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Originally published as JCO Early Release 10.1200/JCO.2005.04.904 on July 11 2005 © 2005 American Society of Clinical Oncology.
Combined-Modality Neoadjuvant Therapy for Rectal CancerNational Surgical Adjuvant Breast and Bowel Project and Allegheny General Hospital Cancer Center, Pittsburgh, PA 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 al1 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, disease-free 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 al2 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 alone3 and that the addition of pelvic radiation to chemotherapy with FU-based regimens improves local tumor control compared with chemotherapy alone.4 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.5-8 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 al9 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 FU-based 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 Oncology Group, the Cancer and Leukemia Group B, the Radiation Therapy Oncology Group, and the NSABP. Because complete tumor response rates after neoadjuvant therapy for rectal cancer have been shown to correlate with local tumor control and disease-free and overall survival,8,10 a current research strategy is to improve pathologic complete response rates by the addition of other active agents, such as oxaliplatin,11 irinotecan,12 or bevacizumab,13 to FU or capecitabine14 and pelvic radiation. Reports of complete pathologic tumor response rates of 25% in two of these studies11,12 are encouraging and should be pursued in phase III clinical trials. Given that distant metastasis is by far the predominate pattern of tumor failure in rectal cancer today, the development of more effective systemic therapy is a prerequisite to making further improvements in the treatment of this disease. Presently, there is an Intergroup study being designed that will offer postoperative systemic therapy with chemotherapy (FU, leucovorin, and oxaliplatin) alone or chemotherapy combined with bevacizumab antiangiogenesis therapy, based on observed survival advantages when bevacizumab was added to FU-based chemotherapy for the treatment of advanced colorectal cancer.15,16 Finally, it is apparent that, in view of the multiple promising new agents for the treatment of colorectal cancer that have only recently come on the scene, it is necessary to conduct clinical trials for rectal cancer in a much more rapid manner. This will be possible in the United States only through increased collaboration by all of the cooperative clinical trial groups in a single coordinated research agenda for rectal cancer. Such a program is being put into place under the auspices of the National Cancer Institute by the NSABP through its neoadjuvant protocol R04 and by the Eastern Cooperative Oncology Group, which is developing the postoperative protocol alluded to earlier on behalf of the Gastroinstestinal Intergroup. To complete these trials in a timely fashion, collaboration on the part of all cancer cooperative clinical trial groups will be vital. Author's Disclosures of Potential Conflicts of Interest
Dollar Amount Codes (A) < $10,000 (B) $10,000–99,999 (C)
REFERENCES
1. Bosset JF, Calais G, Mineur L, et al: Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: Preliminary results—EORTC 22921. J Clin Oncol 23:5620-5627, 2005 2. Moertel C, Childs D, Reitemeier R, et al: Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet 2:865-867, 1969[CrossRef][Medline] 3. Krook J, Moertel C, Gunderson L, et al: Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 324:709-715, 1991[Abstract]
4. Wolmark N, Wieand HS, Hyams DM, et al: Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst 92:388-396, 2000
5. O'Connell MJ, Martenson JA, Wieand HS, et al: Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 331:502-507, 1994
6. Tepper JE, O'Connell M, Niedzwiecki D, et al: Adjuvant therapy in rectal cancer: Analysis of stage, sex, and local control—Final report of Intergroup 0114. J Clin Oncol 20:1744-1750, 2002 7. Smalley SR, Benedetti J, Williamson S, et al: Intergroup 0144: Phase III trial of 5-FU based chemotherapy regimens plus radiotherapy (XRT) in postoperative adjuvant rectal cancer—Bolus 5-FU vs prolonged venous infusion (PVI) before and after XRT + PVI vs bolus 5-FU + leucovorin (LV) + levamisole (LEV) before and after XRT + bolus 5-FU + LV. Proc Am Soc Clin Oncol 22:251, 2003 (abstr 1006) 8. Roh MS, Colangelo L, Wieand S, et al: Response to preoperative multimodality therapy predicts survival in patients with carcinoma of the rectum. J Clin Oncol 22:247, 2004 (suppl, abstr 3505)
9. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731-1740, 2004 10. Valentini V, Coco C, Picciocchi A, et al: Does downstaging predict improved outcome after preoperative chemoradiation for extraperitoneally locally advanced rectal cancer? A long term analysis of 165 patients. Int J Radiat Oncol Biol Phys 53:664-674, 2002[CrossRef][Medline] 11. Ryan DP, Niedzwiecki D, Hollis D, et al: A phase I/II study of preoperative oxaliplatin (O), 5-fluorouracil (5-FU), and external beam radiation therapy (XRT) in locally advanced rectal cancer: CALGB 89901. J Clin Oncol 22:260, 2004 (suppl, abstr 3560) 12. Mitchell EP, Anne PR, Fry R, et al: Chemoradiation with CPT-11, 5FU in neoadjuvant treatment of locally advanced or recurrent adenocarcinoma of the rectum: A phase I/II study update. Proc Am Soc Clin Oncol 22:262, 2003 (abstr 1052) 13. Willett CG, Chung D, Sahani D, et al: Phase I study of neoadjuvant bevacizumab, 5-fluorouracil, and radiation therapy followed by surgery for patients with primary rectal cancer. J Clin Oncol 22:267 2004 (suppl, abstr 3589)
14. Rodel C, Grabenbauer GG, Papadopoulos T, et al: Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer. J Clin Oncol 21:3098-3104, 2003 15. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 16. Mitchell EP, Alberts SR, Schwartz MA, et al: High-dose bevacizumab in combination with FOLFOX4 improves survival in patients with previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200. Am Soc Clin Oncol Gastrointestinal Cancers Symposium, January 2005
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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