Ogni antibiotico è efficace in relazione a un determinato gruppo di microrganismi
comprare ampicillina online in italiain caso di infezioni oculari vengono scelte gocce ed unguenti.
Prostate cancer guidelines forum: 5/6 february 2005
Prostate Cancer Diagnostic and Treatment Guidelines
The Prostate Cancer Foundation of South Africa
Publication Date: June 2013
ORIGINAL AUTHORS
Prof. A M. Segone, Prof. M. Haffejee, Prof. S. Wentzel, Prof. C. F. Heyns, Prof. S. B. A.
Mutambirwa, Dr. L. Coetzee, Prof. R. Barnes, D.r P. Porteous, Dr. M. Mackenzie, Dr. M.
Bongers, Prof. M. L. S. de Kock, Dr. M. Bigalke, Dr. E. M. Moshokoa, Dr. P. Chetty, Dr. A.
Naudé 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 THIS VERSION
Dr. L. J. E. Coetzee MBChB(Pret.), MMed(Urol.) F.C.S (Urol.), Fellow in Uro-Oncology (Duke
Univ. USA), Dr. P. T. Paradza MBChB(UZ),FC Rad(SA) Onc., Prof. M. Haffejee MB;BCh
(Wits), FC(Urol) SA, Dr. M. Mackenzie MB;BCh. (Wits), FRCS Ed., FCS SA Urol., FHKCS.,
Dr. G.F.G.O. de Muelenare, MBChB, MMed(RadT), MD
These guidelines are in the process of being reviewed by: The South Africa Urological Association (SAUA)
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
IMPORTANT
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 treat. 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.
INTRODUCTION
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
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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.
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.
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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 testing.
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:
40 – 50years 0 - 2.5 ng/ml
50 – 60years 0 - 3.5 ng/ml
>60years 0 - 4.0 ng.ml
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.
Biopsy technique
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.
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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
Radiotherapy (RT)
o External beam (3 –dimensional conformal or intensity modulated) o Interstitial brachytherapy
Are still experimental
High intensity focused ultrasound (HIFU)
outside clinical trials
Androgen deprivation therapy (ADT)
Deferred treatment
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.
AS 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
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and PSA. A repeat biopsy is indicated after 12 – 24 months or if there is any sign of
disease progression by examination or markers.
AS is an option in men with a tumor matching or approaching the definition of
"indolent" or insignificant which would include;
PSA <10ng/ml
Gleason score ≤6
PSA density <0,15-0.2
≤ 50% of PCa in any biopsy core
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
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
High risk disease
Clinical stage T3a or T3b and/or
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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
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
Types of ADT
- Parenteral oestrogens
- Luteinizing hormone releasing hormone (LHRH) antagonists
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- Luteinizing hormone releasing hormone (LHRH) agonists
- Combinations of above
- Bilateral orchidectomy or
- Combination of above with antiandrogens
Ketoconazole Withdrawal of antiandrogens
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)
Primary recommended
Neo-adjuvant LHRH agonist
prior to radiotherapy
ADT plus RT or RP
Bicalutamide monotherapy
Intermittent / sequential ADT
Anti-androgen therapy 14 days
prior to LHRH agonists to
prevent flare/spinal
Intermittent / sequential ADT
ADT must continue plus ADT in addition to:
(taxanes Mitoxantrone
+/- corticosteroids)
Estramustine and vinblastine
Platinum based chemotherapy
Strontium, samarium
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.
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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 CANCER THERAPY
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.
Erectile dysfunction
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
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Active surveillance
Treatment Dilatation Optical urethrotomy
Epidemiology 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
Prevention Active surveillance Nerve sparing surgery Controlled exposure to radiation Pelvic floor exercise peri-operatively
MODERATE
(1-2 pads per day)
(2-5 pads per day)
(>5 pads per day)
Pelvic floor exercise
Pelvic floor exercise
Artificial sphincter
Urethral occlusion devices
Pharmacological:
Anticholinergics
- Peripheral and sacral
nerve stimulators
Urethral occlusion devices Urethral occlusion devices
Artificial sphincter
NOTES for invasive management of incontinence:
Wait at least two years, if patient continues to improve If no improvement, wait one year
Radiation proctitis (and other bowel complications after radiation therapy)
CO2 laser therapy Formalin instillation Prednisone enema Hyperbaric oxygen Colostomy/Laparotomy Generally avoid biopsy of rectal lesion
Radiation cystitis
Clorpactin, silver nitrate, formalin instillation Prednisone instillation Hyperbaric oxygen Urinary diversion
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Urinary retention
Alpha blockers Catheterization TUR prostate (recommended to wait at least 6-10 months after real time
Urethral stricture management
Epidemiology
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.
Treatment Subareolar mastectomy
Hot flushes
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
Depression
Prevention and treatment Lifestyle/Exercise/Diet Evaluate patients regularly/referral to psychiatrist/psychologist Anti-depressants
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TREATMENT OF COMPLICATIONS OF ADVANCED PROSTATE CANCER AND
Local complications
A. Infiltration
ADT naive
Palliation
Suprapubic catheter
Urinary diversion
resection prostate
Assess general condition Only if good
Bypass - J-stents
and decide on palliation
performance status
B. Urethral / Bleeding
Cystoscopy + transurethral resection and fulguration in combination with
(Internal iliac artery)
Urinary diversion
Systemic Complications
ADT Naïve
Lymphatic
Supportive therapy
obstruction
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1st line Bisphosphonates +
metastases
Bisphosphonates chemotherapy
2nd line Symptomatic Asymptomatic
Analgesics Follow-up
Corticosteroids
Isotopes (Strontium, Samarium)
Treat medical condition on merit
(e.g. blood transfusion)
condition on merit
Disseminated (e.g. blood
Intravascular transfusion)
Supportive measures
Spinal decompression
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Source: http://prostate.acitravel.co.za/cake/app/webroot/uploads/files/Prostate_Cancer_Guidelines_2013.pdf
Neuron, Vol. 33, 947–958, March 14, 2002, Copyright 2002 by Cell Press Cellular Mechanisms of the Slow (⬍1 Hz) Oscillation in Thalamocortical Neurons In Vitro Stuart W. Hughes,2 David W. Cope,2,3 relate to the slow rhythm is also characterized by re- Kate L. Blethyn, and Vincenzo Crunelli1
Annu. Rev. Genet. 2002. 36:153–73 ° 2002 by Annual Reviews. All rights reserved STUDYING GENE FUNCTION IN EUKARYOTES BYCONDITIONAL GENE INACTIVATION Manfred Gossen1 and Hermann Bujard2 1Max Delbr¨uck Centrum, Robert-R¨ossle-Strasse 10, D-13125 Berlin, Germany;e-mail: [email protected]; 2ZMBH, Universit¨at Heidelberg, Im NeuenheimerFeld 282, D-69120 Heidelberg, Germany; e-mail: [email protected]