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Behandeling van maagkanker in multidisciplinair verband
(CRITICS studie)
Johanna van Sandick, chirurgAntoni van Leeuwenhoek Ziekenhuis
5 juni 2014
Disclosure
Geen (potentiële) belangenverstrengeling
Radiotherapy Surgery
Chemotherapy
Oesophagogastric cancer in the NetherlandsIncidence
Oncoline.nlDikken et al. EJC 2012
Oesophageal cancer Gastric cancer
• Rapidly increasing incidence adenocarcinoma.
• 1800 new patients/year (2011)
• Declining incidence.
• 1500 new patients/year (2011)
Oesophagogastric cancer in the NetherlandsSurvival
Dassen et al. EJC 2010Dikken et al. EJC 2012
Gastric cancer
Improving survival. No improvement in survival.
Gastric cancer
• Presents in an advanced disease stage.
• European mean5 year survival 25%
• Netherlands5 year survival 20%
Sant et al. EJC 2009
Potentially curative treatmentSurgery
500 gastric cancer resections in NL each year
Sites of failure after potentially curative resection
Local-regional recurrence (as any component of failure)
Distant metastasis (alone)
Local-regional recurrence (only failure)
Gunderson LL, Sosin H. Int J Radiat Oncol Biol Phys. 1982;8:1‐11.
88%
26%
54%
• Increasing use of multimodality treatment
• (Neo)adjuvant chemo(radio)therapy
• 5‐year survival 35 ‐ 40%
Cunningham et al. NEJM 2006
Macdonald NEJM 2001
Potentially curative treatmentMultimodality
(Neo‐) adjuvante behandelingen
ECF, epirubicin‐cisplatin‐fluorouracil.
Cunningham D, et al. N Engl J Med. 2006;355:11‐20.
MAGIC TrialDesign
3x ECFn=237
Rn=253
n=250
Surgery < 6 wksn=240
Surgery 3-6 weeksn=209 3x ECF 6-12 weeks
n=104n=13795% 55% 42%
Cunningham D, et al. N Engl J Med. 2006;355:11‐20.
MAGIC TrialOverall Survival
Over
all S
urviv
al
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 12 24 36 48 60 72
Months
Perioperativechemotherapy
Surgery alone
No. at Risk Perioperative 250 168 111 79 52 38 27
chemotherapySurgery 253 155 80 50 31 18 9
P=0.009
(Neo‐) adjuvante behandelingen
(Neo‐) adjuvante behandeling ?
De ene oudere is de andere niet…
Behandelkeuze – (neo)adjuvant
leeftijdleeftijd
DICA congres 2013
Surgery
1x 5-FU
Rn=275
n=281
Observation
Chemoradiotherapy45 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;345:725‐730.
SWOG Intergroup 0116Gastric Surgical Adjuvant Trial
Median 5-year Duration of SurvivalChemoradiotherapy 36 monthsSugery only 27 months
MacDonald JS, et al. N Engl J Med. 2001;345:725‐730.
SWOG Intergroup 0116Overall Survival
P=0.005
Months after Registration
Percentage Surviving
0 24 48 72 96 1200
20
40
60
80
100
Chemoradiotherapy
Surgery only
Europa versus Amerika
CRITICS studie
Chemoradiatie45 Gy in 25 fracties+ capecitabine+ cisplatine
Gastrectomie met D1+
Lymfeklierdissectie
Gastrectomie met D1+
Lymfeklierdissectie
Preoperatieve Chemotherapie
(3x ECC)
Preoperatieve Chemotherapie
(3x ECC)
R
2 weken 3‐6 weken binnen 4‐12 weken
Postoperatieve Chemotherapie
(3x ECC)
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.
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)
3x ECC schedulepre-operative
• 1 cycle = 2 weeks chemotherapy, 1 week rest– Epirubicin 50 mg/m2 i.v. on day 1 – Cisplatin 60 mg/m2 i.v. on day 1 after pre-hydration– Capecitabine 1000 mg/m2 orally bid on day 1-14
• Re-evaluation after the 2nd cycle– CT-chest and abdomen
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
DO NOT FORGET JEJUNOSTOMY
Control arm: 3x ECC schedulepost-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
Experimental arm: Chemoradiotherapypost-operative
Chemoradiotherapy:
• 25 x 1,8 Gy on weekdays (5 weeks)• Cisplatin 20 mg/m2 i.v. on days 1,8,15,22,29 of RT • Capecitabine 575 mg/m2 bid orally on each day of RT
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?
Experimental arm: Chemoradiotherapypost-operative
CRITICS - Statistics
788patients needed
Inclusie CRITICS studiefebruari 2014
669
770
0
5
10
15
20
25
30
35
40
45
0
100
200
300
400
500
600
700
800
inclusion per quarter cumulative inclusion estimation
Inclusie per ziekenhuisd.d. 4 juni 2014
Aantal
1 NKI‐AVL 60
2 AMC 383 Orbis Medisch Centrum 32
4 Amphia Breda 30
5 St Antonius Nieuwegein 25
6 Akademiska Sjukhuset, Uppsala 25
8 Haga Ziekenhuis 25
9 VUMC 25
10 Rijnstate Ziekenhuis 22
Totaal aantal geïncludeerde patiënten 699
Kwaliteitscontrole ‐ lymfeklieropbrengstjanuari 2013
* Total number of patients that underwent gastric cancer resection
• Interim analyse » Ongoing (inclusie wordt niet stop gezet)
• Monitoring» 2e monitoring ronde klaar
• Kwaliteitswaarborging» Meer aandacht voor QoL vragenlijsten nodig
CRITICS studie ‐ conclusies
www.critics.nl [email protected]
Klinische studies maagcarcinoom
• Primair maagcarcinoom– Perioperatieve behandeling (CRITICS)– Neoadjuvant chemoradiotherapie (NARCIS/UMCG)– Peroperatief (PERISCOPE)
• Gemetastaseerd maagcarcinoom– Systemische behandeling (BDOCT)
4-6 weken
Neoadjuvant chemoradiotherapie (CRT) bij lokaaluitgebreid (ir)resectabel maagcarcinoom
NARCIS en UMCG studie
• N = 25• Primaire eindpunten:
haalbaarheid en effectiviteit
CRT45 Gy: 1.8 Gy in 25 fx paclitaxel 50mg/m2 + carboplatin AUC 2 5x q 1wk
ChirurgieD2 resectie
• Toxiciteit graad 3: n=6• Resectie: n=21; R0 n=18• pCR: n=4
CRT45 Gy: 1.8 Gy in 25 fx paclitaxel 50mg/m2 + carboplatin AUC 2 5x q 1wk
ChirurgieD2 resectie
Eerste auteur: Anouk Trip, [email protected]
Neoadjuvant chemoradiotherapie (CRT) bij lokaaluitgebreid (ir)resectabel maagcarcinoom
NARCIS en UMCG studie
Treatment of PERItoneal dissemination in Stomach Cancer patients with cytOreductive surgery and hyperthermic intraPEritoneal chemotherapy
Principal investigatorsJohanna van Sandick, [email protected] van Ramshorst, [email protected] coördinatorHidde Braam, [email protected]
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 LevelDose
Oxaliplatin(mg/m2)
Docetaxel(mg/m2)
Level 1 460 0Level 2 460 50Level 3 460 75Level 4 460 100Level 5 460 125Level 6 460 150
Inclusie criteria• T3‐T4 adenocarcinoom maag• Tumorpositief buikvocht en/of peritonitis carcinomatosa beperkt tot de bovenbuik en/of éénlokatie in de onderbuik bevestigd d.m.v. laparoscopie
Exclusie criteria• Recidief maagcarcinoom• Metachrone peritonitis carcinomatosa
Aantal patiëntenCa. 20‐30 afhankelijk van aantal dosis escalaties
Arm A (n = 60): Bevacizumab 7.5 mg/kgDocetaxel 50 mg/m2
Oxaliplatin 100 mg/m2
Capecitabine 850 mg/m2 bid, day 1-14
Arm B in case of HER2 positive tumor (n = 20):Bevacizumab 7.5 mg/kgDocetaxel 50 mg/m2Oxaliplatin 100 mg/m2
Capecitabine 850 mg/m2 bid, day 1-14Trastuzumab 6 mg/kg (+ 2 mg/kg loading dose 1st day)
B-DOCT, Phase II studyBevacizumab, Docetaxel, Oxaliplatin, Capecitabine (and Trastuzumab) in Locally Advanced or Metastatic Gastric Cancer or Adenocarcinoma of
the Gastro-Oesophageal Junction
www.dccg.nl/trials/B-DOCT
q 3 weeks
q 3 weeks
Primaire eindpunt: PFS
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
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
www.critics.nl [email protected]