Download Prostate Cancer Screening: Biases and the Need for Consensus

Otis W. Brawley
Correspondence to: Otis Brawley, MD, FACP, FASCO, American Cancer Society, Chief Medical Officer, 250 Williams St, Atlanta, GA 30322
(e-mail: [email protected]).
In the 1990s, several studies were published showing that serum
prostate specific antigen (PSA) aided in the diagnosis of localized
prostate cancer (1,2). Widespread screening was adopted quickly
in the United States, where it is dogma that early detection and
aggressive treatment saves lives.
This bias toward screening would delay and hinder study to
determine whether screening truly saves lives. It would be more
1522 Editorials
|
JNCI
than 20 years before the results of well-designed prospective
randomized studies would be published assessing the effectiveness of PSA screening—notably, the Prostate, Lung, Colon and
Ovarian Cancer Screening Trial (PLCO)(3,4), which suggested
that screening does not reduce mortality at 13 years median follow-up, and the European Randomized Study of Prostate Cancer
(ERSPC)(5,6) study and Goteborg (7) trial, which suggested that
Vol. 105, Issue 20 | October 16, 2013
2013
Prostate Cancer Screening: Biases and the Need for Consensus
screening does save lives after 11 and 14 years median follow-up,
respectively.
In this issue of the Journal, Haines and Gabor Miklos (8) provide some much needed critical examination of these trials. Biases
are preventing us from determining which finding is correct. No
clinical study is perfect. The scientific process is at its best when
there is publication of studies and thorough discussion in the literature. When proper analysis of a study defines its limitations, it
actually increases the value of the study. Careful examination of a
study and its results leads to a better understanding of the truth
and, often defines additional important questions.
Many show bias in their interpretation of these trials. Those
who had faith in the value of screening were quick to point out the
weaknesses of the PLCO and claim that the ERSPC and Goteborg
trial justified screening. Also, the ERSPC is commonly referred
to as a trial that showed that screening saves lives. In truth, it
is a pooled analysis of seven clinical trials from seven countries.
Each trial has different inclusion criteria, different screening
schedules, and different PSA cutoffs; some have different randomization schema. When presented in meta-analysis format, five
of the seven clinical trials do not show a statistically significant
benefit to screening at the time of analysis. The ERSPC finding
of a 20% decrease in relative risk is driven by substantial benefits
found in the Dutch and Swedish trials (9). Also, 60% of men in
the Goteborg trial were included in the Swedish component of
ERSPC (7). Goteborg might be considered a prolonged follow
up of a subset of ERSPC.
The randomization methods of some of the European trials
may be biased in favor of a finding that screening is beneficial. This
phenomenon was first described in analysis of some colorectal
screening trials. Studies in which the control group did not know
they were in a trial tend to demonstrate a greater benefit to the
intervention compared with trials in which patients were enrolled
and randomized to a screening or control arm (10).
The ideal prospective screening trial is a study of screening and
effective treatment vs no screening with effective treatment if diagnosed. Some of the European trials may be studies of screening and
one type of prostate cancer treatment vs no screening and a different type of treatment if cancer is diagnosed. Men in the European
intervention groups are perhaps more likely treated by expert physicians running the trial, and those diagnosed in the control group
are perhaps more likely to receive care common to the community.
Evidence of this is the imbalance in type of treatment received, as
discussed by Haines and Gabor (8).
Is it possible that screening and treatment did not lower risk
of death in the intervention arms of the European trials but treatment in the control arms increased risk of death attributed to prostate cancer? The realization that men in the control groups with
high-risk localized disease were twice as likely to receive hormonal
therapy compared with men in the control groups is concerning
(29.5% vs 14.7%) (11).
Could the excess use in hormonal therapy in the control group
have contributed to a number of deaths attributed to prostate cancer? For now it can only be presented as a hypothesis that merits
further consideration. A small negative effect of androgen deprivation therapy (ADT) could be powerful. ERSPC was a study
of 182 160 men. Haines and Gabor (8) point out ERSPC had a
jnci.oxfordjournals.org
difference of 158 men in the high-risk groups and only 11 deaths
attributed to prostate cancer in the control group would have
negated the apparent improvement in prostate cancer mortality.
Like PSA screening, ADT with gonadotrophin-releasing hormone analogs and oral antiandrogens was a promising medical
intervention developed in the 1980s. Because of a bias toward
newer therapies, there was early widespread uptake in Europe and
the United States without full assessment of its benefits and risks.
By 1999, more than half of all American patients with prostate cancer were being treated with ADT within 1 year of diagnosis. One
pattern-of-care study suggested that nearly half of all American
men treated with gonadotrophin-releasing hormone agonists were
receiving them for inappropriate reasons (12).
If ADT does increase risk of cardiovascular and thrombotic
events, it is an amazing treatment bias in these screening studies. It
is also ironic that overuse of ADT in the United States and Europe
may account for some of the decline in prostate cancer death rates
over the past 20 years in a very unfortunate way (13). Early deaths
due to ADT-induced cardiovascular and thrombotic disease would
prevent later deaths actually caused by prostate cancer.
In truth, the evidence of harm from hormonal therapies is
mixed. A number of retrospective studies have demonstrated that
hormonal therapy for prostate cancer increases surrogate markers
for cardiovascular disease and diabetes (14). Several retrospective
studies suggest increased risk of death from cardiovascular disease (15–20). Some studies show increased risk of thromboembolic events (21,22), as does one prospective cohort study (23).
Increased risk of death from cardiovascular disease is not seen in
major prospective randomized trials using short-term hormonal
therapy or hormonal therapy with radiation. Indeed, a meta-analysis that incorporated data from eight prospective randomized
trials showed that the incidence of cardiovascular death was not
substantially different in those treated with ADT compared with
placebo (24).
A handicap in analyses of screening as well as ADT studies is the
fact that cause-of-death analyses are imprecise and vary by country and even within country over time. Indeed, it has been suggested that changes in the interpretation of the cause of death on
death certificates may have caused some of the decline in mortality
attributed to prostate cancer seen over the past two decades in the
United States and Europe (13,25).
The controversies in prostate cancer screening and treatment
will only be further settled if these large trials are rigorously analyzed by an objective panel of experts with access to all the data.
This may be the most appropriate way to deal with bias.
Until then, a few things are true. The harms of screening, such
as overdiagnosis and the risk of overtreatment, have been consistently demonstrated in all screening trials to date. Benefits of
screening have only been seen in the studies done in Sweden and
the Netherlands. Most respected professional organizations have
appropriately warned against mass screening and incorporated recommendations for informed decision-making regarding the risks
and benefits of screening within the physician–patient relationship. There are clear benefits to ADT when used appropriately,
even though the risks are incompletely understood. Therefore,
the potential for harm from ADT should be balanced against the
potential benefits (26).
JNCI | Editorials 1523
References
1. Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. New Engl J
Med. 1991;324(17):1156–1161.
2. Mettlin C, Lee F, Drago J, et al. The American Cancer Society National
Prostate Cancer Detection Project. Findings on the detection of early
prostate cancer in 2425 men. Cancer. 1991;67(12):2949–2958.
3.Andriole GL, Crawford ED, Grubb RL 3rd, et al. Mortality results
from a randomized prostate-cancer screening trial. New Engl J Med.
2009;360(13):1310–1319.
4. Andriole GL, Crawford ED, Grubb RL 3rd, et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer
Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer
Inst. 2012;104(2):125–132.
5.Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostatecancer mortality in a randomized European study. New Engl J Med.
2009;360(13):1320–1328.
6. Schroder FH, Hugosson J, Roobol MJ, et al. Prostate-cancer mortality at
11 years of follow-up. New Engl J Med. 2012;366(11):981–990.
7. Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Goteborg
randomised population-based prostate-cancer screening trial. Lancet Oncol.
2010;11(8):725–732.
8. Haines I, Gabor Miklos GL. Prostate-specific antigen screening trials and
prostate cancer deaths: the androgen deprivation connection. J Natl Cancer
Inst. 2013;105(20):1534–1539.
9.
Chou R, LeFevre ML. Prostate cancer screening—the evidence, the r­ecommendations, and the clinical implications. JAMA.
2011;306(24):2721–2722.
10.Autier P, Boyle P, Buyse M, et al. Is FOB screening really the answer
for lowering mortality in colorectal cancer? Recent Results Cancer Res.
2003;163:254–263.
11. Wolters T, Roobol MJ, Steyerberg EW, et al. The effect of study arm on
prostate cancer treatment in the large screening trial ERSPC. Int J Cancer.
2010;126(10):2387–2393.
12.Shahinian VB, Kuo YF, Gilbert SM. Reimbursement policy and
androgen-deprivation therapy for prostate cancer. New Engl J Med.
2010;363(19):1822–1832.
13.Center MM, Jemal A, Lortet-Tieulent J, et al. International variation in prostate cancer incidence and mortality rates. Eur Urol.
2012;61(6):1079–1092.
14.Alibhai SM, Duong-Hua M, Sutradhar R, et al. Impact of androgen
deprivation therapy on cardiovascular disease and diabetes. J Clin Oncol.
2009;27(21):3452–3458.
DOI:10.1093/jnci/djt267
Advance Access publication October 4, 2013
15.Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol.
2006;24(27):4448–4456.
16. Keating NL, O’Malley AJ, Freedland SJ, et al. Diabetes and cardiovascular
disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst. 2010;102(1):39–46.
17.Saigal CS, Gore JL, Krupski TL, et al. Androgen deprivation therapy
increases cardiovascular morbidity in men with prostate cancer. Cancer.
2007;110(7):1493–1500.
18.Tsai HK, D’Amico AV, Sadetsky N, et al. Androgen deprivation therapy
for localized prostate cancer and the risk of cardiovascular mortality. J Natl
Cancer Inst. 2007;99(20):1516–1524.
19. Nanda A, Chen MH, Braccioforte MH, et al. Hormonal therapy use for prostate cancer and mortality in men with coronary artery disease-induced congestive heart failure or myocardial infarction. JAMA. 2009;302(8):866–873.
20. Hayes JH, Chen MH, Moran BJ, et al. Androgen-suppression therapy for
prostate cancer and the risk of death in men with a history of myocardial
infarction or stroke. BJU Int. 2010;106(7):979–985.
21. Ehdaie B, Atoria CL, Gupta A, et al. Androgen deprivation and thromboembolic events in men with prostate cancer. Cancer. 2012;118(13):3397–3406.
22. Van Hemelrijck M, Adolfsson J, Garmo H, et al. Risk of thromboembolic
diseases in men with prostate cancer: results from the population-based
PCBaSe Sweden. Lancet Oncol. 2010;11(5):450–458.
23. Popiolek M, Rider JR, Andren O, et al. Natural history of early, localized
prostate cancer: a final report from three decades of follow-up. Eur Urol.
2013;63(3):428–435.
24.Nguyen PL, Je Y, Schutz FA, et al. Association of androgen deprivation
therapy with cardiovascular death in patients with prostate cancer: a metaanalysis of randomized trials. JAMA. 2011;306(21):2359–2366.
25.Boyle P. Screening for prostate cancer: have you had your cholesterol
measured? BJU Int. 2003;92(3):191–199.
26.Levine GN, D’Amico AV, Berger P, et al. Androgen-deprivation therapy
in prostate cancer and cardiovascular risk: a science advisory from the
American Heart Association, American Cancer Society, and American
Urological Association: endorsed by the American Society for Radiation
Oncology. CA Cancer J Clin. 2010;60(3):194–201.
Note
The author has no conflicts of interest to declare.
Affiliations of author: Office of the Chief Medical Officer, American Cancer
Society, Atlanta, GA; Department of Hematology and Oncology, Emory
University, Atlanta, GA.
© The Author 2013. Published by Oxford University Press. All rights reserved.
For Permissions, please e-mail: [email protected].
From Papanicolaou to Papillomaviruses: Evolving Challenges
in Cervical Cancer Screening in the Era of Human
Papillomavirus Vaccination
Mahboobeh Safaeian, Mark E. Sherman
Correspondence to: Mahboobeh Safaeian, PhD, MPH, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, 9609 Medical
Center Drive, 6E224, MSC 9767, Bethesda, MD 20892 (e-mail: [email protected]).
February 2012 marked the 50th anniversary of the death of George
Papanicolaou, the inventor of the Pap test for cervical cancer
screening. Pap test screening has contributed to sharp reductions
1524 Editorials | JNCI
in cervical cancer incidence and mortality throughout the developed world (1–5). Despite the success of the Pap test, recognition
that it suffers from inadequate single-test sensitivity and frequent
Vol. 105, Issue 20 | October 16, 2013