This document summarizes the results of the PRODIGE 7 trial, which compared cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery alone for patients with metastatic colorectal cancer and peritoneal carcinomatosis. The trial found no significant difference in overall survival between the two treatment groups. Patients who received HIPEC had higher rates of postoperative complications and longer hospital stays. For patients with 11-15 peritoneal lesions, HIPEC showed a potential survival benefit. However, given the lack of overall survival benefit and increased risks, the addition of HIPEC to standard treatment requires reconsideration.

1. H I P E C F O R M E T A S T A T I C C O L O R E C T A L
C A N C E R S
P R O D I G E 7 T R I A L R E S U L T S … .
D R P R I Y A N K A M A L E K A R
D N B 2 N D Y E A R R E S I D E N T
D E P T O F S U R G I C A L O N C O L O G Y
8 / 1 / 2 0 1 9 …

2. BACKGROUND…
• mCRC with isolated peritoneal metastases :- limited data
• Associated with poor survival
• 8 % of patients at the time of surgery and 25% of patients with recurrent
mCRC : peritoneal metastases (PM)
• Treatment dichotomy….

3. • Reasons for the low inclusion of CRC-PM patients into clinical trials
include:
(I) Mixing all patients with stages IV A and B;
(II) Relative low incidence (less than 20%) of PM
(III) PM are usually associated with other sites of metastases; and
(IV) Patients with low tumor burden are difficult to be evaluated with
RECIST criteria

4. • Selection criteria for treatment type and sequence of therapeutic
modalities ill defined.
• No established non surgical process to rationally select patients for
management
• Prospective trials on metastatic CRC included very few cases of peritoneal
metastases.

5. OUTCOME OF PATIENTS WITH SYSTEMIC THERAPY…
• NCCTG (North Central Cancer
Treatment Group)
• 2104 patients ( 2 arms , first and
second line chemotherapy)
• 17 % of total group had PM
along with LLM ( lung liver
metastases)
• Poor outcome in patients who
had PM
• CAIRO/CAIRO 2:
• CAIRO : 34 pts had PM, 4 had
isolated PM
• CAIRO 2: 47 patients had PM, 5 had
isolated PM
( Combination chemo +/- Bev,
Cituximab)
Trend in decreased survival rate in cases
with PM
Decreased efficacy of std treatment with or without biological agents, because most exist different b
behavior that conveys resistance to chemotherapy

6. OUTCOMES AFTER COMPLETE CYTOREDUCTIVE
SURGERY AND SYSTEMIC THERAPY
Desolneux et al, in PLoS One, 2015
• Reported the OS, PFS & morbidity on 50 pts treated with CRS and
systemic chemo only
• Mean PCI was 8
• 23 pts had LLM + PM
• Median FU – 62 months
• Median survival – 32 months
• 5 yr OS – 29 %
Désolneux G, Mazière C, Vara J, et al. Cytoreductive surgery of colorectal peritoneal metastases: outcomes
after complete cytoreductive surgery and systemic chemotherapy only. PLoS One 2015;10:1-12.

7. Conclusion:
• Despite having equal PCI range and a high rate of LLM
• Survival data on CRS + chemotherapy is equal to the results of same with
additional HIPEC ( as per literature).
• So, HIPEC Is not really necessary and has no additional advantage

8. OUTCOMES OF PATIENTS WITH CRS
AND HIPEC

9. CLINICAL PATHWAY FOR SELECTION
• Clinical symptoms: mild symptoms, :
1. Weight loss <10% of body weight,
2. Mild abdominal pain, some ascites;
• severe symptoms:
1. weight loss >10% of body weight,
2. unremitting pain,
3. bowel obstruction,
4. symptomatic ascites.
• PCI: by imaging (CT, PET, MRI) or
exploration (laparoscopy or evaluation
at time of first operation (in
synchronous peritoneal
carcinomatosis)

11. CLINICAL PATHWAY FOR SELECTION
Investigations before management:
• Recent colonoscopy
• CECT chest/abdomen/ pelvis ( oral + IV constrast)
• A PET scan should be done in those patients in whom there is evidence or
suggestion of hematogenous dissemination on the CT scan
• K-ras in all patients
All patient with LLM ( lung/liver mets) should be refered to medical
oncologist
Cituxiab and panitumumab in pts with potential candidates for resection

12. CLINICAL & RADIOLOGICAL
VARIABLES : CHANCE OF CRS
• Complete removal of Tumor more than 2.5 mm
• ECOG <2
• PCI <10 (<12)
• No E/O extra-abdominal disease
• Up to 3 small, resectable hepatic parenchymal metastases
• No E/O biliary obstruction, ureteral obstruction, intestinal obstruction at
more than one site
• No E/O small bowel involvement, gross disease in mesentery with several
sites of partial obstruction
• Small volume disease in gastrohepatic ligament

13. WHEN TO AVOID CRS..
1. Performance status
2. Tumor marker
3. Radio imaging…
Any deterioration in above….continue systemic therapy

14. • American Society of Peritoneal Surface Malignancices Standardized HIPEC
delivery in patients with colorectal cancer with peritoneal dissemination.
(I) HIPEC method: closed;
(II) Drug: mitomycin C;
(III) Dosage: 40 mg;
(IV) Timing of drug delivery: 30 mg at time zero; 10 mg at 60 minutes;
(V) Volume of perfusate: three liters;
(VI) Inflow temperature: 42 degrees celsius;
(VII)Duration of perfusion: 90 minutes.

16. OUTCOME OF PATIENTS TREATED
WITH CRS AND HIPEC
Patients with Colorectal Cancer May Be Able to Avoid Heated
Chemotherapy During Surgery
By Anne Jacobson, CHCP
2018 ASCO Annual Meeting Highlights: Colorectal Cancer
June 1-5, 2018, Chicago, Illinois
PRODIGE 7………

17. • Approximately 20% of patients with metastatic colorectal cancer (mCRC)
will have peritoneal metastases, also called peritoneal carcinomatosis
(PC).
• In an analysis of mCRC patients with one site of metastasis, the medial
overall survival was 16.3 months for those with peritoneal involvement,
compared with 19.1 months and 24.6 months, respectively, for patients
with liver or lung metastases
Franko J, Shi Q, Meyers JP et al. Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: An
analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive

18. • Current options for treating peritoneal mCRC include cytoreductive surgery with
intraperitoneal and systemic chemotherapy.
• Heated abdominal chemotherapy has become the standard of care in many countries.
• The role of HIPEC as a necessary component of the treatment regimen, however, had
never been formally assessed.

19. PRODIGE 7….
• The phase III , Is the first prospective randomized trial to evaluate HIPEC in patients with
mCRC and peritoneal metastases.
• 265 patients with mCRC with PC and no other metastatic sites.
• To be included in the analysis, patients were required to achieve macroscopically
complete surgical resection (R0/R1) or resection with ≤1 mm residual tumor tissue (R2).
• Patients were randomly assigned to the HIPEC (n = 113) or non-HIPEC (n = 132) groups.

20. • Patients in the HIPEC arm received intraperitoneal oxaliplatin 460 mg/m2 over 30
minutes following cytoreduction. The intraperitoneal oxaliplatin was heated to 43°C
(109.4°F) to increase the effectiveness of treatment.
• Most patients (96%) were also treated with systemic chemotherapy for 6 months before
or after surgery, or both.

21. • Patients had a median of 10 peritoneal
lesions.
• Synchronous PC lesions were present in
approximately 40% of patients.
• Approximately 90% of patients achieved
complete macroscopic cytoreduction.

23. • Postoperative safety outcomes were comparable for all patients, with 30-
day and 60-day mortality rates of 1.5% and 2.6%, respectively.
• After 60 days, 24.1% of patients in the HIPEC group developed
postoperative complications, compared with 13.6% of patients in the
non-HIPEC group (p = .030).
• The mean hospital stay was also 5 days longer for those who received
HIPEC compared with those who did not (18.0 days versus 13.0 days,
respectively; p < .0001).

24. EXPLORATORY ANALYSIS…
• There may be a role for HIPEC in patients with greater PC involvement. In
the subgroup of patients with 11 to 15 PC lesions, the median OS was
41.6 months for those treated with HIPEC, compared with 32.7 months in
those treated with surgery alone (HR, 0.437; 95% CI, 23.5-38.9; p = .0209).

25. • Results may be different with agents other than oxaliplatin, and that other
types of heated chemotherapy may be beneficial for patients with mCRC
and peritoneal metastases.

26. CONCLUSION….
Given the lack of survival benefit and the increased risk of
postoperative complications with HIPEC, it is time to reconsider
incorporating abdominal chemotherapy into the standard
treatment regimen for peritoneal mCRC.