Urology International has been published as a quarterly journal for urology specialists since January 1994, and since October 1996 has also appeared as an on-line version.
Since the introduction of hormonal treatment for prostate cancer there has been a debate about its timing,especially following the failure of the Veterans Administration Cooperative Urology Research Group (VACURG) studies to demonstrate a clear survival benefit in treated patients compared with those initially randomised to placebo.However, since the prime objective of the VACURG studies was not to compare immediate vs deferred treatment, their results were inconclusive and much debated. In the mid-1980s the British Medical Research Council set up a multicentre study to address this question. The first results, with follow-up data to August 1996, have recently been published.
Patients and Trial Design
Nine hundred and thirty-eight patients recently diagnosed with locally advanced or asymptomatic metastatic prostate cancer were randomised either to immediate treatment (orchiectomy or luteinising hormone-releasing hormone analogue) or to treatment deferred until a specific indication such as bone pain occurred. Follow-up and management otherwise were according to the participating clinician’s normal practice. Results were analysed on an intention to treat basis. Standard Kaplan-Meier survival curves and log rank methods were used to analyse times to death and other events. Two-tailed p-values (2p) were cited throughout with 2p<0.05 described as "not significant". Thus the study compared the effects of a policy of immediate treatment with that of deferred treatment in conventional British urological practice.
Follow-up data are available on 934 patients. Fifty-one patients for whom treatment was deferred died from causes other than prostate cancer before treatment was started. On entry all but five of these patients were over 70 years old, and most had M0 disease. Twenty-nine died from prostate cancer before treatment could be started. Treatment was commenced for local progression almost as frequently as for metastatic disease.
Progression from M0 to M1 disease (2p<0.0001) and development of metastatic pain occurred more rapidly in patients for whom treatment was deferred than in patients who were given immediate treatment. Of the deferred patients, 145 needed transurethral resection for local progression, compared to 65 who were given immediate treatment (2p<0.00001). Pathological fracture, spinal cord compression, ureteric obstruction and development of extraskeletal metastases were almost twice as common in deferred patients (Table 1). In patients for whom treatment was deferred, spinal cord compression usually occurred after therapy had been started, for some other reason. Pathological fractures more often presented before treatment. Ureteric obstruction was the indication to commence therapy in about half of the cases where it occurred and in these circumstances most of the patients responded to treatment.
Of patients who died during the study, 67% did so from prostate cancer compared with 41% in the VACURG studies. This reflects the increased life expectation of elderly men. The possibility of death from other causes can no longer be cited as a reason for deferring treatment. Figure 1 illustrates the differences in overall and in disease-specific survival for all patients. The survival benefit from immediate treatment was mainly seen in patients without metastases on entry (Figure 2).
These results have a bearing on the arguments used previously to support the benefits of immediate treatment.
The VACURG studies did not show conclusively that there was no survival benefit resulting from early treatment- the current study suggests that there probably is a benefit.
Hormone treatment is a good method of controlling the primary tumour,and as predicted, immediate treatment does dramatically reduce the number of men who need transurethral resection of the prostate for local tumour progression.
Similarly, the catastrophes of advanced prostatic cancer (spinal cord compression, pathological fracture and ureteric obstruction) are more common in patients in whom treatment is deferred.
Does prostatic cancer become less hormone sensitive as it advances?A survival difference is seen between M0 patients given immediate hormone treatment and those in whom treatment was deferred. In these M0 patients deferred treatment took place after a mean delay of 27 months, often after progression to M1 disease. No clear survival difference between immediate and deferred treatment groups is seen in patients with M1 disease, in whom disease is already advanced and in whom the mean delay in treatment is only 9 months (Figure 2). A reduction in hormone sensitivity of the M0 tumours during progression would explain this difference in response to treatment.
In general, treatment of cancer is likely to be more effective when tumour bulk is low. It is implicit in the philosophy of deferred treatment than when treated, the patient is returned to the same state as if treatment had been given from the start. Spinal cord compression, and to a lesser extent, pathological fractures, usually occur in deferred patients after treatment has been started for another cause. This, and the higher incidence of extraskeletal metastases in deferred patients, suggests that the progression which takes place during the period of treatment deferral does confer an irreversible handicap on the patient.
The results consistently favour immediate treatment, although some of the data, especially on M0 patients, are immature. While some caution is still needed in making categorical recommendations on the timing of hormonal treatment, considerable thought is needed before deferred treatment can be recommended, although it probably still represents a valid option in a fully informed patient with M0 disease who is over 70 years old. Certainly it is now my practice when counselling patients to inform those reluctant to consider early treatment about the results of this study, and to follow up with increased vigilance any who still choose deferred treatment.