Long-Term Results of a Randomized Trial in Locally Advanced Rectal Cancer: No Benefit From Adding a Brachytherapy Boost

Abstract

Purpose/Objective(s) Mature data on tumor control and survival are presented from a randomized trial of the addition of a brachytherapy boost to long-course neoadjuvant chemoradiation (CRT) for locally advanced rectal cancer. Methods and Materials Between March 2005 and November 2008, 248 patients withT3-4N0-2M0 rectal cancer were prospectively randomized to either long-course preoperative CRT (50.4Gy in 28 fractions, peroral UFT and L-leucovorin) alone or the same CRT schedule plus a brachytherapy boost (10Gy in 2 fractions). Primary trial endpoint was pathological complete response (pCR) at time of surgery; secondary endpoints included overall survival (OS), progression-free survival (PFS) and freedom from locoregional failure. Results Results for the primary endpoint have previously been reported. This analysis presents survival data for the 224 patients in the Danish part of the trial. 221 patients (111 control arm, 110 brachytherapy boost arm) had data available for analysis, with a median follow-up of 5.4 years. Despite a significant increase in tumor response at the time of surgery, no differences in 5-year OS (70.6% vs 63.6%, HR=1.24, p=0.34) and PFS (63.9% vs 52.0%, HR=1.22, p=0.32) were observed. Freedom from locoregional failure at 5 years were 93.9% and 85.7% (HR=2.60, 1.00–6.73, p=0.06) in the standard and in the brachytherapy arm, respectively. There was no difference in the prevalence of stoma. Explorative analysis based on stratification for tumor regression grade and resection margin status indicated the presence of response migration. Conclusions Despite increased pathological tumor regression at the time of surgery, we observed no benefit on late outcome. Improved tumor regression does not necessarily lead to a relevant clinical benefit when the neoadjuvant treatment is followed by high-quality surgery.

What is most relevant in preoperative rectal cancer chemoradiotherapy – the chemotherapy, the radiation dose or the timing to surgery?

“…The primary endpoint, pCR rates did not differ (18% in both) but more tumor regressions were seen [26]. In spite of this, again no differences in other outcomes were seen [27]. These results do not exclude that a dose-response relationship is seen also for other and more relevant outcomes than immediate tumor regression.…”

Session 4: Shaping radiotherapy for rectal cancer: should this be personalized?

“…These findings are in contrast to the much larger Danish study which randomized clinically staged T3/T4 rectal cancer patients to either neoadjuvant long‐course CRT alone or the same schedule but with a brachytherapy boost (10 Gy × 2), followed by surgery in both groups. Although there was evidence of tumour regression with brachytherapy boost, the study failed to demonstrate a difference in the ypT0N0 rate or an improvement in local recurrence or survival . The same group have recently reported that in patients with a ‘bad’ low rectal cancer, treatment with high‐dose neoadjuvant CRT and a 5 Gy brachytherapy boost allowed a successful watch‐and‐wait strategy in 78% of patients but with a cumulative local recurrence of 26% at 2 years .…”

The Impact of Novel Radiation Treatment Techniques on Toxicity and Clinical Outcomes in Rectal Cancer

“…Brachytherapy has also been used as a boost to long-course neoadjuvant chemoradiation in order to achieve dose-escalation in several studies (75-78). Gerard et al was the first to determine if contact therapy as a boost to EBRT could increase the pCR and the sphincter-preservation rate.…”

“…After a median follow of 5.4 years, there was no difference in OS, PFS and freedom from local failure between the 2 groups. The authors concluded that despite an improvement in pCR, the addition of endorectal brachytherapy did not translate into an improvement in OS, PFS and locoregional control (75). …”