Perioperative versus adjuvant management of gastric cancer, update 2013

Transcription

1 Perioperative versus adjuvant management of gastric cancer, update 2013 Cornelis J.H. van de Velde, MD, PhD,FRCPS and FACS,Hon. Professor of Surgery President ECCO - the European Cancer Organization Past-President European Society of Surgical Oncology Leiden University Medical Center Leiden, The Netherlands

2 Reasons for multimodality treatment Post-Operative Treat occult residual metastases Successful in other tumor types Better patient selection Peri-operative Eliminating occult micrometastases early Downstaging more R0 resections Better tolerance

3 Postoperative radiotherapy

4 British Stomach Cancer Group Trial Survival after adjuvant radiotherapy or chemotherapy in resectable gastric cancer 40% R1/R2 resection 76% started RT 58% completed MAF Local recurrence rate: RT vs Surgery 32% vs 54% Hallissey et al, Lancet 1994

5 Postoperative radiotherapy Conclusion: no role in daily clinical practice

6 Postoperative chemotherapy

7 Meta-analyses on postoperative chemotherapy No. of trials No. of patients Mortality risk 95% CI Hermans, Earle, Mari, Panzini, Janunger, GASTRIC 2010: 5-year survival benefit 5% GASTRIC - Some more 2010 benefit in node-positive 17 tumors

8 GASTRIC year survival Surgery alone 49.6 % Adjuvant chemotherapy 55.3 % HR = 0.82; p < GASTRIC Group JAMA 2010; 303:

9 RCTs on postoperative chemotherapy n control vs experimental mortality risk 95% CI 5-yr OS (%) ITMO EAP + 5FU/LV vs 52 FFCD (400) 5FU/CDDP vs 47 EORTC/ ICCG 2006 GOIM 2007 GISCAD FAMTX/FEMTX vs epi/lv/5fu/vp vs FU/LV vs PELFw vs 52

10 Sakuramoto et al, NEJM 2007 Japanese trial 1059 patients Surgery (D2) vs Surgery + S1 (6 months) Conclusion: Improved survival after S-1

11 Ajani et al., JCO 2010 S-1 in the West Limited to 1 study on metastatic gastric/gej disease Better toxicity profile compared to infusional 5-FU. No improvement in OS

12 CLASSIC Study: Korea, Taiwan, China 1035 patients Randomized between: A: D2 gastrectomy B: D2 gastrectomy + postoperative capecitabine+oxaliplatin 3-year disease free-survival 3-year overall survival P < P < 0.05

13 Postoperative chemotherapy Effective, 5% increase in overall survival What about more intensive schedules?

14 Italy 2007 more intense schedule N=400 5-FU/LV vs cisplatin/epirubicine/5-fu/lv No difference in PFS/OS Cascinu et al., J Nat Canc Inst 2007; 99:

15 Italy 2012 more intense schedule N= FU/LV vs FOLFIRI + docetaxel /cisplatin No difference in overall survival HR: 1.00; 95%CI ; p=0.98 Bajetta et al., ASCO 2012; abstract LBA 4001

16 US 2011 more intense schedule CALGB N=540 R A N 5-FU/LV x 1 5-FU i.v. CI RT 5-FU/LV x 2 D O M I Z E ECF x 1 5-FU IVCI RT ECF x 2 Fuchs et al., ASCO 2011; # 4003

17 US 2011 more intense schedule No difference in overall survival Overall Survival by Arm Proportion Surviving Years from Study Entry ECF 5-FU

18 Postoperative chemotherapy Conclusions Effective, 5% increase in overall survival No evidence for more intense chemotherapy schedules Capecitabine/oxaliplatin versus 5-FU / LV?

19 Postoperative chemoradiotherapy

20 Smalley et al, IJROBP 2002

21 Intergroup 0116 trial Day FU LV RT (25x1.8 Gy) Post-operative chemoradiation vs Surgery 73 % grade ¾ toxicity 64% completed CRT 9% survival benefit Adjuvant CRT

22 Intergroup 0116 trial Criticised Complex chemoradiotherapy protocol Lack of surgical quality control 54% D0 resection Selection of patients (only R0 resection with adequate recovery) CRT might have compensated for the low number of D2 dissections

23 MacDonald, NEJM 2001, Sakuramoto, NEJM 2007 Japanese vs Intergroup 0116 study Intergroup 0116 study Japanese study red line: 60% survival, surgery only in Japanese trial

24 Kim et al, Int. J. Radiation Oncology Biol. Phys 2005 Korean observational study 1000 patients Surgery (D2) vs Surgery + Intergroup 0116 CRT schedule Conclusion: CRT associated with improved OS after D2 surgery

25 Dutch Observational study 785 patients Surgery or Surgery + Postoperative CRT Capecitabine or capecitabine+cisplatin D1 Surgery (P = 0.04) D2 Surgery (P = NS) Conclusion: CRT associated with improved survival after D1, but not after D2 surgery

26 Dikken van de Velde et al JCO 2010 May 10;28(14): and unpubl Dutch Observational Study Overall Survival Local recurrence D1 D1: HR 1.68 P=0.04 D1: HR 14.6 P<0.01 Conclusion Adjuvant CRT has survival/ recurrence benefit over D1 BUT NOT over D2 surgery D2 D2: HR 0.88 P=0.65 D2: HR 0.98 P=0.96

27 Dikken vd Velde et al, JCO 2010 Dutch Observational study R0-resection HR 1.04 P=0.85 R1-resection HR 3.16 P<0.01

28 Gastric cancer: 15-Year follow-up Dutch D1D2 Trial 711 Patients with curative resection Overall Survival D1: 21% D2: 29% P=0.3 Local recurrence D1: 22% D2: 12%

29 15-Year follow-up Dutch D1D2 Trial Death of Gastric Cancer D1: 48% D2: 37% HR 0.74, P= Patients with curative resection Conclusion D2 dissection should be recommended as standard surgical approach in resectable gastric cancer Death of Other Causes HR=1.22, P=NS

30 Postoperative chemoradiotherapy Conclusions Significant survival benefit after D1 dissection Also after D2 dissection?

31 Preoperative radiotherapy

32 Chinese study 1998 N=370 40Gy + surgery versus surgery alone Resection rate Overall survival 30% vs 20% 90% vs 80% Operative 2.5% vs 0.6% Leakage 4.0% vs 0.8% Local recurrence 39 vs 55% Zhang et al, IJROBP 1998

33 Conclusion Preoperative radiotherapy Limited evidence Suggestion of advantage over surgery alone Only cardia cancer

34 Preoperative chemotherapy

35 Cunningham,van de Velde, NEJM 2006 MAGIC trial Peri-operative chemotherapy vs Surgery 13 % overall survival benefit 10 % more resectability

36 Intergroup 0116 vs MAGIC Intergroup 0116 Randomization after R0 surgery after diagnosis Preoperative therapy not applicable A: ECF (3 courses) B: none Completed preoperative therapy not applicable 86% Surgery D0 gastrectomy: 54% D1 gastrectomy: 36% D2 gastrectomy: 10% R0 resection 100% (if R1/R2: no inclusion) Postoperative Therapy A: 5-FU/LV/RT (45Gy) B: none Completed postoperative therapy 64% 42% Surgery Radiotherapy Result primary endpoint (experimental versus control) D2 recommended Postoperative analysis of extent of LN dissection Central review of RT plan Major deviations corrected A: 42% 5-year OS B: 25% 5-year OS MAGIC oesophagogastrectomy: 23% D1 gastrectomy: 19% D2 gastrectomy: 40% non-curative/unknown: 18% A: 69.3% B: 66.4% A: ECF (3 courses) B: none not reported not applicable A: 36% 5-year OS B: 23% 5-year OS

37 Intergroup 0116 vs MAGIC Studies are incomparable due to selection Intergroup 0116: R0 and adequate postoperative recovery MAGIC: Eligible for surgery Focus on compliance MAGIC: 85% preoperative therapy 42% total regimen Intergroup 0116: 64% CRT regimen

38 Biffi et al, World J Gastroenterol 2010 Swiss-Italian study 70 patients Randomized between: A: Preoperative chemotherapy B: Postoperative chemotherapy Results: Compliance A: 75% Compliance B: 34% Conclusion: Preoperative therapy associated with better compliance

39 R Tissue banking CRITICS (ChemoRadiotherapy after Induction ChemoTherapy in Cancer of the Stomach) Preoperative Trial:n=600 chemotherapy 3x ECC Preoperative chemotherapy 3x ECC D1 + surgery QoL D1 + surgery At least 15 nodes, No splenectomy Postoperative Chemotherapy 3x ECC Chemoradiation 45 Gy/25fx + Capecitabine + Cisplatin Quality assurance - Surgery: surgical audit to individual surgeons - Pathology: pathology audit to individual pathologists - Radiotherapy: check of RT plan before start of treatment RT atlas

40 Principle investigators Prof. M. Verheij Dr. A. Cats Prof. C.J.H. van de Velde For further information on the CRITICS trial Study coördinator Anouk Trip

41 ARTIST study: Korea 458 patients Randomized between: A: D2 gastrectomy + capecitabine + cisplatin B: D2 gastrectomy + capecitabine + cisplatin + radiotherapy 3-year disease free-survival 3-year disease free-survival all patients N+ patients P = P = 0.036

42 Conclusions Asia: most patients receive postoperative therapy S-1 in Japan Capecitabine/oxaliplatin or chemoradiotherapy in Korea USA: perioperative chemotherapy and postoperative chemoradiotherapy Europe: mostly perioperative chemotherapy

43 Conclusions Preoperative chemotherapy recommended Higher compliance More R0 resections When tolerated: postoperative therapy High risk for locoregional relapse (R1) Postoperative chemoradiotherapy High risk for distant metastases (difficult to identify) Postoperative systemic chemotherapy

44 Amsterdam September Multidisciplinary care: can we do better?