Obesity and Prostate Cancer Mortality: Comparison
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Obesity was associated with prostate cancer specific mortality and all-cause mortality. The temporal association was consistent with a dose-response relationship. Obesity, a potentially modifiable prognostic factor, was associated with higher prostate cancer mortality. Obesity had a moderate, consistent, temporal, and dose-response association with PC mortality. Weight control programs may have a role in improving PC survival.

  • body mass index
  • prostate cancer specific mortality
  • all-cause mortality

1. Introduction

Prostate cancer (PC), the second most common cancer and the third leading cause of cancer death in men [1], is steadily increasing in incidence [2]. Worldwide, over 650 million adults are obese [3], and therefore exposed to the second most common cause of preventable death [4], while obesity has been proposed as a risk factor for aggressive PC [5]. Recent large studies, however, showed that this relationship is unclear [6,7][6][7]. The other known factors associated with PC mortality, older age, family history of any cancer and ethnicity [5], are not changeable. As a potentially modifiable factor, obesity merits evaluation as a prognostic factor.
Individual studies on the association between obesity and prostate cancer (PC) mortality show inconsistent results, including both positive [6] and negative [8] association. Evidence syntheses on the association between obesity and PC outcomes [9,10[9][10][11],11], when judged by AMSTAR 2 [12], demonstrate weaknesses in the description of the study population, investigation of the causes of heterogeneity, evaluation of the impact of risk of bias in stratified results, and reporting of funding or conflicts of interest. Since the last meta-analysis [9], 15 prognostic studies have been published [2,7,8,13,14,15,16,17,18,19,20,21,22,23,24][2][7][8][13][14][15][16][17][18][19][20][21][22][23][24] with data from 186,802 new PC patients added to the total. Consequently, the last review [9] could access only a third of the current body of evidence. Importantly, previous evidence syntheses have not formally evaluated causation [25]. Thus, there is need for a robust and reliable evaluation of the association between obesity and prostate cancer specific mortality (PCSM) and all-cause mortality (ACM) in patients diagnosed with PC.

2. Obesity as a Risk Factor for Prostate Cancer Mortality

Compiling all available data for precise quantitative estimation of the prognostic effect of obesity in PC mortality, we found that BMI ≥ 30 was associated with PCSM and ACM compared with normal weight. Both mortality outcomes showed dose-response relationship with every 5 kg/m2 unit increase in BMI. In higher quality prospective studies evaluating temporal association, BMI ≥ 30 was associated with increased PCSM and showed dose-response association.
We performed a comprehensive literature search without language restrictions, increasing our potential to capture all relevant studies. Owing to the large sample size, we were able to undertake powerful analyses, including predefined subgroup analyses, to generate reliable results. There was considerable heterogeneity in the pooled analyses, and we used random effects models to obtain conservative precision estimates. The statistical significance of the observed heterogeneity could reflect the large number of studies we captured [78][26]. The exploration of reasons for heterogeneity showed that the main findings were not sensitive to variations in subgroups based on populations, settings, disease stage, and interventions. The measurement of exposure before or after the diagnosis provides a dichotomized assessment of a wide time range. The results in the postdiagnosis exposure measurement subgroup confirmed the prognostic association of continuous BMI with PCSM, which contributes to the specificity element of the causal criteria [79][27], and with ACM, consistent with the general adverse effects of obesity on overall survival. Conversely, obesity exposure throughout life captured in prediagnosis measurement showed an association with PCSM, although no association was found for ACM. The association between BMI and PC mortality might be different according to the treatment (e.g., better surgical success in patients with normal weight treated with radical prostatectomy). Subgroup analyses by ethnicity and other potentially important factors was not possible given that most of the selected studies did not report stratified results. However, adjusted hazard ratios were considered in the pooled analyses (Table S3) to reduce residual confusion. Our main findings were backed by the high-quality subgroup of studies, highlighting that the observed association of obesity with PC prognosis merits consideration. The assessment of causation is integral to the evaluation of findings of observational meta-analyses [79][27]. We evaluated whether our observed association fulfilled the classical Bradford Hill principles of causation [25]. Our assessment showed evidence of moderate strength of association, consistency, temporality, specificity, dose-response gradient, biological plausibility and analogy (Table S5). The association measured by pooled HR was statistically significant overall. The HR point estimate showed an increased strength of association in the higher-quality subgroup of studies. Consistency of individual studies, analyzed graphically, showed that point estimates of individual HRs on over three-quarters of the studies had an association. Although statistically I2 measurements showed variation, this reflected differences in size of the association observed rather than differences in its direction. The association within subgroups showed lower level of heterogeneity. The association was consistently observed across the subgroups including different stages, treatments (e.g., prostatectomy or androgen deprivation therapy) and populations of PC patients. Studies that analyzed obesity with measurements different from BMI also showed consistent association with PC mortality [80,81,82][28][29][30]. Temporality was established by longitudinal (cohort) studies. The specificity of the association was reflected in the results concerning PCSM. Moreover, the studies synthetized in our meta-analysis were mostly adjusted by several potential confounders, as shown in Table S3. Regarding biological gradient, we showed dose-response relationship by using continuous BMI as exposure, which was associated with PCSM and ACM. The biological plausibility of the association is underpinned by several postulated mechanisms explaining the relationship between BMI and PC death [9]. For instance, obesity is the most common cause of insulin resistance, which has been associated with a greater inflammatory state, a risk factor for cancer progression [83][31]. Also, molecular mechanisms connecting obesity with PC and other urothelial cancers have been broadly established [84][32]. Finally, the relationship with PC outcomes met analogy criterion, as obesity has been linked for the last three decades to mortality from numerous types of cancer [11,85][11][33] and to other outcomes related to PC, for instance, the presence of metastases [86][34]. Therefore, objectively, several criteria for causation were met. The World Cancer Research Fund [87][35] reported an increased risk of being diagnosed with advanced PC in obese patients, although large studies have recently questioned this point [6,7][6][7]. As it is potentially modifiable by lifestyle changes, future evaluations of the role of weight loss among obese patients with PC are required. For example, randomized interventions on diet and physical activity are needed to analyze PC outcomes [88,89][36][37]. Guidelines and patient information documents concerning PC would need to be updated to emphasize the role of obesity in prognosis.

3. Conclusions

Obesity currently poses an alarming burden on individuals, societies, and economies. Our study shows that in PC patients, obesity, a potentially modifiable risk factor, is moderately associated with temporality and a dose-response with PCSM and ACM. Therefore, obesity increases mortality in prostate cancer patients, according to the current observational evidence. This information should be useful in counselling PC patients and in planning future research concerning their lifestyle.

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