Prostate Cancer, PSA, and Questions That Can Only Be Answered By Clinical Trials
Rising prostate-specific antigen (PSA) in nonmetastatic prostate cancer occurs in two main clinical settings: (1) rising PSA to signal failed initial local therapy and (2) rising PSA in the setting of early hormone-refractory prostate cancer prior to documented clinical metastases. Most urologists and radiation oncologists are very familiar with the initial very common clinical scenario, commonly called "biochemical recurrence." In fact, up to 70,000 men each year will have a PSA-only recurrence after failed definitive therapy. The ideal salvage therapy for these men is not clear and includes salvage local therapies and systemic approaches, of which the mainstay is hormonal therapy. Treatment needs to be individualized based upon the patient's risk of progression and the likelihood of success and the risks involved with the therapy. It is unknown how many men per year progress with rising PSA while on hormonal therapy without documented metastases. This rising PSA disease state is sometimes called, "PSA-only hormone-refractory prostate cancer." As in the setting of initial biochemical recurrence, evidence-based treatment options are limited, and taking a risk-stratified approach is justified. In this article, we will explore these prostate cancer disease states with an emphasis on practical, clinically applicable approaches.
When have patients receiving definitive treatment for prostate cancer "failed"? As no one has died of prostate-specific antigen (PSA) toxicity, when does a biochemical recurrence represent clinically significant cancer recurrence in need of treatment? Posttherapy PSA expression has not proven to be a fully accurate surrogate for clinical prostate cancer progression or cancer-related death. In this manuscript, the Duke Prostate Center authors have cited no fewer than 20 prior publications touting the prognostic significance of a particular PSA value or change in PSA over time to serve as a surrogate for a more meaningful future clinical event. The quantity of these retrospective reports is an indicator of the difficulty we continue to have in defining what a clinically meaningful PSA is after definitive therapy, to say nothing about how best to treat this situation.
Many Different Diseases
Prostate cancer is not one disease. It encompasses multiple diseases with a common name. This is true of primary tumors as well as those responsible for biochemical-only recurrence. The ultimate goal of ongoing research is the unraveling of the genetic or epigenetic events that drive prostate cancer metastasis and growth. It is hoped this molecular typing will guide our therapeutic interventions allowing us to limit or prevent prostate cancer progression and avoid unnecessary therapeutic morbidities.
Short of this molecular breakthrough in understanding prostate cancer biology and molecular phenotypes, most patients with biochemical-only recurrence of their prostate cancer are lumped together and presented with similar options-observation until clinical recurrence, radiotherapy if a prior surgical patient and surgery if a prior radiotherapy patient, or hormone therapy. Though not tacitly stating so in their manuscript, these colleagues have highlighted our combined failure to commit ourselves and our patients to the timely conduct of sufficiently powered randomized trials of adjuvant therapies in men with nonmetastatic biochemical recurrence. If, as the authors state, 70,000 men each year experience their first biochemical relapse after definitive therapy, we cannot blame a lack of prospective study subjects for the shroud hiding therapeutic clarity.
The Early Prostate Cancer Programme employing high-dose bicalutamide (Casodex) or placebo after definitive therapy or observation looks not at biochemical-only recurrence, but at the prevention of biochemical recurrence.[1] Treatment of biochemical recurrence is not assessed in this trial, but the reason we conduct clinical trials and try to avoid empiric treatments was emphasized when a 20% worsening in overall survival was noted in low-risk patients receiving high-dose bicalutamide. This should give us pause before initiating salvage therapy based on retrospective data compiled from patients treated in dissimilar manners.
While these salvage therapies are modestly effective, especially when administered to men with low-risk disease, is there an opportunity to manage biochemical recurrence in these men as a chronic disease state? And in men with higher risk of clinical cancer recurrence and prostate cancer death, which therapy or combination of therapies is best, given that our current salvage strategies for these men seem to have little impact on the natural progression of the disease but can have significant impact on quality of life?
Looking to the Future
It is time for us to move beyond our past and look to the future with our patients. The importance of clinical trials to answer all these questions and more begins with prostate cancer physicians who believe trials answer questions and improve care. Multicenter trials are currently enrolling this patient population to trials using ATN-224, lenalidomide (Revlimid), temsirolimus (Torisel), intermittent androgen ablation, satraplatin plus radiation therapy, docetaxel (Taxotere) plus radiation therapy, and pomegranate juice, to name just a few. It is our responsibility to support these investigations and thoughtfully consider the next generation of trials. Before you know it, many of us will be in the shoes of our patients and wondering why we still don't know who, what, or when those with biochemical recurrence should be treated.
Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
References:
1. McLeod DG, Iversen P, See WA, et al: Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU Int 97:247-254, 2006.
