Microsoft word - prostate cancer guidelines 2013 final 1 august 2013.doc
Revised Prostate Cancer Diagnostic and Treatment Guidelines 2013
The Prostate Cancer Foundation of South Africa
Publication Date: August 2013
ORIGINAL AUTHORS before 2012:
Prof. M. Haffejee, Prof. S. Wentzel, Prof. C.F. Heyns, Prof S.B.A. Mutambirwa, Dr. L. Coetzee, Dr C
Steinmann, Dr P Porteus, Dr M Mackenzie, Dr M Bongers, Dr M. Bolus, Dr R. Rencken, Dr S.
Kamba, Dr T. Naidoo, Dr B. Rapoport
These guidelines have subsequently been reviewed, adapted and updated by The Prostate Cancer
Foundation of South Africa and in their current format represent only the views and opinions of the
Prostate Cancer Foundation of South Africa. AUTHORS AND REVIEWERS OF 2013 VERSION:
Dr. L. J. E. Coetzee MBChB(Pret.), MMed(Urol.)SA, F.C.S(Urol.)SA, Fellow in Uro-Oncology (Duke
Univ. USA); Prof. S. B. A. Mutambirwa MBChB(Zim.), F.C.S(Urol.)SA, MMed(Urol.)SA; Dr. G.F.G.O.
De Muelenare MBChB, MMed(RadT), MD; Prof. M. Haffejee MBBCh(Wits), FC(Urol)SA; Dr. M.
Mackenzie MBBCh(Wits), FRCS Ed., F.C.S(Urol)SA, FHKCS.; Dr. P. T. Paradza MBChB(UZ), FC
These guidelines were reviewed and are endorsed by The South Africa Urological Association
(SAUA) in 2013: SAUA REVIEWERS:
Prof. S. B. A. Mutambirwa, Prof. R. Barnes, Dr. M. Bigalke, Dr. M. Bongers, Dr. P. Chetty, Dr. L.
Coetzee, Prof. M. L. S. de Kock, Prof. M. Haffejee, Prof. C. F. Heyns, Dr. M. Mackenzie, Dr. E. M.
Moshokoa, Dr. A. Naudé, D.r P. Porteous, Prof. A M. Segone, Prof. S. Wentzel.
These guidelines are in the process of being reviewed by:
The South African Society of Medical Oncology (SASMO)
The South African Society of Clinical and Radiation Oncologists (SASCRO)
Revised guidelines will be published after obtaining the input of these societies IMPORATNT
Diagnostic and treatment guidelines are intended only as a guide for clinicians and patients. The
obligation to be fully informed of the latest available information pertaining to the diagnosis and
treatment of prostate cancer lies with the clinician. Diagnostic and treatment guidelines cannot
factor in the individual characteristics of each patient, and it is therefore the clinician’s responsibility
to determine whether the guidelines are relevant for each individual patient that they diagnose and
Neither The Prostate Cancer Foundation, nor the authors, nor the reviewers accept any
responsibility for any errors in copyright, printing or omissions which may have occurred before,
during or after publication. Neither The Prostate Cancer Foundation, nor the authors, nor the
reviewers shall be liable for any damages suffered as a result of the usage of the information
contained in these guidelines.
The management of prostate cancer (PCa) is complex and these guidelines serve as a framework
for the treatment of prostate cancer in South Africa with reference to internationally accepted
norms. Dramatic developments in diagnostic and therapeutic modalities have led to significant
changes in the treatment of prostate cancer in the past twenty years. Concepts are continually
evolving as new evidence becomes available so that guidelines or recommendations should be a
continuous process with regular revision and updates. Due to the wide variety of management
choices it is essential that the final decision about treatment should be made by the fully informed
patient, assisted by his wife and/or other family members, who should be given access to complete
and unbiased information from all the experts who may be involved in his treatment. Patient
participation in clinical trials constitutes good clinical practice, and doctors should not allow
preconceived opinions or other biases to prevent them from encouraging their patients to
participate in clinical trials.
A literature guide is given at the end of these guidelines. A
PREVENTION OF PCA
The use of 5-alpha-reductase inhibitors (5ARIs – finasteride & dutasteride) has been shown to reduce prostate cancer risk in placebo-controlled clinical trials.
Two large randomised studies showed that PCa diagnosed in men on 5ARI treatment was of higher grade than in the placebo group. These drugs are effective in the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia (BPH) but can currently not be recommended for prevention of PCa.
DETECTION, DIAGNOSIS AND SCREENING OF PROSTATE CANCER
Digital rectal examination (DRE) and serum prostate specific antigen (PSA) screening of
asymptomatic men reduces PCa mortality but increases overdiagnosis and overtreatment and is unavailable under the current state health system in RSA. PSA testing is recommended in males with a life expectancy of more than 10 years in the following situations:
- From the age of 40 in black African patients and in those with a positive family history of
prostate and/or breast cancer in a first degree relative.
- From the age of 45 years in all other males. - In addition patients with a history of lower urinary tract symptoms (LUTS) and/or clinical
suspicion of prostate cancer regardless of age group should have their PSA tested. Periodic reassessment will be determined by the initial PSA and DRE result.
Diagnostic approach to prostate assessment
A focused urological history and clinical examination form the basis of all assessments. DRE is recommended in all patients. An abnormal DRE is suggested by the presence of nodules, asymmetry, irregularity, and tethering of the overlying mucosa. A normal DRE does not exclude prostate cancer. DRE should include palpation of the rectum and inspection of the faeces.
Prostate specific antigen (PSA)
PSA related to cancer screening is not reliable in the presence of active urinary tract infection
(UTI), recent urinary tract instrumentation and/or urinary retention. Treat the UTI and
repeat the PSA after 6 weeks. Routine DRE does not elevate PSA significantly.
PCA3 is a urine test having the advantage over PSA that it is specific to prostate cancer and
not other conditions such as BPH and prostatitis. This test may be of value in stratifying risk
categories in patients in whom prostate cancer is suspected. It may also be useful in patients
who have had one or more negative prostate biopsies and who demonstrate a rising PSA,
patients with atypical acinar proliferation (ASAP) lesions and even patients on active
surveillance, who may be spared an unnecessary biopsy. This test is done on the first (10ml)
post prostate massage urine. PCA3 is not currently recommended to be used in place of PSA
Indications for prostate biopsy
The indications for prostate biopsy include an abnormal DRE and/or a total PSA above the
age related norm. At first presentation if DRE is normal and PSA is below 10 a repeat PSA in
6 weeks is advised.
Normal age related total PSA reference range:
Free to total PSA ratio (FT) and complex PSA should be performed at the clinician’s request in men with a total PSA above the age related reference range but less than 10ng/ml with a negative first prostate biopsy in order to improve decision making in addition to the DRE. If FT is > 20% follow up as opposed to re biopsy is the preferred option. An increased PSA velocity, (defined as an increase of greater than 0.75ng/ml or 25% per year) is also an indication for a prostate biopsy.
Antibiotic prophylaxis is essential and oral quinolones are recommended as the first choice. Written informed consent is required even if biopsy is done without local anaesthesia as an outpatient procedure. Diagnosis can be made without biopsy in elderly patients with a clinically malignant prostate on DRE, markedly raised PSA and/or other clinical evidence of advanced PCa. Trans-rectal ultrasound (TRUS) images are of limited value in diagnosing prostate cancer. Its most important use is to place needle biopsies accurately. TRUS guided biopsies are optimal, but digital guidance is acceptable if TRUS is not available. Digitally guided biopsies can be used to target palpable nodules. It is recommended that between six and twelve biopsy cores be taken depending on the size of the prostate and localization of the lesion. Biopsy cores should include lateral, para-sagittal and suspicious areas. More biopsies can
be taken at the discretion of the urologist but runs the risk of altering the dynamics of active surveillance (AS) and resulting in overtreatment.
Indications for repeat biopsy
The indications for repeat biopsy are complex and this decision should be based on extensive discussion between the patient and his urologist including the histological finding of high grade prostatic intraepithelial neoplasia [PIN III] and atypical small acinar proliferation (ASAP), rising PSA, DRE changes and possibly use of PCA3.
CLINICALLY LOCALIZED PROSTATE CANCER
Various staging investigations including bone scan, CT scanning, TRUS, lymph node dissection (LND) and MRI may be utilized. Since the incidence of skeletal metastases is negligible when PSA is below 10, bone scans are only advised when PSA is > 10 and/or Gleason score is 8 – 10 and/or T Stage is > T2.
Management options for localized prostate cancer include:
Radical prostatectomy – (RP) o Retropubic o Perineal o Laparoscopic o Robotic assisted laparoscopic
o External beam (3 –dimensional conformal or intensity modulated) o Interstitial brachytherapy
High intensity focused ultrasound (HIFU) outside
o Active surveillance o Watchful waiting
All techniques of radical prostatectomy are acceptable with comparable results in efficacy and morbidity. Salvage radical prostatectomy after radiotherapy has a limited role in a select group of patients. All techniques of radiotherapy are acceptable with comparable results in efficacy and morbidity. According to risk stratification, radiation can be combined with ADT.
Active surveillance (AS)
Active surveillance is an increasingly recognized management option for men with low-risk prostate cancer. Despite encouraging evidence for oncologic efficacy and reduction in morbidity, several barriers contribute to the underuse of this management strategy. Consistent selection criteria as well as identification and validation of triggers for subsequent intervention are essential.
Active surveillance consists of regular monitoring of patients with the intent of curative treatment if disease progression occurs. Patients should commit to a regular follow-up with DRE and PSA. A repeat biopsy is indicated after 12 – 24 months or if there is any sign of disease progression by examination or markers. Active surveillance is an option in men with a tumor matching or approaching the definition of "indolent" or insignificant which would include;
Watchful waiting (WW)
Watchful waiting consists of regular monitoring of patients with intent of palliative treatment
with disease progression. Patients should commit to a regular follow-up with DRE and PSA.
These are usually patients with low risk disease and/or with life expectancy below 10 years
and/or an existing co-morbidity profile which places them at risk of death from other causes
in less than ten years.
Risk stratification is an important part in planning the most appropriate treatment option for the patient and assessing potential outcomes.
Low risk disease
T1 to T2a clinical stage
Gleason score of 2 to 6
PSA less than 10ng/ml
If life expectancy is less than ten years then treatment options include watchful waiting. If
the life expectancy exceeds ten years then treatment options include active surveillance,
external beam radiotherapy (ERBT), interstitial brachytherapy (IB) and radical
prostatectomy (RP). Intermediate risk disease
T2b – T2c clinical stage and/or
Gleason 7 (3+4) and/or
PSA 10 – 20ng/ml
If the expected survival is less than ten years then treatment options include watchful
waiting. If the life expectancy exceeds ten years then treatment options include active
surveillance, external beam radiotherapy, interstitial brachytherapy and radical prostatectomy with a lymph node dissection or combinations of the above.
High risk disease
Clinical stage T3a or T3b and/or
Gleason 7 (4+3) to 10 and/or
This group represents locally advanced but potentially curable disease. Initial therapeutic
options include radiotherapy with ADT, radical prostatectomy with pelvic lymph node
dissection, ADT alone or trimodal therapy (brachytherapy plus EBRT plus ADT).
FAILED LOCAL THERAPY
1. Post radical prostatectomy
In the presence of positive margins options include, ADT, radiation therapy and WW. Where the histology reveals positive lymph nodes or seminal vesicle involvement then ADT and/or ERBT are the preferred options.
2. Rising PSA post definitive management
Options include WW, ADT and targeted radiotherapy to pelvis/prostate bed or metastatic lesions.
3. Post radiation therapy
Management options for recurrences following radiotherapy or brachytherapy include ADT, watchful waiting and possibly salvage radical prostatectomy in highly selected cases.
LOCALLY ADVANCED OR METASTATIC PROSTATE CANCER
The standard treatment for locally advanced PCa is ADT which delays clinical progression
and improves quality of life (QOL). At this stage, chemotherapy should be considered only
in castrate resistant PCa (CRPC). RP and RT can be considered in selected cases in
combination with ADT.
The goals of treatment are delayed disease progression, improved quality of life and
possibly increased survival. The choice of treatment is dependent on an informed patient
decision and also on the availability of treatment, costs and complications.
The other standard indication for ADT is metastatic PCa. Symptomatic patients with
localised prostate cancer unsuitable for curative treatment represent a further indication. Types of ADT
- Parenteral oestrogens - Luteinizing hormone releasing hormone (LHRH) antagonists - Luteinizing hormone releasing hormone (LHRH) agonists - Antiandrogens - Combinations of above
- Bilateral orchidectomy or - Seminectomy - Combination of above with antiandrogens
Ketoconazole Withdrawal of antiandrogens Corticosteroids
First line = Docetaxel Second line = Mitoxantrone/Prednisone In CRPC the use of chemotherapy may be indicated. Neuro-endocrine differentiation represents a small subset in which platinum based chemotherapy is indicated.
Treatment options (androgen sensitive disease unless otherwise stated)
Neo-adjuvant LHRH agonist prior to radiotherapy
Anti-androgen therapy 14 days prior to LHRH agonists to prevent flare/spinal compression Intermittent / sequential ADT
ADT must continue plus ADT in addition to: chemotherapy (taxanes
Estramustine and vinblastine Platinum based chemotherapy Strontium, samarium Bisphosphonate Denosumab, PCa vaccines, MDV3100,Carbazitaxel, Abiraterone acetate
Although surgical and medical castration have been shown to have equivalent efficacy, surgical castration is unacceptable to some men. On the other hand long term LHRH therapy usually is more expensive and requires patient compliance.
Early ADT has been shown to delay time to progression and may have a survival benefit over delayed ADT in locally advanced PCa.
Intermittent therapy could be used as there may be a reduction in side effects as well as cost. Efficacy of intermittent therapy as opposed to continuous ADT remains to be proven, but has shown some QOL benefits.
Timing of chemotherapy is important as chemotherapeutic agents are more effective in patients with good performance status. Chemotherapy should be considered after failure of 2 lines of ADT. After 3 cycles of chemotherapy re-evaluate for response. If there is a significant reduction of PSA and/or improvement in symptom score, response is implied. There is currently no clear indication for second line chemotherapy. Carbazitaxel is registered for use after failure of docetaxel.
Patient monitoring on ADT includes regular history, examination and appropriate laboratory and radiological investigations. Patients on chemotherapy may require more frequent evaluation
PREVENTION AND TREATMENT OF COMPLICATIONS RELATED TO PROSTATE
These complications are possibilities for each mode of therapy and will differ depending on
patient factors, facilities and the intrinsic nature of the procedure performed. 1. Erectile
Frequently coexists in patients with PCa Immediate after surgery, tendency to improve Develops later after radiation therapy- tendency to worsen with time Incidence comparable at 2 years after both surgery and radiation
Prevention Nerve sparing surgery Early phosphodiesterase-5 (PDE5) inhibitor therapy, vacuum device or intra-
cavernosal prostaglandin after radical prostatectomy
Bicalutamide as monotherapy or intermittent ADT Active surveillance
Treatment of erectile dysfunction Phospho-diesterase 5 (PDE5) inhibitors Intracavernosal therapy Vacuum device Penile prosthesis
Stricture/Bladder neck stenosis
Optimal surgical and radiation technique Active surveillance
Treatment Dilatation Optical urethrotomy
Can occur after both surgery and radiation therapy or be independent of PCa
treatment. Incidence, pathogenesis and treatment are different
Always exclude local or systemic cause of incontinence (including medication)
Prevention Active surveillance Nerve sparing surgery Controlled exposure to radiation Pelvic floor exercise peri-operatively
(1-2 pads per day)
(2-5 pads per day)
(>5 pads per day)
Urethral occlusion devices Urethral occlusion devices
NOTES for invasive management of incontinence:
Wait at least two years, if patient continues to improve If no improvement, wait one year
(and other bowel complications after radiation therapy)
CO2 laser therapy Formalin instillation Prednisone enema Hyperbaric oxygen Colostomy/Laparotomy Generally avoid biopsy of rectal lesion
Clorpactin, silver nitrate, formalin instillation Prednisone instillation Hyperbaric oxygen
Alpha blockers Catheterization TUR prostate (recommended to wait at least 6-10 months after real time
Can be primary or secondary to any hormonal manipulation, but is of special
importance when bicalutamide 150 mg monotherapy (B-150) is used.
Notes on B-150 therapy:
Prevention Prophylactic mastectomy or single dose (10Gy) radiotherapy or 3 consecutive
doses of 250 cGy; prophylactic EBRT significantly reduces incidence if employed prior to initiation of therapy.
Prevention and treatment Lifestyle, Diet Cyproterone acetate Bicalutamide monotherapy Intermittent ADT Clonidine Low dose oestrogen and or progesterone
Osteoporosis associated with ADT
Prevention and treatment Lifestyle/Exercise/Diet Bicalutamide monotherapy Intermittent ADT Calcium supplementation Vitamin D Bisphosphonates Denosumab
Prevention and treatment Lifestyle/Exercise/Diet Evaluate patients regularly/referral to psychiatrist/psychologist
TREATMENT OF COMPLICATIONS OF ADVANCED PROSTATE CANCER AND CRPC
B. Urethral / Bleeding
Cystoscopy + transurethral resection and fulguration in combination with ADT
2nd line Symptomatic Asymptomatic Analgesics Follow-up Corticosteroids EBRT Isotopes (Strontium, Samarium)
Intravascular transfusion) Coagulation (DIC)
Lesko SM, Rosenberg L, Shapiro S. Family history and prostate cancer risk. Am J Epidemiol
US Cancer Statistics Group: 2000 Incidence. Atlanta, Georgia.
Giovanucci E, Ascherio A, Rimm EB, Stampfer MJ, Colditz GA, Willet WC. Intake of
carotenoids and retinol in relation to risk of prostate cancer. J Natl Cancer Inst 1995, 87:
Heinonen OP, Albanes D, Virtamo J et al. Prostate cancer and supplementation with alpha-
tocopherol and beta carotene: Incidence and mortality in a controlled trial. J Natl Cancer
Giovanucci E, Rimm EB, Wolk A et al. Calcium and fructose intake in relation to risk of
prostate cancer. Cancer Res 1998; 58: 442 – 447.
Giovanucci E, Rimm EB, Colditz GA et al. A prospective study of dietary fat and risk of
prostate cancer. J Natl Cancer Inst 1993; 85: 1571 – 1579.
Thompson IM, Goodman PJ, Tangen CM et al. The influence of finasteride on the
development of prostate cancer. N Engl J Med 2003; 349: 215 – 224.
Raghow S, Hooshdoven MZ, Katiyov S, Steiner MS. Toremifene prevents prostate cancer in
the transgenic adenocarcinoma mouse prostate model. Cancer Res 2002; 62: 1370 – 1376.
Robinson JW, Moritz S, Fung T. Meta-analysis of rates of erectile function after treatment of
localized prostate carcinoma. Int J Radiat Oncol Biol Phys 2002; 54: 1063 – 1068.
Montorsi F, Brock G, Lee J et al. Effect of Nightly versus On-Demand Vardenafil on
Recovery of Erectile Function in Men Following Bilateral Nerve-Sparing Radical
Prostatectomy. Eur Urol 54 (2008) 924–931.
Zelefsky MJ, McKee AB, Lee H, Lerbel SA. Efficacy of oral sildenafil in patients with erectile
dysfunction after radiotherapy for carcinoma of the prostate. Urology 1999; 53: 775 – 778.
Montorsi F, McCullough A, Brook G et al. Tadalafil in the treatment of erectile dysfunction
following bilateral nerve-sparing radical retropubic prostatectomy. Int J Impot Res 2003; 15
Blackard CE, Borken WD, Lima JS et al. Use of vacuum tumescence device for impotence
secondary to venous leakage. Urology 1996; 41: 225 – 227.
14. Rodriquez VL, Gonzalvo IA, Bono Arino A et al. Erectile dysfunction after radical
prostatectomy: etiology and treatment. Acta Urol Esp 1997; 21: 909 – 921.
Prevention and management of erectile dysfunction following radical
prostatectomy. Urol Clin North Am 2001; 28: 613 – 627.
Moore K. A review of the anatomy of the male continence mechanism and the cause of
urinary incontinence after prostatectomy. J WOCN 1999; 26: 86 – 93.
Fransson P, Widmark A. Late side effects unchanged 4-8 years after radiotherapy for
prostate carcinoma: a comparison with age matched controls. Cancer 1999; 85: 678 –
18. Hunter KF, Moore KN, Cody DJ, Glazener CM. Conservative management for post
prostatectomy urinary incontinence. Cochrane Database Syst Rev 2004; (2): CD 001843.
Schaeffer AJ, Clemens JQ, Ferrari M, Stamey TA. The male bulbo-urethral sling procedure
for post radical prostatectomy incontinence. J Urol 1998; 159: 1510 – 1515.
Haab F, Trockman BA, Zimmem PE, Leach GE. Quality of life and continence assessment of
the artificial urinary sphincter in men with minimum 3,5 years of follow-up. J Urol 1997;
Talcott JA, Manola J, Clark JA et al. Time course and predictors of symptoms after primary
prostate cancer therapy. J Clin Oncol 2003; 21: 3979 – 3986.
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:
Smith MR, Goode M, Zietman AL, McGovern FJ, Lee H, Finkelstein JS. Bicalutamide
monotherapy versus leuprolide monotheray for prostate cancer. J Clin Oncol 2004; 22: 2546
Understanding treatments for bone loss and bone metastases in patients with
prostate cancer: a practical review and guide for the clinician. Urol Clin North Am 2004; 31:
Saad F, Schulman CC. Role of bisphosphonates in prostate cancer. Eur Urol 2004; 45: 26 –
Diamond TH, Winters J, Smith A et al. The anti-osteoporotic efficacy of intravenous
pamidronate in men with prostate carcinoma receiving combined androgen blockade: A
double-blind, randomized, placebo controlled crossover study. Cancer 2001; 92: 1444 –
Tyrrell C, Tammela T, Goedhals L, Payne H. Prophylactic breast irradiation significantly
reduces the incidence of bicalutamide induced gynecomastia. AUA abstract, Orlando
Crawford ED et al: Diagnostic performance of PCA3 to detect prostate cancer in men with
increased prostate specific antigen: A prospective study of 1,962 cases. J Urol 2012; 188:
Steyerberg EW et al: Prediction of indolent prostate cancer: validation and updating of a
prognostic nomogram. J Urol 2007; 177(1): 107-12.
Mortality results from a randomised prostate-cancer screening trial. N Engl J
Screening and prostate-cancer mortality in a randomised European study. N
Zhu et al. Risk-based prostate cancer screening. Eur Urol 2012; 61: 652-661.
Best Practice Statement: 2009 Update (American Urological Association).
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