Neoadjuvant chemotherapy is noninferior to chemoradiotherapy for early-onset locally advanced rectal cancer in the FOWARC trial

The early-onset rectal cancer with rapidly increasing incidence is considered to have distinct clinicopathological and molecular profiles with high-risk features. This leads to challenges in developing specific treatment strategies for early-onset rectal cancer patients and questions of whether early-onset locally advanced rectal cancer (LARC) needs aggressive neoadjuvant treatment.

In this post hoc analysis of FOWARC trial, we investigated the role of preoperative radiation in early-onset LARC by comparing the clinicopathological profiles and short-term and long-term outcomes between the early-onset and late-onset LARCs.

We revealed an inter-tumor heterogeneity of clinical profiles and treatment outcomes between the early-onset and late-onset LARCs. The high-risk features were more prevalent in early-onset LARC. The neoadjuvant radiation brought less benefits of tumor response and more risk of complications in early-onset group (pCR: OR = 3.75, 95% CI = 1.37–10.27; complications: HR = 11.35, 95% CI = 1.46–88.31) compared with late-onset group (pCR: OR = 5.33, 95% CI = 1.83–15.58; complications: HR = 5.80, 95% CI = 2.32–14.49). Furthermore, the addition of radiation to neoadjuvant chemotherapy didn’t improve long-term OS (HR = 1.37, 95% CI = 0.49–3.87) and DFS (HR = 1.05, 95% CI = 0.58–1.90) for early-onset patients.

Preoperative radiation plus chemotherapy may not be superior to the chemotherapy alone in the early-onset LARC. Our findings provide insight into the treatment of early-onset LARC by interrogating the aggressive treatment and alternative regimens.