Age is an important factor affecting the efficacy of NCRT in rectal cancer patients. Few studies have focused on young LARC patients following NCRT. In the present study, we explored the efficacy of NCRT in young (< 40 years) and old (≥ 40 years) LARC patients. The results demonstrated a lower pCR rate in young LARC patients compared with that in old patients, without affecting postoperative complications. For the first time, our study demonstrates that young patients have a higher proportion of CSCs (CD133+), which might contribute to the lower pCR rates.
Young LARC patients often present with aggressive pathological features and advanced stage compared with older patients[4–6]. Additionally, aggressive pathological features could result in a poorer response to NCRT[22–28]. Ou results are consistent with those reported by Li et.al [29] in which analysis of the Surveillance, Epidemiology, and End Results (SEER) population-based database revealed that young patients had a better prognosis than old patients. However, the prognosis was inconsistent with the pathological results in their study, because young patients had more aggressive pathological features compared with old patients. This discrepancy may be explained that by the lack of cancer therapy information, including neoadjuvant and adjuvant treatment, and quality of surgery, in the SEER database, all of which are factors that play an important role in the patient survival outcome. When treating young LARC patients with rectal cancer, it is important to determine how aggressive the tumor is, so that patients can be informed about the advantages and disadvantages of the treatment. In out study, we demonstrated that young LARC patients displayed poorer pathological features, such as a higher probability of mucinous or signet ring cell and poorly differentiated tumors, which is in accordance with the findings of previous studies[23, 24, 26]. These results indicate that young LARC patients have more severe pathological features than those of older patients.
Age is an important factor for survival benefits and risk of complication in cancer patients following CRT. To clarify the influence of age on tumor response to NCRT in LARC patients, we performed a logistic regression analysis. pCR has been proposed as a surrogate endpoint for the efficacy of NCRT and oncological outcome in LARC patients. Our results demonstrated that young age is an independent predictive factor for pCR in LARC patients, as well as tumor size, pre-NCRT clinical N stage, and post-NCRT CEA level. Our results also indicated that young LARC patients have poor responses to NCRT, in terms of lower pCR rates. Therefore, more intense NCRT regimens could be considered in young LARC patients to increase the pCR rate. We further developed a nomogram for predicting pCR to facilitate the decision-making regarding organ-preserving strategies. Our results showed that decisions based on the pCR predictive nomogram yielded more favorable clinical consequences than the treat-all patient and treat-none schemes, even given an extremely small probability threshold. Additionally, the nomogram including age group had superior predictive capability than the nomogram excluding age group.
CSCs are the tumor-initiating cells that are responsible for tumorigenesis[30, 31]. Accumulating evidence has demonstrated that CSCs contribute to resistance to either chemotherapy or radiotherapy in various cancers, including rectal cancer[32–34]. It has been reported that cells expressing CD133, which is a putative marker of CSCs, are more resistant to radiochemotherapy than CD133- tumor cells in rectal cancer[32, 33]. Thus, CD133 expression in the tumor cells was detected as a CSC biomarker in LARC patients. However, the association between CSCs and treatment response in young LARC patients remains unclear. Herein, we hypothesized that young LARC patients have more CSCs, resulting in the resistance to NCRT. In this study, we demonstrated higher CD133 expression in cancer tissue of young LARC patients before NCRT compared with that in the old group. Additionally, higher CD133 expression was correlated with a worse prognosis. Together, these findings suggest that young LARC patients have a higher CD133 + CSC burden, contributing to the lower pCR rates. Nevertheless, prospective studies with large sample sizes are required to confirm the role of CD133 in resistance to NCRT.
Several limitations of our study should be noted. First, our retrospective study was subject to potential selection bias. Second, age-related comorbidities, such as the Charlson comorbidity index, were not evaluated due to the lack of adequate data. Third, the impact of gene profiling on response to NCRT was not assessed owing to the lack of complete medical records in some cases. Fourth, CD133 expression was assessed only in some patients owing to the lack of adequate pretreatment specimens. Nevertheless, our study adds to our understanding of the impact of young age on the efficacy of NCRT in patients with LARC.
In this cohort study of 901 LARC patients treated at a single high-volume cancer center, young age (< 40 years) was identified as a significant determinant for predicting pCR in LARC patients following NCRT. Moreover, for the first time, we have demonstrated that young patients have a higher proportion of CSCs (CD133+) than older patients. Larger-scale prospective studies are warranted to confirm the our findings.