Obese Men Have More Advanced and Aggressive Prostate Cancer
Obese Men Have More Advanced and Aggressive Prostate Cancer
An elevation in PSA blood level (typically>3–4 ng ml) is widely accepted as an indication that a man should undergo a prostate biopsy for suspicion of PCa. Of interest, several investigators have reported data supporting the existence of an inverse association between BMI and PSA levels in men. These reports suggest that this phenomenon could negatively influence PSA-based screening in obese men given that PSA levels are known to positively correlate with the extent of disease and aggressiveness in PCa. That is, if obese men have lower PSA levels when compared with their normal weight counterparts, using a standard cutoff (that is, 3–4 ng ml) to indicate a need for biopsy would result in obese men being inappropriately screened at a later point in their disease course. Citing this, some investigators have proposed regression-based equations for calculating an 'adjusted PSA level' for obese men, while others have suggested lowering the threshold for biopsy in obese men. The documented evidence of lower PSA levels in obese men aside, what remains unclear is the more clinically relevant question of whether this effect is enough to warrant the proposed adjustments in screening practices for obese men. Indeed, if the impact is clinically significant, then we would expect that obese men would present with more advanced and more aggressive PCa compared with normal-weight men after matching on age and PSA level. Herein, we provide evidence from two independent nested case-control studies that after adjusting for PSA and age, obese men present with more advanced (that is, later stage) and more aaggressive (that is, higher grade) PCa compared with non-obese men.
There is a key distinction that needs to be made between the research question we address in this investigation and one that has been previously reported by several investigators. Indeed, there are a number of reports in the literature addressing the more etiologic question of whether obesity itself is a risk factor for PCa. Although several cohort studies suggest a positive association between increasing BMI and PCa risk, there are a number of studies reporting no association as well. The conflicting data regarding an overall association notwithstanding, there is compelling evidence that obesity may increase the risk of developing more aggressive and fatal forms of PCa. As such, this has raised interesting questions about the underlying biology of PCa development and, specifically, whether obesity may be associated with a specific carcinogenic pathway that leads to a more aggressive PCa phenotype. With the obvious strengths of these studies in mind, an alternative explanation of the link between obesity and aggressive/fatal PCa is that cancer detection in obese men is being delayed because of lower PSA levels in these men (most likely due to a hemodilution effect). Recently, Banez et al. began to address this more specific question by comparing the operating characteristics (that is, area under the curve or AUC) of PSA across BMI categories among a cohort of 917 Italian men undergoing prostate biopsy. The authors report no evidence of a difference in the overall AUCs of PSA for predicting presence of PCa among normal-weight (AUC=0.56), overweight (AUC=0.60) and obese men (AUC=0.60; P=0.68) in either DRE-positive or -negative men. Although these results support the lack of a need to adjust PSA levels for obese men with regard to simply detecting the presence of PCa, they do not inform the larger question of whether PSA screening levels should be adjusted to avoid delaying diagnosis and allowing unnecessary advancement of PCa in obese men.
With our nested case-control design, we address for the first time the specific question of whether there is empirical evidence to support the need to adjust screening PSA levels in obese men to avoid a clinically significant postponing of PCa diagnosis. Although our data are supportive of the notion that lower PSA levels in obese men have PCa screening implications, it is important to note that our data are observational and more importantly, there are alternative explanations. For example, it has been reported that obesity is associated with lower PSA-driven biopsy rates. Specifically, Parekh et al. reported data from the National Health Interview Survey indicating biopsy rates were lower among men with a BMI >30 vs BMI <25 (4.6% vs 5.8%; P=.05). This would suggest that a possible reason obese men present with more aggressive tumors is not that a hemodilution effect results in delayed screening but rather that obese men are less likely to undergo PSA-driven biopsy in the first place. Related to this, there is some indication that it is more difficult to palpate the prostate on digital rectal exam (DRE) in obese men, and, in many cases, only the apex can be adequately assessed to detect the presence of a tumor. Although the proposed challenge in performing DRE among obese men has been difficult to quantify, this would have the potential to contribute to our observation of more aggressive PCa for obese men after matching on age and PSA. That being said, we would point out that our observation that obese men present with more aggressive disease after matching on PSA holds true for the subgroup of men with higher PSA levels (that is, >10 ng ml) where a DRE for confirmation of tumor presence would be less likely (that is, they would be more likely to move directly to transrectal biopsy).
Issues of causality aside, we are particularly mindful of the need to interpret our observational data very carefully. It has become clear over the past decade that over-diagnosis and overtreatment of 'insignificant PCa' are real issues that have spurned concerted efforts to improve the ability to distinguish indolent from aggressive forms of PCa. Therefore, any study generating data in support of lower thresholds, even if for a specific subset of the male population, needs to be vetted with significant caution. As such, what will be needed in order to move this discussion forward in a meaningful way will be independent validation from other large, observational data sets, as well as reports from data collected as part of prospective randomized trials. Specifically, we would note that our data are from a large tertiary referral center of men undergoing surgery for PCa and, therefore, have limited generalizability to the general population seeking screening for PCa. Moreover, our study population at both sites is >95% Caucasian and cannot be used to inform the discussion about screening practices for obese men of other racial/ethic backgrounds. Along these same lines, it should also be noted that surgery is less likely to be offered to the most obese men, and therefore they are not adequately represented in our study of surgically treated men. Finally, we are mindful that our data do not provide any evidence that lowering of PSA screening cut-points in obese men would ultimately translate to better survival for these men or simply just alter pathologic outcomes. With the need for external validation and the above mentioned limitations in mind, the specific strengths of our study include the large sample size, the use of a cost-effective, nested case–control design, the inclusion of data from two independent populations, our focus on one treatment modality (that is, surgery), the tight matching on age and PSA level, and the assessment of multiple indicators of both PCa aggressiveness and extent of disease.
Discussion
An elevation in PSA blood level (typically>3–4 ng ml) is widely accepted as an indication that a man should undergo a prostate biopsy for suspicion of PCa. Of interest, several investigators have reported data supporting the existence of an inverse association between BMI and PSA levels in men. These reports suggest that this phenomenon could negatively influence PSA-based screening in obese men given that PSA levels are known to positively correlate with the extent of disease and aggressiveness in PCa. That is, if obese men have lower PSA levels when compared with their normal weight counterparts, using a standard cutoff (that is, 3–4 ng ml) to indicate a need for biopsy would result in obese men being inappropriately screened at a later point in their disease course. Citing this, some investigators have proposed regression-based equations for calculating an 'adjusted PSA level' for obese men, while others have suggested lowering the threshold for biopsy in obese men. The documented evidence of lower PSA levels in obese men aside, what remains unclear is the more clinically relevant question of whether this effect is enough to warrant the proposed adjustments in screening practices for obese men. Indeed, if the impact is clinically significant, then we would expect that obese men would present with more advanced and more aggressive PCa compared with normal-weight men after matching on age and PSA level. Herein, we provide evidence from two independent nested case-control studies that after adjusting for PSA and age, obese men present with more advanced (that is, later stage) and more aaggressive (that is, higher grade) PCa compared with non-obese men.
There is a key distinction that needs to be made between the research question we address in this investigation and one that has been previously reported by several investigators. Indeed, there are a number of reports in the literature addressing the more etiologic question of whether obesity itself is a risk factor for PCa. Although several cohort studies suggest a positive association between increasing BMI and PCa risk, there are a number of studies reporting no association as well. The conflicting data regarding an overall association notwithstanding, there is compelling evidence that obesity may increase the risk of developing more aggressive and fatal forms of PCa. As such, this has raised interesting questions about the underlying biology of PCa development and, specifically, whether obesity may be associated with a specific carcinogenic pathway that leads to a more aggressive PCa phenotype. With the obvious strengths of these studies in mind, an alternative explanation of the link between obesity and aggressive/fatal PCa is that cancer detection in obese men is being delayed because of lower PSA levels in these men (most likely due to a hemodilution effect). Recently, Banez et al. began to address this more specific question by comparing the operating characteristics (that is, area under the curve or AUC) of PSA across BMI categories among a cohort of 917 Italian men undergoing prostate biopsy. The authors report no evidence of a difference in the overall AUCs of PSA for predicting presence of PCa among normal-weight (AUC=0.56), overweight (AUC=0.60) and obese men (AUC=0.60; P=0.68) in either DRE-positive or -negative men. Although these results support the lack of a need to adjust PSA levels for obese men with regard to simply detecting the presence of PCa, they do not inform the larger question of whether PSA screening levels should be adjusted to avoid delaying diagnosis and allowing unnecessary advancement of PCa in obese men.
With our nested case-control design, we address for the first time the specific question of whether there is empirical evidence to support the need to adjust screening PSA levels in obese men to avoid a clinically significant postponing of PCa diagnosis. Although our data are supportive of the notion that lower PSA levels in obese men have PCa screening implications, it is important to note that our data are observational and more importantly, there are alternative explanations. For example, it has been reported that obesity is associated with lower PSA-driven biopsy rates. Specifically, Parekh et al. reported data from the National Health Interview Survey indicating biopsy rates were lower among men with a BMI >30 vs BMI <25 (4.6% vs 5.8%; P=.05). This would suggest that a possible reason obese men present with more aggressive tumors is not that a hemodilution effect results in delayed screening but rather that obese men are less likely to undergo PSA-driven biopsy in the first place. Related to this, there is some indication that it is more difficult to palpate the prostate on digital rectal exam (DRE) in obese men, and, in many cases, only the apex can be adequately assessed to detect the presence of a tumor. Although the proposed challenge in performing DRE among obese men has been difficult to quantify, this would have the potential to contribute to our observation of more aggressive PCa for obese men after matching on age and PSA. That being said, we would point out that our observation that obese men present with more aggressive disease after matching on PSA holds true for the subgroup of men with higher PSA levels (that is, >10 ng ml) where a DRE for confirmation of tumor presence would be less likely (that is, they would be more likely to move directly to transrectal biopsy).
Issues of causality aside, we are particularly mindful of the need to interpret our observational data very carefully. It has become clear over the past decade that over-diagnosis and overtreatment of 'insignificant PCa' are real issues that have spurned concerted efforts to improve the ability to distinguish indolent from aggressive forms of PCa. Therefore, any study generating data in support of lower thresholds, even if for a specific subset of the male population, needs to be vetted with significant caution. As such, what will be needed in order to move this discussion forward in a meaningful way will be independent validation from other large, observational data sets, as well as reports from data collected as part of prospective randomized trials. Specifically, we would note that our data are from a large tertiary referral center of men undergoing surgery for PCa and, therefore, have limited generalizability to the general population seeking screening for PCa. Moreover, our study population at both sites is >95% Caucasian and cannot be used to inform the discussion about screening practices for obese men of other racial/ethic backgrounds. Along these same lines, it should also be noted that surgery is less likely to be offered to the most obese men, and therefore they are not adequately represented in our study of surgically treated men. Finally, we are mindful that our data do not provide any evidence that lowering of PSA screening cut-points in obese men would ultimately translate to better survival for these men or simply just alter pathologic outcomes. With the need for external validation and the above mentioned limitations in mind, the specific strengths of our study include the large sample size, the use of a cost-effective, nested case–control design, the inclusion of data from two independent populations, our focus on one treatment modality (that is, surgery), the tight matching on age and PSA level, and the assessment of multiple indicators of both PCa aggressiveness and extent of disease.
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