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Critical appraisal of laparoscopic vs open rectal cancer surgery.

AIM
To evaluate the long-term clinical and oncological outcomes of laparoscopic rectal resection (LRR) and the impact of conversion in patients with rectal cancer.


METHODS
An analysis was performed on a prospective database of 633 consecutive patients with rectal cancer who underwent surgical resection. Patients were compared in three groups: Open surgery (OP), laparoscopic surgery, and converted laparoscopic surgery. Short-term outcomes, long-term outcomes, and survival analysis were compared.


RESULTS
Among 633 patients studied, 200 patients had successful laparoscopic resections with a conversion rate of 11.1% (25 out of 225). Factors predictive of survival on univariate analysis include the laparoscopic approach (P = 0.016), together with factors such as age, ASA status, stage of disease, tumor grade, presence of perineural invasion and vascular emboli, circumferential resection margin < 2 mm, and postoperative adjuvant chemotherapy. The survival benefit of laparoscopic surgery was no longer significant on multivariate analysis (P = 0.148). Neither 5-year overall survival (70.5% vs 61.8%, P = 0.217) nor 5-year cancer free survival (64.3% vs 66.6%, P = 0.854) were significantly different between the laparoscopic group and the converted group.


CONCLUSION
LRR has equivalent long-term oncologic outcomes when compared to OP. Laparoscopic conversion does not confer a worse prognosis.


INTRODUCTION
Surgical management for rectal cancer remains chal lenging. With the advent of total mesorectal excision (TME) in rectal cancer surgery, local recurrence rates have improved significantly and there is an increasing rate of sphinctersaving surgery when technically and oncologically feasible. However, despite the use of pre or postoperative adjuvant chemoradiotherapy, local and distant tumor recurrence remains a concern.
While laparoscopic colectomy has established its oncologic equivalence compared to open surgery (OP) in colon cancer, laparoscopic rectal resection (LRR) for rectal cancer remains controversial. Although LRR has been shown to confer shortterm benefits, in terms of blood loss, length of stay, recovery of bowel function, and cosmesis, concerns about the long term oncologic outcomes persists [15] . The necessity for a TME creates a more difficult learning curve for LRR compared to a laparoscopic colectomy. There is also the need to achieve a balance between sphincter preservation without compromising the adequacy of the distal resection margin [6] . These challenges induce a higher rate of conversion compared to colonic resection [2] and a recent Cochrane review has noted that conversion rates in LRR can be as high as 35% [7] . This is an important concern as it has been suggested that conversion to OP after attempted LRR not only has higher morbidity, but may also adversely affect long term oncologic outcomes [2,811] . Several publications have attempted to address this issue but the study populations often consisted of a mixture of patients with colon and rectal cancer [1214] . This is suboptimal as the prognosis and recurrence pattern of colon and rectal cancer are distinctly different. There are few publications that address the longterm outcomes of laparoscopic conversion specifically in the context of rectal cancer [10,15,16] . Therefore, the objective of this study is to evaluate the longterm clinical and oncological outcomes of LRR as well as the impact of laparoscopic conversion on the longterm oncological outcomes of patients with rectal cancer.

MATERIALS AND METHODS
An analysis of a prospectively maintained database of 633 consecutive patients with rectal cancer who under went surgical resection from January 2005 to December 2009 in the Department of Colorectal Surgery at Singapore General Hospital was performed. Patients who presented with recurrent cancer, Inflammatory Bowel Disease, Familial Adenomatous Polyposis, or other polyposis syndromes were excluded. Data on patient demographics, preoperative, operative, and postoperative course were collected prospectively and maintained in a database by a research assistant.
All cases were performed by consultant surgeons within the department. The decision for laparoscopic or open approach was left to the discretion of the individual surgeon.
For the laparoscopic approach, we preferred the medial approach with early mobilization, ligation and division of the inferior mesenteric artery at its origin after the ureter has been identified. The inferior mesen teric vein was ligated and divided at the inferior border of the pancreas. This was followed by mobilization of the left colon from the lateral sidewall, with mobilization of the splenic flexure if deemed necessary to achieve a tension free anastomosis. Total mesorectal excision or wide mesorectal excision up to at least 2 cm distal to the tumor was performed for all cases when feasible. Distal transection was performed using articulating staplers. The specimen is exteriorized via extension of the port sites with proximal transection performed extra corporeally. Pneumoperitoneum is then reestablished and intracorporeal circular stapled anastomosis per formed under direct vision.
OP was performed via a midline laparotomy or left iliac fossa incision as described in a previous publi cation [17] .
Patients were compared in three groups: OP, laparoscopic surgery (LS), and converted laparoscopic surgery (CON) with their definitions as follows: (1) OP: Completion of surgical resection and anastomosis via midline laparotomy or left iliac fossa incision; (2) LS: Surgery accomplished using the laparoscopic technique as described above. Patients analyzed under the LS group included patients who underwent laparoscopic assisted surgery as described in a previous publication by our department [18] . These were patients who had vascular ligation and the majority of bowel mobilization was accomplished intracorporeally via the laparoscopic approach with the following modifications: (a) extension of one port site wound or the utilization of a new wound to complete colonic mobilization and bowel transection for reasons such as the presence of adhesions, excessive tumor fixation, or uncertain tumor location; (b) extracorporeal rectal anastomosis due to technical difficulties such as a narrow pelvis, bulky tumor, or defective equipment; and (c) extension of wounds to repair the anastomosis due to leaks on testing after completion of a pure laparoscopic resection; (3) CON: The laparoscopic approach is aborted after insertion of ports and initial bowel mobilization. This can be due to the presence of dense adhesions, undiagnosed tumor invasion of surrounding organs, or trouble shooting complications such as uncontrolled bleeding, bowel perforation, or injury of adjacent viscera such as ureters or small bowel. Conversion is also defined if the anastomosis requires a complete takedown and revision.

Pre-operative staging
All cases were evaluated preoperatively by plain chest radiograph/computed tomography (CT) of the thorax and CT of the abdomen and pelvis. Tstaging with an endorectal ultrasound was performed preoperatively in clinical T1 and T2, mid and low rectal tumors. Magnetic resonance imaging (MRI) of the pelvis was performed for all lower rectum tumors. Upper rectum is defined as 1115 cm, middle rectum as 610 cm, and lower rectum as 05 cm from the anal verge. These measurements were recorded by the consultant surgeon after digital rectal examination and endoscopy. Disease staging according to the American Joint Committee Cancer (AJCC) Cancer Staging Manual 7 th Edition was adopted [19] .

Neoadjuvant/adjuvant therapy
In our institution, a selective neoadjuvant chemora diation policy is adopted based on data from previous publications that have consistently shown low local recurrence rates with oncologically adequate surgery alone [2022] . If sphincter preservation with good margins can be performed after initial evaluation, neoadjuvant treatment is usually not routinely recommended in our local population. Neoadjuvant treatment is mainly performed in patients who present with a threatened circumferential resection margin, defined as within 2 mm of the circumferential resection margin based on preoperative staging.
The neoadjuvant regimen consisted of longcourse preoperative radiotherapy (4550 Gy in 2528 daily fractions over 5 wk) combined with 5fluorouracil or oral capecitabine. Patients proceeded with surgical resection 6 to 8 wk after completion of neoadjuvant chemoradiotherapy. Decision for adjuvant chemotherapy was decided after discussion at a multidisciplinary tumor board meeting. Perioperative care for all patients was standardized using existing clinical care pathways.

Follow-up details
Postoperatively, the patients were followedup at three monthly intervals for the first two years, six monthly for the next three years, and then yearly thereafter. At each consultation, carcinoembryonic antigen (CEA) levels were measured and full history and physical examination (including digital rectal examination) were performed. Colonoscopy was performed within six months of surgery if initial complete evaluation was not possible preoperatively due to tumor obstruction or stenosis. Those who had an initial complete evaluation underwent colonoscopy at the first year follow up, and again at 3yearly intervals postoperatively. Patients with suspicious symptoms and signs of rising CEA trend on followup will be evaluated earlier with colonoscopy and/or radiological imaging (including computerized tomography of the chest, abdomen, and pelvis, bone scan, and positron emission tomography scans if applicable).
Local recurrence was defined as the first clinical, radiologic, and/or pathologic evident tumor of the same histological type, within the true pelvis, at the anastomosis or in the region of the anastomosis. Distant recurrence was defined as similar evidence of spread outside the primary tumor at sites including but not limited to the liver, lungs, bone, brain, and paraaortic region. Patients who were first diagnosed with local recurrence but later developed distant metastasis were classified under the local recurrence group. Mortality data and the cause of death were obtained from the Singapore Cancer Registry.
Longterm outcomes assessed included the occur rence of intestinal obstruction, incisional hernias, and the oncologic outcomes of local/distal recurrence.
Survival analysis was performed via the comparison of progression free survival and overall survival (OS).

Statistical analysis
All statistical analysis was performed by a qualified biostatistician. Demographic and clinicopathological characteristics of the patients were compared across the 3 groups using c 2 and t tests for categorical and continuous variables respectively. Distribution of selected short and longterm outcomes among the patients study duration. The demographic characteristics of the study population are illustrated in Table 1. Two hundred and twentyfive patients (35.5%) underwent attempted laparoscopic resection of the rectal tumor. Among these, 200 patients had successful laparoscopic resection with 77 patients (34.2%) requiring a laparoscopicassisted approach, predominantly due to anatomic difficulties during the LS (50 out of 77 patients). Patients in the OP group were older [66 years old (OP) vs 59 years (LS), P < 0.001] and had slightly higher proportion of patients with ASA 3 and 4 [13.5% (OP) vs 10% (LS), P = 0.002]. The proportion of patients who underwent neoadjuvant chemotherapy and radiotherapy was also higher among patients in the OP group compared to LS group [3.4% vs 2.5% (chemotherapy) and 2.9% vs 1.5% (radiotherapy) respectively]. The laparoscopic conversion rate was 11.1% (25 out of 225) with the reasons for conversion illustrated in Table 2. All conversions to OP were unplanned preoperatively. Close to half (12 out of 25) of the patients were con verted due to the presence of excessive adhesions. The oncologic and perioperative outcomes of the entire study cohort are presented in Table 3. Duration of surgery was significantly longer in the LS compared to the OP group [162 min (LS) vs 119 min (OP), P < 0.001]. Length of hospitalization was shorter in the LS group compared to OP group (7 d vs 8 d, P < 0.001).
Comparison of shortterm and longterm outcomes between the 3 groups is illustrated in Table 4 and there were no significant differences between the 3 groups. The 5year CFS and OS for the 3 group of patients is illustrated in Figure 1. Results of the univariate and multivariate analyses for predictive factors of survival are summarized in Table 5. Factors found to be predictive of survival on univariate analysis include the laparoscopic approach (P = 0.016), together with factors such as age, ASA status, stage of disease, tumor grade, presence of perineural invasion and vascular emboli, CRM < 2 mm, and postoperative adjuvant chemotherapy. The survival benefit of LS was no longer significant on multivariate analysis (P = 0.148) and only age, stage of disease, tumor grade, and CRM < 2 mm remained significant. After excluding open cases, neither 5year OS (70.5% vs 61.8%, P = 0.217) nor 5year CFS (64.3% vs 66.6%, P = 0.854) were undergoing surgery was compared using Fisher's exact test. Comparison of the median duration of hospi talization was performed using the KruskalWallis nonparametric test as it deviates from the Normality assumption.
OS was calculated from the date of diagnosis to the date of death or last followup. Cancerfree survival (CFS) was calculated from the date of diagnosis to the date of disease progression (local or distant relapse) or last followup. The 5year OS and CFS were estimated using Kaplan Meier method and the survival curves were compared using logrank tests. Multivariate Cox proportional hazards models, using variables found to be significant on univariate analysis, were used to estimate hazard ratios with their 95%CI. A significance level of 0.05 was chosen throughout. All analyses were performed using R 3.1.1 (2014, Vienna, Austria).

RESULTS
Six hundred and thirtythree patients underwent surgical resection for primary rectal cancers during the  univariate analysis, this is likely attributed to the inherent selection bias in the study as patients chosen for OP tend to be older and with more advanced ASA status. As such, the differences in survival were no longer significant when subjected to multivariate analysis. There was also no difference in the local or systemic recurrence rates between all groups. These results are in line with several published studies comparing at least 5year survival data of laparoscopic against open rectal resections (Table 6) [4, 6,2330] . They are also congruent with the findings of two recent randomized trials comparing laparoscopic with open resection in rectal cancer [31,32] . However, conflicting results were seen when pathologic adequacy of surgical resection was used as the outcome of interest. Both the ALaCaRT and the ACOSOG Z6051 trial failed to demonstrate non inferiority in terms of oncologic adequacy of resection when LS was compared to OP [33,34] . These results have cast doubt on the role of LS in rectal cancer. Hopefully, the long term follow up data of the above two studies will help shed light on the contentious issue of LS in rectal cancer.
Studies assessing the impact of conversion on oncological outcomes have shown conflicting results and a recent metaanalysis found that conversion was associated with an adverse longterm oncological outcome [35] . Postulated mechanisms include the increased inflammatory response associated with conversion and requirement for blood transfusion in converted cases that may subsequently increase recurrence risks [36] . However, both colonic and rectal resections were included in the above metaanalysis, significantly different between the laparoscopic group and the converted group.   the impact of conversion in LRR for cancer [6,8,10,15,16,37] . While most studies had similar findings to ours, Rottoli et al [15] concluded that conversion could have a negative impact on longterm overall recurrence rate. It is noted in this study, however, that 8 out of 26 (30.7%) patients with the former constituting the majority of the pooled patient population. Subset analysis of laparoscopic conversion in our study cohort revealed that conversion did not have an adverse impact on longterm oncologic outcomes in rectal cancer. Several studies have reported   Figure 1 Kaplan-Meier curves comparing the three surgery groups for cancer free survival and overall survival. 1 Cancer free survival and overall survival is compared.

DISCUSSION
resection and the impact of conversion in patients with rectal cancer.

Research frontiers
The impact of laparoscopic conversion in rectal cancer remains unknown. This study assesses the impact of laparoscopic conversion in patients with rectal cancer.

Innovations and breakthroughs
Laparoscopic surgery for rectal cancer has equivalent long term oncological outcomes when compared with open surgery. Conversion in rectal cancer was not shown to be associated with an adverse outcome.

Applications
Laparoscopic resection for rectal cancer is feasible with no adverse impact on long term oncological outcomes even in the event of conversion.

Peer-review
The paper describes a single-center experience on laparosocpic surgery for rectal cancer. It is well written and references are updated. were converted due to advanced tumors and may thus explain poorer survival. In contrast, the majority of our conversions were due to adhesions (> 50%) and not advanced disease (12%) ( Table 2). Thus it was not surprising that laparoscopic conversion had no impact on longterm oncologic outcomes.

REFERENCES
The major limitation of our study lies in its retro spective nature which makes it susceptible to the effects of confounding and selection bias. While formal matching of the various groups of the study cohort was not performed due to numerical limitations, majority of the clinical demographics and tumor pathological characteristics between groups were similar, allowing for meaningful comparison. While we acknowledge the antecedent limitations of the retrospective nature of our study, it does have several strengths. Firstly, to the best of our knowledge, this is the largest study cohort evaluating the longterm outcomes (5year survival data) of surgical resection in rectal cancers. Unlike other studies, conversions were clearly defined which facilitates comparison of findings in other institutions. Thus, we believe that this study will add value to the available literature on surgical resection for rectal cancer.
LRR is safe and has equivalent longterm oncologic outcomes when compared to OP. Laparoscopic con version does not appear to confer an adverse outcome. Further evaluation of longterm data from updated randomized studies comprising of larger number of patients may be required to discern more differences.

Background
Laparoscopic resection for rectal cancer remains controversial. The authors evaluate the long-term clinical and oncological outcomes of laparoscopic rectal  [25] Retrospective Laparoscopic group had better survival on multivariate analysis as well Baik et al [24] Case-matched Controlled Analysis  [23] Retrospective 225 (all laparoscopic) 50.5% (lap) 10 yr overall survival