What is the recommended treatment approach for rectal cancer using capecitabine (Xeloda) and radiation therapy (rt)?

Capecitabine 825 mg/m² with Radiation Therapy for Rectal Cancer

Capecitabine 825 mg/m² twice daily, administered Monday through Friday during concurrent radiation therapy (45-50.4 Gy), is an acceptable and guideline-recommended alternative to infusional 5-FU for locally advanced rectal cancer, with equivalent survival outcomes and a favorable toxicity profile. 1, 2

Evidence Supporting Capecitabine 825 mg/m² Dosing

Guideline Recommendations

The NCCN explicitly lists capecitabine given concurrently with RT as an acceptable alternative to infusional 5-FU for patients who can manage self-administered oral chemotherapy. 1 This recommendation is based on:

• Non-inferiority to 5-FU for 5-year overall survival (75.7% vs 66.6%, P=0.0004) in a phase III trial of 401 patients with stage II or III rectal cancer 1
• Superior 3-year disease-free survival (75.2% vs 66.6%, P=0.034) compared to 5-FU-based chemoradiotherapy 1
• No differences in locoregional events, complete pathologic response, sphincter-saving surgery, or surgical downstaging in the NSABP R-04 trial of 1,608 patients 1

The specific dose of capecitabine 825 mg/m² twice daily, 5 days per week during radiotherapy, is explicitly recommended in current guidelines. 2

Radiation Therapy Parameters

Standard radiation dosing is 45.0-50.4 Gy delivered in 1.8-2.0 Gy fractions over 25-28 fractions. 2 Key technical specifications include:

• Minimum preoperative dose of 45 Gy in conventional fractionation 2
• Optional boost of 4-6 Gy in 2-4 fractions to the primary tumor after 45 Gy 2
• Three-dimensional precision radiotherapy (3D-CRT, VMAT, or IMRT) should be used 2
• Small bowel dose limited to within 50 Gy 2

Clinical Trial Data Supporting 825 mg/m² Dose

Phase I/II Dose-Finding Studies

The 825 mg/m² twice daily dose was established through rigorous phase I dose escalation studies. 3 In a phase I trial of 28 patients:

• Dose levels tested ranged from 850 to 2000 mg/m² daily 3
• Maximum tolerated dose was 2000 mg/m² daily (1000 mg/m² twice daily) 3
• Recommended phase II dose was 1800 mg/m² daily (900 mg/m² twice daily) 3
• The 825 mg/m² twice daily dose (1650 mg/m² total daily) was well below MTD and demonstrated excellent tolerability 3

Efficacy Data at 825 mg/m² Dose

Multiple phase II studies confirmed the efficacy of capecitabine 825 mg/m² twice daily with concurrent RT:

• Pathologic complete response rate of 24% in a multicentric study of 53 patients 4
• Downstaging rate of 57% with overall clinical response rate of 58% 4
• Sphincter preservation in 59% of patients with low-lying tumors (≤5 cm from anal verge) 4
• 3-year disease-free survival of 59.8% and overall survival of 76.6% in a phase II trial of 31 patients 5

Safety Profile

The toxicity profile at 825 mg/m² twice daily is generally favorable:

• Grade 3/4 toxicity occurred in only 11% of patients in the multicentric study 4
• Most common grade 3 toxicities were leucopenia (4%) and hand-foot syndrome (4%) 4
• Grade 3/4 diarrhea occurred in 30-35.5% of patients across studies 6, 5
• No grade 4 toxicity was reported in the largest phase II study 4
• 89% of patients received 81-100% of planned capecitabine dose 4

Administration Schedule

Capecitabine should be administered as follows:

• Dose: 825 mg/m² orally twice daily 2, 7, 4, 6, 5
• Schedule: Monday through Friday on each day radiation is given 2
• Duration: Throughout the entire 5-6 week radiation course 2, 4
• Timing: Given on days 1-14 and 22-35 of a 5-week radiation schedule 7

Important Clinical Considerations

Patient Selection

Capecitabine is appropriate for patients who:

• Have stage II or III (T3-T4 and/or N+) rectal cancer 1, 4, 6
• Can reliably manage self-administered oral chemotherapy 1
• Are not candidates for or cannot tolerate infusional 5-FU 1

Bolus 5-FU/leucovorin with RT is reserved only for patients unable to tolerate either capecitabine or infusional 5-FU. 1

Oxaliplatin Addition Not Recommended

Adding oxaliplatin to capecitabine/RT is NOT recommended based on multiple phase III trials:

• NSABP R-04 showed no improvement in locoregional events, DFS, OS, or pCR with oxaliplatin addition 1
• ACCORD 12 trial showed similar pCR rates (19.2% vs 13.9%, P=0.09) but no improvement in local recurrence, DFS, or OS at 3 years 1
• Toxicity was significantly increased with oxaliplatin (grade 3/4 adverse events 24% vs 8%, P<0.001) 1
• Based on available data, addition of oxaliplatin to neoadjuvant chemoRT is not recommended 1

Surgical Timing

Surgery should be performed 4-8 weeks after completion of preoperative chemoradiotherapy. 3, 4, 6 Most studies used a 6-8 week interval to allow for maximal tumor regression 4, 6.

Elderly Patients

Chronological age alone should not exclude standard treatment with capecitabine/RT. 1 Fit elderly patients should receive standard guideline-based therapy, with treatment decisions based on comprehensive geriatric assessment rather than age cutoffs 1.