Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR)

Abstract

PURPOSE To ascertain if preoperative short-term radiotherapy followed by chemotherapy is not inferior to a standard schedule of long-term chemoradiotherapy in patients with locally advanced rectal cancer. MATERIALS AND METHODS Patients with distal or middle-third, clinical primary tumor stage 3-4 and/or regional lymph node–positive rectal cancer were randomly assigned (1:1) to short-term radiotherapy (25 Gy in five fractions over 1 week) followed by four cycles of chemotherapy (total neoadjuvant therapy [TNT]) or chemoradiotherapy (50 Gy in 25 fractions over 5 weeks, concurrently with capecitabine [chemoradiotherapy; CRT]). Total mesorectal excision was undertaken 6-8 weeks after preoperative treatment, with two additional cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) in the TNT group and six cycles of CAPOX in the CRT group. The primary end point was 3-year disease-free survival (DFS). RESULTS Between August 2015 and August 2018, a total of 599 patients were randomly assigned to receive TNT (n = 302) or CRT (n = 297). At a median follow-up of 35.0 months, 3-year DFS was 64.5% and 62.3% in TNT and CRT groups, respectively (hazard ratio, 0.883; one-sided 95% CI, not applicable to 1.11; P < .001 for noninferiority). There was no significant difference in metastasis-free survival or locoregional recurrence, but the TNT group had better 3-year overall survival than the CRT group (86.5% v 75.1%; P = .033). Treatment effects on DFS and overall survival were similar regardless of prognostic factors. The prevalence of acute grade III-V toxicities during preoperative treatment was 26.5% in the TNT group versus 12.6% in the CRT group ( P < .001). CONCLUSION Short-term radiotherapy with preoperative chemotherapy followed by surgery was efficacious with acceptable toxicity and could be used as an alternative to CRT for locally advanced rectal cancer.

Association of neutrophil-to-lymphocyte ratio, radiotherapy fractionation/technique, and risk of development of distant metastasis among patients with locally advanced rectal cancer

“…The randomized Swedish trial, Stockholm III trial, which tested “SCRT followed by delayed surgery,” showed that the downstaging effects of SCRT were similar to those of LCRT [ 25 ]. Furthermore, several recent trials, such as the Radiotherapy And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) and the Short Term radiotherapy followed by chEmotherapy versus Long-term chemoradiotherapy in Locally Advanced Rectal cancer (STELLAR) trial which integrated SCRT into TNT strategy, showed outcomes that were promising or at least comparable with those of standard LCRT [ 24 , 26 ]. These studies demonstrated that when the time interval between SCRT and surgery is delayed, SCRT seems to have outcomes comparable with LCRT.…”

Total Neoadjuvant Therapy for Rectal Cancer in the CAO/ARO/AIO-12 Randomized Phase 2 Trial: Early Surrogate Endpoints Revisited

“…In the RAPIDO trial, higher pCR rates translated to improved DFS and lower incidence of distant metastasis [ 10 ]. In the PRODIGE-23 trial, pCR, TRG 4 and low-risk NAR score in the TNT arm correlated with improved DFS, whereas in the STELLAR trial, improved pCR was not associated with better DFS [ 12 , 13 ] ( Table 4 ).…”

“…Unlike pCR, TRG and the NAR score classifies tumor response more gradually beyond a simple binary system that may reflect treatment efficacy better and may have a greater ability than pCR to predict DFS or OS, as proposed by Yothers et al [ 4 , 35 ]. Even if the surrogacy of TRG and NAR for improved DFS has been validated in the CAO/ARO/AIO-04 trial [ 16 , 17 ] and a significant trend to higher tumor regression and low NAR score correlated with improved DFS and lower incidence of distant metastasis in the PRODIGE-23 trial [ 12 ], potential surrogacy of both parameters has not been broadly reported in recent trials ( Table 4 ) [ 10 , 13 , 14 ]. Furthermore, assessment and reporting of TRG is heterogeneous, and no universally approved standardization method is accepted [ 4 , 36 ].…”

“…The value of additional adjuvant chemotherapy (CT) after neoadjuvant therapy and total mesorectal excision (TME) surgery remains unclear for DFS and OS, and the addition of oxaliplatin to neoadjuvant CRT provided inconsistent results [ 5 , 6 , 7 , 8 , 9 ]. More recently, total neoadjuvant treatment (TNT), e.g., SCRT/CRT with either induction or consolidation CT, showed improved distant metastasis-free and disease-free survival (DFS) [ 10 , 11 , 12 , 13 ]. Furthermore, compared to classical SCRT/CRT, TNT can enhance clinical and pathological complete response (c/pCR) rates to explore organ preservation [ 14 ].…”

Reply to O. Sütcüoğlu et al, F. Negri et al, and B.C. Yüksel

“…In the STELLAR study, 4 the 3-year cumulative incidence of locoregional recurrence of 8.4%-11.0% and 3-year DFS of 62.3%-64.5% were reasonable because of the inclusion of more patients with adverse clinical factors, such as middle low location only, more positive EMVI (47.9%), and MRF (56.3%). The STELLAR and Polish II trials only included patients with middle low rectal cancer, 4,6 whereas the RAPIDO and PRODIGE trials included patients with all sites of rectal cancer, with upper rectal cancer of 33% and 13%. 5,7 Moreover, approximately half patients (49.2%) in the STELLAR study had disease localized in low rectal cancer, which were slightly lower than 55.5% in the Polish II trial, but significantly higher than 23.9% in the RAPIDO trial and 36.9% in the PRODIGE trial, leading to a large proportion of our patients (43.2%) treated with abdominoperineal resection.…”