Enter STELLAR.

Top Line: Is total neoadjuvant therapy with short-course radiation non-inferior than standard chemoradiation and adjuvant chemotherapy?

Top Line: If you thought to yourself, “Didn’t RAPIDO address that question,” you’d be right. But here we get another look with the STELLAR trial. STELLAR was a phase 3 non-inferiority trial performed at multiple Chinese centers where 599 patients with cT3-4 and/or N+ adenocarcinoma of the mid to distal rectum staged with MRI were enrolled. Patients were randomized to standard neoadjuvant chemoradiation (CRT) or total neoadjuvant therapy (TNT) consisting of short-course RT followed by 4 cycles of CAPOX. CRT consisted of 50Gy in 25 fractions with concurrent capecitabine while short-course RT consisted of 25Gy in 5 fractions. Patients in both arms were treated with IMRT to the same RTOG consensus target volumes. After surgery, patients in the standard arm received 6 cycles of adjuvant CAPOX while those in the TNT arm received an additional 2 cycles of adjuvant CAPOX. So, in total, both treatment arms received a total of 6 cycles CAPOX.  Let’s skip to the primary outcome. At 3 years, disease-free survival was non-inferior (and not superior) with TNT (64.5% v 62.3%), and there were no differences in the rates of metastasis free survival (77.1% v 75.3%) or locoregional recurrence (8.4% v 11%). Despite these similarities, TNT was associated with a significant improvement in 3-year OS (86.5% v 75.1%). So, what differences were there? More patients in the CRT arm completed all planned neoadjuvant therapy (82.6% v 95.2%), and fewer experienced grade 3+ toxicity prior to surgery (12.6% v 26.5%). More patients in the TNT arm had a clinical complete response (cCR, 11.1% v 4.4%), and 9.4% and 3.4%, respectively, pursued a watch-and-wait approach. Among these, the rate of tumor regrowth was 7.1% in the TNT arm and 10% in the standard arm. The R0 resection rate was similar between arms, but the pCR rate was significantly higher after TNT (21.8% v 12.3%). A  substantial proportion of patients in both arms did not receive adjuvant therapy (23% TNT, 26.1% standard). Furthermore, more patients in the TNT arm completed adjuvant therapy (60% v 48.3%), and the rate of grade 3+ toxicity was higher after surgery in the standard arm (11.8% v 3.3%).

TBL: The STELLAR trial found that disease-free survival with short-course RT and total neoadjuvant therapy was non-inferior to neoadjuvant chemoradiation. The overall survival difference will likely need longer follow-up and a signal it was driven by differences in disease outcomes. | Jin, J Clin Oncol 2022