Linite gastrique / Adénocarcinome à cellules indépendantes. Pr Christophe Marie.e Chirurgie diges2ve et générale CHRU - Lille

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1 Linite gastrique / Adénocarcinome à cellules indépendantes Pr Christophe Marie.e Chirurgie diges2ve et générale CHRU - Lille

2 Definition Diffuse type according to Lauren classification = Signet Ring Cell adenocarcinoma (SRC) according to the WHO classification adenocarcinoma composed of at least 50% of independent tumoral cells, with a signet ring cell morphology, surrounded by a dense and fibrous stroma Large vacuole of mucus Nucleus pushed out Watanabe WHO tumoural classification 1990 Lauren, Acta Pathol Microbiol Scand 1965

3 Advanced form of SRC = Gastric linitis plastica Macroscopic definition Rigid thickening of the gastric wall, fixed stomach Large, thick and erythematous mucosal folds = advanced presentation of signet ring cell gastric cancer (SRC)

4 Epidemiology SRC Both Non-SRC 5 th cause cancer, 2 nd cause of cancer-related death Global decrease in gastric ADC incidence Stricking increase in SRC incidence Incidence 400% USA 32 to 70% of gastric ADC in recent series 2000 cases annually in France Increase incidence in young patients Jemal, CA Cancer J Clin Parkin, CA Cancer J Clin, 1999 Wu, Cancer Epidemiol Biomarkers Prev, 2009 Piessen,Mariette Ann Surg, 2009 Smith, Arch Surg, 2009 Henson, Arch Pathol Lab Med, 2004

5 Year of publication Authors Population n (% SRC) 5Year Survival % SRC vs. NonSRC Prognosis impact of SRC Univariate p 1992 MAEHARA 1500 (3.4%) 74.5 vs 52.4 < KIM 3072 (12.2%) 31.9 vs 35 to 45 <0.05 Published data : controversial results 1998 OTSUJI 1498 (10.3%) 68.2 vs 43.9 < YOKOTA 923 (10.1%) 37 vs 53 NS Multivariate p 1999 THEUER 3020 (15%) 8 vs 11 NS NS 2002 HYUNG 933 (28%) 94.2 vs KUNISAKI 1113 (15%) 98 vs KIM 2358 (8.7%) 60.2 vs 48.9 <0.01 NS 2007 LI 4759 (14%) 42 vs NS 2008 PARK vs 61.3 NS 2009 FANG vs 44.1 < ZHANG 1439 (15%) 44.9 vs NS 2009 KUO 1626 (20.5%) 95.3 vs 90.3 NS

6 Population: among 180 patients resected for gastric ADC 59 pa2ents SRC vs. 100 pa2ents Non- SRC Matched according to: Age, Gender, ASA score, ptnm stage ITT analysis SRC Non- SRC p Median survival (months) Peritoneal carcinomatosis 18.6% 6.0% Lymph node invasion 83.1% 63.0% <0.001 RO resection rate 56.0% 74.0% Time to first recurrence (months) Recurrence with peritoneal carcinomatosis 52.2% 21.4% 0.011

7 Multivariate analysis: SRC histology : independant factor of poor prognosis when compared to non-src histology HR = 1.5 p = Advanced stage at time of diagnosis due to high lymph node and peritoneal affinity Low RO resection rate Early relapse, mainly in peritoneal carcinomatosis form

8 421 patients with ptis or pt1 tumours 104 (25%) SRC and 317 (75%) non SRC Groups were comparable exept on age 5-y OS SRC 85% vs. 76% non SRC, p=0.036 But disapearing when considering cancer specific suvival ð younger patients in SRC! ð SRC disease becomes agressive when going through the submucosa +++

9 Piessen, Messager, Robb, Mariette J Clin Oncol 2013

10 Actual knowledge in SRC gastric cancer? Raising incidence, young patients+++ Established poor prognosis for advanced stages Need for tailored therapeutic strategies Questions to be resolved: a) Is SRC predictible on initial endoscopic biopsies? b) Preoperative work-up specificities? c) Which surgical approach? d) Efficacy of perioperative treatment? e) Predictors for recurrence

11 a) Predictive value of pretherapeutic biopsies?

12 a) Predictive value of pretherapeutic biopsies? Population: 254 patients gastric ADC SRC on biopsy Non- SRC on biopsy SRC Histology Non- SRC Histology Sensibility 88.1% Specificity 95.4% PPV 92.7% NPV 92.4% Biopsy overall accuracy of 92.5% SRC on biopsy = independent predictor of poor prognosis p < Therefore therapeutic strategy can be considered from the initial diagnosis Piessen, Messager, Mariette World J Surg 2012

13 b) Preoperative work-up specificities Poor sensibility of CT scan in detecting peritoneal carcinomatosis ð Laparoscopic examination of the peritoneal cavity Role of PET scan 36 pa2ents with SRC Absence of tumoural fixa2on ð Probably no role of PET scan in gastric SRC Ott, Clin Cancer Res, 2008

14 c) Which surgical approach? No specific guidelines for gastric SRC Total gastrectomy should be recommanded due to Longitudinal infiltration Frozen section analysis of poor accuracy Extended to neighboring organs if needed due to Lateral infiltration D2 lymphadenectomy due to High lymphatic affinity Bozzetti Ann Surg 1999 Gouzi Ann Surg 1989 Piessen, Mariette Ann Surg 2009

15 d) Role of perioperative chemotherapy? Rational EU strategy: perioperative chemotherapy (MAGIC) US strategy: adjuvant radiochemotherapy (Macdonald) ð No stratification on histological subtype ð Small series suggesting poor chemosensitivity of SRC ADCI001 study was designed Cunningham N Engl J Med 2006 Rougier Eur J Cancer 1994 Takiuchi Oncol Rep 2000 Macdonald N Engl J Med 2001

16 ADCI001 Study Design French retrospective multicenter study 19 French centers from January 1997 January 2010 Registration of all consecutive cases of gastric ADC n = 3010 Viewed in surgical departments Wether operated on or not, resected or not, Any stage and histological subtype Considered for curative treatment

17 Study Design From this database Gastric and junctional SRC n = 1050 Comparative intent to treat study Perioperative chemotherapy: PCT group Versus primary surgery: S group Clinicaltrial.gov Protocol record ADCI001 - Identifier: NCT

18 Chemotherapy Decision of perioperative chemotherapy No specific recommandation for SRC center habits Regimen types Doublet 5FU-Cisplatinum 39.2% Triplet 5FU-Cisplatinum-Other (Epirubicin) 42.3% Other 5FU- Irinotecan 8.8%, various (Docetaxel) 8.8% Mainly 2 to 4 cycles in preoperative setting Messager, Mariette Ann Surg 2011

19 Overall population Variables Gender Women Men Age (yr) 60 >60 ASA grade I II III IV MalnutriXon No Yes LocaXon Antropyloric Non- antropyloric Unknown PretherapeuXc ctnm stage I II III Total n= 924 (%) 321 (34.7) 603 (65.3) 426 (46.1) 498 (53.9) 312 (33.8) 433 (46.8) 170 (18.4) 009 0(1.0) 664 (71.9) 260 (28.1) 243(26.3) 586 (63.4) 095 (10.3) 180 (19.5) 238 (25.8) 506 (54.7) S Group n = 753 (%) 268 (35.6) 485 (64.4) 341 (45.3) 412 (54.7) 246 (32.7) 356 (47.3) 144 (19.1) 007 0(0.9) 546 (72.5) 207 (27.5) 213 (28.3) 450 (59.8) 090 (11.9) 151 (20.0) 197 (26.2) 405 (53.8) PCT Group n = 171 (%) 053 (31.0) 118 (69.0) 085 (49.7) 086 (50.3) 066 (38.6) 077 (45.0) 026 (15.2) 0020 (1.2) 118 (69.0) 053 (31.0) 030 (17.5) 136 (79.5) 005 0(2.9) 029 (17.0) 041 (24.0) 101 (59.0) P

20 Operative variables Variables Total n = 864 (%) S Group n = 702 (%) PCT Group n = 162 (%) P Surgical procedure Subtotal gastrectomy Total gastrectomy 351 (40.6) 513 (59.4) 293 (41.7) 409 (58.3) 058 (35.8) 104 (64.2) <0.001 Lymphadenectomy extent D0 D1 D2 Extended resecxon to neighboring organs No Yes 212 (24.5) 283 (32.8) 369 (42.7) 598 (69.2) 266 (30.8) 180 (25.6) 219 (31.2) 303 (43.2) 503 (71.7) 199 (28.3) 032 (19.7) 064 (39.5) 066 (40.8) 095 (58.6) 067 (41.4) PostoperaXve30- day mortality 0280 (3.2) 0260 (3.7) 0020 (1.2) PostoperaXve30- day morbidity 364 (42.1) 298 (42.4) 066 (40.7) 0.691

21 Histological variables Variables Total n = 864 (%) S Group n = 702 (%) PCT Group n = 162 (%) P ptnm stage I II III IV Including PC 125 (14.5) 338 (39.1) 279 (32.3) 122 (14.1) 0860 (9.9) 102 (14.5) 283 (40.3) 215 (30.6) 102 (14.6) 074 (10.5) 023 (14.2) 055 (33.9) 064 (39.5) 020 (12.4) 0120 (7.4) ResecXon R0 R1 R2 564 (65.3) 123 (14.2) 177 (20.5) 463 (65.9) 093 (13.2) 146 (20.9) 101 (62.3) 030 (18.6) 031 (19.1) Mean number of dissected lymph nodes Mean number of invaded lymph nodes (00) (00) (00) (00) (00) 05.0 (0) Adjuvant chemo No Yes 524 (60.7) 340 (39.3) 467 (66.5) 235 (33.5) 057 (35.2) 105 (64.8) <0.001

22 Recurrence in R0 patients Variables Total n = 610 (%) S Group n = 497 (%) PCT Group n = 113 (%) P Recurrence No Yes 335 (54.9) 275 (45.1) 272 (54.8) 225 (45.2) 63 (55.7) 50 (44.3) Recurrence type (n = 275) Locoregional Distant Both Unknown Median Xme to first recurrence (months) [range min max] 049 (17.8) 156 (56.7) 059 (21.5) 0110 (4.0) 11.6 [ ] 044 (19.6) 126 (56.0) 046 (20.4) 0090 (4.0) 12.2 [ ] 05 (10.0) 30 (60.0) 13 (26.0) 020 (4.0) 7.9 [ ]

23 Survival for S and PCT groups Median survival S group 14.0 months PCT group 12.8 months P = 0.043

24 Multivariate analysis Variables HR 95% IC P PretherapeuXc ctnm stages II or III <0.001 Presence of postoperaxve complicaxons Incomplete tumoral resecxon PerioperaXve chemotherapy administraxon ASA grade II or III PretherapeuXc malnutrixon Macroscopic aspect of linixs plasxca

25 Consequently, is there a role for adjuvant chemoradiotherapy? 10 year-results of the INT0116 study 582 resected gastric and junctional ADC, stages Ib to IV Adjuvant 5FU Leucovorin + radiotherapy Survival benefit of CRT in the overall population OS (HR=1.32, p=.004) DFS (HR=1.51, p<.001) Sub-group analysis on Lauren classification Diffuse type HR 0.97 ( ) Diffuse type = independent factor of poor prognosis associated with no survival benefit Macdonald J Clin Oncol 2009 Macdonald ASCO 2009

26 What to do for locally advanced junctional SRC? 97 stage III SRC EGJA treated by neoadjuvant radiochemotherapy followed by surgery (n= 23) or primary surgery (n= 74). Groups were comparable by age, gender, American Society of Anesthesiologists (ASA) score, malnutrition and ctnm stage. Significant tumoral (p=0.003), nodal (p<0.001) and ptnm (p<0.001) downstaging following radiochemotherapy. Neoadjuvant radiochemotherapy = sole independent favorable prognostic factor (HR 0.41, p=0.020). Bekkar, Messager, Robb, Mariette Ann Thorac Surg 2013 Group S Group RCT

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28 The future in SRC gastric cancer? Phase II/III randomized study: PRODIGE 19- ADCI002 trial - Granted by the INCA research program PI: Pr C Mariette Study flowchart 4 semaines max 4 à 6 semaines 6 à 12 semaines 3 à 4 semaines Inclusion RandomisaXon Bras A Début chimiothérapie néo- adjuvante Bilan de réévalua2on Chirurgie Début chimiothérapie adjuvante Chirurgie Début chimiothérapie adjuvante /4 mois, 3 ans Bilan de pré- inclusion 4 semaines max Bras B Piessen, Mariette BMC Cancer à 12 semaines Chimiothérapie ECF

29 The future in SRC gastric cancer? Evaluation of IPC/HIPEC Curative intent HIPEC very low efficacy in gastric SRC Immunotherapy : Role of Catumaxomab in intraperitoneal infusion after gastric surgery (phase I/II) PI Pr. D Elias, IGR Granted by INCA, research program Prophylactic Phase III RCT trial comparing prophylactic HIPEC after surgery vs. surgery alone PI Pr. O. Glehen, Lyon Elias Ann Surg Oncol 2010

30 Take home message 1. Incidence is increasing, ++ in young patients 2. Pronostic of advanced forms of SRC is poor 3. Actual therapeutic strategies are suboptimal ð it is thus mandatory To propose alternative therapeutic strategies dedicated to SRC To stratify according to histological subtype in gastric cancer trials To better undertand SRC tumour biology