An estimated 180,000 cases of prostate cancer will be diagnosed in the United States in the year 2000, with 32,000 men projected to die from their disease, making it the most commonly diagnosed cancer in men and the second leading cause of cancer death in men. Despite its high incidence, we are only beginning to understand the clinical and biological behavior of this disease. The last 10 years have seen an explosion in our understanding of the biology of prostate cancer, and in the development of new treatments. However, our understanding of this disease is confounded by the fact that treatment is constantly changing.
Treatment Options Evolving Slowly
Because of the long natural history of prostate cancer, it may take years or even decades before randomized clinical trials provide definitive answers to the more important questions. Concepts about the treatment of this disease that were once so firmly heldeg, delaying hormonal therapy until a patient is symptomatic, using maximal androgen blockade, and accepting the ineffectiveness of chemotherapy for last-stage diseasehave given way to newer concepts of early hormonal therapy, intermittent blockade, and the fact that we are at least able to palliate with chemotherapy a significant number of patients with hormone-refractory disease.
The common wisdom that patients be told either that they will die with their prostate cancer and not from it or that they are too sick to be offered effective therapy no longer holds true. In fact, in two hormonal studies separated by 2 decades, the percentage of patients dying from prostate cancer increased from 41% to 67%. It is clear that the long natural history of prostate cancer will become a more significant factor as lifespan is extended by improvements in other medical fields, such as cardiovascular disease.
Drs. Hussain and Dawson present an excellent, comprehensive review of advanced prostate cancer management, covering all areas of care and encompassing the biology of the disease. An especially welcome feature of this article is that both laboratory and clinical advances in the disease are described.
Controversies surrounding treatment of this disease will grow as advances in basic science are brought into the clinic. What is clearly needed is a means of rapidly integrating molecular observations made in the laboratory into clinical practice. This is particularly relevant for studies evaluating the use of adjuvant chemotherapy or hormonal therapy after definitive local therapy.
The natural history of the disease is measured in years rather than months, and an evaluation of treatments using the gold standard of survival as an end point will not be available for clinical decisions for years to come. Are there any markers that will help select the patients who would benefit most from early hormonal therapy? Is the paradigm of adjuvant chemotherapyso successful in breast cancerapplicable to prostate cancer? A better understanding of the biology of the disease might help us answer these questions in a timely fashion.
The clinician currently has more options available for the treatment of hormone-refractory disease. These include secondary hormonal manipulations (ketoconazole [Nizoral]/hydrocortisone, antiandrogens), chemotherapy, bisphosphonates, and isotopes. However, we still do not know the optimal time and sequence for these treatments. Which patient will respond to secondary hormonal manipulations? Should chemotherapy be reserved for the symptomatic patient or should it be administered when prostate-specific antigen (PSA) levels begin to rise? Should bisphosphonates be administered? Again, to answer these questions expeditiously without large numbers of patients is a difficult prospect.
Tissue, serum, and imaging correlates may help provide answers more quickly. For example, the intergroup Southwest Oncology Group study SWOG 99-16, a randomized trial comparing mitoxantrone(Drug information on mitoxantrone) (Novantrone) and prednisone to estramustine(Drug information on estramustine) (Emcyt) and docetaxel(Drug information on docetaxel) (Taxotere) in hormone-refractory prostate cancer, had been amended to examine biological markers such as p53, insulin-like growth factor (IGF), and HER2 in the serum, as well as various pro- and antiapoptotic proteins in tissue. The results may shed more light on the best ways to use chemotherapy and design future trials.