Existing adjuvant therapies improve outcomes for resected stage III and IV melanoma patients but fail in almost half to prevent recurrence and death. Large, multi-institution, randomized studies firmly establish the superiority of neoadjuvant to adjuvant therapy alone. Checkpoint inhibition, either anti-programmed cell death protein 1 monotherapy or combination with CTLA-4/LAG-3 blockage, demonstrates more durable event-free survival compared to targeted or targeted/immunotherapy combination therapies. Novel combinations of intralesional immunotherapies and other agents aim to increase clinical efficacy and limit toxicity of therapies. Pathologic response to treatment remains as the best prognostic surrogate for clinical outcomes for patients.

To evaluate the efficacy, recommended phase II dose (RP2D), dose-limiting toxicity (DLT), and safety profiles of PEP503 (NBTXR3) in combination with concurrent chemoradiotherapy (CCRT) in patients with locally advanced or unresectable rectal adenocarcinoma.

A single administration of intratumor injection of PEP503 (NBTXR3) (multiple punctures) was applied, followed by radiotherapy in combination with capecitabine or 5-fluorouacil (5-FU). Surgery was performed 8 to 12 weeks after completion of CCRT.

Thirty-two patients were enrolled (one dropped out before CCRT), comprising 20 in phase Ib and 12 in phase II. The disease control rate was 100% (n = 31). One (3.2%) and 19 (61.3%) patients achieved clinical complete response and partial response, respectively. Twenty-five patients underwent surgery, of whom 24 (96%) had R0 resection and 5 (20%) had pathological complete response. Most of the adverse events were grade 1/2 events.

Intratumor injection of PEP503 (NBTXR3) in patients with locally advanced or unresectable rectal adenocarcinoma is safe and effective. Addition of PEP503 (NBTXR3) to fluoropyrimidine-based neoadjuvant CCRT does not engender increased toxicity. The strong safety profile and encouraging efficacy of PEP503 (NBTXR3) in combination with neoadjuvant CCRT in locally advanced or unresectable rectal cancer warrant further examination in clinical studies.

This study was registered on ClinicalTrials.gov Identifier: NCT02465593.

Patients with locally advanced rectal cancer (LARC) show substantial individual variability and a pronounced imbalance in response distribution to neoadjuvant chemoradiotherapy (nCRT), posing significant challenges to treatment response prediction. This study aims to identify effective predictive biomarkers and develop an ensemble learning-based prediction model to assess the response of LARC patients to nCRT. A two-step feature selection method was developed to identify predictive biomarkers by deriving stable reversal gene pairs through within-sample relative expression orderings (REOs) from LARC patients undergoing nCRT. Preliminary screening utilized four methods-MDFS, Boruta, MCFS, and VSOLassoBag-to form a candidate feature set. Secondary screening ranked these features by permutation importance, applying Incremental Feature Selection (IFS) with an Extreme Gradient Boosting (XGBoost) to determine final predictive gene pairs. The ensemble model BoostForest, combining boosting and bagging, served as the predictive framework, with SHAP employed for interpretability. Through two-step feature selection, the 32-gene pair signature (32-GPS) was established as the final predictive biomarker. In the test set, the model achieved an area under the precision-recall curve (AUPRC) of 0.983 and an accuracy of 0.988. In the validation cohort, the AUPRC was 0.785, with an accuracy of 0.898, indicating strong model performance. The study further demonstrated that BoostForest achieved superior overall performance compared to Random Forest, Support Vector Machine (SVM), and XGBoost. To evaluate the effectiveness of the 32-GPS, its performance was compared with two alternative feature sets: the lasso-gene pair signature (lasso-GPS), derived through lasso regression, and the 15-shared gene pair signature (15-SGPS), consisting of gene pairs identified by all four feature selection methods. The 32-GPS demonstrated superior performance in both comparisons. The two-step feature selection method identified robust predictive biomarkers, and BoostForest outperformed Random Forest, Support Vector Machine, and XGBoost in classification performance and predictive capability.

Organ preservation through a watch-and-wait (W&W) strategy has become a viable option for select rectal cancer patients with clinical complete responses (cCR) to total neoadjuvant therapy (TNT). This approach limits the morbidity associated with multimodal treatment. However, the optimal treatment strategy and predictors of treatment response are still unresolved. Rectal cancer incidence is rising, particularly in developing countries, and the disease is a major public health concern in Chile. Prior to the no operation after short-course radiotherapy followed by consolidation chemotherapy in locally advanced rectal cancer (NOAHS-ARC) trial, TNT-based treatments and W&W programs had not been implemented in Chile.

This single-arm, multicenter, phase II prospective trial, conducted in Santiago, Chile, will enroll patients with stage II/III rectal adenocarcinoma. Treatment involves induction short-course radiotherapy (25 Gy in 5 fractions) followed by consolidation chemotherapy (FOLFOX × 9 or CAPOX × 6 cycles). The response will be assessed 4-8 weeks after chemotherapy completion. Patients achieving cCR will be offered W&W, while those with incomplete responses will undergo total mesorectal excision. The primary endpoint is the rate of complete tumor response, combining pathologic complete responses (pCR) and sustained cCR (> 1 year), compared to a matched cohort treated with neoadjuvant chemoradiation alone. The trial aims to recruit 48 patients, assuming a combined pCR/sustained cCR rate of 12%. Quality of life measures will be assessed, and a biorepository of tissue and plasma samples will be established for future research, alongside serial endoscopic and MRI images.

NOAHS-ARC seeks to advance organ preservation strategies in rectal cancer while pioneering TNT and W&W protocols in Chile. The study will also focus on functional outcomes and provide valuable data for improving patient care both locally and globally.

ClinicalTrials.gov identifier NCT04864067. Registered on April 28, 2021.

Although classified as one stage, T4b rectal cancer actually represents a group of heterogeneous diseases. Our study aimed to assess the prognosis difference of T4b rectal cancer involving inferior pelvic and other pelvic compartments. This information may be helpful in refinement of the current T staging system.

We retrospectively analysed data from 195 patients with magnetic resonance imaging-identified locally advanced T4b rectal cancer who received neoadjuvant chemoradiotherapy between January 2010 and December 2019. 104 patients had only inferior pelvic compartment involvement (group A) while 91 patients had anterior, posterior or lateral pelvic compartment involvement (group B). Short-term and long-term outcomes were compared between the two groups.

After neoadjuvant therapy, 80.8 % patients (84/104) in group A and 92.3 % patients (84/91) in group B underwent surgery. The R0 resection rates were 97.6 % and 89.3 %, respectively. 8.7 % patients (9/104) in group A achieved clinical complete response and adopted watch-and-wait strategy. Patients in group A had significantly superior 5-year progression-free survival (PFS) (67.8 % vs. 55.5 %, P = 0.032) and overall survival (OS) (89.6 % vs. 71.8 %, P = 0.001) than group B. Multivariable Cox regression analysis also identified pelvic compartment involvement classification as an independent predictor of PFS (hazard ratio 1.776, P = 0.046) and OS (hazard ratio 3.477, P = 0.004).

T4b rectal cancers with involvement limited to the inferior pelvic compartment had superior prognosis compared to those involving other pelvic compartments. These differences should be investigated further and taken into consideration in refinement of the current T staging system.

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.

The role of adjuvant chemotherapy in rectal cancer patients downstaged to ypT0-2 N0 after neoadjuvant chemoradiotherapy (CRT), and surgery is still debated. This study investigates the impact of adjuvant chemotherapy on survival outcomes in this patient population.

This retrospective study analyzed hospital records of rectal cancer cases from Shefa Al Orman Cancer Hospital between January 2016 and December 2020, focusing on patients downstaged to ypT0-2 N0 after neoadjuvant CRT and surgery. Patients were divided into two groups based on whether they received adjuvant chemotherapy. Baseline characteristics, DFS, and OS were compared, and survival factors were analyzed using univariate and multivariate Cox regression.

Eighty-five patients met the inclusion criteria; 55 received adjuvant chemotherapy, and 30 did not. The median age was 52, but those receiving adjuvant therapy were younger (47 vs. 60 years, P = 0.006). No significant differences were observed in sex, tumor location, or pathology between groups. Although adjuvant chemotherapy showed a trend toward better 3-year DFS (89.5% vs. 81.9%, P = 0.153) and OS (88.1% vs. 84.6%, P = 0.654), these differences were not statistically significant. Univariate and multivariate analyses confirmed no significant effect of adjuvant chemotherapy on DFS or OS, nor were any other variables significantly associated with survival.

Adjuvant chemotherapy did not significantly improve DFS or OS in rectal cancer patients downstaged to ypT0-2 N0 following neoadjuvant CRT and surgery. Further studies are needed to define the role of adjuvant therapy in this group.

BackgroundLocal advanced rectal cancer (LARC) patients who achieved pathological complete response (pCR) after neoadjuvant chemoradiotherapy (NCRT) generally have a favorable prognosis. This retrospective study aimed to evaluate the prognostic value of magnetic resonance imaging (MRI) parameters and neutrophil-to-lymphocyte ratio (NLR) in LARC patients with pCR.MethodsBetween 2015 and 2019, 180 LARC patients who achieved pCR after NCRT and surgery were included. MRI parameters and NLR were evaluated as potential predictors for 5-year overall survival (OS) and disease-free survival (DFS) using the Kaplan-Meier and COX regression analysis.ResultsWith a median follow-up time of 68.3 months, the 5-year OS and DFS rates were 94.2% and 91.4%, respectively. Thirteen patients (7.2%) died, 2 (1.1%) experienced local recurrence, and 15 (8.3%) experienced distant metastases. Pretreatment MRI parameters and NLR were correlated with 5-year OS and DFS in pCR patients in the univariate analysis. The multivariate analysis identified baseline EMVI and NLR as independent predictors for 5-year OS and DFS (all P < .05). Patients in the low-risk group (EMVI-negative and/or NLR ≤ 2.8, n = 159, 88.3%) had a more favorable 5-year DFS compared to those in the high-risk group (EMVI-positive and NLR > 2.8, n = 21, 11.7%) (95.6% vs 59.4%, P < .001), with similar findings for 5-year OS (97.4% vs 70.6%, P < .001).ConclusionsThis study showed that MRI parameters and NLR were associated with long-term prognosis in patients with pCR. These findings could aid in stratifying pCR patients and guide subsequent treatment and follow-up strategies.

Accurate prediction of pathological complete response (pCR) and disease-free survival (DFS) in locally advanced rectal cancer (LARC) patients undergoing neoadjuvant chemoradiotherapy (NCRT) is essential for formulating effective treatment plans. This study aimed to construct and validate the machine learning (ML) models to predict pCR and DFS using pathomics.

A retrospective analysis was conducted on 294 patients who received NCRT from two independent institutions. Pathomics from pre-NCRT H&E stains were extracted, and five ML models were developed and validated across two centers using ROC, Kaplan-Meier, time-dependent ROC, and nomogram analyses.

Among the five ML models, the Xgboost (XGB) model demonstrated superior performance in predicting pCR, achieving an AUC of 1.000 (p < 0.001) on the internal data-set and an AUC of 0.950 (p = 0.001) on the external data-set.The XGB model effectively differentiated between high-risk and low-risk prognosis patients across all five centers: internal dataset (DFS, p = 0.002; OS, p = 0.004) and external dataset (DFS, p = 0.074; OS, p = 0.224).Furthermore, the COX regression demonstrated that the tumor length (HR = 1.230, 95%CI: 1.050-1.440, p = 0.010), post-NCRT CEA (HR = 1.716, 95%CI: 1.031- 2.858, p = 0.038), and XGB model score (HR = 0.128, 95%CI: 0.026-0.636, p = 0.012) were independent predictors of DFS after NCRT in the internal data-set.Using COX regression, the nomogram model and time-dependent AUC analysis demonstrated strong predictive discrimination for DFS in LARC patients across two independent institutions.

The ML model based on pathomics demonstrated effective prediction of pCR and prognosis in LARC patients. Further validation in larger cohorts is warranted to confirm the findings of this study.

Background: Patients with locally advanced rectal cancer (LARC) treated by neoadjuvant chemoradiotherapy (nCRT) may experience pathological complete response (pCR). Tools that can identify pCR are required to define candidates suitable for the watch and wait (WW) strategy. Automated image analysis is used for predicting clinical aspects of diseases. Texture analysis of magnetic resonance imaging (MRI) wavelets algorithms provides a novel way to identify pCR. We aimed to evaluate wavelets-based image analysis of MRI for predicting pCR. Methods: MRI images of rectal cancer from 22 patients who underwent nCRT were captured at best representative views of the tumor. The MRI images were digitized and their texture was analyzed using different mother wavelets. Each mother wavelet was used to scan the image repeatedly at different frequencies. Based on these analyses, coefficients of similarity were calculated providing a variety of textural variables that were subsequently correlated with histopathology in each case. This allowed for proper identification of the best mother wavelets able to predict pCR. The predictive formula of complete response was computed using the independent statistical variables that were singled out by the multivariate regression model. Results: The statistical model used four wavelet variables to predict pCR with an accuracy of 100%, sensitivity of 100%, specificity of 100%, and PPV and NPV of 100%. Conclusions: Wavelet-transformed texture analysis of radiomic MRI can predict pCR in patients with LARC. It may provide a potential accurate surrogate method for the prediction of clinical outcomes of nCRT, resulting in an effective selection of patients amenable to WW.

This study aimed to stratify patients with locally advanced rectal cancer (LARC) based on their response to neoadjuvant chemoradiation therapy (nCRT) using DNA damage response (DDR)-related proteins measured in peripheral blood monocytes (PBMCs). We optimized and validated an innovative assay to quantify these proteins, providing a predictive framework for nCRT response.

We used PBMCs collected from LARC patients either before or after standard course of ∼5.5 weeks of nCRT, with patients categorized by neoadjuvant rectal (NAR) score. DDR was assessed by immunofluorescence (γH2AX S139 foci), and by Luminex multi-analyte platform (xMAP) assay providing semi-quantitative assessment of phosphorylated Chk1 S345 , Chk2 T68 , γH2AX S139 , p53 S15 and total ATR, MDM2, p21. Assay performance was evaluated using reference controls and banked PBMCs from healthy controls (n=50).

PBMCs from poor responders (PoR; NAR >14; n=21) had significantly lower γH2AX S139 foci than complete responders (CR; NAR <1; n=21) (p<0.0001), with no significant differences between pre- and post-nCRT samples (p=0.4961). The xMAP assay performance assessment showed linear sample curves, precision with acceptable inter- and intra-assay coefficients of variability, and high reproducibility with ∼1% outliers in replicates. Clinical associations using the xMAP assay found levels of six proteins (ATR, MDM2, Chk1 S345 , Chk2 T68 , γH2AX S139 , p53 S15 ) significantly differentiating CRs from PoRs (p ≤ 1e-5). Univariate CART analysis determined thresholds that segregated PoRs from CRs with high precision (p<0.001).

We optimized an assay to assess DDR proteins in PBMCs and identified specific proteins, along with their threshold levels, that can accurately predict response to nCRT in patients with LARC.

Although neoadjuvant chemoradiation therapy followed by surgery is the standard of care for patients with locally advanced rectal cancer (LARC), many patients do not benefit from this treatment and suffer from its side effects. The motivation for this study was to reliably identify patients with LARC who will or will not respond to treatment, thereby permitting more effective direction of therapy only to likely responders. In this report, we describe identification and optimization of a novel multianalyte assay for patients diagnosed with LARC. This assay uses a Luminex xMAP platform to detect DNA damage response (DDR) signaling proteins in peripheral blood monocytes of pre-treatment patients. This assay, detecting the DDR proteins, effectively segregates responders from non-responders (p ≤ 1e-5), supporting optimization of treatment efficacy and reduction of unnecessary toxicity, thus advancing personalized medicine in oncology.

Locally recurrent rectal cancer (LRRC), which occurs in 6-12% of patients previously treated with surgery, with or without pre-operative chemoradiation therapy, represents a complex and heterogeneous disease profoundly affecting the patient's quality of life (QoL) and long-term survival. Its management usually requires a multidisciplinary approach, to evaluate the several aspects of a LRRC, such as resectability or the best approach to reduce symptoms. Surgical treatment is more complex and usually needs high-volume centers to obtain a higher rate of radical (R0) resections and to reduce the rate of postoperative complications. Multiple factors related to the patient, to the primary tumor, and to the surgery for the primary tumor contribute to the development of local recurrence. Accurate pre-treatment staging of the recurrence is essential, and several classification systems are currently used for this purpose. Achieving an R0 resection through radical surgery remains the most critical factor for a favorable oncologic outcome, although both chemotherapy and radiotherapy play a significant role in facilitating this goal. If a R0 resection of a LRRC is not feasible, palliative treatment is mandatory to reduce the LRRC-related symptoms, especially pain, minimizing the effect of the recurrence on the QoL of the patients. The aim of this manuscript is to provide a comprehensive narrative review of the literature regarding the management of LRRC.

This study evaluated surgical complication rates, recurrence-free survival, overall survival (OS), and stoma status of patients with rectal cancer after significant pathologic response following neoadjuvant treatment and curative resection. Pathologic complete response (pCR) and near-pCR patients constitute patients in our study.

Included was a retrospective cohort study of patients with rectal cancer who were diagnosed between July 2011 and September 2022 and who underwent neoadjuvant therapy and surgical resection.

Of 696 patients with rectal cancer, 149 (21.4%) cases achieved significant pathologic response. During the 64 (70.5) months of follow-up, recurrence occurred in 16.1% of patients and distant metastases account for the majority of them. Age (p = 0.014) and receiving adjuvant chemotherapy (p = 0.016) were significantly related to the occurrence of recurrence. The five-year recurrence-free survival (RFS) and OS rates were obtained at 83% and 87%, respectively. Although age and surgical technique were significant factors in univariate Cox regression analysis, none of the candidate variables were significant prognostic factors for RFS in the multiple models. The risk of surgical complications remained in these patients. The most frequent complication attributed to infection (20.8%). Despite the 24.8% presence of permanent stoma at primary surgery, more than 50% of our patients lived without stoma at the last follow-up.

Our recurrence rate was about 16%, and it was related to age and adjuvant chemotherapy. These patients achieved over 80% rates of five-year RFS and OS. No significant prognostic factors were found on RFS in the multivariable model. As a matter of course, the risk of surgical complications and permanent stoma has still remained in these patients.

The treatment of rectal cancer underwent a significant change with the introduction of total mesorectal excision (TME), which substantially improved recurrence rates. However, TME is associated with complications such as fecal incontinence and poor bladder control, especially in tumors located near the anal verge. The watch-and-wait (WW) protocol has emerged as an alternative for patients achieving a clinical complete response (cCR) following neoadjuvant radiochemotherapy. This narrative review, developed according to the Scale for the Assessment of Narrative Review Articles guidelines, evaluates neoadjuvant treatments and the WW protocol for rectal cancer. Literature was sourced from the PubMed database using specific search terms related to neoadjuvant therapy and the WW protocol, resulting in 63 articles selected for discussion. Neoadjuvant treatment, including chemoradiation and short-course radiotherapy, is indicated for T3 and T4 rectal adenocarcinomas. Studies like the German Rectal Cancer Study Group and the PRODIGE 23 trial have shown the benefits of preoperative treatment, including improved disease-free survival and reduced local recurrence rates. However, challenges in adopting the WW protocol include the risk of local regrowth and distant metastasis. Immune checkpoint inhibitors have shown promise in mismatch repair-deficient patients, yet the data are insufficient to fully endorse WW for these cases. The WW protocol is viable for selected rectal cancer patients, with ongoing debates regarding criteria for inclusion. Key challenges include accurately identifying cCR and managing patients with near-complete responses. MRI and endoscopic evaluation are crucial for assessing treatment response, although achieving a pathological complete response remains uncertain. The WW strategy offers a potential organ-preserving approach in rectal cancer management but requires careful patient selection and comprehensive risk-benefit discussions. Further research is needed to refine criteria for inclusion and optimize treatment protocols, enhancing outcomes while minimizing invasive interventions.

This study aimed to develop nomograms that combine clinical factors and MRI tumour regression grade to predict the pathological response of mid-low locally advanced rectal cancer to neoadjuvant chemoradiotherapy.

The retrospective study included 204 patients who underwent neoadjuvant chemoradiotherapy and surgery between January 2013 and December 2021. Based on pathological tumour regression grade, patients were categorized into four groups: complete pathological response (pCR, n=45), non-complete pathological response (non-pCR; n=159), good pathological response (pGR, n=119), and non-good pathological response (non-pGR, n=85). The patients were divided into a training set and a validation set in a 7:3 ratio. Based on the results of univariate and multivariate analyses in the training set, two nomograms were respectively constructed to predict complete and good pathological responses. Subsequently, these predictive models underwent validation in the independent validation set. The prognostic performances of the models were evaluated using the area under the curve (AUC).

The nomogram predicting complete pathological response incorporates tumour length, post-treatment mesorectal fascia involvement, white blood cell count, and MRI tumour regression grade. It yielded an AUC of 0.787 in the training set and 0.716 in the validation set, surpassing the performance of the model relying solely on MRI tumour regression grade (AUCs of 0.649 and 0.530, respectively). Similarly, the nomogram predicting good pathological response includes the distance of the tumour's lower border from the anal verge, post-treatment mesorectal fascia involvement, platelet/lymphocyte ratio, and MRI tumour regression grade. It achieved an AUC of 0.754 in the training set and 0.719 in the validation set, outperforming the model using MRI tumour regression grade alone (AUCs of 0.629 and 0.638, respectively).

Nomograms combining MRI tumour regression grade with clinical factors may be useful for predicting pathological response of mid-low locally advanced rectal cancer to neoadjuvant chemoradiotherapy. The proposed models could be applied in clinical practice after validation in large samples.

Background Neoadjuvant chemotherapy (NCT) is gaining acceptance for the management of locally advanced rectal cancer (LARC) in patients without negative prognostic factors. However, the value of MRI in evaluating tumor response after NCT remains unclear. Purpose To investigate the accuracy of MRI in assessing pathologic complete response in participants with LARC who underwent surgery after NCT without radiation. Materials and Methods A retrospective imaging substudy was conducted within two consecutive prospective clinical trials: the expanded phase II trial (from December 2017 to May 2021) and the COPEC trial (comparison of tumor response to two or four cycles of neoadjuvant chemotherapy alone, ongoing from August 2021). All included participants received four cycles of capecitabine combined with oxaliplatin (or CAPOX) before surgery. Three radiologists who were blinded to the clinicopathologic data independently evaluated the tumor response using five methods, namely, MR tumor regression grade (MR-TRG) alone, diffusion-weighted imaging (DWI) alone, DWI-modified MR-TRG (DWImodMR-TRG), MRI complete response, and radiologic neoadjuvant response score. With pathologic assessment serving as the reference standard, the positive and negative predictive values, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were determined to evaluate the accuracy and performance of these models. The AUCs of the models were compared using the DeLong test. Results A total of 224 participants were included, comprising 119 from the expanded phase II trial (median age, 61 years [IQR, 53-67]; 89 male) and 105 from the COPEC trial (median age, 59 years [IQR, 53-67]; 65 male). MR-TRG, DWI, DWImodMR-TRG, MRI complete response, and the radiologic neoadjuvant response score were associated with pathologic complete response. DWImodMR-TRG achieved the highest AUC of 0.90 (95% CI: 0.85, 0.95), with a specificity of 89% (162 of 182) and a negative predictive value of 93% (162 of 174). Conclusion MRI-based models were accurate for determining pathologic complete response in participants with LARC following NCT. DWI improved the predictive performance of MRI-based assessment. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Santiago and Shur in this issue.

The neoadjuvant rectal score (NAR score) has recently been proposed as a better prognostic model than the conventional TNM classification for rectal cancer patients that have undergone neoadjuvant chemoradiotherapy. We recently developed an apoptosis-detection technique for assessing the viability of residual tumors in resected specimens after chemoradiotherapy. This study aimed to establish an improved prognostic classification by combining the NAR score and the assessment of the apoptosis of residual cancer cells.

We retrospectively enrolled 319 rectal cancer patients who underwent chemoradiotherapy followed by radical surgery. The recurrence-free survival and overall survival of the four models were compared: TNM stage, NAR score, modified TNM stage by re-staging according to cancer cell viability, and modified NAR score also by re-staging.

Downstaging of the ypT stage was observed in 15.5% of cases, whereas only 4.5% showed downstaging of ypN stage. C-index was highest for the modified NAR score (0.715), followed by the modified TNM, TNM, and NAR score. Similarly, Akaike's information criterion was smallest in the modified NAR score (926.2), followed by modified TNM, TNM, and NAR score, suggesting that the modified NAR score was the best among these four models. The overall survival results were similar: C-index was the highest (0.767) and Akaike's information criterion was the smallest (383.9) for the modified NAR score among the four models tested.

We established a novel prognostic model, for rectal cancer patients that have undergone neoadjuvant chemoradiotherapy, using a combination of apoptosis-detecting immunohistochemistry and neoadjuvant rectal scores.

The optimal management of patients with clinical complete response after neoadjuvant treatment for rectal cancer is controversial. The aim of this study is to compare the morbidity between patients with locally advanced rectal cancer who have had a pathological complete response (pCR) or not after neoadjuvant chemoradiotherapy (NCRT) and total mesorectal excision (TME). The study hypothesis was that pCR may impact the surgical complication rate.

A retrospective cohort study was conducted of a prospectively maintained database in Australia and New Zealand, the Binational Colorectal Cancer Audit, that identified patients with locally advanced rectal cancer (<15 cm from anal verge) from 1 January 2007 to 31 December 2019. Patients were included if they had locally advanced rectal cancer and had undergone NCRT and proceeded to surgical resection.

There were 4584 patients who satisfied the inclusion criteria, 65% being male. The mean age was 63 years and 11% had a pCR (ypT0N0). TME with anastomosis was performed in 67.8% of patients, and the majority of the cohort received long-course radiotherapy (81.7%). Both major and minor complications were higher in the TME without anastomosis group (17.3% vs. 14.7% and 30.6% vs. 20.8%, respectively), and the 30-day mortality was 1.31%. In the TME with anastomosis group, pCR did not contribute to higher rates of surgical complications, but male gender (p < 0.0012), age (p < 0.0001), preoperative N stage (p = 0.0092) and American Society of Anesthesologists (ASA) score ≥3 (p < 0.0002) did. In addition, pCR had no significant effect (p = 0.44) but male gender (p = 0.0047) and interval to surgery (p = 0.015) contributed to higher rates of anastomotic leak. In the TME without anastomosis cohort, the only variable that contributed to higher rates of complications was ASA score ≥3 (p = 0.033).

Patients undergoing TME dissection for rectal cancer following NCRT showed no difference in complications whether they had achieved pCR or not.

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).

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.

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.

For LARC patients with a ypT1-4N0 status after NCRT, ypT stage may be a more effective predictor of long-term prognosis than TRG.

Near-pathological complete response (Near-pCR) patients constitute a distinct subgroup with limited research attention. The clinical relevance of adjuvant chemotherapy (ACT) in this patient cohort remains uncertain.

We conducted a retrospective analysis of 245 patients with locally advanced rectal cancer (LARC) who achieved near-pCR following neoadjuvant chemoradiotherapy (NCRT) between 2011 and 2018. Based on their receipt of ACT or not (non-ACT), patients were divided into two groups. We examined their characteristics, treatment modalities, and survival outcomes, particularly focusing on 5-year disease-free survival (DFS) and 5-year overall survival (OS).

Among the 245 near-pCR patients, 191 (77.96%) received ACT, and 42 (17.14%) experienced disease recurrence. All 54 (22.04%) Patients in the non-ACT group exhibited a lower 5-year DFS rate (72.2% vs. 85.9%, P = 0.014) and a similar 5-year OS rate (87.0% vs. 91.1%, P = 0.351). Interestingly, those with ypT3-T4 stage tumors demonstrated a worse DFS (76.8% vs. 89.9%, P = 0.010) and OS (87.5% vs. 97.0%, P = 0.004) compared to their counterparts with ypT1-T2 stage tumors. Patients with Non-Downstage tumors showed inferior DFS (76.9% vs. 88.3%, P = 0.025) and OS (87.2% vs. 93.0%, P = 0.166) in comparison to patients with Downstage tumors. The ACT subgroup in patients with Downstage demonstrated statistically better 5-year DFS (93.0% vs. 71.4%, P = 0.001) but analogous survival rates for 5-year OS (OS: 94.0% vs. 89.3%, P = 0.402). Pathological T stage 3-4, perineural invasion (PNI) (positive) and ACT were independent factors influencing 5-year DFS in multivariate analysis. Both univariate and multivariate analysis demonstrated a link between serum carcinoembryonic antigen (CEA) before treatment ≥5 ng/ml and shorter 5-year OS. Notably, near-pCR patients with positive lymph nodes experienced notably diminished 5-year DFS in the absence of ACT post-surgery (61.1% vs. 93.2%, P < 0.001).

ACT demonstrated a significant positive impact on the prognosis of select near-pCR patients, particularly those with ypT1-T2 stage tumors and positive lymph nodes. ypT staging may emerge as a valuable criterion for precise post-surgical ACT guidance in near-pCR patients.

The introduction of total mesorectal excision into the radical surgery of rectal cancer has significantly improved the oncological outcome with longer survival and lower local recurrence. Traditional treatment modalities of distal rectal cancer, relying on radical surgery, while effective, take their own set of risks, including surgical complications, potential damage to the anus, and surrounding structure owing to the pursuit of thorough resection. The progress of operating methods as well as the integration of systemic therapies and radiotherapy into the peri-operative period, particularly the exciting clinical complete response of patients after neoadjuvant treatment, have paved the way for organ preservation strategy. The non-inferiority oncological outcome of "watch and wait" compared with radical surgery underscores the potential of organ preservation not only to control local recurrence but also to reduce the need for treatments followed by structure destruction, hopefully improving the long-term quality of life. Radical radiotherapy provides another treatment option for patients unwilling or unable to undergo surgery. Organ preservation points out the direction of treatment for distal rectal cancer, while additional researches are needed to answer remaining questions about its optimal use.

Rectal cancer (RC) poses a significant global health challenge, causing substantial morbidity and mortality. This study aims to investigate the survival rates of RC patients and identify the factors that influence their survival. The study considers demographic characteristics, tumor features, and treatment received as the factors under consideration.

A retrospective analysis was conducted on the medical records of 593 RC patients. Data were collected through a comprehensive review of medical records and conducting telephone interviews. Survival rates were estimated using the life table method, and subgroup comparisons were performed using the log-rank test. Cox regression analysis was utilized to assess the independent associations between RC survival time and various covariates.

The study cohort comprised 593 RC patients, with a predominantly male representation. The mean age at diagnosis was 58.18 years, and the majority of patients (78.6 %) underwent surgical interventions. The median age at symptom onset and diagnosis were 58 and 59 years, respectively. Survival rates at 1st, 3rd, 5th, and 10th years were estimated to be 85 %, 59 %, 47 %, and 36 %, respectively. Statistical analysis revealed several significant prognostic factors, including age, education, symptoms, and cancer stage. In the multivariate Cox proportional-hazards analysis, advanced regional stage (HR = 1.54, 95 % CI, 1.13-2.08), presence of metastasis (HR = 3.73, 95 % CI, 2.49-5.58), and age over 70 (HR = 1.65) were associated with a higher risk of mortality.

Given the alarming prognosis of RC observed in the study area and the significant delay between symptom onset and diagnosis, it is crucial to address this issue and potentially improve the survival rates of RC patients.

Assessing clinical tumor response following completion of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer is paramount to select patients for watch-and-wait treatment.

To assess organ preservation (OP) and oncologic outcomes according to clinical tumor response grade.

This was secondary analysis of the Organ Preservation in Patients with Rectal Adenocarcinoma trial, a phase 2, nonblinded, multicenter, randomized clinical trial. Randomization occurred between April 2014 and March 2020. Eligible participants included patients with stage II or III rectal adenocarcinoma. Data analysis occurred from March 2022 to July 2023.

Patients were randomized to induction chemotherapy followed by chemoradiation or chemoradiation followed by consolidation chemotherapy. Tumor response was assessed 8 (±4) weeks after TNT by digital rectal examination and endoscopy and categorized by clinical tumor response grade. A 3-tier grading schema that stratifies clinical tumor response into clinical complete response (CCR), near complete response (NCR), and incomplete clinical response (ICR) was devised to maximize patient eligibility for OP.

OP and survival rates by clinical tumor response grade were analyzed using the Kaplan-Meier method and log-rank test.

There were 304 eligible patients, including 125 patients with a CCR (median [IQR] age, 60.6 [50.4-68.0] years; 76 male [60.8%]), 114 with an NCR (median [IQR] age, 57.6 [49.1-67.9] years; 80 male [70.2%]), and 65 with an ICR (median [IQR] age, 55.5 [47.7-64.2] years; 41 male [63.1%]) based on endoscopic imaging. Age, sex, tumor distance from the anal verge, pathological tumor classification, and clinical nodal classification were similar among the clinical tumor response grades. Median (IQR) follow-up for patients with OP was 4.09 (2.99-4.93) years. The 3-year probability of OP was 77% (95% CI, 70%-85%) for patients with a CCR and 40% (95% CI, 32%-51%) for patients with an NCR (P < .001). Clinical tumor response grade was associated with disease-free survival, local recurrence-free survival, distant metastasis-free survival, and overall survival.

In this secondary analysis of a randomized clinical trial, most patients with a CCR after TNT achieved OP, with few developing tumor regrowth. Although the probability of tumor regrowth was higher for patients with an NCR compared with patients with a CCR, a significant proportion of patients achieved OP. These findings suggest the 3-tier grading schema can be used to estimate recurrence and survival outcomes in patients with locally advanced rectal cancer who receive TNT.

ClinicalTrials.gov Identifier: NCT02008656.

The watch-and-wait (WW) strategy is a potential option for patients with rectal cancer who obtain a complete clinic response after neoadjuvant therapy. The aim of this study is to analyze the long-term oncological outcomes and perform a cost-effectiveness analysis in patients undergoing this strategy for rectal cancer.

The data of patients treated with the WW strategy were prospectively collected from January 2015 to January 2020. A control group was created, matched 1:1 from a pool of 480 patients undergoing total mesorectal excision. An independent company carried out the financial analysis. Clinical and oncological outcomes were analyzed in both groups. Outcome parameters included surgical and follow-up costs, quality-adjusted life years (QALYs), and the incremental cost per QALY gained or the incremental cost-effectiveness ratio (ICER).

Forty patients were included in the WW group, with 40 patients in the surgical group. During a median follow-up period of 36 months, metastasis-free survival (MFS) and overall survival (OS) were similar in the two groups. In the WW group, nine (22%) local regrowths were detected in the first 2 years. The permanent stoma rate was slightly higher after salvage surgery in the WW group compared to the surgical group (48.5% vs 20%, p < 0.01). The cost-effectiveness analysis was slightly better for the WW group, especially for low rectal cancer compared to medium-high rectal cancer (ICER =  - 108,642.1 vs ICER =  - 42,423).

The WW strategy in locally advanced rectal cancer offers similar oncological outcomes with respect to the surgical group and excellent results in quality of life and cost outcomes, especially for low rectal cancer. Nonetheless, the complex surgical field during salvage surgery can lead to a high permanent stoma rate; therefore, the careful selection of patients is mandatory.

Neoadjuvant chemoradiotherapy (CRT) is the standard treatment for advanced rectal cancer. Yet, the response to CRT varies from complete response to zero tumor regression.

The impact of intratumoral budding (ITB) and intratumoral CD8+ cell density on response to CRT and survival were evaluated in biopsy samples from 266 patients with advanced rectal cancer who were treated with long-course neoadjuvant CRT. The expression of epithelial-mesenchymal transition (EMT) markers was compared between patients with high and low ITB, using data from 174 patients with RNA sequencing.

High ITB was observed in 62 patients (23.3%). There was no association between ITB and CD8+ cell density. The multivariable logistic regression analysis showed that high CD8+ cell density (OR, 2.69; 95% CI, 1.45-4.98; P = .002) was associated with good response to CRT, whereas high ITB (OR, 0.33; 95% CI, 0.14-0.80; P = .014) was associated with poor response. Multivariable Cox regression analysis for survival showed that high CD8+ cell density was associated with better recurrence-free survival (HR, 0.41; 95% CI, 0.24-0.72; P = .002) and overall survival (HR, 0.36; 95% CI, 0.17-0.74; P = .005), but significance values for ITB were marginal (P = .104 for recurrence-free survival and P = .163 for overall survival). The expression of EMT-related genes was not significantly different between patients with high and low ITB.

ITB and CD8+ cell density in biopsy samples may serve as useful biomarkers to predict therapy response in patients with rectal cancer treated with neoadjuvant CRT.

Rectal cancer is a heterogeneous disease with complex genetic and molecular subtypes. Emerging progress of neoadjuvant therapy has led to increased pathological and clinical complete response (cCR) rates for microsatellite stable (MSS) rectal cancer, which responds poorly to immune checkpoint inhibitor alone. As a result, organ preservation of MSS rectal cancer as an alternative to radical surgery has gradually become a feasible option. For patients with cCR or near-cCR after neoadjuvant treatment, organ preservation can be implemented safely with less morbidity. Patient selection can be done either before the neoadjuvant treatment for higher probability or after with careful assessment for a favorable outcome. Those patients who achieved a good clinical response are managed with nonoperative management, organ preservation surgery, or radiation therapy alone followed by strict surveillance. The oncological outcomes of patients with careful selection and organ preservation seem to be noninferior compared with those of radical surgery, with lower postoperative morbidity. However, more studies should be done to seek better regression of tumor and maximize the possibility of organ preservation in MSS rectal cancer.

Accurate prediction of response to neoadjuvant chemoradiotherapy (nCRT) is very important for treatment plan decision in locally advanced rectal cancer (LARC). The aim of this study was to investigate whether self-attention mechanism based multi-sequence fusion strategy applied to multiparametric magnetic resonance imaging (MRI) based deep learning or hand-crafted radiomics model construction can improve prediction of response to nCRT in LARC.

This retrospective analysis enrolled 422 consecutive patients with LARC who received nCRT before surgery at two hospitals. All patients underwent multiparametric MRI scans with three imaging sequences. Tumor regression grade (TRG) was used to assess the response of nCRT based on the resected specimen. Patients were separated into 2 groups: poor responders (TRG 2, 3) versus good responders (TRG 0, 1). A self-attention mechanism, namely channel attention, was applied to fuse the three sequence information for deep learning and radiomics models construction. For comparison, other two models without channel attention were also constructed. All models were developed in the same hospital and validated in the other hospital.

The deep learning model with channel attention mechanism achieved area under the curves (AUCs) of 0.898 in the internal validation cohort and 0.873 in the external validation cohort, which was the best performed model in all cohorts. More importantly, both the deep learning and radiomics model that applied channel attention mechanism performed better than those without channel attention mechanism.

The self-attention mechanism based multi-sequence fusion strategy can improve prediction of response to nCRT in LARC.

Our study evaluated whether an MRI reporting system highlighting areas of contiguous and discontinuous extramural venous invasion (EMVI) can improve the accuracy of gross tumour volume (GTV) delineation. Initially, 27 consecutive patients with locally advanced rectal cancer treated between 2012 and 2014 were evaluated. We used an MRI reporting proforma that documented the position of the primary tumour, lymph nodes and EMVI. The new GTVs delineated were compared with historical radiotherapy treatment volumes to identify the frequency of GTV geographical miss. We observed that the delineation of involved nodes and areas of EMVI was more likely to represent sources of uncertainty wherein nodal GTV geographical miss was evident in 5 out of 27 patients (19%). Complete EMVI GTV geographical miss occurred in two patients (7%). We re-evaluated our radiotherapy practice in a further 27 patients after the implementation of a modified MRI reporting system. An improvement was seen; nodal miss was observed in two patients (7%) and partial EMVI miss in one patient (4%), although these areas were encompassed in the planning target volume (PTV). Our study shows that extramural venous invasion and involved nodes need to be highlighted on MRI to improve the accuracy of rectal cancer GTV delineation.

(1) Background: The neoadjuvant rectal (NAR) score has been developed as a prognostic tool for survival in locally advanced rectal cancer (LARC). However, the NAR score only incorporates weighted cT, ypT, and ypN categories. This long-term follow-up study aims to modify a novel prognostic scoring model and identify a short-term endpoint for survival. (2) Methods: The prognostic factors for overall survival (OS) were explored through univariate and multivariate analyses. Based on Cox regression modeling, nomogram plots were constructed. Area under the curve (AUC) and concordance indices were used to evaluate the performance of the nomogram. Receiver operating characteristic (ROC) analysis was conducted to compare the efficiency of the nomogram with other prognostic factors. (3) Results: After a long-term follow-up, the 5-year OS was 67.1%. The mean NAR score was 20.4 ± 16.3. Multivariate analysis indicated that CD8+ T-cell, lymphovascular invasion, and the NAR score were independent predictors of OS. The modified NAR scoring model, incorporating immune infiltration characteristics, exhibited a high C-index of 0.739 for 5-year OS, significantly outperforming any individual factor. Moreover, the predictive value of the nomogram was superior to the AJCC stage and pathological complete regression at 3-year, 5-year, and 10-year time points, respectively. Over time, the model's predictions of long-term survival remained consistent and improved in accuracy. (4) Conclusions: The modified NAR scoring model, incorporating immune infiltration characteristics, demonstrates high accuracy and consistency in predicting OS.

This study investigated the efficacy of chemoradiotherapy (CRT) followed by durvalumab as neoadjuvant therapy of locally advanced rectal cancer.

The PANDORA trial is a prospective, phase II, open-label, single-arm, multicenter study aimed at evaluating the efficacy and safety of preoperative treatment with durvalumab (1500 mg every 4 weeks for three administrations) following long-course radiotherapy (RT) plus concomitant capecitabine (5040 cGy RT in 25-28 fractions over 5 weeks and capecitabine administered at 825 mg/m2 twice daily). The primary endpoint was the pathological complete response (pCR) rate; secondary endpoints were the proportion of clinical complete remissions and safety. The sample size was estimated assuming a null pCR proportion of 0.15 and an alternative pCR proportion of 0.30 (α = 0.05, power = 0.80). The proposed treatment could be considered promising if ≥13 pCRs were observed in 55 patients (EudraCT: 2018-004758-39; NCT04083365).

Between November 2019 and August 2021, 60 patients were accrued, of which 55 were assessable for the study's objectives. Two patients experienced disease progression during treatment. Nineteen out of 55 eligible patients achieved a pCR (34.5%, 95% confidence interval 22.2% to 48.6%). Regarding toxicity related to durvalumab, grade 3 adverse events (AEs) occurred in four patients (7.3%) (diarrhea, skin toxicity, transaminase increase, lipase increase, and pancolitis). Grade 4 toxicity was not observed. In 20 patients (36.4%), grade 1-2 AEs related to durvalumab were observed. The most common were endocrine toxicity (hyper/hypothyroidism), dermatologic toxicity (skin rash), and gastrointestinal toxicity (transaminase increase, nausea, diarrhea, constipation).

This study met its primary endpoint showing that CRT followed by durvalumab could increase pCR with a safe toxicity profile. This combination is a promising, feasible strategy worthy of further investigation.

The purpose of this study was to evaluate the long-term oncological progression pattern of locally advanced rectal cancer patients with post-neoadjuvant nodal metastatic disease (ypN+) and correlate potential prognostic features associated with proven radiochemoresistant nodal biology.

Individual patient data (100 variables) from a 20-year consecutive single-institution multidisciplinary experience (1995-2015), delivering multimodal therapy to rectal cancer patient candidates for radical treatment, including a neoadjuvant component and surgical resection with or without intraoperative radiotherapy followed by optional adjuvant chemotherapy. The ypN+ disease data was registered in the context of initial staging categories post-neoadjuvant T status (ypT).

Data on 487 patients showed histologically confirmed diagnoses of metastatic nodal disease in 108 specimens (ypN+, 22.1). There was a significant age difference (p = 0.009) between the ypN groups: age ≥ 65 was 57.6% in pN0 and 43.5% in ypN+ and patients aged < 65 constituted 42.4% of pN0 and 56.5% of ypN+. According to the clinical stage there were statistically significant differences (p = 0.001) in the categories' distribution: ypN+ patients 10.8% were stage II and 89.2% were stage III. Univariant analysis on outcome variables showed statistically significant differences in overall survival at 7 years (63.8% vs. 55.7%, p = 0.016) disease-free survival (DFS) (78% vs. 53.8%, p = 0.000) and local recurrence-free survival (LRFS) (93.6% vs. 84%, p = 0.002).

The presence of nodal metastases (ypN+) after neoadjuvant therapy containing long-course pelvic irradiation severely impacts the long-term outcome for patients with locally advanced rectal cancer and correlates with multiple clinical and therapeutic variable metrics. Implementation of local and systemic therapies should be adapted and intensified in relation to the finding of ypN+ category in surgical specimens.

The watch-and-wait (W&W) strategy is a novel treatment option for patients with rectal cancer who have a strong desire for organ preservation. The study aimed to explore the long-term outcomes of the W&W strategy in a large cohort of rectal cancer patients who achieved a clinical complete response (cCR) after consolidation total neoadjuvant therapy (TNT), and to compare with patients who achieved a pathological complete response (pCR) after radical surgery.

The W&W group comprised patients who were assessed as having a cCR after consolidation TNT and adopted the W&W strategy. Patients who underwent standard resection and achieved a pCR were compared as a reference. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier analysis with log-rank test was used to compare survival outcomes.

We included 89 and 171 patients in the W&W and pCR groups, respectively. The median follow-up period was 45 and 58 months for the W&W and pCR groups, respectively. After IPTW adjustment, the 2-year local regrowth/recurrence rate for the W&W and pCR groups were 9.9% and 2.0%, respectively (p < 0.001). The W&W and pCR groups had similar 5-year outcomes, including overall survival, disease-free survival, and distant metastasis-free survival (all p > 0.05). No significant difference was observed in the rates of distant metastasis between patients in the W&W group with local regrowth and those without local regrowth (25% versus 6.2%, p = 0.119).

Patients who were managed with a W&W strategy after consolidation TNT had favorable survival outcomes, which were similar to those of patients with a pCR. The rate of local regrowth in W&W patients was lower in our study than in other studies as a result of the implementation of consolidation TNT.

During the past decade, the treatment of locally advanced rectal cancer (LARC) has become more complex. Total neoadjuvant treatment (TNT) has increased the rates of both clinical and pathologic complete response, resulting in improved long-term oncological outcomes. The feasibility to implement nonoperative management (NOM) depends on solving current challenges such as how to correctly identify the best candidates for a NOM without compromising oncologic safety. NOM should be part of the treatment discussion of LARC, considering increasing rates of clinical complete response, potential quality of life gains, avoidance of surgical morbidity, and patient preferences.

The emergence of immunotherapy has revolutionized the traditional treatment paradigm of colorectal cancer (CRC). Among them, immune checkpoint blockade has become the first-line treatment for metastatic colorectal cancer (mCRC) and has made significant progress in the treatment of locally advanced colorectal cancer (LACRC). We reviewed a series of clinical trials that have made breakthrough progress. We will emphasize the breakthrough progress in achieving organ preservation in patients with high microsatellite instability or DNA mismatch repair deficiency (MSI-H/dMMR), and based on this, we propose the concept of selective surgery, which includes selectively removing or preserving lymph nodes, with the aim of proving our idea through more research in the future.

Resistance to neoadjuvant chemoradiation therapy, is a major challenge in the management of rectal cancer. Increasing evidence supports a role for altered energy metabolism in the resistance of tumours to anti-cancer therapy, suggesting that targeting tumour metabolism may have potential as a novel therapeutic strategy to boost treatment response. In this study, the impact of metformin on the radiosensitivity of colorectal cancer cells, and the potential mechanisms of action of metformin-mediated radiosensitisation were investigated. Metformin treatment was demonstrated to significantly radiosensitise both radiosensitive and radioresistant colorectal cancer cells in vitro. Transcriptomic and functional analysis demonstrated metformin-mediated alterations to energy metabolism, mitochondrial function, cell cycle distribution and progression, cell death and antioxidant levels in colorectal cancer cells. Using ex vivo models, metformin treatment significantly inhibited oxidative phosphorylation and glycolysis in treatment naïve rectal cancer biopsies, without affecting the real-time metabolic profile of non-cancer rectal tissue. Importantly, metformin treatment differentially altered the protein secretome of rectal cancer tissue when compared to non-cancer rectal tissue. Together these data highlight the potential utility of metformin as an anti-metabolic radiosensitiser in rectal cancer.