Colon cancer is a major public health problem. The primary treatment is resection. For patients with early-stage disease, surgery results in excellent survival rates. In contrast, patients with locally advanced tumors arising in "anatomically immobile" segments of large bowel have a less satisfactory outcome, in part secondary to compromised surgical clearance. Patterns-of-failure analyses suggest that for tumors that invade adjacent organs, exhibit perforation or fistula, or are subtotally resected, local failure rates exceed 30%. Multiple single-institution retrospective studies have shown improved local control and possibly survival with the addition of external irradiation and/or intraoperative radiation. In contrast, a recent Intergroup trial failed to show any benefit by the addition of adjuvant radiation therapy combined with chemotherapy. Interpretation of this trial's results is handicapped by low patient accrual. With the advent of novel and more effective systemic therapies for metastatic colon cancer, current and future clinical research will address the efficacy of these agents in the adjuvant setting. Adjuvant radiation therapy should be considered in patients with colon cancer at high risk for local failure.
The role of adjuvant radiation in the treatment of colon cancer has been controversial since the seminal report from Gunderson and Sosin examining the patterns of failure after reoperation. In subsets of patients with high-risk features such as T4 and/or node-positive disease in fixed sites in the colon, the incidence of a local failure as a component of failure was almost 50%. Based on these data as well as subsequent reports from other institutions,[2,3] Dr. Willett and his group at the Massachusetts General Hospital retrospectively examined the role of locoregional radiation. They reported a local control benefit in selected patients with T3 or T4, node-positive disease. These encouraging findings lead to the development of the phase III INT 0130 trial of fluorouracil (5-FU)/levamisole (Ergamisol)-which was standard of care at that time-with or without locoregional radiation. The trial did not confirm a local control or survival advantage when locoregional radiation was added to postoperative chemotherapy.
Should the Trial Be Repeated?
In the comprehensive and thought-provoking review by Czito et al, the authors review the rationale and results of INT 0130, emphasizing its primary shortcoming-the suboptimal accrual that left the trial underpowered to answer the primary objective. In addition, it is unclear how relevant these data are today, given the significant advances in systemic chemotherapy and multiple regimens both available and in development.
Given the incomplete accrual of INT 0130 coupled with advances in systemic chemotherapy, should the trial be repeated? Is it still reasonable to recommend locoregional radiation for selected patients who, based on patterns of failure determined in an era when chemotherapy was not routinely delivered, are at high risk for local recurrence? Furthermore, has more effective chemotherapy changed the incidence of locoregional failure? Lastly, as reported in the INT 0114 trial of postoperative adjuvant therapy for rectal cancer, will such treatment only delay late local recurrences? The short answer to these questions is-unknown.
The ideal source for patterns-of-failure data is large phase III adjuvant trials such as intergroup trials. Unfortunately, it is difficult to obtain accurate local recurrence data from these trials as most examine first failure rather than cumulative failure. This method underestimates the true incidence of failure because, after the initial failure site is found, subsequent sites (if and when they develop) may not identified. Systemic chemotherapy may alter both the time and patterns of local recurrence. Until such trials capture this information, the ability to accurately assess patterns of failure will be limited.
Given the availability of more active chemotherapeutic regimens, the shortcomings of retrospective data, and an underpowered randomized adjuvant trial, what is the role of locoregional adjuvant radiation in patients with colon cancer? Dr. Czito et al offer reasonable recommendations. In general, patients with T4 colon cancer adherent to a fixed pelvic structure are treated as if they have rectal cancer, receiving preoperative combined pelvic irradiation and chemotherapy. For patients with primary tumors in the abdomen, postoperative combined radiation therapy plus chemotherapy is limited to settings where the margins are close or positive. In the future, as molecular marker information obtained from the current phase III adjuvant colon cancer trials is correlated with patterns of failure, more informed decisions will likely be possible.
-Bruce D. Minsky, MD
Dr. Minsky receives research funding from Genentech, Pfizer, and Bristol-Myers Squibb, is a member of the speakers bureaus for Genentech, Pfizer, Roche, and Sanofi-Aventis, and is a consultant for Genentech and Sanofi-Aventis.
1. Gunderson LL, Sosin H, Levitt S: Extrapelvic colon-areas of failure in a reoperation series: Implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 11:731-741, 1985.
2. Willett C, Tepper JE, Cohen AM, et al: Local failure following curative resection of colonic adenocarcinoma. Int J Radiat Oncol Biol Phys 10:645-651, 1984.
3. Minsky BD, Mies C, Rich TA, et al: Potentially curative surgery of colon cancer: 1. Patterns of failure and survival. J Clin Oncol 6:106-118, 1988.
4. Willett CG, Goldberg S, Shellito PC, et al: Does postoperative irradiation play a role in the adjuvant therapy of stage T4 colon cancer. Cancer J Sci Am 5:242-247, 1999.
5. Martenson JA, Willett CG, Sargent DJ, et al: Phase III study of adjuvant chemotherapy and radiation therapy compared with chemotherapy alone in the surgical adjuvant treatment of colon cancer: results of Intergroup protocol 0130. J Clin Oncol 22:3277-3288, 2004.
6. Tepper JE, O’Connell MJ, Hollis D, et al: Analysis of surgical salvage after failure of primary therapy in rectal cancer: results from Intergroup study 0114. J Clin Oncol 21:3623-3628, 2003.