Clinical Practice Guidelines for the management of locally advanced ...

Increased impotence, hot flushes, gynaecomastia and breast pain, together with tiredness and asthenia
were also commonly reported with bicalutamide. 6, 22 There was an increased risk of nausea and
vomiting with flutamide. 23
When compared with castration, the non-steroidal anti-androgen, bicalutamide, had similar effects on
lipid levels 25 , resulted in a smaller increase in body fat mass 24 , fewer hot flushes, a lower incidence of
decreased libido but an increased incidence of breast changes 11,24,25 . 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. 24,25
Short-term CAB was reported not to cause significant increases in cardiovascular mortality 26-28, 30, 31 ,
severe gynecomastia or liver function abnormalities 30 , however in another study 17% of patients who
received the anti-androgen flutamide as part of their CAB discontinued flutamide because of liver
toxicity. 26-28 For a more comprehensive comparison of ADT and castration toxicities see section 5.1.4
Toxity. 26-28
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 32 , 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. 33 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.
Clinical practice guidelines for the management of locally advanced and metastatic prostate cancer
20