Early Age of Onset Is an Independent Predictor for a Worse Response to Neoadjuvant Therapies in Sporadic Rectal Cancer Patients

Abstract

The incidence of rectal cancer (RC) is increasing in the population aged ≤ 49 (early-onset RC-EORC). EORC patients are more likely to present with locally advanced disease at diagnosis than late-onset RC (LORC; aged ≥ 50) patients. As a consequence, more EORC patients undergo neoadjuvant therapies. The response to treatment in EORC patients is still unknown. This study aims to explore the effect of age of onset on the pathological response to neoadjuvant therapies in sporadic locally advanced RC (LARC) patients. Based on an institutional prospectively maintained database, LARC patients undergoing neoadjuvant therapies and radical surgery between January 2010 and December 2022 were allocated to the EORC and LORC groups. The primary endpoint was the rate of incomplete response (Dworak 0–2). A total of 326 LORC and 79 EORC patients were included. Pre-neoadjuvant tumor features were comparable. A significantly higher rate of incomplete response was observed in EORC patients (49% vs. 35%; p = 0.028). From multivariable analysis, early age of onset, smoking and extramural invasion presented as independent risk factors for a worse response. This study demonstrates that an early age of onset is related to a worse response and calls for different multimodal strategies in this group of patients.

The Predictors of Complete Pathologic Response in Rectal Cancer during the Total Neoadjuvant Therapy Era: A Systematic Review

“…Between the younger-onset and later-onset cohorts, there were no statistically significant differences in pCR rates (12% and 15%, respectively), with similar 5-year overall survival rates (86% and 84%, respectively). This contradicts earlier findings which hypothesized early-onset rectal cancer responds differently to TNT [36,37]. Additional data is needed to assess whether age or tumor characteristics associated with early-onset disease are risk factors for poor response to TNT, and therefore, not ideal for WW approaches.…”

“…Other studies have shown age is not associated either positively or negatively with pCR [50]. A hypothesis for future research to explore is if younger patients have other tumor and patient characteristics, including more aggressive features, that are not responsive to treatment [48] or if younger patients are more likely to receive maximum and aggressive treatment [36] with no actual differences in pCR rate based on age.…”

“…Two additional studies assessed the impact of the age of patients on response to TNT, with contradictory results. Foppa et al assessed the response to both TNT and standard CRT in the treatment of rectal cancer [36]. A total of 16 patients underwent TNT, which included four late-onset patients (age at diagnosis ≥ 50 years) and twelve early-onset patients (age at diagnosis ≤ 49 years).…”

“…While TNT was not a statistically significant risk factor in the multivariable analysis, early-onset disease was a risk factor for an incomplete response to therapy. Of note, a disease-free survival analysis still needs to be completed to assess systemic control for younger patients who underwent TNT [36].…”

Retrospective Evaluation of the Efficacy of Total Neoadjuvant Therapy and Chemoradiotherapy Neoadjuvant Treatment in Relation to Surgery in Patients with Rectal Cancer

“…Data from the literature regarding the pathological complete response rate (pCR) after neoadjuvant treatment in rectal cancer in relation with the age of the patients are contradictory. Some authors present results that show a better response to treatment in the case of young people [44], whereas in other studies the results are worse [45,46]. Possible mechanisms to explain these differences are given by means of molecular and clinical characteristics.…”