Prostate Prospects

Educational Objectives

The goal of this program is to improve the management and treatment of prostate cancer. After hearing and assimilat­ing this program, the clinician will be better able to:

1.   Discuss the prevention of prostate cancer using the 5-a reductase inhibitor finasteride.

2.   Recommend ideal doses and dosing schedules for patients undergoing radiation therapy for prostate cancer.

3.   Assess advancements in radiation therapy, such as brachytherapy and proton therapy.

4.   Utilize hormone therapy in the treatment of prostate cancer.

5.   Explain the survival benefits and risks associated with radical prostatectomy.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and the planning committee re­ported nothing to disclose. In his lecture, Dr. Beyer presents information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgments

Drs. Crawford and Beyer were recorded at Perspectives in Urology, held November 6-8, 2008, in Scottsdale, AZ, and spon­sored by Grant/Downing Education. The Audio-Digest Foundation thanks the speakers and Grant/Downing Education for their cooperation in the production of this program.

Latest Strategies in Prevention of Prostate Cancer

E. David Crawford, MD, Professor of Surgery, Radiation Oncology, and Urology, University of Colorado, Den­ver, School of Medcicine

Background: study data show increases in vitamin D levels from exposure to sunlight associated with improved prognosis in breast, prostate, and colon cancers; in United States, lifetime risk for prostate cancer 16.7% and >28,000 die annually

Rationale for preventive finasteride: development of prostate cancer linked to androgens; finasteride inhibits 5-a reductase (converts testosterone to dihydrotestosterone [DHT]); men naturally deficient in 5-a reductase do not de­velop prostate cancer or benign prostatic hyperplasia (BPH); DHT  —  active male hormone; heavily involved with prostate; 10 times more potent than testosterone

Prostate Cancer Prevention Trial: all patients given finasteride for 7 yr, then biopsied to look for disease; secondary end points included side effects, survival, quality-of-life, effect on prostate-specific antigen (PSA) levels, incidence of BPH, and association of dietary fat; only patients >55 yr of age with normal digital rectal exam (DRE), no signif­icant comorbid problems, and American Urological Association (AUA) symptom score <20; prostate monitoring conducted during annual examinations (included PSA, DRE, and biopsies); study problems  —  finasteride reduced PSA levels by 50%, skewing biopsy criteria in favor of placebo arm; higher PSA levels allowed blinded clinicians to identify patients receiving placebo; 50% of men >50 yr of age had baseline PSA level >1 ng/mL; 15% of partic­ipants had family history of prostate cancer (20% for total population); low rate of mortality (7%); »25% of each arm refused end-of-study biopsy; results  —  end-of-study biopsies showed significant reductions in prostate cancer in finasteride arm (803 in finasteride arm vs 1100 in placebo arm); similar results found with total cancers and for-cause biopsies; 25% total reduction in incidence of prostate cancer found with finasteride; however, higher-grade cancers more common in finasteride arm (possibly directly induced); discrepancies  —  incidence of disease in for-cause biopsies (conducted earlier in study) equal to incidence of disease in end-of-study biopsies, indicating factors other than finasteride possibly responsible; prostate volume  —  reduction in prostate volume produced by finasteride may increase likelihood of biopsies discovering disease (without increased incidence); finasteride possibly in­creases performance of PSA or shrinks prostate to reveal hidden nodules; no increase in high-grade cancer found after first year (lower incidence in finasteride arm toward end of study); reductions in cancer  —  seen across all ages and racial groups, including patients with family history; results not affected by PSA; low PSA level  —  16% of men with PSA levels <1 ng/mL have prostate cancer, including high-grade disease; positive biopsy rate »30%; finaste­ride side-effects  —  typically well-tolerated (low incidence of breast tenderness, libido loss, and decrease in volume of ejaculate); 50% reduction in prostatitis; reduced urinary retention and incontinence; BPH symptoms improved; higher Gleason grades associated with finasteride decreased over time

Finasteride controversy: examination of malignant cells taken from patients on finasteride revealed no significant differences (compared to typical prostate cancer cells); with tumors of equal size, smaller prostates more likely to yield positive biopsies; results from biopsy consistent with results from radical prostatectomy in »35% of cases; Gleason grades based primarily on cancer volume; no difference in cancer rates between patients taking finasteride and placebo when comparing radical protatectomies; biopsies missed disease in 50% of patients on placebo vs 30% of patients on finasteride; grade shift  —  possibly explained by PSA level–related bias; insufficient PSA decrease in patients on finasteride functions as diagnostic indicator of disease; majority of treated prostate cancers low-grade; sparing patients from treatment typically prolongs life; reductions in high-grade prostatic intraepithelial neoplasia (PIN) found in finasteride arm; conclusion  —  finasteride reduces rate of prostate cancer by »25%; results across all subjects better than any other cancer prevention regimen

Preferred Treatment for
Most Local Prostate Cancer

David C. Beyer, MD, Arizona Oncology Services, Phoenix, AZ

Traditional radiation therapy (RT): older regimens typically lasted 6 to 7 wk, newer regimens last 8 to 9 wk; dos­age steadily increasing during past 15 yr; all modalities effective against early prostate cancer; RT success rates comparable to those of radical and robotic prostatectomies; Kupelian study  —  retrospective study of 3000 men with early prostate cancer; received surgery, RT, or brachytherapy; only patients receiving external beam radiation ther­apy (XRT) to low doses (<72 Gy) showed inferior results; Zelefsky study  —  2000 men received XRT; doses esca­lated from 66 Gy to 86.4 Gy (speaker does not exceed 81 Gy); 50% of patients received short-course androgen-deprivation therapy; at 7 yr (median follow-up), 90% of low-risk patients, 72% of intermediate-risk patients, and 54% of high-risk patients free of disease; doses >75 Gy significantly increased biochemical control rates in all risk groups; 84 Gy superior for high-risk patients; significant reduction in distant metastases at 7 yr

Advancements in RT: brachytherapy  —  lower PSA nadirs, compared to XRT; nadir at 4 yr, vs 2.0 to 2.5 yr with XRT; proton therapy  —  effective; protons comparable to intensity-modulated RT (IMRT) for prostate cancer; gross tumor volumes received 83 Gy with proton therapy (81 Gy for IMRT), rectum received 56 Gy (54 Gy for IMRT; no significant benefit); bladders of proton therapy patients received greater radiation (vs IMRT); no evidence suggest­ing superiority of proton therapy for prostate cancer; Medicare may require enrolling patients in clinical trials be­fore providing coverage; IMRT  —allows modulation of incident radiation beam; movement of beam during treatment varies dose rate; completed in 2 to 3 min (traditional RT requires lying still for »45 min); high-speed dos­ing improves accuracy due to decreased opportunity for movement; fractionation  —  number of treatments deter­mined by alpha/beta ratio (measure of difference between cancer response to irradiation and normal tissue late response); ratio predicts response of healthy tissue to specific doses; ratio revised downward over time; conven­tional treatments utilize 1.8 to 2.0 Gy/day; number of fractions steadily increased from 33 to 45; alpha/beta ratio suggests changes in daily dosage necessary; Kupelian series  —  several hundred patients treated to 70 Gy at 2.5 Gy/day in 28 fractions (reduced 9-wk course to 5.5 wk); efficacy and toxicity comparable to that of standard RT; stereotactic body RT (SBRT)  —  cyberknife; extreme fractionation, typically 5 fractions of 700 to 800 Gy/day (ex­tremely high doses); extremely precise delivery process; aggressive protocols; highly experimental treatment (available only on protocol); no Medicare coverage outside clinical trials, due to limited data

Hormone therapy: European Organization for Research and Treatment of Cancer (EORTC) study  —  415 high-risk patients treated between 1987 and 1995; radiation given only to pelvis and prostate; all patients received concomi­tant and adjuvant hormones (no complete androgen blockade or neoadjuvant hormone therapy); 9-yr median fol­low-up completed; RT plus long-term androgen deprivation (LTAD) found superior to RT alone (overall survival at 10 yr 58% vs 39%; clinical progression-free survival 47% vs 22%; distant progression-free survival 51% vs 30%; freedom from PSA progression 37% vs 17%; prostate cancer mortality 11% vs 31%; no cardiovascular risks associ­ated with LTAD; 3 full years of hormones strongly recommended; increase in pathologic fractures found; Stock and Stone study  —  evaluated hormones in conjunction with brachytherapy for high-grade prostate cancer; short course of hormone therapy (9 mo); each participant received XRT and brachytherapy; all patients high risk; freedom from biochemical failure 74% to 78%; 84% of patients with Gleason grade of 8 free from failure at 10-yr follow-up; >50% of patients with Gleason grade of 9 to 10 remained free of disease at 10 yr; Dosoretz study  —  hazard ratio for all-cause mortality greater among brachytherapy monotherapy patients given neoadjuvant hormones; neoadjuvant hormones found to be significant factor in all-cause mortality; speaker’s data  —hormone therapy produced 50% decreases in overall survival among brachytherapy patients not at high risk for cancer mortality; speaker recom­mends hormones only for high-grade aggressive disease; low-risk patients should only receive hormones in special circumstances

Hormonal Therapy: New Horizons

Dr. Crawford

Background on prostate cancer treatment: specialty of practitioner influences patient treatment (eg, patients see­ing urologists receive surgery, patients seeing radiation oncologists receive RT); speaker recommends considering many factors when deciding on treatment; insufficient comparison exists between various prostate cancer therapies

Prostatectomy: lymph node (LN) staging important; results from specimen important; direct adjuvant therapy as in­dicated; LN status  —  studies support giving extended hormone therapy to patients with positive LNs; New England Journal of Medicine study (1999)  —  all patients received radical prostatectomy; patients with positive LNs received early hormone therapy or delayed hormone therapy; early hormone therapy significantly increased overall cancer-specific survival; survival differences consistent after 14 yr; time to hormone therapy in control arm only 20 mo (PSA level 14 ng/mL), indicating small time window to affect curability; EORTC-positive LN study  —  no local treatment (prostate left intact); at 10 yr, 67% of patients dead from prostate cancer; no difference found between early and delayed hormone therapy; German study  —  135 patients with positive LNs; utilized immediate hormone therapy (no randomization); cause-specific survival similar to speaker’s results; only 25% died from prostate cancer at 10 yr; radical prostatectomy  — local control »99%; Gleason grade follows biopsy to final pathology in only 38% of patients; United States Department of Veteran Affairs (VA) and university study  —  588 patients; in 44% of pa­tients, Gleason grade higher in prostate, compared to biopsy (grade increased by ³2 in 20% of specimens and de­creased by ³2 in 12%); results of transrectal ultrasonography (TRUS) biopsy matched Gleason grade in 59% of patients; university college hospital (UCH) Gleason grade matched final pathology in 51% (outside pathology work less accurate)

Adjuvant therapy: calculators and tables exist based on >15,000 men; predict risk for, eg, positive LNs, PSA recur­rence, based on number of factors; adjuvants for prostate cancer lag behind breast and colorectal cancers; South­west Oncology Group (SWOG)-9921 study  —  assessed adjuvant hormones or hormones during chemotherapy in men with radical prostatectomy; Powell SWOG study  —  nonrandomized phase II trial of men with T3 prostate can­cer, PSA levels of 20-30 ng/mL, and Gleason grades ³7; all participants given 4 mo of hormone therapy and radical prostatectomy; impressive results consistent for >10 yr

High-grade cancer: retrospective review  —  included 453 men with high-grade cancer and Gleason grade ³8 treated between 1980 and 1997; pretreatment variables collected (including zip codes for socioeconomic metrics); radical prostatectomy increased survival; greater numbers of blacks chose conservative therapy (eg, delayed hormone ther­apy); Charlson index well balanced (slightly higher in RT group); after adjustment, risk for death from all causes in men who had radical prostatectomy 32% lower, compared to conservative treatment (42% lower, compared to RT); median overall survival of men undergoing radical prostatectomy was 9.7 yr (5.2 yr for conservative treatment, 6.7 yr for RT); risk for cancer-specific mortality 68% lower after radical prostatectomy (compared to conservative treatment; 49% lower than RT); median survival rate improved; study of treatment among blacks  —  computerized database study of 2046 men; results similar to whites when evaluating local treatment (Charlson indexes similar, despite differing socioeconomics); greater numbers of whites chose radical prostatectomy; no difference in survival rates among black and white men undergoing radical prostatectomy; treatment has greater effect on outcome than race; low incidence of incontinence and impotence associated with radical prostatectomy; micrometastases  —  eventually cause relapse and death from metastatic disease; more susceptible to hormone therapy or chemotherapy eradication than bulkier disease; earlier treatment superior; high-risk patients identifiable in sufficiently narrow tar­get populations for testing adjuvant therapies; chemotherapy  —  »8% response rate; Cancer and Leukemia Group B (CALGB) study  —  mitoxantrone plus prednisone produced slight end point improvements over prednisone alone; benefits shown over time (possibly indicating advantages of earlier use); long-term follow-up of breast, colon, and lung cancer patients shows importance of adjuvant treatment; SWOG-9921 study  —  compared hormone therapy alone to hormone therapy plus chemotherapy; no control arm; high-risk patients; 212 patients; much-needed study closed due to lack of participants; men often more reluctant to join clinical trials; SWOG trial (Ian Thompson prin­cipal investigator)  —  criteria of severe cancer after radical T3 disease; patients randomized to receive RT (immedi­ate or delayed) or observation (stratified based on previous hormone therapy); many high-risk patients survived 14 to 15 yr after surgery; prostate cancer trials involving localized disease typically require long-term follow-up

Removal of primary disease: importance of removing primary disease demonstrated in renal and colorectal cancer; orchiectomy study  —  1286 men with metastatic prostate cancer randomized to orchiectomy plus flutamide or orchi­ectomy plus placebo; 177 patients had previous radical prostatectomy before advancing to metastatic disease; when stratified against men receiving RT or presenting de novo with metastatic disease, previous radical prostatectomies improved survival by 40%; atrasentan  —  endothelin receptor antagonist; study showed superior results in patients in hormone refractory state with previous radical prostatectomy

Suggested Reading

Elliott CS et al: The influence of prostate volume on prostate-specific antigen performance: implications for the prostate cancer pre­vention trial outcomes. Clin Cancer Res 15:4694, 2009; Kupelian PA et al: Hypofractionated intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer. Int J Radiat Oncol Biol Phys 68:1424, 2007; Kupelian PA et al: Radical prostatectomy, external beam radiotherapy <72 Gy, external beam radiotherapy > or =72 Gy, permanent seed implantation, or com­bined seeds/external beam radiotherapy for stage T1-T2 prostate cancer. Int J Radiat Oncol Biol Phys 58:25, 2004; Lucia MS et al: Finasteride and high-grade prostate cancer in the Prostate Cancer Prevention Trial. J Natl Cancer Inst 99:1375, 2007; Messing EM et al: Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 9:341, 1999; Porojnicu A et al: Season of diagnosis is a predictor of cancer survival. Sun-induced vitamin D may be involved: a possible role of sun-induced Vitamin D. J Steroid Biochem Mol Biol 103:675, 2007; Pow­ell IJ et al: Interplay of race, socioeconomic status, and treatment on survival of patients with prostate cancer. Urology 74:1296, 2009; Redman MW et al: Finasteride does not increase the risk of high-grade prostate cancer: a bias-adjusted modeling approach. Cancer Prev Res (Phila Pa) 1:174, 2008; Tewari A et al: Long-term survival probability in men with clinically localized prostate cancer: a case-control, propensity modeling study stratified by race, age, treatment and comorbidities. J Urol 171:1513, 2004; Trofimov A et al: Radiotherapy treatment of early-stage prostate cancer with IMRT and protons: a treatment planning comparison. Int J Radiat On­col Biol Phys 69:444, 2007; Zelefsky MJ et al: Long-term results of conformal radiotherapy for prostate cancer: impact of dose esca­lation on biochemical tumor control and distant metastases-free survival outcomes. Int J Radiat Oncol Biol Phys 71:1028, 2008.