hipec in high risk colon cancer

1. JOURNAL CLUB
Moderator – Dr. Pankaj Kr Garg
Presenter – Dr. Rahul Kumar

2. • Lancet gastroenterology and hepatology, October 2019
• Impact factor 12.586

3. METHODS
Study design
 Multicenter, open label , randomized trial
 Endorsed by DCCG and DPOG
 Nine hospitals specialized in HIPEC
 Amsterdam UMC – coordinating center
 Protocol approval from institutional review board

4. METHODS
Participants
 Clinical or pathological T4N0–2M0
 Perforated colon cancer (perforation/ abscess).
 18- 75 year, good clinical condition
 Intention to start adjuvant chemo
Exclusion criteria
 Neuroendocrine tumors
 Microsatellite instability stage II

5. Randomization and Masking
 Web application based randomization (ALEA 2.2)
 Block randomization method was used
 Stratification – tumor characteristics, surgical approach and age
 Pre-op or postop randomization was done
 Randomization (1:1)
 Adjuvant HIPEC f/b systemic chemo
 Adjuvant chemo

6. Procedures
 HIPEC – immediate or delayed (5-8 weeks)
 Laparoscopic or open approach
HIPEC protocol
 Fluorouracil (400 mg/m2) and leucovorin (20 mg/m2) iv
 f/b Oxaliplatin (460 mg/m2) for 30 min (42–43°C)

7. Adjuvant therapy
 CapeOx 3 weekly
 Fluorouracil plus oxaliplatin 2 weekly
 Started within 6-8 weeks no later than 12 weeks
 Follow up
 Imaging at 6, 12 and 18 months
 CEA 3-6 monthly

8. Follow up
 Recurrence up to 18 months – physician discretion.
 No radiological/ pathological recurrence at 18 months – DL
 Peritoneal staging (ovarian and omental mets included)
 Peritoneal Mets. - CRS plus HIPEC.
 Negative – continued follow up for 5 years

9. Outcomes
 Primary endpoints
 Peritoneal metastasis free survival at 18 months
 Secondary endpoints
 Hospital stay
 Treatment related toxicity after HIPEC
 DFS, OS, QOL and cost

10. Outcomes
 Post hoc analysis
 Proportion receiving adjuvant chemo
 Time to adjuvant chemo
 Time until diagnosis
 Extent of peritoneal metastasis
 HIPEC related complications

11. Statistical analysis
 Expected RR reduction – 60% with HIPEC
 Estimated PFS 18 month – 75 % in control group
 Sample size – 176 (type 1 error 5%, power 80%)
 Intention to treat analysis
 Kaplan Meier survival method for comparison
 Analysis using SPSS (version 25)

12. Results
 April 2015 – Feb. 20,2017
 172 post op randomization
Experimental group
 9 diagnosed with peritoneal
mets. preceding HIPEC
 87 received HIPEC

13. Results
 April 2015 – Feb. 20,2017
 172 post op randomization
Experimental group
 9 diagnosed with peritoneal
mets. preceding HIPEC
 87 received HIPEC

14. Results
 April 2015 – Feb. 20,2017
 172 post op randomization
Experimental group
 9 diagnosed with peritoneal
mets. preceding HIPEC
 87 received HIPEC

15. 18 month post resection
 148 were eligible for DL
 128 under went DL (63 and 65)

17. HIPEC characteristics

18. HIPEC characteristics

19. HIPEC characteristics

20. Outcomes
 Experimental group
 19 diagnosed with peritoneal mets
 Nine before HIPEC, eight during follow up
 Two during DL
 Control group
 23 diagnosed with peritoneal mets
 7 during DL
 16 during follow up

21. Peritoneal metastasis free survival
 18 month PFS
 Exp. – 80.9 % (73.3 -88.5)
 Cont. – 76.2 % (68.0-84.4)
 P= 0.28

22. Subgroup analysis
 No difference between two groups.

23. Secondary outcomes
 Median length of stay
 Simultaneous HIPEC- 16.5 days
 Staged HIPEC- 4 days
 Post operative complications – 12/87
 1 patient – encapsulating peritoneal sclerosis

24. Secondary outcomes
 Median length of stay
 Simultaneous HIPEC- 16.5 days
 Staged HIPEC- 4 days
 Post operative complications – 12/87
 1 patient – encapsulating peritoneal sclerosis

25. Post hoc analysis
 Adjuvant chemo – 85 % vs 88%
 Median time to chemo – 10 weeks vs 6 weeks
 Time to peritoneal mets diagnosis – 8 months vs 14 months
 Peritoneal mets. –
 CRS plus HIPEC in 13/19 vs 15/23 .

26. Post hoc analysis
18 months
 DFS – 69.2 (62.7-75.7)
 OS – 93.5 (90.2 - 96.8)
 DFS – 69.0% vs 69.3 %
 OS – 93.0% vs 94.1 %

27. Discussions
 No difference in PFS
 Similar outcome in subgroups
 HIPEC – longer stay and complications
 Staged HIPEC has lesser complication rate
 Peritoneal mets (42)
 9 during exploration for HIPEC
 24 during follow up
 9 during DL at 18 months
 28/42 were eligible for CRS + HIPEC

28. Limitations
 Staged HIPEC ??
 Delayed adjuvant treatment in HIPEC group
 Dropout for diagnostic laparoscopy (16)
 Detection rate (9)
 Protocol failure ??

29. Strengths
 Design of trial
 Multicentre approach
 Earliest trial to evaluate HIPEC in high risk patients

30. PRODIGE 7

35. Conclusion
 Role of HIPEC alone is doubtful
 Better technique for non invasive staging required
 Immediate HIPEC to be considered
 More intensive surveillance
 PIPAC