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Treatment

1. Localized Prostate Cancer (T1-T4 N0M0)

Localized prostate cancer has a wide variety of biological behaviors ranging from an indolent slowly progressive to a more aggressive rapidly progressive disease.  There are three risk categories derived from the Canadian Consensus initially published by the Radiation Oncologists (7) and later adopted by the Canadian Urologists (8).

Treatment options are based on the following risk categories:

Low Risk:
T1-T2b and Gleason score less than or equal to 6 and PSA less than or equal to 10
Intermediate Risk:
T2c and/or Gleason score 7 and/or PSA greater than 10 but less than or equal to 20
High Risk:
T3 or higher and/or Gleason score greater than or equal to 8 and/or PSA greater than 20

1.1 Low Risk Disease
(stage T1-2b and Gleason score less than or equal to 6 and PSA less than or equal to 10)

Depending on patient's age, life expectancy, comorbidity and patient's preference, management options may include the following:

1.1.1  Active Surveillance

This may be a suitable option for young fit men. It should follow a specific protocol (9),(10),(11).

  • PSA every 3 months for 2 years and 6 monthly thereafter
  • DRE every 6 months
  • Re-biopsy every 3 years or earlier if PSA doubling time (dt) greater than 3 years and less than 10 years
  • Active curative treatment should be commenced if:
    • PSAdt becomes less than 3 years based on minimum of 3 values, or
    • the finding of Gleason 4 or 5 pattern on re-biopsy, or
    • disease progression to stage T3.

1.1.2  Watchful Waiting

More suitable for elderly patients with a life expectancy of less than 10 years, or younger patients who have significant co-morbidity.

  • DRE and PSA every 6 months
  • Active treatment is initiated only at the development of symptomatic disease. This treatment could be hormonal therapy alone (medical or surgical castration), localized palliative radiotherapy for bone metastasis, palliative radiotherapy to the prostate in case of symptomatic local invasion or hematuria, or TURP for bladder neck obstruction or hematuria.

1.1.3  Radical Prostatectomy (RP)

  • Generally restricted to patients not more than 70 years of age and with a minimum 10-year life expectancy. 
  • Retropubic or laparoscopic approach.
  • Pelvic lymph node sampling or dissection is not necessary in low risk patients. 
  • A nerve sparing approach should be attempted, if possible, in patients who are still potent and have small volume disease.

1.1.4  Radiotherapy

a. External Beam Radiotherapy (EBRT)

  • No androgen deprivation therapy (ADT)
  • 3-D Conformal Radiation Therapy (3D-CRT) planning or Intensity-Modulated Radiation Therapy (IMRT).
  • GTV = prostate alone
  • Fiducial marker insertion (insertion of 3-5 gold seeds for prostate localization during radiotherapy) is considered the standard of care and should be offered to all patients especially if dose escalation is used (greater than 7400 cGy).
  • Dose recommended is 7400-7800 cGy at 200 cGy daily fractions. 
  • Patients should be recruited to available clinical trials where possible e.g. radiation dose hypofractionation studies.

b.  Brachytherapy

i.  High Dose Rate (HDR)

Selected patients may be treated with a temporary HDR implant followed by external beam RT to the prostate area

ii.  Low Dose Rate (LDR)

    • There is no prostate brachytherapy program with permanent radioactive seed implant available in Saskatchewan which results in hardship for patients wishing to pursue this treatment having to travel out of province.  The group recommends that this treatment option should be available locally to Saskatchewan patients.
    • Eligibility: Prostate volume less than 50cc.  If 50-65cc, consider short course of hormonal cytoreduction to reduce gland size.  If greater than 65cc usually not eligible.  Patients with one prior TURP may be considered, more than one TURP is not eligible.

1.2  Intermediate Risk Disease (stage T2c and/or Gleason 7 and/or PSA greater than 10 but less than or equal to 20)

Treatment options are:

1.2.1  Watchful Waiting

A reasonable option for patients with life expectancy less than 10 years and PSA less than 15 ug/L and/or Gleason score 7.  Patients who have limited life expectancy may be offered early or delayed androgen blockade.

1.2.2  Radical Prostatectomy (RP)

  • In patients with 10 or more years life expectancy, usually not more than 70 years of age, with no extraprostatic extension on the core biopsy, with low risk of positive margin. 
  • Preferred option with localized tumors in patients with significant lower urinary tract symptoms (LUTS), or with contraindication to radiotherapy e.g. inflammatory bowel disease, collagen vascular disease or previous pelvic radiotherapy.
  • Open or laparoscopic surgical approach with pelvic lymph node dissection. If there are grossly positive pelvic lymph nodes, RP may not be completed, but in case of microscopic disease the RP should be completed.
  • A nerve sparing approach should be avoided on the side of the lesion or with significant apical disease.
  • Neoadjuvant androgen deprivation therapy (ADT) is not routinely recommended.  Although it decreases the risk of negative margin by 50%, there is no evidence it improves local control, biochemical disease free survival, disease free survival or overall survival.

1.2.3  Radiotherapy

a.  External Beam Radiotherapy (EBRT)

  • Neoadjuvant and concurrent androgen deprivation therapy with LHRH agonist for 2-6 months prior to EBRT along with initial oral antiandrogen for 2-4 weeks. Anti-androgen should start at the same time or shortly before (but not after) LHRH agonist. ADT may be omitted for low-intermediate risk (PSA less than 15 ug/L and Gleason score less than or equal to 7) especially if dose escalation is used.
  • 3-Dimensional Conformal Radiotherapy (3D-CRT) with dose escalation, or IMRT.  Fiducial markers for daily prostate localization should be used.
  • Dose escalation to 7800 cGy in 39 fractions over 8 weeks.  May limit the dose to 7400 cGy if fiducial markers localization is not used.

b. Brachytherapy

i. High Dose Rate (HDR)

    • Selected patients may be treated with a temporary HDR (1200-43000 cGy/hour) afterloading implant as a boost with external beam RT to the prostate area.

ii. Low Dose Rate (LDR)

    • Selected patients with low intermediate risk may be eligible.  These are patients with PSA greater than 10 ug/L but not more than 15 ug/L AND Gleason score less than or equal to 6, or patients with PSA 10 or less AND Gleason score 7.  These patients may also be treated with neoadjuvant androgen deprivation therapy for 3 months prior and 3 months after the prostate seed implant.  The prostate volume should be less than 50cc.  Patients with one prior TURP may be considered, more then one TURP is not eligible.

1.2.4  Cryosurgery

  • Still not well established as other options.
  • Available only in a few centres.  Not available in Saskatchewan.  Under certain circumstances, patients may be referred to other centres for consideration of cryosurgery. 
  • Selected patients may be eligible when:
    • Patients with T1-T3 tumors with erectile dysfunction who do not want radical prostatectomy.
    • Local external beam radiation failures.
    • Brachytherapy failures.
    • Poor candidacy for other treatments (patient age and health, prior pelvic radiation, TURP, T3 prostate cancer).
    • Prostate volume less than 50 cc, PSA less than 20 and any Gleason score.

Contraindications for Cryotherapy

  • Prior TURP with a large tissue defect.
  • Significant symptoms of urinary obstruction prior to treatment.
  • Large prostate size (complete ablation of glands larger than 50 cm is difficult, prostate volume may be reduced with neoadjuvant hormonal treatment).
  • History of abdominoperineal resection for rectal cancer.
  • Rectal stenosis, or other major rectal pathology.

1.3  High Risk Disease (stage T3 or T4 and/or Gleason 8-10 and/or PSA greater than 20)

Treatment options are:

1.3.1  Radical radiotherapy with neoadjuvant, concurrent and adjuvant androgen deprivation therapy (ADT)

  • for patients with good performance status
  • neoadjuvant ADT with luteinizing hormone-releasing hormone (LHRH) agonist for 2-6 months plus initial oral non-steroidal antiandrogen for 2-4 weeks, concurrent LHRH agonist with radiotherapy, and subsequent adjuvant LHRH agonist for 2-3 years (12),(13)
  • The duration of ADT may be individualized depending on the balance between toxicity and potential benefit. Patients on long term ADT (greater than or equal to 6 months) should be put on daily vitamin D 800 IU plus calcium 1500 mg, and serum cholesterol should be monitored by the oncologist or the family physician.  A baseline bone density with DEXA scan should be considered.
  • 3D-Conformal techniques or IMRT should be used to minimize morbidity (14).  The prostate and pelvic nodes are treated to a dose of 44 to 50 cGy (15),(16)  with a boost to the prostate +/- seminal vesicles to a total dose to the prostate of at least 7000-7400 cGy.

1.3.2  Radical prostatectomy

  • May be considered for selected young patients with less than or equal to T3a and grossly negative pelvic lymph nodes.
  • The risk of positive margin and its consequences should be discussed with patients.

1.3.3  HDR brachytherapy

  • May be used for boost of prostate dose in selected patients.

1.3.4 Cryosurgery

  • May be considered in selected patients as in the cryosurgery section above.

1.3.5  Androgen Deprivation Therapy (ADT)

  • early ADT alone or with prostate only radiotherapy in patients with multiple co-morbidities or limited life expectancy, or patients who refuse the above treatment
  • delayed ADT is less likely considered
  • ADT alone or with local palliative radiotherapy for T4
  • TURP for obstructive symptoms or bleeding

1.4  Post-radical Prostatectomy Radiation Therapy

  • indications: positive resection margin, capsular penetration (pT3a), or seminal vesicle involvement (pT3b) (17),(18)
  • postoperative radiotherapy to the prostate fossa starts within 4 months after surgery
  • Dose: 6000-6600 cGy in 180-200 cGy daily fractions
  • ADT may be considered if high (greater than 1.0 ug/L) or rapidly rising PSA

2. Metastic Prostate Cancer (Any T, N1 or M1)

2.1  Androgen Deprivation Therapy (ADT)

  • Usually started early after the diagnosis of metastasis.  Continuous rather than intermittent ADT is the standard of care so far.  Delayed ADT until symptoms occur may be suitable for patients with multiple co-morbidities and a short life expectancy (19). 
  • Intermittent ADT is less costly and more tolerable, and it may be as effective as continuous treatment in certain subgroups. 
  • ADT can be achieved surgically with bilateral orchiectomy, or biochemically with LHRH (luteinizing hormone-releasing hormone) agonists. 
  • Side effects from both approaches include loss of libido, impotence, hot flashes and depressed mood. Some medical approaches can be associated with breast swelling and/or tenderness. Longer-term side effects can include anemia, osteoporosis with increased risk of bone fractures, changes in lipid profile and loss of muscle mass. 
  • The goal of medical treatment is to reduce testosterone to castrate levels. This can be achieved with an LHRH agonist (e.g. leuprolide, goserelin or buserelin). 
  • LHRH agonists can cause an initial testosterone surge resulting in a clinically apparent flare reaction in 5 to 10% of patients. This can be prevented by lead-in therapy with a non-steroidal anti-androgen, e.g. flutamide, nilutamide and bicalutamide, for 2-4 weeks, starting at the time of, or just before, the first LHRH-A injection. 
  • Non-steroidal anti-androgens are not recommended as monotherapy (16).  There is no proven benefit from the routine addition of non-steroidal anti-androgen medications following orchiectomy (20).
  • Patients who have initially responded to an LHRH agonist or orchiectomy, but then have PSA or clinical progression, may benefit temporarily from the addition of an oral anti-androgen, but these medications should then be stopped when the PSA again begins to rise. 
  • Possible side effects of non-steroidal anti-androgens include diarrhea, breast swelling and tenderness and liver function test abnormalities. Patients on long-term non-steroidal anti-androgens should have monitoring of liver function tests. 

2.2  Chemotherapy

  • Patients with symptomatic hormone refractory prostate cancer may be referred to a medical oncologist for a discussion about the pros and cons of chemotherapy.

2.3  Radiotherapy

  • Selected patients with T1-3N1M0 with microscopic lymph node metastasis seen on pelvic lymph node biopsy/dissection may be treated similar to high risk patients (neoadjuvant ADT followed by radical radiotherapy with concurrent ADT then adjuvant ADT for 2-3 years).
  • Palliative radiotherapy to the prostate area may be appropriate for symptomatic loco-regional disease among patients who have not previously received radical RT to this area.  Common indications include pain and bleeding. 
  • Treatment volume and time-dose-fractionation are individualized. 
  • Indications for palliative radiotherapy to sites of distant metastatic disease include (but are not limited to) bone pain, spinal cord compression and lymphatic obstruction. 

3. Metastatic Hormone-Refractory Prostate Cancer (MHRPCa)

3.1 Chemotherapy

  • Improves overall survival, disease control, symptom palliation and quality of life.
  • Regimen: Docetaxel (Taxotere) plus prednisone q3 weeks (D3P) x 10 cycles (30 weeks).
    D3P: Docetaxel 75 mg/m2 IV q3 weeks, plus Prednisone 5 mg PO bid.  
            Dose reduction to 50 mg/m2 may be used in elderly patients.
  • If the above regimen could not be used, other regimens may be used for symptom control but without survival benefit e.g.
    • Weekly Taxotere if there is trouble with bone marrow function.
    • Mitoxantrone 12 mg/m2 d1 plus Prednisone 5 mg PO BID daily q3 weeks.
  • Second line chemotherapy
    • After Mitoxantrone: Docetaxel
    • After Docetaxel: Retry Docetaxel, or less likely Mitoxantrone, or experimental drugs on clinical trial.
    • Continue with LHRH-A but discontinue antiandrogen.
  • Retreat with Docetaxel 6-10 cycles for disease progression in previous responders if progression after 3-6 months.

3.2  Bisphosphonate Therapy (Zoledronic Acid)

  • Zoledronic acid reduces skeletal related events in men with hormone refractory prostate cancer and bone metastasis (21) (Level 1 evidence).
  • Dose: 4 mg IV q3 weeks for 2 years.
  • Watch renal function, creatinine clearance before each dose, stop Zoledronic acid if clearance less than 30 mL/min. 
  • Dental clearance before starting Zoledronic acid to reduce the risk of osteonecrosis of the jaw.

3.3   Strontium-89 (Metastron)

  • Sr-89 is a radioisotope that may be administered as an outpatient procedure through nuclear medicine departments. It is not recommended for routine use but it may be effective in the following situations:
    • Metastatic prostate cancer to bone in multiple sites, causing severe pain not relieved by conventional treatment with radiation therapy, hormones or chemotherapy. 
    • Adequate bone marrow reserve, platelet count greater than 100. 
    • No impending spinal cord compression.

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