Is there a difference in survival for intermittent androgen deprivation compared to continuous androgen deprivation?

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Is there a difference in survival for intermittent androgen deprivation compared to continuous androgen deprivation?

As stated previously, ADT is associated with a number of toxicities that are quality-of-life impairing and/or clinically significant and are related to prolonged exposure to castrate level of testosterone. This is particularly relevant for patients who have a good initial response to therapy that portends the potential for long-term benefit from ADT. A strategy to potentially ameliorate the toxicity is to use ADT intermittently (ie withhold when in remission and restart when regrowth occurs). It is also contended, based on preclinical models, that the cyclical exposure to ADT and testosterone will prolong the sensitivity to ADT and hence increase the efficacy of ADT. At the time of writing, the volume of evidence was limited by:

  • lack of data from reported large well-powered randomised studies, that is, the definitive studies are yet to be reported and only smaller studies have been reported
  • inclusion of locally advanced (M0) patients along with patients with evidence of metastatic disease (M1) and thus poorer prognoses
  • findings based on subgroup analyses of the use of differing hormonal therapies such as cyproterone and non-steroidal antiandrogens with LHRH agonists the use of differing hormonal therapies such as cyproterone and non-steroidal antiandrogens with LHRH agonists
  • reporting on progression-free survival whereas overall survival is the more meaningful and reliable endpoint, especially when balanced by quality-of-life data. Specifically, time to PSA (biochemical) progression as an endpoint is not clinically relevant.

The current data with all the caveats listed above have some degree of consistency as they suggest there is no detriment to intermittent versus continuous androgen deprivation. However, the data from well-powered studies are yet not mature enough to comment on improvement in overall survival and time to symptomatic progression. At best, the current data suggest there is no decrease in long-term disease control or overall survival for men with non-metastatic or metastatic disease[1][2][3][4] and that there may be an improvement in quality of life (potency, hot flushes).[2][5][6][7]

Once the final data are available they will be of major importance as a substantial number of patients with metastatic prostate cancer commencing ADT are treated with LHRH agonists (as opposed to orchidectomy) and do achieve a good initial remission with ADT. As such, the more commonly employed mode of androgen deprivation and the number of patients who would be candidates for an intermittent approach makes this an approach possibly relevant in clinical practice. Therefore the data can be directly generalised to the target population with the caveat that larger and better-powered definitive studies to quantify the benefit still await analysis. The mode of therapy required to implement intermittent ADT is readily accessible through the PBS (ie LHRH agonists), so if the definitive datasets confirm its benefit, the data will be directly applicable in the Australian health care context.

Note: Larger well-powered studies have been completed and will clarify the benefit of this approach. Thus the current statements regarding the current data are laced with caveats pending the definitive datasets.

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Evidence summary and recommendations

Evidence summary Level References
The data as of the time of the cut-off are limited but appear to suggest a benefit with lessening of some of the side effects of the androgen deprivation therapy without compromising long-term disease control. However, the quality of life data are limited by the lack of a placebo comparator. II [1], [3], [5], [5], [7]
Evidence-based recommendationQuestion mark transparent.png Grade
No formal recommendation on intermittent or continuous androgen deprivation therapy can be made based on the lack of definitive data. However, it would appear that there may be a quality of life benefit. Intermittent androgen deprivation therapy can be considered for men who (i) achieve a good remission, (ii) are destined to be on ADT for a prolonged period, and (iii) are having intolerable side effects from long-term androgen deprivation.
C


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References

  1. 1.0 1.1 de Leval J, Boca P, Yousef E, Nicolas H, Jeukenne M, Seidel L, et al. Intermittent versus continuous total androgen blockade in the treatment of patients with advanced hormone-naive prostate cancer: results of a prospective randomized multicenter trial. Clin Prostate Cancer 2002 Dec;1(3):163-71 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15046691.
  2. 2.0 2.1 Calais da Silva FE, Bono AV, Whelan P, Brausi M, Marques Queimadelos A, Martin JA, et al. Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group. Eur Urol 2009 Jun;55(6):1269-77 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19249153.
  3. 3.0 3.1 Schasfoort EMC, Heathcote P, Lock MTWT, Zerbib M, Dijkema HE, Vergunst H et al. Intermittent androgen suppression with buserelin and nilutamide for the treatment of prostate canacer patients. European Urology Supplement 2003;2(1):187.
  4. Langenhuijsen JF, Schasfoort EMC, Heathcote P, Lock MTWT Zerbib M, Dijkema HE et al. Intermittent androgen suppression in patients with advanced prostate cancer: An update of the TULP survival data. European Urology Supplement 2008 Jan 1;7(3):205.
  5. 5.0 5.1 5.2 Calais F, Bono A, Whelan P, Queimadelos M, Portillo J, Kirkali Z et al. Phase III study of intermittent MAB versus continuous MAB international cooperative study. European Urology Supplement 2002;1:135.
  6. Calais da Silva FE, Bono A, Whelan P, Brausio M, Queimadelos M, Portillo L et al. Phase 3 study of intermittent MAB versus continuous MAB international cooperative study. European Urology Supplement 2005;4(3):228.
  7. 7.0 7.1 Calais da Silva FE, Bono A, Whelan P, Brausio M, Queimadelos M, Portillo J et al. Phase III study of intermittent MAB versus continuous MAB - An international cooperative study - Quality of life. European Urology Supplement 2006;5(2):289.

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Appendices