Testosterone therapy in men with prostate cancer – new research
November 2016
Testosterone Therapy in Patients with Treated and Untreated Prostate Cancer: Impact on Oncologic Outcomes. Ory J, Flannigan R, Lundeen C, Huang JG, Pommerville P, Goldenberg SL. J Urol. 2016;196(4):1082 1089.
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 we summarise the results of a notable study which investigated the effects of testosterone therapy in men with treated and untreated prostate cancer5, 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 editorial “Testosterone and Prostate Cancer - a paradigm shift” we explained why the relation between testosterone and prostate cancer is not linear and we 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 recurrence8-12 and no biochemical or clinical evidence of prostate cancer recurrence.10
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.12-16 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.17
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.18 One third of men on active surveillance have testosterone deficiency19, which is about the same prevalence as that seen in the general male population.20
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 (age 59 years) with untreated prostate cancer received testosterone therapy for 1 to 8 years. Gleason score at initial biopsy was 6 in 12 men and 7 in 1. Testosterone levels increased from 8.3 nmol/L to 23 nmol/L (p <0.001). Mean PSA and prostate volume did not change with testosterone therapy. 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.20
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.21 Mean age was 60 years, and mean follow-up 40 months for both groups. Biopsy progression rates were similar for both groups.21 It was concluded that biopsy progression in men on active surveillance appears unaffected by testosterone therapy over 3 years.21
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.22 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.23 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, an increase in testosterone (p <0.001) and prostate specific antigen (p = 0.001) was found. 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 years2, and currently there is insufficient evidence to withhold testosterone therapy in certain populations of men with a history of prostate cancer.24
Testosterone therapy in hypogonadal men with a treated prostate cancer results in significant elevations in testosterone levels and improvements in hypogonadal symptoms.9,14-16,25 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.
The longstanding prohibition against testosterone therapy in men with untreated low risk prostate cancer without evidence of metastatic or recurrent disease, also merits reevaluation.26 Especially fascinating is the emerging research on bipolar androgen therapy (BAT) for the treatment of castrate resistant prostate cancer (CRPC).27 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).28-30 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
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- 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. Return to content
- Nguyen TM, Pastuszak AW. Testosterone Therapy Among Prostate Cancer Survivors. Sex Med Rev. 2016;4(4):376-388. Return to content
- Morgentaler A, 3rd, Conners WP. Testosterone therapy in men with prostate cancer: literature review, clinical experience, and recommendations. Asian journal of andrology. 2015;17(2):206-211. Return to content
- Ory J, Flannigan R, Lundeen C, Huang JG, Pommerville P, Goldenberg SL. Testosterone Therapy in Patients with Treated and Untreated Prostate Cancer: Impact on Oncologic Outcomes. J Urol. 2016;196(4):1082-1089. Return to content
- Debruyne FM, Behre HM, Roehrborn CG, 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. Return to content
- Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol. 2009;55(2):310-320. Return to content
- Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol. 2004;172(3):920-922. Return to content
- Agarwal PK, Oefelein MG. Testosterone therapy after primary treatment for prostate cancer. J Urol. 2005;173(2):533-536. Return to content
- Khera M, Grober ED, Najari B, et al. Testosterone therapy following radical prostatectomy. The journal of sexual medicine. 2009;6(4):1165-1170. Return to content
- Sathyamoorthy K, Stein M, Mohammed O, Lipshultz L, Khera M. Testosterone therapy in high risk patients following radical prostatectomy. The Journal of Urology. 2010;183(4):e577. Return to content
- Davila HH, Arison CN, Hall MK, Salup R, Lockhart JL, Carrion RE. 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):428. Return to content
- Sarosdy MF. Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy. Cancer. 2007;109(3):536−541. Return to content
- Morales A, Black AM, Emerson LE. Testosterone administration to men with testosterone deficiency syndrome after external beam radiotherapy for localized prostate cancer: preliminary observations. BJU Int. 2009;103(1):62-64. Return to content
- Pastuszak AW, Pearlman AM, Godoy G, Miles BJ, Lipshultz LI, Khera M. Testosterone therapy in the setting of prostate cancer treated with radiation. Int J Impot Res. 2013;25(1):24-28. Return to content
- Balbontin FG, Moreno SA, Bley E, Chacon R, Silva A, Morgentaler A. Long-acting testosterone injections for treatment of testosterone deficiency after brachytherapy for prostate cancer. BJU Int. 2014;114(1):125-130. Return to content
- Pastuszak AW, Khanna A, Badhiwala N, et al. Testosterone Therapy after Radiation Therapy for Low, Intermediate and High Risk Prostate Cancer. J Urol. 2015;194(5):1271−1276. Return to content
- Hayes JH, Ollendorf DA, Pearson SD, et al. Active surveillance compared with initial treatment for men with low-risk prostate cancer: a decision analysis. JAMA. 2010;304(21):2373-2380. Return to content
- Cohen A, Lapin B, Wang CH, Helfand B, Victorson D, Novakovic K. Variation in Testosterone Levels and Health-related Quality of Life in Men Diagnosed With Prostate Cancer on Active Surveillance. Urology. 2016;94:180-187. Return to content
- Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60(7):762−769. Return to content
- Kacker R, Hult M, San Francisco IF, et al. Can testosterone therapy be offered to men on active surveillance for prostate cancer? Preliminary results. Asian journal of andrology. 2016;18(1):16−20. Return to content
- 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):1369-1373. Return to content
- Millar AC, Elterman DS, Goldenberg L, Van Asseldonk B, Curtis A, Jarvi K. A survey of Canadian urologists' opinions and prescribing patterns of testosterone therapy in men on active surveillance for low-risk prostate cancer. Canadian Urological Association journal = Journal de l'Association des urologues du Canada. 2016;10(5−6):181−184. Return to content
- Gray H, Seltzer J, Talbert RL. Recurrence of prostate cancer in patients receiving testosterone supplementation for hypogonadism. Am J Health Syst Pharm. 2015;72(7):536−541. Return to content
- Pastuszak AW, Pearlman AM, Lai WS, et al. Testosterone therapy in patients with prostate cancer after radical prostatectomy. J Urol. 2013;190(2):639-644. Return to content
- Morgentaler A, Lipshultz LI, Bennett R, Sweeney M, Avila D, Jr., Khera M. Testosterone therapy in men with untreated prostate cancer. J Urol. 2011;185(4):1256-1260. Return to content
- Drazer MW, Stadler WM. The Role of Testosterone in the Treatment of Castration-Resistant Prostate Cancer. Cancer J. 2016;22(5):330-333. Return to content
- Denmeade SR, Isaacs JT. Bipolar androgen therapy: the rationale for rapid cycling of supraphysiologic androgen/ablation in men with castration resistant prostate cancer. Prostate. 2010;70(14):1600-1607. Return to content
- Isaacs JT, D'Antonio JM, Chen S, 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):1491−1505. Return to content
- Schweizer MT, Antonarakis ES, Wang H, et al. Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: results from a pilot clinical study. Science translational medicine. 2015;7(269):269ra2. Return to content
