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Controversies in the Management of Localized Prostate Cancer: After the Rhetoric

Controversies in the Management of Localized Prostate Cancer: After the Rhetoric

For the September and October issues of ­ONCOLOGY, we have assembled a team of experts in the diagnosis and management of early-stage prostate cancer—ie, disease that has not clinically metastasized at first presentation, and which is theoretically curable—and have asked them to take a position on optimal patterns of care. This has been a topic of great controversy for decades, and the choice of optimal therapy has constituted a real challenge for most patients. All of these nationally renowned clinician investigators would normally seek some measure of middle ground; however, we have asked them to be deliberately polemical, and to help to frame the debate for those of us who, in turn, have to advise our patients.

This month, Amin Mirhadi and Howard Sandler defend the position that “Radical Radiotherapy for Prostate Cancer Is the Only Way to Go,” while Heidi Rayala and Jerome Richie maintain, “Radical Prostatectomy Reigns Supreme.” In next month’s ONCOLOGY, Jay Ciezki and Eric Klein consider, “Brachytherapy or Surgery? A Composite View,” and Michael Large and Scott Eggener address “Active Surveillance for Low-Risk Localized Prostate Cancer.” These articles are accompanied by brief commentaries from other noted physicians in the field, including Edward Schaeffer and Stacy Loeb; Deborah Kuban; Joseph Aronovitz and Martin Sanda; and David Penson.

In my view, these manuscripts elegantly indicate that there are not vast differences in survival between the results of surgery or radiotherapy, but that the differences in toxicity are real, and clear understanding of these differences should be important in the decision process for patients. It is clear that many clinicians are inaccurate when reporting patient perceptions of toxicity, and we should increasingly be developing algorithms to quantify these toxicities.[1]

An emerging oddity is the proportion of urologists in clinical practice who have recently taken a 180° change in direction, altering their practices from emphatic emphasis on radical prostatectomy to the purchase of radiotherapy equipment and hiring of radiation oncologists to supervise delivery of this treatment. As noted in the commentary from David Penson, active surveillance is not just idle watching, and is a very reasonable option that should be considered carefully, especially in light of some of the randomized screening trial data discussed below.

Uneven Progress

The field of prostate cancer has been advancing rapidly in some domains, and with less clarity and speed in others. For example, important work is being done to unravel the causation and epidemiology of the disease, with creative gene-mapping,[2] investigation of viral etiology,[3] and studies of the impact of stroma and many other factors.[4] These developments will eventually influence our management of early-stage disease. We are coming to understand the importance of tumor heterogeneity in confounding some management pathways,[5] and thus, the importance of multidisciplinary management.

In particular, it appears that we are altering the natural history of stage C disease, when managed by radiation or surgery, provided that these local modalities are combined with androgen-suppression therapy.[6-9] Of equal importance, it is becoming clear that androgen suppression has its own costs, most specifically the evolution of metabolic syndrome, depression, impaired bone health, and psychosexual consequences, and chemotherapy also may have unanticipated late effects when used in the adjuvant setting for prostate cancer.[10] Thus, there is a real need to anchor each proposed new step with randomized clinical trials that assess outcomes and toxicities carefully.

In developing new drugs, either for advanced disease or the adjuvant setting, an important challenge remains—specifically, to define an optimal surrogate marker of true utility in order to enable increased speed of drug development without the loss of accuracy. The US Food and Drug Administration has been struggling with this for years. In advanced disease, prostate-specific antigen (PSA) response has been studied extensively,[11,12] but this measurement is imperfect and often inaccurate. Similarly, patient-reported outcomes focused on symptoms and well-being are confounded by methodologic flaws and limitations.[13]

Most recently, we have proposed absolute levels and posttreatment fluxes in measurable circulating tumor cells (CTCs) as useful surrogate markers for systemic therapy of advanced disease,[14,15] but this will require validation in well-controlled randomized clinical trials. Further studies would be needed to demonstrate whether CTCs are relevant in the management of localized prostate cancer. Real progress can only be achieved by increasing the participation of our patients in structured clinical trials,[16] analogous to those of the breast cancer community.

The Screening Debate

Perhaps the most vexed issue in early-stage prostate cancer, and the one with the most general impact, is the issue of community-wide screening. The true definition of “screening” refers to the assessment of asymptomatic members of the general population for a particular disease, and requires that when the process is successful (with early identification of the disease), it will result in decreased morbidity of treatment or reduced overall mortality. For many years, an accepted “truth” in the urologic community has been that screening for prostate cancer should be innately beneficial, based on the fair concept that earlier diagnosis is associated with a lower potential for occult established metastases and a higher potential for cure by local therapeutic means. While the theory is attractive, it doesn’t always work out in clinical practice—for example, the failure of annual chest x-rays to achieve improvement in survival from lung cancer in structured clinical trials.

In support of the concept, which has been advocated by influential organizations such as the American Urological Association (AUA) and the American Cancer Society (ACS), it has been claimed that improved outcomes in communities that employ screening of asymptomatic patients are due to those screening activities. For example, the percentage of patients presenting with advanced-stage disease and of those dying from prostate cancer in the Austrian Tyrol, compared to those diagnosed, has fallen since the introduction of routine screening techniques.[17] Similarly, it is claimed that the death rate from prostate cancer has fallen in the United States since the introduction of PSA measurement in the 1980s.

The counterargument is that any increment in survival may also be due to improved patient education, more accurate diagnostic and staging techniques (also contributing to stage migration), a more active approach to salvage care by clinicians (accompanied by improved salvage therapies), and the impact of combined-modality treatment on locally advanced disease. Furthermore, the statistic of absolute number of deaths from prostate cancer in the United States has hovered in the range of 26,000 to 30,000 per year since the 1980s, when PSA testing first became widespread. In the definitive ACS Cancer Statistics overview in 1985, it was noted that there were an estimated 24,000 deaths from prostate cancer.[18] In the equivalent data set from 2007, the estimate was 27,050[19]—hardly a quantum leap forward!

Furthermore, it has been clearly shown that 30% to 50% of men over the age of 60 years have occult prostate cancer present,[20] and yet a vastly smaller proportion of that community succumb to the disease, indicating considerable heterogeneity of its natural history. Finally, there have been previously no published randomized trials of screening for prostate cancer. For these and other reasons, the American College of Physicians and the Agency for Health Care Policy and Research have declined to recommend routine screening of asymptomatic men.

Bottom Line

This year, for the first time, two seminal randomized trials of community screening for prostate cancer have been published.[21,22] The results have been scrutinized, interpreted, manipulated, and discussed ad nauseam at meetings and in print, and do not bear detailed recitation here. However, the bottom line is important: viz, neither trial demonstrated a statistically significant overall survival benefit from screening large numbers of asymptomatic males. No matter how you play with the data, an overall survival benefit was not shown, despite overdiagnosis and treatment of some patients.

While some might accept Benjamin Disraeli’s wry comment about “lies, damned lies, and statistics” when considering the new data, these studies did not provide evidence to support unstructured community-wide screening. Indeed, it is puzzling that the AUA continues to advocate this approach, presumably hoping to save a proportion of those who might die from prostate cancer, at the expense of overtreating many who are not destined to succumb to the disease.

The problem is to identify which patients have potentially bad disease, and thus, this commentary has come full circle. Hopefully the laboratory will provide the answer. Until then, it is essential that we educate our patients, inform them of the options and the available data, identify our own conflicts of interest, offer participation in well structured clinical trials, and if possible, avoid doing harm.

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. Clark JA, Inui TS, Silliman RA, et al: Patients’ perceptions of quality of life after treatment for early prostate cancer. J Clin Oncol 21:3777-3784, 2003.
2. Ostrander EA, Johannesson B: Prostate cancer susceptibility loci: Finding the genes. Adv Exp Biol Med 617:179-190, 2008.
3. Klein EA, Silverman R: Inflammation, infection and prostate cancer. Curr Opinion Urol 18:315-319, 2008.
4. Wikstrom P, Marusic J, Stattin P, et al: Low stroma androgen receptor level in normal and tumor prostate tissue is related to poor outcome in prostate cancer patients. Prostate 69:799-809, 2009.
5. Kang TY, Nichols P, Skinner E, et al: Functional heterogeneity of prostatic intraepithelial neoplasia: The duration of hormonal therapy influences the response. BJU Int 99:1024-1027, 2007.
6. Bolla M, de Reijke TM, Van Tienhoven G, et al: Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med 360:2516-2527, 2009.
7. Messing EM, Manola J, Yao J, et al: Eastern Cooperative Group Study EST 3886. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 7:472-479, 2006.
9. Glode LM, Tangen CM, Hussain MH, et al: Southwest Oncology Group 9921: Prolonged event-free survival in high-risk prostate cancer (PC) patients receiving adjuvant androgen deprivation (abstract 5009). J Clin Oncol 27(15S):237s, 2009.
10. Flaig TW, Tangen CM, Hussain MH, et al: Randomization reveals unexpected acute leukemias in Southwest Oncology Group prostate cancer trial. J Clin Oncol 26:1532-1536, 2008.
11. Petrylak DP, Tangen CM, Hussain MH, et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513-1520, 2004.
12. Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: A Canadian randomized trial with palliative end points. J Clin Oncol 14:1756-1764, 1996.
13. Reeve BB, Potosky AL, Willis GB: Should function and bother be measured and reported separately for prostate cancer quality-of-life domains? Urology 68:599-603, 2006.
14. DeBono JS, Scher HI, Montgomery RB, et al: Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 14:6302-6309, 2008.
15. Scher HI, Jia X, de Bono JS, et al: Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer. A re-analysis of IMMC 38 trial data. Lancet Oncol 10:233-239, 2009.
16. Raghavan D: An essay on rearranging the deck chairs: What’s wrong with the cancer trials system? Clin Cancer Res 12:1949-1950, 2006.
17. Oberaigner W, Horninger W, Klocker H, et al: Reduction of prostate cancer mortality in Tyrol, Austria, after introduction of prostate-specific antigen testing. Am J Epidemiol 164:376-384, 2006.
18. Cancer statistics, 1985. CA Cancer J Clin 35:19-35, 1985.
19. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2007. CA Cancer J Clin 57:43-66, 2007.
20. Yin M, Bastacky S, Chandran U, et al: Prevallence of incidental prostate cancer in the general population: A study of healthy organ donors. J Urol 179:892-895, 2008.
21. Andriole GL, Grubb RL III, Buys SS, et al: Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 360:1310-1319, 2009.
22. Schroder FH, Hugosson J, Roobol MJ, et al: Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 360:1320-1328, 2009.

 
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