Use Of Testosterone In Men With Prostate Cancer. Traditional view: T is dangerous for PCa

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1 Use Of Testosterone In Men With Prostate Cancer Abraham Morgentaler, MD, FACS Director, Men s s Health Boston Associate Clinical Professor of Urology Harvard Medical School Boston, USA Traditional view: T is dangerous for PCa High T causes rapid PCa growth Low T is protective Like feeding a hungry tumor or pouring gasoline on a fire Testosterone

2 Would you consider administering testosterone replacement therapy in a man with a history of prostate cancer? Urology Times Online Poll (accessed March 12, 2009) 73% Yes (in selected cases) 23% Never 4% Unsure Testosterone following RRP TRT in men with undetectable PSA after RRP 3 published retrospective studies N=74 men Results No PSA recurrence Follow-up as long as 12 yr Kaufman JM et al. J Urol. 2004;172:920; Agarwal PK et al. J Urol. 2005;173:533 Khera M et al J Sex Med epub 2009

3 Testosterone Following Brachytherapy 3131 men Median Median duration of TRT: 4.5 yr Median Median follow-up: 5.0 yr End End of study PSA: <1.0 ng/ml in 100% No recurrences Sarosdy MF Cancer 109:536, 2007 How do we make sense of this? T therapy in men with PCa flies in the face of training and tradition

4 Testosterone and Prostate Cancer Is low T protective for PCa? Sextant biopsy in hypogonadal men with PSA<4.0 and normal DRE: PCa in 11/77 (14%) Morgentaler et al, JAMA 1996 Published PCa rates for men with PSA < 4.0 ng/ml as of 1996 Morgentaler et al, JAMA 1996

5 Review of English-language language literature re T and PCa NEJM 2004 Number of articles in PSA era ( ) regarding effect of T therapy in men with PCa Number of articles in PSA era (1985-) demonstrating T Therapy causes PCa progression None!

6 Origin of the Prohibition Against T Therapy in Men with PCa Huggins et al (1941): T caused enhanced rate of growth of PCa: Stated that 3 men received T injections Results given for 2 men One previously castrated Origin of the Prohibition Against T Therapy in Men with PCa Huggins et al assertion that T caused enhanced rate of growth of PCa: The original claim based on erratic results in a single patient!

7 Review of Historical Studies of T Administration in Men with PCa T administration in castrated men -Bad outcomes T administration in non-castrated men -Benign outcomes Fowler et al J Urol 1981; 126:372 Prout et al Cancer 1967; 20:871 Is High T a Problem For PCa? Collaborative pooled worldwide analysis of 18 longitudinal studies 3886 men with PCa, 6438 controls No association of PCa with serum androgens Men with PCa have similar T concentrations as men without PCa Men with highest T at no greater risk of PCa than men with lowest T Roddam AW et al, JNCI 2008; 100:

8 T and Prostate Cancer Meta-analysis analysis of 19 placebo-controlled controlled T therapy studies in men with low or low-nl T Comparison of men treated with T vs placebo revealed no difference in: PCa PSA>4.0 ng/ml Urinary symptom scores Calof et al, J Gerontology 2005;60A: Molecular Basis for Saturation AR becomes maximally bound to androgen (saturated) at 2-33 nmol/l (60-90 ng/dl)

9 a Prostate Cancer Growth b c Serum Testosterone Concentration a Prostate Cancer Growth Near-castrate range b c Serum Testosterone Concentration

10 Saturation: T for PCa is like water for a thirsty tumor Once the thirst has been quenched, additional T has no further effect Serum Testosterone Saturation Model Prostate tissue (benign and malignant) is exquisitely sensitive to changes in serum androgen concentrations at very low levels Prostate tissue (benign and malignant) is indifferent to changes in serum androgens at higher levels AR is maximally bound with androgen (saturated) at ng/dl (2-3 nmol/l)

11 Serum T at Week 16 Serum testosterone and PSA in young men From Bhasin et al Am J Physiol Endocrin Metab 281:e1172, mg 50mg 125 mg 300mg 600mg Weekly testosterone dose Serum PSA Week 20 Testosterone PSA From Bhasin et al. J Clin Endocrinol Metab ; 90:

12 800 Testosterone Flare and PSA in Men with Advanced Prostate Cancer 20 T (ng/dl) Testosterone PSA Days PSA (ng/ml) Tomera et al., J Urol, 165:1585, 2001 Case 84 yo man with ED and low libido PSA 8.1 and 8.5 ng/ml Low free T PNBx- 2/6 cores with PCa, Gleason 6/10 Declines treatment for PCa Requests T therapy! Morgentaler A, J Sex Med, 2009; 6:574

13 T therapy in men with untreated PCa Poster #49 SMSNA (Morgentaler et al) 13 men on surveillance Low grade (Gleason 6), low volume disease Mean age 63 y (49-85) Mean f/u 12.7 mo Baseline PSA 4.9 ng/ml Follow-up PSA 3.9 ng/ml

14 T therapy in men with untreated PCa Poster #49 SMSNA (Morgentaler et al) Follow-up PNBx in 6: 4 without frank PCa (2 with PIN) 2 with Gleason 6 Serum Testosterone and Prostate Cancer Prevalence 25 P=.04 P= Prostate Cancer (%) <250 ng/dl >250 ng/dl <1.0 ng/dl >1.0 ng/dl Total Testosterone Free Testosterone N=345. Reproduced with permission from Morgentaler A, Rhoden EL. Urology. 2006;68(6):

15 Testosterone and PCa Higher tumor grade Stage at presentation Biochemical recurrence Survival Reported with LOW T, not high T T and Prostate Cancer Fiction More T leads to greater PCa growth Fact There is a limit to the ability of androgens to stimulate PCa growth

16 T and Prostate Cancer Fiction T is like food for a hungry PCa tumor Fact T behaves more like water for a thirsty tumor T and Prostate Cancer Fiction High T is worrisome for PCa Fact Low T may be worrisome for PCa

17 New Question Given the multiple known health benefits of T therapy in hypogonadal men, can we justify WITHHOLDING T therapy in men with a history of prostate cancer?