Radiation Oncology/Prostate/Screening and Prevention

Prostate Cancer Screening and Prevention

Screening

ASCO Clinical Opinion

• 2012 PMID 22802323) -- "Screening for prostate cancer with prostate-specific antigen testing: american society of clinical oncology provisional clinical opinion." (Basch E, J Clin Oncol. 2012 Aug 20;30(24):3020-5. Epub 2012 Jul 16.)
  • In men with a life expectancy ≤ 10 years (Social Security Calculator), it is recommended that general screening for prostate cancer with toalPSA be discouraged, because harms seem to outweigh potential benefits
  • In men with a life expectancy >10 years, it is recommended that physicians discuss with their patients whether PSA testing for prostate cancer screening is appropriate for them. PSA testing may save lives but is associated with harms, including complications from unnecessary biopsy, surgery or radiation treatment
  • It is recommended that information written in lay language be available to clinicians and their patients to facilitate the discussion of the benefits and harms associated with PSA testing before the routine ordering of a PSA test

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
  • 12-years; 2012 (metastatic disease) PMID 22704366 PDF -- "Screening for prostate cancer decreases the risk of developing metastatic disease: findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC)." (Schröder FH, Eur Urol. 2012 Nov;62(5):745-52.)
    • M+ prostate cancer detected in 256 men screening group vs 410 controls; cumulative incidence of 0.67% vs 0.87% per 1000 men; relative reduction of 30% (intention to screen; 42% for those actually screened). Absolute risk reduction 3.1 per 1000 men screened (0.31%)
    • Conclusion: "PSA screening significantly reduces the risk of developing metastatic PCa."

• 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).