Radiation Oncology/Prostate/Screening and Prevention

Prostate Cancer Screening and Prevention

Screening

Randomized

• Prostate, Lung, Colorectal, and Ovarian (PLCO) Screening Trial (1993-2001) -- screening vs usual care
  • Randomized. 76,693 men at 10 U.S. centers. Arm 1) Annual PSA screening x6 years and DRE x4 years vs. Arm 2) usual care. Compliance in Arm 1 85% for PSA and 86% for DRE. Rate of control group screening ("contamination"): PSA screening 40-52% and DRE screening 41-46% by year
  • 2009 PMID 19297565 -- "Mortality results from a randomized prostate-cancer screening trial." (Andriole GL, N Engl J Med. 2009 Mar 26;360(13):1310-9. Epub 2009 Mar 18.)Median F/U 7 years
    • Outcome: PCA incidence screening group 116/10,000 vs control group 95/10,000 (RR 1.1, SS). Death from PCA 2/10,000 vs 1.7/10,000 (RR 1.13, NS)
    • Conclusion: After 7 years, rate of death from PCA is very low, and not different between groups
  • 2011 PMID 21041707 -- "Comorbidity and Mortality Results From a Randomized Prostate Cancer Screening Trial." (Crawford ED, J Clin Oncol. 2011 Feb 1;29(4):355-361 .)
    • f/u 10 yrs. 9565 deaths, 164 from PCA. In men with no or minimal comorbidity, the decrease in PCA-specific mortality associated with screening was significant (22 v 38 deaths)(NNTT = 5 pts to prevent 1 death at 10 years). In men with at least 1 significant comorbidity, no decrease in PCSM with screening. (62 v 42 deaths; AHR=1.43; p=0.08).
    • Conclusion: selective use of PSA screening in men with good health appears to reduce the risk of PCSM with minimal overtreatment.

• European Randomized Study of Screening for Prostate Cancer (ERSPC) (1991-2003) -- screening vs no screening
  • Randomized. 162,387 men, different enrollment strategies in different countries. Age 55-69. Arm 1) PSA screening (DRE and other studies per country; interval per country) vs. Arm 2) no screening. Treated with watchful waiting (15%), surgery (28%), RT (17%), RT+ADT (10%), ADT alone (10%)
  • Lead Time Bias; 2003 PMID 12813170 -- "Lead times and overdetection due to prostate-specific antigen screening:estimates from the European Randomized Study of Screening for Prostate Cancer. (Draisma G, J Natl Cancer Inst. 2003 Jun 18;95(12):868-78.)
    • Model. 42,376 men enrolled at Rotterdam for ERSPC, with 1498 cases of PCA.
    • Outcome: Mean lead time bias depends on age at screening. At 55, mean lead time bias 12.3 years and overdetection rate of 27%. At 75, mean lead time bias 6.0 years and 56%. For a screening program with 4-year interval from age 55-67, estimated mean lead time 11.2 years with overdetection rate 48%. Lifetime prostate risk raised from 6% to 11%
    • Conclusion: Model-based lead-time estimates supports screening interval >1 year
  • 9-years; 2009 PMID 19297566 -- "Screening and prostate-cancer mortality in a randomized European study." (Schroder FH, N Engl J Med. 2009 Mar 26;360(13):1320-8. Epub 2009 Mar 18.) Median F/U 9 years
    • Outcome: PCA incidence screening 8% vs control 5%. Death from PCA 3.5/10,000 vs 4.1/10,000 (RR 0.8, SS), rates began to diverge after 8 years; absolute difference 0.07%. NNS 1410:1, NNT 48:1
    • Conclusion: PSA-based screening reduced PCA death by 20%, but was associated with a high risk of overdiagnosis

• Quebec LUPCSP (1988) -- Screening vs control
  • Randomized, 2:1. 46,486 men randomized, true screened 7,348 vs true unscreened 14,2341. Arm 1) annual screening (PSA and DRE) vs Arm 2) control
  • 2004 PMID 15042607 -- "Screening decreases prostate cancer mortality: 11-year follow-up of the 1988 Quebec prospective randomized controlled trial." (Labrie F, Prostate, 2004 May 15;59(3):311-8.). Median F/U 7.9 years
    • Outcome: PCA death screened 0.1% vs. unscreened 0.5% (RR 0.4, SS)
    • Conclusion: Screening showed a 62% reduction in cause-specific mortality, but the absolute benefit was small

Case-control

• Veterans Affairs; 2006 PMID 16401808 — "The effectiveness of screening for prostate cancer: a nested case-control study." Concato J et al. Arch Intern Med. 2006 Jan 9;166(1):38-43.
  • Case control study. 71,000 men in 10 VA hospitals. 501 pts dx with prostate cancer between 1991-95 and died by 1999. Compared with controls.
  • No difference in rate of a screening PSA +/- DRE between cases (14%) and controls (13%)
  • Conclusion: screen does not reduce mortality

Prevention

• REDUCE Trial -- dutasteride vs placebo
  • Randomized. 6729 men, at increased risk for prostate cancer (50-75 years old, PSA 2.5-10.0, one negative biopsy within 6 months). Arm 1) dutasteride 0.5 mg vs Arm 2) placebo. Primary endpoint: PCA on biopsy at 2 and 4 years
  • 2010 PMID 20357281 -- "Effect of dutasteride on the risk of prostate cancer." (Andriole GL,N Engl J Med. 2010 Apr 1;362(13):1192-202.)
    • Outcome: incidence of cancer dutasteride 20% vs placebo 25% (SS, risk reduction 28%). No difference in GS 7-10; less GS 8-10 in dutasteride group. But during years 3 & 4, 12 tumors GS 8-10 the dutasteride group, only 1 in placebo group (SS).
    • Toxicity: dutasteride improved acute urinary retention (2% vs 7%, SS), but had higher cardiac failure (0.7% vs 0.4%, SS)
    • Conclusion: Dutasteride reduced risk of prostate cancer and improved BPH symptoms

• SELECT Trial (2001-4) - Selenium and Vitamin E Cancer Prevention Trial
  • 35,533 men, multinational North American (US, Canada, Puerto Rico) - enrolled men 55 yrs or older (or 50 if African American), no prior prostate cancer, PSA < 4, negative DRE. Randomized to selenium (200 µg/d from L-selenomethionine), vs vitamin E (400 IU/d), or both; placebo-controlled. F/U every 6 months; recommended annual PSA and DRE. Pt self-reported prostate cancer events.
  • Median age 62.
  • PMID 19066370, 2009 -- "Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT)." (Lippman SM, JAMA. 2009 Jan 7;301(1):39-51.)
    • Median f/u 5.5 yrs. No difference in rate of prostate cancer: 5 yr rate 4.43% (placebo), 4.56% (Se), 4.93% (E), 4.56% (Se+E).
  • Conclusion: Selenium, vitamin E, or both (at the tested doses and formulations) did not prevent prostate cancer

• Prostate Cancer Prevention Trial (1994-1997)
  • 18,882 men, multicenter - enrolled men age 55 or older with normal DRE, PSA < 3.0, no medical comorbidities, and AUA score < 20. Randomized to finasteride 5 mg/day vs placebo x 7 yrs (planned). Pts followed with annual DRE and annual PSA. Planned end of study biopsy (min. 6 cores). Biopsy also recommended if abnormal DRE or PSA > 4.
  • PSA values were adjusted for men in finasteride group (initially, adjusted PSA = 2.0 x PSA, but changed to 2.3 at man's fourth year); this was done to ensure a biopsy rate that is approximately equal between the groups.
  • PMID 12824459, 2003 — "The influence of finasteride on the development of prostate cancer." Thompson IM et al. N Engl J Med. 2003 Jul 17;349(3):215-24.
    • Study terminated early in 2003, 15 months before planned end of trial, due to study objective being met.
    • Analysis based on 86.3% of pts who completed 7 yrs by the termination date. Prostate cancer status known (i.e. end of study biopsy completed or interval prostate cancer diagnosis) in 9989 pts (59.6% fin, 63.0% placebo). 9060 pts included in final analysis (excluding pts who had end of study biopsy performed late).
    • Rate of prostate cancer diagnosis: 803(18.4%) F vs 1147(24.4%) P; risk reduction of 24.8%. 45-50% of prostate cancer was diagnosed at end of study biopsy rather than for increased PSA. High grade (Gleason score 7-10) in 280 of 757 graded tumors (37%) of F vs 237 of 1068 (22.2%) of P; RR = 1.67 for high grade.
    • Treatment temporarily discontinued due to side effects in 18.3% of men in F group (vs 9.9% for P).
  • Conclusion: Lowers the risk of prostate cancer by 24.8%. However, the finasteride group developed an increased proportion of patients with high grade tumors (Gleason 7-10).