Associations of fat and muscle mass with overall survival in men with prostate cancer: a systematic review with meta-analysis

Background To systematically review and analyse the associations between fat and muscle mass measures with overall survival in men with prostate cancer. Methods A systematic search was conducted in CINAHL, Cochrane Library, EMBASE, PubMed, and Web of Science databases from inception to December 2020, while abstracts from the American Society of Clinical Oncology (ASCO), Clinical Oncology Society of Australia (COSA), and the American College of Sports Medicine (ACSM) conferences were searched from 2014 to 2020. Eligible articles examined the association of body composition measures, such as fat mass (e.g., fat mass, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and VAT/SAT) and muscle mass measures, with overall survival in prostate cancer patients at any treatment stage. The primary endpoint was overall survival. Random-effect meta-analysis was conducted for studies reporting multivariable or univariable analysis assessing the associations of fat mass measures (i.e., fat mass, VAT, SAT, VAT/SAT) and muscle mass measures with overall survival. Results Sixteen cohort studies that comprised 4807 men with prostate cancer were included. Total adiposity (hazard ratio (HR) 0.98, 95% CI: 0.75–1.28, p = 0.888) and VAT (HR 1.03, 95% CI: 0.74–1.43, p = 0.873) were not significantly associated with overall survival, while higher subcutaneous adipose tissue levels were associated with higher survival (HR 0.68, 95% CI: 0.54–0.84, p = 0.001). Greater mortality risk was found in patients with localised (HR 1.91, 95% CI: 1.40–2.62, p < 0.001) and advanced disease (HR 1.43, 95% CI: 1.07–1.92, p = 0.020) presenting with low levels of muscle mass compared to those presenting with high levels. Discussion These results indicate that although overall adiposity should be cautiously interpreted in regards to survival, high muscle mass and SAT, and low VAT/SAT ratio values are associated with overall survival in men with prostate cancer.


INTRODUCTION
Prostate cancer is one of the most prevalent cancers worldwide, accounting for one in five new cancer cases in men [1]. Among the available treatments, androgen deprivation therapy (ADT) is commonly used alone or in combination with other forms of therapy to delay prostate cancer progression and improve survival in patients with advanced prostate cancer [2]. However, as a result of resistance to treatment [3,4], altered metabolic profile and body composition impairments such as increased fat mass and reduced muscle mass [5,6], patients are at an increased risk of both cancer and non-cancer related mortality with 5-year survival rates as low as 30% depending on health status and stage at the time of prostate cancer diagnosis [7].
Obesity is a potential predictor of mortality in men with prostate cancer [8,9], affecting not only tumour biology [10] but also the outcomes of radical prostatectomy and radiation therapy [8,[11][12][13]. Significant associations between high body mass index (BMI; >30 kg m −2 ) and a 23% increased risk for all-cause mortality [9], or increases of 5 kg m −2 with a 20% increased risk of prostate cancer-specific mortality [8] were reported in previous investigations. However, the association of obesity with all-cause mortality is not consistent across all prostate cancer studies, with some studies challenging this relationship by presenting no significant association between higher BMI values and overall survival in this population [14,15], or presenting an inverse relationship between obesity and survival [16]. This apparent obesity paradox may be related to the reliance on BMI since this measure does not differentiate lean from fat mass or visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) [17,18], masking the relationship of fat mass with overall survival in men with prostate cancer [19,20]. Furthermore, sarcopenia or the loss of muscle mass has also been considered an important prognostic factor [6,[21][22][23], although its association with overall survival in men with prostate cancer is largely controversial depending on the cancer stage or phase of treatment [16,24,25]. Therefore, it remains to be determined if excess fat mass, reduced levels of muscle mass, or both treatment-related changes in body composition have an impact on overall survival in men with prostate cancer [20]. Determining these associations may potentially inform specific and tailored strategies to improve overall survival in this group of patients.
As a result, we investigated in this systematic review the role of body composition on overall survival in men with prostate cancer, analysing the associations of low muscle mass and high fat mass as prognostic factors. In addition, a range of possible clinical (i.e., localised vs. advanced disease) and methodological (i.e., definition of cut-off values for muscle mass, depots of fat mass and controlling for BMI in multivariable analysis) variables that may affect the associations of body composition with overall survival were examined by subgroup analyses.

Study selection procedure
A systematic search was conducted in the following electronic databases: CINAHL, Cochrane Library, EMBASE, PubMed and Web of Science from inception to December 2020. The search strategy is presented in the Supplementary eAppendix 1. In addition, we also performed a manual search of the reference lists provided in the selected papers as well as in abstracts from the American Society of Clinical Oncology, Clinical Oncology Society of Australia and the American College of Sports Medicine conferences from 2014 to 2020. All procedures were undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement [26,27] and based on the minimum criteria established by the Cochrane Back Review Group [28], with registration at the international prospective register of systematic reviews (PROSPERO identifier: CRD42020218736).
This review included published articles and conference abstracts [29] of studies evaluating the association of body composition measures, such as fat mass (e.g., fat mass, VAT, SAT and VAT/SAT) and muscle mass measures, with overall survival in prostate cancer patients at any treatment stage. The primary and only outcome for this review was overall survival, defined as the time in months of death by any cause. The exclusion criteria were: (1) studies involving mixed cancer patients without specific information on the results for prostate cancer patients; (2) studies not including or reporting on the specific outcomes for this review, or did not include sufficient information such as hazard ratios (HR) and 95% confidence intervals (CI) for overall survival analysis; (3) studies evaluating specific interventions for body composition such as nutrition or exercise; and (4) written in a language other than English. In the search strategy, titles and abstracts were first independently evaluated following the eligibility criteria. When abstracts did not provide sufficient information, they were selected for full-text evaluation. In addition, authors were contacted for further information when necessary. Eligibility was assessed independently in duplicate (PL and FS), with differences resolved by consensus.

Data extraction
Data extraction was performed via a standardised form. Clinical and methodological information were extracted from the included studies such as cancer stage and treatment, number of participants at baseline, geographical region, age and BMI at baseline, fat and muscle mass assessments (i.e., method of assessment, location and cut-off values), follow-up period, HR for overall survival with their associated dispersion values such as 95% CI or standard errors (SE) from univariable and multivariable analyses, when available, and the number of covariates included in the multivariable models.

Study quality assessment
The study quality assessment was evaluated according to the Newcastle-Ottawa Quality Assessment Scale (NOS) for cohort studies [30]. The NOS consists of eight items related to representativeness of the exposed cohort, comparability based on the study design or analysis and assessment of outcome and adequacy of follow-up with a total maximum score of 9 [30]. Studies were assessed by the following items: (1) Representativeness of the exposed cohort; (2) Selection of the non-exposed cohort; (3) Ascertainment of exposure; (4) Demonstration that outcome of interest was not present at start of study; (5) Comparability of cohorts on the basis of the design or analysis; (6) Assessment of outcome; (7) Was follow-up long enough for outcomes to occur; (8) Adequacy of follow up of cohorts. The study quality assessment for all included studies were performed independently by two reviewers (PL and FS) with disagreements resolved by consensus.

Data analysis
Data from the associations of body composition with overall survival such as HR and their associated dispersion values were pooled using inverse variance random-effects models. These values were extracted from univariable and multivariable models and log-transformed to be included in further analyses. Analyses were conducted for studies reporting multivariable or univariable analysis and subgroup analyses were provided for the following: (1) removing outliers; (2) for prostate cancer subgroups (stage or phase of treatment); (3) previously defined or median cut-off values for muscle mass outcomes; (4) specific depots of fat and (5) studies using BMI as a covariate or not in the multivariable models. A p value of ≤0.05 was considered statistically significant. Forest plots were generated to present the results for multivariable and univariable analysis of fat and muscle mass. Heterogeneity between studies was assessed by using the I 2 statistic and the p value from χ 2 -based Cochran's Q test with a high heterogeneity defined by a threshold p value of 0.1 or I 2 value greater than 50% [31]. We examined outliers using sensitivity analysis by omitting one study at a time. To check for publication bias, contour-enhanced funnel plots of log HR against its SE were generated and explored using Egger's regression asymmetry test when more than ten studies were available [32]. Analyses were conducted using the Review Manager (RevMan) software from the Cochrane Collaboration (version 5.4, Copenhagen: The Nordic Cochrane Centre) and the package 'meta' from R (R Core Team, 2020).

Studies included and characteristics
Of the 805 retrieved studies, 514 potential records were retained for screening after duplicate removals. Of these, 373 were excluded due to their irrelevance to the research question and 141 articles were deemed eligible and undertaken for review ( Fig. 1 and Supplementary eAppendix 2). A total of 16 cohort studies undertaking retrospective analyses [16,24,25,[33][34][35][36][37][38][39][40][41][42][43][44][45] were included in the primary analysis. During the eligibility assessment, six additional studies [46][47][48][49][50][51] were initially selected and authors contacted given the lack of specific information on the results for prostate cancer patients. Responses were not obtained and, as a result, these studies were not included in our review.

DISCUSSION
In this review we examined the role of fat and muscle mass on survival in men with prostate cancer. The main findings of our study were: (1) although overall fat mass was not a prognostic factor in men with prostate cancer, high levels of subcutaneous fat and low levels of VAT/SAT were associated with a 32% and 50% survival advantage, respectively, in patients at advanced stages of the disease; and (2) patients presenting with low muscle mass levels are at~50% increased risk of mortality compared to those presenting with high levels regardless of the cancer stage or methodological characteristics. These results are clinically relevant and indicate the importance of muscle mass in particular during the course of therapy given the substantial impact on overall survival of patients with prostate cancer. Although obesity and the resulting metabolic environment are deemed important factors for biochemical recurrence, metastatic disease and mortality in men with prostate cancer [8,9], our finding is that total adiposity is not associated with overall survival in prostate cancer patients. Interestingly, the reasons for this particular outcome may be related to the metabolic differences between SAT and VAT [52], with subcutaneous and visceral depots of fat exerting conflicting effects on overall survival in prostate cancer patients. For example, researchers have suggested that VAT is closely associated with inflammatory cytokines (e.g., interleukin-6 and tumour necrosis factor-alpha) which may potentially affect the tumour microenvironment [10,52], while subcutaneous tissue-derived factors such as leptin may act in contrast by increasing insulin sensitivity and lipid metabolism, thereby, effectively improving survival [52][53][54][55]. Another potential explanation for the different findings reported previously [8,9] and this study may be related to cancer cachexia [19]. This phenomenon may mislead the association of obesity with cancer progression or mortality given the unintentional weight loss that can occur during cancer treatment or even before the cancer detection (i.e., reverse causation) in obese cancer patients [19]. Thus, the assessment of BMI alone at the time of cancer may not inform whether prostate cancer patients have been obese before diagnostic, precluding us to specifically observe the influence of obesity on cancer survival in prostate cancer patients. Finally, our data on fat mass and overall survival were derived from studies mostly with advanced prostate cancer patients (i.e., metastatic and castration-resistant patients) and this may explain the difference between our findings and a previous study indicating significant associations between BMI and weight gain with prostate cancer outcomes in nonmetastatic patients [9]. Our results are in line with previous studies concerning the prognostic value of different depots of fat mass in cancer patients [24,52,56] and may indicate the necessity to cautiously interpret total adiposity in this group of patients, as different levels of obesity and depots of fat are influencing overall survival in opposite ways [57]. Therefore, the utilisation of the VAT/SAT ratio may be a good strategy to avoid such conflicting effects derived from different depots of fat. For example, in a previous study [34] high levels of VAT/SAT ratio were significantly associated with shorter survival in normal weight prostate cancer patients, although this relationship was not observed in overweight or obese patients. Consequently, more research is required to elucidate the physiological value of VAT/ SAT ratio on overall survival. Moreover, although high levels of VAT did not significantly increase the risk of mortality in our analysis, previous studies have indicated the association with radical prostatectomy and radiation therapy outcomes [40,58] increasing surgical and recurrence risks, respectively, as well as increased risk of cardiovascular and metabolic disease [59]. Thus, more studies are necessary to elucidate the indirect or direct role of VAT on overall survival in men with prostate cancer.
Contrary to the results regarding total adiposity, a high level of muscle mass was associated with improved overall survival in prostate cancer patients regardless of treatment stage or   methodological characteristics. This may be related to the numerous benefits of muscle mass on metabolic health such as regulating and mobilising natural killer cells into the tumour, or even altering other biomarkers associated with the tumour biology [60,61]. In addition, crosstalk between muscle and other organs has also emerged as a potential mechanism by which the musculoskeletal system supresses cancer growth and therefore increases overall survival in men with prostate cancer [60,61]. Moreover, the present findings on muscle mass are in accordance with several other studies indicating a relationship between sarcopenia and survival in cancer patients [21][22][23] suggesting the importance of improving or maintaining muscle mass in this population before and during treatment [62]. For example, several trials have demonstrated the benefits of exercise, specifically resistance-based exercise programmes (i.e., anabolic exercise) increasing muscle mass during and following ADT [63][64][65][66], as well as preserving muscle mass in high-grade patients [67]. Therefore, the findings from our review are clinically meaningful indicating that muscle mass is an important prognostic factor for men with prostate cancer regardless of cancer stage. Also, accrual or maintenance of muscle mass through prescribed and tailored exercise, specifically resistance-based exercise, undertaken before, during and following cancer treatment would be beneficial in this population to effectively increase the chances of overall survival. The strengths of the present study are: (1) a relatively large number of studies (n = 16) with up to 4807 prostate cancer patients included; (2) the assessment of both univariable and multivariable models; and (3) subgroup analyses based on different clinical and methodological characteristics. However, there are also some limitations which are worthy of comment. First, only cohort studies undertaking retrospective analyses were included in our review and this precludes determining causality of body composition changes such as increase in muscle mass and reduction in fat mass on overall survival. Future prospective analyses are necessary to improve current knowledge by indicating if interventions targeting fat and muscle mass are able to improve overall and disease-specific survival as well as recurrence in men with prostate cancer. In addition, researchers used different definitions for sarcopenia such as the skeletal muscle index, psoas muscle or median values, while no definition for adiposity measures was used, leading to high heterogeneity within the models. Sarcopenia has become a topic of great interest in oncology [68]; however, poorly understood given the lack of reporting on assessment characteristics and definitions. For example, although studies had reported the time of body composition assessment [25,33,34,36,37,[40][41][42][43]45], the high heterogeneity and lack of standardisation could misclassify prostate cancer patients with obesity or sarcopenia and, therefore, mask the impact of these outcomes on overall survival. Future research should better inform definitions (i.e., cut-off values and rationale) and time of assessments, and information about clinical factors associated with muscle mass accrual or maintenance in this group of patients. This will improve the assessment of sarcopenia as well as provide information about its interaction with obesity on overall survival in this group of patients and assist future systematic reviews and meta-analyses. Nonetheless, subgroup analysis was undertaken based on previously defined methods to identify sarcopenia vs. median values to minimise such bias, with the results largely maintained, although the same was not conducted for fat mass given the lack of previous definitions. Finally, data concerning the association of fat mass and muscle mass measures with prostate cancer-specific and cardiovascular mortality as well as specific information about deaths are limited. Therefore, it is not possible to account for deaths directly or indirectly related to prostate cancer treatment comorbidities (e.g., metabolic syndrome, diabetes, cardiovascular disease).
As far as we are aware, the present systematic review and metaanalysis is the first to examine the prognostic value of fat and   Fig. 2 Random-effects meta-analysis. Association of low and high levels of VAT, SAT and VAT/SAT ratio (A, B) and muscle mass (C, D) with overall survival in men with prostate cancer. Analyses derived from multivariable and univariate models were presented in A, C and B, D, respectively. Higher VAT/SAT ratio indicates poorer overall survival. Overall effects analyses conducted with inverse variance random-effects meta-analysis. Squares represent study-specific estimates; diamonds represent pooled hazard ratios estimates of random-effects metaanalysis. *Study-specific estimate based on median values derived from skeletal muscle mass index and skeletal muscle volume indexes; FM fat mass, SAT subcutaneous adipose tissue, VAT visceral adipose tissue.
muscle mass in men with prostate cancer. In summary, increased levels of muscle mass and SAT and reduced VAT/SAT ratio rather than overall adiposity are important prognostic factors in men with prostate cancer, even when controlling for multiple confounding factors. Furthermore, we provide rationale for future prospective analyses investigating the impact of sarcopenia and changes in muscle mass during cancer treatment on prostate cancer outcomes, as well as the investigation of strategies such as exercise and nutritional interventions to improve survival in this population.