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Journal of Clinical Oncology, Vol 23, No 32 (November 10), 2005: pp. 8143-8145 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.10.001
Challenges and Future Directions in the Prevention and Management of Prostate Cancer
Department of Urology, School of Medicine, University of California, San Francisco, San Francisco, CA The first annual multidisciplinary Prostate Cancer Symposium (Orlando, FL, February 17-19, 2005) was a remarkable meeting that brought together 1,035 individuals interested in the prevention and treatment of prostate cancer. This meeting, sponsored jointly by the American Society of Clinical Oncology, the American Society for Therapeutic Radiology and Oncology, the Society of Urologic Oncology, and the Prostate Cancer Foundation, was the culmination of several years of planning, and represented the first truly multidisciplinary scientific and educational meeting dedicated solely to prostate cancer. The meeting included special sessions devoted to mentorship, enhancing accrual to clinical trials, end points, and study design. The scientific program of the meeting was abstract driven, and provided the opportunity for the presentation of important original research. Two hundred seventy-four abstracts were presented in six poster sessions, another 17 were selected for presentation in oral sessions throughout the meeting, and Merit Awards were presented to the top 25 scoring abstracts submitted by researchers in training. Twelve general sessions provided lectures by opinion leaders on state-of-the-art topics ranging from prevention and epidemiology to developmental therapeutics and supportive care. In a sense, this issue of the Journal of Clinical Oncology Special Series is a direct outgrowth of that symposium: In this issue, as in the Prostate Cancer Symposium, we have collected key reviews addressing central challenges and areas of controversy in the clinical management of prostate cancer. This is truly an outstanding compendium, reflecting tremendous expertise and thoughtful analysis. We are grateful to each one of the authors, who responded enthusiastically to a very tight timeline, providing not only concise reviews of the state of the art and summaries of our current knowledge, but much more importantly, focusing on areas of controversy and challenges for the future. EPIDEMIOLOGY Cooperberg et al1 first set the stage by describing the shifts in the patterns of care that we have all experienced in the last decade. This article defines the changing demographics, stage migration, and changes in treatment trends in the CaPSURE and CPDR longitudinal data bases. Although it is inappropriate to draw conclusions that generalize to the population at large from these selected patient groups, these data nevertheless chronicle the changes in treatment practices in the United States, including increasing use of androgen-deprivation therapy (ADT), and relative to another article in this edition, of watchful waiting. Chan et al2 have summarized nicely the epidemiologic data supporting the contention that diet plays a role not only in prostate carcinogenesis, but in the progression of prostate cancer after diagnosis as well. The suggestion that changes in diet may somehow change the tempo at which established prostate cancer progresses, although embraced whole-heartedly by many patients, is still controversial among physicians. The limitations of this kind of research are acknowledged, and point out the need for prospective intervention trials. However, prospective trials, particularly prevention trials, are hugely expensive. Thompson et al3 argue that the $73 million spent on the Prostate Cancer Prevention Trial testing finasteride versus placebo was absolutely justified, given the wealth of information derived from the trial. TREATMENT OPTIONS FOR LOCALIZED PROSTATE CANCER The challenges faced daily by patients and clinicians in trying to identify the optimal treatment strategies for localized prostate cancer are better understood in the context of the manuscripts in this section. Klotz4 makes a powerful argument suggesting that, as a community, we are overtreating patients, and provides the rationale for identifying patients most suited for expectant management with delayed intervention at the time of progression. In these good-risk patients, active surveillance clearly should be presented as an option. Decision making about the modality of therapy has become considerably more complex with recent technological advances. Smith and Herrell5 describe the robotic approach to radical prostatectomy, whereas Speight and Roach6 describe improved radiation outcomes with the use of higher doses, intensity-modulated radiation therapy, and portal imaging. Although these advances, both surgical and radiotherapeutic, are exciting, preliminary enthusiasm should be tempered by the lack of prospective trials demonstrating clear benefits to these approaches. Finally, at the other end of the clinical aggressiveness spectrum, Gleave and Kelly7 provide the rationale for multimodality therapy incorporating systemic androgen deprivation as well as chemotherapy for patients with high-stage, high-risk disease. Although the feasibility of such an approach is demonstrated, the demonstration of clinical benefit awaits completion of randomized trials. WHEN LOCAL THERAPY FAILS As the use of definitive local therapy has spread, so, too, has the number of patients who relapse after such therapy. These relapses, termed "serologic progression," represent a heterogeneous group of patients, some of whom may never require additional therapy, and others who are destined to die from their disease within a relatively short time period. Three articles in this issue, by Lee and D'Amico,8 Stephenson and Eastham,9 and Hayes and Pollack,10 address the challenges faced in the treatment of these patients. A critical issue is identification of those patients best suited for salvage local therapy. The article by Lee and D'Amico points out that prostate-specific antigen (PSA) kinetics are a powerful new tool for predicting local versus systemic relapse. Although such tools are a welcome addition to our diagnostic armamentarium, clearly the future lies in a more careful understanding of the gene expression profiles that might identify patients who are destined to develop metastatic disease, versus those in whom local salvage therapy is appropriate. Stephenson and Eastham define the role of salvage radical prostatectomy after radiation therapy, whereas Hayes and Pollack examine salvage radiation after prostatectomy. Although both approaches clearly offer the potential for significant clinical benefit, it can be argued that the role for multimodality therapy might best be in close succession, as opposed to separated in time. Certainly in the case of radiation therapy, there are increasing data to suggest that immediate adjuvant radiotherapy may be superior to salvage therapy. Nevertheless, second-line local therapies are likely to continue to be employed, and a careful understanding of their utility, and most importantly, of the importance of appropriate patient selection underscores the relevance of these three manuscripts. ANDROGEN-DEPRIVATION THERAPY ADT has become ubiquitous. Ryan and Small11 examine the data supporting the earlier use of ADT. Although clearly ADT appears to provide clinical benefit in many disease states, including patients with nonmetastatic disease, this manuscript appropriately points out that the use of ADT in patients with climbing PSA values after local therapy has not been evaluated prospectively. The adverse effects of ADT are well understood, and, as a community, we are beginning to understand how to address some of these adverse effects. Nevertheless, there is strong interest in developing ADT strategies that may be less morbid, and just as importantly, may be more durable. Bhandari, Crook, and Hussain12 have provided a superb overview of the rationale for intermittent ADT, and of the nonrandomized data available to date that suggest that this approach may provide clinical benefit. No definitive conclusions can be drawn about the comparative efficacy of intermittent therapy until completion of two large randomized studies, one in metastatic disease, the other in patients with PSA-only disease. BIOLOGY OF PROSTATE CANCER Three articles explore the biology of advanced prostate cancer. Scher and Sawyers13 have provided a superb summary of what is known about androgen-receptor signaling in castration-resistant prostate cancer, and how this knowledge can inform the development of novel therapeutics, whereas Loberg et al14 discuss the unique tropism of prostate cancer to bone, and the development of bone-targeted therapeutics. Whereas developmental therapeutics in prostate cancer have historically been characterized by a lack of new agents, we are left with great hope for the future, as the large inventory of currently available novel agents demonstrates. The challenge of developing systems to help understand biologic and clinical activity, prioritize drug development, and develop target-validation strategies for an ever-growing number of agents is beyond the scope of these articles and this issue of the JCO, but has clearly become the front line of research. Finally, Webster et al15 review developmental immunotherapeutics in the context of known biology. In the case of immunologic therapeutics, it has become increasingly clear that prostate cancer can indeed be targeted, that immune tolerance can be broken, and that a variety of strategies hold great promise. CASTRATION-RESISTANT PROSTATE CANCER: WHAT WORKS? Three articles address important clinical questions in the day-to-day treatment of advanced prostate cancer patients. Michaelson and Smith16 define the utility of bisphosphonates for the treatment and prevention of bone metastases. The authors appropriately point out that the enthusiasm for bisphosphonate use should be tempered by the relative lack of randomized data in earlier disease states and the small, but real, risk of significant complications, such as osteonecrosis of the jaw. The approval of docetaxel for advanced prostate cancer is a tremendous advance, but has raised a series of questions as well. Ryan and Eisenberger17 raise the issue of timing of chemotherapy. To date, there are no data supporting the use of chemotherapy earlier in the course of prostate cancer, although the history of chemotherapy use in breast cancer should provide us with insight, and is the basis of a number of randomized clinical trials evaluating the use of chemotherapy in earlier stages of the disease. Finally, the increasing use of docetaxel will result in a growing number of docetaxel-resistant or docetaxel-treated patients. Berthold, Sternberg, and Tannock18 review our common practices, as well as the scant literature describing therapeutic options in this new disease state, which represents a clinical state with unmet needs, and which offers the opportunity for future interventions. We hope you find this compendium both a useful resource and catalog of what's known, but just as importantly, as a provocative documentation of what isn't known, and where our challenges lie. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Cooperburg MR, Moul JW, Carroll PR: The changing face of prostate cancer. J Clin Oncol 23:8146-8151, 2005
2. Chan JM, Gann PH, Giovannucci EL: Role of diet in prostate cancer development and progression. J Clin Oncol 23:8152-8160, 2005
3. Thompson IM, Tangen CM, Klein EA, et al: Phase III prostate cancer prevention trials: Are the costs justified? J Clin Oncol 23:8161-8164, 2005
4. Klotz L: Active surveillance for prostate cancer: For whom? J Clin Oncol 23:8165-8169, 2005
5. Smith JA Jr, Herrell SD: Robotic-assisted laparoscopic prostatectomy: Do minimally invasive approaches offer significant advantages? J Clin Oncol 23:8170-8175, 2005
6. Speight JL, Roach M III: Radiotherapy in the management of clinically localized prostate cancer: Evolving standards, consensus, controversies and new directions. J Clin Oncol 23:8176-8185, 2005
7. Gleave M, Kelly WK: High-risk localized prostate cancer: A case for early chemotherapy. J Clin Oncol 23:8186-8191, 2005
8. Lee AK, D'Amico AV: Utility of prostate-specific antigen kinetics in addition to clinical factors in the selection of patients for salvage local therapy. J Clin Oncol 23:8192-8197, 2005
9. Stephenson AJ, Eastham JA: Role of salvage radical prostatectomy for recurrent prostate cancer after radiation therapy. J Clin Oncol 23:8198-8203, 2005
10. Hayes SB, Pollack A: Parameters for treatment decisions for salvage radiation therapy. J Clin Oncol 23:8204-8211, 2005
11. Ryan CJ, Small EJ: Early versus delayed androgen deprivation for prostate cancer: New fuel for an old debate. J Clin Oncol 23:8225-8231, 2005
12. Bhandari MS, Crook J, Hussain M: Should intermittent androgen deprivation be used in routine clinical practice? J Clin Oncol 23:8212-8218, 2005
13. Scher HI, Sawyers CL: Biology of progressive, castration-resistant prostate cancer: Directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol 23:8253-8261, 2005
14. Loberg RD, Logothetis CJ, Keller ET, et al: Pathogenesis and treatment of prostate cancer bone metastases: Targeting the lethal phenotype. J Clin Oncol 23:8232-8241, 2005
15. Webster WS, Small EJ, Rini B, et al: Prostate cancer immunology: Biology, therapeutics, and challenges. J Clin Oncol 23:8262-8269, 2005
16. Michaelson MD, Smith MR: Bisphosphonates for treatment and prevention of bone metastases. J Clin Oncol 23:8219-8224, 2005
17. Ryan CJ, Eisenberger M: Chemotherapy for hormone-refractory prostate cancer: Now it's a question of ‘‘When?’’ J Clin Oncol 23:8242-8246, 2005
18. Berthold DR, Sternberg CN, Tannock IF: Management of advanced prostate cancer after first-line chemotherapy. J Clin Oncol 23:8247-8252, 2005
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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