To review evidence on the short-term clinical outcomes of laparoscopic (LRR) vs open rectal resection (ORR) for rectal cancer.

A systematic literature search was performed using Cochrane Central Register, MEDLINE, EMBASE, Scopus, OpenGrey and ClinicalTrials.gov register for randomized clinical trials (RCTs) comparing LRR vs ORR for rectal cancer and reporting short-term clinical outcomes. Articles published in English from January 1, 1995 to June, 30 2016 that met the selection criteria were retrieved and reviewed. The Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) statements checklist for reporting a systematic review was followed. Random-effect models were used to estimate mean differences and risk ratios. The robustness and heterogeneity of the results were explored by performing sensitivity analyses. The pooled effect was considered significant when P < 0.05.

Overall, 14 RCTs were included. No differences were found in postoperative mortality (P = 0.19) and morbidity (P = 0.75) rates. The mean operative time was 36.67 min longer (95%CI: 27.22-46.11, P < 0.00001), the mean estimated blood loss was 88.80 ml lower (95%CI: -117.25 to -60.34, P < 0.00001), and the mean incision length was 11.17 cm smaller (95%CI: -13.88 to -8.47, P < 0.00001) for LRR than ORR. These results were confirmed by sensitivity analyses that focused on the four major RCTs. The mean length of hospital stay was 1.71 d shorter (95%CI: -2.84 to -0.58, P < 0.003) for LRR than ORR. Similarly, bowel recovery (i.e., day of the first bowel movement) was 0.68 d shorter (95%CI: -1.00 to -0.36, P < 0.00001) for LRR. The sensitivity analysis did not confirm a significant difference between LRR and ORR for these latter two parameters. The overall quality of the evidence was rated as high.

LRR is associated with lesser blood loss, smaller incision length, and longer operative times compared to ORR. No differences are observed for postoperative morbidity and mortality.

The oncologic principles for the curative treatment of rectal cancer imply the complete removal of the tumor and the mesorectum[1]. In locally advanced rectal cancers, oncologic outcomes can be improved by tailored multi-disciplinary approaches that combine surgery with neoadjuvant chemoradiation therapy[2].

Laparoscopy is currently useful for the resection of rectal cancer. The results of multi-centric randomized clinical trials (RCTs) have shown that laparoscopic rectal resection (LRR) was associated with more favorable short-term outcomes compared to open rectal resection (ORR)[3,4]. Specifically, the COLOR II trial showed statistically significant differences in favor of LRR in terms of blood loss, bowel recovery, and the length of hospital stay, with no differences between the two approaches in postoperative morbidity and mortality[3]. The COREAN study achieved similar results, and showed less postoperative pain and better physical and intestinal recovery after LRR[4]. In the more recent ACOSOG Z6051 and ALaCaRT trials, LRR was associated with longer operative times, less blood loss, and faster post-surgery bowel movements [ACOSOG] or time to flatus compared to ORR [ALACART], despite no observed group differences in the length of hospital stay[5,6]. Two recent meta-analyses had compared the short-term clinical results of LRR vs ORR based on pooled actualized data from the relevant literature on rectal cancer. They shown, among others advantages, a significant lesser postoperative morbidity[7,8] and mortality[7] for patients undergoing LRR over those who received ORR[7,8]. However, they considered both RCTs and non-RCTs, a critical factor that dampens the strength of the results due to the quality of the selected studies and the risk of bias. Furthermore, the results of a recent RCTs-based meta-analysis focusing exclusively on the pathologic outcomes of LRR vs ORR reignited the debate regarding the oncological safety of laparoscopy for rectal cancer in terms of quality of mesorectal resection[9]. Thus, while waiting for the long-term data of the ongoing RCTs, we conducted a systematic review and meta-analysis on RCTs only to evaluate the best level of evidence available so far on the short-term clinical outcomes of laparoscopic vs open rectal resections in patients with rectal cancer.

This systematic review and meta-analysis focuses on the short-term clinical outcomes of laparoscopic vs open resection for the treatment of rectal cancer and shows that there are no differences in postoperative morbidity and mortality between the two approaches. However, LRR is associated with significantly longer operative time, lesser blood loss, and smaller incision than ORR. The length of hospital stay and the time to bowel recovery are shorter for LRR in the overall analysis but are not significantly different when considering the major RCTs only.

Previous meta-analyses have reported contrasting results about the benefits associated with the use of laparoscopy for rectal cancer instead of conventional open surgery. In 2013, Arezzo et al[27] analyzed 8 RCTs and 15 non-RCTs and showed a significantly lower postoperative mortality and morbidity in LRR than ORR. A more recent meta-analysis by Zhao et al[28] and the latest Cochrane review[29], both based on RCTs only, showed no differences in overall morbidity and mortality. However, they found better outcomes for laparoscopy in terms of blood loss, length of hospital stay, wound infection, and bowel recovery compared to open surgery. Noticeably, the above-mentioned meta-analyses were performed before the two largest and most recent RCTs being published, namely the ACOSOG Z6501 and ALaCaRT trials[5,6], which did not confirm the non-inferiority of laparoscopy and questioned the oncological safety of laparoscopy for rectal cancer. Indeed, the topic remains highly debated. Two recent meta-analyses published by Chen et al[8] and by Zheng et al[7] were performed to assess the outcomes of laparoscopy vs open surgery by including data from RCTs and non-RCTs. The study by Chen et al[8] demonstrated longer operative time, lesser blood loss, lesser overall complications, faster bowel recovery, shorter hospitalization, and major distal resection margin for laparoscopic surgery than open surgery[8]. However, there was found a considerable and arbitrary lack of data from the most populated RCTs[3-6] (which represented more than 50% of the patients included) for all the short-term variables analyzed, such as distance of distal resection margin[3,4,6], CRM involvement[5], lymph node harvest[3], operative time[3,4,6], hospital stay[4,6], and estimated blood loss[3,4,6]. Similarly, the meta-analysis by Zheng et al[7] included 38 studies and 13,408 patients, but only less than a third of patients (3978, 29.7%) were treated in RCTs. Moreover, the 32.9% of the included patients (4405 patients) were coming from a unique multi-centric observational study involving 72 Spanish hospitals[30]. Despite the eager of pooling data to gain power and answer the hot question about the advantages of laparoscopic rectal resection, caution should be paid when interpreting meta-analytic results. Contrasting result may be generated by using different statistical models, or when pooling together RCTs with non-RCTs. In general, the choice of the effect model should be assessed prior to start the data analysis and based on the researcher’s understanding of whether or not all the included studies share a common treatment effect. For surgical literature, a random-effect model seems to be more appropriate than a fixed-effect[31,32] due to the nature of the data retrieved from studies performed by researchers operating independently. Deciding between the models after performing the analysis or based upon the level of heterogeneity found (e.g., whether the I² is higher than 40%[29] or 50%[7,8,27] or reaches significance[33]) is strongly discouraged[31,32]. Most importantly, the quality of a meta-analysis is strictly dependent on the quality of the original studies included and robustness of the findings should be tested by sensitivity analyses.

The present systematic review and meta-analysis aimed to analyze the best level of evidence available for LRR vs ORR, thus only high-quality RCTs were included. By applying a strict methodology, the present findings confer fewer advantages to LRR over ORR, especially when only the largest multi-centric RCTs were considered, when compared to the results of previous meta-analyses.

The main intra-operative benefit of LRR, confirmed by both the pooled data analysis and the sensitivity analysis, is a lower blood loss. This might justify the use of laparoscopy for rectal cancer resections despite longer operative times. Indeed, the amount of blood loss has been shown to be an independent predictor of adverse surgical outcomes, such as intra- and postoperative complications, cancer recurrence, and poorer survival[34,35]. Although the reasons why intraoperative blood loss would be associated with morbidity and poor survival remain unclear, some evidence supports that blood loss triggers stress and immune reactions, which may lead to an increased susceptibility of infections and cancer recurrence. Thus, minimizing blood loss, and the consequent risk of blood transfusion by meticulous and gentle dissections in the anatomical planes, may contribute to better outcomes of oncological surgery. However, it remains to be assessed whether the difference observed between the two surgical approaches (i.e., 88.80 mL) is clinically relevant, and may potentially impact on the postoperative and long-term outcomes.

Other markers of surgical quality are the postoperative complication rates and the time to bowel recovery. Based on the pooled data analyses from the major RCTs[3-6], laparoscopy was not associated with a significantly different incidence of postoperative complications, time to bowel recovery or hospital stay compared to open surgery. Concerning bowel recovery, it can be measured with multiple clinical variables, such as the time to the first flatus, the time to a liquid or solid diet, or the time to the first bowel movement. Globally, bowel recovery was not significantly different between LRR and ORR but it must be noted that benefits in at least one of the recovery variables considered (e.g., time to flatus or time to regular diet) were found in all RCTs. Thus, caution should be paid before drawing definitive conclusions; differences among studies did not allow pooling data for all variables (e.g., the COREAN study[4] expressed bowel recovery in hours rather than days and could not be included in the meta-analysis), except for the time to first bowel movement. Despite the non-significant results in the sensitivity analysis, bowel recovery is probably faster after LRR than ORR, but further studies are needed to confirm this finding.

The evidence emerging from this systematic review and meta-analysis can be considered of high quality since it is based exclusively upon RCTs[36], most of which with low risk of bias. However, some limitations must be acknowledged. The pooled data analyses showed high degrees of heterogeneity; this may be linked to multiple factors, such as different sample size (e.g., some studies presented less than 100 patients per group[17,18,20-23,25]), different tumor characteristics (e.g., only upper[21] or lower rectal cancer[22,25]), and different study designs (e.g., non-inferiority study) or protocols. For instance, neoadjuvant treatments were not performed in all studies, and therapies were not standardized. It has been hypothesized that major pathologic responses might translate into greater postoperative morbidities because of the effects of neoadjuvant chemoradiation therapy on pelvic tissues[37]. To date, only a few studies have addressed the influence of the pathologic response to neoadjuvant chemoradiation therapy on intraoperative and short-term morbidity, with contrasting results[37-40], but its impacts could neither be confirmed nor ruled out in this meta-analysis. Finally, the results of this meta-analysis cannot be generalized to the application of LRR and ORR for all types of rectal cancer. Indeed, T4 rectal cancers were excluded from most of the studies[3,4,6,17,19,22,23]. Thus, the outcomes of laparoscopy for this specific subset of tumors cannot be assumed, although a recent propensity score-matched study showed that LRR also achieved similar outcomes to ORR in pT4 rectal cancer patients[41].

The short-term benefits of laparoscopy must be counterbalanced with its safety. Indeed, uncertainty persists concerning the oncological appropriateness of laparoscopy for rectal cancer. A recent meta-analysis[9] focused on the pathologic outcomes of LRR vs ORR and showed that LRR was associated with a significantly higher rate of non-complete mesorectal excision compared with ORR, which represents a critical issue on the choice of the surgical approach. Innovative techniques, such as transanal-TME and robotics, are receiving worldwide attention in the latest years and they may represent a valuable alternative to laparoscopy, especially if they are proved to be oncologically safe, clinically advantageous for the patient, and maybe less challenging for the surgeon[42-45]. Nevertheless, data on the long-term outcomes of the ongoing RCTs are pending and they may be crucial in the definitive assessment of the role of laparoscopy in rectal cancer resection.

In conclusion, LRR and ORR show similar rates of intra- and postoperative complications, as well as morbidity and mortality. However, LRR is associated with a significantly higher operative time, lesser blood loss, and smaller incision length than ORR.