Testosterone e cancro alla prostata: è controindicata la terapia sostitutiva con testosterone?

ALESSANDRO PIZZOCAROU.O. Urologia

Servizio di Andrologia Istituto Clinico Humanitas

Rozzano (MI)

Lack of sound evidence that TRT actually cause prostate cancer (PCA) progression and/or recurrence in men with a history of PCA

• Key points

• The prostate saturation theory

• The association PCA-low testosterone levels

• The possible protective nature of TRT against the development of PCA

Moith Khera, Scott Dept Urol, Baylor College of Medicine, Houston, TX, USA; J. Sex Med, 2013

Is Testosterone Safe?

Traditional view

1. High T → rapid PCa growth

2. Low T → protective against PCa

3. T therapy contraindicated in men with PCa, or even suspicion of PCa

Huggins and Hodges (1941)

1.Reduction of testosterone concentration by

castration or oestrogen treatment results in

regression of prostate cancer

2.Exogenous testosterone results in progression

of prostate cancer

Gooren LJ et al. Aging Male 2007; 10: 173–81.

Mental associations:

Risk of TRT – a survey among physicians in Germany, Spain and England

Endogenous Hormones and Prostate Cancer Collaborative Group J Natl Cancer Inst 2008; 100: 170–83.

Meta-analysis: Pooled data of 18 studies

No. of case patients/Hormone Fifth No. of control subjects RR (95% Cl) RR & 95% Cl 2

1 for trend P

Testosterone 1 784/1302 1.002 761/1309 0.97 (0.85 to 1.11)3 837/1287 1.08 (0.95 to 1.23) 0.17 .68 4 792/1281 1.03 (0.90 to 1.17)5 712/1259 0.94 (0.82 to 1.07)

Free testosterone 1 691/1181 1.00 2 684/1165 1.01 (0.88 to 1.16) 3 750/1155 1.13 (0.98 to 1.29) 2.89 .09

4 707/1162 1.09 (0.95 to 1.25) 5 718/1152 1.11 (0.96 to 1.27)

DHT 1 240/298 1.00 2 192/284 0.83 (0.65 to 1.07) 3 188/282 0.82 (0.63 to 1.06) 1.19 .284 194/295 0.83 (0.64 to 1.08) 5 196/286 0.86 (0.66 to 1.11)

0.

5

0.7

5

1 1.

5

2.

03886 men with PCa and 6438 Controls

serum concentrations of sex hormones were not associated with the risk of prostate cancer.

PCa prevalence increases astestosterone levels decline

40–49 50–59 60–69 70–79

% PCa

Total T

Age (years)

Androgens are essential for normal

development of the prostate

• Secretory functions

• Cellular differentiation

• Normal proliferation

Eugonadal man

Prostate volume 19 mLPSA 0.9 ng/mL

Untreated

hypogonadal man

Prostate volume 8 mLPSA 0.4 ng/mL

Pro

sta

te v

olu

me (

mL

)

Age (years)

Hypogonadal patient without therapy

Normal men

0

10

20

30

40

50

20 30 40 50 60 70 80

Behre HM et al. Clin Endocrinol 1994; 40: 341–9.

Prostate volume measured bytransrectal ultrasonography

Pro

sta

te v

olu

me

(m

L)

Age (years)

0

10

20

30

40

50

20 30 40 50 60 70 80

Hypog. pat. with therapyHypog. pat. without therapy Normal men

Behre HM et al. Clin Endocrinol 1994; 40: 341–9.

Prostate volume measured bytransrectal ultrasonography

Prostate size in 334 hypogonadal men after a total of

6,596 injections of TU (maximal treatment duration 15 years)

Zitzmann M and Saad F Endocrine Reviews 2010 (Abstract Book)

PSA in 334 hypogonadal men after a total of

6,596 injections of TU (maximal treatment duration 15 years)

Zitzmann M and Saad F Endocrine Reviews 2010 (Abstract Book)

Treatment with testosterone

• Incidence of cancer in testosterone treatmentstudies up to 3 years: 1%

• Risk similar to detection in screeningprogrammes

Testosterone and the prostate

Rhoden E & Morgentaler A. New Engl J Med 2004; 350: 482–92.

Can very high doses of testosteroneinduce adverse events in the prostate?

Serum testosterone and PSA in young men treated with escalating doses of testosterone

Bhasin S et al. Am J Physiol Endocrinol Metab 2001; 281: e1172–81.

0

2

4

6

8

10

Seru

m P

SA

at W

eek 2

0

Bhasin S et al. J Clin Endocrinol Metab 2005; 90: 678–88.

Serum testosterone and PSA in older men treated with escalating doses of testosterone

0

2

4

6

8

10S

eru

m P

SA

at W

eek 2

0

12

14

What happens within the prostate?

Date of download: 1/9/2014Copyright © 2012 American Medical

Association. All rights reserved.

From: Effect of Testosterone Replacement Therapy on Prostate Tissue in Men With Late-Onset

Hypogonadism: A Randomized Controlled Trial

JAMA. 2006;296(19):2351-2361. doi:10.1001/jama.296.19.2351

In the testosterone replacement therapy group (n = 9), individuals whose genes were selected for study were those with the greatest

percentage increase in tissue androgens when tissue was available; in the placebo group (n = 7), 3 men with large increases in

tissue androgens were intentionally avoided.

Figure Legend:

by A. Morgentaler

Morgentaler A & Traish AM. Eur Urol 2009; 55: 310–21.

Saturation model

4 nmol/L

(125 ng/dl)

In vivo

(Near-castrate

Range)

Is low testosteronea risk factor for the prostate?

Testosterone levels and Gleason scores in 47 men with prostate cancer before radical prostatectomy

Madersbacher S et al. Urology 2002; 60: 869–74.

p<0.05

Testosterone levels and prostate cancer cases

among 345 hypogonadal men(TT <300 or FT <1.5 ng/dL) with PSA ≤4 ng/mL

Morgentaler A & Rhoden EL. Urology 2006; 68: 1263–7.

p=0.04 p=0.04

Kaplan-Meier PSA failure-free survival curves according topreoperative testosterone levels

Yamamoto S et al. Eur Urol 2007; 52: 696–701.

Kjellman A et al. Eur Urol 2008; 53: 106–11.

Prostate cancer-specific survival for the 65 prostate cancer patients divided into two groups

with dihydrotestosterone (DHT) level above and below the median. There is a significant

improved survival in the group with DHT above the median (log rank p=0.0075).

DHT levels and prostate cancer survival

Shores et al JCEM 2012

Treated n=398, age 61 yrs

baseline T=5.6 nmol/L

incident PCa 1.6%

Untreated n=633, age 63 yrs

baseline T=6.7 nmol/L

incident PCa 2.0%

Log Rank p=0.029

Seattle-Veterans Study

1031 hypogonadal men

Shores M et al. J Clin

Endocrinol Metab 2012; 97:

TRT in menwith prostate cancer

Testosterone Replacement Therapy Following the Diagnosis ofProstateCancer: Outcomes and Utilization TrendsAlan L. Kaplan AL et Al, J Sex Med 2014;11:1063–1070

Conclusion

TRT was not associated with worse overall or cancer-specific mortality nor was it associated with the use of salvage hormone therapy (ADT).

Although our findings suggest TRT may be safe in the setting of prostate cancer diagnosis and treatment, confirmatory prospective studies are needed.

Testosterone Replacement Therapy Following the Diagnosis ofProstateCancer: Outcomes and Utilization TrendsAlan L. Kaplan AL et Al, J Sex Med 2014;11:1063–1070

A New Era of Testosterone and Prostate Cancer: From Physiology to Clinical Implications

Mohit Khera , David Crawford, Alvaro Morales, Andrea Salonia, Abraham MorgentalerEuropean Urology 65, 2014; 115–123

A New Era of Testosterone and Prostate Cancer:

From Physiology to Clinical Implications

Khera M , Crawford D, Morales A, Salonia A, Morgentaler A, EUROPEAN UROLOGY

65 (2014) 115–123

The small size and limited duration of these case series make it impossible to assess the overall safety of

testosterone therapy after definitive treatment for PCa, but so far, these results are reassuring.

Large, randomized prospective studies will be needed to provide reliable safety information.

BPH (LUTS)

and

TRT

Urinary flow rate in untreated hypogonadal men (n=47),

TRT – treated hypogonadal men (n=78) and matched controls (n=75)

Max f

low

(m

L/s

)

untreated treated controls0

5

10

15

20

25

30

35

40

Behre HM et al. Clin Endocrinol 1994; 40: 341–9.

TRT with intramuscular TU over 26 weeksInternational Prostate Symptom Score and PSA in 20

patients with pre-diagnosed LOH and LUTS

p<0.00001

p<0.00001

NS

Kalinchenko SY et al. Aging Male 2008; 11: 57–61.

CONCLUSIONS

The long-held belief that PCa risk is related to high serum androgen concentrations can no longer be supported.

Current evidence indicates that maximal androgen-stimulated PCa growth is achieved at relatively low serum testosterone concentrations (Saturation model)

Accumulating data indicate an important association between low testosterone concentrations and worrisome aspects of PCa

It may therefore be reasonable to consider testosterone therapy in selected men with PCa and symptomatic hypogonadism, despite the limited safety information in this population

*TRT only after

- obtaining informed consent and - beginning with the lowest- risk individuals (such as those with undetectable PSA >1 yr following RP).

Informed consent should include the information that no long-term safety data are available and there is therefore an unknown degree of risk that PCa may recur or progress.

*

TRT in PCa pts

Khera M. 2014

CVD: Cardiovascular diseases; LL: Lower limit; UL: Upper limit;MH-OR: Mantel-Haenszel odds ratio; TT: Total testosterone

100

Odds ratio for MACESource # Trials MH-OR LL p TRT Placebo

#Events # Patients #Events # Patients

Placebo TS

Associated diseases

Elderly men 10 1,22 0,49 3,03 0,67

Men with CVD 2 2,48 0,35 17,45 0,36

Frail men 5 2,25 0,72 7,08 0,17

Men with metabolic diseases 4 0,19 0,04 0,85 0,03

Hypogonadism status

Mixed population 14 1,26 0,58 2,73 0,56

TT < 12 nM 12 0,84 0,32 2,23 0,73

Type of support

Drug company not supported 12 0,94 0,39 2,24 0,88

Drug company supported 14 1,07 0,51 2,24 0,86

Trial duration

≤ 12 weeks 4 1,02 0,20 5,29 0,98

>12 weeks 22 1,01 0,55 1,84 0,98

13 954 6 549

3 62 1 64

13 401 4 355

1 303 5 203

15 1066 11 865

16 829 9 476

10 437 8 332

21 1458 12

2 147 2 145

29 1746 18 1196

0.01 0.1 1 10 UL

1009

Corona G et al. Expert Opin Drug Saf, published online August 19, 2014

Odds Ratio for Major Adverse Cardiovascular Events (MACE) According to Baseline Characteristics in Subjects Treated with Testosterone or Placebo MACE: cardiovascular death, non-fatal myocardial infarction, stroke, acute coronary syndromes, and/or heart failure

MACE in hypogonadism

Corona G.et al, J Sex Med 2010;7:1557–1564

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