For patients with radiologically detectable but asymptomatic disease should hormone therapy be started immediately or should it be started at the onset of symptoms?
Early versus delayed androgen deprivation
One clinical scenario is the management of patients with radiographic evidence of disease without symptoms. The question arises as to whether ADTs should be started immediately or delayed until the onset of symptoms. Two RCTs have addressed this question. These trials took place in different eras. One trial, VACURG-1, was performed in the 1960s and 1970s, while the MRC Prostate Cancer Working Group study was undertaken in the 1980s and 1990s. This complicates the analysis because of:
- issues of stage migration and stage detection with pre bone scan and pre PSA era incorporated with studies of patients who are more accurately staged in the modern era
- different treatments from different eras included oral oestrogens, orchidectomy and LHRH agonist therapy.
In addition, both studies included men with non-metastatic as well as metastatic disease. As a result data findings were based on sub-group analyses, and in the MRC trial the study plan was not always adhered to, with some controls not receiving treatment on progression.
In both RCTs, no clear survival benefit was shown for patients who started castration therapy with symptoms versus those who started therapy when no symptoms were present. This data set is limited as the VACURG study may have included a proportion of patients with symptoms and the MRC study was confounded by some patients in the delayed therapy arm not receiving therapy.
This would suggest there is not a mandate to commence ADT in patients with asymptomatic metastases. It should be noted that the MRC and VACURG-1 studies are not therapy versus no therapy since such studies would be unethical. ADT is an effective therapy for metastatic disease (albeit temporarily) and patients can be salvaged at the time of symptomatic progression.
Evidence summary and recommendations
|The limited data suggest patients with asymptomatic metastatic prostate cancer are not advantaged by early androgen deprivation therapy until symptomatic progression.||II||, |
Androgen deprivation therapy is indicated for metastatic prostate cancer. Immediate
therapy is warranted for symptomatic metastases. The evidence for immediate therapy for asymptomatic metastases is unclear, but it is definitely warranted if delay may result in complications (eg spinal cord compression from vertebral metastases).
A decision about whether to defer therapy for patients with asymptomatic metastases will be a discussion between patient and physician. Patients will require close follow-up if therapy is deferred. Close evaluation would include an MRI of the spine for patients with documented but asymptomatic vertebral metastases to ensure there is no pending spinal canal encroachment which would necessitate more urgent treatment.
- Jordan WP Jr, Blackard CE, Byar DP. Reconsideration of orchiectomy in the treatment of advanced prostatic carcinoma. South Med J 1977 Dec;70(12):1411-3 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/594790.
- 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 1997 Feb;79(2):235-46 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9052476.
- Venkitaraman R, Sohaib SA, Barbachano Y, Parker CC, Huddart RA, Horwich A, et al. Frequency of screening magnetic resonance imaging to detect occult spinal cord compromise and to prevent neurological deficit in metastatic castration-resistant prostate cancer. Clin Oncol (R Coll Radiol) 2010 Mar;22(2):147-52 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20034772.