title: Obesity is associated with castration-resistant disease and metastasis in men treated with androgen deprivation therapy after radical prostatectomy: results from the SEARCH database.
abstract: Study Type - Prognosis (cohort series). Level of Evidence 2a. What's known on the subject? and What does the study add? The incidence and prevalence of obesity in the USA and Europe is increasing. Higher body mass index is associated with a lower risk of overall prostate cancer diagnosis but also with an increased risk of high grade prostate cancer. Obese men undergoing primary therapy with radical prostatectomy or external beam radiation are more likely to experience a biochemical recurrence after treatment compared with normal weight men. Finally, obesity is associated with increased prostate-cancer-specific mortality. We hypothesized that obese men on androgen deprivation therapy may be at increased risk for prostate cancer progression. Previous studies have shown that obese men have lower levels of testosterone compared with normal weight men. Additionally, one previous study found that obese men have higher levels of testosterone on androgen deprivation therapy. Men with higher levels of testosterone on androgen deprivation therapy are at increased risk of prostate cancer progression. We found that men with higher body mass index were at increased risk of progression to castration-resistant prostate cancer, development of metastases and prostate-cancer-specific mortality. When we adjusted for various clinicopathological characteristics, obese men were at increased risk of progression to castration-resistant prostate cancer and development of metastases. The results of our study help generate hypotheses for further study regarding the mechanisms between obesity and aggressive prostate cancer.
  
  
  OBJECTIVE
  • To investigate whether obesity predicts poor outcomes in men starting androgen deprivation therapy (ADT) before metastasis, since previous studies found worse outcomes after surgery and radiation for obese men.
  
  
  METHODS
  • A retrospective review was carried out of 287 men in the SEARCH database treated with radical prostatectomy between 1988 and 2009. • Body mass index (BMI) was categorized to <25, 25-29.9 and ≥ 30 kg/m2. • Proportional hazards models were used to test the association between BMI and time to castration-resistant prostate cancer (PC), metastases and PC-specific mortality adjusting for demographic and clinicopathological data.
  
  
  RESULTS
  • During a median 73-month follow-up after radical prostatectomy, 403 men (14%) received early ADT. • Among 287 men with complete data, median BMI was 28.3 kg/m2. • Median follow-up from the start of ADT was 52 months during which 44 men developed castration-resistant PC, 34 developed metastases and 24 died from PC. • In multivariate analysis, higher BMI was associated with a trend for greater risk of progression to castration-resistant PC (P= 0.063), a more than threefold increased risk of developing metastases (P= 0.027) and a trend toward worse PC-specific mortality (P= 0.119). • Prognostic biomarkers did not differ between BMI groups.
  
  
  CONCLUSIONS
  • Among men treated with early ADT, our results suggest that obese men may have increased risk of PC progression. • These data support the general hypothesis that obesity is associated with aggressive PC, although validation of these findings and further study of the mechanisms linking obesity and poor PC outcomes are required.
authors.affiliation: Duke University School of Medicine and Veterans Affairs Medical Center, Durham, NC 27710, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Keto
authors.forename: William J
authors.initials: WJ
authors.lastname: Aronson
authors.forename: Martha K
authors.initials: MK
authors.lastname: Terris
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Presti
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kane
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Amling
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Freedland
mesh_terms: D000368:Aged; D000726:Androgen Antagonists / Q000627:therapeutic use*; D015992:Body Mass Index; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000209:etiology; D009765:Obesity / Q000150:complications*; D009919:Orchiectomy; D011468:Prostatectomy / Q000379:methods*; D011471:Prostatic Neoplasms / Q000150:complications / Q000473:pathology* / Q000628:therapy*; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D000726:Androgen Antagonists
references.citation: Cancer. 2006 Aug 1;107(3):631-9
references.pmid: 16802288
references.citation: J Urol. 2009 Nov;182(5):2226-31
references.pmid: 19758620
references.citation: Prostate Cancer Prostatic Dis. 2009;12(3):259-63
references.pmid: 19581922
references.citation: Br J Cancer. 2003 Oct 6;89(7):1237-42
references.pmid: 14520453
references.citation: Eur Urol. 2010 May;57(5):836-42
references.pmid: 19962227
references.citation: Curr Opin Urol. 2009 May;19(3):263-7
references.pmid: 19300265
references.citation: Prostate Cancer Prostatic Dis. 2010 Jun;13(2):186-90
references.pmid: 20029402
references.citation: J Clin Oncol. 2004 Feb 1;22(3):439-45
references.pmid: 14691120
references.citation: J Urol. 2003 May;169(5):1670-5
references.pmid: 12686805
references.citation: Cancer Epidemiol Biomarkers Prev. 2006 Oct;15(10):1977-83
references.pmid: 17035408
references.citation: J Urol. 2007 Oct;178(4 Pt 1):1290-5
references.pmid: 17698136
references.citation: Prostate Cancer Prostatic Dis. 2010 Jun;13(2):173-7
references.pmid: 20195294
references.citation: Prostate. 2001 Apr;47(1):52-8
references.pmid: 11304729
references.citation: JAMA. 2007 Nov 21;298(19):2275-80
references.pmid: 18029831
references.citation: JAMA. 2005 Apr 20;293(15):1861-7
references.pmid: 15840860
references.citation: JAMA. 2010 Jan 20;303(3):235-41
references.pmid: 20071471
references.citation: J Natl Cancer Inst. 1997 Mar 5;89(5):385-9
references.pmid: 9060961
references.citation: J Urol. 2008 Jun;179(6):2181-5; discussion 2185-6
references.pmid: 18423743
references.citation: Am J Epidemiol. 2000 Mar 15;151(6):541-9
references.pmid: 10733035
references.citation: Prev Med. 2007 May;44(5):442-6
references.pmid: 17258803
references.citation: J Clin Oncol. 2008 Sep 10;26(26):4333-9
references.pmid: 18779620
references.citation: Clin Cancer Res. 2007 Jan 1;13(1):241-5
references.pmid: 17200361
references.citation: J Clin Oncol. 2005 Sep 20;23(27):6556-60
references.pmid: 16170163
references.citation: J Urol. 2008 Dec;180(6):2453-7; discussion 2458
references.pmid: 18930488
references.citation: Lancet Oncol. 2008 Nov;9(11):1039-47
references.pmid: 18835745
references.citation: BJU Int. 2010 Mar;105(5):648-51
references.pmid: 19747358
references.citation: J Clin Oncol. 2008 Mar 1;26(7):1148-59
references.pmid: 18309951
references.citation: J Clin Oncol. 2004 Feb 1;22(3):446-53
references.pmid: 14691122
references.citation: Eur Urol. 2007 Aug;52(2):331-43
references.pmid: 17507151
references.citation: Urology. 2005 Nov;66(5):1060-5
references.pmid: 16286124
references.citation: Cancer Epidemiol Biomarkers Prev. 2007 Jan;16(1):63-9
references.pmid: 17179486