Effects of Neoadjuvant Radiotherapy on Postoperative Complications in Rectal Cancer: A Meta-Analysis

Objective. Neoadjuvant radiotherapy (nRT) is an important treatment approach for rectal cancer. The relationship, however, between nRT and postoperative complications is still controversial. Here, we conducted a meta-analysis to evaluate such concerns. Methods. The electronic literature from 1983 to 2021 was searched in PubMed, Embase, and Web of Science. Postoperative complications after nRT were included in the meta-analysis. The pooled odds ratio (OR) was calculated by the random-effects model. Statistical analysis was conducted by Review Manager 5.3 and STATA 14. Results. A total of 23,723 patients from 49 studies were included in the meta-analysis. The pooled results showed that nRT increased the risk of anastomotic leakage (AL) compared to upfront surgery (OR = 1.23; 95% CI, 1.07–1.41; p = 0.004 ). Subgroup analysis suggested that both long-course (OR = 1.20, 95% CI 1.03–1.40; p = 0.02 ) and short-course radiotherapy (OR = 1.25, 95% CI, 1.02–1.53; p = 0.04 ) increased the incidence of AL. In addition, nRT was the main risk factor for wound infection and pelvic abscess. The pooled data in randomized controlled trials, however, indicated that nRT was not associated with AL (OR = 1.01; 95% CI 0.82–1.26; p = 0.91 ). Conclusions. nRT may increase the risk of AL, wound infection, and pelvic abscess compared to upfront surgery among patients with rectal cancer.

A Postsurgical Prognostic Nomogram for Locally Advanced Rectosigmoid Cancer to Assist in Patient Selection for Adjuvant Chemotherapy

BackgroundThe perioperative treatment model for locally advanced rectosigmoid junction cancer (LARSC) has not been finalized; whether this model should refer to the treatment model for rectal cancer remains controversial.MethodsWe screened 10,188 patients with stage II/III rectosigmoid junction adenocarcinoma who underwent surgery between 2004 and 2016 from the National Cancer Institute Surveillance, Epidemiology, and End Results database. Among them, 4,960 did not receive adjuvant chemotherapy, while 5,228 did receive adjuvant chemotherapy. Propensity score matching was used to balance the two groups for confounding factors, and the Kaplan-Meier method and log-rank test were used for survival analysis. Cox proportional hazards regression analysis was used to identify independent prognostic factors and build a predictive nomogram of survival for LARSC. X-tile software was used to divide the patients into three groups (low, medium, and high) according to their risk scores. 726 patients in our hospital were included for external validation.ResultsLARSC patients did not show a benefit from neoadjuvant radiotherapy (P>0.05). After further excluding patients who received neoadjuvant radiotherapy, multivariate analysis found that age, grade, tumor size, T stage, and log odds of positive lymph nodes were independent prognostic factors for patients without adjuvant chemotherapy and were included in the nomogram. The C-index of the model was 0.690 (95% confidence interval: 0.668–0.712). We divided the patients into low, moderate, and high risk subgroups based on prediction scores of the nomogram. We found that adjuvant chemotherapy did not improve the prognosis of low risk patients, while moderate and high risk patients benefited from adjuvant therapy. External validation data found that moderate, and high risk patients also benefited from AT.ConclusionDirect surgery plus adjuvant chemotherapy may be the best perioperative treatment for LARSC. Moreover, adjuvant chemotherapy is only recommended for moderate and high risk patients as it did not benefit low risk patients.

Tumor Microenvironment Modifications Recorded With IVIM Perfusion Analysis and DCE-MRI After Neoadjuvant Radiotherapy: A Preclinical Study

PurposeNeoadjuvant radiotherapy (NeoRT) improves tumor local control and facilitates tumor resection in many cancers. Some clinical studies demonstrated that both timing of surgery and RT schedule influence tumor dissemination, and subsequently patient overall survival. Previously, we developed a pre-clinical model demonstrating the impact of NeoRT schedule and timing of surgery on metastatic spreading. We report on the impact of NeoRT on tumor microenvironment by MRI.MethodsAccording to our NeoRT model, MDA-MB 231 cells were implanted in the flank of SCID mice. Tumors were locally irradiated (PXI X-Rad SmART) with 2x5Gy and then surgically removed at different time points after RT. Diffusion-weighted (DW) and Dynamic contrast enhancement (DCE) MRI images were acquired before RT and every 2 days between RT and surgery. IntraVoxel Incoherent Motion (IVIM) analysis was used to obtain information on intravascular diffusion, related to perfusion (F: perfusion factor) and subsequently tumor vessels perfusion. For DCE-MRI, we performed semi-quantitative analyses.ResultsWith this experimental model, a significant and transient increase of the perfusion factor F [50% of the basal value (n=16, p<0.005)] was observed on day 6 after irradiation as well as a significant increase of the WashinSlope with DCE-MRI at day 6 (n=13, p<0.05). Using immunohistochemistry, a significant increase of perfused vessels was highlighted, corresponding to the increase of perfusion in MRI at this same time point. Moreover, Tumor surgical resection during this peak of vascularization results in an increase of metastasis burden (n=10, p<0.05).ConclusionSignificant differences in perfusion-related parameters (F and WashinSlope) were observed on day 6 in a neoadjuvant radiotherapy model using SCID mice. These modifications are correlated with an increase of perfused vessels in histological analysis and also with an increase of metastasis spreading after the surgical procedure. This experimental observation could potentially result in a way to personalize treatment, by modulating the time of surgery guided on MRI functional data, especially tumor perfusion.

Development and Validation of an MRI-Based Nomogram Model for Predicting Disease-Free Survival in Locally Advanced Rectal Cancer Treated With Neoadjuvant Radiotherapy

ObjectivesTo develop a prognostic prediction MRI-based nomogram model for locally advanced rectal cancer (LARC) treated with neoadjuvant therapy.MethodsThis was a retrospective analysis of 233 LARC (MRI-T stage 3-4 (mrT) and/or MRI-N stage 1-2 (mrN), M0) patients who had undergone neoadjuvant radiotherapy and total mesorectal excision (TME) surgery with baseline MRI and operative pathology assessments at our institution from March 2015 to March 2018. The patients were sequentially allocated to training and validation cohorts at a ratio of 4:3 based on the image examination date. A nomogram model was developed based on the univariate logistic regression analysis and multivariable Cox regression analysis results of the training cohort for disease-free survival (DFS). To evaluate the clinical usefulness of the nomogram, Harrell’s concordance index (C-index), calibration plot, receiver operating characteristic (ROC) curve analysis, and decision curve analysis (DCA) were conducted in both cohorts.ResultsThe median follow-up times were 43.2 months (13.3–61.3 months) and 32.0 months (12.3–39.5 months) in the training and validation cohorts. Multivariate Cox regression analysis identified MRI-detected extramural vascular invasion (mrEMVI), pathological T stage (ypT) and perineural invasion (PNI) as independent predictors. Lymphovascular invasion (LVI) (which almost reached statistical significance in multivariate regression analysis) and three other independent predictors were included in the nomogram model. The nomogram showed the best predictive ability for DFS (C-index: 0.769 (training cohort) and 0.776 (validation cohort)). It had a good 3-year DFS predictive capacity [area under the curve, AUC=0.843 (training cohort) and 0.771 (validation cohort)]. DCA revealed that the use of the nomogram model was associated with benefits for the prediction of 3-year DFS in both cohorts.ConclusionWe developed and validated a novel nomogram model based on MRI factors and pathological factors for predicting DFS in LARC treated with neoadjuvant therapy. This model has good predictive value for prognosis, which could improve the risk stratification and individual treatment of LARC patients.

592 ATR-mediated CD47 and PD-L1 upregulation restricts radiotherapy-induced immune priming and abscopal responses in colorectal cancer

BackgroundBackground: Radiotherapy of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)-expressing CRC cells systemically; however, incidences of abscopal tumor remission are extremely rare. We sought to unravel the post-irradiation immune escape mechanisms in CRC.MethodsMethodsFlow cytometry, gene knockdown, RNA and T cell receptor sequencing, and multiple murine syngeneic CRC models were used to interrogate mechanisms of CRC immune evasion following radiotherapy. Comparison of immunohistochemistry staining between pretreatment biopsy and post-irradiation surgical specimens was performed in rectal patients who underwent neoadjuvant radiotherapy with 5 Gy for 5 fractions.ResultsResultsWe find that CRC cells utilize a common DNA repair signaling pathway — ATR/Chk1/STAT3 — to upregulate both CD47 and PD-L1 in response to radiotherapy, which through engagement of SIRPα and PD-1 suppresses the capacity of antigen-presenting cells (APCs) to phagocytose them thereby preventing TAA cross-presentation. This post-irradiation CD47 and PD-L1 upregulation can be observed in CRC cells treated with either photon or proton radiotherapy and across a wide variety of human solid tumor cells. Concordantly, rectal cancer patients who responded poorly (tumor regression grade 4–5, n = 10) to neoadjuvant radiotherapy exhibited significantly elevated post-irradiation CD47 levels (P = 0.005). In murine CRC models, the combination of radiotherapy, αSIRPα, and αPD-1 (RSP) profoundly enhances TAA uptake, activation of innate immune sensors, and TAA cross-priming across various antigen-presenting myeloid populations in the irradiated tumor microenvironment and facilitates TAA-presenting APC migration to secondary lymphoid organs. Furthermore, we observed robust production of TAA-specific CD8 T cells, functional activation of effector T cells, and increased tumor-infiltrating T cell clonality and clonal diversity in mice treated with RSP. Importantly, radiotherapy coupled with phagocytosis checkpoint blockade significantly improves complete response rates in both irradiated and abscopal tumors and prolongs survival in three distinct murine CRC models, including a cecal orthotopic model. In addition, αSIRPα exerts superior tumoricidal efficacy than αCD47 in combination with RT and αPD-1. We find RSP efficacy to be STING dependent as knockout animals lose most benefit of phagocytosis checkpoint blockade.ConclusionATR-mediated CD47 and PD-L1 upregulation restrains radiation-induced immune priming in CRC. Blockade of the phagocytosis checkpoints SIRPα and PD-1 during radiotherapy promotes vigorous anti-CRC immune priming leading to systemic tumor regression.AcknowledgementsThis study is supported in part by NIH grant P30 CA16672, the MD Anderson Andrew Sabin Family Fellowship, and Chang Gung Memorial Hospital grant CMRPG3K1751. RCH was supported by the CPRIT Research Training Grant (RP170067) and Ralph B. Arlinghaus Ph.D. Scholarship. The authors are grateful to the members of the Advanced Cytometry & Sorting Facility at South Campus, Tissue Bank of Chang Gung Memorial Hospital at Linkou, and MHC Tetramer Core Facility at Baylor College of Medicine for their invaluable help.Ethics ApprovalThis study was approved by the Institutional Review Board of Chang Gung Memorial Hospital, Taiwan; approval number: 202001191B0C601.

A systematic review of the current management approaches in leiomyosarcoma of inferior vena cava—Results from analysis of 118 cases

Introduction Primary intravenous leiomyosarcomas are rare vascular tumors with aggressive disease biology. The diagnosis and management have been challenging as little data exist from large databases. Methods A literature search was done to identify all cases of primary leiomyosarcomas in the last five years. Clinicopathological features and management strategies were evaluated. Results The median age was 53 years, predominantly females (2.5:1), presenting as metastases in up to 12.1% cases. Most tumors were locally advanced with a median size of 10cm. Inferior vena cava involvement from renal veins to infrahepatic veins remains the most frequent site (57.1%cases) while nearly half (52.8%) proceeded for surgery without histological proof. Most patients could undergo upfront resection (88.0%) with few patients receiving neoadjuvant chemotherapy (4.3%) or neoadjuvant radiotherapy (2.2%). Significant multivisceral resections included right nephrectomy (41.3%), liver resection (25.7%) and left nephrectomy (2.2%). Most patients (91.8%) needed an inferior vena cava graft placement with remarkable microscopically negative margins (85.5% cases). Doxorubicin and ifosfamide were the most frequently used combination chemotherapy regimens in both pre and postoperative settings with partial responses. The median overall and disease free survival among operated patients was 60 months and 28 months respectively. In multivariate analysis large tumor, extensive inferior vena cava involvement, and need for adjuvant chemotherapy appeared significant predictors for overall survival. Conclusions Aggressive upfront surgical resection with clear margin remains the key for long-term survival. Doxorubicin-based regimens were preferred as neoadjuvant chemotherapy while adjuvant treatment with chemotherapy, radiotherapy, or both may be considered in high-risk patients.