Many studies found that obesity was associated with more aggressive PC and worse PC-specific outcomes [6
], although some studies did not find this association [20
]. Whether obesity specifically increases the progression risk after starting ADT has not been addressed. We hypothesized that obese men treated with early ADT after RP would be more likely to progress to CRPC, metastases and PCSM. To test this hypothesis, we analysed the risk of PC-specific outcomes after initiating ADT in the SEARCH cohort. We found obese men had significantly increased risk of CRPC, metastases and PCSM on unadjusted analyses. On multivariate analyses, obesity remained associated with CRPC, metastases and PCSM, although the association with CRPC and PCSM approached, but did not reach, significance. Moreover, all-cause mortality was unrelated to BMI, suggesting obesity was explicitly associated with poor cancer-specific outcomes. These findings suggest that obese men receiving early ADT after RP represent a high risk group and should be considered for clinical trials.
Obesity is associated with a decreased risk of PC diagnosis, but in contrast is associated with larger tumours and high grade disease [6
]. Moreover, obese men treated with RP are more likely to have PSA recurrence [8
]. Several studies of men treated with primary external radiotherapy found obesity predicted increased risk for recurrence and metastases [11
]. Moreover, multiple studies found obese men have increased PCSM [10
]. What remained unexamined to date is the association between obesity and outcomes after ADT. In line with the above studies showing obesity is associated with aggressive PC in general, we found obese men treated with early ADT after RP had higher risks of CRPC, metastases and PCSM.
There are several reasons why we hypothesized obese men would have worse outcomes. First, ADT may be inadequate in obese men due to an increased volume of drug distribution resulting in lower blood/tissue concentrations, which may be insufficient to fully suppress testosterone secretion and result in inadequate castration relative to a normal weight man. A previous study found obese men treated with continuous leuprolide have higher testosterone at 24 and 48 weeks vs normal weight men [13
]. Other studies showed men with higher post-ADT testosterone levels have worse PC-specific outcomes [14
]. Second, perhaps tumours in obese men are primed for ADT resistance. Given obesity is associated with lower testosterone levels prior to ADT, it is plausible that these tumours are selected to be more aggressive and grow in this low testosterone environment and thus are less affected by ADT. Multiple studies found men with low testosterone at presentation have more aggressive PC [22
]. Third, alternative growth factors associated with obesity, like insulin, IGF-1 and leptin, have all been associated with PC [20
]. Specifically, leptin produced by adipocytes stimulates growth of androgen-independent, but not androgen-sensitive, PC cells in vitro
]. IGF-1 also stimulates the growth of both androgen-independent and androgen-sensitive cells [20
When evaluating PC outcomes, it is always important to think in terms of competing risks. As such, it is noteworthy that, on a population level among otherwise ‘healthy’ individuals, men with a BMI of ~27 kg/m2
have better overall survival than normal weight individuals [24
]. In our cohort of US veterans, median BMI at ADT start was 28.3 kg/m2
. Thus, the classically defined normal weight group (i.e. BMI < 25 kg/m2
) was abnormal for our cohort. We were concerned that in this cohort of older men ‘ normal’ weight may be associated with significant pre-existing comorbidities and possibly shortened overall survival and thus that these men were not living long enough to experience adverse PC outcomes due to increased mortality from competing risks. However, in our cohort, non-PC survival was independent of BMI (log-rank = 0.540) implying that all BMI groups had equal non-PC survival and equal opportunity for PC progression (). Smith et al
. previously also showed similar all-cause mortality across BMI groups [11
]. Thus, this cannot explain the poor cancer-specific outcomes among obese men.
Pre-ADT PSA, pre-ADT PSADT and PSA nadir during ADT are well-known prognostic variables [25
]. Interestingly, all these were similar across BMI groups suggesting that, although on the surface obese men may not appear to harbour more aggressive disease, they experience more rapid progression. Alternatively, due to obesity-related haemodilution [26
], PSA values (and PSA kinetics) in obese men may underestimate disease burden (and aggressiveness). Regardless of why, these findings support the hypothesis that obesity is associated with post-ADT progression.
Beyond obesity, we found absolute PSA level at ADT start and seminal vesicle invasion significantly predicted progression. These findings agree with other studies which found pre-ADT PSA level [25
] and seminal vesicle invasion [28
] predicted worse PC-specific outcomes. Although PSA nadir during ADT is known to be prognostic [25
], we did not include it in our models because it is unavailable until after
ADT and thus cannot be used at ADT start
to predict outcome. We did not use PSADT in our models either because many men did not have enough PSA data to calculate PSADT, although PSADT did not differ by BMI group and thus inclusion of this would probably not have influenced our results [18
Ultimately, if confirmed in larger studies, our results can help guide clinicians in risk stratification of men undergoing ADT based upon BMI. Counselling obese men considering ADT should include discussion about lifestyle changes like weight loss, exercise and dietary modification. Although it is unknown if these measures modify the risk of PC-specific outcomes in obese men, they are known to reduce the risk of heart disease and are unlikely to be harmful [29
]. Moreover, these high risk men should be considered for additional PC therapies such as anti-androgens or clinical trials and should be counselled appropriately. Future studies to improve PC outcomes in obese men undergoing ADT should focus on elucidating the effects of lifestyle changes when starting ADT, additional diagnostic testing and/or more rigorous ADT. For example, perhaps testosterone should be measured after a set time period in obese men after starting ADT, even if PSA is stable. If the testosterone is not below a certain cut-point, then perhaps additional hormonal therapy such as anti-androgens or CYP17 inhibitors (i.e. ketoconazole or, in the future, abiraterone) should be added. Alternatively, as ADT in the Veterans Affairs system is almost always with the LHRH agonist goserelin (exact data unavailable), whether better results would be obtained with an LHRH antagonist, which shows better progression-free survival, is unknown [31
Our study was retrospective and only included men from the Veterans Affairs system; whether these results are generalizable is unclear. Height and weight were not obtained in a standardized manner and are subject to human error in measurement. Testosterone levels were not available in all men to confirm castration. Thus, ‘ CRPC’ may be better described as ‘ADT-resistant’. We only studied men who underwent RP; whether these observations apply to men undergoing other treatments is unknown. Although obesity and poor PC outcomes are associated, the mechanisms responsible remain unknown. Data related to treatments post-ADT (i.e. chemotherapy) were unavailable, although no treatment after ADT to date extends survival by more than several months and thus probably did not influence our results. ADT is well known to induce weight gain and metabolic changes. How these changes influence PC progression is an important topic, but one which is beyond the scope of this paper. Furthermore, such information about changes after starting ADT is not available at the time of starting ADT and the goal of this paper was to test whether obesity at the time of ADT influenced outcomes. One of our outcomes was ‘metastases’ defined typically by a positive bone scan. Probably, these men had micrometastatic disease prior to the bone scan becoming positive. However, the fact that obesity was suggestively correlated with other endpoints such as CRPC and PCSM provides further support for the hypothesis that obesity is linked with PC progression. Finally, our study had a modest sample size and a small number of PC-specific events. Further study using larger populations with longer follow-up are necessary to validate these findings and investigate potential mechanisms underlying the link between obesity and post-ADT progression.
Our data support the hypothesis that obese men are at increased risk of progression to CRPC, metastases and PCSM. On unadjusted analysis these were statistically significant; however, not all reached statistical significance on multivariate analysis. These differences were seen despite similarity in important prognostic variables (pre-ADT PSA, pre-ADT PSADT and PSA nadir during ADT). Future validation studies are required. However, if confirmed, these data suggest that obese men starting ADT should be counselled regarding lifestyle modifications to promote weight reduction, the potential need for additional PC therapies and consideration of clinical trials.