FOIU 2018: Intermittent vs. Continuous ADT

Tel-Aviv, Israel (UroToday.com) Laurence Klotz, MD gave a presentation on intermittent androgen deprivation therapy (IADT) and its association with cardiovascular disease (CVD). He began stating the many advantages of IADT:
Likely:
  1. Improved quality of life, with the recovery of testosterone (hot flashes, libido, erectile function, frailty and more)
  2. Reduced morbidity and mortality (metabolic syndrome, CV disease, diabetes, bone mineral density loss)
  3. Reduced drug costs
Potentially:
  1. Re-exposure of stem/progenitor cells to androgen may prolong the duration of androgen dependence and delay in castration resistance(demonstrated in murine models)
  2. Opportunity for integrated therapy with cell cycle directed interventions
Sex steroids have been shown to act as tumor suppressors in prostate cancer (PC) (Table 1). Klotz then showed all the phase 3 trials of IADT, including more than 100 patients (Table 2). In the PR7 trial, 1486 men with PSA recurrence were given either 8-month IADT induction cycles or continuous long-term ADT.1 This trial demonstrated no difference in both arms with regards to survival (Figure 1). No difference was seen in PC death or CVD mortality. Furthermore, in the SWOG 9346 trial randomizing patients to continuous ADT or IADT, the results were inconclusive and there was no difference in median survival between both arms. (Figure 2). 2

Table 1:  Sex steroids as tumor suppressors in prostate cancer:
UroToday FOIU2018 Sex steroids as tumor suppressors in prostate cancer

Table 2: Phase 3 trials of intermittent androgen deprivation therapy:
UroToday FOIU2018 Phase 3 trials of intermittent androgen deprivation therapy

Figure 1: PR-7 - Overall survival in intermittent and continuous ADT:
UroToday FOIU2018 Overall survival in intermittent and continuous ADT

Figure 2: SWOG 9346 – Overall survival in intermittent and continuous ADT
UroToday FOIU2018 SWOG 9346 Overall survival in intermittent and continuous ADT

The logic behind the benefits of IADT includes the fact that testosterone has favorable health benefits, and there is extensive literature on the value of testosterone replacement. The improved quality of life associated with IADT when compared to continuous ADT has been shown in a plethora of trials (Table 3).

Table 3: Improved quality of life in intermittent ADT:
UroToday FOIU2018 Improved quality of life in intermittent ADT

Klotz then discussed the recovery of testosterone in the off-treatment interval. Usually, testosterone does recover, as long as the induction period is modest (less than 1 year). Approximately 75-90% of patients recover to a normal range by 6 months. Recovery of serum testosterone to levels above 7.5 nmol/l (250 ng/dl) has been observed in 75%, 50%, 40%, and 30% of men in cycles 1-4, respectively. 3 According to Dr. Klotz, the recovery of testosterone is likely to have health benefits, which most likely include cardiovascular benefits as well. According to a population-based study comparing IADT to continuous ADT, there was a significant reduction in cardiovascular events with IADT compared to continuous ADT. 4 Additionally, there has been a published meta-analysis of a cardiovascular event in IADT vs. continuous ADT, demonstrating no difference in cardiovascular or thrombotic event rate, but reduced cardiovascular mortality with IADT. 5

Klotz concluded his great discussion reiterating that there is a clear quality of life and other health benefits in IADT, when compared to continuous ADT. IADT should be the standard treatment for non-metastatic disease and selected patients with metastatic disease. The most evidence clearly suggests that there are improved rates of cardiovascular events with IADT.

References:
1. Crook J, Klotz L. et al. NEJM 137 (10):2012
2. Hussain M. et al. NEJM 368;14 April 4, 2013
3. Bruchovsky N, Klotz L, et al.  Cancer 2007
4. Tsai HT. et al. J Urol 2017
5. Jin C. et al. prostate Cancer Prostatic Disease 2016

Presented by: Laurence Klotz, MD, Sunnybrook Health Science Center, Toronto, Ontario, Canada

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan  at the 2018 FOIU 4th Friends of Israel Urological Symposium, July 3-5. 2018, Tel-Aviv, Israel
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