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Prostate

Notes

​Updated 25 August 2009

Useful links:

The GU Tumour Group is committed to the improvement of the results of cancer treatment by participation in a broad clinical research effort. Detailed protocols are available on request. Because of frequent changes and the complexity of many protocols, it is recommended that the principal investigator be contacted directly regarding patients who meet the listed criteria.

Careful documentation before, during, and after treatment is an integral component of clinical research. The participation of the patient's referring and family physician in this process is essential and appreciated.

1. Predisposing Factors & Prevention

Although prostate cancer is the most common male cancer in B.C. (with the exception of non-melanocytic skin cancer), relatively little is known concerning its etiology.

Ethnic origin appears to be important, with North American blacks having very high rates, whites intermediate rates and North American Asian men, low rates (Gallagher & Fleshner 1998). Family history is also important in prostate cancer. Men with a single first degree relative with the disease have a 2-fold risk of developing it themselves. Men with 2 or more first degree relatives involved, have a 4-5-fold risk. Fortunately only about 1% of men in Canada have such a history.

Consumption of a diet rich in red meat and saturated fat appears to increase risk, particularly of aggressive disease. At present compelling evidence for a protective effect of vitamin A, Beta-carotene, or soy products is lacking for prostate cancer, although results from ongoing or planned studies may alter this assessment in the next 2-3 years. A study conducted in Finland showed a substantial protective effect from vitamin E supplementation, but confirmation of these results is necessary.

Prevention

Primary prevention maneuvers involving diet modification may eventually prove useful. Clinical trials are required in order to demonstrate benefit, however, before these can be recommended to men with any confidence.

Reference

  1. Gallagher RP, Fleshner N. Prostate cancer: epidemiology. Can Med Assoc J; 1998; 159:807-813

2. Screening & Early Detection

Revised 29 November 2010

The standard method of early detection for prostate cancer is the digital rectal examination (DRE) which should be done annually in fit men 50-70 years or if obstructive or other urinary tract symptoms are present.

Serum prostate specific antigen test (PSA) is recommended as a diagnostic adjunct in men with lower urinary tract symptoms or suspicious DRE findings.

Serum PSA is of unknown value however as a population screening test. Although there is good evidence that it increases the detection rate of early stage clinically significant prostate cancer​s, there is little evidence to date that such early detection leads to reduced mortality; the "gold standard" for evaluating screening tests.

Fit men age 50-70 (men with at least 10 years life expectancy) should be made aware of the availability of PSA as a detection test for prostate cancer. They should be aware of the potential benefits and risks of early detection so they can make an informed decision as to whether to have the test performed.

The BC Cancer Agency statement concerning screening with PSA. 

3. Diagnosis

revised Mar. 2001​

3.1 Clinico-pathologic Considerations

The most common histology is adenocarcinoma (acinar) and is dealt with in this guideline. The large duct (previously referred to as endometrioid) variant of prostate carcinoma is generally treated like the more common acinar type of prostatic adenocarcinoma, but as it may behave more aggressively and can be confused pathologically with transitional carcinoma, its presence should be specifically mentioned. Transitional cell carcinoma may be primary or secondary from the bladder and should be treated according to the bladder carcinoma recommendations. Pathologists need to delineate whether the transitional carcinoma invades prostate stroma, merely shows pagetoid extension into prostate ducts or involves tissue in prostate sample that may only represent bladder neck.

Other rare cancers include small cell carcinoma, which requires referral for combined modality therapy. Sarcomas are rare, occurring in younger patients and are dealt with by the Sarcoma Group.

3.2 Classification Criteria

Abnormal DRE and/or elevated PSA are not diagnostic of prostate cancer but place patients into a higher risk group for having cancer, who require further investigation. Diagnosis is confirmed by needle biopsy, most accurately using transrectal ultrasound guided sextant biopsies. Indications for biopsy include:

  • Elevated serum PSA above the age-specific range in an otherwise fit man
  • Suspicious digital rectal examination (asymmetry, nodules, or induration)
  • More accurate evaluation of stage T1a tumours detected on TUPR in fit men under 70 years of age

3.3 Diagnostic Pathology

  1. Pathologists can greatly assist patient management by providing the following information on needle biopsies:
    1. A comment regarding the adequacy of the specimen, particularly if only stroma sampled
    2. The presence or absence of carcinoma including an estimate of the amount of tumour (length of positive core in millimeters), location, and number of positive cores
    3. The histologic type
    4. The histologic grade - Gleason Grades 1-5 and Gleason Score, which is the sum of the two most prevalent grades
    5. The presence of vascular, lymphatic, or perineurial invasion
    6. Invasion into or extension beyond the prostatic capsule into fat
    7. Presence of low vs. high-grade prostatic intraepithelial neoplasia (PIN)
  2. Reports on transurethrally resected specimens should include the same information required for needle biopsy specimens, and clearly indicate extent (and Gleason grade) of involvement to differentiate T1a vs. T1b carcinomas. An estimate of the percent tissue volume that the carcinoma involves should be stated. Cases around the threshold carcinoma volume of 5% should be sampled liberally for microscopy
  3. Radical prostatectomy specimens should be inked and marked at all excisional margins and these should be sampled generously. Obvious tumour should be sampled and random sections of apparently normal prostatic tissue should be taken with particular emphasis at the apex, bladder neck, and peripheral inked margins. Pathology reports should include the following information:
    1. The presence or absence of carcinoma
    2. The size of carcinoma with measurement of at least the largest dimension and preferably all three dimensions.
    3. The location within the prostate, including presence of bilateral involvement
    4. The histologic type
    5. The histologic Gleason grade and score
    6. The presence of PIN
    7. The presence of invasion of lymphatics and/or veins
    8. Presence of extracapsular extension and comment on specific location and extent of extracapsular involvement
    9. Status of resection margins, including comment of specific margin(s) involved, extent of involvement and nature of tissue at involved margin, i.e. incised prostate parenchyma, capsule or fat
    10. Seminal vesicle wall invasion
    11. Nodal metastases, including number of nodes examined, number involved the size of involvement, and presence of extra nodal extension
    12. Comment about extent and degree of pretreatment effect

4. Staging

Revised March 2009

4.1 Classification Criteria

Link to the current TNM system 2010 (UICC 1997)

T - Primary Tumour

 TX  primary tumour cannot be assessed 
 TO  no evidence of primary tumour 
 T1  clinically inapparent tumour not palpable or visible by imaging 
  T1a  tumour incidental histological finding in 5% or less of tissue resected 
  T1b  tumour incidental histological finding in more than 5% of tissue resected 
  T1c  tumour identified by needle biopsy (e.g., because of elevated PSA) 
 T2*  tumour confined within the prostate 
  T2a  tumour involves one lobe 
  T2b  tumour involves both lobes 
 T3**  tumour extends through the prostatic capsule 
  T3a  extracapsular extension (unilateral or bilateral) 
  T3b  tumour invades seminal vesicle(s) 
 T4  tumour is fixed or invades adjacent structures other than seminal vesicles: bladder neck, external sphincter, rectum, levator muscles, and/or pelvic wall 


T2 & T3 apply only to adenocarcinomas. Transitional cell carcinoma of the prostate is classified as a urethral tumour (5.5.2.1).

* tumour found in one or both lobes by needle biopsy, but not palpable or visible by imaging is classified as T1c
** invasion into the prostatic apex or into (but not beyond) the prostatic capsule is not classified as T3, but as T2.

N - Regional Lymph Nodes

The regional lymph nodes are the nodes of the true pelvis which essentially are the pelvic nodes below the bifurcation of the common iliac arteries. Laterality does not affect the N classification.

 NX  regional lymph nodes cannot be assessed 
 NO  no regional lymph node metastasis 
 N1  regional lymph node metastasis 


M - Distant Metastasis

 MX  distant metastasis cannot be assessed 
 MO no distant metastasis 
 M1  distant metastasis 
  M1a  non-regional lymph node(s) 
  M1b  bone(s) 
  M1c  other site(s)



4.2 Staging Diagram 

4.3 Investigations for Staging

Assessment for patients who are being considered for c​urative (radical) surgery or radiation should consist of:

  • History and physical examination
  • CBC, BUN, creatinine, urinalysis
  • PSA (which should be done prior to biopsy)
  • Radionuclide bone scan is indicated only in patients with intermediate or high-risk disease (as defined in 5. Management)

Chest x-ray Other investigations:

  • CT scans are not routinely indicated except in high-risk patients (serum PSA >30, or advanced high-grade tumours)
  • Prostatic acid phosphatase is no longer indicated and is no longer a useful tumour marker having been replaced by PSA

5. Management


Updated 24 June 2009

Prostate cancer exhibits a wide range of biologic behaviour in a heterogeneous patient population. In elderly patients with life expectancies less than ten years, small volume or microscopic cancers, low grade and low PSA, no treatment is necessary. However, it is important to diagnose cancers in men with longer life expectancies who have more aggressive disease and in whom radical therapy offers a curative potential. Such prognostic factors have been grouped according to a Canadian GU Radiation Oncology Consensus, published in Canadian Journal of Urology 2001, as follows:

  1. Low Risk: must have all of the following:
    • PSA <=10 ng/mL
    • Gleason <=6
    • Stage T1/T2a
  2. Intermediate Risk: Neither low nor high risk, and therefore have any of:
    • PSA >10 ng/mL
    • Gleason =7
    • Stage 2B
  3. High Risk: must have any of the following:
    • PSA >20 ng/mL
    • Gleason >=8
    • Stage T3a or worse

A discussion about treatment decision-making may be found at the Can​adian Family Physician web site.

5.1 Low Risk

​Updated 29 July 2009

Low Risk (all of the following):

  • PSA <=10 ng/mL
  • Gleason <=6
  • Stage T1/T2b (2002 TNM)

Management

Patients with low risk cancer have 10-year prostate cancer survival rates in excess of 99% [1, 2], and it is uncertain if intervention improves longer term survival. For this reason the option of active surveillance should always be considered (see below) as a means of avoiding over-treatment which may otherwise occur in over 50% of men with PSA screen-detected cancer [3] [4]. However, as a substantial number of men who are thought to have low risk cancer on sextant biopsy will be found to have more significant cancer if they undertake prostatectomy, it is essential to carefully consider all available diagnostic and clinical information before embarking on a surveillance strategy. For these reasons a protocol for Active Surveillance has been developed to permit the careful management of men with low and minimal risk prostate cancer.

Active Surveillance Protocol for the Management of Patients with Low Risk Prostate Cancer:

Patients with low risk prostate cancer (PSA<=10, T stage <=2, Gleason score <=3+3=6/10) are eligible. Additionally, men with low risk cancers whose PSA is up to 15 will also be considered, as long as the PSA density is <0.2 ng/ml/cc. Patients will be counselled as to the option of Active Surveillance, as well as immediate intervention.

Active Surveillance Protocol Schedule

Re-biopsy upon entry (within 3 months) 8-12 biopsy cores, the greater number being in those with larger prostate glands,[5] unless the initial biopsy was considered adequate. The specimen will be reviewed by a reference pathologist. The specimen will be centrally stored for possible future analysis.

  • PSA (& serum may be frozen and stored for selected patients), every 3 months for 2 years then 6 monthly
  • DRE every 6 months for 2 years then annualy
  • Rebiopsy every 3 years, unless indicated earlier. Rebiopsy if PSA doubling time >3 and <10 years), but no more than 1 biopsy per year
  • Annual re-evaluation point for continuation of Active Surveillance.

Indications to exit the program and consider intervention

  • PSAdt (based on minimum 3 values) faster than 3 years
  • Appearance of primary or secondary Gleason 4 or any Gleason 5 pattern on rebiopsy
  • Clinical stage progression to T3
  • Patient choice

Treatment Options

  1. Radical prostatectomy with or without pelvic lymph node dissection
    1. Node dissection may not be necessary in low risk disease
    2. Positive pelvic nodes at exploration are an indicator of disseminated disease. Radical prostatectomy is not indicated in the presence of grossly positive pelvic lymph nodes and early androgen suppression therapy is indicated. In some patients with microscopic disease in lymph nodes, radical prostatectomy may be completed. This situation should be clarified with the patient prior to surgery
    3. A nerve sparing procedure should be avoided on the side of the lesion (T2a) or with significant apical disease. Neoadjuvant androgen withdrawal therapy reduces the risk of positive margins by 50%, but since the effects on recurrence rates are not yet known, it should not be routinely employed off study
  2. Radical Radiotherapy
    1. External beam radiation. Patients with a bulky primary tumour may additionally benefit from neoadjuvant androgen ablation (see high risk section)
    2. Brachytherapy
      Prostate Brachytherapy is a standard treatment for early stage, localized prostate cancer. The Provincial Prostate Brachytherapy Program was established 11 years ago. Within the BCCA umbrella, over 2,500 patients have been implanted using common selection criteria, treatment algorithms, and quality control. The procedure is done using a real-time ultrasound guidance and fluoroscopy, as originally developed by the Seattle group, 20 years ago. Most implants are done with general or spinal anaesthesia, all as a day-care procedure, over a period of 1 hour. Most men return to their usual daily activity within days after the procedure

References:

  1. Pickles, T. and Prostate Cohort Outcomes Initiative. Low risk prostate cancer carries a minimal risk of prostate mortality and intensification of treatment should be questioned. ASCO-ASTRO Prostate Symposium. 2006.

  2. Murthy, V., et al., Recovery of serum testosterone after neoadjuvant androgen deprivation therapy and radical radiotherapy in localized prostate cancer. BJU Int, 2006. 97(3): p. 476-9.

  3. Draisma, G., et al., Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst, 2003. 95(12): p. 868-78.

  4. Klotz, L., Active surveillance with selective delayed intervention for favorable risk prostate cancer. Urol Oncol, 2006. 24(1): p. 46-50.

  5. Vashi, A.R., et al., A model for the number of cores per prostate biopsy based on patient age and prostate gland volume. J Urol, 1998. 159(3): p. 920-4.

 

5.2 Intermediate Risk

Updated 30 June 2009

Intermediate Risk (neither low nor high risk, and therefore have any of the following):

  • PSA >10 ng/mL
  • Gleason =7
  • Stage 2c (2002 TNM)

In the physically fit individual with life expectancies longer than ten years, radical prostatectomy or radiotherapy should be considered. In general, radical surgery is reserved for patients less than 72 years of age who are otherwise in excellent health.

Treatment Options

a) Radical Surgery

Radical surgery is indicated in selected patients with tumours clinically confined to the prostate and life expectancies longer than 10 years. A nerve sparing procedure should be avoided on the side of the lesion or with significant apical disease. Neoadjuvant androgen withdrawal therapy reduces the risk of positive margins by 50%, but since the effects on recurrence rates are not yet known, it should not be routinely employed off study.

b) Radical Radiotherapy

Patients with high-intermediate risk disease (those with PSA >=15, or Gleason >=7 scores or with a bulky primary tumour) are considered for neoadjuvant-adjuvant androgen ablation as described in the section for high risk disease.

  • External beam radiation
  • Brachytherapy
    A comprehensive program for prostate brachytherapy was introduced at the BC Cancer Agency (BCCA) in November 1997 and the first cases were done July 20, 1998. As of June 2009, nearly 2,600 men have been treated with prostate implants at BCCA, making it the largest prostate brachytherapy program in Canada. On average, eight to ten men in BC undergo this form of treatment each week.

    About two thirds of all newly diagnosed prostate cancer patients are considered good candidates for prostate brachytherapy within the BCCA program. Eligible patients.

    Patients seeking a consultation with a Radiation Oncologist must be referred to one of the regional cancer centres by​ their specialist (Urologist) or family physician. Patients should feel free to request such a referral if it is not initially offered to them.

5.3 High Risk

​Updated 18 August 2009

High Risk (must have any of the following):

  • PSA >20 ng/mL
  • Gleason >=8
  • Stage T3a or greater

Treatment Options

Depending on the patient's age, general health, and disease-related parameters, a variety of therapeutic approaches may warrant consideration including combined radiation and androgen deprivation therapy, radical prostatectomy, radiotherapy alone, or androgen deprivation therapy alone.

Comparison of surgery and radiotherapy is hampered by a lack of randomised head-to-head trials, different definitions of high risk disease and biochemical recurrence, as well as variable addition of androgen deprivation therapy in reported series. Both are considered potential curative treatment options for appropriate cases in a multimodal therapeutic strategy to optimize outcomes in patients with high risk localized disease.

The combination of radiotherapy and androgen deprivation therapy contribute to incremental improvements in disease free and overall survival compared to either alone.

Multi-centre randomized trials have demonstrated improved overall survival, disease free survival, and local tumour control following external beam radiation therapy combined with concurrent and adjuvant androgen suppression of up to three years duration when compared with radiation therapy alone in men with high risk prostate cancer.

Neoadjuvant therapy has also shown benefit when given for several months prior to radiation. [Bolla et al: NEJM 1997:337/5;p295; Pilepich et al: J. Clin. Oncol.1997;15/3;p1013; Pilepich et al Urology, 1995,45:616-63; RTOG 92-02 ASCO 2000].

Three years of androgen deprivation therapy has been shown to be more effective than six months of androgen deprivation therapy with respect to biochemical and a modest improvement in overall survival (Bolla et al, NEJM 2009:360; p2516); however, the optimal duration of androgen ablation continues to be defined. The use and duration of use of androgen ablation prior to the start of radiotherapy (ie neoadjuvant component) is also evolving, but prospective trials suggest that up to eight months of neoadjuvant androgen ablation is an option (Crook et al. Int J Rad Onc Biol Phys: 73(2); 327-333. Denham et al. Lancet Oncology:2005; 6(11);841-850.)

The optimum duration of adjuvant androgen deprivation therapy and the trade-off between toxicity and potential benefit depends on disease and patient factors and will be individualized in consultation with the oncologist. The combination of radiotherapy with non-steroidal anti-androgen based mono-hormonal therapy compared to non-steroidal anti-androgen therapy alone, improved the ten year overall survival by 10% in one large study (Widemark et al: Lancet 2009: 373;301-308).

Patients who are candidates for curative radiation treatment for localized prostate cancer, but who have "high-intermediate" or high-risk criteria may also be offered neoadjuvant androgen deprivation therapy for up to eight months duration, to be followed by concurrent/adjuvant therapy (giving a total duration of up to three years), in addition to their definitive radiotherapy. In addition, selected patients with bulky benign prostate glands containing low-risk tumours may require neoadjuvant therapy to reduce the volume of tissue irradiated and so reduce toxicity.

The use of neoadjuvant androgen deprivation therapy in the 'low-risk' patient should be avoided because the patient will be exposed to toxicity of androgen deprivation treatment with evidence of increased morbidity and mortality from androgen deprivation therapy in some studies. Generally, the survival benefit seen in randomized trials has been limited to those with high risk cancer, and benefits with intermediate risk patients are limited to biochemical control advantages.

Several randomized trials have demonstrated a disease free survival benefit to dose escalation to doses 74 Gy compared to lower doses (Int J Rad Onc Biol Phys 72(4): pg 980, Dearnaley, Lancet Oncology 2007, Kuban, Int J Rad Onc Biol Phys 2007). Selected patients may also be offered total androgen blockade in the neoadjuvant period. The use of image guided and or intensity modulated radiotherapy may improve outcomes with radiotherapy in terms of toxicity or disease control. The role of brachytherapy as a component of dose escalation for high risk prostate cancer patients is evolving. High risk prostate cancer patients may be eligible for clinical trials investigating the role of radiation dose escalation (eg ASCEND RT), or the use of neoadjuvant chemotherapy prior to radiotherapy (eg DART), or prior to surgery (eg NCIC PRC.3/CALGB 90203).

Referring doctors are asked not to institute androgen suppression therapy prior to consultation with a radiation oncologist or the treating urologist because:

  1. the extent of the disease and the appropriate size of potential radiation fields may become difficult to judge after castration-induced tumor regression; and
  2. this may affect a patient's eligibility for proposed and ongoing clinical trials.

The role of radical prostatectomy in the context of potential multimodal therapy for high risk clinically localized prostate cancer is supported by accumulating evidence.

In a series of 240 patients with high risk localized prostate cancer who underwent radical prostatectomy (with androgen deprivation therapy in 71%) at Vancouver General Hospital, PSA recurrence (defined as >0.4 µg/L) was 31%. Those patients with only one adverse factor had good PSA control of ~60% at five years, whereas those with mulitple adverse factors had a brief time to relapse of only ~ two years.

A series of 842 patients from the Mayo Clinic with clinical T3 disease and a median follow-up of > ten years after prostatectomy reported biochemical progression-free survival 43% at ten years; 78% received ADT and 41% radiotherapy at some point after their surgery (Ward BJU 2005).

Similar results are reported from a Belgian surgical series of 235 clinical T3a CaP patients, reported biochemical PFS of 51.5% at ten years (Hsu Eur Urol 2007), although 56% of these patients had either adjuvant or salvage RT and/or ADT.

Post Radical Prostatectomy Adjuvant Radiotherapy

Post-radical prostatectomy radiotherapy is recommended for patients with pathologic T3 (ie extracapsular extension or seminal vesicle invasion) or margin positive disease who are considered at high risk of local recurrence.

Three randomized trials have demonstrated a reduction of the risk of recurrence after early adjuvant radiotherapy for men with pT3 cancer or positive margins after a radical prostatectomy, compared to no early adjuvant radiotherapy (Wigel et al, JCO 2009: 27(8); pg2924. Thompson et al, J Urol. 2009: 181: pg956. Van Der Kwast, JCO 2007: 25(27): pg4178), and one study has showed a 10% increase in ten year overall survival.

As a result, early adjuvant radiotherapy is considered the standard of care for patients with these risk factors. Subgroup analysis from some of the studies have suggested the benefit is restricted to those patients with positive margins (Van Der Kwast, JCO 2007: 25(27): pg 4178.), and the three randomized trials predate the use of routine PSA testing in follow-up, therefore ongoing randomized trials are testing the hypothesis that salvage RT at time of first PSA relapse will provide a similar outcome to adjuvant RT.

We recommend referral to the BC Cancer Agency for consultation with a radiation oncologist for patients with pT3 disease or positive margins, prior to any adjuvant hormonal treatment and early (within three months of surgery) in the postoperative period. Observation alone may be appropriate in some candidates. Patients may be offered enrollment in the RADICALS trial, which is an international phase III study testing whether early adjuvant radiotherapy is more effective than radiotherapy delayed until PSA is rising. This study also randomizes patients to the addition of androgen deprivation therapy for various durations for patients considered to need radiotherapy.

Other clinical trials may be available at the time of PSA relapse after prostatectomy (eg Tax 3503, which is examining the role of Taxotere in addition to salvage androgen ablation). There is a list of Open Clinical Trials on the Genitourinary page.

T4 N0

Treatment needs to be individualized and may involve radical or palliative radiotherapy and/or early or delayed androgen deprivation therapy. Radiotherapy in addition to androgen deprivation therapy is likely to improve local control and may confer additional metastasis free and overall survival benefit for some patients (Widemark et al: Lancet 2009: 373;301-308).

Stage Any T, N1-3

Treatment Options

  • Early or delayed androgen deprivation therapy, and/or

    The general trend is towards immediate androgen withdrawal therapy at the time of diagnosis of metastatic disease rather than waiting for symptomatic progression.

    Increasing and evolving evidence suggests that treatment should commence at the time of diagnosis of locally advanced or metastatic disease. However, some delay of treatment in sexually active, asymptomatic men is a reasonable alternative, and the potentially adverse effect on quality of life should be taken into account (JCO 2006: 24(18S);4513, JCO 2007: 25(18S); 5015).

    The use of intermittent androgen ablation has been examined in several randomized trials and initial results suggest that survival rates are not compromised with intermittent androgen ablation.

Systemic Management of Prostate Cancer

​Reviewed July 2005

Patients are appropriate candidates for androgen withdrawal therapy if they have metastatic disease or locally advanced tumours not considered curable by radical radiotherapy alone. Neoadjuvant therapy may be indicated prior to planned radiotherapy but is not recommended routinely outside of clinical trials prior to radical prostatectomy. For further details, please see the menu of additional topics.

Chemotherapy

Updated: 9 November 2004​

Because of the difficulty of treating many patients in this population and also evaluating the response, cytotoxic chemotherapy is only recommended in suitable selected patients with active drugs with low subjective toxicity. The combination of Mitoxantrone and Prednisone (GUPMX) has demonstrated clinical palliative benefit in patients with painful bone metastases without improvement in overall survival. More recently, in randomized studies, Docetaxel given every three weeks in conjunction with prednisone (GUPDOC) has been shown to improve overall survival and provide superior pain relief and improvement in quality of life parameters, as compared to mitoxantrone. Palliative benefit is most likely to accrue to patients where general condition and marrow function is adequately preserved.

Suitable criteria:

  • Early recognition of hormonal resistance and disease progression e.g., rising PSA despite castrate levels of testosterone and failure of trial of secondary nonsteroidal antiandrogen therapy
  • Minimal prior radiotherapy (less than 25% of bone marrow)
  • At least partially ambulatory
  • A parameter measurable for response (palpable tumour mass, rising serum PSA, or symptoms that can be evaluated)

Refer suitable patients early to the medical oncology service for consideration of chemotherapy, after recognition of development of hormone resistant disease. Chemotherapy may be delayed in asymptomatic patients without visceral disease. Patients in severe and/or uncontrolled pain should be first managed with radiotherapy and analgesics as appropriate.

Details of current protocols are available on request.

References:

  1. Tannock IF. de Wit R. Berry WR. Horti J. Pluzanska A. Chi KN. Oudard S. Theodore C. James ND. Turesson I. Rosenthal MA. Eisenberger MA. TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. New England Journal of Medicine. 351(15):1502-12, 2004 Oct 7.

  2. Tannock IF. Osoba D. Stockler MR. Ernst DS. Neville AJ. Moore MJ. Armitage GR. Wilson JJ. Venner PM. Coppin CM. Murphy KC. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. Journal of Clinical Oncology. 14(6):1756-64, 1996 Jun.

Indications for Antiandrogen Use

Updated January 23, 2014​

Effective immediately bicalutamide 50 mg daily will replace flutamide 250 mg tid as the preferred antiandrogen for prostate cancer. Apart from more convenient once-daily administration it is also better tolerated, and is now available. Patients currently on flutamide may switch to bicalutamide at the physician's discretion.

Indications include:

  • Prevention of the flare phenomenon during the first month of LHRH agonist treatment (bicalutamide 50 mg daily; flutamide 250 mg t.i.d; nilutamide 50 mg daily [class II] if intolerant to bicalutamide or flutamide)
  • Biochemical (PSA) or clinical progression in patients medically or surgically castrated. A three month trial with continuation only if there is a decrease in the serum PSA. Second-line treatment should not be continued in the face of progressive disease although permanent castration (surgical or medical) is recommended to avoid stimulation by androgens
  • During neoadjuvant therapy prior to radical radiation therapy, an antiandrogen will be added if there is a PSA rise, or if an inadequate PSA response is observed (defined as failure to achieve a PSA of greater than 1 ng/mL after 4 months of adequate therapy as defined by castrate testosterone levels)
  • Total androgen blockade of advanced prostate cancer (approved indication only for bicalutamide or flutamide)

Monotherapy with bicalutamide 150 mg/day is not approved. The drug does not have a license for this use in Canada as a result of efficacy and safety concerns.

All three antiandrogens (bicalutamide, flutamide, and nilutamide) are equally efficacious. Side effects of bicalutamide include diarrhea, nipple tenderness and gynecomastia. Side effects of flutamide include diarrhea, abnormalities in liver function enzymes, and occasional jaundice. Liver function tests should be monitored periodically if used continuously for long (over 3 months) periods of time. Side effects of nilutamide include night blindness, alcohol intolerance and rarely, interstitial pneumonitis.

  • Patients who are intolerant to bicalutamide may be switched to other antiandrogens (flutamide, [class1] or nilutamide if flutamide intolerant [Class 2])

Medical Castration

Updated 12 April 2007​


Alternatives to orchidectomy are appropriate when patients refuse surgery, when surgery is contraindicated or in candidates where reversible agents are indicated (i.e. intermittent androgen suppression or neoadjuvant therapy). The goal of medical therapy is to achieve castrate levels of testosterone. The medical equivalents of surgical castration include:

The initial stimulation of the pituitary caused by LHRH agonists produces an acute increase in the concentration of plasma testosterone accompanied by symptoms and signs of a flare reaction in 5 to 10 percent of patients. To avoid the flare reaction, the nonsteroidal antiandrogen bicalutamide (50 mg daily) or flutamide (250 mg t.i.d) should be given concurrently with the first administration of LHRH agonists to block the flare reaction. Nilutamide (150 mg daily) is reserved for patients who are unable to tolerate bicalutamide or flutamide (a class II form must be submitted before this is dispensed to the patient).

Alternatively, cyproterone acetate 100 mg bid should be given as lead-in therapy for three to four weeks prior to the first dose of LHRH agonist.

Since the danger of a flare reaction abates after the second week following LHRH agonists, there is currently a lack of convincing evidence for continuous antiandrogens after the first month of therapy. Side effects of LHRH agonists include loss of libido, impotence, hot flushes, and rarely local tissue reaction at the injection site.​

Palliative Radiation Therapy or Surgery

Reviewed July 2005​


Radiation therapy should be considered early for patients with spine metastases which are symptomatic or associated with significant vertebral body compression or paraspinal mass, so as to minimize the risk of debilitating spinal cord compression. Palliative TURP is indicated for patients in retention or with significant obstructive symptoms, or bleeding, but there may be an increased risk of postoperative incontinence secondary to sphincteric invasion.

Radiation therapy may relieve other symptomatic sites particularly in the setting of hormone refractory disease. For patients with incurable disease but locally extensive and potentially troublesome tumour burden in the prostate, radiation therapy can provide effective local control.​

Radionuclide Therapy for Hormone Resistant Metastatic Disease

Reviewed July 2005​


Radionuclide therapy in the form of systemic Strontium-89 therapy may be useful in the palliation of hormone resistant metastatic carcinoma when multiple skeletal sites are involved in various carefully selected patients. Refer such patients to Radiation Oncology for consideration.​

Surgical Castration

Reviewed July 2005

First-line treatment of metastatic prostate cancer is orchidectomy. This can be done under local or regional anesthesia and remains the standard, as it is permanent and cost-effective. Surgical complications are minimal. In the short term, there are minimal side-effects (loss of libido, impotence, and hot flushes). Long term androgen deprivation may result in anemia, osteoporosis, lipid profile changes and loss of muscle mass. There is no role for routine addition of steroidal or nonsteroidal antiandrogens following orchidectomy. Indications for the use of antiandrogens following orchidectomy are outlined in the Indications for Antiandrogen​ Use section of this page.

Zoledronic Acid

Published: 27 June 2005

There is level 1 evidence that Zoledronate at 4 mg IV adminstered every 3 weeks for 12-24 months reduces skeletal related events (SREs) in men with hormone resistant prostate cancer and bone metastases. SREs were defined as a pathological fracture, radiation thereapy to bone, surgery to bone, or a change in chemotherapy to treat bone pain. Zoledronate produces an 8% absolute reduction (from 44-36%) in SREs at 15 months. The annual incidence of SREs was 0.77 for the 4-mg zoledronic acid group versus 1.47 for the placebo group. This translates into a number need to treat of 12 patients to prevent 1 skeletal related event. This is not associated with any definitive demonstration of survival benefit, pain or quality of life improvement. Repeated intravenous administrations of Zoledronate can have adverse effects and its use must be balanced by the benefit. A request for BCCA funding for Zoledronic Acid was not successful, however, Zoledronate is available for use under the palliative drug benefit program, which is designed to provide support within the last 6 months of life.

Background information on bisphosphonates in prostate cancer

In the context of androgen deprivation therapy osteoporosis may be found or develop. Bisphosphonates have a significant role to play in the treatment of established osteoporosis. Although bisphosphonates (and other products) will benefit bone density in patients without osteoporosis, it is not clear that there will be any reduction in fractures - the key endpoint in prevention. Medical interventions, on the other hand, may have complications and costs. For more detail please see Osteoporosis Screening Guidelines.​

In view of practice trends and requests, the BC Cancer Agency (BCCA) Genitourinary (GU) Tumour Group has reviewed the evidence of the role of bisphosphonates in hormone refractory prostate cancer. We agree with the Ontario guidelines (Berry et al) in regards to the cited references and most of their conclusions. The BCCA GU Tumour Group does not agree with the conclusions of Berry et al on the use of clodronate for metastatic bone pain in prostate cancer patients.

Although evidence supports the use of bisphosphonates in pain relief (9000 patients from 51 randomized trials), the effect is small (about 0.5 in a 10 point pain scale) and delayed by about 12 weeks (Wong 2004). At present there is insufficient evidence to support their first line use for bone pain. When analysis is focused on evidence in the context of metastatic prostate cancer the effects are minimal and only a trend on subset analysis of a clodronate trial. In view of the benefits from analgesics, co-analgesics, radiotherapy (including strontium), chemotherapy and on occasion surgical intervention, the role of bisphosphonates for pain relief should be considered as an adjunct to these approaches where pain control proves difficult.

References:

  1. Genitourinary Cancer Disease Site Group. Berry S, Waldron T, Winquist E, Lukka H. The use of bisphosphonates in men with hormone-refractory prostate cancer [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2005 Jan 10. 34 p. (Practice guideline report; no. 3-14). [43 references] http://www.cancercare.on.ca/pdf/pebc3-14f.pdf

  2. Wong R, Shukla VK, Mensinkai S, Wiffen P. An assessment of bisphosphonate drugs to manage pain secondary to bone metastases [Technology overview no 14]. Ottawa: Canadian Coordinating Office for Health Technology Assessment; 2004.

  3. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma.[comment]. Journal of the National Cancer Institute 2002;94(19):1458-68.

  4. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. Long-Term Efficacy of Zoledronic Acid for the Prevention of Skeletal Complications in Patients With Metastatic Hormone-Refractory Prostate Cancer. J Natl Cancer Inst 2004;96(11):879-882.

Follow-up

The main goal of follow-up is the early detection of recurrence in those situations where the early institution of salvage therapy can cure or prolong life. Local recurrence after radical prostatectomy may be an example. In contrast, most patients who have received primary radical radiation therapy may only be managed palliatively in the event of recurrence, and the value of routine follow-up is questionable.​

Definitions of Biochemical Relapse

A rising PSA profile is indicative of recurrent disease but does not distinguish local from metastatic relapse.

Definition of a PSA recurrence:

  1. after radical prostatectomy: two successive increases to a level >0.3ng/ml
  2. after radical radiation therapy: relapse may occur following achievement of a nadir, which typically takes 12-24 months to be reached

The ASTRO definition of PSA relapse is three consecutive rises from the nadir, with a minimum value of 0.5ng/ml. This definition, although widely accepted, has been criticized and the Vancouver definition is currently preferred. The Vancouver definition is at least two successive rises to a level of at least 1.5ng/ml.

Patients treated with brachytherapy may experience a ‘bounce’ in the PSA level, typically occurring 1-3 years post-therapy, where PSA levels may rise temporarily to 4 ng/ml or greater. This is thought to be due to a non-infective prostatitis or necrosis. In these patients advice from a radiation oncologist should be sought. Prostate biopsy should not be performed as interpretation is difficult and may be misleading due to continuing tumour cell death ( i.e. most "indeterminate" biopsies performed 2-3 years after prostate brachytherapy are false positives and will revert to negative with longer follow-up). Biopsy results post prostate brachytherapy should thus not be used to guide treatment decisions.

In full detail the ‘Vancouver Rules for PSA relapse following radiation’ are as follows:

  1. The true nadir is the lowest post-therapy PSA value. The reference nadir is the lowest reading, which is not followed by a subsequent fall
  2. There must be at least two consecutive increases above the reference nadir, measured at least 1 month apart
  3. A PSA level of at least 1.5ng/ml is required, at any time after the reference nadir, before PSA relapse can be scored
  4. The relapse is timed from mid-way between the reference nadir and the first post-nadir reading
  5. Special rules apply where the true nadir is >4: Relapse is scored at the true nadir time. No further rises are needed. If the true nadir occurs over 1 year out from completion of radiation, the relapse is timed at 1 year
  6. Patients are also scored as relapsing at the time of any therapeutic intervention (as distinct from neo- or adjuvant hormone therapy). For example, hormones, orchiectomy, salvage therapy etc.

Post-Radical Prostatectomy

revised 26 March 2001

Digital rectal examination and tumour marker measurement in the form of PSA are recommended at regularly scheduled intervals (e.g. three-monthly in the first year, increasing to six-monthly). Elevation of PSA (see definitions below), or a palpable nodule (biopsy confirmed) suggests disease recurrence and that local radiotherapy or hormonal therapy may be considered. Patients with positive margins or capsular penetration may benefit from adjuvant therapy (under clinical trials at present). Such patients should be referred for an oncologic opinion.

Post-Radical Radiotherapy

revised 26 March 2001

​Rare younger patients (fit men under 70 years) irradiated for stage T1-T2a disease may be candidates for salvage prostatectomy and should be identified by periodic follow up including PSA (see definitions of relapse below), and clinical examination. The redevelopment of a palpable nodule (biopsy confirmed) is indicative of recurrent local disease. Six-monthly clinical and biochemical examination for three years, then increasing to annually, is suggested.

​For remaining patients, early detection of recurrent disease through PSA, and subsequent earlier hormonal intervention, have not been shown to improve quality of life or overall survival. Results of ongoing randomized studies may lead to the identification of sub-groups of patients who may benefit directly from routine follow-up and subsequent early treatment. In general however, routine examination or tests in such patients are unhelpful and are not recommended.

Long-term complications following radiation are rarely severe (~1% RTOG grade 4 and ~5% grade 3 toxicity). Minor ano-rectal bleeding, alteration of bowel habit, and impotence are more common. Typical post-radiation changes in the rectum are of anterior wall telangiectasia. This area should only be biopsied with caution, as healing may be impaired. Urethral stricture is usually only seen in those who had TURP or other urethral surgery prior to radiation therapy. Urinary incontinence is very unusual (<1%).

Selected groups of patients may be asked to attend routine follow-up at one of the BC Cancer Agency clinics. They are being followed with the aim of providing accurate outcomes information to the treating oncologist.

It should be noted that prostatic cancer usually regresses slowly after radiation and palpable nodularity is frequently present in excess of one year post-radiation. A biochemical nadir may also take up to three years to be reached following radiation.

Brachytherapy Guidelines

​ Revised 28 April 2014

LDR - Prostate Brachytherapy

Prostate brachytherapy can be used as a monotherapy for low and intermediate risk, as a monotherapy or in combination with HT for high-tier intermediate risk, or with external beam radiation therapy (EBRT) as a form of dose escalation for selected intermediate and high risk patients.

BCCA Prostate Brachytherapy Program Brachytherapy Eligibility

 

 

Low risk*

Low-tier Intermediate risk

High-tier Intermediate risk

High risk

Definition

<T2a and iPSA < 10 and GS<6

<T2c and:
iPSA 10-15 with GS=6
or GS=7 with iPSA<10

<T2c and:
iPSA 15-20 and GS=6
or iPSA 10-20 and GS7

T3a or
iPSA 20-40 or
GS 8-10

Recommendation

Brachy monotherapy

Brachy monotherapy

EBRT 44-46Gy & Brachy boost

Min 3-4 mo neoadjuvant HT, followed by EBRT & brachy boost.
HT duration: 12-36 mo.

Notes

 

*Minimal risk

(PSA density<0.2, 1-2 cores GS6 on adequate biopsy sampling, and <T2a. Active surveillance is recommended.

 

Option

1. Brachy & 6 mo HT (3m neoadjuvant & 3m adjuvant)
2. Brachy monotherapy
3. EBRT & Brachy boost & 6-12m HT

Option

CS <T2a, iPSA <10, GS 8-10 in
< 2 cores:

EBRT 44-46GY & Brachy boost, with 6 mo or no HT 

 

 

Additional general eligibility criteria (1)

  • Life expectancy >10 years (2)
  • Patients with Gleason sum ³ 8 and PSA >20 must have a CT pelvis, and nuclear medicine bone scan showing no evidence of nodal (N0) or distant metastases (M0)
  • Must be suitable for general or spinal anaesthetic (anaesthetic consultation suggested during neoadjuvant HT)
  • Patients on Coumadin therapy must be able to stop the therapy safely for at least 5 days.
  • Additional notes (informal consultation with brachy doctor if concerns)
  • Prostate size >50-60cc prior to brachytherapy (which may include anticipated cytoreduction during neoadjuvant ADT)
  • Cytoreduction prior to Brachy monotherapy: 3 mo neoadjuvant and up to 3 mo adjuvant LHRH agonist/ antagonists or 4-6 month combination of Avodart 0.5 mg with Casodex 50 mg.
  • Good baseline urinary function. If IPSS score >20, must have suitable flow rates
  • No, or limited TURP prior to PC treatment
  • No inflammatory bowel disease if EBRT is recommended. Brachy monotherapy +/- HT may be an option
  • EBRT may comprise whole pelvis, small pelvis or prostate only.

Low risk and Low-tier intermediate risk PC

Depending on the patient's age, general health, and disease-related parameters several therapeutic options may warrant consideration including; active surveillance for patients with minimal risk disease (recommended), brachytherapy alone, (with or without HT for cytoreduction only), radical prostatectomy, EBRT (with HT in selected patients), watchful waiting (for patients with significant co- morbidity or old age) or HT alone. [See low risk PC under Management]
LDR monotherapy is a standard treatment option for low risk prostate cancer. Good candidate for brachytherapy include men with > 10 years life expectancy, low co- morbidity, good baseline urinary function, prostate size < 60 cc, limited TURP defect.

High-tier intermediate risk and high risk PC

Depending on the patient's age, general health, and disease-related parameters, a variety of therapeutic approaches may be appropriate including: EBRT combined with hormone therapy (HT) (with or without dose escalated radiation using EBRT or brachytherapy), or brachytherapy +/- HT +/- EBRT (high-tier intermediate risk), or radical prostatectomy, EBRT alone, or HT alone. [See also intermediate risk PC and high risk PC under Management].

  1. Patients with high-tier intermediate risk and selected patients with high risk PCa (CS </=T2a, iPSA<10, and Gleason sum 8-10 provided there are no more than 2 cores with predominate Gleason pattern 4 -5 and the total length of the involvement of pattern 4-5 is </= 10mm) are offered EBRT 44-46Gy directed to the prostate, peri-prostatic tissue and seminal vesicles or small pelvis (or whole pelvis), followed by a LDR prostate brachytherapy boost of 110 Gy or HDR boost. HT in this group of patients is optional, but not mandatory. Patients with high risk disease (PSA <40, GS 8-10 or >T3a) are offered pelvis radiotherapy (44-46Gy) followed with LDR prostate brachytherapy boost of 110 Gy or HDR boost, together with HT(12-36 months). Duration of HT may be modified based on disease and patient and treatment factors (6-36 mo).

Use of Hormone Therapy Together with Prostate Brachytherapy

(HT more information see Medical Castration)

The addition of hormone therapy (HT) to prostate brachytherapy had failed to produce additional benefit to PSA recurrence-free survival (PRFS) with quality brachytherapy (1,3,4). While initial analysis of BCCA data shows small benefit to PRFS with HT(5)(6), recent BCCA 10 year update shows no additional benefit of HT on improving long term PSA outcome in low and low-tier intermediate risk patients with optimal implant dosimetry (good implant quality)(7). Use of HT appears to increase the risk of cardiac morbidity and sudden cardiac death, (this may be restricted to those with other baseline risk factors), and can be associated with a higher risk of diabetes, osteoporosis, glucose intolerance, muscle mass wasting, fatigue, decrease in QOL, decrease in sexual function and cognitive dysfunction(8). Patients with high-risk features being considered for primary EBRT are known to benefit from treatment combined with HT from multiple randomized prospective trials (9,10). Dose escalation using any form of brachytherapy further improves the PSA outcomes, as well as PCa cause specific survival (11)(12). The additional benefit of prolonged HT in combination with dose escalation using EBRT and brachytherapy boost is less significant than with EBRT alone (13,14).(15)(16)

Cytoreduction and Brachytherapy

Hormone therapy (HT) is used in conjunction with PB in order to downsize prostate gland and reduce pubic arch interference (make the implant technically easier/ possible). Cytoreduction can be accomplished by using 3 mo neoadjuvant and up to 3 mo adjuvant LHRH agonist (with antiandrogen given concurrently for one to three months) or LHRH antagonists. Total Androgen Blockade (TAB) has been shown to reduce prostate volume faster and to a greater degree than LHRH agonist alone. Cytoreduction can also be accomplished using combination of Avodart 0.5 mg with Casodex 50 mg daily for at least three months prior to and minimum one month after the implant (17).

Patients with relatively large prostates ( 50 -60cc) may have increased urinary morbidity with prostate brachytherapy (18,19). HT may be used to reduce the prostate volume; however, the morbidity of prostate brachytherapy may be more closely correlated with the pre-cytoreduced volume than the post-cytoreduced volume. Men with median lobes that project superiorly into the bladder are difficult to implant and may have a high risk of acute and prolonged urinary retention. Median lobe resection prior to brachytherapy may be considered and discussed with urologist. The use of peri- and post-operative dexamethasone may reduce the incidence of acute urinary retention in men with large prostates and/or high IPSS scores.

BC Cancer Agency Prostate Brachytherapy Provincial Program

The British Columbia Cancer Agency (BCCA) program started in 1997, and to date has treated over 4500 patients; this is the largest program in Canada and one of the largest in the world. The current volume of over 550 implants per year is shared between 16 Radiation Oncologists. LDR brachytherapy is available at centers in Vancouver, Victoria, Fraser Valley/Abbotsford and Kelowna. All centers use techniques based on the Seattle experience combined with a planning algorithm developed in house and use consistent treatment protocols, selection criteria, and rigorous quality control (20). Numerous series with surgery have shown that the single most important factor affecting surgical outcomes (cure and toxicity) is institutional and individual surgeon experience. Generally a minimum case-volume is 30/year (21). Similar case-volumes exist with brachytherapy (22,23). A large provincial prospective database records baseline disease characteristics, technical (dosimetric) details, as well as follow up PSA and side effect scores on most patients. HDR is offered in context of clinical trial only (Kelowna).

BC Cancer Agency Prostate Brachytherapy Program - Published Outcomes

Low and Low-Tier Intermediate Risk PC

The BC Cancer Agency Brachytherapy Program has recently published10 year biochemical control rates of the first consecutive 1,006 patients (7)(5,6) . With median follow up of 7.5 years (42% intermediate risk and 58% low risk) show 5-year and 10-year disease free survival of 96.7% and 94.1% respectively. (7) Median PSA for the entire group was 0.04 ng/ml, indicating that long-term cancer cure is likely in the majority of patients (24).

Consistent with the PCRSG PC systemic review (25), a recent BC Cancer Agency matched-pair analysis shows that men treated with PB have superior outcomes for PSA control when compared to external beam radiation (EBRT). Five year PSA recurrence free rates are 95% (BT) and 85% (EBRT). After seven years, the BT result was unchanged, but the EBRT had fallen to 75%. Toxicity rates in this study show worse late urinary toxicity with BT, but worse bowel toxicity with EBRT(26).

Figure: The Fine and Gray’s Competing Risks estimates of disease free survival (DFS) and cause specific survival (CSS), and the Kaplan-Meier estimate for overall survival (OS) for all patients in the cohort (N=1006). (7)
 


High -Tier Intermediate and High Risk PC- 2012

In November of 2002, BCCA opened a randomized control phase II trial (accrued 41), which was further expanded to a randomized phase III trial in October 2004 (accrued 357) (ASCENDE RT), to compare the efficacy and toxicity of dose escalated radiating using EBRT vs. EBRT plus brachytherapy. Eligibility criteria included patients with ≤ Clinical stage (CS) T3a, any Gleason score (GS) and an initial PSA (iPSA) ≤40 ng/mL. All patients received 12 months HT (8 months neoadjuvant) and elective pelvic nodal irradiation (46Gy/23 fractions 4 field conformal). Randomization was between high dose conformal EBRT (78Gy total dose to prostate) vs. a brachytherapy boost (115Gy, I125 Permanent Prostate Implant)(27). Trial was closed Dec 1, 2011. Results are pending publication. An interim analysis of ASCENDE-RT phases II-III (including all patients started on LHRH injections on or before Aug 31, 2006 N=161 pts) showed superior outcomes with combination of EBRT with brachytherapy boost as compared with an EBRT alone. Single institution reports (14,29, 30, 31) and comprehensive literature review showed excellent long term outcomes in this group of patients treated with EBRT and brachytherapy, without HT (25).

Prostate Brachytherapy - PSA Outcomes

Based on published retrospective cohorts, PSA recurrence free survival for low and intermediate risk disease is exceeding 90%.(7,14,28,29) Patients treated with “triple therapy” for high risk disease also achieve excellent long term disease control (>85%)(30,31). There no randomized control trials to offer insight into comparative treatment effectiveness.

The Prostate Cancer Results Study Group (PCRSG) comprehensive literature review (BJU 2012) (25) identified 18,000 studies involving treatment of prostate cancer published during 2000–2010. Only 848 were included in the analysis (>50.000 patients), based on key criteria: minimum/median follow-up of 5 years; stratification into low, intermediate- and high-risk groups; clinical and pathological staging; accepted standard definitions for PSA failure; minimum patient number of 100 in each risk group (50 for high-risk)(3). Patients treated with any form of brachytherapy had not only superior long term PSA outcome, but also showed remarkable durability of the results with long follow up. Unlike EBRT, high radiation dose delivered with brachytherapy produce durable long term outcomes in all PC risk groups, suggesting luck of metastatic disease at presentation in majority of patients (including high risk pCa) and ablative effect of high radiation dose on prostate tissue (24). Patients with all risk disease have excellent long term outcomes with any form brachytherapy. The potential difference in treatment outcome seen in this study may be attributed to different patient selection.

High-tier intermediate risk prostate cancer is a heterogeneous group. Based on published retrospective cohorts, patients with several disease risk factors may benefit from addition of EBRT and/or HT (6-12 months) to brachytherapy (13,14)(15). Preliminary results of ASCENDE RT phase III trial support this practice (27). RTOG 0815 randomized clinical trial is assessing the role of HT in patients with intermediate risk disease is ongoing.

Dose escalation using EBRT in prostate cancer has been proven to increase long term PSA recurrence free survival (PRFS) and, prostate cancer cause specific survival (CSS) in some series (32) but not in meta-analysis of dose escalation trials (33). It is acknowledged that PSA outcomes in PCa are not a surrogate for OS outcomes, however, dose escalation using any form of brachytherapy has been shown to improve the PSA outcomes, as well as PC cause specific survival (11,12)(25). For example, SEER data on 12,745 patients shows that at a median follow-up of only 6 years, use of brachytherapy improves prostate cancer cause specific survival in patients with high- risk/high Gleason Score (GS) prostate cancer (11). Recent BCCA outcome analysis of 1060 patients treated with EBRT with or without HT shows that patients treated with EBRT with or without HT for intermediate risk and high risk disease and estimated 10 year OS of >90% based on age and luck of co-morbidities had significantly improved OS when PC was biochemically controlled(2). It could be argued that striving for high cure rates in all patients with PC is unnecessary, as most patients with localized prostate cancer will die of other causes. However, younger patients with long life expectancy are those most likely to benefit from curative treatment, avoiding difficult issues with disease recurrence and need for secondary intervention with lifelong androgen suppression.

Prostate Brachytherapy Side Effects:

Brachytherapy alone

LDR brachytherapy is an hour long surgical day-care procedure where radioactive seeds are implanted permanently into the prostate. Most implants are done with general or spinal anaesthesia. Patients are discharged 2-3 hours later and resume normal daily activities in a few days. Severe long term side effects are uncommon. Side effects present in here are based on BCCA Prostate Brachytherapy Program peer review publications.

Urinary Side Effects:

Most men will experience some urinary symptoms after the procedure; about 50% will have moderate obstructive and/or irritative urinary symptoms lasting 6-12 months. Median time for IPSS to return to baseline is 12 months. At seven years after PB, the majority of patients (92.5%) will have very little or no urinary symptoms (18,34). Patients with larger prostate volume, worse baseline urinary function, and those given hormone therapy are more likely to have more irritative and obstructive urinary symptoms after PB(18,19). Five to ten percent of patients will require a Foley catheter for urinary obstruction (most for <1 week, 3% of all patients for several weeks or months; again this is more often seen in patients with worse baseline urinary function, protruding median lobes, and those with larger prostate size before implant (19). Long-term, < 3% of men will require urethral dilatation or a TURP (transurethral resection of the prostate) to relieve obstructive urinary symptoms. With greater experience in the program, the overall acute rate of urinary side effects has declined. (19).

Rectal Side Effects:

Mild self-limiting rectal irritation affects 20%-30% of patients in the first 1-2 years after the implant. Rectal bleeding is reported in 2-7% of patients (1-5% will require a laser photocoagulation procedure) (35). Serious rectal injury (requiring major surgical intervention such as colostomy) occurres in 1/500 men treated with brachytherapy at the BCCA.

Inflammatory bowel disease and biopsies of the anterior rectal wall had been a major culprit of this serious complication. Anterior rectal wall biopsies are strongly discouraged as even relatively minor tissue trauma can precipitate development of a rectal fistula due to the poor vascular supply to this tissue after an implant. Similarly, laser coagulation for rectal bleeding is only undertaken when conservative measures have failed, and is best performed by a specialist who is familiar with managing post-brachytherapy complications.

Sexual Function:

A recent BC study of >1400 patients showed that the 8 year potency preservation rate is 60-80% in men age <60, 55-60% in those 60-69 and 20-30% in those >70. Loss of erectile function is most prominent in the first 3 years after the treatment, with little additional deterioration in potency rates at 5 and 8 years after brachytherapy. For the entire BC cohort, erectile function preservation was reported in 50% at 8 years (with 30 % of man using phosphodiesterase -5 inhibitors) (36). This is consistent with results published by others (37).Younger patients and those with better pre-treatment erectile function are likely to do better after the treatment (36,38) Many patients will have improvement in their function with oral GMP-specific phosphodiesterase inhibitors (PDE5 inhibitors: Sildenafil, Verdanefil, Tadalafil).

Brachytherapy in combination with EBRT - side effects

Despite EBRT and PB boost being a standard of care in the USA for over a decade, there has been surprisingly little written about the long terms side effects of the combined treatment vs. brachytherapy alone. A recent report of 585 men with high risk PCa treated with EBRT, brachytherapy and HT (median of 5 years, range, 2-11), showed 6.2% urinary retention, 4.3% incontinence (associated with a post implant TURP), 54.7% potency preservation and, 10.6% Grade 1-2 proctitis and 0.7% Grade 3-4 proctitis (2 ulcers and 2 fistulas)(39). Above toxicity profile is consisted with our brachytherapy monotherapy program results.(18,19,34-36). Toxicity analysis of ADCENDE RT study is pending. Preliminary analysis shows no grade 4 toxicity. Late urinary grade 3 toxicity was higher in brachytherapy arm (5.4% vs.1.2%). Late GI grade 3 toxicity was the same in both arms (1.8 and 1.2%).

Implant Procedure:

The prostate brachytherapy implant is a surgical day-care procedure taking about 1 hour. Patients are discharged home two to three hours later. The radiation oncologist places the radioactive seeds into the prostate through the perineum, using between 20-28 needles, each carrying two to six seeds. The seeds are 0.5 cm titanium shells that contain I125 (Iodine 125) radioactive gas. The half life of I125 is 60 days. As radioactive decay is an exponential function, 50% of the radioactivity is released by two months, 88% by six months, 99% by 12 months.

The procedure is done using a real-time ultrasound guidance and fluoroscopy. Seed placement is guided using three-dimensional co-ordinates predetermined by a customized planning algorithm using computer modeling leaving 90-150 seeds permanently in the prostate. Most implants are done with general or spinal anesthesia (occasionally under local anesthesia). After the procedure a CT scan of the prostate is performed to ensure accurate position of the seeds and adequate radiation dose distribution within the prostate. This is a rigorous QA procedure that was built into our program as a standard practice from the outset. Very rarely, (1 in 200) men may be asked to come and have a second procedure done, where additional seeds may be placed in the prostate.

BCCA Prostate Brachytherapy Program: clinical trials

BCCA Prostate Brachytherapy Program is actively participating in several multi-institutional clinical trials, results of which are expected to further refine the treatment of intermediate and high risk PC. In particular, participation in RTOG 0815 and RTOG 0924 is encouraged. Degarelix trial for prostate downsizing and HDR trial for intermediate risk PC is offered in Kelowna. High risk PC registration trial of surgery vs. radiation and HT is pending, and will be offered initially in Vancouver.

 

References:

(1) Davis BJ, Horwitz EM, Lee WR, Crook JM, Stock RG, Merrick GS, et al. American Brachytherapy Society consensus guidelines for transrectal ultrasound-guided permanent prostate brachytherapy. Brachytherapy 2012 Jan-Feb;11(1):6-19.
(2) Herbert C, Liu M, Tyldesley S, Morris WJ, Joffres M, Khaira M, et al. Biochemical control with radiotherapy improves overall survival in intermediate and high-risk prostate cancer patients who have an estimated 10-year overall survival of >90%. Int J Radiat Oncol Biol Phys 2012 May 1;83(1):22-27.
(3) Stone NN, Potters L, Davis BJ, Ciezki JP, Zelefsky MJ, Roach M, et al. Customized dose prescription for permanent prostate brachytherapy: insights from a multicenter analysis of dosimetry outcomes. Int J Radiat Oncol Biol Phys 2007 Dec 1;69(5):1472-1477.
(4) Potters L, Morgenstern C, Calugaru E, Fearn P, Jassal A, Presser J, et al. 12-Year Outcomes Following Permanent Prostate Brachytherapy in Patients with Clinically Localized Prostate Cancer. J Urol 2008 May;179(5 Suppl):S20-4.
(5) Morris WJ, Keyes M, Palma D, Spadinger I, McKenzie MR, Agranovich A, et al. Population-based study of biochemical and survival outcomes after permanent 125I brachytherapy for low- and intermediate-risk prostate cancer. Urology 2009 Apr;73(4):860-5; discussion 865-7.
(6) Herbert C, Morris WJ, Keyes M, Hamm J, Lapointe V, McKenzie M, et al. Outcomes following iodine-125 brachytherapy in patients with Gleason 7, intermediate risk prostate cancer: A population-based cohort study. Radiother Oncol 2012 May;103(2):228-232.
(7) Morris WJ, Keyes M, Spadinger I, Kwan W, Liu M. Population-based 10-year oncologic outcomes after low-dose-rate brachytherapy for low-risk and intermediate-risk prostate cancer. Cancer 2013 Dec 26 2012.
(8) Keating NL, O'Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 2006 Sep 20;24(27):4448-4456.
(9) Bolla M, Van Tienhoven G, Warde P, Dubois JB, Mirimanoff RO, Storme G, et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol 2010 Nov;11(11):1066-1073.
(10) Horwitz EM, Bae K, Hanks GE, Porter A, Grignon DJ, Brereton HD, et al. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol 2008 May 20;26(15):2497-2504.
(11) Shen X, Keith SW, Mishra MV, Dicker AP, Showalter TN. The Impact of Brachytherapy on Prostate CancereSpecific Mortality for Definitive Radiation Therapy of High-Grade Prostate Cancer: A Population-Based Analysis. Int J Radiat Oncol Biol Phys 2012 http://www.redjournal.org/on line.
(12) D'Amico AV, Moran BJ, Braccioforte MH, Dosoretz D, Salenius S, Katin M, et al. Risk of death from prostate cancer after brachytherapy alone or with radiation, androgen suppression therapy, or both in men with high-risk disease. J Clin Oncol 2009 Aug 20;27(24):3923-3928.
(13) Dattoli M, Wallner K, True L, Bostwick D, Cash J, Sorace R. Long-term outcomes for patients with prostate cancer having intermediate and high-risk disease, treated with combination external beam irradiation and brachytherapy. J Oncol 2010;2010:471375. Epub 2010 Aug 18.
(14) Merrick GS, Butler WM, Galbreath RW, Lief J, Bittner N, Wallner KE, et al. Prostate cancer death is unlikely in high-risk patients following quality permanent interstitial brachytherapy. BJU Int 2011 Jan;107(2):226-232.
(15) Ho AY, Burri RJ, Cesaretti JA, Stone NN, Stock RG. Radiation dose predicts for biochemical control in intermediate-risk prostate cancer patients treated with low-dose-rate brachytherapy. Int J Radiat Oncol Biol Phys 2009 Sep 1;75(1):16-22.
(16) Valicenti RK, Bae K, Michalski J, Sandler H, Shipley W, Lin A, et al. Does hormone therapy reduce disease recurrence in prostate cancer patients receiving dose-escalated radiation therapy? An analysis of Radiation Therapy Oncology Group 94-06. Int J Radiat Oncol Biol Phys 2011 Apr 1;79(5):1323-1329.
(17) Merrick GS, Butler WM, Wallner KE, Galbreath RW, Allen ZA, Kurko B. Efficacy of neoadjuvant bicalutamide and dutasteride as a cytoreductive regimen before prostate brachytherapy. Urology 2006 Jul;68(1):116-120.
(18) Keyes M, Miller S, Moravan V, Pickles T, McKenzie M, Pai H, et al. Predictive factors for acute and late urinary toxicity after permanent prostate brachytherapy: long-term outcome in 712 consecutive patients. Int J Radiat Oncol Biol Phys 2009 Mar 15;73(4):1023-1032.
(19) Keyes M, Schellenberg D, Moravan V, McKenzie M, Agranovich A, Pickles T, et al. Decline in urinary retention incidence in 805 patients after prostate brachytherapy: the effect of learning curve? Int J Radiat Oncol Biol Phys 2006 Mar 1;64(3):825-834.
(20) Keyes M, LaPointe V, Pickles T, Crook J, Spadinger I, McKenzie M, et al. Radiation Oncologists Quality Assurance Program In BC Cancer Agency Provincial Prostate Brachytherapy Program. Brachytherapy, Volume 10, Supplement 1, May-June 2011, Page S78 2011;10(May-June):s78.
(21) Barocas DA, Mitchell R, Chang SS, Cookson MS. Impact of surgeon and hospital volume on outcomes of radical prostatectomy. Urol Oncol 2010 May-Jun;28(3):243-250.
(22) Chen AB, D'Amico AV, Neville BA, Steyerberg EW, Earle CC. Provider case volume and outcomes following prostate brachytherapy. J Urol 2009 Jan;181(1):113-8; discussion 118.
(23) Keyes M, Morris WJ, Spadinger I, Araujo C, Cheung A, Chng N, et al. Radiation oncology and medical physicists quality assurance in British Columbia Cancer Agency Provincial Prostate Brachytherapy Program. Brachytherapy 2012 Jun 21.
(24) Hayden AJ, Morris JW, Keyes M, LaPointe V, McKenzie M, Pickles T, et al. The PSA Value at 4-5 years After Permanent Prostate Brachytherapy Predicts for Biochemical Failure Free Survival. Radiotherapy and Oncology 2010;96(Supplement 2, September 25):s2.
(25) Grimm PD, Billiet I, Bostwick DG, Dicker A. P., Frank SJ, Immerzeel J, et al. Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group. BJU Int 2012;109(supp 1):22-29.
(26) Pickles T, Keyes M, Morris WJ. Brachytherapy or conformal external radiotherapy for prostate cancer: a single-institution matched-pair analysis. Int J Radiat Oncol Biol Phys 2010 Jan 1;76(1):43-49.
(27) Morris WJ. ASCENDE-RT: Androgen suppression combined with elective nodal and dose escalated radiation therapy. ;http://clinicaltrials.gov/show/NCT00175396..
(28) Sylvester JE, Grimm PD, Wong J, Galbreath RW, Merrick G, Blasko JC. Fifteen-year biochemical relapse-free survival, cause-specific survival, and overall survival following i(125) prostate brachytherapy in clinically localized prostate cancer: Seattle experience. Int J Radiat Oncol Biol Phys 2011 Oct 1;81(2):376-381.
(29) Taira AV, Merrick GS, Butler WM, Galbreath RW, Lief J, Adamovich E, et al. Long-term outcome for clinically localized prostate cancer treated with permanent interstitial brachytherapy. Int J Radiat Oncol Biol Phys 2011 Apr 1;79(5):1336-1342.
(30) Bittner N, Merrick GS, Wallner KE, Butler WM, Galbreath R, Adamovich E. Whole-pelvis radiotherapy in combination with interstitial brachytherapy: does coverage of the pelvic lymph nodes improve treatment outcome in high-risk prostate cancer? Int J Radiat Oncol Biol Phys 2010 Mar 15;76(4):1078-1084.
(31) Fang LC, Merrick GS, Butler WM, Galbreath RW, Murray BC, Reed JL, et al. High-Risk Prostate Cancer With Gleason Score 8-10 and PSA Level 32) Kuban DA, Levy LB, Cheung MR, Lee AK, Choi S, Frank S, et al. Long-term failure patterns and survival in a randomized dose-escalation trial for prostate cancer. Who dies of disease? Int J Radiat Oncol Biol Phys 2011 Apr 1;79(5):1310-1317.
(33) Viani GA, Stefano EJ, Afonso SL. Higher-than-conventional radiation doses in localized prostate cancer treatment: a meta-analysis of randomized, controlled trials. Int J Radiat Oncol Biol Phys 2009 Aug 1;74(5):1405-1418.
(34) Keyes M, Miller S, Moravan V, Pickles T, Liu M, Spadinger I, et al. Urinary Symptom Flare in 712 (125)I prostate brachytherapy patients: Long-Term Follow-Up. Int J Radiat Oncol Biol Phys 2009 Feb 9.
(35) Keyes M, Spadinger I, Liu M, Pickles T, Pai H, Hayden A, et al. Rectal toxicity and rectal dosimetry in low-dose-rate (125)I permanent prostate implants: a long-term study in 1006 patients. Brachytherapy 2012 May-Jun;11(3):199-208.
(36) Hayden AJ, Keyes M, Moravan V, McKenzie M, Pickles T. Erectile Function Following I125 Permanent Prostate Brachytherapy: 5 and 8 years Results in 1411 men. Radiotherapy and Oncology 2010;96(Supplememt 2, September 25):S3.
(37) Alemozaffar M, Regan MM, Cooperberg MR, Wei JT, Michalski JM, Sandler HM, et al. Prediction of erectile function following treatment for prostate cancer. JAMA 2011 Sep 21;306(11):1205-1214.
(38) Macdonald AG, Keyes M, Kruk A, Duncan G, Moravan V, Morris WJ. Predictive factors for erectile dysfunction in men with prostate cancer after brachytherapy: Is dose to the penile bulb important? International Journal of Radiation Oncology, Biology, Physics 2005;63(1):155-163.
(39) Stone NN, Cesaretti JA, Rosenstein B, Stock RG. Do high radiation doses in locally advanced prostate cancer patients treated with 103Pd implant plus external beam irradiation cause increased urinary, rectal, and sexual morbidity? Brachytherapy 2010 Apr-Jun;9(2):114-118.

HIFU

Updated 12 May 2009

Efficacy data does not allow meaningful assessment as to the benefit-risk ratio of high intensity focus ultrasound (HIFU) as a primary treatment for localized prostate cancer, and hence cannot currently be recommended as standard therapy given current alternatives.

HIFU must be developed in a controlled manner within the context of a clinical trial, which should be approved by an Ethical Review Board (ERB), who should also monitor patient selection, informed consent, accrual, complication rates and other outcomes information. The BC Cancer Agency Genitourinary Tumour Group should also receive patient treatment data so that it may be added to data on other comparative modalities including active surveillance, prostatectomy, and radiotherapy.

In cases of radiorecurrent localized prostate cancer, where treatment options are more limited and associated with significant morbidity, HIFU could be considered a salvage treatment option associated with discussion of alternatives including salvage prostatectomy, cryotherapy, brachytherapy, or androgen deprivation therapy. Although again this should be in the context of an ethics approved protocol with the intention of collecting data prospectively for the purpose of publication in a peer reviewed journal.

You can download the full report, BCCA​-GUTG assessment HIFU for prostate cancer

Osteoporosis Screening Guidelines


All numbered parenthetical ​references in this section, are to the References list for the Osteoporosis Screening Guidelines. 

Prostate Cancer, Androgen Ablation and Osteoporosis

Prostate cancer is the commonest cause of cancer in men in Canada. In 1999 over 2,600 men were diagnosed with prostate cancer in BC. By 2020 we expect a 50% rise in incidence, because of increasing life expectancy and age of the population.

Fifty years ago hormonal therapy was carried out by orchidectomy. Now the majority of men choose medical castration with LHRH agonists. Androgen ablation (AA) is used for:

  1. adjunct with radiotherapy (or surgery) [1];
  2. node positive or metastatic cases; or
  3. biochemical relapse after first line curative treatment.

This third category is the largest and has the longest potential duration of AA. Specifically, estimates of prostate cancer survival five years after PSA failure from radiotherapy can be as high as 76-78% for patients with a biopsy Gleason score of 6 or less or a pre-treatment PSA 10 or less (4). After radical prostatectomy and PSA relapse the median actuarial time to metastases was eight years from the time of PSA level elevation (5). Once men developed metastatic disease, the median actuarial time to death was five years. This gives a potential total of 13 years of androgen deprivation in patients who fail biochemically.

Osteoporosis is only one of several adverse effects of AA. Others include hot flashes, fatigue, an increase in body fat, memory loss and depression. The premise of this work is that earlier diagnosis and prevention of fractures should decrease the medical problems, as well as improve patients' quality of life (QOL).

Osteoporosis in Men Without Cancer

Osteoporosis can be defined as "a systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue with a resultant increase in fragility and risk of fracture".

In Canada 1 in 8 of all men have osteoporosis and with the ageing population this will increase dramatically over the next decade. Estimates of the lifetime risk of an osteoporotic fracture is 13-25% in men – 2-4X less than women. One third of hip fractures occur in men. Men have a gradual age related loss in BMD of about 10% per decade beginning at age 30 years (6).

Many vertebral fractures are occult and asymptomatic but they correlate with a poorer overall survival. Vertebral fractures increase the risk of future fractures. Similarly, osteoporotic hip fractures are associated with increased mortality: being 33% in the year afterwards. In addition, up to 70% of cases with hip fractures never regain to their previous functional status and QOL. Some 20% require long term care.

Early surgical management improves the results. Open vertebral surgery is reserved for rare cases with neurological deficits or instability. Newer procedures include vertebroplasty and kyphoplasty using cement injections into the bone. The care cost for treatment of fractures is estimated at over US$3B in the USA. Most important of all, osteoporotic fractures are preventable.

[1] BC Cancer Agency data shows that testosterone recovery to 5nmol/l takes a year on average with 80% reaching this at two years post cessation of LHRH therapy. Longer acting LHRH formulations may lead to significantly poorer recovery of testosterone.

Bone Mineral Density (BMD)

Most studies reported the use of dual energy x-ray absorptiometry (DXA) to assess BMD. DXA bone measurement is the most effective way to estimate fracture risk. This test is relatively inexpensive, quick and accurate. It has a precision of about 1-3%, depending upon site and absolute degree of mineralization. There is variability between patient measurements of about 3-4% (7). Unfortunately, DXA equipment manufacturers do not allow standardized measurements, so comparisons between machines are therefore difficult at present. In any situation requiring follow-up it is better to use the same machine consistently.

BMD is classified in comparison with a normal young adult group for menopausal white women. There is still debate over the reference group to be used to derive the T-scores in men. The T-score is the number of SD above or below the mean young adult peak bone density.

  1. Normal is a T-score +2.5 to –1.0
  2. Osteopenia [1] is a T-score of –1.1 to –2.4 inclusively
  3. Osteoporosis is a T-score equal to or less than -2.5.
  4. Severe osteoporosis is a T- score equal to or less than -2.5 and a fragility fracture.

While these reference ranges are also used in men, they have not been validated for men. The use of BMD as a basis for therapy in men has not been established (8). For each standard deviation unit of decrease in BMD there is an exponential increase of fracture risk. The presence of vertebral fracture - deformity implies a risk of further fracture equal to the BMD – 1SD.

This work does not address the issues of attempting to measure bone density in men with osteoblastic bony metastatic disease. In some patients it may be necessary to monitor alternative sites. Osteoarthritis also limits the validity and reliability of lumbar spine BMD measurements, but the spine may still be useful for serial examinations of change.

BMD and Identifying Men in the Population at High Risk of Fractures

There is good randomized clinical trial evidence that clinical evaluation combined with BMD outperforms any single method of risk-assessment (9​). BMD should only be measured if it will affect management decisions.

Men over 50 years should be assessed for risk factors. It is now recognised that osteoporosis is common in men (9). It has been estimated that 50% of men with osteoporosis have secondary causes (8).

Major risk factors with level one evidence that they increase the relative risk of future osteoporotic fractures are:

  1. aging;
  2. family history of osteoporosis;
  3. prior fragility fracture defined as a fracture sustained in a fall from a standing height or less (even if BMD not 'osteoporotic'); and
  4. low BMD, which is the most quantifiable measure.

Residents of long-term facilities are at particular risk of fracture – they have low BMD, advanced age, poor function and strength, poor nutrition, are at risk for falls, and use multiple medications (10).

Medical interventions have only been shown to be effective in men over 65 years of age. More than 70% of men with prostate cancer who have external beam radiotherapy are over 65 years.

It may require a large number of BMD screening studies to prevent a single fracture. Until there is good evidence supporting the cost effectiveness of 'routine' screening in healthy men or indeed the efficacy of specific drug interventions, an individualized approach is recommended.

The average 10-year probability of fracture is about 5% age 60-65 rising to >10% over age 75. For a man over 75 years with T-score <-2.5 his risk is 20-25% (Figure 1). It therefore appears that men are as prone to fracture as women at a given BMD are.

Figure 1: Risk of fracture as it relates to the T-score on BMD scans 

Figure 1: Risk of fracture as it relates to the T-score on BMD scans. Data for the sixth to ninth decade are shown (9).

[1] Osteopenia is also used by radiologists in describing low mineral content on plain x-ray film.

Hypogonadism Effects

Testosterone (TTT) affects bone development and resorption. Androgens mediate osteoblast proliferation and differentiation and increase bone matrix production. TTT also effects growth factors such as TGF-beta and IGF-1 that may be important in osteoblast proliferation. Estradiol is a potent product through peripheral aromatization. This enzyme is active in bone and thus bone effects may be mediated through estrogens as in postmenopausal osteoporosis. LHRH therapy can reduce estradiol levels by almost 50% (ref 1​1). TTT loss may also effect calcitonin leading to resorption by decreasing the effect of endogenous calcitonin. The mechanisms of TTT on bone are therefore not well understood.

Jackson (12) found that over 70% of men with hip fractures following falls had hypogonadism. The relationship of hypogonadism and male osteoporosis has been known for decades but only recently has research looked at osteoporosis induced by treatment of prostate cancer.

Melton LJ 3rd 2003 published a population study reviewing 429 men who had orchiectomies from 1956-2000 and compared the fracture risk to the community and found a 3.5-fold increase in risk.

Daniell's (14) 1997 review showed that orchidectomy increased the fracture risk from 1% (no hormonal therapy) to 28% at 7 years and 48% at 9 years (Figure 2). A later report (2000) focused on the rate of BMD loss following 26 men. Overall there was a 4% loss in BMD in years 1 and 2 and 2% pa after year 4. By 18 months it was statistically significant compared to baseline.

Cumulative risk of first fractures in men with prostate cancer with and without orchidectomy
Figure 2. Cumulative risk of first fractures in men with prostate cancer with and without orchidectomy (14).

A much larger study by Oefelein (15) with 181 patients on androgen ablation showed an actuarial 4% fracture rate (median duration of androgen ablation was 44 months) at 5 years and 20% at 10 years. (Combining the 8 patients at risk at 10 years in the Daniell and Oefelein papers yields a 35% crude fracture rate.) In the Oefelein (15) paper there were 9 fractures (5 hip, 4 extremity, 1 spine (one patient had 2 fractures)). Only 5 of the 9 were confirmed to have osteoporosis on BMD scan, the rest were osteopenic on plain X-ray. 62% of these patients had metastatic disease but the authors clearly distinguished osteoporotic from pathologic fractures. Slender white patients are at the greatest risk for AA associated fractures. The fracture rate seen by Oefelein (15) should be compared with men over 65 years who have an incidence of 0.5% for hip fractures from osteoporosis. This gives an odds ratio of about 5 for hip fractures. The risk of any fracture over the age of 70 is 1% giving an odds ratio also of 5.

Townsend (16) in a survey of 224 patients on LHRH treatment for a mean of 22 months showed a 9% fracture rate. Wei (11) studied BMD in 32 men beginning AA. 63% (5/8) had osteopenia / porosis before treatment. A significantly higher percentage, 88% (21/24), met these criteria after more than a year of AA. On the basis of regression analysis, an estimated 48 months of AAA would be necessary to develop BMD criteria for osteopenia in the lumbar spine for a man with average BMD at the initiation of therapy. This has implications for followup practices for men with normal baseline BMDs.

Oefelein (17) has also reported from 195 men that the 24 cases (9 of these cases fractured before initiation of AA) with skeletal fractures had a significantly worse overall survival from prostate cancer. This factor remains on multiple regression analysis to correct for patients with metastatic disease and nadir PSA (RR 7.4). Baseline testosterone levels were not reported and this may affect both cancer response and osteoporosis risk.

Berruti (18) followed 35 men with AA and found the mean gm/cm2 decreases at both the hip and spine at 1 year. BMD decreased 2-5% in 8 men, 5-10% in 8 men and >10% in 3 men for the spine (and 6, 6, 3 respectively for the hip). It should be noted that a few men even had unexpected rises in BMD.

Overall the data shows a 4% annual loss of BMD in the femoral neck (CI 0-7%) in the first 2 years of AA (then 1% annually) and 3% in the hip (CI 2-4%). If you take a bone loss of 3% per year each 2-3 years of AA will double the fracture risk (1 unit SD of T-score is about 8-10%). Added to this are over 60% of cases that are already osteopenic and 5-20% osteoporotic at baseline (19, 20).

Systematic Review of Bone Mineral Density Loss & Fracture Risk in Androgen Ablation

Dr. Paul Blood at the BC Cancer Agency's Vancouver Island Centre has undertaken a systematic review of the literature, and the meta-analysis is summarised as follows:

Bone Mineral Density (BMD) Review:

  1. Cross-sectional studies:
    A total of 154 men with prostate cancer on androgen ablation (AA) have had the BMD analyzed in five cross-sectional studies (14, 21-24). The combination of these studies shows that the hip loses 3% (CI 2-4%) BMD per annum from 2-10 years of AA (Blood, personal communication). The lumbar spine loses 1% (CI 0-2%) per annum from 2-10 years.
  2. Longitudinal studies:
    A total of 161 men with prostate cancer on AA have had BMD analyzed in six longitudinal studies (25-30). The combination of theses studies shows that the femoral neck loses 4% (CI 1-7%) per annum for the first two years of AA. The lumbar spine also loses 4% (CI –1 to 8%) per annum for the first two years.

Fracture Risk Review:

Although BMD loss is of concern, fractures are the main cause of morbidity, mortality, wrong diagnosis, unnecessary investigation and treatment. A total of 836 men with prostate cancer on AA were screened for osteoporotic fractures in four studies (14-16, 3​1). The combination of theses studies yields an odds ratio for all osteoporotic fractures of 7 (CI 3-17). Those at the hip have more serious consequences and the odds ratio for hip fractures is 5 (CI 3-10).

Prevention

One should introduce the following 'interventions' as soon as possible to ensure retention of bone mass and preserve structural integrity of the skeleton, thus preventing fractures.

Nutrition

Bone is a complex tissue that requires essential nutrients for synthesis and maintenance. Good nutrition is essential to normal growth. A balanced diet, adequate calories, and appropriate nutrients are the foundation for development of all tissues including bone.

Calcium and vitamin D are essential to prevent and treat osteoporosis and are adjuncts to preventative therapy (9). Dawson-Hughes (32) showed that non-vertebral fractures in 389 men and women over 65 years were significantly reduced from 26 in the placebo arm to 11 in the calcium - Vitamin D group.

The total of diet and supplemental intake needed is 1500mg calcium/ day. The preferred source of calcium is dietary, but less than 60% of older adults meet this recommendation. About 75% to 80% of the calcium consumed in diets is from dairy products. Calcium supplements need to be absorbable. As we age the body becomes less efficient at absorbing calcium and other nutrients. Vitamin D plays a major role in calcium absorption. Vitamin D3 is preferred at 800 IU/day (9). Chief dietary sources of vitamin D include vitamin D-fortified milk and cereals, egg yolks, saltwater fish, and liver. For detailed information for patients refer to the appended document – "Guidelines for the Prevention of Osteoporosis".

Two studies show that excess caffeine should be avoided (<4 cups/day) (9). Maintaining adequate protein intake (0.8g/kg/day) may be important, especially for those with poor intake (9).

Physical activity/ fall prevention

Any man without established osteoporosis should be encouraged to participate in exercise, particularly weight-bearing exercises. Resistance and high impact activities contribute to bone mass and may also reduce the risk of falls in the elderly. During later years exercise combined with calcium and vitamin D probably has a modest effect on slowing the decline in bone mineral density (BMD). Exercise also improves function and delays loss of independence, improving quality of life (QOL) in the elderly (10). Older men at risk of falls need individual assessment and tailored programs to improve strength and balance. Exercise reduces the risk of falls by about 25%, but has not been proven to reduce fracture rates.

Care must be taken in tailoring any exercise in men with established osteoporosis, as falls and high impact may cause fractures. Balance and rehabilitation will help reduce the risk of falls.

Treatment: bisphosphonates

Placebo-controlled randomized controlled trials (RCTs) of etidronate, alendronate and risedronate analyzed by systematic review and meta-analysis have shown that they all increase bone mineral density (BMD) at the spine and hip in a dose-dependent manner. They consistently reduce the risk of vertebral fractures by 30-50% (10). Since subjects in clinical trials conducted to date may not represent the population of concern here, an individual approach to treatment is warranted.

A: Male population studies

Alendronate has been studied and increases BMD in men while significantly reducing fractures from 7.1% in the control arm to 0.8% in the treatment arm (33).

Orwoll (33) showed that alendronate reduced the rate of vertebral fractures in 241 men, but did not show any alteration in hip or extremity fractures. A large study of men on steroids showed that risedronate decreased vertebral fractures (34).

B: Androgen ablation studies

Diamond T (35) treated 12 men with TAB for 12 months and gave no treatment for bone loss in the first six months, then etridonate and calcium supplements. In the latter six months BMD significantly rose by 7.8%, compared to the initial six months. A later RCT by this author on 21 men showed significant reduction in bone loss with IV pamidronate (26).

Smith (29) also randomized 43 men to pamidronate or placebo and prevented the loss in bone density. He has gone on to do a similar randomized study of 106 men and found a significant increase of BMD with zoledronate 4mg vs loss of BMD for patients receiving placebo (19).

While there are studies showing that bisphosphonates increase BMD, there is as yet no study showing that bisphosphonates reduce fracture incidence in the setting of androgen ablation.

C: Other studies

Glucocorticoid-induced osteoporosis perhaps provides a model of how to approach hypogonadal men. First is the matter of treatment of established osteoporosis, and secondly the prevention of osteoporosis (and its complications). Bisphosphonates are the only therapy shown to reduce vertebral fractures in glucocorticoid-induced osteoporosis, with a high level of evidence for alendronate, risedronate and etidronate (in order).

Overall, taking all the studies of bisphosphonates for osteoporosis, there is ample evidence of the reduction in fracture risk (33, 34, 36-50). The question remains whether the costs, drug benefits, and potential side effects for the individual patient mean that a given drug is utilized. This is at the discretion of the GP or specialist.

Costs and Payment Issues

Updated 18 January 2007​​

The standard first line therapy of osteoporosis according to Pharmacare is etidronate. This is the only drug therapy covered. Presumably this is primarily based on cost:

  • Etidronate (Didrocal®) one tablet daily ($0.43/day)
  • Alendronate (Fosamax®) 10 mg daily ($1.84/day)
  • Risedronate (Actonel®) 5 mg daily ($1.93/day)
  • Raloxifene (Evista®) 60 mg daily ($1.69/day)

Pharmacare criteria for use of alendronate/ risedronate are stringent, for example:

  • Radiographically documented fractures due to osteoporosis plus
  • an adequate trial of etidronate that has failed to prevent clinically significant fractures (i.e. those that are painful, produce disability, or both)

The BC Cancer Agency only covers the use of bisphosphonates (clodronate, pamidronate) for the treatment of multiple myeloma or breast cancer with bone metastases.

Monitoring Change in BMD/ Osteoporosis

​Given that osteoporosis therapy may only produce a few % increase in bone mineral density (BMD), very precise tests are needed. BMD by Dual-energy X-ray Absorptiometry (DXA) can be used to assess response to therapy. Serial measurements therefore must be carried out on the same unit and random fluctuation not confused with real change.

The variability between tests is about 1-3% as stated above. The absolute BMD (g/cm2) should be used to determine change, NOT the T-score. Each DEXA unit measures its precision and can report the least significant change detectable. Because of these limitations, BMD every two years is recommended in general for patients with prostate cancer on androgen ablation (AA). In patients with other risk factors that may accelerate bone loss or where baseline osteopenia is detected, 18 month (rarely 12 months) follow-up BMDs may be justified. Such patients may be best managed under specialist care. Treatment should not be stopped or changed solely on the basis of the BMD.

Referrals to Other Physicians

Indications for obtaining a further opinion and care include:

  1. oncologist unsure re management or interpretation of tests;
  2. patient has questions that the oncologist cannot answer;
  3. failure to respond to therapy; or
  4. possible additional secondary causes of/ risk factors for osteoporosis.

References

  1. Zhang Y, Kiel DP, Ellison RC, Schatzkin A, Dorgan JF, Kreger BE, et al. Bone mass and the risk of prostate cancer: the Framingham Study. American Journal of Medicine. 2002;113(9):734-9.
  2. Oades GM, Coxon J, Colston KW. The potential role of bisphosphonates in prostate cancer. Prostate Cancer & Prostatic Diseases. 2002;5(4):264-72.
  3. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma.[comment]. Journal of the National Cancer Institute. 2002;94(19):1458-68.
  4. D'Amico AV, Cote K, Loffredo M, Renshaw AA, Chen MH. Pretreatment predictors of time to cancer specific death after prostate specific antigen failure. Journal of Urology. 2003;169(4):1320-4.
  5. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy.[comment]. Jama. 1999;281(17):1591-7.
  6. Ross RW, Small EJ. Osteoporosis in men treated with androgen deprivation therapy for prostate cancer. Journal of Urology. 2002;167(5):1952-6.
  7. Wahner HW, Looker A, Dunn WL, Walters LC, Hauser MF, Novak C. Quality control of bone densitometry in a national health survey (NHANES III) using three mobile examination centers. Journal of Bone & Mineral Research. 1994;9(6):951-60.
  8. Eastell R, Riggs BL. Diagnostic evaluation of osteoporosis. Endocrinology & Metabolism Clinics of North America. 1988;17(3):547-71.
  9. Brown JP, Josse RG, Scientific Advisory Council of the Osteoporosis Society of C. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ Canadian Medical Association Journal. 2002;167(10 Suppl):S1-34.
  10. Nih Consensus Development Panel on Osteoporosis Prevention D, Therapy. Osteoporosis prevention, diagnosis, and therapy.[comment]. Jama. 2001;285(6):785-95.
  11. Wei JT, Gross M, Jaffe CA, Gravlin K, Lahaie M, Faerber GJ, et al. Androgen deprivation therapy for prostate cancer results in significant loss of bone density. Urology. 1999;54(4):607-11.
  12. Jackson JA, Riggs MW, Spiekerman AM. Testosterone deficiency as a risk factor for hip fractures in men: a case-control study. American Journal of the Medical Sciences. 1992;304(1):4-8.
  13. Melton LJ, 3rd, Alothman KI, Khosla S, Achenbach SJ, Oberg AL, Zincke H. Fracture risk following bilateral orchiectomy. Journal of Urology. 2003;169(5):1747-50.
  14. Daniell HW. Osteoporosis after orchiectomy for prostate cancer.[comment]. Journal of Urology. 1997;157(2):439-44.
  15. Oefelein MG, Ricchuiti V, Conrad W, Seftel A, Bodner D, Goldman H, et al. Skeletal fracture associated with androgen suppression induced osteoporosis: the clinical incidence and risk factors for patients with prostate cancer. Journal of Urology. 2001;166(5):1724-8.
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  17. Oefelein MG, Ricchiuti V, Conrad W, Resnick MI. Skeletal fractures negatively correlate with overall survival in men with prostate cancer. Journal of Urology. 2002;168(3):1005-7.
  18. Berruti A, Dogliotti L, Terrone C, Cerutti S, Isaia G, Tarabuzzi R, et al. Changes in bone mineral density, lean body mass and fat content as measured by dual energy x-ray absorptiometry in patients with prostate cancer without apparent bone metastases given androgen deprivation therapy. Journal of Urology. 2002;167(6):2361-7; discussion 2367.
  19. Smith MR, Eastham J, Gleason DM, Shasha D, Tchekmedyian S, Zinner N. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. Journal of Urology. 2003;169(6):2008-12.
  20. Smith MR, McGovern FJ, Fallon MA, Schoenfeld D, Kantoff PW, Finkelstein JS. Low bone mineral density in hormone-naive men with prostate carcinoma. Cancer. 2001;91(12):2238-45.
  21. Basaria S, Lieb J, 2nd, Tang AM, DeWeese T, Carducci M, Eisenberger M, et al. Long-term effects of androgen deprivation therapy in prostate cancer patients. Clinical Endocrinology. 2002;56(6):779-86.
  22. Chen Z, Maricic M, Nguyen P, Ahmann FR, Bruhn R, Dalkin BL. Low bone density and high percentage of body fat among men who were treated with androgen deprivation therapy for prostate carcinoma. Cancer. 2002;95(10):2136-44.
  23. Stoch SA, Parker RA, Chen L, Bubley G, Ko YJ, Vincelette A, et al. Bone loss in men with prostate cancer treated with gonadotropin-releasing hormone agonists. Journal of Clinical Endocrinology & Metabolism. 2001;86(6):2787-91.
  24. Kiratli BJ, Srinivas S, Perkash I, Terris MK. Progressive decrease in bone density over 10 years of androgen deprivation therapy in patients with prostate cancer. Urology. 2001;57(1):127-32.
  25. Diamond T, Sambrook P, Williamson M, Flicker L, Nowson C, Fiatarone-Singh M, et al. Guidelines for treatment of osteoporosis in men. Australian Family Physician. 2001;30(8):787-91.
  26. Diamond TH, Winters J, Smith A, De Souza P, Kersley JH, Lynch WJ, et al. The antiosteoporotic efficacy of intravenous pamidronate in men with prostate carcinoma receiving combined androgen blockade: a double blind, randomized, placebo-controlled crossover study. Cancer. 2001;92(6):1444-50.
  27. Eriksson S, Eriksson A, Stege R, Carlstrom K. Bone mineral density in patients with prostatic cancer treated with orchidectomy and with estrogens. Calcified Tissue International. 1995;57(2):97-9.
  28. Maillefert JF, Sibilia J, Michel F, Saussine C, Javier RM, Tavernier C. Bone mineral density in men treated with synthetic gonadotropin-releasing hormone agonists for prostatic carcinoma. Journal of Urology. 1999;161(4):1219-22.
  29. Smith MR, McGovern FJ, Zietman AL, Fallon MA, Hayden DL, Schoenfeld DA, et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer.[comment]. New England Journal of Medicine. 2001;345(13):948-55.
  30. Daniell HW, Dunn SR, Ferguson DW, Lomas G, Niazi Z, Stratte PT. Progressive osteoporosis during androgen deprivation therapy for prostate cancer. Journal of Urology. 2000;163(1):181-6.
  31. Hatano T, Oishi Y, Furuta A, Iwamuro S, Tashiro K. Incidence of bone fracture in patients receiving luteinizing hormone-releasing hormone agonists for prostate cancer. BJU International. 2000;86(4):449-52.
  32. Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older.[comment]. New England Journal of Medicine. 1997;337(10):670-6.
  33. Orwoll E, Ettinger M, Weiss S, Miller P, Kendler D, Graham J, et al. Alendronate for the treatment of osteoporosis in men.[comment]. New England Journal of Medicine. 2000;343(9):604-10.
  34. Reid DM, Adami S, Devogelaer JP, Chines AA. Risedronate increases bone density and reduces vertebral fracture risk within one year in men on corticosteroid therapy. Calcified Tissue International. 2001;69(4):242-7.
  35. Diamond T, Campbell J, Bryant C, Lynch W. The effect of combined androgen blockade on bone turnover and bone mineral densities in men treated for prostate carcinoma: longitudinal evaluation and response to intermittent cyclic etidronate therapy. Cancer. 1998;83(8):1561-6.
  36. Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group.[comment]. New England Journal of Medicine. 1995;333(22):1437-43.
  37. Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group.[comment]. Lancet. 1996;348(9041):1535-41.
  38. Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial.[comment]. Jama. 1998;280(24):2077-82.
  39. Pols HA, Felsenberg D, Hanley DA, Stepan J, Munoz-Torres M, Wilkin TJ, et al. Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: results of the FOSIT study. Foxamax International Trial Study Group. Osteoporosis International. 1999;9(5):461-8.
  40. Black DM, Thompson DE, Bauer DC, Ensrud K, Musliner T, Hochberg MC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group.[erratum appears in J Clin Endocrinol Metab 2001 Feb;86(2):938]. Journal of Clinical Endocrinology & Metabolism. 2000;85(11):4118-24.
  41. Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group.[comment]. Jama. 1999;282(14):1344-52.
  42. McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group.[comment]. New England Journal of Medicine. 2001;344(5):333-40.
  43. Storm T, Thamsborg G, Steiniche T, Genant HK, Sorensen OH. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis.[comment]. New England Journal of Medicine. 1990;322(18):1265-71.
  44. Watts NB, Harris ST, Genant HK, Wasnich RD, Miller PD, Jackson RD, et al. Intermittent cyclical etidronate treatment of postmenopausal osteoporosis.[comment]. New England Journal of Medicine. 1990;323(2):73-9.
  45. Adachi JD, Bensen WG, Brown J, Hanley D, Hodsman A, Josse R, et al. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis.[comment]. New England Journal of Medicine. 1997;337(6):382-7.
  46. Brown JP, Olszynski WP, Hodsman A, Bensen WG, Tenenhouse A, Anastassiades TP, et al. Positive effect of etidronate therapy is maintained after drug is terminated in patients using corticosteroids. Journal of Clinical Densitometry. 2001;4(4):363-71.
  47. Saag KG, Emkey R, Schnitzer TJ, Brown JP, Hawkins F, Goemaere S, et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group.[comment]. New England Journal of Medicine. 1998;339(5):292-9.
  48. Cohen S, Levy RM, Keller M, Boling E, Emkey RD, Greenwald M, et al. Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis & Rheumatism. 1999;42(11):2309-18.
  49. Reid DM, Hughes RA, Laan RF, Sacco-Gibson NA, Wenderoth DH, Adami S, et al. Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. European Corticosteroid-Induced Osteoporosis Treatment Study. Journal of Bone & Mineral Research. 2000;15(6):1006-13.
  50. Wallach S, Cohen S, Reid DM, Hughes RA, Hosking DJ, Laan RF, et al. Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy. Calcified Tissue International. 2000;67(4):277-85.
  51. Lufkin EG, Whitaker MD, Nickelsen T, Argueta R, Caplan RH, Knickerbocker RK, et al. Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial. Journal of Bone & Mineral Research. 1998;13(11):1747-54.
  52. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators.[comment][erratum appears in JAMA 1999 Dec 8;282(22):2124]. Jama. 1999;282(7):637-45.
  53. Iversen P, Tyrrell CJ, Kaisary AV, Anderson JB, Van Poppel H, Tammela TL, et al. Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup. Journal of Urology. 2000;164(5):1579-82.

Guidelines for the Prevention of Osteoporosis for Men with Prostate Cancer

Appendix 1

Hypogonadism and Testosterone Assays

Normal testosterone (TTT) in an assay at the BCCA laboratory is now defined as >3.5ug/ml. It combines free TTT (left) with albumin bound TTT (top right) and sex hormone binding globulin bound TTT (bottom right). These make up approximately 1-2%, 35% and 65% of TTT respectively. The first two combined make up the bioavailable TTT. This is the important component in a ‘true’ diagnosis of hypogonadism, but is not measured by many laboratories. It is therefore possible for a man to have a ‘low normal’ TTT at BCCA and have hypogonadism defined by the bioTTT. Testosterone levels decline with age.​

Increasing incidence of hypogonadism with age by various assays. Harman et al. J Clin endocrinal Metab 2001; 86(2): 724-31.

Committee Members

Committee Chair:

Dr. Graeme Duncan: a Radiation Oncologist at the Vancouver Centre of the BC Cancer Agency and Clinical Associate Professor, University of British Columbia, Vancouver, BC.

Committee Members:

Dr. Winkle Kwan: a Radiation Oncologist at the Fraser Valley Centre of the BC Cancer Agency and Clinical Assistant Professor, University of British Columbia, Vancouver, BC.

Ms. Dianne Kapty: the Pharmacy Professional Practice Leader at the Fraser Valley Centre of the BC Cancer Agency.

Dr. Brian Lentle: Emeritus Professor, University of British Columbia, and Radiologist, BC Children’s and Women’s Health Sciences Centre, Vancouver, BC. He has received honoraria for teaching and research in osteoporosis from Proctor and Gamble.

Dr. David Kendler: Assistant Professor, Department of Medicine (Endocrinology), University of British Columbia, and Director, Osteoporosis Program, Providence Health Care, Vancouver, BC.

Declaration of potential conflicts of interest:

Dr. Brian Lentle has received honoraria for teaching and research in osteoporosis from Proctor and Gamble. Dr. David Kendler has received funding from Merck, Proctor and Gamble / Aventis, Lilly, Novartis, Pfizer, NPS, and Glaxo for teaching, advisory board activities, and research.

Acknowledgements:

Dr. Paul Blood: a Radiation Oncologist at the Victoria Cancer Centre is to be thanked for his contribution to the knowledge base, literature searches and systematic review of published studies. His work will appear independently as his thesis.

Ms. Cheri Van Patten: Clinical Coordinator of Nutrition Services is to be thanked for her contribution in developing the patient handout “Guidelines for the Prevention of Osteoporosis in Men with Prostate Cancer receiving Hormone therapy”.

 

PSA Screening


 Updated 23 May 2012 

Summary

Recommendations:

The Genitourinary Cancer Tumour Group (GUTG) of the BC Cancer Agency and the Vancouver Prostate Centre (VPC) recommend that asymptomatic men 50 years of age or older, with an estimated life expectancy of more than 10 years, who are well informed about the risks of over-diagnosis and over-treatment, consider PSA testing for the early diagnosis of prostate cancer.

The GUTG and VPC do not support unselected, population-wide PSA screening because of the potential for over-diagnosis, over-treatment and detriment to quality adjusted survival.

​Qualifying statements:

There is evidence from randomized controlled trials that the chance of dying of prostate cancer decreases with PSA screening and subsequent treatment. However, a significant number of men will need to be treated (with all the risks that that entails) who would otherwise not have had a problem with prostate cancer in their lifetime.

The decision to use PSA for the early detection of prostate cancer should be individualized.

Abnormal results should trigger referral to a urologist.

Early detection of prostate cancer should be linked to a treatment algorithm that includes discussion and prioritization of active surveillance for men with low risk prostate cancer.

While the statement above represents the consensus view of the GU Tumour Group, it should not be interpreted as a policy or position of the BC Cancer Agency.

1. Prostate Cancer is a Common Disease and Cause of Morbidity and Mortality

Revised 18 May 2012 ​


Prostate cancer is the most common non-skin cancer in men in Canada and the third leading cause of male cancer mortality; 550 men die from it each year in BC and 3000 are diagnosed. If diagnosed early when localized, it can be treated with high cure rates. When advanced, it may cause significant morbidity and mortality, including fatigue, kidney failure, and bone pain. Early detection and treatment of prostate cancer aims to reduce the risks of suffering and death from advanced disease.

Prostate cancer is also a highly prevalent disease as approximately one in three men over the age of 50 years has histologic evidence of prostate cancer, with most of these tumors being clinically insignificant (i.e. not at risk of causing harm in a man’s lifetime). Despite this high prevalence, the lifetime risk of death from prostate cancer is only about 3%, highlighting its generally indolent course, and competing causes of death. Reduction in the risk of prostate cancer diagnosis may be possible by lifestyle modification including weight control, increased exercise, and decreased meat consumption, (level 3 evidence[1]).

Level 1 evidence supports the treatment of localized disease. Prostate cancer mortality is reduced in men younger than 65yrs with surgery[2] or those with a 10 year life expectancy with radiation[3]. However men with ‘low risk’ prostate cancer do not have reduced prostate cancer mortality (Level 1 evidence [4]), and these men should instead be offered active surveillance. Active surveillance involves monitoring patients diagnosed with low risk cancers, and providing radical intervention only if the cancer shows signs of significant growth.

The disparity between the high prevalence of prostate cancer and its relatively low risk of death highlights the importance of distinguishing those cancers that are destined to cause significant illness and premature death from those that are not. Currently there is no test, including PSA that reliably makes this distinction.

​​​

2. Prostate Specific Antigen (PSA)

Revised 18 May 2012

Serum PSA is widely used to aid detection of prostate cancer. Unfortunately it is not a particularly good screening test, with a positive predictive value of ~25%. While it is an independent predictor of disease progression and treatment failure, serum PSA does not distinguish between clinically indolent cancers and those that may go on to cause death.

A continuum of prostate cancer risk exists with varying PSA levels, and ‘normal’ levels vary by age.

PSA level (ng/ml)

Prostate cancer prevalence %

 

Age (years)

Age-specific median value

<1

6-10%

 

40-50 yrs

0.7ng/ml

1-4

17-25%

 

50-60

0.9ng/ml

4-10

20-30%

 

60-70

1.2ng/ml

>20

80%

 

>70

1.5ng/ml


Age-adjusted reference ranges, PSA velocity (rate of change over time), free/total PSA ratio, and PSA density (PSA level relative to gland volume) improves the sensitivity and specificity of PSA as a screening test. Currently, individualized risk assessments of not only of prostate cancer but also of “significant” prostate cancer, is based on these determinants of PSA, as well as digital rectal examination (DRE) of the prostate, patient age, co-morbidities, family history, ethnicity, and prior biopsy history. These refinements have not been subject to randomized studies. Men who are interested in their risk of prostate cancer should consider using an on-line risk calculator such as Your Prostate Cancer Risk Calculator​.

3. Evidence Supporting PSA Testing

24 May 2012 ​


There has been a gradual 30% decline in prostate cancer mortality in the U.S. and Canada which started 4-5 years after the introduction of PSA testing. Statistical modeling studies indicate that PSA testing has played a role in this decline. PSA testing has also led to a marked increase in the diagnosis of early cancers that would not be expected to cause any symptoms had they not been detected (‘over diagnosis’).

Recent European randomized trials [5],[6] demonstrated a 44% and 20% relative reduction in prostate cancer deaths among those offered screening when compared to those that were not. In the more mature Göteborg study (14 years median follow-up)[5] the benefit was greater than in the less mature ERSPC study (11 years median).[6] The Göteborg trial estimated that 293 men would need to be offered screening and 12 men diagnosed for prevention of one prostate cancer death over a 14 year period. The ERSPC trial estimates were 936 and 33, respectively, but are expected to reduce as the trial matures further. The NCI-US PLCO study found no difference in prostate cancer deaths at 13 years of follow-up when comparing unscreened men[7]. However, in this underpowered study, 44% of men were prescreened and screening in the control group was very substantial (52% in the 6th year) which would have masked any impact of screening on mortality. Given the protracted natural history of many prostate cancers, longer follow-up is necessary to address the balance of benefits and harms of screening for prostate cancer. All cause mortality has not been found to be different in any prostate cancer screening trial, which may be expected given the sample size of the trials and duration of follow-up, but also emphasizes the low risk of dying from prostate cancer (in the US PLCO trial, at 13 years there were 303 prostate cancer deaths out of 77,685 men), the long natural history of the disease and the many competing causes of death that aging men face.

Nonetheless it is still unclear whether prostate cancer screening results in more benefit than harm, and thus a thoughtful and balanced approach to PSA testing is critical. The results of the European trials identify a clinically significant benefit from PSA screening, as well as an opportunity to guide prostate cancer screening (and treatment) algorithms in BC. However the use of PSA testing for the early detection of prostate cancer remains controversial owing to the risk for over-diagnosis and over-treatment. The latter may be addressed by uncoupling treatment as an inevitable response to diagnosis. Once this is done, the issue of prostate cancer screening becomes less controversial.

The Canadian Partnership Against Cancer, Screening Action Group recently assessed the current evidence regarding PSA screening and concluded that while expansion of PSA testing practices was not justified and might produce net harm, but there was insufficient evidence to discourage current ‘ad hoc’ PSA testing practices.[8]

At the present time, PSA testing is common (~50% of men over 55yrs have been tested in BC) but is not ideally performed in BC or across Canada. Considerable confusion and misinformation exists amongst public and primary care physicians, leading to inappropriate PSA testing (too young or too old, too frequent, duplication), inappropriate biopsies, leading to over-detection and over-treatment, as well as abnormal PSA values being ignored and not acted upon. Hence, there is a need to refine PSA testing (in whom, and how) with guidelines to systematically manage indications for testing, biopsy, and subsequently treat only those who are likely to benefit from it. Based upon the algorithm that was used in the European trial, we recommend that men who wish to be tested start at age 55, and be tested every 4 years until they reach 70. A result greater than 3 ng/ml should be regarded as abnormal and after being checked, the man should be referred to a Urologist for investigation. There is no role for testing and then ignoring or misinterpreting abnormal results; and likewise no man should be screened unless both he and his primary care physician are in agreement that an abnormal result will lead to further investigation.

It is noted that a baseline PSA level from men in their 40s above the age-adjusted median value is a strong predictor of future risk of prostate cancer; those with a PSA value below the median (0.6 to 0.7ng/mL) are at very low risk while those above the median are at higher risk. [9] At the present time, it is uncertain how and whether to incorporate this information into a PSA testing algorithm.

DRE of the prostate has traditionally played a role in the early detection of prostate cancer. The sensitivity of DRE to detect cancer is less than that of PSA, and the ERSPC trial dropped DRE as part of its screening protocol. Nonetheless some men will develop significant cancers without a rise in PSA, and therefore it may also be considered in those who wish to pursue early detection of prostate cancer.

Taken together, because of the overall potential for a loss of quality-adjusted life years due to over-diagnosis and over-treatment of prostate cancer, the GUTG/VPC does not recommend an unselected, population–wide, PSA screening strategy. The utility analysis however, does support the GUTG/VPC recommended strategy for use of PSA testing for in asymptomatic men who are well informed about the risks of over-diagnosis and over-treatment but still wish to pursue early diagnosis of prostate cancer. In addition, a strategy of early detection of prostate cancer linked to a treatment algorithm that includes prioritization of active surveillance for men with low risk prostate cancer serves to mitigate the potential harms of over-diagnosis, over-treatment and loss of quality of life associated with early detection of prostate cancer by PSA testing.​

Patient Information Document

Revised May 2009

The Pros and Cons of PSA Screening for​ Prostate Cancer  brochure provides information to assist men make an informed decision about screening for prostate cancer using the PSA test.

Print copies of the brochure may be requested by BC and Yukon residents from:

BC Cancer Agency Library
675 West 10th Ave.
Vancouver, B.C. V5Z 1L3
Tel: 1-888.675.8001 Local 8003
Email: library@bccancer.bc.ca

Further patient information is located on the Screening Programs > Prostate Cancer page in the Patient/ Public Info section of our website.

Recommendations

Revised 18 May 2012

  • The Genitourinary Cancer Tumour Group (GUTG) of the BC Cancer Agency and the Vancouver Prostate Centre (VPC) recommend that asymptomatic men 50-55 years of age or older, with an estimated life expectancy of more than 10 years, who are well informed about the risks of over-diagnosis and over-treatment, consider PSA testing for the early diagnosis of prostate cancer.
  • The GUTG and VPC do not support unselected, population-wide PSA screening because of the potential for over-diagnosis, over-treatment and detriment to quality adjusted survival.

1. The decision to use PSA testing for the early detection of prostate cancer should be individualized. Patients should be informed of the known risks and the potential benefits PSA testing.

  • Men need to be informed of the risks and benefits of testing before it is undertaken. The risks of over-detection, over-treatment and active surveillance as a treatment option should be included in this discussion.
  • The following is a brief summary of risks and benefits of early detection of prostate cancer. (Recommended reading [10])

Risks of PSA testing and Early Detection of Prostate Cancer

  • False negative and false positive PSA results
    • A low PSA test does not mean that a person does not have prostate cancer, and a high PSA does not necessarily mean a person does have prostate cancer.
  • Biopsy
    • Pain and very rarely infection.
  • Distress and anxiety
    • Being diagnosed with prostate cancer is associated with anxiety.
  • Overdiagnosis and treatment
    • Overdiagnosis refers to the detection of cancers that would not otherwise have become clinically apparent. This could result in treatment of a prostate cancer that may not have been a problem for a man in his lifetime
    • The risks of treatment such as radiation and surgery include urinary problems and incontinence, sexual dysfunction, and bowel problems.

Benefits of PSA testing and Early Detection of Prostate Cancer

  • Early detection of prostate cancer can save lives.
    • From what we know so far, at its best, 293 men need to be screened and 12 diagnosed with prostate cancer to prevent 1 death over a 14 year period.
  • Early detection and treatment of prostate cancer can avert future prostate cancer-related problems.

2. Early detection and risk assessment of prostate cancer should be offered to asymptomatic men 50-55 years of age or older with an estimated life expectancy of more than 10 years who wish to be screened.

  • Early detection begins at age 50 years for men at average risk of prostate cancer and should generally cease when life expectancy falls below 10 years. The optimal starting age and frequency of PSA testing is not known. The recent studies performed PSA testing every 2 to 4 years. The most cost-effective and evidence-based strategy is for PSA testing every 4 years from age 55 to 70 years.
  • Men with higher risk for prostate cancer should consider testing at age 40 to 45 (African American origin, family history of prostate cancer, BRCA1 or BRCA2 mutation carrier). Individual risk can be assessed by the use of a risk calculator e.g. http://www.prostatecancer-riskcalulator.com/​

3. Abnormal results trigger referral to urologists.

  • Men with a PSA of >3.0 μg/L should be referred to a urologist for consideration of biopsy. A PSA that is > 2.0 but increasing by more than 0.75-1.0 μg/L/year should also be referred.
  • Men with an abnormal digital rectal examination should also be referred to a urologist regardless of the PSA value.
  • Any subsequent decision to recommend biopsy needs to include consideration of life expectancy, co-morbidities, prostate co-conditions (e.g. large BPH, prostatitis), PSA velocity, DRE findings, and patient risk factors and preference.

4. Treatment Guidelines for PSA-detected Cancer.

  • Early detection of prostate cancer should be linked to a treatment algorithm that includes discussion and prioritization of active surveillance for appropriate candidates with low risk prostate cancer. [11]
  • Active surveillance in men with very low and low risk cancers, and some older men with intermediate risk cancer should be carried out in a programmatic manner, as coordinated by a Urologist or Oncologist following established guidelines. .
  • Men with intermediate risk, high risk localized and other cancers should be treated as per current guidelines [12]

References

Revised 18 May 2012


1. Ornish D, Weidner G, Fair WR, et al. Intensive lifestyle changes may affect the progression of prostate cancer. J Urol. 2005 Sep;174(3):1065-9; discussion 9-70.

2. Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2011 May 5;364(18):1708-17.

3. Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet. 2009 Jan 24;373(9660):301-8.

4. Wilt T. Initial results of the Prostate Cancer Intervention Versus Observation Trial (PIVOT) American Urology Association Annual meeting; 2011; Washington DC; 2011.

5. Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol. 2010 Aug;11(8):725-32.

6. Schroder FH, Hugosson J, Roobol MJ, et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med. 2012 Mar 15;366(11):981-90.

7. Andriole GL, Crawford ED, Grubb RL, 3rd, et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst. 2012 Jan 18;104(2):125-32.

8. Pickles T, Group SA. PSA Toolkit: PSA Screening and Testing for Prostate Cancer: Canadian Partnership Against Cancer; 2009.

9. Lilja H, Ulmert D, Bjork T, et al. Long-term prediction of prostate cancer up to 25 years before diagnosis of prostate cancer using prostate kallikreins measured at age 44 to 50 years. J Clin Oncol. 2007 Feb 1;25(4):431-6.

10. Wolf AM, Wender RC, Etzioni RB, et al. American Cancer Society guideline for the early detection of prostate cancer: update 2010. CA Cancer J Clin. 2010 Mar-Apr;60(2):70-98.

11. BC Cancer Agency. Cancer Management Guidelines. Prostate Cancer: Management: Low Risk. 2007.

12. BC Cancer Agency. Cancer Management Guidelines. Prostate Cancer: Management: Intermediate Risk.​  2007.

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