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Keywords = locally advanced rectal cancer (LARC)

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10 pages, 809 KiB  
Article
Circulating Tumor DNA Detects Minimal Residual Disease in Patients with Locally Advanced Rectal Cancer After Total Neoadjuvant Therapy
by Jin K. Kim, Ashley J. Alden, Sarah Knaus, Rishabh Thakkar, Lisa Moudgill, Allen Chudzinski, Paul Cavallaro, Carolina Martinez, Robert D. Bennett and Jorge Marcet
Cancers 2025, 17(15), 2560; https://doi.org/10.3390/cancers17152560 - 3 Aug 2025
Viewed by 196
Abstract
Background/Objectives: Nonoperative management (NOM) of patients with locally advanced rectal cancer (LARC) who achieve a complete clinical response (cCR) to total neoadjuvant therapy (TNT) has been shown to be oncologically safe and is an attractive treatment option for patients. However, identifying responders [...] Read more.
Background/Objectives: Nonoperative management (NOM) of patients with locally advanced rectal cancer (LARC) who achieve a complete clinical response (cCR) to total neoadjuvant therapy (TNT) has been shown to be oncologically safe and is an attractive treatment option for patients. However, identifying responders to TNT that may benefit from nonoperative management is clinically challenging. Circulating tumor DNA (ctDNA) testing has shown promise in detecting minimal residual disease but has not yet been studied extensively within this clinical context. Methods: This is a single-institution retrospective case series study of LARC patients treated with TNT from 2019 to 2023 who underwent ctDNA testing as an adjunct to standard clinical response assessments. Results: A total of 28 patients had ctDNA testing as part of their response assessments after TNT. In total, 9 patients had positive ctDNA, and 19 patients had negative ctDNA during surveillance. Baseline characteristics of these two groups were not different. In this study, 6/9 (67%) patients who had positive ctDNA required surgery for residual rectal cancer, whereas only 4/19 (21%) patients who had negative ctDNA required surgery (p = 0.035). Conclusions: ctDNA testing has the potential to detect MRD in LARC patients treated with TNT. Full article
(This article belongs to the Section Cancer Therapy)
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31 pages, 419 KiB  
Review
Neoadjuvant Treatment for Locally Advanced Rectal Cancer: Current Status and Future Directions
by Masayoshi Iwamoto, Kazuki Ueda and Junichiro Kawamura
Cancers 2025, 17(15), 2540; https://doi.org/10.3390/cancers17152540 - 31 Jul 2025
Viewed by 505
Abstract
Locally advanced rectal cancer (LARC) remains a major clinical challenge due to its high risk of local recurrence and distant metastasis. Although total mesorectal excision (TME) has been established as the gold standard surgical approach, high recurrence rates associated with surgery alone have [...] Read more.
Locally advanced rectal cancer (LARC) remains a major clinical challenge due to its high risk of local recurrence and distant metastasis. Although total mesorectal excision (TME) has been established as the gold standard surgical approach, high recurrence rates associated with surgery alone have driven the development of multimodal preoperative strategies, such as radiotherapy and chemoradiotherapy. More recently, total neoadjuvant therapy (TNT)—which integrates systemic chemotherapy and radiotherapy prior to surgery—and non-operative management (NOM) for patients who achieve a clinical complete response (cCR) have further expanded treatment options. These advances aim not only to improve oncologic outcomes but also to enhance quality of life (QOL) by reducing long-term morbidity and preserving organ function. However, several unresolved issues persist, including the optimal sequencing of therapies, precise risk stratification, accurate evaluation of treatment response, and effective surveillance protocols for NOM. The advent of molecular biomarkers, next-generation sequencing, and artificial intelligence (AI) presents new opportunities for individualized treatment and more accurate prognostication. This narrative review provides a comprehensive overview of the current status of preoperative treatment for LARC, critically examines emerging strategies and their supporting evidence, and discusses future directions to optimize both oncological and patient-centered outcomes. By integrating clinical, molecular, and technological advances, the management of rectal cancer is moving toward truly personalized medicine. Full article
(This article belongs to the Special Issue Multidisciplinary Management of Rectal Cancer)
18 pages, 482 KiB  
Article
Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: Evaluation of Sequencing, Response, and Toxicity in a Single-Institution Cohort
by Maria Cristina Barba, Paola De Franco, Donatella Russo, Elisa Cavalera, Elisa Ciurlia, Sara De Matteis, Giuseppe Di Paola, Corradino Federico, Angela Leone, Antonella Papaleo, Bianca Santo, Dino Rubini, Giuseppe Rubini and Angela Sardaro
Cancers 2025, 17(15), 2416; https://doi.org/10.3390/cancers17152416 - 22 Jul 2025
Viewed by 311
Abstract
Background: Total neoadjuvant therapy (TNT) has emerged as a promising strategy for locally advanced rectal cancer (LARC). By administering both chemoradiotherapy (CRT) and systemic chemotherapy (CHT) pre-surgery, TNT is associated with improved disease-free survival (DFS), reduced distant metastases, and higher pathological complete [...] Read more.
Background: Total neoadjuvant therapy (TNT) has emerged as a promising strategy for locally advanced rectal cancer (LARC). By administering both chemoradiotherapy (CRT) and systemic chemotherapy (CHT) pre-surgery, TNT is associated with improved disease-free survival (DFS), reduced distant metastases, and higher pathological complete response (pCR) rates. Materials and Methods: This study included patients with LARC who received various TNT schedules: induction chemotherapy (iCHT), consolidation chemotherapy (cCHT), or a combination of both (sandwichCHT). We analyzed treatment adherence, toxicity, and pathological response. Local and distant disease recurrence, as well as survival outcomes, were also evaluated. Results: Between May 2021 and January 2025, 70 patients received TNT. Treatment included iCHT (41%), sandwichCHT (49%), and cCHT (10%). Most patients (94%) received long-course radiotherapy (LCRT). Overall, TNT was well tolerated, with grade 2 gastrointestinal toxicity during CRT being the most common frequent adverse event (33%). Disease progression during TNT was noted in five patients (7%); three of these patients were receiving chemotherapy, while two underwent surgical resection of the primary tumor. A watch-and-wait strategy was adopted for five patients (7%) following TNT. Surgical procedures performed included anterior resection (92%), abdominoperineal resection (7%), and local excision (1%). Pathological assessment revealed an overall pCR rate of 30%. With a median follow-up of 17 months, no patients experienced local recurrence. Post-surgery, 10 patients (17%) developed disease progression. The median DFS was 14.7 months. Five patients (7%) died during the follow-up period, with only one death attributed to causes other than disease progression. Conclusions: In this cohort of LARC patients, TNT demonstrated favorable tolerability and encouraging short-term efficacy. Full article
(This article belongs to the Section Cancer Pathophysiology)
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15 pages, 1645 KiB  
Article
Total Lesion Glycolysis (TLG) on 18F-FDG PET/CT as a Potential Predictor of Pathological Complete Response in Locally Advanced Rectal Cancer After Total Neoadjuvant Therapy: A Retrospective Study
by Handan Tokmak, Nurhan Demir and Hazal Cansu Çulpan
Diagnostics 2025, 15(14), 1800; https://doi.org/10.3390/diagnostics15141800 - 16 Jul 2025
Viewed by 350
Abstract
Background: The accurate prediction of pathological complete response (pCR) following total neoadjuvant therapy (TNT) is crucial for optimising treatment protocols in locally advanced rectal cancer (LARC). Although conventional imaging techniques such as MRI show limitations in assessing treatment response, metabolic imaging utilising 18F-fluorodeoxyglucose [...] Read more.
Background: The accurate prediction of pathological complete response (pCR) following total neoadjuvant therapy (TNT) is crucial for optimising treatment protocols in locally advanced rectal cancer (LARC). Although conventional imaging techniques such as MRI show limitations in assessing treatment response, metabolic imaging utilising 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET-CT) provides distinctive information by quantifying tumour glycolytic activity. This study investigates the predictive value of sequential 18F-FDG PET-CT parameters, focusing on Total Lesion Glycolysis (TLG), in predicting pCR after TNT. Methods: We conducted a retrospective analysis of 33 LARC patients (T3–4/N0–1) treated with TNT (neoadjuvant-chemoradiation followed by consolidation FOLFOX chemotherapy). Sequential PET-CT scans were performed at baseline, interim (after 4 cycles of FOLFOX), and post-TNT. Metabolic parameters, including maximum standardised uptake value (SUVmax) and TLG, were measured. Receiver operating characteristic (ROC) analysis assessed the predictive performance of these parameters for pCR. Results: The pCR rate was 21.2% (7/33). Post-TNT TLG ≤ 10 demonstrated excellent predictive accuracy for pCR (AUC 0.887, 92.3% sensitivity, 85.7% specificity, and 96.0% PPV), outperforming SUVmax (AUC 0.843). Interim TLG ≤ 10 also showed a strong predictive value (AUC 0.824, 100% sensitivity, and 71.4% specificity). Conclusions: TLG may serve as a reliable metabolic biomarker for predicting pathologic complete response (pCR) after total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC). Its inclusion in clinical decision-making could improve patient selection for organ preservation strategies, thereby reducing the need for unnecessary surgeries in the future. However, given that the study is based on a small retrospective design, the findings should be interpreted with caution and used alongside other decision-making tools until more comprehensive data are collected from larger studies. Full article
(This article belongs to the Special Issue Applications of PET/CT in Clinical Diagnostics)
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18 pages, 1231 KiB  
Review
Narrative Review: Predictive Biomarkers of Tumor Response to Neoadjuvant Radiotherapy or Total Neoadjuvant Therapy of Locally Advanced Rectal Cancer Patients
by Joao Victor Machado Carvalho, Jeremy Meyer, Frederic Ris, André Durham, Aurélie Bornand, Alexis Ricoeur, Claudia Corrò and Thibaud Koessler
Cancers 2025, 17(13), 2229; https://doi.org/10.3390/cancers17132229 - 3 Jul 2025
Viewed by 816
Abstract
Background/Objectives: Treatment of locally advanced rectal cancer (LARC) very often requires a neoadjuvant multimodal approach. Neoadjuvant treatment (NAT) encompasses treatments like chemoradiotherapy (CRT), short-course radiotherapy (SCRT), radiotherapy (RT) or a combination of either of these two with additional induction or consolidation chemotherapy, namely [...] Read more.
Background/Objectives: Treatment of locally advanced rectal cancer (LARC) very often requires a neoadjuvant multimodal approach. Neoadjuvant treatment (NAT) encompasses treatments like chemoradiotherapy (CRT), short-course radiotherapy (SCRT), radiotherapy (RT) or a combination of either of these two with additional induction or consolidation chemotherapy, namely total neoadjuvant treatment (TNT). In case of complete radiological and clinical response, the non-operative watch-and-wait strategy can be adopted in selected patients. This strategy is impacted by a regrowth rate of approximately 30%. Predicting biomarkers of tumor response to NAT could improve guidance of clinicians during clinical decision making, improving treatment outcomes and decreasing unnecessary treatment exposure. To this day, there is no validated biomarker to predict tumor response to any NAT strategies in clinical use. Most research focused on CRT neglects the study of other regimens. Methods: We conducted a narrative literature review which aimed at summarizing the status of biomarkers predicting tumor response to NAT other than CRT in LARC. Results: Two hundred and fourteen articles were identified. After screening, twenty-one full-text articles were included. Statistically significant markers associated with improved tumor response pre-treatment were as follows: low circulating CEA levels; BCL-2 expression; high cellular expression of Ku70, MIB-1(Ki-67) and EGFR; low cellular expression of VEGF, hPEBP4 and nuclear β-catenin; the absence of TP53, SMAD4, KRAS and LRP1B mutations; the presence of the G-allel of LCS-6; and MRI features such as the conventional biexponential fitting pseudodiffusion (Dp) mean value and standard deviation (SD), the variable projection Dp mean value and lymph node characteristics (short axis, smooth contour, homogeneity and Zhang et al. radiomic score). In the interval post-treatment and before surgery, significant markers were as follows: a reduction in the median value of circulating free DNA, higher presence of monocytic myeloid-derived suppressor cells, lower presence of CTLA4+ or PD1+ regulatory T cells and standardized index of shape changes on MRI. Conclusions: Responders to neoadjuvant SCRT and RT tended to have a tumor microenvironment with an immune–active phenotype, whereas responders to TNT tended to have a less active tumor profile. Although some biomarkers hold great promise, scarce publications, inconsistent results, low statistical power, and low reproducibility prevent them from reliably predicting tumor response following NAT. Full article
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17 pages, 1279 KiB  
Article
The Impact of Adjuvant Chemotherapy on Clinical Outcomes in Locally Advanced Rectal Cancer: A CHORD Consortium Analysis
by Kaveh Farrokhi, Horia Marginean, Anas Al Ghamdi, Essa Al Mansor, Shaan Dudani, Rachel A. Goodwin, Timothy R. Asmis, Erin Powell, Patricia A. Tang, Richard Lee-Ying and Michael M. Vickers
Curr. Oncol. 2025, 32(7), 371; https://doi.org/10.3390/curroncol32070371 - 26 Jun 2025
Viewed by 461
Abstract
Background: The impact of adjuvant chemotherapy (AC) on outcomes in real-world patients with locally advanced rectal cancer (LARC) remains uncertain. Methods: Consecutive patients with LARC (stage II/III) undergoing neoadjuvant chemoradiation before curative-intent surgery from 2005 to 2013 were identified in the Canadian Health [...] Read more.
Background: The impact of adjuvant chemotherapy (AC) on outcomes in real-world patients with locally advanced rectal cancer (LARC) remains uncertain. Methods: Consecutive patients with LARC (stage II/III) undergoing neoadjuvant chemoradiation before curative-intent surgery from 2005 to 2013 were identified in the Canadian Health Outcomes Research Database. The impact of AC on clinical outcomes, including disease-free survival (DFS) and overall survival (OS), was evaluated using the Kaplan–Meier method and Cox proportional hazards modeling. Results: A total of 1448 patients had sufficient data available to be included for analysis with 1085 (74.9%) receiving AC. Of AC patients, 40.5% received oxaliplatin-based treatments. With a median follow-up of 66.43 months, the 5-year DFS rate was 67.7% (95% CI: 64.5–70.1%) vs. 58.7% (95% CI: 52.8–64.2%) in the AC group and non-AC group, respectively (p < 0.001). The 5-year OS rate of the whole cohort was 74.3% (95% CI: 71.5–76.85%) while the 5-year OS rate of the AC group was 77.8% (95% CI: 74.7–80.6%) compared with 63.8% (95% CI: 57.9–69.2%) for the non-AC group (p < 0.001). On multivariate analysis, patients who received AC had improved DFS (HR 0.6, 95% CI: 0.49–0.73, p < 0.001) and OS (HR 0.46, 95% CI: 0.36–0.58, p < 0.001). Conclusions: This large multi-institutional database analysis supports the use of AC in real-world LARC patients treated with nCRT followed by surgical resection. Full article
(This article belongs to the Section Gastrointestinal Oncology)
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31 pages, 922 KiB  
Review
Controversies and Perspectives in the Current Management of Patients with Locally Advanced Rectal Cancer—A Systematic Review
by Roxana Elena Stefan, Rodica Daniela Birla, Mircea Gheorghe, Daniela Elena Dinu, Petre Angel Hoara, Diana Ciuc, Valeriu-Gabi Dinca and Silviu Constantinoiu
Life 2025, 15(7), 1011; https://doi.org/10.3390/life15071011 - 25 Jun 2025
Viewed by 723
Abstract
Traditionally, the therapeutic approach to rectal cancer has involved neoadjuvant chemoradiotherapy followed by surgical resection, and, in some cases, adjuvant chemotherapy. This study aims to present current advances and ongoing controversies in the management of patients with locally advanced rectal cancer (LARC), with [...] Read more.
Traditionally, the therapeutic approach to rectal cancer has involved neoadjuvant chemoradiotherapy followed by surgical resection, and, in some cases, adjuvant chemotherapy. This study aims to present current advances and ongoing controversies in the management of patients with locally advanced rectal cancer (LARC), with a particular focus on clarifying the role of total neoadjuvant therapy (TNT) in contemporary treatment strategies. Methods: We conducted a systematic literature review in Medline/PubMed using various keyword combinations, including “rectal cancer/neoplasia” and“therapy” or “neoadjuvant therapy” or “TNT”, and included articles published between 2015 and 2025. Results: The association of neoadjuvant radiochemotherapy with preoperative systemic chemotherapy has led to the current concept of total neoadjuvant therapy. The advantages of preoperative chemotherapy include better patient compliance, a decrease in the rate of local recurrence and distant metastases via the early destruction of infra-clinical micrometastases, and higher rates of pathological complete response. All of these have led to the inclusion of this strategy in treatment guidelines for patients with locally advanced rectal cancer. Conclusions: However, the selection of patients with advanced rectal tumors for optimal therapy requires comprehensive imaging assessments, molecular and genetic testing, and a multidisciplinary team to determine the most appropriate total neoadjuvant therapy approach. Full article
(This article belongs to the Section Medical Research)
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12 pages, 732 KiB  
Systematic Review
Gut-Microbiome Signatures Predicting Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer: A Systematic Review
by Ielmina Domilescu, Bogdan Miutescu, Florin George Horhat, Alina Popescu, Camelia Nica, Ana Maria Ghiuchici, Eyad Gadour, Ioan Sîrbu and Delia Hutanu
Metabolites 2025, 15(6), 412; https://doi.org/10.3390/metabo15060412 - 18 Jun 2025
Viewed by 550
Abstract
Background and Objectives: Rectal cancer management increasingly relies on watch-and-wait strategies after neoadjuvant chemoradiotherapy (nCRT). Accurate, non-invasive prediction of pathological complete response (pCR) remains elusive. Emerging evidence suggests that gut-microbiome composition modulates radio-chemosensitivity. We systematically reviewed primary studies that correlated baseline or on-treatment [...] Read more.
Background and Objectives: Rectal cancer management increasingly relies on watch-and-wait strategies after neoadjuvant chemoradiotherapy (nCRT). Accurate, non-invasive prediction of pathological complete response (pCR) remains elusive. Emerging evidence suggests that gut-microbiome composition modulates radio-chemosensitivity. We systematically reviewed primary studies that correlated baseline or on-treatment gut-microbiome features with nCRT response in locally advanced rectal cancer (LARC). Methods: MEDLINE, Embase and PubMed were searched from inception to 30 April 2025. Eligibility required (i) prospective or retrospective human studies of LARC, (ii) faecal or mucosal microbiome profiling by 16S, metagenomics, or metatranscriptomics, and (iii) response assessment using tumour-regression grade or pCR. Narrative synthesis and random-effects proportion meta-analysis were performed where data were homogeneous. Results: Twelve studies (n = 1354 unique patients, median sample = 73, range 22–735) met inclusion. Four independent machine-learning models achieved an Area Under the Receiver Operating Characteristic curve AUROC ≥ 0.85 for pCR prediction. Consistently enriched taxa in responders included Lachnospiraceae bacterium, Blautia wexlerae, Roseburia spp., and Intestinimonas butyriciproducens. Non-responders showed over-representation of Fusobacterium nucleatum, Bacteroides fragilis, and Prevotella spp. Two studies linked butyrate-producing modules to radiosensitivity, whereas nucleotide-biosynthesis pathways conferred resistance. Pooled pCR rate in patients with a “butyrate-rich” baseline profile was 44% (95% CI 35–54) versus 21% (95% CI 15–29) in controls (I2 = 18%). Conclusions: Despite heterogeneity, convergent functional and taxonomic signals underpin a microbiome-based radiosensitivity axis in LARC. Multi-centre validation cohorts and intervention trials manipulating these taxa, such as prebiotics or live-biotherapeutics, are warranted before clinical deployment. Full article
(This article belongs to the Special Issue Advances in Gut Microbiome Metabolomics)
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18 pages, 3630 KiB  
Article
Identifying CDCA4 as a Radiotherapy Resistance-Associated Gene in Colorectal Cancer by an Integrated Bioinformatics Analysis Approach
by Lin Chen, Yawei Gao, Zhiqing Hu, Jingwen Si, Yuchao Zhang and Qingping Cai
Genes 2025, 16(6), 696; https://doi.org/10.3390/genes16060696 - 9 Jun 2025
Viewed by 817
Abstract
Background: Colorectal cancer (CRC) remains one of the most prevalent and fatal malignancies globally, with radiotherapy playing a crucial role in the treatment of locally advanced rectal cancer (LARC). However, the efficacy of radiotherapy is limited by significant resistance, with only a small [...] Read more.
Background: Colorectal cancer (CRC) remains one of the most prevalent and fatal malignancies globally, with radiotherapy playing a crucial role in the treatment of locally advanced rectal cancer (LARC). However, the efficacy of radiotherapy is limited by significant resistance, with only a small proportion of patients achieving a pathologic complete response (PCR) to neoadjuvant chemoradiotherapy (nCRT). This study aims to uncover the genetic and molecular factors contributing to radiotherapy resistance in CRC through an integrated analysis of germline mutations, transcriptomic data, and immune microenvironment characteristics. Methods: Whole-exome sequencing (WES) was performed on tumor samples from 12 LARC patients. Transcriptomic data from the TCGA-READ and GSE150082 (LARC with chemoradiotherapy) cohorts were integrated with WES findings. The independent cohort GSE190826 (neoadjuvant therapy in rectal cancer) dataset was utilized to validate the WES data. Single-cell RNA sequencing (scRNA-seq) analysis of GSE132465 (primary CRC) resolved cellular heterogeneity. A random forest algorithm was employed to develop a predictive gene signature. Results: Our findings reveal a mutational landscape associated with radiotherapy resistance, identifying specific germline mutations linked to treatment outcomes. Differential gene expression analysis highlighted pathways involved in DNA replication, DNA repair, and immune regulation, with a focus on the tumor immune microenvironment (TIME). A gene signature, including CDCA4, FANCA, PBRM1, RPL13, and C12orf43, was developed to predict radiotherapy response. Notably, CDCA4 expression was significantly associated with tumor mutation burden (TMB) and microsatellite instability (MSI), and it plays a crucial role in regulating B cell infiltration in the tumor microenvironment. Conclusions: Our study provides novel insights into the molecular mechanisms of radiotherapy resistance in CRC and proposes CDCA4 and B cell-related immune features as potential biomarkers for patient stratification and personalized treatment strategies. Full article
(This article belongs to the Section Bioinformatics)
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26 pages, 7367 KiB  
Article
CD133 and CD166 Stem Cells Markers Expression, Clinicopathological Parameters, and Fragmentation Response Patterns of ypT3 Rectal Cancer Following Neoadjuvant Chemoradiotherapy
by Diana Lavinia Pricope, Adriana Grigoraș, Gabriel Mihail Dimofte, Cristina Terinte and Cornelia Amalinei
Biomedicines 2025, 13(6), 1300; https://doi.org/10.3390/biomedicines13061300 - 26 May 2025
Viewed by 498
Abstract
Background: The effectiveness of neoadjuvant chemoradiotherapy (nCRT) is variable in locally advanced rectal cancer (LARC) patients, the ypT3 stage having a minimal or moderate response. The aim of our study was the evaluation of the association between CD133 (Prominin1) and CD166 (ALCAM) [...] Read more.
Background: The effectiveness of neoadjuvant chemoradiotherapy (nCRT) is variable in locally advanced rectal cancer (LARC) patients, the ypT3 stage having a minimal or moderate response. The aim of our study was the evaluation of the association between CD133 (Prominin1) and CD166 (ALCAM) expression, survival parameters, and clinicopathological characteristics of a subgroup of LARC patients who achieved ypT3, showing post-nCRT and TME tumor fragmentation response and the assessment of these CSCs biomarkers value as indicators of the nCRT tumor response. Methods: Our study group comprised 60 LARC patients who achieved ypT3 status and exhibited a tumor fragmentation pattern following nCRT. Clinicopathological parameter and survival evaluations, along with CD133 and CD166 immunohistochemistry and scoring, were performed and the associations between different parameters were tested. Results: High CD133 expression was significantly associated with ypN category (p = 0.018), lymphovascular invasion (LVI) (p = 0.009), perineural invasion (PnI) (p = 0.006), and tumor grading (p = 0.047), while high CD166 expression was significantly associated with LVI (p = 0.020) and PnI (p = 0.028). Tumors with high CD133 and CD166 expressions were associated with decreased overall survival (OS) (p = 0.004 and p = 0.006). Cox regression analysis identified high CD133 and CD166 expression as independent factors associated with reduced survival (HR = 3.237, p = 0.014 and HR = 2.866, p = 0.020). Conclusions: Our results support the hypothesis that CD133 and CD166 are putative CSC biomarkers associated with aggressive behavior and a poor prognosis in LARC, offering opportunities for personalized targeted therapies. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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12 pages, 1964 KiB  
Article
Radiomic Features of Mesorectal Fat as Indicators of Response in Rectal Cancer Patients Undergoing Neoadjuvant Therapy
by Francesca Treballi, Ginevra Danti, Sofia Boccioli, Sebastiano Paolucci, Simone Busoni, Linda Calistri and Vittorio Miele
Tomography 2025, 11(4), 44; https://doi.org/10.3390/tomography11040044 - 7 Apr 2025
Viewed by 767
Abstract
Background: Rectal cancer represents a major cause of mortality in the United States. Management strategies are highly individualized, depending on patient-specific factors and tumor characteristics. The therapeutic landscape is rapidly evolving, with notable advancements in response rates to both radiotherapy and chemotherapy. For [...] Read more.
Background: Rectal cancer represents a major cause of mortality in the United States. Management strategies are highly individualized, depending on patient-specific factors and tumor characteristics. The therapeutic landscape is rapidly evolving, with notable advancements in response rates to both radiotherapy and chemotherapy. For locally advanced rectal cancer (LARC, defined as up to T3–4 N+), the standard of care involves total mesorectal excision (TME) following neoadjuvant chemoradiotherapy (nCRT). Magnetic resonance imaging (MRI) has emerged as the gold standard for local tumor staging and is increasingly pivotal in post-treatment restaging. Aim: In our study, we proposed an MRI-based radiomic model to identify characteristic features of peritumoral mesorectal fat in two patient groups: good responders and poor responders to neoadjuvant therapy. The aim was to assess the potential presence of predictive factors for favorable or unfavorable responses to neoadjuvant chemoradiotherapy, thereby optimizing treatment management and improving personalized clinical decision-making. Methods: We conducted a retrospective analysis of adult patients with LARC who underwent pre- and post-nCRT MRI scans. Patients were classified as good responders (Group 0) or poor responders (Group 1) based on MRI findings, including tumor volume reduction, signal intensity changes on T2-weighted and diffusion-weighted imaging (DWI), and alterations in the circumferential resection margin (CRM) and extramural vascular invasion (EMVI) status. Classification criteria were based on the established literature to ensure consistency. Key clinical and imaging parameters, such as age, TNM stage, CRM involvement, and EMVI presence, were recorded. A radiomic model was developed using the LASSO algorithm for feature selection and regularization from 107 extracted radiomic features. Results: We included 44 patients (26 males and 18 females) who, following nCRT, were categorized into Group 0 (28 patients) and Group 1 (16 patients). The pre-treatment MRI analysis identified significant features (out of 107) for each sequence based on the Mann–Whitney test and t-test. The LASSO algorithm selected three features (shape_Sphericity, shape_Maximum2DDiameterSlice, and glcm_Imc2) for the construction of the radiomic logistic regression model, and ROC curves were subsequently generated for each model (AUC: 0.76). Conclusions: We developed an MRI-based radiomic model capable of differentiating and predicting between two groups of rectal cancer patients: responders and non-responders to neoadjuvant chemoradiotherapy (nCRT). This model has the potential to identify, at an early stage, lesions with a high likelihood of requiring surgery and those that could potentially be managed with medical treatment alone. Full article
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19 pages, 4144 KiB  
Article
Assessment of Immunoscore, MRI Tumor Regression Grade, and Neoadjuvant Rectal Score in Predicting Pathologic Response in Locally Advanced Rectal Cancer in the Averectal Study
by Mustafa Natout, Ahmad Machmouchi, Hero Hussain, Laudy Chehade, Noura Abbas, Rim Turfa, Joseph Kattan, Sally Temraz, Ayman Tawil, Mousa Elkhaldi, Omar Jaber, Rula Amarin, Tala Alawabdeh, Maya Charafeddine, Monita Al Darazi and Ali Shamseddine
Diagnostics 2025, 15(7), 913; https://doi.org/10.3390/diagnostics15070913 - 2 Apr 2025
Viewed by 821
Abstract
Background/Objectives: Predictive tools are needed to assess the response to treatment and guide treatment decisions for locally advanced rectal cancer (LARC). This study explores the value of combining the immunoscore (IS) and magnetic resonance imaging tumor regression grade (mrTRG) with pathologic and [...] Read more.
Background/Objectives: Predictive tools are needed to assess the response to treatment and guide treatment decisions for locally advanced rectal cancer (LARC). This study explores the value of combining the immunoscore (IS) and magnetic resonance imaging tumor regression grade (mrTRG) with pathologic and radiologic neoadjuvant rectal (NAR) scores in predicting pathologic complete response (pCRs). Methods: The scores were assessed for patients with LARC enrolled in the Averectal study (NCT03503630), who received five fractions of short-course radiotherapy, followed by six cycles of mFOLFOX-6 plus avelumab, and total mesorectal excision. The IS was calculated using the mean density percentiles of CD3- and CD8-positive T-cells on baseline biopsy samples. Baseline and post-treatment MRIs were reviewed to measure the mrTRG. NAR scores were calculated using the pre-treatment T stage and post-treatment pathologic and radiologic N and T stages. Results: Fifteen out of thirty-five patients whose data were available achieved pCR (42.8%), and seven out of fourteen patients with mrTRG = 1 (complete response) attained pCR. In patients with both a mrTRG = 1 and high IS, the pCR rate was 66.7% (6/9). All of the patients who achieved pCR had a low or intermediate pathologic NAR score with a significant correlation between pCR and pathologic NAR scores (p < 0.0001). Both pathologic and radiologic NAR scores were correlated with overall survival and disease-free survival. Conclusions: The IS can supplement the mrTRG to better predict TNT outcomes, along with the use of the NAR score. This combination could potentially help with patient selection for non-operative management and guide treatment strategies for those with different recurrence risks. Full article
(This article belongs to the Special Issue Diagnosis and Management of Colorectal Diseases)
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9 pages, 218 KiB  
Article
Prognostic Nutritional Index as a Predictor of Surgical Morbidity in Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer
by Cem Batuhan Ofluoğlu, Fırat Mülküt, İsa Caner Aydın, Mustafa Kağan Başdoğan and İbrahim Aydın
J. Clin. Med. 2025, 14(6), 1937; https://doi.org/10.3390/jcm14061937 - 13 Mar 2025
Cited by 1 | Viewed by 693
Abstract
Background: The management of locally advanced rectal cancer (LARC) has seen the emergence of total neoadjuvant therapy (TNT) as a promising approach. TNT has shown potential in enhancing tumor regression, increasing pathological complete response (pCR) rates, and improving the control of systemic disease. [...] Read more.
Background: The management of locally advanced rectal cancer (LARC) has seen the emergence of total neoadjuvant therapy (TNT) as a promising approach. TNT has shown potential in enhancing tumor regression, increasing pathological complete response (pCR) rates, and improving the control of systemic disease. However, the impact of TNT on complications during and after surgery remains uncertain. This research aimed to assess surgical complications linked to TNT in comparison with conventional neoadjuvant chemoradiotherapy (nCRT). Additionally, this study explored the potential of the Prognostic Nutritional Index (PNI) as a predictor of surgical outcomes. Methods: A retrospective cohort study was conducted at Sancaktepe Şehit Prof. Dr. İlhan Varank Training and Research Hospital, including patients with LARC who underwent either TNT or nCRT followed by curative excision (TME). Demographic data, perioperative complications, and tumor-related variables were also analyzed. The prognostic value of the PNI in predicting surgical complications was assessed using multivariate logistic regression analysis. Statistical significance was set at p < 0.05. Results: A total of 103 patients with LARC were included, of whom 38 (36.9%) received TNT and 65 (63.1%) underwent nCRT. TNT was associated with significantly higher rates of anastomotic leakage (13.2% vs. 6.2%, p = 0.04) and wound infections (23.7% vs. 9.2%, p = 0.02). The mean tumor size was significantly smaller in the TNT group (3.22 ± 1.10 cm) than in the nCRT group (3.65 ± 1.26 cm, p = 0.02). The PNI was significantly lower in the TNT group (38.96 ± 5.54) than in the nCRT group (41.31 ± 4.65, p = 0.03). Multivariate logistic regression analysis demonstrated that a lower PNI was independently associated with increased surgical complications (β = −1.09, p = 0.028, 95% CI: −2.06–−0.12). Conclusions: Although TNT demonstrates clear oncological benefits in LARC, it is associated with increased perioperative morbidity. Our findings suggest that the PNI is a valuable predictive biomarker of surgical complications in patients treated with TNT. Preoperative nutritional assessment and optimization may improve perioperative outcomes and mitigate the risks associated with TNT. Future prospective studies should explore targeted interventions to enhance the safety profile of TNT while preserving its oncological advantages. Full article
(This article belongs to the Section Oncology)
20 pages, 1511 KiB  
Article
Dose Escalation in Neoadjuvant Chemoradiotherapy for Rectal Cancer: Short-Term Efficacy and Toxicity of VMAT–SIB vs. 3D-CRT
by Suzana Stojanovic-Rundic, Mladen Marinkovic, Aleksandra Stanojevic, Dusica Gavrilovic, Radmila Jankovic, Natasa Maksimovic, Aleksandar Tomasevic, Predrag Petrasinovic, Sandra Radenkovic and Milena Cavic
Medicina 2025, 61(3), 483; https://doi.org/10.3390/medicina61030483 - 11 Mar 2025
Viewed by 1356
Abstract
Background and Objectives: The standard treatment for locally advanced rectal cancer (LARC) includes neoadjuvant chemoradiotherapy (nCRT), followed by surgery with or without adjuvant chemotherapy (CT). This study evaluated the efficacy and safety of dose-escalated radiotherapy (RT) using the volumetric modulated arc therapy–simultaneous [...] Read more.
Background and Objectives: The standard treatment for locally advanced rectal cancer (LARC) includes neoadjuvant chemoradiotherapy (nCRT), followed by surgery with or without adjuvant chemotherapy (CT). This study evaluated the efficacy and safety of dose-escalated radiotherapy (RT) using the volumetric modulated arc therapy–simultaneous integrated boost (VMAT–SIB) technique in patients with LARC compared to 3D conformal radiotherapy (3D-CRT). Materials and Methods: This study prospectively enrolled 75 patients with LARC. All patients received nCRT using VMAT–SIB, delivering a tumor dose (TD) of 54 Gy in 25 fractions, with concomitant CT following the 5-fluorouracil and leucovorin (5-FU–LV) protocol. To compare the treatment outcomes and toxicity associated with the increased RT dose, a retrospective cohort of 62 patients treated with the 3D-CRT technique was analyzed. The 3D-CRT group received a TD of 50.4 Gy in 28 fractions with the same CT. Outcomes, including pathological complete response (pCR), tumor regression grade (TRG), and sphincter preservation rates, were compared. Results: Among operated patients, the group treated with VMAT–SIB demonstrated improved rates of pCR (20.6% vs. 8.9%), with a statistically significant trend (p = 0.06). Sphincter-preserving surgeries were performed in 49 out of 63 operated patients (77.8%) in the VMAT–SIB group, compared to 35 out of 56 (62.5%) in the 3D-CRT group. Analysis of the definitive postoperative stage revealed a significantly higher prevalence of lower T categories (T0–2) (p < 0.01), negative N status (p < 0.05), and lower stages (I + II) (p < 0.05) in patients treated with the intensified RT approach. However, no significant differences in acute toxicity were observed. Conclusions: The implementation of intensified treatment with a higher dose using the VMAT–SIB technique demonstrated significant benefits in downsizing and downstaging compared to the standard treatment approach. These findings support its integration into clinical practice. However, further prospective, multi-center studies are needed to validate these results and assess long-term outcomes. Full article
(This article belongs to the Section Oncology)
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26 pages, 1237 KiB  
Review
Therapeutic Management of Locally Advanced Rectal Cancer: Existing and Prospective Approaches
by Horia-Dan Lișcu, Nicolae Verga, Dimitrie-Ionuț Atasiei, Andreea-Teodora Ilie, Maria Vrabie, Laura Roșu, Alexandra Poștaru, Stefania Glăvan, Adriana Lucaș, Maria Dinulescu, Andreea Delea and Andreea-Iuliana Ionescu
J. Clin. Med. 2025, 14(3), 912; https://doi.org/10.3390/jcm14030912 - 30 Jan 2025
Cited by 2 | Viewed by 2890
Abstract
Rectal cancer (RC) presents significant challenges in diagnosis and treatment, with increasing incidence among younger populations. Treatment approaches, particularly for locally advanced rectal cancer (LARC), have evolved, notably with the introduction of total neoadjuvant therapy (TNT). TNT combines neoadjuvant chemotherapy and chemoradiotherapy before [...] Read more.
Rectal cancer (RC) presents significant challenges in diagnosis and treatment, with increasing incidence among younger populations. Treatment approaches, particularly for locally advanced rectal cancer (LARC), have evolved, notably with the introduction of total neoadjuvant therapy (TNT). TNT combines neoadjuvant chemotherapy and chemoradiotherapy before surgery, improving overall survival and reducing both metastasis and local recurrence rates compared to traditional methods, while enabling more patients to complete the full oncological treatment. Clinical trials, such as RAPIDO, OPRA, and PRODIGE 23, have demonstrated the effectiveness of TNT in tumor downstaging and complete pathological responses, offering better outcomes for patients; however, debates persist regarding the role of neoadjuvant radiotherapy, with novel strategies exploring its omission in specific cases to reduce toxicity and enhance quality of life. In addition, organ preservation strategies, such as the watch-and-wait (WW) approach, have emerged as viable options for patients with a complete response to neoadjuvant therapy. Future directions point towards personalized treatment plans incorporating radiogenomics and the integration of artificial intelligence into diagnostics to optimize patient outcomes. This review aims to synthesize current treatment strategies and ongoing advancements in rectal cancer management, providing insights into potential future innovations. Full article
(This article belongs to the Special Issue Comprehensive Treatment of Rectal Cancer)
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