Clinical trials in prostate cancer


Kirby and Fitzpatrick [1] provide a commentary and assessment of the recently published Scandinavian Prostate Cancer Group prospective randomized trial comparing radical prostatectomy with expectant management [2]. The publication of this trial has garnered significant attention, and so it should; it represents a unique and commendable success in providing evidence-based medicine to address a daily dilemma facing both the urologist and the patients with prostate cancer. As expected, the trial outcome has engendered discussion, extrapolation and ‘spin’.

Kirby and Fitzpatrick rightfully observed that the age, stage and PSA level of the population of patients currently being diagnosed is less than that found in the study patients, and that this might translate into even greater future surgical benefit to these patients. Hopefully, with earlier detection, this will indeed be the case, but the age, stage and PSA level difference between clinically and PSA-detected prostate cancer is a direct reflection of the lead time to diagnosis, which is calculated to be 5, or perhaps more, years [3]. Therefore, as discussed in the study conclusion, when surgery is driven by PSA results, as much as 15 years of follow-up (and also life-expectancy) and not 10 years, may be necessary before there is separation of the curves. Therefore treatment benefit is postponed while treatment morbidity remains immediate. The trial cannot be used to conclude that the strategy of PSA screening is now confirmed to be effective; this issue awaits the results of the PLCO and the ERSPT trials, which specifically address this question. Nor should ‘spin’ detract from the trial findings as some have proposed, by emphasising that the study showed no overall survival benefit, and thereby levelling the critique that ‘the operation was a success but the patient died’[4]. The excess deaths in patients after surgery will need continued monitoring and investigation.

Prolonging the time to metastasis and the morbidity associated with metastatic disease, and the reduction in prostate cancer-specific deaths, are real and welcome. However, these outcomes are, as yet, not as dramatic as implied by relative calculations. While the relative reduction in cancer-specific deaths is 50% at 6.2 years of median follow-up, the absolute reduction is 4.5%. The difference at 5 years was 2%. Recall that combined androgen blockade using nonsteroidal antiandrogens when compared to monotherapy in a meta-analysis showed a 2.9% absolute overall survival benefit at 5 years [5]; this benefit has been the subject of criticism and minimisation. Cancer rarely yields dramatically to single therapeutic interventions. Progress is measured by ‘baby steps’ as one advance is layered upon another; neither over-optimism or over-pessimism is warranted.

Over the 8-year period of observation in this trial, 17 patients required surgery to avoid one death. Clearly better identification and selection of patients for whom a necessary cure can be achieved by surgery will refine and enhance this therapeutic ratio.

In the arena of localized prostate cancer therapy, urology has had a dearth of randomized controlled trial data. Upon completion, randomized trials are analysed and criticised, and thereby discussion points will be generated based on the best currently available data. These discussions will serve as platforms for questions to be tested in subsequent clinical trials. Currently the American College Of Surgeons Oncology Group has initiated the SPIRIT trial to examine the next logical question ( If, as shown by the Scandinavian trial, active therapy by surgery has an advantage when compared with a strategy of postponing immediate active therapy (surveillance or watchful waiting) how then might surgery compare with another active intervention, i.e. interstitial brachytherapy? The SPIRIT trial will randomize patients with low-risk cancer to either radical prostatectomy, by any approach, or to interstitial therapy by either palladium or iodine, comparing both traditional and quality-of-life endpoints. I hope and trust North America can accrue patients to this trial to completion and therefore, like the Scandinavian trial, shed more light through evidence-based medicine on the risk/benefit dilemmas presented by localized prostate cancer treatment. Participation by centres in the UK, an initiative that is currently under consideration, will further assure timely trial completion.