Neoadjuvant capecitabine/oxaliplatin improves outcome of poor-risk rectal cancer

NEW YORK (Reuters Health) - Downstaging locally advanced rectal cancer with capecitabine and oxaliplatin prior to surgery and chemoradiotherapy may improve survival, a phase II trial suggests.

In the January 26 online issue of The Lancet Oncology, authors suggest that intensified preoperative treatment might increase the likelihood of clear margins at surgery and more effectively prevent micro-metastatic spread of disease.

Between 2001 and 2005, Dr. David Cunningham and associates at Royal Marsden Hospital, Sutton, Surrey, UK, enrolled 105 patients with high-risk rectal carcinoma as confirmed by high-resolution magnetic resonance imaging (MRI). Distant metastases were ruled out by computed tomography of the chest, abdomen and pelvis.

Therapy started with four 3-week cycles of oxaliplatin (130 mg/m2 on day 1) and capecitabine (1000 mg/m2 twice daily for 14 days). In the next stage, radiation therapy with 54 Gy over 6 weeks was accompanied by capecitabine (825 mg/m2 twice daily), to be followed 6 weeks later by total mesorectal excision. Capecitabine (1250 mg/m2 twice daily for 14 days every 3 weeks) was then given postoperatively for 12 weeks. The median follow-up was 55 months.

Ninety-seven patients had surgery, with total mesorectal excision in 95. Pathologists documented downstaging in 72, pathological complete response in 21, and microscopically clear resection margins in 93.

Three-year progression-free and overall survival in the intent-to-treat population were 68% and 83%, respectively, while 3-year relapse-free survival among patients who had complete resection was 74%. Median survival had not yet been reached when the authors wrote the paper. There has been no disease recurrence in patients with pathological complete response.

"The 5-year overall survival (75%) compares favorably with rates noted in randomized trials of earlier stage rectal primary tumors," the authors observe.

Nine patients had cardiac and thromboembolic adverse events (4 of which were fatal) during chemotherapy. After 2004, patients with a recent history of clinically significant cardiac problems were excluded.

Dr. Cunningham's group attributes the favorable survival rates in part to aggressive postoperative surveillance, allowing for further potentially curative surgery.

Summing up, they conclude, "As a non-randomized single-arm study, the value of our results is in generation of a hypothesis and in informing the design of future trials."

Among such future trials, they add, is one of their own -- a multicenter, randomized trial in which cetuximab will be added to the present treatment strategy.

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