In this review, we describe how clinical investigators addressed some of the challenges in prostate cancer chemotherapy trials 20 years ago, and we indicate what has evolved in the field since that time. We consider the impact that prostate-specific antigen measurement had in this setting, evolving clinical paradigms, multidisciplinary programs, and the current armamentarium of cancer treatment, including targeted molecular therapy, for patients with hormone-refractory disease.
I was very excited to get the opportunity to comment on Dr. Eisenberger and Ms. Sinibaldi's thoughtful review on the progress in management of hormone-refractory prostate cancer (HRPC) over the past 2 decades. While I consider myself to be of the same "general vintage" as Dr. Eisenberger, I was a junior urology resident at Walter Reed Army Medical Center when he wrote his classic 1985 Journal of ClinicalOncology article (his reference 1). Mario must have also been a junior fellow at the time!
In those days, I worked under Dr. Dave McLeod, the Chief of Urology at Walter Reed and a principal investigator in the National Prostate Cancer Project (NPCP). While it is difficult for my residents today to imagine, we usually had several men on the wards dying of prostate cancer at any one time. I was struck by the pain and misery of these men; it is no wonder most urologists from my generation or older are supportive of prostate-specific antigen (PSA) screening. Interestingly, a number of weeks ago when I was on call, one of my junior residents called me about a "very interesting teaching case." It was the now rare scenario of a patient with HRPC and impending spinal cord compression-oh, how times have changed (for the better).
The PSA Era
Even more amazing now, when looking back 20-plus years, Dr. Eisenberger and I started training before PSA testing was available. I remember well when the first PSA assay became available at our hospital. Initially done through the Nuclear Medicine Department, it was an "exotic" new test, and we were all very wary of it. Much of the first few years of its use involved comparisons to prostatic acid phosphatase (PAP). Some of our junior residents now don't even know what PAP stands for.
Little did I know in the late 1980s that my academic career would be built on the use of PSA as a biomarker.[1-4] A piece of work that I am most proud of was the opportunity to collaborate with Anthony D'Amico, Peter Carroll, and others on the first study to show that a PSA doubling time (PSA-DT) of less than 3 months is a surrogate for prostate cancer-specific death. I am still hopeful that the US Food and Drug Administration will eventually recognize the use of a PSA kinetic construct (such as PSA-DT) to approve new drugs, such as some of the agents that Eisenberger and Sinibaldi describe.
In one of the first meetings at which I heard Dr. Eisenberger speak, I distinctly remember him presenting the now classic survival curve collage shown in his current article's Figure 3. For the next 20 years, we all recited the common knowledge that no chemotherapy had ever been proven to extend survival in HRPC. After our first meeting, Dr. Eisenberger and I became friends and, since then, have actually had several patients in common over the years.
As a urologist, I have enjoyed the opportunity to interact with prominent medical oncologists such as Mario, as well as many academic radiation oncologists, forming the multidisciplinary approach to prostate cancer that is so important. Having "grown up" in the military health-care system at Walter Reed, I found this team approach came as second nature. Like many others, we at Duke are working hard to create a "multi-D" approach to this disease. In this regard, I am very proud of our program and the Duke Prostate Center.
In 2005, a docetaxel study broke with conventional wisdom and showed for the first time that a chemotherapeutic agent could extend survival in HRPC. While not a "home run," it was a clear step in the right direction. Now, many trials are combining docetaxel with newer agents.
Although surely exciting, one can argue that this is the "best of times and the worst of times." I worry that these novel agents may not make it from bench to bedside soon enough. With a looming shortage of physicians (urologists in particular), decreased government funding for cancer research and clinical trials, a growing uninsured population, and shrinking reimbursements, there is tremendous pressure on clinicians, and clinical trials may suffer. Add to this the approaching Baby Boom generation spike in health-care needs-a perfect storm may be brewing. I hope and pray this does not occur, yet worry for the sake of survivors and men in our generation.
In summary, Drs. Eisenberger and Sinibaldi have written an outstanding and timely paper on the state of HRPC management, with a generational perspective that I very much appreciate.
-Judd W. Moul, MD, FACS
Dr. Moul receives research support from Sanofi-Aventis.
1. Moul JW, Sesterhenn IA, Connelly RR, et al: Prostate-specific antigen values at the time of prostate cancer diagnosis in African-American men. JAMA 274:1277-1281, 1995.
2. Morgan TO, Jacobsen SJ, McCarthy WF, et al: Age-specific reference ranges for prostate-specific antigen in black men. N Engl J Med 335:304-310, 1996.
3. Moul JW: Prostate specific antigen only progression of prostate cancer. J Urol 163:1632-1642, 2000.
4. Wu H, Sun L, Moul JW, et al: Watchful waiting and factors predictive of secondary treatment of localized prostate cancer. J Urol 171:1111-1116, 2004.
5. D'Amico AV, Moul JW, Carroll PR, et al: Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy. J Natl Cancer Inst 95:1376-1383, 2003.