Preoperative chemoradiation has become a common approach to treat stage II and III rectal cancer at many institutions, including The University of Texas M. D. Anderson Cancer Center (MDACC) in Houston.[1-4] A study from Uppsala, Sweden, has shown that preoperative radiation alone improves pelvic control as compared with postoperative radiation alone. Another Swedish trial in patients with rectal cancer demonstrated improved pelvic control and overall survival using preoperative radiotherapy compared with surgery alone. These studies, however, used preoperative radiotherapy without concurrent chemotherapy.
Although a randomized trial has not been conducted to compare the efficacy of preoperative chemoradiation to that of radiotherapy alone, concurrent chemoradiation is commonly used in the United States. This practice is based on extrapolation from trials in the postoperative setting[7,8] showing the superiority of combined chemotherapy and radiotherapy over radiotherapy alone. In this respect, the use of a protracted venous infusion of fluorouracil(Drug information on fluorouracil) (5-FU) has become the standard chemotherapy, based on data from a randomized trial conducted by the Gastrointestinal Intergroup.
Patients who have had a complete clinical response to preoperative chemoradiation have had better pelvic tumor control, sphincter preservation, and overall survival than those who have had gross residual disease. Some patients achieving a clinical complete response have even had rectal preserving surgery (full-thickness local excision). These results emphasize the importance of maximizing tumor response. The improvement in overall survival could be due to higher pelvic control rates, or the response may indicate increased sensitivity of distant micrometasteses to chemotherapy. Any increase in the response of local disease to chemoradiation or distant micrometasteses to chemotherapy would logically further improve outcome.
Use of chemotherapeutic agents that may be more effective than 5-FU as radiosensitizers or as systemic agents may also lead to further improvements in response and survival rates. Alternatively, molecular targeting could be used to selectively enhance the efficacy of chemoradiotherapy regimens. Irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) is among the newer chemotherapeutic agents being explored in combination with radiotherapy. Phase I studies have determined the maximum tolerated dose of irinotecan when used with preoperative chemoradiation in rectal cancer patients. The Radiation Therapy Oncology Group (RTOG) is currently evaluating irinotecan as a radiosensitizer in rectal cancer.
Because the primary limitation of chemoradiation is toxicity to normal tissues, an improvement in therapeutic ratio could also be achieved by incorporating tumor-selective agents. A number of processessuch as epidermal growth factor receptor signaling, ras oncogene activation, the cyclooxygenase-2 (COX-2) enzyme, and angiogenesisappear to be tumor-selective in preclinical models. Treatment with inhibitors of these molecular processes has shown therapeutic efficacy in several preclinical tumor models, particularly when combined with cytotoxic agents.
Among molecular target therapeutic strategies, counteracting COX-2 enzyme activity seems promising, and significant preclinical and clinical testing of this approach has been initiated. COX-2 overexpression occurs in various types of human cancer and has been shown to correlate with poor prognosis. Study results have shown that treatment of tumor-bearing mice with selective COX-2 inhibitors enhances tumor response to radiation and chemotherapy. Cyclooxygenase inhibitors have been shown to prevent colon cancer[16,17] and to reduce the number of polyps in patients with familial adenomatous polyposis. Therefore, COX-2 inhibition has the potential to improve outcome for rectal cancer patients treated with preoperative chemoradiation.
Over the past decade at MDACC, patients with rectal cancer have been treated with a preoperative radiotherapy dose of 45 Gy in 25 fractions prescribed to the 95% isodose line, with concomitant protracted venous infusion 5-FU at 300 mg/m2/d, Monday through Saturday morning. Since 1997, patients have been treated in an ongoing prospective phase II trial that includes a concomitant boost technique. With this technique, the same radiation dose is delivered to the tumor and pelvic lymphatics (45 Gy) over 5 weeks, with an additional 1.5-Gy boost as a second daily treatment separated from the first by 6 hours during the fifth treatment week. The total dose to the primary tumor is 52.5 Gy prescribed to the 95% isodose line. The boost is given to the gross tumor volume using a 3D conformal technique, which minimizes normal tissue irradiation. Mesorectal excision is carried out 4 to 8 weeks later. All patients receive four cycles of adjuvant 5-FU and leucovorin after surgery.
Between 1990 and 2000, 390 stage II and III rectal cancer patients were treated with preoperative pelvic chemoradiation followed by surgery. Presence of microscopic or no residual disease was shown to be a favorable predictor of pelvic control on univariate analysis (P = .02, Figure 1). A Cox regression multivariate analysis showed a trend toward improved survival (P = .08, unpublished observations). The only independently significant prognostic factor for freedom from pelvic recurrence was clinical T stage. Actuarial freedom from pelvic recurrence at 4 years was 90% for 354 patients with T3 disease vs 79% for 36 patients with T4 disease. At MDACC, clinical T4 disease is defined as objective evidence of adjacent organ involvement on computed tomography (CT) scan, physical examination, or endoscopic ultrasound.
While the concept is not universally accepted, several investigators have reported that significant numbers of patients who were initially thought to require abdominoperineal resection were able to undergo sphincter-preserving procedures following preoperative chemoradiation. This phenomenon has been demonstrated prospectively by preliminary results of the ongoing National Surgical Adjuvant Breast and Bowel Project (NSABP) R-03 trial, in which patients were randomly assigned to receive preoperative or postoperative chemoradiation. Surgeons entering patients in the study were encouraged to decide prospectively which operation would be necessary. A sphincter-preserving procedure was possible in 23% of those patients initially felt to require abdominoperineal resection.
While studies have suggested that response to preoperative chemoradiation may impact the rate of sphincter-preserving surgery,[2,22] those analyses were not originally designed to answer that question. At MDACC, the sphincter preservation rate in patients with low rectal cancer following preoperative chemoradiation has increased with time and is currently greater than 60% for tumors < 6 cm or less from the anal verge. A logistic regression analysis of clinical, treatment-related, and pathologic factors among 238 patients with tumors < 6 cm from the anal verge indicated that complete clinical response to preoperative chemoradiation is an independent predictor of sphincter preservation.
Clinical complete response rate was 46%, and tumors < 3 cm or less from the anal verge that responded completely to preoperative chemoradiation had the most striking difference in sphincter-preserving surgery (44% vs 23%, P = .01) compared to those who did not respond completely. Importantly, the pelvic recurrence rate among patients undergoing sphincter-preserving surgery has been less than 10% since 1993, and no increase in pelvic recurrence risk has been observed with the use of sphincter-preserving procedures in the low rectum (unpublished observations). Thus, increasing the response rate could lead to increased rates of sphincter preservation or even rectal preservation.
Of 362 patients with T3 rectal cancer treated at MDACC with preoperative chemoradiation and surgery over the past decade, 17 patients with localized disease have been selected for local excision due to patient refusal of abdominoperineal resection, medical comorbidity, physician preference after a complete clinical response, or unknown reasons. Local excision was performed after completion of chemoradiation. With a median follow-up of 34 months (range: 6 to 96 months), only 1 of 17 patients has had intrapelvic recurrence and another has had disease recur in an inguinal lymph node. Two patients have died of metastatic rectal cancer and one has died of unknown causes.
The 5-year actuarial overall survival at 5 years was 67%. Twelve of 17 (71%) patients have achieved pathologic complete response, microscopic residual disease was evident in 4/17 (24%), and gross residual disease was present in one patient. This indicates that the response to preoperative chemoradiation may have played a role in the decision to proceed with local excision rather than abdominoperineal resection in some patients. Furthermore, it appears that preoperative chemoradiation followed by local excision provides effective local control in highly selected cases. This strategy should be studied prospectively in patients with low rectal cancer who respond to chemoradiation.
Previously, we reported that response to preoperative chemoradiation (defined as evidence of microscopic or no residual disease) is a positive predictor of improved overall survival (P = .07). At the time of that analysis, the follow-up duration and patient numbers were insufficient to demonstrate statistical significance. We recently reported results involving a larger patient cohort, which showed that response (defined as evidence for T-stage down-staging without nodal positivity) is a positive predictor of disease-free and overall survival. The presence of microscopic or no residual disease also positively predicted survival on univariate analysis in this updated experience (P = .002, Figure 2). A Cox regression multivariate analysis confirmed this finding as well as the negative influence of poor differentiation on overall survival (unpublished observations).