Prostate Cancers in Men with Low PSA Levels — Must We Find Them?
http://www.100md.com
《新英格兰医药杂志》
Prostate cancer is the second leading cause of death from cancer among men in the United States. In the era before prostate-specific antigen (PSA) screening, most prostate cancers were identified at a stage (T2 or T3) that could not be cured. Today, with the widespread use of PSA screening, most prostate cancers are identified at an earlier stage, which can be treated effectively with surgical or nonsurgical approaches. Once PSA screening became widespread in the United States, the rate of death from prostate cancer declined — for example, in 1997 it fell below the rate recorded in 1986, a year in which PSA testing was rarely performed.1 Although the initial decline could have been the result of improved treatments or other population-screening effects (e.g., a misclassification artifact),2 it is difficult to believe that earlier detection has had no effect on the continued decline in mortality, given the 50 to 70 percent decline in the incidence of distant disease between 1986 and 1999 among men 50 years of age or older.3
There is general agreement among clinicians that the PSA test has the highest predictive value for prostate cancer, that PSA screening can detect early-stage cancers, and that most cancers detected by PSA screening appear to be clinically important when their pathological characteristics are used as a surrogate for biologic potential. There is, however, disagreement as to what level of PSA should prompt a prostate biopsy. The controversy stems from the following: the use of higher PSA thresholds risks missing an important cancer until it is too late for a cure, whereas the use of lower PSA thresholds increases not only unnecessary biopsies but also the proportion of biopsies that identify clinically insignificant disease (disease that would not have been detected in the absence of screening). The use of a PSA threshold of 4.0 ng per milliliter for men over the age of 50 years has been accepted by most clinicians as striking a reasonable balance between these tradeoffs. However, information on the prevalence of biopsy-detectable prostate cancer among men with PSA values of 4.0 ng per milliliter or less and no other indication for biopsy (e.g., an abnormal prostate examination) is limited.
In this issue of the Journal, Thompson et al.4 report the prevalence of prostate cancer among men in the control group of the Prostate Cancer Prevention Trial. During a seven-year period, none of the men in this analysis had PSA levels above 4.0 ng per milliliter or any abnormality on digital rectal examination. All participants underwent a prostate biopsy at the end of the study. Of almost 3000 men in the group, 15 percent had a prostate cancer on the end-of-study biopsy, and of these cancers, 15 percent were high grade (a Gleason score of 7 to 9). The prevalence of cancer increased with the PSA level, from 7 percent among men with PSA values of 0.5 ng per milliliter or less to 27 percent among men with PSA values of 3.1 to 4.0 ng per milliliter. Furthermore, the prevalence of high-grade disease also increased with the PSA level, from 13 percent when the PSA level was 0.5 ng per milliliter or less to 25 percent when the PSA level was 3.1 to 4.0 ng per milliliter. Given this report of the risk of prostate cancer — and the risk of high-grade disease — at PSA levels below the threshold of 4.0 ng per milliliter, which has traditionally been used to prompt prostate biopsy, should we now recommend lowering the threshold for biopsy?
I believe not, for the following reasons. First, it should not be surprising that 10 to 27 percent of the men with PSA values of 4.0 ng per milliliter or less, who ranged in age from 62 to 91 years, were found to have prostate cancer in the study by Thompson et al. On the basis of the results of 5250 autopsies reported in the U.S. literature, the prevalence of prostate cancer was 15 to 60 percent among men 60 to 90 years of age and increased with age.5 Ninety percent of men 50 to 90 years of age have PSA values of 4.0 ng per milliliter or less.6 Thus, quite a few men with PSA levels of 4.0 ng per milliliter or less must harbor a prostate cancer.
Although it would be desirable to detect the small proportion of high-grade cancers — cancers that are likely to be life threatening — in men with low PSA levels, the identification of such cancers will require the development of new biomarkers, because high-grade cancers actually produce less PSA than low-grade cancers, after correction for cancer volume.7 The increasing prevalence of high-grade cancer with increasing PSA levels reflects the finding that higher-grade cancers are more often larger in volume than low-grade cancers, and the PSA level is directly related to the volume of the cancer.7
Second, prostate cancers detected at lower PSA levels are more likely to have a small volume (less than 0.5 ml) and to be low-grade8 and are thus more likely to represent clinically insignificant disease, because cancer volume and grade are surrogates for biologic potential.9 McNeal et al. found that only cancers that were much larger than 1 ml in volume and poorly differentiated were associated with metastatic disease.9 Furthermore, prostate cancers with a volume of less than 1 ml do not usually result in PSA levels above 4.0 ng per milliliter,10 so that the unexpected detection of cancer at lower PSA levels is more likely to identify disease for which treatment not only may be unnecessary but also may fail to improve survival.11 Thompson et al. could provide information about the estimated cancer volume in their population because the PSA density (PSA level divided by prostate volume) and the features of the cancer on biopsy (the grade, the number of cores with cancer, and the percentage of the core that is cancerous) are predictive of the cancer volume determined pathologically after surgery.12
Third, there is no convincing evidence that, with contemporary therapy, men who are treated when their cancers are detected at PSA levels at or below 4.0 ng per milliliter have better outcomes than men who are treated when the PSA is slightly higher than 4.0 ng per milliliter. In short, detection of prostate cancer at a PSA threshold lower than 4.0 ng per milliliter has not been shown to improve the disease-free outcome. With a PSA level in the range of 2.6 to 6.0 ng per milliliter, younger men are more likely than older men to have curable prostate cancer13 and a disease-free outcome14 — observations that are probably driven by the fact that older men are more likely to have high-grade cancers. Hence, the weight of the evidence suggests that the detection of prostate cancer at younger ages should have a greater effect on the likelihood of being free from disease after treatment than would the detection of prostate cancer at a PSA level of 4.0 ng per milliliter or less.
Fourth, in an investigation similar to that of Thompson et al., Gann et al. have shown that men with baseline PSA levels between 1.0 and 4.0 ng per milliliter are at significantly higher risk for a diagnosis of prostate cancer over the next 10 years than are men whose baseline PSA level is below 1.0 ng per milliliter.15 They found that a cutoff value of 3.3 ng per milliliter resulted in optimal sensitivity and specificity, but the gain was minimal as compared with that afforded by a cutoff value of 4.0 ng per milliliter. In addition, Morgan et al.16 have shown that the PSA cutoff value that results in 95 percent sensitivity (the detection of 95 percent of cancers) is close to 4.0 ng per milliliter for men between the ages of 50 and 70 years and 2.5 ng per milliliter for men in the fifth decade of life. Because most of the variability in PSA levels is due to benign prostate enlargement that occurs with age, and men below the age of 50 years are unlikely to have such enlargement, a threshold of 2.5 ng per milliliter seems reasonable for men below the age of 50 years.
Gann et al.15 pointed out that the "dichotomization of PSA results into normal and abnormal obscures important information contained in levels below the usual cutoff." The data of Thompson et al. provide a framework for the risk assessment of men with PSA values of 4.0 ng per milliliter or less and should prompt careful consideration of the likelihood of cancer at these lower PSA levels in men at particularly high risk, such as those with a strong family history of the disease. Given that the risk of a clinically significant prostate cancer increases incrementally with PSA levels between 0 and 4 ng per milliliter, it makes sense to track the rate of rise in PSA values (the PSA velocity), which has previously been shown to correlate directly with the risk of cancer17 and was significantly associated with the risk of cancer in the current study.
Finally, considering that the lifetime risk of death from prostate cancer is 3 percent and the lifetime risk of a diagnosis of prostate cancer is 16 percent, it is apparent that any approach that finds more cancers without quantifying the clinical significance of the detected disease will only increase overdiagnosis and overtreatment, as alluded to by Thompson et al. This, together with the absence of proof that PSA screening saves lives, should cause physicians to be circumspect about routinely recommending a prostate biopsy for men over the age of 50 years who have a PSA level of 4.0 ng per milliliter or less.
Although the value of PSA screening remains controversial, men who present for periodic health examinations should be made aware of the availability of the PSA test, so that they can make an informed decision about the need for routine screening. The enthusiasm for screening in general in the United States suggests that most men will decide to be tested.18
Source Information
From the Department of Urology, Johns Hopkins School of Medicine, Baltimore.
References
Tarone RE, Chu KC, Brawley OW. Implications of stage-specific survival rates in assessing recent declines in prostate cancer mortality rates. Epidemiology 2000;11:167-170.
Feuer EJ, Merrill RM, Hankey BF. Cancer surveillance series: interpreting trends in prostate cancer. II. Cause of death misclassification and the recent rise and fall in prostate cancer mortality. J Natl Cancer Inst 1999;91:1025-1032.
Chu KC, Tarone RE, Freeman HP. Trends in prostate cancer mortality among black men and white men in the United States. Cancer 2003;97:1507-1516.
Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level of 4.0 ng per milliliter. N Engl J Med 2004;350:2239-2246.
Carter HB, Piantadosi S, Isaacs JT. Clinical evidence for and implications of the multistep development of prostate cancer. J Urol 1990;143:742-746.
Smith DS, Catalona WJ, Herschman JD. Longitudinal screening for prostate cancer with prostate-specific antigen. JAMA 1996;276:1309-1315.
Partin AW, Carter HB, Chan DW, et al. Prostate specific antigen in the staging of localized prostate cancer: influence of tumor differentiation, tumor volume and benign hyperplasia. J Urol 1990;143:747-752.
Carter HB, Epstein JI, Chan DW, Fozard JL, Pearson JD. Recommended prostate-specific antigen testing intervals for the detection of curable prostate cancer. JAMA 1997;277:1456-1460.
McNeal JE, Bostwick DG, Kindrachuk RA, Redwine EA, Freiha FS, Stamey TA. Patterns of progression in prostate cancer. Lancet 1986;1:60-63. [CrossRef][ISI][Medline]
Brawn PN, Speights VO, Kuhl D, et al. Prostate-specific antigen levels from completely sectioned, clinically benign, whole prostates. Cancer 1991;68:1592-1599.
Vis AN, Kranse R, Roobol M, van der Kwast TH, Schroder FH. Serendipity in detecting disease in low prostate-specific antigen ranges. BJU Int 2002;89:384-389.
Epstein JI, Walsh PC, Carmichael M, Brendler CB. Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA 1994;271:368-374.
Carter HB, Epstein JI, Partin AW. Influence of age and prostate-specific antigen on the chance of curable prostate cancer among men with nonpalpable disease. Urology 1999;53:126-130.
Khan MA, Han M, Partin AW, Epstein JI, Walsh PC. Long-term cancer control of radical prostatectomy in men younger than 50 years of age: update 2003. Urology 2003;62:86-91.
Gann PH, Hennekens CH, Stampfer MJ. A prospective evaluation of plasma prostate-specific antigen for detection of prostatic cancer. JAMA 1995;273:289-294.
Morgan TO, Jacobsen SJ, McCarthy WF, Jacobson DJ, McLeod DG, Moul JW. Age-specific reference ranges for prostate-specific antigen in black men. N Engl J Med 1996;335:304-310.
Carter HB, Pearson JD, Metter EJ, et al. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA 1992;267:2215-2220.
Schwartz LM, Woloshin S, Fowler FJ Jr, Welch HG. Enthusiasm for cancer screening in the United States. JAMA 2004;291:71-78.(H. Ballentine Carter, M.D)
濠电姷鏁搁崕鎴犲緤閽樺娲偐鐠囪尙顦┑鐘绘涧濞层倝顢氶柆宥嗙厱婵炴垵宕弸銈嗐亜閳哄啫鍘撮柡灞剧☉閳藉宕￠悙宸骄闂佸搫顦弲婊兾涢崘顔艰摕婵炴垶菤閺嬪酣鐓崶銊﹀皑闁稿鎸荤粋鎺斺偓锝庝簽閸旓箑顪冮妶鍡楀潑闁稿鎹囬弻娑㈡偐瀹曞洢鈧帗淇婇崣澶婂闁宠鍨垮畷鍫曞煘閻愵剛浜欓梺璇查缁犲秹宕曢崡鐐嶆稑鈽夐姀鐘靛姦濡炪倖甯掗ˇ顖炴倶閿旂瓔娈介柣鎰▕閸庢梹顨ラ悙鍙夊枠妞ゃ垺妫冨畷銊╊敇閻愰潧鎼稿┑鐘垫暩閸嬬娀骞撻鍡楃筏闁诡垼鐏愬ú顏勭闁绘ê鍚€缁楀姊洪幐搴ｇ畵闁瑰嘲顑夊畷鐢稿醇濠㈩亝妫冮弫鍌滅驳鐎ｎ亜濡奸梻浣告憸閸嬬偤骞愰幎钘夎摕闁哄洢鍨归獮銏ゆ煛閸モ晛孝濠碘€茬矙閺岋綁濮€閳轰胶浠╃紓鍌氱Т閿曨亪鐛繝鍥ㄦ櫢闁绘ǹ灏欓悿鈧俊鐐€栭幐楣冨磻閻斿摜顩烽柟鎵閳锋垿鏌涢敂璇插笌闁荤喐鍣村ú顏勎ч柛銉厛濞肩喖姊洪崘鍙夋儓闁瑰啿姘︾换姘舵⒒娴ｅ懙褰掑嫉椤掑倻鐭欓柟鐑橆殕閸婂灚銇勯弬鍨挃缁炬儳銈搁弻锟犲礃閵娿儮鍋撶粙鎸庢瘎婵犵數濮幏鍐礋閸偆鏉归柣搴㈩問閸犳牠鎮ラ悡搴ｆ殾婵せ鍋撳┑鈩冪摃椤︽娊鏌涢幘鏉戠仸缂佺粯绋撻埀顒佺⊕宀ｅ潡鎯屾繝鍋芥棃鎮╅崣澶嬪枑闂佽桨绶￠崳锝夈€侀弴銏℃櫆闁芥ê顦介埀顒佺☉閳规垿鏁嶉崟顐＄捕婵犫拃鍛珪缂侇喗鐟︾换婵嬪炊閵娧冨箰濠电姰鍨煎▔娑㈡晝閵堝姹查柡鍥╁枑閸欏繘鏌ｉ悢鐓庝喊婵☆垪鍋撻梻浣芥〃缁€浣虹矓閹绢喗鍋╂繝闈涱儏缁€鍐┿亜椤撶喎鐏ｉ柟瀵稿厴濮婄粯鎷呯粵瀣異闂佸摜濮甸幑鍥х暦濠靛﹦鐤€婵炴垼椴搁弲锝囩磽閸屾瑧鍔嶅畝锝呮健閸┿垽寮崼鐔哄幗闂佺懓顕崕鎴炵瑹濞戙垺鐓曢柡鍌氱仢閺嗭綁鏌″畝瀣瘈鐎规洘甯掗～婵嬵敇閻橀潧骞€缂傚倸鍊烽悞锕傘€冮崨姝ゅ洭鏌嗗鍛姦濡炪倖甯掗崰姘缚閹邦喚纾兼い鏃囧亹缁犲鏌ㄥ┑鍫濅槐闁轰礁鍟村畷鎺戭潩閸楃偞鎲㈤梻浣藉吹婵炩偓缂傚倹鑹鹃埢宥夋晲閸モ晝鐓嬮梺鍓茬厛閸犳捇鍩€椤掍礁绗掓い顐ｇ箞椤㈡﹢鎮╅锝庢綌闂傚倷绶氬ḿ褍煤閵堝悿娲Ω閳轰胶鍔﹀銈嗗笒閸嬪棝寮ㄩ悧鍫㈢濠㈣泛顑囧ú瀵糕偓瑙勬磸閸ㄨ姤淇婇崼鏇炵倞闁靛ǹ鍎烘导鏇㈡煟閻斿摜鐭屽褎顨堥弫顔嘉旈崪鍐◤婵犮垼鍩栭崝鏍磻閿濆鐓曢柕澶樺灠椤╊剙鈽夐幘鐟扮毢缂佽鲸甯楀ḿ蹇涘Ω瑜忛悾濂告⒑瑜版帩妫戝┑鐐╁亾闂佽鍠楃划鎾诲箰婵犲啫绶炲璺虹灱濮婄偓绻濋悽闈涗粶妞ゆ洦鍘介幈銊︺偅閸愩劍妲梺鍝勭▉閸樺ジ宕归崒鐐寸厪濠电偟鍋撳▍鍡涙煕鐎ｃ劌濡奸棁澶愭煥濠靛棙鍣归柡鍡欏枑娣囧﹪顢涘鍗炩叺濠殿喖锕ュ浠嬨€侀弴銏℃櫜闁糕剝鐟﹂濠氭⒒娴ｈ櫣甯涢柟纰卞亞閹广垹鈹戠€ｎ剙绁﹂柣搴秵閸犳牜绮婚敐鍡欑瘈濠电姴鍊搁顐︽煙閺嬵偄濮傛慨濠冩そ楠炴劖鎯旈敐鍌涱潔闂備礁鎼悧婊堝礈閻旈鏆﹂柣鐔稿閸亪鏌涢弴銊ュ季婵炴潙瀚—鍐Χ閸℃鐟愰梺缁樺釜缁犳挸顕ｉ幎绛嬫晜闁割偆鍠撻崢閬嶆⒑閻熺増鎯堢紒澶嬫綑閻ｇ敻宕卞☉娆戝帗閻熸粍绮撳畷婊冾潩椤掑鍍甸梺闈浥堥弲婊堝磻閸岀偞鐓ラ柣鏂挎惈瀛濋柣鐔哥懕缁犳捇鐛弽顓炵妞ゆ挾鍋熸禒顖滅磽娴ｆ彃浜炬繝銏ｆ硾閳洝銇愰幒鎴狀槯闂佺ǹ绻楅崑鎰枔閵堝鈷戠紓浣贯缚缁犳牠鏌ｉ埡濠傜仩闁伙絿鍏橀弫鎾绘偐閼碱剦妲伴梻浣藉亹閳峰牓宕滃棰濇晩闁硅揪闄勯埛鎴︽偣閸ワ絺鍋撻搹顐や簴闂備礁鎲￠弻銊︻殽閹间礁鐓濋柟鎹愵嚙缁狅綁鏌ｉ幇顓熺稇妞ゅ孩鎸搁埞鎴︽偐鐠囇冧紣闂佸摜鍣ラ崹鍫曠嵁閸℃稑纾兼慨锝庡幖缂嶅﹪骞冮埡鍛闁圭儤绻傛俊閿嬬節閻㈤潧袥闁稿鎹囬弻鐔封枔閸喗鐏撶紒楣冪畺缁犳牠寮婚悢琛″亾閻㈢櫥鐟版毄闁荤喐绮庢晶妤呮偂閿熺姴钃熸繛鎴欏灩缁犳娊鏌￠崒姘辨皑闁哄鎳庨埞鎴︽倷閸欏娅ｉ梻浣稿簻缁茬偓绌辨繝鍥х妞ゆ棁濮ゅ▍銏ゆ⒑鐠恒劌娅愰柟鍑ゆ嫹There is general agreement among clinicians that the PSA test has the highest predictive value for prostate cancer, that PSA screening can detect early-stage cancers, and that most cancers detected by PSA screening appear to be clinically important when their pathological characteristics are used as a surrogate for biologic potential. There is, however, disagreement as to what level of PSA should prompt a prostate biopsy. The controversy stems from the following: the use of higher PSA thresholds risks missing an important cancer until it is too late for a cure, whereas the use of lower PSA thresholds increases not only unnecessary biopsies but also the proportion of biopsies that identify clinically insignificant disease (disease that would not have been detected in the absence of screening). The use of a PSA threshold of 4.0 ng per milliliter for men over the age of 50 years has been accepted by most clinicians as striking a reasonable balance between these tradeoffs. However, information on the prevalence of biopsy-detectable prostate cancer among men with PSA values of 4.0 ng per milliliter or less and no other indication for biopsy (e.g., an abnormal prostate examination) is limited.
In this issue of the Journal, Thompson et al.4 report the prevalence of prostate cancer among men in the control group of the Prostate Cancer Prevention Trial. During a seven-year period, none of the men in this analysis had PSA levels above 4.0 ng per milliliter or any abnormality on digital rectal examination. All participants underwent a prostate biopsy at the end of the study. Of almost 3000 men in the group, 15 percent had a prostate cancer on the end-of-study biopsy, and of these cancers, 15 percent were high grade (a Gleason score of 7 to 9). The prevalence of cancer increased with the PSA level, from 7 percent among men with PSA values of 0.5 ng per milliliter or less to 27 percent among men with PSA values of 3.1 to 4.0 ng per milliliter. Furthermore, the prevalence of high-grade disease also increased with the PSA level, from 13 percent when the PSA level was 0.5 ng per milliliter or less to 25 percent when the PSA level was 3.1 to 4.0 ng per milliliter. Given this report of the risk of prostate cancer — and the risk of high-grade disease — at PSA levels below the threshold of 4.0 ng per milliliter, which has traditionally been used to prompt prostate biopsy, should we now recommend lowering the threshold for biopsy?
I believe not, for the following reasons. First, it should not be surprising that 10 to 27 percent of the men with PSA values of 4.0 ng per milliliter or less, who ranged in age from 62 to 91 years, were found to have prostate cancer in the study by Thompson et al. On the basis of the results of 5250 autopsies reported in the U.S. literature, the prevalence of prostate cancer was 15 to 60 percent among men 60 to 90 years of age and increased with age.5 Ninety percent of men 50 to 90 years of age have PSA values of 4.0 ng per milliliter or less.6 Thus, quite a few men with PSA levels of 4.0 ng per milliliter or less must harbor a prostate cancer.
Although it would be desirable to detect the small proportion of high-grade cancers — cancers that are likely to be life threatening — in men with low PSA levels, the identification of such cancers will require the development of new biomarkers, because high-grade cancers actually produce less PSA than low-grade cancers, after correction for cancer volume.7 The increasing prevalence of high-grade cancer with increasing PSA levels reflects the finding that higher-grade cancers are more often larger in volume than low-grade cancers, and the PSA level is directly related to the volume of the cancer.7
Second, prostate cancers detected at lower PSA levels are more likely to have a small volume (less than 0.5 ml) and to be low-grade8 and are thus more likely to represent clinically insignificant disease, because cancer volume and grade are surrogates for biologic potential.9 McNeal et al. found that only cancers that were much larger than 1 ml in volume and poorly differentiated were associated with metastatic disease.9 Furthermore, prostate cancers with a volume of less than 1 ml do not usually result in PSA levels above 4.0 ng per milliliter,10 so that the unexpected detection of cancer at lower PSA levels is more likely to identify disease for which treatment not only may be unnecessary but also may fail to improve survival.11 Thompson et al. could provide information about the estimated cancer volume in their population because the PSA density (PSA level divided by prostate volume) and the features of the cancer on biopsy (the grade, the number of cores with cancer, and the percentage of the core that is cancerous) are predictive of the cancer volume determined pathologically after surgery.12
Third, there is no convincing evidence that, with contemporary therapy, men who are treated when their cancers are detected at PSA levels at or below 4.0 ng per milliliter have better outcomes than men who are treated when the PSA is slightly higher than 4.0 ng per milliliter. In short, detection of prostate cancer at a PSA threshold lower than 4.0 ng per milliliter has not been shown to improve the disease-free outcome. With a PSA level in the range of 2.6 to 6.0 ng per milliliter, younger men are more likely than older men to have curable prostate cancer13 and a disease-free outcome14 — observations that are probably driven by the fact that older men are more likely to have high-grade cancers. Hence, the weight of the evidence suggests that the detection of prostate cancer at younger ages should have a greater effect on the likelihood of being free from disease after treatment than would the detection of prostate cancer at a PSA level of 4.0 ng per milliliter or less.
Fourth, in an investigation similar to that of Thompson et al., Gann et al. have shown that men with baseline PSA levels between 1.0 and 4.0 ng per milliliter are at significantly higher risk for a diagnosis of prostate cancer over the next 10 years than are men whose baseline PSA level is below 1.0 ng per milliliter.15 They found that a cutoff value of 3.3 ng per milliliter resulted in optimal sensitivity and specificity, but the gain was minimal as compared with that afforded by a cutoff value of 4.0 ng per milliliter. In addition, Morgan et al.16 have shown that the PSA cutoff value that results in 95 percent sensitivity (the detection of 95 percent of cancers) is close to 4.0 ng per milliliter for men between the ages of 50 and 70 years and 2.5 ng per milliliter for men in the fifth decade of life. Because most of the variability in PSA levels is due to benign prostate enlargement that occurs with age, and men below the age of 50 years are unlikely to have such enlargement, a threshold of 2.5 ng per milliliter seems reasonable for men below the age of 50 years.
Gann et al.15 pointed out that the "dichotomization of PSA results into normal and abnormal obscures important information contained in levels below the usual cutoff." The data of Thompson et al. provide a framework for the risk assessment of men with PSA values of 4.0 ng per milliliter or less and should prompt careful consideration of the likelihood of cancer at these lower PSA levels in men at particularly high risk, such as those with a strong family history of the disease. Given that the risk of a clinically significant prostate cancer increases incrementally with PSA levels between 0 and 4 ng per milliliter, it makes sense to track the rate of rise in PSA values (the PSA velocity), which has previously been shown to correlate directly with the risk of cancer17 and was significantly associated with the risk of cancer in the current study.
Finally, considering that the lifetime risk of death from prostate cancer is 3 percent and the lifetime risk of a diagnosis of prostate cancer is 16 percent, it is apparent that any approach that finds more cancers without quantifying the clinical significance of the detected disease will only increase overdiagnosis and overtreatment, as alluded to by Thompson et al. This, together with the absence of proof that PSA screening saves lives, should cause physicians to be circumspect about routinely recommending a prostate biopsy for men over the age of 50 years who have a PSA level of 4.0 ng per milliliter or less.
Although the value of PSA screening remains controversial, men who present for periodic health examinations should be made aware of the availability of the PSA test, so that they can make an informed decision about the need for routine screening. The enthusiasm for screening in general in the United States suggests that most men will decide to be tested.18
Source Information
From the Department of Urology, Johns Hopkins School of Medicine, Baltimore.
References
Tarone RE, Chu KC, Brawley OW. Implications of stage-specific survival rates in assessing recent declines in prostate cancer mortality rates. Epidemiology 2000;11:167-170.
Feuer EJ, Merrill RM, Hankey BF. Cancer surveillance series: interpreting trends in prostate cancer. II. Cause of death misclassification and the recent rise and fall in prostate cancer mortality. J Natl Cancer Inst 1999;91:1025-1032.
Chu KC, Tarone RE, Freeman HP. Trends in prostate cancer mortality among black men and white men in the United States. Cancer 2003;97:1507-1516.
Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level of 4.0 ng per milliliter. N Engl J Med 2004;350:2239-2246.
Carter HB, Piantadosi S, Isaacs JT. Clinical evidence for and implications of the multistep development of prostate cancer. J Urol 1990;143:742-746.
Smith DS, Catalona WJ, Herschman JD. Longitudinal screening for prostate cancer with prostate-specific antigen. JAMA 1996;276:1309-1315.
Partin AW, Carter HB, Chan DW, et al. Prostate specific antigen in the staging of localized prostate cancer: influence of tumor differentiation, tumor volume and benign hyperplasia. J Urol 1990;143:747-752.
Carter HB, Epstein JI, Chan DW, Fozard JL, Pearson JD. Recommended prostate-specific antigen testing intervals for the detection of curable prostate cancer. JAMA 1997;277:1456-1460.
McNeal JE, Bostwick DG, Kindrachuk RA, Redwine EA, Freiha FS, Stamey TA. Patterns of progression in prostate cancer. Lancet 1986;1:60-63. [CrossRef][ISI][Medline]
Brawn PN, Speights VO, Kuhl D, et al. Prostate-specific antigen levels from completely sectioned, clinically benign, whole prostates. Cancer 1991;68:1592-1599.
Vis AN, Kranse R, Roobol M, van der Kwast TH, Schroder FH. Serendipity in detecting disease in low prostate-specific antigen ranges. BJU Int 2002;89:384-389.
Epstein JI, Walsh PC, Carmichael M, Brendler CB. Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA 1994;271:368-374.
Carter HB, Epstein JI, Partin AW. Influence of age and prostate-specific antigen on the chance of curable prostate cancer among men with nonpalpable disease. Urology 1999;53:126-130.
Khan MA, Han M, Partin AW, Epstein JI, Walsh PC. Long-term cancer control of radical prostatectomy in men younger than 50 years of age: update 2003. Urology 2003;62:86-91.
Gann PH, Hennekens CH, Stampfer MJ. A prospective evaluation of plasma prostate-specific antigen for detection of prostatic cancer. JAMA 1995;273:289-294.
Morgan TO, Jacobsen SJ, McCarthy WF, Jacobson DJ, McLeod DG, Moul JW. Age-specific reference ranges for prostate-specific antigen in black men. N Engl J Med 1996;335:304-310.
Carter HB, Pearson JD, Metter EJ, et al. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA 1992;267:2215-2220.
Schwartz LM, Woloshin S, Fowler FJ Jr, Welch HG. Enthusiasm for cancer screening in the United States. JAMA 2004;291:71-78.(H. Ballentine Carter, M.D)