Are there differences between the different hormone therapy methods in the pattern and severity of toxicity effects for non metastatic disease?

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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.[1][2] 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[3][4] [5][6][7][8]; two compared long-term anti-androgen therapy with no ADT[9] [10][11] three compared castration with long-term anti-androgen therapy[12][13] [14] and three compared short-term CAB with no ADT.[15][16][17][18][19]

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.[3][4][5][6] Bicalutamide (anti-androgen) was associated with a significantly increased likelihood of heart failure in one study (risk ratio = 1.96).[20][10]

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[5] and LHRH agonists were associated with cognitive impairment.[7][8]

Increased impotence, hot flushes, gynaecomastia and breast pain, together with tiredness and asthenia were also commonly reported with bicalutamide. [20][10] There was an increased risk of nausea and vomiting with flutamide.[11]

When compared with castration, the non-steroidal anti-androgen, bicalutamide, had similar effects on lipid levels[14], resulted in a smaller increase in body fat mass[13], fewer hot flushes, a lower incidence of decreased libido but an increased incidence of breast changes[12][13][14]. 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.[13][14]

Short-term CAB was reported not to cause significant increases in cardiovascular mortality[15][16][17][19] [21]severe gynecomastia or liver function abnormalities[19] however in another study 17% of patients who received the anti-androgen flutamide as part of their CAB discontinued flutamide because of liver toxicity.[15][16][17] For a more comprehensive comparison of ADT and castration toxicities see section on Toxity.[15][16][17]

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[22], 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.[23] 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.

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Evidence summary and recommendations

Evidence summary Level References
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 [3], [4], [5], [6], [7], [8], [10], [11], [20]
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 [12], [13], [14]
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 [12], [13], [14]
Three trials showed no significant increase in cardiovascular mortality with short-term CAB. II [15], [16], [17], [19], [24]

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.

Evidence-based recommendationQuestion mark transparent.png Grade
It is recommended that the prescriber take into account the following points when commencing ADT:
  • The use of non-steroidal anti-androgens as monotherapy may have fewer and less severe adverse events than medical or surgical castration but may still have a toxicity profile that impairs quality of life, and there is little to no efficacy data to support their use as monotherapy.
  • Extrapolating from evidence with metastatic disease (see Overt metastatic disease and/or loco-regional progressive disease), Combined androgen blockade (CAB) with an antiandrogen does increase the adverse event profile versus medical or surgical castration monotherapy and this needs to be weighed up against its marginal additional survival benefits seen in patients with metastatic disease.
  • When the unwanted effects of treatment are preferable to the unwanted effects of the tumour (e.g. prevent recurrence with increased overall survival in adjuvant setting), the side-effect profiles of the treatment options should be explained and strategies to minimise these effects should be considered with the patient.
B


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References

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  2. 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.
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