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Originally published as JCO Early Release 10.1200/JCO.2009.22.9112 on September 21 2009 © 2009 American Society of Clinical Oncology.
Is Preoperative Chemoradiotherapy Still the Treatment of Choice for Rectal Cancer?Department of Radiation and Cellular Oncology, University of Chicago Medical Center, Chicago, IL In the early 1990s, postoperative chemoradiotherapy was the standard treatment in the United States for pT3 and node-positive (N+) rectal cancer. Randomized trials confirmed significant improvement in local control and survival with postoperative chemoradiotherapy, compared with surgery alone. However, with these improvements came an increase in acute and long-term toxicities. Furthermore, functional results—most notably in patients who underwent coloanal or low anastomosis—were suboptimal. At the same time, phase I/II data were emerging suggesting that preoperative chemoradiotherapy was superior to radiation alone for pathologic downstaging, was associated with less acute toxicity than postoperative chemoradiotherapy, and appeared to improved the chance of sphincter preservation.1,2 From 1993 to 1994, three randomized phase III trials comparing preoperative with postoperative chemoradiotherapy in patients with cT3/4 rectal cancer were opened. Two trials were performed in the United States (INT [Intergroup] 0147 and NSAPB [National Surgical Adjuvant Breast and Bowel Project] R-03), and one was performed in Europe (CAO/ARO/AIO [Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society] 94). Of the three, only the German trial successfully met its accrual goals. After it was reported in 2004 by Sauer et al,3 the standard of care for patients with cT3 and/or N+ rectal cancer began to change from postoperative to preoperative chemoradiotherapy. The two US trials fell far short of their accrual goals. INT 0147 accrued only 53 patients. For me, as the principal investigator of INT 0147, its failure was a personal disappointment. In a final effort to improve accrual onto NSABP R-03, INT 0147 was closed, and all efforts were channeled into NSABP R-03. Although this did not save NSABP R-03, it did establish a new era of close collaboration within the GI Intergroup, which remains strong to this day. There is a limited window in which phase III questions can be answered. Once a strong bias emerges, the opportunity is lost. We clearly lost that opportunity in the United States with the premature closure of both the NSABP R-03 and INT 0147 trials. The CAO/ARO/AIO 94 trial used the technique of prerandomization, in which patients are randomly assigned to treatment before consent. Perhaps if this method had been allowed, the two US trials would have met their accrual goals. In this issue of Journal of Clinical Oncology, Roh et al4 present the results of NSABP R-03. In brief, 267 of the 900 patients with T3/4 rectal cancer intended to be enrolled onto the trial were randomly assigned to receive, either preoperatively or postoperatively, induction chemotherapy followed by conventional chemoradiotherapy. Surgical techniques were left to the discretion of the operating surgeon. Total mesorectal excision (TME) was not required, and some patients underwent local excision. The primary end points were disease-free and overall survival.
In the NSABP R-03 trial,4 compared with postoperative therapy, patients who received preoperative therapy had a significant improvement in 5-year disease-free survival (65% v 53%; P = .011) and a nonsignificant improvement in 5-year overall survival (75% v 66%; P = .065). There was no difference in 5-year local recurrence (11%). There was a corresponding higher incidence of However, Sauer et al3 reported opposite results in the CAO/ARO/AIO 94 trial. Compared with postoperative therapy, patients who received preoperative therapy had a significantly lower incidence of local recurrence (6% v 15%; P = .006) and acute (27% v 40%; P = .001) and chronic (14% v 24%; P = .012) toxicities, a higher incidence of sphincter preservation (39% v 20%; P = .005), and no difference in 5-year survival (74% v 76%). How do we reconcile such contradictory results? Although the two trials used different chemotherapy regimens and surgical techniques, they were both well-designed, prospective, randomized trials and had more similarities than differences. Roh et al4 offer a number of reasonable explanations for the contradictory results. Most compelling is the fact that of the 900 patients intended to be enrolled onto the trial, only 267 were accrued, thereby limiting the statistical power to detect differences. In contrast with the NSABP R-03 trial, the CAO/ARO/AIO 94 trial successfully randomly assigned more than 800 patients to treatment; all patients underwent TME and were stratified by surgeon. Two weaknesses of CAO/ARO/AIO 94 were a median follow-up of only 46 months and no functional outcome data. We hope to see these data in a future update. Despite these weaknesses, CAO/ARO/AIO 94 remains the definitive trial in chemoradiotherapy for rectal cancer, and I continue to use it to guide treatment decisions. The NSABP R-03 trial, although it had shortcomings, produced some intriguing results. Patient numbers were small, but there were no recurrences in the 15% of patients who achieved pathologic complete response. These favorable results are consistent with other reports in the literature5,6 and may provide an alternative end point for assessing the efficacy of novel preoperative chemoradiotherapy regimens. However, because patients with rectal cancer who receive adjuvant chemoradiotherapy can develop late recurrences, a minimum follow-up of 7 years is necessary.7 Not all patients are appropriately treated with preoperative chemoradiotherapy, particularly those with pathologically negative pelvic nodes. In the German trial reported by Sauer et al,3 18% of patients who were considered to have cT3N0 disease and underwent initial surgery without preoperative therapy actually had pT1-2N0 disease. Those patients would have been overtreated had they received preoperative therapy. The subset of patients with cT3N0 disease were not reported in the NSAPB R-03 trial.4 However, for all patients who underwent surgery first, 4% had pT1-2N0 disease and would have therefore been overtreated had they received preoperative therapy. Although not ideal, administering preoperative therapy is still preferred to performing initial surgery, because even after preoperative chemoradiotherapy (which downstages tumors) 22% of patients will have lymph node–pathologically positive disease at time of surgery.8 In patients who undergo surgery alone, this number is as high as 40%. These patients will then require postoperative chemoradiotherapy, in which inferior local control, higher acute and chronic toxicity, and—when low anastomosis was performed—inferior functional results were demonstrated in the CAO/ARO/AIO 94 trial,3 compared with preoperative chemoradiotherapy. Clearly, the development of more accurate methods to identify lymph node-positive disease, including improved imaging techniques and molecular markers, is essential as more patients are treated with preoperative chemoradiotherapy. Other investigators advocate the selection of preoperative therapy on the basis of risk of a positive circumferential identified by high-resolution magnetic resonance imaging.9 High-resolution magnetic resonance imaging was not used in the CAO/ARO/AIO 94 and NSABP R-03 trials. The most pressing question is not whether preoperative therapy is preferred; rather, it is how to more accurately identify patients with positive nodes so they can be treated with preoperative chemoradiotherapy. Should the lack of an improvement in local control, sphincter preservation, and toxicity in the preoperative compared with the postoperative arm of the NSABP R-03 trial prompt us to reconsider the move to preoperative chemoradiotherapy? Absolutely not. Clearly, there is a need for better patient selection, improved imaging, and the testing of novel chemoradiotherapy programs. However, preoperative chemoradiotherapy remains the treatment of choice for cT3 and N+ rectal cancer. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
NOTES See accompanying article on page 5124 REFERENCES 1. Minsky BD, Cohen AM, Kemeny N, et al: Enhancement of radiation-induced downstaging of rectal cancer by fluorouracil and high-dose leucovorin chemotherapy. J Clin Oncol 10:79–84, 1992.[Medline] 2. Minsky BD, Cohen AM, Kemeny N, et al: Combined modality therapy of rectal cancer: Decreased acute toxicity with the preoperative approach. J Clin Oncol 10:1218–1224, 1992. 3. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731–1740, 2004. 4. Roh MS, Colangelo LH, O'Connell MJ, et al: Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 27:5124–5130, 2009. 5. Valentini V, Coco C, Picciocchi A, et al: Does downstaging predict improved outcome after preoperative chemoradiation for extraperitoneal locally advanced rectal cancer? A long-term analysis of 165 patients. Int J Radiat Oncol Biol Phys 53:664–674, 2002.[CrossRef][Medline] 6. Guillem JG, Chessin DB, Cohen AM, et al: Long-term oncologic outcome following preoperative combined modality therapy and total mesorectal excision of locally advanced rectal cancer. Ann Surg 241:829–836, 2005.[CrossRef][Medline] 7. 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. 8. Guillem JG, Díaz-González J, Minsky BD, et al: cT3N0 rectal cancer: Potential overtreatment with preoperative chemoradiotherapy is warranted. J Clin Oncol 26:368–373, 2008. 9. Sebag-Montefiore D, Stephens RJ, Steele R, et al: Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): A multicentre, randomised trial. Lancet 373:811–820, 2009.[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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grade 4 toxicity (33% v 23%), although the incidence of 
