Long-Course Radiotherapy Versus Concurrent Chemoradiotherapy for Rectal Cancer: Phase 3 TNTCRT Trial Results

A recent phase 3 trial presented at the 2024 American Society of Clinical Oncology Annual Meeting demonstrated promising results for patients with high-risk locally advanced rectal cancer (LARC). The study, conducted across multiple centers, compared the efficacy of total neoadjuvant treatment (TNT) using long-course radiotherapy (LCRT) combined with CAPOX against the standard concurrent neoadjuvant chemoradiotherapy (NCRT) with long-course radiotherapy and capecitabine followed by surgery and adjuvant CAPOX.

LARC remains a significant challenge due to the high risk of distant metastases even after neoadjuvant chemoradiotherapy and surgery. Previous studies have shown survival benefits with TNT using short-course radiotherapy combined with CAPOX and LCRT with mFOLFIRINOX. This trial aimed to explore the benefits of TNT using LCRT combined with CAPOX in patients with high-risk LARC.

The trial enrolled patients diagnosed with stage II/III LARC who possessed at least 1 high-risk factor, including cT4a-b (resectable), cT3c-d with extramural venous invasion, or cN2 and involved mesorectal fascia or enlarged lateral lymph nodes. A total of 458 patients were randomly assigned to 2 groups: arm A (TNT) received LCRT with 6 cycles of neoadjuvant CAPOX (1 cycle of induction CAPOX, 2 cycles of concurrent CAPOX, and 3 cycles of consolidation CAPOX) followed by total mesorectal excision (TME). Arm B (NCRT) received LCRT with concomitant capecitabine, followed by TME and adjuvant CAPOX.

Radiotherapy was administered at 50.0-50.4 Gy in 25-28 fractions in both arms. The primary end point was disease-free survival (DFS), while pathological complete response (pCR) rate, overall survival (OS), metastasis-free survival (MFS), and postoperative 30-day morbidity were the secondary end points.

After a median follow-up of 44 months, the study revealed several key findings. The 3-year DFS was significantly higher in arm A at 77.0% than the 67.9% in arm B (hazard ratio [HR], 0.623; 95% CI, 0.435-0.892; P=.009). The 3-year MFS was also significantly higher in arm A at 83.0% versus 74.2% in arm B (HR, 0.595; 95% CI, 0.392-0.903; P=.013). There were 56 OS events reported, with the 3-year OS at 90.3% in arm A and 87.9% in arm B (HR, 0.747; 95% CI, 0.441-1.266; P=.276).

The study also noted a significant improvement in pCR in arm A, with 27.5% achieving pCR compared with 9.9% in arm B (odds ratio, 3.436; 95% CI, 1.941-6.084; P=.0001). Additionally, clinical complete response was achieved by 13 patients in arm A and 2 in arm B, who subsequently adopted a watch-and-wait strategy.

Both treatment regimens were well tolerated. Thrombocytopenia was the most frequent grade 3-4 hematological adverse event in arm A, occurring in 10.3% of patients. There was no significant difference in severe morbidity within 30 days postoperation between the 2 arms.

The TNT approach using LCRT combined with CAPOX significantly improved DFS, MFS, and pCR rates compared with standard concurrent neoadjuvant chemoradiotherapy in patients with high-risk LARC. These findings suggest that TNT with LCRT and CAPOX could be a more effective treatment strategy, offering improved outcomes with acceptable levels of toxicity.