What are the results and implications of the PRODIGE 7 (Programme de Recherche en Dermatologie et Infectiologie de la Groupe d'Etude 7) trial on the use of Cytoreductive Surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for treating colorectal peritoneal carcinomatosis?

PRODIGE 7 Trial: Key Findings and Clinical Implications

Primary Trial Results

The PRODIGE 7 trial demonstrated that adding 30-minute oxaliplatin-based HIPEC to cytoreductive surgery (CRS) provides no survival benefit and increases late complications in patients with colorectal peritoneal metastases. 1

The phase III randomized controlled trial included 256 patients with colorectal peritoneal metastases who had <1 mm residual disease after CRS. 1 Patients were randomized to receive either CRS alone or CRS plus 30-minute oxaliplatin-based HIPEC, with both groups receiving perioperative systemic chemotherapy (5-FU plus folinic acid, with or without targeted therapy). 1

Survival Outcomes

• Overall survival was identical between groups (HR 1.00; 95% CI 0.63-1.58), with no difference in relapse-free survival (HR 0.91; 95% CI 0.71-1.15). 1
• 15% of patients remained progression-free at 5 years, indicating CRS may be curative in appropriately selected patients, regardless of HIPEC addition. 1
• Complete macroscopic cytoreduction was achieved in 91% of patients, attributed to treatment at specialized high-volume centers. 1

Safety and Toxicity Profile

HIPEC significantly increased late complications without improving outcomes. 1

• Grade 3 or greater adverse events at 30 days showed no significant difference between groups. 1
• At 60 days post-operatively, grade 3+ adverse events were significantly more common with HIPEC (RR 1.69; 95% CI 1.03-2.77). 1, 2
• Creatinine elevation occurred in approximately 15% of HIPEC patients versus 4% without HIPEC. 2
• Anemia requiring intervention occurred in 67% with HIPEC versus 50% without. 2

Current Guideline Recommendations Based on PRODIGE 7

Both ASCO and ESMO now recommend CRS plus systemic chemotherapy without HIPEC for colorectal peritoneal metastases. 1, 3

ASCO Guidelines (2023):

• CRS plus systemic chemotherapy is recommended for selected patients with isolated colorectal peritoneal metastases. 1, 3
• HIPEC is not recommended based on PRODIGE 7 results showing no OS benefit and increased complications. 1
• CRS should only be performed at specialized centers with substantial experience. 1, 3

ESMO Guidelines (2023):

• HIPEC cannot be recommended as standard of care for colorectal peritoneal metastases. 1
• The trial reported absence of OS benefit and more frequent post-operative late complications with HIPEC. 1
• Ongoing trials are evaluating whether other HIPEC regimens (mitomycin-C, different procedures) may produce better outcomes. 1

Critical Patient Selection Criteria

CRS should only be considered in patients meeting ALL of the following criteria: 1, 3

• Isolated peritoneal metastases with no extraperitoneal disease 1, 3
• Amenable to complete macroscopic cytoreduction (CC-0 or CC-1 resection achievable) 1, 3
• Treatment at specialized centers with substantial CRS experience 1, 3
• Adequate performance status (ECOG 0-1) 4

Important Prognostic Factors

Completeness of cytoreduction is the most critical factor affecting long-term survival. 1, 3, 2

• After median follow-up of 21.6 months in the Verwaal trial, only 1 of 18 patients with complete tumor resection had died, compared to 66% (14/21) with limited residual disease and 70% (7/10) with extensive residual disease. 1
• HIPEC can only affect superficial peritoneal layers and is effective only with minimal residual disease. 1, 3

Worldwide Impact of PRODIGE 7

The trial has substantially altered clinical practice globally, despite ongoing debate. 5

A 2021 PSOGI survey of CRS-HIPEC experts from 19 countries revealed: 5

• Reduction in referrals from non-HIPEC centers 5
• Switch towards mitomycin-C based HIPEC regimens and prolonged perfusion times (rather than 30-minute oxaliplatin) 5
• Removal of HIPEC from some national guidelines 5
• Reduced reimbursement rates 5

Multidisciplinary Team Requirements

MDT management is mandatory and must include: 1, 3, 2

• Medical oncology expertise 1, 3, 2
• Surgical oncology with CRS experience 1, 3, 2
• Radiology 1, 3, 2
• Pathology 1, 3, 2

Shared Decision-Making Considerations

Realistic expectations must be discussed with patients: 1, 3

• Only 15% of patients remain progression-free at 5 years 1, 3
• Treatment-related mortality ranges from 0.9-8% 1, 3, 2
• Grade 3-4 complications occur in 15-24% of patients 2
• Quality of life impact from extensive surgery 1, 3
• Need for treatment at specialized centers 1, 3

Critical Caveats About PRODIGE 7

The trial specifically evaluated 30-minute oxaliplatin-based HIPEC only. 1

• Results may not apply to mitomycin-C based regimens or longer perfusion times. 1, 5
• Authors speculated results would not differ with mitomycin-C, but this remains unproven. 1
• Ongoing trials are investigating alternative HIPEC protocols. 1