Contemporary Management of Prostate Cancer With Lethal Potential

Virtually every management decision related to prostate cancer is highly controversial. Should we screen men for prostate cancer with prostate-specific antigen (PSA)? If so, what are the proper cutoff values? If we detect an early prostate cancer, is treatment warranted? If we find an aggressive cancer, is treatment effective? If treatment is deemed warranted, what is the optimal management strategy (radical prostatectomy vs radiation therapy)? If radical prostatectomy is selected, should the procedure be performed robotically or via an open approach? If radiation therapy is selected, does either brachytherapy or external-beam irradiation offer an advantage? Is there a role for neoadjuvant hormonal therapy in men undergoing definitive intervention? It is imperative that we rely on evidence-based approaches for insight into the management of prostate cancer. Because of the typically protracted natural history of prostate cancers detected in the modern era, long-term studies are mandatory in order to demonstrate the survival advantage of intervention. To eliminate selection bias, these studies should be randomized and appropriately powered to detect clinically significant outcomes. They require tremendous human and financial resources. A major frustration related to these long-term, randomized studies is that because of concurrent advances in the field, their conclusions often lose clinical relevance before they are completed and published. High-Risk Prostate Cancer
The optimal management of highrisk prostate cancer is also highly controversial. Davis et al provide a scholarly and balanced summary of the management of prostate cancer patients at high risk. They present a comprehensive review of the literature, highlighting the strengths and pitfalls of pivotal studies. It is generally agreed that men with high PSA levels (> 20 ng/mL), highgrade cancers (Gleason score ≥ 8), and/or large tumor volumes based on digital rectal examination or a review of the biopsy cores are at greater risk for disease progression and death if untreated. In selected high-risk subgroups, radical prostatectomy and radiation therapy increase survival. Unfortunately, due to the lack of untreated controls, the magnitude of the survival advantage is unknown. Disease will progress in many of these men despite aggressive intervention. One of the limitations of nonconcurrent studies comparing different treatment options in high-risk patients is the lack of a uniform definition of high-risk and the lack of homogeneity in the treatment groups. For example, a man with a PSA of 4.1 ng/mL, a Gleason score of 8, disease in a single biopsy core, and a normal prostate on digital rectal exam, and a man with a PSA of 40 ng/mL, an extensive Gleason 8 cancer, and a diffusely indurated palpable prostate gland might both be considered high risk. Most likely, differences in outcome between these two men would depend more on the difference in baseline characteristics than in the treatment selected. Therefore, one must be very cautious of selection bias when examining nonconcurrent studies. Treatment Considerations
Because some men with high-risk prostate cancer are cured following radical prostatectomy and radiation therapy, this group of patients should not be arbitrarily denied curative intervention. Although many of these men will fail radical prostatectomy and radiation therapy, the morbidity of treatment, especially in centers of excellence, is now quite low. Therefore, it is reasonable to embark on a potentially curative intervention for men with high-risk tumors, recognizing that there will be a relatively high failure rate. This is particularly true if the alternative is an experimental, unproven therapy. Such a therapy might be better delivered if a conventional therapy fails. It is intuitive that the ability of radical prostatectomy and radiation therapy to cure high-risk disease depends on total extirpation or total destruction of the local tumor burden and the absence of metastatic disease. The ability of radiation therapy to cure high-risk disease depends on the relative degree of risk, the amount of radiation therapy delivered, and the use of adjuvant hormonal therapy. The compilation of data suggests that neoadjuvant hormonal therapy provides a survival advantage prior to radiation therapy but not prior to surgery. The authors appropriately question whether the survival advantage of neoadjuvant hormonal therapy is solely due to the effect of hormonal therapy or a synergistic effect between radiation therapy and neoadjuvant therapy. Future Study Design
Unfortunately, no randomized studies have compared radical prostatectomy to radiation therapy (with or without neoadjuvant hormonal therapy) for the treatment of high-risk disease. Would such a study definitively resolve the question of optimal therapy for high-risk disease? Most likely, the answer is no. First, the study would require several years to organize and complete enrollment. In addition, follow-up would have to span at least 5 years to determine any survival advantages. It is unlikely that all high-risk patients respond uniformly to different treatments; thus, it is conceivable that high-risk patients with organ-confined disease would respond better to radical prostatectomy, whereas those with extensive extraprostatic disease, with or without involved lymph nodes, would respond better to radiation therapy. As different subgroups respond differently to therapy, the study would require extremely large patient numbers to achieve statistical power sufficient to identify clinically relevant differences in therapeutic outcome. It is also likely that within the next decade, effective neoadjuvant chemotherapy will be identified for high-risk prostate cancer. In addition, it is likely that researchers will identify biochemical or genetic factors that more reliably distinguish men with systemic metastasis. These advances would have a significant impact on the management of high-risk men and, therefore, would likely render the randomized study obsolete. Treatment Plan
The obvious dilemma is how to manage men with high-risk prostate cancer based upon the available evidence. I believe that all men with a life expectancy of 5 years are at risk for disease progression and death if untreated. Moreover, I believe that radical prostatectomy alone, neoadjuvant hormonal therapy and radiotherapy appear to be effective in subsets of men with high-grade prostate cancer. Because of the high likelihood of coexisting systemic disease, effective chemotherapy will likely improve survival outcomes. Aggressive intervention should be offered, providing morbidity is minimal. Fortunately, in this era of PSA screening, few men are initially diagnosed with high-risk disease. I rely on the Partin table to predict the likelihood of extraprostatic disease.[1] If the likelihood of achieving negative margins is high, then I recommend radical prostatectomy. If men fail radical prostatectomy, I consider adjuvant radiation therapy. For men in whom it is unlikely that negative surgical margins can be achieved, I recommend a combination of neoadjuvant hormone therapy, docetaxel(Drug information on docetaxel) (Taxotere), and external-beam irradiation. Although there is no long-term follow-up to justify this treatment algorithm, it is a sensible approach to the management of the high-risk group based upon common sense and the existing literature, which was reviewed in such a scholarly fashion by Davis and associates.