What is the recommended adjuvant chemotherapy regimen for patients with resected rectal cancer, particularly those with stage II or III disease?

Adjuvant Chemotherapy in Resected Rectal Cancer

Primary Recommendation

Adjuvant chemotherapy is recommended for all patients with stage II/III rectal cancer after neoadjuvant chemoradiotherapy and surgery, with FOLFOX or CAPEOX as preferred regimens for higher-risk patients and 5-FU/LV or capecitabine as acceptable alternatives for lower-risk patients who responded well to neoadjuvant fluoropyrimidine-based therapy. 1

Evidence Quality and Nuances

The evidence supporting adjuvant chemotherapy in rectal cancer is notably weaker than in colon cancer, creating a challenging clinical scenario. Despite conclusive data being lacking, the NCCN panel recommends adjuvant therapy use based on the totality of available evidence. 1

Supporting Evidence:

• The ADORE trial demonstrated improved 3-year disease-free survival (DFS) with adjuvant FOLFOX versus 5-FU/LV (71.6% vs 62.9%; HR 0.66, P=0.047) 1
• The CAO/ARO/AIO-04 trial showed improved 3-year DFS when oxaliplatin was added to 5-FU in both neoadjuvant and adjuvant settings (75.9% vs 71.2%; P=0.03) 1
• NCDB analyses of patients achieving pathologic complete response (pCR) found significant overall survival improvement with adjuvant chemotherapy 1

Contradictory Evidence:

• The EORTC 22921 trial showed no overall survival benefit with adjuvant 5-FU chemotherapy, and DFS benefit was not statistically significant (HR 0.91, P=0.29) 1
• A 2017 systematic review of 8 phase III trials concluded data are not robust enough to warrant routine adjuvant therapy 1
• Multiple database studies failed to demonstrate substantial benefit from adjuvant chemotherapy 1

Regimen Selection Algorithm

Choice of adjuvant regimen depends on initial clinical staging and predicted circumferential resection margin (CRM) status: 1

Higher-Risk Patients (FOLFOX or CAPEOX preferred):

• Clinical stage III disease
• Threatened or positive CRM
• T4 tumors
• Extramural vascular invasion
• Tumor deposits
• Node-positive disease 2, 3

Lower-Risk Patients (5-FU/LV or capecitabine acceptable):

• Clinical stage II disease with good response to neoadjuvant therapy
• Patients who responded well to neoadjuvant 5-FU or capecitabine 1
• Patients with significant comorbidities requiring less intensive therapy 2

Timing and Duration

Adjuvant chemotherapy should be initiated as soon as the patient is medically able after surgery, as each 4-week delay results in a 14% decrease in overall survival. 1

Duration recommendations: 1

• 4 months of FOLFOX is justified when preoperative chemoradiotherapy is administered (shorter than the 6-month duration used in colon cancer) 1
• Standard duration for fluoropyrimidine alone remains unclear 1

Special Populations

Patients with Pathologic Complete Response (pCR):

Adjuvant chemotherapy is still recommended even after pCR, despite excellent outcomes in observational studies showing 5-year DFS of 96% and OS of 100% without adjuvant therapy. 1, 4 This recommendation is based on NCDB analyses showing overall survival benefit in pCR patients who received adjuvant chemotherapy 1

MSI-High or dMMR Tumors:

For stage III rectal cancer with microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR), immunotherapy with dostarlimab is preferred over standard total neoadjuvant therapy, achieving 100% clinical complete response in evaluable patients without grade 3+ adverse events. 2

Common Pitfalls and Caveats

Underutilization in Practice:

• Only 61.5% to 76.6% of eligible patients receive adjuvant chemotherapy in real-world settings 1
• Factors associated with not receiving adjuvant therapy include: complete pathologic response, infection, no closure of ileostomy/colostomy, advanced age, poor performance status, and socioeconomic factors 1

Oxaliplatin Toxicity:

Oxaliplatin-induced peripheral neuropathy is cumulative and dose-limiting; monitor closely and consider dose reduction or discontinuation if grade 2-3 neuropathy develops. 2 Elderly patients and those with significant comorbidities may require dose modifications 2

Patient Selection Considerations:

• Patients who did not receive neoadjuvant chemotherapy (only chemoradiotherapy) should definitely receive adjuvant chemotherapy regardless of surgical pathology results 1
• The benefit of adjuvant chemotherapy may be less pronounced in patients who received total neoadjuvant therapy (TNT) with both neoadjuvant chemotherapy and chemoradiotherapy 2, 4

Real-World Effectiveness

Recent observational data suggest that adjuvant chemotherapy provides survival benefit in routine clinical practice. A propensity score-matched analysis demonstrated significantly prolonged disease-free survival with adjuvant treatment (81.8 vs 70.1 months, P<0.001) 5, though the addition of oxaliplatin to adjuvant chemotherapy showed no improvement in DFS in this setting (76.9 vs 79.3 months, P=0.254) 5