Results from 22 years of Followup in the Göteborg Randomized Population-Based Prostate Cancer Screening Trial.

PURPOSE: Our goal was to analyze results from 22 years of followup in the Göteborg randomized prostate cancer (PC) screening trial.
MATERIALS AND METHODS: In December 1994, 20,000 men born 1930-1944 were randomly extracted from the Swedish population register and were randomized (1:1) into either a screening group (SG) or to a control group (CG). Men in the SG were repeatedly invited for biennial prostate specific antigen testing up to an average age of 69 years. Main endpoints were PC incidence and mortality (intention-to-screen principle).
RESULTS: After 22 years, 1,528 men in the SG and 1,124 men in the CG had been diagnosed with PC. In total, 112 PC deaths occurred in the SG and 158 in the CG. Compared with the CG, the SG showed a PC incidence rate ratio (RR) of 1.42 (95% CI, 1.31-1.53) and a PC mortality RR of 0.71 (95% CI, 0.55-0.91). The 22-year cumulative PC mortality rate was 1.55% (95% CI, 1.29-1.86) in the SG and 2.13% (95% CI, 1.83-2.49) in the CG. Correction for nonattendance (Cuzick method) yielded a RR of PC mortality of 0.59 (95% CI, 0.43-0.80). Number needed to invite and number needed to diagnose was estimated to 221 and 9, respectively. PC death risk was increased in the following groups: nontesting men, men entering the program after age 60 and men with >10 years of followup after screening termination.
CONCLUSIONS: Prostate specific antigen-based screening substantially decreases PC mortality. However, not attending, starting after age 60 and stopping at age 70 seem to be major pitfalls regarding PC death risk.

control group

European Randomized Study of Screening for Prostate Cancer

number needed to diagnose

number needed to invite

prostate cancer

Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial

prostate specific antigen

rate ratio

screening group

Reports from the European Randomised Study of Screening for Prostate Cancer (ERSPC) have shown that variations in the screening-algorithm between different centers have a large impact on the efficacy of screening.[1-3] Within the ERSPC (where the Göteborg Trial is one center), there were differences in start and stop age, screening interval, program duration and treatments given.[4] Attempts have been made to analyze how the design of a screening program can be improved to enhance efficacy and specificity for clinically significant tumors (ie reduce mortality and decrease over detection). However, those studies have been based either on a short followup or microsimulation modelling.[5,6]

Here, we report results from 22 years of followup in the Göteborg randomized prostate cancer (PC) screening trial. Our study also focuses on pitfalls within the current screening design to elucidate how PC screening may be improved.

Material and Methods

Selection and Description of Participants

The Göteborg Randomized Population-Based Prostate Cancer Screening Trial was initiated in 1995 after approval by the Ethics Committee of the University of Göteborg, Sweden (ID No. 2019-00814). The study protocol has been described in previous publications and the trial profile is presented in Figure 1.[4,7] Since 1996, this trial has constituted the Swedish section of the ERSPC (registration No. ISRCTN54449243).

Figure 1.

Flow chart, 22 years of screening. FU, followup.

On December 31, 1994 the Swedish population register showed that 32,298 men born between January 1, 1930 and December 31, 1944 lived in the city of Göteborg. From this population, 10,000 men were randomized to a screening group (SG) and 10,000 to a control group (CG). After randomization, 106 men were excluded: 55 men with prevalent PC and 51 men who had emigrated or died before randomization.

Men assigned to the SG were invited to take prostate specific antigen (PSA; DELFIA Prostatus total/free PSA-assay; Perkin-Elmer, Turku, Finland, PMID 7543033) every second year until they reached the stop age (median 69 years, range 67–71). The oldest cohort (born 1930–1931) was invited 3 times and the youngest (born 1944) 10 times.

Participants with PSA above the corrected WHO cut-off level (3.4 ng/ml in 1995–1998, 2.9 ng/ml 1999–2004 and 2.5 ng/ml after 2004) were further invited to a clinical assessment including prostate biopsy. Men with PSA below the cut-off level or a benign biopsy were re-invited after 2 years. Men in the CG were not invited for PSA screening but were subject to opportunistic PSA testing. The final (10th) screening round was completed in 2014. Only minor changes were made in the screening algorithm during the study period.[8] The database was regularly updated through linkage with the Swedish Population Register and the Regional Cancer Register of Western Sweden to provide information on vital status, dates for moving outside the Western Region (censoring date) and PC diagnoses. For men with PC, all medical documentation was collected to establish tumor stage/grade at diagnosis, disease course and treatment(s) received. An independent committee determined cause of death according to a flow chart after analyzing all medical data.[9] The group allocation was blinded to the members of the committee.

The last date of followup for the present report was December 31, 2016. Men in the SG were classified as attenders (attended at least once) or nonattenders (never attended). Men with a PC diagnosis were further divided into subgroups based on how they were detected (screen-detected, nonscreen detected or after stop-age; Fig. 1).

Statistical Analysis

The primary endpoints of the investigation were PC incidence and mortality, analyzed as intention-to-screen, comparing the 2 study arms. Comparisons were made between the groups in terms of rate ratios (RRs) and risk ratios (ratios of number of events per person-years and per man, respectively). Furthermore, cumulated incidences were calculated using the Kaplan-Meier approach. Competing risk estimates of cumulative incidence were calculated as described by Choudhury et al.[10] Adjusted rate RRs for PC mortality were calculated with correction for nonparticipation in the SG, in accordance with the method described earlier.[11] Comparisons of age, PSA at diagnosis, time to PC diagnosis and PC death are based on bootstrapping (the percentile method, 1,000 samples).

Number needed to invite (NNI) for screening to prevent 1 PC death was calculated as 1 divided by the absolute risk reduction in PC mortality. Number needed to diagnose (NND) was calculated as 1 divided by the absolute risk reduction in PC mortality multiplied by the excess incidence.

Results

In the SG, 7,635 men (77%) attended at least once. Altogether, 57,983 invitations were mailed to men in the study arm and 34,646 PSA tests were taken within the study (Table 1). Of the 7,635 men attending the program, 2,672 (35%) had an elevated PSA at least once and 2,525 men (33%) underwent at least 1 biopsy. Invitation to the study led to diagnosis of 1,046 cancers. During 22 years of followup, an additional 482 cancers were diagnosed in the SG, albeit outside the program, resulting in a total of 1,528 cancers in this group. The corresponding number of PC diagnoses in the CG was 1,124. Figure 1 shows the numbers of PC cases and PC deaths in different subgroups of men.

Table 1.

Number and outcome of participants in relation to screening visits

No.	Screening Visit
	1st	2nd	3rd	4th	5th	6th	7th	8th	9th	10th	Total
1st invitation round (1995–1996):
Invited	9,881	―	―	―	―	―	―	―	―	―	9,881
Participating	5,855	―	―	―	―	―	―	―	―	―	5,855
Raised PSA	660	―	―	―	―	―	―	―	―	―	660
PC	144	―	―	―	―	―	―	―	―	―	144
2nd invitation round (1997–1999):
Invited	9,507	―	―	―	―	―	―	―	―	―	9,507
Participating	580	4,681	―	―	―	―	―	―	―	―	5,261
Raised PSA	66	541	―	―	―	―	―	―	―	―	607
PC	15	98	―	―	―	―	―	―	―	―	113
3rd invitation round (1999–2000):*
Invited	8,745	―	―	―	―	―	―	―	―	―	8,745
Participating	460	783	4,034	―	―	―	―	―	―	―	5,277
Raised PSA	79	129	622	―	―	―	―	―	―	―	830
PC	29	23	108	―	―	―	―	―	―	―	160
4th invitation round (2001–2002):
Invited	7,840	―	―	―	―	―	―	―	―	―	7,840
Participating	291	398	651	3,282	―	―	―	―	―	―	4,622
Raised PSA	49	63	124	498	―	―	―	―	―	―	734
PC	13	13	19	87	―	―	―	―	―	―	132
Not invited (passed stop age)	―	―	―	―	―	―	―	―	―	―	867
5th invitation round (2003–2004):
Invited	6,666	―	―	―	―	―	―	―	―	―	6,666
Participating	207	341	428	547	2,591	―	―	―	―	―	4,114
Raised PSA	38	62	54	109	352	―	―	―	―	―	615
PC	10	10	6	20	65	―	―	―	―	―	111
Not invited (passed stop age)	―	―	―	―	―	―	―	―	―	―	1,620
6th invitation round (2005–2006):
Invited	5,754	―	―	―	―	―	―	―	―	―	5,754
Participating	118	188	291	334	470	2,077	―	―	―	―	3,478
Raised PSA	34	34	51	61	104	418	―	―	―	―	702
PC	13	6	14	11	20	81	―	―	―	―	145
Not invited (passed stop age)	―	―	―	―	―	―	―	―	―	―	2,252
7th invitation round (2007–2008):
Invited	4,163	―	―	―	―	―	―	―	―	―	4,163
Participating	68	93	141	230	266	376	1,439	―	―	―	2,613
Raised PSA	20	11	24	42	64	87	294	―	―	―	542
PC	8	3	3	11	10	11	45	―	―	―	91
Not invited (passed stop age)	―	―	―	―	―	―	―	―	―	―	2,895
8th invitation round (2009–2010):
Invited	2,986	―	―	―	―	―	―	―	―	―	2,986
Participating	47	75	86	113	158	182	287	967	―	―	1,915
Raised PSA	16	19	16	21	21	38	61	180	―	―	372
PC	7	3	4	6	5	5	9	42	―	―	81
Not invited (passed stop age)	―	―	―	―	―	―	―	―	―	―	3,598
9th invitation round (2011–2012):
Invited	1,846	―	―	―	―	―	―	―	―	―	1,846
Participating	21	27	40	50	67	109	106	168	539	―	1,127
Raised PSA	5	5	5	9	9	15	27	43	98	―	216
PC	2	2	0	3	2	3	4	9	20	―	45
Not invited (passed stop age)	―	―	―	―	―	―	―	―	―	―	4,264
10th invitation round (2013–2014):
Invited	595	―	―	―	―	―	―	―	―	―	595
Participating	8	6	19	17	18	19	33	34	64	166	384
Raised PSA	0	1	4	4	2	3	6	7	13	37	77
PC	0	1	2	2	0	1	3	3	0	18	30†
Not invited (passed stop age)	―	―	―	―	―	―	―	―	―	―	5,012
Total (1995–2014):
Invitations											57,983
PSA tests											34,646
Elevated PSA tests											5,355
Men with PC											1,052‡
Invitations in men alive not sent due to passed stop age											20,508

Men born between 1932 and 1944 with a total PSA <1 ng/ml in the second screening round were not invited to the third screening round. A total of 1,902 of these men participated in the fourth screening round and have a fictive mean total PSA, which has been calculated retrospectively using the total PSA values from rounds 2 and 4.

Nine with PSA <3 ng/ml.

Six men were diagnosed after they emigrated from the West Region of Sweden and were excluded from the analysis.

Figure 2, A shows the cumulative PC incidence curves. At 22 years, the cumulative incidence was 18.6% in the SG and 14.3% in the CG, an absolute difference of 4.3% (95% CI, 3.1–5.5). Taking competing risk into account reduced the incidence to 15.9% and 11.8% in the SG and CG, respectively.

Figure 2.

A, observed PC incidence up to December 31, 2016 (19,894). B, observed PC mortality up to December 31, 2016 (19,894).

Time from randomization until 10% of men in the SG and CG received a PC diagnosis based on cumulative PC incidence was 11.0 years and 15.8 years, respectively (p <0.001).

Median age at randomization was the same in both groups, 56 (IQR 53–61), while the median age at diagnosis was 66.3 in the SG and 69.2 in the CG (p <0.001). Median PSA at PC diagnosis was lower in men in the SG compared to men in the CG (5.1 vs. 8.6 ng/ml, p <0.001). Table 2 shows the difference in tumor risk group distribution and treatments between the 2 study arms.

Table 2.

Risk group classification and primary treatment of cancers detected

	CG (1,124 PC detected)					SG (1,528 PC detected)
	All PC	Low Risk PC	Intermediate Risk	High Risk	Advanced	All PC	Low Risk PC	Intermediate Risk	High Risk	Advanced
No. pts	1,114*	269	434	206	136	1,528†	723	510	174	89
No. primary treatment (%):
Prostatectomy	329 (30)	95 (35)	162 (37)	34 (16)	8 (6)	549 (36)	232 (32)	236 (46)	54 (31)	9 (10)
Radiation	118 (11)	11 (4)	43 (10)	52 (25)	2 (1)	118 (8)	40 (6)	47 (9)	30 (17)	0
Surveillance	388 (35)	158 (59)	177 (41)	27 (13)	0	662 (43)	440 (61)	191 (37)	21 (12)	0
Endocrine treatment	268 (24)	5 (2)	48 (11)	91 (44)	122 (89)	184 (12)	4 (1)	33 (6)	66 (38)	79 (89)
Unknown	11 (1)	0	4 (1)	2 (1)	4 (4)	15 (1)	7 (1)	3 (1)	2 (1)	1 (1)
Median yrs age at diagnosis (IQR)	69 (65, 73)	67 (63, 70)	69 (66, 73)	70 (66, 75)	69 (65, 74)	66 (63, 69)	65 (62, 68)	67 (64, 70)	69 (65, 76)	71 (66, 77)
No. T3, T4 PC (%)	―	―	―	69 (33)	81 (60)	―	―	―	67 (39)	58 (65)
No. PC deaths	156	1	22	48	82	112	3	19	31	55

Low risk—T1, not N1 or M1, and GS ≤6 and PSA <10 ng/ml. Intermediate risk—T1-2, but not N1 or M1, with a GS ≤7, PSA <20 ng/ml or both; and not meeting the criteria for low risk. High risk—T1-4, but not N1 or M1, with a GS >8, PSA <100 ng/ml or both; and not meeting the criteria for low or intermediate risk. Advanced—N1 or M1, or PSA >100 ng/ml. Unknown—includes 11 cases detected at autopsy.

Ten men had no treatment (detected on autopsy) and 69 men had unknown risk group in the CG; 5 men who died from PC had an unknown risk group.

In the SG 32 men had unknown risk group; 18 men had prostatectomy, 1 man had radiation, 11 surveillance and 2 men had endocrine treatment.

A total of 112 men died of PC in the SG compared with 158 in the CG (RR=0.71, 95% CI, 0.55–0.91, p=0.005). The cumulative risk of PC death at 22 years was 1.55% in the SG and 2.13% in the CG, an absolute reduction of 0.59% (95% CI, 0.15–1.03; Fig. 2, B). Taking competing risk into account reduced the cumulative mortality to 1.2% and 1.7% in the SG and CG, respectively. Time from randomization until 1% of men in the SG and CG died of PC based on cumulative PC mortality was 18.1 and 15.2 years, respectively (p=0.003). Table 3 shows PC incidence and mortality over the years.

Table 3.

Incidence and mortality rates at 14, 18 and 22 years of followup

	14 Yrs Followup	18 Yrs Followup	22 Yrs Followup
No. men screening/No. control	9,945/9,949	9,945/9,949	9,945/9,949
PC incidence:
No. PC cases screening/No. control	1,136/715	1,390/956	1,528/1,124
Person-yrs screening/person-yrs control	116,925/120,735	141,297/146,569	161,456/168,212
RR (95% CI)	1.64 (1.49, 1.80)	1.51 (1.39, 1.64)	1.42 (1.31, 1.53)
Rate difference per 1,000 person-years (95% CI)	3.79 (3.08, 4.51)	3.31 (2.65, 3.98)	2.78 (2.17, 3.40)
Risk ratio (95% CI)	1.59 (1.45, 1.75)	1.45 (1.34, 1.58)	1.36 (1.26, 1.47)
Risk difference per 1,000 men (95% CI)	42.36 (33.88, 50.84)	43.68 (34.13, 53.22)	40.67 (30.52, 50.82)
Cumulative incidence difference (95% CI)	4.5% (3.6%, 5.5%)	4.7% (3.7%, 5.8%)	4.3% (3.1%, 5.5%)
PC mortality:
No. PC deaths screening/No. control	42/76	77/118	112/158
Person-yrs screening/person-yrs control	124,217/124,139	152,760/152,620	177,091/177,152
RR (95% CI)	0.55 (0.37, 0.82)	0.65 (0.48, 0.88)	0.71 (0.55, 0.91)
RR p value	0.002	0.003	0.005
RR, attender adjusted (95% CI)	0.42 (0.27, 0.68)	0.54 (0.38, 0.77)	0.59 (0.43, 0.80)
RR, attender adjusted p value	<0.001	<0.001	<0.001
Rate difference per 1,000 person-yrs (95% CI)	−0.27 (−0.45, −0.10)	−0.27 (−0.45, −0.09)	−0.26 (−0.44, −0.08)
Risk ratio (95% CI)	0.55 (0.37, 0.82)	0.65 (0.48, 0.88)	0.71 (0.55, 0.91)
Risk difference per 1,000 men (95% CI)	−3.42 (−5.56, −1.28)	−4.12 (−6.87, −1.37)	−4.62 (−7.86, −1.38)
NNI (95% CI)	293 (178, 847)	243 (144, 782)	217 (127, 768)
NND	13	11	9
Cumulative incidence difference (95% CI)	−0.4% (−0.7%, −0.2%)	−0.5% (−0.9%, −0.2%)	−0.6% (−1.0%, −0.1%)
All-cause mortality
No. all-cause deaths screening/No. control	1,956/1,945	2,788/2,782	3,806/3,735
Person-yrs screening/person-yrs control	124,217/124,139	152,760/152,620	177,091/177,152
RR, all-cause mortality (95% CI)	1.01 (0.94, 1.07)	1.00 (0.95, 1.06)	1.02 (0.97/1.07)
Rate difference per 1,000 person-yrs (95% CI)	0.08 (−0.91, 1.06)	0.02 (−0.94, 0.98)	0.41 (−0.55, 1.37)
Risk ratio (95% CI)	1.01 (0.94, 1.07)	1.00 (0.95, 1.06)	1.02 (0.97, 1.07)

For men who died from PC, median age at randomization was 58.5 years (IQR 55.8–62.6) in the CG and 60.7 years (IQR 57.2–63.0) in the SG.

A total of 144 PCs were detected at first invitation (Fig. 1). These cancers were generally more advanced than cases detected during subsequent screening rounds (Table 4). Of the 144 cancers, 80 (56%) occurred in men ≥60 years of age at the time of invitation. Fifteen of those 144 men died of PC and 9 of the 15 (60%) were aged ≥60 years at randomization. Another 97 PCs were diagnosed at delayed first screen but those resulted in only 2 PC deaths. The rate of interval cancers was low and led to very few deaths (4). In men who participated in the program and were diagnosed during followup screens (second–tenth round), PC death rate was also low (13 of 805 PC cases).

Table 4.

Characteristics of subgroups of PC detected in 1,528 patients in the SG

	PC Diagnosed in Attendees*						PC in Nonattendees† (148)
	Detected at 1st Screen “Prevalent Ca” (144)	Delayed 1st Screening (97)	Followup Screening (805)	Interval Ca‡ (57)	Noncompliers§ (64)	Detected after the Screening Period (213)
Median yrs age at randomization (IQR)	59.6 (56.5–62.6)	55.4 (52.8–59.2)	55.1 (51.9–59.0)	57.3 (54.4–60.7)	54.8 (52.8–58.4)	60.0 (57.1–63.1)	57.3 (53.8–61.9)
Median yrs age at diagnosis (IQR)	60.5 (57.4–63.7)	64.4 (61.1–67.2)	65.9 (62.8–67.7)	66.7 (62.5–68.9)	65.6 (62.9–67.8)	76.1 (73.3–78.8)	68.8 (64.1–73.5)
Median yrs from randomization to diagnosis (IQR)	0.9 (0.6–1.2)	6.8 (4.9–10.8)	8.9 (5.4–12.9)	8.8 (5.7–11.0)	8.9 (6.1–12.7)	17.1 (14.3–19.7)	10.3 (5.4–16.6)
Median PSA at diagnosis (IQR)	6.2 (4.0–11.1)	5.5 (4.0–9.2)	4.1 (3.4–5.4)	4.6 (3.6–7.2)	6.5 (4.2–12.0)	10.0 (6.4–22.0)	19.0 (7.6–59.0)
Median free-to-total PSA ratio at diagnosis (IQR)	11.8 (8.6–15.3)	15.2 (11.3–20.7)	19.4 (14.1–24.7)	Not available	Not available	Not available	Not available
No. advanced PC (%)‖	4 (3)	4 (4)	5 (0.6)	4 (7)	3 (5)	28 (13)	41 (28)
No. high risk PC (%)¶	19 (13)	11 (11)	36 (4.5)	3 (5)	5 (8)	57 (27)	43 (29)
No. intermediate risk PC (%)**	59 (41)	32 (33)	247 (30.7)	20 (35)	27 (42)	88 (41)	37 (25)
No. low risk PC (%)††	62 (43)	50 (52)	515 (64)	25 (44)	26 (41)	28 (13)	17 (11)
No. risk category not known (%)	0	0	2 (0.2)	5 (9)	3 (5)	12 (6)	10 (7)
No. PC deaths (%)	15 (10)	2 (2.1)	13 (1.6)	4 (7.0)	5 (7.8)	26 (12)	47 (32)
No. PC deaths within 5 yrs after diagnosis	1	1	3	3	3	22	30
No. PC deaths 5–10 yrs after diagnosis	6	0	6	0	1	3	10
Median yrs from randomization to PC death (IQR)	11.6 (9.2–14.0)	10.5 (8.0–13.1)	15.2 (10.1–17.5)	6.5 (4.6–10.3)	8.6 (8.3–12.8)	18.0 (16.5–20.3)	15.9 (9.7–19.9)
Median yrs from diagnosis to PC death (IQR)	10.7 (8.4–12.8)	6.4 (4.2–8.7)	6.6 (5.7–12.2)	2.5 (1.3–6.1)	4.0 (3.4–7.5)	1.8 (0.9–4.0)	3.8 (1.6–7.7)
Median yrs age at PC death (IQR)	71.8 (70.3–72.7)	68.5 (67.9–69.2)	74.6 (70.8–75.6)	70.8 (69.0–73.4)	68.5 (66.3–74.7)	80.4 (77.0–82.7)	73.4 (70.1–77.5)

Participated in the screening program at least once.

Invited but never participated in the screening program.

Participated in the screening program but diagnosed within 2 years from last screening (outside the program).

Participated at irregular intervals and was later diagnosed outside the screening program >2 years after last screen, or denied biopsy.

PSA ≥100 ng/ml and/or N1 and/or M1.

PSA <100 ng/ml and GS ≥8 and/or T1-T4, not N1, not M1.

PSA 10–99 ng/ml and/or Gleason 7 and/or T2.

PSA <10 ng/ml and GS 3+3 and T1.

In the SG, 213 men were diagnosed more than 2 years after stop age. Median age at time of diagnosis was 76.1 years (IQR 73.2–78.8). Twenty-six of these 213 men (12%) died from PC and 23 of these 26 men left the study with a median PSA of 2.3 ng/ml (IQR 1.6–3.2). Median age at death for these 26 men was 80.4 years (IQR 76.6–82.9).

A total of 2,310 men (23%) in the SG never attended the program and 148 of those were diagnosed with PC. Median age at diagnosis was 68.8 years (IQR 64.1–73.7). PC incidence at 22 years was lower in nonattenders (148, 6.4%) than in both attenders (1,380, 18.1%) and men in the CG (1,124, 11.3%). PC-specific mortality at 22 years was higher in nonattenders (47, 2.0%) than in attenders (65, 0.9%; Fig. 2, B).

Discussion

This report provides evidence that an organized screening program with 22 years of followup reduces PC mortality by ∼30% compared to the concurrent rate of nonorganized opportunistic PSA testing and by ∼40% among men attending at least once. This could not be explained by differences in treatment, which per risk group was similar between the arms (Table 2). The absolute risk difference in PC mortality per man randomized increased over time while the relative difference decreased. The continued decrease in absolute mortality in the screening compared to the CG is reflected in a decreasing NNI, which now is 217. Comparing with other cancer screening programs, this is low and should thus be considered in terms of efficacy when evaluating different general health policies.[12,13] As incidence rates in the 2 arms continue to approach each other, a number of 9 men NND is comparable to that of breast cancer screening.[12] This number may, however, be falsely low due to the high rate of opportunistic screening in the CG. It is also far from the NND of 48, which was initially reported from ERSPC, leading to the fear of an enormous overdiagnosis rate.[2] We now conclude that this was mainly due to a too short followup. As NND keeps declining, even further followup of this trial and other trials is essential. The relative reduction of PC mortality decrease over time is mainly explained by the fact that men in our program stopped screening at an average age of 69 years. Men diagnosed after the stop age constitute a substantial part of PC deaths in the SG. In a previous report, we found that the positive effect of screening on PC mortality disappears approximately 10 years after stop age.[14] As half of all men in the Western world who die from PC are above the age of 80,[15] discontinuing screening for all men at age 70 may be too early. However, the selected stop age must be balanced with increased risk of overdiagnosis associated with screening elderly men.[16,17]

Another result from this study is that men who had their first screening after age 60 had an increased risk of being diagnosed with advanced disease at their first screening visit and later death from PC. The optimal start age for PC screening remains to be evaluated but earlier start of screening does not seem to be associated with a significantly higher risk of overdiagnosis.[18] A third result from this study is the doubled mortality rate in men who did not attend screening compared to those who attended (2.0% versus 0.9%). As these men also have a higher overall mortality,[14] their “true” RR will be even higher. On the other hand, early deaths prevent potential later attendance—maybe some men were in fact “potential attenders” had they lived longer. Hence, an immortal time bias exists, which makes calculations about nonattenders’ “true” RR difficult.

However, there is a need to more accurately assess whether the decision to decline screening participation is a well-informed one or whether it is based on other factors. A man’s choice should always be respected, yet it is important to identify which factors play major roles in the decision to attend or not.

No association between screening and reduced PC mortality has been found in neither the CAP trial (RR 0.96; 95% CI, 0.85–1.08)[19] nor the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO; RR 0.93, 95% CI, 0.81–1.08).[20] The CAP trial was based on a single screening test. Our data illustrate that the first screening round detects more advanced and incurable cancers, which dilutes differences in PC mortality between the 2 arms. This observation is supported by data from the Finnish branch of the ERSPC.[21] A comparison of our investigation with the PLCO study clearly reveals that the background risk of dying from PC is very different.[20] Considering the CGs, despite the younger age of the CG in our study vs the PLCO study, PC mortality was higher in our study, indicating that opportunistic screening was probably frequent in the PLCO CG, resulting in lower than expected mortality, ie 5.9/10,000 person-years (men aged 55–64) at 17 years of followup in the PLCO study compared to 7.7/10,000 person-years (ages 50–65) at 18 years in our study (Table 3). It seems doubtful that there would be such a large difference in background risk between men in the United States and those in Sweden. A much more likely explanation is that men in the PLCO study were extensively screened before inclusion but also during and after the screening period.[22,23] Interestingly, Shoag and co-authors reported that among the men in the SG within PLCO and who died from PC, 53.6% were either never screened as part of their trial or had an initial positive screen.[24]

Opportunistic PSA testing has increased considerably over the 22-year study period within our study and seems to be even higher compared to contemporary series from Sweden.[25,26] However, the situation at study start was very different from that in the U.S. with approximately 5% of men tested in our cohort before they entered into the study. During the study period, the PC mortality in Sweden has decreased by 40% in men aged 60–79 years.[27] Whether this is explained by earlier diagnosis or better treatment strategies could be discussed[28] but earlier diagnosis and better risk stratification is often a prerequisite for new and more effective treatments so it is difficult to analyze these separately. It is not unreasonable to believe that the high rate of opportunistic screening that has taken place will lead to a gross underestimation of the true effects of PSA screening but also to an underestimation of the rate of overdiagnosis. Hence, even though these unique, long-term followup results make for a strong contribution to the field, indicating that repeated PSA screening yields a reduction in PC mortality, the challenge of overdiagnosis remains unresolved. For that problem, the ongoing Göteborg-2 Study and others will address the more exact effects of specific diagnostic tools.[29]

This study has strengths and limitations. Major advantages include the population-based design, the long and almost complete followup of all randomized men, and the high validity of Swedish Registries.[30] Limitations mainly include the high rate of opportunistic screening in the CG and nonparticipation in the SG diluting the “true” effects of organized PSA screening.

Conclusions

This extended 22-year followup report of the Göteborg screening study provides further evidence of the efficacy of serial PSA testing. With longer followup, the rate of overdiagnosis decreases but the NND of 9 still indicates that overdiagnosis is not negligible. Increasing the adherence to the program, starting before age 60 and not stopping at age 70 for all men may further improve the efficacy with PC screening but should be balanced by the risk of overdiagnosis.