Neoadjuvant Therapy Supported for Rectal Cancer

BOSTON—Neoadjuvant therapy for adenocarcinoma of the rectum is well tolerated and can produce substantial downstaging and high curative resection rates, according to a retrospective study presented at the American Society of Colon and Rectal Surgeons (ASCRS) annual meeting. The manuscript of the study has been accepted for publication in Diseases of the Colon and Rectum.

Thomas E. Read, MD, of Washington University School of Medicine, St. Louis, and his co-authors evaluated the down-staging effect vs toxicity of various neoadjuvant treatment regimens in 262 patients undergoing proctectomy for rectal cancer between 1990 and 1999.

Patients underwent preoperative short-course radiation therapy (2,000 cGy in 5 fractions), long-course radiation therapy (4,500 cGy in 25 fractions), or chemoradiation (4,500 cGy in 25 fractions with concurrent chemotherapy).

Downtaging was determined by comparing the pretreatment T and N stage of the tumor (based on transrectal ultrasound with or without CT) with final histology.

Although the effect of neoadjuvant therapy was probably underestimated because the authors’ criteria mandated a reduction in T or N stage to indicate downstaging, nearly half of the patients in the study—45% (116 of 260)—had their primary tumors downstaged by neoadjuvant therapy.

There was a trend toward greater downstaging with the more intensive neoadjuvant regimens, though these differences did not reach statistical significance. Down-staging of one or more T stages occurred in 34 of 82 patients (42%) treated with short-course radiation, 55 of 122 patients (45%) treated with long-course radiation, and 27 of 56 patients (48%) treated with chemoradiation prior to proctectomy.

Downstaging of one or more nodal stage occurred in 84 of 176 patients (48%) overall. Longer neoadjuvant treatment regimens produced greater downstaging, with the greatest effect seen in patients treated with long-course radiation therapy (P = .003).

Downstaging of one or more N stage occurred in 12 of 45 patients (27%) treated with short-course radiation, 50 of 87 patients (58%) treated with long-course radiation, and 22 of 44 patients (50%) treated with chemoradiation prior to proctectomy.

Complete pathologic response (no detectable tumor on final histology) was observed in 16 of 260 patients (6%) overall. Complete pathologic response occurred in 4 of 82 patients (5%) treated with short-course radiation, 5 of 122 patients (4%) treated with long-course radiation, and 7 of 56 patients (13%) treated with chemoradiation.

Although there was a trend toward higher complete pathologic response rates with chemoradiation, these differences did not reach statistical significance (P = .08), Dr. Read said.

Resection with negative margins (distal, proximal, and radial) was achieved in 211 of 227 patients (93%) in whom complete radial margin data were available.

The greater downstaging effect of more intensive neoadjuvant treatment regimens came at the price of greater toxicity. Grade 3-4 toxicities occurred in 22 of 260 patients (8%) overall during neoadjuvant therapy.

No patients treated with short-course radiation had toxicity; 9 toxicities occurred in 8 of 122 patients (7%) treated with long-course radiation; 24 toxicities occurred in 14 of 56 patients (25%) treated with chemoradiation. This trend of increasing toxicity with more intensive neoadjuvant therapy was statistically significant (P < .0001).

The most common complications were gastrointestinal, with enteritis being the most frequent and most severe.

Selective Use

Dr. Read said that his data suggest that the selective use of neoadjuvant radiation and chemoradiation may have utility in the management of patients with rectal cancer.

"We have typically used short-course radiation for patients with small, mobile tumors that are ultrasound stage T3N0 or less on pretreatment evaluation," Dr. Read told ONI in an interview.

Currently, he said, long-course radiation is used for patients with T3N0 tumors that are bulky or tethered and for patients with nodal disease who are too frail to tolerate chemoradiation. For such patients, he said, the least morbid and most acceptable treatment approach may be sequential therapy: preoperative radiation followed by surgery and then chemotherapy.

"The local control and functional results with this approach are excellent," Dr. Read said. "There is no evidence that delaying chemotherapy until the postoperative period will compromise its impact on distant disease."

He noted that preoperative chemoradiation is employed primarily for healthy patients with fixed or deeply tethered cancers, or patients with nodal disease on transrectal ultrasound or CT.

Dr. Read said that he hoped that prospective comparisons of the benefits vs the toxicities of various neoadjuvant regimens could help guide selection of these treatments in the future.