Detection of Nodal Involvement, Adjuvant Treatments for Rectal Cancer Debated

Detection of Nodal Involvement, Adjuvant Treatments for Rectal Cancer Debated

The roles of preoperative treatment, local excision, and postoperative chemotherapy following neoadjuvant chemoradiotherapy for patients with rectal cancer were discussed at Friday’s Education Session, “Controversial Issues in the Management of Rectal Cancer.” Speakers noted that neither the use of neoadjuvant therapy nor the extent of downstaging alter the standard of care — adjuvant chemotherapy — for patients with stage II and stage III rectal cancer.

Session Chair Bruce D. Minsky, MD, of the University of Chicago, said the benefit of postoperative radiotherapy for patients with T3N0 tumors who have undergone a total mesorectal excision is clear, provided there are at least 12 negative lymph nodes. “There is a 3% to 4% increase in local control, but the benefits do not outweigh the risks,” he said.

However, when preoperative radiotherapy is examined, as it was in studies that Dr. Minsky reviewed, there was improved local control but conflicting methodologies. A potential problem is the significant overtreatment of patients with preoperative chemotherapy, he said. Discussing a study presented at the ASCO 2008 Annual Meeting by Guillem et al, Dr. Minsky noted that as many as 40% of patients who underwent surgery alone had node-positive disease at the time of surgery, and 22% of patients who had preoperative chemotherapy had positive nodes. These patients then require postoperative treatment that, when compared with preoperative treatment, offers inferior local control, higher toxicity, and inferior functional results.

The risk of positive nodes is not dependent on the distance of the tumor from the anal verge.

“Regardless of where the tumor is located in the rectum, the chances of a positive node are the same,” Dr. Minsky said. His recommendation was that all patients be treated with preoperative chemotherapy. “Although we may be overtreating them, if we send them to surgery and they need postoperative treatment, the results are inferior.”

Philip Paty, MD, of Memorial Sloan-Kettering Cancer Center, noted that local excision of T1 rectal tumors is actually a biopsy and, with more screening, more polyps and small nodular cancers are located and excised. The subsequent presence of positive lymph nodes and metastasis following local excision leads to new questions about the procedure’s long-term efficacy. In one study, he noted that nearly one-third of patients who had local excision also had positive nodes. “The inability to accurately detect regional lymph node metastases is the major barrier to individualizing treatment approaches for patients with localized rectal cancer,” he said. The greatest predictor, he noted, was the depth of the tumor’s invasion into submucosal tissue.

Dr. Paty also noted that local excision may offer inferior oncologic results for those patients whose disease progresses as a result of metastasis. “Local excision is inferior cancer treatment compared with more radical surgery because it yields incomplete staging and a risk of incomplete local resection,” he said. Better imaging and neoadjuvant therapy may expand the number of patients for whom this is an adequate treatment.

Carmen Joseph Allegra, MD, of the University of Florida, reviewed the studies that led to the 1990 National Institutes of Health Consensus statement, which indicated that for rectal cancer, adjuvant therapy combining chemotherapy and radiation therapy improves local control and survival for patients with stage II and III disease.

However, Dr. Allegra noted, “This was based on a study that was woefully underpowered by today’s standards and used chemotherapy combinations we don’t use.” Subsequent pooled analyses indicated that adding chemotherapy improved patient survival, but a 2006 European Organisation for Research and Treatment of Cancer (EORTC) study called that conclusion into question with its finding that chemotherapy — whether administered preoperatively or postoperatively — had no significant effect on survival.

Many factors, however, diminished the power of the EORTC study. Of those patients who underwent resection, 28% assigned to receive adjuvant chemotherapy never received it, and half of the patients assigned to postoperative chemotherapy received 2 months of preoperative chemotherapy. In addition, fewer than half of the study patients had node-positive disease compared with 70% in prior studies [that showed] a benefit for adjuvant chemotherapy. “Patients with node-positive disease have a worse prognosis relative to those with node-negative disease,” noted Dr. Allegra.

Given that there is now a preponderance of evidence strongly favoring the use of chemotherapy for patients with stage II and III rectal cancer, questions remain as to which regimens and dosages are optimal. Much of the available data, Dr. Allegra said, indicates that the available fluorouracil regimens are almost equally efficacious, but the addition of oxaliplatin does confer a benefit, according to results from the Adjuvant Treatment of Colon Cancer (MOSAIC) trial. Agents such as bevacizumab and cetuximab are being investigated for the treatment of patients with colon cancer, and some results are becoming available, including those from a study by Wolmark et al being presented in this afternoon’s Plenary Session.