PROSTATE CANCER


I. Epidemiology, pathophyiology and natural history

  1. 2nd most common cause of Ca death in the U.S. (after lung Ca)
  2. Lifetime prevalence of diagnosis about 17%
  3. Risk factors
    1. Age is the primary risk factor
    2. Incidence and mortality are 2-3x higher in African-American men than in non-African American U.S. men
  4. Frequency of latent prostate Ca is fairly constant across populations, but the transition to progressive Ca varies among populations
    1. Migrants from countries w/low rates of prostate Ca tend to assume higher rates of their new home countries, suggesting environmental factors play a role
  5. In a cohort study of 223 pts with early-stage (T0-2NxM0) prostate Ca, tx'd with only hormonal tx (and that only if experienced sx), over mean 21y f/u, 17% developed generalized disease; prostate Ca mortality over this period was 5.9% (JAMA 291:2713, 2004--abst)

II. Screening

  1. Serum prostate specific antigen level (PSA)
    1. Traditional cutoff for further evaluation is 4.0 ng/mL
    2. False-positive elevation of PSA can occur in benign prostatic hyperplasia and prostatitis
    3. False-negative results are also common
      1. Elevated BMI is associated with lower PSA levels, possibly from larger plasma volume and hemodilution (JAMA 298:2275, 2007--JW)
    4. Prevalence of prostate cancer based on PSA level
      1. In a prospective study of 2,950 men 62-91yo followed for 7y, all of whom had normal digital rectal exams and PSA < 4.0ng/mL, and all of whom underwent random prostatic biopsies, overall prevalence of prostate Ca was 15% and... (NEJM 350:2239, 2004--JW):
        • In men with PSA levels < 0.6 the prevalence was 7%
        • In men with PSA levels 3.1-4.0, it was 27%
    5. Studies in impact of PSA for prostate cancer screening
      1. In a prospective study of prostate Ca deaths in Austria, reduction seen in one province 5y after introduction of freely available PSA testing; in other provinces, which didn't have the free testing, prostate Ca mortality remained stable (Reported at AUA, FP News 6/1/00)
      2. In a study in 182,000 men 50-74yo randomized to PSA screening (interval varied by country) vs. no screening, over mean 9y f/u, the incidence of prostate Ca death in the screened group was statistically significantly (though only slightly) lower (absolute risk reduction 7 cases per 10,000 men screened, NNT 1410); no sig. diff. in all-cause mortality ("ERSPC" trial; NEJM 360:1320, 2009-JW)
      3. In a study in 76,693 men 55-74yo with no h/o prostate Ca randomized to screening (annual DRE + PSA testing, with further evaluation for PSA > 4.0 or suspicious DRE) vs. no screening unless done through regular medical care.  Over 7y f/u, there was no sig. diff. in prostate Ca mortality or overall mortality.  Note that the control group still got some PSA screenings (mean 2.7 PSAs during the first 5y of the trial, vs. 5 in the "screening" arm) ("Prostate, Lung, Colorectal, and Ovarian Cancer Screening" ("PLCO") Trial; NEJM 360:1310, 2009-AFP, JW)
        1. In a follow-up report from the PLCO trial extending through 13y for most subjects, the incidences of overall mortality and death from prostate Ca was not sig. diff. between the groups (J. Nat. Ca Inst. 104:125, 2012-JW)
      1. In a meta-analysis of six randomized studies comparing screening vs. no screening of asymptomatic men with no known h/o prostate cancer by PSA with or without digital rectal examination, there was no sig. diff. in all-cause or disease-specific mortality (BMJ 341:c4543, 2010-AFP)
    6. Rate-of-rise of PSA post-treatment as a predictor of prostate cancer recurrence
      1. Pre-treatment rate-of-rise in PSA of > 2ng/mL/yr was ass'd with sig. greater risk of disease recurrence, death from prostate Ca, and all-cause mortality, compared with lower rate-of-rise, in a prospective trial of 1,095 men with localized prostate Ca who underwent radical prostatectomy followed for median 5y (NEJM 351:125, 2004--JW)
  1. In a retrospective study of Swedish men with prostate cancer, those who had localized disease at Dx had similar survival 15-y survival rate (81%) whether or not they received initial aggressive therapy. (JAMA 277:467, 1997)
  1. Free PSA/Total PSA Ratio
    1. In a study of 779 men (about half with prostate Ca, half with benign prostatic disease, 50-75yo) with no nodules on prostate Px and PSA 4-10, a free PSA of < 25% was 95% sensitive for prostate Ca and using that measure as criteria for Bx would avoid 20% of unneccessary biopsies ; those Ca's with free PSA > 25% were "generally less threatening in tumor grade and volume" (JAMA 279:1542, 1998--abst)
    2. In a case-control study of 430 pts with prostate Ca and 1,642 controls, negative predictive value of PSA 4-10 was found to by 75%; negative predictive value of PSA 4-10 & ree PSA > 26% was 92% (J. Urol. 167:2427, 2002--AFP)
  2. Prostate cancer antigen 3 (PCA3) gene
    1. Highly-expressed in prostate Ca cells but not in normal prostate Ca cells even in presence of hyperplasia or prostatitis
    2. Requires urine specimen obtained after vigorous digital rectal exam
    3. Yields a "PCA3 score"
  3. Serum proteomic profiling
    1. Computer analysis of serum proteomic data was found to have 100% sensitivity and 67% specificity compared with transrectal ultrasound-guided biopsy in a study of 154 men with serum PSA 2.5-15.0 ng/mL and/or abnormal digital rectal examination (J. Urol. 172:1302, 2004--abst)

III. Prevention

  1. Vitamin E
    1. 29,000 male smokers 50-69yo randomized to vit. E (alpha-tocopherol) 50mg QD vs. placebo with f/u up to 8y. RR of new dx of prostate Ca was 0.68 and RR mortality was 0.59 with vit. E c/w placebo. Also had an arm w/beta-carotene supplements ass'd with nonsig. increase in prostate Ca incidence and higher mortality. Stat. nonsig. higher incidence of hemorrhagic CVA in vit. E group.(J. Nat. Ca. Inst. 90:440, 1998--UW Pharm Letter)
  2. 5-alpha reductase inhibitors
    1. In a randomized trial in 18,882 men > 55yo randomized to finasteride 5mg PO QD vs. placebo x 7y, incidence of prostate Ca was sig. lower in finasteride recipients (18.4% vs. 24.4%). However, prostate cancer cases among men on finasteride were more likely to be "aggressive" (37% vs. 25%)--Absolute incidence of high-grade Ca was higher in finasteride group (NEJM 349:213, 2003--UW Pharm. Letter)
    2. In a study in 6,729 men 50-75yo with PSA 2.5-10 ng/mL with a negative prostate biopsy in the prior 6mos randomized to dutasteride 0.5mg QD vs. placebo x 4y, the incidence of prostate Ca was sig. lower in the dutasteride recipients (20% vs. 25%; RR 0.77).  Dutasteride recipients had sig. higher incidence of heart failure (0.7% vs. 0.4%).  (NEJM 362:1192, 2010-abst)
  3. Folic acid supplementation-May increase risk!
    1. In a study in 643 men with recently resected colorectal adenomata randomized to folic acid vs. placebo (in a 2 x 2 study design that also compared aspirin vs. placebo), over median 7y f/u, incidence of new prostate Ca diagnosis was sig. higher in folic acid recipients (9.7% vs. 3.3%) ("Aspirin/Folate Polyp Prevention Study" ("AFPPS"); J. Natl. Canc. Inst. 101:432, 2009-JW)
  4. Ejaculatory frequency
    1. In a prospective study in 29,342 men 46-81yo, over 8y f/u, RR of prostate Ca for men who reported > 20 ejaculations per month in the previous year, compared with men who reported 4-7x/month, was 0.49 (sig.) (JAMA 291:15789, 2004--AFP)

IV. Treatment

  1. Options
    1. Radical prostatectomy
      1. Associated with 60% incidence risk of erectile dysfunction and 8.4% risk of incontinence in a prostpective study of 1291 men (JAMA 283:354, 2000--abst)
      2. Prevalence of incontinence at 5y after radical prostatectomy was 15% in one prospective study (J. Nat. Cancer Inst. 96:1358, 2004--JW)
      3. In a cohort study of 600 men s/p robotic-assisted laparoscopic or open prostatectomy for prostate Ca, at mean 14mo s/p surgery, after controlling for potential confounders, robotically-treated pts had sig. higher prevalence of moderate-to-severe urinary incontinence (OR 1.46); no sig. diff. in incidence of sexual dysfunction (J. Clin. Oncol. 30:513, 2012-JW)
    2. External beam radiation therapy (EBRT)
    3. Radioactive implant (brachytherapy)
    4. Androgen suppression therapy (AST)
      1. Bilateral orchiectomy
      2. Antiandrogen pharmacotherapy
        1. Leuprolide--in combination with flutamide may improve survival in pts with metastatic prostate Ca
        2. Flutamide--may not offer any survival benefit in pts with metastatic prostate Ca who have already undergone orchiectomy (NEJM 339:1036, 1998--AFP)
        3. Goserelin, a GNRH agonist
          1. Tx with goserelin ass'd with RR 0.42 for death (sig.) over median 7y f/u, after radical prostatectomy with pelvic lymphadenectomy in 98 men with clinically localized prostate Ca with nodal metastases (NEJM 341:1837, 1999--JW)
        4. LHRH Q4wks x 3y c/w no hormonal therapy was ass'd with sig. higher 5y survival (78% vs. 62%) over median 66mo f/u in a randomized trial in 415 men < 80yo with locally advanced prostate adenocarcinoma (T3-4 or (T1-2 and grade 3)); all pts also had external irradiation  (Lancet 360:103, 2002--AFP)
        5. In a study in 970 men with locally-advanced prostate Ca who showed no evidence of disease progression after 6mos of external beam radiotherapy + androgen-deprivation therapy, randomized to 2.5y of additional androgren-deprivation therapy vs. no additional androgen-deprivation therapy, over median 6.4y f/u, 5y  overall mortality was 15.2% in the active-treatment group and 19.0% in the group that didn't receive long-term androgen-deprivation therapy (apparently the trial statistics weren't structured to test for whether the diff was sig?).  There were no sig. diffs. in incidence of fatal cardiovascular events; the active-treatment group had higher prevalence during treatment of insomnia, hot flashes, and diminished sexual interest, but no sig. diff. in overall quality of life (NEJM 360:2516, 2009-JW)
    5. EBRT + AST vs. EBRT alone
      1. In a randomized trial in 206 pts with clinically localized prostate Ca, EBRT alone vs. EBRT + 6mos of AST, over median 4.5y f/u, combined group had sig. greater 5y survival (88% vs. 78%), prostate Ca-specific mortality, and 5y survival free of salvage (82% vs. 57%) (JAMA 292:821, 2004--abst)
    6. Tumor vaccines
      1. In a study in 127 pts with stage IV prostate Ca refractory to androgen suppression therapy randomized to the tumor vaccine APC8015 (Provenge) c/w placebo had sig. higher 36mo survival (34% vs. 11%) (study reported at Am. Soc. Clin. Oncol., reported in FP News 3/15/05)
    1. 5-alpha-reductase inhibitors
      1. In a study in 320 men with biopsy-confirmed prostate cancer stages T1c-T2a diagnosed in prior 14mos, Gleason score of 6 or lower, and PSA of 11 ng/mL or lower,  undergoing "active surveillance" randomized to dutasteride 0.5mg QD vs. placebo, at 3y, the dutasteride recipients had sig. lower incidence of pathologic or therapeutic disease progression (38% vs. 48%) (Lancet 1/24/2012, e-pub ahead of printing at http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61619-X/fulltext-JW)
  1. A retrospective, nonrandomized study of 60,000 men age 50-79 who had been treated for prostate Ca with either prostatectomy, radiotherapy, or observation followed for a mean of 4y, using an intention-to-treat analysis, found the following re: estimated 10y disease-specific survival; summary didn't mention which differences were statistically significant:
  Prostatectomy Radiotherapy Observation
Grade 1 tumors 94% 90% 93%
Grade 2 tumors 87% 76% 77%
Grade 3 tumors 67% 53% 45%

(Lancet 349:906, 1997-JW)

  1. In a series of 49 men with clinically localized prostate Ca (T1 or T2; Gleason scores 5-6) followed for mean 32mos, the rate of change of serial (us. Q6mo) PSA's didn't correlate significantly with tumor stage, initial PSA, or Gleason score, suggesting that its utility as a marker for progression may be limited (J. Urol. 159:1243, 1998--JW)
  2. In a randomized trial of 695 mean with early prostate Ca randomized to radical prostatectomy vs. watchful waiting; over avg. 6.2y f/u, prostate Ca-related death was sig. lower in surgery group (4.6% vs. 8.9); all-cause mortality nonsig. lower in surgery group (15.3% vs. 17.8%); no sig diff. for overall physical and psychological quality of life (NEJM 347:781, 2002--JW).  Note-In that trial, the pts had organ-confined disease, serum PSA< 50ng/dL, age < 75y, and life expectancy > 10y.  Pts in the surgery group who had local recurrence received hormonal therapy; those in the obsevation group who developed symptomatic bladder outlet obstruction had transurethral prostate resection; and those with metastases were treated with hormonal therapy.
    1. In a follow-up report on the above study, over mean 8.2y f/u, the radical prostatectomy group had sig.lower all-cause mortality (27% vs. 32%) and prostate Ca-related mortality (9.6% vs. 14.9%) (NEJM 352:1977, 2005--AFP)
    2. In a follow-up report on the above study after median 10.8y f/u, overall mortality was not sig. diff. between the two groups but prostate Ca mortality was sig. lower in the surgery group (13.5% vs. 19.5%) as was the incidence of distant metastases (19% vs. 28%). (J. Nat. Ca. Inst. 100:1144, 2008-JW)

    3. In a follow-up report after median 12.8y, mortality was sig. lower in the surgery group (47.8% vs. 57.8%) as was disease-specific mortality (14.6% vs. 20.7%).  On subgroup analysis, the mortality benefit was seen only in pts < 65yo. (NEJM 364:1770, 2011-JW)

V. Post-prostatectomy f/u--Digital rectal exam & routine x-rays to detect bone mets may be superfluous in men with undetectable PSA levels after radical prostatectomy for prostate Ca; in a prospective study of 1,944 such men followed for 14y, no recurrences were noted in men with undetectable PSA levels (J. Urol. 162:1337, 1999--AFP)

(Sources include: AFP 84:413, 2011)