What are potential research topics regarding novel treatments in colorectal cancer surgery?

Novel Treatment Research Topics in Colorectal Cancer Surgery

Highest Priority: Overcoming Immunotherapy Resistance in MSS/pMMR Tumors

The most impactful research direction is developing combination strategies to sensitize microsatellite stable (MSS)/proficient mismatch repair (pMMR) colorectal cancer to immunotherapy, as this represents 95% of metastatic patients who currently derive minimal benefit from immune checkpoint inhibitors. 1

Specific Research Protocols to Pursue:

• Phase III validation of the Chidamide (histone deacetylase inhibitor) + Bevacizumab + PD-1 antibody regimen in treatment-refractory MSS/pMMR patients, building on phase II data showing 44% objective response rate and 7.3 months median progression-free survival 1

• Moving this triple combination to earlier treatment lines (first-line or second-line) rather than reserving it for refractory disease 1

• Identifying predictive biomarkers for patient selection within the MSS/pMMR population to determine which patients will respond to immunotherapy combinations 1

• KRAS G12C inhibitors combined with anti-EGFR treatment for MSS/pMMR advanced colorectal cancer patients with this specific mutation 1

• Investigating POLE/POLD1 pathogenic mutations as predictors of immune checkpoint inhibitor efficacy, even in MSS/pMMR context 1

Critical Design Elements:

• Use randomized phase II studies with 100-200 patients incorporating predictive marker analysis 1
• Prioritize overall survival and quality of life as primary endpoints, not just objective response rate 1
• Account for primary tumor location (right-sided versus left-sided) as this affects response to targeted therapies 1

Second Priority: Optimizing Curative Surgical Approaches

Novel Technologies and Interventions

Develop and validate novel technologies/interventions that have the potential to improve curative outcomes, particularly for metastatic or recurrent disease. 2

Key Research Questions:

• Can conversion chemotherapy with targeted agents render more patients with unresectable hepatic metastases surgically resectable? Current data shows oxaliplatin added to fluorouracil achieves 13% conversion rate with 30% 5-year survival 2

• What is the role of ablative technologies for cure in oligometastatic disease? This requires defining patient selection criteria and comparing outcomes to surgical resection 2

• Can more effective neoadjuvant chemoradiotherapy reduce the need for aggressive surgery in rectal cancer? Similar to the organ-preservation approach used in anal cancer 2

• Do patients with synchronous asymptomatic primary colon cancer and unresectable stage IV disease require colectomy? Literature suggests only 9-29% develop obstruction, but bevacizumab use may increase perforation risk 2

Biomarker Development

Develop biomarkers that define the optimal curative therapeutic strategy for individuals or groups, preventing overtreatment and improving treatment selection. 2

• Focus on molecular markers beyond standard MSI/MMR status 2
• Identify predictors of response to conversion chemotherapy for liver metastases 2
• Develop better preoperative staging tools (MRI may be superior to endoscopic ultrasound for rectal cancer) 2

Third Priority: Comparative Effectiveness of Surgical Techniques Within ERAS Protocols

Robotic vs. Laparoscopic Surgery

Compare robotic-assisted colorectal surgery to conventional laparoscopy within standardized Enhanced Recovery After Surgery (ERAS) protocols to determine if seven degrees of movement and 3D visualization translate into improved clinical outcomes. 3

Specific Endpoints to Measure:

• Anastomotic leak rates 3
• 30-day complication rates 3
• Long-term oncologic outcomes (5-year recurrence and survival) 4
• Quality of life measures 3

Critical caveat: Laparoscopic surgery already reduces hospital stay by 2 days and reduces morbidity compared to open surgery 3, so robotic surgery must demonstrate superiority over this established standard, not just over open surgery.

Perioperative Optimization Research

• Compare transversus abdominis plane (TAP) blocks to thoracic epidural analgesia for pain control in laparoscopic colorectal procedures within ERAS protocols 3

• Establish goal-directed fluid therapy protocols with optimal monitoring methods and hemodynamic targets specified for colorectal surgery 3

• Identify optimal duration, intensity, and components of prehabilitation programs to maximize reduction in postoperative complications 3

• Re-evaluate mechanical bowel preparation combined with oral antibiotics to determine effects on anastomotic leak rates and surgical site infections in the ERAS era 3

Implementation Science

Identify effective implementation strategies to achieve and maintain high ERAS protocol adherence across diverse hospital settings. 3 Current research shows ERAS reduces hospital stay by 3 days in obstructive colorectal cancer 5, 6 and improves 5-year recurrence rates in advanced stage disease 4, but compliance varies widely.

Fourth Priority: Shared Decision-Making and Patient-Centered Outcomes

Evidence Base for Treatment Choices

Develop an appropriate evidence base to inform shared decision-making for potentially curative therapies, particularly balancing organ preservation versus aggressive surgery. 2

Specific Research Needs:

• Definitive radiotherapy and organ preservation versus major resectional surgery in rectal cancer: Quantify the trade-off between better health-related quality of life with non-surgical approaches versus potentially higher cure rates with surgery 2

• Optimizing curative approaches for metastatic or recurrent disease that balance patients' expectations with treatment efficacy and health-preserving benefit 2

• Establishing optimum peritherapeutic interventions to improve curative outcomes, including better anaesthetic risk assessment tools for frail patients with significant comorbidities 2

Fifth Priority: Methodological Development

Develop research methodologies to optimally evaluate new curative approaches, particularly for surgical and radiotherapy-related devices and procedures. 2

• Build on the IDEAL (Idea, Development, Exploration, Assessment, Long-term follow-up) collaboration framework 2
• Focus on early phase study methodology development 2
• Ensure robust clinical and cost-effectiveness outcomes are demonstrated before widespread adoption 2

Integration of Translational Research

Incorporate state-of-the-art laboratory correlative studies into clinical trials to understand what new therapies work and why 2

• Move beyond traditional cell lines and xenografts to more representative models like patient-derived organoids 2
• Develop pharmacogenomic studies for drug metabolism and target interaction 2
• Identify genetic characteristics (oncogene mutations, tumor suppressor gene loss, chromosomal instability) that provide prognostic information 2

Common Pitfalls to Avoid

• Do not conduct single-agent phase II trials that relegate new agents to third-line therapy where multiple resistance mechanisms have developed 2
• Do not ignore molecular heterogeneity within MSS/pMMR tumors, as subsets like POLE/POLD1-mutant or KRAS G12C-mutant may respond differently 1
• Do not use objective response rate as the sole endpoint when agents may stabilize disease without shrinking tumors 2
• Do not assume ERAS benefits apply equally to emergency surgery without specific validation in obstructive colorectal cancer populations 5, 6