Preop Combined Modality Treatment, Promising Oral Agents

ORLANDO—The new frontiers in colorectal cancer include multimodality treatment used preoperatively and a new group of oral fluoropyramidine drugs, according to presentations at the Society of Surgical Oncology’s 52nd Annual Cancer Symposium.

Bruce D. Minsky, MD, reported early data suggesting that, with conventional doses and techniques, preoperative radiation and chemotherapy may improve survival, enhance sphincter preservation, and decrease adverse effects in patients with colorectal cancer.

Dr. Minsky and his colleagues at Memorial Sloan-Kettering Cancer Center began working with preoperative combined modality therapy out of dissatisfaction with the 25% to 50% rates of grade 3 toxicity seen with postoperative radiation and chemotherapy, which resulted in only 50% to 65% of patients being able to finish all planned therapy.

The researchers hoped that the preop timing would decrease cancer seeding, increase radiosensitivity, reduce adverse effects, and permit more patients to have sphincter-sparing coloanal anastomoses.

The preoperative approach using a short, intensive course of radiation has been successful in only 1 of 10 previous trials. That one, the Swedish Rectal Cancer Trial, had high morbidity.

Dr. Minsky said that careful examination of these preoperative therapy studies suggested that their failure to improve overall survival was due to inadequate total doses of radiation (all of which were below the accepted standard of 180 to 200 cGy/day, to a total 5,040 cGy); poor radiation technique; and too little time between radiation and surgery (which did not allow the tumor to shrink or the patient to fully recover from the effects of radiation).

The Swedish trial showed significantly better local recurrence rates and 5-year survival with preoperative radiation/surgery than with surgery alone (local recurrence, 12% vs 27%, P < .001; 5-year survival, 58% vs 48%, P = .004). Unfortunately, this was accompanied by high morbidity.

Dr. Minsky’s group addressed these problems by improving the radiation technique, maintaining sufficiently high radiation dosages, and allowing 4 to 6 weeks between radiation therapy and surgery. Their pilot study of preoperative radiation in 35 patients with colorectal cancer found that 27 (77%) were able to have coloanal anastomoses, that actuarial 5-year survival was 64% (Table 1), and functional results were excellent or good in more than 80% of patients (Table 2). Current treatment programs use combined radiation plus chemotherapy.

Dr. Minsky stressed the importance of using unirradiated bowel from outside the pelvis to construct the anastomoses. He also suspects that the reduction in acute gastrointestinal toxicity with preop vs postop radiation therapy (13% vs 48%, P = .045) is due to the reduction in radiation damage to the bowel.

“After surgery, the small bowel sits in the pelvis and is more likely to be in the radiation field. We have tried to exclude it by using mesh, but the mesh was largely resorbed by the time the radiation was performed after surgery,” Dr. Minsky said. About one-half of the small bowel typically falls within the radiation field with postoperative radiation (Figure 1), compared with preoperative radiation (Figure 2).

For preoperative radiation, the researchers block the perineum from the radiation field. “For those few patients who require an abdominoperineal resection, this decreases the incidence of perineal wound sepsis,” he said

Dr. Minsky emphasized that his data on the advantages of preoperative combined modality therapy, although promising, require confirmation in prospective, randomized clinical trials.

New Drugs, New Criteria?

Richard Pazdur, MD, of the University of Texas M.D. Anderson Cancer Center, described several new oral fluoropy-rimidines being studied in colorectal cancer. These drugs appear to have favorable toxicity profiles with a reduction in neutropenia and oral mucositis, he said, but these oral agents must demonstrate, in randomized phase III trials, equivalent survival in advanced colorectal cancer to IV fluorouracil plus leucovorin.

Researchers have begun to suspect that even drugs with relatively low response rates may have important clinical potential if they promote disease stabilization. The benefits appear as improvements in performance status, pain control, and weight maintenance. This was seen in studies of irinotecan (Camptosar), which, despite producing only a 15% response rate, improved these clinical parameters as well as 1-year survival.

Other new drugs that may disprove the “nothing is better than fluorouracil” idea include oxaliplatin (approved in France), capcitabine (Xeloda, approved for breast cancer), and UFT (uracil, tegafur, oral leucovorin, known as Orzel), which is in phase III trials in colorectal cancer. In addition, a large adjuvant colon cancer trial under the auspices of the National Surgical Adjuvant Breast and Bowel Project (NSABP) has recently completed accrual. This study randomized patients to UFT plus leucovorin vs IV fluorouracil plus leucovorin.