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Analyze conditional recurrence-free survival (cRFS) for rectal cancer patients with complete clinical response (cCR) after neoadjuvant chemoradiation (nCRT) managed nonoperatively after each year without recurrence.Select patients with cCR after nCRT have been managed nonoperatively. Risk factors for local recurrence, the need for prolonged follow-up, and the risk of recurrence over time are not well defined.Retrospective review of patients with rectal cancer cT2-4N0-2M0 treated with nCRT. Mean follow-up was 64 months. Patients who achieved cCR were managed nonoperatively. cRFS was used to investigate the evolution of recurrence-odds, as patients remain recurrence-free after completion of nCRT. Three-year cRFS was estimated at "x" years after completion of nCRT based on the formula cRFS3 = RFS(x+3)/RFS(x).One hundred ninety-seven patients with cCR after nCRT were included. Overall survival and recurrence-free survival (RFS) at 5 years were 81.9% (95% CI 74.0%-87.6%) and 60.4% (95% CI 52.5%-67.4%) respectively. Using cRFS estimates, the probability of remaining disease-free for an additional 3 years if the patient survived without disease at 1, 3, and 5 years, was 77.4% (95% CI 68.8%-83.8%), 91.0% (95% CI 81.9%-95.7%), and 94.3% (95% CI 82.9%-98.2%), respectively. In contrast, actuarial RFS rates for similar intervals were 79.1% (95% CI 72.5%-84.2%), 64.2% (95% CI 56.5%-70.8%), and 60.4% (95% CI 52.5%-67.4%). After 2 years disease-free, 3 year cRFS became similar for T2 and T3 cancers. In contrast, patients undergoing extended nCRT became less likely to develop recurrences only after initial 2 years of successful organ-preservation.Conditional survival suggests that patients have significantly lower risks (≤10%) of developing recurrences after 2 years of achieving cCR following nCRT.

Objective:To demonstrate the difference in organ-preservation rates and avoidance of definitive surgery among cT2N0 rectal cancer patients undergoing 2 different chemoradiation (CRT) regimens.Background:Patients with cT2N0 rectal cancer are more likely to develop complete response to neoadjuvant CRT

The current standard of care for the treatment of locally advanced rectal cancer includes neoadjuvant chemoradiation (nCRT) followed by total mesorrectal excision (TME). The observation of significant primary tumor response to radiation and chemotherapy led to the idea of organ-preserving strategies in selected patients who achieved clinical, endoscopic and radiological evidence of complete tumor regression. One of these strategies includes no immediate surgery with close surveillance, known as the Watch and Wait strategy (WW). The potential benefits of this approach with the avoidance of radical TME have to be weighed against the potential risk of local tumor regrowth. Exploration of these advantages and disadvantages will attempt to answer why WW may be an attractive alternative to rectal cancer patients and their treating physicians. In order to safely implement this strategy, some key issues related to baseline staging, neoadjuvant treatment regimens, timing for tumor response assessment, must be carefully considered. The combination of these features will attempt to clarify "how" and "to whom" the WW strategy may be considered. Ultimately, in the setting of contemporary neoadjuvant treatment regimens including total neoadjuvant therapy strategies (TNT), the achievement of a clinical complete response is likely to affect a significant proportion of patients. As endoscopic and radiological imaging modalities have evolved and improved, WW is expected to become an integral part during multidisciplinary management decision. Finally, understanding the clinical consequences of local tumor regrowth both in terms of local and distant relapse may allow for optimal and safe selection of patients fully aware of advantages or disadvantages of this strategy.

The possibility of organ preservation in early rectal cancer has gained popularity during recent years. Patients with early tumor stage and low risk for local recurrence do not usually require neoadjuvant chemoradiation for oncological reasons. However, these patients may be considered for chemoradiation exclusively for the purpose of achieving a complete clinical response and avoid total mesorectal excision. In addition, cT2 tumors may be more likely to develop complete response to neoadjuvant therapy and may constitute ideal candidates for organ-preserving strategies. In the setting where the use of chemoradiation is exclusively used to avoid major surgery, one should consider maximizing tumor response. In this article, we will focus on the rationale, indications, and outcomes of patients with early rectal cancer being treated by neoadjuvant chemoradiation to achieve organ preservation by avoiding total mesorectal excision.

BACKGROUND: The strategy of watch and wait (W&W) in patients with rectal cancer who achieve a complete clinical response (cCR) after neoadjuvant therapy is new and offers an opportunity for patients to avoid major resection surgery. However, evidence is based on small-to-moderate sized series from specialist centres. The International Watch & Wait Database (IWWD) aims to describe the outcome of the W&W strategy in a large-scale registry of pooled individual patient data. We report the results of a descriptive analysis after inclusion of more than 1000 patients in the registry.METHODS: Participating centres entered data in the registry through an online, highly secured, and encrypted research data server. Data included baseline characteristics, neoadjuvant therapy, imaging protocols, incidence of local regrowth and distant metastasis, and survival status. All patients with rectal cancer in whom the standard of care (total mesorectal excision surgery) was omitted after neoadjuvant therapy were eligible to be included in the IWWD. For the present analysis, we only selected patients with no signs of residual tumour at reassessment (a cCR). We analysed the proportion of patients with local regrowth, proportion of patients with distant metastases, 5-year overall survival, and 5-year disease-specific survival.FINDINGS: Between April 14, 2015, and June 30, 2017, we identified 1009 patients who received neoadjuvant treatment and were managed by W&W in the database from 47 participating institutes (15 countries). We included 880 (87%) patients with a cCR. Median follow-up time was 3·3 years (95% CI 3·1-3·6). The 2-year cumulative incidence of local regrowth was 25·2% (95% CI 22·2-28·5%), 88% of all local regrowth was diagnosed in the first 2 years, and 97% of local regrowth was located in the bowel wall. Distant metastasis were diagnosed in 71 (8%) of 880 patients. 5-year overall survival was 85% (95% CI 80·9-87·7%), and 5-year disease-specific survival was 94% (91-96%).INTERPRETATION: This dataset has the largest series of patients with rectal cancer treated with a W&W approach, consisting of approximately 50% data from previous cohort series and 50% unpublished data. Local regrowth occurs mostly in the first 2 years and in the bowel wall, emphasising the importance of endoscopic surveillance to ensure the option of deferred curative surgery. Local unsalvageable disease after W&W was rare.FUNDING: European Registration of Cancer Care financed by European Society of Surgical Oncology, Champalimaud Foundation Lisbon, Bas Mulder Award granted by the Alpe d'Huzes Foundation and Dutch Cancer Society, and European Research Council Advanced Grant.

Organ preservation is considered in the management of selected patients with rectal cancer. Complete clinical response observed after neoadjuvant chemoradiation for rectal cancer is one of these cases. Patients who present complete clinical response are candidates to the watch-and-wait approach, when radical surgery is not immediately performed and is offered only to patients in the event of a local relapse. These patients are included in a strict follow-up, and up of 70% of them will never be operated during the follow-up. This strategy is associated with similar oncological outcomes as patients operated on, and the advantage of avoiding the morbidity associated to the radical operation. In this article we will discuss in detail the best candidates for this approach, the protocol itself, and the long-term outcomes.

In recent years, our understanding of rectal cancer has improved, including how locally advanced disease responds to chemotherapy and radiation. This has led to new innovations and advances in the treatment of rectal cancer, which includes organ-preserving strategies for responsive disease, and minimally invasive approaces for the performance of total mesorectal excision/protectomyh for persistently advanced disease. This article discusses new strategies for rectal cancer therapy, including Watch and Wait, local excision, minimally invasive proctectomy, and transanal total mesorectal excision particularly in the setting of preoperative multimodality treatment.

Selected patients with rectal cancer and complete clinical response after neoadjuvant chemoradiation have been managed nonoperatively with acceptable outcomes. However, ≈20% of these patients will develop early tumor regrowth. Identification of these patients could select candidates for more intensive follow-up.The purpose of this study was to investigate the influence of baseline radiological T classification on recurrences after a complete clinical response managed nonoperatively after chemoradiation.This was a retrospective review of a prospective collected database.The study was conducted at a single center.Patients with distal rectal cancer (cT2-4N0-2M0) undergoing extended chemoradiation (54 Gy + 5-fluorouracil-based chemotherapy) were eligible. Patients were reassessed for tumor response at 10 weeks after radiation completion. Patients with complete clinical response (clinical, radiological, and endoscopic) were managed nonoperatively and strictly followed.Complete clinical response rates, early tumor regrowth rates (12 mo), local recurrence-free survival, and distant metastases-free survival were measured.A total of 91 consecutive patients with rectal cancer underwent extended chemoradiation. Sixty-one patients developed initial complete clinical response (67%). cT2 patients developed similar initial complete clinical response rates compared with cT3/T4 (72% vs 63%; p = 0.403). Early tumor regrowths were more frequent among baseline cT3/4 when compared with cT2 patients (30% vs 3%; p = 0.007). There were no differences in late local recurrences (p = 0.593) or systemic recurrences (p = 0.387). Local recurrence-free survival was significantly better for cT2 patients at 1 year (96% vs 69%; p = 0.009). After Cox regression analysis, baseline T stage was an independent predictor of improved local recurrence-free survival at 1 year (p = 0.03; OR = 0.09 (95% CI, 0.01-0.81)).This study was limited by its small sample size, retrospective nature, and short follow-up.cT2 patients who develop complete clinical response after extended chemoradiation managed nonoperatively are less likely to develop early tumor regrowths when compared with cT3/4 patients. cT3/4 patients should undergo more intensive follow-up after a complete clinical response to allow for early detection of early regrowths.

The traditional concept of rectal cancer management has changed significantly over the last few years. Although surgical resection is still the main pillar in the management of distal rectal cancer by proctectomy and total mesorectal excision (TME), organ preservation strategies have gained popularity. Neoadjuvant chemoradiation (nCRT) may result in significant tumor regression and may lead to complete pathological response in up to 42% of patients. In an attempt to avoid considerable morbidity and functional consequences of proctectomy and TME, selected patients that develop complete clinical response to neoadjuvant chemoradiation have been offered organ-preserving strategies including transanal local excision or even no immediate surgery and strict follow-up (watch and wait (WW)) with acceptable oncological outcomes and minimal functional consequences. Transanal local excisions may be an attractive organ-preserving strategy in this setting by providing definitive confirmation of complete primary tumor regression after nCRT. However, specific issues in tumor regression patterns, wound healing, postoperative function, and surveillance may constitute significant disadvantages of this approach over watch and wait.

To estimate the improvement in surgical exposure by removal of the coccyx, during abdomino-perineal resection (APR), in rectal cancer patients. Retrospective study of 29 consecutive patients with rectal cancer was carried out. Using MR T2 sagittal series, the solid angle was estimated using the angle determined by the anterior resection margin and the tip of coccyx (no coccyx resection) or the tip of last sacral vertebra (coccyx resection). The solid angle provides an estimate of the tridimensional surface area provided by an original angle resulting in the best estimate of the surgeon’s view/exposure to the critical dissecting point of choice (anterior rectal wall). The difference (“Gain”) in surgical field exposure by removal of the coccyx was compared by the solid angle variation between the two estimates (with and without the coccyx). Routine removal of the coccyx determines an average 42% (95% CI 27–57%) gain in surgical field exposure area facing the anterior rectal wall at the level of the prostate/vagina by the surgeon. Fifteen (51%) patients had ≥30% (median) estimated gain in surgical field exposure by coccygectomy. There was no association between BMI, age or gender and estimated gain in surgical field exposure area. Routine removal of the coccyx during APR may result in an average increase in 42% in surgical field exposure during APR’s perineal dissection. Precise estimation of surgical field exposure gain by removal of the coccyx may be predicted by MR sagittal series for each individual patient.

The aim of this study was to evaluate the oncological and survival outcomes of a Watch and Wait policy in rectal cancer after a clinical complete response (cCR) following neoadjuvant chemoradiotherapy.The detection of a cCR after neoadjuvant treatment may facilitate a nonoperative approach in selected patients. However, the long-term safety of this strategy remains to be validated.This is a systematic review of the literature to determine the oncological outcomes in Watch and Wait patients. The primary outcome was the cumulative rate of local regrowth, success of salvage surgery, and incidence of metastases. We also evaluated survival outcomes. A pooled analysis of manually extracted summary statistics from individual studies was carried out using inverse variance weighting.Seventeen studies comprising 692 patients were identified; incidence of cCR was 22.4% [95% confidence interval (CI),14.3-31.8]. There were 153 (22.1%) local regrowths, of which 96% (n = 147/153) manifested in the first 3 years of surveillance. The 3-year cumulative risk of local regrowth was 21.6% (95% CI, 16.0-27.8). Salvage surgery was performed in 88% of patients, of which 121 (93%) had a complete (R0) resection. Fifty-seven metastases (8.2%) were detected, and 35 (60%) were isolated without evidence of synchronous regrowths; 3-year incidence was 6.8% (95% CI, 4.1-10.2). The 3-year overall survival was 93.5% (95% CI, 90.2-96.2).In rectal cancer patients with a cCR following neoadjuvant chemoradiotherapy, a Watch and Wait policy appears feasible and safe. Robust surveillance with early detection of regrowths allows a high rate of successful salvage surgery, without an increase in the risk of systemic disease, or adverse survival outcomes.

Neoadjuvant chemoradiation has become one of the preferred initial treatment strategies for the management of distal rectal cancer. Development of significant or even complete tumor regression following this treatment strategy may be considerably frequent depending on baseline disease stage and specific chemoradiation regimen. Management of these patients by standard radical surgery may be associated with significant postoperative morbidity, mortality, and functional consequences with no oncological benefit to other organ-preserving strategies including local excision or even nonoperative management (watch and wait strategy). This treatment strategy requires careful selection of patients and thorough evaluation of primary tumor response. In the present chapter, current key issues during the assessment of tumor response are reviewed. In addition, potential clinical and surgical consequences of these organ-preserving strategies following complete clinical response following neoadjuvant are discussed. Finally, reported outcomes of organ preservation in patients with rectal cancer avoiding radical surgery are also presented.

The incorporation of new treatment modalities has significantly increased the complexity of decision-making for patients with locally advanced rectal cancer. Neoadjuvant chemoradiation (CRT) is considered one of the preferred treatment strategies for these patients. In addition, this treatment strategy may lead to significant tumor regression, ultimately leading to complete pathological response in up to 42% of patients. The assessment of tumor response following CRT and prior to radical surgery may identify patients with complete clinical response that could be managed nonoperatively with strict follow-up (watch and wait strategy) and thus avoiding unnecessary postoperative morbidity, including long-term urinary, sexual, and fecal continence dysfunctions and the frequent need for temporary or definitive stomas.

BACKGROUND:In elderly and comorbid patients with rectal cancer, radical surgery is associated with significant perioperative mortality. Data suggest that a watch-and-wait approach where a complete clinical response is obtained after neoadjuvant chemoradiotherapy might be oncologically safe.OBJECTIVE

Neoadjuvant chemoradiation (CRT) is considered one of the preferred treatment strategies for patients with locally advanced rectal cancer. This strategy may lead to significant tumor regression, ultimately leading to a complete pathologic response in up to 42% of patients. Assessment of tumor response following CRT and before radical surgery may identify patients with a complete clinical response who could possibly be managed nonoperatively with strict follow-up (watch-and-wait strategy). The present article deals with critical issues regarding appropriate selection of patients for this approach.

Background Neoadjuvant chemoradiotherapy (CRT) is one of the preferred initial treatment strategies for locally advanced rectal cancer. Responses are variable, and most patients still require surgery. The aim of this study was to identify molecular mechanisms determining poor response to CRT. Methods Global gene expression and pathway enrichment were assessed in pretreatment biopsies from patients with non-metastatic cT2–4 N0–2 rectal cancer within 7 cm of the anal verge. Downstream Akt activation was assessed in an independent set of pretreatment biopsies and in colorectal cancer cell lines using immunohistochemistry and western blot respectively. The radiosensitizing effects of the Akt inhibitor MK2206 were assessed using clonogenic assays and xenografts in immunodeficient mice. Results A total of 350 differentially expressed genes were identified, of which 123 were upregulated and 199 downregulated in tumours from poor responders. Mitochondrial oxidative phosphorylation (P < 0·001) and phosphatidylinositol signalling pathways (P < 0·050) were identified as significantly enriched pathways among the set of differentially expressed genes. Deregulation of both pathways is known to result in Akt activation, and high immunoexpression of phosphorylated Akt S473 was observed among patients with a poor histological response (tumour regression grade 0–2) to CRT (75 per cent versus 48 per cent in those with a good or complete response; P = 0·016). Akt activation was also confirmed in the radioresistant cell line SW480, and a 50 per cent improvement in sensitivity to CRT was observed in vitro and in vivo when SW480 cells were exposed to the Akt inhibitor MK2206 in combination with radiation and 5-fluorouracil. Conclusion Akt activation is a key event in the response to CRT. Pharmacological inhibition of Akt activation may enhance the effects of CRT. Surgical relevanceOrgan preservation is an attractive alternative in rectal cancer management following neoadjuvant chemoradiotherapy (CRT) to avoid the morbidity of radical surgery. Molecular steps associated with tumour response to CRT may provide a useful tool for the identification of patients who are candidates for no immediate surgery.In this study, tumours resistant to CRT were more likely to have activation of specific genetic pathways that result in phosphorylated Akt (pAkt) activation. Pretreatment biopsy tissues with high immunoexpression of pAkt were more likely to exhibit a poor histological response to CRT. In addition, the introduction of a pAkt inhibitor to cancer cell lines in vitro and in vivo led to a significant improvement in sensitivity to CRT.Identification of pAkt-activated tumours may thus allow the identification of poor responders to CRT. In addition, the concomitant use of pAkt inhibitors to increase sensitivity to CRT in patients with rectal cancer may constitute an interesting strategy for increasing the chance of a complete response to treatment and organ preservation.

Abdominal perineal excision (APE) has been associated with a high risk of positive circumferential resection margin (CRM+) and local recurrence rates in the treatment of rectal cancer. An alternative extralevator approach (ELAPE) has been suggested to improve the quality of resection by avoiding coning of the specimen decreasing the risk of tumor perforation and CRM+. The aim of this study is to compare the quality of the resected specimen and postoperative complication rates between ELAPE and “standard” APE. All patients between 1998 and 2014 undergoing abdominal perineal excision for primary or recurrent rectal cancer at a single Institution were reviewed. Between 1998 and 2008, all patients underwent standard APE. In 2009 ELAPE was introduced at our Institution and all patients requiring APE underwent this alternative procedure (ELAPE). The groups were compared according to pathological characteristics, specimen quality (CRM status, perforation and failure to provide the rectum and anus in a single specimen—fragmentation) and postoperative morbidity. Fifty patients underwent standard APEs, while 22 underwent ELAPE. There were no differences in CRM+ (10.6 vs. 13.6%; p = 0.70) or tumor perforation rates (8 vs. 0%; p = 0.30) between APE and ELAPE. However, ELAPE were less likely to result in a fragmented specimen (42 vs. 4%; p = 0.002). Advanced pT-stage was also a risk factor for specimen fragmentation (p = 0.03). There were no differences in severe (Grade 3/4) postoperative morbidity (13 vs. 10%; p = 0.5). Perineal wound dehiscences were less frequent among ELAPE (52 vs 13%; p

Transanal endoscopic microsurgery has become a very useful surgical tool for the management of selected cases of rectal cancer. However, the considerably high local recurrence rates led to the introduction of neoadjuvant therapies including radiation with or without chemotherapy. This treatment strategy may result in significant rates of tumor regression allowing the procedure to be offered to a significant proportion of cases. On the other hand, neoadjuvant chemoradiation (CRT) may also determine wound-healing difficulties with significant postoperative pain. In addition, salvage total mesorectal excision in the case of local recurrence may also be a challenging task. Finally, accurate selection criteria for this minimally invasive approach are still lacking and may be influenced by baseline staging, post-treatment staging and final pathology information. Ultimately, selection of patients for this treatment modality remains a significant challenge for the colorectal surgeon who should be aware of the pitfalls of this procedure in the setting of neoadjuvant CRT.

Background The main tenets of local excision of rectal cancer following neoadjuvant chemoradiation (CRT) are that the mucosal scar represents the main focus of residual disease and a solid conglomerate around this rather than being scattered (fragmented) through the bowel wall. Methods Retrospective review of a prospective cohort of patients with residual rectal ycT1-2N0 adenocarcinoma with small residual tumors (≤3 cm) following CRT who underwent transanal endoscopic microsurgery (TEM) with 1-cm margins around the residual mucosal abnormality was performed. Distribution and morphology (solid vs. fragmented) of tumor spread were studied and correlated to postoperative oncological outcomes. Results Thirty patients were included. Twenty percent (n = 6) were ypT1, 60% (n = 18) were ypT2, and 20% (n = 6) were ypT3 tumors. Fragmentation was present in 37%. The mean distance between foci of residual scattered tumor was 3.6 ± 2.0 mm. Lateral spread under normal mucosa was present in 19 specimens (53%; mean extension 4.8 ± 2.4 mm). With a median follow up of 32 months, none of these findings impacted upon development of recurrence. Conclusions Both occult lateral spread and fragmented tumor patterns are common findings after CRT. Despite the potential of occult spread to mislead surgeon choice of resection margin, its presence did not influence oncological outcome in this series. J. Surg. Oncol. 2014 109:853–858. © 2014 Wiley Periodicals, Inc.

Surgery remains the cornerstone in rectal cancer treatment. Abdominoperineal excision (APE), described more than 100 years ago, remains as an important procedure for the treatment of selected advanced distal tumors with direct invasion of the anal sphincter or preoperative fecal incontinence. Historically, oncological outcomes of patients undergoing APE have been worse when compared to sphincter preserving operations. More recently, it has been suggested that patients undergoing APE for distal rectal cancer are more likely to have positive circumferential resection margins and intraoperative perforation, known surrogate markers for local recurrence. Recently, an alternative approach known as “Extralevator Abdominoperineal Excision” has been described in an effort to improve rates of circumferential margin positivity possibly resulting in better oncological outcomes compared to the standard procedure. The objective of this paper is to provide a technical description and compare available data of both Extralevator and Standard abdominal perineal excision techniques. Resumo: Um dos pilares mais importantes no tratamento do câncer de reto ainda é a ressecção cirúrgica. A amputação de reto, ou excisão abdomino-perineal do reto (APE), descrita há mais de 100 anos, continua sendo um procedimento importante para o tratamento de tumores retais distais que invadem o aparelho esfincteriano ou em casos de incontinência pré-operatória. Entretanto, os resultados oncológicos dos pacientes submetidos à APE são piores quando comparados com os pacientes submetidos a procedimentos com preservação esfincteriana. Recentemente, foi sugerido que os pacientes submetidos à APE por câncer de reto distal apresentam mais frequentemente margem radial positiva, assim como perfuração intraoperatória do tumor, fatos reconhecidamente associados à recidiva local. Uma nova técnica cirúrgica conhecida como “Amputação de reto extraelevador ou cilíndrica” tem sido descrita em um esforço para reduzir as taxas de margem radial positivas, sugerindo melhores resultados oncológicos quando comparada com o procedimento convencional. O objetivo deste trabalho é descrever a técnica deste procedimento e comparar seus resultados com os obtidos com a técnica convencional de acordo com a evidência disponível. Keywords: Rectal cancer, Total mesorectal excision, Abdominoperineal excision, Extralevator Abdominoperineal excision, Cilindric abdominoperineal excision, Palavras-chave: Câncer de reto, Excisão total do mesorreto, Amputação abdominoperineal, Amputação abdominoperineal extraelevador, Amputação cilíndrica

In the last decade, major advances have been achieved in the treatment of rectal cancer. Results of randomized controlled trials have led to the introduction of total mesorectal excision and preoperative (chemo) radiotherapy as a standard multimodal treatment approach. By combining these different treatment modalities, patients are less likely to suffer local recurrence and are more likely to maintain sphincter function and retain a reasonably good quality of life. To further improve the treatment response, many efforts have been made to integrate targeted biological agents into the conventional therapy. Anti-angiogenic treatment has been shown in preclinical and clinical studies to possibly potentiate chemoradiosensitivity. The researchers present an overview of the mechanisms of action and a summary of published results of chemoradiotherapy with anti-angiogenic drugs in the treatment of locally advanced rectal carcinoma. At present, many obstacles still have to be conquered to use this combination in daily clinical routine. Problems of resistance, invasion and metastasis as well as timing and dosing of the combination therapy when using anti-angiogenic compounds are discussed in this review. Also, attention for better response prediction and better understanding of the complexity of anti-angiogenic therapy in combination with chemoradiation is needed to lead to future improvements in the use of these agents in the clinic.

Owing to the complexity of distal rectal cancer its management requires a multidisciplinary approach. The diagnosis and the response after neoadjuvant chemoradiotherapy are not easy to assess and therefore the surgical approach is heterogeneous. The purpose of this survey is to evaluate the experiences of members of the Italian Society of Surgery in diagnosis and treatment strategies for rectal cancer and compare it with international practice. A questionnaire was devised comprising 18 questions with 11 sub-items making a total of 29 questions and submitted online to all the 2,500 members of the SIC starting from July 2010. The survey was completed in June 2011. The overall response rate was 17.8 % (444). The majority of the Italian surgeons' responses were in line with the international consensus reflecting the complex management of distal rectal cancer. Other opinions, especially those on staging, diverge from the common view of MRI being the gold standard in the assessment of loco-regional diffusion of the disease and on the superiority of FDG PET-CT versus CT for systemic staging. The timing for the re-staging and for surgery following neoadjuvant chemoradiotherapy does not reflect the international opinion. Italian surgeons are also exposed to the common difficulties encountered internationally in the management of distal rectal cancer. Probably, the implementation of an Italian rectal cancer registry and of many national and international multicentre studies may improve the management of rectal cancer in Italy.

Law, WL is one of the members of the International Rectal Cancer Study Group, BACKGROUND: Little is known regarding variations in preoperative treatment and practice for rectal cancer (RC) on an international level, yet practice variation may result in differences in recurrence and survival rates. METHODS: One hundred seventy-three international colorectal centers were invited to participate in a survey of preoperative management of rectal cancer. RESULTS: One hundred twenty-three (71%) responded, with a majority of respondents from North America, Europe, and Asia. Ninety-three percent have more than 5 years' experience with rectal cancer surgery. Fifty-five percent use CT scan, 35% MRI, 29% ERUS, 12% digital rectal examination and 1% PET scan in all RC cases. Seventy-four percent consider threatened circumferential margin (CRM) an indication for neoadjuvant treatment. Ninety-two percent prefer 5-FU-based long-course neoadjuvant chemoradiation therapy (CRT). A significant difference in practice exists between the US and non-US surgeons: poor histological differentiation as an indication for CRT (25% vs. 7.0%, p = 0.008), CRT for stage II and III rectal cancer (92% vs. 43%, p = 0.0001), MRI for all RC patients (20% vs. 42%, p = 0.03), and ERUS for all RC patients (43% vs. 21%, p = 0.01). Multidisciplinary team meetings significantly influence decisions for MRI (RR = 3.62), neoadjuvant treatment (threatened CRM, RR = 5.67, stage II + III RR = 2.98), quality of pathology report (RR = 4.85), and sphincter-saving surgery (RR = 3.81). CONCLUSIONS: There was little consensus on staging, neoadjuvant treatment, and preoperative management of rectal cancer. Regular multidisciplinary team meetings influence decisions about neoadjuvant treatment and staging methods., published_or_final_version

BACKGROUND: Pathological complete response after chemoradiotherapy for rectal cancer occurs in 10% to 30% of patients. The best method to identify such patients remains unclear. Clinical assessment of residual mucosal abnormality is considered the most accurate method. In our institution, magnetic resonance tumor regression grade is performed as routine to assess response. OBJECTIVE: The purpose of this study was to compare the sensitivity of magnetic tumor regression grade against residual mucosal abnormality in detecting patients with a pathological complete response. DESIGN: Magnetic tumor regression grade scores from reported posttreatment MRI scans were documented. Magnetic tumor regression grade 1 to 3 was defined as likely to predict complete or near complete response. Gross appearances of the mucosa were derived from histopathology reports and used as a surrogate for clinical assessment (previously validated). Final histopathological staging was used to determine response. SETTINGS: The study was conducted at Royal Marsden National Health Service Trust, United Kingdom. PATIENTS: A total of 143 patients with rectal adenocarcinoma, diagnosed between September 1, 2009, and September 1, 2013, who received neoadjuvant chemoradiotherapy before curative surgery were included. MAIN OUTCOME MEASURES: The sensitivity of magnetic tumor regression grade and residual mucosal abnormality in detecting patients with pathological complete response were measured RESULTS: Eighteen patients had a pathological complete response. Seventeen were detected using magnetic resonance tumor regression grade 1 to 3, with sensitivity 94% (95% CI, 0.74-0.99), and 10 were detected using residual mucosal abnormality, with sensitivity 62% (95% CI, 0.38-0.81). There was no statistical difference between the false positive rates for either method. Magnetic tumor regression grade identified 10 times more patients with a pathological complete response (diagnostic OR = 10.2 (95% CI, 1.30-73.73)) compared with clinical assessment with RMA. LIMITATIONS: Residual mucosal abnormality was used as a surrogate marker for endoscopic appearances. CONCLUSIONS: Most patients with rectal cancer who have a pathological complete response do not manifest a complete response at the mucosal level. Magnetic tumor regression grade is able to identify 10 times more patients than clinical assessment, with no significant compromise in the false positive rate.

Demonstrate intratumoral genetic heterogeneity in rectal cancer.Several clinical management decisions in rectal cancer may be influenced by pretreatment biopsy information. However, in the setting of significant intratumoral heterogeneity, biopsies may not be representative of the entirety of the tumor and limit the reliability of the information provided from them for clinical decision management.Three fragments from a single rectal adenocarcinoma were chosen for whole-exome sequencing followed by mutation detection analysis. About 25 Gb of unambiguously mapped sequences were generated for each sample resulting in a median fold-coverage of 35x. Captured sequences mapped to the reference human genome were then used for the detection of somatic point mutations.Overall, 193 unique somatic point mutations were identified. Only 53 (27%) of these were shared by all three fragments, including known genes involved in early phases of the adenoma-carcinoma sequence (such as, APC). Approximately, 115 (59%) mutations were exclusively present in only one of the fragments, including mutations in "driver" genes (DNAH12). Jaccard distances showed a median distance of 0.603 for pair-wise comparison of fragments indicating significant heterogeneity between them.Considerable intratumoral heterogeneity is present among naive rectal cancers. The majority of point mutations detected in different fragments from rectal cancers are frequently unique to a single fragment. These findings support that gene mutations found on single pretreatment biopsies will not necessarily be representative of mutations present in the entirety of the tumor and therefore may limit the utility of the biological information provided by single biopsy fragments for clinical management decisions.

Contains fulltext : 171468pub.pdf (Publisher’s version ) (Open Access) 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.

Organ-preserving strategies have been considered for patients with distal rectal cancer and complete or near-complete response to neoadjuvant chemoradiation to avoid the functional consequences of radical surgery. Transanal endoscopic microsurgery and no immediate surgery (watch and wait) have been considered in selected patients.The aim of this study is to compare anorectal function following these 2 organ-preserving strategies (transanal endoscopic microsurgery and watch and wait) for rectal cancer with complete or near-complete response to neoadjuvant chemoradiation.This study is based on the comparison of prospectively collected data.This study was conducted at a single center.Consecutive patients with distal rectal cancer undergoing neoadjuvant chemoradiation (50.4-54 Gy and 5-fluorouracil-based chemotherapy) were prospectively studied. Patients with complete clinical response were managed by watch and wait. Patients with near-complete response (≤3 cm, ycT1-2N0) were managed by transanal endoscopic microsurgery.Functional outcomes were determined by anorectal manometry and Fecal Incontinence Index and Quality of Life assessment.Two groups of patients were included in the study. Twenty-nine patients with near-complete response undergoing transanal endoscopic microsurgery and 53 with complete response after watch and wait were assessed. Baseline features were similar between groups. Patients undergoing transanal endoscopic microsurgery had worse resting/squeeze pressures (p = 0.004) and rectal capacity (p = 0.002). In addition, their incontinence scores (2.3 vs. 6.5; p0.001) and quality-of-life questionnaire responses (in all domains; p ≤ 0.01) were significantly worse in comparison with patients undergoing watch and wait.This study was limited by the small sample size and the absence of baseline anorectal function information.Nonoperative management of patients with complete clinical response following chemoradiation results in better anorectal function in comparison with patients with near-complete response managed by transanal endoscopic microsurgery. In the absence of clinically detectable residual cancer, this latter approach may result in significant worsening of anorectal function.

Aim The study aimed to determine the value of postchemoradiation biopsies, performed after significant tumour downsizing following neoadjuvant therapy, in predicting complete tumour regression in patients with distal rectal cancer. Method A retrospective comparative study was performed in patients with rectal cancer who achieved an incomplete clinical response after neoadjuvant chemoradiotherapy. Patients with significant tumour downsizing (> 30% of the initial tumour size) were compared with controls (

Defecography is the gold standard for assessing functional anorectal disorders but is limited by the need for a specific radiologic environment, exposure of patients to radiation, and inability to show all anatomic structures involved in defecation. Echodefecography is a 3-dimensional dynamic ultrasound technique developed to overcome these limitations.This study was designed to validate the effectiveness of echodefecography compared with defecography in the assessment of anorectal dysfunctions related to obstructed defecation.Multicenter, prospective observational study.Women with symptoms of obstructed defecation.Six centers for colorectal surgery (3 in Brazil, 1 in Texas, 1 in Florida, and 1 in Venezuela).Defecography was performed after inserting 150 mL of barium paste in the rectum. Echodefecography was performed with a 2050 endoprobe through 3 automatic scans.The κ statistic was used to assess agreement between echodefecography and defecography in the evaluation of rectocele, intussusception, anismus, and grade III enterocele.Eighty-six women were evaluated: median Wexner constipation score, 13.4 (range, 6-23); median age, 53.4 (range, 26-77) years. Rectocele was identified with substantial agreement between the 2 methods (defecography, 80 patients; echodefecography, 76 patients; κ = 0.61; 95% CI = 0.48-0.73). The 2 techniques demonstrated identical findings in 6 patients without rectocele, and in 9 patients with grade I, 29 with grade II, and 19 patients with grade III rectoceles. Defecography identified rectal intussusception in 42 patients, with echodefecography identifying 37 of these cases, plus 4 additional cases, yielding substantial agreement (κ = 0.79; 95% CI = 0.57-1.0). Intussusception was associated with rectocele in 28 patients for both methods (κ = 0.62; 95% CI = 0.41-0.83). There was substantial agreement for anismus (κ = 0.61; 95% CI = 0.40-0.81) and for rectocele combined with anismus (κ = 0.61; 95% CI = 0.40-0.82). Agreement for grade III enterocele was classified as almost perfect (κ = 0.87; 95% CI = 0.66-1.0).Echodefecography had limited use in identification of grade I and II enteroceles because of the type of probe used.Echodefecography may be used to assess patients with obstructed defecation, as it is able to detect the same anorectal dysfunctions found by defecography. It is minimally invasive and well tolerated, avoids exposure to radiation, and clearly demonstrates all the anatomic structures involved in defecation.

Transanal endoscopic microsurgery may represent appropriate diagnostic and therapeutic procedure in selected patients with distal rectal cancer following neoadjuvant chemoradiation. Even though this procedure has been associated with low rates of postoperative complications, patients undergoing neoadjuvant chemoradiation seem to be at increased risk for suture line dehiscence. In this setting, we compared the clinical outcomes of patients undergoing transanal endoscopic microsurgery with and without neoadjuvant chemoradiation.Thirty-six consecutive patients were treated by transanal endoscopic microsurgery at a single institution. Twenty-three patients underwent local excision after neoadjuvant chemoradiation therapy for rectal adenocarcinoma, and 13 patients underwent local excision without any neoadjuvant treatment for benign and malignant rectal tumors. Chemoradiation therapy included 50.4 to 54 Gy and 5-fluorouracil-based chemotherapy. All patients underwent transanal endoscopic microsurgery with primary closure of the rectal defect. Complications (immediate and late) and readmission rates were compared between groups.Overall, median hospital stay was 2 days. Immediate (30-d) complication rate was 44% for grade II/III complications. Patients undergoing neoadjuvant chemoradiation therapy were more likely to develop grade II/III immediate complications (56% vs 23%; P = .05). Overall, the 30-day readmission rate was 30%. Wound dehiscence was significantly more frequent among patients undergoing neoadjuvant chemoradiation therapy (70% vs 23%; P = .03). Patients undergoing neoadjuvant chemoradiation therapy were at significantly higher risk of requiring readmission (43% vs 7%; P = .02).Transanal local excision with the use of endoscopic microsurgical approach may result in significant postoperative morbidity, wound dehiscence, and readmission rates, in particular, because of rectal pain secondary to wound dehiscence. In this setting, the benefits of this minimally invasive approach either for diagnostic or therapeutic purposes become significantly restricted to highly selected patients that can potentially avoid a major operation but will still face a significantly morbid and painful procedure.

Multimodality treatment of rectal cancer, with the combination of radiation therapy, chemotherapy, and surgery has become the preferred approach to locally advanced rectal cancer. The use of neoadjuvant chemoradiation therapy (CRT) has resulted in reduced toxicity rates, significant tumor downsizing and downstaging, better chance of sphincter preservation, and improved functional results. A proportion of patients treated with neoadjuvant CRT may ultimately develop complete clinical response. Management of these patients with complete clinical response remains controversial and approaches including radical resection, transanal local excision, and observation alone without immediate surgery have been proposed. The use of strict selection criteria of patients after neoadjuvant CRT has resulted in excellent long-term results with no oncological compromise after observation alone in patients with complete clinical response. Recurrences are detectable by clinical assessment and frequently amenable to salvage procedures.

The traditional concept of rectal cancer management has changed significantly over the last few years. Although surgical resection remains central the treatment of distal rectal cancer by proctectomy and total mesorectal excision (TME), there has been increased interest in organ preservation strategies. Neoadjuvant chemoradiation (nCRT) may result in significant tumor regression and complete pathological response may be observed in up to 42% of patients. In order to avoid the morbidity, mortality and functional consequences of major surgery, selected patients with clinical and radiological evidence of significant tumor regression after nCRT have been managed non-operatively with strict follow-up (Watch & Wait Strategy—WW) with acceptable outcomes and minimal functional consequences. In addition, close surveillance may allow early detection of local recurrences and salvage alternatives with no oncological compromise.

Addition of chemotherapy in the resting period between radiotherapy completion and response assessment during neoadjuvant treatment for distal rectal cancer could potentially increase rates of complete tumor regression. The purpose of this study was to evaluate toxicity rates and the impact of an extended neoadjuvant chemoradiation regimen on complete response rates.Thirty-four consecutive patients with nonmetastatic distal rectal cancer were prospectively included. Patients were managed by 5,400 Gy of radiation and 5-fluorouracil/leucovorin-based chemotherapy given for three consecutive days every 21 days for six cycles (three cycles concomitant with radiotherapy). Tumor response assessment was performed at ten weeks from radiation completion. Patients with complete clinical response were strictly monitored and were not immediately operated on. Patients with incomplete clinical response were referred to surgery.Twenty-nine patients had completed 12 months of follow-up and were included in this preliminary analysis. Twenty-eight (97%) successfully completed treatment. Fifteen of 16 patients had Grade III toxicities that were skin-related (93%). Median follow-up was 23 months. Fourteen patients (48%) were considered as complete clinical responders sustained for at least 12 months (median, 24 months) after chemoradiation completion by clinical assessment alone. An additional five patients (17%) were considered as complete responders with ypT0 results after full-thickness local excision. Overall, the complete response rate was 65%.The addition of chemotherapy during the resting period after neoadjuvant chemoradiation is associated with acceptable toxicity and high tolerability rates. The considerably high rates of complete response in this preliminary series requires further follow-up, but they may provide valuable information for future prospective, randomized trials.

PURPOSE: Carcinoembriogenic antigen (CEA) is the most frequently used tumor marker in rectal cancer. A decrease in carcinoembriogenic antigen after radical surgery is associated with survival in these patients. Neoadjuvant chemoradiotherapy may lead to significant primary tumor downstaging, including complete tumor regression in selected patients. Therefore, we hypothesized that a decrease in CEA after neoadjuvant chemoradiotherapy could reflect tumor response to chemoradiotherapy, affecting final disease stage and ultimately survival. METHODS: Patients with distal rectal cancer managed by neoadjuvant chemoradiotherapy and available pretreatment and postchemoradiotherapy levels of CEA were eligible for the study. Outcomes studied included final disease stage, relapse, and survival, and these were compared according to initial CEA level, postchemoradiotherapy CEA level, and the reduction in CEA. RESULTS: Overall 170 patients were included. Postchemoradiotherapy CEA levels