Adjuvant Therapy for Rectal Cancer Still Needed in Node-Positive Cases

NEW YORK—Total mesorectal excision (TME) has reduced the risk of local recurrence in rectal cancer, but adjuvant therapy is still needed in node-positive cases, according to Bruce Minsky, MD, vice chairman of radiation oncology at Memorial Sloan-Kettering Cancer Center in New York.

"We may not need to treat all patients with T3 and/or N0 disease with postoperative adjuvant therapy, but the INT 0114 data show that there are still local failures and decreased survival even after 5 years," Dr. Minsky said. "Retrospective trials have identified favorable subsets of patients with T3, N0 disease who have 10-year actuarial local recurrence rates of less than 10% after surgery alone, but this has yet to be confirmed in a randomized trial."

Favored Approach

Preoperative chemoradiotherapy is replacing postoperative adjuvant therapy as the favored approach. "In most countries outside of northern Europe, this is usually given as combined chemoradiotherapy," Dr. Minsky said. "Potential advantages include decreased tumor seeding, less acute toxicity, increased radiosensitivity, and enhanced sphincter preservation. The primary disadvantage is the risk of overtreating patients with either early stage disease or undetected metastatic disease."

Dr. Minsky described retrospective studies showing that preoperative combined chemoradiotherapy increases pathologic downstaging compared to preoperative treatment with radiation alone. Most regimens also include a postoperative chemotherapy component, and Dr. Minsky said that the ongoing randomized European Organization for Research and Treatment of Cancer (EORTC) 22921 trial is examining this issue.

Twelve randomized trials of preoperative radiation therapy without chemotherapy have been reported. Only one, the Swedish Rectal Cancer Trial, reported a survival advantage. Two meta-analyses of preoperative radiation therapy reported conflicting results. The standard approach outside of selected northern European countries is to use both chemotherapy and radiation.

Quality of Life Issues

Dr. Minsky pointed out that TME decreases local recurrence rates. The Dutch CKVO 95-04 trial found that adding preoperative radiation decreased the 5-year local recurrence rate to 6% vs 12% with TME alone. There was no difference in 2-year survival in this study.

"Even if future trials confirm a survival benefit [with TME alone], there are other equally important endpoints in rectal cancer that need to be addressed," he said. "These include acute toxicity, sphincter preservation and function, and quality of life. For example, acute toxicity in the Dutch CKVO 95-04 trial included 10% neurotoxicity (3% of which was grade 2 or 3), 29% perineal wound complications, and 12% postoperative leaks. Eighty percent of the patients with postoperative leaks required additional surgery, which resulted in 11% mortality."

Sphincter preservation is an important goal, but Dr. Minsky said that a well-functioning colostomy gives better quality of life than a poorly functioning sphincter. Therefore, sphincter function needs to be assessed as well.

Whether response to preoperative chemoradiotherapy predicts outcome and whether clinical complete response predicts pathologic complete response are also clinically important questions. Dr. Minsky said that retrospective data suggest that response does predict outcome and that in one series, 5-year recurrence-free survival in rectal cancer patients is 94% in those that respond to preoperative therapy, compared to 79% overall. However, there is poor correlation between clinical and pathologic complete response; only 25% of patients with clinical complete response after preoperative chemoradiotherapy have pathologic complete response.

Combinations with newer agents are under active investigation. Dr. Minsky discussed the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 study, which will compare preoperative radiation and capecitabine (Xeloda) to preoperative radiation and continuous infusion fluorouracil (5-FU).The trial will also test the effect of preoperative recombinant human erythropoietin given after the chemoradiotherapy.