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 annually
• Re-biopsy every 3 years, unless indicated earlier. Re-biopsy 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 re-biopsy
• 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.

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.

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 tumour 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 multiple 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 enrolment 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.

​Reviewed July 2005

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 anti-androgen 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.

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])

Updated 12 April 2007​

Reviewed July 2005​

Reviewed July 2005​

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.

Published: 27 June 2005

There is level 1 evidence that Zoledronate at 4 mg IV administered 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 therapy 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]
   

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.

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.​

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.

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.

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.

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.

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

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 11). 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.

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).

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).

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.

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.

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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.
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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, Ricchiuti 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.
16. Townsend MF, Sanders WH, Northway RO, Graham SD, Jr. Bone fractures associated with luteinizing hormone-releasing hormone agonists used in the treatment of prostate carcinoma. Cancer. 1997;79(3):545-50.
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 

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 bio TTT. 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 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”.

Revised 18 May 2012 

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.

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​.

24 May 2012 

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 on prostate cancer can be found in the Health Info section of our website.

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.
• Over-diagnosis and treatment
• Over-diagnosis 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]

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.