Introduction Sarcopenia is a condition described as the progressive generalized loss of muscle mass and strength. While sarcopenia has been linked with poorer outcomes following a variety of malignancies, its relationship with all gynecological cancer clinical outcomes has, to date, not been evaluated. This review interrogates the concept of sarcopenia as a prognostic tool for oncological outcomes and adverse effects of treatments in all primary gynecological malignancies.
Methods This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines, searching PubMed, Embase, and CINAHL without date or language restriction for studies reporting on sarcopenia and gynecological malignancies. Random effects meta-analysis models were used to determine the effects of sarcopenia on progression-free survival, overall survival, and treatment-related adverse events.
Results Data were analyzed from 13 studies, including 2446 patients (range 60–323) with ovarian cancer (n=1381), endometrial cancer (n=354), or cervical cancer (n=481). Sarcopenia was associated with lower progression-free survival (HR 1.69, 95% CI 1.03 to 2.76), overall survival (HR 1.33, 95% CI 1.08 to 1.64), and no increase in adverse events (HR 1.28, 95% CI 0.69 to 2.40). The risk of bias of the studies was mostly rated unclear, and Begg’s and Egger’s test revealed a potential publication bias for progression-free survival and overall survval, although the HRs remained significant when adjusting for it.
Conclusion Sarcopenia is associated with worse progression-free survival and overall survival in gynecological oncology malignancies. Further research is warranted to validate these findings in larger and prospective samples using standardized methodology and to examine if an intervention could reverse its effect in gynecological oncology trials.
- Endometrial Neoplasms
- Cervix Uteri
- Ovarian Cancer
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The overall hazard of disease progression was increased by 69% for those with sarcopenia.
Sarcopenia potentially contributes to worse overall survival, with a pooled HR of 1.33.
Sarcopenia should be a factor considered in future prospective trials.
Sarcopenia is a condition or syndrome described as the progressive and generalized loss of muscle mass and strength.1 The prevalence of sarcopenia increases with age, with up to 53% of individuals in their eighth decade considered sarcopenic and more than 40 million people affected worldwide.1 Sarcopenia can also be acquired as a consequence of several pathological processes, including malignancy.2 The diagnosis of sarcopenia is commonly based on assessment of low muscle mass, strength, and performance3 or on quantifiable objective measures using various imaging modalities including computed tomography (CT), magnetic resonance imaging (MRI), and dual energy x-ray absorptiometry.4 Measurement of the third lumbar vertebral area of skeletal muscle on CT imaging is the most frequently used test and has been shown to correlate well with whole body muscle mass.5 Sarcopenia is not reflective of an individual’s nutritional status and, as such, while it may be more readily diagnosed in normal or underweight individuals,5 body mass index generally correlates poorly with the diagnosis.6 Therefore sarcopenia can also occur concurrently with obesity, which may be associated with worse outcomes in the context of cancer treatments.7
Sarcopenia has been shown to independently impact the course of several diseases including gastrointestinal, renal, and lung malignancies.4 The relationship between sarcopenia and disease outcomes in oncological populations reflects an emerging area of research, and assessment of the impact of sarcopenia on morbidity and mortality in gynecological oncology is therefore a growing area of study.8 Traditionally, gynecological oncologists have placed great emphasis on the detection and management of cachexia (weight loss), as its presence is associated with adverse malignancy-associated outcomes.9 It is clear, however, that body mass index is not correlated with body composition and knowledge of muscle mass—or lack thereof—is an increasingly important consideration in the treatment of malignancy.10 This may be of particular relevance in gynecological oncology given the strong association between obesity and risk of endometrial and ovarian malignancies,11 where there will be a need for improved understanding of the less clinically apparent sarcopenia in overweight and obese patients. Patient factors which allow clinicians to refine their treatment and prognostication are increasingly important in an era of personalized medicine. Sarcopenia may provide clinical information that allows treatment interventions not as readily apparent if one relies on more traditional assessments of nutrition (eg, body mass index),12 and further research is necessary to assess whether this process is of oncological benefit.
This meta-analysis and systematic review of the literature aims to interrogate the concept of sarcopenia as a prognostic tool for oncological outcomes and for its association with treatment-related complications in the context of gynecological cancer.
This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines. We searched PubMed, Embase, and CINAHL to identify all potentially relevant articles with no date limitation, without language restriction. Search strategies were customized to the subject heading and search structure of individual databases. Reference lists from review articles were also searched. The full search strategy can be found in online supplementary appendix 1. The search was completed on June 25, 2019. This study was registered with PROSPERO (registration number CRD42019139488).
Inclusion and exclusion criteria
All identified studies were assessed. Any study reporting on sarcopenia and outcomes in gynecological cancer was considered, with participants in studies defined as women with uterine/endometrial, ovarian, cervical, vulvar, or vaginal cancer. Sarcopenia was defined using an accepted objective measure as determined by the study authors (see Results). Cohort studies (prospective and retrospective) and randomized controlled trials were considered for inclusion. Conference abstracts, case reports, and management recommendations or pharmaceutical treatment studies were excluded. Studies were excluded if they did not report on the pre-determined outcome measures of interest and/or sarcopenia was not defined.
Pre-determined outcomes of interest were progression-free survival, defined as time from enrollment in the study until recurrence of disease; overall survival, defined as time from enrollment in the study until death from any cause; and adverse events associated with treatment, which were defined by the study authors and included intra-operative and post-operative complications as well as complications of chemotherapy (online supplementary appendix 2). We also targeted tolerability of treatment as an outcome measure; however, no study included in the final meta-analysis reported on this.
Selection of studies
Two authors (AC and YP) independently reviewed abstracts to identify all studies that potentially met the inclusion criteria and should be retrieved. The same two authors independently assessed each full-text article to determine whether it met all of the selection criteria. Any disagreement and uncertainties were resolved by discussion, with involvement of a third author (ERA).
Assessment of methodological and reporting quality
Methodological quality was assessed using the Cochrane Risk of Bias tool for randomized trials. For non-randomized studies, the Newcastle–Ottawa Scale was adapted and used for the cohort studies as it included three additional elements (all outcome measures reported, methods of assessment for outcome provided, authors discuss potential sources of bias) from the Strengthening the Reporting of Observational Studies in Epidemiology quality assessment tool when assessing cohort studies.
Study results were summarized in descriptive form, including number of patients involved, study design, year of study, and main outcome measures. We conducted a meta-analysis of the combined data across all studies, regardless of cancer type first. Given the heterogeneity of the included studies, pooled hazard ratios (HRs) were estimated using random-effects. To determine the effects of sarcopenia on progression-free survival, overall survival, and adverse events we calculated the pooled HRs and their corresponding 95% confidence intervals (CI). A two-tailed p value <0.05 was considered statistically significant. Sarcopenia was defined according to the authors of individual studies. Given the range of accepted diagnostic modalities, it was pragmatic to analyze studies together and accept the limitations of this. We used Begg’s and Egger’s tests to evaluate the publication bias, with a two-tailed p<0.1 indicating significant publication bias. All analyses were conducted using Stata software Version 15.1 (Stata Corp, College Station, Texas, USA).
Figure 1 shows the PRISMA flow chart for the selection of studies. The search strategy returned 342 results after duplicates were removed. Of these, after exclusions were applied, 51 full texts were reviewed (14.9%), with 16 studies meeting the inclusion criteria.
The characteristics of the 16 included studies, of which all were retrospective cohort studies, are shown in Table 1. Nine studies (56.25%) reported on sarcopenia in ovarian cancer, three (18.75%) on endometrial cancer, one (6.35%) on both endometrial and ovarian cancer (with data combined), and three (18.75%) on cervical cancer. Sample sizes ranged from 60 to 323 patients. Three studies13–15 had crossover periods and potential crossover patients with other included papers and so were excluded from any further analysis. A total of 2466 patients from 13 studies were included in the final meta-analysis. All included studies were published from 2015 onwards. Sarcopenia was defined in a variety of ways including muscle attenuation,16 skeletal muscle index,9 14 17–25 muscle mass measurement,26 skeletal muscle loss during treatment,13 15 and the psoas index,27 all of which were defined in the included papers. Ten (77%) studies reported on overall survival, four (31%) reported on progression-free survival, and five (38%) studies reported on adverse events (online supplementary appendix 2).
Overall, four studies (two ovarian and one each for endometrial and cervical cancer) contributed data towards analysis of the relationship between sarcopenia and disease progression. The progression-free survival by cancer type and overall is shown in Figure 2. Findings indicate that, overall, the hazard of disease progression was increased by 69% for those with sarcopenia (HR 1.69, 95% CI 1.03 to 2.76, I2=54.6%, p=0.085) with low to moderate heterogeneity in the included studies. The relationship between progression-free survival and sarcopenia is inverse, which means that the presence of sarcopenia has a negative impact on progression-free survival.
Ten studies reported on the relationship between sarcopenia and overall survival. The overall pooled HR was 1.33 (95% CI 1.08 to 1.64, I2=40.8%, p=0.086) with low to moderate heterogeneity in the included studies. Subgroup analyses showed that the magnitude of effect is accentuated for women with endometrial cancer (Figure 3). The relationship between overall survival and sarcopenia is inverse, with the presence of sarcopenia associated with a negative impact on overall survival.
Data from five studies (with high heterogeneity) suggest no significant increase in adverse events in those with sarcopenia (HR 1.28, 95% CI 0.69 to 2.40, I2=69.4%, p=0.011; Figure 4).
Assessment of methodological quality
Online supplementary figure 1 summarizes the assessment of methodological quality of the included studies. The majority of studies had an unclear risk of bias in seven of eight domains. Six of 13 studies (46%) had a high risk of bias in the domain of representativeness of the exposed cohort. Six studies were also at low risk of bias in the domain of comparability of the cohorts.
Publication bias was assessed using both Begg’s and Egger’s tests. For overall survival, potential publication bias was identified (Begg’s test p=0.049, Egger’s test p=0.014); however, the HR remained significant after applying the trim and fill method (HR 1.21, 95% CI 1.03 to 1.42). This was similar in progression-free survival (Begg’s test p=0.089, Egger’s test p=0.063), with a HR after applying the trim and fill method of 1.54 (95% CI 1.07 to 2.18). There was no apparent publication bias for the outcome of adverse events (Begg’s test p=0.324, Egger’s test p=0.115, HR 1.30, 95% CI 0.72 to 2.37)
This systematic review and meta-analysis explored the relationship between sarcopenia and gynecological oncology outcomes. We found evidence from 13 studies that sarcopenia was significantly associated with impaired overall survival and progression-free survival with a trend towards an increased risk of adverse events. The impact of sarcopenia on overall survival was pronounced for patients treated for endometrial cancer. Sarcopenia was also associated with a trend towards a higher risk of adverse events related to cancer treatment (variably defined), although these results should be interpreted with caution as only a few studies reported on this outcome, and there was marked heterogeneity of the included studies as indicated by the high I index (69.4%).
Prior to this review, the relevant body of evidence for gynecological malignancies consisted of only one meta-analysis, including data from eight studies, suggesting a significant association of low skeletal muscle index with overall survival in ovarian cancer (HR 1.11). However, the authors concluded that the quality of the evidence was low in all contributing publications.28 In our meta-analyses there is a trend towards worse overall survival in sarcopenia in ovarian cancer (six studies) and a significant association between sarcopenia and overall survival in endometrial cancer (two publications). Further, although lacking statistical significance, findings relevant to women with cervical cancer were in the same direction as those for women with endometrial and ovarian cancer. The magnitude of effect reported from this review was consistent with those from a variety of other solid malignancies including gastric,29 renal, and colorectal malignancies.30
In our analysis of progression-free survival there were small numbers of included studies but overall a significant association of sarcopenia with progression-free survival. In other oncological studies there are conflicting results with regard to the impact of sarcopenia on this outcome.30 Given the small number of studies, the role of sarcopenia in specific gynecological malignancies is difficult to interrogate. It is, however, apparent that sarcopenia has the potential to be of significance in the progression of both ovarian and endometrial malignancies, and it will be important to explore the mechanisms driving this effect in future prospective studies.
Although less well studied, in a variety of solid malignancies such as gastric and hepatopancreatobiliary tumors, sarcopenia has been associated with increased treatment-related complications.31 32 We did not find a significant relationship between sarcopenia and adverse events in this analysis, although included studies and numbers of patients were limited.
Of particular note are the findings of this meta-analysis pertaining to women with endometrial cancer. Specifically, compared with the overall HR across all gynecological malignancies, HR relating to sub-group analysis for overall survival following endometrial cancer was the most pronounced. Over 60% of women diagnosed with endometrial cancer are obese,33 and the diagnosis of sarcopenia in obese patients may be challenging. Assessment of sarcopenia prior to treatment could assist with identification of patients at high risk of poor outcomes. Those patients could be targeted for future intervention trials.
This systematic review and meta-analysis had broad inclusion criteria and followed rigorous quality protocols. All papers included were published from 2015 onwards, highlighting these findings as likely reflective of current patients and practice. Nonetheless, key limitations of this review include the heterogeneous methods of sarcopenic assessment and retrospective data collection of included studies, with the latter limitation likely contributing to unclear risk of bias and the publication bias identified. The accepted definitions and specific measurement of sarcopenia varied widely between studies, which limits the interpretation of the analysis and the capacity to rigorously compare included studies. We were unable to interrogate the impact of sarcopenia diagnosed at different time points in the course of cancer treatment, and are aware that this may impact the magnitude of the effect of sarcopenia on patient outcomes.34 A standardized approach to the diagnosis will be necessary if we are to consider further the role it may play in trials and assessment of oncological outcomes. Furthermore, while sarcopenia may be acquired as a consequence of cancer treatment—for example, as a side effect of chemotherapy35—it is also clear that it may be associated with age, previous co-morbidities, and declines in physical activity.1 Retrospective studies such as those included in this meta-analysis lack the methodological robustness to provide sufficient detail regarding the direction of the relationship being assessed.
There is also clear scope for rigorous and comprehensive assessment of the potential relationship between adverse events and sarcopenia in gynecological malignancies. It was beyond the scope of this review to evaluate the timing of sarcopenia development and its impact on survival outcomes and adverse events; this represents a clear area in need of future research with high translational potential. The lack of prospective studies in this field remains a significant limitation in being able to comprehensively consider the role of sarcopenia in clinical gynecological oncology, particularly with respect to both its capacity to be modified as well as its potential to guide prognosis at various stages of an oncological diagnosis. Therefore, future prospective research with a uniform definition of sarcopenia and with consideration to the relationship between sarcopenia and other prognostic factors in malignancy is required to obtain high-level evidence on the impact of sarcopenia on treatment-related complications and survival outcomes.
Sarcopenia is associated with worse oncological outcomes in gynecological malignancies in this systematic review of retrospective cohort studies. Given that sarcopenia is a potentially modifiable risk factor, prospective research using pre-defined criteria is warranted to explore the potential of interventions to reverse it.
We would like to acknowledge Mr Lars Eriksson, the liaison librarian for the Faculty of Medicine at the University of Queensland for assistance with development of the search strategy.
Contributors Study design: ERA, AO. Data acquisition: ERA, YP, AC. Quality assessment: ERA, YP, AC. Data analysis and interpretation: YP, SH, MJ. Manuscript draft: ERA. Manuscript review: ERA, YP, AC, SH, MJ, AO. All authors approved the final version of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. Data obtained from included studies. We are happy to provide this.