Accepted Manuscript Implementation of complete mesocolic excision at a university hospital in Denmark: An audit of consecutive, prospectively collected colon cancer specimens Ditte Louise E. Munkedal , MD, Phd Nicholas P. West , Ph.D Lene H. Iversen , DMSci, Ph.D. Rikke Hagemann-Madsen , MD Philip Quirke , PhD Søren Laurberg , DMSci PII:
S0748-7983(14)00401-6
DOI:
10.1016/j.ejso.2014.04.004
Reference:
YEJSO 3817
To appear in:
European Journal of Surgical Oncology
Received Date: 22 January 2014 Revised Date:
21 March 2014
Accepted Date: 8 April 2014
Please cite this article as: Munkedal DLE, West NP, Iversen LH, Hagemann-Madsen R, Quirke P, Laurberg S, Implementation of complete mesocolic excision at a university hospital in Denmark: An audit of consecutive, prospectively collected colon cancer specimens, European Journal of Surgical Oncology (2014), doi: 10.1016/j.ejso.2014.04.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title:
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Implementation of complete mesocolic excision at a university hospital in Denmark: An audit of consecutive, prospectively collected colon cancer specimens
Authors: [email protected]
Nicholas P. West b
[email protected]
Lene H. Iversen a
[email protected]
Rikke Hagemann-Madsen
Rikke.Hjarno.Hagemann-
Ph.D
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c
MD
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Ditte Louise E. Munkedal a
DMSci, Ph.D. MD
[email protected] Philip Quirke b
[email protected]
Professor, PhD
Søren Laurberg a
[email protected]
Professor, DMSci
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Affiliations:
a) Department of Surgery P, Aarhus University Hospital, 8000 Aarhus C, Denmark b) Pathology, Anatomy & Tumour Biology, Leeds Institute of Cancer and Pathology,
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University of Leeds, St. James's University Hospital, Leeds, LS9 7TF, UK c) Pathology Department, Aarhus University Hospital, 8000 Aarhus C, Denmark
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Corresponding author MD Ditte Louise E. Munkedal, PhD-student Department of Surgery P Aarhus University Hospital Tage-Hansens Gade 2 8000 Aarhus C Denmark E-mail: [email protected] Tel: +45 22 52 13 33
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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.
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Method: 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.
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Results: 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.
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Conclusion: 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.
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What does this paper add to the literature? (max. 50 words) This study demonstrated that a laparoscopic approach resulted in more tissue resected between the tumour and the arterial tie in CME-surgery. It emphasises the importance of continuous feedback to surgeons in order to maintain high surgical quality, and it indicates other factors that may influence the indicators of surgical quality.
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Key words Colon cancer; complete mesocolic excision; pathological evaluation; laparoscopic approach; post-operative team meetings
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Introduction Colon cancer has a high incidence and is one of the most frequent cancers in the Western world. In Denmark, with a population of 5.5 million people, there are 2,700 new cases per year resulting in 1,375 deaths. In the 1980’s, patients with colon cancer had a better prognosis when compared to those with rectal cancer [1], however, today the opposite is true [2,3]. This is thought to be mainly due to the introduction of total mesorectal excision (TME) which has optimized and standardised rectal cancer surgery [4,5]. However, the introduction of magnetic resonance imaging, pre-operative treatment [6,7], improved histopathology techniques and the integration of care through multidisciplinary teams have undoubtedly contributed to the improved outcomes in rectal cancer.
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During the same period, colon cancer surgery has focused on the introduction of laparoscopic-assisted techniques, the number of lymph nodes harvested [8,9], and staging of the disease. The success of TME inspired the enhancement of colon cancer surgery, and the importance of meticulous dissection has been clarified through the recent description of complete mesocolic excision (CME) [10]. The concept of CME is to create an intact specimen encompassing the primary tumour along with all of the potential routes for tumour spread [11] through central ligation of the artery at its origin [12]. Early studies have suggested that the procedure reduces tumour recurrence and improves survival [13]. A pathological evaluation of the quality of the specimen can be applied to CME surgery in a similar way as for TME, and it seems to provide valuable feedback to surgical teams [14].
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Aarhus University Hospital (AUH) in Denmark implemented CME surgery as standard practice for all elective curative colon cancer resections at the beginning of 2008 following a post-graduate development course (PgDC). During the same period, laparoscopicassisted surgery increased to become a standard of care. After 2010, post-operative team meetings were held for all patients following colon cancer resection, where pathologists demonstrated the surgical plane of resection on specimen photographs to the surgical team.
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The aim of the present study was to evaluate the pathological quality of colon cancer surgery at AUH between 2008 and 2011 and to determine the effect of the implementation of CME and laparoscopic-assisted surgery. Secondly, we aimed to evaluate the impact of the introduction of post-operative team meetings on the quality of surgery.
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Material and methods
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Specimens A consecutive series of specimens from patients with primary colon cancer resected at AUH were collected prospectively between January 1st 2008 and December 31st 2011. High resolution digital photographs were taken of all specimens following resection. Information on patient characteristics and surgery were obtained from the Danish Colorectal Cancer Group (DCCG) database [15] and medical charts. Exclusion criteria included patients with disseminated disease at the time of presentation, emergency surgery, palliative surgery, and specimens with photos not suitable for tissue morphometry. National screening for colorectal cancer had not been implemented in Denmark during the study period and therefore all patients presented with symptomatic disease. In 2011, AUH performed 220 resections for colorectal cancer. Fourteen consultant surgeons either performed or supervised all 162 operations. Of these only four were trained in the laparoscopic approach and did both types of surgery. Evaluation of specimens All specimens were evaluated blinded to surgeon and surgical approach. The pathology department used the DCCG guidelines for the histopathological dissection processing and reporting of colon cancer specimens [16].
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Grading of the specimens: All specimens were graded according to the plane of surgery using a previously published technique [13]. Briefly, all specimens were classified into one of three groups based on the integrity of the mesocolon. 1. The mesocolic plane. The specimen has an intact mesocolon with a smooth peritoneal-lined surface with no defects deeper than 5 mm. 2. The intramesocolic plane. The specimen has a moderate amount of mesocolon but with some irregularity. Any defects are deeper than 5 mm but do not reach the muscularis propria. 3. The muscularis propria plane. The specimen has only a small amount of mesocolon and any disruptions expose the muscularis propria. The grading was performed independently and retrospectively by one specialist gastrointestinal pathologist (RHM) following specialist training (by PQ) using photographs of both the fresh and formalin-fixed specimens in March 2013. Tissue morphometry: All tissue morphometry was performed on fresh specimen photographs only by the one author (DLEM) following training (by NW and PQ) in Leeds [11,17]. Aperio ImageScope version 11 (Aperio Technologies, California, USA) was used to determine the area of the mesocolon, the length of the large bowel, the distance from the arterial tie to the tumour and the distance from the arterial tie to the nearest bowel wall (Fig. 1). Tissue morphometry was only performed if optimum photographs were available
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defined as having the whole specimen visible with the image being taken directly from above to prevent measurement distortion.
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Implementation and education In 2007 and 2008, multidisciplinary PgDC’s were held for all specialists involved in colorectal cancer treatment in our region. Surgeons, histopathologists, oncologists and radiologists from the middle and northern part of Jutland (population 1.9 million) participated. The concept of CME surgery was first introduced in December 2007 by surgeon Professor Werner Hohenberger and histopathologist Professor Phil Quirke. The course was followed by an on-site-visit in February 2008. Professor Hohenberger came to AUH to supervise the surgeons in the operative technique and Professor Quirke introduced the pathologists the evaluation of the specimens.
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Laparoscopic-assisted colon cancer surgery was implemented after the PgDC in 2008 and an on-site-visit from Professor Mike Parker, an internationally renowned laparoscopic colorectal cancer surgical specialist. Laparoscopic-assisted surgery was introduced as the standard of care initially for left sided colon cancers and later for right sided cancers. Cancers located in the transverse colon and flexures were not treated laparoscopically, and were therefore excluded in the comparison between open and laparoscopic surgery. Patients were allocated to undergo surgery on the first available day in theatre. If a laparoscopic surgeon was available on the day, the patient was considered for laparoscopic-assisted surgery. All operations were either performed or supervised by a consultant colorectal surgeon.
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After 2010, formal post-operative multidisciplinary team meetings were held every other week where pathologists would provide feedback regarding the plane of surgery through the demonstration of specimen photographs. Each surgeon received individual feedback on their own surgery.
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Statistical analyses Statistical analyses were performed using Stata IC 12 with the chi-squared, student t-test, ANOVA and rank sum test as appropriate for univariate analysis. Multivariate regression and logistic regression were used to control for potentially influencing variables including gender, age, body mass index (BMI), year of surgery, Union for International Cancer Control (UICC) stage of disease, tumour site, and surgical approach. It was necessary to transform the variables “area of mesocolon” and “length of large bowel” in order to obtain correct statistical analyses. “Area of mesocolon” was transformed by the square root to fit into multiple regression analyses, therefore it was not possible to determine the exact 95% confidence interval for the difference between outcomes in Table 3. An estimated interval was therefore calculated. P values less than 0.05 were considered statistically significant.
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Ethical approval The study represented an audit project and therefore individual patient consent was not needed according to Danish laws. The Danish Data Protection Agency approved the study (reference number = J.nr. 2012-41-0374).
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Results
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Patients In total, 356 specimens were identified during the initial search. After exclusions, (Fig 2) 209 specimens were entered into the study including 47 transverse colon cancers that were not used during analyses of surgical approach. Patient clinicopathological characteristics are shown in Table 1.
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Laparoscopic-assisted versus open approach Eighty-three patients underwent laparoscopic-assisted surgery for either right or left sided cancers (Table 1). Patients in the laparoscopic-assisted group were younger and had a greater BMI when compared to patients in the open surgery group. There was a significant increase in the proportion of laparoscopic-assisted resections between 2008 and 2011, and a greater proportion of left sided tumours were resected laparoscopically.
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Plane of surgery Univariate analysis: Overall, an intact mesocolic plane was achieved in 128 specimens (61 %), the intramesocolic plane in 75 (36 %) and in only six specimens (3 %) the surgeon reached the muscularis propria plane. The rate of mesocolic plane surgery was significantly higher in the years 2008 (67 %) and 2011 (76 %) when compared to 2009 (53 %) and 2010 (52 %). The rate of mesocolic plane surgery was slightly lower for left sided tumours (51 %, p = 0.075) when compared to right sided (68 %), and transverse colon and flexure tumours (72 %), however, the difference was not statistically significant. There was no difference in the rate of mesocolic plane surgery according to patient age, gender, BMI, UICC stage of disease, or surgical approach.
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Logistic regression: After an adjustment for potential influencing factors we determined that the proportion of mesocolic plane excisions had improved significantly in 2011 when compared to 2010, and that left sided specimens had a significantly lower mesocolic plane rate than specimens from the right side or transverse colon and flexures. Furthermore, an increase in patient age appeared to reduce the odds of an excision in the mesocolic plane (Table 2).
Tissue morphometry Univariate analysis: In all cases, the mean distance from the arterial tie to the tumour was 97 mm, 95% confidence interval (95% CI)(92 – 102 mm) and the mean distance from the arterial tie to the nearest bowel wall was 82 mm, 95% CI(76 – 86 mm). The mean area of resected mesocolon was 12,689 mm2, 95% CI (11,784 – 13,628 mm2) and the mean length of large bowel resected was 290 mm, 95% CI (276 – 304 mm).
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Multivariate regression: Specimens in the laparoscopic-assisted group had a longer distance between the tumour or nearest bowel wall and the arterial tie with more than 25 mm of additional tissue when compared to specimens in the open group. Surgical approach did not appear to influence the area of mesocolon or length of large bowel resected (Table 3a). BMI showed a positive correlation with the distance from the nearest bowel wall to the arterial tie (coefficient: 1.3 mm/BMI, p = 0.005) and the area of mesocolon (coefficient: 327 mm2/BMI, p < 0.0001). When assessed by the year of surgery, the amount of tissue resected appeared to reduce over the duration of the study (Table 3b). There were no differences in any morphometric measurements between left and right sided specimens.
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Discussion
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In this study, we have evaluated the implementation of CME and laparoscopic-assisted surgery for colon cancer at a single university hospital in Denmark over a four year period. We have demonstrated that the laparoscopic-assisted approach was associated with the removal of more tissue between the tumour and the arterial tie when compared to the open approach. We have also shown that the majority of specimens were resected in the mesocolic plane, and that there was no difference in the plane of surgery between the open and laparoscopic groups. Interestingly we found that the quality of the specimens improved following a PgDC held in 2008, however, in the years following this the proportion of specimens resected in the mesocolic plane fell. This reduction was reversed following a refocussing on the importance of surgical planes in 2010 through the introduction of post-operative multidisciplinary team meetings. This highlights the importance of regular feedback from pathologists to surgical teams in order to ensure consistent high quality dissection.
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Colon cancer has a high incidence in the western world and with the reversal in outcomes for rectal and colon cancer, a renewed focus is now required for this disease. Some authors have advocated the widespread introduction of CME, the principles of which are based upon those of TME surgery, the international introduction of which has led to marked improvements in rectal cancer outcomes [6,18]. There are three seperate components of optimum CME surgery: 1) the surgeon must remain within the mesocolic plane, 2) the surgeon must perform central ligation of the tumour-feeding artery and 3) the surgeon must remove an appropriate length of large bowel on either side of the tumour. Whereas the mesocolic plane is generally accepted as the gold standard [6,10], the height of the vessel ligation is still actively debated. Some studies have demonstrated a benefit with central ligation [19,20], however, others have shown no difference between high and low ligation [21,22]. Patient morbidity is also a concern with one study identifying a greater risk of genitourinary dysfunction following high tie [23]. Colon cancers are well recognised to metastasise to lymph nodes located along the tumour-feeding artery [12,24]. Removal of these high tie nodes is likely to be more important than the actual number of lymph nodes removed as substantial longitudinal spread is uncommon. The length of large bowel resected is also controversial, and the Japanese have proposed alternative principles for the amount of normal colon resected [17]. Rigorous scientific evaluation of CME and the importance of central ligation of the vessels, as has been undertaken in the present study, is therefore urgently required [25]. In the current study, we aimed to describe the effect of the implementation of two new surgical techniques at a university hospital in Denmark. CME and laparoscopic-assisted colon cancer surgery were implemented in 2008 after a PgDC for multi-disciplinary teams. We found that laparoscopic-assisted surgery was associated with a greater amount of tissue resected between the tumour and the arterial tie with more than 25 mm of additional mesentery resected. The development of the surgical technique and the fact that
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laparoscopic-assisted surgery had increased significantly during the period were taken into account in a multivariate regression analysis. Other studies in the literature have reported both a shorter distance [26] and opposite longer distance [17,27] with laparoscopic surgery. Theoretically, if the artery is ligated at the origin there should be no difference between open and laparoscopic surgery, however, it is possible that laparoscopic dissection may facilitate a more central arterial tie. Despite the increase in the amout of central tissue resected, the laparoscopic approach was not associated with a greater area of mesocolon or a length of the large bowel. These results confirm that a laparoscopicassisted approach can be used effectively to undertake the CME technique.
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We found a clear increase in the proportion of specimens resected in the mesocolic plane in 2011 when compared to 2010. This most likely corresponds with the introduction of post-operative multidisciplinary team meetings, although we are not able to definitely prove this. It was interesting that when CME was first implemented in 2008, the percentage of specimens resected in the mesocolic plane was high. The number fell in 2009 and 2010 prior to the later improvement, which could also reflect the learning curve associated with the introduction of laparoscopic surgery before a refocussing of surgical planes in the postoperative multidisciplinary meetings. We feel that individual feedback and demonstration of specimen defects may have increased awareness of the importance of staying in embryological tissue planes during surgery. This emphasizes the importance of surgical education and continuous feedback as has been demonstrated in other studies [18,27].
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The morphometric measurements and mesocolic plane rate reported in the current study are not as good as the results reported in Erlangen, where 88 % of the specimens were resected in the mesocolic plane, the median distance from the tumour to the arterial was 119 mm, the median distance from the nearest bowel wall to the arterial tie was 100 mm and the median area of mesocolon was on average 17,957 mm2 [17]. However, we have demonstrated an improvement when compared to conventional low tie surgery from Leeds, where CME was not used. They reported that only 40 % of their specimens were resected in the mesocolic plane, the distance from the tumour to the arterial was 89 mm, the distance from the nearest bowel wall to the arterial tie was 79 mm, and the area of mesocolon was 11,024 mm2 [11]. The optimal distance between the bowel wall and the arterial tie is not yet defined, but the results from Erlangen are considered to represent the current “gold standard”. In the present study, the distance between the tumour and the arterial tie and the area of the mesocolon significantly decreased in 2011. We have no clear explanation for this finding, and no new surgeons were appointed to the department that year. A novel aspect of our study is the identification of potential influencing factors on the morphometric measurements. An increase in patient BMI resulted in a larger area of mesocolon and a longer distance between the bowel wall and the arterial tie. This relationship is similar to that described in a previous study [17], and suggests that more tissue will be present in specimens from countries with a large proportion of obese
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patients. This questions whether morphometric measurements on the resected specimen are actually the best marker of surgical quality and suggests that focusing on the amount of tissue left behind in the patient may be preferable [28]. Age also had an influence on the quality of the specimen produced. Older patients had a higher risk of a suboptimal resection when compared to younger patients, and showed a tendency towards smaller morphometric measurements. This could be explained by a reduction in the amount of connective tissue in the body with age.
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A significantly lower proportion of specimens from the left side of the colon were found to be in the mesocolic plane. This may represent the position of the left colon, where the bowel is positioned more centrally and closer to the ureter making it more difficult to reach the mesocolic plane during surgery. To our knowledge, no other study has reported left sided specimens to show a lower mesocolic plane resection rate [11,17,26,27].
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A major strength of our study is the fact that the data and specimens were collected prospectively from a single centre. The pathological evaluation of the plane of surgery was undertaken by one specialist gastrointestinal pathologist over a short period of time and all pathological evaluation was performed blinded to surgical approach. The limitations include the fact that as a single centre, only a small number of specimens were available in each group. Whilst multivariate regression analysis was undertaken to account for other potentially influencing factors, we do not have the strength of a randomised trial. A large number of surgeons performed the open cases whereas only four surgeons performed the laparoscopic-assisted ones. These four surgeons performed a larger proportion of the operations overall due to the increasing volume of laparoscopic surgery over the duration of the study. It is possible that the differences in morphometric measurements may reflect a learning curve for these surgeons instead of actual differences between the surgical approaches [29]. Unfortunately there are too few specimens to include the individual surgeon as a variable in the analysis.
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Conclusions We have shown that the introduction of CME in a large university hospital results in a high proportion of cases resected in the mesocolic tissue plane. The introduction of laparoscopic-assisted surgery increased the amount of central tissue resected and demonstrates that laparoscopic CME is feasible. Finally, multidisciplinary education and continual pathological feedback regarding the quality of surgery is essential to first optimize and then maintain a high surgical standard.
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Conflict of interest: No author of this manuscript has any financial and personal relationships with other people or organisations that could inappropriately influence their work.
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Acknowledgments:
Professor MD. Werner Hohenberger, Surgical Clinic, Erlangen University Hospital, Germany
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Professor MD Michael Parker, Consultant Laparoscopic, General and Colorectal Surgeon, Darent Valley Hospital, United Kingdom Professor Michael Væth, Department of Biostatistics, Aarhus University, Denmark
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The Danish Colorectal Cancer Group
References
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ACCEPTED MANUSCRIPT Table 1: Patient clinicopathological characteristics For all cases Patient characteristics, open vs. laparoscopic surgery (n = 162) (n = 209) No.
Open surgery (n = 79) No. %
Laparoscopic surgery (n =83) No. % P value
72.9 42 - 91
69.1 35 - 87
116 93
41 38
44 56
53 30
56 44
49 55 56 49
29 25 15 10
78 57 35 26
8 19 28 28
22 43 65 74
25 16 - 42
25 16 - 42
71 47 91
41 0 38
121 88
44 35
27 1 - 75
28 4 - 71
5 1 - 35
5 1 - 28
58 0 42
30 0 53
47 51
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> 0.0001
0.039
42 0 58
50 33
53 49
0.043
0.56
25 1 - 75
0.32
5 1 - 30
0.59
Tumours in the transverse colon or flexures were excluded
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26 16 - 40
0.012
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71.3 35 - 91
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Characteristic Age, years Mean Range Gender Male Female Year of surgery 2008 2009 2010 2011 Body mass index (Kg/m2) Mean Range Site of tumor Right Transverse/flexures Left UICC stage of disease Stage I + II Stage III + IV Total lymph node count Mean Range Number of involved nodes Mean Range
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Table 2 Logistic regression for specimens in the mesocolic plane, all data (n=209)
a
Nb (%)
P . 0.99
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Odds ratio 95% CI Operative technique Open surgery 79 (64) 1.00 . Laparoscopic surgey 49 (58) 0.996 (0.49 - 2.02) BMI Baseline . 1.00 . One increase in points 0.98 (0.91 - 1.05) Gender Male 64 (55) 1.00 . Female 64 (69) 1.45 (0.77 - 2.7) Age (years) Baseline . 1.00 . One increase in years 0.98 (0.94 - 1.00) Year of surgery 2008 33 (67) 0.66 (0.25 - 1.74) 2009 29 (53) 0.38 (0.15 - 0.93) 2010 29 (52) 0.34 (0.14 - 0.82) 2011 37 (76) 1.00 . UICC stage of disease I - II 75 (62) 1.00 . III IV 53 (60) 0.7 (0.71 - 1.14 Tumour site Right colon 48 (68) 1.00 . Transverse/flexures 34 (72) 1.16 (0.48 - 2.8) Left colon 46 (51) 0.43 (0.22 - 0.87) a) Variables taken into account: gender, age, BMI, year of surgery, UICC stage of disease, and tumour site b) Number of specimens in the mesocolic plane
. 0.50 . 0.25 . 0.03 0.4 0.03 0.02 . . 0.38 . 0.73 0.02
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Basic numbers Crude analysis
49 55 56 49
99 (87 - 110) 100 (90 - 110) 100 (91 - 109) 87 (78 - 96)
49 55 56 49
82 (73 - 91) 83 (74 - 93) 85 (77 - 93) 76 (68 - 84)
P-value
0.23
0 27 (16 - 38)
< 0.0001
0 26 (16 - 36)
S0748-7983(14)00401-6
DOI:
10.1016/j.ejso.2014.04.004
Reference:
YEJSO 3817
To appear in:
European Journal of Surgical Oncology
Received Date: 22 January 2014 Revised Date:
21 March 2014
Accepted Date: 8 April 2014
Please cite this article as: Munkedal DLE, West NP, Iversen LH, Hagemann-Madsen R, Quirke P, Laurberg S, Implementation of complete mesocolic excision at a university hospital in Denmark: An audit of consecutive, prospectively collected colon cancer specimens, European Journal of Surgical Oncology (2014), doi: 10.1016/j.ejso.2014.04.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title:
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Implementation of complete mesocolic excision at a university hospital in Denmark: An audit of consecutive, prospectively collected colon cancer specimens
Authors: [email protected]
Nicholas P. West b
[email protected]
Lene H. Iversen a
[email protected]
Rikke Hagemann-Madsen
Rikke.Hjarno.Hagemann-
Ph.D
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c
MD
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Ditte Louise E. Munkedal a
DMSci, Ph.D. MD
[email protected] Philip Quirke b
[email protected]
Professor, PhD
Søren Laurberg a
[email protected]
Professor, DMSci
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Affiliations:
a) Department of Surgery P, Aarhus University Hospital, 8000 Aarhus C, Denmark b) Pathology, Anatomy & Tumour Biology, Leeds Institute of Cancer and Pathology,
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University of Leeds, St. James's University Hospital, Leeds, LS9 7TF, UK c) Pathology Department, Aarhus University Hospital, 8000 Aarhus C, Denmark
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Corresponding author MD Ditte Louise E. Munkedal, PhD-student Department of Surgery P Aarhus University Hospital Tage-Hansens Gade 2 8000 Aarhus C Denmark E-mail: [email protected] Tel: +45 22 52 13 33
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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.
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Method: 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.
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Results: 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.
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Conclusion: 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.
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What does this paper add to the literature? (max. 50 words) This study demonstrated that a laparoscopic approach resulted in more tissue resected between the tumour and the arterial tie in CME-surgery. It emphasises the importance of continuous feedback to surgeons in order to maintain high surgical quality, and it indicates other factors that may influence the indicators of surgical quality.
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Key words Colon cancer; complete mesocolic excision; pathological evaluation; laparoscopic approach; post-operative team meetings
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Introduction Colon cancer has a high incidence and is one of the most frequent cancers in the Western world. In Denmark, with a population of 5.5 million people, there are 2,700 new cases per year resulting in 1,375 deaths. In the 1980’s, patients with colon cancer had a better prognosis when compared to those with rectal cancer [1], however, today the opposite is true [2,3]. This is thought to be mainly due to the introduction of total mesorectal excision (TME) which has optimized and standardised rectal cancer surgery [4,5]. However, the introduction of magnetic resonance imaging, pre-operative treatment [6,7], improved histopathology techniques and the integration of care through multidisciplinary teams have undoubtedly contributed to the improved outcomes in rectal cancer.
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During the same period, colon cancer surgery has focused on the introduction of laparoscopic-assisted techniques, the number of lymph nodes harvested [8,9], and staging of the disease. The success of TME inspired the enhancement of colon cancer surgery, and the importance of meticulous dissection has been clarified through the recent description of complete mesocolic excision (CME) [10]. The concept of CME is to create an intact specimen encompassing the primary tumour along with all of the potential routes for tumour spread [11] through central ligation of the artery at its origin [12]. Early studies have suggested that the procedure reduces tumour recurrence and improves survival [13]. A pathological evaluation of the quality of the specimen can be applied to CME surgery in a similar way as for TME, and it seems to provide valuable feedback to surgical teams [14].
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Aarhus University Hospital (AUH) in Denmark implemented CME surgery as standard practice for all elective curative colon cancer resections at the beginning of 2008 following a post-graduate development course (PgDC). During the same period, laparoscopicassisted surgery increased to become a standard of care. After 2010, post-operative team meetings were held for all patients following colon cancer resection, where pathologists demonstrated the surgical plane of resection on specimen photographs to the surgical team.
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The aim of the present study was to evaluate the pathological quality of colon cancer surgery at AUH between 2008 and 2011 and to determine the effect of the implementation of CME and laparoscopic-assisted surgery. Secondly, we aimed to evaluate the impact of the introduction of post-operative team meetings on the quality of surgery.
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Material and methods
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Specimens A consecutive series of specimens from patients with primary colon cancer resected at AUH were collected prospectively between January 1st 2008 and December 31st 2011. High resolution digital photographs were taken of all specimens following resection. Information on patient characteristics and surgery were obtained from the Danish Colorectal Cancer Group (DCCG) database [15] and medical charts. Exclusion criteria included patients with disseminated disease at the time of presentation, emergency surgery, palliative surgery, and specimens with photos not suitable for tissue morphometry. National screening for colorectal cancer had not been implemented in Denmark during the study period and therefore all patients presented with symptomatic disease. In 2011, AUH performed 220 resections for colorectal cancer. Fourteen consultant surgeons either performed or supervised all 162 operations. Of these only four were trained in the laparoscopic approach and did both types of surgery. Evaluation of specimens All specimens were evaluated blinded to surgeon and surgical approach. The pathology department used the DCCG guidelines for the histopathological dissection processing and reporting of colon cancer specimens [16].
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Grading of the specimens: All specimens were graded according to the plane of surgery using a previously published technique [13]. Briefly, all specimens were classified into one of three groups based on the integrity of the mesocolon. 1. The mesocolic plane. The specimen has an intact mesocolon with a smooth peritoneal-lined surface with no defects deeper than 5 mm. 2. The intramesocolic plane. The specimen has a moderate amount of mesocolon but with some irregularity. Any defects are deeper than 5 mm but do not reach the muscularis propria. 3. The muscularis propria plane. The specimen has only a small amount of mesocolon and any disruptions expose the muscularis propria. The grading was performed independently and retrospectively by one specialist gastrointestinal pathologist (RHM) following specialist training (by PQ) using photographs of both the fresh and formalin-fixed specimens in March 2013. Tissue morphometry: All tissue morphometry was performed on fresh specimen photographs only by the one author (DLEM) following training (by NW and PQ) in Leeds [11,17]. Aperio ImageScope version 11 (Aperio Technologies, California, USA) was used to determine the area of the mesocolon, the length of the large bowel, the distance from the arterial tie to the tumour and the distance from the arterial tie to the nearest bowel wall (Fig. 1). Tissue morphometry was only performed if optimum photographs were available
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defined as having the whole specimen visible with the image being taken directly from above to prevent measurement distortion.
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Implementation and education In 2007 and 2008, multidisciplinary PgDC’s were held for all specialists involved in colorectal cancer treatment in our region. Surgeons, histopathologists, oncologists and radiologists from the middle and northern part of Jutland (population 1.9 million) participated. The concept of CME surgery was first introduced in December 2007 by surgeon Professor Werner Hohenberger and histopathologist Professor Phil Quirke. The course was followed by an on-site-visit in February 2008. Professor Hohenberger came to AUH to supervise the surgeons in the operative technique and Professor Quirke introduced the pathologists the evaluation of the specimens.
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Laparoscopic-assisted colon cancer surgery was implemented after the PgDC in 2008 and an on-site-visit from Professor Mike Parker, an internationally renowned laparoscopic colorectal cancer surgical specialist. Laparoscopic-assisted surgery was introduced as the standard of care initially for left sided colon cancers and later for right sided cancers. Cancers located in the transverse colon and flexures were not treated laparoscopically, and were therefore excluded in the comparison between open and laparoscopic surgery. Patients were allocated to undergo surgery on the first available day in theatre. If a laparoscopic surgeon was available on the day, the patient was considered for laparoscopic-assisted surgery. All operations were either performed or supervised by a consultant colorectal surgeon.
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After 2010, formal post-operative multidisciplinary team meetings were held every other week where pathologists would provide feedback regarding the plane of surgery through the demonstration of specimen photographs. Each surgeon received individual feedback on their own surgery.
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Statistical analyses Statistical analyses were performed using Stata IC 12 with the chi-squared, student t-test, ANOVA and rank sum test as appropriate for univariate analysis. Multivariate regression and logistic regression were used to control for potentially influencing variables including gender, age, body mass index (BMI), year of surgery, Union for International Cancer Control (UICC) stage of disease, tumour site, and surgical approach. It was necessary to transform the variables “area of mesocolon” and “length of large bowel” in order to obtain correct statistical analyses. “Area of mesocolon” was transformed by the square root to fit into multiple regression analyses, therefore it was not possible to determine the exact 95% confidence interval for the difference between outcomes in Table 3. An estimated interval was therefore calculated. P values less than 0.05 were considered statistically significant.
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Ethical approval The study represented an audit project and therefore individual patient consent was not needed according to Danish laws. The Danish Data Protection Agency approved the study (reference number = J.nr. 2012-41-0374).
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Results
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Patients In total, 356 specimens were identified during the initial search. After exclusions, (Fig 2) 209 specimens were entered into the study including 47 transverse colon cancers that were not used during analyses of surgical approach. Patient clinicopathological characteristics are shown in Table 1.
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Laparoscopic-assisted versus open approach Eighty-three patients underwent laparoscopic-assisted surgery for either right or left sided cancers (Table 1). Patients in the laparoscopic-assisted group were younger and had a greater BMI when compared to patients in the open surgery group. There was a significant increase in the proportion of laparoscopic-assisted resections between 2008 and 2011, and a greater proportion of left sided tumours were resected laparoscopically.
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Plane of surgery Univariate analysis: Overall, an intact mesocolic plane was achieved in 128 specimens (61 %), the intramesocolic plane in 75 (36 %) and in only six specimens (3 %) the surgeon reached the muscularis propria plane. The rate of mesocolic plane surgery was significantly higher in the years 2008 (67 %) and 2011 (76 %) when compared to 2009 (53 %) and 2010 (52 %). The rate of mesocolic plane surgery was slightly lower for left sided tumours (51 %, p = 0.075) when compared to right sided (68 %), and transverse colon and flexure tumours (72 %), however, the difference was not statistically significant. There was no difference in the rate of mesocolic plane surgery according to patient age, gender, BMI, UICC stage of disease, or surgical approach.
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Logistic regression: After an adjustment for potential influencing factors we determined that the proportion of mesocolic plane excisions had improved significantly in 2011 when compared to 2010, and that left sided specimens had a significantly lower mesocolic plane rate than specimens from the right side or transverse colon and flexures. Furthermore, an increase in patient age appeared to reduce the odds of an excision in the mesocolic plane (Table 2).
Tissue morphometry Univariate analysis: In all cases, the mean distance from the arterial tie to the tumour was 97 mm, 95% confidence interval (95% CI)(92 – 102 mm) and the mean distance from the arterial tie to the nearest bowel wall was 82 mm, 95% CI(76 – 86 mm). The mean area of resected mesocolon was 12,689 mm2, 95% CI (11,784 – 13,628 mm2) and the mean length of large bowel resected was 290 mm, 95% CI (276 – 304 mm).
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Multivariate regression: Specimens in the laparoscopic-assisted group had a longer distance between the tumour or nearest bowel wall and the arterial tie with more than 25 mm of additional tissue when compared to specimens in the open group. Surgical approach did not appear to influence the area of mesocolon or length of large bowel resected (Table 3a). BMI showed a positive correlation with the distance from the nearest bowel wall to the arterial tie (coefficient: 1.3 mm/BMI, p = 0.005) and the area of mesocolon (coefficient: 327 mm2/BMI, p < 0.0001). When assessed by the year of surgery, the amount of tissue resected appeared to reduce over the duration of the study (Table 3b). There were no differences in any morphometric measurements between left and right sided specimens.
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Discussion
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In this study, we have evaluated the implementation of CME and laparoscopic-assisted surgery for colon cancer at a single university hospital in Denmark over a four year period. We have demonstrated that the laparoscopic-assisted approach was associated with the removal of more tissue between the tumour and the arterial tie when compared to the open approach. We have also shown that the majority of specimens were resected in the mesocolic plane, and that there was no difference in the plane of surgery between the open and laparoscopic groups. Interestingly we found that the quality of the specimens improved following a PgDC held in 2008, however, in the years following this the proportion of specimens resected in the mesocolic plane fell. This reduction was reversed following a refocussing on the importance of surgical planes in 2010 through the introduction of post-operative multidisciplinary team meetings. This highlights the importance of regular feedback from pathologists to surgical teams in order to ensure consistent high quality dissection.
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Colon cancer has a high incidence in the western world and with the reversal in outcomes for rectal and colon cancer, a renewed focus is now required for this disease. Some authors have advocated the widespread introduction of CME, the principles of which are based upon those of TME surgery, the international introduction of which has led to marked improvements in rectal cancer outcomes [6,18]. There are three seperate components of optimum CME surgery: 1) the surgeon must remain within the mesocolic plane, 2) the surgeon must perform central ligation of the tumour-feeding artery and 3) the surgeon must remove an appropriate length of large bowel on either side of the tumour. Whereas the mesocolic plane is generally accepted as the gold standard [6,10], the height of the vessel ligation is still actively debated. Some studies have demonstrated a benefit with central ligation [19,20], however, others have shown no difference between high and low ligation [21,22]. Patient morbidity is also a concern with one study identifying a greater risk of genitourinary dysfunction following high tie [23]. Colon cancers are well recognised to metastasise to lymph nodes located along the tumour-feeding artery [12,24]. Removal of these high tie nodes is likely to be more important than the actual number of lymph nodes removed as substantial longitudinal spread is uncommon. The length of large bowel resected is also controversial, and the Japanese have proposed alternative principles for the amount of normal colon resected [17]. Rigorous scientific evaluation of CME and the importance of central ligation of the vessels, as has been undertaken in the present study, is therefore urgently required [25]. In the current study, we aimed to describe the effect of the implementation of two new surgical techniques at a university hospital in Denmark. CME and laparoscopic-assisted colon cancer surgery were implemented in 2008 after a PgDC for multi-disciplinary teams. We found that laparoscopic-assisted surgery was associated with a greater amount of tissue resected between the tumour and the arterial tie with more than 25 mm of additional mesentery resected. The development of the surgical technique and the fact that
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laparoscopic-assisted surgery had increased significantly during the period were taken into account in a multivariate regression analysis. Other studies in the literature have reported both a shorter distance [26] and opposite longer distance [17,27] with laparoscopic surgery. Theoretically, if the artery is ligated at the origin there should be no difference between open and laparoscopic surgery, however, it is possible that laparoscopic dissection may facilitate a more central arterial tie. Despite the increase in the amout of central tissue resected, the laparoscopic approach was not associated with a greater area of mesocolon or a length of the large bowel. These results confirm that a laparoscopicassisted approach can be used effectively to undertake the CME technique.
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We found a clear increase in the proportion of specimens resected in the mesocolic plane in 2011 when compared to 2010. This most likely corresponds with the introduction of post-operative multidisciplinary team meetings, although we are not able to definitely prove this. It was interesting that when CME was first implemented in 2008, the percentage of specimens resected in the mesocolic plane was high. The number fell in 2009 and 2010 prior to the later improvement, which could also reflect the learning curve associated with the introduction of laparoscopic surgery before a refocussing of surgical planes in the postoperative multidisciplinary meetings. We feel that individual feedback and demonstration of specimen defects may have increased awareness of the importance of staying in embryological tissue planes during surgery. This emphasizes the importance of surgical education and continuous feedback as has been demonstrated in other studies [18,27].
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The morphometric measurements and mesocolic plane rate reported in the current study are not as good as the results reported in Erlangen, where 88 % of the specimens were resected in the mesocolic plane, the median distance from the tumour to the arterial was 119 mm, the median distance from the nearest bowel wall to the arterial tie was 100 mm and the median area of mesocolon was on average 17,957 mm2 [17]. However, we have demonstrated an improvement when compared to conventional low tie surgery from Leeds, where CME was not used. They reported that only 40 % of their specimens were resected in the mesocolic plane, the distance from the tumour to the arterial was 89 mm, the distance from the nearest bowel wall to the arterial tie was 79 mm, and the area of mesocolon was 11,024 mm2 [11]. The optimal distance between the bowel wall and the arterial tie is not yet defined, but the results from Erlangen are considered to represent the current “gold standard”. In the present study, the distance between the tumour and the arterial tie and the area of the mesocolon significantly decreased in 2011. We have no clear explanation for this finding, and no new surgeons were appointed to the department that year. A novel aspect of our study is the identification of potential influencing factors on the morphometric measurements. An increase in patient BMI resulted in a larger area of mesocolon and a longer distance between the bowel wall and the arterial tie. This relationship is similar to that described in a previous study [17], and suggests that more tissue will be present in specimens from countries with a large proportion of obese
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patients. This questions whether morphometric measurements on the resected specimen are actually the best marker of surgical quality and suggests that focusing on the amount of tissue left behind in the patient may be preferable [28]. Age also had an influence on the quality of the specimen produced. Older patients had a higher risk of a suboptimal resection when compared to younger patients, and showed a tendency towards smaller morphometric measurements. This could be explained by a reduction in the amount of connective tissue in the body with age.
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A significantly lower proportion of specimens from the left side of the colon were found to be in the mesocolic plane. This may represent the position of the left colon, where the bowel is positioned more centrally and closer to the ureter making it more difficult to reach the mesocolic plane during surgery. To our knowledge, no other study has reported left sided specimens to show a lower mesocolic plane resection rate [11,17,26,27].
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A major strength of our study is the fact that the data and specimens were collected prospectively from a single centre. The pathological evaluation of the plane of surgery was undertaken by one specialist gastrointestinal pathologist over a short period of time and all pathological evaluation was performed blinded to surgical approach. The limitations include the fact that as a single centre, only a small number of specimens were available in each group. Whilst multivariate regression analysis was undertaken to account for other potentially influencing factors, we do not have the strength of a randomised trial. A large number of surgeons performed the open cases whereas only four surgeons performed the laparoscopic-assisted ones. These four surgeons performed a larger proportion of the operations overall due to the increasing volume of laparoscopic surgery over the duration of the study. It is possible that the differences in morphometric measurements may reflect a learning curve for these surgeons instead of actual differences between the surgical approaches [29]. Unfortunately there are too few specimens to include the individual surgeon as a variable in the analysis.
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Conclusions We have shown that the introduction of CME in a large university hospital results in a high proportion of cases resected in the mesocolic tissue plane. The introduction of laparoscopic-assisted surgery increased the amount of central tissue resected and demonstrates that laparoscopic CME is feasible. Finally, multidisciplinary education and continual pathological feedback regarding the quality of surgery is essential to first optimize and then maintain a high surgical standard.
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Conflict of interest: No author of this manuscript has any financial and personal relationships with other people or organisations that could inappropriately influence their work.
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Acknowledgments:
Professor MD. Werner Hohenberger, Surgical Clinic, Erlangen University Hospital, Germany
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Professor MD Michael Parker, Consultant Laparoscopic, General and Colorectal Surgeon, Darent Valley Hospital, United Kingdom Professor Michael Væth, Department of Biostatistics, Aarhus University, Denmark
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The Danish Colorectal Cancer Group
References
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[26] N Gouvas, G Pechlivanides, N Zervakis, M Kafousi, E Xynos. Complete Mesocolic Excision In Colon Cancer Surgery: A Comparison Between Open And Laparoscopic Approach Distal RightSided Colon Cancer Remains A Challenge For Laparoscopy, Colorectal Dis. (2012).
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ACCEPTED MANUSCRIPT Table 1: Patient clinicopathological characteristics For all cases Patient characteristics, open vs. laparoscopic surgery (n = 162) (n = 209) No.
Open surgery (n = 79) No. %
Laparoscopic surgery (n =83) No. % P value
72.9 42 - 91
69.1 35 - 87
116 93
41 38
44 56
53 30
56 44
49 55 56 49
29 25 15 10
78 57 35 26
8 19 28 28
22 43 65 74
25 16 - 42
25 16 - 42
71 47 91
41 0 38
121 88
44 35
27 1 - 75
28 4 - 71
5 1 - 35
5 1 - 28
58 0 42
30 0 53
47 51
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> 0.0001
0.039
42 0 58
50 33
53 49
0.043
0.56
25 1 - 75
0.32
5 1 - 30
0.59
Tumours in the transverse colon or flexures were excluded
AC C
0.123
SC
26 16 - 40
0.012
RI PT
71.3 35 - 91
M AN U
Characteristic Age, years Mean Range Gender Male Female Year of surgery 2008 2009 2010 2011 Body mass index (Kg/m2) Mean Range Site of tumor Right Transverse/flexures Left UICC stage of disease Stage I + II Stage III + IV Total lymph node count Mean Range Number of involved nodes Mean Range
ACCEPTED MANUSCRIPT
Table 2 Logistic regression for specimens in the mesocolic plane, all data (n=209)
a
Nb (%)
P . 0.99
AC C
EP
TE D
M AN U
SC
RI PT
Odds ratio 95% CI Operative technique Open surgery 79 (64) 1.00 . Laparoscopic surgey 49 (58) 0.996 (0.49 - 2.02) BMI Baseline . 1.00 . One increase in points 0.98 (0.91 - 1.05) Gender Male 64 (55) 1.00 . Female 64 (69) 1.45 (0.77 - 2.7) Age (years) Baseline . 1.00 . One increase in years 0.98 (0.94 - 1.00) Year of surgery 2008 33 (67) 0.66 (0.25 - 1.74) 2009 29 (53) 0.38 (0.15 - 0.93) 2010 29 (52) 0.34 (0.14 - 0.82) 2011 37 (76) 1.00 . UICC stage of disease I - II 75 (62) 1.00 . III IV 53 (60) 0.7 (0.71 - 1.14 Tumour site Right colon 48 (68) 1.00 . Transverse/flexures 34 (72) 1.16 (0.48 - 2.8) Left colon 46 (51) 0.43 (0.22 - 0.87) a) Variables taken into account: gender, age, BMI, year of surgery, UICC stage of disease, and tumour site b) Number of specimens in the mesocolic plane
. 0.50 . 0.25 . 0.03 0.4 0.03 0.02 . . 0.38 . 0.73 0.02
ACCEPTED MANUSCRIPT
Basic numbers Crude analysis
49 55 56 49
99 (87 - 110) 100 (90 - 110) 100 (91 - 109) 87 (78 - 96)
49 55 56 49
82 (73 - 91) 83 (74 - 93) 85 (77 - 93) 76 (68 - 84)
P-value
0.23
0 27 (16 - 38)
< 0.0001
0 26 (16 - 36)
