Comparation of Laparoscopic Intersphincteric Resection and Abdominoperineal Resection for Ultra-Low Rectal Cancer Patients - a Retrospective Analysis, and a Meta-analysis of Oncology Outcome

Purpose The aim of the study is to evaluate the surgical and oncology outcomes between laparoscopic Intersphincteric Resection (LISR) and laparoscopic-assisted Abdominoperineal Resection (LARC) for ultralow rectal cancer patients by using a retrospective analysis, and a meta-analysis of the literature was carried out to further validate the oncology outcome. resection;


Introduction
Rectal cancer accounts for approximately 30% of colorectal cancers and is a leading cause of cancer death worldwide [1]. The introduction of total mesorectal excision (TME) and preoperative chemoradiotherapy (CRT) has dramatically decreased the local recurrence rates and improved survival in rectal cancer patients [2]. However, these improvements have been relatively modest for patients with very low rectal cancer, compared with those with mid-to-upper rectal cancer.
In China, most of the rectal cancer was low-lying [3], traditionally, most rectal carcinomas lying less than 5 cm from the anal verge or less than 2 cm from the dentate line are treated by laparoscopic Page 3/16 abdominoperineal resection (LAPR) [4]. Intersphincteric resection (ISR) is a procedure that is performed to avoid permanent colostomy in patients with very low rectal cancer [5]. It enables preservation of the sphincter in patients who would have undergone abdominoperineal resection in the past. However, with ISR, there is a potential risk of increased recurrence [6], because preservation of the anal canal, external sphincter, and levator ani muscles for such low tumors may compromise distal margins [7]. Thus, the oncologic outcomes may vary greatly depending on the skills of the surgeons. There have been only limited studies on the oncologic outcomes after ISR compared with APR.
Totally laparoscopic intersphincteric resection (LISR) is not yet an established technique and its safety and feasibility are unclear. Our aim was to clarify the safety and feasibility of LISR for clinical stage I-III rectal cancer comparing to LAPR.

Study design
Patients who received LISR or LAPR for ultra-low rectal cancer located below the peritoneal re ection at the Guangxi Cancer Hospital, between Between April 2014 and December 2015 were assessed retrospectively. Our methodology conformed to the principals outlined in the Declaration of Helsinki [8].
The patients were fully informed about the operation and a detailed inform consent form reporting the operation details were signed by the patients. In addition to routine investigations, computed tomography (CT) of chest, abdomen and pelvis, positron emission tomography-computed tomography (PET-CT), and colonoscopy was performed in all patients as part of preoperative work-up.
Patient demographics, preoperative and operative data, and outcomes were included in the analysis. Key variables of interest included age, sex, body mass index (BMI), preoperative diagnosis, duration of surgery, duration of ileocolic anastomosis, intraoperative blood loss, total length of hospital stay, postoperative duration of intestinal function recovery, postoperative pain, and incidence of postoperative in-hospital complications (infection, obstruction, and bleeding). Pathological data, including tumor-nodemetastasis (TNM) stage and the number of nodes dissected, were also reviewed. All pathological data fell into the category of T1-4NxM0.
Inclusion Criteria For ISR ISR was offered to patients with preoperative T1-4 tumors that were circumferential resection margin (CRM) negative according to the TNM classi cation (seventh edition) and showed no evidence of extension into the external anal sphincter or the levator ani muscle and to those in whom resection could be performed with a distal margin of at least 2 cm for T 2 or T 3 tumors or 1 cm for T 1 tumors. Patients with prior history of abdominal surgery, previous malignancy or those who had psychiatric disorders or severe organ dysfunction such as severe cardiopulmonary disorders were excluded.

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Neoadjuvant chemoradiotherapy (NAC) was performed for patients with tumors that invaded the other organs or structures (T4) [9]. Patients with stage III tumor who provided their informed consent for adjuvant chemotherapy were given postoperative systemic chemotherapy with a 5-uorouracilbased regimen.
Surgical Procedure For LISR And LAPR A circular incision of the rectal mucosa and of the internal muscular layer was made at least 1 cm below the lower margin of the tumor via a transanal dissection. LISR was basically performed according to the methods described by Schiessel and colleagues. In the abdominal approach, ligation and dissection were performed at the root of the inferior mesenteric artery with mobilization of the splenic exure. The rectum was mobilized to the level of the puborectalis muscle using the technique of total mesorectal excision (TME). Autonomic nerve preservation was routinely performed for patients without tumors invading the nerves. Dissection of the intersphincteric space between the internal anal sphincter and the external anal sphincter was advanced as low as possible from the abdomen to facilitate the transanal approach. After the operator moved to a transanal approach, the rectum and anal canal were irrigated with povidone iodine and saline to prevent scatter of cancer cells. Following closure of the anal ori ce at the distal cut end, the internal sphincter was circumferentially incised, and the intersphincteric plane was dissected. After specimen removal and irrigation of the pelvic cavity, lateral pelvic lymph node dissection was performed for advanced.
The surgical procedure for LAPR was as previous descripted [10].

Follow-up And Oncologic Outcomes
All patients were followed on an outpatient basis. Patients were examined with chest and abdominopelvic CT and carcinoembryonic antigen measurement every 3 months for 1 years and then yearly for at least 3 years. The date and rst site of recurrence were recorded for each patient. Local recurrence was de ned as intrapelvic recurrence, recurrence at the pelvic oor or anastomotic site, or recurrence at lateral pelvic lymph nodes. Other recurrences were de ned as distant metastases.

Meta-analysis
Search strategy: The Pubmed, Embase, Cochrane Library electronic databases, and Wanfang Data and DNKI (China National Knowledge Infrastructure) were searched for comparative studies published up to January 2020. The following medical subject heading (MeSH) terms and words were used for the search in all possible combinations: "Intersphincteric Resection," "ISR," "Abdominoperineal Resection," "ARC," "laparoscopic," and "laparoscopy."

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A manual search of the reference lists of relevant articles was also performed. No language or time restriction was used. Data were extracted from each study by two independent reviewers (Xianwei Mo and Hao Lai). Disagreements were resolved by consensus.
Eligibility criteria: Inclusion criteria were described as follows: (1) The study design was a case-match design (randomized, controlled trials (RCTs) or controlled clinical trials (CCTs)) that compared LISR to LARC; (2) LISR or LARC can be performed using any type of laparoscopic or endoscopic instruments; (3) studies that were included contained information on at least one of the following outcome measures: disease free survival rate (DFS), and 5-years overall survival rate (OS). Exclusion criteria were as follows: (1) case reports, reviews, and quasi-randomized trials; and (2) over-lapping data.

Patient and tumor characteristics
The characteristics of the patients who underwent LISR or LAPR are listed in Table 1. Histologically curative resection was performed for all patients. No signi cant differences were observed between the two groups in age, gender, BMI, ASA Score, T stage, N stage, histology, and distance from anus. However, tumor size was differed signi cantly.

Survival And Patterns Of Recurrence
The actuarial distant metastases-free survival rate was 63.16% in LISR group and 70.73% in LAPR group, respectively (Table 1). Patients undergoing LISR had a similarly 5-year local recurrence and overall survival rate with LAPR. The most common seen recurrence place was pelvic cavity. In addition, patients with advanced tumors, as assessed by restaging MRI and luminal circumferential involvement, suffered local recurrence signi cantly more frequently if they had been treated using APR rather than ISR.

Meta-analysis
The whole process of study selection is abided to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and PRISMA-Protocol guidelines [11]. Its results will be presented in a PRISMA ow chart with clearly reasons of exclusion and inclusion at each stage. A total of 352 articles that mentioned LISR and LAPR from the database was carefully screen. We screened the full Page 11/16 texts, titles, abstracts, and so on, or a combination of these, and removed the duplicate results. At last, four studies were eligible for this nal meta-analysis [12][13][14][15].

5-years recurrence rate
The available data for the 5-years recurrence rate was provided by four studies [12][13][14], which included 688 patients. No signi cant difference was noted for the 5-years recurrence rate between the ISR and APR subgroups (Fig. 1), without heterogeneity across the trials, and without publication bias (P = 0.59).

5-years Survival Rate
Three studies, which included 304 patients, provided available data regarding 5-years survival rate [12,14,15], and showed no statistically signi cant difference between the ISR and APR subgroups (Fig. 2), without heterogeneity across trials, and without publication bias (P = 0.76).

Discussion
In the past 20 years, ISR has been performed as an anus-preserving alternative to avoid the need for permanent colostomy in patients with invasive low rectal cancer located near the anal canal [16,17]. Only a small number of reports have compared the long-term outcomes of ISR with those of APR [14], and very few report descript the LISR. We compared surgical outcomes of patients with ultra-low rectal cancer who underwent duet LISR or LAPR. The main ndings were as follows: short-term surgical outcomes, including operating times, blood loss during surgery, postoperative pain, and postoperative morbidities, were similar in both groups. Our ndings also generally agree with previous studies, in which patients undergoing ISR had similarly oncology outcomes compared with patients undergoing restorative surgery.
Previous studies have shown that LAR and especially ISR often lead to severe functional problems both in short and long term and may result in a poor defecatory function. Patients with very low anastomoses are especially prone to develop a condition termed "low anterior resection syndrome"[18], which incorporates a number of unpleasant symptoms such as frequent defecation, urgency, and stool incontinence, and severely impairs QoL. These commonly occurring problems after deep sphincterpreserving surgery are probably the reason why recent studies have shown that QoL after ISR and LAR, contrary to former beliefs, is not better than QoL after APR. This is in accordance with the results of our study which show an equivalent global health status for all three groups. There were no signi cant differences in most of the QoL items. However, diarrhea and constipation were signi cantly worse in ISR and LAR compared to APR patients. Patients with ISR showed signi cantly more symptoms in the gastrointestinal tract and more defecation problems, which is consistent with current literature and well explicable as the operation impairs anorectal function the most.

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Fecal incontinence was common in patients after ISR[19]. This is well explicable as patients undergoing ISR generally have direct impairment of anal sphincter function as the cranial part of the internal sphincter is removed. Moreover, most of or the entire transition zone are also removed resulting in an impairment of sensibility and hence also to more incontinence. Finally, radiation therapy may have to involve the anal sphincter more in very low tumors in need for intersphincteric resection.
Our ndings also generally agree with previous studies, in which patients undergoing ISR had similarly oncology outcomes compared with patients undergoing restorative surgery. It has also been suggested that inadequate excision, resulting in a greater CRM involvement and a less intact TME plane, is a major determinate of outcome. Nagtegaal et al reported that local recurrence rates were higher among patients with positive CRMs, regardless of the surgical technique used, and a more positive margin was present in patients undergoing APR (30.4%) compared with anterior resection (AR) (10.7%, P¼0.01) [20].
This study has a number of limitations. First, the exact indication of APR is not included. As discussed above, invasion of the external sphincter was rare, and some of the factors that may have in uenced the choice of surgical method could not always be determined. Second, it can be argued this study includes too few patients, and in fact, although tumor perforation is regarded as an important predictive factor for local recurrence following resection of low rectal cancer, we could not fully assess its impact in our study due to its rarity. Finally, more re ned MRI predictors, such as CRM involvement, were not used.In a future study, a more detailed and informative analysis based on preoperative MRI may provide more individualized treatment guidelines.

Conclusion
This study suggests that LISR is as technically feasible, safe, and effective as LARC for treating patients with low rectal cancer. Additional high-powered randomized trials are needed to determine whether LISR truly offers any advantages.

Declarations
Availability of data and materials The data came from our hospital's data system.