1. Re: Randomised prostate cancer screening: 20 year follow-up

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Aubrey Wilkinson
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1 1. Re: Randmised prstate cancer screening: 20 year fllw-up Harriet E Burn, Fundatin year 1 dctr Miss Sheila Fraser, and Mr. Sabapathy Balasubramanian Ryal Hallamshire Hspital, Sheffield Dear Editr, We read with interest the recent paper entitled 'Randmised prstate cancer screening: 20 year fllw-up'. The clinical relevance f this paper and its applicability t the general ppulatin led t its discussin at ur jurnal club meeting. Whilst this study has many strengths including its large sample size, lng-term fllw-up and extensive data set it did raise a few questins. 1. The methdlgy fr the screening test evlved ver the study perid. It is nt clear why men frm the screening grup aged 69 years r abve were nly excluded frm the 4th screening sessin rather than cnsistently thrugh ut. 2. This study began with DRE as the screening test. PSA was nly included in the third screening sessin. In additin t the cmbined utility f DRE and PSA, it wuld be useful t understand the individual cntributins f these tests t the early detectin f prstate cancer.. 3. Overdiagnsis f indlent tumurs has been rightly emphasised as a significant drawback t screening. There has hwever been little emphasis n 'unnecessary investigatins', need fr early repeat testing and 'patient anxiety' as a cnsequence f a 'false psitive' DRE r PSA. It wuld be useful t knw the number f 'false psitive' results frm PSA, DRE and the cmbinatin f the tw. We are als unable t tell if the cmbinatin f DRE and PSA reduced r increased the number f false psitive results. 4. What are the predictive values f the individual tests and the cmbinatin? This is f clinical significance fr a screening test and we are unable t calculate it frm the infrmatin given. 5. Figures xx and yy demnstrate verall and disease specific mrtality nly in patients diagnsed with prstate cancer in the tw grups, which may be misleading. We believe that it may be mre apprpriate t have demnstrated verall and disease specific mrtality in the tw grups verall as per allcatin. Kind regards, Dr. H. Burn, FY1 General Surgery Miss S. Fraser, SpR General Surgery

2 Mr S Balasubramanian, Cnsultant General Surgen harriet.burn@nhs.net Cmpeting interests: Nne declared 2. Re:Evidence f verdiagnsis due t screening fr prstate cancer Gil D Tlan, Physician University f Texas Health Science Center at San Antni In the lwer right crner f page 3 f 6, the authrs state: "In a Cx prprtinal hazard analysis, the hazard rati fr death frm prstate cancer was 1.23 (0.94 t 1.62; P=0.13) and 1.58 (1.06 t 2.36; P=0.024) after adjustment fr age at start f the study." Des the hazard rati f 1.23 mean being assigned t the uninvited grup increases prstate cancer mrtality by 23% cmpared t the invited grup r des 1.23 mean nly thse assigned t the uninvited grup with prstate cancer have 23% mre deaths than the invited grup with prstate cancer, i.e., what is the denminatr? Is the hazard rati f 1.23 unadjusted fr age at assignment while 1.58 was adjusted fr age? Was adjustment fr age pre-specified BEFORE the investigatrs analized their mrtality rates r was this pst hc analysis. If pst hc analysis, hw many mrtality risk factrs were tested fr an effect n case rate mrtality? If the assignment t grup was based n date f birth, the age distributins f the tw grups shuld be nearly identical. Why then was the Cx prprtinal hazard analysis adjusted fr age at start f the study? Certainly screening detects mre slw grwing/relatively benign prstate cancers such that case rate mrtality with nly prstate cancers in the denminatr will favr screening ver n screening with fewer slw grwing prstate cancers. Mrever, screening asymptmatic men is intended t detect at an earlier stage befre metastases. Cnsequently detecting any cancer at an earlier stage prlngs survival pst diagnsis even if n treatment was given t any case in either grup. Fr these reasns, please cmpare bth prstate cancer mrtality and all cause mrtality by assigned grup beginning n the day f assignment, nt day f diagnsis. In their discussin f plicy indicatins, the authrs list adverse effects f treatment. Please cmpare the rates f each f these adverse effects with assigned grup in the denminatr. Cmpeting interests: Nne declared 3. This is nt a randmised trial Martin Bland, Prfessr f Health Statistics University f Yrk The title f this paper is "Randmised prstate cancer screening trial: 20 year fllw-up". But this is nt a randmised trial. In the Methds we are tld "1494 men were randmly allcated t be screened by including every sixth man frm a list f dates f birth." Selecting every sixth man frm a list is systematic, nt randm. "Randm" implies that chance has a rle in the selectin, but here the members f the

3 treatment grup are determined as sn as the first ne is selected. In this particular study, the allcated grups may be cmparable, but they are nt randm. Cmpeting interests: Nne declared 4. Re: Randmized prstate cancer screening trial: 20 year fllw-up Fritz H. Schrder, urlgist Erasmus Medical Center, Rtterdam, the Netherlands Dear Editr, As the internatinal crdinatr f the Eurpean Randmized study f Screening fr Prstate Cancer (ERSPC) I shuld like t react t the recent publicatin f the reprt by Sandblm et al n the 20-year fllw-up study f cancer screening cnducted in the lake area f Sweden. Our grup has fllwed previus publicatins with attentin and interest. The present paper presents the 20-year fllw-up f this study, the lngest duratin f any randmized screening trial s far. The authrs are t be cngratulated with this achievement. Unfrtunately the trial has majr shrtcmings f which I shuld like t address sme: 1. The grup f men randmized t screening is rather small. Of the 1,494 men nly 1,161 participated in the initial screening (78%). The 22% refusers are apparently excluded frm the intentin-t-screen analysis which is nt crrect an intentin-t-screen analysis. 2. Infrmatin n the sample size calculatin is cntradictry in the paper. The authrs state in the methds sectin that 'the sample size was calculated t allw assessing the acceptance and feasibility f a prstate cancer screening prgram'. Further dwn in the statistics sectin it is stated that 'the study was designed t detect a plausible reductin f prstate cancer specific mrtality within 20 years'. Which f the statements is crrect? 3. Of the 85 prstate cancers diagnsed in the screening arm, 42 (49%) were detected as interval cancers. This pints at ineffective screening by rectal examinatin during the first tw screening runds. These interval cancers, if ne fllws table 2, are likely t have a very high adverse prgnstic impact if ne cnsiders their unfavrable stage and grade distributin and the imbalance in applied treatments. 4. Kaplan-Meier prjectins are used t present trial results n mrtality as 'survival curves'. The authrs d nt take accunt f the lead-time bias which is inherent t this cmparisn f 'survival'. In cnclusin, it seems unlikely that this trial has the capability f answering the questin whether screening is effective r nt.

4 Prf.dr. F.H. Schrder Internatinal crdinatr ERSPC Cmpeting interests: Nne declared 5. Cmment n Sanblm, et al Jesse N. Arnwitz, Physician University f Massachusetts Medical Schl Sandblm, et al, reprt the lng-term results f a series f men randmised t a prgramme f prstate cancer screening. Screening cnsisted f 2-4 digital rectal exams and 1-2 PSA determinatins (dependent upn subjects' age). With fllw-up f up t 20 years, there des nt appear t be a statistically significant survival benefit fr screening. There are three pints abut this reprt that are wrthy f cnsideratin: 1. A quarter f the men randmised t the screening chrt did nt attend. 2/3 f the attendees were nt invited fr a secnd PSA determinatin (due t age). This suggests that, n average, the 'screened' ppulatin had a single PSA determinatin. This was likely nly slightly mre ften than the 'cntrl' grup ('Until 1994, less than ne (PSA) test per man was perfrmed in Sweden'). Can a single PSA test seriusly be cnstrued as a 'screening prgramme'? 2. Only a quarter f the men diagnsed with prstate cancer in the 'screened' chrt were treated with curative intent (radical prstatectmy, brachytherapy, r external raditherapy). 3. Abut half the men diagnsed with prstate cancer, whether in the 'screened' r 'cntrl' grup, died f their disease. We have read the authrs' cnclusins. It wuld be equally valid t cnclude that the reasn fr the dismal prstate cancer survival amng Nrrkping's men is that they were underscreened and undertreated. Cmpeting interests: Nne declared 6. Bias in the presentatin and interpretatin f study results favurs prstate cancer screening Maren Dreier, Senir researcher Ulla Walter, Thrsten Meyer Medical Schl Hannver

5 The main utcme t examine the effect f prstate screening is prstate cancer specific mrtality. T determine a difference in the ttal mrtality (assuming a 25 % relative risk reductin in prstate cancer specific mrtality and a 10 year fllw-up) is nearly impssible, because this wuld need mre than a millin study participants due t the lw prprtinate mrtality frm prstate cancer [1]. Sandblm et al. [2] present valuable data f a ppulatin-based randmised cntrlled study n the effect f prstate cancer screening. The authrs' aim is t assess the prstate cancer specific mrtality, which is in accrdance with the current scientific status. Hwever, the number f the prstate cancer specific mrtality is nt presented in the paper. Instead, the authrs indicate a "prstate cancer specific mrtality" in the screening grup f 35 % and in the cntrl grup f 45 %, which actually represents the case fatality rate. The true prstate cancer specific mrtality calculated by the numbers given in the paper was 30 / (2.0 %) in the screening grup and 130 / (1.7 %) in the cntrl grup resulting in an abslute excess risk in the screened cmpared t the unscreened f 0.3 % and a relative excess risk f 16.3 %. The differences between the grups are nt significant because f the size f the study ppulatin. This pint estimate f the relative excess risk is similar t the effect f mammgraphy screening [3] and clrectal screening using the fecal ccult bld test [4] - albeit in the ther directin. In additin, the authrs present tw misleading figures with survival rates. These figures suggest that screening results in higher, thugh nn- significant, survival. Hwever, survival f patients diagnsed with prstate cancer is nt an adequate utcme measure in the cntext f screening because it is prne t (1) lead time bias and (2) verdiagnsis bias [5]. (1) Lead time is the time perid by which screening advances the diagnsis cmpared t n screening. S the benefit fr the screened persn starts when survival time minus lead time is higher than the survival time f the nn-screened. The mean lead time in the first screening rund with prstate-specific-antigen (PSA) in the Eurpean Randmised Study f Screening fr Prstate Cancer (ERSPC) was estimated t be 6.8 years (95 % cnfidence interval ) [6]. The lead time in this study can be estimated t be 1.6 years (mean age f prstate cancer diagnsis in the cntrl grup minus mean age f the prstate cancer diagnsis in the screening grup). S, unless the lead time will be taken int accunt, survival curves are biased in favur f the screening grup. (2) Bias frm verdiagnsis means that in screening nnprgressive cancers might be detected, which withut screening wuld never have been diagnsed. Cnsequently, these cancers wuld have never been treated and als wuld never have caused death. The verdiagnsis f prstate cancer in this study can be estimated t be (abslute) 1.8 % f all men in the screening grup r (relative) 32 % f the prstate cancer cases in the screening grup. S, verdiagnsis is anther imprtant factr that biases the cmparisn f survival in the cntext f screening, if the denminatr nly includes men diagnsed with prstate cancer. Fr n apparent reasn, the nly significant result f the analysis is nt discussed. The authrs calculated the risk rati (RR = 1.16; 95 % cnfidence interval ) and the hazard rati (HR) fr death frm prstate cancer (HR = 1.23; 95 % cnfidence interval ; p = 0.13). After adjustment fr age, the hazard rati becmes significant: HR = 1.58 (95 % cnfidence interval ; p = 0.024). Taken seriusly, this result shuld at least be viewed as an indicatin that prstate cancer screening practised like

6 in this study is assciated with a substantially higher risk f prstate cancer specific mrtality. It is t ur knwledge the first study t find this and shuld be discussed apprpriately. The subject has a big impact n public health and the PSA test as a screening tl is discussed cntrversially based n the tw main studies [7, 8]. Due t the knwn pssible severe negative effects f verdiagnsis we shuld be very sensitive fr an impartial presentatin and interpretatin f results. One might agree with the authrs verall cnclusin that the prstate cancer specific mrtality des nt differ between the grups. Hwever, it shuld als taken int accunt that this might be the first randmised study that suggests that prstate cancer screening might cause mre harm than benefit with regard t the disease specific mrtality. Cmpeting interests: nne declared References 1. Dubben HH. Trials f prstate-cancer screening are nt wrthwhile. Lancet Oncl 2009; 10: Sandblm G, Varenhrst E, Rsell J, Lfman O, Carlssn P. Randmised prstate cancer screening trial: 20 year fllw-up. BMJ 2011:342:d Gtzsche PC, Nielsen M. Screening fr breast cancer with mammgraphy. Cchrane Database Syst Rev 2011;(1):CD Hewitsn P, Glasziu P, Irwig L, Twler B, Watsn E. Screening fr clrectal cancer using the faecal ccult bld test, Hemccult. Cchrane Database Syst Rev 2007;1:CD Gigerenzer G, Gaissmaier W, Kurz-Milcke E, Schwartz LM, Wlshin S. Helping dctrs and patients t make sense f health statistics. Psychl Sci Public Interest 2007;8: di: /j x. 6. Finne P, Fallah M, Hakama M, Ciatt S, Hugssn J, de KH, et al. Lead-time in the Eurpean Randmised Study f Screening fr Prstate Cancer. Eur J Cancer 2010 Nv;46(17): Andrile GL, Grubb RL, Buys SS et al. Mrtality Results frm a Randmized Prstate-Cancer Screening Trial. NEJM 2009; 360 (13): Schreder FH, Hugssn J, Rbl MJ et al. Screening and Prstate -Cancer Mrtality in a Randmized Eurpean Study. NEJM 2009; 360 (13): Cmpeting interests: Nne declared 7. Evidence f verdiagnsis due t screening fr prstate cancer

7 Bernard Jund, Researcher Rbert M. Kaplan, Philippe Fucras, Dminique Dupagne, and Philippe Nict Frmindep The paper "Randmised prstate cancer screening trial: 20 year fllw -up" by Gabriel Sandblm et al. [1] suggested that the chances f death ver 20 years are 35% fr thse assigned t screening and 45% amng thse nt randmly chsen t get a screening invitatin. In a randmised ppulatin RCT, death due t prstate cancer shuld be the mst significant utcme variable. But the paper uses "prstate cancer specific mrtality", that is ccurrence f death amng cases, r in ther terms, case fatality rate. As public health researchers and general practitiners, we asked if the prbability f death frm prstate cancer was significantly lwer in the grup randmly selected fr screening. The data available in the publicatin suggests that it was nt. Amng 1494 men invited t screening, 30 (2.0 %) died frm prstate cancer. Amng 7532 men nt invited t screening, 130 (1.7 %) died frm prstate cancer. These bserved prprtins f death frm prstate cancer are nt given in the paper and they clearly d nt differ at the p<.05 level. Using data available in the reprt, we lked fr ther differences between the interventin and the cntrl grups. The paper gives the risk f "prstate cancer" diagnsis: 5.7 % in the interventin grup versus 3.9% in the cntrl grup. The chance prbability f this difference is clse t.001. The increased risk f "prstate cancer" in the invited grup is 5.7 % % = 1.8 %. In the paper, cases due t this increased risk are cnsidered "indlent tumurs that d nt reduce prstate cancer specific survival r verall survival". Such cases fit well the classical definitin f verdiagnsis [2]. The expected number f verdiagnsed cases in the invited grup amunts t 1.8 % f 1494 r 27 cases. The gd new fr the cntrl grup is that 137 men (1.8 % f 7532) escaped verdiagnsis because they were nt invited t screening. Overdiagnsis des nt favur patient's health: it is assciated with vertreatment. It des nt favur sund research either. It gives the illusin f favurable prgnsis: verdiagnsed cases d nt die frm the disease. Survival analysis that is limited t diagnsed cases is cnfusing because it is influenced by verdiagnsis. A cmparisn between cases nly shuld first remve abut 27 verdiagnsed cases in excess wh did nt die frm prstate cancer within the grup invited t screening. Survival analysis given in Figure 2 and 3 f the paper [1] shws an illusinary imprved prgnsis amng cases in the interventin versus cntrl grup because it des nt cmpare equivalent cases. Each verdiagnsed case cntributes t the illusin f increased survival. Figure 4 f the paper [1] gives cumulative rates f prstate cancer specific mrtality, that is the risk f death due t prstate cancer amng cases nly. Instead, the paper wuld have been mre infrmative if it reprted mrtality due t prstate cancer in each whle grup btained after randm allcatin. Such a cmparisn f the cumulative risk f dying frm prstate cancer between interventin and cntrl grups wuld give a result

8 independent f verdiagnsis. It wuld serve evidence-based medicine requiring distinctin and independence f any misleading influence [3]. Cnflict f interest in prstate cancer care: nne declared References 1. Sandblm G, Varenhrst E, Rsell J, Lfman O, Carlssn P. Randmised prstate cancer screening trial: 20 year fllw-up. BMJ 2011:342:d Etzini R, Pensn DF, Legler JM, et al. Overdiagnsis due t prstate- specific antigen screening: Lessns frm U.S. prstate cancer incidence trends. JNCI 2002;94(13):

The principles of evidence-based medicine

The principles of evidence-based medicine The principles f evidence-based medicine By the end f this mdule yu shuld be able t: Describe what evidence based medicine is Knw where t find quality evidenced based medicine n the internet Be able t