Weight up the risks and benefits of IAD in prostate cancer
Intermittent androgen deprivation (IAD) resulted in fewer side-effects from hormonal therapy, compared with continuous therapy, but a shorter time to progression of prostate cancer in a randomised trial.
Patients with locally advanced or metastatic prostate cancer were randomised to receive either IAD or conventional continuous therapy. A total of 766 patients entered the study and after a 3-month induction period 626 patients (whose PSA had dropped either below 4ng/ml or to 80% below their initial value) were randomised. The primary outcome measure was time to progression (e.g. development of new metastases or biochemical progression with serial rises of PSA of >20% per month). Secondary outcome measures were survival and quality of life.
There was a higher number of progressions in the IAD arm of the study, 127 compared with 107 in the continuous arm, and the time to progression was longer in the continuous arm (HR of progression 0.81 (95% CI: 0.63-1.05; p=0.11). There were 170 deaths in the intermittent group and 169 in the continuous group. The study was unable to detect any difference in overall survival. However, there were more prostate cancer deaths in the IAD group, 23.6% (74) compared with 20.8% (65) in the continuous group. This was balanced by a higher number of deaths from cardiovascular disease and other causes in the continuous arm.
The side-effects of androgen deprivation were reduced in the IAD arm, particularly hot flushes and sexual dysfunction, but without a placebo arm in the study it is difficult to know how much of this reduction is a genuine benefit of IAD.
Interestingly, overall quality of life (on both generic and disease specific questionnaires) was not seen to change as a result of IAD.
Hormonal therapy for prostate cancer results in significant side- effects of androgen deprivation (e.g. sexual dysfunction, fatigue, osteoporosis etc), and will often eventually end in tumour cells developing androgen independence, resulting in rising PSA levels despite continued treatment.
The concept of intermittent androgen deprivation (IAD), as discussed in an editorial accompanying this paper in European Urology, is an example of ‘conventional wisdom' over evidence- based medicine. The technique is widely used despite a limited evidence base. The principle is that in a patient with established prostate cancer, hormone therapy is used until PSA levels reach a predefined nadir (e.g. <1.0), at which time therapy is discontinued. PSA levels are monitored monthly and hormone deprivation reintroduced when the PSA rises above another pre-defined level (e.g. >4.0). This theoretically has two advantages – first, decreased side-effects of androgen deprivation, and second prolongation of the time to androgen independence, as seen in animal studies.
For advocates of IAD the results of this study will clearly be disappointing, given the finding of shorter time to progression. The study authors conclude that IAD ‘should be considered for use in routine practice because it is associated with no reduction in survival, no clinically meaningful impairment in quality of life, better sexual activity, and considerable economic benefit to the individual and the community'. An accompanying editorial, however, concludes ‘we should only offer IAD in selected, well-informed cases and surely not acknowledge it as standard treatment in all patients'.
It would seem that IAD represents an option for patients who have prostate cancer that is highly sensitive to androgen deprivation, as represented by low PSA readings while on treatment, particularly those with a high side-effect burden that may benefit from a ‘hormone holiday'. The widespread use of IAD, however, remains to be justified by clinical evidence.
• Calais da Silva F, Bono AV, Whelan P et al. Intermittent androgen deprivation for locally advanced and metastatic prostate cancer. Results from a randomised phase 3 study of the South European Uroncological group. Eur Urol 2009; 55: 1269-1277
• Tombal B. Intermittent androgen deprivation therapy: conventional wisdom versus evidence. Eur Urol 2009; 55: 1278-1280Reviewer
Dr Jonathan Rees
GPwSI Urology, Bristol