Jianhao Geng

Background: Compared to male cancer patients, female patients have a higher incidence and severity of adverse events (AEs) associated with anticancer treatment. The mechanism underlying these disparities is largely unknown, especially in the context of radiotherapy. Notably, the composition and metabolism of the gut microbiota differ between sexes, and such differences have been implicated in multiple physiological and pathological processes. In this study, we aimed to investigate the sex differences in hematologic toxicities during chemoradiotherapy in patients with locally advanced rectal cancer (LARC) and to explore the potential role of the gut microbiota in mediating these differences. Materials and Methods: This real-world study included 329 patients with LARC receiving neoadjuvant chemoradiotherapy (nCRT). Hematologic AEs were evaluated according to Common Terminology Criteria for Adverse Events 5.0. 16S rRNA sequencing, metatranscriptome sequencing, and metabolome detection were performed on longitudinal fecal samples. Mendelian randomization analyses were performed to investigate the correlation between stem cell and gut microbial traits. Results: In this cohort, females had a higher severity of hematologic AEs than males. Using integrated longitudinal multi-omics data, we identified sex-biased bacterial species (e.g., Parasutterella excrementihominis and Bifidobacterium adolescentis ) and microbiota-mediated arginine metabolism associated with hematologic toxicities. Gut microbiome-mediated arginine metabolism is associated with an abundance of hematopoietic stem cells and may be involved in the occurrence of sex-biased radiotherapy-induced hematologic AEs. Conclusion: These results indicate that the differences in gut microbial composition and metabolism between the two sexes are associated with the sex-biased hematologic AEs induced by nCRT. Females require greater attention regarding the hematologic toxicity of chemoradiotherapy, and that gut microbes may serve as potential targets for sex-tailored strategies to restore hematopoietic function following chemoradiotherapy.

Purpose: Residual lymph node metastases (RLNM) remained a great concern in the implementation of organ-preserving strategies and led to poor prognosis in locally advanced rectal cancer (LARC). In this study, we aimed to identify the clinicopathological factors correlated with RLNM in LARC patients with ypT0-2 after neoadjuvant chemoradiotherapy (NCRT). Methods: We retrospectively analyzed 417 patients histologically diagnosed middle-low LARC after NCRT and total mesorectal excision (TME), whose pathological staging was ypT0-2. All patients received pelvic magnetic resonance imaging (MRI) before NCRT. The radiation doses were 50–50.6 Gy for the planning gross tumor volume and 41.8–45 Gy for the planning target volume, respectively. A nomogram for predicting RLNM was constructed using a binary logistic regression. Nomogram performance was assessed by receiver operating characteristic (ROC) curve, calibration curve, decision curve analysis (DCA) and clinical impact curve (CIC). Results: After surgery, 191 patients (45.8%) were ypT0, 43 patients (10.3%) were ypT1 and 183 patients (43.9%) were ypT2, and a total of 49 patients (11.8%) were found the presence of RLNM. Multivariable analyses identified MRI-defined mesorectal fascia (MRF)-positive, high-grade histopathology at biopsy, advanced ypT-category, and the presence of perineural invasion (PNI) as the predictive factors. The nomogram, incorporating all these predictors, showed good discrimination and calibration efficacy, with the areas under the ROC curve of 0.690 (95% CI: 0.610–0.771). Both DCA and CIC demonstrated that this nomogram has good clinical usefulness. Conclusion: The nomogram model can predict RLNM in patients with ypT0-2 tumors. It can help select suitable patients for performing organ-preserving strategies after NCRT.

Purpose This study aimed to assess the impact of ypT stage and tumor regression grade (TRG) on the long-term prognosis of patients with locally advanced rectal cancer (LARC) stage ypT1-4N0 after neoadjuvant chemoradiotherapy (NCRT). Methods We retrospectively analyzed 585 patients with histologically diagnosed middle-low LARC (cT3-4 or cN + by pelvic MRI) from 2014 to 2019. All patients underwent NCRT, followed by total mesorectal excision. Disease-free survival (DFS) rates were compared among patients with different ypT stages and TRGs by Kaplan–Meier survival analysis. The chi-square test was used to analyze the relationship between clinicopathological or therapeutic factors and ypT stage. Results The median follow‐up was 35.8 months (range 2.8–71.8 months). The 3-year DFS was 79.5%. A better 3-year DFS was achieved in patients with a pathologic complete response (94.0% vs. 74.3%, p < 0.001) and those in the ypT0-2 (86.5% vs. 66.6%, p < 0.001), ypN0 (85.0% vs. 60.2%, p < 0.001), and TRG0 + 1 (83.1% vs. 73.0%, p = 0.004) subgroups. A total of 309 patients (52.8%) achieved stage ypT1-4N0 after surgery. Among these patients, the ypT1-2N0 subgroup achieved a significantly higher 3-year DFS than the ypT3-4N0 subgroup (85.4% vs. 72.8%, p = 0.018); in contrast, the 3-year DFS did not significantly differ between the TRG1 and TRG2 + 3 subgroups (79.9% vs. 81.1%, p = 0.833). In the ypT1-2N0 or ypT3-4N0 subgroup, different TRG had no significant effect on failure patterns. Conclusions For LARC patients with a ypT1-4N0 status after NCRT, ypT stage may be a more effective predictor of long-term prognosis than TRG.

Purpose. In theory, the hyperfractionated radiotherapy can enhance biological effect dose against tumor and alleviate normal tissue toxicity. This study is to assess the efficacy and safety of preoperative hyperfractionated intensity-modulated radiotherapy (IMRT) with oral capecitabine in patients with locally advanced rectal cancer (LARC). Methods. We retrospectively screened patients with LARC from January 2015 to June 2016. Patients that received hyperfractionated IMRT or conventional fractionated IMRT were eligible in the hyperfractionation (HF) group or conventional fractionation (CF) group, respectively. The primary outcome was the complete response rate. Secondary outcomes included toxicity, postoperative complications, anus-reservation operation rate, local recurrence and distant metastases rate, overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS). Results. 335 patients were included in the analysis. The complete response rate for the hyperfractionated and conventional fractionated IMRT was 20.41% vs. 23.47% ( ). The anus-reservation operation rate was 68.37% vs. 65.31% ( ). There were no cases of grade 4 toxicity during radiotherapy; the rate of grade 3 toxicity and postoperative complications was both comparable between groups. However, in the CF group, more patients had a second operation due to complications (0.0% vs. 5.68%, ). The cumulative local regional recurrence and distant metastases rates of the HF group and CF group were 5.10% vs. 9.18% ( ) and 22.45% vs. 24.49% ( ), respectively. The 5-year OS, CSS, and DFS in the HF group and CF group were 86.45% vs. 73.30% ( ), 87.34% vs. 75.23% ( ), and 70.80% vs. 68.11% ( ), respectively. Conclusions. The preoperative hyperfractionated IMRT with oral capecitabine, with an acceptable toxicity and favorable response and survival, could reduce the rate of secondary surgery.

The aim of this study was to explore the impact of including or excluding the ischiorectal fossa (IRF) within the clinical target volume during neoadjuvant chemoradiotherapy (NCRT) using intensity modulated radiotherapy, in locally advanced lower rectal cancer (LALRC). We retrospectively analysed the data of 220 LALRC patients who received NCRT followed by abdominoperineal resection between January 2009 and January 2015. Six patients were excluded because of loss to follow-up, 90 patients received IRF irradiation (IRF group) while 124 patients did not (NIRF group). Survival, patterns of recurrence, and treatment toxicities were compared between the two groups. Overall, patient/treatment variables were well balanced except for surgical technique. Perineal wound complications in the IRF and NIRF groups, were 40.0 and 24.2%, respectively (p = 0.010); corresponding 3-year perineal recurrence rates, local recurrence free survival, overall survival, and distant relapse free survival were 4.4% vs. 2.4% (p = 0.670), 88.1% vs. 95.0% (p = 0.079), 82.6% vs. 88.4% (p = 0.087), and 61.9% vs. 81.0% (p = 0.026), respectively. Multivariate analyses demonstrated the following factors to be significantly related to perineal wound complications: irradiation of the IRF (odds ratio [OR] 2.892, p = 0.002), anaemia (OR 3.776, p = 0.010), operation duration > 180 min (OR 2.486, p = 0.007), and interval between radiotherapy and surgery > 8 weeks (OR 2.400, p = 0.010). Exclusion of the IRF from the clinical target volume during NCRT using intensity-modulated radiotherapy in LALRC could lower the incidence of perineal wound complications after abdominoperineal resection, without compromising oncological outcomes.

Introduction: Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced non-small cell lung cancer (LA-NSCLC), but is associated with poor chest tumor control. Here we report results of a randomized phase 3 study comparing two CCRT regimens in improving chest tumor control by low-dose paclitaxel chemoradiation for LA-NSCLC. Methods: Due to the logistics of local referral pattern, the study was designed to enroll patients with stage III LA-NSCLC who had completed 2-4 cycles of full-dose chemotherapy. One hundred thirty four were randomized to either Arm 1 (paclitaxel at 15 mg/m2, three times/wk [M, W, F] for 6 weeks, n=74), or Arm 2 (weekly paclitaxel at 45 mg/m2 for 6 weeks, n=60). Chest RT was 60-70 Gy in standard fractionation. Response rate was the primary endpoint, with recurrence-free survival (RFS) as the secondary endpoint. Results: From March 2006 to February 2013, seventy-one patients completed Arm 1 treatment, and 59 completed Arm 2 treatment. The response rate for Arm 1 was significantly higher (83.1%) than Arm 2 (54.2%) (p＝0.001). RFS was superior in Arm 1: median 14.6 months vs. 9.4 months, p=0.005, Hazard ratio (HR) 1.868 (95% CI 1.203, 2.901). Overall survival was not significantly different: median 32.6 months in Arm 1 vs. 31.3 months in Arm 2, p = 0.91, HR 0.969 (95% CI 0.552, 1.703). Toxicity was significantly lower in Arm 1 for grade 3 and 4 leucopenia/neutropenia (p<0.001). Conclusions: Pulsed low-dose paclitaxel CCRT resulted in significantly better RFS and tumor response rate, and less hematologic toxicities than weekly CCRT for LA-NSCLC.