In a multicenter Chinese randomized phase III trial published in the Journal of Clinical Oncology, Wang et al found that an intensified total neoadjuvant therapy approach integrating long-course radiotherapy with uninterrupted capecitabine and oxaliplatin chemotherapy improved disease-free survival compared with conventional neoadjuvant chemoradiotherapy in patients with high-risk locally advanced rectal cancer.
Study Details
The multicenter, open-label trial enrolled 458 patients between June 2017 and December 2023. Study participants had stage II or III rectal adenocarcinoma and at least one MRI-defined high-risk feature (47.82% of patients had cT4 disease, 75.98% cN2 disease, 70.96% threatened mesorectal fascia, and 54.80% extramural venous invasion).
Patients were randomly assigned 1:1 at nine Chinese institutions to receive either total neoadjuvant therapy integrating long-course radiotherapy with induction, concurrent, and consolidation capecitabine and oxaliplatin (doublet-LC TNT; 232 patients) (experimental regimen) or conventional neoadjuvant chemoradiotherapy with capecitabine and long-course radiotherapy followed by surgery and adjuvant chemotherapy (nCRT; 226 patients) (control group). The primary endpoint was disease-free survival.
Key Results
At a median follow-up of 51 months, 3-year disease-free survival was 74.8% with doublet-LC TNT compared with 66.0% for conventional neoadjuvant chemoradiotherapy (hazard ratio [HR] = 0.674, 95% confidence interval [CI] = 0.489–0.929, P = .016). Three-year metastasis-free survival also favored the experimental arm (77.7% vs 67.6%, HR = 0.655, 95% CI = 0.469–0.915, P = .013). Overall survival at 3 years was numerically higher with doublet-LC TNT (90.2% vs 87.5%, HR = 0.727, P = .167), and locoregional failure was similar between groups (6.03% vs 6.19%).
The experimental regimen also produced greater tumor regression. Among patients who underwent surgery, the pathologic complete response rate was 26.37% with doublet-LC TNT compared with 9.80% with neoadjuvant chemoradiotherapy (P < .001). Favorable tumor regression (TRG 0–1) occurred in 49.25% vs 28.92% of patients, and ypN0 status was achieved in 81.09% vs 69.12%, respectively.
Grade ≥ 3 adverse events during neoadjuvant therapy were more frequent with doublet-LC TNT (27.59% vs 8.56%), but the incidence of severe adverse events across the entire treatment course was comparable (28.02% vs 24.32%), as were major postoperative complications. Thrombocytopenia was the most common grade ≥ 3 adverse event during neoadjuvant doublet-LC TNT and during adjuvant chemotherapy in the nCRT group.
The investigators noted that longer follow-up is needed to assess long-term outcomes and that the conventional neoadjuvant chemoradiotherapy control arm, given the trial’s long accrual period, reflects an earlier treatment paradigm than current practice.
The investigators concluded: “Compared with conventional [neoadjuvant chemoradiotherapy], doublet-LC TNT improved [disease-free survival], [metastasis-free survival], and [pathologic complete response] rates with manageable toxicity. These findings support this intensified, doublet-based regimen as a standard option within the modern total neoadjuvant therapy paradigm. Further comparative studies are warranted to evaluate these results against other short-course radiotherapy‑based or non-doublet-concurrent TNT regimens.”
Ziqiang Wang, MD, PhD, of Colorectal Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China, is the corresponding author for the Journal of Clinical Oncology article.
DISCLOSURE: The study was supported by Sichuan Science and Technology Support Project. For full disclosures of the study authors, visit ascopubs.org.
