Combined-Modality Neoadjuvant Therapy for Rectal Cancer

The preliminary results of a multicenter phase III clinical trial of adjuvant therapy for rectal cancer conducted by the European Organisation for Research and Treatment of Cancer were reported by Bosset et al in this issue. This randomized study used a factorial design intended to address, in patients with T3-4 operable rectal adenocarcinoma, the value of adding fluorouracil (FU) plus leucovorin to preoperative (neoadjuvant) pelvic radiation therapy and administering four cycles of FU plus leucovorin after surgical resection. The study enrolled 1,011 patients between 1993 and 2003. No clinical outcome data were presented concerning local tumor control, diseasefree survival, or overall survival. Rather, this article highlighted the impact on pathologic parameters of adding chemotherapy to preoperative radiation. The major conclusions were that patients treated with chemoradiotherapy had smaller tumors, fewer regional lymph nodes containing metastases, and more favorable histologic features of tumor in the resected specimen compared with patients receiving radiation therapy alone. The pathologic complete response rate for the primary rectal tumor was increased from 5.3% to 13.7% with the addition of chemotherapy. The authors appropriately concluded that the influence of chemoradiotherapy on pathologic parameters demonstrated an enhanced tumoricidal effect compared with radiation therapy alone, although longer follow-up is required to determine whether these histologic changes correlate with patient outcome. As noted by the authors, there was no central review of pathology. Rather, standardized forms were filled out by a number of individual pathologists from multiple institutions over a 10-year period. Although the additional variability introduced into the analysis by lack of central pathology review may well have affected the results to some degree, the large sample size and randomized study design allowed the conclusions put forth by the authors to be reasonably drawn. Furthermore, the authors were cautious not to prematurely extrapolate their pathology data to clinical outcomes. The pathology data from the European Organisation for Research and Treatment of Cancer is consistent with the early clinical observations by Moertel et al that the addition of FU administered concomitantly with radiation therapy could improve palliation and prolong survival in patients with locally unresectable colorectal cancer. Phase III clinical trials performed by the North Central Cancer Treatment Group and National Surgical Adjuvant Breast and Bowel Project (NSABP) have demonstrated that the use of FU combined with postoperative pelvic radiation therapy improves local tumor control and patient survival compared with radiation therapy alone and that the addition of pelvic radiation to chemotherapy with FU-based regimens improves local tumor control compared with chemotherapy alone. Thus, all of the more recent phase III clinical trials of adjuvant therapy for rectal cancer in the United States have used radiation therapy and chemotherapy in combination. But this is old news. Much more promising for current clinical practice and clinical trials alike are the results of the German Rectal Cancer Group trial reported by Sauer et al in 2004, which provide the rationale for a preoperative combined-modality platform for rectal cancer clinical trials going forward. This large, randomized, clinical trial showed convincingly that neoadjuvant pelvic radiation therapy combined with FU and leucovorin chemotherapy improved local tumor control, increased the ability to perform sphincter-sparing surgery, and decreased treatment-related side effects compared with the same treatment regimen administered postoperatively for patients with operable rectal cancer. Because pelvic radiation therapy combined with FUbased chemotherapy is generally well tolerated and has been shown to be effective in the postoperative setting, the combined-modality approach has already been adopted in numerous cooperative group neoadjuvant trials conducted or in progress in the United States by the Eastern Cooperative JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 24 AUGUST 2