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How Early Is Early: Androgen Deprivation for Prostate-Specific Antigen Relapse in Prostate Cancer

Peter MacCallum Cancer Centre, Melbourne, Australia, Melbourne, Australia, The Cancer Council Victoria, Melbourne, Australia

To the Editor:

We noted with interest the review article by Ryan and Small in the November 10, 2005 issue of the Journal of Clinical Oncology, entitled "Early Versus Delayed Androgen Deprivation for Prostate Cancer: New Fuel for an Old Debate."¹ As the authors record, there are now mature data from large scale randomized trials addressing the use of neoadjuvant and adjuvant androgen deprivation, but no randomized data to support decision making in the most difficult of clinical scenarios—isolated biochemical failure after curative treatment. Although studies of more advanced disease stages, such as the Medical Research Council trial,² suggest a benefit to earlier intervention, other reports have suggested no such advantage. Studer et al³ found no benefit in overall survival for early treatment of asymptomatic incurable primary disease, and a later report from the Medical Research Council trial in fact suggested a deficit in survival beyond 5 years for early intervention.⁴ The large data sets from Bianco⁵ and Wallace,⁶ reviewed by Ryan¹ do not yet answer the question of when the optimal timing is to introduce androgen deprivation in these patients, only suggesting that earlier rather than later is better. Opinion is indeed widely divided regarding the correct time point to start treatment.^7,8

The issue with immediate early intervention is the prolonged natural history for many of these men: untreated prostate-specific antigen (PSA) failure after radical prostatectomy has a median time to clinical disease progression of 8 years.⁹ Although there are suggestions that waiting until overt relapse might be detrimental, we have no evidence to say whether we need to start treatment immediately at relapse or whether intervention can safely be delayed until certain biochemical trigger points are reached but before the development of overt clinical disease. Intervention at relapse introduces treatment-related morbidity potentially years before it is required. Any potential gain in terms of overall survival must be balanced against the effects on quality of life.

We opened a randomized trial in Australia and New Zealand 1 year ago (Timing of Androgen Deprivation, VCOG PR 1-03 and TROG 03.06) to address these issues. Patients diagnosed with PSA relapse are randomly assigned to immediate or deferred androgen deprivation, with either continuous or intermittent therapy being permitted. We are stratifying for the interval between primary treatment and relapse (< 2 years or > 2 years) and PSA doubling time (< 10 months or > 10 months). Patients with doubling times less than 3 months are excluded. There has been considerable discussion about the timing of intervention in the delayed arm. To avoid blurring of the outcomes through short delay times, we have recommended that at least 2 years should elapse, unless certain triggers make the treating physician want to start therapy: a PSA over 10 ng/mL with a doubling time of less than 12 months, or any PSA with a doubling time less than 6 months. A spectrum of intervals to treatment in the deferred arm will allow analysis of optimal intervention time related to disease characteristics. The primary end point is overall survival, with quality of life and morbidity as secondary end points. Recently, many authors have recommended that these trials must be undertaken. It is only by supporting trials such as this that we will reach the definitive answer.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

ACKNOWLEDGMENTS

Clinical trial supported by grants from National Health and Medical Research Council Funding Australia (350201), and The Cancer Councils of Australia. Untied educational grants received from Mayne-Pharma and Astra-Zeneca.

REFERENCES

1. Ryan CJ, Small EJ: Early versus delayed androgen deprivation for prostate cancer: New fuel for an old debate. J Clin Oncol 23:8225-8231, 2005[Abstract/Free Full Text]

2. The Medical Research Council Prostate Cancer Working Party Investigators Group: Immediate versus deferred treatment for advanced prostatic cancer: Initial results of the Medical Research Council Trial. Br. J Urol 79:235-246, 1997

3. Studer UE, Hauri D, Hanselmann S, et al: Immediate versus deferred hormonal treatment for patients with prostate cancer who are not suitable for curative local treatment: Results of the randomized trial SAKK 08/88. J Clin Oncol 22:4109-4118, 2004[Abstract/Free Full Text]

4. Kirk D, on behalf of the MRC Prostate Cancer Working Party Investigators Group: Immediate vs deferred hormone treatment for prostate cancer: How safe is androgen deprivation? Br J Urol Int 86:220, 2000 (suppl 3)

5. Bianco FJ, Dotan ZA, Kattan MW, et al: Duration of response to androgen deprivation therapy and survival after subsequent biochemical relapse in men initially treated with radical prostatectomy. J Clin Oncol 22: 394s, 2004 (abstr 4552)

6. Wallace KL, Elkin EP, Latini DM, et al: Timing of LHRH treatment after PSA failure in prostate cancer patients: A survival analysis from the CAPSURE database. Proc Am Urol Assoc, 2004 (abstr 434)

7. Duchesne GM, Millar JL, Moraga V, et al: What to do for prostate cancer patients with a rising PSA?—A survey of Australian practice. Int J Radiat Oncol Biol Phys 55:986-991, 2003[CrossRef][Medline]

8. Salminen EK, Wickstrom JE, Vahlberg T, et al: Trends in the use of androgen deprivation in prostate cancer. Acta Oncol 43:382-387, 2004[CrossRef][Medline]

9. Pound CR, Partin AW, Eisenberger MA, et al: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281:1591-1597, 1999[Abstract/Free Full Text]

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