Health-related quality of life for immediate versus delayed androgen-deprivation therapy in patients with asymptomatic, non-curable prostate cancer (TOAD): a randomised, multicentre, non-blinded, phase 3 trial: Beyond the Abstract

The publication “Health-related quality of life for immediate versus delayed androgen-deprivation therapy in patients with asymptomatic, non-curable prostate cancer (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial”1 is the companion paper to the survival results2 for the TOAD (timing of androgen deprivation) prostate cancer trial published last year in the Lancet Oncology.

The main question being addressed by the trial, which commenced back in 2004, was whether starting androgen deprivation therapy (ADT) immediately upon the diagnosis of PSA relapse after definitive treatment, rather than waiting for further progression, would prolong survival. (A small subgroup of participants consisted of asymptomatic men with newly diagnosed cancer who were not going for curative treatment). The results of the trial, although it was underpowered, suggested that the immediate approach did offer a survival advantage, particularly for men with poorer risk factors at relapse (rapid PSA doubling time or short relapse-free interval), who tended to need to start ADT relatively soon anyway. The counter-balance of any survival gain is of course the potential detriment in health-related quality of life (HRQOL) related to treatment toxicity. We therefore asked the trial participants to complete quality of life questionnaires (EORTC QLQ-C30 and PR-25) prior to randomisation and on seven subsequent occasions over five years. We achieved over 90% response rate across the five years, giving validity to our findings.

No statistically or clinically significant differences in global quality of life or in physical, role or emotional functioning, were found between the immediate and delayed trial arms over the five year period from trial entry. When examining those HRQOL domains relating to possible toxicity of treatment, men starting immediate therapy had clinically significant HRQOL detriments, to be expected, from hot flushes, nipple tenderness or enlargement and lower levels of sexual activity than those in the delayed arm. These differences were evident early, but had essentially disappeared after about two years, reflecting increasing numbers of men in the delayed arm who started therapy, or perhaps ongoing ageing in this older age-group. Interestingly, there were no differences found in the prevalence of ‘feeling less masculine’ or in sexual functioning for those who were sexually active, but low levels of sexual activity were reported in both arms. No other differences were noted.

These findings are interesting for several reasons. This is a group of men who have already experienced a cancer diagnosis, and who have undergone attempted curative therapy that has failed. They may have already experienced a significant detriment in HRQOL related to their primary therapy, followed by a diagnosis of relapse, albeit early and asymptomatic. The low levels of sexual activity in both arms prior to randomisation or to the introduction of hormonal therapy attests to both the effects of prior treatment and possibly to the age-group of this cohort (a median age of 70+ years), although we do not have a control group of men of this age without prostate cancer to compare. It may be that the overall quality of life in the immediate therapy group might have been favourably influenced by the perception that their disease was being brought under control and that nuisance side-effects from therapy were worth putting up with.

The questionnaire responses indicated that up to 20% of men on androgen deprivation therapy (ADT) did not experience any particular ‘bother’. The other side of this coin is that some men may experience profound distress when on ADT, a point emphasised in the accompanying editorial by Dr Saad3, and that this might go unrecognised when undertaking standard statistical analyses of the whole cohort. We have not yet looked at individual responses from the participants to address this question, however it should be remembered that these are men with significant HRQOL detriments from prior therapy, such as reduced sexual function, and adding another insult to such injury might not have a large incremental effect. We also permitted intermittent ADT protocols, which may have lessened the overall impact of ADT on participants. It must also be noted that the majority of these men will need to embark on ADT for disease control at some stage (60% by 5 years), so it is perhaps a question of when rather than if at all.

It is always appropriate to try and tailor patient management to the severity of the condition. Men facing this treatment choice need to know what their risks of rapid progression are to add to the equation of benefit versus risk. We found that a rapid PSA doubling time at the time of relapse (less than 10 months, which was the cut-off defined when the protocol was developed in 2003), or a relapse-free interval after primary treatment shorter than two years were significant predictors of starting therapy in the delayed group earlier than the protocol-recommended interval. For these men particularly, it can be argued that the potential survival gain of early intervention would outweigh any HRQOL benefit from delaying treatment a few months or so.

In summary, we have provided useful information to discuss future management options with this group of patients, in terms of the likely HRQOL effects of treatment and the natural history of disease progression without intervention depending on an individual’s disease profile.

Read the Abstract

Written By: Gillian M Duchesnea and Henry H Woob

aDepartment of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
bSydney Adventist Hospital Clinical School, University of Sydney, Sydney, NSW, Australia

References
1. Duchesne GM, Woo HH, King MT, Bowe SJ, Stockler MR, Ames AG, D’Este C, Frydenberg M, Loblaw A, Malone S, Millar J, Tai KH, Turner S. Health-related quality of life outcomes from the Timing of Androgen Deprivation Therapy (TOAD) randomised, multicentre, non-blinded, phase 3 trial (TROG 03.06 and VCOG PR 01-03) for asymptomatic incurable prostate cancer patients. The Lancet Oncology Published on line 28 July 2017 http://dx.doi.org/10.1016/S1470-2045(17)30426-6

2. Duchesne GM, Woo HH, Bassett J, Bowe S, D’Este C, Frydenberg M, King M, Ledwich L, Loblaw A, Malone S, Millar J, Milne R, Smith R, Spry N, Stockler M, Syme R, Tai KH, Turner S. TROG 03.06 and VCOG PR 01-03:  the ‘Timing of androgen deprivation therapy in prostate cancer patients with a rising PSA (TOAD)’ collaborative randomised Phase III trial. The Lancet Oncology 17 (6), 727-737, 2016.

3. Saad F.  Androgen deprivation in prostate cancer: first do no harm. The Lancet Oncology. Published on line 28 July 2017. http://dx.doi.org/10.1016/PII
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