EUROPEAN UROLOGY 63 (2013) 101 107 available at www.sciencedirect.com journal homepage: www.europeanurology.com Platinum Priority Prostate Cancer Editorial by Laurence Klotz on pp. 108 110 of this issue Outcome Following Active Surveillance of Men with Screen-detected Prostate Cancer. Results from the Göteborg Randomised Population-based Prostate Cancer Screening Trial Rebecka Arnsrud Godtman a, *, Erik Holmberg b, Ali Khatami a, Johan Stranne a, Jonas Hugosson a a Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Göteborg, Göteborg, Sweden; b Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Göteborg, Göteborg, Sweden Article info Article history: Accepted August 28, 2012 Published online ahead of print on September 5, 2012 Keywords: Active surveillance Outcome Prostate cancer Prostate-specific antigen Screening Abstract Background: Active surveillance (AS) has emerged as a treatment strategy for reducing overtreatment of screen-detected, low-risk prostate cancer (PCa). Objective: To assess outcomes following AS of men with screen-detected PCa. Design, setting, and participants: Of the 968 men who were diagnosed with screendetected PCa between 1995 and 2010 in the Göteborg randomised, population-based PCa screening trial, 439 were managed with AS and were included in this study. Median age at diagnosis was 65.4 yr of age, and median follow-up was 6.0 yr from diagnosis. Intervention: The study participants were followed at intervals of 3 12 mo and were recommended to switch to deferred active treatment in case of a progression in prostate-specific antigen, grade, or stage. Outcome measurements and statistical analysis: The end points overall survival (OS), treatment-free survival, failure-free (no relapse after radical treatment) survival, and cancer-specific survival were calculated for various risk groups (very low, low, intermediate, and high) with Kaplan-Meier estimates. A Cox proportional hazards model as well as a competing risk analysis were used to assess whether risk group or age at diagnosis was associated with failure after AS. Results and limitations: Forty-five per cent of all screen-detected PCa were managed with AS, and very low-risk and low-risk PCa constituted 60% of all screen-detected PCa. Thirty-seven per cent (162 of 439) switched from surveillance to deferred active treatment, and 39 men failed AS. The 10-yr OS, treatment-free survival, and failurefree survival were 81.1%, 45.4%, and 86.4%, respectively (Kaplan-Meier estimates). Men with low-, intermediate-, and high-risk tumours had a hazard ratio for failure of 2.1 ( p = 0.09), 3.6 ( p = 0.002), and 4.6 ( p = 0.15), respectively, compared to very low-risk tumours (Cox regression). Only one PCa death occurred, and one patient developed metastasis (both in the intermediate-risk group). The main limitation of this study is the relatively short follow-up. Conclusions: A large proportion of men with screen-detected PCa can be managed with AS. AS appears safe for men with low-risk PCa. # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Institute of Clinical Sciences, Department of Urology, Bruna Stråket 11 B, SE-413 45 Göteborg, Sweden. Tel. +46 313 423809; Fax: +46 314 15617. E-mail address: r.godtman@gmail.com (R.A. Godtman). 0302-2838/$ see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.eururo.2012.08.066
102 EUROPEAN UROLOGY 63 (2013) 101 107 1. Introduction According to two recently published randomised controlled trials, screening for prostate cancer (PCa) with prostatespecific antigen (PSA) prevents PCa deaths [1,2]. Nevertheless, whether to screen for PCa with PSA is the subject of ongoing debate, and the US Preventive Task Force stated recently that PSA screening is associated with overdiagnosis and harm and recommended against PSA screening [3]. Overdiagnosis that is, diagnosis of a cancer that would never have been diagnosed in the absence of screening is a major potential disadvantage of PSA screening and has been estimated at >50% of all screen-detected PCa. However, it varies with definition and screening context [4,5]. Active surveillance (AS) has emerged as a strategy for reducing overtreatment resulting from overdiagnosis. The aim of AS is to avoid or postpone active treatment (radical prostatectomy [RP], radiation therapy [RT]) in men with early, lowrisk PCa without missing the window of opportunity for cure [6]. A common criterion for identifying low-risk PC suitable for AS is the one originally described by Epstein in 1994 [7]. The criteria for selecting men with PCa for AS are not yet evidence based, and published surveillance series have used slightly different criteria to find eligible patients [6,8 15]. The aim of the present study was to evaluate AS as a strategy for managing screen-detected PCa within the Göteborg randomised, population-based PCa screening trial. 2. Materials and methods 2.1. Study design The Göteborg randomised, population-based PCa screening trial, which formed the basis of the present study, is an ongoing study that started in 1995 following approval by the Ethical Review Committee at the University of Göteborg. Since 1996, it has been a part of the European Randomised Study of Screening for Prostate Cancer. Among men 50 64 yr of age who were living in Göteborg as of 31 December 1994, 10 000 were randomised to a screening group and 10 000 to a control group (Fig. 1). Men in the screening group were invited every second year for a PSA test until they reached the upper age limit for invitation (averaging 69 yr of age). All men with elevated PSA (the cut-off varied between 2.5 and 3.4 ng/ml) were referred for prostate biopsy. This study has been described extensively in previous publications [2]. 2.2. Follow-up strategy After the diagnosis of PCa, a treatment strategy was chosen at the discretion of the treating physician and patient. In the majority of cases, the reason for choosing AS was a presumed low-risk PCa, although AS could also be on the patient s initiative or because of comorbidities. Patients have been followed at intervals of 3 6 mo with PSA measurements and clinical follow-up. The majority of the study population was followed using an AS approach, aiming for curative treatment if there were signs of disease progression; however, as men grew older and comorbidities surfaced, AS in some cases changed to a watchful waiting approach. All patients with a diagnostic biopsy containing <2-mm cancer were recommended for early rebiopsy. Further rebiopsies were not regulated in any protocol but were recommended at signs of PSA or T stage progression; patients with stable disease were also recommended for rebiopsy typically every second to third year, but this referral depended on initial biopsy outcome, patient age, comorbidity, and preferences. Assessment by means of bone scan, magnetic resonance imaging or computed tomography scans for lymph node metastases or distant metastases wasnot performed unless the patient hadsymptoms or clinical features (PSA >20 ng/ml or Gleason score >7) indicating a risk of metastasized disease. An established progression in PSA, grade, or stage was an indication of a shift in management from AS to deferred active treatment: RP, RT, or hormone therapy (HT) [16]. Active treatment could also be initiated at the request of the patient. After active treatment, the patient was followed at intervals of 3 6 mo with determination of PSA and regular clinical follow-up. 2.3. Risk group classification For analysis of the data, tumours were divided into five risk groups. Those fulfilling the Epstein criteria very low-risk (T1c, not N1 or M1; Gleason score 6; PSA density <0.15 ng/ml; fewer than three cores with cancer; and 50% cancer in any core), low-risk (T1, not N1 or M1; Gleason score 6; and PSA <10 ng/ml but not meeting the very low-risk criteria), intermediate-risk (T1 2, not N1 or M1; Gleason score 7; and/or PSA <20 ng/ml and not meeting the very low-risk or low-risk criteria), high-risk (T1 4, not N1 or M1; Gleason score 8; and/or PSA <100 ng/ml and not meeting the other risk group s criteria), and advanced disease (N1 or M1 or PSA 100 ng/ml). 2.4. End point definitions and statistical analysis Failure after AS was defined as PSA recurrence after RP, RT, or RP with salvage radiation; initiation of HT; diagnosis of PCa metastases (M1); or death from PCa. PSA recurrence was defined as a PSA 0.2 ng/ml after RP or RP with salvage radiation and the PSA nadir +2 ng/ml for those who received RT. Survival analysis using the Kaplan-Meier method was performed to calculate the cumulative incidence of overall survival (OS), PCa-specific survival, treatment-free survival, and failure-free survival. Follow-up time was calculated from the date of diagnosis to the date of the event. Men who did not have an event were censored at the date of the last clinical follow-up, death, or emigration. For men with multiple events (ie, PSA recurrence, M1 disease, and death from PCa), time was calculated to the first occurring event. A Cox proportional hazards model was used to assess whether risk group or age at diagnosis were associated with failure after AS. Because many men with PCa die of causes other than PCa, competing risk analyses were performed to investigate the effects of competing risks [17 19]. All statistical analyses were performed using Stata v.12.1 (StataCorp, College Station, TX, USA) and IBM SPSS Statistics v.20 (IBM Corp., Armonk, NY, USA) software. 3. Results Between 1 January 1995 and 31 December 2010, a total of 1288 men were diagnosed with PCa in the screening arm, and 968 men were diagnosed as a result of the screening program. Approximately half of all screen-detected PCa (442 of 968; 45.7%) were managed with AS, and that proportion seemed to be stable throughout the entire study period (Fig. 2). Two men were diagnosed with PCa after they had moved to another area in Sweden and were not followed at Sahlgrenska University Hospital. They were therefore excluded from further analyses. Another man, who refused all active treatment and did not attend any
[(Fig._1)TD$FIG] EUROPEAN UROLOGY 63 (2013) 101 107 103 Fig. 1 Consolidated Standards of Reporting Trials diagram of the Göteborg randomised, population-based prostate cancer screening trial. PCa = prostate cancer; PSA = prostate-specific antigen. * Treatment strategy was chosen at the discretion of the treating physician and patient. follow-up visits, was also excluded, resulting in a study population of 439 men. The median age at PCa diagnosis was 65.4 yr of age (range: 51.2 70.4), and the median follow-up time from date of diagnosis to last follow-up, date of death, or emigration was 6.0 yr (range: 0.08 15.1). Of the 439 men managed with AS, 51.0% (224 of 439) fulfilled the very low-risk criteria, 26.7% (117 of 439) were low risk, 21.0% (92 of 439) were intermediate risk, 1.4% (6 of 439) were high risk, and none fulfilled the advanced criteria (Table 1). Sixty-three per cent (277 of 439) of all men continued in AS throughout the entire study period. Of the 162 men who at some point during AS switched to deferred active treatment, 106 (65.4%) were treated with RP, 32 (19.8%) received RT, and 24 (14.8%) received HT. Figure 3 shows the Kaplan-Meier curve of treatment-free survival. The median time in AS was 8.2 yr (Kaplan-Meier estimation). The cumulative risk of receiving treatment at 2, 5, 10, and 14 yr calculated using Kaplan-Meier estimates was 24.0%, 38.5%, 54.6%, and 62.9%, respectively. The corresponding risk estimates calculated using a competing risk model were
104 [(Fig._2)TD$FIG] EUROPEAN UROLOGY 63 (2013) 101 107 [(Fig._3)TD$FIG] Fig. 2 Cumulative incidence of screen-detected prostate cancer and active surveillance. Fig. 3 Treatment-free survival for the various risk groups. 24.0%, 37.5%, 51.4%, and 56.9%. The reasons for discontinuing AS were as follows: increase in cancer involvement or Gleason grade at repeat biopsy in 77 men (47.5%); T stage progress in 7 men (4.3%); an increase in PSA in 45 men (27.7%); anxiety in 4 men (2.5%); and urinary tract symptoms in 4 men (2.5%). Active treatment had been deferred at the patient s initiative in 15 men (9.3%), and in 10 men (6.2%), the reason for discontinuing AS was unknown. Sixty men died during follow-up, resulting in a 10-yr OS of 81.1% (Kaplan-Meier estimate). Fifty-nine men died from causes other than PCa, and one man in the intermediate-risk group who received HT after 8.6 yr in AS developed distant metastases and died from PCa 12.7 yr after diagnosis. Thirty-nine men were classified as failures (Table 2). One man, described above, died from PCa; another man developed distant PCa metastases. Further, 23 men initiated HT but did not die from PCa, nor did they develop metastases during follow-up, and 14 men had a PSA recurrence after RP (n = 10), RT (n = 3), or RP with salvage radiation (n = 1). Eleven of these 39 men died of other causes during follow-up. Figure 4 shows the Kaplan-Meier curve of failure-free survival. The 5-, 10-, and 14-yr Kaplan- Meier estimates of cumulative incidence of failure were Table 1 Proportion of patients managed by active surveillance in relation to all screen-detected cases per age and risk group Age, yr Very low risk Low risk Intermediate risk High risk Advanced Unknown Total 50 54 3/4 3/8 0/5 0/3 0/0 0/0 6/20 55 59 17/37 19/57 6/38 0/8 0/1 0/1 42/142 60 64 89/133 38/91 24/106 2/20 0/5 0/1 153/356 65 115/159 57/92 62/160 4/31 0/7 0/1 238/450 Total 224/333 117/248 92/309 6/62 0/13 0/3 439/968 The number before the slash represents the number of men managed with active surveillance; the number after the slash represents the total number of men with screen-detected prostate cancer, including those managed with active surveillance. Table 2 Causes of failure and status at last follow-up for different risk groups Very low (n = 224) Low (n = 117) Intermediate (n = 92) High (n = 6) PCa death, no. (%) 1 (1) M1, no. (%) * 1 (1) HT, no. (%) y 5 (2) 5 (4) 12 (13) 1 (17) PSA recurrence after radical treatment, no. (%) z 5 (2) 7 (6) 2 (2) Death during follow-up: non-pca, no. (%) 24 (11) 16 (14) 17 (18) 2 (33) Received radical treatment without signs of disease relapse, no. (%) 57 (25) 31 (26) 13 (14) 0 Still in AS at last follow-up, no. (%) 133 (59) 58 (50) 46 (50) 3 (50) PCa = prostate cancer; HT = hormone therapy; PSA = prostate-specific antigen; AS = active surveillance. * M1 but not death from PCa. y Initiation of HT but not death from PCa or M1. z PSA recurrence but not death from PCa, M1, or initiation of HT.
[(Fig._4)TD$FIG] EUROPEAN UROLOGY 63 (2013) 101 107 105 Fig. 4 Failure-free survival for the various risk groups. 6.7%, 13.6%, and 30.2%, respectively. The corresponding competing risk estimates were 6.4%, 12.6%, and 24.5%, respectively. Both risk group and age at diagnosis were associated significantly with failure in a Cox proportional hazards model (Table 3). 4. Discussion Almost 50% of men diagnosed with screen-detected PCa in the Göteborg screening trial did not receive immediate active treatment but were instead managed with AS (Fig. 2). The results indicate that AS is a safe treatment strategy in low-risk PCa. During a median follow-up of 6 yr, one man died from PCa, and another man developed metastatic disease. Both were in the intermediate-risk group. The 10-yr failure-free survival was 86.4%, despite the fact that both PSA recurrence after curative treatment and initiation of HT were regarded as a failure, and the study population included men with intermediate-risk and high-risk PCa. One-third of all screen-detected cancers in the Göteborg screening trial met the Epstein criteria for insignificant cancer, and 60% of all cancers were low-risk cancers (very low or low risk). This finding is close to what is reported in the United States, with 36% meeting the Epstein criteria. As this is a population-based study with a high attendance rate (77%) and a high biopsy rate (93%) [2], the results indicate that PCa screening will detect a substantial number of men with a low risk of disease progression within 15 yr. Despite the fact that this screening program started with relatively young men (50 64 yr of age at randomisation) and stopped at an average age of 69 yr of age, almost half (450 of 968) of the screen-detected cancers were diagnosed in men 65 yr of age or older. These data clearly indicate that AS should be an option for avoiding overtreatment. The ratio between the number of men receiving AS and total PCa incidence was around 50% during the whole study period, except for the first 2 yr (Fig. 2). The initial lower rate of AS is probably because during prevalence screening (first screening round), relatively more men with aggressive or advanced PCa were diagnosed, and for them AS was not an option [20]. The relatively low age at first screening (50 66 yr of age) may also have influenced the choice of treatment. One limitation of this study is the lack of a strict AS protocol. However, patients have been followed mainly in one centre, where the same treatment policy has been applied and maintained during the whole study period. The stable rate of AS after the initial screen is an indication that no major changes in patient selection occurred during the 16-yr study period; in the Göteborg trial, compared to several other centres, AS has been a common treatment strategy since the study started in 1995. Table 3 (a) The influence of risk group and age at diagnosis on failure-free survival expressed as hazard ratio; (b) the influence of risk group and age at diagnosis on overall survival expressed as hazard ratio (a) Covariate HR, univariate model p value HR, multivariate model p value HR, multivariate competing risk model p value Risk group Very low (n = 224) 1.0 1.0 1.0 Low (n = 117) 2.0 (0.9 4.7) 0.11 2.1 (0.9 4.8) 0.09 2.1 (0.9 4.9) 0.08 Intermediate (n = 92) 3.9 (1.8 8.7) 0.001 3.6 (1.6 8.0) 0.002 3.7 (1.6 8.4) 0.002 High (n = 6) 5.3 (0.7 41.6) 0.11 4.6 (0.6 35.9) 0.15 4.6 (0.7 29.9) 0.11 Age 1.1 (1.0 1.2) 0.03 1.1 (1.0 1.2) 0.09 1.1 (1.0 1.2) 0.22 (b) Covariate HR, univariate model p value HR, multivariate model p value Risk group Very low (n = 224) 1.0 1.0 Low (n = 117) 1.0 (0.5 1.9) 0.99 1.1 (0.6 2.0) 0.87 Intermediate (n = 92) 1.7 (0.9 3.2) 0.07 1.6 (0.9 3.0) 0.13 High (n = 6) 5.2 (1.2 22.2) 0.03 4.5 (1.1 19.1) 0.04 Age 1.1 (1.0 1.2) 0.001 1.1 (1.0 1.2) 0.002 HR = hazard ratio. Within parentheses: 95% confidence interval.
106 EUROPEAN UROLOGY 63 (2013) 101 107 Sixty-three per cent continued in AS throughout the entire follow-up, and the 10-yr treatment-free survival was 45.4%, which is in line with the current literature [10,12,21]. The most common cause for discontinuing AS in this study was progression in cancer involvement or Gleason grade at repeat biopsy. Only four men stated that they came off AS because of anxiety. This is also in line with several other studies, which have reported low levels of anxiety and a preserved quality of life (QoL) during AS [22,23]. A sextant biopsy was the standard up to 2008, after which a 10-core biopsy was used. Even if men with low-volume cancer (<2 mm) were recommended for early rebiopsy, this was not the case for all patients, which has possibly led to a high risk of undersampling, as indicated by the high incidence of delayed active treatment during the first 2 yr of follow-up (Fig. 3). There is a risk that this undersampling may have led to a delay in proper risk grouping, thereby missing the opportunity for cure in some patients. This idea is supported by 1-yr biopsy data from the Prostate Cancer Research International: Active Surveillance study [24]. Men taking part in PCa screening probably do so hoping that if they were diagnosed with the disease, it would be found and treated at an early stage, when it is still curable. Consequently, the definition of failure after AS in this study not only included PCa death and metastatic disease but also PSA recurrence after curative treatment and HT, as it is a palliative treatment. This strict definition of failure could be a matter for discussion, as 11 of the 39 failed men died from other causes during follow-up. For the large group of men with very low-risk and lowrisk PCa, AS appears safe. There were no deaths from PCa, and no man developed metastatic disease during a median follow-up of 6 yr. To further reduce overtreatment, it has been discussed whether the inclusion criteria for AS could be expanded so that selected men (high age or comorbidity) with intermediate-risk PCa could also be candidates for AS [25]. In the present study, a clear association was seen between risk group and the risk of failure after AS. Men with intermediate- and high-risk PCa had a four-fold higher risk of failure (Table 3a) than very low-risk PCa, although the failure rate was still rather low during the first 10 yr. Previous studies have confirmed the favourable outcomes in patients with low-risk cancers [9,10,12,13,21,26], while the outcome among men with intermediate-risk and highrisk cancers varies in the literature [11,12,26 28]. According to this study, patients with intermediate-risk PCa should be carefully informed that delaying radical treatment is associated with a higher risk of developing incurable disease. Interestingly, the high-risk group had a significantly higher risk of overall mortality (Table 3b). The reason for this finding is probably selection, because only high-risk patients with severe comorbidities are offered delayed active therapy (watchful waiting approach). Age was as expected related to OS, but in the univariate analysis, it was also related to failure-free survival. In the multivariate analysis, the statistical significance of this association disappeared (Table 3a). Age is related to risk group the higher age, the greater the risk for more advanced disease and it might be that within each risk group, age is related to prognostic factors. Age has also previously been identified as an independent risk factor for death in PCa [29]. Competing risk analyses were performed to investigate any potential effect of competing risks on the results. As the competing risk estimates for cumulative incidence of treatment and failure were similar to those from the Kaplan-Meier analyses, the potential bias from competing risks in the survival estimates should be small. With longer follow-up, competing risk models will be of greater importance. Unfortunately, because we currently miss data on comorbidity, future research is planned to link this database with different Swedish registries, giving us the opportunity to incorporate this important knowledge. Another limitation is the lack of QoL data. The follow-up is relatively short (median: 6 yr). However, 93 men have been followed for >10 yr. Although the follow-up is longer than in many other published AS series [6], it is too short to conclude that AS is safe in the long term. As shown by Johansson et al, localised PCa may have an indolent course for many years but still develop into a life-threatening disease in men with long life expectancy [30]. The lead time for PCa, which is the time that screening advances the diagnosis, has been estimated at up to 11 yr [5], implying that a long follow-up is needed before definitive conclusions regarding the long-term safety of AS can be drawn, especially for younger men with no comorbidities. However, as shown in Table 1, almost half of the low-risk PCa was detected in men 65 yr of age. 5. Conclusions Our results indicate that overtreatment one of the major potential drawbacks of PSA screening can be reduced, as a large proportion of screen-detected PCa can be managed safely with AS. Men with very low- and low-risk PCa constituted more than half of all screen-detected PCa, and for these men, AS appears to be an attractive alternative, especially in men >65 yr of age. This study was presented as an extended poster presentation at the European Association of Urology 2012 annual congress in Paris, France, and as a poster at the European School of Oncology meeting in Rotterdam, The Netherlands, in 2012. Author contributions: Rebecka Arnsrud Godtman had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Godtman, Khatami, Stranne, Hugosson. Acquisition of data: Godtman, Khatami, Stranne, Hugosson. Analysisand interpretation of data: Godtman, Holmberg, Stranne, Hugosson. Drafting of the manuscript: Godtman, Holmberg, Khatami, Stranne, Hugosson. Critical revision of the manuscript for important intellectual content: Godtman, Holmberg, Khatami, Stranne, Hugosson. Statistical analysis: Godtman, Holmberg, Stranne, Hugosson. Obtaining funding: Godtman, Hugosson. Administrative, technical, or material support: None. Supervision: Godtman. Other (specify): None.
EUROPEAN UROLOGY 63 (2013) 101 107 107 Financial disclosures: Rebecka Arnsrud Godtman certifies thatallconflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Jonas Hugosson has received lecture fees from GlaxoSmithKline and Abbot, and Johan Stranne has received lecture fees from Astellas and Abbot. Funding/Support and role of the sponsor: Grants have been received from the Swedish Cancer Society (Contract numbers 11 0598), Märta and Gustaf Ågren s Research Foundation, and Percy Falk s Foundation for Prostate and Breast Cancer Research. 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