Women are predisposed to early dose-limiting toxicities during adjuvant CAPOX for colorectal cancer.

AIM: Oxaliplatin-based adjuvant chemotherapy was demonstrated to be beneficial for stage III or high-risk stage II colorectal cancer (CRC). Moreover, a recent international collaborative trial suggested 3-months CAPOX as an alternative regimen for low-risk stage III colorectal cancer (CRC) patients. Thus, it is important to clarify the frequency and predictive markers of dose-limiting toxicities (DLTs) developed within the short-course CAPOX cycles. METHODS: We investigated CRC patients who underwent radical surgery and adjuvant CAPOX therapy at our hospital between December 2010 and February 2021. Patients who received initially reduced doses of CAPOX and those who had early recurrence were excluded. We reviewed the age, sex, comorbidities, physical, laboratory and oncological data and other perioperative factors. The associations between these variables and early DLTs within four cycles of CAPOX were examined by multivariate analyses using logistic regression models. RESULTS: Among 168 patients (96 men, mean age: 58.3 years), 120 (71%) developed early DLTs. Patients with early DLTs were predominantly women and sarcopenic and habitual alcohol consumers. On multivariate analyses, only the female sex was an independent predictive factor for early DLTs (odds ratio: 2.61, P = .027). CONCLUSION: Women were prone to early DLTs during adjuvant CAPOX in the current study. Doctors should be aware of the sex difference in the incidence of early DLTs, adjust the CAPOX dosage and provide supportive care for female CRC patients.

Chemoradiation provides a physiological selective pressure that increases the expansion of aberrant TP53 tumor variants in residual rectal cancerous regions.

Neoadjuvant chemoradiotherapy has been introduced in patients with surgically resected rectal cancer and reduced the local recurrence. Heterogeneity exists in rectal cancer, and we hypothesized that there are subclones resistant to chemoradiotherapy within the cancer mass. We performed DNA-targeted sequencing of pre- and post-treatment tumor tissues obtained from 20 rectal cancer patients who received chemoradiotherapy. The variant frequency of the mutant clones was compared between pre- and post-treatment samples of nine non-responder patients. RNA-targeted sequencing of 57 genes related to sensitivity to chemotherapy and radiotherapy was performed for the paired samples. Immunohistochemical analyses of p53 expression were also performed on the paired samples from the nine non-responder patients. DNA-sequencing detected frequent mutations of suppressor genes including TP53, APC and FBXW7 in the post-treatment samples of the nine non-responders. The frequency of TP53 mutations showed significant increases after chemoradiotherapy. RNA-targeted sequencing of 29 tumor tissues demonstrated that decreased expression of three genes and increased expression of four genes were detected in the post-treatment samples. Significantly increased expression of TP53 was observed in the post-treatment samples. Immunohistochemical staining for p53 revealed that increased p53 intensity scores were observed after chemoradiotherapy. These results suggest that the tumors with TP53 mutations tend to accumulate through chemoradiotherapy.