The

n e w e ng l a n d j o u r na l

of

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2. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node

Mark B. Faries, M.D. John Wayne Cancer Institute at Saint John’s Health Center Santa Monica, CA [email protected] Since publication of their article, the authors report no further potential conflict of interest. 1. Thomas JM, Newton-Bishop J, A’Hern R, et al. Excision mar-

gins in high-risk malignant melanoma. N Engl J Med 2004;350: 757-66.

biopsy or nodal observation in melanoma. N Engl J Med 2006; 355:1307-17. [Erratum, N Engl J Med 2006;355:1944.] 3. Faries MB, Thompson JF, Cochran A, et al. The impact on morbidity and length of stay of early versus delayed complete lymphadenectomy in melanoma: results of the Multicenter Selective Lymphadenectomy Trial (I). Ann Surg Oncol 2010;17: 3324-9. DOI: 10.1056/NEJMc1402989

Management of Early Prostate Cancer To the Editor: In reporting on 23.2 years of follow-up in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4), Bill-Axelson et al. (March 6 issue)1 state that radical prostatectomy was superior to watchful waiting with respect to overall and cancer-specific mortality. The conclusions based on this randomized, controlled trial are completely different from those based on the American Prostate Cancer Intervention versus Observation Trial (PIVOT),2 which showed no difference between surgery and watchful waiting. The study designs were very similar. Both were randomized, controlled trials involving roughly 700 patients of a similar mean age, and the inclusion criteria were the same. The mean prostate-specific antigen (PSA) level was 10.1 ng per milliliter in PIVOT and 13 ng per milli­ liter in SPCG-4. PIVOT, as compared with SPCG-4, involved more patients with stage T1c disease (50% vs. 12%), and overall mortality in the watchful-waiting group was similar in the two trials (49.9% vs. 44.8%). Nevertheless, at approximately the same follow-up (10.0 years in PIVOT and 10.8 years in SPCG-43), cancer-specific mortality was less than half as high in the watchful-waiting group (8.4% in PIVOT vs. 19.5% in SPCG-4). It should be clarified whether adherence to the randomized treatment assignment (which was not negligible in PIVOT) or, much more likely, a considerable attribution bias can explain such significant differences in cancerspecific mortality. Bernardo Rocco, M.D. Andrea Conti, M.D. Elisa De Lorenzis, M.D. Ospedale Maggiore Policlinico di Milano Milan, Italy [email protected]

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No potential conflict of interest relevant to this letter was reported. 1. Bill-Axelson A, Holmberg L, Garmo H, et al. Radical prosta-

tectomy or watchful waiting in early prostate cancer. N Engl J Med 2014;370:932-42. 2. Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012;367:203-13. [Erratum, N Engl J Med 2012;367:582.] 3. Bill-Axelson A, Holmberg L, Filén F, et al. Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian Prostate Cancer Group-4 randomized trial. J Natl Cancer Inst 2008;100:1144-54. DOI: 10.1056/NEJMc1403862

To the Editor: Bill-Axelson et al. report longterm follow-up results showing that the benefit of prostatectomy was greater than that of watchful waiting with respect to death from prostate cancer. “Watchful waiting” in this study was defined as doing nothing for cancer until the development of overt metastasis or the occurrence of any symptom related to cancer. However, in 2003, Klotz1 proposed “active surveillance,”2,3 and that concept has been widely adopted recently. As compared with watchful waiting, active surveillance consists of more aggressive policies such as initial selection of low-risk patients according to a specific criterion, strict and systematic monitoring, and early transfer to aggressive intervention even in patients who do not have symptoms.4 Therefore, in the current state of the art, high-risk patients should not be randomly assigned to a passive watchful-waiting group. Clinicians who want to reduce the rate of death from prostate cancer and avoid complications of surgery such as urinary incontinence and erectile dysfunction must be aware that the results of this study cannot be simply applied to daily clinical practice, since the treatment strategy

n engl j med 370;22 nejm.org may 29, 2014

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correspondence

in this study was different from the current Shaheen Alanee, M.D., M.P.H. Danuta Dynda, M.D. standard. Kevin McVary, M.D. Masayoshi Nagata, M.D., Ph.D. Hiroshi Watanabe, M.D. National Center for Global Health and Medicine Tokyo, Japan [email protected]

Masahiro Kami, M.D., Ph.D.

No potential conflict of interest relevant to this letter was reported. 1. Surveillance, Epidemiology, and End Results (SEER) Program.

University of Tokyo Tokyo, Japan No potential conflict of interest relevant to this letter was reported. 1. Klotz L. Active surveillance with selective delayed interven-

tion: a biologically nuanced approach to favorable-risk prostate cancer. Clin Prostate Cancer 2003;2:106-10. 2. Choo R, Klotz L, Danjoux C, et al. Feasibility study: watchful waiting for localized low to intermediate grade prostate carcinoma with selective delayed intervention based on prostate specific antigen, histological and/or clinical progression. J Urol 2002; 167:1664-9. 3. Klotz L. Active surveillance with selective delayed intervention using PSA doubling time for good risk prostate cancer. Eur Urol 2005;47:16-21. 4. Idem. Active surveillance for prostate cancer: overview and update. Curr Treat Options Oncol 2013;14:97-108. DOI: 10.1056/NEJMc1403862

Southern Illinois University School of Medicine Springfield, IL [email protected]

SEER 18 Regs research data + Hurricane Katrina impacted Louisiana cases, Nov 2012 Sub (1973-2010 varying) (http://www .seer.cancer.gov/data/seerstat/nov2012/#). DOI: 10.1056/NEJMc1403862

The Authors Reply: The difference between SPCG-4 and PIVOT with respect to the rate of death from prostate cancer after watchful waiting may be less dramatic than indicated by Rocco et al., because PIVOT had limited statistical power with wide confidence intervals. Furthermore, unlike SPCG-4, PIVOT included many PSA-detected cancers; this contributed to a lead time (during which, by definition, no prostate cancer deaths occur) and an overdiagnosis of clinically insignificant, nonlethal disease. As Nagata et al. emphasize, active surveillance has been suggested during the past decade as a means to reduce overtreatment and its side effects while retaining the benefits of radical treatment when needed. Although these goals are attractive, data are lacking from randomized, controlled trials to support the idea that they are achievable. With regard to the comments by Alanee et al.: possible differences in the benefit of radical prostatectomy between white patients and black patients cannot be studied in the predominantly white Scandinavian population.

To the Editor: Bill-Axelson et al. report that in SPCG-4, radical prostatectomy was protective against death from prostate cancer mainly in men with intermediate-risk disease. These results corroborate those of the PIVOT trial, which suggested a survival benefit from surgery in patients with intermediate-risk and high-risk disease. However, we cannot ascertain whether there are differences in the benefit of radical prostatectomy between white men and black men, since SPCG-4 did not stratify results according to race and only one third of the patients in PIVOT were black. A gross analysis of the Surveillance, Epidemiology, and End Results1 data on 40,930 pa- Hans-Olov Adami, M.D., Ph.D. tients (including 5557 black patients) younger Karolinska Institutet than 65 years of age with a diagnosis of prostate Stockholm, Sweden cancer who were treated with radical prostatec- Anna Bill-Axelson, M.D., Ph.D. tomy between 1989 and 1999 showed a higher Uppsala University Hospital risk of death from prostate cancer among black Uppsala, Sweden men than among white men (relative risk, 1.32; [email protected] 95% confidence interval, 1.22 to 1.43). It is ex- Jan-Erik Johansson, M.D., Ph.D. tremely important to address racial and cultural Örebro University Hospital disparities in health outcomes. Data are lacking Örebro, Sweden from trials to address the possible higher risk of Since publication of their article, the authors report no furdeath from prostate cancer in black and rural ther potential conflict of interest. populations. DOI: 10.1056/NEJMc1403862

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