Are there differences between the different hormone therapy methods in the pattern and severity of toxicity effects in metastatic disease?
Are there differences between the different hormone therapy methods in the pattern and severity of toxicity effects in metastatic disease?
Numerous trials examining hormone therapy as a treatment for metastatic disease reported adverse events and toxicities. Many included patients without clinical metastatic disease and as a result patient populations were often markedly heterogeneous. Furthermore, the duration of follow-up ranged from less than six months to many years and, in a number of studies, this was unclear. Finally, as with the trials of ADT for non-metastatic disease, most of these RCTs had the limitations of focusing on efficacy outcomes rather than toxicities with adverse events. The latter were rarely comprehensively recorded and evaluated rigorously and so are potentially understated. A final concern is that many studies were sponsored by the pharmaceutical industry and this may have introduced a bias.
Early versus delayed androgen deprivation
There were three RCTs comparing immediate castration with delayed treatment that included patients with metastatic disease. Two of these studies included patients with M0 disease and the third was a M1 subgroup analysis. Two examined cardiovascular mortality and one examined haemoglobin levels. Castration did not significantly increase cardiovascular mortality , however it did cause a significant decrease in haemoglobin levels.
CAB versus monotherapy
As cyproterone accetate is not recommended for first-line ADT by the UK Committee on the Safety of Medicines and in the ASCO Guidelines, this medication was not considered. Despite this exclusion, the overall body of evidence comparing CAB with castration is considerable. Five RCTs examined the addition of nilutamide to castration; 11 RCTs examined the addition of flutamide to castration; one RCT examined the addition of bicalutamide to castration. Only patients with metastatic disease were included in the nilutamide trials. The addition of anti-androgens did not significantly increase the risk of cardiovascular adverse events (nilutamide, three trials; flutamide, three trials). The addition of flutamide significantly increased the incidence of liver abnormalities in three of six trials and significantly increased hot flushes in one of nine trials. Nilutamide did not significantly affect the incidence of hot flushes (three trials) while bicalutamide appeared to decrease the incidence of hot flushes. In a single trial, nilutamide had no effect on gynecomastia. However, flutamide appeared to increase the incidence of breast changes, with one of the seven trials of flutamide showing a significant increase in gynecomastia. Nilutamide did not appear to affect gastrointestinal symptoms (four trials) whereas four of eight trials showed a significant increase in gastrointestinal side effects with the addition of flutamide. There was a trend towards decreased flare with anti-androgens and this was almost significant in the only nilutamide trial examining flare and in one of the four flutamide trials examining flare. Anaemia was significantly increased with flutamide, whereas anaemia and asthenia decreased with nilutamide. Nilutamide is also reported to be associated with alcohol intolerance and night blindness. In terms of clinically relevant studies, there are many trials with a CAB arm, particularly with flutamide and more recently, bicalutamide, as these two drugs had the benefit of patent protection and hence the motivation of industry to support studies looking to define a clinical advantage for these agents.
There were a large number of RCTs comparing different hormone therapies for metastatic disease. Many of the treatments, such as oestrogens, LHRH agonists triptorelin and buserelin nasal spray, the LHRH antagonist abarelix and the steroidal anti-androgen chlormadinone acetate are not approved or listed by the Pharmaceutical Benefits Scheme (PBS) for use in Australia. When studies involving these drugs are removed, the volume of evidence is good rather than excellent. This review focuses on castration (surgical or medical) and peripheral blockade (anti-androgen or cyproterone) in order to provide a discussion that is relevant to current practice.
There were five RCTs comparing non-steroidal anti-androgens with castration one RCT comparing cyproterone acetate with castration, one RCT comparing the non-steroidal anti-androgen, flutamide with cyproterone acetate and one RCT comparing flutamide with bicalutamide as part of CAB therapy.
There is a general consistency in findings in a majority of studies, although this is not universal.
Three of the four trials comparing bicalutamide with castration used the lower 50mg dose. In these studies sexual dysfunction was reported as part of a quality of life assessment. Cyproterone acetate and flutamide did not differ significantly in their effects on sexual activity, with over 70% of patients experiencing a loss of sexual activity.
Only one study comparing non-steroidal anti-androgens with castration reported results for liver dysfunction. In that trial there was no significant difference in liver toxicities. The trial was small and would not have been sufficiently powered to detect significant differences in the incidence of rare events, such as liver dysfunction. Its findings contrast with warnings of an increased risk of liver toxicities with anti-androgens, which are acknowledged in product information documents and apparent in trials comparing CAB with castration. This apparent anomaly highlights the paucity and possible limitations of the randomised evidence for this adverse event and more broadly, the importance of reporting adverse events to agencies such as the Adverse Drug Reactions Advisory Committee (ADRAC) and post-marketing surveillance. Liver toxicity was significantly higher with flutamide compared with cyproterone acetate.The incidence of abnormal liver function tests did differ significantly when flutamide was compared with bicalutamide.
In all five RCTs there was a significantly lower risk of hot flushes with non-steroidal anti-androgens compared with castration. The incidence of hot flushes did not differ significantly between cyproterone acetate and flutamide or bicalutamide and flutamide.
Gynaecomastia and breast tenderness
In all five RCTs there was a significantly higher risk of gynaecomastia and/or breast tenderness with non-steroidal anti-androgens compared with castration. The incidence of gynaecomastia was also significantly higher with flutamide compared with cyproterone acetate.
Three of the five studies showed a significant increase in gastrointestinal adverse events with bicalutamide compared with castration. Flutamide was associated with a higher risk of diarrhoea when compared with bicalutamide.
One of two trials found increased asthenia with bicalutamide compared with castration and, for patients also receiving leuprolide, flutamide carried a significantly higher risk of anaemia than bicalutamide
No increase in cardiovascular mortality was reported in non-oestrogen trials. This concern is more relevant for patients treated for risk relevant disease with rising PSA, no metastases and expected indolent course, rather than patients with metastatic disease needing anti-cancer therapy to prolong overall survival and prevent cancer complications.
Although there are no randomised cognition studies of patients with metastatic prostate cancer, those few undertaken with patients with non-metastatic disease are applicable. Thus a significant proportion of patients receiving ADT can be expected to have adverse cognitive changes such as impaired memory, attention and executive functions.
The fact that toxicities are only secondary end-points in most studies and the uncertain influence of industry (e.g. to possibly downplay the significance in data analysis and reporting) in many of the trials raise the possibility that toxicities are understated, as substantiated by the relative recent awareness of some of these problems (as mentioned above).
As stated above, many of the trials published do not relate to the Australian health care environment. Bilateral orchidectomy and LHRH analogue therapy are recognised and approved by the PBS for ADT monotherapy, as is the steroidal anti-androgen cyproterone acetate and non-steroidal agents bicalutamide, flutamide and nilutamide. However, because of its toxicity profile, cyproterone is not recommended by several bodies to be suitable as first-line ADT therapy (either alone or in combination with castration). The anti-androgens bicalutamide and flutamide are approved for use in combination with LHRH agonists (to offset flare effect and as part of CAB as a longer-term strategy), with nilutamide also approved for use with bilateral orchidectomy to achieve CAB.
Evidence summary and recommendations
|Castration did not significantly increase cardiovascular mortality (two trials). However, it did cause a significant decrease in haemoglobin levels (one trial).||II||, , , |
|The addition of non-steroidal anti-androgens to castration can result in an additive increase in toxicities that impair quality of life, such as hot flushes and gynaecomastia, as well as liver function
abnormalities. With respect to the most common unwanted effects of androgen deprivation therapy:
|II||, , , , , , , , , , , , , , , , , , , , , , , |
|Complications and cumulative treatment toxicity). This will permit the commencement and nature of treatment to be tailored and allow an assessment of the cause of adverse effects if they emerge. The common side effects need to be discussed with the patient before commencing any ADT.
The benefits of androgen deprivation therapy in controlling a patient’s cancer outweigh the ADT adverse-event profile. However, given the clinically relevant and quality-of-life impairing litany of unwanted effects of ADT, the timing of commencement of ADT as a palliative treatment needs to be considered carefully. Assessment of liver function tests, risk of osteoporosis and bone density measurements as required is recommended. Baseline information on what is important to each individual patient should be ascertained (refer ||C|
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- ↑ 2.0 2.1 The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. Br J Urol 1997 Feb;79(2):235-46 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9052476.
- ↑ 3.0 3.1 Kirk D. Immediate vs. deferred hormone treatment for prostate cancer: how safe is androgen deprivation? BJU International 2000.
- ↑ Studer UE, Hauri D, Hanselmann S, Chollet D, Leisinger HJ, Gasser T, et al. Immediate versus deferred hormonal treatment for patients with prostate cancer who are not suitable for curative local treatment: results of the randomized trial SAKK 08/88. J Clin Oncol 2004 Oct 15;22(20):4109-18 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15483020.
- ↑ 5.0 5.1 Iversen P, Christensen MG, Friis E, Hornbøl P, Hvidt V, Iversen HG, et al. A phase III trial of zoladex and flutamide versus orchiectomy in the treatment of patients with advanced carcinoma of the prostate. Cancer 1990 Sep 1;66(5 Suppl):1058-66 Available from: http://www.ncbi.nlm.nih.gov/pubmed/2144207.
- ↑ 6.0 6.1 Akaza H, Yamaguchi A, Matsuda T, Igawa M, Kumon H, Soeda A, et al. Superior anti-tumor efficacy of bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist monotherapy as first-line treatment for advanced prostate cancer: interim results of a randomized study in Japanese patients. Jpn J Clin Oncol 2004 Jan;34(1):20-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15020659.
- ↑ 7.0 7.1 Tyrrell CJ, Altwein JE, Klippel F, Varenhorst E, Lunglmayr G, Boccardo F, et al. A multicenter randomized trial comparing the luteinizing hormone-releasing hormone analogue goserelin acetate alone and with flutamide in the treatment of advanced prostate cancer. The International Prostate Cancer Study Group. J Urol 1991 Nov;146(5):1321-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/1834864.
- ↑ 8.0 8.1 Eisenberger MA, Blumenstein BA, Crawford ED, Miller G, McLeod DG, Loehrer PJ, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 1998 Oct 8;339(15):1036-42 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9761805.
- ↑ 9.0 9.1 Dijkman GA, Fernandez del Moral P, Debruyne FM, Janknegt RA. Improved subjective responses to orchiectomy plus nilutamide (anandron) in comparison to orchiectomy plus placebo in metastatic prostate cancer. International Anandron Study Group. Eur Urol 1995;27(3):196-201 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7601182.
- ↑ 10.0 10.1 10.2 Boccon-Gibod L, Fournier G, Bottet P, Marechal JM, Guiter J, Rischman P, et al. Flutamide versus orchidectomy in the treatment of metastatic prostate carcinoma. Eur Urol 1997;32(4):391-5; discussion 395-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9412794.
- ↑ 11.0 11.1 11.2 Chodak G, Sharifi R, Kasimis B, Block NL, Macramalla E, Kennealey GT. Single-agent therapy with bicalutamide: a comparison with medical or surgical castration in the treatment of advanced prostate carcinoma. Urology 1995 Dec;46(6):849-55 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7502428.
- ↑ 12.0 12.1 12.2 Kaisary AV, Tyrrell CJ, Beacock C, Lunglmayr G, Debruyne F. A randomised comparison of monotherapy with Casodex 50 mg daily and castration in the treatment of metastatic prostate carcinoma. Casodex Study Group. Eur Urol 1995;28(3):215-22 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8536775.
- ↑ 13.0 13.1 Tyrrell CJ. Tolerability and quality of life aspects with the anti-androgen Casodex (ICI 176,334) as monotherapy for prostate cancer. International Casodex Investigators. Eur Urol 1994;26 Suppl 1:15-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7537664.
- ↑ Iversen P, Tyrrell CJ, Kaisary AV, Anderson JB, Baert L, Tammela T, et al. Casodex (bicalutamide) 150-mg monotherapy compared with castration in patients with previously untreated nonmetastatic prostate cancer: results from two multicenter randomized trials at a median follow-up of 4 years. Urology 1998 Mar;51(3):389-96 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9510340.
- ↑ 15.0 15.1 Thorpe SC, Azmatullah S, Fellows GJ, Gingell JC, O'Boyle PJ. A prospective, randomised study to compare goserelin acetate (Zoladex) versus cyproterone acetate (Cyprostat) versus a combination of the two in the treatment of metastatic prostatic carcinoma. Eur Urol 1996;29(1):47-54 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8821690.
- ↑ 16.0 16.1 16.2 16.3 Schröder FH, Whelan P, de Reijke TM, Kurth KH, Pavone-Macaluso M, et al. Metastatic prostate cancer treated by flutamide versus cyproterone acetate. Final analysis of the "European Organization for Research and Treatment of Cancer" (EORTC) Protocol 30892. Eur Urol 2004 Apr;45(4):457-64 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15041109.
- ↑ 17.0 17.1 Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, et al. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Casodex Combination Study Group. Urology 1995 May;45(5):745-52 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7538237.
- ↑ 18.0 18.1 Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, et al. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Casodex Combination Study Group. Urology 1997 Sep;50(3):330-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9301693.
- ↑ 19.0 19.1 Sarosdy MF, Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, et al. Comparison of goserelin and leuprolide in combined androgen blockade therapy. Urology 1998 Jul;52(1):82-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9671875.
- ↑ 20.0 20.1 Iversen P, Tveter K, Varenhorst E. Randomised study of Casodex 50 MG monotherapy vs orchidectomy in the treatment of metastatic prostate cancer. The Scandinavian Casodex Cooperative Group. Scand J Urol Nephrol 1996 Apr;30(2):93-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8738052.
- ↑ 21.0 21.1 21.2 Schröder FH, Collette L, de Reijke TM, Whelan P. Prostate cancer treated by anti-androgens: is sexual function preserved? EORTC Genitourinary Group. European Organization for Research and Treatment of Cancer. Br J Cancer 2000 Jan;82(2):283-90 Available from: http://www.ncbi.nlm.nih.gov/pubmed/10646878.
- ↑ Tyrrell CJ, Kaisary AV, Iversen P, Anderson JB, Baert L, Tammela T, et al. A randomised comparison of 'Casodex' (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer. Eur Urol 1998;33(5):447-56 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9643663.
- ↑ Brisset JM, Boccon-Gibod L, Botto H, Camey M, Cariou G, Duclos JM, et al. Anandron (RU 23908) associated to surgical castration in previously untreated stage D prostate cancer: a multicenter comparative study of two doses of the drug and of a placebo. Prog Clin Biol Res 1987;243A:411-22 Available from: http://www.ncbi.nlm.nih.gov/pubmed/3309973.
- ↑ Béland G, Elhilali M, Fradet Y, Laroche B, Ramsey EW, Trachtenberg J, et al. Total androgen ablation: Canadian experience. Urol Clin North Am 1991 Feb;18(1):75-82 Available from: http://www.ncbi.nlm.nih.gov/pubmed/1992574.
- ↑ Ferrari P, Castagnetti G, Ferrari G, Pollastri CA, Tavoni F, Dotti A. Combination treatment in M1 prostate cancer. Cancer 1993 Dec 15;72(12 Suppl):3880-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8252509.
- ↑ Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989 Aug 17;321(7):419-24 Available from: http://www.ncbi.nlm.nih.gov/pubmed/2503724.
- ↑ Zalcberg JR, Raghaven D, Marshall V, Thompson PJ. Bilateral orchidectomy and flutamide versus orchidectomy alone in newly diagnosed patients with metastatic carcinoma of the prostate--an Australian multicentre trial. Br J Urol 1996 Jun;77(6):865-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8705223.
- ↑ Schulze H, Kaldenhoff H, Senge T. Evaluation of total versus partial androgen blockade in the treatment of advanced prostatic cancer. Urol Int 1988;43(4):193-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/2973169.
- ↑ Bono AV, DiSilverio F, Robustelli della Cuna G, Benvenuti C, Brausi M, Ferrari P, et al. Complete androgen blockade versus chemical castration in advanced prostatic cancer: analysis of an Italian multicentre study. Italian Leuprorelin Group. Urol Int 1998;60 Suppl 1:18-24 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9563140.
- ↑ Denis LJ, Keuppens F, Smith PH, Whelan P, de Moura JL, Newling D, et al. Maximal androgen blockade: final analysis of EORTC phase III trial 30853. EORTC Genito-Urinary Tract Cancer Cooperative Group and the EORTC Data Center. Eur Urol 1998;33(2):144-51 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9519355.