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Testosterone Therapy in Men with Prostate Cancer – Yes or No?

Historically, prostate cancer – both active and treated - has been an absolute contraindication to testosterone therapy and – from a regulatory perspective – still is. The incidence of prostate cancer is higher in older men, in whom prostate cancer accounts for one in five new cancer diagnoses.[1]
 
Thanks to improvement in early detection and treatment of prostate cancer, prostate cancer mortality has decreased 50% during the past two decades, and more men are living with a history of prostate cancer. 
 
The aging of the male population and the increasing number of prostate cancer survivors have resulted in a significant increase in the number of men presenting with hypogonadism and treated prostate cancer. Therefore, it is important to consider the growing number of recent studies which have challenged the long-standing belief that prostate cancer is an absolute contraindication to testosterone therapy.[2-4]
 
Here I summarize the results of a notable study which investigated the effects of testosterone therapy in men with treated and untreated prostate cancer [5], and conclude with the latest recommendations on managing testosterone deficiency in men with history of prostate cancer.
 

Key Points

 
- An initial increase in PSA when starting testosterone therapy is normal and is not synonymous with prostate disease progression.
 
- Emerging research shows that testosterone therapy in men after radical prostatectomy or radiation, and in men on active surveillance, in most cases does not cause prostate cancer recurrence or worsening.
 
- The risk of prostate cancer recurrence appears to be lower after radical prostatectomy than after radiation.
 

What is known

 
In a previous article “Testosterone and Prostate Cancer - Bye Androgen Hypothesis, Welcome Saturation Model I explained why the relation between testosterone and prostate cancer is not linear, and I have also presented studies investigating whether testosterone therapy increases risk of prostate cancer in men with no history of prostate issues, see “Dispelling the myth of testosterone treatment and prostate cancer”.
 
Briefly, even large elevations in testosterone levels within the normal range will only cause minor increases (if any) in PSA, and testosterone therapy does not increase prostate cancer incidence or BPH/LUTS progression compared to matched untreated men.[6] The explanation for this is the saturation model, which postulates that within the normal range of testosterone levels, prostate cells are saturated to the stimulating effect of androgens that is seen at hypogonadal testosterone levels, and therefore unresponsive to further increases in testosterone concentration. In other words, testosterone exerts its maximal effect on androgen receptors and prostate cancer growth at low concentrations while having little to no impact at higher concentrations.[7] The saturation model also explains why an initial increase in PSA in hypogonadal men who start testosterone therapy does not necessarily (more precisely, rarely) reflect prostate disease progression. 
 

Recent studies on testosterone therapy in men with a history of prostate cancer 

 
Over the last two decades a growing number of studies have shown provocative results, questioning the deeply rooted long held view that testosterone therapy is an absolute contraindication in men with a history of prostate cancer.
 
The most common treatments for prostate cancer are radical prostatectomy (surgical removal of the prostate gland), radiation and brachytherapy (insertion of radioactive implants directly into the prostate tissue).
 
Testosterone therapy after radical prostatectomy
 
Several studies examining testosterone therapy in hypogonadal men who have been treated with prostatectomy found no PSA recurrence [8-12] and no biochemical or clinical evidence of prostate cancer recurrence.[10] In one prospective study, only 1 of 22 men had a PSA recurrence at 17 months after radical prostatectomy. He had high-risk prostate cancer (Gleason score 8), and was on transdermal testosterone for 12 months at time of PSA elevation.[13] This study concluded that when patients are carefully selected (Gleason score <7, organ confined disease, at least 2 PSA levels undetectable, 7-year Progression free probability, PFP > 90%) testosterone therapy for the treatment of hypogonadal symptoms appears to be safe at 2 years post-T administration.[13]
 
In a notable study, 103 hypogonadal men treated with testosterone were compared with 49 non-hypogonadal men with low-, intermediate-, and high-risk prostate cancer; all men were treated with prostatectomy.[14] After a median follow-up of 27.5 months, testosterone levels significantly increased in the testosterone treatment group. A statistically, albeit not clinically, significant increase in PSA was observed in the high-risk and low-risk subgroups. 
 
To better understand whether the observed PSA increases in men on testosterone were indicative of prostate cancer recurrence, PSA velocity was calculated. Despite the small PSA increases in men on testosterone, PSA velocities were not supportive of prostate cancer growth or recurrence in these men.[14] Notably, there were twice as many prostate cancer recurrences among high-risk men who were not on testosterone therapy, compared to high-risk men who were treated with testosterone (8 vs. 4, respectively).[14] No prostate cancer recurrence was observed in the low- or intermediate-risk subgroups.[14]
 
Testosterone therapy after radiation
 
Studies examining testosterone therapy in patients who had been treated for prostate cancer with radiotherapy have shown either no or small increases in PSA, largely in the absence of prostate cancer progression or recurrence.[12, 15-18] One study with long-acting testosterone undecanoate injections in 20 men (age 49-74 years) with prostate cancer treated with brachytherapy found no cases of rising serum PSA, prostate cancer progression or recurrence after a median of 31-months follow-up, and resulted in significant clinical benefits.[18] A retrospective analysis of clinical records on testosterone therapy in 98 older hypogonadal men (age 63-74 years) with prostate cancer treated with radiation therapy found no increase in PSA in men with low- or medium-risk prostate cancer, but a small statistically significant increase in PSA in the high-risk subgroup. Only six men (6.1%) met criteria for biochemical recurrence.[19] 
 
Testosterone therapy in men on active surveillance
 
Active surveillance is a strategy of close monitoring for men with low-risk prostate cancer. The purpose of active surveillance is to avert treatment unless prostate cancer progression occurs, or a patient chooses curative treatment.[20] One third of men on active surveillance have testosterone deficiency [21], which is about the same prevalence as that seen in the general male population.[22]
 
While only a few studies are available on the effect of testosterone therapy in men with low-risk prostate cancer on surveillance, data are promising. In one study, 13 symptomatic testosterone deficient men with untreated prostate cancer received testosterone therapy for a median of 2.5 years (range 1 to 8 years). Mean age was 58.8 years. Gleason score at initial biopsy was 6 in 12 men and 7 in 1. Testosterone levels increased from 238 to 664 ng/dL (8.3 nmol/L to 23 nmol/L). Mean PSA and prostate volume did not change with testosterone therapy. Mean number of follow-up biopsies was 2. No cancer was found in 54% of follow-up biopsies. Biopsies in 2 men suggested upgrading, and subsequent biopsies in 1 and radical prostatectomy in another indicated no progression. No local prostate cancer progression or distant disease was observed.[22]
 
In another study, 28 men with testosterone deficiency underwent testosterone therapy while on active surveillance for prostate cancer (Gleason 3 + 3 and Gleason 3 + 4). A comparison group of 96 men on active surveillance with untreated testosterone deficiency was identified at the same institution.[23] Mean age was 60 years, and mean follow-up 40 months for both groups. Biopsy progression rates were similar for both groups, as well as for historical controls. [23] It was concluded that biopsy progression in men on active surveillance appears unaffected by testosterone therapy over 3 years.[23]
 
The most recent study used prostate magnetic resonance imaging – a technology to improve detection, localization, and cancer risk stratification - to examine 12 men treated with testosterone therapy while on active surveillance for low-risk prostate cancer.[24] After testosterone therapy there was a significant increase in testosterone levels from 203 to 517 ng/dL (7 nmol/L to 17.9 nmol/L), PSA (3.3 ng/mL to 4.2ng/mL), and prostate volume (39.4 cm3 to 55.2 cm3). Of the 12 subjects, 2 had prostate cancer progression (detected by biopsy). Of these 2 patients, 1 patient underwent radical treatment due to clinical progression. The other 10 men had no changes in either prostate biopsy or prostate magnetic resonance imaging parameters after testosterone therapy. [24]
 
It should be noted that responses to testosterone therapy in men with active low-grade prostate cancer is variable. Some men have little change in PSA velocity (a criterion to discontinue testosterone therapy) after years of treatment, while others have a rapid and significant increase. Nevertheless, interruption of testosterone therapy always has been found to lead to a decrease in PSA to baseline levels seen before initiation of testosterone therapy.[25] This should encourage consideration of testosterone therapy in these men, as no irreversible potentially damaging changes are incurred that would cause permanent elevations in PSA levels.
 
In a survey of Canadian urologists who actively prescribe testosterone therapy and are involved in the treatment of prostate cancer, only 35% of the surveyed physicians had ever offered testosterone for men on active surveillance.[26] This underscores the need for further continuing medical education in this area.
 

What this study adds

 
A recent study published in the Journal of Urology analyzed a group of 82 hypogonadal men (age 70 to 82 years at last follow-up) with prostate cancer who were treated with testosterone therapy.[5] Included were 50 men treated with radiation therapy, 22 treated with radical prostatectomy, 8 on active surveillance, 1 treated with cryotherapy and 1 who underwent high intensity focused ultrasound. Testosterone therapy duration ranged between 22 to 57 months.
 
In the entire group, there was a significant increase in testosterone and PSA. However, no men on active surveillance were upgraded to a higher Gleason score on subsequent biopsies and none have yet gone on to definitive treatment.[5] No biochemical prostate cancer recurrence was found among patients treated with radical prostatectomy, but 3 men (6%) treated with radiation therapy experienced biochemical recurrence. It is unclear whether these cases were related to testosterone therapy or reflected the natural biology of the disease.[5] Mean PSA velocity was 0.001, 0.12 and 1.1 µg/L per year in the radical prostatectomy, radiation therapy and active surveillance groups, respectively.
 
This study concluded that testosterone therapy may be oncologically safe in hypogonadal men who have had curative treatment for prostate cancer, and in men on active surveillance for prostate cancer.[5]
 

Comment

 
The significant impact that hypogonadism has on quality of life and the need to treat a growing population of men, many of whom will have prostate cancer during their lives, raises the question of whether testosterone therapy can be considered in men with prostate cancer.
 
A history of prostate cancer has been a longstanding contraindication to the use of testosterone therapy due to the belief that higher serum testosterone causes more rapid prostate cancer growth. Recent evidence has called this belief into question by showing that testosterone therapy does not appear to cause prostate cancer recurrence in men who have been treated for prostate cancer. Early data also suggest that testosterone does not cause prostate cancer progression in men with active low-grade prostate cancer. These findings challenge a medical maxim that dates back 75 years [2], and currently there is insufficient evidence to withhold testosterone therapy in certain populations of men with a history of prostate cancer.[27] In other words, it is not medical malpractice to prescribe testosterone therapy to men with a history of prostate cancer.
 
Testosterone therapy in hypogonadal men with a treated prostate cancer results in significant elevations in testosterone levels and improvements in hypogonadal symptoms.[9, 14, 16-18] Needless to say, despite the reassuring new findings in terms of safety and efficacy, men with low-grade or treated prostate cancer need extra vigilant monitoring if put on testosterone therapy.
 
Table: Expert recommendations in managing testosterone deficiency in men with history of prostate cancer.[2]
 

 

Prior to initiating testosterone therapy

 

The clinical history should be consistent with a laboratory diagnosis of testosterone deficiency.

 

The clinician must disclose that data are limited confirming safety and that true risk is unknown.

 

The clinician should use shared decision-making and obtain informed consent.

 

Confirm there are no medical contraindications (eg, erythrocytosis) to testosterone therapy.

 

PSA should be either undetectable following radical prostatectomy or stable following radiation treatment over a 6-month period. Exercise extreme caution in men at high risk for recurrence or progression.

 

Testosterone therapy should not be given with ADT unless in a clinical trial.

 

 

Suitable options for testosterone therapy

 

Short-acting formulations are preferred for initial treatment. Longer-acting treatments such as intramuscular testosterone undecanoate or subcutaneous pellets may be considered once it becomes clear that testosterone therapy has not caused progression or recurrence.

 

 

Following initiation of testosterone therapy

 

Clinicians must be prepared for prostate cancer recurrence. This may or may not be related to testosterone therapy but may be interpreted as such by the patient, his family, or other clinicians.

 

Measure hematocrit and/or hemoglobin 2–4 times in the 1st year, then annually.

 

Measure PSA every 3–4 month in the 1st year after initiating testosterone and twice a year thereafter.

 

Perform DRE 1–2 times within 1st year, then annually.

 

Men on active surveillance should undergo annual prostate biopsy to ensure cancer stability. Longer intervals may be considered after disease stability has been determined, as per local AS protocols.

 

From Kaplan AL, Hu JC, Morgentaler A, Mulhall JP, Schulman CC, Montorsi F. Testosterone Therapy in Men With Prostate Cancer. Eur Urol. 2016;69(5):894-903.

The longstanding prohibition against testosterone therapy in men with untreated low risk prostate cancer without evidence of metastatic or recurrent disease, also merits reevaluation.[28] Especially fascinating is the emerging research on bipolar androgen therapy (BAT) for the treatment of castrate resistant prostate cancer (CRPC).[29]In CRPC, androgen receptor expression and sensitivity persists despite maximal androgen ablation. Paradoxically, androgen receptor-expressing ‘‘androgen-sensitive’’ prostate cancer cells can be inhibited by cycles of supraphysiologic / ablation levels of testosterone (BAT).[30-32] This underscores that testosterone is not an inherent foe for the prostate, and that time has come to revisit long-standing beliefs on testosterone and prostate cancer outcomes.

 

References:

1.            Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2016. CA Cancer J Clin, 2016. 66(1): p. 7-30.

2.            Kaplan, A.L., et al., Testosterone Therapy in Men With Prostate Cancer. Eur Urol, 2016. 69(5): p. 894-903.

3.            Nguyen, T.M. and A.W. Pastuszak, Testosterone Therapy Among Prostate Cancer Survivors. Sex Med Rev, 2016. 4(4): p. 376-88.

4.            Morgentaler, A., 3rd and W.P. Conners, Testosterone therapy in men with prostate cancer: literature review, clinical experience, and recommendations. Asian J Androl, 2015. 17(2): p. 206-11.

5.            Ory, J., et al., Testosterone Therapy in Patients with Treated and Untreated Prostate Cancer: Impact on Oncologic Outcomes. J Urol, 2016. 196(4): p. 1082-9.

6.            Debruyne, F.M., et al., Testosterone treatment is not associated with increased risk of prostate cancer or worsening of lower urinary tract symptoms: prostate health outcomes in the Registry of Hypogonadism in Men. BJU Int, 2016.

7.            Morgentaler, A. and A.M. Traish, Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. European Urology, 2009. 55(2): p. 310-20.

8.            Kaufman, J.M. and R.J. Graydon, Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol, 2004. 172(3): p. 920-2.

9.            Agarwal, P.K. and M.G. Oefelein, Testosterone replacement therapy after primary treatment for prostate cancer. J Urol, 2005. 173(2): p. 533-6.

10.          Khera, M., et al., Testosterone replacement therapy following radical prostatectomy. J Sex Med, 2009. 6(4): p. 1165-70.

11.          Sathyamoorthy, K., et al., Testosterone replacement therapy in high risk patients following radical prostatectomy. The Journal of Urology, 2010. 183(4): p. e577.

12.          Davila, H.H., et al., Analysis of the PSA response after testosterone supplementation in patients who previously received management for their localized prostate cancer. The Journal of Urology, 2008. 179(4; Suppl): p. 428.

13.          Nabulsi, O., et al., Outcomes analysis of testosterone supplementation in hypogonadal men following radical prostatectomy. The Journal of Urology, 2008. 179(4; Suppl): p. 426-427.

14.          Pastuszak, A.W., et al., Testosterone replacement therapy in patients with prostate cancer after radical prostatectomy. J Urol, 2013. 190(2): p. 639-44.

15.          Sarosdy, M.F., Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy. Cancer, 2007. 109(3): p. 536-41.

16.          Morales, A., A.M. Black, and L.E. Emerson, Testosterone administration to men with testosterone deficiency syndrome after external beam radiotherapy for localized prostate cancer: preliminary observations. BJU Int, 2009. 103(1): p. 62-4.

17.          Pastuszak, A.W., et al., Testosterone replacement therapy in the setting of prostate cancer treated with radiation. Int J Impot Res, 2013. 25(1): p. 24-8.

18.          Balbontin, F.G., et al., Long-acting testosterone injections for treatment of testosterone deficiency after brachytherapy for prostate cancer. BJU Int, 2014. 114(1): p. 125-30.

19.          Pastuszak, A.W., et al., Testosterone Therapy after Radiation Therapy for Low, Intermediate and High Risk Prostate Cancer. J Urol, 2015. 194(5): p. 1271-6.

20.          Hayes, J.H., et al., Active surveillance compared with initial treatment for men with low-risk prostate cancer: a decision analysis. JAMA, 2010. 304(21): p. 2373-80.

21.          Cohen, A., et al., Variation in Testosterone Levels and Health-related Quality of Life in Men Diagnosed With Prostate Cancer on Active Surveillance. Urology, 2016. 94: p. 180-7.

22.          Mulligan, T., et al., Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract, 2006. 60(7): p. 762-9.

23.          Kacker, R., et al., Can testosterone therapy be offered to men on active surveillance for prostate cancer? Preliminary results. Asian J Androl, 2016. 18(1): p. 16-20.

24.          Hashimoto, T., et al., Prostate magnetic resonance imaging findings in patients treated for testosterone deficiency while on active surveillance for low-risk prostate cancer. Urol Oncol, 2016.

25.          Morales, A., Effect of testosterone administration to men with prostate cancer is unpredictable: a word of caution and suggestions for a registry. BJU Int, 2011. 107(9): p. 1369-73.

26.          Millar, A.C., et al., A survey of Canadian urologists' opinions and prescribing patterns of testosterone replacement therapy in men on active surveillance for low-risk prostate cancer. Can Urol Assoc J, 2016. 10(5-6): p. 181-184.

27.          Gray, H., J. Seltzer, and R.L. Talbert, Recurrence of prostate cancer in patients receiving testosterone supplementation for hypogonadism. Am J Health Syst Pharm, 2015. 72(7): p. 536-41.

28.          Morgentaler, A., et al., Testosterone therapy in men with untreated prostate cancer. J Urol, 2011. 185(4): p. 1256-60.

29.          Drazer, M.W. and W.M. Stadler, The Role of Testosterone in the Treatment of Castration-Resistant Prostate Cancer. Cancer J, 2016. 22(5): p. 330-333.

30.          Denmeade, S.R. and J.T. Isaacs, Bipolar androgen therapy: the rationale for rapid cycling of supraphysiologic androgen/ablation in men with castration resistant prostate cancer. Prostate, 2010. 70(14): p. 1600-7.

31.          Isaacs, J.T., et al., Adaptive auto-regulation of androgen receptor provides a paradigm shifting rationale for bipolar androgen therapy (BAT) for castrate resistant human prostate cancer. Prostate, 2012. 72(14): p. 1491-505.

32.          Schweizer, M.T., et al., Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: results from a pilot clinical study. Sci Transl Med, 2015. 7(269): p. 269ra2.

Last modified on Wednesday, 23 November 2016 00:39
Monica Mollica

Medical Writer & Nutritionist

MSc in Nutrition

University of Stockholm & Karolinska Institute, Sweden 

   Baylor University, TX, USA

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