Is neoadjuvant long course chemo (chemotherapy) radiotherapy with concurrent capecitabine (Xeloda) followed by consolidation CAPOX (capecitabine + oxaliplatin) effective for rectal cancer instead of FOLFOX (folinic acid + fluorouracil + oxaliplatin)?

Neoadjuvant Long-Course Chemoradiotherapy with Capecitabine Followed by Consolidation CAPOX for Rectal Cancer

Yes, consolidation CAPOX (capecitabine plus oxaliplatin) after long-course chemoradiotherapy with concurrent capecitabine is a guideline-supported approach for locally advanced rectal cancer and represents the preferred total neoadjuvant therapy (TNT) strategy. 1, 2, 3

Evidence Supporting CAPOX as Consolidation Chemotherapy

The most recent Chinese Society of Clinical Oncology (CSCO) 2024 guidelines explicitly recommend CAPEOX (CAPOX) as an acceptable consolidation chemotherapy regimen after long-course chemoradiotherapy, alongside FOLFOX, 5-FU/LV, or capecitabine monotherapy. 1 The recommended duration is 12-16 weeks of consolidation chemotherapy, with surgery performed 2-4 weeks after completion following MRI reassessment. 1

The American Society of Clinical Oncology (ASCO) recommends consolidation chemotherapy with either FOLFOX or CAPOX after long-course chemoradiotherapy for stage III rectal cancer, with both regimens considered acceptable alternatives. 3 CAPOX is typically administered for 6-8 cycles in the consolidation phase. 3

Clinical Trial Evidence Directly Addressing Your Question

The Spanish GCR-3 Trial

The Spanish GCR-3 randomized phase II trial directly examined CAPEOX (CAPOX) in the neoadjuvant setting for rectal cancer. 1 This trial randomized patients to receive CAPEOX either before chemoradiotherapy (induction) or after surgery (adjuvant). 1

Key findings from GCR-3:

• Similar pathologic complete response (pCR) rates were observed between arms (13.5% vs 14.3%). 4
• Induction chemotherapy with CAPOX appeared less toxic and better tolerated than postoperative adjuvant chemotherapy. 1
• Overall chemotherapy treatment exposure was significantly higher with neoadjuvant CAPOX than with postoperative adjuvant chemotherapy (P < .0001 for both oxaliplatin and capecitabine). 4
• Grade 3-4 adverse events during chemoradiotherapy were similar, but postoperative adjuvant chemotherapy had significantly higher toxicity than induction chemotherapy. 4

The EXPERT-C Trial

The EXPERT-C trial evaluated a regimen where patients received CAPEOX followed by capecitabine/radiotherapy, then surgery followed by CAPEOX. 1 While this trial included cetuximab in one arm, the control arm demonstrated the feasibility of using CAPOX in both the induction and adjuvant phases around chemoradiotherapy. 1

The AVACROSS Study

The phase II AVACROSS study assessed induction therapy with CAPEOX prior to capecitabine-chemoradiotherapy and surgery. 1 The regimen was well tolerated with a pCR rate of 36%, though this included bevacizumab which is not recommended outside clinical trials. 1

Why Consolidation Rather Than Induction?

ASCO recommends that for patients who are candidates for TNT, chemotherapy should be delivered after radiation (consolidation) rather than before (induction), with conditional strength based on moderate-quality evidence. 2, 3 This recommendation is based on:

• Higher pathologic complete response rates with consolidation (25% vs 17% with induction). 2
• Superior local control with long-course chemoradiotherapy followed by consolidation chemotherapy. 2
• The CAO/ARO/AIO-12 trial demonstrated that chemoradiotherapy followed by consolidation chemotherapy achieved 25% pCR compared to 17% with induction chemotherapy followed by chemoradiotherapy. 2

CAPOX vs FOLFOX: Key Differences

While FOLFOX has more robust trial evidence and is often preferred 3, CAPOX offers several practical advantages:

• Oral administration: Capecitabine is taken orally, eliminating the need for continuous infusion pumps required for 5-FU in FOLFOX. 5
• Convenience: Patients take capecitabine 825 mg/m² twice daily within 30 minutes after meals. 5, 6
• Similar efficacy: Retrospective data suggests capecitabine may have superior efficacy compared to continuous infusion 5-FU (25% vs 13% pCR, P = 0.008). 7
• Comparable toxicity profile: Both regimens are generally well tolerated, though capecitabine causes more hand-foot syndrome while 5-FU causes more diarrhea. 7

Important Caveats and Pitfalls

Oxaliplatin During Concurrent Chemoradiotherapy

Do not add oxaliplatin during concurrent chemoradiotherapy. 1 The NCCN panel explicitly states they do not endorse the use of oxaliplatin with concurrent radiotherapy for rectal cancer. 1

The ACCORD 12/0405-Prodige 2 trial compared capecitabine/radiotherapy versus capecitabine/oxaliplatin/radiotherapy and found:

• Significantly more preoperative grade 3-4 toxicity with concurrent oxaliplatin (25% vs 1%, P < .001). 8
• The benefit of oxaliplatin was not demonstrated and should not be used with concurrent irradiation. 8

Similarly, the RTOG 0822 trial using CAPOX with concurrent IMRT showed 17.6% grade 3-4 diarrhea and did not reduce GI toxicity. 9

Proper Sequencing

The correct sequence is:

1. Long-course chemoradiotherapy (45-50.4 Gy) with concurrent capecitabine 825 mg/m² twice daily. 1, 6
2. Consolidation CAPOX for 12-16 weeks (typically 6-8 cycles). 1, 3
3. Surgery 2-4 weeks after completion of consolidation chemotherapy following MRI reassessment. 1
4. Consider additional adjuvant chemotherapy to complete 6 months total perioperative treatment. 1

Monitoring Requirements

• Warfarin interaction: Capecitabine significantly increases the effect of warfarin, requiring more frequent INR monitoring and dose adjustments. 5
• Oxaliplatin neuropathy: Monitor for cumulative peripheral neuropathy and consider dose reduction or discontinuation if grade 2-3 neuropathy develops. 3
• Renal function: Dose adjustments may be necessary for patients with kidney problems. 5

Patient Selection

CAPOX consolidation is particularly appropriate for:

• Patients with high-risk features (T4, EMVI+, threatened mesorectal fascia, cN2, enlarged lateral lymph nodes). 2
• Patients seeking organ preservation who may benefit from higher pCR rates. 1, 2
• Patients who prefer oral chemotherapy over continuous infusion. 7

Postoperative Management

Patients receiving preoperative TNT with CAPOX consolidation should still undergo postoperative adjuvant chemotherapy, with a recommended total treatment duration of 6 months including the preoperative consolidation period. 1 For patients with pathological stage ≤ypII after preoperative TNT, fluoropyrimidine monotherapy may be considered. 1