Editorial – referring to the article published on pp. 1028–1035 of this issue

What Do We Really Know about Prostate Cancer?

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avai lable at www.sc iencedi rect .com

journal homepage: www.europeanurology.com

Peter Albertsen *

Division of Urology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030 USA

The appropriate management of localized prostatecancer remains an enigma. As urologists, we are alltoo familiar with the tragic course followed by menwith advancing metastatic disease. From a urolo-gist’s perspective, disease progression is inevitableand justifies aggressive screening for prostate-specific antigen (PSA) and treatment of localizeddisease with either surgery or radiation. Unfortu-nately, this may not be the appropriate strategy tocare for many patients.

In their manuscript in this issue of EuropeanUrology Adolfsson et al remind us that only 42 of112 patients presenting with localized prostatecancer between 1978 and 1982 died of their disease[1]. The other 70 men died from a cause unrelated toprostate cancer. Even if we assume that all men withclinically localized disease can be cured with surgeryor radiation, their study suggests that at most only38% of men are likely to benefit from a program ofscreening and treatment. Public health officials andadministrators who control health care budgetsare becoming increasingly aware of these data.Therefore, as urologists, we need to develop moresophisticated algorithms for diagnosing and treatingprostate cancer if we are to remain the experts whomanage this disease.

What do we know about prostate cancer? First, itis clear that prostate cancer is a chronic disease inthe vast majority of patients. Adolfsson and severalothers have shown us that most men can live withprostate cancer for a very long time [1–3]. Manyrequire no treatment. Second, these same studieshave shown us that prostate cancer continues to

DOI of original article: 10.1016/j.eururo.2007.04.002* Tel. +1 860 679 3676; Fax: +1 860 679 1318.E-mail address: Albertsen@nso.uchc.edu.

0302-2838/$ – see back matter # 2007 European Association of Urology. Publis

progress even as long as 20 yr following diagnosis.There is no time following diagnosis when we canreassure a man that his disease will never pose aclinical problem. Third, PSA testing results in adramatic increase in the number of men diagnosedwith this disease.

What are we less certain about regarding prostatecancer? We do not fully understand who is destinedto have progressive disease and who harborsindolent disease. Pathologists have taught us thatmen with poorly differentiated disease have a muchworse prognosis than men with well or moderatelydifferentiated disease. Several decades ago aspira-tion cytology was the standard method of detectingprostate cancer in Sweden. Pathologists therebecame adept at discerning men with bad cancersfrom those with less aggressive disease. In theUnited States, Gleason disseminated his system ofidentifying men with poorly differentiated diseasefrom those with well-differentiated disease. Sincethen researchers have explored many other geneticprobes including the analysis of cellular ploidy toseparate bad cancers from good cancers [4]. Unfor-tunately, these studies have yet to yield significant,new information independent from that provided bybasic histology. Also, unfortunately, even thisstandard is not absolute. Contemporary Gleasonscoring has inflated values so that many tumorspreviously read as low grade are now reported asGleason 6 disease [5].

We are also uncertain about the efficacy of ourtreatments. The Swedish randomized trial compar-ing outcomes following radical surgery versus

hed by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2007.04.021

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watchful waiting has provided us with critical data[6]. Their most recent update shows a modestbenefit to surgery after 10 yr of follow-up. Fourteenpercent of men treated with watchful waiting havedied from their disease as compared with only 7% ofmen who underwent radical prostatectomy. Weknow even less about outcomes following radiationtherapy other than that the results are probablycomparable with surgery for at least 10 yr and areimproved in men with advanced, localized disease ifradiation is supplemented with androgen ablation[7].

What do we know the least about prostatecancer? At this point we have no real understandingof the natural history of screen-detected prostatecancer. All of the natural history studies publishedto date, including the one by Adolfsson et al [1],include only men presenting with obstructivesymptoms or with a palpable nodule on rectalexamination. In contemporary practice in NorthAmerica, these patients are rare. More commonlymen with an elevated PSA value following 1, 2, or 3 yrand sometimes as many as 10 yr of PSA testingundergo a transrectal ultrasound and biopsy of theirprostate. This, in turn, has produced a dramaticincrease in the number of new cases of prostatecancer. What percentage of these men are destinedto die from their disease in the absence oftreatment?

Several studies have shown us that the pool ofmenwith subclinical disease is considerably greater thanthe pool of men who present with obstructivesymptoms or prostate nodules [8]. As a consequence,repeated PSA testing is uncovering large numbers ofpatients who never would have presented withlocalized disease similar to the cohort assembledby Adolfsson et al. It maybe true that some of the menidentified by PSA testing are destined to developmetastatic disease if left untreated, but there is amuch higher probability that a significant number ofmen identified by PSA testing are not destined tosuffer effects of their disease at all.

PSA testing also leads to the diagnosis of prostatecancer in men at much younger ages than wascommon during the era when the Adolfsson et alcohort was assembled. Do we actually alter thecourse of this disease by finding and treating itearlier or are we just witnessing the typical effects oflead time that have been estimated by Draisma et al[9] to be at least 10 yr among men diagnosed in theirfifties and >5 yr among men diagnosed in theirseventies?

Randomized trials are currently underway thatwill help provide important insights into theseuncertainties. The European Randomized Trial of

Screening for Prostate Cancer is soon expected topresent results concerning the efficacy of popula-tion-based PSA testing. The Prostate, Lung, Color-ectal, Ovary (PLCO) trial being conducted in theUnited States will provide some insights concerningthe actual impact of PSA testing in a primary caresetting. The Prostate Cancer Intervention versusObservation Trial (PIVOT) being conducted in theUnited States by the Veterans Affairs Administra-tion should provide information concerning theefficacy of radical prostatectomy in a population ofmen whose cancers have been identified by PSAtesting. Finally, the Prostate Testing for Cancer andTreatment (ProTeCT) trial being conducted in theUnited Kingdom should provide answers concern-ing the impact of both screening and treatment witheither surgery or radiation.

Unfortunately, many of these trials are stillseveral years away from reporting results. Howshould we manage this disease in the interim?Although still controversial, a growing number ofresearchers have begun to advocate a policy ofactive surveillance for men with localized, low-grade, small-volume disease [10]. Urologists prac-ticing in countries where widespread PSA testinghas occurred for many years have noticed anincreasing number of men diagnosed with minutequantities of Gleason 6 disease. One or two cores of 10or 12 obtained often have <20% involvement withdisease. This is clearly not the disease described inthe present paper by Adolfsson et al. Furthermore,these patients are likely to have a prognosis that ismuch better than those described in that paper. Infact, there is a high probability that this disease willprogress very slowly over the next several decades.No protocol has been established to monitor men onan active surveillance program, but those proposedare similar to the one outlined by Adolfsson et al.Most researchers suggest periodic PSA testing,possibly every 4–6 mo. Most researchers also suggesta repeat biopsy, usually between 1 and 2 yr followingthe initial diagnosis. After that most protocolssuggest periodic prostate biopsy every 1–3 yr. Activesurveillance is continued provided a patient’s serumPSA remains stable and there is no evidence ofdisease progression either by volume or by increasedgrade. Early reports suggest that a number of men willprogress during the first few years based on thesestrict criteria, but a significant number will not.Hopefully this approach will match aggressive treat-ments with those men who have aggressive diseaseand no treatment for those men who harbor indolentdisease.

Whitmore’s saying ‘‘Is treatment possible, whenit is necessary and is it necessary when it is

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possible?’’ has become an axiom among urologists.By publishing their results, Adolfsson et al remindus that this challenge is still very real. All mendiagnosed with prostate cancer following PSAtesting are not destined to die from their diseasejust as all men in Sweden who presented withprostate symptoms or a nodule in 1978–1982 did notdie of theirs. Data from these historical series shouldprovide contemporary clinicians with the courage torecommend active surveillance for some of theirpatients. Advising all men with newly diagnosed,localized prostate cancer to undergo surgery orradiation would have been wrong in 1980 just as it iswrong today. Similarly, advising all men to undergowatchful waiting was wrong in 38% of cases in 1980as it would be today. In contemporary practice wehave only two tools, serum PSA and tissue histology.We should try to use them to their best advantageuntil research into genetic markers provides us withbetter alternatives.

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