[Show abstract][Hide abstract] ABSTRACT: Background The last 30 years have witnessed a signifi-cant increase in the diagnosis of early-stage rectal cancer and the development of new strategies to reduce the treatment-related morbidity. Currently, there is no con-sensus on the definition of early rectal cancer (ERC), and the best management of ERC has not been yet defined. The European Association for Endoscopic Surgery in collabo-ration with the European Society of Coloproctology developed this consensus conference to provide recom-mendations on ERC diagnosis, staging and treatment based on the available evidence. Methods A multidisciplinary group of experts selected on their clinical and scientific expertise was invited to critically review the literature and to formulate evidence-based recommendations by the Delphi method. Recommendations were discussed at the plenary session of the 14th World Congress of Endoscopic Surgery, Paris, 26 June 2014, and then posted on the EAES website for open discussion. Results Tumour biopsy has a low accuracy. Digital rectal examination plays a key role in the pre-operative work-up. Magnification chromoendoscopy, endoscopic ultrasound and magnetic resonance imaging are complementary staging modalities. Endoscopic submucosal dissection and transanal endoscopic microsurgery are the two established approaches for local excision (LE) of selected ERC. The role of all organ-sparing approaches including neoadjuvant therapies followed by LE should be formally assessed by randomized controlled trials. Rectal resection and total mesorectal excision is indicated in the presence of unfa-vourable features at the pathological evaluation of the LE
[Show abstract][Hide abstract] ABSTRACT: Aim
Over recent years there has been a new focus on the quality of colon cancer surgery following the description and introduction of complete mesocolic excision (CME). In the same period, laparoscopic surgery has been widely applied to the treatment of colon cancer. We aimed to evaluate the introduction of both CME and laparoscopic-assisted surgery at Aarhus University Hospital, Denmark between 2008 and 2011. Secondly we aimed to evaluate the impact on the quality of surgery of post-operative team meetings where pathologists demonstrated the plane of surgery on the specimens.
A series of 209 consecutive and prospectively collected colon cancer specimens were evaluated by assessing the plane of surgery and measuring the amount of tissue resected. Multivariate analyses were used to control for influencing factors.
The proportion of specimens resected in the mesocolic plane was high and increased significantly following the introduction of post-operative team meetings (52 % to 76 %, p = 0.02). Laparoscopic surgery enhanced the distance between the tumour and the arterial tie by a mean of 27 mm (p < 0.0001) and the distance between the nearest bowel wall and the arterial tie by 26 mm (p < 0.0001) when compared to an open approach. Factors such as body mass index and age influenced the outcome for surgical quality.
Implementation of CME and laparoscopic-assisted surgery for colon cancer is a challenge and requires continuous training and feedback. Post-operative multidisciplinary team meetings may be a key element in this process.
European Journal of Surgical Oncology 11/2014; · 2.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose: To determine the prevalence and prognostic value of mismatch repair (MMR) status and its relation to BRAF mutation (BRAF(MT)) status in metastatic colorectal cancer (mCRC). Experimental Design: A pooled analysis of four phase III studies in first-line treatment of mCRC (CAIRO, CAIRO2, COIN and FOCUS) was performed. Primary outcome parameter was the hazard ratio (HR) for median progression-free survival (PFS) and overall survival (OS) in relation to MMR and BRAF. For the pooled analysis, Cox regression analysis was performed on individual patient data. Results: The primary tumors of 3063 patients were analyzed, of which 153 (5.0%) exhibited deficient MMR (dMMR) and 250 (8.2%) a BRAF(MT). BRAF(MT) was observed in 53 (34.6%) of patients with dMMR tumors compared to 197 (6.8%) of patients with proficient MMR (pMMR) tumors (p<0.001). In the pooled data set, median PFS and OS were significantly worse for patients with dMMR compared to pMMR tumors (HR 1.33, 95% CI 1.12-1.57 and HR 1.35, 95% CI 1.13-1.61, respectively), and for patients with BRAF(MT) compared to BRAF wild-type (BRAF(WT)) tumors (HR 1.34, 95% CI 1.17-1.54 and HR 1.91, 95% CI 1.66-2.19, respectively). PFS and OS were significantly decreased for patients with BRAF(MT) within the group of patients with pMMR, but not for BRAF status within dMMR, or MMR status within BRAF(WT) or BRAF(MT). Conclusions: Prevalence of dMMR and BRAF(MT) in mCRC patients is low and both biomarkers confer an inferior prognosis. Our data suggest that the poor prognosis of dMMR is driven by BRAF(MT) status.
Clinical Cancer Research 08/2014; · 8.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Complete mesocolic excision with central vascular ligation (CME) produces an optimal colonic cancer specimen. The ability of expert laparoscopic surgeons to produce equivalent specimens is unknown.Methods
Fresh specimen photographs and clinicopathological data from patients undergoing laparoscopically assisted CME at St Mark's Hospital, Harrow, were submitted for independent pathological review. Surgery was performed by a mixture of consultant specialists and trainees under consultant specialist supervision, between February 2010 and July 2011. The planes of surgery were graded and tissue morphometry was performed using standard methods. The results were compared with published data from open CME and non-CME surgery.ResultsIn total, 69 patients were identified, and in 96 per cent resection was performed completely or partially by surgical trainees. Laparoscopic CME produced a similar specimen to open CME. The laparoscopic mesocolic plane resection rate was similar to that for open surgery (90 versus 88 per cent). The distance between the bowel wall and site of vascular division was similar for laparoscopic and open right-sided CME (92 versus 95 mm respectively). The corresponding values for left-sided CME were also similar (103 versus 107 mm). Compared with values from two non-CME series, laparoscopic CME had a higher mesocolic plane rate (90 versus 40 and 48 per cent), and resected more tissue between the bowel wall and the vascular division (right-sided: 92 versus 72 and 76 mm; left-sided: 103 versus 85 and 70 mm). The lymph node yield remained low following laparoscopic CME compared with open CME (median 18 versus 32; P < 0·001) and identical to that of non-CME surgery (median 18).Conclusion
Laparoscopic CME can be performed to the same standard as open surgery by supervised trainees. However, this did not increase the lymph node yield.
British Journal of Surgery 08/2014; · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Most cancers arise and evolve as a consequence of somatic mutations. These mutations influence tumor behavior and clinical outcome. Consequently, there is considerable interest in identifying somatic variants within specific genes (such as BRAF, KRAS and EGFR) so that chemotherapy can be tailored to the patient's tumor genotype rather than using a generic treatment based on histological diagnosis alone. Owing to the heterogeneous nature of tumors, a somatic mutation may be present in only a subset of cells, necessitating the use of quantitative techniques to detect rare variants. The highly quantitative nature of next-generation sequencing (NGS), together with the ability to multiplex numerous samples, makes NGS an attractive choice with which to screen for somatic variants. However, the large volumes of sequence data present significant difficulties when applying NGS for the detection of somatic mutations. To alleviate this, we have developed methodologies including a set of data analysis programs, which allow the rapid screening of multiple formalin-fixed, paraffin-embedded samples for the presence of specified somatic variants using unaligned Illumina NGS data.Laboratory Investigation advance online publication, 28 July 2014; doi:10.1038/labinvest.2014.96.
[Show abstract][Hide abstract] ABSTRACT: Colorectal adenomas measuring ten millimetres or more are at increased neoplastic risk and therefore undergo more rigorous follow up. Currently there is no standardised method of assessing polyp size. We aimed to determine the correlation between endoscopic and histopathological measurements to determine the most appropriate method for clinical use.
[Show abstract][Hide abstract] ABSTRACT: Histopathologic grading using poorly-differentiated clusters predicts outcome in colorectal carcinoma.
Hector Li-Chang,1 Bojana Mitrovic2, Kelly Handley3, Richard Gray3, Naziheh Assarzadegan2, Gordon Hutchins4, Philip Quirke4, Robert Riddell2, Richard Kirsch2
1 Department of Molecular Oncology, BC Cancer Agency, Vancouver, Canada
2 Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom
3 Department of Pathology, Mount Sinai Hospital, Toronto, Canada
4 Department of Pathology and Tumour Biology, Leeds Institute of Cancer & Pathology
Background: Tumour grade is an independent prognostic factor in colorectal cancer (CRC), and is considered when deciding on the administration of adjuvant treatment. However, current grading schemes may overlook the significance of small but clinically significant high-grade components. The grading of CRC through the quantification of poorly-differentiated clusters (PDCs) has been proposed as being superior to conventional grading schemes in terms of both reproducibility and prognostic power. However, its impact on response to chemotherapy has not been studied.
Methods: A pathologist, blinded to outcome and case information, used PDC quantification to grade whole-slide digital hematoxylin and eosin images of 770 CRC cases from the QUick And Simple And Reliable (QUASAR) trial. The latter is the largest reported randomized study of observation versus adjuvant chemotherapy in patients with resected stage II colon cancer, and demonstrated that adjuvant 5-FU/leucovorin treatment benefits a small but significant population of stage II patients. PDCs were defined as groups of 5 or more tumour cells that lacked gland formation. Tumors were graded as follows: Grade 1: <5 PDCs; Grade 2: 5-9 PDCs and Grade 3: >9 PDCs in any high-power (400x) microscopic field at the leading edge of the tumor. Grading based on PDCs was compared to other clinicopathologic features, including outcome.
Results: PDC grades among the 770 CRC cases were follows:, Grade 1 (n=399), Grade 2(n=149) and grade 3 (n=102). No differences in T-stage amongst the 3 PDC grades were noted. A trend towards more frequent lymph node metastases was present amongst those subjects with PDC grade 3 tumors. PDC grade 3 tumors were significantly associated with proximal location (p = 0.03), vascular invasion (p = 0.01), microsatellite instability (p = 0.001), and wild-type KRAS status (p = 0.02). PDC grades of 2 and 3 were significantly associated with the presence of high-grade tumor budding (p < 0.0001). Log-rank tests showed that PDC grade showed prognostic significance for both the risk of recurrence (p = 0.01) and mortality (p = 0.03) following study follow-up periods of 10 years. Subgroup analysis showed no differences in 2-year recurrence rates within individual PDC grades between those receiving and not receiving chemotherapy.
Conclusions: Grading through the quantification of PDCs is prognostically valid in CRC patients, but does not predict response to adjuvant 5-FU with leucovorin. The use of this grading method may improve the prognostic power of histopathologic examination, and warrants further study.
[Show abstract][Hide abstract] ABSTRACT: Background:Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies.Patients and Methods:Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload.Results:A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival.Conclusions:Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.British Journal of Cancer advance online publication, 17 April 2014; doi:10.1038/bjc.2014.182 www.bjcancer.com.
British Journal of Cancer 04/2014; · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A key factor in the prognosis of colorectal cancer, and its response to chemoradiotherapy, is the ratio of cancer cells to surrounding tissue (the so called tumour:stroma ratio). Currently tumour:stroma ratio is calculated manually, by examining H&E; stained slides and counting the proportion of area of each. Virtual slides facilitate this analysis by allowing pathologists to annotate areas of tumour on a given digital slide image, and in-house developed stereometry tools mark random, systematic points on the slide, known as spots. These spots are examined and classified by the pathologist. Typical analyses require a pathologist to score at least 300 spots per tumour. This is a time consuming (10- 60 minutes per case) and laborious task for the pathologist and automating this process is highly desirable. Using an existing dataset of expert-classified spots from one colorectal cancer clinical trial, an automated tumour:stroma detection algorithm has been trained and validated. Each spot is extracted as an image patch, and then processed for feature extraction, identifying colour, texture, stain intensity and object characteristics. These features are used as training data for a random forest classification algorithm, and validated against unseen image patches. This process was repeated for multiple patch sizes. Over 82,000 such patches have been used, and results show an accuracy of 79%, depending on image patch size. A second study examining contextual requirements for pathologist scoring was conducted and indicates that further analysis of structures within each image patch is required in order to improve algorithm accuracy.
[Show abstract][Hide abstract] ABSTRACT: A number of studies have demonstrated that lymph node metastasis is a poor prognostic factor in colon cancer. Advances of surgical procedure have improved the outcomes of colon cancer treatment. The aim of this study was to compare the characteristics of surgery for stage III colon cancer between England, Germany, and Japan.
Using the data of patients with colon cancer from one English, one German, and two Japanese centers, the characteristics of clinicopathologic features were compared. Conventional surgery, complete mesocolic excision (CME) with central vascular ligation, and D3 lymph node dissection were performed in England, Germany, and Japan, respectively.
Nineteen English, 26 German, and 60 Japanese patients were enrolled. There was no difference in tumor location, pT, and pN factors among the three groups. The length of resected bowel and the area of resected mesentery of the English and CME specimens were significantly greater than those of the D3 specimens (P < 0.0001 and P < 0.0001, respectively), whereas the length of the vascular tie to the bowel wall was similar between the CME and D3 specimens (P = 0.87), which was longer than that of the English specimens. The number of lymph nodes retrieved in the CME specimens was greatest among three groups (P < 0.0001), although the number of positive nodes was comparable (P = 0.64). The rates of mesocolic plane surgery in the English, CME, and D3 specimens were 47.4, 88.5, and 71.7 %, respectively (P = 0.022).
Three types of surgery for colon cancer differed in terms of the length of the resected bowel and the area of mesentery, although the length of the vascular tie to the bowel wall was similar between CME and D3 specimens. The high rates of mesocolic plane surgery were demonstrated in the CME and D3 specimens.
Annals of Surgical Oncology 02/2014; · 3.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It has been evident for a while that the result after resection for colon cancer may not have been optimal. Several years ago, this was showed by some leading surgeons in the USA but a concept of improving results was not consistently pursued. Later, surgeons in Europe and Japan have increasingly adopted the more radical principle of complete mesocolic excision (CME) as the optimal approach for colon cancer. The concept of CME is a similar philosophy to that of total mesorectal excision for rectal cancer and precise terminology and optimal surgery are key factors.
There are three essential components to CME. The main component involves a dissection between the mesenteric plane and the parietal fascia and removal of the mesentery within a complete envelope of mesenteric fascia and visceral peritoneum that contains all lymph nodes draining the tumour area (Hohenberger et al., Colorectal Disease 11:354-365, 2009; West et al., J Clin Oncol 28:272-278, 2009). The second component is a central vascular tie to completely remove all lymph nodes in the central (vertical) direction. The third component is resection of an adequate length of bowel to remove involved pericolic lymph nodes in the longitudinal direction.
The oncological rationale for CME and various technical aspects of the surgical management will be explored.
The consensus conference agreed that there are sound oncological hypotheses for a more radical approach than has been common up to now. However, this may not necessarily apply in early stages of the tumour stage. Laparoscopic resection appears to be equally well suited for resection as open surgery.
International Journal of Colorectal Disease 01/2014; 29(4). · 2.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Care for patients with colon and rectal cancer has improved in the last 20 years; however, a considerable variation still exists in cancer management and outcome between European countries. Large variation is also apparent between national guidelines and patterns of cancer care in Europe. Therefore, EURECCA, which is the acronym of European Registration of Cancer Care, is aiming at defining core treatment strategies and developing a European audit structure in order to improve the quality of care for all patients with colon and rectal cancer. In December 2012, the first multidisciplinary consensus conference about cancer of the colon and rectum was held. The expert panel consisted of representatives of European scientific organizations involved in cancer care of patients with colon and rectal cancer and representatives of national colorectal registries.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 01/2014; 464(2). · 2.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The prognostic relevance of preoperative high-resolution magnetic resonance imaging (MRI) assessment of circumferential resection margin (CRM) involvement is unknown. This follow-up study of 374 patients with rectal cancer reports the relationship between preoperative MRI assessment of CRM staging, American Joint Committee on Cancer (AJCC) TNM stage, and clinical variables with overall survival (OS), disease-free survival (DFS), and time to local recurrence (LR).
Patients underwent protocol high-resolution pelvic MRI. Tumor distance to the mesorectal fascia of ≤ 1 mm was recorded as an MRI-involved CRM. A Cox proportional hazards model was used in multivariate analysis to determine the relationship of MRI assessment of CRM to survivorship after adjusting for preoperative covariates.
Surviving patients were followed for a median of 62 months. The 5-year OS was 62.2% in patients with MRI-clear CRM compared with 42.2% in patients with MRI-involved CRM with a hazard ratio (HR) of 1.97 (95% CI, 1.27 to 3.04; P < .01). The 5-year DFS was 67.2% (95% CI, 61.4% to 73%) for MRI-clear CRM compared with 47.3% (95% CI, 33.7% to 60.9%) for MRI-involved CRM with an HR of 1.65 (95% CI, 1.01 to 2.69; P < .05). Local recurrence HR for MRI-involved CRM was 3.50 (95% CI, 1.53 to 8.00; P < .05). MRI-involved CRM was the only preoperative staging parameter that remained significant for OS, DFS, and LR on multivariate analysis.
High-resolution MRI preoperative assessment of CRM status is superior to AJCC TNM-based criteria for assessing risk of LR, DFS, and OS. Furthermore, MRI CRM involvement is significantly associated with distant metastatic disease; therefore, colorectal cancer teams could intensify treatment and follow-up accordingly to improve survival outcomes.
Journal of Clinical Oncology 11/2013; · 17.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Care for patients with colon and rectal cancer has improved in the last 20years; however considerable variation still exists in cancer management and outcome between European countries. Large variation is also apparent between national guidelines and patterns of cancer care in Europe. Therefore, EURECCA, which is the acronym of European Registration of Cancer Care, is aiming at defining core treatment strategies and developing a European audit structure in order to improve the quality of care for all patients with colon and rectal cancer. In December 2012, the first multidisciplinary consensus conference about cancer of the colon and rectum was held. The expert panel consisted of representatives of European scientific organisations involved in cancer care of patients with colon and rectal cancer and representatives of national colorectal registries.
The expert panel had delegates of the European Society of Surgical Oncology (ESSO), European Society for Radiotherapy & Oncology (ESTRO), European Society of Pathology (ESP), European Society for Medical Oncology (ESMO), European Society of Radiology (ESR), European Society of Coloproctology (ESCP), European CanCer Organisation (ECCO), European Oncology Nursing Society (EONS) and the European Colorectal Cancer Patient Organisation (EuropaColon), as well as delegates from national registries or audits. Consensus was achieved using the Delphi method. For the Delphi process, multidisciplinary experts were invited to comment and vote three web-based online voting rounds and to lecture on the subjects during the meeting (13th-15th December 2012). The sentences in the consensus document were available during the meeting and a televoting round during the conference by all participants was performed. This manuscript covers all sentences of the consensus document with the result of the voting. The consensus document represents sections on diagnostics, pathology, surgery, medical oncology, radiotherapy, and follow-up where applicable for treatment of colon cancer, rectal cancer and metastatic colorectal disease separately. Moreover, evidence based algorithms for diagnostics and treatment were composed which were also submitted to the Delphi process.
The total number of the voted sentences was 465. All chapters were voted on by at least 75% of the experts. Of the 465 sentences, 84% achieved large consensus, 6% achieved moderate consensus, and 7% resulted in minimum consensus. Only 3% was disagreed by more than 50% of the members.
Multidisciplinary consensus on key diagnostic and treatment issues for colon and rectal cancer management using the Delphi method was successful. This consensus document embodies the expertise of professionals from all disciplines involved in the care for patients with colon and rectal cancer. Diagnostic and treatment algorithms were developed to implement the current evidence and to define core treatment guidance for multidisciplinary team management of colon and rectal cancer throughout Europe.
European journal of cancer (Oxford, England: 1990) 10/2013; · 4.12 Impact Factor