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Background: The clinical value of different modes of CRM involvement in rectal cancer patients is unclear. This study aims to determine the clinical impact of different modes of circumferential resection margin (CRM) involvement in patients with a locally advanced rectal carcinoma., Patients and Methods: A cohort of patients who were diagnosed with stage III rectal cancer between June 2014 and June 2020 was selected from the prospective Dutch nationwide pathology databank (PALGA). Histopathological and clinical data were analyzed according to the nature of CRM involvement (via primary tumor invasion, lymph node metastasis, tumor deposit, multiple factors) and analyses on recurrence and overall survival (OS) were performed., Results: 3020 patients were included, of whom 12.4 % had a positive CRM. The majority of these patients (63.2 %) had CRM involvement by primary tumor invasion and in 9 % of patients multiple factors caused the positive CRM. The rates of local recurrence and distant metastasis were related to the nature of the CRM involvement, with lowest rate for lymph node metastasis and highest rate for multiple factors. On multivariate analysis, CRM involvement by primary tumor invasion, tumor deposits and multiple factors, but not by lymph node metastasis, were associated with poor OS., Conclusion: This nationwide population based study highlights the clinical importance of reporting the nature of CRM involvement in rectal cancer patients. Lymph node metastasis involving the CRM does not bear the same risks for local recurrence, distant metastases and OS as CRM involvement by primary tumor invasion or CRM involvement by multiple factors., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: A pathological complete response (pCR) following chemoradiation (CRT) or short-course radiotherapy (scRT) leads to a favourable prognosis in patients with rectal cancer. Total neo-adjuvant therapy (TNT) doubles the pCR rate, but it is unknown whether oncological outcomes remain favourable and whether the same characteristics are associated with pCR as after CRT., Methods: Comparison between patients with pCR in the RAPIDO trial in the experimental [EXP] (scRT, chemotherapy, surgery, as TNT) and standard-of-care treatment [STD] (CRT, surgery, postoperative chemotherapy depending on hospital policy) groups. Primary and secondary outcomes were time-to-recurrence (TTR), overall survival (OS) and association between patient, tumour, and treatment characteristics and pCR., Results: Among patients with a resection within six months after preoperative treatment, 120/423 (28%) [EXP] and 57/398 (14%) [STD] achieved a pCR. Following pCR, 5-year cumulative TTR and OS rates in the EXP and STD arms were 8% vs. 7% (hazard ratio 1.04, 95%CI 0.32-3.38) and 94% vs. 93% (hazard ratio 1.41, 95%CI 0.51-3.92), respectively. Besides the EXP treatment (odds ratio 2.70, 95%CI 1.83-3.97), pre-treatment carcinoembryonic antigen (CEA) <5, pre-treatment tumour size <40 mm and cT2 were associated with pCR. Distance from the anal verge was the only characteristic with a statistically significant difference in association with pCR between the EXP and STD treatment (P interaction =0.042). pCR rates did not increase with prolonged treatment time., Conclusions: The doubled pCR rate of TNT compared to CRT results in similar oncological outcomes. Characteristics associated with pCR are the EXP treatment, normal CEA, and small tumour size., Competing Interests: Declaration of Competing Interest PJN reports honoraria from Ethicon, Johnson & Johnson, and Amgen. GAPH reports consulting fees from Roche, MSD, Amgen and Novartis; consulting fees and research support to their institution from Bristol Myers Squibb; and research support to their institution from Seerave Foundation. SJDT was fully funded, and AGHR and CJHvdV were partially funded by the EU’s Horizon Skłodowska Curie grant award (H2020MSCAITN2019, grant agreement number 857894; project acronym: CAST). BG reports research support from the Swedish Cancer Society. All other authors have declared no conflicts of interest. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The first authors had full access to all data and had final responsibility for the decision to submit for publication. All other authors report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: Lymph node metastases (LNM) are one of the most important prognostic indicators in solid tumours and a major component of cancer staging. Neoadjuvant therapy might influence nodal status by induction of regression. Our aim is to determine the prevalence and role of regression of LNM on outcomes in patients with rectal cancer., Methods and Results: Four independent study populations of rectal cancer patients treated with similar regimens of chemoradiotherapy were pooled together to obtain a total cohort of 469 patients. Post-treatment nodal status (ypN) and signs of tumour regression (Reg) were incorporated to form three-tiered (ypN- Reg+, ypN- Reg- and ypN+) and four-tiered (ypN- Reg+, ypN- Reg-, ypN+ Reg+ and ypN+ Reg-) classifications. In our cohort, 31% of patients presented with ypN+ rectal cancer. As expected, we found significantly worse overall survival (OS) in ypN+ patients compared to ypN- patients (P = 0.002). The percentage of ypN- patients with lymph nodes with complete regression was 20% in our cohort. While node-negative patients with and without regression had similar OS (P = 0.09), disease-free survival (DFS) was significantly better in node-negative patients with regression (P = 0.009)., Conclusions: Regression in lymph nodes is frequent, and node-negative patients with evidence of lymph node regression have better DFS compared to node-negative patients without such evidence., (© 2024 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Background:  Screen-detected colorectal cancers (CRCs) are often treated less invasively than stage-matched non-screen-detected CRCs, but the reasons for this are not fully understood. This study evaluated the treatment of stage I CRCs detected within and outside of the screening program in the Netherlands. METHODS : Data from the Netherlands Cancer Registry for all stage I CRCs diagnosed between January 1, 2008 and December 31, 2020 were analyzed, comparing patient, tumor, and treatment characteristics of screen-detected and non-screen-detected stage I CRCs. Multivariable logistic regression was used to assess the association between treatment (local excision only vs. surgical oncologic resection) and patient and tumor characteristics, stratified for T stage and tumor location., Results:  Screen-detected stage I CRCs were relatively more often T1 than T2 compared with non-screen-detected stage I CRCs (66.9 % vs. 53.3 %; P  < 0.001). When only T1 tumors were considered, both screen-detected colon and rectal cancers were more often treated with local excision only than non-screen-detected T1 cancers (odds ratio [OR] 2.19, 95 %CI 1.93-2.49; and OR 1.29, 95 %CI 1.05-1.59, respectively), adjusted for sex, tumor location, lymphovascular invasion (LVI) status, and tumor differentiation. CONCLUSIONS : Less invasive treatment of screen-detected stage I CRC is partly explained by the higher rate of T1 cancers compared with non-screen-detected stage I CRCs. T1 stage I screen-detected CRCs were also more likely to undergo less invasive treatment than non-screen-detected CRCs, adjusted for risk factors such as LVI and tumor differentiation. Future research should investigate whether the choice of local excision was related to unidentified cancer-related factors or the expertise of the endoscopists., Competing Interests: The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Aims: Partial response to neoadjuvant chemoradiotherapy (CRT) presents with one of two main response patterns: shrinkage or fragmentation. This study investigated the relevance of these response patterns in rectal cancer, correlation with other response indicators, and outcome., Methods and Results: The study included a test (n = 197) and a validation cohort (n = 218) of post-CRT patients with rectal adenocarcinoma not otherwise specified and a partial response. Response patterns were scored by two independent observers using a previously developed three-step flowchart. Tumour regression grading (TRG) was established according to both the College of American Pathologists (CAP) and Dworak classifications. In both cohorts, the predominant response pattern was fragmentation (70% and 74%), and the scoring interobserver agreement was excellent (k = 0.85). Patients with a fragmented pattern presented with significantly higher pathological stage (ypTNM II-IV, 78% versus 35%; P < 0.001), less tumour regression with Dworak (P = 0.004), and CAP TRG (P = 0.005) compared to patients with a shrinkage pattern. As a predictor of prognosis, the shrinkage pattern outperformed the TRG classification and stratified patients better in overall (fragmented pattern, hazard ratio [HR] 2.04, 95% confidence interval [CI] 1.19-3.50, P = 0.008) and disease-free survival (DFS; fragmented pattern, HR 2.50, 95% CI 1.23-5.10, P = 0.011) in the combined cohorts. The multivariable regression analyses revealed pathological stage as the only independent predictor of DFS., Conclusions: The heterogeneous nature of tumour response following CRT is reflected in fragmentation and shrinkage. In rectal cancer there is a predominance of the fragmented pattern, which is associated with advanced stage and less tumour regression. While not independently associated with survival, these reproducible patterns give insights into the biology of tumour response., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Background: Accurate biomarkers to monitor tumor load and response in metastatic colorectal cancer patients undergoing surgery could optimize treatment regimens., Objective: This study aimed to explore the clinical validity of tumor-informed quantification of circulating tumor DNA in blood using ultradeep sequencing., Design: Resection specimens from 53 colorectal cancer patients were analyzed for tumor-specific mutations in 15 genes. These mutations were used to measure the presence of circulating tumor DNA in preoperatively collected plasma samples using hybrid capture-based sequencing. Additional postoperative measurements were performed 1 week after surgery in 16 patients., Settings: The study was conducted at the Radboud University Medical Center., Patients: A total of 53 colorectal cancer patients undergoing surgery of metastases were included., Main Outcome Measures: The detection of circulating tumor DNA., Results: At least 1 tumor-specific mutation was detected in all tumor samples. In preoperative plasma samples, circulating tumor DNA was detected in 88% (37/42) of systemic treatment-naïve patients and in 55% (6/11) of patients who received preoperative chemotherapy. More specifically, circulating tumor DNA was detected in 0% (0/3) of cases with a subtotal or partial pathologic response and in 75% (6/8) of cases without a pathologic response in the resection specimen ( p = 0.06). In postoperative plasma samples, circulating tumor DNA was detected in 80% (4/5) of patients with an incomplete resection and in 0% (0/11) of those with a complete resection ( p = 0.003)., Limitations: The study was limited by the heterogeneity of the cohort and the small number of postoperative plasma samples., Conclusions: These data indicate that tumor-informed circulating tumor DNA detection in the plasma of patients undergoing surgery for metastatic colorectal cancer is feasible and may have clinical value in response monitoring and predicting residual disease. Prospective studies are needed to establish the clinical utility of circulating tumor DNA analysis to guide treatment decisions in these patients. See Video Abstract at http://links.lww.com/DCR/B990 ., Validez Clnica Del Anlisis De Adn Del Tumor Circulante Informado Por El Tumor En Pacientes Sometidos a Ciruga De Metstasis Colorrectales: ANTECEDENTES:Los biomarcadores precisos para monitorear la carga tumoral y la respuesta en pacientes con cáncer colorrectal metastásico que se someten a cirugía podrían optimizar los regímenes de tratamiento.OBJETIVO:Este estudio explora la validez clínica de la cuantificación informada por el tumor del ADN tumoral circulante en sangre mediante secuenciación ultraprofunda.DISEÑO:Se analizaron muestras de resección de 53 pacientes con cáncer colorrectal en busca de mutaciones específicas del tumor en quince genes. Estas mutaciones se usaron para medir la presencia de ADN tumoral circulante en muestras de plasma recolectadas antes de la operación usando secuenciación basada en captura híbrida. Se realizaron mediciones postoperatorias adicionales una semana después de la cirugía en dieciséis pacientes.AJUSTES:El estudio se realizó en el centro médico de la universidad de Radboud.PACIENTES:Se incluyeron un total de 53 pacientes con cáncer colorrectal sometidos a cirugía de metástasis.PRINCIPALES MEDIDAS DE RESULTADO:La detección de ADN tumoral circulante.RESULTADOS:Se detectó al menos una mutación específica de tumor en todas las muestras de tumor. En muestras de plasma preoperatorias, se detectó ADN tumoral circulante en el 88% (37/42) de los pacientes sin tratamiento sistémico previo y en el 55% (6/11) de los pacientes que recibieron quimioterapia preoperatoria. Más concretamente, en el 0% (0/3) de los casos con respuesta patológica subtotal o parcial y en el 75% (6/8) de los casos sin respuesta patológica en la pieza de resección ( p = 0,06). En muestras de plasma postoperatorio se detectó ADN tumoral circulante en el 80% (4/5) de los pacientes con una resección incompleta y en el 0% (0/11) de los que tenían resección completa ( p = 0,003).LIMITACIONES:El estudio estuvo limitado por la heterogeneidad de la cohorte y el pequeño número de muestras de plasma postoperatorias.CONCLUSIONES:Estos datos indican que la detección de ADN tumoral circulante informado por el tumor en el plasma de pacientes sometidos a cirugía por cáncer colorrectal metastásico es factible y puede tener valor clínico en el control de la respuesta y la predicción de la enfermedad residual. Se necesitan estudios prospectivos para establecer la utilidad clínica del análisis de ADN tumoral circulante para guiar las decisiones de tratamiento en estos pacientes. Consulte Video Resumen en http://links.lww.com/DCR/B990 . (Traducción-Dr. Mauricio Santamaria )., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Colon and Rectal Surgeons.)

Background: Here we present updated survival of the CAIRO2 trial and assessed whether the addition of anti-EGFR to anti-VEGF therapy could still be an effective treatment option for patients with extended RAS/BRAF wildtype and left-sided metastatic colorectal cancer (mCRC)., Materials and Methods: Retrospective updated survival and extended RAS and BRAF V600E mutational analysis were performed in the CAIRO2 trial, a multicenter, randomized phase III trial on the effect of adding cetuximab to a combination of capecitabine, oxaliplatin (CAPOX), and bevacizumab in mCRC., Results: Updated survival analysis confirmed that the addition of cetuximab did not provide a benefit on either progression free (PFS) or overall survival (OS) in the intention-to-treat population. With the extended mutational analyses 31 KRAS, 31 NRAS and 12 BRAF V600E additional mutations were found. No benefit of the addition of cetuximab was observed within the extended wildtype group, even when selecting only left-sided tumors (PFS HR 0.96, p = 0.7775). However, compared to the original trial an increase of 6.5 months was seen for patients with both extended wildtype and left-sided tumors (median OS 28.6 months)., Conclusion: Adding cetuximab to CAPOX and bevacizumab does not provide clinical benefit in patients with mCRC, even in the extended wildtype group with left-sided tumors. However, in the extended wildtype group we did observe clinically relevant higher survival compared to the initial trial report, indicating that it is important to analyze a broader panel of RAS and BRAF variants using more recent sequencing techniques when assessing survival benefit after anti-EGFR therapy., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Neoadjuvant therapy is the cornerstone of modern rectal cancer treatment. Insights into the biology of tumor responses are essential for the successful implementation of organ-preserving strategies, as different treatments may lead to specific tumor responses. In this study, we aim to explore treatment-specific responses of the tumor microenvironment. Patients with locally advanced adenocarcinoma of the rectum who had received neo-adjuvant chemotherapy (CT), neo-adjuvant radiochemotherapy (RCT), neo-adjuvant radiotherapy with a long-interval (LRT) or short-interval (SRT) or no neoadjuvant therapy (NT) as control were included. Multiplex-immunofluorescence was performed to determine the presence of cytotoxic T-cells (T-cyt; CD3+CD8+), regulatory T-cells (T-reg; CD3+FOXP3+), T-helper cells (T-helper; CD3+CD8-FOXP3-), B cells (CD20+), dendritic cells (CD11c+) and tumor cells (panCK+). A total of 80 rectal cancer patients were included. Treatment groups were matched for gender, tumor location, response to therapy, and TNM stage. The pattern of response (shrinkage vs. fragmentation) was, however, different between treatment groups. Our analyses reveal that RCT-treated patients exhibited lower stromal T-helper, T-reg, and T-cyt cells compared to other treatment regimens. In conclusion, we demonstrated treatment-specific differences in the immune microenvironment landscape of rectal cancer patients. Understanding the underlying mechanisms of this landscape after a specific therapy will benefit future treatment decisions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Graham Martínez, Barella, Kus Öztürk, Ansems, Gorris, van Vliet, Marijnen and Nagtegaal.)

Purpose: The COVID-19 pandemic had a major impact on the health services worldwide. We aimed to investigate the impact of the pandemic on colorectal cancer (CRC) care in the Netherlands in 2020., Methods: CRC patients, diagnosed in 2018-2020 in the Netherlands, were selected from the Netherlands Cancer Registry (NCR). The year 2020 was divided in four periods reflecting COVID-19 developments in the Netherlands (pre-COVID, 1st peak, recovery period, 2nd peak) and compared with the same periods in 2018/2019. Patient characteristics and treatment were compared using the Chi-squared test. Median time between diagnosis and treatment, and between (neo)adjuvant therapy and surgery were analyzed by the Mann-Whitney U test., Results: In total, 38,021 CRC patients were diagnosed in 2018/2019 (n = 26,816) and 2020 (n = 11,205). Median time between diagnosis and initial treatment decreased on average 4 days and median time between neoadjuvant radiotherapy and surgery in clinical stage II or III rectal cancer patients increased on average 34 days during the three COVID-19 periods compared to the same periods of 2018/2019. The proportion of colon cancer patients that underwent elective surgery significantly decreased with 3.0% during the 1st peak. No differences were found in the proportion of patients who received (neo)adjuvant therapy, systemic therapy, or no anti-cancer treatment., Conclusion: Only minor changes in the care for CRC patients occurred during the COVID-19 pandemic, mostly during the 1 st peak. In conclusion, the impact on CRC care in the Netherlands was found to be limited. However, long-term effects cannot be precluded., (© 2022. The Author(s).)

Aim: Currently, compelling evidence illustrates the significance of determining microsatellite instability (MSI) in colorectal cancer (CRC). The association of MSI with proximal CRC is well established, however, its implications in patients with rectal cancer remain undefined. We therefore aimed to determine the role of MSI with respect to incidence and outcome in patients with rectal cancer., Methods and Results: For this we examined patients from two prospective phase III trials: TME trial and PROCTOR-SCRIPT trial (n = 1250). In addition, we performed a literature review to evaluate the overall prevalence, the effect on survival and the response to neo-adjuvant treatment in patients with MSI rectal cancer compared with microsatellite stable (MSS) rectal cancer. Our TME and PROCTOR-SCRIPT cohort showed no differences in terms of overall survival (OS) (hazard ratio [HR] 1.00, 95% confidence interval [CI] 0.69-1.47) and disease-free survival (DFS) (HR 1.00, 95% CI 0.68-1.45) in patients with MSI compared to MSS rectal cancer. The total number of MSI cases in all included studies (including our own) was 1220 (out of 16,526 rectal cancer patients), with an overall prevalence of 6.7% (standard error 1.19%). Both for OS as for DFS there was no impact of MSI status on prognosis (HR 1.00, 95% CI 0.77-1.29 and HR 0.86, 95% CI 0.60-1.22, respectively). The risk ratio (RR) for downstaging and pathological complete response showed also no impact of MSI status (RR 1.15, 95% CI 0.86-1.55 and RR 0.81, 95% CI 0.54-1.22, respectively)., Conclusion: Rectal cancer patients with MSI form a distinct and rare subcategory, however, there is no prognostic effect of MSI in rectal cancer patients., (© 2022 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Objectives: To identify the main problem areas in the applicability of the current TNM staging system (8 th ed.) for the radiological staging and reporting of rectal cancer and provide practice recommendations on how to handle them., Methods: A global case-based online survey was conducted including 41 image-based rectal cancer cases focusing on various items included in the TNM system. Cases reaching < 80% agreement among survey respondents were identified as problem areas and discussed among an international expert panel, including 5 radiologists, 6 colorectal surgeons, 4 radiation oncologists, and 3 pathologists., Results: Three hundred twenty-one respondents (from 32 countries) completed the survey. Sixteen problem areas were identified, related to cT staging in low-rectal cancers, definitions for cT4b and cM1a disease, definitions for mesorectal fascia (MRF) involvement, evaluation of lymph nodes versus tumor deposits, and staging of lateral lymph nodes. The expert panel recommended strategies on how to handle these, including advice on cT-stage categorization in case of involvement of different layers of the anal canal, specifications on which structures to include in the definition of cT4b disease, how to define MRF involvement by the primary tumor and other tumor-bearing structures, how to differentiate and report lymph nodes and tumor deposits on MRI, and how to anatomically localize and stage lateral lymph nodes., Conclusions: The recommendations derived from this global survey and expert panel discussion may serve as a practice guide and support tool for radiologists (and other clinicians) involved in the staging of rectal cancer and may contribute to improved consistency in radiological staging and reporting., Key Points: • Via a case-based online survey (incl. 321 respondents from 32 countries), we identified 16 problem areas related to the applicability of the TNM staging system for the radiological staging and reporting of rectal cancer. • A multidisciplinary panel of experts recommended strategies on how to handle these problem areas, including advice on cT-stage categorization in case of involvement of different layers of the anal canal, specifications on which structures to include in the definition of cT4b disease, how to define mesorectal fascia involvement by the primary tumor and other tumor-bearing structures, how to differentiate and report lymph nodes and tumor deposits on MRI, and how to anatomically localize and stage lateral lymph nodes. • These recommendations may serve as a practice guide and support tool for radiologists (and other clinicians) involved in the staging of rectal cancer and may contribute to improved consistency in radiological staging and reporting., (© 2022. The Author(s).)

Background: The rising incidence of early onset colorectal cancer (EOCRC) might reflect a novel tumour entity., Aims: To evaluate clinicopathological characteristics of sporadic EOCRC (in patients < 50 years old) and investigate changes over time METHODS: All patients with sporadic EOCRC between 1989 and 2016 were included and divided by age: 20-29 years (group I), 30-39 years (group II) and 40-49 years (group III)., Results: We included 6400 patients. The presence of signet-ring cells and more poorly differentiated tumours were more common in the younger age groups: 5.4% and 3.7% for signet-ring cells in group I and II vs 1.4% in group III (P < 0.01), and 28.5% and 20.3% for poorly differentiated in group I and II vs 16.6% in group III, (P < 0.01 group I; P = 0.07 group II). Positive lymph nodes were more frequently observed in the younger age groups: 16.2% in group I vs 9.3% in group II (P = 0.01) and 7.9% (P < 0.01) in group III. Over time, a greater proportion of CRCs were diagnosed in women in group I (34.5% < 2004 vs 54.9%>2005, P = 0.09), and a higher percentage of rectal cancer was found in age group III (34.3% < 2004 vs 40.7% > 2005, P < 0.01). Mean overall survival was 6.3 years and improved over time., Conclusions: EOCRC is not only characterised by age of onset but also by the more frequent presence of signet-ring cells, more poorly differentiated tumours, and higher risk of lymph node metastases. In the most recent years, a higher proportion of rectal cancer was found from the age of 30 years, and a higher proportion of CRCs were diagnosed in females below the age of 30 years., (© 2021 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Aim: Mucinous carcinoma is a histological subtype of rectal cancer and has been associated with a poor response to neoadjuvant chemoradiotherapy (CRT). The primary aim of this study was to analyse the response on MRI of mucinous locally advanced rectal cancer (LARC) after CRT compared to regular adenocarcinoma., Method: Patients with LARC (defined as cT4 and/or cN2), who underwent CRT followed by restaging MRI and surgery in two tertiary referral hospitals were retrospectively included in the study. Pre- and post-treatment MRI was reviewed by an experienced abdominal radiologist., Results: A total of 102 patients, of whom 29 were diagnosed with mucinous carcinoma, were included for analysis. At restaging MRI, adenocarcinoma patients demonstrated significantly less clinical involvement of the mesorectal fascia (37% vs. 62%, P = 0.003) while this was not demonstrated in mucinous carcinoma patients (86% vs. 97%, P = 0.16). Significant downstaging after CRT in adenocarcinoma patients (P = 0.01) was seen while, in mucinous carcinoma patients, no downstaging after CRT (P = 0.89) was seen. Pathology revealed significantly higher rates of an involved circumferential resection margin in mucinous carcinoma versus adenocarcinoma patients (27.6% vs. 1.4%; P < 0.001). After multivariate regression analysis, mucinous carcinoma remained an independent prognostic factor for local recurrence (hazard ratio 3.6; 95% CI 1.1-12.4), although no differences in overall or disease-free survival were observed., Conclusion: Mucinous rectal carcinoma is associated with a poor clinical response at restaging MRI after CRT, leading to relatively higher rates of involved circumferential resection margins at pathology. In this cohort, mucinous carcinoma seems to be a prognostic factor for increased risk of local recurrence, without an effect on overall survival., (© 2021 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Aim: Tumour budding ('attacker') and CD8 + T cells ('defender') are recognised as important parameters for risk stratification in colon cancers and, combined, may have an even stronger clinical impact. Here, we determine the value of tumour budding and CD8 + in rectal cancer patients treated with/without neoadjuvant therapy., Methods and Results: Using digital scans of all tumour slides/case, we analysed CD8 + T cell counts in two patient cohorts: 45 neoadjuvantly treated and 47 primarily surgically treated (totalling n = 543 slides) after double-staining of the surgical resection specimen for pan-cytokeratin and CD8 + . Tumour buds in hot-spots were manually counted (area = 0.785 mm 2 ) and CD8 + T cell counts were analysed separately both in tumour budding hot-spots and the densest CD8 + regions throughout the tumour. In neoadjuvantly treated patients, only tumour budding and not CD8 + T cells was associated with tumour features, including more advanced ypT (P = 0.0062), venous invasion (P = 0.002), lymphatic invasion (P = 0.0003) and perineural invasion (P = 0.0017), as well as higher American Joint Committee on Cancer (AJCC) tumour regression score (P = 0.0035), indicating less tumour response. Overall survival was also worse in patients with high-grade budding in univariate analysis only. In contrast, all three variables, namely tumour budding (P = 0.0347), CD8 + T cells in budding hot-spots (P = 0.0382) and CD8 + T cells in the densest areas (P = 0.0117) were also associated with worse (budding) and better (CD8) survival time in the multivariate setting., Conclusion: In rectal cancer, tumour budding has clinical relevance in both primarily surgically treated patients and in those with neoadjuvantly treated patients, where it characterises highly aggressive residual disease. CD8 + T cell counts appear not to have prognostic relevance in the neoadjuvant context., (© 2020 John Wiley & Sons Ltd.)

Purpose: To evaluate the initial results of predicting lymph node metastasis in rectal cancer patients detected in-vivo with USPIO-enhanced MRI at 3 T compared on a node-to-node basis with histopathology., Methods: Ten rectal cancer patients of all clinical stages were prospectively included for an in-vivo 0.85 mm 3 isotropic 3D MRI after infusion of Ferumoxtran-10. The surgical specimens were examined ex-vivo with an 0.29 mm 3 isotropic MRI examination. Two radiologists evaluated in-vivo MR images with a classification scheme to predict lymph node status. Ex-vivo MRI was used for MR-guided pathology and served as a key link between in-vivo MRI and final histopathology for the node-to-node analysis., Results: 138 lymph nodes were detected by reader 1 and 255 by reader 2 (p = 0.005) on in-vivo MRI with a median size of 2.6 and 2.4 mm, respectively. Lymph nodes were classified with substantial inter-reader agreement (κ = 0.73). Node-to-node comparison was possible for 55 lymph nodes (median size 3.2 mm; range 1.2-12.3), of which 6 were metastatic on pathology. Low true-positive rates (3/26, 11 % for both readers) and high true negative rates were achieved (14/17, 82 %; 19/22, 86 %). Pathological re-evaluations of 20 lymph nodes with high signal intensity on USPIO-enhanced MRI without lymph node metastases (false positives) did not reveal tumor metastasis but showed benign lymph node tissue with reactive follicles., Conclusions: High resolution MRI visualizes a large number of mesorectal lymph nodes. USPIO-enhanced MRI was not accurate for characterizing small benign versus small tumoral lymph nodes in rectal cancer patients. Suspicious nodes on in-vivo MRI occur as inflammatory as well as metastatic nodes., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Systemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, the Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) trial aimed to reduce distant metastases without compromising locoregional control., Methods: In this multicentre, open-label, randomised, controlled, phase 3 trial, participants were recruited from 54 centres in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the USA. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, had a biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for chemotherapy, and could be assessed for staging within 5 weeks before randomisation. Eligible participants were randomly assigned (1:1), using a management system with a randomly varying block design (each block size randomly chosen to contain two to four allocations), stratified by centre, ECOG performance status, cT stage, and cN stage, to either the experimental or standard of care group. All investigators remained masked for the primary endpoint until a prespecified number of events was reached. Patients allocated to the experimental treatment group received short-course radiotherapy (5 × 5 Gy over a maximum of 8 days) followed by six cycles of CAPOX chemotherapy (capecitabine 1000 mg/m 2 orally twice daily on days 1-14, oxaliplatin 130 mg/m 2 intravenously on day 1, and a chemotherapy-free interval between days 15-21) or nine cycles of FOLFOX4 (oxaliplatin 85 mg/m 2 intravenously on day 1, leucovorin [folinic acid] 200 mg/m 2 intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m 2 intravenously and fluorouracil 600 mg/m 2 intravenously for 22 h on days 1 and 2, and a chemotherapy-free interval between days 3-14) followed by total mesorectal excision. Choice of CAPOX or FOLFOX4 was per physician discretion or hospital policy. Patients allocated to the standard of care group received 28 daily fractions of 1·8 Gy up to 50·4 Gy or 25 fractions of 2·0 Gy up to 50·0 Gy (per physician discretion or hospital policy), with concomitant twice-daily oral capecitabine 825 mg/m 2 followed by total mesorectal excision and, if stipulated by hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4. The primary endpoint was 3-year disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death, assessed in the intention-to-treat population. Safety was assessed by intention to treat. This study is registered with the EudraCT, 2010-023957-12, and ClinicalTrials.gov, NCT01558921, and is now complete., Findings: Between June 21, 2011, and June 2, 2016, 920 patients were enrolled and randomly assigned to a treatment, of whom 912 were eligible (462 in the experimental group; 450 in the standard of care group). Median follow-up was 4·6 years (IQR 3·5-5·5). At 3 years after randomisation, the cumulative probability of disease-related treatment failure was 23·7% (95% CI 19·8-27·6) in the experimental group versus 30·4% (26·1-34·6) in the standard of care group (hazard ratio 0·75, 95% CI 0·60-0·95; p=0·019). The most common grade 3 or higher adverse event during preoperative therapy in both groups was diarrhoea (81 [18%] of 460 patients in the experimental group and 41 [9%] of 441 in the standard of care group) and neurological toxicity during adjuvant chemotherapy in the standard of care group (16 [9%] of 187 patients). Serious adverse events occurred in 177 (38%) of 460 participants in the experimental group and, in the standard of care group, in 87 (34%) of 254 patients without adjuvant chemotherapy and in 64 (34%) of 187 with adjuvant chemotherapy. Treatment-related deaths occurred in four participants in the experimental group (one cardiac arrest, one pulmonary embolism, two infectious complications) and in four participants in the standard of care group (one pulmonary embolism, one neutropenic sepsis, one aspiration, one suicide due to severe depression)., Interpretation: The observed decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer., Funding: Dutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Tumour deposits (TDs) are a poor prognostic marker when seen on pathology, and are worse than lymph node metastases (LNMs). They are now being reported on MRI as discontinuous nodules of extramural venous invasion but this diagnosis has not been validated and it is unclear how it correlates with the diagnosis of TDs on pathology., Methods and Analysis: This is a prospective interventional clinical trial which aims to directly map the location of TDs on MRI and correlate what is seen on MRI with the pathology findings at each location. All patients with rectal cancer undergoing resectional surgery are eligible (including those undergoing preoperative therapy). The primary outcome is the prevalence of TDs seen on pathology. Secondary outcomes are to assess radiological and pathological interobserver agreement, assess the effect of TDs on prognosis and carry out exploratory work looking at differences between TDs and LNMs. The estimated sample size is 100 to detect a twofold increase in the pathological diagnosis of TD when MRI mapping is used., Ethics and Dissemination: Ethical approval has been granted from the South Central-Hampshire B Research and Ethics Committee (IRAS 217627). The study will be carried out under standard operative procedures within the Royal Marsden Hospital., Trial Registration Number: NCT03303547., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Various methods categorize tumour response after neoadjuvant therapy, including down-staging and tumour regression grading. Response categories allow comparison of different treatments within clinical trials and predict outcome. A reproducible response categorization could identify subgroups with high or low risk for the most appropriate subsequent treatments, like watch and wait. Lack of standardization and interpretation difficulties currently limit the usability of these approaches. In this review we describe these difficulties for the evaluation of chemoradiation in rectal cancer. An alternative approach of tumour response is based on patterns of residual disease, including fragmentation. We summarise the evidence behind this alternative method of response categorisation, which explains a number of very relevant clinical discrepancies. These issues include differences between downstaging and tumour regression, high local regrowth in advanced tumours during watchful waiting procedures, the importance of resection margins, the limited value of post-treatment biopsies and the relatively poor outcome of patients with a near complete pathological response. Recognition of these patterns of response can allow meaningful development of novel biomarkers in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Rectal cancer can spread in a number of ways which have been previously recognised and validated as prognostic markers. These routes of spread are not adequately recognised in the stage grouping of the tumour-node-metastasis system, which focuses predominantly on the depth of invasion and nodal status, thus limiting its prognostic accuracy. Tumour spread involving veins occurs in 40% of patients. Venous channels have greater direct access to distant sites by means of a vascular 'anatomical highway'. This rapid spread of tumour cells to distant metastatic sites by veins cannot occur by means of lymph node pathways. Thus, lymph nodes have been overestimated in their importance. Distinction between local tumour spread (lymph node metastases, perineural and lymphatic invasion) and tumour spread mediated by a direct vascular pathway to distant dissemination (extramural venous invasion and tumour deposits) must be made as the implications for prognosis and choice of treatment are not likely to be equal. Improved precision of radiological and pathological assessment is needed to scrutinise and carefully document each route of tumour spread. Only with this accurate information will it be possible to correctly weight each feature and develop a more prognostically accurate staging method that would allow separation of true high- and low-risk groups and subsequent improvements in patient care., Competing Interests: Conflict of interest statement The authors declare no conflicts of interest., (Copyright © 2019. Published by Elsevier Ltd.)

Background: The aim of this study was to analyse the association between pelvic radiation therapy (RT) and the development of rectal cancer as a second primary cancer., Methods: Data on patients treated for a primary pelvic cancer between 1989 and 2007 were retrieved from the population-based Netherlands Cancer Registry. Patients treated for more than one pelvic cancer were excluded. To estimate the cumulative incidence of rectal cancer, Fine and Gray's competing risk model was used with death as a competing event. Survival was calculated using multivariable Cox regression., Results: A total of 192,658 patients were included, of which 62,630 patients were treated with RT for their pelvic cancer. Primary tumours were located in the prostate (50.1%), bladder (19.2%), endometrium (13.9%), ovaries (10.0%), cervix (6.4%) and vagina (0.4%). At a median interval of 6 years (range 0-24), 1369 patients developed a rectal cancer. Overall, the risk for rectal cancer was increased in patients who underwent RT for the previous pelvic cancer (subhazard ratio [SHR]: 1.72, 95% confidence interval [CI]: 1.55-1.91). Analysis for each tumour location specifically showed an increased risk in patients who received RT for prostate (SHR: 1.89, 95% CI: 1.66-2.16) or endometrial cancer (SHR: 1.50, 95% CI: 1.13-2.00). A protective effect of RT was observed for patients with bladder cancer (SHR 0.67, 95% CI: 0.47-0.94). There was no survival difference between patients with rectal cancer with or without previous RT (hazard ratio: 0.94, 95% CI: 0.79-1.11)., Conclusions: Patients who received RT for a previous pelvic cancer were at increased risk for rectal cancer. The risk was modest and pronounced in patients receiving RT for prostate and endometrial cancer., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Preoperative chemoradiation therapy (CRT) may induce downstaging in rectal cancer (RC). Short-course radiation therapy (SC-RT) with immediate surgery does not cause substantial downstaging. However, the TNM classification adds the "y" prefix in both groups to indicate possible treatment effects. We aim to compare stage-specific survival in these patients. RC patients treated with surgery only, preoperative SC-RT followed by surgery within 10 days, or preoperative CRT, and diagnosed between 2008 and 2014 were included in this population-based study. Clinicopathological and outcome characteristics were analyzed. The study included 11,925 patients. Large discrepancies existed between clinical and pathological stages after surgery only. Surgery-only patients were older with more comorbidities compared with SC-RT and CRT and had worse 5-year survival (64%, 76%, and 74%, respectively; p < 0.001). Five-year survival for stage I was similar after CRT and SC-RT (85% vs. 85%; p = 0.167) and comparable between CRT-treated patients with stage I and those reaching a pathological complete response (pCR; 85% vs. 89%; p = 0.113). CRT was independently associated with worse overall survival compared with SC-RT for stage II (HR 1.57 [95%CI 1.27-1.95]; p < 0.001) and stage III (HR 1.43 [95%CI 1.23-1.70]; p < 0.001). Stage I disease after CRT has an excellent prognosis, comparable with pCR and with same-stage SC-RT-treated patients without regression. Stage II or III after CRT has worse prognosis than after SC-RT with immediate surgery. TNM should take the impact of preoperative therapy type on stage-specific survival into account. In addition, clinical stage was a poor predictor of pathological stage.

Background: The wide global variation in the definition of the rectum has led to significant inconsistencies in trial recruitment, clinical management, and outcomes. Surgical technique and use of preoperative treatment for a cancer of the rectum and sigmoid colon are radically different and dependent on the local definitions employed by the clinical team. A consensus definition of the rectum is needed to standardise treatment., Methods: The consensus was conducted using the Delphi technique with multidisciplinary colorectal experts from October, 2017 to April, 2018., Results: Eleven different definitions for the rectum were used by participants in the consensus. Magnetic resonance imaging (MRI) was the most frequent modality used to define the rectum (67%), and the preferred modality for 72% of participants. The most agreed consensus landmark (56%) was "the sigmoid take-off," an anatomic, image-based definition of the junction of the mesorectum and mesocolon. In the second round, 81% of participants agreed that the sigmoid take-off as seen on computed tomography or MRI achieved consensus, and that it could be implemented in their institution. Also, 87% were satisfied with the sigmoid take-off as the consensus landmark., Conclusion: An international consensus definition for the rectum is the point of the sigmoid take-off as visualized on imaging. The sigmoid take-off can be identified as the mesocolon elongates as the ventral and horizontal course of the sigmoid on axial and sagittal views respectively on cross-sectional imaging. Routine application of this landmark during multidisciplinary team discussion for all patients will enable greater consistency in tumour localisation.

Background and Purpose: The aim of this study was to assess the effect of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) on tumor response to preoperative chemoradiation for rectal cancer., Materials and Methods: Data on patients who received chemoradiation prior to surgery for rectal cancer between 2010 and 2015 were retrieved from linkage between the PHARMO Database Network, Dutch Pathology Registry and Netherlands Cancer Registry. Pathological complete response rates (pCR) were compared between patients who did or did not use ACEIs/ARBs during treatment. Multivariable analysis was performed using logistic regression., Results: Out of 345 patients, 92 patients (26.7%) used ACEIs/ARBs during treatment. Median age was 65 years (range 30-85). Older and male patients were more likely to use ACEIs/ARBs. pCR (ypT0N0) was observed in 17.4% of patients using ACEIs/ARBs compared to 14.6% of patients who did not use ACEIs/ARBs (p = 0.595). A good response (ypT0-1N0) was observed in 21.7% of ACEIs/ARBs patients vs. 19.4% of patients who did not use ACEIs/ARBs (p = 0.724). Multivariable analysis, taking into account background variables and co-medication, showed increased pCR in patients using beta-blockers (odds ratio 2.3, 95% confidence interval 1.0-5.4)., Conclusion: In this retrospective cohort, the use of ACEIs/ARBs was not associated with tumor response to preoperative chemoradiation in rectal cancer patients. Thereby, the suggested potentiating effect of ACEIS/ARBs could not be confirmed in our study. Further research could be directed to investigate a possible benefit of beta-blockers or other anti-hypertensive drugs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Tumor-stroma ratio (TSR) serves as an independent prognostic factor in colorectal cancer and other solid malignancies. The recent introduction of digital pathology in routine tissue diagnostics holds opportunities for automated TSR analysis. We investigated the potential of computer-aided quantification of intratumoral stroma in rectal cancer whole-slide images., Methods: Histological slides from 129 rectal adenocarcinoma patients were analyzed by two experts who selected a suitable stroma hot-spot and visually assessed TSR. A semi-automatic method based on deep learning was trained to segment all relevant tissue types in rectal cancer histology and subsequently applied to the hot-spots provided by the experts. Patients were assigned to a 'stroma-high' or 'stroma-low' group by both TSR methods (visual and automated). This allowed for prognostic comparison between the two methods in terms of disease-specific and disease-free survival times., Results: With stroma-low as baseline, automated TSR was found to be prognostic independent of age, gender, pT-stage, lymph node status, tumor grade, and whether adjuvant therapy was given, both for disease-specific survival (hazard ratio = 2.48 (95% confidence interval 1.29-4.78)) and for disease-free survival (hazard ratio = 2.05 (95% confidence interval 1.11-3.78)). Visually assessed TSR did not serve as an independent prognostic factor in multivariate analysis., Conclusions: This work shows that TSR is an independent prognosticator in rectal cancer when assessed automatically in user-provided stroma hot-spots. The deep learning-based technology presented here may be a significant aid to pathologists in routine diagnostics.

Importance: Treatment of rectal cancer is shifting toward organ preservation aiming to reduce surgery-related morbidity. Short-term outcomes of organ-preserving strategies are promising, but long-term outcomes are scarce in the literature., Objective: To explore long-term oncological outcomes and health-related quality of life (HRQL) in patients with cT1-3N0M0 rectal cancer who underwent neoadjuvant chemoradiotherapy (CRT) followed by transanal endoscopic microsurgery (TEM)., Design, Setting, and Participants: In this multicenter phase II feasibility study, patients with cT1-3N0M0 rectal cancer admitted to referral centers for rectal cancer throughout the Netherlands between February 2011 and September 2012 were prospectively included. These patients were to be treated with neoadjuvant CRT followed by TEM in case of good response. An intensive follow-up scheme was used to detect local recurrences and/or distant metastases. Data from validated HRQL questionnaires and low anterior resection syndrome questionnaires were collected. Data were analyzed from February 2011 to April 2017., Main Outcomes and Measures: The primary study outcome of the study was the number of ypT0-1 specimens by performing TEM. Secondary outcome parameters were locoregional recurrences and HRQL., Results: Of the 55 included patients, 30 (55%) were male, and the mean (SD) age was 64 (39-82) years. Patients were followed up for a median (interquartile range) period of 53 (39-57) months. Two patients (4%) died during CRT, 1 (2%) stopped CRT, and 1 (2%) was lost to follow-up. Following CRT, 47 patients (85%) underwent TEM, of whom 35 (74%) were successfully treated with local excision alone. Total mesorectal excision was performed in 16 patients (4 with inadequate responses, 8 with completion after TEM, and 4 with salvage for local recurrence). The actuarial 5-year local recurrence rate was 7.7%, with 5-year disease-free and overall survival rates of 81.6% and 82.8%, respectively. Health-related quality of life during follow-up was equal to baseline, with improved emotional well-being in patients treated with local excision (mean score at baseline, 72.0; 95% CI, 67.1-80.1; mean score at follow-up, 86.9; 95% CI, 79.2-94.7; P = .001). Major, minor, and no low anterior resection syndrome was experienced in 50%, 28%, and 22%, respectively, of patients with successful organ preservation., Conclusions and Relevance: In early-stage rectal cancer (cT1-3N0M0), CRT enables organ preservation with additional TEM surgery in approximately two-thirds of patients with good long-term oncological outcome and HRQL. This multimodality treatment triggers a certain degree of bowel dysfunction, and one-third of patients still undergo radical surgery and are overtreated by CRT.

Background: Several histological high-risk factors are used as an indication for adjuvant therapy in stage II colon cancer. Those and other factors, including lymphatic invasion, perineural invasion (PNI), venous invasion and tumour budding are associated with decreased outcome. In this study, we evaluated the prognostic and predictive values of these biomarkers in a cohort of rectal cancer patients., Materials and Methods: The trial-based cohort consisted of 221npTNM stage II-III rectal cancer patients, included in the PROCTOR/SCRIPT trial, a multicentre randomised phase III trial. Patients treated with neoadjuvant radiotherapy and TME surgery were randomised between adjuvant chemotherapy or observation. Lymphatic invasion, PNI, extramural venous invasion, intramural venous invasion and tumour budding were determined in standard tissue slides., Results: The presence of PNI (HR 3.36; 95% CI 1.82-6.21), extramural vascular invasion (HR 1.93; 95% CI 1.17-3.19) and tumour budding (HR 1.83, 95% CI 1.11-3.03) was associated with a significant worse overall survival. The presence of ≥2 adverse biomarkers resulted in a stronger prediction of adverse outcome in terms of overall survival (HR 2.82; 95% CI 1.66-4.79), disease-free survival (HR 2.27; 95% CI 1.47-3.48), and distant recurrence (HR 2.51; 95% CI 1.56-4.02). None of these markers alone or combined predicted a beneficial effect of adjuvant chemotherapy., Discussion: We confirmed that several stage-independent biomarkers were significantly associated with a decreased outcome in rectal cancer patients. More importantly, these markers did not have predictive value and are thus not useful to select for adjuvant therapy in rectal cancer., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Total mesorectal excision (TME) is the highly effective standard treatment for rectal cancer but is associated with significant morbidity and may be overtreatment for low-risk cancers. This study is designed to determine the feasibility of international recruitment in a study comparing organ-saving approaches versus standard TME surgery., Methods and Analysis: STAR-TREC trial is a multicentre international randomised, three-arm parallel, phase II feasibility study in patients with biopsy-proven adenocarcinoma of the rectum. The trial is coordinated from Birmingham, UK with national hubs in Radboudumc (the Netherlands) and Odense University Hospital Svendborg UMC (Denmark). Patients with rectal cancer, staged by CT and MRI as ≤cT3b (up to 5 mm of extramural spread) N0 M0 can be included. Patients will be randomised to either standard TME surgery (control), organ-saving treatment using long-course concurrent chemoradiation or organ-saving treatment using short-course radiotherapy. For patients treated with an organ-saving strategy, clinical response to (chemo)radiotherapy determines the next treatment step. An active surveillance regime will be performed in the case of a complete clinical regression. In the case of incomplete clinical regression, patients will proceed to local excision using an optimised platform such as transanal endoscopic microsurgery or other transanal techniques (eg, transanal endoscopic operation or transanal minimally invasive surgery). The primary endpoint of this phase II study is to demonstrate sufficient international recruitment in order to sustain a phase III study incorporating pelvic failure as the primary endpoint. Success in phase II is defined as randomisation of at least four cases per month internationally in year 1, rising to at least six cases per month internationally during year 2., Ethics and Dissemination: The medical ethical committees of all the participating countries have approved the study protocol. Results of the primary and secondary endpoints will be submitted for publication in peer-reviewed journals., Trial Registration Number: ISRCTN14240288, 20 October 2016. NCT02945566; Pre-results, October 2016., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Vulvar Paget disease is a rare skin disorder, considered an in situ adenocarcinoma. It is characterized by intraepithelial Paget cells, of which the origin is unclear. About 75% of cases have a cutaneous origin; the other 25% originate from an intestinal or urological malignancy. We report the first case of retrograde pagetoid spread from a rectal adenocarcinoma to the vulva and cervix. A 66-year-old woman presented with postmenopausal bleeding and a history of Crohn disease. Gynecological workup revealed vulvar and endocervical lesions consisting of Paget cells and adenocarcinoma, respectively. A rectal adenocarcinoma with in situ adenocarcinoma was diagnosed. The surgical specimen demonstrated Paget cells in the squamous epithelium of the anus and vulva. Immunohistochemistry demonstrated an intestinal phenotype of these cells. Genetic testing revealed the same TP53 mutation in tumor cells of the rectal adenocarcinoma and vulvar and endocervical lesions, demonstrating that the Paget cells originated from the same intestinal tumor., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Preoperative therapy reduces local recurrences and may facilitate surgery in rectal cancer patients. However, in patients with inflammatory bowel disease (IBD) this treatment is often withheld due to the perceived risk of excessive side-effects, even though evidence is limited. The purpose of this study is to investigate the effects of preoperative therapy on acute toxicity and post-operative complications in IBD patients with rectal cancer., Methods: The Dutch pathology registry (PALGA) was searched for patients with IBD and rectal cancer treated between January 1991 and May 2010. Histopathology and clinical charts were reviewed to confirm IBD diagnosis and evaluate clinical and pathological characteristics., Results: Out of 161 patients, 66 received preoperative therapy (41%), including short-course radiation therapy (SC-RT), long course radiation therapy (LC-RT), and chemoradiation therapy (CRT) in 32, 13, and 21 patients respectively. Grade≥3 acute toxicity occurred in 0 patients (0.0%), 1 patient (7.7%), and 6 patients (28.6%) respectively (p=0.004). Systemic corticosteroids were used by 10.5% of patients at time of treatment. Grade≥3 post-operative 30-day complication rate (28.1% overall) was not associated with type of preoperative therapy., Conclusion: Results did not show excessive rates of toxicity or post-operative complications and support the use of standard preoperative therapies for rectal cancer (especially SC-RT) in IBD patients with relatively indolent disease. Caution is warranted in patients with active IBD, since the exact impact of active bowel inflammation could not be determined retrospectively. Prospective studies should investigate the influence of active IBD on acute and late toxicity in patients receiving pelvic irradiation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aims: Changes in rectal cancer treatment include increasing emphasis on organ preservation. Local excision after chemoradiotherapy (CRT) for rectal cancer with excellent clinical response reduces morbidity and mortality compared to total mesorectal excision, although residual lymph node metastases (LNM) may cause local recurrence. Our aim is to identify clinicopathological factors predicting the presence of residual LNM in rectal cancer patients with ypT0-2 tumours after neoadjuvant CRT. These risk factors may help to select patients who can be spared radical surgery without compromising oncological outcomes., Methods and Results: Rectal cancer patients with ypT0-2 tumours after CRT and radical resection from five centres treated between June 1999 and February 2012 were included. Histopathology was reviewed extensively. Clinicopathological characteristics and their association with residual LNM were investigated. Of 657 consecutive CRT-treated rectal cancer patients 210 with ypT0-2 disease were included. Residual nodal disease was found in 44 cases (21.0%). Independent predictors of LNM were clinical nodal involvement (cN + ) [odds ratio (OR): 2.79, 95% confidence interval (CI): 1.04-7.48, P = 0.042], high-grade histopathology assessed in the post-CRT resection specimen (OR: 6.46, 95% CI: 1.23-34.02, P = 0.028) and residual tumour diameter (RTD) ≥10 mm (OR: 2.54, 95% CI: 1.06-6.09, P = 0.036). An algorithm combining these factors stratified patients adequately according to LNM risk, independently of ypT category., Conclusions: Clinical nodal involvement, high-grade histopathology and RTD ≥10 mm are strong and independent predictors of residual nodal disease in rectal cancer patients with ypT0-2 tumours after CRT. Risk stratification based on these factors may help to identify patients suitable for organ preserving therapy and should be validated in appropriately selected populations., (© 2016 John Wiley & Sons Ltd.)

Primary treatment of rectal cancer was the focus of the second St. Gallen European Organisation for Research and Treatment of Cancer (EORTC) Gastrointestinal Cancer Conference. In the context of the conference, a multidisciplinary international expert panel discussed and voted on controversial issues which could not be easily answered using published evidence. Main topics included optimal pretherapeutic imaging, indication and type of neoadjuvant treatment, and the treatment strategies in advanced tumours. Here we report the key recommendations and summarise the related evidence. The treatment strategy for localised rectal cancer varies from local excision in early tumours to neoadjuvant radiochemotherapy (RCT) in combination with extended surgery in locally advanced disease. Optimal pretherapeutic staging is a key to any treatment decision. The panel recommended magnetic resonance imaging (MRI) or MRI + endoscopic ultrasonography (EUS) as mandatory staging modalities, except for early T1 cancers with an option for local excision, where EUS in addition to MRI was considered to be most important because of its superior near-field resolution. Primary surgery with total mesorectal excision was recommended by most panellists for some early tumours with limited risk of recurrence (i.e. cT1-2 or cT3a N0 with clear mesorectal fascia on MRI and clearly above the levator muscles), whereas all other stages were considered for multimodal treatment. The consensus panel recommended long-course RCT over short-course radiotherapy for most clinical situations where neoadjuvant treatment is indicated, with the exception of T3a/b N0 tumours where short-course radiotherapy or even no neoadjuvant therapy were regarded to be an option. In patients with potentially resectable tumours and synchronous liver metastases, most panel members did not see an indication to start with classical fluoropyrimidine-based RCT but rather favoured preoperative short-course radiotherapy with systemic combination chemotherapy or alternatively a liver-first resection approach in resectable metastases, which both allow optimal systemic therapy for the metastatic disease. In general, proper patient selection and discussion in an experienced multidisciplinary team was considered as crucial component of care., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Unlabelled: Small and flat adenomas are known to carry a high miss-rate during standard white-light endoscopy. Increased detection rate may be achieved by molecular fluorescence endoscopy with targeted near-infrared (NIR) fluorescent tracers. The aim of this study was to validate vascular endothelial growth factor A (VEGF-A) and epidermal growth factor receptor (EGFR)-targeted fluorescent tracers during ex vivo colonoscopy with an NIR endoscopy platform., Methods: VEGF-A and EGFR expression was determined by immunohistochemistry on a large subset of human colorectal tissue samples--48 sessile serrated adenomas/polyps, 70 sporadic high-grade dysplastic adenomas, and 19 hyperplastic polyps--and tissue derived from patients with Lynch syndrome--78 low-grade dysplastic adenomas, 57 high-grade dysplastic adenomas, and 31 colon cancer samples. To perform an ex vivo colonoscopy procedure, 14 mice with small intraperitoneal EGFR-positive HCT116(luc) tumors received intravenous bevacizumab-800CW (anti-VEGF-A), cetuximab-800CW (anti-EGFR), control tracer IgG-800CW, or sodium chloride. Three days later, 8 resected HCT116(luc) tumors (2-5 mm) were stitched into 1 freshly resected human colon specimen and followed by an ex vivo molecular fluorescence colonoscopy procedure., Results: Immunohistochemistry showed high VEGF-A expression in 79%-96% and high EGFR expression in 51%-69% of the colorectal lesions. Both targets were significantly overexpressed in the colorectal lesions, compared with the adjacent normal colon crypts. During ex vivo molecular fluorescence endoscopy, all tumors could clearly be delineated for both bevacizumab-800CW and cetuximab-800CW tracers. Specific tumor uptake was confirmed with fluorescent microscopy showing, respectively, stromal and cell membrane fluorescence., Conclusion: VEGF-A is a promising target for molecular fluorescence endoscopy because it showed a high protein expression, especially in sessile serrated adenomas/polyps and Lynch syndrome. We demonstrated the feasibility to visualize small tumors in real time during colonoscopy using a NIR fluorescence endoscopy platform, providing the endoscopist a wide-field red-flag technique for adenoma detection. Clinical studies are currently being performed in order to provide in-human evaluation of our approach., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background: Mucinous carcinoma (MC) is a distinct form of rectal cancer (RC) comprising 10 % of all cases and has been associated with an impaired prognosis compared with non-mucinous adenocarcinoma (AC). The benefit of today's modern treatment for MC patients is unknown but a prospective randomized trial to answer this does not seem feasible. This study provides an analysis of the modern treatment of rectal MC and efficacy of preoperative therapies for MC patients., Methods: Data from three large (trial) cohorts were used. Data from the Netherlands Cancer Registry (NCR) were used to analyze the prognosis of RC patients over time (N = 38,035). To study the benefit of preoperative short-term radiotherapy, patients from the total mesorectal excision (TME) trial (N = 1,530) were selected, and the benefit from preoperative chemoradiotherapy was analyzed with data on 540 locally advanced RC (LARC) patients from two hospitals., Results: Data from the NCR confirmed that 5-year overall survival for MC was significantly worse from 1989 to 1998, but no longer different from AC from 1999 onwards. MC patients had a higher rate of positive circumferential resection margin than AC patients (TME trial 27.2 vs. 16.5 %, p = 0.006; LARC cohort 34.5 vs. 9.8 %, p < 0.0001), but there was no difference in outcome between MC and AC patients after preoperative short-term radiotherapy or chemoradiotherapy., Conclusions: Modern treatment of RC has benefited MC patients, leading to equal survival for MC and AC patients. Enhancements in the fields of imaging and quality of surgery have improved outcome and preoperative therapies should be recommended for both histological subtypes.

Purpose: This study investigated the long-term probability of developing a second cancer in a large pooled cohort of patients treated with surgery with or without radiotherapy (RT)., Patients and Methods: All second cancers diagnosed in patients included in the TME, PORTEC-1, and PORTEC-2 trials were analyzed. In the TME trial, patients with rectal cancer (n = 1,530) were randomly allocated to preoperative external-beam RT (EBRT; 25 Gy in five fractions) or no RT. In the PORTEC trials, patients with endometrial cancer were randomly assigned to postoperative EBRT (46 Gy in 2-Gy fractions) versus no RT (PORTEC-1; n = 714) or EBRT versus vaginal brachytherapy (VBT; PORTEC-2; n = 427)., Results: A total of 2,554 patients were analyzed (median follow-up, 13.0 years; range 1.8 to 21.2 years). No differences were found in second cancer probability between patients who were treated without RT (10- and 15-year rates, 15.8% and 26.5%, respectively) and those treated with EBRT (10- and 15-year rates, 15.4% and 25.6%, respectively) or VBT (10-year rate, 14.9%). In the individual trials, no significant differences were found between treatment arms. All cancer survivors had a higher risk of developing a second cancer compared with an age- and sex-matched general population. The standardized incidence ratio for any second cancer was 2.98 (95% CI, 2.82 to 3.14)., Conclusion: In this pooled trial cohort of > 2,500 patients with pelvic cancers, those who underwent EBRT or VBT had no higher probability of developing a second cancer than patients who were treated with surgery alone. However, patients with rectal or endometrial cancer had an increased probability of developing a second cancer compared with the general population., (© 2014 by American Society of Clinical Oncology.)

Background: After preoperative chemoradiotherapy (CRT) for rectal cancer, clinically undetectable residual tumour deposits or pathologic lymph nodes may remain in the mesorectum., Aim: The aim of this study was to report histopathological effects of CRT and factors affecting outcome in a uniformly treated series of locally advanced rectal cancer (LARC) patients., Methods: Between 2004 and 2008, 107 patients with cT3 (threatening the mesorectal fascia or <5 cm from the anal verge), cT4 or cN2 rectal cancer were treated with preoperative CRT (25 × 2 Gy with capecitabine) and TME 6-8 weeks later. Central histopathological review followed. Tumour regression grade (TRG) was scored in pCR, near-pCR, response and no response. Cox regression was performed to identify prognosticators., Results: The 3-year distant metastasis-free interval, disease-free rate and overall survival rate were 82%, 73% and 87% (median 44 months follow-up). TRG consisted of 20% pCR, 11% near-pCR, 55% response and 14% no response. 6/21 pCR patients harboured nodal metastases. 5/12 near-pCR had ypT3 disease, while 6 harboured node metastases. 5/12 near-PCR patients developed distant metastases. ypN and TRG were powerful outcome discriminators., Conclusion: The high number of near-pCR with ypT3 or ypN1/2 and their poor outcome demonstrates that "watch-and-wait" in LARC patients should be applied with care., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Current standard for most of the locally advanced rectal cancers is preoperative chemoradiotherapy, and, variably per institution, postoperative adjuvant chemotherapy. Short-course preoperative radiation with delayed surgery has been shown to induce tumour down-staging in both randomized and observational studies. The concept of neo-adjuvant chemotherapy has been proven successful in gastric cancer, hepatic metastases from colorectal cancer and is currently tested in primary colon cancer., Methods and Design: Patients with rectal cancer with high risk features for local or systemic failure on magnetic resonance imaging are randomized to either a standard arm or an experimental arm. The standard arm consists of chemoradiation (1.8 Gy x 25 or 2 Gy x 25 with capecitabine) preoperatively, followed by selective postoperative adjuvant chemotherapy. Postoperative chemotherapy is optional and may be omitted by participating institutions. The experimental arm includes short-course radiotherapy (5 Gy x 5) followed by full-dose chemotherapy (capecitabine and oxaliplatin) in 6 cycles before surgery. In the experimental arm, no postoperative chemotherapy is prescribed. Surgery is performed according to TME principles in both study arms. The hypothesis is that short-course radiotherapy with neo-adjuvant chemotherapy increases disease-free and overall survival without compromising local control. Primary end-point is disease-free survival at 3 years. Secondary endpoints include overall survival, local control, toxicity profile, and treatment completion rate, rate of pathological complete response and microscopically radical resection, and quality of life., Discussion: Following the advances in rectal cancer management, increased focus on survival rather than only on local control is now justified. In an experimental arm, short-course radiotherapy is combined with full-dose chemotherapy preoperatively, an alternative that offers advantages compared to concomitant chemoradiotherapy with or without postoperative chemotherapy. In a multi-centre setting this regimen is compared to current standard with the aim of improving survival for patients with locally advanced rectal cancer., Trial Registration: ClinicalTrials.gov NCT01558921.

Background: After abdominoperineal excision (APE), the presence of tumor cells in the circumferential resection margin (R1) and iatrogenic tumor perforations are still frequent and result in an increased rate of local recurrences. In this study, a standardized supine APE with an increased focus on the perineal dissection (sPPD) is compared to the customary supine APE., Methods: From 2000 to 2010, a total of 246 patients underwent APE for rectal cancer (sPPD and customary supine APE). All patients were staged with preoperative magnetic resonance imaging (MRI) and received neoadjuvant treatment (n = 203) when margins were involved or threatened (cT3 + and T4). As a result of a quality improvement program in 2006, the surgical technique was modified: it became standardized, emphasis was placed on the perineal dissection, and pelvic dissection was limited to avoid false routes when following the total mesorectal excision planes deep into the pelvis., Results: Overall, the percentage of involved circumferential resection margins (CRMs) was 10%. In the period before introducing sPPD, the R1 percentages for cT0-3 and cT4 tumors were 6.8 and 30.2%, compared to 2.2 and 5.7% after introduction of sPPD (P = 0.001). Risk factors for R1 resection were preoperative T4 tumors (14.9%, P = 0.011), tumor perforation (33.3%, P = 0.002), fistulating tumors (35.7%, P = 0.002), mucus-producing tumors (23.1%, P = 0.006), or bulky tumors (66.7%, P < 0.001)., Conclusions: The objective of surgical treatment of low rectal cancer is to obtain negative resection margins and subsequently reduce the risk of local recurrence. A combination of the appropriate preoperative treatment and standardized surgical technique such as sPPD can achieve this goal.

Background: The CARTS study is a multicenter feasibility study, investigating the role of rectum saving surgery for distal rectal cancer., Methods/design: Patients with a clinical T1-3 N0 M0 rectal adenocarcinoma below 10 cm from the anal verge will receive neoadjuvant chemoradiation therapy (25 fractions of 2 Gy with concurrent capecitabine). Transanal Endoscopic Microsurgery (TEM) will be performed 8 - 10 weeks after the end of the preoperative treatment depending on the clinical response.Primary objective is to determine the number of patients with a (near) complete pathological response after chemoradiation therapy and TEM. Secondary objectives are the local recurrence rate and quality of life after this combined therapeutic modality. A three-step analysis will be performed after 20, 33 and 55 patients to ensure the feasibility of this treatment protocol., Discussion: The CARTS-study is one of the first prospective multicentre trials to investigate the role of a rectum saving treatment modality using chemoradiation therapy and local excision. The CARTS study is registered at clinicaltrials.gov (NCT01273051).

Background: The TME trial investigated the value of preoperative short-term radiotherapy in combination with total mesorectal excision (TME). Long-term results are reported after a median follow-up of 12 years., Methods: Between Jan 12, 1996, and Dec 31, 1999, 1861 patients with resectable rectal cancer without evidence of distant disease were randomly assigned to TME preceded by 5 × 5 Gy radiotherapy or TME alone (ratio 1:1). Randomisation was based on permuted blocks of six with stratification according to centre and expected type of surgery. The primary endpoint was local recurrence, analysed for all eligible patients who underwent a macroscopically complete local resection., Findings: 10-year cumulative incidence of local recurrence was 5% in the group assigned to radiotherapy and surgery and 11% in the surgery-alone group (p<0·0001). The effect of radiotherapy became stronger as the distance from the anal verge increased. However, when patients with a positive circumferential resection margin were excluded, the relation between distance from the anal verge and the effect of radiotherapy disappeared. Patients assigned to radiotherapy had a lower overall recurrence and when operated with a negative circumferential resection margin, cancer-specific survival was higher. Overall survival did not differ between groups. For patients with TNM stage III cancer with a negative circumferential resection margin, 10-year survival was 50% in the preoperative radiotherapy group versus 40% in the surgery-alone group (p=0·032)., Interpretation: For all eligible patients, preoperative short-term radiotherapy reduced 10-year local recurrence by more than 50% relative to surgery alone without an overall survival benefit. For patients with a negative resection margin, the effect of radiotherapy was irrespective of the distance from the anal verge and led to an improved cancer-specific survival, which was nullified by an increase in other causes of death, resulting in an equal overall survival. Nevertheless, preoperative short-term radiotherapy significantly improved 10-year survival in patients with a negative circumferential margin and TNM stage III. Future staging techniques should offer possibilities to select patient groups for which the balance between benefits and side-effects will result in sufficiently large gains., Funding: The Dutch Cancer Society, the Dutch National Health Council, and the Swedish Cancer Society., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Purpose: Identifying rectal cancer patients at risk for local recurrence would allow for refinement in the selection of patients who would benefit from preoperative radiotherapy. PIK3CA, KRAS, and BRAF mutations are commonly found in colon cancers, but their prevalence has not been clearly assessed in rectal cancer. In this study, we aim to determine the mutation frequencies of PIK3CA, KRAS, and BRAF and to investigate whether a mutation may be used as a prognostic parameter in rectal cancer patients., Experimental Design: We evaluated DNA mutations in PIK3CA, KRAS, and BRAF in 240 stage I to III rectal tumors obtained from nonirradiated patients from the Dutch Total Mesorectal Excision trial., Results: PIK3CA, KRAS, and BRAF mutations were identified in 19 (7.9%), 81 (33.9%), and 5 (2.1%) rectal cancers. Patients with PIK3CA mutations developed more local recurrences (5-year risks, 27.8% versus 9.4%; P = 0.006) and tended to develop these recurrences more rapidly after surgery (median local recurrence-free interval since surgery: 7.9 versus 19.6 months; P = 0.07) than patients without PIK3CA mutations. In multivariate analysis, PIK3CA mutations remained as an independent predictor for the development of local recurrences (hazard ratio, 3.4; 95% confidence interval, 1.2-9.2; P = 0.017), next to tumor-node-metastasis stage., Conclusion: PIK3CA mutations can be used as a biomarker in identifying rectal cancer patients with an increased risk for local recurrences. Currently, our findings suggest that prospective evaluation of PIK3CA mutation status could reduce overtreatment by preoperative radiotherapy for the low-risk patients who might otherwise only experience the side effects.

Lymph node status is the strongest prognostic factor for survival in colorectal cancer. There are several guidelines concerning the minimum numbers of lymph nodes that need to be examined to make reliable staging possible, but there is no consensus in the available literature. In this study, we determine in patients with rectal cancer factors that relate to the number of lymph nodes found and the presence of lymph node metastasis. In addition, the number of examined lymph nodes was correlated with prognosis. A total of 1227 patients were selected from a multicenter prospective randomized trial investigating the value of neoadjuvant radiotherapy. The median number of examined lymph nodes in all patients was 7.0. The number of retrieved lymph nodes in patients with node metastasis was significantly higher than in node negative patients. After neoadjuvant radiotherapy fewer lymph nodes were retrieved (6.9 vs. 8.5; P<0.0001). Variations in lymph node yield between pathology laboratories and individual pathologists were striking. The following patient and tumor characteristics are associated with a significant lower lymph node retrieval: age over 60 years, overweight, small size, and low invasion depth of the tumor, poor differentiation grade, and absence of a lymphoid reaction. Node negative patients in whom seven or less lymph nodes were examined had a lower recurrence free interval than patients in whom at least 8 lymph nodes were examined (17.0% vs. 10.7%, P=0.016). We conclude that in pathology laboratories a median of at least 8 lymph nodes need to be examined in rectal cancer specimens, but that higher numbers are desirable and achievable in most cases, even after preoperative radiotherapy.

Purpose: Treatment of rectal cancer has changed dramatically over the last decade. The worldwide introduction of total mesorectal excision in combination with the increasing use of radio(chemo)-therapy has led to an improved prognosis. One of the main prognostic factors in rectal cancer is the circumferential resection margin (CRM). Since the initial description of its clinical importance in 1986, the involvement of this margin (also called lateral or radial resection margin) has been associated with a poor prognosis., Methods: In the current review, the evidence for the importance of the CRM in more than 17,500 patients is reviewed, and the relevance of this assessment to modern treatment is assessed., Results: We demonstrate that, after neoadjuvant therapy (both radiotherapy and radiochemotherapy), the predictive value of the CRM for local recurrence is significantly higher than when no preoperative therapy has been applied (hazard ratio [HR] = 6.3 v 2.0, respectively; P < .05). Furthermore, involvement of the CRM is a powerful predictor of both development of distant metastases (HR = 2.8; 95% CI, 1.9 to 4.3) and survival (HR = 1.7; 95% CI, 1.3 to 2.3). In addition to the prognostic data, this review describes different modes of margin involvement, exact definitions, and factors influencing its presence., Conclusion: CRM involvement is one of the key factors in rectal cancer treatment.

Purpose: After preoperative (radio)chemotherapy, histologic determinants for prognostication have changed. It is unclear which variables, including assessment of tumor regression, are the best indicators for local recurrence and survival., Experimental Design: A series of 201 patients with locally advanced rectal cancer (cT3/T4, M0) presenting with an involved or at least threatened circumferential margin (CRM) on preoperative imaging (<2 mm) were evaluated using standard histopathologic variables and four different histologic regression systems. All patients received neoadjuvant radiochemotherapy or radiotherapy. The prognostic value of all factors was tested with univariate survival analysis of time to local recurrence and overall survival., Results: Local recurrence occurred in only 8% of the patients with a free CRM compared with 43% in case of CRM involvement (P < 0.0001). None of the four regression systems were associated with prognosis, not even when corrected for CRM status. However, we did observe a higher degree of tumor regression after radiochemotherapy compared with radiotherapy (P < 0.001). Absence of tumor regression was associated with increasing invasion depth and a positive CRM (P = 0.02 and 0.03, respectively)., Conclusions: Assessment of CRM involvement is the most important pathologic variable after radiochemotherapy. Although tumor regression increases the chance on a free CRM, in cases with positive resection margins prognosis is poor irrespective of the degree of therapy-induced regression.

Objective: To investigate the efficacy of preoperative short-term radiotherapy in patients with mobile rectal cancer undergoing total mesorectal excision (TME) surgery., Summary Background Data: Local recurrence is a major problem in rectal cancer treatment. Preoperative short-term radiotherapy has shown to improve local control and survival in combination with conventional surgery. The TME trial investigated the value of this regimen in combination with total mesorectal excision. Long-term results are reported after a median follow-up of 6 years., Methods: One thousand eight hundred and sixty-one patients with resectable rectal cancer were randomized between TME preceded by 5 x 5 Gy or TME alone. No chemotherapy was allowed. There was no age limit. Surgery, radiotherapy, and pathologic examination were standardized. Primary endpoint was local control., Results: Median follow-up of surviving patients was 6.1 year. Five-year local recurrence risk of patients undergoing a macroscopically complete local resection was 5.6% in case of preoperative radiotherapy compared with 10.9% in patients undergoing TME alone (P < 0.001). Overall survival at 5 years was 64.2% and 63.5%, respectively (P = 0.902). Subgroup analyses showed significant effect of radiotherapy in reducing local recurrence risk for patients with nodal involvement, for patients with lesions between 5 and 10 cm from the anal verge, and for patients with uninvolved circumferential resection margins., Conclusions: With increasing follow-up, there is a persisting overall effect of preoperative short-term radiotherapy on local control in patients with clinically resectable rectal cancer. However, there is no effect on overall survival. Since survival is mainly determined by distant metastases, efforts should be directed towards preventing systemic disease.

Background & Aims: Staging of cancer is based on the TNM system. This valuable system takes only tumor-related parameters into account, but in the era of refined surgery and preoperative therapy treatment-related factors are of equal importance. By using rectal cancer as a model we explored the hypothesis that a combination of tumor- and treatment-related parameters will result in improved prognostication., Methods: Standardized clinicopathologic and histologic factors considered predictive for survival were studied in eligible patients treated in a trial for rectal cancer (n = 1324). These factors were analyzed in relation to survival using log-rank tests, Kaplan-Meier curves, and Cox regression both individually and in combination, the latter including TNM staging. A second data set from an independent trial (n = 316) was used for data validation., Results: Multivariate analysis identified nodal status (P = .001) and circumferential margin (P = .001) involvement as the most important prognostic factors for survival. The combination of these factors formed an improved staging system (node status and circumferential margin [NCRM]) compared with the present TNM staging with respect to 5-year cancer-specific survival. The results were confirmed in our independent patient population., Conclusions: NCRM staging of rectal cancer results in a broad range of survival rates and favorable patient grouping. Our data give strong evidence that a staging system combing tumor- and treatment-related factors provides better prognostic information than the classic TNM system, which is based solely on tumor-related factors. Similar results might be obtained in other types of cancer in which quality of treatment is important for outcome.

Objective: This study was performed to identify tumor- and patient-related risk factors for distal rectal cancer in patients treated with an abdominoperineal resection (APR) associated with positive circumferential resection margin (CRM), local recurrence (LR), and overall survival (OS)., Background: The introduction of total mesorectal excision (TME) has improved the outcome of patients with rectal cancer. However, survival of patients treated with an APR improved less than of those treated with low anterior resections (LAR). Besides, an APR is associated with a higher LR rate., Methods: Patients were selected from the TME trial, which is a randomized, multicenter trial, studying the effects of preoperative radiotherapy (RT) in 1861 patients. Of the Dutch patients, 455 underwent an APR. Location of the bulk of the tumor was scored with surgery, pathology, or other reports. CRM was available from pathology reports., Result: A positive CRM was found in 29.6% of all patients, 44% for anterior, 21% for lateral, 23% for posterior, and 17% for (semi)circular tumor location (P < 0.0001). In a multivariate analysis, T-stage, N-stage, and tumor location were independent risk factors for CRM. If a (partial) resection of the vaginal wall was performed in women, 47.8% of patients still had a positive CRM. T-stage, N-stage, and CRM were risk factors for LR and age, T-stage, N-stage, CRM, and distance of the inferior tumor margin to the anal verge for OS., Conclusion: Age, T-stage, N-stage, CRM, distance of the tumor to the anal verge, and tumor location were independent risk factors for adverse outcome in patients treated with an APR for low rectal cancer. Anterior location, specifically in women, more often requires downstaging and/or more extended resection to obtain free margins.

Purpose: The combination of radiotherapy and good quality surgery reduces local recurrence rate for rectal cancer patients. This study assesses the prognostic value of both intrinsic and radiotherapy-induced apoptosis and evaluates the relevance of radiotherapy for outcome of rectal cancer patients., Experimental Design: Tumor samples (1,198) were available from the Dutch Total Mesorectal Excision trial, in which rectal cancer patients were treated with standardized surgery and randomized for preoperative short-term radiotherapy or not. Tumor samples were obtained at time of surgery. Tissue microarrays were constructed and stained with the active caspase-specific M30 antibody to determine the amount of apoptotic epithelial tumor cells., Results: Nonirradiated patients with a negative circumferential margin displaying lower than median levels of apoptosis developed more local recurrences (10.5% versus 6.1%; P=0.06) and more rapidly after surgery than patients with high intrinsic apoptosis in their tumors (median time to recurrence, 13.0 versus 21.3 months; P=0.04). In multivariate analysis, intrinsic apoptosis was an independent predictor for the development of local recurrences (hazard ratio, 2.0; P=0.05). Radiotherapy increased apoptosis level (11 versus 23 apoptotic cells/mm2 tumor epithelium; P<0.001), but this apoptosis did not influence patients' prognosis., Conclusions: Rectal cancer patients with low intrinsic apoptosis will benefit from radiotherapy with respect to the development of local recurrences. Because apoptosis is an inherent characteristic of tumors, patients who do not need radiotherapy may be selected based on the apoptotic index of the primary tumor.

Purpose: Despite the major improvements that have been made due to total mesorectal excision (TME), low rectal cancer still remains a challenge., Methods: By investigating a prospective randomized rectal cancer trial in which surgeons had undergone training in TME the factors responsible for the poor outcome were determined and a new method for assessing the quality of surgery was tested., Results: Survival differed greatly between abdominoperineal resection (APR) and anterior resection (AR; 38.5% v 57.6%, P = .008). Low rectal carcinomas have a higher frequency of circumferential margin involvement (26.5% v 12.6%, P < .001). More positive margins were present in the patients operated with APR (30.4%) compared to AR (10.7%, P = .002). Furthermore, more perforations were present in these specimens (13.7% v 2.5%, P < .001). The plane of resection lies within the sphincteric muscle, the submucosa or lumen in more than 1/3 of the APR cases, and in the remainder lay on the sphincteric muscles., Conclusion: We systematically described and investigated the pathologic properties of low rectal cancer in general, and APR in particular, in a prospective randomized trial including surgeons who had been trained in TME. The poor prognosis of the patients with an APR is ascribed to the resection plane of the operation leading to a high frequency of margin involvement by tumor and perforation with this current surgical technique. The clinical results of this operation could be greatly improved by adopting different surgical techniques and possibly greater use of radiochemotherapy.