Prostate cancer mortality in areas with high and low prostate cancer incidence

Vol. 106, Issue 3 | dju007 | Ma ch 12, 2014 DOI:10.1093/jnci/dju007 Fi s published online Ma ch 4, 2014 1 o 9 A icle | JNCI © Ox o d Uni e si y P ess 2014. This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion- NonComme cial-NoDe i s licence h p://c ea i ecommons.o g/licenses/by-nc-nd/3.0/), which pe mi s non-comme cial ep oduc ion and dis ibu ion o he wo k, in any medium, p o ided he o iginal wo k is no al e ed o ans o med in any way, and ha he wo k is p ope ly ci ed. Fo comme cial e-use, please con ac [email p o ec ed] A icle P os a e cance Mo ali y in A eas Wi h High and low P os a e cance incidence Pä S a in, Sig idCa lsson, BennyHolms öm, And ewVicke s, JonasHugosson, HansLilja, HåkanJonsson Manusc ip ecei ed June 14, 2013; e ised No embe 25, 2013; accep ed Decembe 19,2013. Co espondence o: Pä S a in, MD, PhD, Depa men o Su ge y and Pe iope a i e Sciences, U ology and And ology, Umeå Uni e si y, Umeå, Sweden (e-mail: pa .s a [email p o ec ed]). Backg ound The e ec o p os a e-speci ic an igen (PSA) sc eening on p os a e cance mo ali y emains deba ed, despi e e idence om andomized ials. We in es iga ed he associa ion be ween p os a e cance incidence, e lec ing up ake o PSA es ing, and p os a e cance mo ali y. Me hods The s udy popula ion consis ed o all men aged 50 o 74yea s esiding in eigh coun ies in Sweden wi h an ea ly inc ease in p os a e cance incidence and six coun ies wi h a la e inc ease du ing wo ime pe iods. Incidence o me as a ic p os a e cance was in es iga ed in he pe iod om 2000 o 2009, and p os a e cance –speci ic mo al- i y and excess mo ali y we e in es iga ed in he pe iod om 1990 o 1999 and he pe iod om 2000 o 2009 by calcula ing a e a ios o high- s low-incidence coun ies and a e a ios o he pe iod om 2000 o 2009 s he pe iod om 1990 o 1999 wi hin hese wo g oups. All s a is ical es s we e wo-sided. Resul s The e we e 4 528 134 pe son-yea s a isk, 1577 dea hs om p os a e cance , and 1210 excess dea hs in men wi h p os a e cance in high-incidence coun ies and 2 471 373 pe son-yea s a isk, 985 p os a e cance dea hs, and 878 excess dea hs in low-incidence coun ies in he pe iod om 2000 o 2009. Ra e a ios in coun ies wi h high s low incidence adjus ed o ime pe iod we e 0.81 (95% con idence in e al [CI]=0.73 o 0.90) o p os a e cance – speci ic mo ali y and 0.74 (95% CI=0.64 o 0.86) o excess mo ali y, and he a e a io o me as a ic p os a e cance was 0.85 (95% CI=0.79 o 0.92). Conclusions The lowe p os a e cance mo ali y in high-incidence coun ies e lec ing a high PSA up ake sugges s ha mo e- in ense as compa ed wi h less-in ense oppo unis ic PSA sc eening educes p os a e cance mo ali y. JNCI J Na l Cance Ins (2014) 106(3): dju007 doi:10.1093/jnci/dju007 The use o p os a e-speci ic an igen (PSA) sc eening o de ec ion o p os a e cance emains con o e sial. Two la ge, popula ion- based, andomized clinical ials— he Eu opean Randomized S udy o Sc eening o P os a e Cance (ERSPC) and he Gö ebo g ial—demons a ed 21% o 44% s a is ically signi ican dec eases in p os a e cance –speci ic mo ali y a e 11 o 14yea s o ollow- up in sc eened s unsc eened men (1,2). In con as , he p os a e a m o he US P os a e, Lung, Colo ec al, and O a ian cance sc eening ial (PLCO) ound no bene i om sys ema ic sc een- ing compa ed wi h oppo unis ic sc eening (3). Thus, a con o e sy on PSA sc eening s ill emains, and in 2012 he US P e en i e Se ices Task Fo ce ecommended agains sc eening, s a ing “ he e is mode a e o high ce ain y ha he bene i s o PSA-based sc eening o p os a e cance [in e ms o educed p os a e cance mo ali y] do no ou weigh he ha m [in e ms o o e diagnosis]” (4). This ecommenda ion has been c i i- cized (5–7), and mo e da a on he associa ion be ween PSA sc een- ing and p os a e cance mo ali y a e needed. In addi ion o ex ended da a om ERSPC and he Gö ebo g ial and he awai ed esul s om he ongoing UK P o ecT ial, ca e ully designed and conduc ed obse a ional popula ion-based s udies may p o ide aluable in o ma ion on he associa ion be ween PSA es ing, ea ly diagnosis, and ea men and p os a e cance mo ali y (8,9). Resul s om p e ious obse a ional s ud- ies ha e been inconsis en ; some s udies ha e shown dec eased p os a e cance mo ali y in a eas wi h high PSA es ing (10,11), whe eas o he s ha e ound no such di e ence (12,13). In Sweden, as in many o he Wes e n coun ies, he in oduc- ion o PSA es ing in he 1990s esul ed in an inc ease in p os- a e cance incidence. Excep o a andomized ial on sys ema ic sc eening conduc ed in he ci y o Gö ebo g, he in oduc ion o PSA es ing was in he o m o oppo unis ic sc eening (14). Among he 24 Swedish coun ies, he e we e la ge di e ences in p os a e cance incidence, wi h an es ima ed ou old a ia ion in he p opo ion o men unde going PSA es ing despi e a uni o m, equal-access heal h-ca e sys em (15). JNCI | A icle 2 o 9 jnci.ox o djou nals.o g To capi alize on his na u al expe imen , we e ie ed ou come da a om h ee na ion-wide, popula ion-based egis ies in Sweden and assessed he incidence o me as a ic p os a e cance , p os a e can- ce –speci ic mo ali y, and excess mo ali y in coun ies wi h an ea ly inc ease in he incidence o p os a e cance and in coun ies wi h a la e inc ease, e lec ing di e ences in up ake o PSA es ing, o in es iga e he associa ion be ween PSA es ing and p os a e cance mo ali y. Me hods The Swedish Cance Regis e , Cause o Dea h Regis e , and Na ional P os a e Cance Regis e Swedish law manda es and egula es he egis a ion o inciden can- ce cases in he Swedish Cance Regis e and dea hs in he Cause o Dea h Regis e . The Cance Regis e con ains each pa ien ’s 10-digi pe sonal iden i y numbe , da e o diagnosis, coun y o esidence, and cance si e. The Cause o Dea h Regis e con ains he pe sonal iden- i y numbe , da e o dea h, and unde lying and con ibu o y causes o dea h. Since 1998, app oxima ely 98% o all inciden p os a e cance cases in he Swedish Cance Regis e we e also egis e ed in he Na ional P os a e Cance Regis e , including he eason o he wo k-up ha led o diagnosis, umo s age, Gleason sco e, se um PSA a ime o diagnosis, and p ima y ea men (16,17). Iden i ica ion o P os a e Cance Case Pa ien s and Endpoin s We used he Swedish Cance Regis e o iden i y p os a e cance case pa ien s diagnosed om Janua y 1, 1980, o Decembe 31, 2009, and linked by pe sonal iden i y numbe s (18) o he Na ional P os a e Cance Regis e o ob ain in o ma ion on me as ases a he ime o diagnosis, e idenced by adiog aphic e alua ion (bone scans) o he la ge majo i y o men o se um PSA le els g ea e han 100 ng/mL (16). We ob ained da e and cause o dea h by linkage o he Swedish Cause o Dea h Regis e o dea h a ibu ed o p os a e cance when i was coded as “unde lying cause o dea h.” The s udy was app o ed by he Resea ch E hics Boa d a Umeå Uni e si y Hospi al. S a is ical Analysis We calcula ed he p edic ed p os a e cance incidence— ha is, he incidence ha would be expec ed i no PSA es ing had occu ed. Because PSA es ing was in oduced in clinical p ac ice in Sweden in he 1990s, he p edic ion o each yea up o 2009 was based on he obse ed incidence o he pe iod om 1980 o 1990. We used a linea eg ession model wi h a common slope o calenda yea bu sepa a e in e cep s o each coun y. Age-adjus ed p os a e can- ce incidence o men aged 50 o 74yea s was calcula ed by di ec s anda diza ion wi h weigh s om he Swedish popula ion census o 2000 (19). We hen calcula ed he cumula i e di e ence be ween he obse ed and p edic ed age-adjus ed p os a e cance incidence in men aged 50 o 74yea s s a ing om 1995 and ound a ange o −126 pe 100 000 o 1634 pe 100 000. We used his di e ence o ca ego ize coun ies as ha ing high, in e media e, o low p os a e cance incidence and chose he cu o s o 100 pe 100 000 be ween low- and in e media e-incidence coun ies and 800 pe 100 000 be ween in e media e- and high-incidence coun ies. We used wo measu es o p os a e cance mo ali y—p os a e can- ce –speci ic mo ali y, which was based on he unde lying cause o dea h gi en in he Cause o Dea h Regis e (20,21), and excess mo ali y (22), based on he excess numbe o dea hs (obse ed minus expec ed) ega d- less o cause o dea h among men wi h p os a e cance . We calcula ed he expec ed numbe o dea hs as he p oduc o pe son-yea s among he inciden p os a e cance case pa ien s and he o al mo ali y a e in he popula ion, calcula ed pe yea and pe a ained age in g oups o 5yea s. We de e mined p os a e cance mo ali y du ing wo calenda pe iods, 1990 o 1999 and 2000 o 2009. We calcula ed incidence-based mo ali y o each o he mo ali y measu es based on dea hs among men diagnosed wi h p os a e cance du ing he s udy pe iod (20,21). In addi ion, we calcula ed he 2000 o 2009 incidence o me as a ic p os a e cance (23). To de e mine incidence and mo ali y a es, we used pe son- yea s based on popula ion s a is ics by yea and by 5-yea age g oup. All a es we e measu ed a he popula ion le el (wi h he male popula ion, no he numbe o men wi h p os a e cance as denomina o ). We calcula ed a e a ios (RRs) o high- s low-incidence coun- ies and he a e a ios o he pe iod om 2000 o 2009 s he pe iod om 1990 o 1999 wi hin hese wo g oups. Finally we also de e - mined a e a ios o high- s low-incidence coun ies adjus ed o ime pe iod by di iding by he co esponding a e a io in he pe iod om 1990 o 1999. We calcula ed a e a ios o men aged 50 o 74yea s and he subg oup aged 55 o 69yea s, which was he co e age g oup in he ERSPC s udy (24). We based con idence in e als (CIs) on he assump ion o a Poisson dis ibu ion o he numbe o e en s and calcula ed a iances using he del a me hod on he loga- i hm o he es ima es ollowed by no mal app oxima ion (25). esul s Be ween 1980 and 2009, 197 014 Swedish men aged 50 o 74yea s we e diagnosed wi h p os a e cance , and o hose, 6900 men wi h nonin asi e o seconda y p os a e cance s we e excluded om he s udy. Figu e1 p esen s a low cha o he s udy coho . The e we e 4 528 134 pe son-yea s a isk, 1577 dea hs om p os a e cance , and 1210 excess dea hs in men wi h p os a e cance in high-incidence coun ies and 2 471 373 pe son-yea s, 985 p os- a e cance dea hs, and 878 excess dea hs in low-incidence coun- ies in he pe iod om 2000 o 2009. A apid inc ease in p os a e cance incidence began in some coun ies in 1990 bu no un il 10yea s la e in o he coun ies (Figu e2A). Figu e2B shows he cumula i e di e ence be ween obse ed and p edic ed p os a e cance incidence in each coun y om 1995 o 2009. The di e - ence in incidence be ween he high- and low-incidence coun ies was la ges in 2005 and dec eased he ea e , disappea ing in 2009 (Supplemen a y Figu e1, a ailable online). In he pe iod om 2000 o 2009, he cumula i e incidence o me as a ic disease, p os a e cance –speci ic mo ali y, and excess mo ali y was s a is ically signi ican ly lowe in high-incidence coun ies han in low incidence coun ies (Figu e3, A–C), wi h a e a ios o 0.85 (95%=0.79 o 0.92) o me as a ic disease, 0.87 (95% CI=0.81 o 0.95) o p os a e cance –speci ic mo ali y, and 0.75 (95% CI=0.66 o 0.86) o excess mo ali y (Figu e4A). In high-incidence coun ies, p os a e cance –speci ic mo aliy and excess mo ali y we e s a is ically signi ican ly lowe du - ing he pe iod om 2000 o 2009 han du ing he pe iod om 1990 o 1999, and we obse ed simila , albei somewha weake di e ences in low-incidence coun ies (Figu e4B). When aking Vol. 106, Issue 3 | dju007 | Ma ch 12, 2014 3 o 9 A icle | JNCI bo h coun y g oup and ime pe iod in o conside a ion, he di e - ences in cance -speci ic mo ali y and excess mo ali y be ween high- s low-incidence coun ies emained s a is ically signi ican (Figu e4C). The a e a ios adjus ed o ime pe iod o high- s low-incidence coun ies we e 0.81 (95% CI=0.73 o 0.90) o p os a e cance –speci ic mo ali y and 0.74 (95% CI = 0.64 o 0.86) o excess mo ali y, and he a e a ios o he subg oup o men aged 55 o 69yea s we e simila . The es ima ed a e a io o p os a e cance speci ic mo ali y o 0.81 would co espond o an annual absolu e educ ion a 0.23 pe 1000 men when applied o he Swedish p os a e cance mo ali y yea 2000 in he age g oup 55 o 79yea s. Da a in he Na ional P os a e Cance Regis e om 2000 o 2009 indica ed ha diagnos ic and he apeu ic ac i i y was highe in high-incidence coun ies han in low-incidence coun ies (Table1). In he high-incidence coun ies, median age a diagno- sis was lowe , a highe p opo ion o men had low- isk cance (clinical s age T1–T2, Gleason sco e 2–6, and PSA < 10 ng/mL a diagnosis), a highe p opo ion unde wen adical p os a ec omy, and median se um PSA a diagnosis was lowe . The di e ence be ween high- s low-incidence coun ies in diagnos ic PSA le els was la ges in 2000 (10.0 s 17.6 ng/mL) and dec eased s eadily a e ha (Supplemen a y Table1, a ailable online). The use o adio he apy and adical p os a ec omy showed simila empo al ends wi h he highes use in high-incidence coun ies and wi h a dec easing di e ence o e ime (Supplemen a y Figu e2, a ail- able online). Discussion In his egis e -based, popula ion-based s udy in Sweden, incidence o me as a ic p os a e cance was 15% lowe , and p os a e cance – speci ic mo ali y and excess mo ali y adjus ed o ime pe iod we e 19% and 26% lowe , espec i ely, in coun ies wi h high s low incidence o p os a e cance , e lec i e o ea ly s la e up ake o PSA es ing. These esul s sugges ha oppo unis ic PSA sc een- ing dec eases p os a e cance mo ali y. The s eng h o ou s udy lies in i s popula ion-based design, i s magni ude, he comple eness o he egis e s, and he equal access heal h ca e in he wo s udy g oups. I co e ed nea ly 7 million pe son-yea s a isk and 2562 p os a e cance dea hs egis e ed be ween 2000 and 2009 and had he powe o de ec mode a ely s ong associa ions be ween PSA es ing and p os a e cance dea h. Fu he mo e, PSA es ing is likely o be pa icula ly e ec i e in Sweden because p os a e cance mo ali y is highe in Sweden han in o he coun ies, wi h a li e ime isk o p os a e cance dea h o 5% o 6%, so Swedish men wi h p os a e cance a e a high isk o disease p og ession (26). O he s eng hs o ou s udy we e he use o incidence-based mo ali y, which enabled us o a oid dilu ing isk es ima es by including dea hs among men diagnosed be o e P os a e cance case pa ien s 1980−2009 (n = 197 014) Exclusion o men wi h nonin asi e p os a e cance s ( = PIN) and second p os a e cance (n=6900) S udy popula ion (n = 190 114) In o ma ion on da e and cause o dea h 1980−2009 (n = 118 150) In o ma ion on dis an me as asis 1996−2009 (n = 18 117) Low-incidence coun ies In e media e-incidence coun ies High-incidence coun ies The Swedish Cance Regis e The Swedish Cause o Dea h Regis e The Na ional P os a e Cance Regis e o Sweden 1990−1999 P os a e cance -speci ic mo ali y and excess mo ali y among p os a e cance case pa ien s (2 195 294 pe son-yea s) 2000−2009 Incidence o dis an me as ases p os a e cance -speci ic mo ali y and excess mo ali y among p os a e cance case pa ien s (2 471 373 pe son-yea s) 1990−1999 P os a e cance -speci ic mo ali y and excess mo ali y among p os a e cance case pa ien s (3 925 621 pe son-yea s) 2000−2009 Incidence o dis an me as ases p os a e cance -speci ic mo ali y and excess mo ali y among p os a e cance case pa ien s (4 528 134 pe son-yea s) Figu e1. Flow cha o linkages be ween he Swedish Cance Regis e , he Swedish Cause o Dea h Regis e , and he Na ional P os a e Cance Regis e o Sweden and inal s udy popula ion. * Dis an me as asis de ined as M1 and/o p os a e-speci ic an igen ≥ 100 ng/mL. ======= indica es egis y linkage. JNCI | A icle 4 o 9 jnci.ox o djou nals.o g Figu e 2. Coun ies anked by he cumula i e di e ence be ween obse ed and p edic ed p os a e cance incidence pe 100 000 om 1995 h ough 2002. A) Obse ed and p edic ed age-s anda dized p os a e cance incidence in men aged 50–74 yea s in 24 Swedish coun ies du ing he pe iod om 1980 o 2009. S eady line is p e- dic ed incidence, and undula ing line is obse ed incidence. B) Cumula i e di e ence be ween obse ed and p edic ed incidence o p os a e cance du ing he pe iod om 1995 o 2009. Nega i e di e - ences esul ing om he p edic ed incidence being highe han he obse ed incidence in low-incidence coun ies we e se o ze o. G & B=Gö ebo g and Bohus coun y; H=high-incidence coun y; L=low incidence coun y. Vol. 106, Issue 3 | dju007 | Ma ch 12, 2014 5 o 9 A icle | JNCI Figu e3. P os a e cance incidence and mo ali y in men in Sweden aged 50 o 74yea s, 2000 o 2009. A) Cumula i e incidence o me as a ic dis- ease. B) P os a e cance -speci ic mo ali y. C) Excess mo ali y. JNCI | A icle 6 o 9 jnci.ox o djou nals.o g Figu e4. Risk o p os a e cance mo ali y acco ding o coun y o esi- dency (in g oups o coun ies wi h high and low incidence) and ime pe iod in g oups o coun ies wi h high, in e media e and low incidence o p os a e cance A) Ra e a io (RR) o incidence o me as a ic p os a e can- ce , p os a e cance –speci ic mo ali y, and excess mo ali y in high- s low-incidence coun ies. B) Ra e a io o p os a e cance –speci ic mo ali y and excess mo ali y in he pe iod om 2000 o 2009 s he pe iod om 1990 o 1999. C) Ra e a io o high- s low-incidence g oup adjus ed o ime pe iod. * Me as a ic p os a e cance de ined as M1 and/o p os a e- speci ic an igen ≥ 100 ng/mL a diagnosis. ** Excess mo ali y de ined as he excess numbe o dea hs (obse ed minus expec ed), ega dless o cause o dea h among men wi h p os a e cance . CI=con idence in e al. Vol. 106, Issue 3 | dju007 | Ma ch 12, 2014 7 o 9 A icle | JNCI he in oduc ion o PSA es ing, and he use o h ee sepa a e end- poin s—incidence o me as a ic p os a e cance , p os a e cance - speci ic mo ali y, and excess mo ali y. The Swedish Cance Regis e cap u es 96% o all cance diagnoses, and he cap u e a e is pa icula ly high o solid umo s and in subjec s aged less 70yea s (27). The alidi y o he Cause o Dea h Regis e is high o p os a e cance . Fo exam- ple, in he Gö ebo g sc eening ial, he e was a 96% ag eemen be ween a cha e iew o dea h ce i ica es and he Cause o Dea h Regis e (28), and in ano he s udy wi h a wide ange in s age and g ade, he ag eemen was 86% (29). Besides p os- a e cance –speci ic mo ali y, we also in es iga ed he incidence o me as a ic p os a e cance , which was he i s indica ion o he e icacy o PSA sc eening in he Eu opean ials (1,2). We assessed he occu ence o me as a ic disease a da e o diagnosis by use o da a on he p esence o bone me as ases o a se um le el g ea e han 100 ng/mL a ailable om 2000 in he Na ional P os a e Cance Regis e . Ou s udy also had some limi a ions because we we e unable o di ec ly measu e he ex en o PSA es ing in he popula ion. Ins ead, we used he di e ence be ween he obse ed and p edic ed cumula- i e incidence o p os a e cance unde he assump ion ha a high incidence indica ed an ea ly in oduc ion and a high p e alence o PSA es ing wi h ensuing ea ly p os a e cance diagnosis and ea - men . This assump ion was co obo a ed by da a in he Na ional P os a e Cance Regis e on dis ibu ion o isk ca ego ies wi h lowe median se um PSA le els a diagnosis, highe p opo ion o clinically localized low- isk cance s, highe p opo ion o cu a i e ea men s, and a lowe age a diagnosis in high- s low-incidence coun ies. Geog aphical compa isons can be hampe ed by di e ences in baseline isk, and p io obse a ional s udies compa ing high and low p os a e cance incidence a eas in he Uni ed S a es epo ed no di e ence in p os a e cance mo ali y (12,13). In he i s ime pe iod o ou s udy, p os a e cance –speci ic mo ali y was highe in high-incidence coun ies han in low-incidence coun ies, showing ha he subsequen ly lowe p os a e cance mo ali y in high-inci- dence coun ies was no simply he esul o di e ences in baseline isk. Tempo al compa isons can be hampe ed by changes in diagnos- ic c i e ia o e ime and hus can also be a ec ed by bias. To add ess hese issues, we made sepa a e geog aphical and empo al compa i- sons and used a combined app oach as well, including adjus men o ime pe iods in he analysis o geog aphical di e ences. Ou isk es ima es we e a ec ed by o he sou ces o bias. The dec ease in excess mo ali y was consis en ly la ge han he dec ease in p os a e cance –speci ic mo ali y. Excess mo ali y likely o e es- ima es he bene i o sc eening because i e lec s a lowe mo ali y om causes o he han p os a e cance . The e may be selec ion bias o heal hy Swedish men wi h a long li e expec ancy who unde go PSA es ing and ea ly de ec ion, as sugges ed in a p e ious s udy in he Na ional P os a e Cance Regis e , which showed lowe 10-yea all-cause mo ali y among men wi h low- and in e medi- a e- isk p os a e cance compa ed wi h he backg ound popula ion, indica ing a heal hy sc eenee e ec (30). In con as , p os a e can- ce –speci ic mo ali y unde es ima es he isk educ ion because i Table1. Cha ac e is ics o men aged 50 o 74yea s wi h p os a e cance in he Na ional P os a e Cance Regis e o Sweden, 2000 o 2009* Cha ac e is ic Coun y Incidence High (n=33 780) In e media e (n=37 624) Low (n=16 377) Age a diagnosis, y Median (IQR) 70 (63–77) 70 (63–77) 72 (65–79) Mean (SD) 70.0 (9.3) 70.2 (9.2) 71.7 (9.1) Se um PSA le el, ng/mL Median (IQR) 10.8 (6.0–27.0) 12.0 (6.6–32.0) 15.0 (7.6–43.0) No. missing (%) 506 (1.5) 1114 (3.0) 385 (2.4) Mode o de ec ion, No. (%) PSA es ing as a pa o heal h check-up 10 684 (31.6) 10 101 (26.8) 3646 (22.3) Lowe u ina y ac symp oms 10 533 (31.2) 10 668 (28.4) 5793 (35.4) O he symp oms/unknown 12 563 (37.2) 16 855 (44.8) 6938 (42.4) Planned ea men , No. (%)† Su eillance 8937 (26.5) 8613 (22.9) 4079 (24.9) Radical p os a ec omy 8444 (25.0) 8425 (22.4) 2419 (14.8) Radia ion he apy 4198 (12.4) 4891 (13.0) 2501 (15.3) Ho monal he apy 10 931 (32.4) 12 600 (33.5) 6620 (40.4) O he /missing 1270 (3.8) 3095 (8.2) 758 (4.6) Risk ca ego y, No. (%)‡ Low isk 9874 (29.2) 9593 (25.5) 3366 (20.6) In e media e isk 8651 (25.6) 8997 (23.9) 3867 (23.6) High isk 7908 (23.4) 9917 (26.4) 4570 (27.9) Regionally me as a ic 2097 (6.2) 2735 (7.3) 1407 (8.6) Dis an me as ases 4524 (13.4) 5158 (13.7) 2891 (17.7) Missing 726 (2.1) 1224 (3.3) 276 (1.7) * IQR=in e qua ile ange; PSA=p os a e-speci ic an igen; SD=s anda d de ia ion. † Ini ia ed o planned wi hin he 6mon hs a e diagnosis. ‡ Risk g oups acco ding o modi ica ion o he Na ional Comp ehensi e Cance Ne wo k. Low isk: T1 o 2, Gleason sco e 2 o 6, and PSA < 10 ng/mL. In e media e isk: T1 o 2, Gleason sco e 7, and/o PSA 10 o <20 ng/mL. High isk: T3, and/o Gleason sco e 8 o 10, and/o PSA 20 o <50 ng/mL. Regionally me as a ic disease: T4 and/o N1 and/o PSA 50 o <100 ng/mL in he absence o dis an me as ases (M0 o Mx). Dis an me as ases: M1 and/o PSA ≥100 ng/mL. JNCI | A icle 8 o 9 jnci.ox o djou nals.o g is a ec ed by a ibu ion bias; dea h om an unce ain cause is mo e likely a ibu ed o p os a e cance in men wi h a p os a e cance diagnosis han in o he men (31). Fu he mo e, ou ollow-up ime was 10yea s a maximum, which is likely oo sho a ime o eap he ull e ec o ea ly de ec ion. Finally, con ounding by unknown ac o s canno be uled ou . Despi e hese sho comings, a highe incidence o p os a e cance was consis en ly associa ed wi h lowe isk es ima es in all 18 isk analyses. The ERSPC s udy, he la ges andomized sc eening ial o da e wi h 761 p os a e cance dea hs, showed i ually he same educ ion (21%) in mo ali y obse ed a e 11yea s o ollow-up as ou s udy (1). In he Gö ebo g sc eening ial in Sweden, based on 122 p os a e cance dea hs, a la ge educ ion in mo ali y was obse ed (44%), likely because o he longe median ollow-up o 14yea s. Specula i ely, he la ge e ec in he Gö ebo g ial com- pa ed wi h ou obse a ions may, in addi ion o a longe ollow-up, also be because o a mo e s ingen wo k-up o men wi h ele a ed se um PSA in a ial se ing and o a supe io diagnos ic and he - apeu ic le el o ca e in a high- olume se ing as compa ed wi h ou esul s ha we e based on ou ine clinical p ac ice among all heal h-ca e p o ide s in 14 Swedish coun ies. Ou esul s om a popula ion-based, eal-li e s udy indica e ha mo e-in ense as compa ed wi h less-in ense oppo unis ic PSA sc eening dec eases p os a e cance mo ali y, which econ- ciles he indings o he wo la ges ials on PSA sc eening o da e, namely ERSPC (o ganized s no sc eening) and PLCO (o ganized s oppo unis ic sc eening) and is cong uen wi h he educ ion o p os a e cance mo ali y ha has occu ed in he Uni ed S a es du ing he las decades, du ing which ime pe iod ea ly diagnosis and ea ly ea men has inc eased d as ically (32). Howe e , oppo unis ic sc eening as i is cu en ly imple- men ed in eal li e is ine icien and is implemen ed oo equen ly in he w ong age g oups. In a ecen Swedish s udy, 6% o men aged 40 o 49yea s, 16% o men age 50 o 59yea s, 27% o men aged 60 o 69yea s, 30% o men aged 70 o 79yea s, and 23% o men age 80 o 89yea s had an annual PSA es (33), whe eas in he Uni ed S a es, 45% o men aged 75 yea s and olde ha e a yea ly PSA es (34). The equen PSA es ing o olde men leads o o e de ec ion and o e ea men , and o maximize he bene i s while a he same ime minimizing he ad e se e ec s o sc eening and ensuing ea men , isk-s a i ied sc eening wi h egula bu in equen PSA es ing o middle-aged men holds p omise (35). In conclusion, in ou popula ion-based s udy we obse ed lowe incidence o me as a ic p os a e cance , lowe p os a e cance –spe- ci ic mo ali y, and lowe excess mo ali y in coun ies wi h high s low incidence o p os a e cance , e lec ing PSA up ake. This indica es ha mo e-in ense as compa ed wi h less-in ense oppo - unis ic PSA sc eening educes p os a e cance mo ali y. e e ences 1. Sch ode FH, Hugosson J, Roobol MJ, e al. P os a e-cance mo ali y a 11yea s o ollow-up. N Engl J Med. 2012;366(11):981–990. 2. Hugosson J, Ca lsson S, Aus G, e al. Mo ali y esul s om he Go ebo g andomised popula ion-based p os a e-cance sc eening ial. Lance Oncol. 2010;11(8):725–732. 3. And iole GL, C aw o d ED, G ubb RL 3 d, e al. 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Funding This wo k was unded by The Swedish Resea ch Council 825-2008-5910 and he Swedish Cance Socie y 11 0471, Väs e bo en Coun y Council, and Lions Cance Resea ch Founda ion a Umeå Uni e si y, Sweden. HL is suppo ed by g an s om he Na ional Cance Ins i u e (R33 CA 127768-03, P50-CA92629); he Swedish Cance Socie y (11–0624); he Sidney Kimmel Cen e o P os a e and U ologic Cance s; Da id H.Koch h ough he P os a e Cance Founda ion; he Na ional Ins i u e o Heal h Resea ch, Ox o d Biomedical Resea ch Cen e, Ox o d Uni e si y Hospi als NHS T us and Uni e si y o Ox o d; and Fundación Fede ico SA. SC is suppo ed by g an s om he Swedish Cance Socie y, he Sweden Ame ica Founda ion, he Swedish Council o Wo king Li e and Social Resea ch, and he Swedish Socie y o Medical Resea ch. No es None o he s udy sponso s had any ole in he design o he s udy, he da a col- lec ion, analysis, in e p e a ion o he da a, manusc ip w i ing, o decision o submi he manusc ip o publica ion. The p ojec was made possible by he con inuous wo k o he Na ional P os a e Cance Regis e o Sweden s ee ing g oup: Pä S a in (chai man), Ande s Widma k, Camilla Thellenbe g, O e And én, Anna Bill-Axelsson, Ann- So i F ansson, Magnus Tö nblom, S e an Ca lsson, Ma ie Hjälm-E iksson, Bodil Wes man, Bill Pe e sson, Da id Robinson, Ma s Andén, Jan-E ik Dambe , Jonas Hugosson, Ingela F anck-Lissb an , Ma ia Nybe g, Gö an Ahlg én, Ola B a , René Blom, La s Ege ad, Calle Walle , Jan-E ik Johansson, Olo Ak e, Pe F ansson, E a Johansson, F ed ik Sandin, Hans Ga mo, Ma s Lambe, Ka in Hells öm, Anne e Wige z, and E ik Holmbe g. Mi iam Bloom, PhD (SciW i e Biomedical W i ing & Edi ing Se ices), p o ided linguis ic edi ing. A ilia ions o au ho s: Depa men o Su ge y and Pe iope a i e Sciences, U ology and And ology (PS, BH) and Depa men o Radia ion Sciences, Oncology (HJ), Umeå Uni e si y, Umeå, Sweden; Depa men o Su ge y, U ology Se ice (PS, SC), Depa men o Epidemiology and Bios a is ics (AV), Depa men o Labo a o y Medicine (HL), Depa men o Su ge y (HL), and Depa men o Medicine (HL), Memo ial Sloan-Ke e ing Cance Cen e , New Yo k, NY; Depa men o U ology, Sahlg enska Academy a Gö ebo g Uni e si y, Gö ebo g, Sweden (SC, JH); Nu ield Depa men o Su gical Sciences, Uni e si y o Ox o d, Ox o d, UK (HL); Ins i u e o Biomedical Technology, Uni e si y o Tampe e, Tampe e, Finland (HL); Depa men o Labo a o y Medicine in Malmö, Lund Uni e si y, Malmö, Sweden (HL).