Chemoradiotherapy In Locally Advanced Rectal Cancer Research Articles

Expression of ZNF281 in colorectal cancer correlates with response to radiotherapy and survival

Background The treatment of Colorectal cancer (CRC) is extremely complex and survival rates vary depending on the stage of the disease at the time of diagnosis. Neoadjuvant chemoradiotherapy (NACRT), is the conventional treatment for locally advanced rectal cancer (LARC); however, the resistance to chemoradiotherapy in LARC is difficult to predict. Materials and methods In this study, clinical data of 126 LARC patients were collected and analyzed, and relevant validation was performed using GEO database and in vitro and in vivo experiments, including Western blotting and Real-time quantitative PCR, immunohistochemistry, immunofluorescence, clonogenic cell survival assays, and nude-mouse xenograft models. Results In patients with LARC who were treated with neoadjuvant radiotherapy (NART), higher ZNF281 expression in malignant tissue was associated with a poorer prognosis and lesser degree of tumor regression. Cell and mouse experiments have shown that ZNF281 reduces the damage caused by X-rays to CRC cells and tumors grown in mice. Conclusion We found that the expression of ZNF281 predicted the radiation response of CRC cells and suggested the prognosis of patients with LARC who received neoadjuvant radiation therapy.

A Phase 1 Trial of the Safety, Tolerability, and Biological Effects of Intravenous Enadenotucirev (EnAd), a Novel Oncolytic Virus, in Combination with Chemoradiotherapy in Locally Advanced Rectal Cancer (CEDAR)

Novel treatment combinations are required to increase response rates in rectal cancer. EnAd is an intravenous, tumor selective, oncolytic adenovirus with high affinity for malignant colorectal epithelial cells. Pre-clinical evidence of synergy with radiation warranted further clinical evaluation and assessment of safety in combination with chemoradiation (CRT), 25 × 2Gy and concurrent capecitabine. EnAd was escalated using 2 dose levels of viral particles (1 × 1012, 3 × 1012), given Monday, Wednesday, Friday over 3 schedules (pre-CRT, pre & post CRT). Toxicity and efficacy were used as dual end points in escalation decisions. A 2-parameter and 3-parameter logistic Time to Event Continual Reassessment Method (TiTE-CRM) were used estimate the dose-toxicity and dose-efficacy relationship, respectively. Results are shown as probability and 95% credible interval (Cr.I). The dose limiting toxicity (DLT) window was 13 weeks. Patients who had not completed their DLT window at the time of a dose decision were included in the safety analysis but down-weighted according to their follow-up time and amount of IMP received. Efficacy was assessed at 13 weeks using MRI Tumor Regression Grade (mrTRG), where mrTRG 1-2 equals response. The trial (NCT03916510) was conducted in 4 UK centers. A total of 13 patients were enrolled, 12 of whom were evaluable. Median age was 57 (range 31-84), and 10/13 were male. One patient had two G3 adverse events (AE); diarrhea, acute kidney injury. All other adverse events (AEs) were G1 or 2, with no G4/5 events. The most common AE by organ system was gastrointestinal (20.8%, G1). There were two observed DLTs on Dose schedule 3; leg swelling and acute kidney injury. Responses and toxicities increased with escalating schedules of EnAd (Table 1). CEDAR is the first trial to successfully combine an intravenous oncolytic adenovirus with radiation, demonstrating the feasibility and acceptability of this approach, and a new paradigm in radiosensitization in rectal cancer. Within this small Phase I study, EnAd demonstrated an acceptable safety profile with evidence of a higher-than-expected rate of response by mrTRG. Translation analysis of tissue, blood and microbiome for biological correlates of radiation synergy is underway. PsiOxus, CRUK (A24474). University of Oxford.

Deregulation of the miR-19b/PPP2R5E Signaling Axis Shows High Functional Impact in Colorectal Cancer Cells.

MicroRNA (miR)-19b is deregulated in colorectal cancer (CRC) and locally advanced rectal cancer (LARC), predicting worse outcome and disease progression in CRC patients, and acting as a promising prognostic marker of patient recurrence and pathological response to 5-fluorouracil (5-FU)-based neoadjuvant chemoradiotherapy in LARC. Moreover, there is a strong inverse correlation between miR-19b and PPP2R5E in LARC, and both predict the response to neoadjuvant therapy in LARC patients. However, the functional role of the miR-19b/PPP2R5E axis in CRC cells remains to be experimentally evaluated. Here, we confirm with luciferase assays that miR-19b is a direct negative regulator of PPP2R5E in CRC, which is concordant with the observed decreased PP2A activity levels after miR-19b overexpression. Furthermore, PPP2R5E downregulation plays a key role mediating miR-19b-induced oncogenic effects, increasing cell viability, colonosphere formation ability, and the migration of CRC cells. Lastly, we also confirm the role of miR-19b mediating 5-FU sensitivity of CRC cells through negative PPP2R5E regulation. Altogether, our findings demonstrate the functional relevance of the miR-19b/PPP2R5E signaling pathway in disease progression, and its potential therapeutic value determining the 5-FU response of CRC cells.

Updates to improve oncological results in rectal cancer

Background: Preoperative radiotherapy (RT) or chemoradiotherapy (CRT) followed by a total mesorectal excision (TME) has become the standard of care for locally advanced rectal cancer (LARC). The optimal timing of surgery after neoadjuvant CRT in LARC is still controversial. Aim of this study was to evaluate the effect of increasing time interval between the end of CRT and surgery on pathological outcomes.

Promises and Challenges of Predictive Blood Biomarkers for Locally Advanced Rectal Cancer Treated with Neoadjuvant Chemoradiotherapy

The treatment of locally advanced rectal cancer (LARC) requires a multimodal approach combining neoadjuvant radiotherapy or chemoradiotherapy (CRT) and surgery. Predicting tumor response to CRT can guide clinical decision making and improve patient care while avoiding unnecessary toxicity and morbidity. Circulating biomarkers offer both the advantage to be easily accessed and followed over time. In recent years, biomarkers such as proteins, blood cells, or nucleic acids have been investigated for their predictive value in oncology. We conducted a comprehensive literature review with the aim to summarize the status of circulating biomarkers predicting response to CRT in LARC. Forty-nine publications, of which forty-seven full-text articles, one review and one systematic review, were retrieved. These studies evaluated circulating markers (CEA and CA 19-9), inflammatory biomarkers (CRP, albumin, and lymphocytes), hematologic markers (hemoglobin and thrombocytes), lipids and circulating nucleic acids (cell-free DNA [cfDNA], circulating tumor DNA [ctDNA], and microRNA [miRNA]). Post-CRT CEA levels had the most consistent association with tumor response, while cfDNA integrity index, MGMT promoter methylation, ERCC-1, miRNAs, and miRNA-related SNPs were identified as potential predictive markers. Although circulating biomarkers hold great promise, inconsistent results, low statistical power, and low specificity and sensibility prevent them from reliably predicting tumor response following CRT. Validation and standardization of methods and technologies are further required to confirm results.

T2 relaxation time for the early prediction of treatment response to chemoradiation in locally advanced rectal cancer

ObjectivesPoor responders to chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC) can still have a good prognosis if the treatment strategy is changed in time. However, no reliable predictor of early-treatment response has been identified. The purpose of this study was to investigate the role of T2 relaxation time in magnetic resonance imaging (MRI) for the early prediction of a pathological response to CRT in LARC.MethodsA total of 123 MRIs were performed on 41 LARC patients immediately before, during, and after CRT. The corresponding tumor volume, T2 relaxation time, and apparent diffusion coefficient (ADC) values at different scan time points were obtained. The Mann–Whitney U test was used to compare the T2 relaxation time between pathological good responders (GR) and non-good responders (non-GR). The area under the curve (AUC) value was used to quantify the diagnostic ability of each parameter in predicting tumor response to CRT.ResultsTwenty-one (51%) and 20 (49%) were GRs and non-GRs, respectively. T2 relaxation time showed an excellent intraclass correlation coefficient (ICC) of > 0.85 at three-time points. It was significantly lower in the GR group than in the non-GR group during and after CRT. The early T2 decrease had a high AUC of 0.91 in differentiating non-GRs and GRs, similar to 0.90 of the T2 value after CRT.ConclusionsT2 relaxation time may help predict treatment response to CRT for LARC earlier, rather than having to wait until the end of CRT, thereby alleviating the physical burden for patients with no good response.

A Novel Scoring System for Response of Preoperative Chemoradiotherapy in Locally Advanced Rectal Cancer Using Early-Treatment Blood Features Derived From Machine Learning.

BackgroundPreoperative chemoradiotherapy (CRT) is a standard treatment for locally advanced rectal cancer (LARC). However, individual responses to preoperative CRT vary from patient to patient. The aim of this study is to develop a scoring system for the response of preoperative CRT in LARC using blood features derived from machine learning.MethodsPatients who underwent total mesorectal excision after preoperative CRT were included in this study. The performance of machine learning models using blood features before CRT (pre-CRT) and from 1 to 2 weeks after CRT (early-CRT) was evaluated. Based on the best model, important features were selected. The scoring system was developed from the selected model and features. The performance of the new scoring system was compared with those of systemic inflammatory indicators: neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and the prognostic nutritional index.ResultsThe models using early-CRT blood features had better performances than those using pre-CRT blood features. Based on the ridge regression model, which showed the best performance among the machine learning models (AUROC 0.6322 and AUPRC 0.5965), a novel scoring system for the response of preoperative CRT, named Response Prediction Score (RPS), was developed. The RPS system showed higher predictive power (AUROC 0.6747) than single blood features and systemic inflammatory indicators and stratified the tumor regression grade and overall downstaging clearly.ConclusionWe discovered that we can more accurately predict CRT response by using early-treatment blood data. With larger data, we can develop a more accurate and reliable indicator that can be used in real daily practices. In the future, we urge the collection of early-treatment blood data and pre-treatment blood data.

Prediction of Complete Pathological Response to Neo-Adjuvant Chemoradiotherapy Using Magnetic Resonance Imaging-Based Radiomics Analysis in Locally Advanced Rectal Cancer.

In locally advanced rectal cancer (LARC) patients treated with neoadjuvant chemoradiotherapy (CRT), surgery could be omitted in patients with complete pathological response (pCR) without compromising progression-free and overall survivals. Our objective is to develop a radiomic model based on Magnetic Resonance Imaging (MRI) and contrast-enhanced computed tomography (CT) scans to predict the pathologic complete response (pCR) to neoadjuvant CRT in LARC.All patients treated for a LARC with neoadjuvant CRT and subsequent surgery in 2 centers in the West of France (Insitut of Cancerologie Brittany Occidental (ICBO) and Nantes) were considered. Both pre-CRT pelvic MRIs and contrast-enhanced CT-scans were mandatory for inclusion. The tumor was manually segmented on the T2-weighted and diffusion axial sequences and on the contrast-enhanced CT-scan. Eighty-eight radiomic parameters (15 shape and geometry features, 11 first-order and 62 second-order) were extracted from each sequence using the in-house MirasÓ software, with a total of 1056 features by patient. The overall cohort was randomly split into two independent cohorts (training: 70% and testing: 30%). A strict feature set selection workflow based on the Spearman's correlation coefficient and the Area Under the Curve (AUC) was developed to reduce the number of features. Based on these selected features, three pCR prediction models (clinical, radiomics and combined: clinical + radiomics) were developed on the training set only with a random forest approach and a Bootstrap internal validation with n = 1000 replications. An optimal cut-off maximizing the model's performance was defined on the training set. Each model was then evaluated on the testing set, based on the AUC and the C-statistic calculated with the pre-defined cut-off. Finally, a posteriori harmonization using the ComBat approach was applied to account for imaging modalities heterogeneity.Of the 124 included patients, 14 had a complete response (11,3%). In the training set, the clinical model based on 2 parameters (initial T-stage and degree of tumor differentiation) obtained an AUC of 0.67 and a C-statistic of 0.65. The radiomic model based on 1 parameter (entropy histogram derived from T2 sequence) obtained an AUC of 1 and a C-statistic of 1. The combined clinical and radiomic model was strictly identical to the radiomics model and thus had the same performance. On the testing set, models resulted in a C-statistic of 0.70/0.73/0.73 for the clinical, radiomics and combined models, respectively. Finally, after harmonization, the radiomic model achieved a C-statistic of 0.77 on the testing set while the combined resulted in a C-statistic of 0 .75.Radiomic model based on T2-weighted pre-therapeutic MRIs sequences could help to predict pCR after neoadjuvant CRT in LARC.

Validation of microRNA-199b as A Promising Predictor of Outcome and Response to Neoadjuvant Treatment in Locally Advanced Rectal Cancer Patients.

The absence of established predictive markers with value to anticipate response to neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) represents a current major challenge in locally advanced rectal cancer (LARC). The tumor suppressor microRNA (miR)-199b has been reported to play a key role determining 5-FU sensitivity of colorectal cancer cells through the regulation of several signaling pathways, and has emerged as a novel molecular target to overcome the 5-FU resistant phenotype. Moreover, miR-199b downregulation was described as a common alteration that predicts lack of response to preoperative CRT in LARC but this issue needs to be confirmed in independent larger cohorts. Here, we evaluate the clinical impact of miR-199b in LARC and perform additional analyses to further clarify its potential relevance as novel marker in this disease. Thus, miR-199b expression was quantified by real-time-PCR in a cohort of 185 LARC patients, observing this miR downregulated in 22.2% of cases and significantly associated with higher tumor size (p = 0.026) and positive lymph node after CRT (p = 0.005), and higher pathological stage (p = 0.004). Notably, this alteration showed a strong independent predictive value of poor pathological response to neoadjuvant CRT (p = 0.004). Moreover, the subgroup of cases with low miR-199b levels had a markedly shorter overall (p < 001) and event-free survival (p < 0.001), and multivariate analyses showed that miR-199b deregulation represents an independent prognosticator for patient outcome in LARC. Interestingly, the prognostic impact of this miR was strongly significant in both younger and elderly patients, and was very effective determining patient recurrence (p = 0.004). Finally, we compared miR-199b expression profiles in a set of cases with pre and post-treatment samples available, observing that only a minimal response leads to miR-199b increase levels, further suggesting its potential clinical and therapeutic relevance as a promising marker and novel molecular target for the management of LARC.

A phase 1 trial of the safety, tolerability and biological effects of intravenous Enadenotucirev, a novel oncolytic virus, in combination with chemoradiotherapy in locally advanced rectal cancer (CEDAR)

BackgroundChemoradiotherapy remains the standard of care for locally advanced rectal cancer. Efforts to intensify treatment and increase response rates have yet to yield practice changing results due to increased toxicity and/or absence of increased radiosensitization. Enadenotucirev (EnAd) is a tumour selective, oncolytic adenovirus which can be given intravenously. Pre-clinical evidence of synergy with radiation warrants further clinical testing and assessment of safety with radiation.MethodsEligibility include histology confirmed locally advanced rectal cancer that require chemoradiation. The trial will use a Time-to-Event Continual Reassessment Model-based (TiTE-CRM) approach using toxicity and efficacy as co-primary endpoints to recommend the optimal dose and treatment schedule 30 patients will be recruited. Secondary endpoints include pathological complete response the neoadjuvant rectal score. A translational program will be based on a mandatory biopsy during the second week of treatment for ‘proof-of-concept’ and exploration of mechanism. The trial opened to recruitment in July 2019, at an expected rate of 1 per month for up to 4 years.DiscussionChemoradiation with Enadenotucirev as a radiosensitiser in locally Advanced Rectal cancer (CEDAR) is a prospective multicentre study testing a new paradigm in radiosensitization in rectal cancer. The unique ability of EnAd to selectively infect tumour cells following intravenous delivery is an exciting opportunity with a clear translational goal. The novel statistical design will make efficient use of both toxicity and efficacy data to inform subsequent studies.Trial registrationClinicalTrial.gov, NCT03916510. Registered 16th April 2019.

Exosomal microRNA-199b-5p as a potential circulating biomarker to predict response of preoperative chemoradiotherapy for locally advanced rectal cancer.

e15161 Background: Preoperative chemoradiotherapy (CRT) followed by total mesorectal excision has become the standard treatment for locally advanced rectal cancer (LARC). However, the effect of CRT varies from complete response to complete resistance, and predicting response to CRT have not been well characterized yet. Previous studies have shown the potential of micro-RNA (miRNA) based approaches to enhance tumor radiation response. Accordingly, the present study attempted to identify biomarkers to predict response for preoperative CRT using comprehensive miRNA analysis in patients with LARC. Methods: This study included 65 rectal cancer tissues and 90 serum samples from patients who diagnosed with LACR and received preoperative CRT at Kyungpook National University Chilgok Hospital. Tissue specimens and serum samples were collected before CRT to evaluate the biologic differences between the good CRT response group and the poor CRT response group. For discovery of specific miRNAs, 800 miRNAs were analyzed using NanoString in 30 rectal cancer tissues. Thereafter, a total of 65 tissues, and 90 serum samples were investigated using real-time PCR for validation. Results: The median age was 59 years (range, 30-82), and the ratio of male to female was 3.05 to 1. The pathologic stages after preoperative CRT were as follows: pathologic complete response (n=13, 14.4%), pathologic stage I (n=13, 14.4%), pathologic stage II (n=27, 30.0%), pathologic stage III (n=28, 31.1%), and pathologic stage IV (n=9, 10.0%). In the discovery set, 16 target miRNAs were detected. In the validation set with tissue specimens, expression of 3 miRNAs (miR-199a/b-3p ( p=0.032), miR-199a-5p ( p=0.023), miR-199b-5p ( p=0.005)) was significantly upregulated which was associated with better response of CRT. Moreover, among the 3 candidate miRNAs, miR-199b-5p level was significantly upregulated in serum, and it was also found to be related with better response of CRT in LARC (pathologic stage 0/I versus II/III/IV, p=0.027). Conclusions: In the present study, high level of exosomal miR-199b-5p was associated with better response, suggesting it to be a promising non-invasive biomarker to predict response of CRT in patients with LARC. Accordingly, specific miRNAs can be predictive biomarker or therapeutic target to overcome radiotherapy resistance in LARC with a functional study.

A six-gene model using an artificial neural network to predict regional lymph node metastasis after neo-adjuvant chemoradiotherapy for locally advanced rectal cancer

Objective To screen out the potential gene to predict regional lymph node metastasis after neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC) and develop a 6-gene model using an artificial neural network (ANN). Methods The gene expression profiles (GSE46862) of locally advanced rectal cancer undergoing preoperative chemoradiotherapy from 64 specimens (21 with ypN- and 43 with ypN+ ) were downloaded from the gene expression omnibus (GEO) database. The differentially expressed genes were identified to screen out the potential biomarkers through the Gene-Cloud of Biotechnology Information (GCBI) platform. The top 6 genes were screened out for building model. An ANN model was trained and validated using the SPSS Modeler software. The study samples were allocated randomly into the training sample group and testing sample group with a 7∶3 ratio. The training samples and testing samples were respectively used for building an ANN model and independent back-substitution test. Observation indicators: (1) screening results of differentially expressed genes; (2) analysis results of ANN model. The receiver operating characteristic (ROC) curve was drawn and the area under the curve (AUC) was calculated to evaluate the predictive abilities of ANN and each biomarker. Results (1) Screening results of differentially expressed genes: A total of 50 genes were screened. Six top genes included IL6, AKR1B1, AREG, SELE, ROBO1 and CD274. (2) Analysis results of ANN model: Six top genes were selected to construct a three-layer ANN model with a 7-5-2 structure. The IL6 made the greatest effect on the ANN model, followed by ROBO1, AKR1B1, AREG, CD274 and SELE. The AUC was 0.929. The sensitivity and specificity of ANN model were 96.7% and 85.7%, and accuracy of training samples was 93.2%. In the independent back-substitution test, sensitivity and specificity were 92.3% and 85.7%, and accuracy of testing samples was 90.0%. Conclusion The prediction ANN model based on multiple molecular markers (IL6, ROBO1, AKR1B1, AREG, CD274 and SELE) for regional lymph node metastases in LARC patients after CRT would be beneficial in selecting potential candidates for rectum-preserving surgery following CRT for LARC. Key words: Rectal neoplasms; Neoadjuvant radiotherapy; Neoadjuvant chemotherapy; Regional lymph node; Artificial neural network

Research progress of neoadjuvant therapy for locally advanced rectal cancer

The clinical application of novel chemotherapeutic drugs including oral 5-FU and targeted drugs and preoperatively accurate imaging grading has brought challenges to the indication criteria developed by NCCN and ESMO for neoadjuvant chemoradiotherapy in locally advanced rectal cancer (LARC). Extended hotspots have focused on the effectiveness of using capecitabine instead of fluorouracil infusion, the combination of multiple drugs and the feasibility of using neoadjuvant chemotherapy instead of neoadjuvant chemoradiotherapy for selective patients. Traditionally, the evaluation of the effect of neoadjuvant therapy has been based on the effect on the pathological complete remission (pCR) rate. However, current studies recommend the disease-free survival (DFS) as a more important outcome. Besides, seeking for effective biomarkers as predictive markers for neoadjuvant therapies or as prognostic markers remains a hotspot in the field of neoadjuvant chemoradiotherapy. The "watch and wait" approach refers to taking a close follow-up strategy instead of direct operation for patients achieving clinically complete remission (cCR) after neoadjuvant therapy. However, there is no unified evaluation criteria and time point for the evaluation of cCR following neoadjuvant therapy. Therefore, there remain a lot of controversies regarding the clinical application of neoadjuvant chemoradiotherapy in LARC. In this manuscript, research progress in the indication for neoadjuvant therapy, improvement in the neoadjuvant therapeutic schedule, advancement of the efficacy evaluation criteria of neoadjuvant therapy, the "watch and wait" approach and other hot topics is summarized to provide references for clinical practice.

Synergistic antitumor interaction between valproic acid, capecitabine and radiotherapy in colorectal cancer: critical role of p53

BackgroundRecurrence with distant metastases has become the predominant pattern of failure in locally advanced rectal cancer (LARC), thus the integration of new antineoplastic agents into preoperative fluoropyrimidine-based chemo-radiotherapy represents a clinical challenge to implement an intensified therapeutic strategy.The present study examined the combination of the histone deacetylase inhibitor (HDACi) valproic acid (VPA) with fluoropyrimidine-based chemo-radiotherapy on colorectal cancer (CRC) cells.MethodsHCT-116 (p53-wild type), HCT-116 p53−/− (p53-null), SW620 and HT29 (p53-mutant) CRC cell lines were used to assess the antitumor interaction between VPA and capecitabine metabolite 5′-deoxy-5-fluorouridine (5′-DFUR) in combination with radiotherapy and to evaluate the role of p53 in the combination treatment. Effects on proliferation, clonogenicity and apoptosis were evaluated, along with γH2AX foci formation as an indicator for DNA damage.ResultsCombined treatment with equipotent doses of VPA and 5′-DFUR resulted in synergistic effects in CRC lines expressing p53 (wild-type or mutant). In HCT-116 p53−/− cells we observed antagonist effects. Radiotherapy further potentiated the antiproliferative, pro-apoptotic and DNA damage effects induced by 5′-DFUR/VPA combination in p53 expressing cells.ConclusionsThese results highlighted the role of VPA as valuable candidate to be added to preoperative chemo-radiotherapy in LARC. On these bases we launched the ongoing phase I/II study of VPA and short-course radiotherapy plus capecitabine as preoperative treatment in low-moderate risk rectal cancer (V-shoRT-R3).

Systemic chemotherapy (CT) as salvage treatment for locally advanced rectal cancer (LARC) patients (pts) who fail to respond to neoadjuvant chemoradiotherapy (CRT).

709 Background: International guidelines suggest that RT dose escalation, intraoperative RT or brachytherapy could be considered for LARC pts with positive resection margins, pT4 or unresectable tumours after standard neoadjuvant CRT. However, data to support these approaches are scarce. The potential of systemic CT as salvage treatment after failure of neoadjuvant CRT for LARC has never been explored. We conducted a single-centre, retrospective analysis to address this question. Methods: Pts with newly diagnosed rectal adenocarcinoma who were deemed inoperable or candidates for extensive (i.e. beyond total mesorectal excision, TME) surgery after completion of long-course RT and received salvage systemic CT were included. The primary objective was to estimate the proportion of pts who became potentially suitable for TME after CT. Secondary objectives included the proportion of pts who ultimately underwent TME and survival outcomes. Results: 45 pts (2001-2015) met the study inclusion criteria (39 candidates for extensive surgery and 6 with unresectable tumours). Previous RT was given concurrently with CT in 43 cases (median dose: 54.0 Gy; range: 34.0-55.8). Salvage oxaliplatin-based and irinotecan-based CT was administered in 40 (88.9%) and 5 (11.1%) cases, respectively. 8 pts (17.8%) became suitable for TME based on the MRI after CT, 10 (22.2%) ultimately underwent TME with clear margins and 2 (4.4%) were managed with a watch &amp; wait approach following radiological clinical complete response. Additionally, 13 pts had a beyond-TME surgery with curative intent. 3-year progression-free survival and 5-year overall survival in the entire population were 30.0% (95% CI: 15.0-46.0) and 44.0% (95% CI: 26.0-61.0), respectively. For the curatively resected and watch &amp; wait pts these figures were 52.0% (95% CI: 27.0-73.0) and 67.0% (95% CI: 40.0-84.0), respectively. Conclusions: Systemic CT may be an effective salvage strategy for LARC pts who fail to respond to long-course CRT and are inoperable or candidates for beyond-TME surgery. According to our study, 1 out of 4 pts may become resectable or being spared from an extensive surgery after systemic CT.

A scoring system basing pathological parameters to predict regional lymph node metastasis after preoperative chemoradiotherapy for locally advanced rectal cancer: implication for local excision.

Local excision is an alternative to radical surgery that is indicated in patients with locally advanced rectal cancer (LARC) who have a good response to chemoradiotherapy (CRT). Regional lymph node status is a major uncertainty during local excision of LARC following CRT. We retrospectively reviewed clinicopathologic variables for 244 patients with LARC who were treated at our institute between December 2000 and December 2013 in order to identify independent predictors of regional lymph node metastasis. Multivariate analysis of the training sample demonstrated that histopathologic type, tumor size, and the presence of lymphovascular invasion were significant predictors of regional nodal metastasis. These variables were then incorporated into a scoring system in which the total scores were calculated based on the points assigned for each parameter. The area under the curve in the receiver operating characteristic analysis was 0.750, and the cutoff value for the total score to predict regional nodal metastasis was 7.5. The sensitivity of our system was 73.2% and the specificity was 69.4%. The sensitivity was 77.8% and the specificity was 51.2% when the scoring system was applied to the testing sample. Using this system, we could accurately predict regional nodal metastases in LARC patients following CRT, which may be useful for stratifying patients in clinical trials and selecting potential candidates for organ-sparing surgery following CRT for LARC

Predictors of pathologic complete response after neoadjuvant chemoradiotherapy for locally advanced rectal cancer

Objective To evaluate the potential influencing factors associated with pathologic complete response (pCR) after neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC). Methods A retrospective analysis was performed on the clinical data 265 patients with stage Ⅱ and Ⅲ(the 7th version of AJCC) rectal cancer admitted to our hospital from 2011 to 2013. All patients underwent neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery with/or without induction chemotherapy during the interval between the complete of CCRT and surgery. The predictors associated with pCR were analyzed by univariate and multivariate logistic regression analyses. With the use of the independent predictive variables for pCR from multivariate analysis, a clinical risk score model was established according to the following criteria: no-risk group (0 factor); low-risk group (1 factor); high-risk group (2 factors). Results Among these 265 patients, 50(18.9%) achieved pCR. The univariate analysis showed that carcinoembryonic antigen (CEA) level before CCRT (P=0.017), T stage before CCRT (P=0.001), interval between complete of CCRT and surgery (P=0.000), and the maximum tumor thickness before CCRT (P=0.040) were significantly associated with pCR. The multivariate analysis showed that pre-CCRT CEA level (P=0.021 or 0.446) and interval between the complete of CCRT and surgery (P=0.000 or 3.774) were significant predictors of pCR. When stratifying for smoking status, only low pre-CCRT CEA level was significantly associated with pCR in the non-smoking patients (P=0.044). For the prediction of pCR by the clinical risk score model, the sensitivity was 0.805, the specificity was 0.460, the area under the receiver operating curve was 0.690(95% CI=0.613-0.767), the positive predictive value was 35.49%, the negative predictive value was 86.5%, and the predictive accuracy was 73.9%. Conclusions For locally advanced rectal cancer, pCR can be achieved in some patients after neoadjuvant therapy. Low pre-CCRT CEA level and long interval time between CCRT and surgery are independent factors associated with pCR, and only low pre-CCRT CEA level is an associated factor in the group of nonsmokers. The clinical risk score model based on pre-CCRT CEA level>5 ng/ml and time interval from CCRT completion to surgery ≤8 weeks can be used to predict pCR after neoadjuvant chemoradiotherapy for LARC. Key words: Rectal neoplasms/neoadjuvant therapy; Pathologic complete response; Factors analysis

PWE-333 Rectal cancer resection specimen quality and pathological response at 6 vs. 12 weeks after long-course chemoradiotherapy: data from a pilot randomised controlled trial

Introduction Long-course chemoradiotherapy (CRT) is often delivered to down-stage locally-advanced rectal cancer prior to surgical resection. Surgery is performed after an interval period to allow time for radiation-induced tumour shrinkage and to facilitate more accurate surgery. The optimal time interval remains unclear, with little high-quality evidence to guide clinical decisions about when to operate. Method This study explores pathological outcomes from a pilot Randomised Controlled Trial (RCT) comparing an interval of six weeks versus an interval of 12 weeks between CRT and rectal cancer resection surgery. Thirty one patients requiring CRT for locally-advanced rectal cancer were recruited from seven UK centres between June 2012 and May 2014 and randomised to an interval of either 6 or 12 weeks. Photographs were taken of the intact mesorectal surfaces, and of the serial slices of resected specimens. These were assessed by an, blinded histopathologist to describe the quality of mesorectal dissection using a three-point scale. Rates of complete response, down-staging, and circumferential resection margin (CRM) involvement were assessed according to Royal College of Pathology guidelines. For tumour cell density (TCD) assessment, slides from the resected specimen and baseline biopsy were scanned at x40 magnification. For each patient, the slide with the greatest amount of residual tumour was selected and between 285 and 315 data-points were analysed by a blinded expert to describe the percentage of different tissue components for the whole tumour area. Results Twenty three patients underwent tumour resection within the trial (10 patients from the 6-week arm and 13 patients from the 12-week arm). A mesorectal specimen score of 3/3 (mesorectal fascia plane) was assigned to seven specimens from the 6-week arm (70%) and eight from the 12-week arm (62%). Three patients at 6-weeks and two patients at 12-weeks had a complete pathological response to CRT. Only one patient (from the 12-week arm) had an involved CRM. TCD was 0.3% (IQR 0.7) for the 6-week arm and 4.3% (IQR 8) for the 12 week arm (p = 0.12) Conclusion In this small randomised study, rates of mesorectal specimen quality, complete pathological response, and TCD were broadly similar when rectal cancer was resected after either a 6 or 12 week interval following CRT. Further studies are needed to further clarify whether a longer interval actually does facilitate ongoing down-staging. Disclosure of interest None Declared.

Standardized Index of Shape (SIS): a quantitative DCE-MRI parameter to discriminate responders by non-responders after neoadjuvant therapy in LARC

To investigate the potential of DCE-MRI to discriminate responders from non-responders after neoadjuvant chemo-radiotherapy (CRT) for locally advanced rectal cancer (LARC). We investigated several shape parameters for the time-intensity curve (TIC) in order to identify the best combination of parameters between two linear parameter classifiers. Seventy-four consecutive patients with LARC were enrolled in a prospective study approved by our ethics committee. Each patient gave written informed consent. After surgery, pathological TNM and tumour regression grade (TRG) were estimated. DCE-MRI semi-quantitative analysis (sqMRI) was performed to identify the best parameter or parameter combination to discriminate responders from non-responders in response monitoring to CRT. Percentage changes of TIC shape descriptors from the baseline to the presurgical scan were assessed and correlated with TRG. Receiver operating characteristic analysis and linear classifier were applied. Forty-six patients (62.2%) were classified as responders, while 28 subjects (37.8%) were considered as non-responders. sqMRI reached a sensitivity of 93.5% and a specificity of 82.1% combining the percentage change in Maximum Signal Difference (ΔMSD) and Wash-out Slope (ΔWOS), the Standardized Index of Shape (SIS). SIS obtains the best result in discriminating responders from non-responders after CRT in LARC, with a cut-off value of -3.0%. • DCE-MRI shape descriptors are investigated to assess preoperative CRT response in LARC. • Identification of the best TIC shape descriptors combination through a linear classifier. • Identification of a single MRI index to predict neoadjuvant treatment response.

Oxaliplatin and capecitabine initially concomitant to radiotherapy then administered in the resting period in high-risk locally advanced rectal cancer.

581 Background: Although neoadjuvant chemoradiotherapy (CRT) has dramatically reduced the risk of local recurrence in locally advanced rectal cancer (LARC), it fails to reduce the risk of systemic failure. To enhance systemic control, we develop an alternative approach, combining intense chemotherapy using Oxaliplatin and Capecitabine (XELOX regimen) concomitant to radiation and extending the chemotherapy regimen to the resting period (consolidation chemotherapy) for high risk LARC. The aim of the present study was to evaluate the efficacy and toxicities of this strategy. Methods: Patients with high risk LARC were treated with CRT. Two cycles of XELOX regimen was administered concomitant to radiation. Then an additional cycle of the same regimen was extended to the resting period one week after completion of chemoradiation. Tumor response, toxicities associated with CRT and consolidation chemotherapy, and surgical complications were recorded. Results: Thirty-six patients with high risk LARC were identified treated with the strategy from 2010 to 2012. All patents completed the planned dose of radiation and concurrent chemotherapy, and two patient was unable to complete the consolidation chemotherapy because of grade 3 toxicities. Grade 3 acute toxicities were 2.8% leucopenia, 2.8% diarrhea, and 2.8% radiation dermatitis. All patients underwent optimal surgery with TME, among whom sphincter-saving procedure was performed in 27 patients (75%). There was no peri-operative mortality in this cohort. Seven patients (19.4%) developed postoperative complications. Complete regression (pCR), major regression (nearly pCR), and moderate or minimal regression were achieved in 13 (36.1%), 16 patients (44.4%), and 7 patients (19.5%), respectively. Conclusions: The preliminary results suggest that XELOX regimen concomitant to radiation and extended to the “resting period” after radiation completion are well tolerated. This strategy is associated with high pCR and nearly pCR rates. The promising results warrant further investigation of the impact of consolidation chemotherapy following CRT for LARC in future clinical trials.