An article in just published in Onkologie reports the diagnosis and (short-term) treatment of widely disseminated, metastatic prostate cancer in a 64-year-old Croatian man with a PSA of > 21,000 ng/ml.
Quite apart from the fact that this is believed to be the highest known PSA level at the time of initial diagnosis is the fact that this man was still, according to Persec et al., completely free of any symptomatic evidence of disease at the time of diagnosis: no bone pain, no problems with urination, etc.
One of the things that has been evident in the management of prostate cancer since the advent of the PSA test is the degree to which management of patients’ PSA levels has become a driving force behind discussions about patient treatment. Patients commonly express enormous concern when their PSA levels rise — even if it is from one near to undetectable level to another near to undetectable level — and physicians need to be able to offer sound guidance and make good clinical decisions based on such information.
The patient discussed by Persec et al. was actually diagnosed with a PSA level of 21,380 ng/ml (although we do wonder about the accuracy of PSA tests in assessing such a level of prostate specific antigen). He was subsequently shown to have chronic anemia, an elevated alkaline phosphatase, a Gleason score of 9, multiple liver metastases, and diffuse bone metastasis. He was treated with a bilateral subcapsular orchiectomy and bicalutamide. At 3 months of follow-up, his PSA had dropped to 29 ng/ml. Based on historic evidence in the management of patients diagnosed with metastatic disease, his prognosis would be a survival time of 18-36 months. Of course what we don’t know is just how long this gentleman has been living with his disease. Is it 1 year or 25?
For many years, a small subset of clinicians has argued that treatment of patients with hormone therapy for a rising PSA is not clinically justified until there is clear evidence of metastasis or other symptomatic evidence of progression that needs to be treated. Why have they made this argument? Because the data to support early hormone therapy is associated with limited evidence of a real survival benefit, and hormone therapy very definitely is associated with a broad range of complications, including complications that can lead to patient deaths. Some patients who have been on such long-term hormone therapy have also been vociferous in making the argument that such long-term treatment may not be worth the adverse effects for men who have no clinical symptoms of metastatic disease.
The case reported here does make one wonder, yet again, when it is most appropriate to initiate hormone therapy for the majority of patients. It seems sad to us that after 60 years of using hormone therapy as the “gold standard” for the treatment of metastatic prostate cancer (because it has a very definite palliative effect on the symptoms of late-stage, metastatic disease), we are little wiser today than we were 20 or so years ago about the appropriate timing of such therapy, and the need to customize hormone therapy in ways that will optimize both the quantity and the quality of life of individual patients.
Certainly the advent of intermittent androgen ablation has allowed many patients to limit the amount of hormonal ablation they may need once it is clear that their PSA is rising and their disease will no longer respond to localized treatments. However, we also suspect that a large number of men who are started on hormone therapy when their PSA levels are well below 5 ng/ml may not be benefitting from such treatment. Indeed, it is arguable that early hormone therapy may actually accelerate the development of hormone-refractory disease in patients with a long PSA doubling time.
We don’t even know with certainty that early hormone therapy is benefical for men with a low PSA doubling time of 3 months or less after the failure of localized therapies. It may be time for us to go back and really see if we can do better at assessing the appropriate timing of hormone therapy in subsets of patients so as to optimize their survival and their quality of life. Managing PSA levels alone is certainly not always in the patient’s best interest.
Since the PSA test became available, the identification of patients with very high PSA levels like this patient’s at the time of diagnosis has become very rare indeed — and this is a wonderful thing. However, it is also in the best interests of the largest number of patients to know whether traditional hormonal therapies have a real clinical impact on survival — especially since very different, new therapies are likely to be available in the near future which can also be used to treat men with a rising PSA after first-line therapy, and parhaps as alternatives to traditional androgen deprivation. We are still treating far too many men with early hormone therapy with minimal evidence for its clinical benefit.