=26), 3 (11%) developed a relapse (local or distant) whereas thirty patients relapsed in the non-imatinib group (34%). Seven patients who underwent PD and 26 who underwent LR (P = 0.412) relapsed. 7

9 For For the resected GIST population, EFS and OS rates at 3 years were 75.5%, and 91.7% respectively (see Figures 1 and 2). EFS and OS were similar for patients in the LR and the DP groups (P>0.05). Prognostic analysis: Analyses were done on patients with resected D-GIST.The results of the Univariate analyses are presented in Table 4. In multivariate analysis, ECOG PS, and CD34 lack of expression are independent and significant prognostic factors on OS (P< and P=0.021, see Figures 3 and 4). Miettinen risk and spindle cell type are independent predictive factors for relapse (P=0.009, P=0.008). Discussion Duodenal GISTs are characterized by their complexity related to the anatomy of pancreatic and duodenal area. This study demonstrates that when feasible, LR achieves the same rates of R0 resection, EFS and OS than PD. It suggests that a pancreas preserving surgery is preferable when there is no anatomic contra indications, such as size or location (pancreas side or not) and the ability to achieve an R0 margin. LR exhibited clearly a lowest risk of post operative morbidity (9), which is confirmed in our series (17% vs. 30%). In line with previous data (2, 8, 9), most D-GISTs were located in the second portion of the duodenum (33%) with a high incidence of lesions of both the third/fourth portions of the duodenum (36%). Furthermore, 45% of D-GISTs were classified as Mittienen low risk suggesting that D-GISTs belong to a better prognostic category than other small bowel GISTs (8, 10, 11). Use of neoadjuvant Imatinib for GISTs is indicated in case of locally advanced GIST not amenable to resection or pancreas preservation. It should be considered for locally advanced tumor, GISTs situated in the second part of the duodenum on pancreas side, and in patients candidate to PD. Indeed, it may facilitate the surgical procedure and increase the chance of preserving normal biliary and pancreatic structures. When PD is finally required, it is safer when tumor is smaller (9) and may decrease the risk of tumors rupture which is known to have a strong bad impact on survival (19). As shown in our patients for whom a tumor genotype was available, even if that was for a minor proportion, both KIT exon 9 mutant and KIT/PDGFRA wild-type tumors, are not so uncommon at this site (20). 8

10 In our series, adjuvant imatinib was mostly administered according to ongoing trials. Although assessed retrospectively, it achieved a possible impact on the outcome in the highrisk group of patients. This is in line with data from a randomized study that showed a DFS and OS benefit in patients with high-risk GIST and treated with adjuvant imatinib during 3 years (14). Based on these results, the recommendation of adjuvant imatinib for 3 years is now a standard of care for patients with high-risk GIST at any site. Indeed in our series, the median duration of adjuvant imatinib was short, and the number of treated patients was limited, preventing us to draw any conclusion about the impact of adjuvant imatinib. OS and EFS rates at 3 years were 91.7% and 86.5% respectively. These results are comparable with the main D-GISTs series (7-11, 19, 21) presented in Table 5. In multivariate analysis, specific tumors factors were strongly associated with outcome, as independent prognostic factors, with relapse for Miettinen risk category and spindle cell type, and with OS for CD34 expression. As expected, Mittienen risk category was a major determinant of outcome (11, 22, 30). Nevertheless, the prognostic effect of tumor morphology in GIST is not clear. In some series, epithelioid morphology is associated with poor prognosis (1, 22,23), but some others revealed no relationship between tumor morphology and survival (24,25). In our study, spindle cell morphology was the predominant histology. The EFS of patients with spindle cell morphology was significantly longer than that of patients with the other two histotypes. The predictive and prognostic effects of immunohistochemical markers were investigated in a few number of GIST studies only, that reported divergent results. Some studies revealed no relationship between CD34 expression and prognosis (23, 25,26). The predictive role of CD34 expression was examined in only one study. This was a retrospective analysis of the BFR14 study (27), in which the FSG established that CD34+ tumors were associated with longer PFS on imatinib. Conversely with these results, CD34+ patients had a significantly shorter OS in our series, as reported by Demir et al. (28). In conclusion, this multi-center retrospective study favors preservation of pancreas when there are no anatomical constraints. LR exhibits similar survival and smaller morbidity. The administration of Imatinib must be discussed before and after surgery. 9

11 Disclosure: The authors have declared no conflicts of interest 10

12 Tables and Figure s legends: Table 1: Patients and tumor characteristics (calculation of proportions done on data available) Table 2: Treatment and outcome Table 3: Comparisons between LR vs. PD procedures Table 4: Univariate analysis on EFS and OS Table 5: Main D-GISTs series published Figure 1: EFS of patients with resected D-GISTs Figure 2: Overall Survival of patients with resected D-GISTs 11

13 References 1. Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential disgnosis. Arch Pathol Labol Med 2006; 130: Miettinen M, Kopczynski J, Makhlouf HR, et al. Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the duodenum: a clinicopathologic, immunohistochemical, and molecular genetic study of 167 cases. Am J Surg Pathol 2003; 27: De Matteo RP, Lewis JJ, Leung D, et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 2000; 231: Woodall CE, Scoggins CR. Retroperitoneal and visceral sarcomas: issues for the general surgeons. The American Surgeons 2007; 73 (6): De Matteo RP, Heinrich MC, El-Rifai WM, Demetri G. Clinical management of gastrointestinal stromal tumors. Hum Pathol 2002; 33 (5): Gold JS, de Matteo RP. Combined surgical and molecular therapy Ann Surg 2006 ; 244: Goh BK, Chow PK, Kesavan S, Yap WM, Wong WK. Outcome after surgical treatment of suspected gastrointestinal stromal tumors involving the duodenum: is limited resection appropriate? J Surg Oncol 2008; 97: Johnston FM, Kneuertz PJ, Cameron JL et al. Presentation and management of gastrointestinal stromal tumors of the duodenum: A multi-institutional Analysis. Ann Surg Oncol 2012; 19: Colombo C, Ronnellenfitsch U, Yuxin Z et al. Clinical, pathological and Surgical characteristics of duodenal gastrointestinal stromal tumor and their influence on survival: A multi-center study. Ann Surg Oncol 2012; 19: Yang WL, Yu R, Wu YJ, et al. Duodenal gastrointestinal stromal tumor: clinical, pathologic, immunohistochemical characteristics, and surgical prognosis. J Surg Oncol 2009, 100: Tien YW, Lee CY, Huang CC, Hu RH, Lee PH,. Surgery for gastrointestinal stromal tumors of the duodenum. Ann Surg Oncol2010; 17: Lanuke K J, Bathe OF, Mack LA. Local excision of duodenal gastrointestinal stromal tumor. J Surg Oncol 2007; 95:

14 13. De Matteo RP, Ballman KV, Antonescu CR et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour : a randomised, double-blind, placebo-controlled trial. Lancet 2009 ; 373 : Joensuu H, Eriksson M, Sundby Hall K, et al. One versus three years of adjuvant imatinib for operable gastro intestinal stromal tumor: a randomized trial. JAMA 2012 ; 307 (12) : Fiore M, Palassani E, Fumagalli E, et al. Preoperative imatinib mesylate for unresectable or locally advanced primary gastrointestinal stromal tumors (GIST). Eur J Surg Oncol 2009; 35: Miettinen M, Lasota J. Gastrointestinal stromal tumors: Pathology and prognosis at different sites. Semin Diagn Pathol 2006; 23: Dindo D, Demartines N, Clavien PA. Classification of Surgical Compplications. A new proposal with evaluation of 6336 patients and Results of a Survey. Annals of Surgery 2004; 240 (2): Hermanek P, Wittekind C. The pathologist and the residual tumor (R) classification. Pathol Res Pract. 1994; 190(2): Chung JC, Chu CW, Cho GS, et al. Management and outcome of gastrointestinal stromal tumors of the duodenum. J Gastrointest Surg 2010; 14: Emile JF, Brahimi S, Coindre JL et al. Frequencies of KIT and PDGFRA mutations in the molecgist prospective population-based study differ form those of advanced GISTs. Med Oncol. 2011; doi: /s _0074-y. 21. Beham A, Schaefer IM, Cameron S, et al. Duodenal GIST: a single-center experience. Int J Colorectal Dis 2012; doi /s Rutkowski P, Nowecki ZI, Michej W et al. Risk criteria and prognostic factors for predicting recurrences after resection of primary gastrointestinal stromal tumor. Annals of Surg Oncol 2007; 14(7): Kang YN, Jung HR, Hwang I. Clinicopathological and immunohistochemical features of gastrointestinal stromal tumors. Cancer Res Treat 2010; 42(3): Martin J, Poveda A, Llombart-Bosch A et al. Deletions affecting codons of the c- KIT gene indicate a poor prognosis in patients with completely resected gastrointestinal stromal tumors : a study by the Spanish Group for Sarcoma Research (GEIS). J Clin Oncol 2005; 23: Sciot R, Debiec-Rychter M, Daugaard S et al. Distribution and prognostic value of histopathologic data immunohistochemical markers in GISTs: an analysis of the EORTC 13

15 phase III trial of treatment of metasatic GISTs with imatinib. Eur J Cancer 2008; 44: Chireac LR, Trent JC, Steinert DM et al. Correlation of immunophenotype with progression-free survival in patients gastrointestinal stromal tumors treated with imatinib. Cancer 2006, 107: Bertucci F, Blesius A, Cassier PA et al. Prognostic factors for progression-free and overall survival in patients with advanced GIST treated with standard-dose imatinib: results from the BFR14 phase III trial of the French Sarcoma Group. ASCO meeting 2011, Abst. 29, J Clin Oncol 2011, Demir L, Ekinci N, Erten C et al. Does immunohistochemistry provide additional prognostic data in gastrointestinal stromal tumors? Asian Pacific Journal of Cancer prevention 2013, 14:

16 Table 3 Surgical procedures PD (n=23 ) LR (n= 82) P value Median Tumor size (cm) Miettinen (Low vs. High) 7/15 36/ Margins status (R0/R1/ R2) 17/2/1 68/6/ Margins status (R0-R1 vs R2) 19/1 74/ Tumor rupture (yes/no) 2/19 3/ Post operative complications (yes/no) Recurrences (local and distant)

17 Table 1 Sex ratio Male/ Female 59 /55 Median Age (years) 57 (22-84) History of Neurofibromatosis 12 (11%) ECOG 0-1 (%) 94 (82%) 2-3 (%) 6 (5%) UK * 14 (13%) Symptoms Abdominal symptoms (pain/ GI bleeding) 24 / 24 (21%/ 21%) Anemia 30 (25%) Asymptomatic (discovered incidentally) 27 (23%) Tumor characteristics Primary Tumor site 1st duodenum (D1) / 2d duodenum (D2) 8 (7%) / 38 (33%) 3d and 4th duodenum (D3/D4) 27/15 (24%/13%) Multiple duodenal segments/ No precision (UK*) 5/21 Tumor Size (mm) Median (min-max) 50 (4-310) Miettinen risk classification Very Low and Low/ High risk** /UK* 43 (39%) / 52 (54.7%)/19 (16%) Spindle cell / epithelioid / mixed /UK* 86/3/9/16 Histology/Genotype CD (92%), UK* (9, 8%) CD (51%), UK* (16, 14%) Mitotic index (MI) 5/50 HPF 73 (64%) > 5/50 HPF, UK* 26 (23%) / 15 (13%) Mutational analysis done on 39 (34%) cases, 30 (76%) exon 11 KIT mutations, 2 (5%) exon 9 KIT mutations, and 7 (18%) WT *UK= unknown, ** according to Miettinen et al. Semin Diag Pathol 2006: duodenal Gist have a high risk of recurrence if : Mitotic index 5/50 HPF and size > 5cm 10 cm or size > 10 cm: 34% risk of recurrence, and if Mitotic index > 5/50 HPF, and size > 2cm 5cm : 50% risk of relapse, and with 1

18 size > 5 cm 10 cm or size > 10 cm: 86% risk of relapse. We considered all these risk groups as high risk categorie, with no intermediate risk category. 2

19 Table 2 Surgery of Primary Tumor 109 (95.5%) Local Resection (LR) 82 (74%) Segmental duodenectomy 34 (31%) Wedge resection 32 (29%) Local excision 7 (6%) Extended surgery 9 (8%) Pancreatoduodenectomy (PD) 23 (21%) Unknown procedure/still on Imatinib 4/1 Margins Resection R0 87 (79%) Resection R1 /R2 8/6 (7/5.5%) Tumor rupture No / Yes 97 (85%) / 5 (4%) Primary surgery 103 (78%) Post Imatinib surgery 6 of 11 Imatinib (IM) therapy (400mg/d) (pre and/or post-op) 26 (23%) Preoperative IM 11 Post operative IM 20 Median duration (pre-op.; in months) 3 (2-11) Efficacy of Pre-op. IM therapy 12 PR/CR/SD /PD 5/0/5/ 1 (PR+SD=10) Follow-up (median), of 109 resected patients 36 (2-250) months Prognosis (109 pts) 16 deaths, 33 (30%) relapses [30 (26%) metastases, and 7 locoreg.] 3 (11%) relapses only observed in the 26 pts treated with IM at some time 7 (30%) relapses in the PD group, 26 (31%) in the LR group EFS rates at 2 and 5 years 82% (95%CI, ) and 54.5% (95%CI, ) OS rates at 3 and 5 years 94.9% (95%CI, ) and 86.5 % ( 95%CI, ) 1

20 Table 4 Univariate analysis (109 pts) OS EFS HR 95% CI Log-rank test p- value HR 95% CI Log-rank test p-value Age > [0.8 to 6.28] [0.52 to 2.31] 0.81 Male sex 0.64 [0.22 to 1.85] [0.62 to 2.62] 0.5 ECOG = 2 to [3.28 to 82.63] <0.001 NC* R0 vs R [0.2 to 2.95] [0.31 to 2.62] 0.86 R2 vs R [0.46 to 10.04] [0.24 to 4.38] 0.96 Tumor rupture 0.05 [0 to ] [0 to 58.37] 0.19 Post operative complications 1.84 [0.47 to 7.21] [0.47 to 2.95] 0.72 GISTCD [0.9 to 54.04] [0.57 to 2.85] 0.55 Necrosis 1.32 [0.41 to 4.25] [2.08 to 12.32] <0.001 Spindle cell type 0.84 [0.18 to 3.9] [0.06 to 0.44] <0.001 Imatinib 2.03 [0.53 to 7.8] [0.11 to 2.03] 0.31 Mitotic Index > 5 / 50 HPF 2.65 [0.85 to 8.28] [4.48 to 24.45] <0.001 Miettinen = high 1.65 [0.42 to 6.44] [2.03 to 17.59] <0.001 PD procedure 1.06 [0.33 to 3.46] [0.68 to 3.56] 0.29 Tumor size > 5 cm 1.94 [0.49 to 7.62] [1.79 to 11.66] <0.001 *NC: non computable (lack of follow-up in ECOG 2 to 3 group) 1

21 Table 5 Series Study Patients LR/PD Neoad/Adj Risk assessment FU OS DFS Rec(h) Period (number) Imatinib (L/I/H) (median)g (mo)g (mo)g Beham et al. (21) NA* 13 8/5 2/5 5/0/8 NA 66a 41a 5 Chung et al. (19) /0 0/0 7/2/0 22 (13-61) 22a 22a 0 Tien et al.(11) /9 NA 11/5/8 18 (9-92) NA NA NA Colombo et al. (9) /28 11/23 42 (2-135) 89%b 64%b 23 Johnston et al. (8) /38 3/22/1d 46/25/16c 22 (4-81) 82%b 63%e 18 Goh et al. (7) /7 NA 5/3/6c 42 (2-174) 130f NA 3 Yang et al. (10) /9 NA NA 44 (19-101) NA 95%e 1 Duffaud et al /23 12/19 43/0/52 36 (2-250) 86.5%b 54.5%b 33 *: NA= not applicable a : median b : at 60 months c : NIH Classification d : perioperative e : at 36 months f : mean g: (mo) = months h: Rec= includes local and/or distant recurrences 1

22 Figure 1 1

23 Figure 2 1

24 Conflict of interest statement We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that are no other persons who satisfied the criteria for authorship but are not listed. On behalf all the co authors Florence Duffaud All co authors have signed the EJSO author form 1

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