• A systematic review of prostate cancer screening RTCs

    Two months ago, Mia Djulbegovic and colleagues published in BMJ a systematic review and meta-analysis of randomized controlled trials of prostate cancer screening. Since it’s the latest available such paper and very well done I consider it the source document on this subject. Below I quote and summarize some key findings of greatest importance to me.

    I’ll start with the limitations. The authors write,

    Existing studies have considerable methodological shortcomings that resulted in downgrading of the quality of evidence from high to moderate for all cause mortality and disease specific mortality (critical outcomes) and from high to low quality evidence for diagnosis of prostate cancer (important outcome), as well as considerable inconsistency. […]

    Another limitation of the available evidence relates to the short length of follow-up of reported studies. [Median follow-up was 4, 9, 11, 11.5, 14, and 15 years among the studies examined]. [… F]ollow-up might not have been long enough to detect differences in mortality given the low number of deaths from prostate cancer. Lastly, there was insufficient evidence to analyse the impact of screening on high risk populations, such as patients with a strong family history of prostate cancer or African-Americans.

    One of our predefined objectives was the analysis of the effect of screening interventions based on participants’ age. This analysis was limited by the lack of available data […]

    These are important limitations, but are common among RTCs and slowly progressing diseases. They are limitations that can be overcome to a certain extent and are most easily and cheaply done so with observational studies that can exploit random variations that are akin to the randomization of clinical trials (e.g. practice pattern variations). Of course, observational studies have their own limitations. No study is perfect.

    The authors review six recent prostate cancer screening RTCs that enrolled a total of 387,286 participants, complementing a 2006 study that had examined older trials (see reference [12] below). Like the prior review, the authors did not find evidence to support the routine use of prostate specific antigen (PSA) screening tests.

    [W]e failed to find a significant impact of prostate cancer screening on overall mortality or death from prostate cancer, the most critical outcomes for patients. Evidence for both all cause mortality and death from prostate cancer was of moderate quality […]. In contrast, based on low quality evidence, screening was associated with a 46% relative increase in diagnoses of prostate cancer in the screening arm compared with no screening. A predefined subgroup analysis based on disease stage indicated that this relative increase was attributable mainly to an increase in the number of men diagnosed with stage I prostate cancer. There was no significant impact of screening on the diagnosis of stage II and stages III and IV prostate cancer. These findings suggest that screening leads to an increase in diagnosis of early stage prostate cancer that does not seem to translate into a benefit in overall survival and survival specific to prostate cancer. […] Our results confirm previously voiced concerns about overdiagnosis of prostate cancer—that is, detection of cancer that will not negatively affect survival.

    The paper references many relevant and important articles on this topic, which I will be reading (or have already read). Below is the subset of referenced papers of most interest to me. Reference numbers are as cited in the article.

    References

    4 Schroder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl JMed 2009;360:1320-8.

    5 Boyle P, Brawley OW. Prostate cancer: current evidence weighs against population screening. CA Cancer J Clin 2009;59:220-4.

    6 Esserman L, Shieh Y, Thompson I. Rethinking screening for breast cancer and prostate cancer. JAMA 2009;302:1685-92.

    7 Barry MJ. Screening for prostate cancer—the controversy that refuses to die. N Engl JMed 2009;360:1351-4.

    8 Wolf AMD, Wender RC, Etzioni RB, Thompson IM, D’Amico AV, Volk RJ, et al. American Cancer Society guideline for the early detection of prostate cancer: update 2010. CA Cancer J Clin 2010;60:70-98.

    9 Brawley OW, Gansler T. Introducing the 2010 American Cancer Society prostate cancer screening guideline. CA Cancer J Clin 2010;60:68-9.

    10 American Urological Association. AUA responds to American Cancer Society guideline for the early detection of prostate cancer 2010. American Urological Association. March 3, 2010. www.auanet.org/ content/press/press_releases/article.cfm?articleNo=178.

    12 Ilic D, O’Connor D, Green S, Wilt T. Screening for prostate cancer. Cochrane Database Syst Rev 2006;3:CD004720.

    13 Jegu J, Tretarre B, Grosclaude P, Rebillard X, Bataille V, Malavaud B, et al. Results and participation factors to the European randomized study of screening for prostate cancer (ERSPC) with prostate specific antigen: French departments of Tarn Herault. Prog Urol 2009;19:487-98.

    14 Andriole GL, Crawford ED, Grubb RL, 3rd, Buys SS, Chia D, Church TR, et al. Mortality results from a randomized prostate-cancer screening trial.N Engl J Med 2009;360:1310-9.

    15 Hugosson J, Carlsson S, Aus G, Bergdahl S, Khatami A, Lodding P, et al. Mortality results from the Göteborg randomised populationbased prostate-cancer screening trial. Lancet Oncol 2010;11:725-32.

    23 Hoffman R. Randomized trial results did not resolve controversies surrounding prostate cancer screening. Curr Opin Urol 2010;20:189-93.

    24 Brawley OW, Ankerst DP, Thompson IM. Screening for prostate cancer. CA Cancer J Clin 2009;59:264-73.

    26 Sandblom G, Varenhorst E, Löfman O, Rosell J, Carlsson P. Clinical consequences of screening for prostate cancer: 15 years follow-up of a randomised controlled trial in Sweden. Eur Urol 2004;46:717-24.

    27 Varenhorst E, Carlsson P, Capik E, Lofman O, Pudersen K. Repeated screening for carcinoma of the prostate by digital rectal examination in a randomly selected population. Acta Oncol 1992;31:815-21.

    28 Labrie F, CandasB, Cusan L, Gomez JL, Belanger A, BrousseauG, et al. Screening decreases prostate cancer mortality: 11-year followup of the 1988 Quebec prospective randomized controlled trial. Prostate 2004;59:311-8.

    29 Labrie F, Candas B, Dupont A, Cusan L, Gomez JL, Suburu RE, et al. Screening decreases prostate cancer death: first analysis of the 1988 Quebec prospective randomized controlled trial. Prostate 1999;38:83-91.

    30 Labrie F, Cusan L, Gomez J, Levesque J, Candas B. Screening and treatment of localized prostate cancer decreases mortality: first analysis of the first prospective and randomized study on prostate cancer screening. Aging Male 1999;2:33-43.

    36 Welch HG, Black WC. Overdiagnosis in cancer. J Natl Cancer Inst 2010;102:1-9.

    37 Etzioni R, PensonDF, Legler JM, di TommasoD, Boer R, Gann PH, et al. Overdiagnosis due to prostate-specific antigen screening: lessons from U.S. prostate cancer incidence trends. J Natl Cancer Inst 2002;94:981-90.

    38 Draisma G, Boer R, Otto SJ, van der Cruijsen IW,Damhuis RAM, Schroder FH, et al. Lead times and overdetection due to prostatespecific antigen screening: estimates fromthe European randomized study of screening for prostate cancer. J Natl Cancer Inst 2003;95:868-78.

    39 Draisma G, Etzioni R, Tsodikov A, Mariotto A, Wever E, Gulati R, et al. Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context. J Natl Cancer Inst 2009;101:374-83.

    43 Donovan J, Hamdy F, Neal D, et al. Prostate testing for cancer and treatment (ProtecT) feasibility study. Health Technol Assess 2003;7:1-81.

    44 The ProtecT trial. Evaluating the effectiveness of treatment for clinically localised prostate cancer 2007. ISRCTN Register. 11 June 2010. www.controlled-trials.com/ISRCTN20141297.

    45 Evaluating population-based screening for localised prostate cancer in the United Kingdom: an extension to the ProtecT treatment trial 2006. ISRCTN Register 17 March

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    • Interesting. Will ask urology buddies about this one.

      Slightly OT. I cannot actively recall economists using much, if any, meta-analysis in their literature. Am I just missing it, or is that something more limited to medicine?

      Steve