Are there differences between the different hormone therapy methods in the pattern and severity of toxicity effects for non metastatic disease?
Complications and cumulative treatment toxicity
For men with non-metastatic prostate cancer, androgen deprivation has been shown to provide a survival benefit as an adjuvant to radiation therapy for high-risk and in many studies for intermediate risk prostate cancer and as an adjuvant to radical prostatectomy but only for lymph node positive fully respected disease. These treatments may last over two years, with the minimum duration for maximal survival benefit unclear. As a result, adverse events or unwanted effects have the potential to have a significant impact on quality of life. These men have relatively long life expectancies and thus the potential longer-term side effects of these therapies are important. Observational studies have suggested that, with relatively long life expectancies, there may be a higher risk of metabolic syndrome, sudden cardiac death, myocardial infarctions, diabetes mellitus and a higher rate of fractures. The longer the duration of ADT with LHRH agonist therapy or orchidectomy, the greater the likelihood of the serious adverse effects of reduced bone mineral density and pathological fracture in particular. (See section on Quality of life for a fuller discussion).
There are a large number of randomised controlled trials reporting ADT adverse events. However, many of these trials are not applicable since medications employed, such as oral oestrogens, finasteride and cyproterone acetate, are not recommended as first-line drugs for prostate cancer, even for short periods to offset the flare effect of LHRH agonists. This review focuses on the adverse events associated with the clinically relevant therapies of castration (medical or surgical) and nonsteroidal anti-androgens for the treatment of non-metastatic prostate cancer.
Five RCTs compared castration (surgical or medical) with no ADT ; two compared long-term anti-androgen therapy with no ADT  three compared castration with long-term anti-androgen therapy  and three compared short-term CAB with no ADT.
Limited data from four randomised trials failed to demonstrate an increase in cardiovascular mortality or myocardial infarction with orchidectomy or long-term LHRH agonist treatment. Bicalutamide (anti-androgen) was associated with a significantly increased likelihood of heart failure in one study (risk ratio = 1.96).
The effects of castration on sexual function were not reported in these studies, possibly because they are so well accepted. Castration was associated with hot flushes and breast changes and LHRH agonists were associated with cognitive impairment.
Increased impotence, hot flushes, gynaecomastia and breast pain, together with tiredness and asthenia were also commonly reported with bicalutamide.  There was an increased risk of nausea and vomiting with flutamide.
When compared with castration, the non-steroidal anti-androgen, bicalutamide, had similar effects on lipid levels, resulted in a smaller increase in body fat mass, fewer hot flushes, a lower incidence of decreased libido but an increased incidence of breast changes. The effects of bicalutamide and LHRH agonist therapy on bone mineral density were highly significantly different at 12 and 96 months; mean bone density decreased with LHRH agonist treatment, but was unchanged with bicalutamide.
Short-term CAB was reported not to cause significant increases in cardiovascular mortality severe gynecomastia or liver function abnormalities however in another study 17% of patients who received the anti-androgen flutamide as part of their CAB discontinued flutamide because of liver toxicity. For a more comprehensive comparison of ADT and castration toxicities see section on Toxity.
The findings above are consistent with clinical experience for the major toxicities, however, they may understate the problems associated with ADT medications as there are a number of limitations associated with this body of evidence. Firstly, the scope of the problem which is widely known is not addressed; most of the RCTs focused on efficacy outcomes and as a result toxicities and adverse events were rarely evaluated rigorously in terms of scope, and the gamut of well-known adverse effects such as cognitive impairment, liver toxicity and sexual dysfunction were rarely assessed. In addition, using clinical trials to assess adverse events has a number of limitations. As noted by Aronson et al, these limitations apply to the ADT trials for prostate cancer and include trials not being large enough to capture rare events, incomplete reporting of adverse events, varying modes of reporting adverse events and differing methods of measuring adverse event. In addition many of these studies were sponsored by the pharmaceutical industry and as such there is the potential for a pervading influence on reporting these ‘softer’ endpoints of toxicity from a number of studies.
Thus there are limitations in appreciating toxicity in relation to clinical impact of ADT based on this review alone. Evidence of this is provided by the more recent demonstration of the metabolic syndrome as an issue in patients with long-term ADT. There is a need for studies targeting putative side effects as primary end-points and RCTs examining the recently emerging issues of the longerterm problems of cognitive changes, metabolic syndrome and bone loss.
It can be appreciated from the above that there is a significant adverse event profile from ADT, but there are limitations in quantifying exactly the toxicity from ADT and its clinical impact. It is also clear that studies are needed to more accurately define the side effects of ADT as primary end-points and to examine more insidious adverse events, including the longer-term problems of cognitive changes and the metabolic syndrome. New agents such as Receptor Activator of Nuclear Kappa B (RANK) ligand inhibitors, which have recently been shown to prevent bone loss and osteoporotic fractures, have just been evaluated in RCTs in this patient population and are more accurately detailing the impact of ADT on bone health.
Evidence summary and recommendations
|For men without clinical evidence of metastatic disease, four trials showed no increase in cardiovascular mortality or myocardial infarction with orchidectomy or long-term LHRH agonist treatment. However, larger population-based studies are required to reveal the small impact. Castration was associated with hot flushes and breast changes (one trial) and cognitive decline (one trial).||II||, , , , , , , , |
|Anti-androgens were associated with a significantly increased likelihood of heart failure (bicalutamide), increased impotence, hot flushes, gynaecomastia and breast pain, nausea and vomiting, tiredness and asthenia.||II||, , |
|When compared with castration, bicalutamide resulted in smaller increases in body fat mass, fewer hot flushes and a lower incidence of decreased libido, but an increased incidence of breast changes. Unlike castration, bicalutamide did not decrease bone density at 12 and 96 months.||II||, , |
|Three trials showed no significant increase in cardiovascular mortality with short-term CAB.||II||, , , , |
It should first be clarified that the recommendations are made with the observation that with the exception of adjuvant therapy with radiation therapy for high-risk and intermediate-risk prostate cancer and lymph node positive fully resected disease, there is no known survival advantage in commencing ADT early (as indicated by increasing serum PSA levels alone after definitive local therapy) rather than later (with radiographically evident metastases). This is particularly important as there is a significant number of unwanted effects (understated in this review) that have a significant impact on quality of life. Therefore, that which is important to the patient should be considered together with his co-morbidities. Specifically, the early commencement of ADT with castration (either as monotherapy or with an anti-androgen) may be more undesirable for individuals for whom sexual activity is very important and for those struggling to cope with declining cognitive abilities or with baseline osteopaenia.
It is recommended that the prescriber take into account the following points when commencing ADT:
- Taylor LG, Canfield SE, Du XL. Review of major adverse effects of androgen-deprivation therapy in men with prostate cancer. Cancer 2009 Jun 1;115(11):2388-99 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19399748.
- Singer EA, Golijanin DJ, Miyamoto H, Messing EM. Androgen deprivation therapy for prostate cancer. Expert Opin Pharmacother 2008 Feb;9(2):211-28 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18201145.
- Jordan WP Jr, Blackard CE, Byar DP. Reconsideration of orchiectomy in the treatment of advanced prostatic carcinoma. South Med J 1977 Dec;70(12):1411-3 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/594790.
- Schröder FH, Kurth KH, Fosså SD, Hoekstra W, Karthaus PP, et al. Early versus delayed endocrine treatment of pN1-3 M0 prostate cancer without local treatment of the primary tumor: results of European Organisation for the Research and Treatment of Cancer 30846--a phase III study. J Urol 2004 Sep;172(3):923-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15310999.
- Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 1999 Dec 9;341(24):1781-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10588962.
- Lawton CA, Winter K, Murray K, Machtay M, Mesic JB, Hanks GE, et al. Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001 Mar 15;49(4):937-46 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11240234.
- Green HJ, Pakenham KI, Headley BC, Yaxley J, Nicol DL, Mactaggart PN, et al. Altered cognitive function in men treated for prostate cancer with luteinizing hormone-releasing hormone analogues and cyproterone acetate: a randomized controlled trial. BJU Int 2002 Sep;90(4):427-32 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12175403.
- Green HJ, Pakenham KI, Headley BC, Yaxley J, Nicol DL, Mactaggart PN, et al. Quality of life compared during pharmacological treatments and clinical monitoring for non-localized prostate cancer: a randomized controlled trial. BJU Int 2004 May;93(7):975-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15142146.
- McLaughlin BT, Gokhale AS, Shuai Y, Diacopoulos J, Carrau R, Heron DE, et al. Management of patients treated with chemoradiotherapy for head and neck cancer without prophylactic feeding tubes: the University of Pittsburgh experience. Laryngoscope 2010 Jan;120(1):71-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19877245.
- Wirth MP, See WA, McLeod DG, Iversen P, Morris T, et al. Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: results from the second analysis of the early prostate cancer program at median followup of 5.4 years. Casodex Early Prostate Cancer Trialists' Group,. J Urol 2004 Nov;172(5 Pt 1):1865-70 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15540740.
- Wirth MP, Weissbach L, Marx FJ, Heckl W, Jellinghaus W, Riedmiller H, et al. Prospective randomized trial comparing flutamide as adjuvant treatment versus observation after radical prostatectomy for locally advanced, lymph node-negative prostate cancer. Eur Urol 2004 Mar;45(3):267-70; discussion 270 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15036669.
- Iversen P, Tyrrell CJ, Kaisary AV, Anderson JB, Van Poppel H, Tammela TL, et al. Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup. J Urol 2000 Nov;164(5):1579-82 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11025708.
- Smith MR, Goode M, Zietman AL, McGovern FJ, Lee H, Finkelstein JS. Bicalutamide monotherapy versus leuprolide monotherapy for prostate cancer: effects on bone mineral density and body composition. J Clin Oncol 2004 Jul 1;22(13):2546-53 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15226323.
- Sieber PR, Keiller DL, Kahnoski RJ, Gallo J, McFadden S. Bicalutamide 150 mg maintains bone mineral density during monotherapy for localized or locally advanced prostate cancer. J Urol 2004 Jun;171(6 Pt 1):2272-6, quiz 2435 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15126801.
- Lamb DS, Denham JW, Mameghan H, Joseph D, Turner S, Matthews J, et al. Acceptability of short term neo-adjuvant androgen deprivation in patients with locally advanced prostate cancer. Radiother Oncol 2003 Sep;68(3):255-67 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/13129633.
- Christie D, Denham J, Steigler A, Lamb D, Turner S, Mameghan H, et al. Delayed rectal and urinary symptomatology in patients treated for prostate cancer by radiotherapy with or without short term neo-adjuvant androgen deprivation. Radiother Oncol 2005 Nov;77(2):117-25 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16271786.
- Denham JW, Steigler A, Lamb DS, Joseph D, Mameghan H, et al. Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01 randomised controlled trial. Trans-Tasman Radiation Oncology Group,. Lancet Oncol 2005 Nov;6(11):841-50 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16257791.
- Pilepich MV, Krall JM, al-Sarraf M, John MJ, Doggett RL, Sause WT, et al. Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group. Urology 1995 Apr;45(4):616-23 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7716842.
- D'Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A, Kantoff PW. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA 2004 Aug 18;292(7):821-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15315996.
- McLeod DG, Iversen P, See WA, Morris T, Armstrong J, et al. Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU Int 2006 Feb;97(2):247-54 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16430622.
- Pilepich MV, Winter K, Lawton CA, Krisch RE, Wolkov HB, Movsas B, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005 Apr 1;61(5):1285-90 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15817329.
- Seidenfeld J, Samson DJ, Aronson N, Albertson PC, Bayoumi AM, Bennett C, et al. Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostate cancer. Evid Rep Technol Assess (Summ) 1999 May;(4):i-x, 1-246, I1-36, passim Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11098244.
- Braga-Basaria M, Dobs AS, Muller DC, Carducci MA, John M, Egan J, et al. Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J Clin Oncol 2006 Aug 20;24(24):3979-83 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16921050.
- Pilepich MV, Buzydlowski JW, John MJ, Rubin P, McGowan DG, Marcial VA. Phase II trial of hormonal cytoreduction with megestrol and diethylstilbestrol in conjunction with radiotherapy for carcinoma of the prostate: outcome results of RTOG 83-07. Int J Radiat Oncol Biol Phys 1995 Apr 30;32(1):175-80 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7721614.