Age at diagnosis and prostate cancer treatment and prognosis: a population-based cohort study

Age at diagnosis and prostate cancer treatment and prognosis: a population-based cohort study Abstract Background Old age at prostate cancer diagnosis has been associated with poor prognosis in several studies. We aimed to investigate the association between age at diagnosis and prognosis, and if it is independent of tumor characteristics, primary treatment, year of diagnosis, mode of detection and comorbidity. Patients and methods We conducted a nation-wide cohort study including 121 392 Swedish men aged 55–95 years in Prostate Cancer data Base Sweden 3.0 diagnosed with prostate cancer in 1998–2012 and followed for prostate cancer death through 2014. Data were available on age, stage, grade, prostate-specific antigen (PSA)-level, mode of detection, comorbidity, educational level and primary treatment. We used Cox regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results With increasing age at diagnosis, men had more comorbidity, fewer PSA-detected cancers, more advanced cancers and were less often treated with curative intent. Among men with high-risk or regionally metastatic disease, the proportion of men with unknown M stage was higher among old men versus young men. During a follow-up of 751 000 person-years, 23 649 men died of prostate cancer. In multivariable Cox-regression analyses stratified by treatment, old age at diagnosis was associated with poorer prognosis among men treated with deferred treatment (HRage 85+ versus 60–64: 7.19; 95% CI: 5.61–9.20), androgen deprivation therapy (HRage 85+ versus 60–64: 1.72; 95% CI: 1.61–1.84) or radical prostatectomy (HRage 75+ versus 60–64: 2.20; 95% CI: 1.01–4.77), but not radiotherapy (HRage 75+ versus 60–64: 1.08; 95% CI: 0.76–1.53). Conclusion Our findings argue against a strong inherent effect of age on risk of prostate cancer death, but indicate that in current clinical practice, old men with prostate cancer receive insufficient diagnostic workup and subsequent curative treatment. cohort study, prostate cancer, age at diagnosis, treatment, prognosis Key Message Swedish nation-wide cohort study showing that older age at prostate cancer diagnosis is associated with higher risk of prostate cancer death among men treated with radical prostatectomy, deferred treatment or androgen depravation therapy, but not radiotherapy. The findings indicate that old men with prostate cancer receive insufficient diagnostic workup and subsequent curative treatment. Introduction Management of old men with prostate cancer is a growing clinical dilemma. Prostate cancer primarily affects old men, life expectancy is rapidly improving and old patients are often excluded from clinical trials [1, 2]. Indeed, despite that almost a quarter of men diagnosed with prostate cancer are 75 years or older [3], none of the major clinical randomized trials comparing radical to conservative treatment included men older than 75 years [4–6]. Old age at prostate cancer diagnosis has been associated with poor prognosis in several observational studies [7, 8]. The association is likely largely explained by less prostate-specific antigen (PSA) screening, worse cancer characteristics at diagnosis and less treatment with curative intent in old compared with young men [8–10]. The association between old age at diagnosis and poor prognosis is however difficult to assess in observational studies as most population-based studies lack detailed data on clinicopathologic factors and comorbidity, whereas most institutional based studies include select patient populations. It is moreover possible that prostate cancer in old men is inherently different from that in younger men. Old age at diagnosis has been associated with increased risk of upstaging and upgrading at radical prostatectomy [11–13], indicating that prostate cancer in old men is more aggressive. The aim of this study was to investigate the association between age at diagnosis and prostate cancer death, and to assess if it is independent of tumor characteristics, primary treatment, year of diagnosis, mode of detection and comorbidity, in a population-based cohort with detailed data on clinicopathologic factors and comorbidity. To this end, we conducted a nation-wide cohort study including 121 392 Swedish men aged 55–95 years in Prostate Cancer data Base Sweden (PCBaSe) 3.0 diagnosed with prostate cancer in 1998–2012 and followed for prostate cancer death through 2014. Patients and methods Data sources We used The National Prostate Cancer Register (NPCR) to assemble the study cohort [14]. NPCR includes 98% of all men diagnosed with prostate cancer in Sweden since 1998. Data on mode of detection (PSA-screening, lower urinary tract symptoms, other), clinical TNM stage, biopsy tumor differentiation (Gleason score or WHO grade), serum PSA level (ng/ml) at diagnosis and planned primary treatment within 6 months of diagnosis [radical prostatectomy, radiotherapy, deferred treatment (i.e. watchful waiting or active surveillance), primary androgen depravation therapy] have been reported to NPCR since 1998. Detailed radiotherapy data (total dose, fractionation, etc.) have been registered in NPCR since 2008. For the period 1998–2007, detailed radiotherapy data have been retrieved from RETRORAD, a retrospective collection of radiotherapy data from the Oncology Information Systems and local databases at the Oncology Departments throughout Sweden [14]. Data on pathological stage and grade, the total number of diagnostic biopsy cores and the number of diagnostic biopsy cores containing cancer have been registered in NPCR since 2007. Additional covariate and outcome data were obtained through linkage to other nationwide registries in PCBaSe 3.0 [14]. Data on comorbidity and surgical procedures were obtained from The National Patient Register, which includes all in-patient medical and procedural discharge diagnoses according to International Classification of Disease (ICD) codes. Migration data were obtained from the Register of Population and Population Changes, and causes of death data from the Cause of Death Registry; agreement between cause of death according to the Cause of Death Registry and medical charts is estimated to be 86% [15]. Education level data were obtained from the LISA database. Study cohort We restricted the study cohort to men aged 55–95 years at diagnosis [16, 17]. The men were divided into five risk categories based on a modified version of the National Comprehensive Cancer Network (NCCN) guidelines: low risk (cT1-T2, PSA < 10 and Gleason score ≤ 6/WHO grade 1), intermediate risk (cT1-T2 and PSA 10–<20 or Gleason score 7/WHO grade 2), high risk (cT3 or PSA 20–<50 or Gleason score ≥ 8/WHO grade 3), regionally metastatic (cT4 or N1 or PSA 50–<100) and metastatic (M1 or PSA ≥ 100). Men with unknown risk category were excluded [18]. Comorbidity at diagnosis was categorized according to the Charlson Comorbidity Index [19] based on ICD discharge codes up to 10 years before the prostate cancer diagnosis. Education level was categorized as low (≤9 school years), middle (10–12 school years) or high (≥13 school years). Statistical analyses We calculated the proportion of men undergoing different treatments stratified by risk category as well as by age at diagnosis. To further assess differences in baseline cancer characteristics by age at diagnosis among men undergoing curative treatment, we calculated tumor characteristics stratified by treatment (radical prostatectomy versus radiotherapy) and by age at diagnosis. To assess if pretreatment radiological workup differed among men treated with radical prostatectomy versus radiotherapy, we calculated the proportion of men with unknown M stage (i.e. Mx according to UICC 6th edition 2002) at the time of treatment by risk category and age at diagnosis. Finally, to assess if age at diagnosis was associated with upstaging or upgrading at radical prostatectomy, we calculated the proportion of men in each pathological stage and grade category stratified by preoperative stage and grade as well as by age at diagnosis. In survival analyses, men were followed from the date of diagnosis to the date of death due to prostate cancer (end point), death due to other causes, emigration or 31 December 2014, whichever occurred first. The cumulative incidence of prostate cancer death was calculated in 1-year classes and smoothed by locally weighted regression [20]. Relative risks were estimated by calculating hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazard regression. In Cox regression models, age at diagnosis was modeled as a categorical variable in 5-year age groups (age 60–64 reference category), with the exception of those aged 85–95 years who were combined due to small numbers. We ran unadjusted models and models adjusted for year of diagnosis, comorbidity, education level, clinical TNM stage, Gleason score, PSA level at diagnosis, mode of detection and treatment. For variables containing missing values (11% for mode of detection, <5% for all other covariates; Table 1), we imputed the missing values using chained equations with five imputation data sets per value [21]. Table 1. Characteristics at baseline for 121 392 men in Prostate Cancer data Base Sweden (PCBaSe) diagnosed with prostate cancer between 1998 and 2012, stratified by age   Age at diagnosis     55–59 years (N = 10 597)   60–64 years (N = 19 981)   65–69 years (N = 24 900)   70–74 years (N = 23 076)   75–79 years (N = 20 351)   80–84 years (N = 14 411)   85 years  +  (N = 8076)   All (N = 121 392)     N  %  N  %  N  %  N  %  N  %  N  %  N  %  N  %  Year of diagnosis                                  1998–2002  2338  (22.1)  4009  (20.1)  5706  (22.9)  6768  (29.3)  7185  (35.3)  4994  (34.7)  2674  (33.1)  33 674  (27.7)  2003–2007  4304  (40.6)  7777  (38.9)  8600  (34.5)  7940  (34.4)  7091  (34.8)  5150  (35.7)  2721  (33.7)  43 583  (35.9)  2008–2012  3955  (37.3)  8195  (41.0)  10 593  (42.5)  8368  (36.3)  6075  (29.9)  4267  (29.6)  2681  (33.2)  44 134  (36.4)  Comorbidity (CCI)                                  0  9536  (90.0)  17 096  (85.6)  19 874  (79.8)  16 661  (72.2)  13 167  (64.7)  8206  (56.9)  4177  (51.7)  88 717  (73.1)  1  663  (6.3)  1694  (8.5)  2882  (11.6)  3458  (15.0)  3648  (17.9)  2958  (20.5)  1803  (22.3)  17 106  (14.1)  2  279  (2.6)  856  (4.3)  1441  (5.8)  1870  (8.1)  2148  (10.6)  1872  (13.0)  1191  (14.7)  9657  (8.0)  3+  119  (1.1)  335  (1.7)  703  (2.8)  1087  (4.7)  1388  (6.8)  1375  (9.5)  905  (11.2)  5912  (4.9)  Education level                                  High  3352  (31.6)  5542  (27.7)  5875  (23.6)  4302  (18.6)  3097  (15.2)  1840  (12.8)  794  (9.8)  24 802  (20.4)  Middle  4580  (43.2)  8223  (41.2)  9523  (38.2)  8097  (35.1)  6481  (31.8)  4235  (29.4)  2061  (25.5)  43 200  (35.6)  Low  2629  (24.8)  6118  (30.6)  9317  (37.4)  10 482  (45.4)  10 482  (51.5)  8087  (56.1)  4338  (53.7)  51 453  (42.4)  Missing  36  (0.3)  98  (0.5)  185  (0.7)  195  (0.8)  291  (1.4)  249  (1.7)  883  (10.9)  1937  (1.6)  Risk categorya                                  Low-risk  4960  (46.8)  8064  (40.4)  8245  (33.1)  5152  (22.3)  2675  (13.1)  1111  (7.7)  298  (3.7)  30 505  (25.1)  Intermediate-risk  2902  (27.4)  6067  (30.4)  7667  (30.8)  6687  (29.0)  4632  (22.8)  2494  (17.3)  875  (10.8)  31 324  (25.8)  High-risk  1453  (13.7)  3277  (16.4)  5125  (20.6)  6145  (26.6)  7006  (34.4)  5349  (37.1)  2874  (35.6)  31 229  (25.7)  Regionally metastatic  456  (4.3)  960  (4.8)  1440  (5.8)  1767  (7.7)  1975  (9.7)  1869  (13.0)  1308  (16.2)  9775  (8.1)  Metastatic  826  (7.8)  1613  (8.1)  2423  (9.7)  3325  (14.4)  4063  (20.0)  3588  (24.9)  2721  (33.7)  18 559  (15.3)  Clinical T stage                                  T1c  5936  (56.0)  10 611  (53.1)  11 497  (46.2)  8035  (34.8)  4709  (23.1)  2302  (16.0)  879  (10.9)  43 969  (36.2)  T1a  193  (1.8)  436  (2.2)  657  (2.6)  777  (3.4)  770  (3.8)  563  (3.9)  231  (2.9)  3627  (3.0)  T1b  80  (0.8)  192  (1.0)  369  (1.5)  547  (2.4)  694  (3.4)  560  (3.9)  292  (3.6)  2734  (2.3)  T2  2931  (27.7)  5630  (28.2)  7605  (30.5)  7638  (33.1)  7053  (34.7)  4864  (33.8)  2405  (29.8)  38 126  (31.4)  T3  1193  (11.3)  2575  (12.9)  3990  (16.0)  4955  (21.5)  5783  (28.4)  4834  (33.5)  3190  (39.5)  26 520  (21.8)  T4  193  (1.8)  394  (2.0)  583  (2.3)  834  (3.6)  1011  (5.0)  970  (6.7)  848  (10.5)  4833  (4.0)  Missing  71  (0.7)  143  (0.7)  199  (0.8)  290  (1.3)  331  (1.6)  318  (2.2)  231  (2.9)  1583  (1.3)  N stage                                  N0  1856  (17.5)  3372  (16.9)  3972  (16.0)  2531  (11.0)  841  (4.1)  354  (2.5)  214  (2.6)  13 140  (10.8)  N1  312  (2.9)  516  (2.6)  638  (2.6)  477  (2.1)  247  (1.2)  132  (0.9)  74  (0.9)  2396  (2.0)  NX  8348  (78.8)  15 947  (79.8)  20 111  (80.8)  19 887  (86.2)  19 081  (93.8)  13 808  (95.8)  7734  (95.8)  104 916  (86.4)  Missing  81  (0.8)  146  (0.7)  179  (0.7)  181  (0.8)  182  (0.9)  117  (0.8)  54  (0.7)  940  (0.8)  M stage                                  M0  4091  (38.6)  7972  (39.9)  10 700  (43.0)  9121  (39.5)  6288  (30.9)  3543  (24.6)  1593  (19.7)  43 308  (35.7)  M1  606  (5.7)  1163  (5.8)  1721  (6.9)  2188  (9.5)  2442  (12.0)  2007  (13.9)  1247  (15.4)  11 374  (9.4)  MX  5832  (55.0)  10 727  (53.7)  12 326  (49.5)  11 617  (50.3)  11 459  (56.3)  8757  (60.8)  5190  (64.3)  65 908  (54.3)  Missing  68  (0.6)  119  (0.6)  153  (0.6)  150  (0.7)  162  (0.8)  104  (0.7)  46  (0.6)  802  (0.7)  Gleason/WHO                                  2–6  6272  (59.2)  10 903  (54.6)  11 989  (48.1)  8966  (38.9)  5845  (28.7)  3113  (21.6)  1155  (14.3)  48 243  (39.7)  WHO = 1  119  (1.1)  252  (1.3)  468  (1.9)  622  (2.7)  796  (3.9)  586  (4.1)  282  (3.5)  3125  (2.6)  3 + 4  1736  (16.4)  3495  (17.5)  4529  (18.2)  3841  (16.6)  3048  (15.0)  1841  (12.8)  844  (10.5)  19 334  (15.9)  4 + 3  761  (7.2)  1714  (8.6)  2416  (9.7)  2502  (10.8)  2226  (10.9)  1640  (11.4)  903  (11.2)  12 162  (10.0)  Gleason = 7  335  (3.2)  620  (3.1)  858  (3.4)  1025  (4.4)  1128  (5.5)  820  (5.7)  392  (4.9)  5178  (4.3)  WHO = 2  180  (1.7)  332  (1.7)  633  (2.5)  979  (4.2)  1399  (6.9)  1049  (7.3)  738  (9.1)  5310  (4.4)  8  619  (5.8)  1390  (7.0)  2112  (8.5)  2373  (10.3)  2602  (12.8)  2192  (15.2)  1408  (17.4)  12 696  (10.5)  9–10  449  (4.2)  973  (4.9)  1453  (5.8)  1972  (8.5)  2236  (11.0)  2054  (14.3)  1355  (16.8)  10 492  (8.6)  WHO = 3  84  (0.8)  191  (1.0)  290  (1.2)  511  (2.2)  664  (3.3)  607  (4.2)  437  (5.4)  2784  (2.3)  Missing  42  (0.4)  111  (0.6)  152  (0.6)  285  (1.2)  407  (2.0)  509  (3.5)  562  (7.0)  2068  (1.7)  PSA (ng/ml)                                  0–4  1560  (14.7)  2428  (12.2)  2470  (9.9)  1512  (6.6)  981  (4.8)  554  (3.8)  220  (2.7)  9725  (8.0)  4.1–10  5541  (52.3)  10 161  (50.9)  11 636  (46.7)  8492  (36.8)  4903  (24.1)  2237  (15.5)  716  (8.9)  43 686  (36.0)  10.1–20  1684  (15.9)  3693  (18.5)  5041  (20.2)  5302  (23.0)  4716  (23.2)  2998  (20.8)  1283  (15.9)  24 717  (20.4)  20.1–50  886  (8.4)  1808  (9.0)  2856  (11.5)  3657  (15.8)  4439  (21.8)  3680  (25.5)  2106  (26.1)  19 432  (16.0)  50.1–100  305  (2.9)  703  (3.5)  1127  (4.5)  1546  (6.7)  1936  (9.5)  1851  (12.8)  1205  (14.9)  8673  (7.1)  100+  576  (5.4)  1110  (5.6)  1647  (6.6)  2370  (10.3)  3060  (15.0)  2809  (19.5)  2280  (28.2)  13 852  (11.4)  Missing  45  (0.4)  78  (0.4)  123  (0.5)  197  (0.9)  316  (1.6)  282  (2.0)  266  (3.3)  1307  (1.1)  Treatmentb                                  Radical prostatectomy  5475  (51.7)  8847  (44.3)  7919  (31.8)  2529  (11.0)  151  (0.7)  24  (0.2)  4  (0.0)  24 949  (20.6)  Radiotherapy  1783  (16.8)  3860  (19.3)  5314  (21.3)  4032  (17.5)  880  (4.3)  22  (0.2)  2  (0.0)  15 893  (13.1)  Deferred treatmentc  1726  (16.3)  3903  (19.5)  5990  (24.1)  7380  (32.0)  7062  (34.7)  4093  (28.4)  1723  (21.3)  31 877  (26.3)  Anti-androgen  206  (1.9)  498  (2.5)  906  (3.6)  1591  (6.9)  1892  (9.3)  1141  (7.9)  446  (5.5)  6680  (5.5)  GnRH agonist  972  (9.2)  2158  (10.8)  3902  (15.7)  6779  (29.4)  9798  (48.1)  8746  (60.7)  5641  (69.8)  37 996  (31.3)  Missingd  435  (4.1)  715  (3.6)  869  (3.5)  765  (3.3)  568  (2.8)  385  (2.7)  260  (3.2)  3997  (3.3)  Mode of detection                                  PSA screening  4870  (46.0)  8515  (42.6)  9295  (37.3)  6215  (26.9)  3531  (17.4)  1674  (11.6)  624  (7.7)  34 724  (28.6)  LUTSe  2261  (21.3)  5036  (25.2)  6897  (27.7)  7154  (31.0)  6839  (33.6)  5217  (36.2)  3060  (37.9)  36 464  (30.0)  Other symptoms  2536  (23.9)  4729  (23.7)  6271  (25.2)  6907  (29.9)  7172  (35.2)  5691  (39.5)  3354  (41.5)  36 660  (30.2)  Missing  930  (8.8)  1701  (8.5)  2437  (9.8)  2800  (12.1)  2809  (13.8)  1829  (12.7)  1038  (12.9)  13 544  (11.2)    Age at diagnosis     55–59 years (N = 10 597)   60–64 years (N = 19 981)   65–69 years (N = 24 900)   70–74 years (N = 23 076)   75–79 years (N = 20 351)   80–84 years (N = 14 411)   85 years  +  (N = 8076)   All (N = 121 392)     N  %  N  %  N  %  N  %  N  %  N  %  N  %  N  %  Year of diagnosis                                  1998–2002  2338  (22.1)  4009  (20.1)  5706  (22.9)  6768  (29.3)  7185  (35.3)  4994  (34.7)  2674  (33.1)  33 674  (27.7)  2003–2007  4304  (40.6)  7777  (38.9)  8600  (34.5)  7940  (34.4)  7091  (34.8)  5150  (35.7)  2721  (33.7)  43 583  (35.9)  2008–2012  3955  (37.3)  8195  (41.0)  10 593  (42.5)  8368  (36.3)  6075  (29.9)  4267  (29.6)  2681  (33.2)  44 134  (36.4)  Comorbidity (CCI)                                  0  9536  (90.0)  17 096  (85.6)  19 874  (79.8)  16 661  (72.2)  13 167  (64.7)  8206  (56.9)  4177  (51.7)  88 717  (73.1)  1  663  (6.3)  1694  (8.5)  2882  (11.6)  3458  (15.0)  3648  (17.9)  2958  (20.5)  1803  (22.3)  17 106  (14.1)  2  279  (2.6)  856  (4.3)  1441  (5.8)  1870  (8.1)  2148  (10.6)  1872  (13.0)  1191  (14.7)  9657  (8.0)  3+  119  (1.1)  335  (1.7)  703  (2.8)  1087  (4.7)  1388  (6.8)  1375  (9.5)  905  (11.2)  5912  (4.9)  Education level                                  High  3352  (31.6)  5542  (27.7)  5875  (23.6)  4302  (18.6)  3097  (15.2)  1840  (12.8)  794  (9.8)  24 802  (20.4)  Middle  4580  (43.2)  8223  (41.2)  9523  (38.2)  8097  (35.1)  6481  (31.8)  4235  (29.4)  2061  (25.5)  43 200  (35.6)  Low  2629  (24.8)  6118  (30.6)  9317  (37.4)  10 482  (45.4)  10 482  (51.5)  8087  (56.1)  4338  (53.7)  51 453  (42.4)  Missing  36  (0.3)  98  (0.5)  185  (0.7)  195  (0.8)  291  (1.4)  249  (1.7)  883  (10.9)  1937  (1.6)  Risk categorya                                  Low-risk  4960  (46.8)  8064  (40.4)  8245  (33.1)  5152  (22.3)  2675  (13.1)  1111  (7.7)  298  (3.7)  30 505  (25.1)  Intermediate-risk  2902  (27.4)  6067  (30.4)  7667  (30.8)  6687  (29.0)  4632  (22.8)  2494  (17.3)  875  (10.8)  31 324  (25.8)  High-risk  1453  (13.7)  3277  (16.4)  5125  (20.6)  6145  (26.6)  7006  (34.4)  5349  (37.1)  2874  (35.6)  31 229  (25.7)  Regionally metastatic  456  (4.3)  960  (4.8)  1440  (5.8)  1767  (7.7)  1975  (9.7)  1869  (13.0)  1308  (16.2)  9775  (8.1)  Metastatic  826  (7.8)  1613  (8.1)  2423  (9.7)  3325  (14.4)  4063  (20.0)  3588  (24.9)  2721  (33.7)  18 559  (15.3)  Clinical T stage                                  T1c  5936  (56.0)  10 611  (53.1)  11 497  (46.2)  8035  (34.8)  4709  (23.1)  2302  (16.0)  879  (10.9)  43 969  (36.2)  T1a  193  (1.8)  436  (2.2)  657  (2.6)  777  (3.4)  770  (3.8)  563  (3.9)  231  (2.9)  3627  (3.0)  T1b  80  (0.8)  192  (1.0)  369  (1.5)  547  (2.4)  694  (3.4)  560  (3.9)  292  (3.6)  2734  (2.3)  T2  2931  (27.7)  5630  (28.2)  7605  (30.5)  7638  (33.1)  7053  (34.7)  4864  (33.8)  2405  (29.8)  38 126  (31.4)  T3  1193  (11.3)  2575  (12.9)  3990  (16.0)  4955  (21.5)  5783  (28.4)  4834  (33.5)  3190  (39.5)  26 520  (21.8)  T4  193  (1.8)  394  (2.0)  583  (2.3)  834  (3.6)  1011  (5.0)  970  (6.7)  848  (10.5)  4833  (4.0)  Missing  71  (0.7)  143  (0.7)  199  (0.8)  290  (1.3)  331  (1.6)  318  (2.2)  231  (2.9)  1583  (1.3)  N stage                                  N0  1856  (17.5)  3372  (16.9)  3972  (16.0)  2531  (11.0)  841  (4.1)  354  (2.5)  214  (2.6)  13 140  (10.8)  N1  312  (2.9)  516  (2.6)  638  (2.6)  477  (2.1)  247  (1.2)  132  (0.9)  74  (0.9)  2396  (2.0)  NX  8348  (78.8)  15 947  (79.8)  20 111  (80.8)  19 887  (86.2)  19 081  (93.8)  13 808  (95.8)  7734  (95.8)  104 916  (86.4)  Missing  81  (0.8)  146  (0.7)  179  (0.7)  181  (0.8)  182  (0.9)  117  (0.8)  54  (0.7)  940  (0.8)  M stage                                  M0  4091  (38.6)  7972  (39.9)  10 700  (43.0)  9121  (39.5)  6288  (30.9)  3543  (24.6)  1593  (19.7)  43 308  (35.7)  M1  606  (5.7)  1163  (5.8)  1721  (6.9)  2188  (9.5)  2442  (12.0)  2007  (13.9)  1247  (15.4)  11 374  (9.4)  MX  5832  (55.0)  10 727  (53.7)  12 326  (49.5)  11 617  (50.3)  11 459  (56.3)  8757  (60.8)  5190  (64.3)  65 908  (54.3)  Missing  68  (0.6)  119  (0.6)  153  (0.6)  150  (0.7)  162  (0.8)  104  (0.7)  46  (0.6)  802  (0.7)  Gleason/WHO                                  2–6  6272  (59.2)  10 903  (54.6)  11 989  (48.1)  8966  (38.9)  5845  (28.7)  3113  (21.6)  1155  (14.3)  48 243  (39.7)  WHO = 1  119  (1.1)  252  (1.3)  468  (1.9)  622  (2.7)  796  (3.9)  586  (4.1)  282  (3.5)  3125  (2.6)  3 + 4  1736  (16.4)  3495  (17.5)  4529  (18.2)  3841  (16.6)  3048  (15.0)  1841  (12.8)  844  (10.5)  19 334  (15.9)  4 + 3  761  (7.2)  1714  (8.6)  2416  (9.7)  2502  (10.8)  2226  (10.9)  1640  (11.4)  903  (11.2)  12 162  (10.0)  Gleason = 7  335  (3.2)  620  (3.1)  858  (3.4)  1025  (4.4)  1128  (5.5)  820  (5.7)  392  (4.9)  5178  (4.3)  WHO = 2  180  (1.7)  332  (1.7)  633  (2.5)  979  (4.2)  1399  (6.9)  1049  (7.3)  738  (9.1)  5310  (4.4)  8  619  (5.8)  1390  (7.0)  2112  (8.5)  2373  (10.3)  2602  (12.8)  2192  (15.2)  1408  (17.4)  12 696  (10.5)  9–10  449  (4.2)  973  (4.9)  1453  (5.8)  1972  (8.5)  2236  (11.0)  2054  (14.3)  1355  (16.8)  10 492  (8.6)  WHO = 3  84  (0.8)  191  (1.0)  290  (1.2)  511  (2.2)  664  (3.3)  607  (4.2)  437  (5.4)  2784  (2.3)  Missing  42  (0.4)  111  (0.6)  152  (0.6)  285  (1.2)  407  (2.0)  509  (3.5)  562  (7.0)  2068  (1.7)  PSA (ng/ml)                                  0–4  1560  (14.7)  2428  (12.2)  2470  (9.9)  1512  (6.6)  981  (4.8)  554  (3.8)  220  (2.7)  9725  (8.0)  4.1–10  5541  (52.3)  10 161  (50.9)  11 636  (46.7)  8492  (36.8)  4903  (24.1)  2237  (15.5)  716  (8.9)  43 686  (36.0)  10.1–20  1684  (15.9)  3693  (18.5)  5041  (20.2)  5302  (23.0)  4716  (23.2)  2998  (20.8)  1283  (15.9)  24 717  (20.4)  20.1–50  886  (8.4)  1808  (9.0)  2856  (11.5)  3657  (15.8)  4439  (21.8)  3680  (25.5)  2106  (26.1)  19 432  (16.0)  50.1–100  305  (2.9)  703  (3.5)  1127  (4.5)  1546  (6.7)  1936  (9.5)  1851  (12.8)  1205  (14.9)  8673  (7.1)  100+  576  (5.4)  1110  (5.6)  1647  (6.6)  2370  (10.3)  3060  (15.0)  2809  (19.5)  2280  (28.2)  13 852  (11.4)  Missing  45  (0.4)  78  (0.4)  123  (0.5)  197  (0.9)  316  (1.6)  282  (2.0)  266  (3.3)  1307  (1.1)  Treatmentb                                  Radical prostatectomy  5475  (51.7)  8847  (44.3)  7919  (31.8)  2529  (11.0)  151  (0.7)  24  (0.2)  4  (0.0)  24 949  (20.6)  Radiotherapy  1783  (16.8)  3860  (19.3)  5314  (21.3)  4032  (17.5)  880  (4.3)  22  (0.2)  2  (0.0)  15 893  (13.1)  Deferred treatmentc  1726  (16.3)  3903  (19.5)  5990  (24.1)  7380  (32.0)  7062  (34.7)  4093  (28.4)  1723  (21.3)  31 877  (26.3)  Anti-androgen  206  (1.9)  498  (2.5)  906  (3.6)  1591  (6.9)  1892  (9.3)  1141  (7.9)  446  (5.5)  6680  (5.5)  GnRH agonist  972  (9.2)  2158  (10.8)  3902  (15.7)  6779  (29.4)  9798  (48.1)  8746  (60.7)  5641  (69.8)  37 996  (31.3)  Missingd  435  (4.1)  715  (3.6)  869  (3.5)  765  (3.3)  568  (2.8)  385  (2.7)  260  (3.2)  3997  (3.3)  Mode of detection                                  PSA screening  4870  (46.0)  8515  (42.6)  9295  (37.3)  6215  (26.9)  3531  (17.4)  1674  (11.6)  624  (7.7)  34 724  (28.6)  LUTSe  2261  (21.3)  5036  (25.2)  6897  (27.7)  7154  (31.0)  6839  (33.6)  5217  (36.2)  3060  (37.9)  36 464  (30.0)  Other symptoms  2536  (23.9)  4729  (23.7)  6271  (25.2)  6907  (29.9)  7172  (35.2)  5691  (39.5)  3354  (41.5)  36 660  (30.2)  Missing  930  (8.8)  1701  (8.5)  2437  (9.8)  2800  (12.1)  2809  (13.8)  1829  (12.7)  1038  (12.9)  13 544  (11.2)  a Low risk (cT1-T2, PSA <10 ng/ml, and Gleason score ≤ 6/WHO grade 1), intermediate risk (cT1-T2, and PSA 10–<20 ng/ml or Gleason score 7/WHO grade 2), high risk (cT3 or PSA 20–<50 ng/ml or Gleason score ≥8/WHO grade 3), regionally metastatic (cT4 or N1 or PSA 50–<100 ng/ml) and metastatic (M1 or PSA ≥ 100 ng/ml). b According to primary treatment in NPCR. c Deferred treatment includes watchful waiting and active surveillance. d Including 0.6% registered as unspecified curative treatment in NPCR. e Lower urinary tract symptoms. CCI, Charlson Comorbidity Index. To investigate if the association between age at diagnosis and prognosis differs by treatment, we ran the fully adjusted model stratified by treatment. For men treated with radical prostatectomy or radiotherapy, we combined all age groups ≥75 years as few men >79 years received either of those treatments (Table 1). In these stratified analyses of curative treatment, we excluded 2653 men for whom we could not validate receipt of treatment, or who had metastatic disease, defined by a positive bone imaging or PSA ≥ 100 ng/ml. Among men treated with radical prostatectomy or radiotherapy in 2007–2012, we also conducted a sensitivity analysis additionally adjusting for the proportion of biopsy cores positive for cancer. Among men treated with radical prostatectomy in 2007–2012, we also ran sensitivity analyses adjusting for pathological rather than preoperative stage and grade. Statistical analyses were carried out using R version 2.15.0. All P-values were two sided. P-values < 0.05 were considered statistically significant. The study was approved by the Ethical Review Board in Umeå, Sweden. Results The study cohort included 121 392 men aged 55–95 years diagnosed with prostate cancer in 1998–2012 and followed for outcome through 2014. In total 24 949 men had been treated with radical prostatectomy, 15 893 with radiotherapy, 31 887 with deferred treatment and 44 676 with primary androgen deprivation therapy. The mean age at diagnosis was 71 years (SD: 8.5 years). During a follow-up of 751 000 person-years (mean 6.2 years, SD: 3.9 years), 23 649 (19%) men died of prostate cancer and 29 368 (24%) men died of other causes. Table 1 presents baseline characteristics overall and stratified by age at diagnosis. With increasing age at diagnosis, men had more comorbidity, lower education level, fewer PSA-detected cancer, more advanced cancers and were less often treated with curative intent (Table 1). The proportion of men treated with curative intent started to decrease more steeply at approximately age 65, especially for men with intermediate- or high-risk disease (Figure 1). Figure 1. View largeDownload slide Proportion of men treated with radical prostatectomy, radiotherapy, deferred treatment (i.e. watchful waiting or active surveillance) or androgen deprivation therapy by age at diagnosis among 121 392 men in PCBaSe diagnosed with prostate cancer between 1998 and 2012. Proportions were calculated in 1-year classes and smoothed by locally weighted regression. Figure 1. View largeDownload slide Proportion of men treated with radical prostatectomy, radiotherapy, deferred treatment (i.e. watchful waiting or active surveillance) or androgen deprivation therapy by age at diagnosis among 121 392 men in PCBaSe diagnosed with prostate cancer between 1998 and 2012. Proportions were calculated in 1-year classes and smoothed by locally weighted regression. In all age groups, men treated with radiotherapy had worse tumor characteristics than men treated with radical prostatectomy (supplementary Table S1, available at Annals of Oncology online). With increasing age at diagnosis, however, cancer characteristics generally worsened more among men treated with radical prostatectomy than among men treated with radiotherapy. For example, among men treated with radical prostatectomy, the proportion of men with T3 tumors increased from 3% among those aged 55–59 years at diagnosis to 10% among those aged 75+ years. The corresponding proportions among men treated with radiotherapy were stable at 20%. The proportion of men with unknown M stage at the time of treatment was higher among men treated with radical prostatectomy than among men treated with radiotherapy across risk categories and age groups (Figure 2). Among men with low- or intermediate-risk cancer, the proportion of men with unknown M stage decreased with increasing age at diagnosis both among men treated with radical prostatectomy and among men treated with radiotherapy. Among men with high-risk or regionally metastatic disease the proportion of men with unknown M stage was rather stable across age groups among men treated with radiotherapy, whereas it generally increased by age group among men treated with radical prostatectomy. Figure 2. View largeDownload slide The proportion of men with unknown M status in PCBaSe diagnosed with prostate cancer between 1998 and 2012. Figure 2. View largeDownload slide The proportion of men with unknown M status in PCBaSe diagnosed with prostate cancer between 1998 and 2012. Old age at diagnosis was associated with both higher risk of upstaging and upgrading at radical prostatectomy (supplementary Table S2, available at Annals of Oncology online). Figure 3 shows the 5-year cumulative incidence of prostate cancer death by age at diagnosis. The risk increased steeply after age 65; it was <10% at <65 years and rose to >30% at age 85. Figure 3. View largeDownload slide Five-year cumulative incidence of prostate cancer death by age at diagnosis among 121 392 men in PCBaSe diagnosed with prostate cancer between 1998 and 2012. Figure 3. View largeDownload slide Five-year cumulative incidence of prostate cancer death by age at diagnosis among 121 392 men in PCBaSe diagnosed with prostate cancer between 1998 and 2012. Table 2 presents relative risks for prostate cancer death by 5-year age groups. Among men aged 85 or more, adjusting for year of diagnosis had a weak effect on the risk estimates, whereas adjusting for cancer characteristics strongly decreased the risk; the HR was 8.59 (95% CI: 8.10–9.10) in the unadjusted model, 8.18 (95% CI: 7.72–8.67) after adjustment for year of diagnosis and 3.35 (95% CI: 3.16–3.55) after adjustment for cancer characteristics. After additional adjustment for mode of detection and treatment, the HR decreased to 2.14 (95% CI: 2.02–2.28). In general, adjustments had less influence on the risk estimates among younger men. Table 2. Univariable and multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) of prostate cancer–specific death by 5-year age groups         Model 1a   Model 2b   Model 3c   Model 4d   Model 5e   Model 6f     N  Pyrs  Events  HR  (95% CI)  HR  (95% CI)  HR  (95% CI)  HR  (95% CI)  HR  (95% CI)  HR  (95% CI)  Age at diagnosis                                55–59  10 597  81 692  995  0.87  (0.80–0.94)  0.86  (0.80–0.93)  0.94  (0.87–1.01)  0.95  (0.88–1.03)  0.96  (0.89–1.04)  1.01  (0.94–1.10)  60–64  19 981  145 496  2027  1.00  Reference  1.00  Reference  1.00  Reference  1.00  Reference  1.00  Reference  1.00  Reference  65–69  24 900  171 259  3122  1.31  (1.24–1.38)  1.29  (1.22–1.37)  1.18  (1.12–1.25)  1.17  (1.10–1.23)  1.16  (1.09–1.22)  1.06  (1.01–1.13)  70–74  23 076  149 755  4617  2.23  (2.11–2.35)  2.15  (2.04–2.26)  1.52  (1.44–1.60)  1.47  (1.39–1.55)  1.43  (1.35–1.50)  1.13  (1.07–1.19)  75–79  20 351  114 001  5582  3.58  (3.40–3.76)  3.37  (3.20–3.55)  1.99  (1.89–2.09)  1.90  (1.80–2.00)  1.82  (1.73–1.92)  1.30  (1.23–1.37)  80–84  14 411  63 578  4463  5.22  (4.95–5.50)  4.95  (4.69–5.22)  2.39  (2.26–2.53)  2.26  (2.14–2.39)  2.15  (2.03–2.27)  1.54  (1.45–1.63)  85+  8076  25 014  2843  8.59  (8.10–9.10)  8.18  (7.72–8.67)  3.35  (3.16–3.55)  3.12  (2.94–3.32)  2.94  (2.77–3.12)  2.14  (2.02–2.28)          Model 1a   Model 2b   Model 3c   Model 4d   Model 5e   Model 6f     N  Pyrs  Events  HR  (95% CI)  HR  (95% CI)  HR  (95% CI)  HR  (95% CI)  HR  (95% CI)  HR  (95% CI)  Age at diagnosis                                55–59  10 597  81 692  995  0.87  (0.80–0.94)  0.86  (0.80–0.93)  0.94  (0.87–1.01)  0.95  (0.88–1.03)  0.96  (0.89–1.04)  1.01  (0.94–1.10)  60–64  19 981  145 496  2027  1.00  Reference  1.00  Reference  1.00  Reference  1.00  Reference  1.00  Reference  1.00  Reference  65–69  24 900  171 259  3122  1.31  (1.24–1.38)  1.29  (1.22–1.37)  1.18  (1.12–1.25)  1.17  (1.10–1.23)  1.16  (1.09–1.22)  1.06  (1.01–1.13)  70–74  23 076  149 755  4617  2.23  (2.11–2.35)  2.15  (2.04–2.26)  1.52  (1.44–1.60)  1.47  (1.39–1.55)  1.43  (1.35–1.50)  1.13  (1.07–1.19)  75–79  20 351  114 001  5582  3.58  (3.40–3.76)  3.37  (3.20–3.55)  1.99  (1.89–2.09)  1.90  (1.80–2.00)  1.82  (1.73–1.92)  1.30  (1.23–1.37)  80–84  14 411  63 578  4463  5.22  (4.95–5.50)  4.95  (4.69–5.22)  2.39  (2.26–2.53)  2.26  (2.14–2.39)  2.15  (2.03–2.27)  1.54  (1.45–1.63)  85+  8076  25 014  2843  8.59  (8.10–9.10)  8.18  (7.72–8.67)  3.35  (3.16–3.55)  3.12  (2.94–3.32)  2.94  (2.77–3.12)  2.14  (2.02–2.28)  a Model 1 is unadjusted. b Model 2 is adjusted for year of diagnosis (continuous). c Model 3 is adjusted for the same variable as in Model 2, plus additionally for Gleason score (categorical: 2–6, 3 + 4, 4 + 3, 8, 9–10), PSA level at diagnosis (categorical: 0–4, 4, 10, 10–20, 20–50, 50–100,  >100), clinical T stage (categorical: cT1a, cT1b, cT1c, cT2, cT3, cT4), N stage (categorical: N0, N1, NX), M stage (categorical: M0, M1, MX). d Model 4 is adjusted for the same variables as in Model 3, plus additionally for comorbidity/CCI (categorical: 0, 1, 2,  ≥3) and education level (categorical: low, middle, high). e Model 5 is adjusted for the same variables as in Model 4, plus additionally for mode of detection (categorical: PSA screening, lower urinary tract symptoms, other). f Model 6 is adjusted for the same variables as in Model 5, plus additionally for treatment (categorical: radical prostatectomy, radiotherapy, deferred treatment, androgen deprivation therapy). Table 3 presents relative risks from the fully adjusted model stratified by treatment. Among men treated with radical prostatectomy, the risk increased stepwise from HR 0.78 (95% CI: 0.59–1.02) among men age 55–59 to HR 2.20 (95% CI: 1.01–4.77) among men above age 75. In contrast, there was no association between age and risk of prostate cancer death after radiotherapy, HR 1.03 (95% CI: 0.81–1.30) among men age 55–59 and HR1.08 (95% CI: 0.76–1.53) among men above 75. Among men who received deferred treatment or androgen deprivation therapy, old men had a much higher risk of prostate cancer death. Table 3. Multivariablea hazard ratios (HRs) and 95% confidence intervals (CIs) of prostate cancer-specific death stratified by treatment   Radical prostatectomyb   Radiotherapyc     Deferred treatmentd   Androgen depravation therapye   Age at diagnosis  HR  (95% CI)  HR  (95% CI)  Age at diagnosis  HR  (95% CI)  HR  (95% CI)  55–59  0.78  (0.59–1.02)  1.03  (0.81–1.30)  55–59  0.76  (0.49–1.17)  1.08  (0.98–1.18)  60–64  1.00  Reference  1.00  Reference  60–64  1.00  Reference  1.00  Reference  65–69  1.08  (0.87–1.34)  1.06  (0.89–1.26)  65–69  1.54  (1.20–1.97)  1.01  (0.94–1.08)  70–74  1.34  (1.01–1.77)  0.98  (0.81–1.19)  70–74  2.55  (2.03–3.20)  0.99  (0.93–1.05)  75+  2.20  (1.01–4.77)  1.08  (0.76–1.53)  75–79  3.45  (2.75–4.32)  1.09  (1.03–1.16)            80–84  4.72  (3.74–5.96)  1.26  (1.18–1.34)            85+  7.19  (5.61–9.20)  1.72  (1.61–1.84)    Radical prostatectomyb   Radiotherapyc     Deferred treatmentd   Androgen depravation therapye   Age at diagnosis  HR  (95% CI)  HR  (95% CI)  Age at diagnosis  HR  (95% CI)  HR  (95% CI)  55–59  0.78  (0.59–1.02)  1.03  (0.81–1.30)  55–59  0.76  (0.49–1.17)  1.08  (0.98–1.18)  60–64  1.00  Reference  1.00  Reference  60–64  1.00  Reference  1.00  Reference  65–69  1.08  (0.87–1.34)  1.06  (0.89–1.26)  65–69  1.54  (1.20–1.97)  1.01  (0.94–1.08)  70–74  1.34  (1.01–1.77)  0.98  (0.81–1.19)  70–74  2.55  (2.03–3.20)  0.99  (0.93–1.05)  75+  2.20  (1.01–4.77)  1.08  (0.76–1.53)  75–79  3.45  (2.75–4.32)  1.09  (1.03–1.16)            80–84  4.72  (3.74–5.96)  1.26  (1.18–1.34)            85+  7.19  (5.61–9.20)  1.72  (1.61–1.84)  a Adjusted for year of diagnosis (continuous), Gleason score (categorical: 2–6, 3 + 4, 4 + 3, 8, 9–10), PSA level at diagnosis (categorical: 0–4, 4, 10, 10–20, 20–50, 50–100, >100), clinical T stage (categorical: cT1a, cT1b, cT1c, cT2, cT3, cT4), N stage (categorical: N0, N1, NX), M stage (categorical: M0, M1, MX), comorbidity/CCI (categorical: 0, 1, 2,  ≥3), education level (categorical: low, middle, high) and mode of detection (categorical: PSA screening, lower urinary tract symptoms, other). b Analysis based on 24 047 men and 500 events. c Analysis based on 14 776 men and 860 events. d Deferred treatment includes men treated with watchful waiting or active surveillance. Analysis based on 31 887 men and 3003 events. e Analysis based on 44 676 men and 18 492 events. In sensitivity analyses, among men treated with radical prostatectomy, additional adjustment for number of biopsy cores positive for cancer (supplementary Table S3, available at Annals of Oncology online) or for pathological stage and grade rather than preoperative stage and grade did not materially alter the risk estimates (supplementary Table S4, available at Annals of Oncology online). Discussion In this large cohort study, old age at diagnosis was associated with higher risk of prostate cancer death even after adjustment for cancer characteristics, primary treatment, year of diagnosis, mode of detection and comorbidity. In analyses stratified by treatment, old age was associated with a higher risk of prostate cancer death among men treated with radical prostatectomy, deferred treatment or androgen depravation therapy, but not among men treated with radiotherapy. A main concern in this and other observational studies investigating the association between age at prostate cancer diagnosis and prognosis is selection bias and confounding by indication. Ideally, treatment selection is based on cancer characteristics, life expectancy based on chronological age, comorbidity and patient preference. Several studies have, however, reported under-treatment of old men with prostate cancer [8–10]. Likewise, in this study, we found substantial differences in baseline characteristics, treatment patterns and pretreatment workup by age at diagnosis. Taken together, biases stemming from these sources are difficult to fully control for. Hence, although we had high-validity covariate data in this study, residual confounding remains a concern. Few contemporary studies have specifically studied age at diagnosis as a prognostic factor for men with prostate cancer. Bechis et al. found poorer prognosis with increasing age at diagnosis in 11 790 men in CaPSURE treated with radical prostatectomy, radiotherapy, watchful waiting or primary androgen deprivation therapy for localized prostate cancer [8]. Contrasting to our finding, however, the association disappeared after adjustment for treatment. There are differences between the CaPSURE study and our study that may explain the contrasting findings, including patient selection (the CaPSURE study only included localized disease and is not population based) and statistical power (our study was about 10 times larger). Importantly, the CaPSURE study did not present results stratified by treatment. In our cohort, the risk of prostate cancer death increased stepwise with increasing age at diagnosis in men treated with radical prostatectomy. Results from prior studies are mixed and appear to differ between population-based studies and institutional series. In a SEER study including 160 787 men treated with radical prostatectomy, old age at diagnosis was associated with higher prostate cancer death rates [7]. In most [13, 22–25], though not all [11, 26], institutional series of men treated with radical prostatectomy, older age at diagnosis was not associated with poorer prognosis. A possible explanation for these divergent findings is that institutional series, in contrast to registry-based studies, typically adjust for pathological rather than preoperative tumor characteristics, thereby indirectly adjusting for upstaging and upgrading. We did not find support for this notion in our study; in sensitivity analyses, adjusting for pathological instead of preoperative stage and grade, the results remained. Another possible explanation is that older men treated with radical prostatectomy at major institutions undergo more extensive preoperative workup and/or are a select and homogenous group of men with a more favorable prognosis. We observed no association between age at diagnosis and prostate cancer death among men treated with curatively intended radiotherapy. These results argue against the notion that tumors in old men are inherently more aggressive. Results from prior studies are mixed. In a SEER study including 149 967 men treated with radiotherapy, older age at diagnosis was associated poorer prognosis among men with low- or intermediate-risk disease, but less so among men with high-risk disease [7]. Institutional radiotherapy series have reported older age at diagnosis to be associated with poorer prognosis [27], unassociated [28, 29] or better prognosis [30]. The divergent finding in our cohort between men treated with radical prostatectomy versus radiotherapy can, aside from chance, be explained by at least two different, nonmutually exclusive mechanisms: (i) older versus younger men treated with radical prostatectomy undergo less extensive preoperative workup and/or are a select group of men with more advanced and aggressive cancer and (ii) radical prostatectomy is less effective in older versus younger men. In support of the first explanation, our data indicate that a rather large proportion of older men treated with radical prostatectomy, especially men with high-risk tumors, did not undergo appropriate preoperative workup/imaging. Moreover, our data indicate that older versus younger men treated with radical prostatectomy generally have worse cancer characteristics. The second explanation is line with the results from the SPCG4 trial [4], which found less treatment effect of radical prostatectomy in men aged ≥65 versus <65 years. The recently published updated results from the PIVOT trial did however not replicate this finding, arguing against the hypothesis that radical prostatectomy is less effective in older versus younger men [6]. The ProtecT trial did also not find any treatment differences by age, but was limited to men aged 50–69 years and had low power [5]. Among men undergoing deferred treatment in our cohort, old age at diagnosis was associated with substantially poorer prognosis. Speculatively, this association could be caused a high proportion of young men on active surveillance subsequently receiving curative treatment [30]. Alternatively, a larger proportion of old men with aggressive cancer receive watchful waiting compared with younger men with less aggressive cancer [30]. Other contributing factors may be that old men receive less aggressive treatment at disease progression. Among men treated with androgen deprivation therapy, we also observed higher risk of prostate cancer death among men above age 75. As for men undergoing deferred treatment, this may be explained by older men being frailer and/or receiving less aggressive secondary treatment. Strengths of this study include its population-based design, virtually complete follow-up, large sample size and well-annotated covariate data. The main limitation lies in the observational study design, as discussed above. Additional limitations include the lack of data before 2008 distinguishing active surveillance from watchful waiting, and lack of data on secondary treatment and pathological stage and grade. Conclusion In conclusion, the possible selection mechanisms among older versus younger men in the radical prostatectomy and deferred treatment groups discussed above, combined with the null-association between age at diagnosis and prognosis after radiotherapy, argue against a strong inherent effect of age on risk of prostate cancer death as the explanation for our findings. Rather, our findings indicate that in current clinical practice, old men with prostate cancer receive insufficient diagnostic workup and subsequent curative treatment. Stronger adherence to guidelines on workup and treatment of prostate cancer is warranted also in old men, in particular given the strong increase in life expectancy. Acknowledgements This project was made possible by the continuous work of the National Prostate Cancer Register of Sweden (NPCR) steering group: Pär Stattin (chairman), Anders Widmark, Camilla Thellenberg, Ove Andrén, Eva Johansson, Ann-Sofi Fransson, Magnus Törnblom, Stefan Carlsson, Marie Hjälm Eriksson, David Robinson, Mats Andén, Johan Stranne, Jonas Hugosson, Ingela Franck Lissbrant, Maria Nyberg, Göran Ahlgren, René Blom, Calle Walller, Per Fransson, Fredrik Sandin and Karin Hellström. Funding The Swedish Research Council (825-2012-5047); The Swedish Cancer Society (16 0700); Uppsala County Council (no grant number applies). Disclosure The authors have declared no conflicts of interest. References 1 Droz JP, Aapro M, Balducci L et al.   Management of prostate cancer in older patients: updated recommendations of a working group of the International Society of Geriatric Oncology. Lancet Oncol  2014; 15: e404– e414. 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Population based study of use and determinants of active surveillance and watchful waiting for low and intermediate risk prostate cancer. J Urol  2013; 190( 5): 1742– 1749. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Oncology Oxford University Press

Age at diagnosis and prostate cancer treatment and prognosis: a population-based cohort study

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© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Abstract

Abstract Background Old age at prostate cancer diagnosis has been associated with poor prognosis in several studies. We aimed to investigate the association between age at diagnosis and prognosis, and if it is independent of tumor characteristics, primary treatment, year of diagnosis, mode of detection and comorbidity. Patients and methods We conducted a nation-wide cohort study including 121 392 Swedish men aged 55–95 years in Prostate Cancer data Base Sweden 3.0 diagnosed with prostate cancer in 1998–2012 and followed for prostate cancer death through 2014. Data were available on age, stage, grade, prostate-specific antigen (PSA)-level, mode of detection, comorbidity, educational level and primary treatment. We used Cox regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results With increasing age at diagnosis, men had more comorbidity, fewer PSA-detected cancers, more advanced cancers and were less often treated with curative intent. Among men with high-risk or regionally metastatic disease, the proportion of men with unknown M stage was higher among old men versus young men. During a follow-up of 751 000 person-years, 23 649 men died of prostate cancer. In multivariable Cox-regression analyses stratified by treatment, old age at diagnosis was associated with poorer prognosis among men treated with deferred treatment (HRage 85+ versus 60–64: 7.19; 95% CI: 5.61–9.20), androgen deprivation therapy (HRage 85+ versus 60–64: 1.72; 95% CI: 1.61–1.84) or radical prostatectomy (HRage 75+ versus 60–64: 2.20; 95% CI: 1.01–4.77), but not radiotherapy (HRage 75+ versus 60–64: 1.08; 95% CI: 0.76–1.53). Conclusion Our findings argue against a strong inherent effect of age on risk of prostate cancer death, but indicate that in current clinical practice, old men with prostate cancer receive insufficient diagnostic workup and subsequent curative treatment. cohort study, prostate cancer, age at diagnosis, treatment, prognosis Key Message Swedish nation-wide cohort study showing that older age at prostate cancer diagnosis is associated with higher risk of prostate cancer death among men treated with radical prostatectomy, deferred treatment or androgen depravation therapy, but not radiotherapy. The findings indicate that old men with prostate cancer receive insufficient diagnostic workup and subsequent curative treatment. Introduction Management of old men with prostate cancer is a growing clinical dilemma. Prostate cancer primarily affects old men, life expectancy is rapidly improving and old patients are often excluded from clinical trials [1, 2]. Indeed, despite that almost a quarter of men diagnosed with prostate cancer are 75 years or older [3], none of the major clinical randomized trials comparing radical to conservative treatment included men older than 75 years [4–6]. Old age at prostate cancer diagnosis has been associated with poor prognosis in several observational studies [7, 8]. The association is likely largely explained by less prostate-specific antigen (PSA) screening, worse cancer characteristics at diagnosis and less treatment with curative intent in old compared with young men [8–10]. The association between old age at diagnosis and poor prognosis is however difficult to assess in observational studies as most population-based studies lack detailed data on clinicopathologic factors and comorbidity, whereas most institutional based studies include select patient populations. It is moreover possible that prostate cancer in old men is inherently different from that in younger men. Old age at diagnosis has been associated with increased risk of upstaging and upgrading at radical prostatectomy [11–13], indicating that prostate cancer in old men is more aggressive. The aim of this study was to investigate the association between age at diagnosis and prostate cancer death, and to assess if it is independent of tumor characteristics, primary treatment, year of diagnosis, mode of detection and comorbidity, in a population-based cohort with detailed data on clinicopathologic factors and comorbidity. To this end, we conducted a nation-wide cohort study including 121 392 Swedish men aged 55–95 years in Prostate Cancer data Base Sweden (PCBaSe) 3.0 diagnosed with prostate cancer in 1998–2012 and followed for prostate cancer death through 2014. Patients and methods Data sources We used The National Prostate Cancer Register (NPCR) to assemble the study cohort [14]. NPCR includes 98% of all men diagnosed with prostate cancer in Sweden since 1998. Data on mode of detection (PSA-screening, lower urinary tract symptoms, other), clinical TNM stage, biopsy tumor differentiation (Gleason score or WHO grade), serum PSA level (ng/ml) at diagnosis and planned primary treatment within 6 months of diagnosis [radical prostatectomy, radiotherapy, deferred treatment (i.e. watchful waiting or active surveillance), primary androgen depravation therapy] have been reported to NPCR since 1998. Detailed radiotherapy data (total dose, fractionation, etc.) have been registered in NPCR since 2008. For the period 1998–2007, detailed radiotherapy data have been retrieved from RETRORAD, a retrospective collection of radiotherapy data from the Oncology Information Systems and local databases at the Oncology Departments throughout Sweden [14]. Data on pathological stage and grade, the total number of diagnostic biopsy cores and the number of diagnostic biopsy cores containing cancer have been registered in NPCR since 2007. Additional covariate and outcome data were obtained through linkage to other nationwide registries in PCBaSe 3.0 [14]. Data on comorbidity and surgical procedures were obtained from The National Patient Register, which includes all in-patient medical and procedural discharge diagnoses according to International Classification of Disease (ICD) codes. Migration data were obtained from the Register of Population and Population Changes, and causes of death data from the Cause of Death Registry; agreement between cause of death according to the Cause of Death Registry and medical charts is estimated to be 86% [15]. Education level data were obtained from the LISA database. Study cohort We restricted the study cohort to men aged 55–95 years at diagnosis [16, 17]. The men were divided into five risk categories based on a modified version of the National Comprehensive Cancer Network (NCCN) guidelines: low risk (cT1-T2, PSA < 10 and Gleason score ≤ 6/WHO grade 1), intermediate risk (cT1-T2 and PSA 10–<20 or Gleason score 7/WHO grade 2), high risk (cT3 or PSA 20–<50 or Gleason score ≥ 8/WHO grade 3), regionally metastatic (cT4 or N1 or PSA 50–<100) and metastatic (M1 or PSA ≥ 100). Men with unknown risk category were excluded [18]. Comorbidity at diagnosis was categorized according to the Charlson Comorbidity Index [19] based on ICD discharge codes up to 10 years before the prostate cancer diagnosis. Education level was categorized as low (≤9 school years), middle (10–12 school years) or high (≥13 school years). Statistical analyses We calculated the proportion of men undergoing different treatments stratified by risk category as well as by age at diagnosis. To further assess differences in baseline cancer characteristics by age at diagnosis among men undergoing curative treatment, we calculated tumor characteristics stratified by treatment (radical prostatectomy versus radiotherapy) and by age at diagnosis. To assess if pretreatment radiological workup differed among men treated with radical prostatectomy versus radiotherapy, we calculated the proportion of men with unknown M stage (i.e. Mx according to UICC 6th edition 2002) at the time of treatment by risk category and age at diagnosis. Finally, to assess if age at diagnosis was associated with upstaging or upgrading at radical prostatectomy, we calculated the proportion of men in each pathological stage and grade category stratified by preoperative stage and grade as well as by age at diagnosis. In survival analyses, men were followed from the date of diagnosis to the date of death due to prostate cancer (end point), death due to other causes, emigration or 31 December 2014, whichever occurred first. The cumulative incidence of prostate cancer death was calculated in 1-year classes and smoothed by locally weighted regression [20]. Relative risks were estimated by calculating hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazard regression. In Cox regression models, age at diagnosis was modeled as a categorical variable in 5-year age groups (age 60–64 reference category), with the exception of those aged 85–95 years who were combined due to small numbers. We ran unadjusted models and models adjusted for year of diagnosis, comorbidity, education level, clinical TNM stage, Gleason score, PSA level at diagnosis, mode of detection and treatment. For variables containing missing values (11% for mode of detection, <5% for all other covariates; Table 1), we imputed the missing values using chained equations with five imputation data sets per value [21]. Table 1. Characteristics at baseline for 121 392 men in Prostate Cancer data Base Sweden (PCBaSe) diagnosed with prostate cancer between 1998 and 2012, stratified by age   Age at diagnosis     55–59 years (N = 10 597)   60–64 years (N = 19 981)   65–69 years (N = 24 900)   70–74 years (N = 23 076)   75–79 years (N = 20 351)   80–84 years (N = 14 411)   85 years  +  (N = 8076)   All (N = 121 392)     N  %  N  %  N  %  N  %  N  %  N  %  N  %  N  %  Year of diagnosis                                  1998–2002  2338  (22.1)  4009  (20.1)  5706  (22.9)  6768  (29.3)  7185  (35.3)  4994  (34.7)  2674  (33.1)  33 674  (27.7)  2003–2007  4304  (40.6)  7777  (38.9)  8600  (34.5)  7940  (34.4)  7091  (34.8)  5150  (35.7)  2721  (33.7)  43 583  (35.9)  2008–2012  3955  (37.3)  8195  (41.0)  10 593  (42.5)  8368  (36.3)  6075  (29.9)  4267  (29.6)  2681  (33.2)  44 134  (36.4)  Comorbidity (CCI)                                  0  9536  (90.0)  17 096  (85.6)  19 874  (79.8)  16 661  (72.2)  13 167  (64.7)  8206  (56.9)  4177  (51.7)  88 717  (73.1)  1  663  (6.3)  1694  (8.5)  2882  (11.6)  3458  (15.0)  3648  (17.9)  2958  (20.5)  1803  (22.3)  17 106  (14.1)  2  279  (2.6)  856  (4.3)  1441  (5.8)  1870  (8.1)  2148  (10.6)  1872  (13.0)  1191  (14.7)  9657  (8.0)  3+  119  (1.1)  335  (1.7)  703  (2.8)  1087  (4.7)  1388  (6.8)  1375  (9.5)  905  (11.2)  5912  (4.9)  Education level                                  High  3352  (31.6)  5542  (27.7)  5875  (23.6)  4302  (18.6)  3097  (15.2)  1840  (12.8)  794  (9.8)  24 802  (20.4)  Middle  4580  (43.2)  8223  (41.2)  9523  (38.2)  8097  (35.1)  6481  (31.8)  4235  (29.4)  2061  (25.5)  43 200  (35.6)  Low  2629  (24.8)  6118  (30.6)  9317  (37.4)  10 482  (45.4)  10 482  (51.5)  8087  (56.1)  4338  (53.7)  51 453  (42.4)  Missing  36  (0.3)  98  (0.5)  185  (0.7)  195  (0.8)  291  (1.4)  249  (1.7)  883  (10.9)  1937  (1.6)  Risk categorya                                  Low-risk  4960  (46.8)  8064  (40.4)  8245  (33.1)  5152  (22.3)  2675  (13.1)  1111  (7.7)  298  (3.7)  30 505  (25.1)  Intermediate-risk  2902  (27.4)  6067  (30.4)  7667  (30.8)  6687  (29.0)  4632  (22.8)  2494  (17.3)  875  (10.8)  31 324  (25.8)  High-risk  1453  (13.7)  3277  (16.4)  5125  (20.6)  6145  (26.6)  7006  (34.4)  5349  (37.1)  2874  (35.6)  31 229  (25.7)  Regionally metastatic  456  (4.3)  960  (4.8)  1440  (5.8)  1767  (7.7)  1975  (9.7)  1869  (13.0)  1308  (16.2)  9775  (8.1)  Metastatic  826  (7.8)  1613  (8.1)  2423  (9.7)  3325  (14.4)  4063  (20.0)  3588  (24.9)  2721  (33.7)  18 559  (15.3)  Clinical T stage                                  T1c  5936  (56.0)  10 611  (53.1)  11 497  (46.2)  8035  (34.8)  4709  (23.1)  2302  (16.0)  879  (10.9)  43 969  (36.2)  T1a  193  (1.8)  436  (2.2)  657  (2.6)  777  (3.4)  770  (3.8)  563  (3.9)  231  (2.9)  3627  (3.0)  T1b  80  (0.8)  192  (1.0)  369  (1.5)  547  (2.4)  694  (3.4)  560  (3.9)  292  (3.6)  2734  (2.3)  T2  2931  (27.7)  5630  (28.2)  7605  (30.5)  7638  (33.1)  7053  (34.7)  4864  (33.8)  2405  (29.8)  38 126  (31.4)  T3  1193  (11.3)  2575  (12.9)  3990  (16.0)  4955  (21.5)  5783  (28.4)  4834  (33.5)  3190  (39.5)  26 520  (21.8)  T4  193  (1.8)  394  (2.0)  583  (2.3)  834  (3.6)  1011  (5.0)  970  (6.7)  848  (10.5)  4833  (4.0)  Missing  71  (0.7)  143  (0.7)  199  (0.8)  290  (1.3)  331  (1.6)  318  (2.2)  231  (2.9)  1583  (1.3)  N stage                                  N0  1856  (17.5)  3372  (16.9)  3972  (16.0)  2531  (11.0)  841  (4.1)  354  (2.5)  214  (2.6)  13 140  (10.8)  N1  312  (2.9)  516  (2.6)  638  (2.6)  477  (2.1)  247  (1.2)  132  (0.9)  74  (0.9)  2396  (2.0)  NX  8348  (78.8)  15 947  (79.8)  20 111  (80.8)  19 887  (86.2)  19 081  (93.8)  13 808  (95.8)  7734  (95.8)  104 916  (86.4)  Missing  81  (0.8)  146  (0.7)  179  (0.7)  181  (0.8)  182  (0.9)  117  (0.8)  54  (0.7)  940  (0.8)  M stage                                  M0  4091  (38.6)  7972  (39.9)  10 700  (43.0)  9121  (39.5)  6288  (30.9)  3543  (24.6)  1593  (19.7)  43 308  (35.7)  M1  606  (5.7)  1163  (5.8)  1721  (6.9)  2188  (9.5)  2442  (12.0)  2007  (13.9)  1247  (15.4)  11 374  (9.4)  MX  5832  (55.0)  10 727  (53.7)  12 326  (49.5)  11 617  (50.3)  11 459  (56.3)  8757  (60.8)  5190  (64.3)  65 908  (54.3)  Missing  68  (0.6)  119  (0.6)  153  (0.6)  150  (0.7)  162  (0.8)  104  (0.7)  46  (0.6)  802  (0.7)  Gleason/WHO                                  2–6  6272  (59.2)  10 903  (54.6)  11 989  (48.1)  8966  (38.9)  5845  (28.7)  3113  (21.6)  1155  (14.3)  48 243  (39.7)  WHO = 1  119  (1.1)  252  (1.3)  468  (1.9)  622  (2.7)  796  (3.9)  586  (4.1)  282  (3.5)  3125  (2.6)  3 + 4  1736  (16.4)  3495  (17.5)  4529  (18.2)  3841  (16.6)  3048  (15.0)  1841  (12.8)  844  (10.5)  19 334  (15.9)  4 + 3  761  (7.2)  1714  (8.6)  2416  (9.7)  2502  (10.8)  2226  (10.9)  1640  (11.4)  903  (11.2)  12 162  (10.0)  Gleason = 7  335  (3.2)  620  (3.1)  858  (3.4)  1025  (4.4)  1128  (5.5)  820  (5.7)  392  (4.9)  5178  (4.3)  WHO = 2  180  (1.7)  332  (1.7)  633  (2.5)  979  (4.2)  1399  (6.9)  1049  (7.3)  738  (9.1)  5310  (4.4)  8  619  (5.8)  1390  (7.0)  2112  (8.5)  2373  (10.3)  2602  (12.8)  2192  (15.2)  1408  (17.4)  12 696  (10.5)  9–10  449  (4.2)  973  (4.9)  1453  (5.8)  1972  (8.5)  2236  (11.0)  2054  (14.3)  1355  (16.8)  10 492  (8.6)  WHO = 3  84  (0.8)  191  (1.0)  290  (1.2)  511  (2.2)  664  (3.3)  607  (4.2)  437  (5.4)  2784  (2.3)  Missing  42  (0.4)  111  (0.6)  152  (0.6)  285  (1.2)  407  (2.0)  509  (3.5)  562  (7.0)  2068  (1.7)  PSA (ng/ml)                                  0–4  1560  (14.7)  2428  (12.2)  2470  (9.9)  1512  (6.6)  981  (4.8)  554  (3.8)  220  (2.7)  9725  (8.0)  4.1–10  5541  (52.3)  10 161  (50.9)  11 636  (46.7)  8492  (36.8)  4903  (24.1)  2237  (15.5)  716  (8.9)  43 686  (36.0)  10.1–20  1684  (15.9)  3693  (18.5)  5041  (20.2)  5302  (23.0)  4716  (23.2)  2998  (20.8)  1283  (15.9)  24 717  (20.4)  20.1–50  886  (8.4)  1808  (9.0)  2856  (11.5)  3657  (15.8)  4439  (21.8)  3680  (25.5)  2106  (26.1)  19 432  (16.0)  50.1–100  305  (2.9)  703  (3.5)  1127  (4.5)  1546  (6.7)  1936  (9.5)  1851  (12.8)  1205  (14.9)  8673  (7.1)  100+  576  (5.4)  1110  (5.6)  1647  (6.6)  2370  (10.3)  3060  (15.0)  2809  (19.5)  2280  (28.2)  13 852  (11.4)  Missing  45  (0.4)  78  (0.4)  123  (0.5)  197  (0.9)  316  (1.6)  282  (2.0)  266  (3.3)  1307  (1.1)  Treatmentb                                  Radical prostatectomy  5475  (51.7)  8847  (44.3)  7919  (31.8)  2529  (11.0)  151  (0.7)  24  (0.2)  4  (0.0)  24 949  (20.6)  Radiotherapy  1783  (16.8)  3860  (19.3)  5314  (21.3)  4032  (17.5)  880  (4.3)  22  (0.2)  2  (0.0)  15 893  (13.1)  Deferred treatmentc  1726  (16.3)  3903  (19.5)  5990  (24.1)  7380  (32.0)  7062  (34.7)  4093  (28.4)  1723  (21.3)  31 877  (26.3)  Anti-androgen  206  (1.9)  498  (2.5)  906  (3.6)  1591  (6.9)  1892  (9.3)  1141  (7.9)  446  (5.5)  6680  (5.5)  GnRH agonist  972  (9.2)  2158  (10.8)  3902  (15.7)  6779  (29.4)  9798  (48.1)  8746  (60.7)  5641  (69.8)  37 996  (31.3)  Missingd  435  (4.1)  715  (3.6)  869  (3.5)  765  (3.3)  568  (2.8)  385  (2.7)  260  (3.2)  3997  (3.3)  Mode of detection                                  PSA screening  4870  (46.0)  8515  (42.6)  9295  (37.3)  6215  (26.9)  3531  (17.4)  1674  (11.6)  624  (7.7)  34 724  (28.6)  LUTSe  2261  (21.3)  5036  (25.2)  6897  (27.7)  7154  (31.0)  6839  (33.6)  5217  (36.2)  3060  (37.9)  36 464  (30.0)  Other symptoms  2536  (23.9)  4729  (23.7)  6271  (25.2)  6907  (29.9)  7172  (35.2)  5691  (39.5)  3354  (41.5)  36 660  (30.2)  Missing  930  (8.8)  1701  (8.5)  2437  (9.8)  2800  (12.1)  2809  (13.8)  1829  (12.7)  1038  (12.9)  13 544  (11.2)    Age at diagnosis     55–59 years (N = 10 597)   60–64 years (N = 19 981)   65–69 years (N = 24 900)   70–74 years (N = 23 076)   75–79 years (N = 20 351)   80–84 years (N = 14 411)   85 years  +  (N = 8076)   All (N = 121 392)     N  %  N  %  N  %  N  %  N  %  N  %  N  %  N  %  Year of diagnosis                                  1998–2002  2338  (22.1)  4009  (20.1)  5706  (22.9)  6768  (29.3)  7185  (35.3)  4994  (34.7)  2674  (33.1)  33 674  (27.7)  2003–2007  4304  (40.6)  7777  (38.9)  8600  (34.5)  7940  (34.4)  7091  (34.8)  5150  (35.7)  2721  (33.7)  43 583  (35.9)  2008–2012  3955  (37.3)  8195  (41.0)  10 593  (42.5)  8368  (36.3)  6075  (29.9)  4267  (29.6)  2681  (33.2)  44 134  (36.4)  Comorbidity (CCI)                                  0  9536  (90.0)  17 096  (85.6)  19 874  (79.8)  16 661  (72.2)  13 167  (64.7)  8206  (56.9)  4177  (51.7)  88 717  (73.1)  1  663  (6.3)  1694  (8.5)  2882  (11.6)  3458  (15.0)  3648  (17.9)  2958  (20.5)  1803  (22.3)  17 106  (14.1)  2  279  (2.6)  856  (4.3)  1441  (5.8)  1870  (8.1)  2148  (10.6)  1872  (13.0)  1191  (14.7)  9657  (8.0)  3+  119  (1.1)  335  (1.7)  703  (2.8)  1087  (4.7)  1388  (6.8)  1375  (9.5)  905  (11.2)  5912  (4.9)  Education level                                  High  3352  (31.6)  5542  (27.7)  5875  (23.6)  4302  (18.6)  3097  (15.2)  1840  (12.8)  794  (9.8)  24 802  (20.4)  Middle  4580  (43.2)  8223  (41.2)  9523  (38.2)  8097  (35.1)  6481  (31.8)  4235  (29.4)  2061  (25.5)  43 200  (35.6)  Low  2629  (24.8)  6118  (30.6)  9317  (37.4)  10 482  (45.4)  10 482  (51.5)  8087  (56.1)  4338  (53.7)  51 453  (42.4)  Missing  36  (0.3)  98  (0.5)  185  (0.7)  195  (0.8)  291  (1.4)  249  (1.7)  883  (10.9)  1937  (1.6)  Risk categorya                                  Low-risk  4960  (46.8)  8064  (40.4)  8245  (33.1)  5152  (22.3)  2675  (13.1)  1111  (7.7)  298  (3.7)  30 505  (25.1)  Intermediate-risk  2902  (27.4)  6067  (30.4)  7667  (30.8)  6687  (29.0)  4632  (22.8)  2494  (17.3)  875  (10.8)  31 324  (25.8)  High-risk  1453  (13.7)  3277  (16.4)  5125  (20.6)  6145  (26.6)  7006  (34.4)  5349  (37.1)  2874  (35.6)  31 229  (25.7)  Regionally metastatic  456  (4.3)  960  (4.8)  1440  (5.8)  1767  (7.7)  1975  (9.7)  1869  (13.0)  1308  (16.2)  9775  (8.1)  Metastatic  826  (7.8)  1613  (8.1)  2423  (9.7)  3325  (14.4)  4063  (20.0)  3588  (24.9)  2721  (33.7)  18 559  (15.3)  Clinical T stage                                  T1c  5936  (56.0)  10 611  (53.1)  11 497  (46.2)  8035  (34.8)  4709  (23.1)  2302  (16.0)  879  (10.9)  43 969  (36.2)  T1a  193  (1.8)  436  (2.2)  657  (2.6)  777  (3.4)  770  (3.8)  563  (3.9)  231  (2.9)  3627  (3.0)  T1b  80  (0.8)  192  (1.0)  369  (1.5)  547  (2.4)  694  (3.4)  560  (3.9)  292  (3.6)  2734  (2.3)  T2  2931  (27.7)  5630  (28.2)  7605  (30.5)  7638  (33.1)  7053  (34.7)  4864  (33.8)  2405  (29.8)  38 126  (31.4)  T3  1193  (11.3)  2575  (12.9)  3990  (16.0)  4955  (21.5)  5783  (28.4)  4834  (33.5)  3190  (39.5)  26 520  (21.8)  T4  193  (1.8)  394  (2.0)  583  (2.3)  834  (3.6)  1011  (5.0)  970  (6.7)  848  (10.5)  4833  (4.0)  Missing  71  (0.7)  143  (0.7)  199  (0.8)  290  (1.3)  331  (1.6)  318  (2.2)  231  (2.9)  1583  (1.3)  N stage                                  N0  1856  (17.5)  3372  (16.9)  3972  (16.0)  2531  (11.0)  841  (4.1)  354  (2.5)  214  (2.6)  13 140  (10.8)  N1  312  (2.9)  516  (2.6)  638  (2.6)  477  (2.1)  247  (1.2)  132  (0.9)  74  (0.9)  2396  (2.0)  NX  8348  (78.8)  15 947  (79.8)  20 111  (80.8)  19 887  (86.2)  19 081  (93.8)  13 808  (95.8)  7734  (95.8)  104 916  (86.4)  Missing  81  (0.8)  146  (0.7)  179  (0.7)  181  (0.8)  182  (0.9)  117  (0.8)  54  (0.7)  940  (0.8)  M stage                                  M0  4091  (38.6)  7972  (39.9)  10 700  (43.0)  9121  (39.5)  6288  (30.9)  3543  (24.6)  1593  (19.7)  43 308  (35.7)  M1  606  (5.7)  1163  (5.8)  1721  (6.9)  2188  (9.5)  2442  (12.0)  2007  (13.9)  1247  (15.4)  11 374  (9.4)  MX  5832  (55.0)  10 727  (53.7)  12 326  (49.5)  11 617  (50.3)  11 459  (56.3)  8757  (60.8)  5190  (64.3)  65 908  (54.3)  Missing  68  (0.6)  119  (0.6)  153  (0.6)  150  (0.7)  162  (0.8)  104  (0.7)  46  (0.6)  802  (0.7)  Gleason/WHO                                  2–6  6272  (59.2)  10 903  (54.6)  11 989  (48.1)  8966  (38.9)  5845  (28.7)  3113  (21.6)  1155  (14.3)  48 243  (39.7)  WHO = 1  119  (1.1)  252  (1.3)  468  (1.9)  622  (2.7)  796  (3.9)  586  (4.1)  282  (3.5)  3125  (2.6)  3 + 4  1736  (16.4)  3495  (17.5)  4529  (18.2)  3841  (16.6)  3048  (15.0)  1841  (12.8)  844  (10.5)  19 334  (15.9)  4 + 3  761  (7.2)  1714  (8.6)  2416  (9.7)  2502  (10.8)  2226  (10.9)  1640  (11.4)  903  (11.2)  12 162  (10.0)  Gleason = 7  335  (3.2)  620  (3.1)  858  (3.4)  1025  (4.4)  1128  (5.5)  820  (5.7)  392  (4.9)  5178  (4.3)  WHO = 2  180  (1.7)  332  (1.7)  633  (2.5)  979  (4.2)  1399  (6.9)  1049  (7.3)  738  (9.1)  5310  (4.4)  8  619  (5.8)  1390  (7.0)  2112  (8.5)  2373  (10.3)  2602  (12.8)  2192  (15.2)  1408  (17.4)  12 696  (10.5)  9–10  449  (4.2)  973  (4.9)  1453  (5.8)  1972  (8.5)  2236  (11.0)  2054  (14.3)  1355  (16.8)  10 492  (8.6)  WHO = 3  84  (0.8)  191  (1.0)  290  (1.2)  511  (2.2)  664  (3.3)  607  (4.2)  437  (5.4)  2784  (2.3)  Missing  42  (0.4)  111  (0.6)  152  (0.6)  285  (1.2)  407  (2.0)  509  (3.5)  562  (7.0)  2068  (1.7)  PSA (ng/ml)                                  0–4  1560  (14.7)  2428  (12.2)  2470  (9.9)  1512  (6.6)  981  (4.8)  554  (3.8)  220  (2.7)  9725  (8.0)  4.1–10  5541  (52.3)  10 161  (50.9)  11 636  (46.7)  8492  (36.8)  4903  (24.1)  2237  (15.5)  716  (8.9)  43 686  (36.0)  10.1–20  1684  (15.9)  3693  (18.5)  5041  (20.2)  5302  (23.0)  4716  (23.2)  2998  (20.8)  1283  (15.9)  24 717  (20.4)  20.1–50  886  (8.4)  1808  (9.0)  2856  (11.5)  3657  (15.8)  4439  (21.8)  3680  (25.5)  2106  (26.1)  19 432  (16.0)  50.1–100  305  (2.9)  703  (3.5)  1127  (4.5)  1546  (6.7)  1936  (9.5)  1851  (12.8)  1205  (14.9)  8673  (7.1)  100+  576  (5.4)  1110  (5.6)  1647  (6.6)  2370  (10.3)  3060  (15.0)  2809  (19.5)  2280  (28.2)  13 852  (11.4)  Missing  45  (0.4)  78  (0.4)  123  (0.5)  197  (0.9)  316  (1.6)  282  (2.0)  266  (3.3)  1307  (1.1)  Treatmentb                                  Radical prostatectomy  5475  (51.7)  8847  (44.3)  7919  (31.8)  2529  (11.0)  151  (0.7)  24  (0.2)  4  (0.0)  24 949  (20.6)  Radiotherapy  1783  (16.8)  3860  (19.3)  5314  (21.3)  4032  (17.5)  880  (4.3)  22  (0.2)  2  (0.0)  15 893  (13.1)  Deferred treatmentc  1726  (16.3)  3903  (19.5)  5990  (24.1)  7380  (32.0)  7062  (34.7)  4093  (28.4)  1723  (21.3)  31 877  (26.3)  Anti-androgen  206  (1.9)  498  (2.5)  906  (3.6)  1591  (6.9)  1892  (9.3)  1141  (7.9)  446  (5.5)  6680  (5.5)  GnRH agonist  972  (9.2)  2158  (10.8)  3902  (15.7)  6779  (29.4)  9798  (48.1)  8746  (60.7)  5641  (69.8)  37 996  (31.3)  Missingd  435  (4.1)  715  (3.6)  869  (3.5)  765  (3.3)  568  (2.8)  385  (2.7)  260  (3.2)  3997  (3.3)  Mode of detection                                  PSA screening  4870  (46.0)  8515  (42.6)  9295  (37.3)  6215  (26.9)  3531  (17.4)  1674  (11.6)  624  (7.7)  34 724  (28.6)  LUTSe  2261  (21.3)  5036  (25.2)  6897  (27.7)  7154  (31.0)  6839  (33.6)  5217  (36.2)  3060  (37.9)  36 464  (30.0)  Other symptoms  2536  (23.9)  4729  (23.7)  6271  (25.2)  6907  (29.9)  7172  (35.2)  5691  (39.5)  3354  (41.5)  36 660  (30.2)  Missing  930  (8.8)  1701  (8.5)  2437  (9.8)  2800  (12.1)  2809  (13.8)  1829  (12.7)  1038  (12.9)  13 544  (11.2)  a Low risk (cT1-T2, PSA <10 ng/ml, and Gleason score ≤ 6/WHO grade 1), intermediate risk (cT1-T2, and PSA 10–<20 ng/ml or Gleason score 7/WHO grade 2), high risk (cT3 or PSA 20–<50 ng/ml or Gleason score ≥8/WHO grade 3), regionally metastatic (cT4 or N1 or PSA 50–<100 ng/ml) and metastatic (M1 or PSA ≥ 100 ng/ml). b According to primary treatment in NPCR. c Deferred treatment includes watchful waiting and active surveillance. d Including 0.6% registered as unspecified curative treatment in NPCR. e Lower urinary tract symptoms. CCI, Charlson Comorbidity Index. To investigate if the association between age at diagnosis and prognosis differs by treatment, we ran the fully adjusted model stratified by treatment. For men treated with radical prostatectomy or radiotherapy, we combined all age groups ≥75 years as few men >79 years received either of those treatments (Table 1). In these stratified analyses of curative treatment, we excluded 2653 men for whom we could not validate receipt of treatment, or who had metastatic disease, defined by a positive bone imaging or PSA ≥ 100 ng/ml. Among men treated with radical prostatectomy or radiotherapy in 2007–2012, we also conducted a sensitivity analysis additionally adjusting for the proportion of biopsy cores positive for cancer. Among men treated with radical prostatectomy in 2007–2012, we also ran sensitivity analyses adjusting for pathological rather than preoperative stage and grade. Statistical analyses were carried out using R version 2.15.0. All P-values were two sided. P-values < 0.05 were considered statistically significant. The study was approved by the Ethical Review Board in Umeå, Sweden. Results The study cohort included 121 392 men aged 55–95 years diagnosed with prostate cancer in 1998–2012 and followed for outcome through 2014. In total 24 949 men had been treated with radical prostatectomy, 15 893 with radiotherapy, 31 887 with deferred treatment and 44 676 with primary androgen deprivation therapy. The mean age at diagnosis was 71 years (SD: 8.5 years). During a follow-up of 751 000 person-years (mean 6.2 years, SD: 3.9 years), 23 649 (19%) men died of prostate cancer and 29 368 (24%) men died of other causes. Table 1 presents baseline characteristics overall and stratified by age at diagnosis. With increasing age at diagnosis, men had more comorbidity, lower education level, fewer PSA-detected cancer, more advanced cancers and were less often treated with curative intent (Table 1). The proportion of men treated with curative intent started to decrease more steeply at approximately age 65, especially for men with intermediate- or high-risk disease (Figure 1). Figure 1. View largeDownload slide Proportion of men treated with radical prostatectomy, radiotherapy, deferred treatment (i.e. watchful waiting or active surveillance) or androgen deprivation therapy by age at diagnosis among 121 392 men in PCBaSe diagnosed with prostate cancer between 1998 and 2012. Proportions were calculated in 1-year classes and smoothed by locally weighted regression. Figure 1. View largeDownload slide Proportion of men treated with radical prostatectomy, radiotherapy, deferred treatment (i.e. watchful waiting or active surveillance) or androgen deprivation therapy by age at diagnosis among 121 392 men in PCBaSe diagnosed with prostate cancer between 1998 and 2012. Proportions were calculated in 1-year classes and smoothed by locally weighted regression. In all age groups, men treated with radiotherapy had worse tumor characteristics than men treated with radical prostatectomy (supplementary Table S1, available at Annals of Oncology online). With increasing age at diagnosis, however, cancer characteristics generally worsened more among men treated with radical prostatectomy than among men treated with radiotherapy. For example, among men treated with radical prostatectomy, the proportion of men with T3 tumors increased from 3% among those aged 55–59 years at diagnosis to 10% among those aged 75+ years. The corresponding proportions among men treated with radiotherapy were stable at 20%. The proportion of men with unknown M stage at the time of treatment was higher among men treated with radical prostatectomy than among men treated with radiotherapy across risk categories and age groups (Figure 2). Among men with low- or intermediate-risk cancer, the proportion of men with unknown M stage decreased with increasing age at diagnosis both among men treated with radical prostatectomy and among men treated with radiotherapy. Among men with high-risk or regionally metastatic disease the proportion of men with unknown M stage was rather stable across age groups among men treated with radiotherapy, whereas it generally increased by age group among men treated with radical prostatectomy. Figure 2. View largeDownload slide The proportion of men with unknown M status in PCBaSe diagnosed with prostate cancer between 1998 and 2012. Figure 2. View largeDownload slide The proportion of men with unknown M status in PCBaSe diagnosed with prostate cancer between 1998 and 2012. Old age at diagnosis was associated with both higher risk of upstaging and upgrading at radical prostatectomy (supplementary Table S2, available at Annals of Oncology online). Figure 3 shows the 5-year cumulative incidence of prostate cancer death by age at diagnosis. The risk increased steeply after age 65; it was <10% at <65 years and rose to >30% at age 85. Figure 3. View largeDownload slide Five-year cumulative incidence of prostate cancer death by age at diagnosis among 121 392 men in PCBaSe diagnosed with prostate cancer between 1998 and 2012. Figure 3. View largeDownload slide Five-year cumulative incidence of prostate cancer death by age at diagnosis among 121 392 men in PCBaSe diagnosed with prostate cancer between 1998 and 2012. Table 2 presents relative risks for prostate cancer death by 5-year age groups. Among men aged 85 or more, adjusting for year of diagnosis had a weak effect on the risk estimates, whereas adjusting for cancer characteristics strongly decreased the risk; the HR was 8.59 (95% CI: 8.10–9.10) in the unadjusted model, 8.18 (95% CI: 7.72–8.67) after adjustment for year of diagnosis and 3.35 (95% CI: 3.16–3.55) after adjustment for cancer characteristics. After additional adjustment for mode of detection and treatment, the HR decreased to 2.14 (95% CI: 2.02–2.28). In general, adjustments had less influence on the risk estimates among younger men. Table 2. Univariable and multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) of prostate cancer–specific death by 5-year age groups         Model 1a   Model 2b   Model 3c   Model 4d   Model 5e   Model 6f     N  Pyrs  Events  HR  (95% CI)  HR  (95% CI)  HR  (95% CI)  HR  (95% CI)  HR  (95% CI)  HR  (95% CI)  Age at diagnosis                                55–59  10 597  81 692  995  0.87  (0.80–0.94)  0.86  (0.80–0.93)  0.94  (0.87–1.01)  0.95  (0.88–1.03)  0.96  (0.89–1.04)  1.01  (0.94–1.10)  60–64  19 981  145 496  2027  1.00  Reference  1.00  Reference  1.00  Reference  1.00  Reference  1.00  Reference  1.00  Reference  65–69  24 900  171 259  3122  1.31  (1.24–1.38)  1.29  (1.22–1.37)  1.18  (1.12–1.25)  1.17  (1.10–1.23)  1.16  (1.09–1.22)  1.06  (1.01–1.13)  70–74  23 076  149 755  4617  2.23  (2.11–2.35)  2.15  (2.04–2.26)  1.52  (1.44–1.60)  1.47  (1.39–1.55)  1.43  (1.35–1.50)  1.13  (1.07–1.19)  75–79  20 351  114 001  5582  3.58  (3.40–3.76)  3.37  (3.20–3.55)  1.99  (1.89–2.09)  1.90  (1.80–2.00)  1.82  (1.73–1.92)  1.30  (1.23–1.37)  80–84  14 411  63 578  4463  5.22  (4.95–5.50)  4.95  (4.69–5.22)  2.39  (2.26–2.53)  2.26  (2.14–2.39)  2.15  (2.03–2.27)  1.54  (1.45–1.63)  85+  8076  25 014  2843  8.59  (8.10–9.10)  8.18  (7.72–8.67)  3.35  (3.16–3.55)  3.12  (2.94–3.32)  2.94  (2.77–3.12)  2.14  (2.02–2.28)          Model 1a   Model 2b   Model 3c   Model 4d   Model 5e   Model 6f     N  Pyrs  Events  HR  (95% CI)  HR  (95% CI)  HR  (95% CI)  HR  (95% CI)  HR  (95% CI)  HR  (95% CI)  Age at diagnosis                                55–59  10 597  81 692  995  0.87  (0.80–0.94)  0.86  (0.80–0.93)  0.94  (0.87–1.01)  0.95  (0.88–1.03)  0.96  (0.89–1.04)  1.01  (0.94–1.10)  60–64  19 981  145 496  2027  1.00  Reference  1.00  Reference  1.00  Reference  1.00  Reference  1.00  Reference  1.00  Reference  65–69  24 900  171 259  3122  1.31  (1.24–1.38)  1.29  (1.22–1.37)  1.18  (1.12–1.25)  1.17  (1.10–1.23)  1.16  (1.09–1.22)  1.06  (1.01–1.13)  70–74  23 076  149 755  4617  2.23  (2.11–2.35)  2.15  (2.04–2.26)  1.52  (1.44–1.60)  1.47  (1.39–1.55)  1.43  (1.35–1.50)  1.13  (1.07–1.19)  75–79  20 351  114 001  5582  3.58  (3.40–3.76)  3.37  (3.20–3.55)  1.99  (1.89–2.09)  1.90  (1.80–2.00)  1.82  (1.73–1.92)  1.30  (1.23–1.37)  80–84  14 411  63 578  4463  5.22  (4.95–5.50)  4.95  (4.69–5.22)  2.39  (2.26–2.53)  2.26  (2.14–2.39)  2.15  (2.03–2.27)  1.54  (1.45–1.63)  85+  8076  25 014  2843  8.59  (8.10–9.10)  8.18  (7.72–8.67)  3.35  (3.16–3.55)  3.12  (2.94–3.32)  2.94  (2.77–3.12)  2.14  (2.02–2.28)  a Model 1 is unadjusted. b Model 2 is adjusted for year of diagnosis (continuous). c Model 3 is adjusted for the same variable as in Model 2, plus additionally for Gleason score (categorical: 2–6, 3 + 4, 4 + 3, 8, 9–10), PSA level at diagnosis (categorical: 0–4, 4, 10, 10–20, 20–50, 50–100,  >100), clinical T stage (categorical: cT1a, cT1b, cT1c, cT2, cT3, cT4), N stage (categorical: N0, N1, NX), M stage (categorical: M0, M1, MX). d Model 4 is adjusted for the same variables as in Model 3, plus additionally for comorbidity/CCI (categorical: 0, 1, 2,  ≥3) and education level (categorical: low, middle, high). e Model 5 is adjusted for the same variables as in Model 4, plus additionally for mode of detection (categorical: PSA screening, lower urinary tract symptoms, other). f Model 6 is adjusted for the same variables as in Model 5, plus additionally for treatment (categorical: radical prostatectomy, radiotherapy, deferred treatment, androgen deprivation therapy). Table 3 presents relative risks from the fully adjusted model stratified by treatment. Among men treated with radical prostatectomy, the risk increased stepwise from HR 0.78 (95% CI: 0.59–1.02) among men age 55–59 to HR 2.20 (95% CI: 1.01–4.77) among men above age 75. In contrast, there was no association between age and risk of prostate cancer death after radiotherapy, HR 1.03 (95% CI: 0.81–1.30) among men age 55–59 and HR1.08 (95% CI: 0.76–1.53) among men above 75. Among men who received deferred treatment or androgen deprivation therapy, old men had a much higher risk of prostate cancer death. Table 3. Multivariablea hazard ratios (HRs) and 95% confidence intervals (CIs) of prostate cancer-specific death stratified by treatment   Radical prostatectomyb   Radiotherapyc     Deferred treatmentd   Androgen depravation therapye   Age at diagnosis  HR  (95% CI)  HR  (95% CI)  Age at diagnosis  HR  (95% CI)  HR  (95% CI)  55–59  0.78  (0.59–1.02)  1.03  (0.81–1.30)  55–59  0.76  (0.49–1.17)  1.08  (0.98–1.18)  60–64  1.00  Reference  1.00  Reference  60–64  1.00  Reference  1.00  Reference  65–69  1.08  (0.87–1.34)  1.06  (0.89–1.26)  65–69  1.54  (1.20–1.97)  1.01  (0.94–1.08)  70–74  1.34  (1.01–1.77)  0.98  (0.81–1.19)  70–74  2.55  (2.03–3.20)  0.99  (0.93–1.05)  75+  2.20  (1.01–4.77)  1.08  (0.76–1.53)  75–79  3.45  (2.75–4.32)  1.09  (1.03–1.16)            80–84  4.72  (3.74–5.96)  1.26  (1.18–1.34)            85+  7.19  (5.61–9.20)  1.72  (1.61–1.84)    Radical prostatectomyb   Radiotherapyc     Deferred treatmentd   Androgen depravation therapye   Age at diagnosis  HR  (95% CI)  HR  (95% CI)  Age at diagnosis  HR  (95% CI)  HR  (95% CI)  55–59  0.78  (0.59–1.02)  1.03  (0.81–1.30)  55–59  0.76  (0.49–1.17)  1.08  (0.98–1.18)  60–64  1.00  Reference  1.00  Reference  60–64  1.00  Reference  1.00  Reference  65–69  1.08  (0.87–1.34)  1.06  (0.89–1.26)  65–69  1.54  (1.20–1.97)  1.01  (0.94–1.08)  70–74  1.34  (1.01–1.77)  0.98  (0.81–1.19)  70–74  2.55  (2.03–3.20)  0.99  (0.93–1.05)  75+  2.20  (1.01–4.77)  1.08  (0.76–1.53)  75–79  3.45  (2.75–4.32)  1.09  (1.03–1.16)            80–84  4.72  (3.74–5.96)  1.26  (1.18–1.34)            85+  7.19  (5.61–9.20)  1.72  (1.61–1.84)  a Adjusted for year of diagnosis (continuous), Gleason score (categorical: 2–6, 3 + 4, 4 + 3, 8, 9–10), PSA level at diagnosis (categorical: 0–4, 4, 10, 10–20, 20–50, 50–100, >100), clinical T stage (categorical: cT1a, cT1b, cT1c, cT2, cT3, cT4), N stage (categorical: N0, N1, NX), M stage (categorical: M0, M1, MX), comorbidity/CCI (categorical: 0, 1, 2,  ≥3), education level (categorical: low, middle, high) and mode of detection (categorical: PSA screening, lower urinary tract symptoms, other). b Analysis based on 24 047 men and 500 events. c Analysis based on 14 776 men and 860 events. d Deferred treatment includes men treated with watchful waiting or active surveillance. Analysis based on 31 887 men and 3003 events. e Analysis based on 44 676 men and 18 492 events. In sensitivity analyses, among men treated with radical prostatectomy, additional adjustment for number of biopsy cores positive for cancer (supplementary Table S3, available at Annals of Oncology online) or for pathological stage and grade rather than preoperative stage and grade did not materially alter the risk estimates (supplementary Table S4, available at Annals of Oncology online). Discussion In this large cohort study, old age at diagnosis was associated with higher risk of prostate cancer death even after adjustment for cancer characteristics, primary treatment, year of diagnosis, mode of detection and comorbidity. In analyses stratified by treatment, old age was associated with a higher risk of prostate cancer death among men treated with radical prostatectomy, deferred treatment or androgen depravation therapy, but not among men treated with radiotherapy. A main concern in this and other observational studies investigating the association between age at prostate cancer diagnosis and prognosis is selection bias and confounding by indication. Ideally, treatment selection is based on cancer characteristics, life expectancy based on chronological age, comorbidity and patient preference. Several studies have, however, reported under-treatment of old men with prostate cancer [8–10]. Likewise, in this study, we found substantial differences in baseline characteristics, treatment patterns and pretreatment workup by age at diagnosis. Taken together, biases stemming from these sources are difficult to fully control for. Hence, although we had high-validity covariate data in this study, residual confounding remains a concern. Few contemporary studies have specifically studied age at diagnosis as a prognostic factor for men with prostate cancer. Bechis et al. found poorer prognosis with increasing age at diagnosis in 11 790 men in CaPSURE treated with radical prostatectomy, radiotherapy, watchful waiting or primary androgen deprivation therapy for localized prostate cancer [8]. Contrasting to our finding, however, the association disappeared after adjustment for treatment. There are differences between the CaPSURE study and our study that may explain the contrasting findings, including patient selection (the CaPSURE study only included localized disease and is not population based) and statistical power (our study was about 10 times larger). Importantly, the CaPSURE study did not present results stratified by treatment. In our cohort, the risk of prostate cancer death increased stepwise with increasing age at diagnosis in men treated with radical prostatectomy. Results from prior studies are mixed and appear to differ between population-based studies and institutional series. In a SEER study including 160 787 men treated with radical prostatectomy, old age at diagnosis was associated with higher prostate cancer death rates [7]. In most [13, 22–25], though not all [11, 26], institutional series of men treated with radical prostatectomy, older age at diagnosis was not associated with poorer prognosis. A possible explanation for these divergent findings is that institutional series, in contrast to registry-based studies, typically adjust for pathological rather than preoperative tumor characteristics, thereby indirectly adjusting for upstaging and upgrading. We did not find support for this notion in our study; in sensitivity analyses, adjusting for pathological instead of preoperative stage and grade, the results remained. Another possible explanation is that older men treated with radical prostatectomy at major institutions undergo more extensive preoperative workup and/or are a select and homogenous group of men with a more favorable prognosis. We observed no association between age at diagnosis and prostate cancer death among men treated with curatively intended radiotherapy. These results argue against the notion that tumors in old men are inherently more aggressive. Results from prior studies are mixed. In a SEER study including 149 967 men treated with radiotherapy, older age at diagnosis was associated poorer prognosis among men with low- or intermediate-risk disease, but less so among men with high-risk disease [7]. Institutional radiotherapy series have reported older age at diagnosis to be associated with poorer prognosis [27], unassociated [28, 29] or better prognosis [30]. The divergent finding in our cohort between men treated with radical prostatectomy versus radiotherapy can, aside from chance, be explained by at least two different, nonmutually exclusive mechanisms: (i) older versus younger men treated with radical prostatectomy undergo less extensive preoperative workup and/or are a select group of men with more advanced and aggressive cancer and (ii) radical prostatectomy is less effective in older versus younger men. In support of the first explanation, our data indicate that a rather large proportion of older men treated with radical prostatectomy, especially men with high-risk tumors, did not undergo appropriate preoperative workup/imaging. Moreover, our data indicate that older versus younger men treated with radical prostatectomy generally have worse cancer characteristics. The second explanation is line with the results from the SPCG4 trial [4], which found less treatment effect of radical prostatectomy in men aged ≥65 versus <65 years. The recently published updated results from the PIVOT trial did however not replicate this finding, arguing against the hypothesis that radical prostatectomy is less effective in older versus younger men [6]. The ProtecT trial did also not find any treatment differences by age, but was limited to men aged 50–69 years and had low power [5]. Among men undergoing deferred treatment in our cohort, old age at diagnosis was associated with substantially poorer prognosis. Speculatively, this association could be caused a high proportion of young men on active surveillance subsequently receiving curative treatment [30]. Alternatively, a larger proportion of old men with aggressive cancer receive watchful waiting compared with younger men with less aggressive cancer [30]. Other contributing factors may be that old men receive less aggressive treatment at disease progression. Among men treated with androgen deprivation therapy, we also observed higher risk of prostate cancer death among men above age 75. As for men undergoing deferred treatment, this may be explained by older men being frailer and/or receiving less aggressive secondary treatment. Strengths of this study include its population-based design, virtually complete follow-up, large sample size and well-annotated covariate data. The main limitation lies in the observational study design, as discussed above. Additional limitations include the lack of data before 2008 distinguishing active surveillance from watchful waiting, and lack of data on secondary treatment and pathological stage and grade. Conclusion In conclusion, the possible selection mechanisms among older versus younger men in the radical prostatectomy and deferred treatment groups discussed above, combined with the null-association between age at diagnosis and prognosis after radiotherapy, argue against a strong inherent effect of age on risk of prostate cancer death as the explanation for our findings. Rather, our findings indicate that in current clinical practice, old men with prostate cancer receive insufficient diagnostic workup and subsequent curative treatment. Stronger adherence to guidelines on workup and treatment of prostate cancer is warranted also in old men, in particular given the strong increase in life expectancy. Acknowledgements This project was made possible by the continuous work of the National Prostate Cancer Register of Sweden (NPCR) steering group: Pär Stattin (chairman), Anders Widmark, Camilla Thellenberg, Ove Andrén, Eva Johansson, Ann-Sofi Fransson, Magnus Törnblom, Stefan Carlsson, Marie Hjälm Eriksson, David Robinson, Mats Andén, Johan Stranne, Jonas Hugosson, Ingela Franck Lissbrant, Maria Nyberg, Göran Ahlgren, René Blom, Calle Walller, Per Fransson, Fredrik Sandin and Karin Hellström. Funding The Swedish Research Council (825-2012-5047); The Swedish Cancer Society (16 0700); Uppsala County Council (no grant number applies). Disclosure The authors have declared no conflicts of interest. References 1 Droz JP, Aapro M, Balducci L et al.   Management of prostate cancer in older patients: updated recommendations of a working group of the International Society of Geriatric Oncology. Lancet Oncol  2014; 15: e404– e414. 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Annals of OncologyOxford University Press

Published: Feb 1, 2018

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