An Update of the European/ Swedish Screening Trials
Per-Anders Abrahamsson MD, PhD, Professor Department of Urology Lund University, Malmö, Sweden Secretary General of EAU 2007–2015
27th Interna onal Prostate Cancer Update (IPCU), Colorado, 2017 Disclosures
• FERRING Pharmaceu cals A/S • CAMURUS AB, Sweden • CERNELLE AB; Sweden • GOAR HOLDING AS, Norway 3 large-scale randomized trials addressing the effec veness of Prostate-Specific An gen (PSA) screening on prostate cancer mortality • Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) • European Randomised Study of Screening for Prostate Cancer (ERSPC) • Göteborg Randomised Popula on-Based Prostate Cancer Screening Trial (Göteborg)
Andriole GL, et al. New Engl J Med. 2009;360(13):1310-9. Schröder FH, et al. New Engl J Med. 2009;360(13):1320-8. Hugosson J, Carlsson S et al. Lancet Oncol. 2010;11:725-32. History of ERSPC
• Ini ated by Prof. Fritz H. Schröder (The Netherlands) in the early 1990’s
1991-1993 – Netherlands and Belgium 1995-1996 – The Göteborg trial (Sweden) led by Prof. Jonas Hugosson started as an independent trial with N=20,000 men ages 50–69; it joined ERSPC in 1996 with men in the core age group 55–69 1996 – Finland, Spain, Italy, Switzerland 2002 – France
• 8 European countries • 162,388 men aged 55–69 were randomized • Study is s ll ongoing (2017), with support from EAU • Now led by Prof. Jonas Hugosson
Schröder FH, Roobol MJ. Eur Urol. 2010;58(1):46-52. ERSPC trial shows 21% reduc on in cancer deaths at 13 years
NNI = number needed to invite to screening to save one man from dying from prostate cancer
NND = number needed to diagnose to save one man from dying from prostate cancer Schröder, et al. Lancet. 2014;384(9959):2027-35. Prostate cancer deaths reduced by ≈ 40% at more than 14 years follow-up in Göteborg trial
Hugosson J, Carlsson S et al. Lancet Oncol. 2010;11:725-32. • Prostate cancer incidence: – HR 5.2 in year 1 à 1.1 during follow-up • Prostate cancer mortality: – Screening: 0.98% – Control: 1.50% HR 0.65, 95% CI 0.49-0.87 = 35% rela ve risk reduc on • Even if the rela ve difference in mortality is decreasing between the arms with longer follow-up, the prostate cancer incidence difference is also decreasing. • This together with an increased absolute difference in prostate cancer mortality results in more favorable outcome measures: NNI=231 and NND=10.
Arnsrud Godtman R, et al. Abstract presented at EAU annual mee ng in Munich 2016. No evidence of a prostate cancer mortality benefit for organized versus opportunis c screening at 15 years in the PLCO trial
Screening group
Control group
RR PCDx: 1.27 (95% CI, 1.20-1.35) RR PCSM: 1.04 (95% CI, 0.87-1.24) # prostate cancer deaths
Years from randomiza on Pinsky P, et al. Cancer. 2016. In press. Substan al PSA tes ng in the control arm of PLCO
•~90% of control par cipants had at least one PSA test before/during the trial (Shoag, 2016) •86% of the men in the control arm and 99% of the men in the interven on arm received any PSA tes ng during the trial (15 years of follow-up) (Pinsky, 2016) •Yearly PSA tes ng rates were 46% and 84%, respec vely (Pinsky, 2016)
Shoag J et al. N Engl J Med. 2016:374;18. Pinsky P et al. Clin Trials. 2010;7:303. Andriole GL, et al. JNCI. 2012;104(2):125-32. Pinsky P, et al. Cancer. 2016 In press. PSA tes ng in Europe/Sweden was low at study start
• Na onal guidelines do not recommend PSA screening • Only 3% pre-screened in the Göteborg trial • Exposure to PSA-tes ng increased over me; PSA uptake in men aged 55 to 69 years increased from 0 to 56% between 1997 and 2007 in Sweden in general • 40% of the cancers in the control group in Göteborg were diagnosed through opportunis c screening in asymptoma c men at 18 years of follow-up
Hugosson J, et al. Lancet Oncology. 2010;11(8):725-32. Schröder F, et al. Eur Urol. 2010; 58:46-52. Jonsson H, et al. Int J Cancer. 2014;106(3):dju007. Arnsrud Godtman R, et al. Eur Urol. 2015;68(3):354-60. Organized PSA-tes ng in Göteborg reduces the risk of dying from prostate cancer but increases the number of cancers detected
PROSTATE CANCER INCIDENCE
Göteborg screening arm Göteborg control arm = =organized opportunis c
overdiagnosis
no screening no screening
Arnsrud Godtman R, et al. Eur Urol. 2015;68(3):354-60. Opportunis c PSA-tes ng has li le -- if any -- effect on prostate cancer mortality at 18 years and results in overdiagnosis
PROSTATE CANCER MORTALITY
No effect on no screening no screening prostate cancer mortality organized opportunis c
Arnsrud Godtman R, et al. Eur Urol. 2015;68(3):354-60. Almost twice the number of men needed to be diagnosed to save one man from dying from prostate cancer with opportunis c screening compared to organized screening
18 years of Organized screening Opportunis c screening follow-up vs. no screening vs. no screening NNI 139 493 (95% CI 107 to 200) (95% CI 213 to -1563) NND 13 23
NNI = number needed to invite to screening to save one man from dying from prostate cancer NND = number needed to diagnose to save one man from dying from prostate cancer
Arnsrud Godtman R, et al. Eur Urol. 2015;68(3):354-60. Possible reasons why Göteborg trial show a large reduc on in prostate cancer mortality
• Younger men at start – median age 56 at baseline; 60 in ERSPC • Lower PSA-threshold for prostate biopsy – ≥ 2.5-3 ng/mL; ≥ 3-4 ng/mL in ERSPC • More intense screening – every 2 years; 4-7 years in ERSPC (although less intense as PLCO=annual) • Long dura on of screening – every 2 years from ages 50-64 up to the age of 70 (median 10 years) • High biopsy compliance – 93%; 30-40% in PLCO • Limited contamina on • Long reported follow-up – 14-18 years
Hugosson J, Carlsson S et al. Lancet Oncol. 2010;11:725-32. Schröder FH, et al. Lancet. 2014;384(9959):2027-35.
• Screened group =1,756 par cipants in the screening arm of the Göteborg trial (screened every 2 years) • Unscreened group = 1,162 unscreened men par cipa ng in the Malmö Preven ve Project in 1974-86, with PSA levels measured retrospec vely in stored blood samples
Carlsson S, et al. BMJ 2014:348:g2296. The ra o of benefits to harms of PSA screening varies no ceably with blood PSA levels at age 60
• Median PSA at age 60 is ~1.0 ng/mL • For men with PSA < 2 ng/mL (72% of the popula on) at age 60, con nued screening lead to a large increase in prostate cancer incidence, but no decrease in mortality over 15 years of follow-up • For men with PSA ≥ 2 ng/mL at age 60, con nued screening was associated with a large reduc on in cancer death; NNI=23 and NND=6
Carlsson S, et al. BMJ 2014:348:g2296. Star ng regular screening at ages 50-54 reduced prostate cancer mortality by 71% at 17 years compared to no screening
71% ↓ @ 17 yrs
NNI 176 Unscreened NND 16 (Malmö Preven ve Project, Sweden)
Screened (Göteborg screening arm, Sweden)
N=3479 screened (50-54) Prostate cancer mortality N=4060 unscreened (51-55) PSA ≥3 ng/mL cut-off for biopsy RR PCDx: 2.56 (95% CI 2.18-3.02); 15% vs. 6.3% RR PCSM: 0.29 (95% CI 0.11-0.67); 0.2% vs. 0.8% ARR PCSM: 57 fewer PC deaths / 10,000 men (95% CI 22-92) Carlsson S, et al. Eur Urol. 2017;71(1):46-52. The Stockholm-3 (STHLM3) study was innova ve in tes ng a mul plex ,“next-genera on”, one- me, screening strategy
• Stockholm, Sweden • N=145,905 men • Age 50-69 • Paired, screen- posi ve design • Non-inferiority • PSA ≥ 1 • 10% STHLM3 risk of high- grade PC = equal sensi vity to PSA ≥ 3 ng/mL
Grönberg H, et al. Lancet Oncol. 2015;16:1667-76. Eklund M, et al. Nat Rev Clin Oncol. 2016;13:394. Consistent with prior observa ons (PHI, 4Kscore), adding kallikrein markers to the STHLM3 model improves predic ons of high-grade prostate cancer over PSA alone
It is unclear whether the gene c score adds predic ve value to the protein markers, since it was added to the stepwise model before the markers
Feasibility of DRE and TRUS- volume as screening tools? No repeat screening? Carlsson S, Ka an M. Nat Rev Clin Oncol. 2016;13(3):140-2. Grönberg H, et al. Lancet Oncol. 2015;16:1667-76. Eklund M, et al. Nat Rev Clin Oncol. 2016;13:394. The STHLM3 test reduced overdiagnosis by 17% and unnecessary biopsies by 32%
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Number of high-grade cancers caught/missed by the model compared to PSA alone not reported (due to the paired design) Grönberg H, et al. Lancet Oncol. 2015;16:1667-76. Eklund M, et al. Nat Rev Clin Oncol. 2016;13:394. Summary of an update of the European/Swedish screening trials • With longer follow-up in the trials, the effect of regular PSA- based screening on significantly reducing prostate cancer mortality is sustained • NNI and NND become favorable with longer follow-up • Screening should not start too late in life (likely no later than 55) • Regular, organized, screening may be more beneficial than opportunis c screening in terms of net benefit • Screening can be risk-stra fied, taking into account a man’s age, PSA-levels, and general health to determine who, when and how o en to screen I appreciate your a en on!!!