What are potential research topics on colorectal peritoneal metastasis in surgery?

Research Topics on Colorectal Peritoneal Metastasis in Surgery

High-Priority Research Gaps Based on Current Evidence

1. Alternative HIPEC Regimens Beyond Oxaliplatin

The PRODIGE 7 trial definitively showed that oxaliplatin-based HIPEC provides no survival benefit and increases complications, but ongoing trials are evaluating mitomycin and other HIPEC regimens that may yield better outcomes. 1 This represents the most critical research gap, as the field needs to determine whether HIPEC has any role at all or should be abandoned entirely. The ESMO 2023 guidelines explicitly state that other HIPEC regimens using mitomycin and different procedures are under investigation 1, making this a priority area where surgical research could definitively answer whether any form of HIPEC improves mortality and quality of life.

2. Optimal Timing and Regimens for Systemic Chemotherapy in CRS Patients

Post-operative systemic chemotherapy is associated with improved overall survival (HR 0.81, p<0.00001), but the optimal timing, duration, and specific regimens remain undefined. 2 Current evidence shows:

• Pre-operative chemotherapy alone does not improve survival compared to surgery alone (p=0.59) 2
• Post-operative chemotherapy demonstrates clear benefit 2
• The role of perioperative (pre + post) chemotherapy versus post-operative alone is unclear 2

Research should focus on randomized trials comparing different systemic chemotherapy timing strategies (neoadjuvant vs. adjuvant vs. perioperative) specifically in patients undergoing CRS for peritoneal metastases, with mortality and quality of life as primary endpoints 3, 4.

3. Patient Selection Criteria and Prognostic Biomarkers

Only 15% of patients remain progression-free at 5 years after CRS, indicating that current selection criteria fail to identify the minority who truly benefit. 4, 5 Critical research areas include:

• Molecular markers beyond RAS/BRAF that predict complete cytoreduction feasibility 3
• Genomic signatures that identify patients likely to achieve durable disease control 3
• Validation of PCI thresholds (current cutoff <20) across different populations 3
• Role of tumor lateralization and microsatellite instability status in surgical decision-making 3

The ASCO 2023 guidelines emphasize that complete cytoreduction is the most critical prognostic factor 3, 4, but pre-operative prediction of achievability remains imprecise.

4. Novel Intraperitoneal Chemotherapy Delivery Methods

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) and sequential postoperative intraperitoneal chemotherapy (SPIC) represent emerging modalities with limited evidence in colorectal peritoneal metastases. 6 While PIPAC has been evaluated in gastric cancer peritoneal metastases 1, its role in colorectal disease requires dedicated investigation. Research should compare:

• PIPAC versus systemic chemotherapy alone in unresectable disease 6
• SPIC as adjuvant therapy following complete CRS 6
• Normothermic intraperitoneal chemotherapy (NIPEC) versus no intraperitoneal therapy 6

These modalities may offer survival benefits without the toxicity profile of HIPEC 5.

5. Conversion Surgery After Systemic Chemotherapy

The proportion of patients with initially unresectable peritoneal metastases who can be converted to resectable disease with modern systemic therapy is unknown. 1 Research should define:

• Response rates to triplet chemotherapy (FOLFOXIRI) plus biologics in peritoneal-only disease 1
• Optimal duration of neoadjuvant therapy before reassessment for CRS 1
• Imaging criteria that accurately predict complete cytoreduction after downsizing 3
• Outcomes of conversion surgery versus continued systemic therapy in responders 3, 4

The ESMO 2023 guidelines note that median survival after resection is two- to threefold higher than systemic therapy alone 1, making conversion strategies potentially high-impact.

6. Quality of Life and Long-Term Functional Outcomes

Treatment-related mortality ranges from 0.9-8%, and grade 3+ complications occur in 15-24% of patients, but comprehensive quality of life data are lacking. 5 Research priorities include:

• Patient-reported outcomes comparing CRS alone versus CRS + systemic chemotherapy 4
• Long-term bowel function, nutritional status, and return to baseline activities 5
• Decision aids incorporating realistic survival expectations (15% progression-free at 5 years) 4, 5
• Cost-effectiveness analyses given the high morbidity and modest survival benefit 5

The NICE guidelines emphasize that shared decision-making must include quality of life impact 4, but current data are insufficient to inform these discussions.

7. Prophylactic Strategies in High-Risk Primary Colorectal Cancer

Patients with T4 tumors, perforated tumors, or positive peritoneal cytology at primary resection have high rates of subsequent peritoneal metastases, but prophylactic interventions remain unproven. 1 Research should evaluate:

• Adjuvant intraperitoneal chemotherapy (via peritoneal port) in high-risk patients 1
• Prophylactic HIPEC at time of primary resection in T4b disease 1
• Intensive surveillance protocols to detect peritoneal recurrence earlier 1

The gastric cancer literature shows that prophylactic HIPEC reduces peritoneal recurrence rates 1, suggesting potential applicability to colorectal cancer.

8. Standardization of Surgical Technique and Center Requirements

The PRODIGE 7 trial achieved 91% complete cytoreduction rates due to center expertise, but minimum volume and technical standards for CRS centers are undefined. 4, 5 Research should establish:

• Minimum annual case volumes required to maintain acceptable morbidity/mortality 5
• Standardized surgical technique protocols for peritoneal stripping 5
• Training curricula and credentialing requirements for surgeons performing CRS 5
• Centralization models and their impact on outcomes 3, 4

The ASCO and ESMO guidelines mandate treatment at specialized centers 3, 4, 5, but specific criteria are lacking.

Common Pitfalls to Avoid in Research Design

• Avoid combining appendiceal and colorectal peritoneal metastases in outcome analyses, as these represent distinct biological entities with different prognoses 7
• Ensure completeness of cytoreduction (CC-0 vs CC-1/2) is reported separately, as this is the dominant prognostic factor 3, 4, 5
• Use intention-to-treat analysis rather than per-protocol, as many patients deteriorate during neoadjuvant therapy and never reach surgery 8
• Report 60-day rather than 30-day complications, as late toxicity is significant and often missed 5
• Include patients with synchronous and metachronous disease separately, as outcomes differ substantially 9