Early Versus Delayed Endocrine Treatment Of T2-T3 PN1-3 M0 Prostate Cancer Without Local Treatment Of The Primary Tumour

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology;  Endocrinology
Article Date: 02 Nov 2008 - 0:00 PDT

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UroToday.com - Protocol 30846 of the EORTC-GU Group recruited 234 patients with histologically proven lymph node positive disease (pN1-3) according to the TNM classification of 1992. This included regional but not para-aortic lymph node disease. At the time the study was initiated in 1983, lymph node positive disease was encountered in 20 to 50% of cases that were clinically considered to be eligible for radical prostatectomy or radiotherapy. Also, except for the reported experience of the MAYO Clinic where in lymph node positive disease immediate endocrine treatment was combined with removal of the primary tumour, the best management of the primary tumour in this setting was unknown. There was no evidence from randomised studies on this issue. Considering ignorance about the best management of lymph node positive disease, the EORTC-GU Group deemed this group of patients as suitable to study the open issue of the best timing of endocrine intervention in prostate cancer and wished to make a contribution to a better understanding of the timing of endocrine treatment in this disease in general. This question, unfortunately, has still remained open today, 15 years after the design of this protocol.

Also, the issue whether the primary tumour should be aggressively treated or not was heavily discussed at the time of the design of the protocol. Observations that were available from randomised and phase II studies showed that under endocrine management the primary tumours responded in a very favourable fashion with volume reductions of 30 to 50% - results that were not seen in metastatic disease. Also, removal of the primary tumour in the presence of metastases had rarely been shown to be effective in other human malignancies. It seemed that the side effects of treatment could be avoided for this group of patients.

Our trial, unfortunately, never reached a sample size that would have allowed showing or excluding that the 22% difference in overall survival seen for early endocrine treatment would be statistically significant. If that had been shown, clinicians still would have remained impressed by the fact that 13-year median in prostate cancer mortality was very close for the two arms and amounted to 60.9% in the delayed 58.0% in the immediate treatment arm.

Recruitment to our study was considered to be very difficult from the onset. Patients who were initially told they needed a radical prostatectomy or potentially curative radiotherapy were subsequently informed that this treatment could not take place because there were metastases. The next step was that in the given situation it might not be necessary to immediately treat them but to delay endocrine treatment. These conversations took a very long time and led to a large proportion of refusals. Recruitment was further hampered by the increasing use of PSA in diagnosing prostate cancer from 1987 onward. It is well established that the use of PSA has led to a remarkable stage reduction at the time of diagnosis. The prevalence of lymph node metastases with radical prostatectomy decreased in most series to below 5% as a result of the PSA-related stage shift. Unfortunately, due to these circumstances, our study remained underpowered and could not resolve the issue of early versus delayed endocrine treatment in lymph node positive prostate cancer. This information, if the trial had been positive, could have been extrapolated to many other clinical situations.

What did our trial show?

1. Delay of endocrine treatment in this study was by an average of 18 months. During this period of time, patients could obviously enjoy a normal sexual life and avoid all other side effects of endocrine treatment. The indication for initiating endocrine treatment was loosely defined to allow for patients' anxiety as well as the judgement of urologists to play a role. There are other studies available which show that the time to progression of lymph node positive disease may be much longer than 18 months.

2. The natural history of lymph node positive cancer is unexpectedly long, particularly in comparison to other distant spread of prostate cancer. In the early endocrine treatment arm, the median period of time of endocrine treatment was 5.1 years. The five-year cumulative incidence of prostate cancer mortality was only 28% in the delayed and 23% in the immediate treatment arm. The respective data after 10 years amount to 55% and 52%.

3. Differences between immediate and delayed endocrine treatment in terms of all outcomes were small. This allows for the application of clinical judgement and accounting for aspects of quality of life that may be balanced against the potential and small advantage in survival which may be attained by immediate treatment.

The question of early versus delayed treatment is still open. However, the group of patients for whom this question is relevant has changed. There is consensus that in the presence of distant metastatic disease, immediate endocrine treatment should be applied. Uncertainty, however, exists with respect to the most common clinical situation in which endocrine treatment is an option for patients: the situation of a rising PSA after potentially curative management. Natural history data indicate that in this setting, treatment periods between 8 and 13 years may be necessary. Taking account of the small differences seen in the present study and the unknown type and extent of side effects that are likely to occur with very prolonged endocrine treatment, the information in the last report of 30846 may prove to be relevant in determining appropriate judgement in the future and in a situation of persisting uncertainty.

Written by Fritz H. Schrödera, Karl-Heinz Kurthb, Sophie D. Fossac, Wytse Hoekstrad, Peter P. Karthause, Linda De Prijckf, and Laurence Collettef, as part of Beyond the Abstract on UroToday.com

a Department of Urology, Erasmus MC, Rotterdam, The Netherlands
b Academic Medical Centre, Amsterdam, The Netherlands
c Rikshospitalet University Hospital, Oslo, Norway
d Medicenter, Den Bosch, The Netherlands
e Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
f EORTC Data Center, Brussels, Belgium

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