Long-Term Follow-Up of a Paradigm-Changing Study: The Paradigm Still Holds

By 1990, when a National Institutes of Health Consensus Conference was recommending postoperative chemotherapy and radiation for locally advanced rectal cancer, many oncologists were already thinking ahead and favoring preoperative chemoradiotherapy. Perceived advantages included a higher likelihood of achieving a resection with negative margins (ie, an R0 resection), a higher rate of sphincter preservation, a reduction in toxicity, particularly enteritis, and higher compliance, given that the ability to deliver treatment is not contingent on recovery from surgery. However, there were also reasons to be cautious about neoadjuvant therapy, including the fact that clinical staging is less accurate than pathologic staging, concern that tumor progression during neoadjuvant therapy would result in losing the window of opportunity for curative resection, and the possibility of increased postoperative complications such as impaired wound healing or anastomotic leaks when operating on radiated tissue. Several retrospective and single-arm prospective studies suggested that neoadjuvant chemoradiotherapy was a viable alternative to adjuvant therapy, but these were limited by small numbers and the potential for selection bias that is inherent to nonrandomized trials. The need for a prospective, randomized comparison of preoperative versus postoperative chemoradiotherapy for rectal cancer was clearly recognized, and the US Cooperative Groups accepted the challenge. The Radiation Therapy Oncology Group trial RTOG 94-01 was a prospective comparison of preoperative versus postoperative chemoradiotherapy, but it closed after accruing only 53 of the intended 770 patients. National Surgical Adjuvant Breast and Bowel Project (NSABP) trial R-03 also closed early because of poor accrual, but did accrue 267 of a planned 900 patients, enough to report the results, albeit without the intended power. Findings included improved disease-free survival and a suggestion of improved overall survival (OS) with preoperative therapy, but no difference in local control. The very small number of events, however, may have limited the ability to analyze local failures accurately. Although the two American trials fell short of their accrual goals, the German Rectal Cancer Study Group succeeded in completing a similarly designed trial, which was largely responsible for a paradigm shift, establishing preoperative chemoradiotherapy as a standard of care for locally advanced rectal cancer. Key findings from this study included a decrease in local failures from 13% to 6%, an improvement in sphincter preservation from 20% to 39% in patients for whom a surgeon anticipated the need for an abdominoperineal resection, and decreased acute and late toxicities, all of which favored preoperative therapy. A limitation of the preoperative approach was that clinical staging, which was based on ultrasound and computed tomography, resulted in significant overstaging, given that 18% of the patients who were randomly assigned to undergo initial surgery were found to have T1-2 N0 tumors, although their eligibility for the study was predicated on preoperative staging that suggested T3 or node-positive disease. OS was the same in both arms, which suggested that concerns about losing the opportunity to perform curative resection as a result of delaying surgery were not borne out. Similarly, there was no increase in postoperative complications in patients who received preoperative radiation. Virtually all clinical trials for locally advanced rectal cancer that have been developed since the publication of this trial have focused on preoperative rather than postoperative chemoradiotherapy, or on short-course preoperative radiation, as reported by Swedish and Dutch investigators. In the article that accompanies this editorial, the German Rectal Cancer Study Group provides 10-year outcomes for the patients in the original 2004 publication. In general, the original findings have been confirmed. Preoperative and postoperative chemoradiotherapy resulted in equivalent OS (60%) and disease-free survival (68%) at 10 years. As in the original publication, there was a statistically significant improvement in the rate of local control with preoperative therapy, although the absolute difference was somewhat smaller with longer follow-up. Beyond confirming the original findings, what is the value of long-term follow-up of a paradigm-changing study? What does this study tell us about the treatment of rectal cancer specifically, and can these lessons be applied to other cancers in general? A consideration that supports extended follow-up is that for data to be considered mature, the length of follow-up should be commensurate with the natural history of the disease. As demonstrated in other studies, including a pooled analysis of multiple intergroup adjuvant rectal trials, failures beyond 5 years are not uncommon in patients with locally advanced rectal cancer. The current report similarly found that 12% of local recurrences (seven of 60) and 7.5% of distant metastases (17 of 226) occurred beyond 5 years. Longer follow-up also provides more complete data, allowing for hypothesis-generating subgroup analyses. An example is the analysis of low-lying tumors, for which local recurrence at 10 years was 21% to 23% with postoperative treatment, compared with 6% to 12% in patients who were treated preoperatively, a much larger difference than for the population as a whole. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 16 JUNE 1 2012