Tumor regression grading after preoperative hyperfractionated radiotherapy/ chemoradiotherapy for locally advanced rectal cancers: interim analysis of phase III clinical study

Abstract

We investigated the tumor regression grading (TRG) as a prognostic marker for disease-free survival (DFS) in patients with advanced rectal cancer treated within phase III randomized study (ClinicalTrials.gov Identifier: NCT01814969). The study is still recruiting prospective trial of preoperative hyperfractionated radiotherapy (HART) compared with concomitant hyperfractionated radiotherapy with co-administration of chemotherapy based on 5-FU (HART-CT) in patients with T2/N+ or T3/any N resectable rectal cancer. This preplanned interim analysis examined the pathological outcome in the group of 136 patients who were randomly assigned to HART (n=69) and HART-CT (n=67). The pelvis was irradiated twice a day (28 fractions of 1.5 Gy), with a minimal interfraction interval of 8 h to a total dose of 42 Gy over 18 days (HART) or mentioned scheme with concurrent chemotherapy: 5-FU 325 mg/m2 (bolus) on days 1-3 and days 16-18 (HART-CT). Surgery was performed 6-7 weeks after HART/HART-CT. Postoperative 5-FU-based chemotherapy was given to ypN positive patients. The TRG was recorded using the following 4-point scale: TRG0 (pCR) denoted no cancer cells; TRG1 was diagnosed when a few cancer foci had been seen in less than 10% of a tumor mass; TRG2 denoted cancer cells seen in 10-50% of a tumor mass; in order to diagnose TRG3, cancer cells had to be seen in more than 50% of a tumor mass. Multivariable analysis was performed using Cox regression models and Cox proportional hazard model was used in the survival analysis. The crude rate of patients with any serious acute 3 toxicity during the follow-up was 16% vs. 25% for HART and HART-CT. Twenty-two patients (16%) presented with postoperative complications. Anterior resection was performed in 52% vs. 62% for HART and HART-CT respectively (p=0.06). Of the 136 patients evaluable for pathologic response, there were 3 (4%) vs. 9 (13%), 16 (23%) vs. 24 (36%), 40 (58%) vs. 30 (45%), and 10 (15%) vs. 4 (6%) patients with TRG 0, 1, 2, and 3, respectively in HART vs. HART-CT, the difference was statistically significant p=0.002. The addition of 5-FU infusion to HART was not associated with statistically significant improved loco-regional relapse-free survival (LRC), metastasis-free survival (MFS), and DFS. Significant differences in the tumor regression grading (TRG) were found. Both LRC and DFS of rectal cancer patients treated with HART vs. HART-CT had favorable outcomes in the HART-CT arm. Also, the sphincter preservation rate tended to favor HART-CT.