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Originally published as JCO Early Release 10.1200/JCO.2009.24.4533 on August 31 2009 © 2009 American Society of Clinical Oncology.
Evidence-Based Medicine, Conscience-Based Medicine, and the Management of Low-Risk Prostate CancerRadiation Oncology, Harvard Medical School, Massachusetts General Hospital, Boston, MA What began as a small crack in the solid concept of early detection and early treatment for prostate cancer has now widened and spread. Despite imperfections which limit their interpretation, the recently published randomized screening trials show there is only a small—or even no—improvement in survival from early detection over the first 10 years.1,2 One trial also showed that the number of patients (around 50) that must be treated to save one life is alarmingly high.1 These data come at a time when medical spending, long recognized to be beyond the nation's means, is to be tightened and restructured along evidence-based guidelines with care being directed preferentially toward areas of proven benefit. The Institute of Medicine has drawn up national priorities for comparative effectiveness research, and the management of localized prostate cancer sits squarely in the first quartile.3 Indeed, it is the top-ranking oncologic priority. A perfect storm of clinical evidence and economic reality has arisen in which urologists and radiation oncologists need to examine the evidence, examine their souls, and start to carefully look at every new patient asking, before anything else—is treatment really needed at all? If it is not, and that will frequently be the answer, then they must be prepared to lead the patient along the less financially rewarding and decidedly unglamorous path of active surveillance. The training of resident doctors has to date been so focused on cure, and the culture of early detection/early treatment so deeply in-grained, that it is little wonder that this shift in thinking is yet to reflect itself in everyday practice. What is respectfully acknowledged at major meetings and in editorials is not, in the daily reality of the clinic, being applied to patients. Indeed, in the United States, the proportion of men being managed conservatively has actually been declining.4 The explanations, as hinted, are complex and rooted in a conflict between knowledge and belief with disturbing undertones of economic self-interest. It is time to practice conscience-based medicine. The PCPT (Prostate Cancer Prevention Trial) trial reported in 2004 demonstrated that systematic needle biopsy could find prostate cancer in 27% of all men with a normal prostate-specific antigen (PSA).5 Klotz6 has estimated that at current rates, one in five men will be diagnosed with prostate cancer during their lifetime. We know from the days when no attempt at curative treatment was the norm that no more than 3% of men ever died from this disease, and more recent experience tells us that a significant proportion of men are incurable even when their disease is detected early. Large mismatches between incidence and fatality occur elsewhere in medicine and have been reconciled in different ways. How this has been reconciled in prostate cancer forms the kernel of this debate. Until recently, United States physicians and advocacy groups have strongly favored immediate, curative treatment for all or most men with early prostate cancer. They have argued that this is little different from the treatment of high blood pressure or high serum cholesterol, strategies almost universally applauded. To address prostate cancer differently, it has been said, would be to apply double standards. The absolute risk reduction of stroke or a coronary event is low for any individual but treatment for the entire diagnosed population is justified because the treatments are effective, well tolerated, and relatively inexpensive. How does therapy for prostate cancer compare? Firstly, is it effective? The Scandinavian trials of both surgery and radiation therapy prove that some men with clinically significant, life-threatening, localized disease live longer as a result of their treatment.7,8 At 10 years, 19 men in one trial and 10 in the other needed treatment for a single life saved in a relatively advanced, nonscreen detected group of patients. It is far from clear, however, that low-risk, PSA-detected patients, such as we now most commonly see, would ever progress to the starting line to even enter the Scandinavian trials. Thus, the gains in a screen-detected population must be smaller, and the European Trial of Prostate Cancer Screening (ERSPC) has borne this out.1 Further, in the surgical study, the benefits were only seen for men younger than 65 years. This is important, as screening in the United States now frequently continues well beyond the seventh decade. Tens of thousands of men in their 70s and 80s are being diagnosed with early prostate cancer, men who have relatively little, if anything, to gain from either knowledge of the diagnosis or treatment. It is argued that there are advantages to a patient short of a saved life. They may be prevented from troublesome local progression and spared the misery of future androgen deprivation. Contemporary data do show that local failure is now infrequent after radical treatment but it is also true that symptomatic local progression is unlikely even without treatment and thus little, in reality, is gained. In addition, Barry9 has shown that, far from reducing the use of androgen deprivation through a reduction in metastases and local progression, our heightened responsiveness to the behavior of PSA after therapy has actually increased its use substantially. Many feel that technological advances have tremendously reduced the morbidity and increased the convenience of both surgery and radiation such that they can be regarded as little different from a statin or an antihypertensive. Unfortunately, multicenter studies continue to document a significant impact on the quality of a patient's subsequent life, suggesting that this is not the case.10 If treatments were usefully curative in only a small proportion of patients and really could be made free from all but trivial morbidity could they still be judged sufficiently cost-effective to justify their widespread use? This, of course, depends on the costs of treatment and their future trajectory. In the United States, the costs of prostatectomy have been declining due to better anesthesia, better postoperative pain control, and shorter hospital stays. This is laudable, though recently widespread investment in costly robots to gain a market rather than a therapeutic edge may work against this. Radiation therapy has been headed in two different directions. Brachytherapy became popular in the 1990s due to its speed and convenience. It also happened to be remarkably inexpensive and something of a therapeutic bargain. Unfortunately, recent concerning disclosures about prostate brachytherapy at the Philadelphia Veterans' Administration Hospital and new restrictive regulations that may arise from them could act as a disincentive to both patients and physicians to use this option. The alternative form of radiation, external beam, has increased in complexity with intensity modulation, image guidance, and daily prostate tracking. This has come at greatly increased cost and, for physicians and hospitals, greatly increased reimbursement. The latter has lead to a sharp increase in the use of intensity-modulated radiation, not only among radiation oncologists but also among some urology groups. Urologists have been rapidly establishing intensity modulated radiation therapy centers, referring their own patients, and capitalizing on the windfall. There is now evidence that this has acted as a disincentive to less rewarding options, including brachytherapy and active surveillance.11 Sadly, it may take structural changes to our physician reimbursement system that currently incentivizes intervention and high technology before we see any substantial shift in practice patterns. Klotz6 has been the most potent advocate of a good sense blend of curative treatment and active surveillance. He argues that the test of time can be used as an important prognostic guide, one that is unavailable at the time of diagnosis. The vast majority of men with low-risk disease and many older men with intermediate-risk disease could be subjected to this low-cost, high-yield test. Clear boundaries now exist for safe progression and any patient who deviates from this path will have earned treatment. A large Canadian cohort, now followed close to 10 years, suggest that little is lost by such a strategy. Those who need treatment declare themselves over time and, assuming no other more pressing medical crises intervene, receive it successfully. These men enter into treatment knowing that they need it and are more likely to accept any morbidity that comes with it. The remainder will not receive treatment they do not need. They will be spared the morbidity and society will be spared the cost. It is often said that the anxiety that emerges from a cancer diagnosis is such that men cannot be dissuaded from treatment. Recent work from Canada and the United Kingdom suggests that this need not be the case and that the confidence and initial presentation of the physician is paramount in sparing patients from needless worry.12 The work reported in this edition of Journal of Clinical Oncology by Shappley et al13 is not a randomized study but it is a sufficiently large enough study that we must listen to its findings. It adds to the body of evidence reassuring physicians that it is safe to observe before treating many men with localized disease. They used data from the large Health Professionals Follow-up Study (HPFS) to look at men managed either by immediate treatment or by active surveillance. First, they found that 50% of those diagnosed and not immediately treated ultimately came to some form of treatment. This is a higher proportion than in the Canadian study, but in the HPFS neither clear rules defining progression nor standardized rules triggering intervention were in place. Second, they showed that those most likely to avoid treatment altogether were, as would be anticipated, those with lower-risk cancers and the elderly. Finally, they showed that the relative hazard of either metastasis or time to death from prostate cancer were the same, regardless of whether the patient was treated immediately or not. In the HPFS, only a small proportion of men (10.3%) were not treated immediately reflecting the more traditional aversion of patients and physicians to conservative management during this era. We are all awaiting the results of the massive and comprehensive British ProtecT study, a randomized controlled trial comparing prostatectomy, radiation therapy and active surveillance. We are all impatient for the molecular markers or the functional imaging that will distinguish the Gleason 6 cancer that kills from the majority that do not. In the meantime, the Shappley et al study helps physicians reassure patients, particularly those above the median age for detection, that active surveillance is a safe strategy and one that burns no bridges. Delayed treatment remains an option should the cancer ever prove the need. The evidence is mounting, the advocates of surveillance are finding their voice, and the economic incentives are changing. I am optimistic that we can break our cultural addiction to immediate treatment for all and move toward discriminating, selective, and more socially responsible behavior in this challenging disease. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
NOTES See accompanying article on page 4980 REFERENCES
1. 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. 2. Andriole GL, Crawford ED, Grubb RL, et al: Mortality results from a randomized prostate cancer screening trial. N Engl J Med 360:1310–1319, 2009. 3. Institute of Medicine. Initial National Priorities for Comparative Effectiveness research. http://www.iom.edu/CMS/3809/63608/71025.aspx. 4. Cooperberg MR, Lubeck DP, Meng MV, et al: The changing face of low-risk prostate cancer: Trends in clinical presentation and primary management. J Clin Oncol 22:2141–2149, 2004. 5. Thompson IM, Goodman PJ, Tangen CM, et al: The influence of finasteride on the development of prostate cancer. N Engl J Med 349:215–224, 2003. 6. Klotz L: Active surveillance for prostate cancer: For whom? J Clin Oncol 23:8165–8169, 2005. 7. Bill-Axelson A, Holmberg L, Ruutu M, et al: Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 352:1977–1984, 2005. 8. Widmark A, Klepp O, Solberg A, et al: Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): An open randomized phase III trial. Lancet 373:301–308, 2009.[CrossRef][Medline] 9. Barry MJ, Delorenzo MA, Walker-Corkery ES, et al: The rising prevalence of androgen deprivation among older American men since the advent of PSA testing: A population based cohort study. BJU Int 98:973–978, 2006.[CrossRef][Medline] 10. Sanda MG, Dunn RL, Michalski J, et al: Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 358:1250–1261, 2008. 11. Konski AA, Howald A, Starkey R, et al: The impact of a single disease site treatment facility on prostate cancer care in a community-hospital based radiation oncology practice. J Clin Oncol 26:367s; 2009 (suppl) abstr 6626. 12. Burnet KL, Parker C, Dearnaley D, et al: Does active surveillance for men with localized prostate cancer carry psychological morbidity? BJU Int 100:540–543, 2007.[CrossRef][Medline] 13. Shappley WV III, Kenfield SA, Kasperzyk JL, et al: Prospective study of determinants and outcomes of deferred treatment or watchful waiting among men with prostate cancer in a nationwide cohort. J Clin Oncol 27:4981–4986, 2009.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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