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META-ANALYSIS
Sarcopenia and Postoperative Complication Risk
in Gastrointestinal Surgical Oncology
A Meta-analysis
Casper Simonsen, MSc,  Pieter de Heer, MD, PhD,y Eik D. Bjerre, MSc,z
Charlotte Suetta, MD, PhD, DMSc,§ Pernille Hojman, MSc, PhD,  Bente K. Pedersen, MD, DMSc, 
Lars B. Svendsen, MD, DMSc,y and Jesper F. Christensen, MSc, PhD 
Objective: The aim of the study was to evaluate sarcopenia as a predictor of
postoperative risk of major and total complications after surgery for gastro-
intestinal cancer.
Background: Sarcopenia is associated with poor survival in gastrointestinal
cancer patients, but the role of sarcopenia as prognostic tool in surgical
oncology has not been established, and no consensus exists regarding
assessment and management of sarcopenic patients.
Methods: We performed a systematic search for citations in EMBASE, Web
of Science, and PubMed from 2004 to January 31, 2017. Random effects
meta-analyses were used to estimate the pooled risk ratio for postoperative
complications by Clavien-Dindo grade (total complications: grade 2; major
complications: grade 3) in patients with sarcopenia versus patients without
sarcopenia. Stratified analyses were performed by sarcopenia criteria, cutoff
level, assessment methods, study quality, cancer diagnosis, and ‘‘Enhanced
Recovery After Surgery’’ care.
Results: Twenty-nine studies (n ¼ 7176) were included with sarcopenia
prevalence ranging between 12% and 78%. Preoperative incidence of sarcopenia
was associated with increased risk of major complications (risk ratio 1.40; 95%
confidence interval, 1.20–1.64; P < 0.001; I2 ¼ 52%) and total complications
(risk ratio 1.35; 95% confidence interval, 1.12–1.61; P ¼ 0.001; I2 ¼ 60%).
Moderate heterogeneity was found for both meta-analyses. Subgroup analyses
showed that sarcopenia remained a consistent risk factor across stratification by
sarcopenia criteria, assessment methods, study quality, and diagnoses.
Conclusions: Sarcopenia was associated with an increased risk of complications
after gastrointestinal tumor resection, but lack of methodological consensus
hampers the interpretation and clinical utilization of these findings. Combining
assessment of muscle mass with measures of physical function may increase the
prognostic value and accuracy in preoperative risk stratification.
From the Centre of Inflammation and Metabolism/Centre for Physical Activity
Research (CIM/CFAS), Rigshospitalet, Copenhagen, Denmark; yDepartment
of Surgical Gastroenterology C, Rigshospitalet, Copenhagen, Denmark;
zUniversity Hospital Centre for Health Research, Rigshospitalet, Copenhagen,
Denmark; and §Department of Clinical Physiology, Nuclear Medicine & PET,
Rigshospitalet Glostrup, University of Copenhagen, Rigshospitalet, Copenha-
gen, Denmark.
The Centre for Physical Activity Research (CFAS) is supported by a research grant
from TrygFonden. JFC is supported by grants from the Danish Cancer Society,
the Capital Region of Denmark, Rigshospitalet and TrygFonden. The funding
sources had no role in the design and conduct of the study; collection of data,
analysis, and interpretation; preparation, review, or approval of the manuscript;
and decision to submit the manuscript for publication.
The authors report no conflicts of interests.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions of
this article on the journal’s Web site (www.annalsofsurgery.com).
Reprints: Jesper F. Christensen, MSc, PhD, Centre for Physical Activity Research
(CFAS), Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
E-mail: jesper.frank.christensen@regionh.dk.
Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0003-4932/16/XXXX-0001
DOI: 10.1097/SLA.0000000000002679
Annals of Surgery  Volume XX, Number XX, Month 2018
Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Keywords: Clavien-Dindo grade, gastrointestinal cancer, muscle dysfunction,
postoperative complications, sarcopenia, surgery
(Ann Surg 2018;xx:xxx–xxx)
S urgery is a cornerstone in gastrointestinal cancer treatment and
comprises the primary therapeutic option associated with possi-
ble long-term survival.1–4 However, the prognostic gain of major
abdominal or thoraco-abdominal tumor resection must be balanced
against the significant risk of adverse reactions such as anastomotic
leakage, stenosis, and risk of surgical site or extrasurgical site
infections. Postoperative complications can have critical implica-
tions including increased risk of mortality and disease recurrence,
and impaired tolerance to adjuvant therapies,5,6 and thus, clinical
assessments to determine individuals’ complication risk are war-
ranted. In particular, the identification of modifiable risk factors,
which can be targeted with prophylactic strategies, holds promising
potential to improve treatment outcomes after gastrointestinal tumor
resection.7
Sarcopenia was traditionally defined as an age-related decline
in muscle mass,8 but the European Working Group on Sarcopenia in
Older People (EWGSOP) recently proposed that the sarcopenic
phenotype should also include impaired muscular strength and/or
physical function.9 Compelling evidence shows that sarcopenia,
irrespective of definition, is independently associated with poor
prognosis across a wide range of oncology settings,10,11 suggesting
that muscle dysfunction is an important intermediate outcome across
the cancer continuum.12 In surgical oncology, however, sarcopenia
has received less attention, and assessment of muscle mass and/or
function is not part of standard perioperative management.
Against this background, we performed the present systematic
review and meta-analysis of the literature with the primary objective
to explore whether preoperative incidence of sarcopenia is a predictor
for postoperative complication risk after gastrointestinal cancer
surgery. Second, we performed stratified analyses by study method-
ology characteristics (ie, sarcopenia criteria, muscle assessment
methods, diagnosis, study quality, etc.) to determine if these variables
moderated the association between sarcopenia and postoperative
complication risk and/or the level of heterogeneity of the meta-
analyses. Finally, we explored the interplay between sarcopenia and
other risk factors such as advanced age, comorbidity burden, and
malnutrition, by review of available multivariate analyses to deter-
mine the adjusted prognostic value of sarcopenia compared with
traditional risk factors.
METHODS
The present study is a meta-analysis reported according to the
guidelines of Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA).13
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Simonsen et al
Eligibility Criteria
We included studies based on the following predefined crite-
ria: (1) patients with resectable gastrointestinal cancer, (2) assess-
ment of sarcopenia performed before surgery, and (3) postoperative
complications reported and graded according to the Clavien-Dindo
classification.14 Postoperative complications included any compli-
cations occurring after surgery, and were not limited to in-hospital
complications during the primary hospital stay. We limited our
search to include studies based on 2 overall criteria for sarcopenia:
(1) muscle mass (only) criteria, or (2) EWGSOP criteria, including
low muscle mass in combination with low handgrip strength and/or
low walking speed.9
Search Strategy
A systematic literature search was performed using the data-
bases PubMed, EMBASE, and Web of Science. Three blocks of
keywords were applied related to cancer, surgical complications, and
muscle mass or muscle function. The searches were adjusted to
accommodate the setup of each of the individual search engines, with
the use of keywords searched in titles, abstracts, and subject headings
(eg, MeSH in PubMed). The searches were limited to articles
published in 2004 to present, as the Clavien-Dindo classification,
published in 2004, was used as an inclusion criterion. In addition, a
manual search of the references of the included studies was con-
ducted. The latest searches were conducted on January 31, 2017 (the
full search strategy is available in Supplement, pp. 2–4, http://links.
lww.com/SLA/B371).
Screening of titles and abstracts to determine eligibility was
performed by the first author (CS), and screening of full-text records
was examined by 2 authors independently (CS and JFC). Disagree-
ments were solved by discussion.
Data Extraction
CS performed the data extraction and EB independently
checked correctness of all extractions. Disagreements were solved
by discussion. For each cohort study, we extracted information on
design (prospective or retrospective); year of publication; number of
patients included by tumor site; type of surgery; median age; sex
proportion; study country; sarcopenia definition (muscle mass or
EWGSOP); assessment methods and cutoff values, and prevalence;
and the incidence of postoperative complications.
We summarized postoperative complications using the Clav-
ien-Dindo classification,14 and defined ‘‘major complications’’ as
Clavien-Dindo grade 3, whereas ‘‘total complications’’ were
defined as Clavien-Dindo graded 2. We excluded grade 1 compli-
cations, as these were rarely included in retrieved citations. If
potentially eligible citations did not provide all necessary informa-
tion, we contacted the corresponding author to request missing data.
Quality Assessment
Quality assessment of the included studies was performed by
using the Newcastle–Ottawa scale for cohort studies.15 A score of 5
or below was considered low quality; a score of 6 or 7 was considered
moderate quality; and a score of 8 or 9 was considered high quality.
In addition, the Grading of Recommendations Assessment, Devel-
opment, and Evaluation (GRADE) system was used to assess the
overall quality of the evidence.16
Data Synthesis and Analysis
For each study, we calculated risk ratios and 95% confidence
intervals (CIs) for postoperative complications in sarcopenic patients
compared with nonsarcopenic patients.17 For the extracted cases
and noncases of postoperative complications, we summarized the
results quantitatively using inverse variance random effects models.
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Annals of Surgery  Volume XX, Number XX, Month 2018
Random effects models were used as we expected considerable
variation in ethnicity, types of cancer, definitions of sarcopenia,
and surgical procedures.
We further wished to explore the impact of various methodo-
logical considerations and patient characteristics on heterogeneity.
We therefore performed subgroup analyses with studies stratified by
(1) sarcopenia criteria; (2) choice of cutoff level; (3) skeletal muscle
assessment methods; (4) study quality; (5) cancer diagnosis; and (6)
with/without concurrent ‘‘Enhanced Recovery After Surgery’’
(ERAS) care. These explorative subanalyses were performed for
major complication risk only, as this comprised the majority of the
retrieved citations. Finally, we summarized citations which included
adjusted/multivariate analyses to explore the independent role of
sarcopenia and its interplay with other risk factors.
Cochrane Review Manager 5.2 software was used to perform
the metaanalyses, produce forest plots, and assess heterogeneity.
Heterogeneity was assessed using the I2 statistics, for describing the
proportion of variability of the observed effect estimates that is
caused by heterogeneity of studies rather than sampling error.18
Small study effects were addressed using Egger and Harbord small
study effect test19 using STATA/IC version 13.1 software.
RESULTS
From 5914 retrieved citations (Fig. 1), 35 publications fulfilled
the inclusion criteria. Among these, we identified 6 studies presenting
data from subgroups already included in studies within our search
(these citations are listed in Supplement, p. 5, http://links.lww.com/
SLA/B371). Accordingly, we identified 29 studies20–48 fulfilling the
inclusion criteria comprising a total of 7176 patients (Table 1). Twenty-
five studies20–36,38–41,43–45,48 were retrospective and 3 studies37,46,47
were prospective. The diagnoses included were pancreatic cancer (n ¼
1195),23–25 colorectal (n ¼ 1231),35–38,46 gastric cancer (n ¼
1948),20–22,45,47 liver cancer (n ¼ 1159),28–34,48 esophageal cancer
(n ¼ 575),39–41 colorectal cancer liver metastases (n ¼ 430),26,27
mixed cancers (n ¼ 266),42 and other cancers, which included peri-
ampullary cancer (n ¼ 166)43 and peritoneal carcinomatosis of
colorectal cancer (n ¼ 206).44 Among the included studies, 5 reported
that treatment was conducted under ERAS care21,23,26,37,44 and only 1
study reported using interventions specific to the needs of each
patient.47
Thirteen studies20,21,24,26–29,31,33–36,43 did not report informa-
tion regarding the frequency of specific types of complications, and 7
studies22,23,37–39,44,46 reported no difference between sarcopenic and
nonsarcopenic patients. In contrast, 9 studies25,30,32,40–42,45,47,48
reported that sarcopenia was associated with an increased risk of
specific types of complications. Specifically, sarcopenia was associ-
ated with increased the risk of respiratory complications,41 nonsurgical
site infections,45 medical complications,47 bile leak,25 renal compli-
cations,25 sepsis,30 liver-related morbidities,30,32,48 anastomotic leak-
age,40 pancreatic fistulas,42 and intra-abdominal abscess.32
Sarcopenia Definition, Assessment Methods, and
Prevalence
Sarcopenia was determined by 22 unique diagnostic definitions
(Table 2). Muscle mass criteria were applied in 26 studies,20–44,48
and the EWGSOP criteria were applied in 3 studies.45–47 Four different
assessment methods were used to quantify muscle mass. Three assess-
ments were based on computed tomography (CT) scan [L3 skeletal
muscle index, total psoas volume (TPV), or total psoas index (TPI)],
and 1 assessment was based on bioelectrical impedance analysis.
Sarcopenia prevalence ranged between 12% and 78% (Table 1). In
studies applying muscle mass criteria, the majority (18 of 26 stud-
ies)20,22,23,26,28–31,34,36,37,39–44,48 applied CT scan-based assessment
of skeletal muscle index (SMI) [prevalence range: 27.4%–78%], 5
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ANNSURG-D-17-01482
Annals of Surgery  Volume XX, Number XX, Month 2018
FIGURE 1. Flowchart of the citation screening procedures.
studies24,27,32,35,38 measured CT scan-based TPI [prevalence range:
15%–33%], 2 studies25,33 used TPV [prevalence range: 19.9%–
48.9%], and a single study21 applied bioelectrical impendence
analysis [prevalence 20%]. For studies applying the EWGSOP
criteria, sarcopenia prevalence was 12.0% to 21.2%, with 2 studies46,47
applying CT scan-based SMI measures [prevalence range: 12.0%–
16.8%] and 1 study45 using bioelectrical impedance measurement
[prevalence 21.2%].
Quality Assessment
The quality assessment of the included studies is available in
Table 3, and shows study quality ranging from low to moderate with
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Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Sarcopenia and Complication Risk in Gastrointestinal Surgical Oncology
scores ranging from 3 to 7 on the Newcastle–Ottawa scale. Thirteen
studies20,21,23,29,30,34,35,37,42– 45,47 of the 28 included studies scored 6
or 7 and were considered of moderate quality. The remaining 16
studies22,24 –28,31– 33,36,38– 41,46,48 scored 5 or lower and were consid-
ered low quality. According to GRADE, we found the overall quality
of the evidence for sarcopenia as a risk factor for both major and total
complications to be rated as ‘‘very low’’ due to the observational
nature of the available literature (Supplementary, p. 7, Table 1, http://
links.lww.com/SLA/B371).
Risk of Bias
For total complications, neither Egger nor Harbord test
revealed any small study effects. For major complications, Har-
bord, but not Egger, test revealed a small study effect (P ¼ 0.02
and P ¼ 0.072, respectively). Full risk of bias analyses and funnel
plots are available in Supplement, pp. 6–7, http://links.lww.com/
SLA/B371.
Meta-analysis Main Effects: Postoperative
Complication Risk
Postoperative major and total complication risk for patients
with sarcopenia versus nonsarcopenia is presented in Figure 2.
Major Complications
Based on 28 studies20,22–48 comprising 6883 patients and
1247 major complications (Clavien-Dindo grade 3), preoperative
incidence of sarcopenia was associated with an increased risk of
major complications by [RR 1.40; 95% CI, 1.20–1.64; P < 0.001; I2
52%], as shown in Figure 2A.
Total Complications
Based on 12 studies20,21,23,28,35,37,39–41,45 –47 comprising 3051
patients and 935 complications (Clavien-Dindo grade 2), preoper-
ative incidence of sarcopenia was associated with an increased risk of
total complications (RR 1.35; 95% CI, 1.12–1.61; P < 0.001; I2
60%), as illustrated in Figure 2B.
Subgroup Analyses for Major Complications
Next, we performed subgroup analyses for the meta-analyses
of major complication risk (Clavien-Dindo grade 3), to elucidate
factors explaining the moderate level of heterogeneity.
Sarcopenia Criteria
Our subgroup analysis showed that sarcopenia remained a
significant risk factor of postoperative complications independent of
sarcopenia criteria; however, we found a significant difference
between studies using muscle mass and EWGSOP criteria (P ¼
0.02). In 25 studies20,22–44,48 using muscle mass criteria, patients
presenting with sarcopenia had an increased risk of major postoper-
ative complications (RR 1.35; 95% CI, 1.15–1.58; P < 0.001; I2
52%, n ¼ 6172), whereas the 3 studies using EWGSOP criteria45– 47
found patients presenting with sarcopenia had a higher increase in
risk ratio (RR 2.77; 95% CI 1.52–5.06; P < 0.001; I2 0%, n ¼ 711)
(Fig. 3A).
Sarcopenia Cutoff Level
To further explore the significant heterogeneity in studies
using muscle mass criteria, we stratified these by choice of cutoff
level, that is, predefined cutoff compared with study-specific
percentiles or optimum stratification cutoff. The pooled risk
estimate of the 12 studies20,24,25,27,30 – 32,38,40,43,48 using study data
to define the sarcopenia cutoff demonstrated reduced and nonsignifi-
cant heterogeneity and an increased risk of postoperative complica-
tions for sarcopenic patients (RR 1.47; 95% CI, 1.23–1.77; P < 0.001;
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Simonsen et al Annals of Surgery  Volume XX, Number XX, Month 2018

TABLE 1. Study Characteristics

Cancer Sample Male Median Sarcopenia Prevalence
References Site Design Country Size (%) Age Criteria at Risk (%)
Grotenhuis 201639 Esophagus Retrospective The Netherlands 120 88 (73.3) 62 Muscle mass 45
Harada 201640 Esophagus Retrospective Japan 256 n/a n/a Muscle mass 33
Nishigori 201641 Esophagus Retrospective Japan 199 164 (82.4) 65.2 Muscle mass 75
Zhuang 201620 Gastric Retrospective China 937 730 (77.9) 64.0 Muscle mass 41.5
Sato 201621 Gastric Retrospective Japan 293 192 (65.5) 66 Muscle mass 20
Tegels 201522 Gastric Retrospective The Netherlands 152 87 (57.2) 69.6 Muscle mass 57.7
Fukuda 201645 Gastric Retrospective Japan 99 66 (66.7) 75.6 EWGSOP 21.2
Huang 201747 Gastric Prospective China 470 364 (77.4) 65 EWGSOP 16.8
Pecorelli 201623 Pancreas Retrospective Italy 202 108 (53.5) 66.8 Muscle mass 65.3
Okumura 201524 Pancreas Retrospective Japan 230 124 (53.9) 67 Muscle mass 27.8
Amini 201525 Pancreas Retrospective United States 763 418 (54.8) 67 Muscle mass 19.9
Voron 201528 Liver Retrospective France 109 92 (84.4) 61.7 Muscle mass 54
Zhou 201529 Liver Retrospective China 67 22 (32.8) 61 Muscle mass 49.3
Coelen 201530 Liver Retrospective The Netherlands 100 64 (64) 62 Muscle mass 42
Takagi 201631 Liver Retrospective Japan 254 207 (81.5) 65.7 Muscle mass 46.5
Otsuji 201532 Liver Retrospective Japan 256 162 (63.2) 68 Muscle mass 33
Valero 201533 Liver Retrospective United States 96 59 (61.4) 61.9 Muscle mass 48.9
Harimoto 201334 Liver Retrospective Japan 186 145 (80.0) 66.4 Muscle mass 40.3
Higashi 201648 Liver Retrospective Japan 91 76 (83.5) 65.7 Muscle mass 49.5
Lodewick 201526 CRC liver mets Retrospective The Netherlands 171 104 (60.8) 64 Muscle mass 46.8
Peng 201127 CRC liver mets Retrospective United States 259 155 (59.8) 58 Muscle mass 15.8
Jones 201535 Colorectal Retrospective United Kingdom 100 60 (60) 68.6 Muscle mass 15
Malietzis 201636 Colorectal Retrospective United Kingdom 805 472 (58.6) 69 Muscle mass 60.2
Pedziwiatr 201637 Colorectal Prospective Poland 124 73 (58.5) 65.9 Muscle mass 27.4
Ouchi 201638 Colorectal Retrospective Japan 60 35 (58) 69 Muscle mass 33
Huang 201546 Colorectal Prospective China 142 88 (62.0) 62.0 EWGSOP 12.0
Nishida 201642 Mixed Retrospective Japan 266 181 (68.0) 69 Muscle mass 49.6
Van Rijssen 201743 Other Retrospective The Netherlands 166 104 (62.7) 64.8 Muscle mass 78
Van Vugt 201544 Other Retrospective The Netherlands 206 100 (48.5) n/a Muscle mass 43.7
CRC liver mets indicates colorectal cancer liver metastases; EWGSOP, European Working Group of Sarcopenia in Older People.
Data are n (%), except for median age.

I2 36%, n ¼ 3468). For 13 studies22,23,26,28,29,34–37,39,41,42,44 using
predefined cutoffs, sarcopenia was not a significant risk factor and the
heterogeneity remained significant (RR 1.22; 95% CI, 0.95–1.57; P ¼
0.12; I2 57%, n ¼ 2704) (Fig. 3B).
Muscle Mass Assessment Methods
Our subgroup analysis stratified by muscle mass assessment
methods demonstrated that sarcopenia remained a consistent risk
factor for postoperative complications across most assessment meth-
ods. Twenty studies20,22,23,26,28 –31,34,36,37,39–44,46 –48 used SMI (RR
1.28; 95% CI, 1.07–1.52; P ¼ 0.006; I2 51%, n ¼ 5020), 5
studies24,27,32,35,38 applied TPI (RR 1.88; 95% CI, 1.27–2.77;
P ¼ 0.001; I2 27%, n ¼ 905), 2 studies25,33 used TPV (RR 4.15;
95% CI, 0.30–57.67; P ¼ 0.29; I2 73%, n ¼ 859), and 1 study45 used
bioelectrical impedance (RR 3.18; 95% CI, 1.20–8.47; P ¼ 0.02, n ¼
99) (Fig. 3C).
Quality Score
In the subgroup analysis stratified by quality score according
to the Newcastle–Ottawa scale, sarcopenia remained a significant
risk factor across stratification with no subgroup differences for
studies with low quality22,24– 28,31–33,36,38– 41,46,48 (RR 1.31; 95% CI,
1.14–1.51; P < 0.001; I2 17%, n ¼ 3960) compared with studies with
moderate quality20,23,29,30,34,35,37,42– 45,47 (RR 1.52; 95% CI, 1.10–
2.10; P ¼ 0.01; I2 72%, n ¼ 2923), as shown in Figure 3D.
Diagnoses
The pooled risk ratios from the subgroup analysis stratifying
studies by diagnoses indicated an increased risk for all diagnoses,
although several of these were not significant and included colorectal
cancer35– 38,46 (RR 1.51; 95% CI, 0.63–3.63; P ¼ 0.35, I2 62%, n ¼
1231), colorectal liver metastases26,27 (RR 1.91; 95% CI, 0.97–3.75;
P ¼ 0.06; I2 54%, n ¼ 430), esophageal cancer39– 41 (RR 1.15; 95%
CI, 0.89–1.48; P ¼ 0.29; I2 0%, n ¼ 575), gastric cancer20,22,45,47
(RR 1.97; 95% CI, 1.11–3.51; P ¼ 0.04; I2 65%, n ¼ 1655), liver
cancer28– 34,48 (RR 1.25, 95% CI, 0.92–1.71; P ¼ 0.16; I2 62%, n ¼
1159), pancreatic cancer23–25 (RR 1.39; 95% CI, 1.03–1.88; P ¼
0.03; I2 0%, n ¼ 1195), mixed and other cancers42– 44 (RR 1.52; 95%
CI, 1.01–2.28; P ¼ 0.04; I2 61%, n ¼ 638) (Fig. 4A).
ERAS
We found no difference in the subgroup analysis between
studies stratified by use of ERAS care; however, the pooled risk
estimate of the 4 studies23,26,37,44 applying ERAS care did not
demonstrate a significant increase in risk (RR 1.29; 95% CI,
0.91–1.83; P ¼ 0.15; I2 12%, n ¼ 703), whereas the 24 stud-
ies20,22,24,25,27 –36,38– 43,45–48 which did not report ERAS care were
associated with an increased risk (RR 1.44; 95% CI, 1.21–1.71; P <
0.001; I2 56%, n ¼ 6180) (Fig. 4B).
Review of Multivariate Analyses: Sarcopenia Versus
Other Risk Factors
From 29 studies exploring the potential association
between sarcopenia and complication risk, a total of 13 stud-
ies20,21,25,27,30,33,35,37,41,43,45–47 further presented complication risk
estimates based on multivariate analyses to account for the potential
confounding impact of interrelated risk factors (Supplementary, p. 8,
Table 2, http://links.lww.com/SLA/B371).

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Annals of Surgery  Volume XX, Number XX, Month 2018 Sarcopenia and Complication Risk in Gastrointestinal Surgical Oncology

TABLE 2. Unique Sarcopenia Definitions, Assessments and Prevalence

No Criteria Assessments Outcomes Cutoff, M Cutoff, F Prevalence Method Reference
2 2
1 Muscle mass L3 CT scan SMI (cm /m ) 53.5 46.4 78% Optimum stratification Van Rijssen 201743
2 Muscle mass L3 CT scan SMI (cm2/m2) 53/43 41 46.8–57.7% Cutoff from Martin Tegels 201522
(over/under et al.71 Lodewick 201526
BMI of 25) Nishida 201642
3 Muscle mass L3 CT scan SMI (cm2/m2) 52.4 38.9 54% Cutoff from Prado Voron28
et al.10
2 2
4 Muscle mass L3 CT scan SMI (cm /m ) 52.4 38.5 27.4–75% Cutoff from Prado Pecorelli 201623
et al.10 Grotenhuis 201639
Nishigori 201641
Pedziwiatr 201637
Van Vugt 201544
5 Muscle mass L3 CT scan SMI (cm2/m2) 46.8 39.1 42% Optimum stratification Coelen 201530
6 Muscle mass L3 CT scan SMI (cm2/m2) 46.4 37.5 46.5% Optimum stratification Takagi 201631
7 Muscle mass L3 CT scan SMI (cm2/m2) 44.5 36.5 33% Lowest gender specific Harada 201640
tertile
8 Muscle mass L3 CT scan SMI (cm2/m2) 43.75 41.10 40.3–49.3% Van Vledder et al.72 Harimoto 201334
Zhou 201529
9 Muscle mass L3 CT scan SMI (cm2/m2) 43.2 35.3 49.5% Median SMI Higashi 201648
10 Muscle mass L3 CT scan SMI (cm2/m2) 40.8 34.9 41.5% Optimum stratification Zhuang 201620
11 Muscle mass L3 CT scan SMI (cm2/m2) - - 60.2% Cutoff not presented Malietzis 201636
12 Muscle mass L3 CT scan TPI (mm2/m2) 589.6 406.7 27.8% Optimum stratification Okumura 201524
13 Muscle mass L3 CT scan TPI (mm2/m2) 545 385 15% Cutoff from Fearon Jones 201535
et al.73
14 Muscle mass L3 CT scan TPI (mm2/m2) 538 346 33% Lowest gender specific Ouchi 201638
tertile
15 Muscle mass L3 CT scan TPI (mm2/m2) 536 378 33% Lowest gender specific Otsuji 201532
tertile
16 Muscle mass L3 CT scan TPI (mm2/m2) 500 500 15.8% Optimum stratification Peng 201127
17 Muscle mass L3 CT scan TPV (cm3/m) 34.14 22.93 48.9% Optimum stratification Valero 201533
18 Muscle mass L3 CT scan TPV (cm3/m2) 17.2 12.0 19.9% Optimum stratification Amini 201525
19 Muscle mass Bio Imp SMI (kg/m2) 15.8 13.8 20% Lowest gender specific Sato 201621
20%
20 EWGSOP L3 CT scan SMI (cm2/m2) 40.8 34.9 16.8% Cut off from Zhuang Huang 201747
Hand grip strength Strength (kg) 26 18 et al.20 and
10m-walk test Speed (m/s) 0.8 0.8 AWGS69
21 EWGSOP L3 CT scan SMI (cm2/m2) 36.0 29.0 12.0% Cut-off from Iritani Huang 201546
Hand grip strength Strength (kg) 26 18 et al.74
10m-walk test Speed (m/s) 0.8 0.8
22 EWGSOP Bio Imp aSMI (kg/m2) 8.87 6.42 21.2% Cut off from Fukuda 201645
Hand grip strength Strength (kg) 30 20 EWGSOP9 and
10m-walk test Speed (m/s) 0.8 0.8 AWGS69
aSMI indicates appendicular skeletal muscle index; AWGS, Asian Working Group of Sarcopenia; Bio Imp: Bioelectrical impedance; Cutoff, F, Cutoff females; Cutoff, M, Cutoff
males; EWGSOP: European Working Group on Sarcopenia in Older People; L3 CT scan: Third Lumbar Vertebrae Computed Tomography scan; SMI: Skeletal muscle index; TPI: Total
psoas index; TPV: Total psoas volume.

For EWGSOP criteria, sarcopenia was defined as low muscle mass combined with either low handgrip strength or low gait speed or both.

Ten studies20,21,25,27,30,33,35,37,41,43 applying muscle mass cri-
teria reported odds ratios from multivariate analyses (Supplementary,
p. 8 Table 2, http://links.lww.com/SLA/B371). Sarcopenia was a
significant independent predictor of postoperative complication risk
in 6 studies,20,25,27,33,35,41 with adjusted odds ratios ranging from 1.7
to 3.1. Diabetes (1 studies20), ASA grade (1 study41), male sex
(2 studies21,33) and ‘‘BMI >25’’ (1 study25), muscle attenuation
(1 study43), and intraoperative factors, that is, type of surgery/
procedure (4 studies21,25,33,41), were also independently associated
with postoperative complication risk.
In 2 of 3 studies applying the EWGSOP criteria,45,46 sarco-
penia was an independent predictor of complication risk with an
adjusted odds ratio of 4.76, whereas prior abdominal surgery46 was
the only other variable which remained significant in multivariate
analyses. For the remaining study,47 ‘‘severe sarcopenia’’ (defined as
low muscle with low hand grip strength and low gait speed) was
independently associated with complication risk in multivariate
analyses with an adjusted odds ratio of 8.9, together with ASA
score, tumor location in cardia, and visceral fat area relative to L3
SMI (Supplementary, p. 9, Table 2, http://links.lww.com/SLA/
B371).47
DISCUSSION
This meta-analysis demonstrates that sarcopenia was associ-
ated with approximately 30% to 40% increased risk of major and
total complications after gastrointestinal tumor resection, although
the evidence had moderate heterogeneity and was rated ‘‘very low’’
according to GRADE. Subgroup analyses for risk of major compli-
cations demonstrated that sarcopenia was a consistent risk factor
across stratification by sarcopenia criteria, most muscle mass assess-
ment methods, quality score, and for gastric, pancreatic and mixed or
other cancers. For studies using ERAS care, TPV assessments, and

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TABLE 3. Quality Assessment

Quality Indicators From Newcastle–Ottawa Scale
Studies 1 2 3 4 5A 5B 6 7 8 Total Score
Amini 201525  þ   þ þ þ  þ 5
Coelen 201630  þ þ  þ þ þ þ þ 7
Fukuda 201645 þ þ   þ þ þ  þ 6
Grotenhuis 201639  þ þ    þ  þ 4
Harada 201640 þ þ þ    þ  þ 5
Harimoto 201334 þ þ þ    þ þ þ 6
Higashi 201648 þ þ þ    þ  þ 5
Huang 201546  þ þ   þ þ  þ 5
Huang 201747  þ þ   þ þ þ þ 6
Jones 201535  þ   þ þ þ þ þ 6
Lodewick 201526  þ þ    þ þ þ 5
Malietzis 201636  þ þ    þ þ þ 5
Nishida 201642 þ þ þ  þ  þ  þ 6
Nishigori 201641  þ þ    þ þ þ 5
Okumura 201624  þ     þ  þ 3
Otsuji 201532 þ þ     þ  þ 4
Ouchi 201638  þ   þ  þ  þ 4
Pecorelli 201623 þ þ þ  þ  þ þ þ 7
Pedziwiatr 201637 þ þ þ   þ þ  þ 6
Peng 201127  þ   þ þ þ  þ 5
Sato 201621 þ þ   þ þ þ þ þ 7
Takagi 201631 þ þ þ    þ  þ 5
Tegels 201522 þ þ þ    þ  þ 5
Vakero 201533  þ   þ þ þ  þ 5
Van Rijssen 201743 þ þ þ    þ þ þ 6
Van Vugt 201544  þ þ  þ þ þ  þ 6
Voron 201528  þ þ    þ þ þ 5
Zhou 201529  þ þ  þ  þ þ þ 6
Zhuang 201620  þ þ  þ þ þ þ þ 7
1: Representativeness of the exposed cohort—consecutive series of patients with >90% available CT scans or comparison with patients without CT scans; 2: selection of the
nonexposed cohort—taken from the same cohort; 3: ascertainment of exposure—measurement of sarcopenia (ie, muscle mass measured using the L3 skeletal muscle index with sex-
specific cutoffs); 4: demonstration that outcome of interest was not present at start of study—no cancer diagnosis present at start of the study; 5A: comparability of cohorts on the basis of
the design or analysis (A)—standardized type of surgery or adjusted for type of surgery; 5B: comparability of cohorts on the basis of the design or analysis (B)—adjusted for other
factors (eg, age, tumor stage, comorbidity, nutritional status, sex); 6: assessment of outcome—independent blind assessment or record linkage; 7: had follow-up long enough for
outcomes to occur—followed at least 30 days after surgery; 8: adequacy of follow-up of cohorts—all patients accounted for or <10% lost to follow-up.

for colorectal cancer, colorectal liver metastases, esophageal cancer,
and liver cancer, the sarcopenia risk ratio was not statistically
significant. Moreover, studies applying muscle mass criteria with
a study-specific cutoff level demonstrated higher risk of postopera-
tive complications and lower level of heterogeneity, whereas studies
using predefined cutoffs did not demonstrate an increased risk of
complications and were more heterogeneous. In studies reporting
adjusted/multivariate analyses, we found that sarcopenia was among
the strongest independent risk factors and may comprise a tran-
scending symptom mediating the impact of other risk factors regard-
less of the underlying etiology. In concert, our analyses suggest that
sarcopenia likely comprises a clinically relevant risk factor for
postoperative complication after gastrointestinal tumor resection,
but the lack of consensus on definitions and methodology remains
a serious problem and hampers the clinical utilization of these
findings.
Despite technological advances and improved surgical tech-
niques, postoperative morbidity burden remains a significant clinical
challenge in gastrointestinal cancer care.49 Compelling evidence
demonstrates that such complications affect not only the patient’s
symptom burden and recovery, but has detrimental implications for
long-term risk of disease progression and mortality.5,6 Thus, preop-
erative clinical evaluation procedures have gained increasing impor-
tance for clinicians to optimally manage patients undergoing
combination therapies with surgery and adjuvant regimens. Recent
reviews have demonstrated that sarcopenia may be associated with
poor prognoses and increase the risk of treatment complications in
patients with cancer.50,51 The present study adds to this growing body
of evidence showing impaired treatment tolerability and efficacy
associated with sarcopenia with a specific focus on the surgical
oncology setting. Thus, the present study is the first to examine the
association between sarcopenia and postoperative complication risk
in surgical oncology by standardized complication outcomes, and
subgroup stratification by sarcopenia criteria, assessment methods,
and study quality, to attempt to explain the moderate levels of
heterogeneity. Subgroup analyses based on methods used to estimate
muscle mass did not correct for heterogeneity, whereas choosing
cutoffs from previous studies or cutoffs derived from within study
data (ie, percentiles or optimum stratification) revealed marked
differences. The studies using predefined cutoffs had an average
prevalence of sarcopenia of 52.7% compared with 35.1% in the
studies using within study data to define a cutoff. Moreover, only
studies using within study data to define the cutoff showed reduced
heterogeneity and a significant association between sarcopenia and
risk of postoperative complications. This discrepancy may, in part,
stem from cutoffs being used on noncomparable populations, thus
increasing the risk of misclassifying patients. This observation
emphasizes the need for population-specific data, from which to

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FIGURE 2. Forrest plots of risk ratio for
postoperative risk of (A) major and (B)
total complications for subjects with
sarcopenia versus nonsarcopenia.
determine valid cutoff levels associated with increased morbidity
risk.
Furthermore, our comparison of overall sarcopenia criteria
showed significant and important differences indicating methodo-
logical challenges beyond that of muscle mass assessment methods
and cutoff levels. Our subgroup analysis of studies using the EWG-
SOP criteria showed higher risk ratios associated with sarcopenia and
less heterogeneity, supporting an added value of functional measures,
although the analysis included only 10% of all patients. The
difference in predictive value may, to some extent, be explained
by almost exclusive reliance on cross-sectional abdominal CT scans
performed for tumor diagnostic/evaluation purposes to evaluate
muscle mass. CT scans are gold-standard assessments of tissue
composition of clinical relevance, and various measures obtainable
from CT scans, including muscle attenuation,52 measures of adipos-
ity (subcutaneous and visceral),23 and sarcopenic obesity,10 have
been associated with impaired cancer outcomes. Although quantifi-
cation of muscle area from a single abdominal cross-sectional image
is found to correlate with whole body lean mass,53 it may not
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Sarcopenia and Complication Risk in Gastrointestinal Surgical Oncology
precisely predict appendicular muscle mass, which may explain
the added value of hand-grip strength (upper body function) and
gait speed (lower body function). Furthermore, muscle mass is only
one of a range of neuromuscular components, including cardiopul-
monary and/vascular function, muscle fiber architecture, phenotype
and oxidative capacity, and supraspinal neural drive. Limitations in 1
or more of these components may cause important functional
limitations which are not detectable by assessment of muscle mass
alone.54,55 Several systematic reviews have also demonstrated that an
impaired physical or muscle function before surgery is associated
with poorer postoperative outcomes including postoperative com-
plications56,57. The physiologic reserve, that is, overall bodily func-
tional capacity including all organ systems,58 may be assessed
advantageously by the additional measures included in EWGSOP
criteria.
The present study adds to an emerging body of evidence,
showing sarcopenia is independently associated with cancer end-
points.50,51 These findings have important implications for surgical
practice,10 particularly in regard to the growing application of
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Simonsen et al Annals of Surgery  Volume XX, Number XX, Month 2018

FIGURE 3. Forrest plots of risk ratio in subgroup analyses for subjects with sarcopenia versus nonsarcopenia for postoperative risk
of major complications (Clavien-Dindo 3) stratified by (A) sarcopenia criteria (EWGSOP vs muscle mass); (B) sarcopenia cutoff
level (predefined vs study-specific percentiles or optimum stratification); (C) muscle mass assessment methods [skeletal muscle
index (SMI) vs psoas muscle index vs total psoas volume]; (D) quality score (moderate vs low). For this analysis only studies using
muscle mass only criteria for sarcopenia were included, as only this criteria resulted in significant heterogeneity. EWGSOP indicates
European Working Group on Sarcopenia in Older People.

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Annals of Surgery  Volume XX, Number XX, Month 2018 Sarcopenia and Complication Risk in Gastrointestinal Surgical Oncology

FIGURE 4. Forrest plots of risk ratio in subgroup analyses for subjects with sarcopenia vs nonsarcopenia for postoperative risk of
major complications (Clavien-Dindo 3) stratified by (A) cancer diagnosis, and (B) with/without Enhanced Recovery After
Surgery (ERAS) care. ERAS indicates Enhanced Recovery After Surgery.

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Simonsen et al
FIGURE 4. (Continued)
ERAS.59 ERAS has led to the evolvement of standardized care plans,
including evaluation of prognostic risk factors, for example, nutri-
tional and performance status and hematology (albumin, hemoglo-
bin), as well as multimodal therapeutic programmes including pain
relief, stress reduction, early nutrition, and mobilization. Importantly,
we did not find a statistically significant increase in risk of postop-
erative complications in studies performed under ERAS care, which
involves ‘‘patient preconditioning’’ before surgery, including man-
agement of pathological risk factors,60 and thus may modify/lower
the risk associated with sarcopenia in surgical patients. However,
muscle-specific deficiencies (ie, low muscle mass and function) are
not considered in the general ERAS evaluation of ‘‘organ dysfunc-
tion’’ and remains underappreciated compared with other known risk
factors. To this end, the present study revealed that sarcopenia
remained significantly associated with complication risk in the
majority of studies after adjustment for traditional risk factors such
as advanced age, comorbidity, and nutritional status, which are
commonly associated with sarcopenia. This may indicate that sar-
copenia comprises a mediating factor of complication risk from other
factors, regardless of its underlying cause. Conceptually, this could
change clinical perception and management of certain patients based
on preoperative risk profile, simply because many known risk factors
(eg, age, diabetes, or other chronic diseases) are either not modifiable
or unlikely to improve during a short preoperative time period.
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Annals of Surgery  Volume XX, Number XX, Month 2018
Contrarily, the reversal of an observed decline in muscle mass
and particularly in physical function has been successfully achieved
in a number of clinical settings.61,62 Optimal strategies may involve a
combination of pharmacological/nutritional63 and exercise-based64
countermeasures, but more research is needed to explore such
interventions with the aim to improve postoperative morbidity in
the oncology setting. The role of ‘‘prehabilitation’’ is rapidly emerg-
ing in surgical oncology, and holds major potential targeting sarco-
penic patients undergoing gastrointestinal cancer surgery, by
improving physiologic reserve which can translate into higher adap-
tive capacity and resilience to surgical stress.65 In terms of utilizing
prehabilitation to improve physiological reserve, it is generally
recommended that prehabilitation should be multimodal and include
physical, nutritional, and mental optimization.58 The current prelim-
inary evidence suggests that multimodal prehabilitation is feasible in
sarcopenic patients66 and may improve functional capacity and
recovery from surgery67. Several clinical trials are currently ongoing
using prehabilitation with an overall aim of improving perioperative
treatment68 and to investigate its impact on frail cancer patients
(NCT03097224).
The current study has important limitations. First, only 2
studies applying the EWGSOP criteria and 1 study applying muscle
mass criteria conducted a prospective design, and the vast majority of
included studies were retrospective with clear disadvantages
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Annals of Surgery  Volume XX, Number XX, Month 2018
regarding risk of bias and potential missing data. Second, we did not
restrict our search to specific diagnoses, and applied a broad sarco-
penia definition which resulted in the identification of 22 unique
cutoff levels and sarcopenia prevalence of approximately 12% to
78%, which may be attributed to subsets of studies applying pre-
defined cutoff levels invalid for the specific population.69 Conse-
quently, we applied random effects analyses, and the impact of
sarcopenia on postoperative complications specific to different types
of gastrointestinal surgical procedures can therefore not be deter-
mined. Third, the Clavien-Dindo classification allowed aggregation
and synthesis of a wide array of studies, but recent evidence suggests
that sarcopenia may increase risk of specific types of complications,
for example, respiratory complications,70 and medical, but not
surgical, complications.47 Finally, only 3 studies comprising 711
patients used EWGSOP criteria, and more studies are needed to
explore the potential added value of functional assessments across
different diagnoses and surgical procedures.
In summary, sarcopenia is a strong predictor of postoperative
complications across a wide range of gastrointestinal cancers. This
study further indicates that inclusion of functional measures in
sarcopenia criteria may be beneficial, and that sarcopenia may, to
a large extent, mediate the increased complication risk associated
with other risk factors. However, practical utilization of sarcopenia
assessments in surgical oncology is hampered by heterogeneity and
an overall very low quality of the evidence; thus, more work is
required to address these important issues. There is an urgent need for
establishing standardized methodological approaches, and determin-
ing diagnosis- and/or treatment-specific risk criteria. Nonetheless,
the relatively simple and low-cost evaluability as well as its modifi-
able nature provides an intriguing potential for sarcopenia to be
included in standard preoperative clinical evaluation in the future
with the added possibility of targeting high-risk individuals with
prophylactic countermeasures. Similar to other routine preoperative
assessments (eg, renal, liver, cardiac, and pulmonary function), such
evaluations can provide clinicians with important information to
guide and individualize patient management and ultimately improve
surgical outcomes.
ACKNOWLEDGMENTS
The authors thank Anna Banck-Petersen and Anita Herrsted
(Center for Physical Activity Research, Rigshospitalet) and Char-
lotte Egeland (Department of Surgical Gastroenterology C, Rigsho-
spitalet) for their insightful feedback and discussion of the analyses
and article. The authors also thank Sarah Heywood for her assis-
tance in preparing the final manuscript.
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