Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. - Beyond the Abstract

The results delivered by this trial have been both unexpected and thought-provoking. Despite the fact that the trial recruitment was prolonged and fell well short of its target, the results are clinically and statistically in favour of immediate intervention when survival and disease progression end points are considered, with hazard ratios around the 0.5 mark. The key clinical point is that we can now advise men what likely lies ahead of them, who is at greater risk if delaying treatment, and what delays they might achieve if that is their choice.

The results also add further weight to the hypothesis that treating small volume or occult disease is more effective than treating overt disease. This trial was predominantly for patients who had failed curative treatments, but who had only microscopic disease at randomization. This concept obviously underpins the use of adjuvant therapy, but here we are treating only those known to have disease, rather than the whole population most of whom would not benefit from adjuvant therapy. PSA as an early harbinger of relapse is useful indeed.

Where the unexpected results are concerned, we have the following: firstly that the effects on overall survival are not just from a reduction in prostate cancer deaths but also from deaths from other causes. Other trials have also shown this, which suggests a real finding, the causes of which remain unclear. Secondly, the effects on global health-related quality of life, at least over the first two years, showed no major difference between immediate and delayed therapy, meaning that men may choose to start relatively early with major detriment. This may relate to the use of intermittent schedules for two thirds of both arms, which did not appear to have an impact on disease control (data not shown in the publication), despite the lack of firm evidence supporting its use. An exploratory unplanned analysis in fact suggested that the highest survival rate was seen in men treated with immediate intermittent therapy.

One of the most thought-provoking findings was that the development of the castration-resistant phase occurred significantly earlier in the men who started treatment after a delay, a counter-intuitive finding. This may again be linked to treating low volume disease before it grows resistant clones.

We are undertaking two further major analyses, the long-term detailed quality of life, and the combined analysis with the Canadian ELAAT trial, to add further evidence in this arena.

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Author: Prof Gillian Duchesne Radiation Oncologist
Professor, Radiation Oncology Research