Urological Oncology. Sam Ladjevardi, Anders Berglund*, Eberhard Varenhorst, Ola Bratt, Anders Widmark and Gabriel Sandblom.

Transcription

1 Urological Oncology Treatment with curative intent and survival in men with high-risk prostate cancer. A population-based study of men with serum PSA level ng/ml Sam Ladjevardi, Anders Berglund*, Eberhard Varenhorst, Ola Bratt, Anders Widmark and Gabriel Sandblom Department of Urology, University Hospital, Uppsala, *Oncology Centre, Uppsala University Hospital, Uppsala, Department of Urology, Linköping University Hospital, Linköping, Department of Urology, Helsingborg Hospital, Lund University, Helsingborg, Department of Radiation Sciences, Oncology, Umeå University Hospital, Umeå, and Division of Surgery, Department of Clinical Sciences, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden What s known on the subject? and What does the study add? There are two randomized controlled trials showing that radiotherapy can be beneficial for men with locally advanced prostate cancer. The present study confirms the importance of curative treatment for men with high-risk prostate cancer. Objective To investigate the influence of curative treatment on cause-specific mortality in men diagnosed with prostate cancer (PCa) with serum prostate-specific antigen (PSA) levels between 20 and 100 ng/ml. Materials and Methods Patients with PCa (T1 4, N0/N1/NX, M0/MX), PSA ng/ml and age 75 years were identified in the National Prostate Cancer Register of Sweden. Data on co-morbidity diagnoses were obtained from the National Patient Register and cause of death from the Cause of Death Register. Following adjustment for age at diagnosis, co-morbidity burden, Gleason score, T-category, PSA level and cause-specific mortality in relation to treatment were estimated using Cox regression analysis. Result A total of men were diagnosed with PCa between 1996 and 2008 and fulfilled the inclusion criteria. The cumulative 10-year PCa-specific mortality was 36% for patients receiving only palliative treatment and 13% for those treated with curative intent. For the 8462 (74%) patients with PSA levels from 20 to 50 ng/ml at diagnosis, the hazard ratio for death from PCa was 0.23 (95% confidence interval ) for those treated with curative intent compared with those given palliative treatment after adjusting for age, co-morbidity, T category, PSA level and Gleason score. The corresponding hazard ratio was 0.22 (95% confidence interval ) for patients with PSA levels from 51 to 100 ng/ml. Conclusion Treatment with curative intent for men with high-risk PCa was associated with reduced cause-specific mortality and should be considered even when serum PSA exceeds 20 ng/ml. Keywords prostate cancer, prostate-specific antigen, high-risk tumours, curative treatment, palliative treatment, population-based study 2012 BJU International 111, doi: /j x x 381

2 Ladjevardi et al. Introduction The widespread use of PSA testing has led to a significant migration in stage and grade of prostate cancer (PCa), with >90% of men in the current era diagnosed with clinically localized disease [1]. Despite the trends towards lower-risk PCa, 20 35% of patients with newly diagnosed PCa are still classified as high risk, based on either PSA >20 ng/ml, Gleason score 8 10, or an advanced clinical stage [2]. Nevertheless, despite the high incidence of high-risk tumours, the mortality rate associated with PCa has declined in Europe since the 1990s [3]. This trend has also been seen in a Swedish study based on the National Prostate Cancer Register (NPCR) of Sweden [4]. The treatment of men with high-risk PCa remains controversial because of the lack of conclusive well-controlled or randomized studies comparing outcomes with palliative treatment, radiotherapy (RT), and radical prostatectomy (RP). Whereas the Swedish Prostate Cancer Group 4 trial has provided firm support for treatment with curative intent for men with localized PCa [5], the benefit from RT or RP is more uncertain for men with tumours that could be expected to have spread beyond the prostate capsule. There are two randomized controlled trials on men with high-risk PCa that have shown longer overall survival rates for those treated with RT in combination with hormonal treatment, than the ones on hormonal treatment as sole therapy [6,7]. The outcome after surgery for men with PSA level >20 ng/ml is crucial in the treatment decision for men with high-risk tumours. A threshold PSA measurement of 20 ng/ml is used in prognostic grouping of PCa in the latest edition of the TNM-classification [8]. Men with PSA level >20 ng/ml but without signs of distant metastases, judged by bone scan, may, on the one hand, have too extensive local growth to guarantee beneficial outcome from RT or RP. On the other hand, considering the inevitably poor prognosis of these men if left untreated, denying them at least a small chance of cure is unethical. Besides the randomized controlled trials mentioned above [6,7] there are no other studies that compare overall or cancer-specific survival in relation to treatment in patients with high-risk PCa. Moreover randomized studies are time consuming and cost consuming, and there is normally a significant delay before initiation of the study and outcome of the results. Because of this, the best evidence in this clinically important group is provided by large population-based studies. Even if androgen deprivation therapy (ADT) before and during RT and RP may give a longer cancer-free and overall survival than RP and RT as mono-therapy, the crucial question is whether or not treatment with curative intent gives better survival than ADT as mono-therapy. Even the risk for recurrence after RT and RP in men with high PSA levels is high, and if overall survival is prolonged substantially, any harm from treatment is acceptable. The purpose of the present study was to investigate treatment modalities in relation to cause-specific mortality in a large unselected population-based cohort of men with PCa and serum PSA levels between 20 and 100 ng/ml. Materials and Methods The present study is based on the NPCR of Sweden [9] with additional information retrieved by record-linkage to the National Cancer Register, and the Cause of Death Register, using the unique 10-digit personal registration number assigned to every resident in Sweden [10]. The NPCR of Sweden was established in 1996 to provide a base for quality assurance of PCa care in Sweden. It covers 98% of all PCa cases registered in the National Cancer Register since 1998 [11]. By 31 December 2008, the NPCR had assembled data on more than incident PCa cases, with information on mode of detection, tumour stage, tumour differentiation, serum PSA levels and treatment initiated within 6 months of diagnosis [9]. The National Patient Register includes information on hospital admissions and discharges from all national health-care hospitals in Sweden. Each inpatient record contains dates of hospital admissions and up to eight discharge diagnoses, coded according to the International Classification of Diseases. Information on date and the underlying cause of death, coded according to the International Classification of Diseases, was obtained from the Cause of Death Register. The number of non-reported events in the Cause of Death Register was estimated to be 0.7% of all deaths in 2006 [12]. The Charlson Co-morbidity Index was used to assess the burden of concomitant disease for each PCa patient [13] and has been shown in a study based on NPCR to have an impact on management and survival [14]. The number of men who were diagnosed with PCa was 133 per in 1996 and 193 per in 2008 [15]. A total of men diagnosed with PCa were identified in the NPCR of Sweden. The inclusion criteria in the present study were; age 75 years or less at date of diagnosis, any primary tumour category (T1 T4), any lymph node category (NX/N0/N1), without evidence of distant metastases (MX/M0) and serum PSA level between 20 and 100 ng/ml, date of diagnosis between 1 January 1996 and 31 December In time-to-event analysis, the outcome of interest was PCa-specific mortality (C61 in International Classification of Diseases, version 10). Survival time was defined as the BJU International

3 Treatment with curative intent in high-risk PC interval between the date of PCa diagnosis and the date of outcome, emigration or end of follow-up 31 December To see if the treatment groups differed in PCa-specific survival, we estimated the cumulative probability of PCa death using Kaplan Meier estimates. Cox regression with relative risks expressed as hazard ratios (HR) and 95% CI were calculated to assess PCa-specific mortality in relation to treatment, adjusting for age at diagnosis, T category, serum PSA, co-morbidity and Gleason Score. All analyses were performed with the R statistical software package (R Foundation for Statistical Computing, Vienna, Austria). The study was approved by the Central Research Ethics Committee and the Research Ethics Committee at Uppsala University. Results The cohort assembly is shown in Fig. 1. The final study population in the present study consisted of men. Of these, 8462 (74%) men were diagnosed with a serum level of PSA ng/ml and 2918 (26%) had PSA level between 51 and 100 ng/ml (Table 1). Among these patients, 10.6% were younger than 60 years and most (74%) of the patients had palpable tumours. Of all patients, 44% were diagnosed after local symptoms, whereas 17.3% of patients were diagnosed in an asymptomatic stage after PSA testing. In 24.9% of the patients the disease was categorized as N0, in 69% as NX and in 6.3% as N1. According to clinical practice in Sweden, classification of N-category was almost exclusively based on a limited pelvic lymphadenectomy. Of men who were included in this study, 64% had their cancer classified as M0. More than 90% of all patients had a Charlson Co-morbidity Index of 0 or 1 at the time of Fig. 1 Flow chart of cohort assembly recorded in the National Prostate Cancer Register of Sweden between 1996 and National Prostate Cancer Register of Sweden diagnosed (n = 98,924) To analysis (n = 11,380) Excluded cases > 75 years old (n = 34,190) PAS level 0 20 (n = 44,490) >100 (n = 5,742) Missing PSA (n = 1,206) Distant metastases (M1) (n = 1572) Missing treatment (n = 344) diagnosis, and only 8.5% of men had a Charlson Co-morbidity Index of 2 or more. A total of 32% of patients presented with Gleason score 6 or less, 42.2% with Gleason score 7 and 25.8% with Gleason score As shown in Table 1 almost two-thirds of all patients in the study only received palliative treatment. Treatment distribution is shown in Table 2. Table 3 shows a multivariable analysis of the study cohort. It shows a significant difference in cancer-specific survival between curative and non-curative treatments after adjusting for age, co-morbidity, Gleason score, T category and PSA level at the time of diagnosis. Age and co-morbidity were not, as expected, associated with cancer-specific survival. Gleason score, PSA and T category, however, had significant impact. The 10-year cumulative probability of PCa death is shown in Fig. 2. We did not find any differences in cancer-specific mortality between N0 and NX patients. Cancer-specific mortality was, however, significantly higher for patients with MX compared with M0. Primary treatment is shown in Table 1. The 10-year cause-specific mortality for patients with PSA level of ng/ml was 36% for patients treated without and 13% for patients treated with curative intent. For patients with PSA level of ng/ml, the 10-year cause-specific mortality was 55% for palliative treatment and 20% for patients treated with curative intent. The same survival benefit from treatment with curative intent rather than palliative treatment was seen for men with PSA levels of >50 ng/ml and for those with levels <50 ng/ml. Discussion Our study indicates that treatment with curative intent is associated with better cancer-specific survival even for patients with PSA levels of ng/ml (Fig. 3). The cumulative 10-year PCa-specific mortality was 36% for patients treated without, and 13% for those treated with curative intent. Androgen deprivation therapy is often the first line of treatment for men with PSA levels >20 ng/ml, but according to these results ADT alone is not sufficient for these men. Either RP or RT in combination with ADT should therefore be considered for men without evidence of distant metastases, even with PSA levels close to 100 ng/ml. Although there are no universally accepted criteria for defining risk categories in PCa, one of the most stringent and reproducible criteria for high-risk PCa is PSA level [16]. Even if PSA has poorer sensitivity as well as specificity for identifying locally advanced tumours, men with PSA levels >20 ng/ml undoubtedly constitute a high-risk group [8] BJU International 383

4 Ladjevardi et al. Table 1 Clinical characteristics of patients diagnosed with primary prostate cancer between 1996 and 2008, by level of prostatic-specific antigen (PSA) and planned initial treatment. PSA ng/ml PSA ng/ml PSA ng/ml Curative Conservative Curative Conservative Curative Conservative n (%) n (%) n (%) n (%) n (%) n (%) All 3387 (100.0) 5075 (100.0) 517 (100.0) 2401 (100.0) 3904 (100.0) 7476 (100.0) Calendar period (25.8) 2116 (41.7) 162 (31.3) 981 (40.9) 1037 (26.6) 3097 (41.4) (25.5) 1313 (25.9) 115 (22.2) 623 (25.9) 979 (25.1) 1936 (25.9) (48.7) 1646 (32.4) 240 (46.4) 797 (33.2) 1888 (48.4) 2443 (32.7) Age of diagnosis < (20.0) 241 (4.7) 124 (24.0) 168 (7.0) 800 (20.5) 409 (5.5) (59.7) 1678 (33.1) 298 (57.6) 899 (37.4) 2319 (59.4) 2577 (34.5) (20.4) 3156 (62.2) 95 (18.4) 1334 (55.6) 785 (20.1) 4490 (60.1) Mode of detection* Screening 956 (35.0) 638 (18.7) 110 (28.8) 261 (16.0) 1066 (34.2) 899 (17.8) Symptoms 1400 (51.2) 2241 (65.9) 227 (59.4) 1159 (70.9) 1627 (52.2) 3400 (67.5) Other reason 206 (7.5) 285 (8.4) 15 (3.9) 95 (5.8) 221 (7.1) 380 (7.5) Missing 173 (6.3) 239 (7.0) 30 (7.9) 120 (7.3) 203 (6.5) 359 (7.1) Clinical T-stage T0 7 (0.2) 39 (0.8) 1 (0.2) 13 (0.5) 8 (0.2) 52 (0.7) T1ab 75 (2.2) 212 (4.2) 11 (2.1) 47 (2.0) 86 (2.2) 259 (3.5) T1c 1035 (30.6) 1039 (20.5) 117 (22.6) 273 (11.4) 1152 (29.5) 1312 (17.5) T (40.6) 1768 (34.8) 176 (34.0) 698 (29.1) 1552 (39.8) 2466 (33.0) T3 865 (25.5) 1780 (35.1) 209 (40.4) 1166 (48.6) 1074 (27.5) 2946 (39.4) T4 12 (0.4) 172 (3.4) 2 (0.4) 171 (7.1) 14 (0.4) 343 (4.6) TX 17 (0.5) 65 (1.3) 1 (0.2) 33 (1.4) 18 (0.5) 98 (1.3) N-stage N (65.5) 200 (3.9) 349 (67.5) 63 (2.6) 2569 (65.8) 263 (3.5) N1 88 (2.6) 463 (9.1) 20 (3.9) 146 (6.1) 108 (2.8) 609 (8.1) NX/Missing 1079 (31.9) 4412 (86.9) 148 (28.6) 2192 (91.3) 1227 (31.4) 6604 (88.3) M-stage M (84.3) 2671 (53.1) 439 (85.1) 1351 (56.8) 3278 (84.4) 4022 (54.3) MX/Missing 529 (15.7) 2360 (46.9) 77 (14.9) 1026 (43.2) 606 (15.6) 3386 (45.7) Gleason Score GS (37.7) 1708 (33.7) 136 (26.3) 552 (23.0) 1413 (36.2) 2260 (30.2) GS (44.4) 1995 (39.3) 257 (49.7) 1045 (43.5) 1760 (45.1) 3040 (40.7) GS (17.1) 1215 (23.9) 119 (23.0) 751 (31.3) 699 (17.9) 1966 (26.3) Level of PSA, mean (SD) 29.0 (8.1) 31.5 (8.7) 65.8 (12.6) 71.9 (14.6) 33.9 (15.3) 44.5 (21.8) Comorbidity Index CCI (85.8) 3703 (73.0) 466 (90.1) 1760 (73.3) 3371 (86.3) 5463 (73.1) CCI (10.0) 803 (15.8) 36 (7.0) 397 (16.5) 376 (9.6) 1200 (16.1) CCI (4.2) 569 (11.2) 15 (2.9) 244 (10.2) 157 (4.0) 813 (10.9) CCI, Charlson Co-morbidity Index. Table 2 Distribution of treatment in the group of men receiving treatment with curative intent. PSA ng/ml PSA ng/ml Total n (%) n (%) n (%) Radical prostatectomy (RP) 1028 (30.4) 71 (13.7) 1099 (28.2) RP + radiotherapy (RT) 61 (1.8) 7 (1.4) 68 (1.7) RT brachy 332 (9.8) 46 (8.9) 378 (9.7) RT external 1384 (40.9) 297 (57.4) 1681 (43.1) RT brachy and external 509 (15.0) 86 (16.6) 595 (15.2) Other 73 (2.2) 10 (1.9) 83 (2.1) Total 3387 (100.0) 517 (100.0) 3904 (100.0) PSA, prostate-specific antigen BJU International

5 Treatment with curative intent in high-risk PC Table 3 Cause-specific survival estimated by multivariate proportional hazard models with hazard ratios (HR) and 95% confidence intervals (CI). PSA ng/ml PSA ng/ml PSA ng/ml HR (CI 95%) HR (CI 95%) HR (CI 95%) Initially planned treatment Conservative 1.00 ref ref ref. Curative 0.28 ( ) 0.30 ( ) 0.29 ( ) Age at diagnosis (years) < ref ref ref ( ) 0.83 ( ) 0.84 ( ) ( ) 0.87 ( ) 0.81 ( ) Log PSA (ng/ml) 1.14 ( ) 1.68 ( ) 1.45 ( ) Charlson Co-morbidity Index CCI ref ref ref. CCI ( ) 0.89 ( ) 0.94 ( ) CCI ( ) 1.20 ( ) 1.19 ( ) Gleason Score GS ref ref ref. GS ( ) 1.46 ( ) 1.63 ( ) GS ( ) 2.66 ( ) 3.21 ( ) Clinical T-stage T1c 1.00 ref ref ref. T1ab 1.71 ( ) 1.93 ( ) 1.74 ( ) T ( ) 1.31 ( ) 1.52 ( ) T3 T ( ) 1.84 ( ) 2.32 ( ) CCI, Charlson Co-morbidity Index; PSA, prostate-specific antigen. Subgroup 1. Level of PSA 20 50, M0/MX. Subgroup 2. Level of PSA , M0/MX. Subgroup 3. Level of PSA , M0/MX. Fig. 2 Prostate cancer-specific mortality. Cumulative probability of PCa death a PSA 20 50, MX/MO Log-rank test Curative vs Conservative: p-value <0.01 Curative Conservative b PSA , MX/MO Log-rank test Curative vs Conservative: p-value < Curative Conservative 0.4 Cumulative probability of PCa death Years since diagnosis Years since diagnosis Years since diagnosis c Cumulative probability of PCa death PSA , MX/MO Log-rank test Curative vs Conservative: p-value < Curative Conservative In a recently published study based on the PCBaSe of Sweden, men with locally advanced PCa (T3 tumours and/or PSA level of ng/ml) receiving palliative treatment had high PCa-specific mortality [17], suggesting under-treatment of this group. The PCBaSe study, although having different inclusion criteria and no comparison of treatment strategies, supports the findings of the current study. These studies indicate that we should not withhold curative treatment from men with high-risk PCa for fear of treatment failure. The gain in survival after radical treatment of men with high-risk PCa may be even more pronounced than that for men with localized tumours. Inman et al. [18] studied long-term outcomes of RP in men with a preoperative PSA level 50 ng/ml and found that 25% of patients with serum PSA values 50 ng/ml had Gleason score 8 10 tumours. Furthermore, nearly half of the patients had extraprostatic extension of their cancer, and a third had pelvic lymph node involvement. The cancer-specific survival for patients with PSA levels between 50 and 99 ng/ml was 94%, 79% and 72% at 5, BJU International 385

6 Ladjevardi et al. Fig. 3 Hazard ratio for death from prostate cancer for men undergoing treatment with curative intent, with adjustment for age at diagnosis, T category, serum prostate-specific antigen (PSA) level, co-morbidity and Gleason Score, and men receiving only palliative treatment as reference group. The shaded field indicates 95% confidence interval. Hazard Ratio PSA , MX/MO Curative Vs. Conservative Level of PSA and 15 years, respectively, i.e. survival rates similar to those in the present study. Androgen deprivation therapy alone has been considered the treatment of choice for men with high-risk PCa [18], though ultimately most tumours become hormone refractory and require second-line or third-line treatments. However, this treatment alternative has been questioned in recent years because of controversy over the outcome of men with locally advanced disease. Furthermore, the morbidity as well as mortality associated with endocrine treatment should not be neglected. A recent study based on data from the NPCR of Sweden showed a twofold increased risk for thromboembolic diseases in men on endocrine therapy [19]. Furthermore, increased relative risks for non-fatal and fatal cardiovascular disease have been reported, especially in patients treated with endocrine therapy [20]. In a literature review it was concluded that patients with lymph node metastases benefit in terms of cancer-specific survival when treated with curative intent [21]. This is in accordance with the present study, showing that patients with cancer-positive lymph nodes have longer cancer-specific survival when treated with curative intent. Whereas there are numerous studies on men with localized tumour [5,9,22], the outcome after treatment of men with PSA levels between 20 and 100 ng/ml and locally advanced tumour at diagnosis is not so clear, despite the fact that this group is almost as large and has a much poorer prognosis. In a study by Han et al. [23], men with palpable tumour (T2 to T3) and PSA level >15 ng/ml show overall PSA-free survival rates at 5 years and 10 years of 56% and 40%, respectively. However, whereas early PSA relapse cannot be ruled out in the cohort of the present study, the overall, relative and cancer-specific survival benefit from treatment with curative intent strongly argues against an attitude of defeatism regarding this group, even if attempted radical cure is often followed by tumour recurrence [24]. In another study of patients with cancer-positive lymph nodes, overall and relative survival rates were higher with RP than when regional metastases were confirmed and RP was abandoned [25]. These studies suggest that treatment with curative intent is beneficial even in patients with advanced local growth and regional metastases. In the Scandinavia Prostate Cancer Group 7 trial, cancer-specific mortality and cumulative overall mortality were compared between men treated with ADT only and those with combined RT [6]. In another recently published study, overall survival for men treated with ADT and ADT in combination with RT was compared [7]. These studies also showed that treatment with curative intent can be optimized and should not be withheld from men with locally advanced growth as long as distant metastases are not present. The crucial question is whether it is beneficial to begin curative treatment even if the PSA level raises suspicion of tumour growth beyond the boundaries of the prostate. The outcome of the present study indicates that survival may be prolonged despite the potential risk of a cancer-positive resection margin, early PSA relapse and other surrogate measures of treatment failure. With a population of men, the current study is to our knowledge the second largest study analysing cancer-specific mortality for men with high-risk PCa. The risk of selection bias when assessing the outcome after different treatments is, however, a well-known fact and should not be neglected. Even when adjusting for age, co-morbidity and stage of disease, PSA level and Gleason score, there may be residual bias that cannot be accounted for. The diagnoses retrieved from the NPR gave information on hospital care diagnoses only. Co-morbidity is therefore, underestimated in our study, especially for patients with minor co-morbidity, i.e. Charlson score 1. However, data regarding treatment in the NPCR are based on the first 6 months after diagnosis. This may have affected the outcome of the study because delayed treatment is not included and variations in the practice of adjuvant and salvage therapies may confound the study. In studies on disease-specific survival, the uncertainties regarding cause of death are often a source of bias. The reliability of death certificates for patients with PCa included in the NPCR has, on the contrary, been shown be high [26]. The Charlson Co-morbidity Index has also been validated as a good indicator of disease burden in patients with PCa [9]. However, it cannot be excluded that the validity of cause-of-death information is lower in older men, in particular those with a high co-morbidity burden. Furthermore, lymph node staging and screening of distant BJU International

7 Treatment with curative intent in high-risk PC metastases was only performed in a few members of the group. We did not find any differences in cancer-specific mortality between N0 and NX patients. Cancer-specific mortality was, however, significantly higher for patients with MX compared with M0. This may be a result of the presence of non-detected metastases in the MX group. This supports the practice of routine screening for distant metastasis in all men with PSA levels >20 ng/ml that are under consideration for treatment with curative intent. In conclusion, this study shows that treatment with curative intent is beneficial in the group of men with PCa, absence of distant metastases and PSA levels between 20 and 100 ng/ml. Many patients with such tumours were under-treated in Sweden during the study period. Conflict of Interest None declared. References 1 Makarov DV, Trock BJ, Humphreys EB et al. Updated nomogram to predict pathologic stage of prostate cancer given prostate-specific antigen level, clinical stage, and biopsy Gleason score (Partin tables) based on cases from 2000 to Urology 2007; 69: Shao YH, Demissie K, Shih W et al. Contemporary risk profile of prostate cancer in the United States. JNatlCancerInst2009; 101: Bray F, Lortet-Tieulent J, Ferlay J, Forman D, Auvinen A. Prostate cancer incidence and mortality trends in 37 European countries: an overview. Eur J Cancer 2010; 46: Varenhorst E, Garmo H, Holmberg L et al. The National Prostate Cancer Register in Sweden : trends in incidence, treatment and survival. Scand J Urol Nephrol 2005; 39: Bill-Axelson A, Holmberg L, Ruutu M et al. Radical prostatectomy versus watchful waiting in early prostate cancer. NEnglJMed2011; 364: Widmark A, Klepp O, Solberg A et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet 2009; 373: Warde P, Mason M, Ding K. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet 2011; 378: Sobin LH, Gospodarowicz MK, Wittekind C eds. International Union Against Cancer (UICC) TNM Classification of Malignant Tumors, 7th edn. Oxford: Wiley-Blackwell, Stattin P, Holmberg E, Johansson JE et al. Outcomes in localized prostate cancer: National Prostate Cancer Register of Sweden follow-up study. JNatlCancerInst 2010; 102: Ludvigsson JF, Otterblad-Olausson P, Pettersson BU, Ekbom A. The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research. Eur J Epidemiol 2009; 24: Adolfsson J, Garmo H, Varnehorst E et al. Clinical characteristics and primary treatment of prostate cancer in Sweden between 1996 and ScandJUrol Nephrol 2007; 41: Cause of Death Register Available at: Kastner C, Armitage J, Kimble A, Rawal J, Carter PG, Venn S. The Charlson comorbidity score: a superior comorbidity assessment tool for the prostate cancer multidisciplinary meeting. Prostate Cancer Prostatic Dis 2006; 9: Berglund A, Garmo H, Tishelman C, Holmberg L, Stattin P, Lambe M. Comorbidity, treatment and mortality: a population based cohort study of prostate cancer in PCBaSe Sweden. J Urol 2011; 185: The Swedish Cancer Register Available at: Sandblom G, Holmberg L, Damberg JE et al. Prostate-specific antigen as surrogate for characterizing prostate cancer subgroups. Scand J Urol Nephrol 2002; 36: Akre O, Garmo H, Adolfsson J, Lambe M, Bratt O, Stattin P. Mortality among men with locally advanced prostate cancer managed with noncurative intent: a nationwide study in PCBaSe Sweden. Eur Urol 2011; 60: Inman BA, Davies JD, Rangel LJ et al. Long-term outcomes of radical prostatectomy with multimodal adjuvant therapy in men with a preoperative serum prostate-specific antigen level > or =50 ng/ml. Cancer 2008; 113: Van Hemelrijck M, Adolfsson J, Garmo H et al. Risk of thromboembolic diseases in men with prostate cancer: results from the population-based PCBaSe Sweden. Lancet Oncol 2010; 11: Van Hemelrijck M, Garmo H, Holmberg L et al. Absolute and relative risk of cardiovascular disease in men with prostate cancer: results from the Population-Based PCBaSe Sweden. J Clin Oncol 2010; 28: Verhagen PC, Schröder FH, Collette L, Bangma CH. Does local treatment of the prostate in advanced 2012 BJU International 387

8 Ladjevardi et al. and/or lymph node metastatic disease improve efficacy of androgen-deprivation therapy? A systematic review. Eur Urol 2010; 58: Albertsen PC, Hanley JA, Gleason DF, Barry MJ. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 1998; 280: Han M, Partin AW, Pound CR, Epstein JI, Walsh PC. Long-term biochemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North Am 2001; 28: Gontero P, Spahn M, Tombal B et al. Is there a prostate-specific antigen upper limit for radical prostatectomy? BJU Int 2011; 108: Engel J, Bastian PJ, Baur H et al. Survival benefit of radical prostatectomy in lymph node-positive patients with prostate cancer. Eur Urol 2010; 57: Fall K, Strömberg F, Rosell J, Andrèn O, Varenhorst E, South-East Region Prostate Cancer Group. Reliability of death certificates in prostate cancer patients. Scand J Urol Nephrol 2008; 42: Correspondence: Sam Ladjevardi, Department of Urology, University Hospital, Uppsala, Sweden. Sam.ladjevardi@surgsci.uu.se Abbreviations: PCa, prostate cancer; NPCR, National Prostate Cancer Register; RT, radiotherapy; RP, radical prostatectomy; ADT, androgen deprivation therapy BJU International