Search Results (1,570)

Background/Objectives: Malignant PEComa is a rare sarcoma subtype and usually represents PEComa-NOS (not otherwise specified), one of the several entities of the PEComa family. Surgery is the primary treatment for localized disease; chemotherapy is used mainly for metastatic or unresectable cases. Radiotherapy (RT) may be considered in selected cases; however, its role remains unclear due to the rarity of the disease and limited radiotherapy-specific studies. Methods: This is a descriptive literature review of a limited number of reports on RT use in PEComa. Descriptive statistics were used to summarize reported case characteristics and outcomes. Results: We identified 28 publications reporting 33 cases. In neoadjuvant settings, there was a significant local response to RT in one case. In other neoadjuvant cases, although quantitative response assessments were not reported, most showed no recurrence during follow-up, with the longest follow-up at 34 months, suggesting that a possible benefit in local disease control may exist. In the adjuvant setting, some reports described prolonged disease-free survival following RT, though the lack of direct comparisons between surgery with versus without RT and heterogeneous follow-up periods limit definitive conclusions. In selected metastatic cases, palliative RT achieved notable local responses, potentially contributing to durable local control. Conclusions: In conclusion, although the only available data on RT in PEComas come from case studies with overall heterogeneous management approaches, RT has shown some potential as a therapeutic option across neoadjuvant, adjuvant, and palliative settings, warranting further dedicated clinical studies. Full article

Background: The CD163+ macrophage is considered a key component of the tumor immune microenvironment (TIME) in osteosarcoma (OS) in relation to tumor progression and chemotherapy resistance. However, the relationship between CD163+ macrophage infiltration and the efficacy of neoadjuvant chemotherapy (NACT) in OS remains unexplored. Methods: This study collected a total of 195 biopsy samples from newly diagnosed, pretreated OS patients. The infiltration of CD163+ macrophages was evaluated using immunohistochemical (IHC) staining with anti-CD163 antibody. Additionally, multiplex fluorescence staining (CD8, CD68, CD163, and PDL1) was employed to further characterize the TIME profiles associated with different levels of CD163+ macrophage infiltration. The relationships between various clinical characteristics, survival outcomes, and CD163+ macrophage infiltration levels were also assessed. Results: CD163+ macrophages in biopsy tissues ranged from 2.25 cells/mm² to 3974.79 cells/mm² and 1.37 cells/mm² to 3027.20 cells/mm² in the training and validation cohorts respectively. Multivariate analysis identified that CD163+ macrophage density was an independent predictor for NACT response. Importantly, patients with high CD163+ macrophage infiltration exhibited poorer DFS, DMFS, and RFS than their counterparts. Conclusions: CD163+ macrophage infiltration was an independent predictor for NACT response. Patients with high CD163+ macrophage density benefited less from NACT and exhibited a more immunosuppressive TIME than low-density patients. Full article

Background/Objectives: Claudin-18.2 (CLDN18.2) has recently emerged as a therapeutic target in gastric cancer; however, its prognostic relevance in the neoadjuvant setting remains insufficiently defined. We evaluated the clinical significance of CLDN18.2 and fibroblast growth factor receptor 2b (FGFR2b) expression in patients with locally advanced gastric cancer treated with neoadjuvant therapy. Methods: This retrospective single-center study included 64 patients with locally advanced gastric cancer who received neoadjuvant chemotherapy followed by curative surgery. Pretreatment endoscopic biopsy specimens were analyzed using immunohistochemistry to assess CLDN18.2 and FGFR2b expression. Survival outcomes were evaluated using Kaplan–Meier analysis and Cox proportional hazards regression models. Results: CLDN18.2 positivity was detected in 29.7% of patients and was not associated with baseline clinicopathological characteristics or pathological treatment response. However, CLDN18.2-positive tumors demonstrated significantly shorter relapse-free survival (median 19.0 vs. 36.6 months, p = 0.038) and overall survival (median 28.9 vs. 53.4 months, p = 0.005). In multivariable analysis, CLDN18.2 positivity remained an independent predictor of relapse-free survival. FGFR2b positivity was observed in 14.1% of patients and was evaluated descriptively due to limited case numbers. Conclusions: CLDN18.2 expression may represent a clinically relevant prognostic biomarker reflecting aggressive tumor biology in locally advanced gastric cancer treated with neoadjuvant therapy. Full article

Background: Neoadjuvant therapy (NAT) is increasingly investigated in operable pancreatic ductal adenocarcinoma (PDAC), yet its role in strictly resectable disease remains controversial. Randomized trials have been conducted both in borderline resectable and resectable PDAC and have demonstrated survival advantages, while evidence in strictly resectable tumors remains poor. We conducted an umbrella review of systematic reviews and meta-analyses (SRMAs) to comprehensively evaluate the highest level of available evidence on NAT versus upfront surgery in operable PDAC. Methods: We performed an umbrella review of completed SRMAs assessing neoadjuvant chemotherapy (NAC) and/or chemoradiotherapy (NACRT) in resectable and borderline resectable PDAC. MEDLINE/PubMed, Embase, and Cochrane Library were searched from inception through November 2025. Eligible SRMAs reported at least one clinical outcome, including overall survival (OS), disease-free/event-free survival (DFS/EFS), resection rate, R0 resection, nodal status, or perioperative outcomes. Methodological quality was appraised using AMSTAR-2 and ROBIS tools. Overlap among SRMAs was quantified using the Corrected Covered Area (CCA), and RCT-only evidence was prioritized for causal inference. Evidence credibility was graded using an Ioannidis-style classification framework. Results: Thirty-four SRMAs published between 2010 and 2025 were included. In strictly resectable PDAC, RCT-only meta-analyses showed no definitive OS benefit for NAT compared with upfront surgery (pooled HR approximately 0.85, 95% CI 0.68–1.05), although a significant improvement in EFS was observed (HR approximately 0.77, 95% CI 0.65–0.90). Trial sequential analyses suggested insufficient information size for conclusive OS benefit in resectable disease. Conversely, in pooled resectable and borderline resectable populations, NAT significantly improved OS (HR approximately 0.66, 95% CI 0.52–0.85), with subgroup analyses indicating that the survival advantage was primarily driven by borderline resectable tumors. NAT consistently increased R0 resection and node-negative (pN0) rates and reduced non-curative explorations. However, neoadjuvant strategies were associated with treatment-related attrition and, in some analyses, lower overall resection rates. Comparative evidence suggested improved pathological outcomes with chemoradiotherapy versus chemotherapy alone, without a consistent survival advantage. Conclusions: Current high-level evidence supports NAT as the preferred strategy for borderline resectable PDAC, demonstrating consistent survival and pathological benefits. In strictly resectable disease, NAT improves disease-control endpoints and pathological surrogates, but a definitive OS advantage has not been consistently demonstrated in RCT-only syntheses. This should not be interpreted as evidence of equivalence between NAT and a surgery-first strategy, given the heterogeneity, limited power, and therapeutic-era effects of the available literature. Treatment decisions in resectable PDAC should therefore be individualized, balancing potential oncologic benefits against attrition risk. Future adequately powered randomized trials employing contemporary multi-agent regimens are needed to clarify the survival impact of NAT in strictly resectable disease. Full article

Objective: We evaluated whether a deep-learning model could predict the response to neoadjuvant chemotherapy (NAC) in breast cancer using the pre-treatment B-mode ultrasound. Methods: This retrospective study included 245 female patients (253 lesions) treated with NAC between 2017 and 2019. Lesions were categorized as complete response (CR; 103) or non-CR (150) based on postoperative pathology. We trained ResNet18-based models using pre-treatment B-mode ultrasound images (Image) and clinical features. Three training strategies were evaluated: training from scratch (SC); transfer learning (TL); and domain-specific pretraining (USP). Predictive performance was assessed using descriptive statistics. Results: The best-performing model (USP Image) achieved 0.76 accuracy (specificity: 0.80; sensitivity: 0.72), significantly outperforming all other models, including those that used additional clinical features ($p<0.05$). USP improved performance across most model types compared to SC and TL, highlighting the value of domain-specific pretraining. Clinical features added value with SC or TL, but not with USP, suggesting that pretrained models can extract the most relevant information directly from images. Grad-CAM analysis revealed that non-CR predictions focused on the tumor and posterior shadowing—features linked to chemoresistant subtypes. CR predictions focused mainly on more heterogeneous, peritumoral regions. Conclusion: This finding underscores ultrasound’s potential as a low-cost, accessible tool for predictive oncology in personalized, AI-driven treatment planning. Full article

Background/Objectives: Total neoadjuvant therapy (TnT) has emerged as a treatment option for locally advanced rectal cancer. Few studies have evaluated specifically the use of chemotherapy and short-course radiation therapy (SCRT) in obtaining a complete clinical response (cCR) or near-complete clinical response (nCR) and offering non-operative management (NOM). This phase II study sequences FOLFOX followed by SCRT with the primary aim of evaluating the rate of cCR or nCR. Methods: Treatment-naïve adults with non-metastatic clinical T2-3N0 or T1-3 with N1-2a rectal adenocarcinoma deemed candidates for total mesorectal excision (TME) were eligible for this open-label, single-arm clinical trial. This trial evaluated TnT with 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) followed by SCRT. The primary endpoint was the rate of cCR or nCR. Those with cCR or nCR after TnT were offered NOM and close surveillance; all others underwent TME. Secondary endpoints included 1-year disease-free survival (DFS), overall survival (OS), and R0 surgical resection rate. Results: Twelve patients of a planned 40 were enrolled with a median follow-up duration of 4.1 years. The study was closed early after results of the OPRA trial suggested a benefit of sequencing radiation prior to chemotherapy when seeking organ preservation. Four of the twelve patients (33%, 95% CI = (9.9%, 65.1%)) achieved cCR or nCR after TnT and underwent NOM; one patient had local regrowth 5.5 months after the completion of TnT and underwent TME. All four were free of disease at time of analysis. The 1-year DFS was 100%. The median OS was not reached. All surgical resections were R0 with no local recurrence after TME. Conclusions: This paper suggests that TnT with FOLFOX followed by SCRT is a safe and effective approach for treating locally advanced rectal cancer. This approach can be considered in select patients. The 33% of patients offered NOM is lower than the published 74% in OPRA, however, suggesting that chemotherapy followed by SCRT may not be the most optimal approach if organ preservation is the primary treatment aim. Full article

Background: Non-Wilms renal tumours (NWRTs) are rare paediatric malignancies and account for a small but clinically significant proportion of childhood renal cancers. Due to their low incidence and biological heterogeneity, outcome data are limited, and management is largely extrapolated from international collaborative protocols. No national data describing the incidence and outcomes of NWRTs in children in the Republic of Ireland (ROI) have previously been published. Objective: To determine the incidence, treatment strategies, and survival outcomes of NWRTs in children in the ROI. Methods: A retrospective cohort study was conducted of all children under 16 years of age with histologically confirmed renal tumours diagnosed and treated at Children’s Health Ireland (CHI) at Crumlin between January 2005 and December 2025. As CHI Crumlin is the single national paediatric oncology centre in the ROI, this cohort represents national case ascertainment for the study period. A total of 143 paediatric renal tumours were identified; Wilms tumours (n = 118) were excluded, leaving 25 children (17.48%) with NWRTs for analysis. No cases of bilateral renal tumours were identified. Histological subtypes included renal cell carcinoma (RCC), clear cell sarcoma of the kidney (CCSK), congenital mesoblastic nephroma (CMN), malignant rhabdoid tumour of the kidney (MRTK), and anaplastic sarcoma of the kidney. Demographic characteristics, treatment strategies, and survival outcomes were analysed. Results: Twenty-five children with NWRTs were identified: CCSK (n = 9), RCC (n = 7), CMN (n = 6), MRTK (n = 2), and anaplastic sarcoma of the kidney (n = 1). At a median follow-up of 107.9 months (range 4.5–181.3 months), overall survival for the cohort was 76%. Overall survival by histology was 100% for CMN, CCSK and anaplastic sarcoma, 43% for RCC, and 0% for MRTK. Treatment strategies varied by histology, with 68% undergoing upfront surgery, 32% receiving neoadjuvant chemotherapy, 60% receiving adjuvant systemic therapy, and 44% receiving radiotherapy. Tumour recurrence occurred in 4/25 patients (16%), confined to the RCC (3) and CMN (1) subgroups. Seven Event-Free Survival events were observed, comprising three RCC relapses and one RCC progression, one CMN relapse, and two MRTK progression-related deaths. No recurrences occurred in CCSK. Conclusions: NWRTs comprised 17.5% of all paediatric renal tumours diagnosed nationally during the study period and demonstrated marked heterogeneity in outcomes according to histological subtype. CMN showed excellent survival with six out of seven requiring surgery alone, whereas MRTK remained associated with dismal outcomes despite multimodal therapy. These national data support histology-driven, risk-adapted management and highlight the importance of continued international collaboration to improve outcomes in NWRTs. Full article

Background and Objectives: Neoadjuvant chemoradiotherapy is a key component of the treatment strategy for locally advanced rectal cancer (LARC), both through its direct impact on oncological prognosis and by increasing the likelihood of sphincter-preserving surgery. Oncological prognosis improves dramatically following a complete pathological response to neoadjuvant therapy. Identifying predictors of response to neoadjuvant therapy has been a challenge over the past two decades, and these factors have not been fully identified. This study aimed to analyze the clinical, biological, and therapeutic factors associated with tumor response following neoadjuvant therapy in patients with locally advanced rectal cancer, with the aim of identifying independent predictors of the absence of a complete pathological response and optimizing personalized treatment strategies. Materials and Methods: This retrospective study included a cohort of 122 patients (81 men and 41 women), with a mean age of 63.5 years, diagnosed with locally advanced rectal cancer at two centers with expertise in colorectal surgery between January 2018 and December 2023. Patients received neoadjuvant treatment in two regimens: long-course chemoradiotherapy with oral radiosensitizing chemotherapy (82 patients) and total neoadjuvant therapy consisting of chemoradiotherapy followed by consolidation chemotherapy (40 patients). A series of clinical, biological, and therapeutic variables was analyzed for their association with pathological responses. Results: According to the Ryan score, the overall complete response rate following neoadjuvant therapy was 17.2%. pCR was observed more frequently in patients treated with total neoadjuvant therapy than in those treated with standard chemoradiotherapy. Elevated pre-treatment CEA levels were independently associated with a higher risk of unfavorable tumor response. The radiation dose and interval between completion of radiotherapy and surgery were significantly associated with tumor regression. Conclusions: These results underscore the importance of personalizing neoadjuvant therapy to improve cancer prognosis. Furthermore, optimizing tumor regression could lead to the potential expansion of sphincter-preserving resection techniques, which would have a direct and significant impact on the quality of life of these patients. Full article

Background: Triple-negative breast cancer (TNBC) is associated with poor prognosis, highlighting the need for innovative therapeutic strategies. Chronomodulated chemotherapy yielded improved efficacy and tolerability in several malignancies; however, evidence in breast cancer remains limited. This study investigated the association between the time of day of administration (ToDA) of neoadjuvant chemotherapy (NAC) and clinical outcomes in patients with TNBC treated in a day hospital setting. Methods: This retrospective cohort included patients treated at Saint-Louis Hospital with neoadjuvant dose-dense, dose-intense cyclophosphamide–epirubicin followed by weekly paclitaxel. Infusion start times of each chemotherapy agent were systematically recorded. The primary endpoint was pathological complete response (pCR; Residual Cancer Burden [RCB] = 0). Secondary endpoints included RCB classes, early metabolic response, treatment tolerance, and 36-month event-free survival (EFS). Patients were classified into early or late infusion groups using multiple ToDA cut-offs, and cosine-based analyses were performed. Results: Ninety-four patients (median age 51 years) received NAC between 9:00 and 17:40 which aligns with the day hospital unit’s opening hours. With a median follow-up of 39.9 months, the pCR rate was 48.9%. No significant differences were observed between early and late infusion groups for any endpoint, regardless of ToDA cut-off or analytical approach. Conclusions: This first chronotherapeutic study in patients with early TNBC showed no association between ToDA of NAC administered between 9:00 and 17:40 and histological response or EFS. Although limited by sample size and the restricted infusion time window, our study provides novel data and methodological insights supporting further investigation of chronotherapy in patients with breast cancer. Full article

Objective: To evaluate the Tumor-Immune-Proliferation-Inflammation (TIPI) score as a composite biomarker for predicting pathological complete response (pCR) in human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with neoadjuvant therapy. Methods: This retrospective single-center study included 75 patients with HER2-positive invasive breast cancer treated with neoadjuvant chemotherapy plus dual anti-HER2 blockade (trastuzumab and pertuzumab). The association between the TIPI score and pCR was assessed using receiver operating characteristic (ROC) analysis and logistic regression. Results: pCR was achieved in 34 patients (45.3%). The optimal TIPI cut-off was 11.41. Patients with high TIPI scores had a higher pCR rate than those with low TIPI scores (56.3% vs. 25.9%, p = 0.016). However, the discriminative performance of the score was modest (AUC 0.598, 95% CI: 0.467–0.730; p = 0.145). In the adjusted analysis, hormone receptor negativity remained the most consistent factor associated with pCR. Conclusions: The TIPI score was developed as a preliminary composite model integrating selected tumor- and host-related biological variables and showed an exploratory association with pCR in this single-center HER2-positive cohort. Given the modest discriminative performance and lack of external validation, these findings should be interpreted cautiously. Further validation in larger independent cohorts is required before the score can be considered for clinical stratification or implementation. Full article

Background: Neoadjuvant chemotherapy (NAC) is widely used in the management of stage I–III breast cancer, with tumor regression serving as an important surrogate for long-term outcome. Identifying reliable pathological biomarkers predictive of residual disease remains clinically relevant. Methods: We conducted a retrospective cohort study of 165 patients with non-metastatic breast cancer treated with neoadjuvant chemotherapy followed by surgery between 2019 and 2022. Pathological response was assessed using the Residual Cancer Burden (RCB) index. The primary study endpoint was extensive residual disease (RCB-III), defined as the poorest category of tumor regression, indicating treatment resistance. Associations between the Nottingham Score together with other histopathological parameters, immunohistochemical markers (ER, PR, HER2), Ki67 proliferation index, and RCB were analyzed using univariate and multivariable logistic regression. Results: In univariate analysis, higher Nottingham scores (OR = 1.807, p = 0.0017), negative ER expression (OR = 3.017, p = 0.0255), the absence of lymphovascular invasion (OR = 0.1877, p = 0.0069) and elevated Ki67 (OR = 1.034, p = 0.0003) were significantly associated with RCB III. In multivariable analysis, only Ki67 and lymphovascular invasion remained independent predictors of RCB III, while Nottingham score and ER expression lost statistical significance. Correlation analysis demonstrated strong associations between Nottingham score, Ki67, hormone receptor loss, and tumoral necrosis. Conclusions: Ki67 is an independent predictor of poor tumor regression following neoadjuvant chemotherapy and appears to capture much of the prognostic information traditionally attributed to histologic grade and Nottingham score. However, the absence of lymphovascular invasion remains a significant positive prognostic factor. These observations support further investigation into the integration of proliferation markers into multivariable predictive models to improve response stratification in breast cancer. Full article

Background: Localized soft tissue sarcoma (STS) is primarily treated with surgical resection with or without radiotherapy (RT), while the role of chemotherapy (CT) as a radiosensitizer remains unclear. We report our single-institution experience with combined chemoradiotherapy (CCRT) in treating localized STS. Methods: We conducted a retrospective analysis of patients with localized STS treated at Mayo Clinic with mitomycin, cisplatin, and doxorubicin (MitoAP) concurrently with RT between 1/1/85 and 12/12/19. Results: We identified 179 patients (median age 58 years; median tumor size 9.5 cm), with 83.8% of tumors located in the extremities or trunk. Among them, 77.1% received perioperative CT in addition to CCRT, with 95% of those treated in the neoadjuvant setting. Median RT dose was 50 Gray. The 5-year disease-specific survival (DSS) was 77.9% (95% confidence interval, CI: 70.8–83.4%). The addition of perioperative CT to CCRT was associated with improved DSS compared with CCRT alone (p = 0.01, Hazard Ratio, HR: 0.48, 95% CI: 0.27–0.85). Median post-CCRT tumor viability was 30% and did not differ by CT use (p = 0.39), but varied significantly by histology (p < 0.001). Conclusions: Our institutional protocol utilizing two cycles of MitoAP with RT was well tolerated. DSS in our cohort was similar to historical data using perioperative RT alone, suggesting no clear benefit from CCRT. However, the majority of patients in our cohort were classified as high risk, which may have attenuated a potential survival benefit in the absence of appropriate comparative controls. Furthermore, additional perioperative CT to CCRT was associated with improved DSS and differential histology-specific responses in tumor viability, suggesting that a more aggressive neoadjuvant and perioperative approach may be beneficial in selected patients. Full article

Upper-tract urothelial carcinoma (UTUC) represents a biologically distinct and clinically challenging subset of urothelial malignancies, accounting for only 5–10% of urothelial cancers but carrying a disproportionately high risk of advanced disease and recurrence. Historically, management strategies for UTUC have been extrapolated from bladder cancer data, with limited prospective evidence specific to the upper urinary tract. However, recent years have witnessed an expanding number of UTUC-focused clinical trials that are reshaping treatment paradigms across localized, locally advanced, and metastatic disease states. This review examines the evolving landscape of clinical trials in UTUC, highlighting pivotal and ongoing studies that will inform contemporary management. We summarize evidence supporting perioperative systemic therapy, including neoadjuvant and adjuvant chemotherapy, and discuss the expanding role of immune checkpoint inhibitors in both perioperative and metastatic settings. Additionally, we review trials evaluating kidney-sparing approaches, intraluminal therapies, and novel drug-delivery platforms aimed at preserving renal function while maintaining oncologic control. Emerging trial designs incorporating molecular profiling, fibroblast growth factor receptor (FGFR)-targeted therapies, and biomarker-driven patient selection are also explored. Despite meaningful progress, significant gaps remain, including the underrepresentation of UTUC patients in large urothelial cancer trials, heterogeneity in risk stratification, and challenges in trial accrual for this rare disease. We conclude by outlining future directions for UTUC-specific clinical research, emphasizing the need for collaborative, multicenter trials, innovative endpoints, and integrated translational studies to further refine personalized treatment strategies. As the clinical trial ecosystem for UTUC continues to mature, these efforts hold promises for improving outcomes while balancing oncologic efficacy with renal preservation. Full article

Purpose: To compare the efficacy of Superb Microvascular Imaging (SMI) with grayscale ultrasound (US) and dynamic contrast-enhanced MRI in predicting pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in invasive breast cancer. Methods: A total of 115 patients included in the study were evaluated based on their pre-treatment imaging findings (US, mammography, and MRI). Following completion of NAC, all patients underwent grayscale US and SMI examinations. In patients with available post-NAC MRI, treatment response was additionally assessed by comparing MRI findings. Imaging results were correlated with postoperative pathological outcomes, which served as the reference standard. pCR was defined as the absence of residual invasive carcinoma, regardless of ductal carcinoma in situ. Molecular subtype, Ki-67, and axillary status were recorded. Statistical analyses included chi-square tests and stepwise multiple logistic regression. Significance was set at p < 0.05 (95% CI). Results: The median age was 51 years (range: 30–75). Most tumors were high-grade (55%) and invasive ductal carcinoma (95%). Breast-pCR was achieved in 43% of patients. Significant predictors of pCR included hormone receptor negativity, HER-2 positivity, high Ki-67 expression (≥40%), non-luminal subtype, and complete radiologic response on US and MRI (p < 0.05). Lower SMI index values were strongly associated with pCR (p < 0.001), with an optimal cut-off of 1.8 demonstrating good diagnostic performance (AUC = 0.804, 95% CI: 0.721–0.887). In multivariate analysis, the combined model including US, SMI, HER-2 status, and MRI showed the highest predictive performance (AUC = 0.890, 95% CI: 0.829–0.950), explaining 55.1% of the variance in pCR. Conclusions: An SMI index < 1.8, HER-2 positivity, and complete response on US and MRI are independent predictors of pCR after NAC. Combining SMI with multimodal imaging significantly improves predictive accuracy. Full article

Background/Objectives: Total neoadjuvant therapy (TNT), integrating systemic chemotherapy and radiotherapy before surgery or surveillance, has become a standard approach for locally advanced rectal cancer (LARC). However, optimal sequencing strategies and long-term outcomes of watch-and-wait (W&W) following sandwich TNT remain insufficiently characterized. We evaluated oncologic outcomes and treatment response in patients treated with an institutional sandwich TNT protocol. Methods: We conducted a retrospective cohort study of consecutive patients with LARC treated with sandwich TNT (induction chemotherapy followed by hypofractionated intensity-modulated radiotherapy with simultaneous integrated boost [IMRT-SIB] chemoradiotherapy and consolidation chemotherapy) at the Institute of Oncology Ljubljana between 2016 and 2023. The primary endpoint was an overall complete response (CR; pathological [pCR] and clinical [cCR]). Secondary endpoints included tumor regression grade (TRG), major pathological response (MPR), R0 resection rate, organ preservation, overall survival (OS), and disease-free survival (DFS). Results: Among 205 patients (median age 61 years), overall CR was 29.5% (pCR 19.3% and cCR 10.2%). Major pathological response (TRG 3–4) occurred in 37.6%. R0 resection was achieved in 94.5%. In the W&W cohort (n = 21), local regrowth occurred in 33.3% (95% CI, 14.6–57.0%) over a median follow-up of 4.96 years. Total mesorectal excision (TME)-free survival at 5 years was 73.1% (95% CI, 55.0–97.2%). Estimated 5-year OS was 81.1% (95% CI, 75.5–87.2%) and 5-year DFS was 75.2% (95% CI, 69.0–82.0). In multivariable analysis, non-R0 resection (HR 6.06, 95% CI, 1.99–18.42), MRI circumferential resection margin positivity (HR 3.11, 95% CI, 1.53–6.33), and MRI extramural vascular invasion positivity (HR 1.97, 95% CI, 1.05–3.91) remained independent predictors of DFS. Conclusions: Institutional sandwich TNT yields meaningful tumor response and durable survival in MRI-defined high-risk LARC. Structured W&W offers organ preservation with acceptable oncologic control under intensive surveillance. Full article