Should Testosterone Replacement be Offered to Hypogonadal Men Treated Previously for Prostatic Carcinoma?
D. Landau; T. Tsakok; S. Aylwin; S. Hughes*
Posted: 02/01/2012; Clin Endocrinol. 2012;76(2):179-181. © 2012 Blackwell Publishing
Summary
Role of Androgen Deprivation Therapy in the Management of Prostate Cancer
Testosterone Replacement in Men Treated for Prostate Cancer
Summary
Androgen administration can cause prostate cancer progression, and androgen deprivation therapy is a commonly used therapeutic modality in the treatment of prostate cancer. In trying to answer the posed clinical question, this article reviews the risks and benefits of testosterone replacement therapy in this setting and the published data from clinical series. Recommendations are made based on the available evidence.
Clinical Background
Androgen replacement with testosterone in any of the available formulations is recommended for patients with hypogonadism – both for symptomatic benefit and for its effects on metabolic parameters and body composition. Whilst metastatic or locally persistent prostate cancer is recognized as a contraindication, a dilemma arises in those individuals with a history of previously treated prostate cancer who are in long-term remission. In this article, we consider whether there are individual subjects with previous prostate cancer in whom the risk/benefit ratio favours treatment with androgen replacement.
Role of Androgen Deprivation Therapy in the Management of Prostate Cancer
Before considering the possible use of androgen replacement in patients with previously treated prostate cancer, it is appropriate to consider the role of androgen deprivation therapy (ADT) in the management of established prostate cancer. It is estimated that there will be over 200 000 new cases of prostate cancer diagnosed in the US during 2010, exceeding that predicted for breast cancer in women.[1] In the UK, over 37 000 cases were diagnosed in 2008 alone (http://info.cancerresearchuk.org/cancerstats/types/prostate/incidence). It has been estimated that the lifetime risk of being diagnosed with prostate cancer in the UK is one in nine. For many of these men, ADT will form part of their therapy.
In 1942, Huggins first described androgen dependence in metastatic prostate cancer, demonstrating sustained clinical improvement in men with well-differentiated tumours following surgical castration.[2] Castration still forms the basis of treatment for metastatic disease today, although medical castration [most commonly with luteinizing hormone-releasing hormone (LHRH) agonist therapy] is more commonly used, because of both patient choice and the potential for reversibility. The aim of castration is to reduce circulating testosterone levels to below 50 ng/dl.[3]
Data for treatment with ADT as adjuvant therapy in the curative setting are available from a number of randomized clinical trials. Prolonged (>3 months) postoperative maximum androgen blockade has been shown to improve prostate specific antigen (PSA) progression-free survival after radical prostatectomy.[4] Indefinite androgen deprivation has been shown to produce an overall survival benefit in the postoperative setting for lymph node-positive disease.[5] Following radical radiotherapy, the use of long-course (2-3 years) post-treatment ADT has also been shown to delay the development of metastatic disease and improve overall survival (Gleason ≥8; T3-4; N0-1).[6,7]
Overall, the available data suggest that ADT may be beneficial for at least 2-3 years after prostatectomy or radical radiotherapy. By extension, it would make sense to withhold testosterone replacement from hypogonadal men in the early years after diagnosis and radical treatment of even early-stage prostate cancer.
Testosterone Replacement in Men Treated for Prostate Cancer
The Endocrine Society Clinical Practice Guideline recommends against starting testosterone replacement therapy (TRT) in hypogonadal patients with a history of prostate cancer.[8] Yet, 70 years from the seminal studies conducted by Huggins,[2] some now question our continuing adherence to their original hypotheses. The central issue is this: it is widely accepted that lowering serum testosterone may induce regression of metastatic prostate cancer, but it does not necessarily follow that an increase in serum testosterone invariably stimulates tumour growth. Indeed, review of the literature reveals a striking paucity of data to support the latter statement, prompting some to ask whether denying TRT to symptomatic hypogonadal men can be ethically justified.[9] This question has been brought sharply into focus by the increasing numbers of patients affected by both prostate cancer and late-onset hypogonadism in our ageing population.
To answer the title’s clinical question, we should delve deeper into the – albeit limited – data on TRT in men previously treated for prostate cancer with curative intent. The importance of this last caveat lies in the fact that men still suspected of harbouring prostate cancer cells are broadly accepted to be unsuitable candidates for TRT.[9] By contrast, patients in long-term remission after radical surgery or radiotherapy are even more vulnerable than the average elderly men to suffer from hypogonadism, and the risk/benefit ratio of treating this has been the subject of some investigation.[10-16] On the whole, the published series, summarised in Table 1, were not prospective protocols but either open-label use in clinical settings or retrospective chart reviews.
Testosterone replacement therapy after radical prostatectomy was the focus of Kaufman and Graydon’s[17] study in seven patients with hypogonadism over a maximum follow-up period of 12 years. They reported symptomatic improvement of hypogonadism, with no evidence of cancer recurrence. Agarwal and Oefelein[18] administered TRT to a similar group of 10 patients and also reported that no PSA recurrences were associated with rises in mean serum testosterone from 197 to 591 ng/dl. In a study by Khera et al.,[19] 57 men received testosterone for an average of 36 months following radical prostatectomy – no increases in PSA were seen over a mean follow-up of 13 months. Of note is the larger study by Sathyamoorthy et al. [20] in 133 postprostatectomy patients, 21 (16%) of whom had either Gleason score ≥ 8, positive margins or nodes. There were no significant PSA rises associated with increases in mean testosterone levels from 262 to 418 ng/dl over a 1 year follow-up. A prospective study of 22 patients by Nabulsi et al. [21] reported that one patient (4·5%) experienced biochemical recurrence after TRT postradical prostatectomy.
Despite the intuitive concern that residual prostate tissue is more likely to result in residual microscopic disease susceptible to androgen stimulation, some studies evaluating the use of TRT after radiotherapy and brachytherapy have also produced encouraging data. Sarosdy[22] followed 31 men receiving testosterone after brachytherapy with a median 5 year follow-up, finding no incidence of cancer recurrence or progression. Morales et al. [23] looked at five men post external beam radiotherapy and noted marked symptomatic improvement, with no biochemical recurrence for up to 27 months. Davila et al. [24] analysed PSA response after TRT in a split cohort of 20 patients after either prostatectomy or external beam radiation therapy. There were no biochemical recurrences and no differences between the two groups in PSA levels after testosterone replacement. Finally, Leibowitz et al [25] reported a retrospective study of a heterogeneously treated population of 96 patients. 60% of participants had not received definitive local therapy and consequently had both malignant and benign prostatic tissue in situ; notably, 11 men in the study group had metastatic disease in remission after ADT. After a mean treatment duration of 15 months, 41 men (43%) had PSA progression. This high rate of PSA progression can in part be explained by the relatively high proportion of patients with aggressive disease (25% had Gleason score ≥ 8). However, it is also possible that stimulation of residual benign prostatic tissue contributed to the raised PSA levels, which in most cases returned to baseline following cessation of testosterone replacement. Elevated baseline PSA before testosterone replacement was associated with a significantly increased risk of PSA progression, serving as a reminder that this therapy should be restricted to patients in overt biochemical remission.
We have summarized a small number of mostly retrospective case series evaluating the safety of initiating TRT in postprostatectomy patients with negative margins and undetectable PSA levels. Overall, 42 of 381 (11%, range 0-43%) experienced biochemical recurrence, whilst the majority benefited from symptomatic improvement in their hypogonadism without adverse effects on PSA or tumour progression. It is likely that research in this field suffers from publication bias as well as the modest quality of most studies. Nevertheless, the data presented here are largely at odds with the longstanding taboo regarding the use of androgens in men with prostate cancer and again raises the question: is it of clinical consequence if a normal serum testosterone level is achieved in a prostate cancer survivor by natural or pharmacological means? Until more studies have been published on this subject, we should take a cautious and conservative approach.
Conclusions
Taking account of the available evidence, we recommend the following:
Risk of relapse is likely to be lowest in patients whose PSA has been under control for at least 4 years and whose initial cancer characteristics were of low risk.
The relative risk of untreated hypogonadism and potential for cancer relapse in each patient should be jointly assessed by an endocrinologist and oncologist or urologist.
Full restaging, including rebiopsy of the prostate, should be considered before starting replacement therapy.
An agreed plan for increased PSA surveillance should be instituted with testosterone replacement therapy.
The level of circulating testosterone should be kept as low as possible to satisfy each patient’s replacement requirements.
Ideally, prospective studies should examine the safety and benefit of androgen replacement in hypogonadal patients in remission from prostate cancer. Until such data are available, administration of androgen replacement to these patients may be considered, but should be undertaken cautiously, with a clear description of the potential risk and certainly with prior determination of the surveillance protocol.
References
Jemal, A., Siegel, R., Xu, J. et al. (2010) Cancer statistics, 2010. CA: A Cancer Journal for Clinicians, 60, 277-300.
Huggins, C. (1942) Effect of orchidectomy and irradiation on cancer of the prostate. Annals of Surgery, 115, 1192-2000.
Morote, J., Orsola, A., Planas, J. et al. (2007) Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. Journal of Urology, 178, 1290-1295.
Meyer, F., Moore, L., Bairati, I. et al. (1999) Neoadjuvant hormonal therapy before radical prostatectomy and risk of prostate specific antigen failure. Journal of Urology, 162, 2024-2028.
Messing, E.M., Manola, J., Yao, J. et al. (2006) Immediate versus deferred androgen deprivation treatment in patients with nodepositive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. The Lancet Oncology, 7, 472-479.
Bolla, M., Van Tienhoven, G., Warde, P. et al. (2010) External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. The Lancet Oncology, 11, 1066-1073.
Pilepich, M.V., Winter, K., Lawton, C.A. et al. (2005) Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma – long-term results of phase III RTOG 85-31. International Journal of Radiation Oncology, Biology, Physics, 61, 1285-1290.
Bhasin, S., Cunningham, G.R., Hayes, F.J. et al. (2010) Testosterone therapy in men with androgen deficiency syndrome: an Endocrine Society Practice Guideline. Journal of Clinical Endocrinology and Metabolism, 95, 2536-2559.
Morgentaler, A. (2009) Testosterone therapy in men with prostate cancer: scientific and ethical considerations. Journal of Urology, 181, 972-979.
Wheeler, M.J. & Barnes, S.C. (2008) Measurement of testosterone in the diagnosis of hypogonadism in the ageing male. Clinical Endocrinology, 69, 515-525.
Nieschlag, E. (2006) Testosterone treatment comes of age: new options for hypogonadal men. Clinical Endocrinology, 65, 275-281.
Bassil, N., Alkaade, S. & Morley, J.E. (2009) The benefits and risks of testosterone replacement therapy: a review. Therapeutics and Clinical Risk Management, 5, 427-448.
Grossman, M. & Zajac, J.D. (2011) Androgen deprivation therapy in men with prostate cancer: how should the side effects be monitored and treated? Clinical Endocrinology, 74, 289-293.
Padula, G.D., Zelefsky, M.J., Venkatraman, E.S. et al. (2002) Normalization of serum testosterone levels in patients treated with neoadjuvant hormonal therapy and three-dimensional conformal radiotherapy for prostate cancer. International Journal of Radiation Oncology, Biology, Physics, 52, 439-443.
Bolona, E.R., Uraga, M.V. & Haddard, R.M. (2007) Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clinic Proceedings, 82, 20-28.
Morales, A. (2002) Androgen replacement therapy and prostate safety. European Urology, 41, 113-120.
Kaufman, J.M. & Graydon, R.J. (2004) Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. Journal of Urology, 172, 920-922.
Agarwal, P.K. & Oefelein, M.G. (2005) Testosterone replacement therapy after primary treatment for prostate cancer. Journal of Urology, 173, 533-536.
Khera, M., Grober, E.D., Najari, B. et al. (2009) Testosterone replacement therapy following radical prostatectomy. The Journal of Sexual Medicine, 6, 1165-1170.
Sathyamoorthy, K., Stein, M., Mohammed, O. et al. (2010) Testosterone replacement therapy in high risk patients following radical prostatectomy [abstract 1498]. Journal of Urology, 183(Suppl), e577.
Nabulsi, O., Tal, R., Gotto, G. et al. (2008) Outcomes analysis of testosterone supplementation in hypogonadal men following radical prostatectomy. Journal of Urology, 179(Suppl), 426-427.
Sarosdy, M.F. (2007) Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy. Cancer, 109, 536-541.
Morales, A., Black, A.M. & Emerson, L.E. (2009) Testosterone administration to men with testosterone deficiency syndrome after external beam radiotherapy for localized prostate cancer: preliminary observations. BJU International, 103, 62-64.
Davila, H.H., Arison, C.N., Hall, M.K. et al. (2008) Analysis of the PSA response after testosterone supplementation in patients who previously received management for their localized prostate cancer [abstract]. Journal of Urology, 179(Suppl), 428.
Leibowitz, R., Dorff, T.B., Tucker, S. et al. (2010) Testosterone replacement in prostate cancer survivors with hypogonadal symptoms. BJU International, 105, 1397-1401.