Preoperative Short-Term Radiotherapy Followed by Chemotherapy vs Standard Schedule of Long-Term Chemoradiotherapy for the Treatment of Locally Advanced Rectal Cancer
For locally advanced rectal cancer, the best neoadjuvant treatment strategy has yet to be determined. One first-line treatment option is long-course, concurrent chemoradiotherapy (CRT) before total mesorectal excision. However, after surgery, adjuvant chemotherapy is controversial because it is poorly tolerated and compliance with therapy is low; roughly half of patients typically complete adjuvant chemotherapy after chemoradiotherapy and surgery.
When rectal cancer is resectable, another treatment option is total neoadjuvant therapy (TNT), or short-course, hypofractionated radiotherapy consisting of 5Gy given in 5 fractions, followed by chemotherapy. To determine whether this treatment strategy is noninferior to standard long-term chemoradiotherapy in these patients, researchers in China conducted a multicenter, randomized, Phase III trial known as the STELLAR study (JCO. 2022; doi:10.1200/JCO.21.01667).
This trial enrolled 599 patients with distal or middle-third rectal cancers that were either stage 3 or 4 or regional lymph node positive. Between August 2015 and August 2018, patients were randomly assigned in a 1:1 ratio to receive short-term radiotherapy followed by 4 cycles of chemotherapy (TNT) or to chemoradiotherapy consisting of 50 Gy given in 25 fractions during 5 weeks concurrently with capecitabine (CRT). Six to eight weeks after preoperative treatment, patients had total mesorectal excision and, for the TNT group (n=302), 2 additional cycles of CAPOX, consisting of capecitabine, 1,000 mg/m2 twice daily from Days 1 to 14, and IV oxaliplatin, 130 mg/m2 once daily on Day 1, or, for the CRT group (n=297), 6 cycles of CAPOX. The study’s primary endpoint was 3‑year disease-free survival (DFS).
As a result, after a median follow-up or 35 months, 3-year DFS was 64.5% in the TNT group and 62.3% in the CRT group (hazard ratio, 0.9; one-sided 95% confidence interval, not applicable to 1.1; P<0.001 for noninferiority). “This finding provides additional evidence supporting the clinical practice of hypofractionated radiotherapy followed by neoadjuvant chemotherapy for locally advanced rectal cancer,” wrote Jing Jin, MD, Department of Radiation Oncology, National Cancer Center, Beijing, China, and colleagues.
Although no significant difference was found between the groups in metastasis-free survival or locoregional recurrence, 3-year overall survival (OS) was better in the TNT group (86.5%) than in the CRT group (75.1%) (P=0.033). Moreover, prognostic factors had no impact on the effects of treatment on DFS and OS. However, Dr Jin and colleagues noted that “Although a better 3-year OS rate was observed in the TNT group, there was no significant difference in OS upon subgroup analysis.”
“In conclusion, despite the higher acute toxicity, sequential neoadjuvant short-course radiotherapy and chemotherapy could be used as an alternative to CRT and adjuvant chemotherapy for patients with middle and low LARC [locally advanced rectal cancer],” Dr Jin and team wrote.
However, during preoperative treatment, the rate of acute, Grade III to V toxicities in the TNT group was nearly twice that in the CRT group; in the TNT group, the rate was 26.5%, and in the CRT group, it was 12.6% (P<0.001).
