Short-Term Radiotherapy with Preoperative Chemotherapy Followed by Surgery is Efficacious with Acceptable Toxicity in Locally Advanced Rectal Cancer

A randomised, phase III STELLAR study evaluated whether a total neoadjuvant therapy approach comprising hypofractionated radiation (5 Gy × 5) followed by chemotherapy is non-inferior to standard chemoradiotherapy (CRT) in patients with locally advanced rectal cancer. The study demonstrated non-inferiority for the primary endpoint, 3-year disease-free survival (DFS), in patients who received the total neoadjuvant therapy versus standard CRT. Although the compliance rate was high, total neoadjuvant therapy was associated with an approximately twofold rate of grade 3-plus toxicity compared with CRT. The findings provide additional evidence supporting the clinical practice of hypofractionated radiotherapy followed by neoadjuvant chemotherapy in this patient population according Dr. Jing Jin of the National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing and Shenzhen Hospital in Shenzhen, China and colleagues, who published the study findings on 9 March 2022 in the Journal of Clinical Oncology.

The authors wrote in the study background that long-course concurrent CRT followed by total mesorectal excision (TME) is a first-line treatment for locally advanced rectal cancer. However, only approximately 50% of patients finish adjuvant chemotherapy after CRT and surgery. Short-course radiotherapy (5 Gy in 5 fractions) followed by surgery is another treatment option for resectable rectal cancer. Given the potential advantage of total neoadjuvant therapy and limited clinical prospective data at time when the study was initiated, the study team believed that short-term radiotherapy could improve the treatment efficiency and save medical resources, as neoadjuvant chemotherapy had the advantage of high completion.

The study investigators designed this multicentre, randomised controlled study to compare short-term radiotherapy plus neoadjuvant chemotherapy with CRT followed by surgery and adjuvant chemotherapy in patients with local advanced rectal cancer. The authors hypothesised that short-course radiotherapy followed by neoadjuvant chemotherapy may not be inferior to standard CRT in locally advanced rectal cancer, even if the patients would undergo slightly more, but still acceptable toxicities. 

Patients with distal or middle-third, clinical primary tumour stage 3-4 and/or regional lymph node–positive rectal cancer were randomly assigned (1:1) to short-term radiotherapy (25 Gy in 5 fractions over 1 week) followed by 4 cycles of chemotherapy (total neoadjuvant therapy) or CRT (50 Gy in 25 fractions over 5 weeks, concurrently with capecitabine). TME was undertaken 6-8 weeks after preoperative treatment, with 2 additional cycles of CAPOX in the total neoadjuvant therapy group and 6 cycles of CAPOX in the CRT group. The primary endpoint was 3-year DFS.

Between August 2015 and August 2018, a total of 599 patients were randomly assigned to receive total neoadjuvant therapy (302 patients) or CRT (297 patients). At a median follow-up of 35 months, 3-year DFS was 64.5% and 62.3% in the total neoadjuvant therapy and CRT groups (hazard ratio 0.883; one-sided 95% confidence interval not applicable to 1.11; p < 0.001 for non-inferiority).

There was no significant difference in metastasis-free survival (MFS) or locoregional recurrence, but the total neoadjuvant therapy group had better 3-year overall survival (OS) than the CRT group (86.5% versus 75.1%; p = 0.033). Treatment effects on DFS and OS were similar regardless of prognostic factors.

The prevalence of acute grade 3-5 toxicities during preoperative treatment was 26.5% in the total neoadjuvant therapy group versus 12.6% in the CRT group (p < 0.001).

The authors concluded that in the STELLAR study, short-course radiotherapy with preoperative chemotherapy before TME was not inferior to standard preoperative CRT followed by postoperative chemotherapy with regard to DFS for patients with locally advanced rectal cancer. There was no significant difference in MFS or locoregional recurrence between treatment groups. Although a better 3-year OS rate was observed in the total neoadjuvant therapy group, there was no significant difference in OS upon subgroup analysis. Treatment strategy with total neoadjuvant therapy offered at least as favourable locoregional control and survival as CRT while preserving a high degree of tolerability and compliance. This finding provides additional evidence supporting the clinical practice of total neoadjuvant therapy in the modern era according to study team.

The study was supported by grants from the Chinese Academy of Medical Science Innovation Fund for Medical Sciences, National Key Projects of Research and Development of China, National Natural Science Foundation of China, Key Projects of Capital Health Development, Collaborative Innovation Centre for Cancer Medicine, Beijing Hope Run Special Fund of Cancer Foundation of China and Sanming Project of Medicine in Shenzhen.

Reference

Jin J, Tang Y, Hu C, et al. Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR). Journal of Clinical Oncology; Published Online 9 March 2022. DOI: 10.1200/JCO.21.01667

Source