Sarcopenia as a predictor of postoperative risk of complications, mortality and length of stay following gastrointestinal oncological surgery

Abstract

Introduction

Sarcopenia has drawn considerable attention as a predictor of postoperative risk, although the relationship between sarcopenia and postoperative risk is contentious. This meta-analysis was conducted to evaluate this relationship.

Methods

A systematic literature search up to May 2020 was carried out and 43 studies were identified (with 16,716 patients) reporting on the relationship between sarcopenia and postoperative risk. In order to evaluate this relationship, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using the dichotomous and continuous method with a random or fixed effects model.

Results

Compared with non-sarcopenic patients, those with sarcopenia have a higher major complications rate (OR: 4.03, 95% CI: 2.49–5.57, p<0.001), a higher total complications rate (OR: 1.77, 95% CI: 1.40–2.24, p<0.001), a higher 30-day mortality rate (OR: 2.38, 95% CI: 1.56–3.63, p<0.001) and a longer hospital stay (mean difference: 4.54 days, 95% CI: 2.49–6.59 days, p<0.001).

Conclusions

Sarcopenia significantly increases the risk of major complications, total complications, 30-day mortality and length of hospital stay. For this reason, it is recommended that sarcopenia is added to preoperative risk evaluation to avoid any possible negative outcomes following gastrointestinal oncological surgery.

Introduction

Surgery is the cornerstone of management in gastrointestinal cancer and primary treatment is associated with possible long-term survival.¹ Nevertheless, the prognostic gain of major abdominal or thoracoabdominal tumour resection must be balanced against the significant risk of adverse events such as anastomotic leakage, stenosis and surgical site or other infections. Postoperative problems can have serious implications including increased risk of death and disease recurrence as well as reduced tolerance to adjuvant therapies.² Clinical evaluation to define a patient’s risk of complications is therefore critical.

Identification of modifiable risk factors, which can be targetted with prophylactic planning, may be able to improve treatment results following gastrointestinal tumour surgery.³ Sarcopenia is generally defined as an age associated decline in muscle mass. The European Working Group on Sarcopenia in Older People has furthermore suggested that the sarcopenic phenotype should include weakened muscular strength and/or physical function.⁴ Sarcopenia is related to poor prognosis across a wide range of oncological settings,⁵ suggesting that muscle dysfunction is a vital component across the cancer field.⁶ Studies have demonstrated that complications (major and total), mortality and length of hospital stay after gastrointestinal oncological surgery increase with presence of sarcopenia.⁷ In the field of invasive oncology, however, sarcopenia has received less attention and evaluation of muscle mass and/or function is not part of standard perioperative management.

Our meta-analysis was conducted with the primary aim of discovering whether preoperative presence of sarcopenia is a predictor of postoperative risk after gastrointestinal cancer resection. Second, stratified analysis was undertaken for problems related to sarcopenia (major complications, total complications, 30-day mortality and length of hospital stay).

Methods

This study was undertaken in accordance with the consensus statement of the MOOSE (Meta-analysis Of Observational Studies in Epidemiology) working group, following an established protocol.⁸ Reviewed papers included observational studies evaluating sarcopenia as a predictor of postoperative risks. Only human studies in the English language were considered. Inclusion was not limited by study size or publication type. Exclusion criteria comprised review articles, commentaries and studies that did not report on the association between sarcopenia and postoperative risk. The process for assessment and exclusion is summarised in Figure 1.

Figure 1 .

Flowchart of study selection

Identification

A systematic search was conducted for literature published up to May 2020 using the Ovid^®, Embase™, Cochrane Library, PubMed and Google Scholar™ databases. The search used a blend of keywords and similar words for sarcopenia, postoperative effect, major complications, total complications, 30-day mortality, length of hospital stay and gastrointestinal surgical oncology. All identified studies were pooled in an EndNote^® file, duplicates were omitted, and the title and abstracts were reviewed to exclude studies that did not report on the association between sarcopenia and postoperative risk.

Screening

Papers were screened based on the following data: study related and patient related characteristics; primary author, period of study, year of publication, country, region of the study and study design; population type, total number of sarcopenic patients, demographic data, and clinical and treatment characteristics; postoperative risks, qualitative and quantitative method of evaluation, information source and outcomes evaluation; and statistical analysis. In cases where a single study included separate data for different postoperative risks, these were extracted independently. The risk of bias in individual studies was assessed using the Quality in Prognosis Studies tool, which evaluates validity and bias across six domains: participation, attrition, prognostic factor measurement, confounding measurement and account, outcome measurement, and analysis and reporting.⁹ Any inconsistencies were addressed on re-evaluation of the original article.

Eligibility

The primary outcome measure of our study was the effect of sarcopenia as a predictor of postoperative risks (major complications, total complications, 30-day mortality and length of hospital stay).

Inclusion

Sensitivity analyses were limited only to studies reporting on the effect of sarcopenia as a predictor of postoperative risk compared with non-sarcopenic patients. For subcategory and sensitivity analysis, comparisons between sarcopenic patients and non-sarcopenic patients were used as a reference.

Statistical analysis

The dichotomous and continuous method with a random or fixed effects model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). The I² statistic was used to measure the level of heterogeneity between studies. I² values of 25%, 50% and 75% were considered to represent low, medium and high heterogeneity respectively.¹⁰ When I² was >50%, the random effects model was chosen and when it was <50%, the fixed effects model was employed.

Subanalysis was conducted by stratifying data according to the different postoperative risks (major complications, total complications, 30-day mortality and length of hospital stay). In this analysis, a p-value of <0.05 for differences between subcategories was considered statistically significant. Publication bias was evaluated quantitatively, using Egger’s regression test (publication bias considered present if p≥0.05), and qualitatively, by visual examination of funnel plots of the logarithm of ORs versus their standard errors.¹¹ All p-values were two-tailed. All calculations were performed using RevMan version 5.3 (Nordic Cochrane Centre, Copenhagen, Denmark).

Results

A total of 2,343 unique studies were identified, of which 43 fulfilled the inclusion criteria and were included in this review (Table 1).^12–54 The 43 studies included 16,716 patients. Of these, 5,402 had sarcopenia. All studies investigated whether sarcopenia was a predictor of postoperative risk.

Table 1 .

Summary of included studies

Study	Sarcopenic patients	Non-sarcopenic patients	Total	Type of surgery	Country
Peng, 201112	41	218	259	Colorectal	US
Harimoto, 201313	75	111	186	Colorectal	US
Kaido, 201314	10	62	72	Hepatic	Japan
Amini, 201515	152	611	763	Pancreatic	US
Coelen, 201516	42	58	100	Hepatic	Netherlands
Huang, 201517	17	125	142	Colorectal	China
Ida, 201518	61	77	138	Oesophageal	Japan
Jones, 201519	15	85	100	Colorectal	UK
Lodewick, 201520	80	91	171	Colorectal	Netherlands
Otsuji, 201521	85	171	256	Hepatic	Japan
Tegels, 201522	86	63	149	Gastric	Netherlands
Valero, 201523	47	49	96	Hepatic	US
van Vugt, 201524	90	116	206	Other	Netherlands
Voron, 201525	59	50	109	Hepatic	France
Zhou, 201526	33	34	67	Hepatic	China
Fukuda, 201627	21	78	99	Gastric	Japan
Grotenhuis, 201628	54	66	120	Oesophageal	Netherlands
Harada, 201629	84	172	256	Oesophageal	Japan
Higashi, 201630	45	46	91	Hepatic	Japan
Huang, 201631	47	97	144	Gastric	China
Makiura, 201632	29	75	104	Oesophageal	Japan
Malietzis, 201633	485	320	805	Colorectal	UK
Nishida, 201634	132	134	266	Mixed	Japan
Nishigori, 201635	149	50	199	Oesophageal	Japan
Okumura, 201636	64	166	230	Pancreatic	Japan
Ouchi, 201637	20	40	60	Colorectal	Japan
Pecorelli, 201638	132	70	202	Pancreatic	Italy
Pędziwiatr, 201639	34	90	124	Colorectal	Poland
Sato, 201640	58	235	293	Gastric	Japan
Takagi, 201641	118	136	254	Hepatic	Japan
Wang, 201642	32	223	255	Gastric	China
Zhuang, 201643	389	548	937	Gastric	China
Elliott, 201744	49	143	192	Oesophageal	Ireland
Harimoto, 201745	24	78	102	Hepatic	Japan
Huang, 201746	79	391	470	Gastric	China
Paireder, 201747	80	50	130	Oesophageal	Austria
Van Rijssen, 201748	130	36	166	Other	Netherlands
Zhou, 201749	10	62	72	Gastric	China
Kawamura, 201850	111	840	951	Gastric	Japan
Makiura, 201851	31	67	98	Oesophageal	Japan
Nakanishi, 201852	298	196	494	Oesophageal	Japan
Nakashima, 201853	166	175	341	Colorectal	Japan
Zhang, 201954	1,638	4,809	6,447	Digestive tract	China
Total	5,402	11,314	16,716

Study sizes ranged from 60 to 6,447 patients at the start of the study, with 20–1,638 sarcopenic patients. Of the studies included in this meta-analysis, 36 reported data on major complications, 20 on total complications, 8 on 30-day mortality and 15 on length of hospital stay. The extent of the increase of major complications, total complications, 30-day mortality and length of hospital stay was significantly higher in sarcopenic patients, and this was statistically significant in all populations studied.

Compared with non-sarcopenic patients, those with sarcopenia were significantly more likely to experience major complications (OR: 4.03, 95% CI: 2.49–5.57, p<0.001, I²=45%), total complications (OR: 1.77, 95% CI: 1.40–2.24, p<0.001, I²=55%), 30-day mortality (OR: 2.38, 95% CI: 1.56–3.63, p<0.001, I²=42%) and a longer hospital stay (mean difference: 4.54 days, 95% CI: 2.49–6.59 days, p<0.001, I²=93%) (Figures 2–5). Stratified analysis of studies that did and did not adjust for the effect of sex and ethnicity was not conducted because no studies reported or adjusted for this factor. According to visual inspection of the funnel plot and quantitative measurement with Egger’s regression test, there was no evidence of publication bias (p=0.86).

Figure 2 .

Forest plot comparing major complications for sarcopenic patients and non-sarcopenic patients

Figure 3 .

Forest plot comparing total complications for sarcopenic patients and non-sarcopenic patients

Figure 4 .

Forest plot comparing 30-day mortality for sarcopenic patients and non-sarcopenic patients

Figure 5 .

Forest plot comparing length of hospital stay for sarcopenic patients and non-sarcopenic patients

Discussion

In our meta-analysis of 43 studies with 16,716 patients at baseline, 5,402 patients were sarcopenic. The effect of sarcopenia as a predictor of postoperative risk was variable in the selected studies. Patients with sarcopenia had significantly higher major complications, total complications, 30-day mortality and length of hospital stay than non-sarcopenic patients. These effects were observed in all patient groups.^12–54 This finding indicates that sarcopenia is a predictor of postoperative risk and it follows that sarcopenia should be added to preoperative risk evaluation. Clinicians need to analyse risk factors for sarcopenia in patients who plan to undergo gastrointestinal oncological surgery, and should then suggest interventions according to specific disease and nutritional need based on those risk factors to improve postoperative outcomes.

This study illustrates the importance of further research on sarcopenia as a predictor of postoperative risk. Prognosis following surgery for gastrointestinal cancer is unfavourable; consequently, improved recovery after surgery, new surgical techniques, perioperative nursing and preoperative risk evaluation have received attention as a way of improving the prognosis. Currently, preoperative risk evaluation includes ASA (American Society of Anesthesiologists) grade, nutritional risk screening and routine preoperative investigation. However, these indicators are not precise. Guidelines from the American College of Surgeons also point out the significance of sarcopenia for evaluation in older patients.⁵⁵ Although the authors of the studies included in our meta-analysis have explored the relationship between sarcopenia and the risk of poor outcomes following gastrointestinal oncological surgery, their conclusions are conflicting. The reasons for the effect of sarcopenia as a predictor of postoperative risk are likely to be multifactorial.

When a patient ages, not only does the musculoskeletal system deteriorate owing to loss in muscle and bone mass but this is also accompanied by a decrease in serum levels of insulin-like growth factor 1, which is responsible for whole body regeneration.⁵⁶ The problem of decline in muscle mass (and therefore in physical function) has been recognised in many clinical trials.⁵⁷ Strategies to combat this may include a mixture of pharmacological, nutritional⁵⁸ and exercise-based⁵⁹ interventions but more research is needed to identify additional means of decreasing postoperative problems following gastrointestinal surgical oncology. Prehabilitation has a great role to play in sarcopenic patients undergoing surgery for gastrointestinal cancer. Evidence has shown that prehabilitation is possible in sarcopenic patients,⁶⁰ and may increase functional capability and recovery from surgery.⁶¹ Many studies have also demonstrated that reduced physical or muscle function before surgery is related to a lower risk of postoperative complications.⁶²

According to the present meta-analysis, sarcopenia is independently related to postoperative risk following gastrointestinal oncological surgery in terms of major complications, total complications, 30-day mortality and length of hospital stay. This finding has important implications for surgical practice.⁶³ We recommend that sarcopenia is added to preoperative risk evaluations so as to avoid any possible adverse outcomes after gastrointestinal tumour resection.

Study limitations

There is potential for selection bias in our study as so many of the articles initially identified were excluded from the meta-analysis. However, these excluded studies did not satisfy the inclusion criteria of our meta-analysis. Only English language articles were considered in our review. Furthermore, the method of assessment of postoperative complications following gastrointestinal oncological surgery in the selected studies was variable and several studies did not report data on physical activity. Finally, it was not possible to investigate whether the effect of sarcopenia as a predictor of postoperative risk is associated with sex, ethnicity or the type of operation performed as none of the selected studies gave this information.

Conclusions

Sarcopenia has been related to negative outcomes following surgery for gastrointestinal cancer. A significantly higher major complications rate, total complications rate and 30-day mortality rate as well as a longer hospital stay were observed in sarcopenic patients. These findings indicate that sarcopenia should be added to preoperative risk evaluation for patients undergoing gastrointestinal oncological surgery in order to avoid any possible negative postoperative outcomes.