What is the Habr-Gama (non-operative management) approach for patients with rectal cancer who have undergone chemoradiation and shown a complete clinical response?

Habr-Gama Non-Operative Management of Rectal Cancer

Non-operative management (NOM), also known as the "watch-and-wait" approach, is a viable organ preservation strategy for highly selected rectal cancer patients who achieve clinical complete response (cCR) after neoadjuvant therapy, offering comparable oncological outcomes to surgery while preserving anorectal function, though it requires strict patient selection criteria, intensive surveillance, and acceptance of higher local recurrence rates that are typically salvageable with surgery. 1, 2

Patient Selection Criteria for NOM

The decision to pursue NOM requires meeting all of the following strict criteria for cCR 1, 3:

• No palpable tumor on digital rectal examination 1, 3
• No residual tumor material and no erythematous ulcer on rectoscopy (only white scar or normal mucosa acceptable) 1, 3
• Substantial tumor downsizing with no observable residual tumor on MRI (or residual fibrosis only) 1, 3
• Negative endoscopic biopsy of any suspicious areas 1
• No suspicious lymph nodes on MRI 3

Critical caveat: Clinical complete response does NOT equal pathological complete response—cCR rates are generally much lower than pCR rates, and MRI has only 64% overall accuracy for response assessment. 3 This means some patients with apparent cCR will harbor microscopic residual disease or lymph node metastases. 2

Optimal Neoadjuvant Regimen to Maximize cCR

Total neoadjuvant therapy (TNT) with long-course chemoradiotherapy followed by consolidation chemotherapy is the preferred regimen to maximize the likelihood of achieving cCR suitable for NOM. 1, 4

The specific TNT protocol should include 1, 4:

• Long-course chemoradiation: 50 Gy in 1.8 Gy fractions with concurrent 5-FU-based chemotherapy 1
• Followed by consolidation chemotherapy: FOLFOX or similar regimen (NOT induction chemotherapy before radiation) 4
• Timing of response assessment: 8 ± 4 weeks after completion of TNT 3

The OPRA trial demonstrated that TNT achieves organ preservation in approximately 50% of patients, with 5-year disease-free survival of 69-71% and TME-free survival of 39-54%. 2 Importantly, consolidation chemotherapy after radiation is superior to induction chemotherapy for achieving organ preservation. 4

Special Population: MSI-H/dMMR Tumors

For patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) locally advanced rectal cancer, immunotherapy (such as dostarlimab) is the preferred treatment and may result in exceptionally high rates of complete response approaching 100%. 1, 2 A prospective phase II trial showed all 12 patients with dMMR rectal cancer achieved cCR after dostarlimab, with no evidence of tumor on any assessment modality. 2

Oncological Outcomes: NOM vs Surgery

The International Watch & Wait Database (IWWD) provides the most robust evidence for NOM outcomes 2:

Recurrence patterns:

• 2-year local recurrence rate: 25.2% (88% of local recurrences occur within first 2 years) 2
• 5-year overall survival: 85% 2
• 5-year disease-specific survival: 94% 2
• Distant metastases: 8% of patients 2

Salvage surgery success: Among patients who develop local regrowth, 94% of recurrences occur within 2 years and 99% within 3 years, and the vast majority can be successfully salvaged with surgery. 2 In one study, 80% of local recurrences in the NOM group were surgically salvaged. 5

Comparative outcomes: A retrospective study comparing 42 NOM patients to 69 surgical patients with pathological complete response found no difference in overall survival (71.6% vs 89.9%, p=0.316), but NOM had higher recurrence rates and lower disease-free survival (60.9% vs 82.8%, p=0.011). 5 However, NOM patients avoided surgical morbidity and maintained anorectal function. 5

Functional Outcomes and Quality of Life

The primary advantage of NOM is preservation of anorectal function and avoidance of permanent colostomy. 2 In the OPRA trial, patients managed with NOM had better bowel function scores, less incontinence, and 10 patients avoided permanent colostomy compared to those who underwent resection. 2

This is particularly important for low rectal tumors where the surgical alternative would be abdominoperineal resection with permanent colostomy. 4 The watch-and-wait approach enables patients to avoid the morbidities associated with radical surgery while maintaining quality of life. 2

Intensive Surveillance Protocol

Patients selecting NOM must commit to intensive surveillance, particularly in the first 2-3 years when 94-99% of recurrences occur. 2, 1

The recommended surveillance schedule includes 1, 2:

Years 1-2 (every 3-4 months):

• Digital rectal examination 1
• Flexible sigmoidoscopy/endoscopy 1
• Pelvic MRI with diffusion-weighted imaging 1
• Serum CEA monitoring 1

Years 3-5 (every 6 months):

• Same modalities as above but less frequently 2

Chest/abdominal CT:

• Every 6-12 months during year 1 2
• Annually during years 2-5 2

After 3 years of disease-free survival: The probability of remaining free of local recurrence for an additional 2 years is 97.3%, and after 5 years of DFS it is 98.6%. 2 This allows for less intensive surveillance after the high-risk period.

Patient Counseling and Shared Decision-Making

Patients must be thoroughly counseled about both the benefits and risks of NOM before making this decision. 1, 2

Benefits to discuss:

• Preserved anorectal function and quality of life 1
• Avoidance of surgical morbidity and mortality 1
• Reduced risk of permanent ostomy if successful 1
• Comparable long-term survival if recurrences are salvaged 2

Risks to discuss:

• Higher local recurrence rate (25% at 2 years) compared to immediate surgery 2
• Intensive surveillance requirements for at least 3 years 1
• Small risk that delayed surgery for recurrence may be more difficult or have worse outcomes 6
• Uncertainty in clinical assessment—cCR does not guarantee absence of microscopic disease 3
• Potential for lymph node metastases even with apparent cCR 2

The NCCN panel emphasizes that NOM should only be considered in centers with experienced multidisciplinary teams after careful discussion with the patient about their risk tolerance. 2

Common Pitfalls and How to Avoid Them

Pitfall 1: Inadequate response assessment

• Do not rely on a single modality for cCR assessment 3
• Always use multimodal assessment combining digital rectal examination, endoscopy with biopsy, and MRI with diffusion-weighted imaging 1, 3
• MRI alone has only 64% accuracy and tends to overestimate residual tumor 3

Pitfall 2: Inappropriate patient selection

• Do not offer NOM to patients with incomplete clinical response 1
• Do not pursue NOM outside of experienced multidisciplinary centers 2
• Recognize that clinical lymph node staging has limited accuracy 4

Pitfall 3: Insufficient surveillance intensity

• Do not use standard surveillance schedules—NOM requires much more intensive follow-up 1
• Focus surveillance intensity in the first 2-3 years when 94-99% of recurrences occur 2
• Ensure patient commitment to long-term surveillance before selecting NOM 1

Pitfall 4: Using short-course radiotherapy for NOM candidates

• Do not use short-course RT for patients seeking organ preservation 4
• Long-course chemoradiotherapy is more appropriate when the goal is achieving cCR for potential NOM 4
• The RAPIDO trial showed higher locoregional failure with short-course RT-based TNT (10% vs 6%) 4

Pitfall 5: Extrapolating results inappropriately

• Do not extrapolate results from small low rectal cancers to more advanced cancers where nodal involvement is common 6
• Recognize that most evidence comes from retrospective series with heterogeneous inclusion criteria 6, 7

Current Evidence Level and Standard of Care

Despite promising results, total mesorectal excision after neoadjuvant therapy remains the standard of care for locally advanced rectal cancer. 1 The evidence for NOM consists primarily of retrospective and prospective cohort studies, with only one small randomized trial. 2

The first randomized trial (from Brazil) comparing watch-and-wait versus surgery in patients with cCR was closed prematurely due to poor patient accrual, highlighting the challenges of conducting definitive trials in this area. 2 Therefore, NOM should ideally be pursued within the context of prospective clinical trials or at experienced centers with established protocols. 8

For frail elderly patients with low rectal tumors who achieve cCR, NOM may be particularly appropriate as it offers comparable oncological outcomes with better functional results. 2 The Italian Society of Geriatric Surgery recommends NOM as a safe strategy in this selected population with stringent surveillance and candid discussion of risks. 2