We found that higher BMI in initially cancer-free population was significantly associated with higher risk of future prostate cancer mortality. Among diagnosed patients, higher BMI was associated with a significantly higher risk of biochemical recurrence after primary treatment, and a borderline non-significantly elevated risk of prostate cancer-specific mortality. To our knowledge, this is the first meta-analysis that comprehensively summarized and quantitatively analyzed the current findings on obesity and outcomes of prostate cancer.
Previously, two meta-analyses on BMI and risk of prostate cancer were published, but each addressed different hypothesis compared to our study. Robinson et al
summarized findings on the association of childhood and young adulthood BMI and risk of advanced prostate cancer and fatal prostate cancer (only 1 study on fatal outcome), and the RR was close to the null (RR 1.01, 95% CI: 0.89–1.14) for each 5-unit increase in BMI (49
), indicating little impact of young adulthood BMI on risk of advanced prostate cancer. MacInnis et al
meta-analyzed both cohort and case controls studies on BMI and risk of advanced prostate cancer, and found that BMI was associated with 12% higher risk of advanced prostate cancer (RR 1.12, 95% CI: 1.01–1.23) for each 5-unit increase (2
). However, the association of BMI and fatal prostate cancer was not addressed in that study. In the present study, we assessed endpoints of disease progression such as prostate cancer mortality and biochemical recurrence among healthy population as well as among the diagnosed patients to specifically evaluate the role of adiposity on prostate cancer progression.
Overall, we found that the magnitude of the pooled effect estimates were quite similar with 15%–21% increased risk for each 5 kg/m2 increase in BMI, despite different study designs (cohort or survival studies), study settings (cohort from healthy group or clinical studies), outcome assessments (prostate cancer-specific mortality or recurrence), or from multiple countries with different social economic or racial (Caucasians, African Americans, and Asian men) backgrounds. The similar pooled estimates across different types of clinical treatments further suggest the robust association between obesity and prostate cancer progression.
Several possible explanations have been proposed. First, such association could be due to delayed diagnosis and more advanced stage at diagnosis in obese men. It has been suggested that obesity makes prostate cancer early detection more difficult due to less PSA screening, lower accuracy of digital rectal examination in obese men and lower PSA values caused by obesity-related hemodilution (33
). Obese individual has higher chance to be missed as the cancer detected by PSA screening is so small and larger prostate gland (51
) makes the detection of existent cancer less likely (52
). Although the existence of such detection bias could not be fully ruled out, studies by Wright et al
and Ma et al
suggested that elevated BMI was significantly associated with higher risk of prostate cancer-specific mortality in those without PSA screening (4
) and in both pre and PSA screening era (11
). Alternatively, difficulties in treatment, such as increased risk of positive surgical margins (12
), and the greater day-to-day variation of prostate location that leads to lower dose and less effective radiation (53
), could also contribute to the poorer outcome observed in diagnosed patients. However, the association with recurrence is still strong and significant after adjusting for margin status in many of the studies included in our analysis ().
Potential biological mechanisms of adiposity and prostate cancer progression have been proposed and under investigation. Hormonal and metabolic changes in obese men are the primary concern. One hypothesis is that certain obesity-related metabolic dysregulation such as hyperinsulinemia and/or hypoadiponectinemia favors aggressive neoplastic behavior (11
). It was also found that lower levels of testosterone in obese men may be linked to poorly differentiated and hormone insensitive tumors (55
). Obesity is also associated with increased levels of free IGF-1, which is found to stimulate growth of prostate cell lines in vitro and be more closely related to advanced stage prostate cancer in human (57
High heterogeneity was detected among the studies reviewed in the present analysis. The stratified meta-analyses suggested strong and consistent association between BMI and higher prostate cancer mortality and biochemical recurrence in studies conducted in the United States. Smaller relative risks in the few available studies from Europe could be attributable to large variability in the linear transformed RRs under a lower prevalence of obesity in European countries. We also found that studies using self-reported BMI presented stronger association than studies utilizing measure BMI, and different magnitudes of association between BMI and biochemical recurrence among patients on different radiation therapies were also observed. These evidence reflected the need of investigations in different countries and among different subgroup of patients.
In further reviewing the heterogeneity between cohort studies and clinical studies, several issues are worth noting. First, missing data of BMI and shorter period of follow-up in clinical studies could bias the estimate and limit the findings. For example, in the study by Siddiqui et al
, 23% of the patients had missing BMI and in Davies et al
, only 53% of the patients in the CaPSURE database were included. Both studies and the study by van Roermund et al
had lower prostate cancer-specific mortality (3–4%) compared to other studies either due to short follow-up of 3–4 years or selection of much healthier individuals. Secondly, clinical studies have detailed treatment information but many of these studies lack of data for major confounding factors such as cigarette smoking. The J-shape association of BMI with total mortality confounded by cigarette smoking (58
) may apply similarly to BMI and prostate cancer mortality, as current smokers may have increased risk of dying of prostate cancer (60
). However, none of the clinical studies included in our analysis controlled for smoking. In contrast, although large prospective cohort studies tend to have a more valid measurement of exposure and covariates, as well as complete follow-up, these studies usually lack detailed clinical treatment information. Therefore, the totality of the evidence obtained from different population, study settings, and outcome assessments in our meta-analysis provide a more objective conclusion.
Over the past two decades, widespread PSA screening significantly increased the number of prostate cancers detected at very early stage, whereas cancer-specific mortality remains relatively constant over time (62
). Many men with localized tumors, especially those obese or overweight men are likely to have diabetes and cardiovascular disease and are more likely to die of diseases other than prostate cancer. Since the majority of the studies reviewed in this meta-analysis did not control for competing causes of death, the pooled RR could be an attenuated estimate.
Timing of the BMI assessment is important to evaluate the possibility of reverse causation, i.e. weight change influenced by disease severity or treatments (i.e. ADT causes weight gain even after a short period of treatment (63
), and is crucial to the design of intervention strategy. In our study, all of the 6 cohort studies and study by Ma et al
assessed BMI years in mid-life and found stronger association, suggesting that adiposity precede cancer progression. This observation provides encouraging evidence for using weight management as a long term strategy to prevent death from prostate cancer at the population level. Although whether weight control will help improve outcomes among overweight and obese patient remains unknown, our findings from BMI measured at diagnosis or before surgery suggest additional clinical benefit to improve outcome from prostate cancer. These interventions may include increasing self-awareness, more early detection efforts by health professionals, more counseling on healthy lifestyle (i.e. exercise) after diagnosis and appropriate individualized treatment for overweight or obese patients.
The strengths of our study include the use of generalized least square methods for relative risk transformations associated with a standard per 5 kg/m2 increase in BMI to allow for comparisons among different studies using different BMI categories, the use of the random-effect model to incorporate heterogeneity, separated analysis on BMI and fatal prostate cancer by different study design and different outcomes, sensitivity analysis, and estimation of population attributable risk.
Meta-analysis of observational studies cannot avoid undetected biases and confounding factors inherent in the original studies. Analyzing BMI as a continuous variable by first transforming all the relative risk estimates to the corresponding RRs for every 5kg/m2
increase in BMI was a way to allow for comparisons among studies but it also assumed the risk increment was constant. We validated such methods in studies that presented RRs for both continuous and categorical BMI, and found that the RR per kg/m2
increase obtained by conversion was similar with the RR for continuous BMI shown in the paper (11
We did not include four studies (27
) on biochemical recurrence that did not present relative risk estimates or confidence intervals. Among these four studies, two studies in Canada showed that BMI was predictive of reduced biochemical disease free survival among patients treated with radiation therapy (27
) or radical prostatectomy (30
). Another two consecutive studies by Merrick et al
showed null association between BMI and biochemical recurrence free survival in patients treated with brachytherapy, which were consistent with studies included in our meta-analysis (). We also excluded two studies that presented only univariate relative risk estimates since the association of BMI and prostate cancer outcome are potentially confounded by confounding factors such as age. Among these two, Motamedinia et al
found no difference in the obese and nonobese patients’ actual observed biochemical failure rate, whereas Amling et al
showed that obesity alone predicted biochemical recurrence with RR 1.20 (95% CI 1.02–1.42) for obese vs non-obese patients. The association was not significant in the multivariate model after adjusting for pathologic variables but the study unfortunately did not present the data. They also found that increased BMI was associated worse pathologic outcomes, i.e. BMI was an independent predictor of higher Gleason grade cancer, thus suggested that the association between obesity and poor biochemical recurrence could be mediated by pathologic factors. If true, our pooled RR would be a conservative estimate of the association between BMI and biochemical recurrence as majority of the studies included in our meta-analysis had adjusted for pathologic variables.
In conclusion, this meta-analysis provides the first quantitative assessment of the evidence accumulated up to date from 26 studies of a pooled population of 1,302,246 from different countries, various study designs, and majority were published within the past 5 years. It showed a consistent 15–21% increased risk of fatal prostate cancer or biochemical recurrence, and an estimated 12–20% of prostate cancer deaths could be attributable to overweight and obesity. Further investigations are needed to evaluate the role of BMI measured at different stages of life, before, at, or after prostate cancer diagnosis, the impact of weight control on prostate cancer-specific and all-cause mortality. Studies of biomarkers and genetic markers related to adiposity and energy metabolism will provide biological plausibility for a causal role and can guide the development of effective and targeted cancer prevention and therapeutic strategies. Randomized weight control interventions in clinical setting or community-based program could provide a more definitive answer.