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r e v i e w o n c o l o g y Active Surveillance in prostate cancer Author L. Denis Key words Prostate Cancer - Screening – Active Surveillance – Watchful Waiting - Overtreatment Summary Careful observation of epidemiological data on incidence of and mortality from prostate cancer suggest an ever-increasing incidence (number of new cancers per year) relative to a stable or slightly declining mortality. This observation may in part be explained by the ageing of the male population in Europe, but mostly by overdetection of the disease due to the frequent use of the Prostate Specific Antigen (PSA) test and subsequent prostate biopsies. The results of the European Randomised study for Screening of Prostate Cancer (ERSPC) revealed that screening leads to overdetection of prostate cancer. Approximately half of all cancers detected by PSA-driven screening are at low risk of progressing during the lifetime of the patient and are referred to as either latent cancer (in the epidemiological setting) or indolent cancer (in the clinical setting). There is sufficient evidence for managing these Introduction Virtually all historical and contemporary evidence points to unavoidable overdetection of cancer in screening studies.1 This overdetection should be constantly on the mind of screening physicians to avoid subsequent overtreatment. Epidemiological and clinical data support the AS option as primary treatment in men with localized prostate cancer and favourable prognostic factors.2 However, in view of even the slightest chance of missing the opportunity for potential cure, a meticulous follow-up is recommended to allow changing management if prognostic factors indicate possible progression. The PRIAS study is part of the proposed PROCABIO project in the Health FP7 programme of the European Union. This prospective study aims to provide AS in the context of a scientific study, focused on the iden- B E L G I A N J O U R N A L O F M E D I C A L cancers with a strategy of ‘Active Surveillance’ (AS) rather than any form of aggressive curative treatment, such as radical prostatectomy and/or external/internal radiotherapy. This option for disease management and patient choice for deferred curative treatment should not be confused with the frequently used Watchful Waiting (WW) option. In watchful waiting, curative treatment is avoided because of advanced age or co-morbidity of the patient, and the deferred treatment, usually androgen deprivation treatment (ADT), is intended as palliative treatment when symptomatic progression occurs. The routine introduction of AS as a primary treatment option for the management of localised prostate cancer aims to reduce the existing levels of overtreatment. However, carriers of indolent prostate cancer do remain at some small risk, and patients are advised to seek careful, scientific medical follow-up. (BJMO 2007:1;3-7) tification of new diagnostic or therapeutic biomarkers in prostate cancer, and the evaluation of PSA kinetics, velocity and doubling time as possible markers of progressive disease in the follow-up programme.3 What can epidemiological and natural history studies of prostate cancer teach us? The introduction of the serum PSA test in the mid 80’s provoked the ever-increasing incidence of prostate cancer in most European countries, along with an impressive shift towards the detection of cancers of low grade and stage.2 PSA is still the most effective biomarker in solid tumours, and despite its non-specificity for prostate cancer and a lot of false positive and false negative results, remains - together with its many derivatives - a standard test for measuring the risk of prostate cancer in a given individual. O N C O L O G Y vol. 1 issue 1 - 2007 3 r e v i e w o n c o l o g y Table 1. Incidence and Mortality 2004-2006 in thousands - European Union.25 MEN – Prostate WOMEN – Breast Cases Deaths Cases Deaths 2004 202.1 68.2 275.1 88.4 2006 301.5 67.8 319.9 85.3 IARC, 2004-2006 However, its application in population screening, coupled with increasing indications for and numbers of TransRectal UltraSound (TRUS) guided biopsies is directly responsible for a tsunami of newly-diagnosed prostate cancers in Europe. This fact becomes obvious when comparing the incidence and mortality figures for prostate cancer in the European Union from 2004 to 2006.4,5 Prostate cancer is the most frequently diagnosed form of cancer in men, accounting for 24,1% of all cases and is the third leading cause of death (10,4%) in men. Overall breast, prostate, colon and lung cancers are the most common forms of cancer. Together, they count for more than half of the entire cancer population in the European Union (25 members in 2006). Compared to the figures for breast cancer (Table 1), which increased by approximately 15% over this two year period, much like other solid tumours, the incidence of prostate cancer increased by an impressive 50%. A small part of the incidence may be due to the increased life expectancy of the male population, but these newly detected cancers are identified by the combination of a PSA test, a set of TRUS-directed biopsies and dedicated urologists intent on diagnosing prostate cancer in its early stages. Confirmation came from the ERSPC-released results, indicating that a large proportion (53%) of newly found cancers were categorized as ‘overdetection’.6 The major factor leading to this overdetection results from the detection of small histological cancers and the ubiquitous preneoplastic, high-grade prostatic intraepithelial neoplasia (HGPIN) lesions that are only detectable on autopsy or incidental upon surgery for benign disease of the prostate. These lesions start in the 3rd decade of life, affect half of all men at age 50 to reach a staggering 80% at age 80.7,8 Before the PSA era, these foci of cancer were labelled latent on incidental discovery and classified as T1a or T1b prostate cancer in the UICC TNM classification.9 The proposed classification by Jewett ended a 4 vol. 1 issue 1 - 2007 twenty year debate on whether these cancers, detected as incidental findings in the pathology specimen, required treated. A general consensus developed among clinicians to follow expectant management for the T1a lesions, but apply additional treatment where the tumour volume exceeded more than 5% of the total specimen.10 Deferred treatment of localised prostate cancer has been a consistent choice in primary treatment in the European Association of Urology (EAU) guidelines for low grade, low stage, localised tumours.11 Defining latent cancer, active surveillance and watchful waiting Today the most frequent clinical classification of prostate cancer is T1c disease. The tumour is impalpable, invisible to imaging and is detected by a set of core biopsies (minimum of 6) driven by an ‘elevated’ PSA and guided by TRUS. This is where the diagnostic dilemma begins; should a detected cancer be labelled as indolent and of no consequence to the patient, or aggressive being a potential lethal threat to the patient? If tumour volume exceeds 0.5 cc, is present in more than two of the core biopsies, is classified as a Gleason score of more than 3+3 or carries any sign of grade 4 or 5 disease, there is consensus that these cancers need treatment, and if feasible curative treatment. Additional prognostic factors, including total PSA or PSA density are used to confirm the nature of the cancer. However, PSA in the lower ranges, as clearly shown in the biopsy results of the Prostate Cancer Prevention Trial (PCPT) in Table 2, has no clear cutoff value below 4 ng/ml. High-grade prostate cancer with a possible lethal pathway, even if it takes more than 10 years, is present in up to 15% of the patients diagnosed with cancer.12 This explains two clinical facts: a number of the aggressive tumours with PSA above 4 ng/ml, the accepted ‘normal’ value, lead to underdiagnosis in up to 30% of cases. On the other hand, an indolent cancer meeting all the criteria for benign disease as presented in Table 3 may still harbour cancer cells, leading to progression over time in fewer than 5% of cases. For this reason alone, the trial entry criteria require willingness and discipline from participants to follow a strict follow-up as outlined in Table 4. This schedule provides the opportunity choosing curative treatment, should any signs of progression be noted on the subsequent check-ups. The patient stops following the schedule if grade 4 or 5 is detected in the B E L G I A N J O U R N A L O F M E D I C A L O N C O L O G Y Table 2. PCa and HGca (>7 Gleason) by PSA level (> 4 ng/ml) in the Prostate Cancer Prevention Trial study. PSA ng/ml Number of men Number (%) with prostate cancer Number (% of cancer) with high-grade prostate cancer < 0.5 486 32 (6.6) 4 (12.5) 0.6 – 1.0 791 80 (10.1) 8 (10.0) 1.1 – 2.0 998 170 (17.0) 20 (11.8) 2.1 – 3.0 482 115 (23.9) 22 (19.1) 3.1 – 4.0 193 52 (26.9) 13 (25.0) Total 2950 449 (15.2) 67 (14.9) follow-up biopsies, PSA DT is less than 3 years, and of course, if the patient changes his mind on deferring a curative option in the event the patient or his treating physician is less than fully confident in the rationale for the treatment. Active Surveillance is quite different from the often discussed watchful waiting. Only healthy people with a life expectancy of at least 10 years can choose to defer treatment, as shown in Table 5 at page 6. Watchful waiting is the preferred treatment term when curative treatment is not indicated because of co-morbidity or crippling age, where hormonal treatment would be a first choice should the cancer cause symptoms. score, probably the most reliable prognostic factor as clearly observed in longitudinal studies, has revealed a gradual shift towards higher Gleason scores.13 This results in most patients receiving similar Gleason scores, leading to overtreatment.14 We focus on screening detected prostate cancers, as the lead and length bias in screening studies favour the detection of the slow growing tumours. In the ERSPC study, a comparison of two rounds of screening showed that indolent cancer was diagnosed in 31.6% of patients in the first round and in 42.6% in the second, around four years later. These data suggest that overdetection increases with repeated screening and confirm the model estimates of 53% of overdetection.15 What can clinical trials tell us? Of course, stakeholders in this discussion try to use impressive numbers to convince readers. Based on the Surveillance Epidemiology and End-Results (SEER) data, Miller calculated the overtreatment of the 71,602 men with recorded tumour grade, categorised as low risk and higher risk. He argued that 45% of the lower risk group (10,973 patients) were potentially over-treated with radiation therapy, while 2,564 patients (10%) were potentially over-treated with radical prostatectomy.16 Arguments against Active Surveillance are based on reports that underdiagnosis in a prostate screening Active Surveillance, no matter how promising as a choice of treatment, remains a burden for patient and doctor alike. Scylla and Charybdis, a choice between the nasty side-effects of curative treatment and the tiniest chance of missing out on curative treatment. In particular younger patients with a long life expectancy fear disease progression. Adding to the discomfort is the fact that the Gleason Table 3. Criteria for inclusion in the Active Surveillance option in the PRIAS trial. Histology proven adenocarcinoma. Table 4. Active Surveillance (PRIAS) followup criteria. Gleason score 3+3=6 (or less). Minimal number of biopsies. Maximum one or two cores positive. Clinical T1c or T2. PSA test every 3 months for 2 years, if stable, every 6 months thereafter. Serum PSA level at diagnosis < 10 ng/ml. PSA D and PSA kinetics (velocity and doubling time) to evaluate variability in prognosis. PSA density (PSA D) less than 0,2. Digital Rectal Examination (DRE) every 6 months. Patient fit for curative treatment. Repeat biopsy at 1,4,7 and 10 years. One extra biopsy if PSA doubling time comes into the 3-10 years range. Willing to attend follow-up. B E L G I A N J O U R N A L O F M E D I C A L O N C O L O G Y vol. 1 issue 1 - 2007 5 r e v i e w o n c o l o g y Table 5. Active Surveillance vs. Watchful Waiting. Table 6. Expected advantages of Active Surveillance. Active Surveillance Watchful Waiting Fit patient Co-morbidity / age 1. Reducing the rampant overtreatment caused by the overdetection of PCa by screening. Option cure Palliation if needed Indolent tumour Any tumour PSA DT Gleason score > 3+3 Clinical progression 3. Providing a prospective base to study PSA dynamics to replace unreliable PSA results. Repetitive biopsies Symptoms 4. Providing a prospective biorepository for the development and validation of a new PCa marker for indolent vs. progressive disease. population with PSA ranging from 2 to 10 ng/ml was higher than overdiagnosis in their series (we prefer the term overdetection).17 Frankly, we cannot in any way justify the treatment of patients who do need treatment in the first place. Excellent studies were performed in Scandinavia, essentially observations of 223 men with early stage cancer that did not seek treatment. At 15-year followup, the outcomes were identical to a control group without prostate cancer. However, at later follow-up, more cancer-specific deaths occurred in the cancer group 15-20 years after initial diagnosis.18 Another study, the Scandinavian Cancer Group Study, compared the long-term outcomes of radical prostatectomy with watchful waiting. A total of 395 men with early stage prostate cancer (clinical, not through screening) received surgery or watchful waiting in a randomised trial (level of evidence 1b). After 8 years, 8.6% of men in the surgery group had died compared to 14% in the observation group. Although it was calculated that 17 men had to be operated to prevent one death (maybe 22 for screening), it instilled clinicians some caution regarding foregoing treatment.19 One of the pioneers and enthusiastic researchers in Active Surveillance developed a treatment algorithm combining PSA doubling time and followup biopsies. The (ongoing) study involves 299 men being followed for 8 years. The outcome results are encouraging; most patients (65%) continue Active Surveillance. Overall, 85% are alive and only 2 of 299 died of prostate cancer.20 Two new randomized trials have been launched. The PROTECT treatment trial aims to study the effectiveness and cost-effectiveness of radical prostatectomy, radical conformal radiotherapy and active monitoring for PSA detected localised prostate cancer. Effectiveness comprises survival at 5, 10 and 15 6 vol. 1 issue 1 - 2007 2. Assuring quality of life of PCa carriers by avoiding unnecessary treatment. 5. Providing evidence based guidelines for the management of early prostate cancer in the PRIAS study. Europa Uomo, 2007 years, biochemical and clinical disease progression, impact of treatment and economic evaluation. The trial is compared to a comparison arm, with the first analysis expected by 2015. The National Cancer Institute (USA) has launched the START trial, a randomised controlled trial to evaluate active surveillance. Conclusions The debate among the different stakeholders will continue, but the compelling evidence to support deferred treatment is here to stay. Quality of life has emerged as a central issue in treatment options, and buying time to delay crippling treatment looks attractive to a middle-aged male. It is true that this option requires patients to be well informed of all aspects of the disease. However, we are still in great need of adequate models for cancer progression and are still searching for the Holy Grail, a reliable, specific biomarker for diagnosis and progression of prostate cancer. The key messages regarding Active Surveillance as an equivalent choice in primary treatment of prostate cancer are presented in Table 6. References 1. Welch H.G. Should I be tested for Cancer? University of California Press, Berkely – Los Angeles – California, 2004: 224. 2. J. McConnell, L. Denis, H. Akaza, S. Khoury, J. Schalken. Prostate Cancer. Health Publication, Paris, 2006. 3. Prias study www.prias-project.org 4. P. Boyle, J. Ferlay. Cancer incidence and mortality in Europe, 2004. Annals of Oncology 2005; 16: 481-488. B E L G I A N J O U R N A L O F M E D I C A L O N C O L O G Y Key messages for clinical practice 1.All cancer screening leads to overdetection. Prostate Cancer is no exception to this rule. 2.Knowledge and insight into the natural history of prostate cancer makes it clear that not all newly detected cancers need immediate curative treatment. 3.Active Surveillance with an open option to deferred curative treatment is an accepted primary treatment option for patients and practitioners. Active Surveillance is included in the Guidelines of the European Association of Urology. 4.A multinational prospective study, PRIAS (www. prias-project.org), provides patients with security by following PSA dynamics (velocity and doubling time) and PSA density. It provides the scientific community with an established biorepository and test data for the development and validation of new biological markers for diagnosis and prognosis of clinically relevant prostate cancer. 5. J. Ferlay, P. Autier, M. Boniol, M. Heanue, M. Colomber, P. Boyle. Estimates of the cancer incidence and mortality in Europe in 2006. Annals of Oncology 2007; 18: 581-592. 6. Draisma G, Boer R, Otto S.J. et al. Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer. JNCI 2003; 95: 868. 7. Montironi R, Mazzucchelli R, Lopez-Beltran A, Cheng L, Scarpelli M. Mechanisms of disease: high-grade prostatic intraepithelial neoplasia and other proposed preneoplastic lesions in the prostate. Nat Clin Pract 2007; 4: 321-332. 8. Sakr WA et al. Age and racial distribution of prostatic intraepithelial neoplasia. Eur Urol 1996; 30: 138-144. 9. Hermanek P, Henson D.E, Hutter RVP, Sobin LH. TNM Supplement 1993. A commentary on uniform use. SpringerVerlag , Berlin – Heidelberg, 1993: 143 10. Jewett HJ. Present status of radical prostatectomy for stages A and B prostate carcinoma. Urol Clinics of North Am 1975; 2: 759-766. 11. Heidenreich A, Aus G, Abbou CC et al. European Association of Urology Guidelines 2007 on Prostate Cancer. Gelderland bv. Arnhem, The Netherlands 2007: 26-30. 12. Thompson IM et al. Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. JNCI 2006; 98: 529-534. 13. Albertsen PC, Hanley JA, Fine J. 20-year Outcomes Following Conservative Management of Clinically Localized Prostate Cancer. JAMA, 2005; 293: 2095-2101. 14. Thompson IM et al. Stage migration and grade inflation in prostate cancer: Will Rogers meets Garrison Keillor. JNCI 2005; 97: 1236-1237. 15. Postma R, Schröder FH, van Leenders GJLH et al. B E L G I A N J O U R N A L O F M E D I C A L Cancer Detection and Cancer Characteristics in the European Randomized Study of Screening for Prostate Cancer (ERSPC) Section Rotterdam. A comparison of two rounds of screening. Eur Urol 2007; 52: 89-97. 16. Miller DC et al. Incidence of initial local therapy among men with lower-risk prostate cancer in the United States. J Natl Cancer Inst 2006; 98: 1134-1141. 17. Graif T, Loeb S, Roehl KA et al. Under Diagnosis and Over Diagnosis of Prostate Cancer: Under Diagnosis and Over Diagnosis of Prostate Cancer in a Screening Population with Serum PSA 2 to 10 ng/ml. J Urol 2007; 178: 88-92. 18. Johansson JE, Andren O, Andersson SO et al. Natural History of Early, Localized Prostate Cancer. JAMA 2004; 291: 2713-2719. 19. Bill-Axelson A, Holmberg L, Ruutu M et al. Radical Prostatectomy Versus Watchful Waiting in Early Prostate Cancer. New Engl J Med 2005; 352: 1977-1984. 20. Klotz L. Active Surveillance with Selective Delayed Intervention for Favorable Risk Prostate Cancer. Urological Oncology 2006; 24: 46-50. Correspondence address Louis Denis, MD FACS Lange Gasthuisstraat 35-37 2000 Antwerpen Tel.: +32.3.223.53.50 Fax.: +32.3.223.53.52 E-mail: [email protected] Conflicts of interest: no conflicts of financial interest declared. O N C O L O G Y vol. 1 issue 1 - 2007 7