Chemoradiotherapy For Rectal Cancer Research Articles

Beneficiaries of radical surgery among clinical complete responders to neoadjuvant chemoradiotherapy in rectal cancer.

This study aimed to identify patients who benefit from radical surgery among those with rectal cancer who achieved clinical complete response (cCR). Patients with locally advanced rectal cancer (LARC; stage II/III) who achieved cCR after neoadjuvant chemoradiotherapy (nCRT) were included (n = 212). Univariate/multivariate Cox analysis was performed to validate predictors for distant metastasis‐free survival (DMFS). A decision tree was generated using recursive partitioning analysis (RPA) to categorize patients into different risk stratifications. Total mesorectal excision (TME) was compared with the watch‐and‐wait (W&W) strategy in each risk group. Two molecular predicators of CEA and CA19‐9 were selected to establish the RPA‐based risk stratification, categorizing LARC patients into low‐risk (n = 139; CA19‐9 < 35 U/mL and CEA < 5 ng/mL) and high‐risk (n = 73; CA19‐9 ≥ 35 U/mL or CEA ≥5 ng/mL) groups. Superior 5‐y DMFS was observed in the low‐risk group vs. the high‐risk group (92.9% vs. 76.2%, P = .002). Low‐risk LARC patients who underwent TME had significantly improved 5‐y DMFS compared with their counterparts receiving the W&W strategy (95.9% vs. 84.3%; P = .028). No significant survival difference was observed in high‐risk patients receiving the 2 treatment modalities (77.9% vs. 94.1%; P = .143). LARC patients with cCR who had both baseline CA19‐9 < 35 U/mL and CEA < 5 ng/mL may benefit from radical surgery.

Identification of Blood-Based Biomarkers for the Prediction of the Response to Neoadjuvant Chemoradiation in Rectal Cancer.

Simple SummaryAlthough pathologic complete response (pCR) to neoadjuvant chemoradiation (nCRT) in locally advanced rectal cancer (LARC) is associated with better outcomes, a subset of tumors exhibit resistance to nCRT. Therefore, there is a need of biomarkers to predict the nCRT response and increment efforts for personalized therapeutic options. To this end, we analyzed pretreatment plasma proteome of a mouse model of rectal cancer treated with concurrent chemoradiation, resulting in identification and validation of plasma VEGFR3 as a potential predicting biomarker. In addition, plasma levels of EGFR and COX2, previously validated tissue-based predicting biomarkers, were significantly higher in non-pCR than pCR LARC patients, indicating that EGFR and COX2 can also serve as blood-based biomarkers. The performance of the biomarker panel combining VEGFR3, EGFR, and COX2 were significantly improved compared to that of each marker alone, providing a rationale for further integration and refinement of the biomarker panel and validation in the larger sample sets.The current standard of care for patients with locally advanced rectal cancer (LARC) is neoadjuvant chemoradiation (nCRT) followed by total mesorectal excision surgery. However, the response to nCRT varies among patients and only about 20% of LARC patients achieve a pathologic complete response (pCR) at the time of surgery. Therefore, there is an unmet need for biomarkers that could predict the response to nCRT at an early time point, allowing for the selection of LARC patients who would or would not benefit from nCRT. To identify blood-based biomarkers for prediction of nCRT response, we performed in-depth quantitative proteomic analysis of pretreatment plasma from mice bearing rectal tumors treated with concurrent chemoradiation, resulting in the quantification of 567 proteins. Among the plasma proteins that increased in mice with residual rectal tumor after chemoradiation compared to mice that achieved regression, we selected three proteins (Vascular endothelial growth factor receptor 3 [VEGFR3], Insulin like growth factor binding protein 4 [IGFBP4], and Cathepsin B [CTSB]) for validation in human plasma samples. In addition, we explored whether four tissue protein biomarkers previously shown to predict response to nCRT (Epidermal growth factor receptor [EGFR], Ki-67, E-cadherin, and Prostaglandin G/H synthase 2 [COX2]) also act as potential blood biomarkers. Using immunoassays for these seven biomarker candidates as well as Carcinoembryonic antigen [CEA] levels on plasma collected before nCRT from 34 patients with LARC (6 pCR and 28 non-pCR), we observed that levels of VEGFR3 (p = 0.0451, AUC = 0.720), EGFR (p = 0.0128, AUC = 0.679), and COX2 (p = 0.0397, AUC = 0.679) were significantly increased in the plasma of non-pCR LARC patients compared to those of pCR LARC patients. The performance of the logistic regression model combining VEGFR3, EGFR, and COX2 was significantly improved compared with the performance of each biomarker, yielding an AUC of 0.869 (sensitivity 43% at 95% specificity). Levels of VEGFR3 and EGFR were significantly decreased 5 to 7 months after tumor resection in plasma from 18 surgically resected rectal cancer patients, suggesting that VEGFR3 and EGFR may emanate from tumors. These findings suggest that circulating VEGFR3 can contribute to the prediction of the nCRT response in LARC patients together with circulating EGFR and COX2.

Complete response to neoadjuvant chemoradiotherapy in rectal cancer is associated with RAS/AKT mutations and high tumour mutational burden

BackgroundPathological complete response (pathCR) in rectal cancer is beneficial, as up to 75% of patients do not experience regrowth of the primary tumour, but it is poorly understood. We hypothesised that the changes seen in the pre-treatment biopsies of pathCR but not seen in residual tumour after chemoradiotherapy were the determinants of responsiveness.MethodsTwo groups of patients with either complete response (pathCR group, N = 24) or no response (poor response group, N = 24) were retrieved. Pre-treatment biopsies of cancers from these patients underwent high read depth amplicon sequencing for a targeted panel, exome sequencing, methylation profiling and immunohistochemistry for DNA repair pathway proteins.ResultsTwenty four patients who underwent pathCR and twenty-four who underwent poor response underwent molecular characterisation. Patients in the pathCR group had significantly higher tumour mutational burden and neoantigen load, frequent copy number alterations but fewer structural variants and enrichment for driver mutations in the PI3K/AKT/mTOR signalling pathway. There were no significant differences in tumour heterogeneity as measured by MATH score. Methylation analysis demonstrated enrichment for hypomethyation in the PI3K/AKT/mTOR signalling pathway.DiscussionThe phenomenon of pathCR in rectal cancer may be related to immunovisibility caused by a high tumour mutational burden phenotype. Potential therapy resistance mechanisms involve the PI3K/AKT/mTOR signalling pathway, but tumour heterogeneity does not seem to play a role in resistance.

A radiomic signature model to predict the chemoradiation-induced alteration in tumor-infiltrating CD8+ cells in locally advanced rectal cancer

Background and purposeRegarding the altered tumor immune status following cytotoxic treatment, this study aims to develop a radiomic signature to predict CD8+ tumor-infiltrating lymphocyte (TIL) density changes in chemoradiotherapy (CRT) of rectal cancer. Materials and methodsWe used the magnetic resonance imaging (MRI) and immunohistochemistry data before and after neoadjuvant CRT. The discovery datasets consisted of pre-CRT dataset A1 (n = 113), post-CRT datasets A2 (n = 32; predominance of tumor) and A3 (n = 20; pure fibrosis). The developed model was validated in dataset B (n = 28). Thirty-eight radiomic features from T2-weighted MRI scans were incorporated into the least absolute shrinkage and selection operator method. ResultsIn pre-CRT dataset A1, the area under the receiver operating characteristic curve (AUC) values of radiomic score for predicting CD8+ TILs were 0.760 and 0.729 for training and validation subsets, respectively. A significant correlation was observed between the signature and CD8+ TIL density in the post-CRT dataset A2 (Pearson’s R = −0.372, P = 0.036), whereas no association was found in dataset A3 (Pearson’s R = −0.069, P = 0.77). The association was also observed in the validation dataset B (Pearson’s R = −0.374, P = 0.049). In dataset A2, the radiomic score difference predicted changes in CD8+ TIL density (AUC = 0.824). ConclusionWe established the MRI-derived radiomic signature for predicting CRT-induced alterations in CD8+ TILs. This study suggests the clinical utility of radiomics-immunophenotype modeling to evaluate tumor immune status following neoadjuvant chemoradiation in rectal cancer.

Improvement in the Assessment of Response to Preoperative Chemoradiotherapy for Rectal Cancer Using Magnetic Resonance Imaging and a Multigene Biomarker.

Simple SummaryPreoperative chemoradiotherapy is now the gold standard for treating locally advanced rectal cancer and has been demonstrated to decrease local recurrence and promote sphincter preservation. Therefore, developing methods to accurately predict patients’ response to chemoradiation is imperative for choosing the best surgical option after chemoradiation and predicting the oncologic outcomes of patients. Radiological tools and endoscopy are the most commonly used tools for post-treatment response assessment. In addition, examining the expression levels of genes correlated with treatment response could provide clinicians with more power to gauge each patient’s potential to respond. In this study, we explored how biological and radiological tools can be used together to provide a more tailored and multidimensional representation of patients’ response status.The response to preoperative chemoradiotherapy (PCRT) is correlated with oncologic outcomes in patients with locally advanced rectal cancer. Accurate prediction of PCRT response before surgery can provide crucial information to aid clinicians in further treatment planning. This study aimed to develop an evaluation tool incorporating a genetic biomarker and magnetic resonance imaging (MRI) to improve the assessment of response in post-CRT patients with locally advanced rectal cancer. A total of 198 patients who underwent PCRT followed by surgical resection for locally advanced rectal cancer between 2010 and 2016 were included in this study. Each patient’s response prediction index (RPI) score, a multigene biomarker developed in our previous study, and magnetic resonance tumor regression grade (mrTRG) score were added to create a new predictive value for pathologic response after PCRT, called the combined radiation prediction value (cRPV). Based on the new value, 121 and 77 patients were predicted to be good and poor responders, respectively, showing significantly different cRPV values (p = 0.001). With an overall predictive accuracy of 84.8%, cRPV was superior to mrTRG and RPI for the prediction of pathologic chemoradiotherapy response (mrTRG, 69.2%; RPI, 77.3%). In multivariate analysis, cRPV was found to be the sole predictor of tumor response (odds ratio, 32.211; 95% confidence interval, 14.408–72.011; p = 0.001). With its good predictive value for final pathologic regression, cRPV may be a valuable tool for assessing the response to PCRT before surgery.

Prevalence of nodal involvement in rectal cancer after chemoradiotherapy.

The purpose of this study was to investigate the prevalence of ypN+ status according to ypT category in patients with locally advanced rectal cancer treated with chemoradiotherapy and total mesorectal excision, and to assess the impact of ypN+ on disease recurrence and survival by pooled analysis of individual-patient data. Individual-patient data from 10 studies of chemoradiotherapy for rectal cancer were included. Pooled rates of ypN+ disease were calculated with 95 per cent confidence interval for each ypT category. Kaplan-Meier and Cox regression analyses were undertaken to assess influence of ypN status on 5-year disease-free survival (DFS) and overall survival (OS). Data on 1898 patients were included in the study. Median follow-up was 50 (range 0-219) months. The pooled rate of ypN+ disease was 7 per cent for ypT0, 12 per cent for ypT1, 17 per cent for ypT2, 40 per cent for ypT3, and 46 per cent for ypT4 tumours. Patients with ypN+ disease had lower 5-year DFS and OS (46.2 and 63.4 per cent respectively) than patients with ypN0 tumours (74.5 and 83.2 per cent) (P < 0.001). Cox regression analyses showed ypN+ status to be an independent predictor of recurrence and death. Risk of nodal metastases (ypN+) after chemoradiotherapy increases with advancing ypT category and needs to be considered if an organ-preserving strategy is contemplated.

P-22 Role of timing to laparoscopic or robotic surgery after neoadjuvant chemoradiotherapy for rectal cancer: The TiMiSNAR trial

Chemoradiotherapy (CRT) is a well-known, risk-reducing treatment of local recurrence in the treatment of rectal cancer, followed by total mesorectal excision (TME). In low rectal tumors, surgery alone has the 30% overall survival and a local recurrence rate of about 55-65%, with a disease-free survival of 30%-35%. Preoperative administration of fluorouracil-based chemotherapy improves local recurrence rates by 7%. The optimal timing of surgery in relation to chemoradiation is still controversial and it is the target of numerous studies, either retrospective or randomized controlled trials.

Associations between clinical characteristics and tumor response to neoadjuvant chemoradiotherapy in rectal cancer

Following standard neoadjuvant chemoradiotherapy and total mesorectal excision, some patients with locally advanced rectal cancer achieve good response (pathological T0–2N0), while others show nonresponse (pathological T3–4N0 or node‐positive). To date, the clinicopathological predictors of good response and the necessity of adjuvant chemotherapy treatment (ACT) in good responders remain unclear. In this retrospective study, clinicopathological characteristics were surveyed to investigate the correlation with good response; furthermore, a propensity score matching (PSM) model was designed to balance the confounding factors between good responders treated with ACT or observation. A total of 2255 patients were enrolled, including 1069 good responders and 1186 nonresponders. The results of the survival analysis showed a good response predicted a better 3‐year prognosis (p < 0.001). The logistic regression analysis showed less advanced T and N stages (T3 vs. T4; N0 vs. N1–2), more neoadjuvant chemotherapy (nCT) cycles (≥4 vs. 1–3), and delayed surgery (≥8 weeks vs. <8 weeks) were independent predictors of a good response (p < 0.05). Especially, patients treated with both more nCT cycles and a delay in surgery included the greatest number of good responders (p < 0.001). For good responders, after PSM (1:3), 235 observation cases were matched to 705 ACT cases. As compared with observation, ACT had no greater impact on prognosis analysis (p > 0.05). In conclusion, more cycles of nCT and a delay in surgery predicted a better response, and the delivery of ACT might be omitted in good responders.

Effect of mistletoe extract on tumor response in neoadjuvant chemoradiotherapy for rectal cancer: a cohort study

BackgroundMistletoe extract, used as a complementary chemotherapeutic agent for cancer patients, has anticancer effects against various malignancies. The aim of the present study was to evaluate the effect of mistletoe extract (Abnoba Viscum Q®) on tumor responses to neoadjuvant chemoradiotherapy (NCRT) for locally advanced rectal cancer.MethodsThis study included patients with rectal cancer who underwent NCRT between January 2018 and July 2020. In the mistletoe group (MG), the patients were administered Abnoba Viscum Q® subcutaneously during chemoradiotherapy—maintained just before surgery. Patient demographics, clinical outcomes, histopathological outcomes, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) assay results were compared between the MG and non-mistletoe group (NMG). Two rectal cancer cell lines (SNU-503 and SNU-503R80Gy) were treated with Abnoba Viscum Q® to assess its mechanistic effects in vivo.ResultsOverall, the study included 52 patients (MG: n = 15; NMG: n = 37). Baseline demographics between the two groups were similar, except carbohydrate antigen 19-9 levels and tumor location from the anal verge. There was no difference in the clinical stage between the two groups. A better tumor response in the MG, relative to the NMG, was observed with respect to tumor regression grade (TRG), T stage, and overall tumor–node–metastasis stage. Tumor response was significantly better in the MG than in the NMG in terms of pathologic complete response rate (53.3% vs. 21.6%, P = 0.044), good TRG response (66.7% vs. 32.4%, P = 0.024), T downstaging (86.7% vs. 43.2%, P = 0.004), and overall downstaging (86.7% vs. 56.8%, P = 0.040). The toxicities during NCRT were minimal in both groups. More apoptotic cells were noted in MG samples than in the NMG samples on TUNEL staining. Cleaved caspase-3 level following treatment with Abnoba Viscum Q® was higher in SNU-503R80Gy cells than in SNU-503 cells.ConclusionPatients treated with chemoradiation combined with mistletoe extract showed better outcomes than patients not treated with mistletoe extract in terms of tumor responses. This diversity in treatment may improve the efficacy of NCRT, leading to better oncologic outcomes. Prospective and randomized studies with long-term follow-up are warranted to confirm and extend these results.

Association Between Three-Dimensional Transrectal Ultrasound Findings and Tumor Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer: An Observational Study

BackgroundThere is a significant demand for the development of non-surgical methods for the evaluation of complete response to tumor therapy. Predicting ability and image quality of routine imaging has not been satisfactory. To avoid the deficiencies, we assessed the capability of three-dimensional transrectal ultrasound in predicting the response to neoadjuvant chemoradiotherapy in rectal cancer patients.MethodsThe inclusion criteria were patients with locally advanced rectal adenocarcinoma, receiving capecitabine-based neoadjuvant chemoradiotherapy, distance from anal verge (≤6 cm), clinical stage T3-4 and/or N+ without evidence of distant metastasis, and restaging ycT0-3a (T3a <5 mm) after the end of neoadjuvant chemoradiotherapy. Three-dimensional transrectal ultrasound was performed 7 weeks after neoadjuvant chemoradiotherapy to discern the patients with complete response from the others. Eight main parameters were obtained from three-dimensional transrectal ultrasound: thickness of muscularis on the residual side, thickness of contralateral muscularis, angle of residual arc, regularity of the shape, integrity of the mucosal layer, blurring of the margin, internal echo, and posterior echo. The association between tumor response and three-dimensional transrectal ultrasound parameters was analyzed, and a model was developed by logistic regression.ResultsBetween 2014 and 2019, 101 patients were recruited; 72 cases received total mesorectal excision, and 29 cases underwent watch-and-wait. Among the three-dimensional transrectal ultrasound parameters, the adjusted-thickness of the muscularis (P<0.01), angle of the residual arc (P<0.01), and regularity of the residual shape (P<0.01) were strongly associated with tumor response. In the dataset with total mesorectal excision cases (TME dataset), the residual adjusted-thickness (odds ratio [OR]=4.88, 95% confidence interval [CI]=1.44–16.6, P=0.01) and regularity of the residual shape (OR=5.00, 95% CI=1.13–22.2, P=0.03) were kept in the final logistic model. The area under the curve of the logistic model was 0.84. Among these parameters, residual adjusted-thickness correlated significantly with tumor response. Additionally, we observed similar results in the whole population of 101 cases (whole dataset) and in the cross-validation.ConclusionThree-dimensional transrectal ultrasound model is a valuable method for predicting tumor response in rectal cancer patients undergoing neoadjuvant chemoradiotherapy, which should be included as a factor for evaluating clinical complete response.Trial RegistrationThis trial was registered with ClinicalTrials.gov, number NCT02605265. Registered 9 November 2015 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/record/NCT02605265

Development of a novel apoptosis-based tumor regression grade to assess the efficacy of preoperative chemoradiotherapy for rectal cancer: a retrospective single-center study.

Preoperative chemoradiotherapy is used preferably for locally advanced rectal cancer, followed by a watch-and-wait strategy for cases showing clinical complete response. However, there is a discordance between pathological and clinical complete response rates. We aimed to propose a tumor regression grade (TRG) that truly reflects the therapeutic effects of preoperative chemoradiotherapy in locally advanced rectal cancer. Overall, 293 consecutive patients with T3/T4a/T4b rectal cancer who underwent chemoradiotherapy followed by radical surgery between Sep 2003 and Dec 2018 were retrospectively reviewed. We assessed apoptosis using M30 cytoDEATH immunostaining and correlated that with conventional TRG (convTRG) evaluated using hematoxylin-eosin staining, and created a new TRG by evaluating apoptosis and convTRG. The modified TRG1-4 (modifTRG) classification was as follows: modifTRG1 comprised poor TRG, modifTRG2 moderate TRG, modifTRG3 good TRG, modifTRG4 complete apoptosis and convTRG3 (pathological complete response). We assessed the overall survival, relapse-free survival, and local recurrence rate. Pathological complete response rate was 10.6% when evaluated using conventional staining. Using M30 staining, apoptosis was observed in the residual disease in convTRG 1a 0%, convTRG 1b 0.3%, convTRG 2 9.2%. Combining the two, modifTRG4 was observed in 20.1%. The survival rates were similar between modifTRG4 and convTRG3, suggesting that modifTRG4 was equivalent to pathological complete response. However, in multivariate analysis, modifTRG but not convTRG was an independent risk factor for local and distant recurrences. The proposed modifTRG truly reflected the therapeutic effects of chemoradiotherapy and may be superior to the convTRG to stratify rectal cancer patients treated with chemoradiotherapy.

LincRNA-p21 as predictive response marker for preoperative chemoradiotherapy in rectal cancer.

e15534 Background: Preoperative chemoradiotherapy (CRT) is a standard treatment for locally advanced rectal cancer (RC) patients (pts). Despite the benefits of CRT, its use in non-responder pts can be associated with increased toxicities and resection delay. The identification of CRT response biomarkers, such as long non-coding RNAs (lncRNA), could improve the management of these pts. LincRNA-p21 is a lncRNA involved in the p53 pathway and angiogenesis regulation that acts as prognostic marker in several tumors. We aim to study lincRNA-p21 expression in pretreatment samples from RC pts treated with CRT to evaluate whether lincRNA-p21 can act as a predictive biomarker for CRT response. Methods: RNA from pretreatment endoscopy biopsies from 58 RC pts treated with preoperative CRT at Mutua Terrassa University Hospital were analyzed. Pathological response was classified according to the tumor regression grade (TRG) Dworak classification. LincRNA-p21 expression was determined by RTqPCR and was correlated with CRT response and, time to relapse (TTR), disease-free survival (DFS) and overall survival (OS). Results: Samples from 58 pts were analyzed. Most of them males (n = 40, 69%). Median age at diagnosis of 67 (44-82) years. Fifty (86.2%) pts reported stage III and, 42 (72.4%) pts assessed TRG 0-3 with a 70.7% of downstaging reported. LincRNA-p21 was upregulated in stage III tumors (p &lt; 0.0001) and also in tumors with worst response to CRT regarding TRG, TGR0-3 (TRG0-3, n = 42 vs TRG4, n = 16, p = 0.019). In this line, the ROC curve analysis showed that lincRNA-p21 expression had capacity to distinguish pts with maximum response (TRG4) from others (AUC:0.7; p = 0.02). The binary logistic regression analysis validated its independence as response biomarker. LincRNA-p21 levels correlated with pts relapse after surgery. When the pts were classified in 3 groups, high, medium and low, according to lincRNA-p21 levels, RC pts with highest lincRNA-p21 expression had the shortest TTR. TTR for pts with high levels was 74.5 months (m) (95% CI:31-117), while it was 114 m (95% CI:95-133) for those with Medium levels and 123 m (95% CI:111-134) for those with low levels (p = 0.047). Conclusions: LincRNA-p21 is a marker of advanced disease and worse response to CRT. LincRNA-p21 may add valuable information for individualizing pre-operative CRT in locally advanced RC pts.

Lincp21-RNA as Predictive Response Marker for Preoperative Chemoradiotherapy in Rectal Cancer.

Preoperative chemoradiotherapy (CRT) is a standard treatment for locally advanced rectal cancer (RC) patients, but its use in non-responders can be associated with increased toxicities and resection delay. LincRNA-p21 is a long non-coding RNA involved in the p53 pathway and angiogenesis regulation. We aimed to study whether lincRNA-p21 expression levels can act as a predictive biomarker for neoadjuvant CRT response. We analyzed RNAs from pretreatment biopsies from 70 RC patients treated with preoperative CRT. Pathological response was classified according to the tumor regression grade (TRG) Dworak classification. LincRNA-p21 expression was determined by RTqPCR. The results showed that lincRNA-p21 was upregulated in stage III tumors (p = 0.007) and in tumors with the worst response regarding TRG (p = 0.027) and downstaging (p = 0.016). ROC curve analysis showed that lincRNA-p21 expression had the capacity to distinguish a complete response from others (AUC:0.696; p = 0.014). LincRNA-p21 was shown as an independent marker of preoperative CRT response (p = 0.047) and for time to relapse (TTR) (p = 0.048). In conclusion, lincRNA-p21 is a marker of advanced disease, worse response to neoadjuvant CRT, and shorter TTR in locally advanced RC patients. The study of lincRNA-p21 may be of value in the individualization of pre-operative CRT in RC.

Early and late morbidity of local excision after chemoradiotherapy for rectal cancer.

BackgroundLocal excision (LE) after chemoradiotherapy is a new option in low rectal cancer, but morbidity has never been compared prospectively with total mesorectal excision (TME). Early and late morbidity were compared in patients treated either by LE or TME after neoadjuvant chemoradiotherapy for rectal cancer.MethodThis was a post-hoc analysis from a randomized trial. Patients with clinical T2/T3 low rectal cancer with good response to the chemoradiotherapy and having either LE, LE with eventual completion TME, or TME were considered. Early (1 month) and late (2 years) morbidities were compared between the three groups.ResultsThere were no deaths following surgery in any of the three groups. Early surgical morbidity (20 per cent LE versus 36 per cent TME versus 43 per cent completion TME, P = 0.025) and late surgical morbidity (4 per cent versus 33 per cent versus 57 per cent, P < 0.001) were significantly lower in the LE group than in the TME or the completion TME group. of LE, was associated with the lowest rate of early (10 versus 18 versus 21 per cent, P = 0.217) and late medical morbidities (0 versus 7 versus 7 per cent, P = 0.154), although this did not represent a significant difference between the groups. The severity of overall morbidity was significantly lower at 2 years after LE compared with TME or completion TME (4 versus 28 versus 43 per cent grade 3–5, P < 0.001).ConclusionThe rate of surgical complications after neoadjuvant chemoradiotherapy in the LE group was half that of TME group at 1 month and 10 times lower at 2 years. LE is a safe approach for organ preservation and should be considered as an alternative to watch-and-wait in complete clinical responders and to TME in subcomplete responders.

Predictive Factors for Pathologic Complete Response Following Neoadjuvant Chemoradiotherapy for Rectal Cancer.

Background:An accurate assessment of potential pathologic complete response(pCR) following neoadjuvant chemoradiotherapy(NCRT) is important for the appropriate treatment of rectal cancer. However, the factors that predict the response to neoadjuvant chemoradiotherapy have not been well defined. Therefore, this study analyzed the predictive factors on the development of pCR after neoadjuvant chemoradiation for rectal cancer. Methods: From January 2008 to January 2018, a total of 432 consecutive patients from a single institution patients who underwent a long-course neoadjuvant chemoradiotherapy were reviewed in this study. The clinicopathological features were analyzed to identify predictive factors for pathologic complete response in rectal cancer after neoadjuvant chemoradiation. Results:The rate of pathologic complete response in rectal cancer after neoadjuvant chemoradiation was 20.8%, patients were divided into the pCR and non-pCR groups. The two groups were well balanced in terms of age, gender, body mass index, ASA score, tumor stage, tumor differentiation, tumor location, surgical procedure, chemotherapy regimen and radiation dose. The multivariate analysis revealed that a pretreatment carcinoembryonic antigen (CEA) level of ≤5 ng/mL and an interval of ≥8 weeks between the completion of chemoradiation and surgical resection were independent risk factors of an increased rate of pCR. Conclusions: Pretreatment carcinoembryonic antigen (CEA) level of ≤5 ng/mL and an interval of ≥8 weeks between the completion of chemoradiation and surgical resection are predictive factors for pathologic complete response in rectal cancer after neoadjuvant chemoradiation. Using these predictive factors, we can predict the prognosis of patients and develop adaptive treatment strategies. A wait-and-see policy might be possible in highly selective cases.

The role of modern neoadjuvant radiotherapy in the combined treatment of locally advanced rectal cancer

Currently, rectal cancer is one of the leading pathologies in the structure of cancer morbidity and mortality, both in Russia and around the world. Thus, despite the improvement of existing and development of new methods for surgical treatment and anesthesia, as well as the introduction of the use of radio-and chemotherapy as an adjunct to surgical stage of the treatment, colorectal cancer still has a very high mortality rate among this cohort of cancer patients, and, primarily, due to the fact that approximately 30% of cases it is diagnosed at a very late stages of the disease. And, at the same time, combined and complex therapy to date does not contribute to improving the long-term results of special treatment, which, in the end, range from a complete response, in particular, during radiotherapy treatment, up to absolute resistance to its implementation. However, to date, there are already studies confirming the link between radioresistance and gene expression, which induce a response to the DNA damage checkpoint and increase the ability to repair DNA. At the same time, molecular biomarkers have a definite potential to predict the response to, in particular, neoadjuvant chemoradiotherapy for rectal cancer. This brief review examines the evolution and current state of neoadjuvant (preoperative) chemoradiotherapy for locally advanced rectal cancer (MRPC). At the same time, it should be emphasized that randomized studies and meta-analyses of recent publications justify the expediency of its use in this category of cancer patients. Modern strategies for treating patients with locally advanced rectal cancer and radiotherapy regimens used in this clinical situation are also briefly considered, as well as the prospects for using molecular genetic markers of radiosensitivity and their possible impact on the prognosis of this cancer.

ASO Visual Abstract: Systemic Inflammatory Markers Combined with Tumor-Infiltrating Lymphocyte Density for the Improved Prediction of Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer

ASO Visual Abstract: Systemic Inflammatory Markers Combined with Tumor-Infiltrating Lymphocyte Density for the Improved Prediction of Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer

Systemic Inflammatory Markers Combined with Tumor-Infiltrating Lymphocyte Density for the Improved Prediction of Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer.

Previous studies have reported the utility of systemic inflammatory markers and CD8+ tumor-infiltrating lymphocyte (TIL) separately in predicting response to chemoradiotherapy (CRT) in rectal cancer; however, the efficacy of combining these markers remains unclear. This study aimed to elucidate the predictive efficacy of systemic inflammatory markers combined with CD8+ TIL density on response to neoadjuvant CRT in locally advanced rectal cancer. Ten systemic inflammatory markers and CD8+ TIL density were assessed in 267 patients with rectal cancer using pretreatment clinical data and biopsy samples. Response to CRT was determined using the Dworak tumor regression grade (TRG), with good responders classified as TRG3-4. Receiver operating characteristic curve analysis showed high areas under the curve for the lymphocyte-to-C-reactive protein ratio (LCR) and neutrophil×monocyte (N×M) value (0.58 and 0.62, respectively). In the multivariate analysis, LCR, N×M value, and CD8+ TIL density were independently associated with good responders (p=0.016, 0.005, and 0.002, respectively). Stratified analysis with these three markers showed a positive correlation between TRG3-4 ratio and the number of positive predictive factors (8.2%, 20.0%, 34.2%, and 59.1% in patients with 0, 1, 2, and 3 predictors, respectively). Overall and disease-free survival were significantly worse in patients with zero factors present compared with those with one to three factors present. LCR, N×M value, and CD8+ TIL density are independently associated with response to CRT. Assessing local TIL density along with systemic inflammatory markers may be useful for selecting a multimodal neoadjuvant approach in rectal cancer therapy.

ASO Author Reflections: Combinations of Systemic Inflammatory Markers and CD8+ Tumor-infiltrating Lymphocyte Density: Predictive Utility for Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer.

ASO Author Reflections: Combinations of Systemic Inflammatory Markers and CD8+ Tumor-infiltrating Lymphocyte Density: Predictive Utility for Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer.

The evaluation of follow‐up strategies of watch‐and‐wait patients with a complete response after neoadjuvant therapy in rectal cancer

Many of the current follow-up schedules in a watch-and-wait approach include very frequent MRI and endoscopy examinations to ensure early detection of local regrowth (LR). The aim of this study was to analyse the occurrence and detection of LR in a watch-and-wait cohort and to suggest a more efficient follow-up schedule. Rectal cancer patients with a clinical complete response after neoadjuvant therapy were prospectively and retrospectively included in a multicentre watch-and-wait registry between 2004 and 2018, with the current follow-up schedule with 3-monthly endoscopy and MRI in the first year and 6 monthly thereafter. A theoretical comparison was constructed for the detection of LR in the current follow-up schedule against four other hypothetical schedules. In all, 50/304 (16%) of patients developed a LR. The majority (98%) were detected at ≤2years, located in the lumen (94%) and were visible on endoscopy (88%). The theoretical comparison of the different hypothetical schedules suggests that the optimal follow-up schedule should focus on the first 2years with 3-monthly endoscopy and 3-6 monthly MRI. Longer intervals in the first 2 years will cause delays in diagnosis of LR ranging from 0 to 5months. After 2 years, increasing the interval from 6 to 12months did not cause important delays. The optimal follow-up schedule for a watch-and-wait policy in patients with a clinical complete response after chemoradiation for rectal cancer should include frequent endoscopy and to a lesser degree MRI in the first 2years. Longer intervals, up to 12months, can be considered after 2years.