PROSTATE CANCER

I. Pathophyiology and natural history

  1. Frequency of latent prostate Ca is fairly constant across populations
  2. 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
  3. Primary risk factor is age, also family hx
  4. 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. 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%; in men with PSA levels < 0.6 the prevalence was 7%; in men with PSA levels 3.1-4.0, it was 27% (NEJM 350:2239, 2004--JW)
    3. Pre-treatment rate-of-rise in PSA of > 2ng/mL/yr was ass'd with sig. greater risk fo 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)
    4. 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)
    5. In a study in 77,000 men 55-74yo randomized to (annual PSA x 6y + digital rectal exam x 4y) vs. no screening, there was no sig. diff. in 10y incidence of overall mortality or mortality attributed to prostate Ca ("PLCO" trial; NEJM 360:1310, 2009-JW)
    6. 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)
    7. Elevated BMI is associated with lower PSA levels, possibly from larger plasma volume and hemodilution (JAMA 298:2275, 2007--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. 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. Finasteride
    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)
  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)
    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 gree 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. 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)
    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)

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)