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In Reply

Department of Urology, University Hospital of Bern, Bern, Switzerland

Collette Laurence

Department of Statistics, European Organisation for Research and Treatment of Cancer, Brussels, Belgium

We appreciate the interest and detailed analysis of our trial, which showed a statistically significant but surprisingly small difference in overall survival of men with nonmetastatic prostate cancer who were not candidates for local therapy and were treated with immediate androgen deprivation therapy (ADT).¹ While the trial was appropriately powered to exclude meaningful differences in overall survival, the number of the various causes of death is still so small that any overinterpretation of the per-cause survival must be avoided. The difference in absolute numbers of the three most frequent causes of death is only between five and nine events. Furthermore, as Gulley et al correctly state, there remains the possibility of misclassification bias. To what extent the benefit in overall survival that seems to favor immediate ADT may be caused by an antitumor effect or by a possible change in lifestyle remains an open question.

We disagree with the statement by Gulley et al that our trial demonstrated "statistically significant improvements in subjective and objective disease progression." In fact, our trial shows a significantly longer time interval to disease progression in patients receiving immediate ADT (Fig 7¹). However, when the disease progresses in these patients, it is hormone refractory. In contrast, progressive disease in patients on the deferred treatment arm is, albeit diagnosed much earlier, still sensitive to ADT. After the deferred start of ADT these patients respond for several more years. It seems to us of great interest that the times to symptomatic progression of hormone refractory disease after immediate or deferred androgen deprivation eventually seem comparable (Fig 8¹). This figure illustrates that the number of patients with hormone refractory metastatic disease is similar with approximately 35% for both arms at 10 years. This lack of a significant difference in the incidence of documented hormone refractory metastatic disease coincides with the apparent lack of a significant difference in cancer specific mortality (Fig 5A¹). However, the number of deaths due to prostate cancer is too small to exclude any small yet relevant difference. Therefore, the comments of Gulley et al that the apparent absence of a difference in time to progression after androgen independent prostate cancer would exclude the potential risk of earlier progressive disease with androgen independent prostate cancer in the immediately treated patients cannot be concluded from our data due to lack of power.

To a certain extent we differ with the authors' interpretation that our data provides evidence for early ADT in patients with nonmetastatic prostate cancer who are not candidates for local therapy. The impact on overall survival is minimal and this has to be weighed against the detrimental adverse effects of ADT, especially its negative impact on quality of life. Although this was not an end point of our trial, it is a well-established fact.

Although 82% of our patients had palpable prostate cancer at their initial diagnosis, comorbidity is the reason for the majority of them dying from causes other than prostate cancer. Therefore, we believe that early ADT is not justified for all patients with nonmetastatic prostate cancer who are not candidates for local therapy. Recently presented subgroup analyses suggest that men older than 70 years with a serum prostate specific antigen (PSA) more than 50 µg/L, as well as patients younger than 70 years with a serum PSA more than 20 µg/L, would benefit from immediate ADT.² Patients on the deferred treatment arm with a PSA doubling time less than 12 months were found to have a four-fold elevated risk of dying from prostate cancer. To focus on high-risk groups of patients who are more likely to benefit from early androgen deprivation seems more appropriate to us than to advocate early ADT in a patient population in which the majority of them will never require it.³

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflict of interest.

REFERENCES

1. Studer UE, Whelan P, Albrecht W, et al: Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) trial 30891. J Clin Oncol 24 : 1868 -1876, 2006[Abstract/Free Full Text]

2. Studer UE, Collette L, Whelan P, et al: Baseline PSA and PSA doubling time predict the risk of objective progression and death in patients with T0-4 N0-2 M0 prostate cancer on watchful waiting. J Urol 175 : 215 , 2006 (suppl; abstr 665)[CrossRef]

3. Studer UE, Collette L, Whelan P, et al: Patients with T0-4 N0 M0 prostate cancer not suitable for local treatment with curative intent (EORTC 30891): Which subgroup needs or does not need immediate treatment? J Urol 175 : 513 , 2006 (suppl; abstr 1592)

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