CRITICS studie - symposium oncologie in perspectief

Behandeling van maagkanker in
multidisciplinair verband
(CRITICS studie)
Johanna van Sandick, chirurg
Antoni van Leeuwenhoek Ziekenhuis
5 juni 2014
Disclosure
Geen (potentiële) belangenverstrengeling
Radiotherapy
Surgery
Chemotherapy
Oesophagogastric cancer in the Netherlands
Incidence
Oesophageal cancer
Gastric cancer
Dikken et al. EJC 2012
Oncoline.nl
•
Rapidly increasing incidence adenocarcinoma.
• Declining incidence.
•
1800 new patients/year (2011)
• 1500 new patients/year (2011)
Oesophagogastric cancer in the Netherlands
Survival
Gastric cancer
Dikken et al. EJC 2012
Improving survival. Dassen et al. EJC 2010
No improvement in survival. Gastric cancer
• Presents in an advanced disease stage.
• European mean
5 year survival ̴ 25% • Netherlands
5 year survival ̴ 20% Sant et al. EJC 2009
Potentially curative treatment
Surgery
̴ 500 gastric cancer resections in NL each year
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.
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
(Neo‐) adjuvante behandelingen
MAGIC Trial
Design
Surgery < 6 wks
n=240
n=253
R
n=250
3x ECF
n=237
95%
Surgery 3-6 weeks
n=209
n=137
55%
ECF, epirubicin‐cisplatin‐fluorouracil.
Cunningham D, et al. N Engl J Med. 2006;355:11‐20.
3x ECF 6-12 weeks
n=104
42%
MAGIC Trial
Overall Survival
1.0
0.9
0.8
Overall Survival
0.7
0.6
0.5
Perioperative
chemotherapy
0.4
0.3
Surgery alone
0.2
0.1
P=0.009
0.0
0
12
24
36
48
60
72
Months
No. at Risk
Perioperative
chemotherapy
Surgery
250
168
111
79
52
38
27
253
155
80
50
31
18
9
Cunningham D, et al. N Engl J Med. 2006;355:11‐20.
(Neo‐) adjuvante behandelingen
(Neo‐) adjuvante behandeling ? De ene oudere is de andere niet…
Behandelkeuze – (neo)adjuvant
leeftijd
DICA congres 2013
leeftijd
SWOG Intergroup 0116
Gastric Surgical Adjuvant Trial
Observation
n=275
Surgery
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;345:725‐730.
SWOG Intergroup 0116
Overall Survival
Median 5-year Duration of Survival
Chemoradiotherapy
Sugery only
Percentage
Surviving
100
P=0.005
80
60
Chemoradiotherapy
40
20
Surgery only
0
0
24
48
72
96
Months after Registration
MacDonald JS, et al. N Engl J Med. 2001;345:725‐730.
120
36 months
27 months
Europa versus Amerika
CRITICS studie
Preoperatieve Chemotherapie
(3x ECC)
Gastrectomie met D1+ Lymfeklierdissectie
Postoperatieve Chemotherapie
(3x ECC)
Preoperatieve Chemotherapie
(3x ECC)
Gastrectomie met D1+ Lymfeklierdissectie
Chemoradiatie
45 Gy in 25 fracties
+ capecitabine
+ cisplatine
R
2 weken
3‐6 weken
binnen 4‐12 weken
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 schedule
pre-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 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
Experimental arm: Chemoradiotherapy
post-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
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?
CRITICS - Statistics
788
patients needed
Inclusie CRITICS studie
februari 2014
inclusion per quarter
cumulative inclusion
estimation
45
800
770
700
40
669
600
35
30
500
25
400
20
300
15
200
10
100
5
0
0
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
25
10
Rijnstate Ziekenhuis
22
Totaal aantal geïncludeerde patiënten
699
Kwaliteitscontrole ‐ lymfeklieropbrengst
januari 2013
* Total number of patients that underwent gastric cancer resection
CRITICS studie ‐ conclusies
• Interim analyse » Ongoing (inclusie wordt niet stop gezet)
• Monitoring
» 2e monitoring ronde klaar
• Kwaliteitswaarborging
» Meer aandacht voor QoL vragenlijsten nodig
www.critics.nl
[email protected]
Klinische studies maagcarcinoom
• Primair maagcarcinoom
– Perioperatieve behandeling (CRITICS)
– Neoadjuvant chemoradiotherapie (NARCIS/UMCG)
– Peroperatief (PERISCOPE)
• Gemetastaseerd maagcarcinoom
– Systemische behandeling (BDOCT)
Neoadjuvant chemoradiotherapie (CRT) bij lokaal
uitgebreid (ir)resectabel maagcarcinoom
NARCIS en UMCG studie
CRT
Chirurgie
45 Gy: 1.8 Gy in 25 fx
paclitaxel 50mg/m2 +
5x q 1wk
carboplatin AUC 2
•
•
N = 25
Primaire eindpunten: haalbaarheid en effectiviteit
D2 resectie
4-6 weken
Neoadjuvant chemoradiotherapie (CRT) bij lokaal
uitgebreid (ir)resectabel maagcarcinoom
NARCIS en UMCG studie
CRT
45 Gy: 1.8 Gy in 25 fx
paclitaxel 50mg/m2 +
5x q 1wk
carboplatin AUC 2
Chirurgie
D2 resectie
• Toxiciteit graad 3: n=6
• Resectie: n=21; R0 n=18
• pCR: n=4
Eerste auteur: Anouk Trip, [email protected]
Treatment of PERItoneal dissemination in Stomach Cancer patients with cytOreductive surgery and hyperthermic intraPEritoneal chemotherapy
Principal investigators
Johanna van Sandick, [email protected]
Bert van Ramshorst, [email protected]
Studie coördinator
Hidde 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
Dose Level
Level 1
Level 2
Level 3
Level 4
Level 5
Level 6
Oxaliplatin
(mg/m2)
460
460
460
460
460
460
Docetaxel
(mg/m2)
0
50
75
100
125
150
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. 20‐30 afhankelijk van aantal dosis escalaties
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/m2
Oxaliplatin 100 mg/m2
Capecitabine 850 mg/m2 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/m2
Capecitabine 850 mg/m2 bid, day 1-14
Trastuzumab 6 mg/kg (+ 2 mg/kg loading dose 1st day)
q 3 weeks
Primaire eindpunt: PFS
www.dccg.nl/trials/B-DOCT
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]

Download Report