Accepted Manuscript Long Term Prognostic Value of Mesorectal Grading after Neoadjuvant Chemoradiotherapy for Rectal Cancer Khaled M. Madbouly, MD., Ph.D.,FACS, FASCRS, MRCS(Glasg) Ahmed M. Hussein, MCh, Ch Eman Abdel Zaher, MD, PhD PII:
S0002-9610(14)00029-4
DOI:
10.1016/j.amjsurg.2013.10.023
Reference:
AJS 11070
To appear in:
The American Journal of Surgery
Received Date: 22 August 2013 Revised Date:
22 September 2013
Accepted Date: 3 October 2013
Please cite this article as: Madbouly KM, Hussein AM, Zaher EA, Long Term Prognostic Value of Mesorectal Grading after Neoadjuvant Chemoradiotherapy for Rectal Cancer, The American Journal of Surgery (2014), doi: 10.1016/j.amjsurg.2013.10.023. 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.
ACCEPTED MANUSCRIPT
Long Term Prognostic Value of Mesorectal Grading after Neoadjuvant Chemoradiotherapy for Rectal Cancer
RI PT
Running head: TME grade & long-term oncologic outcome
Khaled M. Madbouly, MD., Ph.D.,FACS, FASCRS, MRCS(Glasg)1 Ahmed M. Hussein, MCh, Dr.Ch1
SC
Eman Abdel Zaher, MD, PhD2
Department of Surgery, University of Alexandria, Egypt
2
Department of Pathology, University of Alexandria, Egypt
Contributions:
M AN U
1
Khaled Madbouly: conception and design, acquisition of data, analysis and interpretation of data; drafting the article
TE D
Ahmed Hussein: revision of the article Eman Abdel Zaher: Pathologic study
Correspondence to:
EP
Khaled Madbouly, MD, Ph.D., FASCRS, FACS, MRCS (Glasg)
AC C
Department of Surgery- University of Alexandria El Raml Station, Alexandria, Egypt +201002033676 [email protected]
No financial support was received for this study. Manuscript count: 2986
Abstract count: 309
ACCEPTED MANUSCRIPT
Abstract Background: Mesorectal grading was reported to be a valuable prognostic factor in rectal
RI PT
cancer surgery. Previous studies were retrospective, had short follow up. Objective: to assess the long-term influence of total mesorectal excision quality on disease recurrence in mid and low rectal cancer patients who received preoperative neoadjuvant chemoradiotherapy and postoperative chemotherapy.
SC
Methods:
121 patients with rectal cancer had either low anterior (LAR) or abdominoperineal
M AN U
resections (APR). All patients received neoadjuvant chemoradiotherapy and postoperative chemotherapy. Main outcome measures included TNM staging, circumferential resection margin involvement (ICRM), mesorectal grading, local and systemic recurrences were recorded. Results:
TE D
Follow up was done for at least 5 years or up to disease recurrence whatever comes first. Mean follow up time was 59.4 months. Twenty nine patients had APR and 92 had LAR. 7.5% had positive CRM which was significantly correlated to mesorectal grading. Grade 3 mesorectal
EP
specimens were obtained in approximately 60% of patients versus 27% had grade 2 and only 13% had grade 1 (poor) mesorectal specimens. Poorer mesorectal grading increased with APR
AC C
and lower rectal tumors. Recurrences occurred in 20% of patients (40% in the first 2 years, 32% in the third year and 28% in 4th and 5th years), factors affecting recurrence included lymphovascular invasion, ICRM and N stage. Mesorectal grading was not a valuable prognostic factor for recurrence unless it resulted in ICRM. Recurrences occurred earlier with poorer mesorectal grade yet this was not statistically significant.
ACCEPTED MANUSCRIPT
Conclusion: Mesorectal grading is a pathologic description that reflects the quality of surgery. However, in patients received neoadjuvant chemoradiotherapy and postoperative chemotherapy, grading had
AC C
EP
TE D
M AN U
SC
RI PT
no long-term prognostic value regarding recurrences unless it resulted in ICRM.
ACCEPTED MANUSCRIPT
Abstract Background: Mesorectal grading was reported to be a valuable prognostic factor in rectal
RI PT
cancer surgery. Previous studies were retrospective, had short follow up. Objective: to assess the long-term influence of total mesorectal excision quality on disease recurrence in mid and low rectal cancer patients who received preoperative neoadjuvant chemoradiotherapy and postoperative chemotherapy.
SC
Methods:
One hundred and twenty one patients with rectal cancer had either low anterior (LAR) or
M AN U
abdominoperineal resections (APR). All patients received neoadjuvant chemoradiotherapy and postoperative chemotherapy. Main outcome measures included TNM staging, circumferential resection margin involvement (ICRM), mesorectal grading, local and systemic recurrences were recorded.
TE D
Results:
Follow up was done for at least 5 years or up to disease recurrence whatever comes first. Mean follow up time was 59.4 months. Twenty nine patients had APR and 92 had LAR. 7.5%
EP
had positive CRM which was significantly correlated to mesorectal grading. Grade 3 mesorectal specimens were obtained in approximately 60% of patients versus 27% had grade 2 and only
AC C
13% had grade 1 (poor) mesorectal specimens. Poorer mesorectal grading increased with APR and lower rectal tumors. Recurrences occurred in 20% of patients (40% in the first 2 years, 32% in the third year and 28% in 4th and 5th years), factors affecting recurrence included lymphovascular invasion, ICRM and N stage. Mesorectal grading was not a valuable prognostic factor for recurrence unless it resulted in ICRM. Recurrences occurred earlier with poorer mesorectal grade yet this was not statistically significant.
ACCEPTED MANUSCRIPT
Limitation: The number in each group couldn’t be determined upfront, so detectable differences between patients of various grades depended on the event rate in the whole group, relative sizes of the groups and the specific statistical test used.
RI PT
Conclusion:
Mesorectal grading is a pathologic description that reflects the quality of surgery. However, in patients received neoadjuvant chemoradiotherapy and postoperative chemotherapy,
Key words: TME Mesorectal grade Rectal cancer
AC C
EP
TE D
Circumferential resection margin
M AN U
SC
grading had no long-term prognostic value regarding recurrences unless it resulted in ICRM.
ACCEPTED MANUSCRIPT
Background Tumors in the middle and lower thirds of rectum have always been a challenge in their
RI PT
management in terms of a higher local recurrence rate compared to upper rectal cancers.[1] Radical resection with total mesorectal excision (TME) has become the gold standard of treatment of these tumors. TME was introduced to avoid the unacceptably high local recurrence rates (30–40%) associated with the conventional techniques. [2] Differences in outcomes after
SC
TME have been observed in different trials.[3-5] Local recurrence is attributed to both surgery related (technical) and tumor-related (biologic) factors. The stage of the tumor at presentation
M AN U
and pathologic type are the most important tumor-related factor influencing recurrence. While technical factors are directly related to the quality of surgery.[6] Currently, there are two important parameters that can assess the surgical quality: First one is the involvement of the circumferential resection margin (ICRM) which prognostic importance was proved in many
TE D
publications.[7-10] The second is the adequacy of excision of the mesorectal envelope consisting of all the lymphatics, lymph node, and neural tissue around the rectum; the concept that was proposed by Nagtegaal et al [11]as mesorectal grading. Analyses investigating the relationship
different results. [12]
EP
between oncological outcomes, mesorectal grading and/or CRM status have, however, yielded
AC C
The use of neoadjuvant chemoradiotherapy (CRT) is now a part of the standard treatment of locally advanced middle and low rectal tumors. It has been proved that it is more effective than postoperative chemotherapy in preventing tumor recurrence. [13] Previous studies regarding prognostic value of mesorectal grading were done either on patients operated upon before the era of neodjuvant CRT, used preoperative short course radiotherapy or had mixed
ACCEPTED MANUSCRIPT
population of different types of adjuvant treatment.[11, 12, 14] Moreover, all of them were retrospective with short follow up. Up till now, there is no publication that assesses the prognostic value of mesorectal
RI PT
grading in patients who had neoadjuvant CRT and postoperative chemotherapy.
The aim of the current study was to answer these key questions: Is the prospective mesorectal grading an independent prognostic factor for local or systemic recurrence? Does
SC
preoperative neoadjuvant CRT with postoperative chemotherapy compensate a poor mesorectal
AC C
EP
TE D
M AN U
quality?
ACCEPTED MANUSCRIPT
Specific aims The aim of this study was to assess the long-term influence of quality of total mesorectal
RI PT
excision on disease recurrence in middle and lower third rectal cancer patients who received
AC C
EP
TE D
M AN U
SC
preoperative neoadjuvant chemoradiotherapy and postoperative chemotherapy.
ACCEPTED MANUSCRIPT
Patients and methods The current study prospectively included 121 adult patients with rectal adenocarcinoma
RI PT
(within 12 cm above the anal verge) in the period from January 2005 to May 2008. All patients included had T3 or T4 tumors and received preoperative long course neoadjuvant CRT.
Patients were excluded if they had recurrent cancer, mucoid carcinoma, distant or peritoneal metastasis. The study was performed after approval of Alexandria University Ethical
SC
Committee and informed consent was obtained from each patient before undergoing preoperative CRT.
M AN U
Preoperative evaluation was done by clinical examination, colonoscopy, abdominal CT and pelvic MRI. Patient was not included if the potential circumferential resection margin was involved in pelvic MRI.
Distance of a tumor from anal verge was measured by rigid
proctoscopy. CEA and CA19.9 were measured before any therapy for follow-up. All patients
TE D
received neoadjuvant CRT (45-50.4 Grays pelvic irradiation and chemotherapy using 5-FU and leucovorin). Treatment
EP
Radical surgery with TME was performed 8–10 weeks following the completion of the neoadjuvant therapy with curative intent. Patients were operated upon with either low anterior
AC C
resection (LAR) and proximal diversion or abdominoperineal resection (APR) based upon the distance from the anal verge. All surgeries were done by two experienced surgeons with a volume more than 50/year for each of them. All patients in this study were done by open surgery. Gross examinations by the surgeon and an experienced pathologist were done before formalin fixation and quality of mesorectum was graded according to the Quirke’s mesorectal grading[11] as follows:
ACCEPTED MANUSCRIPT
Grade 3 (good) Intact mesorectum with smooth mesorectal surface. No defect deeper than 5 mm. No
RI PT
coning on the specimen. Smooth circumferential resection margins on slicing. Grade 2 (moderate)
Moderate bulk of the mesorectum but there is irregularity the mesorectal surface.
SC
Moderate coning of the specimen toward the distal margin. At no site is the muscularis propria
circumferential resection margin. Grade 1 (poor)
M AN U
visible with exception of the insertion of the levator muscles. Moderate irregularity of the
Little bulk of the mesorectum with defects down into the muscularis propria and/or very irregular circumferential resection margin.
TE D
All specimens were photographed and the three authors reviewed all the photographs while blinded to the operating surgeon for reconfirmation of the mesorectal grade. Staging was done based upon the seventh edition of the classification of the American Joint Committee on
AC C
Adjuvant therapy
EP
Cancer (AJCC). [15]
Postoperative adjuvant chemotherapy consisted of a bolus of 5-FU (450 mg/m2) and leucovorin (20 mg/m2) administered daily for 5 days every 28 days for 6 cycles. Follow up
Follow up was done by abdominal CT, CEA and CA19.9 every 6 months. Colonoscopy was done annually. Data collected included demographics, tumor pathology, TNM staging,
ACCEPTED MANUSCRIPT
number of LN retrieved, and recurrences. Recurrence was determined by clinical and radiological examinations followed by histological confirmation. Pelvic MRI was done only in
surgery, incidence of recurrence or mortality whatever comes first.
Statistical Analysis
RI PT
cases with suspected local recurrence in the CT scan. End points for follow up were 5 years from
SC
The study was designed to detect a 10 % difference in the recurrence rate between different study groups with 80 per cent power, at a significance level of 0.05. A total sample size
M AN U
of 121 patients was required. Statistical analysis was performed by XLSTAT 2013.1.01 software. Endpoints were local, systemic recurrence, mortality or end of 5 years. Univariate analysis was done using two tailed chi square test or fisher exact test for categorical variables and Mann Whitney test for numerical variables. Multivariate analyses were performed using a Cox proportional hazards regression model. The main objective of the multivariate analysis was to
TE D
assess the independent prognostic value of mesorectal grading.
A multivariate model was
constructed using forward selection with the selected covariates (p ≤ 0.1 at univariate analysis).
EP
To this model, mesorectal grading was added. For each variant, hazard ratio was calculated including 95% confidence intervals (95% CI). Time to local and overall recurrences (cumulative
AC C
risk at certain time) were estimated using the Kaplan Meier method and comparison was done using log rank test. All tests were two tailed and statistical significance was stated as p ≤ 0.05.
ACCEPTED MANUSCRIPT
Results One hundred and twenty one patients were included in the study. Hundred and sixty eight
RI PT
patients were screened for enrollment in the current study. Study exclusions included: 19 patients with distant metastases, 10 patients underwent palliative resections, 11 patients didn’t continue postoperative chemotherapy due to complications, 5 patients refused to have APR, 2 patients refused to be enrolled in the study and one patient died in the immediate postoperative period.
was reported.
SC
All patients were followed up till recurrence or for at least 60 months if no recurrence or death The mean follow up period was 59.4 months. Patient characteristics and
M AN U
treatments received are described in table 1. The mean age of patients was 49.3 years with slight male predominance (M: F ratio= 1.3:1). LAR was done in 92 patients (76%) and an APR in 29 patients (24%).
CRM was negative (FCRM) in 112 patients (92.5%) and positively involved
TE D
circumferential resection margin (ICRM) in 9 patients (7.5%). We defined ICRM as tumor extension (continuous or discontinuous) or presence of positive lymph nodes < 2 mm from the radial, non-peritonealised edge. [11]
EP
Seventy two patients (59.5%) had good (grade 3) mesorectal resections on examination. Of the remaining 49 specimens, 33 (27.3%) were considered moderate (grade 2), and only 16
AC C
(13.2%) were poor (grade 1) specimens. Univariate analysis observed that tumor location within the lower 5 cm of rectum (p
S0002-9610(14)00029-4
DOI:
10.1016/j.amjsurg.2013.10.023
Reference:
AJS 11070
To appear in:
The American Journal of Surgery
Received Date: 22 August 2013 Revised Date:
22 September 2013
Accepted Date: 3 October 2013
Please cite this article as: Madbouly KM, Hussein AM, Zaher EA, Long Term Prognostic Value of Mesorectal Grading after Neoadjuvant Chemoradiotherapy for Rectal Cancer, The American Journal of Surgery (2014), doi: 10.1016/j.amjsurg.2013.10.023. 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.
ACCEPTED MANUSCRIPT
Long Term Prognostic Value of Mesorectal Grading after Neoadjuvant Chemoradiotherapy for Rectal Cancer
RI PT
Running head: TME grade & long-term oncologic outcome
Khaled M. Madbouly, MD., Ph.D.,FACS, FASCRS, MRCS(Glasg)1 Ahmed M. Hussein, MCh, Dr.Ch1
SC
Eman Abdel Zaher, MD, PhD2
Department of Surgery, University of Alexandria, Egypt
2
Department of Pathology, University of Alexandria, Egypt
Contributions:
M AN U
1
Khaled Madbouly: conception and design, acquisition of data, analysis and interpretation of data; drafting the article
TE D
Ahmed Hussein: revision of the article Eman Abdel Zaher: Pathologic study
Correspondence to:
EP
Khaled Madbouly, MD, Ph.D., FASCRS, FACS, MRCS (Glasg)
AC C
Department of Surgery- University of Alexandria El Raml Station, Alexandria, Egypt +201002033676 [email protected]
No financial support was received for this study. Manuscript count: 2986
Abstract count: 309
ACCEPTED MANUSCRIPT
Abstract Background: Mesorectal grading was reported to be a valuable prognostic factor in rectal
RI PT
cancer surgery. Previous studies were retrospective, had short follow up. Objective: to assess the long-term influence of total mesorectal excision quality on disease recurrence in mid and low rectal cancer patients who received preoperative neoadjuvant chemoradiotherapy and postoperative chemotherapy.
SC
Methods:
121 patients with rectal cancer had either low anterior (LAR) or abdominoperineal
M AN U
resections (APR). All patients received neoadjuvant chemoradiotherapy and postoperative chemotherapy. Main outcome measures included TNM staging, circumferential resection margin involvement (ICRM), mesorectal grading, local and systemic recurrences were recorded. Results:
TE D
Follow up was done for at least 5 years or up to disease recurrence whatever comes first. Mean follow up time was 59.4 months. Twenty nine patients had APR and 92 had LAR. 7.5% had positive CRM which was significantly correlated to mesorectal grading. Grade 3 mesorectal
EP
specimens were obtained in approximately 60% of patients versus 27% had grade 2 and only 13% had grade 1 (poor) mesorectal specimens. Poorer mesorectal grading increased with APR
AC C
and lower rectal tumors. Recurrences occurred in 20% of patients (40% in the first 2 years, 32% in the third year and 28% in 4th and 5th years), factors affecting recurrence included lymphovascular invasion, ICRM and N stage. Mesorectal grading was not a valuable prognostic factor for recurrence unless it resulted in ICRM. Recurrences occurred earlier with poorer mesorectal grade yet this was not statistically significant.
ACCEPTED MANUSCRIPT
Conclusion: Mesorectal grading is a pathologic description that reflects the quality of surgery. However, in patients received neoadjuvant chemoradiotherapy and postoperative chemotherapy, grading had
AC C
EP
TE D
M AN U
SC
RI PT
no long-term prognostic value regarding recurrences unless it resulted in ICRM.
ACCEPTED MANUSCRIPT
Abstract Background: Mesorectal grading was reported to be a valuable prognostic factor in rectal
RI PT
cancer surgery. Previous studies were retrospective, had short follow up. Objective: to assess the long-term influence of total mesorectal excision quality on disease recurrence in mid and low rectal cancer patients who received preoperative neoadjuvant chemoradiotherapy and postoperative chemotherapy.
SC
Methods:
One hundred and twenty one patients with rectal cancer had either low anterior (LAR) or
M AN U
abdominoperineal resections (APR). All patients received neoadjuvant chemoradiotherapy and postoperative chemotherapy. Main outcome measures included TNM staging, circumferential resection margin involvement (ICRM), mesorectal grading, local and systemic recurrences were recorded.
TE D
Results:
Follow up was done for at least 5 years or up to disease recurrence whatever comes first. Mean follow up time was 59.4 months. Twenty nine patients had APR and 92 had LAR. 7.5%
EP
had positive CRM which was significantly correlated to mesorectal grading. Grade 3 mesorectal specimens were obtained in approximately 60% of patients versus 27% had grade 2 and only
AC C
13% had grade 1 (poor) mesorectal specimens. Poorer mesorectal grading increased with APR and lower rectal tumors. Recurrences occurred in 20% of patients (40% in the first 2 years, 32% in the third year and 28% in 4th and 5th years), factors affecting recurrence included lymphovascular invasion, ICRM and N stage. Mesorectal grading was not a valuable prognostic factor for recurrence unless it resulted in ICRM. Recurrences occurred earlier with poorer mesorectal grade yet this was not statistically significant.
ACCEPTED MANUSCRIPT
Limitation: The number in each group couldn’t be determined upfront, so detectable differences between patients of various grades depended on the event rate in the whole group, relative sizes of the groups and the specific statistical test used.
RI PT
Conclusion:
Mesorectal grading is a pathologic description that reflects the quality of surgery. However, in patients received neoadjuvant chemoradiotherapy and postoperative chemotherapy,
Key words: TME Mesorectal grade Rectal cancer
AC C
EP
TE D
Circumferential resection margin
M AN U
SC
grading had no long-term prognostic value regarding recurrences unless it resulted in ICRM.
ACCEPTED MANUSCRIPT
Background Tumors in the middle and lower thirds of rectum have always been a challenge in their
RI PT
management in terms of a higher local recurrence rate compared to upper rectal cancers.[1] Radical resection with total mesorectal excision (TME) has become the gold standard of treatment of these tumors. TME was introduced to avoid the unacceptably high local recurrence rates (30–40%) associated with the conventional techniques. [2] Differences in outcomes after
SC
TME have been observed in different trials.[3-5] Local recurrence is attributed to both surgery related (technical) and tumor-related (biologic) factors. The stage of the tumor at presentation
M AN U
and pathologic type are the most important tumor-related factor influencing recurrence. While technical factors are directly related to the quality of surgery.[6] Currently, there are two important parameters that can assess the surgical quality: First one is the involvement of the circumferential resection margin (ICRM) which prognostic importance was proved in many
TE D
publications.[7-10] The second is the adequacy of excision of the mesorectal envelope consisting of all the lymphatics, lymph node, and neural tissue around the rectum; the concept that was proposed by Nagtegaal et al [11]as mesorectal grading. Analyses investigating the relationship
different results. [12]
EP
between oncological outcomes, mesorectal grading and/or CRM status have, however, yielded
AC C
The use of neoadjuvant chemoradiotherapy (CRT) is now a part of the standard treatment of locally advanced middle and low rectal tumors. It has been proved that it is more effective than postoperative chemotherapy in preventing tumor recurrence. [13] Previous studies regarding prognostic value of mesorectal grading were done either on patients operated upon before the era of neodjuvant CRT, used preoperative short course radiotherapy or had mixed
ACCEPTED MANUSCRIPT
population of different types of adjuvant treatment.[11, 12, 14] Moreover, all of them were retrospective with short follow up. Up till now, there is no publication that assesses the prognostic value of mesorectal
RI PT
grading in patients who had neoadjuvant CRT and postoperative chemotherapy.
The aim of the current study was to answer these key questions: Is the prospective mesorectal grading an independent prognostic factor for local or systemic recurrence? Does
SC
preoperative neoadjuvant CRT with postoperative chemotherapy compensate a poor mesorectal
AC C
EP
TE D
M AN U
quality?
ACCEPTED MANUSCRIPT
Specific aims The aim of this study was to assess the long-term influence of quality of total mesorectal
RI PT
excision on disease recurrence in middle and lower third rectal cancer patients who received
AC C
EP
TE D
M AN U
SC
preoperative neoadjuvant chemoradiotherapy and postoperative chemotherapy.
ACCEPTED MANUSCRIPT
Patients and methods The current study prospectively included 121 adult patients with rectal adenocarcinoma
RI PT
(within 12 cm above the anal verge) in the period from January 2005 to May 2008. All patients included had T3 or T4 tumors and received preoperative long course neoadjuvant CRT.
Patients were excluded if they had recurrent cancer, mucoid carcinoma, distant or peritoneal metastasis. The study was performed after approval of Alexandria University Ethical
SC
Committee and informed consent was obtained from each patient before undergoing preoperative CRT.
M AN U
Preoperative evaluation was done by clinical examination, colonoscopy, abdominal CT and pelvic MRI. Patient was not included if the potential circumferential resection margin was involved in pelvic MRI.
Distance of a tumor from anal verge was measured by rigid
proctoscopy. CEA and CA19.9 were measured before any therapy for follow-up. All patients
TE D
received neoadjuvant CRT (45-50.4 Grays pelvic irradiation and chemotherapy using 5-FU and leucovorin). Treatment
EP
Radical surgery with TME was performed 8–10 weeks following the completion of the neoadjuvant therapy with curative intent. Patients were operated upon with either low anterior
AC C
resection (LAR) and proximal diversion or abdominoperineal resection (APR) based upon the distance from the anal verge. All surgeries were done by two experienced surgeons with a volume more than 50/year for each of them. All patients in this study were done by open surgery. Gross examinations by the surgeon and an experienced pathologist were done before formalin fixation and quality of mesorectum was graded according to the Quirke’s mesorectal grading[11] as follows:
ACCEPTED MANUSCRIPT
Grade 3 (good) Intact mesorectum with smooth mesorectal surface. No defect deeper than 5 mm. No
RI PT
coning on the specimen. Smooth circumferential resection margins on slicing. Grade 2 (moderate)
Moderate bulk of the mesorectum but there is irregularity the mesorectal surface.
SC
Moderate coning of the specimen toward the distal margin. At no site is the muscularis propria
circumferential resection margin. Grade 1 (poor)
M AN U
visible with exception of the insertion of the levator muscles. Moderate irregularity of the
Little bulk of the mesorectum with defects down into the muscularis propria and/or very irregular circumferential resection margin.
TE D
All specimens were photographed and the three authors reviewed all the photographs while blinded to the operating surgeon for reconfirmation of the mesorectal grade. Staging was done based upon the seventh edition of the classification of the American Joint Committee on
AC C
Adjuvant therapy
EP
Cancer (AJCC). [15]
Postoperative adjuvant chemotherapy consisted of a bolus of 5-FU (450 mg/m2) and leucovorin (20 mg/m2) administered daily for 5 days every 28 days for 6 cycles. Follow up
Follow up was done by abdominal CT, CEA and CA19.9 every 6 months. Colonoscopy was done annually. Data collected included demographics, tumor pathology, TNM staging,
ACCEPTED MANUSCRIPT
number of LN retrieved, and recurrences. Recurrence was determined by clinical and radiological examinations followed by histological confirmation. Pelvic MRI was done only in
surgery, incidence of recurrence or mortality whatever comes first.
Statistical Analysis
RI PT
cases with suspected local recurrence in the CT scan. End points for follow up were 5 years from
SC
The study was designed to detect a 10 % difference in the recurrence rate between different study groups with 80 per cent power, at a significance level of 0.05. A total sample size
M AN U
of 121 patients was required. Statistical analysis was performed by XLSTAT 2013.1.01 software. Endpoints were local, systemic recurrence, mortality or end of 5 years. Univariate analysis was done using two tailed chi square test or fisher exact test for categorical variables and Mann Whitney test for numerical variables. Multivariate analyses were performed using a Cox proportional hazards regression model. The main objective of the multivariate analysis was to
TE D
assess the independent prognostic value of mesorectal grading.
A multivariate model was
constructed using forward selection with the selected covariates (p ≤ 0.1 at univariate analysis).
EP
To this model, mesorectal grading was added. For each variant, hazard ratio was calculated including 95% confidence intervals (95% CI). Time to local and overall recurrences (cumulative
AC C
risk at certain time) were estimated using the Kaplan Meier method and comparison was done using log rank test. All tests were two tailed and statistical significance was stated as p ≤ 0.05.
ACCEPTED MANUSCRIPT
Results One hundred and twenty one patients were included in the study. Hundred and sixty eight
RI PT
patients were screened for enrollment in the current study. Study exclusions included: 19 patients with distant metastases, 10 patients underwent palliative resections, 11 patients didn’t continue postoperative chemotherapy due to complications, 5 patients refused to have APR, 2 patients refused to be enrolled in the study and one patient died in the immediate postoperative period.
was reported.
SC
All patients were followed up till recurrence or for at least 60 months if no recurrence or death The mean follow up period was 59.4 months. Patient characteristics and
M AN U
treatments received are described in table 1. The mean age of patients was 49.3 years with slight male predominance (M: F ratio= 1.3:1). LAR was done in 92 patients (76%) and an APR in 29 patients (24%).
CRM was negative (FCRM) in 112 patients (92.5%) and positively involved
TE D
circumferential resection margin (ICRM) in 9 patients (7.5%). We defined ICRM as tumor extension (continuous or discontinuous) or presence of positive lymph nodes < 2 mm from the radial, non-peritonealised edge. [11]
EP
Seventy two patients (59.5%) had good (grade 3) mesorectal resections on examination. Of the remaining 49 specimens, 33 (27.3%) were considered moderate (grade 2), and only 16
AC C
(13.2%) were poor (grade 1) specimens. Univariate analysis observed that tumor location within the lower 5 cm of rectum (p
