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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