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Prostate CancerManagementClinical Guidelines

Prepared by The Clinical Guidelines CommitteeRoyal College of Surgeons in Ireland

February 2002

Royal College of Surgeons in Ireland123 St. Stephen’s Green, Dublin 2, Ireland

Tel: 353-1 402 2100. Fax: 353-1 402 2460. Web: www.resi.ie

Prostate Cancer Management Clinical Guidelines 1

Foreword

FOREWORDAwareness of prostate cancer amongst the generalpublic has risen sharply, due to a number of factorsnot least of which has been the profiling ofprominent sufferers by the media.

There is a body of information about prostatecancer available through the Internet, men’s andwomen’s magazines, and interest groups. Much ofthis information is available in a fragmented form,and it is not always possible to synthesise the fullpicture easily. These guidelines are designed abouta series of recommendations, which have beendeveloped from an attempt to gather concisely andaccurately the relevant information about prostatecancer. Consequently it is hoped that therecommendations and the supporting informationwill prove to be an accessible source of knowledgeto the medical profession, medical students, thenursing profession and the general public.

Considerable effort has gone into publishing theguidelines. We acknowledge that they will have alimited shelf-life and it is our intention to revisethem in two or three years so that advances inknowledge can be incorporated,

Many people were involved and contributed in avariety of ways to the project. We would like tothank our panel of co-writers and reviewers – Dr. John Armstrong, Mr. David Quinlan andProf. John Fitzpatrick, all of whom contributed tothe manuscript. Marjorie White-Flynn at theUrology Department in Tallaght did trojan work,and typed many drafts of the manuscript before itwas deemed suitable for publication. Weappreciate her patience and good humour. PaulaWilson co-ordinated the project in the RoyalCollege of Surgeons in Ireland and we thank herfor putting her organising skills at our disposal.We also wish to thank our publishers who havemetamorphosed a rather drab-looking documentinto a beautiful production.

Michael ButlerChairman, Urology Group, Clinical Guidelines Committee

Niall O’HigginsChairman, Clinical Guidelines Committee

February, 2002.

Contents

Introduction 3

Purpose of guidelines 3

Keys to level of evidence and grading of recommendations 3

Summary of recommendations 4

Presentation 6

Management of asymptomatic and symptomatic patients 6

Investigation and Diagnosis 9

Tumour markers 9

Obtaining prostatic tissue for histology 9

TNM clinical classification of prostate cancer 11

Histological reporting 12

Imaging 13

Treatment of Prostate Cancer 15

Selection of therapy for localised prostate cancer 15

Management of potentially curable carcinoma of the prostate 15

Surgery of prostate cancer 16

Relapse after prostate surgery: diagnosis, treatment and prognosis 17

The role of adjuvant X-ray therapy 18

XRT for localised prostate cancer 19

Relapse after XRT: diagnosis and treatment 20

Management after failed XRT: cryotherapy andsalvage prostatectomy 20

XRT for locally advanced prostate cancer 21

Brachytherapy 21

Conservative Management of Prostate Cancer 23

Surveillance 23

Metastatic Prostate Cancer 24

Hormonal therapy 24

Clinical management of patients with metastatic disease 26

Management of complications of advanced prostate cancer 26

Hormone-refractory prostate cancer 27

Cryotherapy 28

References 29

Prostate Cancer Management Clinical Guidelines2

PURPOSE OF GUIDELINESCancer of the prostate is the commonest non-cutaneous cancer amongst men in the Republic ofIreland. It represents 11% of all male cancers. Therisk of developing prostate cancer before the age of75 is 5% and has increased by 1.3% since 1994.The disease-specific risk of death before 75 is 1.6%.Approximately five hundred and twenty men die ofcarcinoma of the prostate per annum.1

The aims of these guidelines are to increaseawareness of prostate cancer in the Irishcommunity. The guidelines provide a source ofinformation, the ultimate aim of which is tofacilitate and promote optimum care for patientspresenting with carcinoma of the prostate. Byreference to the guidelines and enactment of therecommendations disease-free intervals andincreased survival in patients with prostatic cancermay be achieved.

In publishing the guidelines we aspire to informclinicians about best clinical practice. Promotion ofbest available standards should lead to theelimination of the unacceptable.

The guidelines are not intended to be rigidlydogmatic and are not written as protocols. Clinicalfreedom is preserved within the limits of goodpractice.

Ultimately it is hoped that the guidelines will lead tobetter uniform care throughout the country withimprovement in survival for all patients withprostate cancer.

KEY TO LEVELS OF EVIDENCEAND GRADING OFRECOMMENDATIONSThe definitions of the type of evidence of and thegrades of recommendations used in these guidelinesoriginated from the United States Agency ForHealth Care Policy and Research and are set out inthe following tables.

Level Type of EvidenceIa Evidence obtained from meta-analysis

of randomised trials.

Ib Evidence obtained from at least onerandomised controlled trial

IIa Evidence obtained from at least onewell-designed controlled studywithout randomisation.

IIb Evidence obtained from at least oneother type of well-designed quasi-experimental study.

III Evidence obtained from well-designed, non-experimental,descriptive studies such ascomparative studies, correlationstudies and case series.

IV Evidence obtained from expertcommittee reports or opinions and/orclinical experience of respectedauthorities.

GRADES OF RECOMMENDATIONGrade A requires at least one randomised controlledtrial as part of the body of literature of overall goodquality and consistency addressing the specificrecommendation. (Evidence levels Ia, Ib).

Grade B requires the availability of well-conductedclinical studies but no randomised clinical trials onthe topic of the recommendation. (Evidence levelsIIa, IIb, III).

Grade C requires evidence obtained from expertcommittees reports or opinions and/or clinicalexperiences of respected authorities. Indicates theabsence of directly applicable clinical studies ofgood quality. (Evidence level IV).


Introduction

Introduction

SUMMARY OF RECOMMENDATIONS

Screening1. Because of a relative increased risk of

developing carcinoma in certain subgroups aselective approach to investigation by digitalrectal examination (DRE) and prostatic specificantigen (PSA) estimation is warranted.

Grade B

2. Standardised information should be madeavailable to all asymptomatic patientsundergoing PSA examination. Informationshould include the following:

■ Likelihood that failure to screen willincrease the chance of an undetectedcarcinoma of the prostate in a man’slifetime.

■ Whether PSA screening will lengthen orimprove quality of life.

■ The risk of that a raised PSA may resultin unnecessary single or serial biopsies.

■ The value of a normal result.

Grade B

3. In patients with lower urinary tract symptomsPSA should be routinely included ininvestigations.

Grade C

4. Currently it is recommended that screening isbest achieved by a combination of DRE andPSA on an annual basis to age 70.

Grade B

5. A screening programme should be introduced inIreland in the context of a randomised trial formen between 50 and 69 years.

Grade C

Tumour Markers and Histology6. PSA testing needs further refinement to limit

the number of unnecessary biopsies. Age-adjusted total PSA and the ratio of free to totalPSA values are the most effective format ofreporting PSA results.

Grade B

7. Histological evidence of prostatic carcinoma ingeneral is essential. Only in exceptionalcircumstances with overwhelming evidence ofadvanced cancer should treatment commencewithout histological confirmation.

Grade C

8. Systematic sextant transrectal ultrasound(TRUS)-guided biopsy is the preferred methodof obtaining biopsies. Positive biopsy rates canbe improved by modifying the sextant biopsytechnique to include biopsies of the peripheralzone obtained more laterally, and inclusion ofsome biopsy from the transitional zone inlarger prostates.

Grade C

9. Appropriate antibiotics should always be givenwhen transrectal biopsies are carried out.

Grade C

10. Repeat biopsy is necessary where there is (a)inadequate tissue sampling, (b) cellular atypia,(c) high-grade (3) prostatic intraepithelialneoplasia (PIN) or (d) a rising PSA after anegative first biopsy.

Grade B

11. Biopsied specimens should be labelled andorientated according to local protocol.

Grade C

12. The Gleason system is the grading system ofchoice.

Grade C

13. Sampling and reporting protocols should bestandardised throughout the country.

Grade C

Imaging14. Further studies and radiological developments

are needed to define the most appropriatemodality to stage carcinoma of the prostatepre-operatively.

Grade C

15. Routine bone scans should be included inpatients undergoing radical surgery or X-raytherapy (XRT).

Grade C


Selection of Therapy and Pre-operative Assessment16. As far as is practical, information should be

given about best available treatments,individualised to the patient’s cancer, healthstatus and life expectancy.

Grade C

17. Prior to surgery (radical prostatectomy) patientsshould be informed about major morbiditywhich includes the risks and incidence ofimpotence and incontinence of urine.

Grade C

18. Radical prostatectomy should be performed bysurgeons appropriately trained in theprocedure, within an institution with medicaland nursing personnel trained in the care ofsuch patients.

Grade C

19. Patients with local recurrence after radicalprostatectomy should be given 3D conformalradiotherapy plus hormones.

Grade B

20. Before radiotherapy patients should beinformed of the potential complications ofradiation proctitis/cystitis and impotence.

Grade C

Treatment21. For patients assigned to radiotherapy,

3-dimensional conformal radiotherapy (3DCRT) has become the standard of care becauseof its advantages in delivering optimal dosagemost accurately to the prostate.

Grade B

22. XRT combined with neoadjuvant hormoneablation should continue to be evaluated byrandomised controlled clinical trials.

Grade B

23. Neoadjuvant or adjuvant hormone therapyshould be included in the protocol for high-riskpatients with localised prostatic tumours.

Grade A

24. Surveillance without specific treatment is anacceptable form of management for somepatients with T1a tumours with a poor lifeexpectancy (<10 years) due to the age at whichthe disease is detected or co-morbid factors.

Grade B

25. Patients with symptomatic metastatic disease,especially bone disease, should be managed byandrogen deprivation therapy. The choice oftreatment by LHRH analogues or orchidectomyis determined by many issues including patientpreference.

Grade B

26. Combined androgen blockade should not beused routinely on current evidence.

Grade A

27. Spinal cord compression is an indication forurgent referral for radiotherapy or surgery.

Grade C

28. A multidisciplinary team approach should beavailable to patients with advanced hormone-refractory prostatic carcinoma. The teamshould include palliative care specialists,radiotherapists and urologists.

Grade C

Prostate Cancer Management Clinical Guidelines 5Introduction

Presentation

PRESENTATION■ Historically in Ireland most patients with

prostate cancer were referred for specialistconsultation by their general practitioner whensymptoms of bladder-outlet obstruction haddeveloped. Lower urinary tract symptoms maysuggest locally advanced prostatic carcinomawith infiltration into the bladder neck or theurethra. In all patients with bladder-outletobstructive symptoms a digital rectalexamination (DRE) is indicated. The presenceof a nodule, induration or irregularity alerts thegeneral practitioner or urologist to thepossibility of cancer of the prostate.

■ Patients may present with peripheral limboedema due to pelvic and abdominallymphadenopathy.

■ Bone pain due to metastases may be thepresenting symptom.

■ Signs of spinal cord compression due tometastases may be the first indication ofprostatic cancer.

■ Anaemia occurs with widespread bonymetastases.

■ Occasionally uraemia due to bilateralobstruction of the ureters by prostaticcarcinoma is the presenting feature.

■ With the widespread introduction of prostaticspecific antigen (PSA) testing an increasingnumber of patients are referred by their generalpractitioner with elevated PSA for furtherinvestigation by transrectal ultrasound (TRUS)and for TRUS-guided biopsies. Many of thesepatients are asymptomatic and without clinicalfindings, but are found after investigation tohave prostate cancer. This mode of presentationof prostate cancer is increasing and patientnumbers in this sub-group have increasedsignificantly in recent years.

MANAGEMENT OF ASYMPTOMATICAND SYMPTOMATIC PATIENTS

Asymptomatic PatientsIn contemporary practice it is common forasymptomatic patients, who are otherwise healthy, torequest that a PSA be obtained. PSA is increasingly astandard investigation in preventive health care.

A raised PSA increases the likelihood that a patienthas prostate cancer. In addition, a raised PSAincreases the incidence of clinically importanttumours without significantly increasing the detectionof clinically insignificant tumours. Treatmentoutcome data suggests that potential treatments forcure of PSA-detected tumours is available. Currentlythere are some data confirming that screening by PSAreduces morbidity and mortality.2 The Surveillance,Epidemiology and End Results (SEER) programme isthe basis of most American trends for cancer. Thedata for prostatic cancer were analysed to determinethe effect of screening. No other malignancy has beenassociated with a greater increase in incidence, andthe tumours detected with PSA are mostly clinicallysignificant. Additionally the detection of advanceddisease has decreased, that is the incidence of distantdisease which influenced mortality rate has decreasedwith prostate screening of men older than 50 years ofage, but the incidence of local and regional diseasehas increased.

The SEER Study3 showed that in the USA between1973 and 1992 age-adjusted prostate cancerincidence rates for all males increased dramatically.The rate increase was linear between 1973 and 1976and exponential between 1976 and 1992. Between1987 and 1992, the age-adjusted incidence increasedfrom 102.9 to 189.4 per 100,000 men, an increase of84%, while the mortality rate fell by 6.3% from1991 to 1993. A contrary view4 noted that thechanges observed in the SEER data cannot beattributed to increased numbers of men undergoingscreening, and resulting earlier detection is alsoconsistent with lead-time bias, length bias, and adecline in mortality. These conclusions were that thebenefits of screening and early detection aretheoretical, but not well supported by the SEER data,whereas the costs and risks are well known. Anattempt to estimate the annual cost of screeningasymptomatic men for prostatic carcinoma inCanada was carried out by Krahn and associates.


They provided important information. Theconclusions were that PSA screening and attendantdown-stream costs consume a very small part of thetotal direct health care budget, and that priorestimates that PSA screening would ultimatelyconsume 5% of the health care budget areexaggerated. In the end the decision to implementPSA screening depends on the results of clinical trialsin this area. If found effective, screening is affordable,and needs support. The converse is equally true – noimproved trial outcomes, no support.5

Many factors must be considered by doctors andtheir patients who contemplate routine PSA forscreening for prostate cancer. The results of a refusalto obtain a PSA on patient request could be seriousparticularly if prostate cancer occurs in the patient ata future date. Because of the implications of theresults explicit information should be given to anasymptomatic, healthy patient before PSA estimationis done. Unfortunately PSA is not specific forcarcinoma of the prostate. Other factors, particularlybenign prostatic hyperplasia (BPH), cause elevationof serum PSA and distinguishing PSA elevations dueto carcinoma of the prostate from BPH remainsproblematical. A raised PSA is more likely to lead toa sequence of further studies such as a TRUSexamination of the prostate or TRUS-guided biopsies.

A significant problem for patients and urologists is apersistently elevated PSA with negative biopsies.Repeated TRUS examinations and biopsies may berequired and may lead on occasions to two or eventhree biopsy sessions. A healthy, asymptomaticpatient will be required to be fully acquainted withthe potential sequence of investigative events resultingfrom obtaining a PSA. Recent editorials have calledfor standardised, informed consent before ordering aPSA test.6 Suggested information should attempt toanswer questions as to the likelihood that a non-screened asymptomatic man will be adversely effectedby prostate cancer in his lifetime (see table opposite),whether the screening test will lengthen, or improvethe quality of life, the chances of having a falsepositive result and its consequences, the value of anormal result, and perhaps the differingrecommendations of various experts. A physician andpatient-focused study by Chan et al7 confirm the lackof consensus on which information is consideredappropriate by both. More work is needed to decidepertinent information for men with concerns overPSA testing.

The European Randomised Study of Screening forProstate Cancer (ERSPC), a multi-nationalcollaborative randomised trial of screening forprostate cancer, began in 1992. The primaryobjective was to determine whether screening couldcause a specific mortality reduction of 20%. Alsounder investigation are: the best method of screening,what groups are at risk and would benefit most froma screening programme, evaluation of quality of life(QOL) of the participants and the cost-effectivenessof screening to death. The participating centres are inBelgium, Finland, Italy, The Netherlands andSweden. Screening includes DRE, PSA and TRUS.Some preliminary results and conclusions areavailable. False-positive rates for TRUS as a primaryscreening test are too high and it is to be excluded asa screening test in the near future.

The first study results will be available in 2007 andwill include results from 180,000 men over a 10 yearscreening period. There are some discrepanciesamong countries concerning eligibility criteria andindications for biopsy, but collaboration has resultedin a uniform definition of end-points, trial type,recruitment and methods of assessing disease-relatedmortality. In four of the five countries randomisationoccurs after consent with Sweden opting forrandomisation before consent.

The importance of this study is the recognition thatDRE/PSA screening is desirable but should beconducted in the context of a randomised controlledclinical trial. Based on available data there is a biasthat relatively young, healthy, asymptomatic men beencouraged to undergo screening by DRE and PSA.Moreover, screening is encouraged in certain sub-groups with a higher risk of disease or highermortality rates such as those with a significant familyhistory of cancer of the prostate. Present data suggestthat screening is best achieved by a combination ofDRE and serum PSA.8, 9

Prostate Cancer Management Clinical Guidelines 7Presentation

Probability of Prostate Cancer by Age

> 40 years 1 : 10,000

40 – 59 1 : 103

60 – 79 1 : 8

Wingo PA et al10

Presentation

StatementPSA screening increases the incidence of localiseddisease and decreases the incidence of metastaticdisease.

Level of evidence III

StatementEstimates of cost of PSA-based screeningprogrammes may be exaggerated and a screeningprogramme is likely to be affordable and cost-effective.

Level of evidence IIb

Recommendation 1Because of a relative increased risk of developingcarcinoma in certain subgroups, a selectiveapproach to examination by DRE and PSA iswarranted.Grade B

Recommendation 2Standardised information should be made availableto all asymptomatic patients undergoing PSA.Information should include the following:

� Likelihood that failure to screen will increase thechance of an undetected carcinoma of theprostate in a man’s lifetime.

� Whether PSA screening will lengthen or improvequality of life.

� The risk of that a raised PSA results inunnecessary single or serial biopsies.

� The value of a normal result. Grade B

Recommendation 3In patients with lower urinary tract symptoms PSAshould be routinely included in investigations.Grade C

Recommendation 4Currently it is recommended that screening is bestachieved by a combination of DRE and PSA on anannual basis to age 70.Grade B

Recommendation 5A screening programme should be introduced inIreland in the context of a randomised trial for menbetween 50 and 69 years. Grade C


Management of Symptomatic MenRoutine evaluation of the prostate is necessary inmen presenting with lower urinary tract symptoms.Rectal examination and PSA estimation constitutepart of standard clinical evaluation. If an elevatedPSA is detected, patients require referral for furtherstudies which are determined by factors such as theage and co-morbidity. These factors will assist indetermining whether the patient will benefit fromfurther treatment.

TUMOUR MARKERS

Role of Prostatic Specific AntigenStrategies to refine PSA for cancer detection havebeen explored. The common goal is to increase thesensitivity and specificity and positive predictivevalue of the test leading to a reduction inunnecessary prostatic biopsies. Refinement of PSAvalues include PSA velocity, PSA density, ageadjusted reference ranges for PSA and estimationsof free and bound PSA.

PSA VelocityPSA velocity refers to the rate of change of serumPSA over time. A number of studies have shownthat men with prostate cancer have a more rapidlyrising serum PSA in the years before diagnosis thando men without prostate cancer. Patients whoseserum PSA increases by 0.75 ng/ml per year suggeststhat a cancer may be present.11 PSA velocity must beinterpreted with caution. An elevated PSA velocityshould be considered significant only when severalassays are carried out by the same laboratory over aperiod of at least eighteen months.12

PSA DensityThe PSA levels are proportional to the volume ofBPH tissue. PSA levels are 0.12 ng/ml per gram ofBPH tissue. As patients with enlarged glands due toBPH have elevated PSAs estimation of the PSAdensity can be useful. There are problems utilisingthe PSA density to determine whether a patientrequires prostatic biopsy. Many authors have notfound PSA density to be useful.13, 14, 15

Problems using a PSA density includes thefollowing: (1) epithelial/stroma ratios vary fromgland to gland, and only the epithelium produces

PSA (2) errors in calculating prostatic volume mayapproach 25%.

Age-Adjusted Reference Ranges For PSAThere is evidence that the rise in PSA withincreasing age results from prostatic gland growthdue to BPH, and the possible increasing prevalenceof microscopic, clinically insignificant prostatecancers. Age-adjusted PSA values for normal menare shown in (see table below).16

Age Adjusted Reference Ranges for PSA

Age (Years) PSA ng/ml

40-49 0-2.4

50-59 0-3.5

60-69 0-4.5

70-79 0-6.5

Oesterling JE et al12

MOLECULAR FORMS OF PSA (THERATIO OF FREE TO BOUND PSA)A large multicentre study has shown that in menwith normal rectal examination and a total PSA levelbetween 4 and 10 ng/ml, a 25% free PSA cut-offwould detect 95% of cancers while avoiding 20% ofunnecessary biopsies. The cancers associated withgreater than 25% free PSA are more likely in olderpatients and generally are of a lower tumour gradeand volume.17, 18

Recommendation 6PSA testing needs further refinement to limit thenumber of unnecessary biopsies. Age-adjusted totalPSA and free to total PSA results are the mosteffective format of reporting PSA results. Grade B

OBTAINING PROSTATIC TISSUEFOR HISTOLOGICAL DIAGNOSISAs a general rule histological confirmation is essentialprior to commencing treatment of prostaticcarcinoma. Very exceptionally the clinical evidence oflocally advanced disease combined with the presenceof unequivocal evidence of multiple metastases on


Investigation and Diagnosis



bone scan and a significantly raised PSA may lead tocommencement of treatment with hormones beforehistological confirmation is obtained.

Transrectal ultrasound examination of the prostatealone is insufficient to define prostatic carcinoma.Despite an array of findings on TRUS indicative ofprostatic cancer these are only seen in a quarter ofaffected patients. In addition, despite newtechniques and improved ultrasonography imagingit is important to be realistic in accepting that, atpresent, biopsy of the prostate is essential.

TRUS-guided systematic sextant prostatic biopsieshave been the most commonly employed techniquefor confirming prostatic carcinoma. Initiallybiopsies were targeted at hypoechoic areas in theperipheral zone. This technique was shown to beless effective in detecting cancer than randomsystematic sextant biopsies.19, 20 In sextant biopsiestissue is obtained from the apex, mid-section andbase on each side of the prostate in the mid-saggitalline, half way between the lateral border and themid-line. Modification of the systematic biopsystrategy is under study. Laterally directed biopsiesof the peripheral zone at the base and mid-sectorincrease the sensitivity of TRUS-guided biopsies by14%. In large prostates with a volume in excess of50 grams the addition of TRUS-guided biopsies ofthe transition zone increases the sensitivity ofcancer detection by 13%.21

TRUS biopsies have associated risks andcomplications. Some degree of haematuria may beseen in a third of patients undergoing biopsy.

Haematospermia and rectal bleeding are commoncomplications, but usually are limited in durationand in clinical importance. A major risk oftransrectal biopsy is septicaemia. Reported paperscite an incidence of up to 2% of patients.

A common clinical dilemma is negative biopsies withpersistent suspicion of underlying cancer. All currentbiopsy protocols sample a limited volume ofprostatic tissue, and the disease is multifocal. Hencefalse-negative biopsies occur. Despite the number andsite of biopsies taken the possibility of missed cancerexists. The question of repeat biopsies then arises.

Repeat biopsies should be considered if inadequatetissue for diagnosis or findings suspicious butinconclusive of cancer are reported. The presence ofhigh grade prostatic intraepithelial neoplasia (PIN)

mandates repeat biopsies because it is associatedwith prostate cancer in 50% of repeat biopsies.22

A rising PSA velocity after negative first biopsy isassociated with a significant incidence of positivebiopsy on the second or third sampling. Patients inthe group have a re-biopsy cancer rate of 31%.23

Recommendation 7Histological evidence of prostatic carcinoma ingeneral is essential. Only in exceptionalcircumstances with overwhelming evidence ofadvanced cancer should treatment commencewithout histological confirmation.Grade C

StatementHypoechoic-directed biopsies are less efficaciousthan systematic biopsies especially when combinedwith laterally placed peripheral zone biopsies and inbigger prostates, transition zone biopsy sampling.Despite improved biopsy techniques tumours aremissed and repeat biopsies are then indicated.


Statement Transrectal ultrasound examination of the prostatealone is insufficient to define prostate carcinoma.TRUS-guided biopsies are essential.

Level of evidence IIB

Recommendation 8Systematic sextant TRUS-guided biopsy is themethod of choice. Positive biopsy rates can beimproved by modifying the sextant biopsytechnique to include biopsies of the peripheral zoneobtained more laterally, and inclusion of somebiopsy from the transitional zone in largerprostates. Grade C

Recommendation 9Patients undergoing transrectal biopsies shouldalways be given appropriate antibiotics.Grade C

Recommendation 10Repeat biopsy is necessary if tissue samples areinadequate, if cellular atypia is identified, wherehigh-grade (3) PIN is seen or in the presence of arising PSA after a negative first biopsy.Grade B

Recommendation 11Biopsied specimens should be labelled andorientated according to local protocol.Grade C

TNM CLINICAL CLASSIFICATIONOF PROSTATE CANCER

T – Primary TumourTX Primary tumour cannot be assessed

TO No evidence of primary tumour

T1 Clinically inapparent tumour not palpableor visible by imaging

T1a Tumour incidental histologicalfinding in 5% or less of tissueresected

T1b Tumour incidental histologicalfinding in more than 5% of tissueresected

T1c Tumour identified by needle biopsy(e.g., because of elevated PSA)

T2 Tumour confined within the prostate1

T2a Tumour involves one lobe

T2b Tumour involves one lobes

T3 Tumour extends through the prostaticcapsule2

T3a Extracapsular extension (unilateralor bilateral)

T3b Tumour invades seminal vesicle(s)

T4 Tumour is fixed or invades adjacentstructures other than seminal vesicles:bladder neck, external sphincter, rectum,levator muscles, and/or pelvic wall

Notes: 1. Tumour found in one or both lobes byneedle biopsy, but not palpable or visibleby imaging, is classified as T1c.

2. Invasion into the prostatic apex or into(but not beyond) the prostatic capsule isnot classified as T3, but as T2.

N – Regional Lymph NodesNX Regional lymph nodes cannot be assessed

N0 No regional lymph nodes metastasis

N1 Regional lymph nodes metastasis

M – Distant MetastasisMX Distant metastasis cannot be assessed

M0 No distant metastasis

M1 Distant metastasis

M1a Non-regional lymph node(s)

M1b Bone(s)

M1c Other site(s)

Note: When more than one site of metastasis ispresent, the most advanced category should be used.

PTNM PATHOLOGICALCLASSIFICATIONThe pT, pN, and pM categories correspond to the T, N, and M categories.However, there is no pT1 category because there isinsufficient tissue to assess the highest pT category.

G HISTOPATHOLOGICAL GRADINGGX Grade cannot be assessed

G1 Well differentiated (slight anaplasia)

G2 Moderately differentiated (moderateanaplasia)

G3-4 Poorly differentiated/undifferentiated(marked anaplasia)

Prostate Cancer Management Clinical Guidelines 11Investigation and Diagnosis

Stage I T1a N0 M0 G1

Stage II T1a N0 M0 G2,3-4

T1b N0 M0 Any G

T1c N0 M0 Any G

T1 N0 M0 Any G

T2 N0 M0 Any G

Stage III T3 N0 M0 Any G

Stage IV T4 N0 M0 Any G

Any T N1 M0 Any G

Any T Any N M1 Any G

Stage Grouping


RECOMMENDATIONS FOR THEHISTOLOGICAL REPORTING OFPROSTATIC CARCINOMAThe Association of Directors of Anatomic andSurgical Pathology (ADASP) has appointed acommittee to recommend the format of surgicalpathological reports for common malignant tumours.The Association recommends that the followingspecific features which are generally accepted as ofprognostic value in prostatic cancer be included:24

■ The type of specimen should be specified(prostate, prostate plus seminal vesicles).

■ The procedure to obtain specimens should bestated, that is, radical prostatectomy,transurethral resection of prostate (TURP),needle biopsy or Millin or Freyer prostatectomy.

1. Microscopic features specific to carcinoma ofthe prostate should include the type of prostaticcarcinoma. Classification includes:adenocarcinoma of the acinar type, ductal

carcinoma, mucinous carcinoma, signet ringcarcinoma, neuro-endocrine carcinoma, smallcell (oat-cell carcinoma), transitional cellcarcinoma, squamous adenocarcinoma,sarcomatous carcinoma.

2. The tumour grade is important. The Gleasonsystem is highly recommended. The systemproposes histological grades from 1 to 5 basedon the patterns of prostatic glandular formation.Adding together the two most prominentpatterns gives a Gleason score which hasprognostic significance.

3. Tumour amount in the radical prostatectomyspecimen should be reported. The percentage ofprostate invaded by carcinoma should be notedin relation to the weight of the whole prostate.In TURP specimens the percentage of chipsinvolved is stated but the number of microscopicfoci seen is difficult to apply. Combiningpercentage volume involved with Gleason gradeleads to a pathological stage. Volume of tumourin needle biopsies in millimetres should berecorded along with the measurement of eachbiopsy core.

4. The presence of PIN (grade 2 and 3) should bereported. Grade 1 PIN is not necessarilyreported.

5. Surgical margins in radical prostatectomyspecimens should be recorded. All prostaticsurfaces are considered surgical margins. Areasof particular importance and common sites ofextra-capsular extension are at the apex,especially on the lateral and anterior surfaces,and the bladder margin. Any site of extra-capsular penetration is identified and reported.Involvement of seminal vesicle by tumour shouldbe recorded.

6. Reporting of perineural invasion is importantand has predictive value.

7. The presence of metastases in lymph nodes withthe size and number of nodes is recorded.24, 25

Recommendation 12The Gleason system is the grading system of choice.Grade C

Recommendation 13Sampling and reporting protocols should bestandardised throughout the country.Grade C


Prostate

T1 Not palpable or visible

T1a ≤5%

T1b >5%

T1c Needle biopsy

T2 Confined within prostate

T2a One lobe

T2b Both lobes

T3 Through prostatic capsule

T3a Extracapsular

T3b Seminal vesicle(s)

T4 Fixed or invades adjacent structures:bladder neck, external sphincter, rectum,levator muscles, pelvic wall

N1 Regional lymph node(s)

M1a Non-regional lymph node(s)

M1b Bone(s)

M1c Other site(s)

Summary

IMAGING

Transrectal UltrasoundTransrectal ultrasound is useful for guided prostaticbiopsy and affords some, if limited, staginginformation. Most needle biopsies are TRUS-guided, allowing regional sampling of the prostateand lesion-directed biopsies.

TRUS provides more accurate staging informationthan DRE. However, staging by TRUS is not asaccurate as initially reported.26 This is particularlyso in less advanced tumours which are now morecommonly seen with the use of PSA. Ultrasound hasat best an overall accuracy of 60% in staging ofsuspected localised cancer of the prostate.27

Magnetic Resonance Imaging (MRI)The reported staging accuracy for localised diseasewith MRI varies from 51 to 92%. High qualityimages can be obtained but are dependent onindividual operator skills and reporting expertise.A comparative trial comparing TRUS and MRI inevaluating the stage of prostate cancer failed todemonstrate a significant difference between thetwo modalities.28 Ongoing trials seeking to identifypatients who might benefit from MRI studies arein progress.29, 30, 31

Axial Imaging by Magnetic Resonance orComputerised Tomography (MRI or CT)Cross-sectional imaging of the pelvis is performed inselected patients to exclude lymph node metastasesin high-risk patients being considered for radicallocal therapy either by surgery or irradiation. Theincidence of involved lymph nodes in recent radicalprostatectomy series is low (<10%). A review of theliterature by Wolfe et al 1995 encompassing 15series and 1,354 patients revealed an incidence oflymph node metastases of 22%. The sensitivity forCT and MRI in this analysis was 36% and thespecificity was 97%. Imaging for lymph nodes isexpensive and inaccurate.

The likelihood of lymph node metastases can bequantified on the basis of PSA, tumour grade, andlocal tumour stage. Several nomograms andprobability curves exist that aid in predictingpathological stage.32, 33


Gleason Score

2 to 5 Low-grade cancer

6 to 7 Middle-grade cancer

8 to10 High-grade cancer

Gleason Grade based on Acinar Pattern

1 to 2 Mainly well-formedacini

3 to 4 Moderate – to poorly- formed acini

5 No visible acinar pattern

Grading for Prostate Carcinoma

GLEASON SCORE = sum of the 2 highest grades detected



Statement Staging of prostate cancer by TRUS is inaccurate,particularly in smaller tumours detected by PSA.

� Imaging is more accurate than staging by DRE.

� MRI has not been shown to be significantly moreefficacious in comparative trials.

� CT and MRI to detect lymph nodes have asensitivity of 36% and a specificity of 97%.Imaging for lymph nodes is expensive andinaccurate.

� Risk of lymph nodes best quantified bycombination of PSA, Gleason score and DRE.

Level of evidence IV

Recommendation 14Further studies and radiological developments areneeded to define the most appropriate modality tostage carcinoma of the prostate pre-operatively. Grade C

Bone ScanThe merits of obtaining a bone scan to stage diseaseextent prior to radical local therapy is underconsideration at present. Oesterling and colleaguesconducted studies to assess the ability of PSA topredict bone scan findings (1993). Their resultsshowed that bone scans can be omitted in patientswith newly diagnosed, untreated prostatic cancerwho are asymptomatic and have PSA less than 20ng/ml. PSA levels alone were the best predictor ofbone scan results.34

There have been recommendations that bone scansmay be omitted in patients with PSA between 10and 20 ng/ml. However, bone scans are readilyavailable and are not associated with serioustoxicity, are relatively cheap and have a highsensitivity. Failure to recognise metastases prior toradical therapy subjects patients to significant andunwarranted risks. Bone scans should be includedas a standard part of the evaluation of all patientsundergoing surgery or XRT.35

Recommendation 15Routine bone scans should be included in patientsundergoing radical surgery or XRT.Grade C


RECOMMENDATIONS FORSELECTION OF THERAPY FORLOCALISED PROSTATE CANCERThe biological behaviour of prostate cancer can bepredicted using clinically available data. Thecombination of clinical stage, Gleason score, andthe level of prostate specific antigen (PSA) can beused to predict the risk category of individualpatients. Nomograms have been published whichrelate these pre-treatment prognostic factors to thepathologic stage.36 Such information allowsidentification of categories of patients suitable forlocal treatment (surgery or radiation) and also thosefor whom a local treatment alone is inadequate.

Screen-detected cancer (T1c stage)Screen-detected cancers are clinically heterogenous.If the patient has T1c clinical stage, PSA less than10, and Gleason score less than 6 the probability ofhaving organ-confined disease when treated withradical prostatectomy is 67% to 89%. If thepatient has T1c clinical stage, PSA in the range of10.1 to 20, and Gleason score under 5 theprobability of having organ-confined disease whentreated with radical prostatectomy is 60-75%. Theabove categories can be treated with radicalprostatectomy, external beam radiation, orbrachytherapy. For T1c clinical stage, PSA in therange of 10.1 to 20, and Gleason Score of 6 theprobability of having organ-confined disease whentreated with radical prostatectomy drops to 55%.If the PSA is > 20 or if the Gleason score is 7 orhigher the probability of organ-confined diseasebecomes low and other strategies are appropriate.

Identifying non-screen-detected, low risklocalised cancersFor patients with clinical stage T1 cancers and PSAof 0-20 and Gleason score of 6 or less, theprobability of having organ-confined disease whentreated with radical prostatectomy is generallyapproximately 55-84%. If the PSA is close to 20 itis useful to specifically consult the Partinnomograms. These patients can be treated withradical prostatectomy, external beam radiation, orbrachytherapy. For patients with clinical stage T2cancer and PSA of 0-10 and Gleason score of 4 orless, the probability of having organ-confineddisease when treated with radical prostatectomy is

generally approximately 60%-81%. For T2tumours with a Gleason score of 5 or higher or aPSA above 10 it is necessary to consult a publishednomogram to assess the probability of organ-confined disease before embarking on a purely localtreatment alone.

High-risk localised cancersIf the Gleason score reaches 7 or higher, regardlessof PSA or clinical stage, the probability of organ-confined disease is less than 50%.

If the PSA is > 20 regardless of Gleason score orclinical stage it is unusual (<50%) to have organ-confined disease. Furthermore, this probabilitydeclines dramatically in proportion to the Gleasonscore and the clinical stage.

Historically such patients have been treated withradiation alone with a high resulting rate of PSAdetected failure. This is because there is a high riskof relapse by spread to other parts of the body.Similarly all patients with nodal metastases are atextremely high risk of developing furthermetastatic disease. All such patients should betreated with adjuvant hormonal therapy. In suchhigh-risk patients radiation is the usuallocoregional treatment.37

MANAGEMENT OF POTENTIALLYCURABLE PROSTATIC CARCINOMA(T1-T2, NO,MO)Optimal forms of therapy for all stages ofcarcinoma of the prostate remains debatable.Dilemmas in the management of T1 and T2prostate carcinoma persist because of theuncertainty about the relative efficacy of availabletreatment modalities. There are three viabletreatment options; radical prostatectomy, X-raytherapy, and surveillance. Well-designed randomisedtrials comparing these three treatment options forlocalised prostate cancer are lacking.

Despite the lack of strong data certain agreedpractices can be considered as minimum standard ofcare in early prostatic cancer.


Treatment of Prostate Cancer


Total assessment of the health status ofthe patientThis factor impinges on the choice of treatment forany individual patient. Life expectancy is animportant consideration. The presence of co-morbidity is highly relevant, as many patients withcarcinoma of the prostate have intercurrent diseaseprocesses which represent competing risks for deathbefore and especially after radical treatment.Intercurrent disease reduces the chance thatsuffering related to advancing prostatic cancer orcancer-specific death will occur. In addition, co-morbid conditions weaken the resilience of patientsto adverse effects of treatment.

In a relatively young man (<60 years of age) thelifetime chances of disease progression is high. Awindow of opportunity for cure exists and someform of curative therapy should be on offer to sucha patient.38, 39

The pathological stage of prostate cancerThe stage of cancer is crucial. Small-volume, well-differentiated tumours in the older patient may beindolent, while large-volume, more poorly-differentiated (Grade 7 and 8) are aggressive. As aconsequence, specific patient and tumour-relatedfactors may determine the treatment of choice.Because of the uncertainty concerning efficacy oftreatment patients must be fully informed ofavailable treatment options. After full disclosure ofinformation patient preference must be part of thedecision-making process.

StatementThere is uncertainty about the relative efficacy ofavailable treatment modalities. Well-designedprospective randomised trials comparing radicalprostatectomy, XRT and surveillance for localisedprostate cancer are lacking.


StatementIn the absence of clear advantages of one treatmentover another, the treatment decision is based on thestage and grade of tumour, the health status and lifeexpectancy of the patient, efficacy of therecommended treatment to ensure prolongeddisease-free survival, the associated complicationrate, and patient and surgeon preference.


Recommendation 16As far as is practical, information should be givenabout best available treatments for the individualcircumstances of the patient’s cancer, health statusand life expectancy. Grade C

SURGERY OF PROSTATIC CANCER

Radical ProstatectomyInformation to the patient must include theadvantages and disadvantages of the procedure.There is an opportunity for cure which means life-long freedom from recurrence of the disease. Theperi-operative mortality (up to 30 days) is low at0.3%, and consistent across most published series.40

Local control of the disease is improved by radicalsurgery even if the impact on disease-free survival isuncertain. The complications of surgery aresignificant and may impact more severely on younger,otherwise healthy, patients who are the group mostlikely to be targeted for surgery. A high risk ofimpotence remains after radical prostatectomy andrelates particularly to the stage of disease and the ageof the patient. An anatomical approach using nerve-sparing techniques has lowered the incidence oferectile dysfunction. There may, however, be somecompromise in regard to total excision of the tumour.This may be a particular problem as capsularpenetration is often seen in the neuro-vascular grooveespecially at the apex.41

Urinary incontinence rates have improved with bettersurgical technique, due to better understanding of theanatomy of the apex of the prostate and therelationship of the dorsal venous complex to thesphincteric mechanism. Total urinary incontinence israre (<3%) as reported. A variable degree of stressincontinence may occur in up to 20% of patients. Ingeneral return of continence after surgery is gradualwith 75% of patients dry at 6 months.42, 43 Detailedfollow-up after radical prostatectomy is required toassess the patient’s quality of life of which continenceand erectile function are important dimensions. In aquality surgical programme less than 3 to 5% ofpatients should need continence appliances or morethan 2 pads per day. The rate of artificial sphincterrequired should be very low. Survival after surgeryfor organ- confined disease ranged from 70 – 85% inseveral series.


The Results of Radical Surgery

Most long-term results come from the U.S., Walshreporting on nearly 1000 men undergoing surgeryfound 11.2% to have a raised PSA at 5 years as theonly evidence of tumour recurrence. Actuariallikelihood of a stable progression-free PSA at 5 and10 years was 87 and 77% respectively. Aninternational pool group of 2,975 radicalprostatectomies in men with localised prostaticcancer reported 10-year disease-specific survival of94%, 85% and 77% from men with grade 1, 2, 3tumours respectively.

Since the introduction of PSA testing there has beenan increase in the incidence of prostate cancer and areduction in those presenting with advanced disease.There has been a large rise in the radicalprostatectomy rate from 9% of all new cases ofprostatic cancer in 1983 to 29% in 1991. Thesechanges in practice coincide with the first fall inoverall mortality from prostatic cancer in the U.S.A.from 26.5 to 17.3 deaths per 100,000 men between1990 and 1995.44, 45

Quality Standard 1

Less than 3% of patients should be wet to sucha degree at one year as to require multiple pads,or implantation of an artificial sphincter.

Quality Standard 2

Patients should be followed in a specialisedurology department. Data relating to qualityof life, detected clinical recurrence rate,recurrence rate by PSA or imaging, survivalrates, and complications can thereby berecorded and analysed.

StatementRadical prostatectomy improves local control ofdisease, but its impact on survival remainsuncertain. Recently there has been evidence of a fallin mortality which coincides with an increase indetection of earlier disease and a significant rise inthe number subjected to radical prostatectomy(between 1990 and 1995).


Recommendation 17Prior to surgery (radical prostatectomy) patientsmust be informed about major morbidity whichincludes the risks and incidence of impotence andincontinence of urine. Grade C

Recommendation 18Radical prostatectomy should be performed bysurgeons appropriately trained in the procedure,within an institution with medical and nursingpersonnel trained in the care of such patients. Grade C

DISEASE RELAPSE AFTERPROSTATE SURGERY FORLOCALISED PROSTATE CANCERA rise in PSA after surgery indicates tumour relapse.Recurrence after radical prostatectomy is related tocancer grade, pathological stage, and degree ofcapsular penetration. Local recurrence is morecommon in those with positive margins, seminalvesicle invasion, extra-capsular extension and a highGleason score. The site of relapse of tumour afterradical prostatectomy can be established withreasonable certainty by the interval from surgery toa detectable rise in PSA. Patients with persistentelevated PSA detected immediately or shortly aftersurgery or those with a rapid doubling of PSA in thepost-operative period (6 months) are likely to havesystemic spread of the disease. Local recurrence ismore likely if the rise in PSA occurs a long time aftersurgery, and the PSA doubling-rate is prolonged.Average time to detection of a raised PSA is longerin local as opposed to distant relapse.46, 47

Initially patients with relapse will be detected by arise in PSA but localised recurrence may bedetected by DRE or TRUS or both. Confirmationof relapse by biopsy is useful, but several biopsysessions may be needed to document a localrecurrence, because of the difficulty of obtainingtissue in these circumstances.

Prostate Cancer Management Clinical Guidelines 17Treatment of Prostate Cancer


PrognosisIn men who develop elevated serum PSA afterradical prostatectomy, the natural history ofprogression to distant metastases and death as aresult of adenocarcinoma of the prostate is virtuallyunknown.48, 49 A study was done on 1,997 men withlocalised prostate cancer after radical prostatectomy.None received neoadjuvant or adjuvant hormonesprior to documentation of metastases.

■ Actuarial metastatic free survival was 88%fifteen years after surgery.

■ Of the 1,997 men 15% developed PSAelevation and 34% of these developedmetastatic disease within the length of the study(15 years).

■ Median time to metastases was 8 years fromtime of PSA elevation.

■ After metastases developed, median time todeath was 5 years.

Patients who relapse may be offered radiotherapyalone or radiotherapy plus hormones. The role ofradiotherapy with or without hormones for localrecurrence is unclear. There is often a good initialbiochemical response but prolonged survivalremains to be demonstrated with or withouttreatment.50

Evidence of local recurrence after radicalprostatectomy is a rise in PSA, palpable recurrenceof tumour and biopsy-proven recurrence of cancer.The dose of radiation can be increased with XRTtechniques as described for primary treatment. Upto 70 Gy (Gray) can be delivered for early recurrentdisease with higher doses reserved for patients withbulky local recurrent disease.

THE ROLE OF ADJUVANT X-RAYTHERAPY FOLLOWING RADICALPROSTATECTOMYThe object of adjuvant XRT is to improve localcontrol by eliminating microscopic residual tumoursin the surgical bed and peri-prostatic tissues. Severalindications for adjuvant XRT may arise. Despitebest practice pre-operative staging of the disease thefollowing situations occur: (a) positive surgicalmargins, (b) seminal vesicle involvement and (c)extra-capsular extension. The presence of any ofthese variables is associated with a high probabilityof local recurrence. Several early studies suggest thatadjuvant XRT appears to reduce the incidence oflocal recurrence in patients with post-surgicalpositive margins. Studies suggest that those treatedmay have improved disease-free survival andimproved time to distant metastases and a lowerincidence of PSA failure.51, 52 However, the impact ofadjuvant radiation on survival outcomes remainsuncertain. There is a high complication rate withpost-operative XRT particularly utilising oldertreatment techniques. Contemporary series suggestthat with more modern planning techniques andequipment the incidence of complications is lower.53

Statement A rise in PSA after surgery indicates tumourrecurrence. Detectable rise in PSA soon after surgery(a doubling time in 6 months) is indicative ofsystemic spread of disease.


Statement Confirmation by TRUS biopsy of local recurrence isuseful but difficult to achieve.


Statement Patients with positive margins, capsular involvementor seminal vesicle involvement may benefit fromadjuvant X-ray therapy with or without hormones.Impact on survival rates is unknown. Complicationrates with 3-dimensional conformal radiotherapy(3D CRT) are reportedly lower than withconventional XRT. Doses up to 70 Gy with lowcomplication rates are reported.


Recommendation 19Patients with local recurrence after radicalprostatectomy should be given 3D conformalradiotherapy plus hormones.Grade B


RADIATION THERAPY EXTERNALBEAM THERAPY FOR LOCALISEDCANCER (T1-T2, N0, M0)Traditional external beam radiotherapy (XRT)enables delivery of 65 to 70 Gy to the prostate.Older X-ray techniques fail to provide adequatedosage of radiation to the target volume in as manyas 20-40% of patients.

Improved imaging and the use of 3-dimensionaltreatment planning software can now guarantee thatthe treatment field is accurately targeted. A higherdose of radiation can be delivered to the prostatewithout exceeding the tolerance of surrounding tissue,mainly the bladder and rectum. This is achieved byconforming the radiation beam to the shape of theprostate. Conformal radiotherapy is achieved bydesigning “blocks” from re-constructed CT images asviewed from the vantage point of the beam source.When viewed from the central axis, they are usuallycalled “beam-eye views”. Computer assisted “beam-eye views” can be generated to design oblique andout-of-plane or non-co-planar beam arrangements.This approach constitutes 3-dimensional conformalradiotherapy. The technique enables dosage to becalculated in 3-dimensions enabling scatteredradiation to be accounted for, the ability to generate 3-dimensional dose displays and dose volumehistograms. 3-dimensional dose displays allow “hot”and “cold” spots (over- and under-dosing) to berecognised while dose-volume histograms allowalteration in technique to be ranked for differentialsparing of surrounding tissues.

Compared with standard technique 3-dimensionalconformal radiotherapy (3 D CRT) is associated with30% reduction in dose received by 50% of therectum.54 Advantages in treatment planning haveresulted in 3 D CRT as the new standard of care.55

The main advantage of 3 D CRT is the increasedradiation dosage that can be given whichtheoretically may lead to improved local control.Data from Memorial Sloan Kettering Cancer Centreand M.D. Anderson Cancer Centre suggest PSAresponse improves with higher doses of radiation.Early results from these centres suggests that 10%increase in dosage improves local control by 20%.56, 57

Normal tissue toxicity is the limiting factor. Twoprospective randomised trials had demonstrated nodifference in acute toxicity in patients with localisedprostatic carcinoma treated with 3 D#CRT versus

conventional radiotherapy. Of more importance, inthe MD Anderson studies higher doses were given topatients receiving 3 D#CRT and the incidence ofchronic rectal toxicity was reduced.58, 59, 60

Statement Conventional XRT fails to provide adequate radiationdosage to the prostate in upwards of 20-40% ofpatients.


Statement With 3D CRT radiation dosage can be increasedmore safely which theoretically may improvetumour control.


Recommendation 20Before radiotherapy patients should be informed ofpotential complications of radiation proctitis/cystitisand impotence.Grade C

Recommendation 21Where patients are assigned to XRT the advantagesin delivery to the prostate makes 3D CRT the newstandard of care in XRT treatment of carcinoma ofthe prostate. Grade B

Statement In several randomised trials XRT plus hormones(neoadjuvant or adjuvant) has proved superior toXRT alone in certain categories of localisedprostatic cancer.

Level of evidence IA

Recommendation 22XRT combined with neoadjuvant hormone ablationshould continue to be evaluated by randomisedcontrolled clinical trials.Grade B

Quality Standard 3

Following radical radiotherapy of the prostate,the incidence of severe late complications(beyond 90 days) to bladder and rectum,should be less than 5% at 2 years.

Quality Standard 4

Patients undergoing radical radiotherapy shouldbe followed by a specialist unit. Data regardingquality of life, survival, local and distantrecurrence, and morbidity can thereby be recorded.



RELAPSE AFTER RADIATIONTHERAPY – DIAGNOSIS ANDTREATMENTAfter X-ray therapy PSA levels may decline slowlyand take many months to reach its nadir. The rateof decline is not a reliable prognosticator ofoutcome, but a rising PSA following definitive XRTis indicative of a cancer relapse as clinical relapseinevitably follows “biochemical failure”. TRUS-guided biopsy of the prostate may identify localrecurrence while bone scan and pelvic CT identifydistant recurrences. Standards set by the AmericanSociety for Therapeutic and Oncological ConsensusPanel requires three consecutive increases in PSAobtained at intervals of three to four months in thetwo years after the completion of radiotherapy.61

Recurrence of disease (as in failure after surgery)can be judged to be local if the rise in PSA occurs ata long interval after therapy, while early elevationafter XRT may indicate metastatic relapse. The siteof relapse of cancer is indicated by the PSAdoubling-time. Metastatic disease predictably has adoubling-time of less than 6 months, while a longerdoubling-time is more consistent with local relapse.

MANAGEMENT OF PROSTATECANCER AFTER FAILED RADIATIONTHERAPY

Cryotherapy and Salvage ProstatectomyFailure of radiation therapy promotes tumouraggressiveness and outcome is poor. In somepatients the persistent disease appears to belocalised. Use of cryotherapy has been reported assalvage therapy for patients with local recurrenceafter full dose radiation therapy, with or withouthormones.

Best results are obtained with a double rather thana single freeze-thaw cycle. Reports on 150 patientsfrom MD Anderson with locally recurrent diseaseafter radiation or other combined therapies are notimpressive.62 One-third of patients had undetectablePSA but 20 to 33% of patients had persistentpositive prostatic biopsies. The complication rate issignificant, including high rates of incontinence andurinary obstruction.

Salvage radical prostatectomy was reported byScardino and colleagues.63 The complication ratewas high. Contemporary studies suggest thatsalvage cryotherapy and salvage prostatectomyshould be used only in the context of a prospectivestudy in patients with persistent disease afterradiotherapy.

Statement Salvage therapy by radical prostatectomy orcryotherapy give poor results and a highcomplication rate. Salvage prostatectomy orcryotherapy should be used as part of a studyprotocol.

Level of evidence IV



RADIATION THERAPY FOR FORLOCALLY ADVANCED PROSTATICCANCER HIGH RISK LOCALISEDDISEASE (T3-T4, N0,MO DISEASE)In several randomised trials hormones (neo-adjuvant)plus XRT has proved superior to XRT alone. Pilepichand colleagues65 demonstrated improved diseasecontrol and disease-specific survival with neo-adjuvant hormone priming and X-ray therapy. Fourhundred and fifty-six patients were included in thestudy. Patients had high volume T2, T3 and T4disease and were randomised to either XRT withtotal androgen blockade (two months before and twomonths during XRT) or to XRT alone. The results ofthe study showed disease control of 63% versus 51%in favour of the combined therapy. Distant failureoccurred in 34% versus 48% and disease-specificsurvival was 51% versus 43%. There was noevidence of progressive disease in 35% versus 23% inthe study arm compared with the control arm of thestudy. Bolla and his colleagues studied 401 patientswith predominantly T3 localised disease. The patientswere randomised to receive 3 years of androgenablation and XRT compared with XRT alone.Improved survival in patients receiving combinationtherapy was demonstrated. Results showed betterlocal control in 97% of patients versus 77%, disease-free status in 85% versus 48% for the controls andoverall survival 79% versus 62% in the controls.64, 65, 66

Many studies, both prospective and retrospective,confirm the efficacy of radiation therapy in thecontrol of localised prostatic cancer (stage T3). Theend point of the studies was based on clinicalassessment of “local control”. In the PSA and TRUSbiopsy era clinically judged end points are nowknown to underestimate the true incidence of localfailures because of missed cancers in clinicallyassessed patients. Many patients clinically free ofdisease can be shown by PSA or TRUS or both tohave persistent disease.

The median interval between PSA failure and clinicalfailure can be as long as 4-5 years67 and a number ofstrategies to obtain and maintain the lowest possiblenadir have been developed. Dose escalation of XRTbeyond 70 Gy to ≥ 84 Gy by 3-dimensionalconformal radiotherapy has been tested and shownto reduce the risk of biochemical failure.

Statement Prospective and retrospective studies confirm theefficacy of XRT in the control of localised advancedprostatic cancer (T2b, 3 and 4). Failure rate asdetermined by PSA decrease when XRT dose isescalated.

Level of evidence IB

Statement XRT plus neoadjuvant hormones is superior toXRT alone. Patients with T3 and T4 tumours needto be the subject of continuing clinical trials.


Recommendation 23Neoadjuvant or adjuvant hormone therapy shouldbe included in the protocol for high risk localisedprostatic tumours.Grade A

BRACHYTHERAPYThe most common form of alternative radiation isbrachytherapy. A major theoretical advantage is theability to deliver high dose-radiation to a localisedarea and fewer treatment visits. Contemporaryseries report the use of CT- or TRUS-guided closedtechniques. The high failure rates reported in olderseries suggest that permanent implants withoutaccurate placement were less effective than XRT.Poor placement of radioactive seeds led to sub-optimal dosimetry. More recent techniquesemploying CT- or TRUS-based guidance with siteand spacing predetermined by imaging have led tobetter results. Commonly used isotopes are Iodine125 or Palladium 130 which are left in placepermanently. Permanent implants mean lower doserates and higher total doses. Brachytherapy can beused alone in early disease (T1/T2) or incombination with XRT. Many comparative studiessuggest that brachy therapy alone is a reasonabletreatment option for low risk patients with organconfined disease with minimal extra-capsularextension. Because of rapid dose fall-off, when usedin high risk patients or those with more extensivelocal disease it should be combined with XRT.

Recently there has been increased interest intemporary or high dose-rate implants. Theadvantages are decreased exposure risks to hospitalpersonnel and compensatory effects of sub-optimalseed placement. Temporary seed implantation is



associated with higher morbidity, and needs in-patient treatment. Iridium-192 is the only widely-used isotope for temporary implantation. Availablenumbers of patients for meaningful follow-up aresmall and no firm conclusions about efficacy canbe drawn.

In summary, results continue to suggest thatinterstitial therapy appears to be a promisingtherapy for selected patients with early stagedisease. A benefit in more advanced local disease isbest achieved in combination with XRT. 68, 69

Statement In older series of patients treated withbrachytherapy poor placement of radioactive seedsled to sub-optimal dosimetry. More recenttechniques using CT- or TRUS- guidance with siteand spacing pre-determined by imaging have led toimproved results.

Level of evidence IIA

StatementComparative studies suggest that brachytherapyalone is useful in low-risk patients with organ-confined disease or minimal extra-capsularextension.


StatementRapid dose fall-off makes brachytherapy lesssuitable for extensive local disease unless combinedwith XRT.


Conservative Management of Prostatic Cancer

SURVEILLANCEIn some patients with localised prostatic cancer aslow rate of progression of the disease occurs andsurveillance may be a genuine alternative to pro-active treatment by surgery or radiotherapy. Severalstudies have shown that surveillance alone may bean appropriate form of treatment for selectedpatients with prostatic carcinoma (see table below).No randomised control trial has been reported onsurveillance to date. All reports on the subjectconsist of a cohort of men selected for a variety ofdifferent reasons. The studies suffer fromshortcomings due to selection bias, short follow-up,predominant inclusion of older patients, initiationof delayed treatment in many patients andincomplete records as to cause of death. A poolingof data from 4 studies demonstrated that arelatively consistent pattern emerges:

(1) At ten years after diagnosis 8-10% of men withlow-grade disease will die of carcinoma of theprostate following watchful waiting comparedto those treated with surgery or X-ray therapy.

(2) The risk of observed metastases is high at 10years in men on watchful waiting. Eight to tenpercent men with low-grade disease and 15-20%with moderately-differentiated disease developmetastases at 10 years.

(3) With time prostate cancer progresses in asubstantial percentage of patients requiringpalliative treatment for pain, urinary obstructionor haematuria. Few of the studies address thequality of life issues which include side-effects ofhormones, impact of refractory hormonedisease, the need for repeated transurethralresections, bone pain and the need for treatmentof bone pain by palliative radiotherapy and pain

control clinics. The potential for these events tooccur is offset by the fact that a patient may dieof an unrelated illness.

(4) Competing mortality rates from unrelateddisease is significant and is higher thanprostatic cancer mortality rates.

(5) The disease-specific survival rate at 10 years forpatients with well- or moderately- differentiatedtumours is 87% and for patients with poorly-differentiated tumours the disease-specificsurvival is 34% at 10 years.70

In summary a policy of surveillance is associatedwith a significant rate of tumour progression but isoften consistent with protracted survival. Co-morbidity is a significant cause of mortality. Long-term survival occurs despite the presence of prostatecancer. Expectant treatment, however, will notprovide a resolution of prostate cancer problemsand better criteria for patient selection and qualityof life issues require further definition. 73, 76

Statement Expectant treatment does not provide a resolutionof cancer problems, and is associated with asignificant rate of tumour progression but is oftenconsistent with protracted survival.

Level of evidence IIA

Recommendation 24Surveillance is an acceptable form of treatment inmen with T1a tumours with a poor life expectancy(less than 10 years) due to the age at which thedisease is detected or co-morbid factors. Grade B


Results Of “Surveillance” Studies71, 72, 74, 75

Study Year Number Follow-up Overall % Disease-specific Disease(years) Mortality Mortality Progression

Johansson (1994) 223 12.5 56% 10% 34

George (1998) 120 7 44% 4% 83

Whitmore, Warner & Thompson (1991) 75 9.5 39% 15% 69

Adolfsson J (1992) 172 6.75 ±3 44% 12%

Metastatic Prostate Cancer

HORMONAL THERAPYHormonal therapy is the optimum treatment forlocally advanced and distant disease, and is equallyeffective whether administered by orchidectomy orby LHRH agonists. Response rates in patientstreated with hormones is high. Most prostaticcancers are hormone-dependent, and initial therapydecreases or stabilises PSA values and clinicalsymptoms in approximately 90% of patients. Theaverage duration of response to hormones is 18 to36 months.

Patients with metastatic disease, whethersymptomatic or not, should be offered some form ofhormonal therapy. The options for first line therapyto induce androgen deprivation are bilateralorchidectomy or LHRH analogue therapy by eithermonthly or 3 monthly depot injection. Thetherapeutic efficacy of orchidectomy and LHRHanalogues is comparable and all current LHRHanalogues are equally effective.77 LHRH analoguesrequire anti-androgen blockade for 7-10 days priorto administration of LHRH analogue to preventtumour flare.

Orchidectomy can be either total or sub-capsular.Both have equal therapeutic value. Retaining somecapsular tissue in the scrotum may improve thepatient body image and have a psychologicaladvantage.

Timing of Hormone ManipulationMetastases causing bone pain is a clear indication tostart hormone therapy. Systemic effects ofmetastatic disease including weight loss, anaemia,and poor performance status indicate the need forimmediate therapy. Cord compression is a seriouscomplication and requires urgent treatment.

Hormone manipulation, in conjunction with X-raytherapy and surgery, forms an important componentof treatment of cord compression and pathologicalfracture. Timing of initial endocrine treatment inasymptomatic patients with multiple metastases is asubject of some debate.

A randomised study from the Medical ResearchCouncil compared early and deferred hormonemanipulation in patients with locally advanced ormetastatic disease. Therapy was mainly by LHRHagonists but occasionally by orchidectomy.Approximately 50% of the patients were M1 or M0.Within the immediate androgen deprivation arm,there was a statistically significant decrease inmorbidity secondary to disease. In addition therewas a lower complication rate from cordcompression, ureteric obstruction andpathological fractures in patients treated by earlyendocrine therapy.78

While early treatment has been demonstrated tohave advantages, the main deterrents are the effectson the quality of life (QOL). Decreased libido anderectile dysfunction are inevitable, but insidiousmorbidity includes muscle wasting, anaemia,depression and osteoporosis. Several treatmentstrategies are employed to address these problems.Pulse therapy, in which cycles of therapy withLHRH agonists are given at intervals of 3 to 4months, allows restoration of testosterone levels andrehabilitation from side-effects. This programme oftreatment is currently under investigation in aninter-group study in the U.S.A.79 Another approachinvolves high doses of non-steroidal anti-androgensto block androgen receptors in the prostate whilepreserving serum testosterone levels peripherally. Alarge randomised trial using bicalutamide (Casodex)150 mgs versus orchidectomy in men with M0 stage


Immediate Versus Delayed Hormone Therapy MRC Study (1997)9

Complication Immediate Hormonal Therapy Delayed Hormonal Therapy

Pathological bone fracture 2.3% 4.5% (N/S)

Spinal cord compression 1.9% 4.9% (p < 0.025)

Ureteric obstruction 7.0% 11.8% (p < 0.025)

Extra-skeletal metastases 7.9% 11.8% (p < 0.05)

TURP 13.9% 30.3% (p < 0.001)

disease is under way. A 4-year median follow-upshows significant improvement in QOL and nodifference in survival.

OestrogensOestrogens have a proven record in control ofadenocarcinoma of the prostate. They areassociated with a significant incidence ofthromboembolic complications and aggravation ofvascular episodes such as stroke and myocardialinfarction. The complications are dose-related andless common in patients receiving doses of 1-2 mgsof stilboestrol daily.

Cyproterone Acetate (Androcur)The value of cyproterone acetate is in themanagement of “hot flushes” in patients withacutely induced castrate levels of testosterone byorchidectomy or by LHRH analogues.

Bicalutamide (Casodex)The most widely used method of androgendeprivation for advanced prostatic cancer isbilateral orchidectomy or medical castration.Orchidectomy or medical castration affect adverselythe quality of life and result in loss of libido andcause erectile dysfunction. Bicalutamide, a potentanti-androgen effectively blocks androgen receptors,and could eliminate the need for surgical (which isirreversible) or medical castration. The standarddaily dose of bicalutamide is 50 mgs, but higherdoses (150 mgs per day) have been shown to reducethe level of PSA more quickly and to a lower level.Monotherapy at higher doses might be as effectiveas castration with fewer adverse effects.

Two open multi-centre randomised trials comparedthe efficacy, tolerance and quality of life benefits ofbicalutamide with castration. Patients included inthe study had stage T3/T4 locally advanced (Mo)prostate cancer with PSA levels greater than 20ng/ml. All patients were untreated for prostatecancer. In a 2:1 ratio, 458 patients were randomisedto either bicalutamide 150 mgs per day (N=320) orcastration by orchidectomy or goserelin acetate(N=138). Primary end-points were time to death,objective progression, treatment failure and qualityof life. Demographic characteristics were similar inboth groups.

At median follow-up of approximately 4 years therisk of death was similar in both arms. However,bicalutamide demonstrated significant advantagesover castration in retention of sexual interest anderectile capacity. There was a higher rate ofgynaecomastia and breast pain with bicalutamide.

The main advantage of bicalutamide is that it istaken orally, is reversible, and preserves libido andsexual function.

This study was expanded to enroll a total of 1,453patients. All of these patients had confirmedmetastatic disease (M1) or T3-T4 non-metastaticdisease with raised PSA. At 100 weeks follow-upshowed that bicalutamide was less effective thancastration in men with M1 disease with a mediansurvival difference of 6 weeks. In symptomaticpatients with M1 disease bicalutamide wasassociated with significant improvement insubjective response compared with castration andwas superior to castration in maintenance of sexualinterest and capacity. The incidence of hot flusheswas significantly lower with bicalutamide.

The conclusions of the study were that in menwith M1 prostate cancer bicalutamide 150 mgs perday is less effective than castration but leads to abetter quality of life and subjective response insymptomatic men with M1 disease and is well-tolerated.80, 81

StatementMonotherapy with bicalutamide at 150mgs per dayis an option for men with T3-T4 (M0), or M1disease for whom surgical or medical castration isnot acceptable.


Complete Androgen BlockadeAlthough testosterone is the major circulatingandrogen, the adrenal gland secretesdehydroepiandrosterone and androstenedione. Someinvestigators believe that suppression of both testesand adrenal androgens improves initial and long-term response rates compared to testis blockadealone. Complete androgen blockade (CAB) can beachieved by combining LHRH analogues ororchidectomy with an anti-androgen agent. Patientswith good performance status and limitedmetastatic disease treated by CAB seem to survivelonger than those treated by LHRH agonists alone.In patients with advanced disease and poorperformance status response to CAB is poor.82

Prostate Cancer Management Clinical Guidelines 25Metastatic Prostate Cancer


CLINICAL MANAGEMENT OFPATIENTS WITH METASTATICDISEASEPatients with metastatic disease require regularfollow-up by clinical, biochemical andhaematological assessment. Bone scan is requiredto identify specific metastases which may give riseto localised severe bone pain. These locallypainful metastases should be amenable to XRT(regional irradiation).

Patients on deferred treatment protocols requirecareful monitoring. Detection of a rapidlyaccelerating PSA or increasing bone pain orsystemic manifestations of prostate cancer areindications to commence hormone treatment.

StatementResponse rates to hormone therapy in patients withmetastatic prostatic cancer are 90%.


StatementOrchidectomy and LHRH analogue are equallyeffective in treatment of prostate cancer.Acceptability and QOL factors of orchidectomyrequire further study.


Recommendation 25Patients with symptomatic metastatic disease,especially bone disease, should commence therapyby androgen deprivation. The choice of primarytreatment by LHRH analogues or orchidectomy isdetermined by many issues including patientpreference.Grade B

StatementCurrent evidence shows no clear treatmentadvantage in combined androgen blockade,especially in patients with poor performance statusand advanced disease.


Recommendation 26Combined androgen blockade should not be usedroutinely on current evidence.Grade A

MANAGEMENT OF THECOMPLICATIONS OF ADVANCEDPROSTATIC CANCER

Spinal Cord CompressionMetastases to the subdural space often lead to cordcompression. Lower limb weakness, paraesthesia,bladder and bowel dysfunction are consequences ofthis emergency situation. Prevention of paraplegia isimportant as restoration of function in establishedparalysis occurs in less than 10% of patients.Urgent investigation by MRI will identify the site orsites of spinal involvement and the extent ofpathological compression of the cord. Inambulatory patients radiation rather than surgery iseffective in relieving cord compression. However,paraplegic patients often do not recover functionwhen treated with radiation, steroids or androgendeprivation. In these patients laminectomy with orwithout radiation may be a suitable alternative.However, surgery should be offered cautiously inthose patients as survival averages 3.9 months inthis group of patients after laminectomy. Whenindicated urgent surgery to decompress the spinalcord should be undertaken by a specialist in spinalsurgery. Patients should initially be treated withdexamethasone to decrease cord oedema andandrogen deprivation.83

Recommendation 27Spinal cord compression is an indication for urgentreferral for radiotherapy or surgery.Grade C


URETERIC OBSTRUCTIONUreteric obstruction occurs from direct invasion bythe tumour or compression of the ureters byenlarged lymph nodes. When this occurs despitehormone therapy the prognosis is poor. In the eventof an untreated patient presenting with renal failuredue to bilateral ureteric obstruction, resolution ofthe problem may be induced by androgendeprivation.

Management usually involves placement of a J stentin both ureters. Cystoscopic placement can bedifficult if trigone invasion by the prostate cancer ispresent. Ureteric orifices are often obscured bydisease and bilateral percutaneous nephrostomiesmay be required followed by J stents placedantegradely into the ureter. These measures arepalliative and may offer a variable survival withgood quality of life.

HORMONE REFRACTORYPROSTATE CANCER (HRPC)Treatment of patients with prostatic cancer inwhom hormone therapy has failed is disappointing.Mean survival is approximately one year.Management of the terminal manifestations of thedisease require input from palliative care specialists,medical oncologists, radiotherapists and urologists.

Depending on the presentation and previoustreatment there are a number of possible treatmentstrategies in patients presenting with a rise in PSA:

■ Patients on LHRH analogues should continueon their therapy and addition of an anti-androgen may induce a temporary response in10% of patients.

■ Fifteen to 30% of patients on completeandrogen blockade will have a fall in their PSAwhen the anti-androgen is withdrawn.Withdrawal of the androgen should be triedbefore introducing new treatments.

■ Second-line hormone manoeuvres such ascortisone, adrenal androgen deprivation withketoconazole may help reduce bone pain.

Patients Presenting with ObstructiveSymptomsPatients presenting with significant obstructivesymptoms or acute urinary retention may be dealtwith by transurethral resection of the prostate.Rectal and perineal pain can be controlled byadequate and appropriate analgesia with thedirection or advice of palliative care specialists.World guidelines are available. Occasionallyradiation to the pelvis may be indicated.

Patients Presenting with Bone PainBone pain can be very severe. Bone scan is indicatedto identify the site of painful metastases. Simplefraction XRT provides pain relief in 80% ofpatients for about 6 months. Widespread bone painmay require hemi-body radiation on an in-patientbasis. Strontium-89 or Rhenium-186 is helpful andis equal to hemi-body radiation in efficacy. Bonemarrow depression occurs after Strontium-89 orRhenium-186 and hemi-body radiation. Evaluationof response in patients with bone involvement aloneis difficult.

In refractory patients use of PSA has been evaluatedand seems a reasonable end-point surrogate of theefficacy of treatment. A sharp fall of 50% ispredictive of longer survival of the patient.However, the mean survival in patients withhormone refractory disease is 40-60 weeks and nosingle agent or combination of agents has yet beenshown to impact on this. HRPC is incurable.Several agents or combinations of agents induce asignificant decline in PSA with some objectiveresponse in patients, especially those with soft-tissuedisease. Pain palliation is often possible in patientsunresponsive to narcotics and endocrine therapy.Mitoxantrone, an anthracycline with a relativelybroad-spectrum of activity against human tumours,has recently been shown in a randomised trial torelieve bone pain, and to improve the quality of lifemeasurements in patients. Twenty-nine percent ofpatients treated with a combination of prednisoloneand mitoxantrone experienced a valuable degree ofpain control compared to 15% receivingprednisolone alone. Toxicity is mild, and while bothgroups of patients have the same mean survival ofone year, activity of mitoxantrone was definable inhormone-relapsed prostate cancer.84, 85, 86, 87

Prostate Cancer Management Clinical Guidelines 27Metastatic Prostate Cancer


StatementLocalised bone pain is often severe and can berelieved by simple fraction XRT with pain relief in80% of patients for about 6-8 months.


StatementWidespread bone pain can be relieved by Strontium-89 or Rhenium-186.


Statement Mean survival in patients with hormone-refractorydisease averages 40-60 weeks.


Statement Mitoxantrone submitted to randomised controlledtrials relieved bone pain and improved patients’quality of life especially when combined withprednisolone.


Recommendation 28A multidisciplinary team approach should be madeavailable to patients with advanced hormone-refractory prostatic carcinoma and include palliativecare specialists, radiotherapists, medical oncologistsand urologists.Grade C

CRYOTHERAPY (AS MONOTHERAPY)A recent report on 66 patients undergoing surgicalcryotherapy as monotherapy for localised prostaticcarcinoma suggests that cryosurgery does notachieve effective local control of prostatic cancer. Inthis series most patients died of prostatic cancer andmost had local relapse at the time of death. Forty ofthe 51 patients died of prostatic carcinoma iftreated with cryotherapy alone, suggesting thatcryotherapy has limited abilities to provide effectivelocal control.88


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Prostate CancerManagementClinical Guidelines

Prepared by The Clinical Guidelines CommitteeRoyal College of Surgeons in Ireland

February 2002

Royal College of Surgeons in Ireland123 St. Stephen’s Green, Dublin 2, Ireland

Tel: 353-1 402 2100. Fax: 353-1 402 2460. Web: www.resi.ie

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