Behandeling van maagkanker in multidisciplinair verband (CRITICS studie) Johanna van Sandick, chirurg Antoni van Leeuwenhoek Ziekenhuis 5 juni 2014

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1 Behandeling van maagkanker in multidisciplinair verband (CRITICS studie) Johanna van Sandick, chirurg Antoni van Leeuwenhoek Ziekenhuis 5 juni 2014

2 Disclosure Geen (potentiële) belangenverstrengeling

3 Radiotherapy Surgery Chemotherapy

4 Oesophagogastric cancer in the Netherlands Incidence Oesophageal cancer Gastric cancer Dikken et al. EJC 2012 Rapidly increasing incidence adenocarcinoma. Declining incidence. Oncoline.nl 1800 new patients/year (2011) 1500 new patients/year (2011)

5 Oesophagogastric cancer in the Netherlands Survival Gastric cancer Dikken et al. EJC 2012 Improving survival. Dassen et al. EJC 2010 No improvement in survival.

6 Gastric cancer Presents in an advanced disease stage. European mean 5 year survival 25% Netherlands 5 year survival 20% Sant et al. EJC 2009

7 Potentially curative treatment Surgery 500 gastric cancer resections in NL each year

8 Sites of failure after potentially curative resection Local-regional recurrence (as any component of failure) 88% Distant metastasis (alone) 26% Local-regional recurrence (only failure) 54% Gunderson LL, Sosin H. Int J Radiat Oncol Biol Phys. 1982;8:1 11.

9 Potentially curative treatment Multimodality Increasing use of multimodality treatment Macdonald NEJM 2001 (Neo)adjuvant chemo(radio)therapy 5 year survival 35 40% Cunningham et al. NEJM 2006

10 (Neo ) adjuvante behandelingen

11 MAGIC Trial Design Surgery < 6 wks n=240 n=253 R n=250 3x ECF n=237 95% ECF, epirubicin cisplatin fluorouracil. Surgery 3-6 weeks n=209 n=137 55% 3x ECF 6-12 weeks n=104 42% Cunningham D, et al. N Engl J Med. 2006;355:11 20.

12 MAGIC Trial Overall Survival Overall Survival Perioperative chemotherapy Surgery alone P= Months No. at Risk Perioperative chemotherapy Surgery Cunningham D, et al. N Engl J Med. 2006;355:11 20.

13 (Neo ) adjuvante behandelingen

14 (Neo ) adjuvante behandeling? De ene oudere is de andere niet

15 Behandelkeuze (neo)adjuvant leeftijd leeftijd DICA congres 2013

16 SWOG Intergroup 0116 Gastric Surgical Adjuvant Trial Observation Surgery n=275 R n=281 1x 5-FU Chemoradiotherapy 45 Gy/25 fx + 5-FU/ LV 2x 5-FU 5 FU, 5 fluorouracil; LV, leucovorin; SWOG, Southwest Oncology Group. MacDonald JS, et al. N Engl J Med. 2001;345:

17 SWOG Intergroup 0116 Overall Survival Percentage Surviving Median 5-year Duration of Survival Chemoradiotherapy 36 months Sugery only 27 months P=0.005 Chemoradiotherapy 20 0 Surgery only Months after Registration MacDonald JS, et al. N Engl J Med. 2001;345:

18 Europa versus Amerika

19 CRITICS studie Preoperatieve Chemotherapie (3x ECC) Gastrectomie met D1+ Lymfeklierdissectie Postoperatieve Chemotherapie (3x ECC) R Preoperatieve Chemotherapie (3x ECC) Gastrectomie met D1+ Lymfeklierdissectie Chemoradiatie 45 Gy in 25 fracties + capecitabine + cisplatine 2 weken 3 6 weken binnen 4 12 weken

20 CRITICS - Endpoints Primary Overall survival Secondary Disease free survival Toxicity profile Health-related quality of life Tissue and blood for translational research Dikken JL, et al. BMC Cancer. 2011;11:329.

21 CRITICS - Inclusion criteria Resectable adenocarcinoma of the stomach or oesophagogastric junction (bulk in the stomach) Stage Ib-IVa (no distant metastases) Tumour negative laparoscopy when CT suggests peritoneal carcinomatosis WHO < 2 Adequate caloric intake (e.g. > 1500 kcal/day)

22 3x ECC schedule pre-operative 1 cycle = 2 weeks chemotherapy, 1 week rest Epirubicin 50 mg/m 2 i.v. on day 1 Cisplatin 60 mg/m 2 i.v. on day 1 after pre-hydration Capecitabine 1000 mg/m 2 orally bid on day 1-14 Re-evaluation after the 2 nd cycle CT-chest and abdomen

23 Surgical Technique Wide resection of the tumour bearing part of the stomach: (sub) total gastrectomy D1+ lymph node dissection (1-9 and 11): 15 lymph nodes No routine pancreatico-splenectomy

24 DO NOT FORGET JEJUNOSTOMY

25 Control arm: 3x ECC schedule post-operative Same 3 weekly ECC schedule Start after 4-12 weeks Dietary support essential low threshold for enteral tube feeding through in situ jejunostomy NB! early progression / pre-op problems / bone marrow depression

26 Experimental arm: Chemoradiotherapy post-operative Chemoradiotherapy: 25 x 1,8 Gy on weekdays (5 weeks) Cisplatin 20 mg/m 2 i.v. on days 1,8,15,22,29 of RT Capecitabine 575 mg/m 2 bid orally on each day of RT

27 Experimental arm: Chemoradiotherapy post-operative NB! Baseline referral to radiation oncologist Check renal function First 3 patients AvL (inter-observer variation study) Dietary support essential Mucositis Who is responsible for data-management / SAE?

28 CRITICS - Statistics 788 patients needed

29 Inclusie CRITICS studie februari 2014 inclusion per quarter cumulative inclusion estimation

30 Inclusie per ziekenhuis d.d. 4 juni 2014 Aantal 1 NKI AVL 60 2 AMC 38 3 Orbis Medisch Centrum 32 4 Amphia Breda 30 5 St Antonius Nieuwegein 25 6 Akademiska Sjukhuset, Uppsala 25 8 Haga Ziekenhuis 25 9 VUMC Rijnstate Ziekenhuis 22 Totaal aantal geïncludeerde patiënten 699

31 Kwaliteitscontrole lymfeklieropbrengst januari 2013 * Total number of patients that underwent gastric cancer resection

32 CRITICS studie conclusies Interim analyse Monitoring» Ongoing (inclusie wordt niet stop gezet)» 2 e monitoring ronde klaar Kwaliteitswaarborging» Meer aandacht voor QoL vragenlijsten nodig info@critics.nl

33 Klinische studies maagcarcinoom Primair maagcarcinoom Perioperatieve behandeling (CRITICS) Neoadjuvant chemoradiotherapie (NARCIS/UMCG) Peroperatief (PERISCOPE) Gemetastaseerd maagcarcinoom Systemische behandeling (BDOCT)

34 Neoadjuvant chemoradiotherapie (CRT) bij lokaal uitgebreid (ir)resectabel maagcarcinoom NARCIS en UMCG studie CRT 45 Gy: 1.8 Gy in 25 fx paclitaxel 50mg/m 2 + carboplatin AUC 2 5x q 1wk Chirurgie D2 resectie N = 25 Primaire eindpunten: haalbaarheid en effectiviteit 4-6 weken

35 Neoadjuvant chemoradiotherapie (CRT) bij lokaal uitgebreid (ir)resectabel maagcarcinoom NARCIS en UMCG studie CRT 45 Gy: 1.8 Gy in 25 fx paclitaxel 50mg/m 2 + carboplatin AUC 2 5x q 1wk Chirurgie D2 resectie Toxiciteit graad 3: n=6 Resectie: n=21; R0 n=18 pcr: n=4 Eerste auteur: Anouk Trip, a.trip@nki.nl

36 Treatment of PERItoneal dissemination in Stomach Cancer patients with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy Principal investigators Johanna van Sandick, Bert van Ramshorst, Studie coördinator Hidde Braam,

37 Multicenter, open label, fase I/II dosis escalatie studie Doel: het bepalen van 1) Veiligheid en uitvoerbaarheid van HIPEC na neoadjuvante chemotherapie als primaire behandeling bij maagkanker patiënten met beperkte peritonitis carcinomatosa en/of tumorpositieve cytologie van buikvocht 2) Dosering docetaxel intraperitoneaal in combinatie met een vaste dosering oxaliplatin Dose Dose Level Oxaliplatin (mg/m 2 ) Docetaxel (mg/m 2 ) Level Level Level Level Level Level

38 Inclusie criteria T3 T4 adenocarcinoom maag Tumorpositief buikvocht en/of peritonitis carcinomatosa beperkt tot de bovenbuik en/of één lokatie in de onderbuik bevestigd d.m.v. laparoscopie Exclusie criteria Recidief maagcarcinoom Metachrone peritonitis carcinomatosa Aantal patiënten Ca afhankelijk van aantal dosis escalaties

39 B-DOCT, Phase II study Bevacizumab, Docetaxel, Oxaliplatin, Capecitabine (and Trastuzumab) in Locally Advanced or Metastatic Gastric Cancer or Adenocarcinoma of the Gastro-Oesophageal Junction Arm A (n = 60): Bevacizumab 7.5 mg/kg Docetaxel 50 mg/m 2 Oxaliplatin 100 mg/m 2 Capecitabine 850 mg/m 2 bid, day 1-14 q 3 weeks Arm B in case of HER2 positive tumor (n = 20): Bevacizumab 7.5 mg/kg Docetaxel 50 mg/m2 Oxaliplatin 100 mg/m 2 Capecitabine 850 mg/m 2 bid, day 1-14 Trastuzumab 6 mg/kg (+ 2 mg/kg loading dose 1 st day) q 3 weeks Primaire eindpunt: PFS

40 Conclusions Gastric cancer has poor survival Surgery alone leads to high recurrence rates Perioperative chemotherapy and postoperative CRT improve outcome Neoadjuvant CRT in selected cases Phase III trials will provide answers

41 Acknowledgements A. Cats, gastroenterologist, AvL H. Boot, gastroenterologist, AvL E.P.M. Jansen, radiation oncologist, AvL M. Verheij, radiation oncologist, AvL A. Trip, study coördinator CRITICS, AvL