Neoadjuvant Chemoradiotherapy with Capecitabine for Locally Advanced Rectal Cancer (LARC)
{submitted by Frances Cusano}
Neoadjuvant Chemoradiotherapy with Capecitabine for Locally Advanced Rectal Cancer (LARC)
What is the standard of care for patients with LARC?
Preoperative (neoadjuvant) chemoradiotherapy is the standard of care for patients with locally advanced rectal cancer. The results of the German Intergroup trial demonstrated that patients treated with preoperative chemoradiotherapy had lower rates of local recurrence and toxicity with similar rates of overall survival when compared to patients who received post-operative chemoradiotherapy (1). In this trial, the chemotherapy was continuous infusion 5-fluorouracil during the first and fifth weeks of radiotherapy.
Randomized trials have studied different methods of dosing 5-fluorouracil during chemoradiotherapy for rectal cancer. A nonrandomized prospective study compared 22 patients who received continuous infusion of 5-fluorouracil to 12 patients who received bolus 5-fluorouracil with concurrent radiation in the neoadjuvant setting for LARC (2). The bolus 5-fluorouracil was administered on the first 3 – 5 days of radiation and repeated on days 28 – 33. The infusional 5-fluorouracil (225 mg/m² daily) was administered for the duration of radiation. Pathologic complete response was observed in 2 of 21 (10%) of patients treated with bolus 5-fluorouracil verses 8 of 12 (67%) of patients treated with continuous 5-fluorouracil infusion. There was no statistically significant difference in overall survival between the two groups. Based on these results, continuous 5-fluoruracil has been used in the neoadjuvant treatment of LARC.
What is the evidence for capecitabine replacing continuous 5-fluorouracil in the neoadjuvant chemoradiotherapy of LARC?
Currently, there are no published phase III trials comparing capecitabine-based therapies with continuous 5-fluorouracil based therapies as neoadjuvant therapy in LARC.
A phase I trial established that the maximal tolerated dose of capecitabine with radiation therapy for rectal cancer was 825 mg/m² orally twice daily (a daily dose of 1650 mg/m²) (3).
A Phase II trial published by Krishnan et al. (4) enrolled 54 patients with LARC. For radiotherapy, patients received 45 Gy over 25 fractions, with an additional 5 fractions of concomitant boost treatment during the last week. Patients received capecitabine 825 mg/m2 orally twice daily for the duration of radiotherapy, with the initial dose starting approximately 1 to 2 hours before radiotherapy. Of the 51 patients evaluated for pathologic response, 9 patients (18%) had a complete pathological response (pCR). Twenty-six of all 54 patients (51%) achieved T-downstaging and 15 of the 29 initially node positive patients (52%) achieved N-downstaging. Other phase II studies have shown similar results, with pCR between 9 and 24% (5).
The NSABP R-04 is a Phase III randomized trial currently in progress. This trial will compare the rate of local-regional relapse in patients receiving preoperative oral capecitabine + radiotherapy to patients receiving preoperative infusional 5-fluorouracil + radiotherapy.
What are the toxicities of capecitabine + radiotherapy vs infusional 5-fluorouracil + radiotherapy in the neoadjuvant setting in patients with LARC?
Phase II prospective studies of neoadjuvant capecitabine + radiotherapy in patients with LARC have shown that the treatment is generally well tolerated with no grade IV toxicity (5).
A retrospective Phase II study by Das et al. (6) compared preoperative chemoradiotherapy with capecitabine versus infusional 5-fluorouracil for rectal cancer. 89 patients with nonmetastatic rectal adenocarcinoma were treated with preoperative RT (45 Gy in 25 fractions in 5 weeks) and capecitabine (1650 mg/m2/day during radiotherapy). These patients were matched to 89 control patients who received preoperative radiotherapy (the same dose as in the capecitabine group) and continuous infusion 5-fluorouracil (median dose 300 mg/m2/day administered Monday to Friday each week of radiotherapy). No statistically significant differences were found between patients treated with capecitabine and those treated with continuous infusion for the rates of local control, distant control and overall survival. Patients treated with capecitabine had a greater rate of hand-foot syndrome (22% vs 3%, p< 0.01), but these were all Grade 1 or 2. Patients treated with protracted infusional 5-fluorouracil had a greater rate of mucositis (19% vs 6%, p = 0.03). Two patients in the capecitabine group experienced Grade 4 diarrhea, and 1 patient in the infusional 5-fluorouracil group experienced Grade 4 mucositis.
Conclusion
The results of NSABP-R04 will be used to evaluate whether capecitabine should be used as an alternative to infusional 5-fluorouracil in neoadjuvant chemoradiotherapy for LARC. While the evidence to date does not indicate that capecitabine is superior to infusional 5-fluorouracil or that it reduces the toxicity of neoadjuvant chemoradiotherapy, use of capecitabine does eliminate the need for indwelling catheters, which carry a risk of infections and thrombosis.
References
1. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-1740.
2. Mohiuddin M, Regine WF, John WJ et al. Preoperative chemoradiation in fixed distal rectal cancer: dose time factors for pathological complete response. Int J Radiat Oncol Biol Phys 2000;46:883.
3. Dunst J, Reese T, Sutter T et al. Phase I Trial Evaluating the Concurrent Combination of Radiotherapy and Capecitabine in Rectal Cancer. J Clin Oncol 2002;20:3983-3991.
4. Krishnan S, Janjan N, Skibber J et al. Phase II study of capecitabine and concomitant boost radiotherapy in patients with locally advanced rectal cancer. Int J Radiation Oncology Biol Phys 2006;66(3):762-771.
5. Saif M, Hashmi S, Zelterman D et al. Capecitabine vs continuous infusion 5-FU in neoadjuvant treatment of rectal cancer. A retrospective review. Int J Colorectal Dis 2008;32:139-145.
6. Das P, Lin EH, Bhatia S et al. Preoperative chemoradiotherapy with capecitabine versus protracted infusion 5-fluorouracil for rectal cancer : A matched pair analysis. Int J Radiation Oncology Biol Phys 2006;66(5):1378-1383.
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