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The n e w e ng l a n d j o u r na l of m e dic i n e Edi t or i a l s Treatment or Monitoring for Early Prostate Cancer Anthony V. D’Amico, M.D., Ph.D. The “best” initial approach to early (low-risk or intermediate-risk)1 prostate cancer remains unknown. Specifically, does active monitoring with the use of prostate-specific antigen (PSA) testing as opposed to treatment lead to increased metastasis and death from prostate cancer? If yes, then which treatment, radical prostatectomy or radiation with or without short-term (3 to 6 months) androgen-suppression therapy, minimizes metastasis and death from prostate cancer? Hamdy and colleagues now report in the Journal the results of a randomized comparison of three of these four approaches after a median follow-up of 10 years,2 and Donovan and colleagues present data on patient-reported healthrelated quality of life at 6 years of follow-up.3 Men were screened with PSA testing and presented at a median age of 62 years with favorable clinical characteristics: 76% had stage T1c (PSAdetected) disease, 77% and 21% had tumors with Gleason scores of 6 and 7, respectively (on a scale from 6 to 10, with higher scores indicating a worse prognosis), and the median PSA level was 4.6 ng per milliliter. Although a median follow-up of 10 years was too short to evaluate the primary outcome of prostate-cancer mortality in this favorable cohort (death from prostate cancer occurred in 8 of the 545 men assigned to active monitoring, 5 of the 553 men assigned to surgery, and 4 of the 545 men assigned to radiotherapy), it was adequate to evaluate the secondary outcome of the incidence of metastatic disease, defined as bony, visceral, or lymph-node metastasis on imaging or a PSA level above 100 ng per milliliter. Several important observations were made. First, men assigned to active monitoring were significantly more likely to have metastatic dis1482 ease than those assigned to treatment (P = 0.004 for the overall comparison), with an incidence that was more than twice as high (6.3 per 1000 person-years vs. 2.4 to 3.0 per 1000 person-years). There was also a trend toward decreased death from prostate cancer among men assigned to surgery (hazard ratio, 0.63; 95% confidence interval [CI], 0.21 to 1.93) or radiation and androgendeprivation therapy (hazard ratio, 0.51; 95% CI, 0.15 to 1.69) versus active monitoring. Although further follow-up will determine whether these trends become significant, causality between an increase in metastatic disease and the use of active monitoring versus treatment was established. The clinical significance of this finding is that with the use of active monitoring, more men will have metastasis and the side effects of salvage treatment (meaning at least lifelong intermittent androgen-deprivation therapy), which are not inconsequential.4 Second, within the prerandomization stratum of age, a near-significant interaction (P = 0.09 for interaction) was observed given that men 65 years of age or older were more likely to die from prostate cancer if assigned to active monitoring than if assigned to treatment. This finding probably reflects the fact that advancing age is associated with higher-grade disease than disease identified at an initial biopsy5 owing to sampling error, resulting in undergrading, the risk of which rises with the increasing prostate-gland volume6 that occurs with advancing age.7 Should the interaction between age and death from prostate cancer among men assigned to treatment versus monitoring become significant, it would support recommending treatment as opposed to monitoring to otherwise healthy men 65 years of age or older with early prostate cancer who today are n engl j med 375;15 nejm.org October 13, 2016 The New England Journal of Medicine Downloaded from nejm.org on March 11, 2017. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved. Editorials increasingly being placed on active surveillance,8 given that the reduction in death from prostate cancer (hazard ratio, 0.63; 95% CI, 0.36 to 1.09) in the Prostate Cancer Intervention versus Observation Trial (PIVOT) only trended toward significance (P = 0.09).9 However, the increasing use of surveillance is already of potential concern, considering that men enrolled in PIVOT had a shorter life expectancy owing to coexisting disease than men of similar age entered into the Surveillance, Epidemiology, and End Results database.10 Finally, a trend favoring radiation and shortcourse androgen-deprivation therapy over surgery was observed. Specifically, the point estimate for the hazard ratio for death from prostate cancer when comparing these two treatments was 0.80 (95% CI, 0.22 to 2.99). If this trend becomes significant, then one may consider radiation and androgen-deprivation therapy as a preferred option for otherwise healthy men 65 years of age or older with early prostate cancer for whom treatment as compared with monitoring may be more effective (P = 0.09 for interaction) in reducing death from prostate cancer. For today, we can conclude on the basis of level 1 evidence2 that PSA monitoring, as compared with treatment of early prostate cancer, leads to increased metastasis. Therefore, if a man wishes to avoid metastatic prostate cancer and the side effects of its treatment,3 monitoring should be considered only if he has life-shortening coexisting disease such that his life expectancy is less than the 10-year median follow-up of the current study.2 In addition, given no significant difference in death due to prostate cancer with surgery versus radiation and short-course androgen-deprivation therapy, men with low-risk or intermediate-risk1 prostate cancer should feel free to select a treatment approach using the data on health-related quality of life3 and without fear of possibly selecting a less effective cancer therapy. Disclosure forms provided by the author are available with the full text of this editorial at NEJM.org. From the Department of Radiation Oncology, Brigham and Women’s Hospital and Dana–Farber Cancer Institute, Boston. This editorial was published on September 14, 2016, at NEJM.org. 1. Mohler JL, Armstrong AJ, Bahnson RR, et al. Prostate can- cer, version 1.2016. J Natl Compr Canc Netw 2016;14:19-30. 2. Hamdy FC, Donovan JL, Lane JA, et al. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med 2016;375:1415-24. 3. Donovan JL, Hamdy FC, Lane JA, et al. Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med 2016;375:1425-37. 4. Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA 2005;294:238-44. 5. Anderson CB, Sternberg IA, Karen-Paz G, et al. Age is associated with upgrading at confirmatory biopsy among men with prostate cancer treated with active surveillance. J Urol 2015;194: 1607-11. 6. Moussa AS, Kattan MW, Berglund R, Yu C, Fareed K, Jones JS. A nomogram for predicting upgrading in patients with lowand intermediate-grade prostate cancer in the era of extended prostate sampling. BJU Int 2010;105:352-8. 7. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. J Urol 1984; 132:474-9. 8. Cooperberg MR, Carroll PR. Trends in management for patients with localized prostate cancer, 1990-2013. JAMA 2015; 314:80-2. 9. Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012;367:203-13. 10. Aizer AA, Chen MH, Hattangadi J, D’Amico AV. Initial management of prostate-specific antigen-detected, low-risk prostate cancer and the risk of death from prostate cancer. BJU Int 2014; 113:43-50. DOI: 10.1056/NEJMe1610395 Copyright © 2016 Massachusetts Medical Society. Solving the Problem of Overdiagnosis Joann G. Elmore, M.D., M.P.H. My patients’ fear of breast cancer is palpable. I see them fret over whether or not to have a mammogram, worry about false positive abnormalities, and struggle to pay for diagnostic evaluations for which they are not reimbursed. This collateral damage of screening is obvious to clinicians. However, increasing evidence now indicates a less obvious outcome of cancer screen- ing — overdiagnosis of diseases that would never cause symptoms or death. The presence and effects of overdiagnosis are less tangible, buried in population statistics rather than patient encounters. Overdiagnosis of breast cancer has been suggested on the basis of multiple studies that used different designs and approaches and is acknowl- n engl j med 375;15 nejm.org October 13, 2016 The New England Journal of Medicine Downloaded from nejm.org on March 11, 2017. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved. 1483