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A. Management Overview [18]navigator

  1. Many prostate cancers (PrCa) now detected are localized to the gland
    1. Localized Disease includes Stages A or B with T1 or T2 tumors
    2. Decision to treat localized PrCa depends on several factors
    3. Option is "watchful waiting" which inlcudes monitoring PSA (prostate specific antigen) [28]
    4. Patients with >10 years to live or unfavorable prognosis or high risk offered therapy
  2. Unfavorable: PSA >10ng/mL, Gleason score on biopsy 7-10, cancer or radiographic evidence of extracapsular extension, and/or seminal vesicle invasion using endorectal MRI [24]
  3. Very Favorable Prognosis
    1. GS 3 or 4
    2. PSA levels <5.1ng/mL
    3. These patients may do well with "watchful waiting"
    4. However, there may be mortality benefit of treatment in low risk patients [3]
  4. Risk Stratification [18]
    1. Low Risk: T1c, T2a, and PSA level <10ng/mL, and GS <7 [28]
    2. Intermediate Risk: T2b or T2c or GS 7 or PSA 10-20ng/mL
    3. High Risk: Stage T3a or or GS 8-10 or PSA >20ng/mL
    4. Very High Risk: Stage T3b or T4
    5. Variants on this composite system have been developed
  5. Management Options for Low Risk [6,7]
    1. Life Expectancy <10 years: "watchful waiting", 3D conformal radiotherapy, brachytherapy
    2. Life Expectancy >10 years: "watchful waiting", 3D conformal radiotherapy, brachytherapy, or radical prostatectomy ± dissection of pelvic LN
    3. Treatment of organ-confined, Gleason <8 PrCa associated with reduced mortality versus watchful waiting [3]
    4. Primary androgen suppression therapy (ASTx) in men with localized PrCa did not improve survival compared with conservative management [46]
  6. Management Options for Intermediate Risk
    1. Life Expectancy <10 years: "watchful waiting" [6,7], 3D conformal radiotherapy ± brachytherapy OR radical prostatectomy ± dissection of pelvic LN
    2. Life Expectancy >10 years: 3D conformal radiotherapy ± brachytherapy, OR radical prostatectomy ± dissection of LN
    3. Certain patients with intermediate risk (but unfavorable prognosis) may benefit from combined ASTx and radiation therapy [24]
  7. Management Options for High Risk
    1. 3D conformal radiotherapy with ASTx OR
    2. Radical prostatectomy with dissection of pelvic LN
  8. Management Options for Very High Risk
    1. 3D conformal radiotherapy with ASTx OR
    2. Androgen suppression therapy alone
    3. Combined ASTx + radiation beneficial versus radiation alone in unfavorable prognosis [24]

B. Treatment Modalitiesnavigator

  1. Radical Prostatectomy
  2. External Beam Radiation
  3. Radioactive Implants
  4. Androgen Suppression Therapy (ASTx, Hormone Ablation Therapy)
    1. Several mechanisms to suppress production and/or action of testosterone
    2. Mainstay of therapy are LHRH agonists leading to suppression of FSH and LH
    3. Androgen Receptor Blockers - nonsteroidal and steroidal types
    4. Finasteride (Proscar®) for benign prostatic hyperplasia reduces PSA from non- cancerous tissue and may be useful in patients on "watchful waiting" [28]
    5. Used alone or in combination with other modalities
  5. Treatment of Pain
  6. Treatment modality often depends on type of specialist consulted
  7. Therapeutic Efficacy
    1. For localized disease, monitoring for recurrence done by serial PSA ± PAP levels
    2. For disseminated disease, PSA and clinical symptoms are used
  8. Finasteride (Proscar®) Chemoprevention [4]
    1. 5-alpha-reductase inhibitor which reduces prostate volume 20-30%
    2. Reduces obstructive BPH symptoms, also slightly decreases libedo
    3. Finasteride 5mg qd for 7 years in 4368 men reduced PrCa from 24.4% to 18.4%
    4. High Grade (GS >6) tumors increased 5.1% in finasteride treated group but careful retrospective evaluation of these tumors suggests this increase was artifactual [45]

C. Treatment of Localized PrCa [18]navigator

  1. Decision to treat as described above
  2. Lack of data on comparitive effectiveness and harms of various treatment modalities [19]
  3. External-beam radiotherapy, brachytherapy, and prostatectomy are potentially curative
  4. Monitoring Disease Course
    1. PSA should drop to near 0 after therapy; increase in PSA is called "biochemical failure"
    2. Biochemical failure (PSA increase) is being used increasingly to assess therapies
    3. Clinical symptoms may not occur for years after biochemical failure
    4. However, most PrCa patients opt for some therapy initiated when PSA increases
  5. Watchful Waiting
    1. In general, persons with expected >10-15 year survival should be treated (see above)
    2. Tumor volume <20 cubic cm generally remains asymptomatic
    3. After 8.2 years followup, 14% of watchful waiting patients died from PrCa [6]
    4. For Gleason <6, risk of death from PrCa is small over 20 years [7]
    5. For localized disease, T1b,c / T2 (GS <6), death due to PrCa was 50% lower (4.6%) with surgery than with watchful waiting (8.9%) [8]
    6. Overall mortality and quality of life was no different for surgery or watchful waiting at 6 years [8,9]
    7. 15 year survival with watchful waiting was similar to surgery in low risk disease [10]
    8. 8 year survival with watchful waiting was ~85% versus ~91% with surgery overall [6]
    9. Monitoring probably okay for GS 3 or 4 and PSA <5.1ng/mL [6,7]
  6. Role of ASTx in Localized PrCa [24]
    1. In localized, unfavorable prognosis PrCa, ASTx for 6 months added to radiation therapy superior to radiation therapy alone on mortality
    2. Mortality benefit (at ~7 years) only seen in men without significant comorbidities
    3. 30% of the men in the radiation therapy only group were given ASTx for PSA failures (PSA >10ng/mL)
    4. Men with >7-10 year lifespan should be presented with option for aggressive treatment of localized, unfavorable prognosis PrCa

C. Non-Pharmacologic Treatmentnavigator

  1. Nerve Sparing Radical Prostatectomy (RP)
    1. Surgery may reduce metastatic disease by ~50% and shows overall mortality benefit [6]
    2. ~35% of patients with RP will have PrCa recurrence
    3. RP is preferred over watchful waiting for Gleason >5, usually with >10 year life expectancy [6,7,10]
    4. ~15% of patients with clinically localized PrCa have PSA increases after surgery
    5. However, androgen suppression therapy added to radiation therapy may also be effective in intermediate and high risk patients with clinically localized disease [10,12]
    6. PSA change >2.0ng/mL over year prior to diagnosis has high risk of death from PrCa even after EBRT [13]
    7. Detection of tumors earlier with PSA screening may allow simpler, safer surgeries
    8. Salvage radiotherapy for recurrence after RP may be curative, particularly when PSA doubling times <10 months [14]
    9. Rapid (<9 month) PSA doubling time, Gleason 8-10, and time to biochemical (PSA) recurrence <3 years after RP are independent predictors of PrCa specific mortality [11]
  2. Complications of RP
    1. Mortality with surgical procedure is 1-2%
    2. Chronic complications include impotence and urinary symptoms
    3. Impotence is usually due to nerve damage and may be less with unilateral nerve damage
    4. At 18 months, impotence was 60% and incontinence ~8% [17]
    5. Overall, 60-80% of men recover erectile function, but recovery occurs in 1-2 years [41]
    6. PDE5 inhibitors and other erectile dysfunction treatments are usually effective [41]
    7. Urinary complications include incontinence and stricture formation
    8. Uncontrolled bleeding after RP may be stopped with activated factor VII [15]
    9. Postoperative and urinary complications are reduced in high volume hospitals and when surgeon performs high case volume [16]
    10. Rectal injury may occur as well
    11. Epidural pain control initiated preoperatively reduces long term pain sequellae
  3. External Beam Irradiation (EBRT) [18]
    1. Substantially less acute morbidity than RP
    2. High dose (>72 GY) radiotherapy is likely as effective as RP at preventing relapses in intermediate and high risk patients [7]
    3. Mortality <0.5%
    4. Impotence ~25% but may be higher over longer term followup [41]
    5. Incontinance ~40% and/or stricture
    6. Radiation Proctitis (rectal injury) in most patients, often delayed >3 months
    7. Conformal radiotherapy leads to significantly less proctitis than conventional [18]
    8. Androgen suppression therapy for 6 months added to EBRT reduces PSA recurrence [12]
    9. Also improves cancer specific an overall survival [21] in intermediate and high risk patients with clinically localized disease
    10. LHRH induced androgen suppression added to EBRT improves survival and relapse rate [22]
    11. Pretreatment PSA doubling time >2.0ng/mL per year has a 12X risk from PrCa after external beam radiation therapy (EBRT) [43]
    12. Patients with rapid PSA doubling time prior to EBRT may benefit from androgen suppression therapy after EBRT [43]
    13. Postoperative EBRT after radical prostatectomy for pT3 or high risk N0M0 tumors improves PSA-progression free survival (74% versus 53%) [5]
    14. Increasing EBRT dose from 70.2 Gy (conventional) to 79.2 Gy (high dose) through conformal photon/proton beams reduced risk of biochemical (PSA) progression [29]
    15. Salvage radiotherapy within 2 years of biochemical (PSA) recurrence associated with improved PrCa specific survival [44]
    16. Higher dose EBRT had minimal acute or late urinary or rectal complications [29]
    17. In general, doses of 75-80Gy conformal radiotherapy to the prostate recommended [18]
  4. Radioactive Implant Therapy (Brachytherapy)
    1. In general, for PrCa with PSA <10ng/dL, GS <7, and T1c or smaller lesions, radioactive implants are recommended (may be combined with conformal EBRT)
    2. Reduced risk of bladder and potency complications compared with other modalities
    3. Implants appear to be worse than RP or EBRT for intermediate and high risk patients [7]
    4. Addition of androgen blockade (neoadjuvant therapy) to implants does not reduce 5-year recurrence rates in low risk patients [7]
    5. Recommended in patients with low risk disease or with reduced expected lifespan
    6. Urethral damage is reduced if implant is loaded away from geometric center of gland
    7. Major issue is damage to nearby tissues including rectum and bladder
    8. Delayed impotence occurs, probably in majority of patients [41]
    9. Some 10-20 radioactive "seeds" are placed into "holes" made by core biopsy needles
  5. Cryoablation therapy is also gaining in use

D. Treatment of Stage C (Stage III) Diseasenavigator

  1. Stage C is also called Localized Advanced Disease
  2. Swedish 15 year survival was 57% for Stage C [6]
  3. EBRT - 15 year surivival in 20-60% range for Stage C disease [6]
    1. Pretreatment PSA doubling time >2.0ng/mL per year has a 12X risk from PrCa after external beam radiation therapy (EBRT) [43]
    2. Patients with rapid PSA doubling time prior to EBRT may benefit from androgen suppression therapy after EBRT [13]
    3. Pretreatment PSA doubling time >2.0ng/mL per year has a 12X risk from PrCa after EBRT [43]
    4. In men with pathologically advanced PrCa (on radical prostatectomy) with adjuvant EBRT improved metastasis-free survival 25% but not overall survival [20]
    5. EBRT associated with 3% rectal complications, 8% urethral strictures, ~4% urinary incontinence above supportive care (non-EBRT) rates [20]
  4. Local relapse after initial radiation predicts poor long term survival
  5. Hormonal Therapy (see below)
    1. Direct testosterone antagonism with androgen receptor blockers
    2. GnRH analogs induce "medical castration"
  6. Orchiectomy is rarely performed for Stage C disease
  7. Combined hormonal (goserelin) and radiation therapy increased 5 year survival in T3-4, N0-2, M0 disease from 62% to 79% and increased relapse free survival

E. Treatment of Stage D (Stage IV) Diseasenavigator

  1. Stage D is metastatic disease, graded based on number of lymph nodes involved
  2. Swedish 15 year survival was 6% for Stage D [6]
  3. Median survival for Stage D is 24-36 months
  4. Surgery
    1. Prostatectomy provides relief only in persons with localized symptoms
    2. Probably does not alter survival in Stage IV disease
    3. Radiation therapy may be preferred to shrink enlarged prostate
  5. Androgen Suppression Therapy (ASTx) [2]
    1. Mainstay of initial therapy for metastatic androgen dependent PrCa
    2. Combination medical hormonal ablation therapies more effective than single agents
    3. Luteinizing hormone releasing hormone (LHRH) analogs equivalent to surgical orchiectomy
    4. Use of single agent nonsteroidal androgen receptor blockers is associated with lower survival than use of single agent LHRH analogs
    5. Immediate ASTx is superior than observation in patients with positive LN following prostate surgery
    6. Abarelix (Plenaxis®) GnRH antagonist approved for patients who should not take an LHRH agonist (due to testosterone surge) and who refuse surgical castration [25]
  6. Chemotherapy [26]
    1. Various single agents show 5-20% response rates in AIPC
    2. Combination therapies have 40-70% response rates on PSA levels
    3. Mitoxantrone (Novantrone®) + prednisone associated with improvement
    4. Docetaxel (Taxotere®) is single most active agent
    5. Docetaxel + prednisone has superior survival than mitoxantrone + prednisone [33]
    6. Docetaxel + estramustine is superior to mitoxantrone + prednisone [34]
    7. Docetaxel containing regimens are now standard of care first line [33,34]
    8. Liposomal doxorubicin (Doxil®)
  7. Adjunctive Therapy [27]
    1. High dose glucocorticoids for spinal cord compression
    2. Glucocorticoids may also be combined with mitoxantrone for added chemo effects
    3. Strontium radioisotope for Bone Pain
  8. Other Agents [27]
    1. Retinoids
    2. Interferons
    3. Progesterones
    4. Ketoconazole
  9. PSA Monitoring
    1. PSA is standard for screening and to monitor tumor in patients declining treatment
    2. PSA is used to monitor disease recurrence and efficacy of treatment
    3. PSA reductions of >50% for >4 weeks associated with 23 month survival in AIPC
    4. PSA reductions <50% are associated with 11 months survival in AIPC

F. Hormonal Ablation Therapy [42] navigator

  1. Utility
    1. Mainstay of therapy with clear benefits for metastatic disease
    2. Improves outcomes for high risk patients with localized PrCa treated with radiation therapy
    3. Unclear benefits for patients with rising PSA after treatment for localized PrCa
    4. Also called androgen deprivation therapy
  2. Disseminated Disease
    1. ~80% of patients have objective responses initially
    2. Most patients remit for ~2 years
    3. Disease then becomes androgen independent
    4. Withdrawal of androgen blockade can induce temporary regression in ~20% of cases
    5. Indicated for all Stage IV and Stage D disease
  3. Types of Agents
    1. Orchiectomy - about as effective as combination hormonal blockade
    2. LHRH agonists - inhibit FSH and LH secretion by desensitizing receptors
    3. LHRH antagonists - in clinical development phases for PrCa [30]
    4. Androgen receptor blockers
    5. 5-alpha reductase inhibitors
    6. Estrogens
  4. Side Effects (>90%)
    1. Gynecomastia
    2. Loss of libido
    3. Loss of erectile function / impotence
    4. Hot flashes
    5. Change in mood, cognition
    6. Osteopenia / Osteoporosis
  5. LHRH (GnRH) Analogs [2,31]
    1. Induce medical castration as effectively and better tolerated than orchiectomy
    2. Initially cause surge in FSH and LH, then suppress pituitary production of gonadotrophins
    3. Goserelin (Zoladex®): 3.6mg monthly or 10.8mg every 12 weeks subcutaneously (SC)
    4. Leuprolide (Lupron®): 7.5mg monthly intramuscular (IM) or 30mg every 16 weeks IM
    5. Leuprolide (Eligard®): 7.5mg for monthly SC
    6. Leuprolide Subdural (Viadur®): 65mg annually (surgically placed in inner upper arm)
    7. Triptorelin Depot (Trelstar® Depot): 3.75mg monthly IM
    8. Triptorelin LA (Trelstar® LA): 11.25mg every 12 weeks IM
    9. LHRH agonists prolong life better than androgen receptor blockers used alone
    10. LHRH agonists also better tolerated than androgen receptor blockers
    11. As effective as and better tolerated than diethylstilbestrol (DES)
    12. May be used in combination with androgen receptor blockers
    13. However, combination therapy adds minimal benefit to LHRH analogs alone [32]
    14. Androgen receptor blocker needs to be present when LHRH agonists are used due to androgen surge induced initially by agonists
    15. Direct LHRH antagonists are being developed which do not induce androgen surge [30]
    16. Pamidronate 60mg IV q12 weeks prevents GnRH induced osteoporosis [35]
  6. Androgen Receptor Blockers [2]
    1. Non-steroidal agents which block binding of DHT to its receptor
    2. Flutamide (Eulexin®) - dose is 250mg po tid; drug induced hepatitis and diarrhea seen
    3. Bicalutamide (Casodex®) - similar to flutamide but given once daily (50mg po qd) [36]
    4. Nilutamide (Nilandron®): 300mg po qd x 30 days, then 150mg po qd; induces hepatitis
    5. Cyproterone acetate is a steroidal antiandrogen still used occasionally
    6. Survival may be lower if androgen receptor blockers are used alone (versus LHRH agonist alone or combination therapy)
    7. Androgen blockers provide little benefit when added to LHRH analog therapy [32]
    8. Withdrawal of androgen blockers when PSA increases can lead to PSA reduction in ~20%
  7. Finasteride (Proscar®) [45]
    1. 5 alpha-reductase inhibitor (enzyme needed for DHT formation)
    2. Finasteride 5mg qd x 7 years reduces PrCa incidence from 24% to 18%
  8. Estrogens - diethylstilbestrol (DES) is sometimes used
  9. Androgen ablation therapy associated with osteoporosis, increased fracture risk [40]
  10. Once weekly alendronate (Fosamax®) 70mg prevents bone loss in men receiving ASTx [23]

G. Treatment of Androgen Independent PrCa (AIPC) [27,37]navigator

  1. Most PrCa are initially highly androgen dependent
    1. Androgen withdrawal leads to apoptosis of most PrCa cells
    2. Eventually, many tumors become androgen-independent, usually in 12-18 months
  2. Most metastatic AIPC express high levels of androgen receptor
  3. About 50% of the androgen-independent PrCa androgen receptors have mutations
  4. Androgen Receptor Pathway Mutations
    1. Receptor is active independent of ligand
    2. Receptor binds anti-androgen (such as flutamide) and is activated
    3. Post-receptor signalling pathway is activated (as in her-2/neu positive PrCa)
    4. Mutations independent of androgen receptor maintain neoplastic growth
    5. ay render receptor active even in absence of ligand
  5. Unlike breast cancer, a second hormonal therapy is not associated with a response
  6. Treatment
    1. Various chemotherapeutic agents have been used (see above)
    2. Docetaxel (Taxotere®) regimens are superior to mitoxantrone containing regimens
    3. Docetaxel with either prednisone or estramustine should be first line chemotherapy [33,34]
    4. Docetaxel + estrumustine + carboplatin has also been used [37]
    5. Treatment of bone with 89-Strontium reduces pain
    6. Combination of 89-Sr+doxorubicin given weekly for 6 weeks improves overall survival [38]
    7. PC SPES®, an herbal estrogenic supplement, has shown some PSA reductions [39]
    8. Estrogen and PC SPES® cause pulmonary embolism and other estrogen-side effects
    9. Salvage radiotherapy within 2 years of biochemical (PSA) recurrence associated with improved PrCa specific survival [44]

H. Followup Evaluationsnavigator

  1. PSA and Prosatic Acid Phosphatase (PAP)
    1. Used to follow disease response and recurrence
    2. ~5% with localized PrCa have rise in PSA 3-5yrs post radical prostatectomy
    3. PSA doubling time after treatment is likely most important prognostic indicator [14]
    4. Rapid (<9 month) PSA doubling time, Gleason 8-10, and time to biochemical (PSA) recurrence <3 years after RP are independent predictors of PrCa specific mortality [11]
    5. PSA change >2.0ng/mL over year prior to diagnosis has high risk of death from PrCa even after EBRT [13]
  2. Digital rectal is sometimes repeated but is insensitive
  3. Bone scans done q3-12 months depending on staging
  4. Regional lymph node assessment (Stages C and D): 1 and 3 years or as clinically indicated
  5. Prostate volume measurement
  6. Biopsy - Stages A/B and C: 18-24 months after radiation or as clinically indicated
  7. Upper Urinary Tract Evaluation as clinically indicated, especially with hydronephrosis

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