Meta‐analysis of the impact of postoperative infective complications on oncological outcomes in colorectal cancer surgery

Background Cancer outcomes are complex, involving prevention, early detection and optimal multidisciplinary care. Postoperative infection and surgical site‐infection (SSI) are not only uncomfortable for patients and costly, but may also be associated with poor oncological outcomes. A meta‐analysis was undertaken to assess the oncological effects of SSI in patients with colorectal cancer. Methods An ethically approved PROSPERO‐registered meta‐analysis was conducted following PRISMA guidelines. PubMed and Scopus databases were searched for studies published between 2007 and 2017 reporting the effects of postoperative infective complications on oncological survival in colorectal cancer. Results were separated into those for SSI and those concerning anastomotic leakage. Articles with a Methodological Index for Non‐Randomized Studies score of at least 18 were included. Hazard ratios (HRs) with 95 per cent confidence intervals were computed for risk factors using an observed to expected and variance fixed‐effect model. Results Of 5027 articles were reviewed, 43 met the inclusion criteria, with a total of 154 981 patients. Infective complications had significant negative effects on overall survival (HR 1·37, 95 per cent c.i. 1·28 to 1·46) and cancer‐specific survival (HR 2·58, 2·15 to 3·10). Anastomotic leakage occurred in 7·4 per cent and had a significant negative impact on disease‐free survival (HR 1·14, 1·09 to 1·20), overall survival (HR 1·34, 1·28 to 1·39), cancer‐specific survival (HR 1·43, 1·31 to 1·55), local recurrence (HR 1·18, 1·06 to 1·32) and overall recurrence (HR 1·46, 1·27 to 1·68). Conclusion This meta‐analysis identified a significant negative impact of postoperative infective complications on overall and cancer‐specific survival in patients undergoing colorectal surgery.


Introduction
Colorectal cancer affects 17 people per 100 000 worldwide and 30 per 100 000 in Europe 1 , with an average 5-year survival rate of 65 per cent 2 . Optimizing cancer outcomes is a complex interaction involving key strategies: prevention, early detection and optimal management 3 . Many treatment paradigm shifts in both surgical and oncological treatment have improved cancer outcomes. Recurrence, which affects over 40 per cent of patients, has classically been associated with tumour stage, grade, emergency presentation and resection margin status 4,5 .
Surgical-site infections (SSIs), including superficial, deep and organ space infections, are coming increasingly under the spotlight, causing discomfort for patients and family, anxiety for surgeons, and cost to healthcare systems 6 . In addition, they are associated with potential delay in, or omission of, adjuvant therapy.
A recent long-term analysis from the German Rectal Cancer Trial 7 suggested that surgical complications were associated with both oncological and overall outcomes. Immunological forces influence survival 8 . As SSI occurs in approximately 15 per cent of patients undergoing colorectal surgery, a clear understanding of any adverse relationship is important 9 . Although surgeons and patients alike fear the morbidity and mortality associated with postoperative complications, their potential negative impact on oncological outcomes is not widely understood or reported routinely 10,11 . A meta-analysis was undertaken to determine the impact of postoperative infections on oncological outcomes in colorectal cancer surgery.

Methods
A study was conducted to assess the impact of postoperative infective complications on oncological outcomes in colorectal cancer surgery. The study was registered with PROSPERO (registration number: 42017069038) and followed PRISMA guidelines 12 . PubMed and Scopus were searched for studies that met the eligibility criteria. Original articles, published between June 2007 and May 2017, which reported the effect of infective complications on oncological survival in both colonic and rectal cancer were identified. The search strategy used the following keywords: Colon Cancer, Colorectal Cancer, Rectal Cancer, Complication, Infection, Oncological Outcomes, Anastomotic Leak, Survival and SSI. Animal studies, review articles, non-English papers, duplicate data sets and results published only in abstracts were excluded. Details of the search strategy and data management are available in Tables S1 and S2 (supporting information).

Data extraction and quality assessment
The abstracts were screened by one author and full texts by three authors. The descriptive and quantitative data from the screened studies were extracted and papers were graded using the Methodological Index for Non-Randomized Studies (MINORS) 13 . The MINORS criteria have been designed to assess the quality of comparative and   Artinyan et al. 24 Cone et al. 18 Duron et al. 28 Haruki et al. 44 Huang et al. 45 Kerin Povšič et al. 49 Law et al. 33 Platt et al. 35 Richards et al. 37 Thorgersen et al. 40 Tsujimoto et al. 59 Heterogeneity: χ 2 = 34·39, 10 d.f., P < 0·001; I 2 = 71% Test for overall effect: Z = 9·06, P < 0·001

Reference Yes No
Hazard ratios are shown with 95 per cent confidence intervals. A fixed-effect model was used for meta-analysis. O-E, observed to expected; V, variance; OS, overall survival.
non-comparative surgical studies using a three-point scale (0, not reported; 1, reported but inadequate; 2, reported and adequate), with assessment of eight items for non-comparative studies and 12 items for comparative studies. The ideal global scores for comparative and non-comparative studies are 24 and 16 respectively. Articles were graded by three reviewers initially, and only those that scored at least 18 of 24 were included in the statistical analysis. If there was disagreement on whether a paper should be included or not, another reviewer graded it and made the final decision. At the outset both rectal and colonic cancer procedures were grouped into a single category.
Results were separated into two key categories: infective complications (SSI, organ space infections, infectious complications, sepsis) and anastomotic leakage. SSI was defined according to the Centers for Disease Control and Prevention 14 definition, whereas anastomotic leak was defined as reported in each article.
Overall survival, disease-free survival, cancer-specific survival and cancer recurrence data were analysed for each outcome where data were available and applicable. Survival terms were defined in accordance with National Institutes of Health-National Cancer Institute definitions 15 .

Statistical analysis
For oncological outcomes, hazard ratios (HRs) were taken from papers or calculated using the MedCalc ® statistical calculator (MedCalc, Ostend, Belgium). Observed minus expected (O-E) values and variance were calculated 16 , and used to compute statistical values for use in the analysis.
Statistical analysis was performed in Review Manager (RevMan) version 5 (Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark) using O-E and variance, a fixed-effect model for analysis and HR as effect measure, with 95 per cent confidence intervals. Significance was assessed at the two-sided 5 per cent level using HRs. The complication has a significant effect on the measured oncological outcome if the 95 per cent confidence interval of the HR does not include 1⋅00.

Results
A total of 5027 individual articles were reviewed in this study (Fig. 1), of which 145 were found to be relevant and underwent MINORS grading. Forty-three articles  met all inclusion criteria and were used in the data analysis, with a total cohort size of 154 981 patients ( Table 1). Publications were from the USA (7), Korea (5), the UK (4), Japan (4), China (4), Germany (4) and other countries (15). There were 23 retrospective and 20 prospective studies in this meta-analysis. Ten studies were from multicentre databases (6 prospective, 4 retrospective).

Hazard ratio Exp[(O-E)/V)]
Hazard ratios are shown with 95 per cent confidence intervals. A fixed-effect model was used for meta-analysis. O-E, observed to expected; V, variance; AL, anastomotic leak; LR, local recurrence.

Discussion
This meta-analysis of 154 981 patients in 43 studies evaluated the impact of both wound-related non-anastomotic infective complications and anastomotic leakage, and identified a statistically significant negative oncological effect.
From the outset of this extensive literature review there were a number of limitations. In the overall cohort, narrowed by the quality of data and MINORS analysis, there was significant heterogeneity. SSI definitions are problematic, with variation from study to study. This is unfortunately common in all forms of surgery. In a 20-year period up to 2015, only 18 per cent of the top 50 cited peer-reviewed publications on ventral hernia were found to use a standardized definition of SSI and surgical-site occurrence after ventral hernia repair 60,61 . The absence of a common language impedes comparisons in the literature and accurate metrics of hospital quality measures 60 . In addition, the period of surveillance used to report SSI varies between 30 and 60 days 42,60 . Anastomotic leak itself has a heterogeneous spectrum of presentation, depending on the effort made to detect leakage and the criteria used, whether based on combined clinical, radiological or endoscopic features. This may give rise to heterogeneity representing a potential limitation of this meta-analysis. Few articles, in general, addressed the effect of SSI on oncological outcomes; some evaluated overall survival, a few reported disease-free survival and none considered the recurrence rate. Furthermore, owing to the limited numbers of papers, it was not possible to undertake a subset analysis for different stages of colorectal cancer, nor to differentiate between colonic and rectal cancers.
The mean leak rate was 7⋅4 per cent across the 31 articles included in the analysis of anastomotic leak; this is in keeping with the mean leak rate in international data 62 . Anastomotic leakage is increasingly topical; there have been paradigm shifts in surgical, prehabilitation, intraoperative and postoperative approaches to reducing leakage [62][63][64] .
This meta-analysis reinforces the findings of a meta-analysis 65 in 2016, which showed that complication severity had a significant impact on both disease-free and overall survival. Three other studies 66-68 identified a negative impact of anastomotic leakage on long-term cancer-specific survival, particularly noting an increase in local recurrence. Current efforts at SSI management after colorectal surgery focus on compliance with guidelines and evaluation of infection rates, but Gantz and colleagues 69 recently suggested that improvement is needed. Martinez et al. 70 suggested establishing national SSI bundles. Historically, mechanical and oral bowel preparations were favoured, but then bowel preparation went out of vogue. Now there is the potential for reintroduction of bowel cleansing and recognition of the importance of other factors including those relating to the gut microbiome. The gut microbiome potentially has an effect on infection and also a separate oncological effect. A variety of environmental factors, including diet, antibiotics, bowel preparation and surgical stress, act on the microbiome, altering its architecture and function, with a negative effect on oncological outcomes after surgery 71 . It is clear from the present data that anastomotic leakage is associated with increased local recurrence and decreased overall survival. The recent German rectal trial CAO/ARO/AIO-94 7 showed that surgical complications are significantly associated with reduced overall survival. Patients with complications are more likely to have distant metastasis and local recurrences. The reason for this is somewhat unclear, although it is known that cancer cells shed from the bowel may embed themselves on stapling devices, leading to enhanced tumour dissemination in the event of anastomotic leak or reoperation. Exfoliated cancer cells have been detected in the colonic lumen and on stapling devices, suggesting that anastomotic leakage could enhance dissemination 72,73 .
There are many confounders to the potential negative oncological effects of infection. Systemic inflammation has been shown to promote micrometastasis 74 . An infection-led inflammatory cascade will activate cytokines, and cell-and humoral-mediated immunity.
Local recurrence is an important clinical outcome for patients with colorectal cancer; many treatment modalities have been investigated with the aim of reducing pelvic occurrence from total mesorectal excision to neoadjuvant chemoradiotherapy. The present study has identified that additional measures and routine use of SSI prevention bundles need to be implemented to reduce infective complications 75 . Infection prevention should become a potential target for oncological improvement; opportunities to reduce deep wound infection need to be revisited, incorporating wound bundles, intraoperative protective measures such as use of wound protectors, potential antibiotic solution and rectal washouts, and closer monitoring with intra-abdominal pressure measurement after surgery.
This study had a number of limitations. An initial trawl of the literature identified almost 13 000 potential publications. On deeper analysis, including qualitative evaluation using the MINORS criteria, it was found that many of these papers lacked a definition of either SSI or anastomotic leakage 60,61 and, most importantly, no relationship between adverse events and oncological outcome was reported. In contrast, it is increasingly being recognized in other fields of oncology, such as breast cancer, that there may be a relationship between infection and cancer recurrence 76 . Surprisingly SSI data have not been included in cancer registries. Uniform data definitions and data analysis would make analysis easier. The small number of papers reporting infective complications may have led to bias in the present results. Subset analysis of SSI effects at different cancer stages was not possible.
This meta-analysis has identified a statistically significant association between both anastomotic leak and wound infection/SSI and adverse oncological outcomes. Oncological registries incorporating infective and adverse events as part of their outcome analysis may help in understanding the relationship between SSI and oncological outcomes. Reduction in SSI may prove to be a noteworthy part of adjuvant cancer therapy, and wound bundles should become mandatory. There needs to be greater adoption and monitoring of strategies that might reduce SSIs and their negative impact.