More on Screening Mammography

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1 correspondence 1. Fairman JA, Rowe JW, Hassmiller S, Shalala DE. Broadening the scope of nursing practice. N Engl J Med 2011;364: Aiken LH. Nurses for the future. N Engl J Med 2011;364: Institute of Medicine. The future of nursing: leading change, advancing health. Washington, DC: National Academies Press, Patchin RJ. AMA responds to IOM report on future of nursing. October 5, ( news/nursing-future-workforce.shtml.) 5. Larkin GL, Hooker RS. Patient willingness to be seen by physician assistants, nurse practitioners, and residents in the emergency department: does the presumption of assent have an empirical basis? Am J Bioeth 2010;8: Freed GL, Dunham KM, Lamarand KE, Loveland-Cherry C, Martyn KK. Pediatric nurse practitioners: roles and scope of practice. Pediatrics 2010;126: American Medical Association GeoMapping Initiative. Chicago: AMA, To the Editor: In their Perspective article, Broadening the Scope of Nursing Practice, Fairman et al. highlight the findings and recommendations of the recent Institute of Medicine (IOM) report, The Future of Nursing: Leading Change, Advancing Health. 1 The report advocates reliance on collaborative, multidisciplinary, team-based care to improve the quality and delivery of care in a transformed health care system. The American College of Physicians strongly supports this model. Nurses, physician assistants, physicians, and other health care professionals should practice to the full level of their training and clinical skills, working as part of a collaborative team, and inappropriate barriers that stand in their way should be examined and revised accordingly. We agree that certified nurse practitioners can provide many core primary care services, but it is important that this not be misunderstood as suggesting that nurses are interchangeable with physicians in providing the full depth and breadth of services that primary care physicians provide. The two professions are complementary but not equivalent. For diagnostic evaluation of clinical presentations that are not straightforward and for ongoing management of complex or interacting medical problems, the most appropriate clinician is a physician who has received in-depth training in the diagnosis and treatment of conditions affecting all organ systems and who can effectively integrate current and evolving scientific knowledge with the delivery of clinical care. Any examination of state licensing laws, as the IOM recommends, should therefore distinguish between inappropriate restrictions on nurses or other licensed health care professionals that prevent them from practicing to the full level of their training and experience as part of a collaborative team and laws designed to ensure that licensed health care professionals are providing care consistent with their level of training and skills. The IOM has done a great service by providing a comprehensive set of recommendations that, although focusing on the nursing profession, appropriately emphasize the importance of physicians, nurses, physician assistants, and other health care professionals working together to provide high-quality, patient-centered care, through delivery systems (such as the patientcentered medical home) that use everyone s skills and training optimally. It is essential, however, that further discussions of and communications relating to the IOM report provide sufficient clarity on the issues to prevent misunderstanding. Care should be taken by everyone involved in the implementation of the IOM recommendations to ensure that they are not misconstrued as blurring the important differences in training and skills between the medical and nursing professions and in their respective contributions to team-based and patient-centered care. J. Fred Ralston, Jr., M.D. Steven E. Weinberger, M.D. American College of Physicians Philadelphia, PA Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. 1. Institute of Medicine. The future of nursing: leading change, advancing health. Washington, DC: National Academies Press, These letters ( /NEJMc ) were published on December 15, 2010, at NEJM.org. More on Screening Mammography To the Editor: Kalager et al. (Sept. 23 issue) 1 report that in their observational study, they found a 10% reduction in breast-cancer related mortality associated with their national screening program. However, a number of important issues require clarification by the authors. First, why was disease-specific mortality used as the measured outcome when all-cause mortality is n engl j med 364;3 nejm.org january 20,

2 T h e n e w e ngl a nd j o u r na l o f m e dic i n e considered more robust and unambiguous? In the Cochrane review in 2001, all-cause mortality was unchanged or higher among women who underwent screening mammography in eight of the nine trials. 2 There is now a consensus that all-cause mortality is a more valid outcome than disease-specific mortality in detecting the effect of cancer screening. 3 Second, could the authors comment on the disparity between their findings (an increase in mortality of 4% among women younger than 50 years of age) and those of the World Health Organization (WHO) breast-cancer mortality database, which shows a reduction in mortality of 35% among women younger than 50 years of age in Norway between 1989 and 2006? 4 Third, is it possible that the overall findings of Kalager et al. are due to the population benefit of the introduction of a screening program that increases breast health awareness and leads to increased self-examination and subsequent opportunistic mammography? 5 John P. Burke, Ph.D. Mitchel Barry, M.D. Malcolm R. Kell, M.D. Mater Misericordiae University Hospital Dublin, Ireland drjohnpburke@yahoo.ie 1. Kalager M, Zelen M, Langmark F, Adami HO. Effect of screening mammography on breast-cancer mortality in Norway. N Engl J Med 2010;363: Olsen O, Gotzsche PC. Cochrane review on screening for breast cancer with mammography. Lancet 2001;358: [Erratum, Lancet 2006;367:474.] 3. Newman DH. Screening for breast and prostate cancers: moving toward transparency. J Natl Cancer Inst 2010;102: Autier P, Boniol M, La Vecchia C, et al. Disparities in breast cancer mortality trends between 30 European countries: retrospective trend analysis of WHO mortality database. BMJ 2010; 341:c Stockton D, Davies T, Day N, McCann J. Retrospective study of reasons for improved survival in patients with breast cancer in East Anglia: earlier diagnosis or better treatment. BMJ 1997; 314: [Erratum, BMJ 1997;314:721.] To the Editor: Kalager et al. find a smaller effect of breast-cancer screening on breast-cancer mortality than previously reported estimates. 1,2 We think that their approach, although well executed, underestimates the true effect of breastcancer screening considerably. If we use U.S. data on incidence, survival, and mortality, and we use the exact same method, with a 77% attendance and a follow-up time of an average of 2.2 years, we also find an identical 10% effect of screening on incidence-based mortality among women who were between the ages of 50 and 69 years at diagnosis. The microsimulation model known as microsimulation of screening analysis fatal diameter (MISCAN-Fadia), 3 which was developed to estimate screening and treatment effects in the United States, 1,3,4 enables us to simulate a longer follow-up time. When the follow-up time is prolonged by 5 years, the effect of screening is predicted to increase to 16% (Table 1). Furthermore, an additional benefit is expected for women 70 years of age or older, since screening reduces the incidence and thus the incidence-based mortality in this age group. Table 1. Rate Ratios for Death from Breast Cancer among Women between the Ages of 50 and 69 Years at Diagnosis.* Study and Input Assumption Rate Ratio Screening Effect No Screening Screening percent Kalager et al. 77% attendance and follow-up time (average, 2.2 yr) MISCAN-Fadia 77% attendance and short follow-up time % attendance and short follow-up time % attendance and 5 yr longer follow-up time % attendance and 5 yr longer follow-up time * MISCAN-Fadia denotes microsimulation of screening analysis fatal diameter. The rate ratios are calculated by dividing the rate of death in the current group by the rate of death in the historical group. For the screening effect, the value shown is the difference between the rate ratio for death among women in the screening group and the rate ratio for death among women in the nonscreening group. 282 n engl j med 364;3 nejm.org january 20, 2011

3 correspondence The reported modest reduction in mortality is associated with the very short follow-up time. The actual effect of the Norwegian breast program is predicted to be larger. Nicolien T. van Ravesteyn, M.Sc. Eveline A.M. Heijnsdijk, Ph.D. Harry J. de Koning, M.D., Ph.D. Erasmus Medical Center Rotterdam, the Netherlands 1. Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 2005;353: Otto SJ, Fracheboud J, Looman CW, et al. Initiation of population-based mammography screening in Dutch municipalities and effect on breast-cancer mortality: a systematic review. Lancet 2003;361: Tan SY, van Oortmarssen GJ, de Koning HJ, Boer R, Habbema JD. The MISCAN-Fadia continuous tumor growth model for breast cancer. J Natl Cancer Inst Monogr 2006;36: Mandelblatt JS, Cronin KA, Bailey S, et al. Effects of mammography screening under different screening schedules: model estimates of potential benefits and harms. Ann Intern Med 2009;151: [Erratum, Ann Intern Med 2010;152:136.] To the Editor: The conclusion by Kalager et al. that mammography was associated with only a modest reduction in the rate of death from breast cancer is premature because of what may be the shortest average follow-up time in the published screening literature. Moreover, the authors state, without explanation, that the first year of screening was included in both the nominally screening-exposed and nonscreening-exposed groups. This inclusion cancels the results of the first year of screening, during which the greatest number of screen-detected cases would occur. Since the authors do not report the actual exposure to screening, tumor characteristics in patients in geographic areas with and without screening, or basic measures of screening performance, the study is handicapped in terms of both scope and depth. Moreover, it is disingenuous to claim that this method is new in isolating the contributions of screening versus therapy and awareness. There is a rich literature that has grappled with these challenges and done so with more adequate follow-up. Unsurprisingly, these studies show that mammography screening accounts for a considerably greater proportion of the trend in reduced breast-cancer mortality. Stephen W. Duffy, M.Sc. Queen Mary, University of London London, United Kingdom s.w.duffy@qmul.ac.uk Robert A. Smith, Ph.D. American Cancer Society Atlanta, GA To the Editor: Little scientific attention has been paid to the interaction of cancer screening and treatment. When early treatment during the asymptomatic phase does not improve the outcome, screening is not useful. But what about screening when treatments become highly effective regardless of symptoms? The U.S. Preventive Services Task Force recommends against screening for testicular cancer, partly because treatment is so successful. 1 In breast cancer, improvements in therapy have coincided with study results showing less certainty about screening effects. Besides the article by Kalager et al., 10- year mortality results were not statistically significant in the most recent randomized trial in the United Kingdom, with lower-than-expected mortality in the unscreened group 2 ; a population-based case control study in the United States in 2005 also showed no significant effect of breast-cancer screening. 3 Screening has been important in the fight against cancer, but it is an imperfect tool, with the need for repeated screens in millions of people over decades, false positive results, and overdiagnosis. We should all look forward to the time when better treatments (and new primary prevention strategies such as vaccinations) reduce the need for cancer screening. Suzanne W. Fletcher, M.D. Harvard Medical School Boston, MA suzanne_fletcher@hms.harvard.edu Joann G. Elmore, M.D., M.P.H. University of Washington School of Medicine Seattle, WA 1. Screening for testicular cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement draft. Rockville, MD: Agency for Healthcare Research and Quality, ( 2. Moss SM, Cuckle H, Evans A, Johns L, Waller M, Bobrow L. Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years follow-up: a randomized controlled trial. Lancet 2006;368: Elmore JG, Reisch LM, Barton MB, et al. Efficacy of breast cancer screening in the community according to risk level. J Natl Cancer Inst 2005;97: n engl j med 364;3 nejm.org january 20,

4 T h e n e w e ngl a nd j o u r na l o f m e dic i n e To the Editor: Kalager et al. report a 10% reduction in breast-cancer mortality with the introduction of screening in Norway, but this could have been caused by centralization and specialization of care, rather than by screening. Denmark has a unique control group, since only 20% of the population was screened during a 17-year period. Our results reported in March support those of Kalager et al. Breastcancer mortality was reduced by 1% per year in the areas of the country with access to screening as compared with 2% in the areas without screening in women who could benefit (i.e., women between 55 and 74 years of age). In women who were too young to benefit (those who were between 35 and 55 years of age), the decrease was 5% per year in the screened areas and 6% in the areas without screening. Autier et al. found that in 30 European countries, breast-cancer mortality decreased by 37% among women younger than 50 years and by 21% among women between 50 and 69 years of age. 2 These data provide strong evidence that better treatment and breast-cancer awareness, not mammography screening, are responsible for the declines in breast-cancer mortality. Karsten J. Jørgensen, M.D. Nordic Cochrane Center Copenhagen, Denmark Per-Henrik Zahl, M.D. Norwegian Institute of Public Health Oslo, Norway Peter C. Gøtzsche Nordic Cochrane Center Copenhagen, Denmark 1. Jørgensen KJ, Zahl PH, Gøtzsche PC. Breast cancer mortality in organised mammography screening in Denmark: comparative study. BMJ 2010;340:c Autier P, Boniol M, La Vecchia C, et al. Disparities in breast cancer mortality trends between 30 European countries: retrospective trend analysis of WHO mortality database. BMJ 2010; 341:c3620. To the Editor: In his editorial, Welch 1 stresses the importance of informing patients adequately about the nature and magnitude of the trade-off involved in screening mammography. It is necessary to highlight that the estimates of reductions in breast-cancer mortality, overdiagnosis, and false positive rates vary between organized screening programs and contexts in which Table 1. Cumulative Risk of a False Positive Result and a False Positive Result Leading to an Invasive Procedure.* No. of Mammographic Examinations False Positive Result Cumulative Risk False Positive Result Leading to an Invasive Procedure percent * Invasive procedures are cytologic tests and biopsies. early diagnosis is based on opportunistic access to mammographic testing. In Italy, estimates of false positive rates in organized screening programs are much lower than those reported in the United States. 2,3 In a screening program in Florence that began in 1991, a total of 28,500 women between 50 and 69 years of age were screened at the first round and followed for 15 years. A total of 2963 women had at least one useless assessment (i.e., a false positive result), and 329 had a subsequent invasive assessment (i.e., cytologic examination or biopsy). Table 1 shows the cumulative risk of a false positive result according to the number of mammographic examinations. In conclusion, we agree with the author about guaranteeing to each woman a real, personal, informed choice. However, to reach that goal, we strongly support the use of reliable and contextspecific information. Donella Puliti, M.Sc. Guido Miccinesi, M.D. Marco Zappa, M.D. Istituto per lo Studio e la Prevenzione Oncologica Florence, Italy m.zappa@ispo.toscana.it 1. Welch HG. Screening mammography a long run for a short slide? N Engl J Med 2010;363: Paci E, Giorgi D, Del Turco MR. False positive rate of screening mammography. N Engl J Med 1998;339: n engl j med 364;3 nejm.org january 20, 2011

5 correspondence 3. Elmore JG, Barton MB, Moceri VM, Polk S, Arena PJ, Fletcher SW. Ten-year risk of false positive screening mammograms and clinical breast examinations. N Engl J Med 1998;338: The Authors Reply: We agree with Burke et al. that all-cause mortality is important, although there is no consensus on the use of all-cause mortality as a primary end point in cancerscreening studies. 1 We found no difference in allcause mortality between the screening and nonscreening groups in our study. Among women younger than 50 years of age, we found a decreased reduction in mortality of 23 to 27% in the current screening and nonscreening groups as compared with the historical groups; this is consistent with the WHO report. The 4% increase referred to by Burke et al. is the difference between the screening and nonscreening groups. The role of opportunistic screening is discussed in our article. Van Ravesteyn et al. and Duffy and Smith question the follow-up time in our study. In most clinical trials, follow-up time is defined as the time from randomization or invitation to death, exclusion, or the end of follow-up. The average of 2.2 years of follow-up in our study is the time from the diagnosis of breast cancer to one of the above-mentioned end points. The follow-up time will always be limited, since newly eligible subjects enter a continuing program. Our followup time is similar to that of several other studies on breast-cancer screening programs. 2-4 Moreover, among patients in region I, which consisted of more than 40% of the study population, there were 10 years of follow-up and a mortality reduction similar to the reduction seen in the whole study. Finally, the mortality reduction was limited to the first years of follow-up, with no sign of additional benefit after that (Fig. 1). The predictions by the MISCAN-Fadia model are interesting but require assumptions about key variables. If the model incorporated our findings in Figure 1, it would be difficult to explain a very large change in mortality reduction with a 5-year average follow-up time. Duffy and Smith may have misunderstood our analysis; all screen-detected cancers are included in the screening group. The Supplementary Appendix, available with the full text of our article at NEJM.org, explains the calculation of personyears. Even though surrogate measures such as screening performance and tumor characteristics Smoothed Rate of Death from Breast Cancer (per 100,000 person-yr) Historical screening group Historical nonscreening group 5 Current screening group Current nonscreening group Years of Follow-up Figure 1. Smoothed Incidence-Based Rates of Death from Breast Cancer per 100,000 Person-Years, According to Follow-up Time among Women between 50 and 69 Years of Age at Diagnosis. are scientifically interesting, there was no room for these measures within the space limitations of our article. We have included the variables necessary to evaluate the program. Previous studies have estimated the benefit of screening versus breast-cancer awareness and treatment to be between 28 and 65%; this estimate is in line with our results. 5 Fletcher and Elmore and Jørgensen et al. address a very interesting topic: how early does one have to detect breast cancer to cure the patient? With improved and more individually tailored treatment, greater awareness that leads women to seek health care for early symptoms may be sufficient to detect tumors at a curable stage. Hence, the role of mammography screening could be less important than it was some decades ago, when the clinical trials of mammography were carried out. In closing, we have to remind readers that our article evaluates the Norwegian breast-cancer screening program. The program is about breastcancer screening, but it is not an evaluation of breast-cancer screening. Mette Kalager, M.D. Marvin Zelen, Ph.D. Hans-Olov Adami, M.D., Ph.D. Harvard School of Public Health Boston, MA mkalager@hsph.harvard.edu n engl j med 364;3 nejm.org january 20,

6 T h e n e w e ngl a nd j o u r na l o f m e dic i n e Since publication of their article, the authors report no further potential conflict of interest. 1. Tabar L, Duffy SW, Yen MF, et al. All-cause mortality among breast cancer patients in a screening trial: support for breast cancer mortality as an endpoint. J Med Screen 2002;9: Olsen AH, Njor SH, Vejborg I, et al. Breast cancer mortality in Copenhagen after introduction of mammography screening: cohort study. BMJ 2005;330: Jørgensen KJ, Zahl PH, Gøtzsche PC. Breast cancer mortality in organised mammography screening in Denmark: comparative study. BMJ 2010;340:c Duffy SW, Tabár L, Chen HH, et al. The impact of organized mammography service screening on breast carcinoma mortality in seven Swedish counties. Cancer 2002;95: Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 2005;353: The Editorialist Replies: The point made by Puliti et al. is very well taken: women do need context-specific information on how the risk of false positive results increases with repeated screening mammography. They are also correct in highlighting that this risk is lower in organized screening programs throughout Europe than in the more haphazard mammography practice of the United States. However, the context-specific information women most need to make an informed choice about screening is more challenging to acquire that is, data on the current mortality benefit and the harm of overdiagnosis. H. Gilbert Welch, M.D., M.P.H. Dartmouth Institute for Health Policy and Clinical Practice Lebanon, NH Since publication of his article, the author reports no further potential conflict of interest. mtor Inhibitors and Autosomal Dominant Polycystic Kidney Disease To the Editor: We are concerned that findings in the two studies of autosomal dominant polycystic kidney disease (ADPKD) (Aug. 26, 2010, issue) one by Walz and colleagues 1 and the other by Serra and colleagues 2 may be misconstrued. Rather than condemning renal volume as a surrogate marker of disease progression, as Walz and colleagues conclude from their study of everolimus for the treatment of ADPKD, the results may be viewed as confirming that rates of kidney-volume increase can be substantially decreased by means of a mammalian target of rapamycin (mtor) inhibitor, as predicted by prior studies. 3,4 The everolimus study includes patients with late-stage ADPKD, an experimental design that precluded the observation of improved renal function in many participants; more than half of everolimus-treated subjects had stage III or IV chronic kidney disease. We suggest that everolimus therapy may benefit renal function in patients whose kidneys have not passed the point of no return. In the study by Serra and colleagues, 2 patients with ADPKD with smaller kidneys and better function (94% with stage I or II chronic kidney disease) received sirolimus, which had no significant effect on changes in kidney and cyst volume or estimated glomerular filtration rate (GFR); we suggest that the sirolimus dose may have been suboptimal. The potential effect of mtor inhibitors to preserve GFR before irreversible damage has occurred remains to be determined. The use of kidney and cyst volumes as surrogate markers of disease progression in patients with early stage ADPKD is rational and supported by strong scientific evidence. 5,6 Jared J. Grantham, M.D. Kansas University Medical Center Kansas City, KS jgrantha@kumc.edu William M. Bennett, M.D. Legacy Good Samaritan Hospital Portland, OR Ronald D. Perrone, M.D. Tufts Medical Center Boston, MA Dr. Grantham reports receiving consulting fees from Otsuka; and Dr. Perrone, research support from Otsuka. Otsuka manufactures tolvaptan. No other potential conflict of interest relevant to this letter was reported. 1. Walz G, Budde K, Mannaa M, et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2010;363: [Errata, N Engl J Med 2010;363:1190, 1977.] 2. Serra AL, Poster D, Kistler AD, et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med 2010;363: Torres VE, Boletta A, Chapman A, et al. Prospects for mtor 286 n engl j med 364;3 nejm.org january 20, 2011