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Suspension of ADT in patients with a long-term, stable response to treatment

Posted Jul 20 2010 12:00am

There has long been discussion about the theoretical possibility of suspending androgen deprivation therapy (ADT) in men with a long-term, stable response to this form of hormonal therapy. However, there have been few long-term data reported on responses to this strategy.

Castagneto et al. have reported on the outcomes of 44 patients with advanced prostate cancer all ≥ 60 years of age who had prolonged clinical and biochemical responses to ADT and came off therapy.

Their data are based on a series of 371 consecutive patients, all diagnosed with advanced prostate cancer and treated with ADT. Of these 371 patients, 44 older men were defined as having a long-term, stable response to treatment, including no significant pain or difficulty on urination (dysuria), a normal DRE, and a PSA level < 0.50 ng/ml. Androgen deprivation was initially given as goserelin acetate alone in 11/44 patients and as goserelin acetate + flutamide in 33/44 patients.

ADT was suspended in these 44 patients with the understanding that it would be re-initiated if: (a) there was any onset of dysuria; (b) there was a positive DRE result; (c) the patient’s PSA rose to > 10 ng/ml (or above pre-treatment values if these were < 10 ng/ml). In addition, disease progression was defined as a two consecutive increases in the patient’s PSA level, evidence of new lesions, and/or evidence of progression on the basis of a DRE.

The results of this small study are given below:

  • The median age of the 44 patients was 78.5 years (range, 60 to 88 years) at the time of cessation of ADT.
  • Clinical stages of the patients at the time of initial treatment with ADT were: T3/4NxM0 = 15; TxN1Mo = 4; TxNxM1 = 25.
  • 27/44 patients (61.4 percent) resumed ADT after a period of time off therapy.
  • 14/44 patients (31.8 percent) showed disease progression after a median follow-up of 93.9 months (nearly 8 years) after coming off ADT and 7/14 patients with disease progression died.
  • 7/44 patients (15.9 percent) had serum testosterone levels that never exceeded 0.5 ng/ml, indicating an absence of gonadal activity.
  • The median time to resumption of therapy was 30.8 months from cessation of ADT.
  • The median time to disease progression (for all 44 patients) was 138.2 months (> 11 years) from the start of ADT and 85.6 months ( > 7 years) from the time of cessation of ADT.
  • The median cumulative survival (for all 44 patients) from the start of ADT was 105.5 months (> 9 years) from the start of ADT and 64.1 months (> 5 years) from the time of cessation of ADT.
  • 9/44 patients died after coming off ADT but before disease recurrence or resumption of treatment.

What can we reasonably conclude from the data presented by Castagneto and his colleagues?

Well first, it is clear that there is a significant subset of men, known or assumed to have at least micrometastatic disease at the time of initiation of hormone therapy, who reach a stable status after initiation of hormone therapy. If the data from this study are to be believed, it is about 12 percent of all patients who start on hormone therapy who are assumed to have at least micrometastic disease.

Second, as Castagneto et al. note in their paper, these patients are at risk for over-treatment with hormone therapy after their disease stabilizes. In  other words, they are at high risk for metabolic syndrome, skeletal-related events, and other complications of hormone therapy relative to any actual benefit of the ADT.

Third, in these patients, intermittent use of hormone therapy clearly works, because Casegnato et al. report that 11/44 patients were able to suspect ADT for a second cycle, and 5/44 patients were able to suspend it for a third cycle.

Fourth, the researchers also note that the median cumulative survival of these patients (105 months from the start of ADT) is comparable to the normal life expectancy of a similar group of 75-year-old Italian men (108 months). In other words, Italian men with prostate cancer that is assumed to be at least micrometastatic at the time of initiation of ADT, and who achieve a stable response to this treatment, have a similar total lifespan as the average 75-year-old Italian if their hormone therapy is stopped after they have stable disease.

Last the researchers also point out that, even in this relatively small group of men, there was a major cost saving associated with stopping hormone therapy. The researchers estimate this at more than €750,000 (roughly US$1 million) or about  €17,000 per patient which is a significant amount of money when looked at from a payer’s point of view.

The expanded use of intermittent hormone therapy in the USA over the past decade has probably limited the practical application of the data from this study in the USA, but it does reinforce the idea that many men with stable disease at some point after initiation of hormone therapy (say 12-15 months?) may be candidates for stopping their therapy, at least on an interim basis, to see if their PSA remains within well-defined limits (while checking to ensure that there are no other signals of urinary bother or disease progression).

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