PREOPERATIVE CHEMORADIOTHERAPY DECREASES ONLY LOCAL RELAPSE 

May 4, 2012 — Preoperative chemoradiotherapy (CRT) is the standard treatment for locally advanced rectal cancer. This strategy appears to be superior to postoperative CRT in terms of patient compliance, toxicity, downstaging, and sphincter preservation.

However, German researchers have found that there is no survival benefit with preoperative CRT over the long term. The updated long-term results of a previous trial show that at 10 years, preoperative and postoperative CRT resulted in equivalent overall survival (59.5% vs 59.9%; P = .85), according to Rolf Sauer, MD, from the University of Erlangen, Germany, and colleagues.

Disease-free survival was also similar for the preoperative and postoperative groups (68.5% vs 67.5%; P = .54).

However, there was a statistically significant improvement in the rate of local control with preoperative CRT, which confirms the previous findings.

The long-term updated results were published online April 23 in the Journal of Clinical Oncology.

Paradigm Shift

The previous study, from the German Rectal Cancer Study Group (N Engl J Med. 2004;351:1731-1740), was largely responsible for establishing preoperative CRT as the standard of care for locally advanced rectal cancer, notes Harvey J. Mamon, MD, PhD, from the Dana-Farber Cancer Institute, Boston, Massachusetts, in anaccompanying editorial.

In the previous study, there was a decrease in local failures from 13% to 6%, an improvement in sphincter preservation from 20% to 39% in patients in whom the need for an abdominoperineal resection was anticipated, and a lower rate of both acute and late toxicities, writes Dr. Mamon.

With the long-term results, the original findings were confirmed. There is value in having this long-term follow-up, according to Dr. Mamon. The data are now mature, and follow-up should be commensurate with the natural history of the disease. In locally advanced rectal cancer, it is not uncommon for patients to have failure beyond 5 years.

Another reason that long-term follow-up is important is that the later results do not always confirm initial findings, he writes.

These long-term results confirm "that a standard of care for locally advanced rectal cancer remains neoadjuvant chemoradiotherapy, followed by total mesorectal excision and adjuvant chemotherapy," Dr. Mamon explains.

Even though the general approach of neoadjuvant combined-modality therapy has been validated, "there is still much room for additional improvement in the treatment of rectal cancer," he notes.

"One future objective would be to modify the neoadjuvant approach by applying less intensive treatment regimens, with the aim of improving quality of life in carefully selected patients for whom this can be accomplished without compromising local control or survival," he writes.

Dr. Mamon adds that these updated results might have "implications for combined-modality therapy of other malignancies, both within and outside of the GI tract."

Reduction in Local Recurrence

The original trial randomized 823 patients with stage II to III rectal cancer to preoperative CRT with fluorouracil (FU), total mesorectal excision surgery, and adjuvant FU chemotherapy, or to the same schedule of CRT but initiated postoperatively.

When the 5-year results were reported in 2004 (median follow-up, 46 months), there was no difference in overall survival in the 2 study groups, note the authors.

As of December 2010, there were 450 surviving patients who had been followed for a median of 134 months (range, 90 to 184 months). Of this group, 100% were followed for at least 5 years, 98% for at least 8 years, and 71% for at least 10 years.

Of the 341 deaths during the follow-up period, 223 were associated with rectal cancer.

The hazard ratio (HR) for death with preoperative CRT, compared with postoperative CRT, was 0.98 (95% confidence interval, 0.79 to 1.21).

Local recurrences after macroscopically complete resection of the primary rectal cancer occurred in 23 of the 397 patients (5.79%) randomly assigned to preoperative CRT and in 37 of the 393 patients (9.41%) randomly assigned to postoperative CRT.

The cumulative incidence of local recurrence at 5 and 10 years in the intention-to-treat population was 5.0% and 7.1%, respectively, in the preoperative CRT group and 9.7% and 10.1%, respectively, in the postoperative group (HR, 0.60; P = .048).

There was no significant difference between the preoperative and postoperative groups in the 10-year cumulative incidence of distant metastases in the intention-to-treat population (29.8% vs 29.6%; P = .9). A total of 17 of 226 (7.6%) distant metastases occurred beyond 5 years of follow-up — 9 (7.8%) in the preoperative group and 8 (7.2%) in the postoperative group.

The researchers also conducted an exploratory nonprotocol-specified subgroup analysis to identify factors associated with the risk of developing local recurrences after macroscopically complete resection of the primary tumor. On multivariate Cox regression analysis, they found that incomplete local resection and receiving no CRT were significantly associated with a higher risk for local recurrence.

An increased hazard ratio was confirmed for patients with stage III or IV disease and for those who had surgery that included intersphincteric or abdominoperineal resection.

New Data in the Works

"Any improvement in overall survival rates will require better control of systemic disease," the researchers conclude. "Integrating more effective systemic therapy into multimodal therapy has been the challenge."

A phase 3 trial by the same group has completed accrual, with more than 1250 patients recruited. It will study the addition of oxaliplatin to preoperative CRT and postoperative chemotherapy.

The initial results of that study have been presented (J Clin Oncol. 2011;29[15 Suppl]:LBA3505)(J Clin Oncol. 2011;29[15 Suppl]:LBA3505), the researchers explain, and indicate that the addition of oxaliplatin to preoperative FU-CRT is well tolerated and associated with increased pathologic complete response rates. The primary end point of this study is disease-free survival. Results "on this primary end point will be available in late 2013," they researchers report.

The study was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe e.V). Coauthor Claus Rödel, MD, from the University of Frankfurt, Germany, reports receiving honoraria from sanofi-aventis and Roche, and research funding from Roche.

J Clin Oncol. Published online April 23, 2012. Abstract, Editorial