Prevalence and predictive value of pre-therapeutic sarcopenia in cancer patients: A systematic review

Clinical Nutrition xxx (2017) 1e13

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Review

Prevalence and predictive value of pre-therapeutic sarcopenia in cancer patients: A systematic review
de
ric Pamoukdjian a, b, *, Thierry Bouillet c, Vincent Le
vy d, Michael Soussan e, Fre Laurent Zelek c, Elena Paillaud f, g a

APHP, Avicenne Hospital, Geriatric Department, Coordination Unit in Geriatric Oncology, F-93000, Bobigny, France Universit
e Paris 13, Sorbonne Paris Cit
e, Health Education and Practices Laboratory (LEPS EA3412), F-93017, Bobigny, France APHP, Avicenne Hospital, Department of Medical Oncology, F-93000, Bobigny, France d APHP, Avicenne Hospital, Clinical Research Unit/Clinical Research Center, F-93000, Bobigny, France e APHP, Avicenne Hospital, Department of Radiology, F-93000, Bobigny, France f APHP, Henri-Mondor Hospital, Geriatric Department, Geriatric Oncology Unit, F-94000, Cr
eteil, France g Universit
e Paris-Est, UPEC, DHU A-TVB, IMRB- EA 7376 CEpiA (Clinical Epidemiology And Ageing Unit), F-94000, Cr
eteil, France b c

a r t i c l e i n f o

s u m m a r y

Article history: Received 30 March 2017 Accepted 5 July 2017

Background & aims: To assess the prevalence of sarcopenia before cancer treatment and its predictive value during the treatment. Methods: We searched MEDLINE via PubMed for articles published from 2008 to 2016 that reported prospective observational or interventional studies of the prevalence of pre-therapeutic sarcopenia and its consequences in adults with cancer who were 18 years or older. Two independent reviewers selected articles based on titles and/or abstracts before a complete review. Sarcopenia had to be measured before cancer treatment. Methods recommended by consensuses (CT scan, MRI, dual X-ray absorptiometry or bio-impedancemetry) to assess sarcopenia were considered. Characteristics of the studies included the prevalence of pre-therapeutic sarcopenia and the prognostic value for outcomes during the cancer treatment. Results: We selected 35 articles involving 6894 participants (in/out patients, clinical trials). The mean age ranged from 53 to 69.6 years. Pre-therapeutic sarcopenia was found in 38.6% of patients [95% CI 37.4 e39.8]. Oesophageal and small-cell lung cancers showed the highest prevalence of pre-therapeutic sarcopenia. Pre-therapeutic sarcopenia was significantly and independently associated with postoperative complications, chemotherapy-induced toxicity and poor survival in cancer patients. Conclusions: Pre-therapeutic sarcopenia is highly prevalent in cancer patients and has severe consequences for outcomes of cancer patients. © 2017 Published by Elsevier Ltd.

Keywords: Sarcopenia Cancer Survival Chemotherapy Toxicity Post-operative complications

1. Introduction The issue of sarcopenia in cancer patients has been a focus over the last decade. Three consensus statements have been reported: European Working Group on Sarcopenia (EWGOS) in 2010, International Working Group on Sarcopenia (IWGS) in 2011, and Asian Working Group on Sarcopenia (AWGOS) in 2014 [1e3]. These consensus statements agreed to define sarcopenia as a syndrome


de coordination en oncoge
riatrie (UCOG) b^ * Corresponding author. Unite atiment ^ pital Avicenne (HUPSSD, APHP), 125 rue de Stalingrad, 93000, Bobigny, Larey A, ho France. Fax: þ33 (0)1 48 95 70 36. E-mail address: [email protected] (F. Pamoukdjian).

characterized by the age-associated loss of skeletal muscle mass (quantitative impairment: skeletal muscle index [SMI]) and function (qualitative impairment: loss of muscle strength and/or physical performance) associated or not with increasing fat mass (sarcopenic obesity). These consensus statements had a similar approach to assess the syndrome: a measurement of gait speed to screen for sarcopenia and an objective measure of SMI with different methods. CT scan, MRI, dual X-ray absorptiometry (DXA) or bio-impedancemetry (BIA) were the most recommended methods to measure the SMI. Sarcopenia must be distinguished from cachexia, which may be involved [2]. Sarcopenia is physiologic with ageing but may be associated with some aetiologies. The European consensus

http://dx.doi.org/10.1016/j.clnu.2017.07.010 0261-5614/© 2017 Published by Elsevier Ltd.

Please cite this article in press as: Pamoukdjian F, et al., Prevalence and predictive value of pre-therapeutic sarcopenia in cancer patients: A systematic review, Clinical Nutrition (2017), http://dx.doi.org/10.1016/j.clnu.2017.07.010

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distinguished primary sarcopenia when no aetiology is found from secondary sarcopenia when associated with physical inactivity or some chronic conditions: chronic diseases, inflammatory disease, endocrinopathies, malnutrition or cancer [1]. Moreover, this consensus defined pre-sarcopenia as an isolated loss of skeletal muscle without impaired muscle function [1]. The prevalence of sarcopenia varied by the population studied and methods used. It ranges from 1% to 30% in a communitydwelling older people [4e12], 14% to 68% in long-term care institutions [13,14] and was found to be 10% in older inpatients [15]. Moreover, this prevalence seemed to be independent of gender [12]. In addition, sarcopenia has been independently associated with adverse outcomes such as poor survival, disability, falls and nosocomial infections in the geriatric medicine setting [1,2]. Cancer is a major cause of secondary sarcopenia and was recently highlighted in numerous studies of cancer patients. The prevalence and consequences of sarcopenia in the oncology setting might differ from those in the geriatric medicine setting. Furthermore, the cancer population is heterogeneous in terms of cancer type, cancer stage and treatment trajectories. To our knowledge, few reviews have investigated the overall prevalence of sarcopenia and its consequences for cancer patients. In a recent systematic review of 38 studies published from 2008 to 2015, the prevalence of pre-therapeutic sarcopenia (defined by only low SMI) in cancer patients ranged from 15% to 74%. This review focused on only survival predicted by pre-therapeutic sarcopenia in cancer patients, with other outcomes during cancer treatment not considered [16]. The objectives of this review were to determine the overall prevalence of sarcopenia before cancer treatment (i.e., surgery, chemotherapy, targeted therapy, hormonotherapy or radiotherapy) and its predictive value during the treatment. 2. Material and methods 2.1. Data sources This review was based on a systematic comprehensive search of only MEDLINE via PubMed for articles published in English or French between January 1, 2008 and March 31, 2016. The MeSH term “Sarcopenia” was combined with “Cancer” or “Tumors” or “Malignancies”. We followed the recommendations of the Preferred Reporting Items for Systematic reviews and MetaAnalyses (PRISMA) method for reporting this systematic review [17]. 2.2. Study eligibility criteria For this review, the following issues were discussed: a) What is the prevalence of sarcopenia before a cancer treatment modality in adults? b) What are the definitions used to screen for pre-therapeutic sarcopenia in adults with cancer? c) Is pre-therapeutic sarcopenia associated with post-operative complications? d) Is pre-therapeutic sarcopenia associated with toxicity related to chemotherapy and targeted therapy and dose-limiting toxicity during the cancer treatment? e) Is pre-therapeutic sarcopenia associated with toxicity of hormonotherapy or radiotherapy during the cancer treatment? f) Is pre-therapeutic sarcopenia associated with overall survival, progression-free survival and relapse-free survival? g) Is pre-therapeutic sarcopenia associated with disability or nosocomial infections during the cancer treatment?

To answer these questions, we pre-defined eligibility criteria of articles by using Patient, Intervention, Comparator, Outcome, Study (PICOS) criteria (summarized in Box 1). We included all studies of adults aged 18 years and over. Sarcopenia had to be measured before starting a treatment, whether surgery, chemotherapy, targeted therapy, hormonotherapy or radiotherapy. The term “sarcopenia” had to be mentioned in the title and/or abstract. The measurement of sarcopenia had to use methods recommended by consensus statements: CT scan, MRI, DXA or BIA. We included only observational prospective cohort studies and clinical trials and excluded editorials, case studies, studies published as an abstract, retrospective studies and review articles. Hence, the MeSH terms “death,” “overall survival,” “progression free survival,” “relapse,” “chemotherapy,” “targeted therapy,” “radiotherapy,” “hormonotherapy,” “surgery,” “toxicity,” “disability,” “infection,” and “NOT review” were combined with the initial search. 2.3. Study selection Two independent senior specialists in geriatric oncology (FP, EP) evaluated the selected articles. Articles with the eligibility criteria Box 1 Eligibility criteria of studies by the PICOS criteria.

Criteria

Included

Excluded

Population

Adults 18y and over with cancer In/out patients, patients from clinical trials Intervention Pre-therapeutic sarcopenia Sarcopenia defined by defined by using a consensual other methods not method: recommended by CT scan (muscle area consensual method:

or muscle volume or skeletal muscle index), MRI (muscle area or muscle volume or skeletal muscle index), DXA (skeletal muscle index), BIA (skeletal muscle index). Comparison Not assessed Outcomes Prevalence of pre-therapeutic sarcopenia Survival: overall survival, progression-free survival, relapse-free survival Surgery: post-operative complications Chemotherapy/targeted therapy: toxicity, dose limiting toxicity Radiotherapy: toxicity Hormonotherapy: toxicity Nosocomial infections Disability Study design Clinical trials with randomization Observational prospective cohort studies

Urinary creatinine measured over 24 h, Total body potassium, Arm circumference, Skin fold thickness. Cachexia

Retrospective studies with no consecutive inclusion Systematic and narrative reviews Letter to editor Case report Abstract of congress

Please cite this article in press as: Pamoukdjian F, et al., Prevalence and predictive value of pre-therapeutic sarcopenia in cancer patients: A systematic review, Clinical Nutrition (2017), http://dx.doi.org/10.1016/j.clnu.2017.07.010

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were first selected on the basis of titles and abstracts, then selected on the basis of reading the full text. If multiple articles reported similar results, only the article with the most complete information was retained. We also reviewed the references of all selected articles to identify any additional relevant articles. Disagreements were resolved by consensus. Data recorded included publication date, country, study design and follow-up time, gender of participants, in/outpatients or those specifically included in clinical trials, mean ± SD or median (minemax) age of all participants when described, the sarcopenia assessment method used, the prevalence of sarcopenia in studies and finally the outcomes associated with the pre-therapeutic sarcopenia. 2.4. Risk of bias To assess risk of bias of studies, we used A Cochrane Risk of Bias Assessment Tool: for Non-Randomized Studies of Interventions (ACROBAT-NRSI) (https://sites.google.com/site/riskofbiastool/). The risk of bias was classified as low, moderate, serious, critical or no information. 2.5. Quality assessment To assess quality of studies, we used the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies published by the National Heart Lung and Blood Institute (http://www. nhlbi.nih.gov/health-pro/guidelines/in-develop/cardiovascularrisk-reduction/tools/cohort). The quality of studies was classified as good, fair or poor. 2.6. Statistical analysis Data were described with number (%) and for quantitative data, with 95% confidence intervals (95% CIs). Data were analysed by using R v3.2.2 R Foundation for Statistical Computing, Vienna, Austria (http://www.R-project.org). P < 0.05 was considered statistically significant. 3. Results 3.1. Articles included The comprehensive search yielded 207 articles potentially eligible for this review. After excluding articles, 35 remained for review (Fig. 1). Studies included 6894 participants (4093 men). The mean age ranged from 53 to 69.6 years and follow-up time from 0.7 to 96 months. 3.2. Risk of bias of studies Among the 35 studies included [18e52], risk of bias was low for 60% [95% CI 42.1e76.1] and moderate for 37.1% [95% CI 21.5e51.1] (Table 1). For one study, the risk of bias could not be assessed because of lack of information [23]. No studies met serious or critical risk of bias. Fig. 2 shows the proportion of low risk of bias for various categories of risk of bias for the 35 studies. 3.3. Quality of studies Among the 35 studies included, quality was good for 77.1% [95% CI 59.9e89.6] and fair for 22.9% [95% CI 10.4e40.1]; no study had

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poor quality (Table 2). Overall, 20 studies were prospective and 15 were retrospective with consecutive inclusions. 3.4. Prevalence of pre-therapeutic sarcopenia in adults with cancer and characteristics of participants Among the observational studies included (n ¼ 26), 20 (5306 participants) included inpatients and 6 (n ¼ 547) outpatients. We identified 7 interventional studies (680 participants) among clinical trials. For 2 studies (n ¼ 361), the status of participants could not be specified. Overall, 60.8% of tumors were digestive, local and/or metastatic, including colorectal, oesophagus, stomach, pancreas and bile duct and hepatocellular carcinoma. The remaining 39.2% of tumors included various solid and/or haematological cancers. Surgery was the most frequent treatment modality, representing 19 studies [18e22,24e28,30,31,33,34,36,37,40,44,47]. Seven studies concerned chemotherapy [35,38,39,41,42,46,51], 2 did not specify the treatment modality (27, 28), and 4 concerned targeted therapy [43], intra-hepatic infusion [49], hematopoietic stem-cell transplantation [32] and palliative care [50]. In all, 32/35 studies (6505 participants) reported an overall prevalence of pre-therapeutic sarcopenia, which was 38.6% [95% CI 37.4e39.8] overall. The prevalence of sarcopenia before surgery was 37.1% [95% CI 35.8e38.4] and before chemotherapy was 29% [95% CI 25.8e32.4]. A total of 26 studies (n ¼ 5936) reported the prevalence by gender: among participants with sarcopenia, 24.6% [95% CI 23.5e25.7] were men and 13.1% [95% CI 12.3e14.0] were women. Characteristics of studies are in Table 2. 3.5. Definitions used to screen for pre-therapeutic sarcopenia in adults with cancer Only 3 studies [20,24,28] focused on a consensual definition for sarcopenia (EWGOS and/or AWGOS). No studies used the IWGS definition for cancer patients. SMI by CT scan at lumbar 3 (L3) was the most common method used to define sarcopenia in 29 studies [18e20,23e29,32e37,39e52], and total psoas or total muscle area by CT scan at L3 was used to define sarcopenia in 3 other studies [21,22,30]. SMI by BIA and fat free mass index by BIA were used to define sarcopenia in 2 studies [24,31] and 1 study [38], respectively. DXA was never used to define sarcopenia. 3.6. Pre-therapeutic sarcopenia as an independent predictor of post-operative complications in adults with cancer Eleven studies involving 2480 participants [18,20,24,26e28,30,31,33,37,44] assessed post-operative complications related to sarcopenia (Table 2). The mean age of participants ranged from 62 to 69.6 years. Pre-therapeutic sarcopenia was independently associated with severe post-operative complications according to the Clavien-Dindo score after gastrectomy [20,24,27], pancreatectomy [30], resection of hepatocellular carcinoma [27] and esophagectomy [18,31]. Severe post-operative complications included heart failure, pulmonary embolism and obstructive atelectasis [20], anastomotic leakage, intra-abdominal abscess, pneumoniae and renal dysfunction [24], early death [27] and bile leakage [30]. Two studies reported pre-therapeutic sarcopenia independently associated with nosocomial infection after colectomy [28,44]. Three studies involving 664 participants found pre-therapeutic sarcopenia not associated with post-operative complications including post-operative sepsis after colectomy [37], post-operative mortality within 2 months after pancreaticoduodenectomy [22] and in-

Please cite this article in press as: Pamoukdjian F, et al., Prevalence and predictive value of pre-therapeutic sarcopenia in cancer patients: A systematic review, Clinical Nutrition (2017), http://dx.doi.org/10.1016/j.clnu.2017.07.010

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Fig. 1. Flow of selection of studies to assess the prevalence of sarcopenia in cancer patients before treatment and consequences on outcomes.

hospital mortality/severe post-operative complications after gastrectomy [26]. 3.7. Pre-therapeutic sarcopenia as an independent predictor of chemotoxicity in adults with cancer Six studies involving 386 participants [29,35,39,41,43,51] reported chemotoxicity related to sarcopenia (Table 2). The mean age of participants ranged from 54.8 to 68 years. The study follow-up time ranged from 0.7 to 52 months. Pre-therapeutic

sarcopenia was independently associated with dose-limiting toxicity of cisplatin and 5-FU for oesophageal cancer [29,35], various chemotherapies for various solid and haematological cancers [39] and sunitinib for renal cell cancer [43]. Pretherapeutic sarcopenia was independently associated with chemotoxicity of various chemotherapies for various cancers [39] and with capecitabine as second line treatment for metastatic breast cancer [51]. In one study [41], pre-therapeutic sarcopenia was not independently associated with grade III/IV chemotoxicity of temsirolimus for various solid cancers.

Please cite this article in press as: Pamoukdjian F, et al., Prevalence and predictive value of pre-therapeutic sarcopenia in cancer patients: A systematic review, Clinical Nutrition (2017), http://dx.doi.org/10.1016/j.clnu.2017.07.010

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Table 1 Risk of bias across studies. Studies

Bias due to confounding

Bias in selection of participants in the study

Bias in measurement of interventions

Bias due to departures from intended interventions

Bias due to missing data

Bias in measurement of outcomes

Bias in selection of the reported results

Overall bias

Nishigori T et al. [18] 2016 Okumura S et al. [19] 2016 Wang SL et al. [20] 2016 Buettner S et al. [21] 2015 Pecorelli N et al. [22] 2015 Kim EY et al. [23] 2015 Fukuda Y et al. [24] 2015 Tamandl D et al. [25] 2015 Tegels JJW et al. [26] 2015 Levolger S et al. [27] 2015 Huang DD et al. [28] 2015 Anandavadivelan P et al. [29] 2015 Amini N et al. [30] 2015 Ida S et al. [31] 2015 Caram MV et al. [32] 2015 van Vugt JL et al. [33] 2015 Lodewick TM et al. [34] 2015 Tan BH et al. [35] 2015 Voron T et al. [36] 2015 Reisinger KW et al. [37] 2015 Gonzalez MC et al. [38] 2014 Cousin S et al. [39] 2014 Harimoto N et al. [40] 2013 Veasey-Rodrigues H et al. [41] 2013 Veasey-Rodrigues H et al. [42] 2013 Huillard O et al. [43] 2013 Lieffers JR et al. [44] 2012 Dalal S et al. [45] 2012 Mir O et al. [46] 2012 van Vleder MG et al. [47] 2012 Parsons HA et al. [48] 2012 Parsons HA et al. [49] 2012 Tan BH et al. [50] 2009 Prado CM et al. [51] 2009 Prado CM et al. [52] 2008

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LR: low risk, MR: moderate risk, SR: serious risk, CR: critical risk, NI: no information.

Please cite this article in press as: Pamoukdjian F, et al., Prevalence and predictive value of pre-therapeutic sarcopenia in cancer patients: A systematic review, Clinical Nutrition (2017), http://dx.doi.org/10.1016/j.clnu.2017.07.010

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Fig. 2. Proportion of low risk of bias for 35 studies included in the systematic review.

3.8. Pre-therapeutic sarcopenia as a predictor of hormonotoxicity and radiotoxicity We found no study assessing the predictive value of pretherapeutic sarcopenia for hormonotherapy or radiotherapyrelated toxicity in adults with cancer. 3.9. Pre-therapeutic sarcopenia as an independent predictor of survival in adults with cancer In total, 22 studies involving 5351 participants [19,21e23,25e27,30,34,36e38,40,42,43,45e50,52] reported survival related to sarcopenia (Table 2). The mean age of participants ranged from 56 to 69 years and study follow-up time 1e96 months. Pretherapeutic sarcopenia was independently associated with overall survival after surgery, including colectomy [21,37], hepatectomy [21,27,34,36,40,47], extrahepatic biliary surgery [19], esophagectomy [25], gastrectomy [26], and pancreatectomy [21,30]; however, in 3 studies involving 371 participants [26,34,49], presurgery sarcopenia was not associated with overall survival. Pre-therapeutic sarcopenia was independently associated with overall survival during chemotherapy [23,38,42,45,46] but not in one study of sunitinib for renal cell cancer [43]. It was independently associated with relapse-free survival after surgery for extrahepatic biliary cancer [19], hematopoietic stem-cell transplantation [32] and hepatectomy [40] and with progression-free survival after chemotherapy for hepatocellular carcinoma [46] and metastatic breast cancer [51]. 3.10. Pre-therapeutic sarcopenia as a predictor of disability in adults with cancer We found no study assessing the predictive value of pretherapeutic sarcopenia for disability in adults with cancer. 4. Discussion This review estimates the overall prevalence and predictive value of pre-therapeutic sarcopenia in a large sample of patients

with various cancer types and stages and treatment modalities. The overall prevalence of pre-therapeutic sarcopenia in cancer patients was 38.6%. Pre-therapeutic sarcopenia was associated with poor outcomes during cancer treatment. It was associated with postoperative complications, chemotherapy-induced and doselimiting toxicity and overall, relapse-free and progression-free survival. By comparison with a recent systematic review assessing the prevalence of sarcopenia in non-cancer patients aged 50 and older, we found a higher overall prevalence of pre-therapeutic sarcopenia in cancer patients [12]. Some reasons could explain our results. First, this discrepancy might be related to the different sarcopenia definitions used. In the review conducted in non-cancer patients, sarcopenia was defined by only EWGSOP criteria (i.e., based on muscle mass and muscle strength or physical performance) [12]. In our review, only 3 studies [20,24,28] used a consensual definition (i.e., EWGOS or AWGOS): the prevalence of pre-therapeutic sarcopenia was lower than in other studies that did not use a consensual definition (12e21.2% vs 19e79.2%) and which probably overestimated the prevalence by using only a measurement of muscle mass (i.e., pre-sarcopenia according to the EWGOS criteria). Second, our review investigated studies of cancer, which is a major risk factor of sarcopenia in part because of the inflammation that induces catabolism and high protein consumption [1,2]. Furthermore, the prevalence of pre-therapeutic sarcopenia that we found was consistent with results from a recent systematic review [16]. We highlighted that no studies concerned specifically older cancer patients, who are at high risk of sarcopenia. Many studies did not focus on older cancer patients, which underlines the limited data on this topic. The prevalence varied widely by tumor site and tumor stage. Indeed, local oesophageal cancer and small-cell lung cancer (local and/or diffuse) represented the highest prevalence of pre-therapeutic sarcopenia, with corresponding values of 75% and 79.2% [18,23]; local gastric and colorectal cancer represented the lowest prevalence: 12.5% and 12% [20,28]. The most-used definition of pre-therapeutic sarcopenia was based on CT scan at L3 with measurement of SMI. However, the studies featured a wide range of thresholds, which probably explains also the wide range of prevalence of pre-therapeutic

Please cite this article in press as: Pamoukdjian F, et al., Prevalence and predictive value of pre-therapeutic sarcopenia in cancer patients: A systematic review, Clinical Nutrition (2017), http://dx.doi.org/10.1016/j.clnu.2017.07.010

Country Author Year published

Study design Follow-up time Days (d) Months (m) Years (y)

Participants M/F In/Outpatients Patients from clinical trials

Cancer type Cancer extension Treatment modality

Age (y) Mean (±SD) or median (range)

Measure of sarcopenia Consensus used (Y/N) Before treatment (Y/N)

Prevalence of sarcopenia (%) M/F (%)

Outcomes associated with sarcopenia

Quality rating Good (G) Fair (F) Poor (P)

Japanese cohort Nishigori T et al. [18] 2016

Retrospective with consecutive inclusion Follow-up: 1m

N ¼ 199 M/F: 164/35 Inpatients

Oesophageal Locale Esophagectomy

Mean: 65.4 ± 7.7

SMI by CT scan at L3 level Consensus used: N Before treatment: Y

P ¼ 75 M/F: 89/11

G

Japanese cohort Okumura S et al. [19] 2016

Retrospective with consecutive inclusion Follow-up: 5y

N ¼ 207 M/F: 111/96 Inpatients

Extra-hepatic biliary Locale and metastatic Surgery

Median: 68 [33 e85]

PMI by CT scan at L3 level Consensus used: N Before treatment: Y

P ¼ 34.3 M/F: 51/49

Chinese cohort Wang SL et al. [20] 2016

Prospective Follow-up: NA

N ¼ 255 M/F: 190/65 Inpatients

Gastric Locale Gastrectomy

Mean: 65.1 ± 10.8

SMI by CT scan at L3 level Consensus used: Y (EWGSOP, AWGS) Before treatment: Y

P ¼ 12.5 M/F: 81.2/18.8

American cohort Buettner S et al. [21] 2015

Retrospective with consecutive inclusion Follow-up: 1y

N ¼ 1326 M/F: 730/596 Inpatients

TPA, TPV, TPD by CT scan at L3 level Consensus used: N Before treatment: Y

P ¼ 30 M/F: 55/45

Italian cohort Pecorelli N et al. [22] 2015

Prospective Follow-up: 2m

N ¼ 202 M/F: 108/94 Inpatients

Median: 62.5 [53 Hepatobiliary, pancreatic, e70] colorectal Locale and metastatic Hepatectomy, pancreatectomy, colectomy Mean: 66.8 ± 10.7 Pancreatic Locale and metastatic Pancreaticoduodenectomy

Sarcopenia was independently associated with post-operative complications (pulmonary) according to the Clavien-Dindo (2) OR: 2.96 [1.14e7.69], 95%CI, P ¼ 0.02 Sarcopenia was independently associated with OS HR: 2.92 [1.92e4.47], 95%CI, P < 0.001 Sarcopenia was independently associated with RFS: HR: 2.14 [1.46e3.12], 95%CI, P < 0.001 Sarcopenia was independently associated with severe postoperative complications (ClavienDindo  3) OR: 5.02 [2.22e11.31], 95%CI, P < 0.001 Sarcopenia was independently associated with OS HR: 1.98 [1.36e2.88], 95%CI, P < 0.001

P ¼ 65.3 M/F: 60/40

Sarcopenia was not associated with G post-operative mortality within 60 days in univariate analysis (P ¼ 0.2)

Korean cohort Kim EY et al. [23] 2015

Retrospective with consecutive inclusion Follow-up: 2y

N ¼ 149 M/F: 127/22 Outpatients

P ¼ 79.2 M/F: 93.2/6.8

Sarcopenia was independently associated with OS HR: 1.68 [1.04e2.72], 95%CI, P ¼ 0.03

F

Japanese cohort Fukuda Y et al. [24] 2015

Prospective Follow-up: NA

N ¼ 99 M/F: 66/33 Inpatients

Small-cell lung Mean: 68.6 ± 9.5 Limited and extensive Active treatment (chemotherapy, chemoradiotherapy, chest radiotherapy) and support care Median: 75 [66 Gastric e91] Locale and metastatic Gastrectomy

TAMA by CT scan at L3 level Consensus used: N Before treatment: Y SMI by CT scan at L3 level Consensus used: N Before treatment: Y

SMI by BIA Consensus used: Y (EWGSOP) Before treatment: Y

P ¼ 21.2 M/F: 90.5/9.5

G

Austrian cohort Tamandl D et al. [25] 2015

Retrospective with consecutive inclusion Follow-up: 5y

N ¼ 200 M/F: 151/49 Inpatients

Oesophageal Locale Esophagectomy

SMI by CT scan at L3 level Consensus used: N Before treatment: Y

P ¼ 65 M/F: 82.3/17.7

Sarcopenia was independently associated with severe postoperative complications (ClavienDindo  3) OR: 4.76 [1.03e24.30], 95%CI, P ¼ 0.04 Sarcopenia was independently associated with OS HR: 1.87 [1.15e3.03], 95%CI, P ¼ 0.01

Median: 63.9 [56.6 e70.0]

G

G

G

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Please cite this article in press as: Pamoukdjian F, et al., Prevalence and predictive value of pre-therapeutic sarcopenia in cancer patients: A systematic review, Clinical Nutrition (2017), http://dx.doi.org/10.1016/j.clnu.2017.07.010

Table 2 Prevalence of sarcopenia and its consequences on outcomes in 35 selected studies including cancer adults before treatment.

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Measure of sarcopenia Consensus used (Y/N) Before treatment (Y/N)

Country Author Year published

Study design Follow-up time Days (d) Months (m) Years (y)

Participants M/F In/Outpatients Patients from clinical trials

Cancer type Cancer extension Treatment modality

Age (y) Mean (±SD) or median (range)

Dutch cohort Tegels JJW et al. [26] 2015

Retrospective with consecutive inclusion Follow-up: 6m

N ¼ 152 M/F: 87/65 Inpatients

Gastric Locale and metastatic Gastrectomy

Mean: 69.6 [37e88] SMI by CT scan at L3 level Consensus used: N Before treatment: Y

Dutch cohort Levolger S et al. [27] 2015

Retrospective with consecutive inclusion Follow-up: 3y

N ¼ 90 M/F: 63/27 Inpatients

Hepatocellular carcinoma Locale and advanced Surgery and radiofrequency ablation

Median: 62 [22 e86]

Chinese cohort Huang DD et al. [28] 2015

Prospective Follow-up: 1m

N ¼ 142 M/F: 88/54 Inpatients

Colorectal Locale Surgery

Mean: 62 ± 12.5

Swedish cohort Anandavadivelan P et al. [29] 2015

Prospective Follow-up: 21d

N ¼ 72 M/F: 61/11 Patients included in a phase III trial

Oesophageal Locale and advanced Neo-adjuvant therapy: radiotherapy and/or chemoradiotherapy (cisplatin and 5-fluorouracil)

Mean: 67 ± 7

American cohort Amini N et al. [30] 2015

Prospective Follow-up: 5y

N ¼ 763 M/F: 418/345 Inpatients

Pancreatic Locale and advanced Pancreaticoduodenectomy

Median: 67 [58 e74]

Prevalence of sarcopenia (%) M/F (%)

P ¼ 57.7 M/F: 44.2/56.8

Outcomes associated with sarcopenia

Sarcopenia was not associated with outcomes in univariate analysis: In-hospital mortality (P ¼ 0.5), severe post-operative complications according to the Clavien-Dindo  3 (P ¼ 1) and 6m mortality (P ¼ 0.6) P ¼ 57.7 Sarcopenia was independently SMI by CT scan at L3 M/F: 75/25 associated with OS: level HR: 3.75 [1.77e7.93], 95%CI, Consensus used: N P ¼ 0.001 Before treatment: Y Sarcopenia was not associated with DFS in univariate analysis (P ¼ 0.6) Severe post-operative complications according to the Clavien-Dindo  3 were more frequent in sarcopenic patients (P ¼ 0.03) P ¼ 12 Sarcopenia was independently SMI by CT scan at L3 M/F: 65/35 associated with post-operative level complications (infections) Consensus used: Y according to the Clavien-Dindo (EWGSOP, AWGS) (2) Before treatment: Y OR: 4.75 [1.62e13.91], 95%CI, P ¼ 0.004 P ¼ 43 Sarcopenia was not independently SMI by CT scan at L3 M/F: NA associated with DLT during cycle 1 level chemotherapy: Consensus used: N OR: 2.47 [0.88e6.93], 95%CI, Before treatment: Y P ¼ 0.09 Sarcopenia with overweight/ obesity (BMI  25 kg/m2) was independently associated with DLT during cycle 1 chemotherapy: OR: 5.54 [1.12e27.44], 95%CI, P ¼ 0.04 TPA and TPV by CT scan P ¼ 25.1 by TPA Sarcopenia defined by TPA was not P ¼ 19.9 by TPV independently associated with at L3 level overall post-operative M/F: NA Consensus used: N complications (P ¼ 0.72) Before treatment: Y Sarcopenia defined by TPV was independently associated with overall post-operative complications (including severe complications by ClavienDindo  3): OR: 1.69 [1.16e2.46], 95%CI, P ¼ 0.006 Sarcopenia defined by TPV was independently associated with OS: HR: 1.46 [1.11e1.91], 95%CI, P ¼ 0.006

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Table 2 (continued )

Prospective Follow-up: 1m

N ¼ 138 M/F: 121/17 Inpatients

Oesophageal Locale and metastatic Esophagectomy

Mean (sarcopenia): SMI by BIA 67.8 ± 1 Consensus used: N Before treatment: Y

P ¼ 44.2 M/F: 77/23

American cohort Caram MV et al. [32] 2015

Prospective Follow-up: 5y

N ¼ 121 M/F: 73/48 Inpatients

Lymphoma Diffuse disease Hematopoietic stem-cell transplant (HSCT)

Mean: 53 ± 13.1

NA

Dutch cohort van Vugt JL et al. [33] 2015

Prospective Follow-up: 1m

N ¼ 206 M/F: 100/106 Inpatients

Colorectal Peritoneal carcinomatosis Cyto-reductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIC)

Mean (sarcopenia): SMI by CT scan at L3 62.1 ± 10 level Consensus used: N Before treatment: Y

P ¼ 43.7 M/F: 51/49

N ¼ 171 M/F: 104/67 Inpatients

Colorectal Liver metastatis Partial liver resection

Median: 64 [24 e86]

SMI by CT scan at L3 level Consensus used: N Before treatment: Y

P ¼ 46.7 M/F: 56/44

Mean (sarcopenia): SMI by CT scan at L3 68.6 ± 7 level Consensus used: N Before treatment: Y

P ¼ 49.4 M/F: 77/23

Mean: 61.6 ± 13.3

SMI by CT scan at L3 level Consensus used: N Before treatment: Y

P ¼ 54.1 M/F: 89.8/10.2

Prospective Dutch cohort Lodewick TM et al. [34] Follow-up: 5y 2015

SMI by CT scan at L4 level Consensus used: N Before treatment: Y

British cohort Tan BH et al. [35] 2015

Retrospective with consecutive inclusion Follow-up: 4y

N ¼ 89 M/F: 67/22 Outpatients

French cohort Voron T et al. [36] 2015

Prospective Follow-up: 4y

N ¼ 109 M/F: 92/17 Inpatients

Oesophago-gastric Locally-advanced Neo-adjuvant chemotherapy: Cisplatin and 5-fluorouracil based Hepatocellular carcinoma Locale Hepatectomy

Netherland cohort Prospective Reisinger KW et al. [37] Follow-up: 1m 2015

N ¼ 310 M/F: 155/155 Inpatients

Colorectal Locale and metastatic Colectomy

Mean: 69 ± 0.6

SMI by CT scan at L3 level Consensus used: N Before treatment: Y

P ¼ 47.7 M/F: 61/39

Prospective Brazilian cohort Gonzalez MC et al. [38] Follow-up: 3y 2014

N ¼ 175 M/F: 60/115 Outpatients

Various cancer with hematological malignancies Locale and Metastatic Chemotherapy in first line

Mean: 56.9 ± 12.8

Fat free mass index by BIA Consensus used: N Before treatment: Y

P ¼ NA M/F: NA

Sarcopenia was independently associated with post-operative complications (pulmonary) according to the Clavien-Dindo (2) OR: 5.55 [2.15e15.6], 95%CI, P ¼ 0.0003 Sarcopenia was measured as continuous variable (by decrease of 100 units of total psoas index) Sarcopenia was independently associated with RFS: Men: HR: 2.37 [1.01e5.58], 95%CI, P ¼ 0.048 Women: HR: 2.67 [1.04e6.86], 95% CI, P ¼ 0.041 Sarcopenia was independently associated with the number of complications during the 100d following HSCT: IRR: 1.18 [1.07 e1.29], 95%CI, P ¼ 0.001 Sarcopenia was measured as continuous variable (by 1 cm2/m2) Sarcopenia was independently associated with severe postoperative complications according to the Clavien-Dindo  3: OR: 0.93 [0.87e0.99], 95%CI, P ¼ 0.01 Sarcopenia was not independently associated with OS in univariate analysis (P ¼ 0.64) Sarcopenia was not independently associates with DFS in univariate analysis (P ¼ 0.48) Sarcopenia was independently associated with DLT: OR: 2.95 [1.23e7.09], 95%CI, P ¼ 0.01 Sarcopenia was independently associated with OS after hepatectomy HR: 3.19 [1.28e7.96], 95%CI, P ¼ 0.013 Sarcopenia was independently associated with mortality in 30 days' post-operative OR: 43.30 [2.74e685.2], 95%CI, P ¼ 0.007 Sarcopenia was not predictive of anastomotic Leakage Sarcopenia was not predictive of sepsis Sarcopenia was independently associated with OS HR: 4.35 [2.11e8.99], 95%CI, P < 0.001

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Japanese cohort Ida S et al. [31] 2015

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Country Author Year published

Study design Follow-up time Days (d) Months (m) Years (y)

Participants M/F In/Outpatients Patients from clinical trials

Cancer type Cancer extension Treatment modality

Age (y) Mean (±SD) or median (range)

Measure of sarcopenia Consensus used (Y/N) Before treatment (Y/N)

Prevalence of sarcopenia (%) M/F (%)

Outcomes associated with sarcopenia

French cohort Cousin S et al. [39] 2014

Prospective Follow-up: 1y

N ¼ 93 M/F: 50/43 Patients included in phase I trials

Various cancer with haematological malignancies Advanced and metastatic Chemotherapy

Median: 57 [21 e77]

SMI by CT scan at L3 level Consensus used: N Before treatment: Y

P ¼ NA M/F: NA

Japan cohort Harimoto N et al. [40] 2013

Prospective Follow-up: 5y

N ¼ 186 M/F: 145/41 Inpatients

Hepatocellular carcinoma Locale Hepatectomy

Mean (sarcopenia): SMI by CT scan at L3 67 ± 11 level Consensus used: N Before treatment: Y

P ¼ 40.3 M/F: 67/33

American cohort Veasey-Rodrigues H et al. [41] 2013 American cohort Veasey-Rodrigues H et al. [42] 2013

Prospective Follow-up: 2m

N ¼ 16 M/F: 5/11 Patients included in phase I trials N ¼ 306 M/F: 159/147 Patients included in phase I trials

Various cancer Advanced solid tumors Chemotherapy (Temsirolimus)

Median: 60 [36 e71]

P ¼ 44 M/F: NA

Sarcopenia was measured as continuous variable Sarcopenia was independently associated with DLT (P ¼ 0.01) and with severe toxicity events (P ¼ 0.02) Sarcopenia measured as continuous G variable was independently associated with OS: HR: 0.90 [0.84e0.96], 95%CI, P ¼ 0.002 Sarcopenia measured as continuous variable was independently associated with RFS: HR: 0.97 [0.95e1$00], 95%CI, P ¼ 0.016 F Sarcopenia at baseline was not associated with grade III/IV chemotoxicity

Median: 56 [16 e84]

French cohort Huillard O et al. [43] 2013

Retrospective with consecutive inclusion Follow-up: 52m

N ¼ 61 M/F: 38/23 Outpatients

Various cancer with haematological malignancies Advanced and metastatic Chemotherapy and/or targeted therapy and/or intra-arterial hepatic infusion Renal cell cancer Metastatic Targeted therapy (Sunitinib)

Canadian cohort Lieffers JR et al. [44] 2012

Retrospective with consecutive inclusion Follow-up: 1m

N ¼ 234 M/F: 135/99 Inpatients

American cohort Dalal S et al. [45] 2012

Prospective Follow-up: 7.5y

N ¼ 41 M/F: 18/23 Patients included in phase I trials

French cohort Mir O et al. [46] 2012

Retrospective with consecutive inclusion Follow-up: 16m

N ¼ 18 M/F: 15/3 Outpatients

Netherland cohort van Vledder MG et al. [47] 2012

Prospective Follow up: 8y

N ¼ 196 M/F: 120/76 Inpatients

Prospective Follow-up: 3m

SMI by CT scan at L3 level Consensus used: N Before treatment: Y SMI by CT scan at L3 level Consensus used: N Before treatment: Y

Quality rating Good (G) Fair (F) Poor (P)

P ¼ 47 M/F: 64.6/35.4

Sarcopenia was independently associated with OS after systemic therapy HR: 1.34, P ¼ 0.01

G

Sarcopenia was not independently associated with OS (P ¼ 0.21) and PFS (P ¼ 0.11) Sarcopenia was not independently associated with DLT (P ¼ 0.17) Sarcopenia was independently associated with post-operative infections OR: 4.6 [1.5e13.9], 95%CI, P ¼ 0.007 Sarcopenia was not independently associated with OS (p ¼ 0.24) Sarcopenic obesity was associated with OS in univariate analysis only (p ¼ 0.004) Sarcopenia was the only variable independently associated with OS (p < 0.001) and PFS (p ¼ 0.008) in univariate analysis

F

Median: 60 [29 e83]

SMI by CT scan at L3 level Consensus used: N Before treatment: Y

P ¼ 52.5 M/F: 75/25

Colorectal Locale and metastatic Colectomy

Mean: 63 ± 12

P ¼ 39 M/F: 62.6/37.4

Pancreatic cancer Advanced, inoperable Chemo (capecitabine ± bevacizumab)radiation Hepatocellular carcinoma Advanced disease Gemcitabine and Oxaliplatin in second line after disease progression with sorafenib Colorectal Liver metastases resection

Median: 58.9 [41.7 e81.0]

SMI by CT scan at L3 level Consensus used: N Before treatment: Y SMI by CT scan at L3 level Consensus used: N Before treatment: Y

P ¼ 37 M/F: NA

Median: 64 [25 e77]

SMI by CT scan at L3 level Consensus used: N Before treatment: Y

P ¼ 50 M/F: NA

Median: 64.5 [31 e86]

SMI by CT scan at L3 level Consensus used: N Before treatment: Y

P ¼ 19.4 M/F: 29/71

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G Sarcopenia was independently associated with recurrence disease following liver metastases resection HR: 1.96 [1.29e2.97], 95%CI, P ¼ 0.002 Sarcopenia was independently associated with OS HR: 2.69 [1.67e4.32], 95%CI, P < 0.001

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Table 2 (continued )

P ¼ 51 M/F: 55/44

SMI by CT scan at L3 level Consensus used: N Before treatment: Y SMI by CT scan at L3 level Consensus used: N Before treatment: Y

P ¼ 42 M/F: NA

Mean: 54.8 ± 10.4 Breast Metastatic Resistant to anthracycline and/ or taxane treatment Capecitabine in second line

SMI by CT scan at L3 level Consensus used: N Before treatment: Y

P ¼ 25.5 M/F: 0/100

Respiratory tract, digestive tract Mean: 63.9 ± 10.4 and pancreas Locale and metastatic Treatment modalities not specified

SMI by CT scan at L3 level Consensus used: N Before treatment: Y

P (sarcopenic obesity) ¼ 15.2 M/F: 74/26

Retrospective with consecutive inclusion Follow-up: 2.2y

N ¼ 104 M/F: 65/39 Patients included in phase I trials

Various solid cancers Advanced disease Treatment non-specified

American cohort Parsons HA et al. [49] 2012

Retrospective with consecutive inclusion Follow-up: 2.2y

British cohort Tan BH et al. [50] 2009

Prospective Follow up: 3.5y

N ¼ 48 M/F: 19/29 Patients included in phase I trials N ¼ 111 M/F: 52/59 NA

Various solid cancers Liver metastases Intra-arterial hepatic infusion (oxaliplatin) Pancreatic Locale and advanced Palliative treatment

Canadian cohort Prado CM et al. [51] 2009

Prospective Follow up: 1.6y

N ¼ 55 M/F: 0/55 Outpatients

Canadian cohort Prado CM et al. [52] 2008

Prospective Follow-up: 3.3y

N ¼ 250 M/F: 136/114 NA

Mean (sarcopenia): BMI < 25 kg/m2: 61 ± 1.6 BMI  25 kg/m2: 64 ± 1.9 Mean: 56 ± 11

Mean: 64.4 ± 9.3

P ¼ 55.9 M/F: 53.2/46.8

Sarcopenia measured as continuous F variable was independently associated with OS HR: 0.95 [0.92e0.98], 95%CI, P ¼ 0.009 Sarcopenia was not independently F associated with OS (P ¼ 0.7)

Sarcopenia in overweight/obese G patients was independently associated with OS: HR: 2.07 [1.22e3.49], 95%CI, P ¼ 0.006 Sarcopenia alone was not associated with OS (P ¼ 0.2) F Sarcopenia was independently associated with PFS: HR: 2.6 [1.2e5.6], 95%CI, P ¼ 0.01 Sarcopenia was the only variable independently associated with chemotoxicity: HR: 4.1, P ¼ 0.04 F Sarcopenic obesity was independently associated with OS: HR: 4.2 [2.4e7.2], 95%CI, P < 0.0001

AWGOS: Asian working group on sarcopenia, DFS: disease free survival, DLT: dose limiting toxicity, EWGOS: European working group on sarcopenia, HR: hazard ration, OR: odd ratio, aOR: adjusted odd ratio, BIA: bioimpedancemetry analysis, NA: non-available, OS: overall survival, PFS: progression free survival, PMI: psoas muscle index, RFS: recurrence free survival, SMI: skeletal muscle index, TAMA: total abdominal muscle area, TPA: total psoas area, TPD: total psoas density, TPV: total psoas volume.

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Please cite this article in press as: Pamoukdjian F, et al., Prevalence and predictive value of pre-therapeutic sarcopenia in cancer patients: A systematic review, Clinical Nutrition (2017), http://dx.doi.org/10.1016/j.clnu.2017.07.010

SMI by CT scan at L3 level Consensus used: N Before treatment: Y

American cohort Parsons HA et al. [48] 2012

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sarcopenia we found. The use of CT scan was probably due to the feasibility for using this imagery in cancer patients. Indeed, CT scan is mostly used for cancer staging before treatment. The major limitation of this method is the need for systematic post-review of CT scans by a radiologist. As expected, pre-therapeutic sarcopenia was found significantly associated with the poorest outcomes during cancer treatment. Sarcopenia was consensually described as an impaired body composition that involved decreased functional reserves, particularly in older people [1,2]. The decreased functional reserves is a central element in the pathophysiology of people with the frailty phenotype [53]. Thus, sarcopenia was described in the pathophysiology of the frailty syndrome suggested by Fried et al. [53]. The close link between sarcopenia and frailty functional syndrome was probably the principal reason for our findings concerning the prognostic value of pre-therapeutic sarcopenia during cancer treatment. Hence, screening for pre-therapeutic sarcopenia in cancer patients is important for therapeutic decisions, particularly for the oldest patients, which indeed have the narrowest therapeutic margin. We found no studies assessing the predictive value of pretherapeutic sarcopenia for disability in adults with cancer. One of the strengths of this review is that it estimated the sarcopenia before the cancer treatment and that it investigated all treatment modalities. Thus, we provided an overview of the impact of pre-therapeutic sarcopenia on the treatment of cancer patients. However, we found a strong overrepresentation of digestive cancers and surgery, probably due to the close link between digestive cancers and undernutrition. Hence, we lacked data for nondigestive cancers such as lung cancer, breast cancer, and urological malignancies in particular. Second, we found 7 negative studies involving 960 participants [22,26,34,37,41,43,49]. For one of these studies [37], sarcopenia was not the primary objective, but the study reported sarcopenia as a covariate, which probably affected the results. Moreover, 3 other studies [41,43,49] included few participants (n ¼ 16, n ¼ 61 and n ¼ 48, respectively) and probably lacked power. Another limitation of our systematic review was that the search concerned only English and French articles from only one database. This review emphasized the importance of screening pretherapeutic sarcopenia in cancer patients because we found pretherapeutic sarcopenia strongly and independently associated with the poorest outcomes during cancer treatment. Moreover, sarcopenia could potentially be prevented with physical rehabilitation, appropriate nutrition and vitamin D supplementation [12]. Indeed, numerous intervention studies have demonstrated a benefit for muscle performance in mostly older patients, but we lack evidence showing an improvement in muscle mass [12]. Otherwise, sarcopenia is the first way to conduct toward cancer cachexia, which is not fully reversible with nutritional intervention and could lead to disability and limit treatment efficacy [54,55]. Therefore, the management of sarcopenia may increase the efficacy of cancer treatment and limit poor outcomes during follow-up, particularly in older cancer patients. Prospective cohort studies are needed to validate the diagnostic algorithms for sarcopenia in cancer patients, particularly in the oldest patients. Finally, future therapeutics to treat cancer cachexia should be an important part of the management of loss of skeletal muscle mass. 5. Conclusion Pre-therapeutic sarcopenia was highly prevalent in adults with cancer. It was independently associated with the poorest outcomes during cancer treatment and affects post-operative complications, chemotherapy-induced toxicity and survival. Sarcopenia needs to

be screened before cancer treatment to enhance rehabilitation and limit progression toward cachexia and disability. Conflict of interest The authors declare no conflicts of interest. Acknowledgment We thank L Smales for revising the manuscript. References [1] Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, et al. Sarcopenia: European consensus on definition and diagnosis report of the European working group on sarcopenia in older people. Age Ageing 2010 Jul 1;39(4):412e23. [2] Fielding RA, Vellas B, Evans WJ, Bhasin S, Morley JE, Newman AB, et al. Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia. J Am Med Dir Assoc 2011 May;12(4):249e56. [3] Chen L-K, Liu L-K, Woo J, Assantachai P, Auyeung T-W, Bahyah KS, et al. Sarcopenia in Asia: consensus report of the Asian working group for sarcopenia. J Am Med Dir Assoc 2014 Feb;15(2):95e101. [4] Landi F, Cruz-Jentoft AJ, Liperoti R, Russo A, Giovannini S, Tosato M, et al. Sarcopenia and mortality risk in frail older persons aged 80 years and older: results from ilSIRENTE study. Age Ageing 2013 Mar;42(2):203e9. [5] Landi F, Liperoti R, Russo A, Giovannini S, Tosato M, Barillaro C, et al. Association of anorexia with sarcopenia in a community-dwelling elderly population: results from the ilSIRENTE study. Eur J Nutr 2013 Apr;52(3):1261e8. [6] Lee W-J, Liu L-K, Peng L-N, Lin M-H, Chen L-K, ILAS Research Group. Comparisons of sarcopenia defined by IWGS and EWGSOP criteria among older people: results from the I-Lan longitudinal aging study. J Am Med Dir Assoc 2013 Jul;14(7). 528.e1e7. [7] Legrand D, Vaes B, Matheï C, Swine C, Degryse J-M. The prevalence of sarcopenia in very old individuals according to the European consensus definition: insights from the BELFRAIL study. Age Ageing 2013 Nov;42(6):727e34. [8] Murphy RA, Ip EH, Zhang Q, Boudreau RM, Cawthon PM, Newman AB, et al. Transition to sarcopenia and determinants of transitions in older adults: a population-based study. J Gerontol A Biol Sci Med Sci 2014 Jun;69(6):751e8. [9] Patel HP, Syddall HE, Jameson K, Robinson S, Denison H, Roberts HC, et al. Prevalence of sarcopenia in community-dwelling older people in the UK using the European working group on sarcopenia in older people (EWGSOP) definition: findings from the hertfordshire cohort study (HCS). Age Ageing 2013 May;42(3):378e84. [10] Tanimoto Y, Watanabe M, Sun W, Sugiura Y, Tsuda Y, Kimura M, et al. Association between sarcopenia and higher-level functional capacity in daily living in community-dwelling elderly subjects in Japan. Arch Gerontol Geriatr 2012 Oct;55(2):e9e13. [11] Volpato S, Bianchi L, Cherubini A, Landi F, Maggio M, Savino E, et al. Prevalence and clinical correlates of sarcopenia in community-dwelling older people: application of the EWGSOP definition and diagnostic algorithm. J Gerontol A Biol Sci Med Sci 2014 Apr;69(4):438e46. ~ iga C, Arai H, Boirie Y, et al. [12] Cruz-Jentoft AJ, Landi F, Schneider SM, Zún Prevalence of and interventions for sarcopenia in ageing adults: a systematic review. Report of the international sarcopenia initiative (EWGSOP and IWGS). Age Ageing 2014 Nov;43(6):748e59. [13] Bastiaanse LP, Hilgenkamp TIM, Echteld MA, Evenhuis HM. Prevalence and associated factors of sarcopenia in older adults with intellectual disabilities. Res Dev Disabil 2012 Dec;33(6):2004e12. [14] Landi F, Liperoti R, Fusco D, Mastropaolo S, Quattrociocchi D, Proia A, et al. Prevalence and risk factors of sarcopenia among nursing home older residents. J Gerontol A Biol Sci Med Sci 2012 Jan;67(1):48e55. [15] Gariballa S, Alessa A. Sarcopenia: prevalence and prognostic significance in hospitalized patients. Clin Nutr Edinb Scotl 2013 Oct;32(5):772e6. [16] Shachar SS, Williams GR, Muss HB, Nishijima TF. Prognostic value of sarcopenia in adults with solid tumours: a meta-analysis and systematic review. Eur J Cancer 2016 Apr;57:58e67. [17] Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 2009 July;6(7), e1000100. [18] Nishigori T, Okabe H, Tanaka E, Tsunoda S, Hisamori S, Sakai Y. Sarcopenia as a predictor of pulmonary complications after esophagectomy for thoracic esophageal cancer. J Surg Oncol 2016 May;113(6):678e84. [19] Okumura S, Kaido T, Hamaguchi Y, Fujimoto Y, Kobayashi A, Iida T, et al. Impact of the preoperative quantity and quality of skeletal muscle on outcomes after resection of extrahepatic biliary malignancies. Surgery 2016 Mar;159(3):821e33. [20] Wang S-L, Zhuang C-L, Huang D-D, Pang W-Y, Lou N, Chen F-F, et al. Sarcopenia adversely impacts postoperative clinical outcomes following

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Please cite this article in press as: Pamoukdjian F, et al., Prevalence and predictive value of pre-therapeutic sarcopenia in cancer patients: A systematic review, Clinical Nutrition (2017), http://dx.doi.org/10.1016/j.clnu.2017.07.010