Has TOAD resolved a real and long-standing question?

So TOAD stands for “Timing of Androgen Deprivation” and refers to a randomized, multi-center, Phase III trial carried out in Australia, New Zealand, and Canada between September 3, 2004, and July 13, 2012. And the real and long-standing question is this one:

  • Does early use of androgen deprivation therapy (ADT) in men with progressive, non-metastatic prostate cancer extend patient survival?

This is by no means the first time people have tried to answer this question, and to date the results have been mixed (see for example, the data published by the Medical Research Council in 1997, by Messing et al. in 2006, and by Schröder et al. in 2009).

The results of the TOAD trial have recently been reported by Duchesne et al. in The Lancet Oncology.

TOAD was a complex trial that enrolled 293 patients and randomized them to immediate or delayed ADT. These 293 patients fell into one or other of two groups:

  • Group 1: Men with PSA relapse after initial curative therapy (n = 261)
  • Group 2: Men considered to have non-curable disease at initial diagnosis (n = 32), but excluding any men with evident metastatic disease.

Why was it complex? Because the forms of androgen deprivation that could be used were left almost entirely to the discretion of the treating physicians and their patients. They could therefore include surgical orchiectomy, continuous LHRH agonist therapy, intermittent LHRH agonist therapy, etc.. The only serious constraints appear to have been the following:

  • The form of ADT to be used had to be disclosed to the patient prior to randomization.
  • It was recommended that delayed ADT be started no earlier than 2 years after randomization (unless started earlier for clinical symptoms, evidence of metastasis, or a PSA doubling time of 6 months or less).
  • A specific schedule needed to be followed for patients on intermittent ADT.

The use of these differing management options is both a good thing (it is more like the real world) and a less good thing (one is less likely to be comparing apples to apples).

The authors are also clear about two key limitations of the study: (1) It took a lot longer than expected to accrue and enroll the necessary number of patients, because only about a third of the eligible patients were willing to participate. (2) Many eligible post-surgical patients may not have been screened for eligibility because the majority of recruiting study sites were radiation oncology centers.

The primary endpoint for the study was overall survival from time of randomization to time of death, and there was a whole spectrum of secondary endpoints, including quality of life measures. The final cutoff for data collection in the study was on February 26, 2014, which meant that every patient enrolled in the study was followed for at least 18 months or longer.

So … what did Duchesne and her colleagues discover?

Here are the major findings (and there are a lot of them):

  • Of the 293 patients enrolled,
    • 142 men were randomized to immediate therapy
    • 151 men were randomized to deferred therapy
  • Men with PSA relapse (Group 1) were, on average, about 9 years younger than the men with non-curable disease (Group 2).
  • Among the men in Group 1,
    • 77/261 (29.6 percent) had had a relapse-free interval of < 2 years.
    • 117/261 (44.8 percent) had a PSA doubling time of < 10 months.
  • Average (median) follow-up was 5.0 years.
  • With regard to types of therapy,
    • About two-thirds of participating physicians chose to treat the patients with intermittent ADT.
    • 182/229 men (79.4 percent) who received ADT were initially treated with LHRH monotherapy, followed by other other agents (e.g., an antiandrogen) as appropriate.
    • 27/229 men (11.7 percent) who received ADT were treated with maximal androgen deprivation (an LHRH agonist + an antiandrogen)
    • 11/229 men (4.8 percent) who received ADT were treated with cyproterone acetate or antiandrogen monotherapy.
    • 9/229 men (3.9 percent) who received ADT were treated with an LHRH antagonist.
    • No patient was treated with surgical orchiechtomy.
  • 46/293 patients (15.7 percent) died during the course of the trial.
    • 16/142 (11.3 percent) in the immediate therapy arm
    • 30/151 (19.8 percent) men in the delayed therapy arm
  • A difference between overall survival rates first became evident at 5 years of follow-up.
  • By 7 years of follow-up, estimated overall survival rates were
    • 81.0 percent in the immediate therapy arm
    • 65.5 percent in the delayed therapy arm
  • 18/293 patients (6.1 percent) died of prostate cancer during the course of the trial.
    • 6/142 (4.2 percent) in the immediate therapy arm
    • 12/151 (7.9 percent) in the delayed therapy arm
    • All 18 patients came from Group 1.
  • Times to either local or distant progression  were longer in men treated with immediate therapy.
    • 18/140 patients (12.8 percent) had local progression while on immediate therapy.
    • 30/150 patients (20.0 percent) had local progression while on delayed therapy.
    • The adjusted hazard ratio (aHR) for time to local progression was 0.51 (p = 0.001).
    • 27/140 patients (19.3 percent) had distant progression while on immediate therapy.
    • 30/150 patients (20.0 percent) had distant progression while on delayed therapy.
  • 41 percent of patients  in the delayed therapy arm did not reach a trigger point for initiation of therapy within 2 years (as defined above).
  • Castration-resistant prostate cancer developed in
    • 45/141 patients (31.9 percent) in the immediate therapy arm
    • 37/89 patients receiving therapy (41.6 percent) in the delayed therapy arm
  • ADT-related symptoms of prostate cancer were reported by < 75 percent of men who actually received ADT,
    • 31/140 patients (22.1 percent) who actually received ADT in the immediate therapy arm
    • 19/89 patients (21.3 percent) who actually received ADT in the delayed therapy arm
  • At least one adverse event related to ADT was reported by
    • 109 patients (78 percent) who actually received ADT in the immediate therapy arm
    • 70 patients (47 percent) who actually received ADT in the delayed therapy arm
  • Differences in quality of life between men on the immediate and delayed therapy arms were small.

Duchesne and her colleagues draw a small but important set of conclusions from these data:

  • Overall patient survival was significantly longer among men treated with immediate as opposed to delayed ADT.
  • The TOAD trial showed a significant benefit to immediate ADT for almost every predefined outcome, with the notable exception of prostate cancer-specific survival (where the numbers of deaths in each arm were very low).
  • Global quality of life deteriorated more, in the first 2 years of the trial, by a small but clinically significant amount, among the men treated with immediate ADT.
  • These data provide important information that can be used to inform conversations between doctors and their patients about the relative risks and benefits of immediate and delayed ADT in management of progressive, non-metastatic disease.

In all honesty it is very hard to interpret the potential impact of this trial. On the one hand it has clearly shown that immediate therapy is associated with an improved rate of overall survival compared to delayed therapy. This effect appears to have “kicked in” at about 5 years after randomization. On the other hand, the numbers of men dying of prostate cancer in this trial are very small indeed, so what is really going on? And then there is the whole question of whether the wide range of types of therapy also affected the possible outcomes in this trial.

To the “New” Prostate Cancer InfoLink, the TOAD trial looks like a brave effort to solve a complex question that could have done with two or three times the number of patients who were enrolled within a much shorter time frame, thus allowing for more like a 10-year median follow-up. But then it’s always easy to be wise after the event.

Editorial comment: The “New” Prostate Cancer InfoLink thanks Prof. Gillian Duchesne of the Peter MacCallum Cancer Centre and Melbourne University in Melbourne, Victoria, Australia, for kindly and promptly providing us with the full text of this article for our careful evaluation.

3 Responses

  1. For anyone wondering, I believe ‘delayed’ is defined (in the abstract) as a 2-year interval from immediate intervention unless clinically contraindicated.

  2. Rick:

    That is correct, as I carefully stated in the article above. :O)

  3. Whoops — apologies. … I read through a couple of times and missed it — but not this time!

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