Korean J Urol Oncol 2013;11(1):1-5 전립선암선별검사로서 PSA 의유용성 경북대학교의과대학비뇨기과학교실 최석환ㆍ권태균 Current Status in PSA Screening Seock Hwan Choi, Tae Gyun Kwon Department of Urology, School of Medicine, Kyungpook National University, Daegu, Korea The rapid and widespread use of prostate-specific antigen (PSA) screening into clinical field was based on the assumption that PSA may increase the chance of earlier detection and cure of prostate cancer with minimal harms. In US, the introduction of PSA testing nearly doubled the lifetime risk of receiving a diagnosis of prostate cancer. However, many studies reported that PSA screening also can increase overdiagnosis and subsequent overtreatment. To evaluate the value of PSA screening on prostate cancer mortality, numerous studies have been conducted with contradictory results. Moreover, most of them were not randomized, controlled study. Recently, early results of two large, randomized, controlled trials of screening have published. A European study showed a modest decrease in prostate-cancer mortality, whereas a United States study showed no decrease in prostate-cancer mortality. Considering these inconsistent results of trials, men considering prostate-cancer screening should be informed about the potential benefits and harms of screening and early treatment. In this article, we address the current status and value of PSA screening with the review of the literature on PSA screening for prostate cancer. (Korean J Urol Oncol 2013;11:1-5) Key Words: Prostate-specific antigen, Prostate cancer, Early detection of cancer 서론전립선암은미국과유럽의남성에서가장흔히진단되는고형암중하나로미국의암사망원인중폐암에이어두번째를차지하고있다. 1-4 1980년대부터시행된혈청전립선특이항원 (prostate specific antigen; PSA) 검사는전립선암의진단과치료에획기적인변화를가져온검사로현재전립선암의진단및치료후추적검사에필수적인검사로자리잡았다. 5 하지만무증상의남성을대상으로시행하는 PSA screening이전립선암으로인한사망률을실제로낮출수있는지에대해서는아직까지도뚜렷한결론이없는상태이다. 여기에서는최근에보고된유럽과미국의대규모임상시험인 European Randomized Study of Screening for Prostate Cancer (ERSPC) 와 Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) 의결과와함께지금까지보고된 PSA screening의효용성에대한다른보고들을함께고찰하여현위치에서전립선암에대한 PSA screening의위치와역할에대해기술하고자한다. 논문접수일 :2013 년 3 월 18 일, 수정일 :2013 년 3 월 26 일, 채택일 :2013 년 3 월 27 일교신저자 : 권태균, 칠곡경북대학교병원비뇨기암센터대구시북구호국로 807, 702-210 Tel: 053-200-3012, Fax: 053-200-2029 E-mail: tgkwon@knu.ac.kr Screening Tests 선별검사 (screening) 를시행하는주된목적은임상적으로증상이있기이전단계에서암을조기에발견하여치료함으로써질병의이환률과사망률을줄이고자하는것으로, 1
2 대한비뇨기종양학술지 : 제 11 권제 1 호 2013 이상적인선별검사법은정확하고신뢰성이있으며검사방법이쉬운것이어야한다. 또한임상적으로의미있는암을조기에발견하였을때조기치료가가능해야하고, 그결과로통상적으로진단되어치료받는경우에비해건강상태에대한이득이반드시있어야한다. 전통적으로전립선암의 screening에는직장수지검사 (DRE) 가이용되었다. 그러나 DRE는전립선암의검사에서오랫동안사용되어온방법이지만검사자에따라그결과가차이를보일수있고, 직장수지검사를통해진단된전립선암은대부분진행된상태인경우가많은단점이있다. 6,7 PSA 검사는현재전립선암의진단에가장중요한검사중의하나로 2001년 50세이상의미국남성중 75% 가 PSA 검사를받았을정도로대중화되었고, 이러한 PSA 검사로인해과거에비해최근진단되는전립선암은저병기인경우가많다. 5 하지만 PSA 검사가 screening 검사로서의의가있는지에대해서는논란이있는데, 그이유는첫째 PSA 검사로인한전립선암의조기진단이실제로전립선암으로인한사망위험을감소시킬수있는지에대해서는명확한증거는없기때문이다. 둘째 PSA는전립선암이외에양성전립선비대, 전립선염, 방광염, 사정, 회음부손상, 요로계검사및시술후에도증가할수있기때문이다. 실제로 PSA가 3 혹은 4ng/ml 이상으로증가된경우는전립선암보다는다른원인으로인한경우가더많은실정이다 (Table 1). 8 또한직장수지검사에서이상이없고 PSA가 4ng/ml 이하인환자의 15% 에서전립선생검상전립선암이발견된다는보고가있을만큼 PSA 수치가정상이더라도전립선암을배제할수없다는점역시선별검사로서 PSA 검사를시행하는데장애요인으로작용하고있다. 9 이러한 PSA 검사의한계를극복하고진단적정확도를향상시키기위해 PSA velocity, PSA ratio (free/total), PSA density, 나이와인종에기초한 PSA 기준값등을보조적으로사용하고있지만임상적유용성에대해서는의문이많다. 10 Table 1. Diagnostic performance characteristics of PSA testing, according to cutoff value* Characteristic Test positivity Cancer-detection rate Sensitivity Specificity Positive predictive value *Data are from Wolf et al. 8 4.0ng/ml 12 3 21 91 30 PSA cutoff level Percent 3.0ng/ml 18 4 32 85 28 Potential Benefits of Screening 지금까지 PSA screening과전립선암사망률의상관관계를밝히기위해많은연구들이진행되었지만대부분이전향적인무작위대조연구가아니며또한서로상충되는결과들이발표되었다. 따라서전립선암에서 PSA screening의유용성을정립하고자최근유럽의 ERSPC와미국의 PLCO 등두가지대규모의전향적, 무작위연구가진행되었고최근에그중간결과가발표되었다. 11,12 하지만이두가지연구도서로다른결과를보이고있어아직까지전립선암에서 PSA screening에대한 consensus는없는실정이다. 두가지대규모연구의연구방법, 결과및, 문제점등은다음과같다. 1. European Randomized Study of Screening for Prostate Cancer (ERSPC) 유럽의 7개센터에서시행된대규모임상시험인 ERSPC 는주로 4년의간격 ( 스웨덴 2년 ) 으로 PSA screening을시행한검진군 (screening arm) 과시행하지않은대조군 (control arm) 을무작위로나누어전립선암사망률의차이를분석하였다. 양군모두에서주로 PSA 3mg/ml를절단치 (cut off value) 로하여그이상인경우 6군데전립선생검을권유하였고, 양군에동등한조건하에서전립선암사망률을추적관찰하였다. 55세부터 69세사이의 162,243명을 9년의중앙추적관찰기간동안분석한결과, 검진군과대조군의전립선암진단율은각각 8.2%, 4.8% 로검진군에서높았고 PSA screening을시행한검진군에서대조군보다전립선암사망률이 20% 더낮은것으로나타났다. 그러나절대적위험도의차이는 1,000명당 0.71명사망에불과하였고, 이는전립선암으로인한 1명의죽음을막기위해 1,410명이 9년동안 2회의선별검사를시행하여야하고 48명이전립선암으로진단되어야한다고보고하였다. 더욱이 50-54세와 70-74세에서는전립선암사망률이감소하지않는것으로나타났다. 11 ERSPC 중일부인스웨덴 Göteborg 연구에서는, 50-64세의 20,000명을대상으로 14년의추적관찰기간동안 PSA screening을시행한군에서전립선암사망률이 44% 감소한다고보고하였다. 하지만이연구역시 1명의전립선암사망을막기위해 293명의선별검사가필요하고, 12명이전립선암으로진단되어야한다는문제를내포하고있다. 13 2. Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) 미국의대규모임상시험인 PLCO는 55세에서 74세사이
최석환ㆍ권태균 : 전립선암선별검사로서 PSA 의유용성 3 의 76,693명을대상으로 6년동안매년 PSA와 4년동안매년직장수지검사를시행한검진군과시행하지않은대조군의결과를보고하였다. 7년의추적관찰결과검진군과대조군에서전립선암으로진단된경우는 2,820명과 2,322명으로검진군에서더많았고, 병기및악성도역시검진군에서더낮았다고보고하였다. 하지만전립선암사망률은두군에서의미있는차이를보이지않았다. 12 하지만 PLCO의경우몇가지요소에의한바이어스가존재한다. 우선임상시험에포함된대상의 40% 이상이임상시험전 3년내에적어도한번이상의 PSA 검사를받았고, PSA 검사와관련된긴 lead time을고려한다면, PLCO는 PSA screening에의한생존효과 (survival benefit) 가나타날정도로추적관찰기간이길지않았다는것이다. 또한대조군의 50% 이상이임상시험시작후 6년내에 PSA 검사를받았고, PSA 검진군에서최초 PSA 값에이상이있던대상중 40% 정도에서만조직검사가시행되었다는것이다. 14 Potential Harms of Screening PSA screening이전립선암의조기진단측면에서는유용하다고할수있겠으나부수적인단점또한무시할수없는데대표적인것으로과잉진단과치료, 전립선생검에따르는환자의고통과합병증등이있다. PSA screening을통해전립선암이의심되면즉, PSA 수치가정상보다높게나오게되면전립선암의확진을위해조직검사를시행하게되는데, 전립선생검은출혈, 통증, 그리고감염등의합병증을일으킬수있다. 8 전립선생검은환자에게많은불편감을줄뿐만아니라, 조직검사에서이상이없다고하더라도일부의환자는잠재적암의가능성으로인해불안감을가지게된다. 15 과잉진단과치료즉인측면에서 Fowler 등은 Mathematical model을이용한연구에서진단시점의여명과전립선암의자연사를고려하였을때 23-42% 의전립선암은과잉진단되었고이러한전립선암은환자의생존동안임상적문제를야기하지않는다고보고하였다. 16 나아가 Wilt 등은이들환자에게시행하는침습적인치료인전립선절제술및방사선치료는요자제, 성기능그리고장기능등에불필요한합병증을발생시킬수있어삶의질에악영향을미칠수있다고하였다. 17 Informed Decision Making 전문가들은 PSA screening 검사의장단점을고려하여선별검사의시행을결정하기앞서환자와충분히상의할것 을권유하고있다. 18,19 하지만실제로는 PSA screening을시행함으로써얻을수있는이득과피해에대해충분한상의나동의없이 PSA 검사가이루어지고있다. 19,20 최근의한보고에서 PSA screening을시행하기앞서환자에게영상물, 출판물그리고인터넷등의자료를이용하여선별검사의결정에도움을주고이를메타분석을하였을때, 여러자료를통해환자에게충분한정보를주고상의하는것이선별검사에대한환자의지식과신뢰성을증가시키고 PSA screening의빈도역시감소시키는결과를보여주었다. 21 Areas of Uncertainty 앞서언급한두개의대규모임상시험에서도알수있듯이 PSA screening을시행한군에서전립선암이많이진단되지만그중상당수에서과잉진단과과잉치료의문제가발생할수있다. 16 임상적으로전립선암이진단되면 PSA 수치와직장수지검사소견, 그리고전립선생검을통해얻어진 Gleason score 등을종합하여환자의위험도를분류하고있지만, 아직까지전립선암의정확한임상적경과를예측하는것은매우어려워, 실제임상에서는조기전립선암의대부분에서수술적절제와방사선치료등과같은근치적인치료방법이시행된다. 21,22 과잉진단과치료의피해를최소화할수있는방법으로저위험도의전립선암 (a PSA level of 10ng/ml, Gleason score of 6) 에서주기적인 PSA, 직장수지검사, 전립선생검을이용한 active surveillance를시행할수있다. 23 Klotz 등은 2,130명을대상으로한 7개의 observational study에서 active surveillance를받는환자의 0.3% 만이전립선암으로사망하였고, 43개월의추적관찰기간동안 64% 에서근치적치료를시행하지않고 active surveillance를시행할수있었다고보고하였다. 24 50-69세의조기전립선암 2,050명을대상으로 active surveillance와근치적치료를비교한 The Randomized Prostate Testing for Cancer and Treatment Trial (NCT00632983) 의결과가보고된다면조기전립선암에서의 active surveillance의역할을더명확히알수있을것으로기대된다. 25 Guidelines ERSPC와 PLCO의연구결과가보고된이후개정된 American Urological Association (AUA) 와 American Cancer Society의 guideline을살펴보면여명이적어도 10년이상인환자에서 PSA 검사를실시하는것을권유하고있다 (Table 2). 8,10 최근 US Preventive Services Task Force (USPSTF) 는나이, 인종그리고가족력에관계없이무증상인남성에서 PSA
4 대한비뇨기종양학술지 : 제 11 권제 1 호 2013 Table 2. Prostate-Cancer screening guidelines Recommendation American Urological Association American Cancer Society U.S. Preventive Services Task Force Shared decision making between patient and clinician Yes Yes (consider use of decision aid) Yes (when patient requests screening) Age to begin offering screening-yr Average-risk patients 40 50 Not applicable High-risk patients (black 40 40-45 Not applicable patients and those with first-degree relative with prostate cancer) Discontinuation of screening Life expectancy <10yr Life expectancy <10yr Not applicable Screening tests PSA, digital rectal examination PSA, optional digital rectal Not applicable examination Frequency of screening Annual (possibly less often for Annual (every other year when PSA Not applicable men in their 40s) <2.5ng/ml) Criteria for biopsy referral Age, family history, race or ethnic group, findings on digital rectal examination, total PSA, free PSA, PSA velocity, PSA density, previous biopsy findings, coexisting conditions PSA 4.0ng/ml, Abnormal digital rectal examination; individualized risk assessment if PSA is 2.5-4.0ng/ml Not applicable screening을시행하지않을것을권고하고있다. 26 하지만 USPSTF의권고는많은문제점이제기되었던 PLCO의결과에근거를두고있어많은논란을일으키고있다. 결론 ERSPC와 PLCO 등의대규모임상시험결과가발표되었지만 PSA screening이전립선암사망률을감소시킬수있는가에대한명확한해답은없는실정이다. 현재까지의연구에서살펴보면전립선암의조기진단을위해모든남성에서 PSA screening을시행하는것은적절하지않고, 환자에게전립선암의자연사는물론검사의이득과손실그리고전립선암으로진단되었을때시행할수있는치료방법에대한충분한설명과상의가이루어진후 PSA screening을시행하여야할것으로생각한다. 또한 PSA screening에적절한시작연령과검사의간격, 선별검사에서조기전립선암으로진단된환자에대한치료방법의결정등에대해서는향후추가적인연구가필요할것으로생각한다. REFERENCES 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90 2. Boyle P, Ferlay J. Cancer incidence and mortality in Europe 2004. Ann Oncol 2005;16:481-8 3. Quinn M, Babb P. Patterns and trends in prostate cancer incidence, survival, prevalence and mortality. Part I: international comparisons. BJU Int 2002;90:174-84 4. Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture. Eur J Cancer 2001;37(Suppl 8):S4-66 5. Sirovich BE, Schwartz LM, Woloshin S. Screening men for prostate and colorectal cancer in the United States: does practice reflect the evidence? JAMA 2003;289:1414-20 6. Smith DS, Catalona WJ. Interexaminer variability of digital rectal examination in detecting prostate cancer. Urology 1995;45:70-4 7. Chodak GW, Keller P, Schoenberg HW. Assessment of screening for prostate cancer using the digital rectal examination. J Urol 1989;141:1136-8 8. Wolf AM, 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. Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level < or = 4.0 ng per milliliter. N Engl J Med 2004;350:2239-46 10. Greene KL, Albertsen PC, Babaian RJ, Carter HB, Gann PH,
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