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.

Trial registration: ClinicalTrials.gov NCT02533271.

FIG 1.

CONSORT diagram. TNT group: short-term radiotherapy (5 Gy × 5) followed by four cycles of CAPOX, surgery, and two cycles of CAPOX. CRT group: 50 Gy in 25 fractions over 5 weeks concurrently with capecitabine followed by surgery and six cycles of CAPOX. Disease progression included any locoregional progression, recurrence or regrowth, and/or distant metastases. CRT, chemoradiotherapy; ITT, intention-to-treat; NOM, nonoperative management; TNT, total neoadjuvant therapy.

FIG 2.

Kaplan-Meier curves of (A) DFS, (B) OS, (C) MFS, and (D) LRR in patients with LARC. TNT group: short-term radiotherapy (5 Gy × 5) followed by four cycles of CAPOX, surgery, and two cycles of CAPOX. CRT group: 50 Gy in 25 fractions over 5 weeks concurrently with capecitabine followed by surgery and six cycles of CAPOX. CRT, chemoradiotherapy; DFS, disease-free survival; HR, hazard ratio; ITT, intention-to-treat; LARC, locally advanced rectal cancer; LRR, locoregional recurrence; MFS, metastasis-free survival; OS, overall survival; TNT, total neoadjuvant therapy.

FIG 3.

HRs for DFS and OS of TNT versus CRT in subgroup analysis. TNT group: short-term radiotherapy (5 Gy × 5) followed by four cycles of CAPOX, surgery, and two cycles of CAPOX. CRT group: 50 Gy in 25 fractions over 5 weeks concurrently with capecitabine followed by surgery and six cycles of CAPOX. c, clinical; CRT, chemoradiotherapy; DFS, disease-free survival; ECOG, Eastern Cooperative Oncology Group; EMVI, extramural vascular venous invasion; HR, hazard ratio; MRF, mesorectal fascia; MRI, magnetic resonance imaging; N, regional lymph node; OS, overall survival; T, primary tumor; TNT, total neoadjuvant therapy.