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Professor Stephen Langley isProfessor of Urology at the RoyalSurrey County Hospital in Guildford,Surrey, UK, and Director of theProstate Cancer Centre. Since his training, he has developedan international reputation andexpertise in prostate cancer – inparticular, prostate brachytherapy –and has treated over 800 patientswith this technique. He also has akeen interest in prostate cancerresearch at the PostgraduateMedical School of the University ofSurrey and is co-lead of a largeMultidisciplinary Research Unitinvestigating the molecular aspectsof prostate cancer and noveltherapies, including gene andvaccine therapies. Professor Langleyhas run numerous internationalcourses for consultants acrossEurope in prostate brachytherapyand is currently establishing aBritish Urological FoundationFellowship programme inbrachytherapy in association withcolleagues from Seattle, US. Hetrained to Medical School at St.Bartholomew’s Hospital, London. Heundertook a Masters of Surgerythesis at St. Thomas’ Hospital,London, and was a SeniorUrological Registrar in Bristol beforebeing appointed a ConsultantUrologist in Guildford in 1998.

a report by

S t e p h e n E M L a n g l e y

Professor of Urology, Department of Urology, St Luke’s Cancer Centre,

Royal Surrey County Hospital, Guildford

Modern-day prostate brachytherapy using permanentimplants was born in the 1980s following thedevelopment of transrectal ultrasound in Denmark.The use of transrectal ultrasound allows the accurateimplantation of radioactive seeds into the prostate,which had previously been attempted at openoperation but without clinical success.

B r a c h y t h e r a p y P r o c e d u r e

There are a number of different techniques available toperform prostate brachytherapy, all of which, whenperformed in experienced hands, provide reproduciblehigh-dose radiation targeted to the prostate. Theredoes not appear to be any clinical difference betweenthe isotopes of iodine-125 and palladium-103, and thelatter is currently unavailable in the UK and much ofEurope. The implant procedure as popularised inSeattle is a two-stage technique involving an initialplanning transrectal ultrasound scan. The ultrasoundimages generated of the prostate are digitised toproduce a three-dimensional (3-D) computerisedmodel of the prostate, urethra and rectum. The precisenumber and position of the seeds required are thencalculated to ensure coverage of the prostate with asuitable margin. The patient returns to the hospitaltwo to four weeks later for the implantation of theradioactive sources. The patient is anaesthetised andplaced in a similar extended lithotomy position as forthe planning scan. The transrectal ultrasound is used toguide the needles, pre-loaded with radioactive seeds,into their predetermined positions within the prostategland. The procedure takes 30–45minutes, after whichthe patient is catheterised. This catheter may then beremoved later the same day, with the patient beingdischarge once they have voided or the following day.

Stranded iodine seeds (Rapid Strand™, Oncura, UK)allow a greater coverage of radiation just outside thegland and the risk of individual seed migrationthrough the venous plexus around the prostate isavoided. In our audit of 40 patients who underwent achest X-ray a minimum of three months after theirRapid Strand implant there were no cases of seedmigration to the lungs. Implants are typically plannedwith a minimum margin of 5mm around the prostate,

extending to 10mm at the base and apex in an attemptto treat any localised extra capsular spread of disease.

Some centres favour a one-stage technique where anestimate of the numbers of seeds required for aprocedure is calculated from the prostate volume,which is assessed in clinic. The dosimetric calculationsare then performed using computer software, whilstthe patient is anaesthetised. This technique is morecomplex to learn and requires the use of loose ratherthan stranded seeds, with the risk of seed migration tothe lungs reported in up to 20% of cases. Bothtechniques, when performed in experienced hands,however, may deliver high- quality implants.

A post-operative computer tomography (CT)performed either immediately for four weeks after theimplant is used to calculate the post-implant dosimetrydelivered to the prostate. It may be considered anindicator of the quality of the procedure.

The minimum prescribed dose to the prostate glandis 145Gy using iodine-125 implants, withapproximately 50% of the gland receiving 150% ofthe dose, i.e. 217Gy (see Figure 1). The implants arearranged to allow relative sparing of the prostaticurethra to minimise urinary morbidity. In caseswhere there is an increased chance of local extensionof the prostate cancer, a combined treatment using45Gy external beam radiation to the whole pelvis,given as 1.8Gy/fraction, followed by a 110Gybrachytherapy implant, has been used to good effectand will be discussed below. In some series, theaddition of three months of neo-adjuvant hormonetherapy is also being utilised.

B r a c h y t h e r a p y R e s u l t s

L o n g - t e r m R e s u l t s

The first 10-year results of transperineal ultrasound-guided prostate brachytherapy that derived fromSeattle were reported in 1998. The 152 patientstreated from 1986 to 1987 were the first ever to betreated by this technique and therefore include boththe learning curve, as well as the curve of discovery for

Permanent Low-dose- ra te Pros ta te Brachytherapy

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DOI: 10.17925/EOH.2006.0.1.59

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the procedure. Sixty-four per cent of patients weretreated by implant alone (either iodine-125 orpalladium-103) and the remaining 36% of patients,judged to be at higher risk of extra-prostatic extension,underwent combined external beam radiation therapy(EBRT) to 45Gy, followed by brachytherapy. Fiveand 10-year prostate-specific antigen (PSA),biochemical-free survival as defined with a PSA of<0.5µg/l revealed results of 74% and 66%,respectively. This learning curve was demonstrated ina more contemporary series of similar low-risk patients(defined in Table 1) treated in Seattle from 1988 to1999. Improvements in the technique revealed anincreased 10-year biochemical-free survival rate from65% to 87% for this group of patients.

A further cohort of 125 patients treated by iodine-125 monotherapy, with an average follow-up of 77months, revealed 100% cancer-specific survival andan 85% progression-free survival at 10 years.8,9 Theoverall Seattle published series of 634 patients – 402treated with an implant alone (iodine-125/palladium-103) and 232 treated by an implantand external beam radiation – revealed a progression-free survival rate of 77%. No patients underwentlymph node sampling or androgen ablation, andbiochemical survival was determined by twosuccessive PSA rises rather than the AmericanSociety for Therapeutic Radiology and Oncology(ASTRO) criteria of three. When stratified by riskfactors (see Table 1), low-, intermediate- and high-

risk disease had progression-free survival rates of87%, 74% and 45%, respectively. Similar 10-yearresults have been recently reported by others withPSA-free survival rates of 79% from a cohort of 883patients, and results on 619 patients at 13 yearscontinue to show a PSA-free survival of 77%.

Ten-year disease-specific survival rates for 1,561 mentreated by brachytherapy, with or without EBRTand hormone therapy, have recently been publishedwith a 96% survival, suggesting that the excellentresults obtained using PSA as a surrogate markerappear to translate to actual clinical outcomes.

R ep r o du c i b i l i t y o f B r a c h y t h e r a p yR e s u l t s

Several centres across America have reported similarresults for low risk patients, as indicated in Table 2. Incentres with demonstrable high-quality implants andthat are regularly performing brachytherapy, excellentresults have also been seen in intermediate-risk patientswith biochemical-free survival of this group of patientsmatching those obtained from Seattle.

The benefit of treating patients with intermittent riskfactor disease by brachytherapy alone or incombination with EBRT has yet to be clarified andthere are proponents of each technique. A currentRadiation Therapy Oncology Group (RTOG) studyrandomising intermediate risk patients tobrachytherapy alone or combination therapy shouldanswer the question as to the necessity of EBRT.

The results achieved in the US appear exportable tothe UK. We have treated over 800 patients andprospectively assessed outcomes of both PSA-freesurvival using the ASTRO criteria as well ascontinence, potency and quality-of-life parametersusing validated questionnaires.

The demographics and results of the first 300 patientstreated with median follow-up of 45 months (range33–82) shows an overall actuarial PSA-free survivalof 93% at five years.

Stratified by risk group, the actuarial survival were96%, 89% and 93% for low-, intermediate- and high-risk disease. There was no statistical difference insurvival between hormone-naïve patients and thosetreated with three months of neo-adjuvant therapy(95% versus 93%, p=0.3, respectively).

The Leeds group, UK, have also recently presentedtheir seven-year PSA-free survival results, showingsimilar outcomes to those from America with rates of84%, 72% and 54% for low-, intermediate- and high-risk disease from a cohort of 669 patients.

Figure 1: Post-implant CT Scan Taken with the Patient Catheterised at Mid

Gland and Apical Levels of the Prostate

The Iodine-125 sources are clearly seen within the prostate tissue. The dashed white line shows the peripehery of the

prostate. The green isodose line is a simulation showing coverage of the prescribed radiation dose, 145Gy. The red isodose

line simulates that portion of the prostate receiving 150% of the prescirption dose, 217Gy. The blue isodoseline simulates

the 72Gy isodose showing the rapid fall off in radition to the surrounding structures

Table 1: Risk Group Classification of Prostate Cancer Patients

Seattle Risk Groups PSA Stage Gleason Grade

Low ≤10 T1a–T2b 2–6

Intermediate: 1 factor >10 ≥T2c ≥7

High: 2 or more factors >10 ≥T2c ≥7

Stage is based on the 1992 American Joint Committee on Cancer staging where T2b involves more than 50% on one side of

the gland and T2c involves both sides as assessed by a digital rectal exam (DRE).

Mid gland Apex of gland

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T h e R o l e o f H o rmon e T h e r a p y i nB r a c h y t h e r a p y

Hormone therapy may be used to reduce gland size toallow patients with larger prostates(55–75cc) to betreated by brachytherapy without incurring pubic archinterference at the time of implantation. It has alsobeen used in a neo-adjuvant setting in higher-riskpatients in an analogous situation to patients treated byEBRT. However, the excellent results demonstratedin patients treated with low-risk prostate cancerimplies that neo-adjuvant therapy in this group isunwarranted. When volume reduction is the goal,goserelin has been shown to provide a significantlygreater reduction in prostate size than bicalutimide,mean volume reduction 26% versus 8%, respectively.

The value of neo-adjuvant hormone therapy in atherapeutic role is more contentious. Following thework of Pilepich et al., where an improved survivalwas demonstrated in patients treated with fourmonths of combined androgen blockade withEBRT, many patients in the UK are treated in asimilar way when undergoing such therapy. Furtherstudies have suggested that high-grade tumoursrequire longer adjuvant treatment. There are norandomised studies evaluating the benefit of neo-adjuvant hormones in brachytherapy. To date, somestudies have shown an advantage for intermediate-and high-risk patients at five years, whereas othershave failed to identify a benefit in case-matchedseries. Furthermore, any such advantages must bebalanced by the side effects of hormone therapy,which, in our experience, can adversely affecterectile function up to one year after implantation.

Compa r i s o n R e s u l t s

There are currently no randomised studiescomparing brachytherapy to either radicalprostatectomy or EBRT available. In a study of over6,500 patients treated with either brachytherapy,radiotherapy or radical prostatectomy, who werestratified according to a PSA and Gleason score, therewould appear to be no significant difference betweenany of the primary treatment options in PSA-freesurvivals. The only consistent finding was thatconformal beam T, but no individual treatment hadoverall superiority. A further retrospectivecomparison of 1,305 patients treated for stage T1-2prostate cancer by either radical prostatectomy orbrachytherapy failed to demonstrate any clearsuperiority of one treatment over the other.

Kupelian reported data from a large cohort of 2,991patients treated with either brachytherapy with orwithout EBRT, conformal beam radiotherapy to>72Gy or <72Gy and radical prostatectomy. EBRT

given to <72Gy appeared less effective than the othermodalities, all of which appeared indistinguishablewhen assessed at five years by biochemical-free survival.

It appears highly unlikely, given the size of thesecohorts, that one will be able to determine a significantdifference between treatment groups until randomisedstudies are available, and at present brachytherapy,radical prostatectomy and conformal beamradiotherapy would appear to hold similar chances ofcure for patients. The durability of brachytherapy hasbeen demonstrated in 10- and 13-year results fromSeattle. No further recurrences were identified inpatients who were deemed biochemically free at 10years compared to 12 or 13 years of follow-up.

Comp l i c a t i o n s

Incontinence is rare, occurring in <1% in our workand most contemporary series. The primarycomplication of prostate brachytherapy is atemporary deterioration of urinary function withincreased irritative and obstructive symptoms.Patients are routinely treated with α-blockers. Wehave found that such urinary symptoms assessed bythe International Prostate Symptom Score (IPSS)are improved at three months and return to baselineby nine months. Urinary retention can occur in2–27% of patients, although with improved caseselection the risk can be minimised. This side effectis best managed by intermittent self-catheterisationand is usually resolves within four weeks. Atransurethral resection of the prostate (TURP)should be avoided for at least nine months assymptom will often resolve and we have a <2%incidence of our patients requiring any outflowtract surgery. Although urinary obstruction canoften be readily relieved at operation, a 26% rate ofstress incontinence has been reported. Urethralstrictures may develop in ~5% followingbrachytherapy typically at the membranous urethra.They respond well to simple dilatation followed byweekly intermittent self-catheterisation. A similarincidence of strictures has been reported in patientstreated by both radical prostatectomy and EBRT.

Proctitis is relatively uncommon, occurring inapproximately 5% of cases and, in our experience, hasalways resolved with conservative medication alone. Itis more troublesome in patients with combined EBRTand brachytherapy as the rectal dose is increased.Patient-administered questionnaires have shown thatthere is relatively little long-term bowel dysfunction.

Erectile dysfunction (ED) seems significantly lesscommon than with radical prostatectomy, whereimpotence from UK and European studies is as highas 86% despite utilising nerve sparing techniques.

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Potters reported on the potency of 482 patientspotent pre-treatment and revealed a potency rate ashigh as 90% in men younger than 60 treated with animplant alone. The potency rates gradually worsenedwith increasing age of the patient, the addition ofEBRT and the use of neo-adjuvant androgendepravation therapy. In those patients that doexperience impotence, a >80% response to sildenafilcan be expected. Pre-implant erectile status is a strongpredictor of brachytherapy-induced impotence. Atsix years post-implant, 70% of patients remainedpotent enjoying normal erectile function pre-treatment compared with only 34% of patients whosepre-treatment erectile function were sufficient forintercourse but considered sub-optimal.54 In ourprospective study at Guildford, we have a 67%potency rate at one year in patients with InternationalIndex of Erectile Function (IIEF) score of greaterthan ≥11/25, who were potent pre-treatment.

The literature lacks any randomised studiescomparing side effect profiles with EBRT, radicalprostatectomy or brachytherapy. A recent reviewarticle in the Lancet, discussing the clinical decision-making aspects of the treatment of early prostatecancer, highlighted the relatively low risk of urinaryincontinence, rectal complications and sexualdysfunction following brachytherapy compared withradical prostatectomy or external beam radiotherapy.However, the risk of retention followingbrachytherapy is appreciable and highlights theimportance of careful case selection to minimise thissignificant, although temporary, deterioration inurinary symptoms. A meta-analysis comparingerectile function outcomes of men with prostatecancer treated with curative intent suggests that, ofthe different radical treatments, brachytherapy offersthe higher risk of remaining potent at 76% (reducingto 60% with combination therapy). Quality-of-lifestudies suggest that the greatest deterioration inurinary continence and sexual function occurs inpatients treated by radical prostatectomy comparedwith brachytherapy, although, often, more globalquality-of-life measures remain similar.

P a t i e n t S e l e c t i o n I s s u e s f o rB r a c h y t h e r a p y

Patient selection for prostate brachytherapy involvesboth cancer issues and more general urologicalissues. In accordance with the recommendations ofthe American Brachytherapy Society and theEuropean Association of Urology/EuropeanOrganisation for Research and Treatment ofCancer (EAU/E ORTC), patients with low-riskprostate cancers may be treated effectively with abrachytherapy implant alone. Those withintermediate-risk prostate cancer pose a more

difficult question, and the current RTOG studyrandomising patients to a brachytherapy implantalone or combination treatment with EBRT willhelp to determine which is the optimal treatmentstrategy. Factors such as patient age, competing co-morbidities, the percentage of cores positive forcancer and the presence of perineural invasion caninfluence the decision as whether to offercombination treatment.

For patients with high-risk cancers, the role ofbrachytherapy is less certain. If there is evidence ofseminal vesicle invasion, combination treatment ofbrachytherapy and EBRT does not provide as high adose to the vesicles as conformal beam radiotherapy,which would be considered the optimum treatment.However, if the seminal vesicles appear clear,combination therapy has been used with good effect,as demonstrated in a number of series with up to 50%biochemical-free survival at 10 years.

The urological issues surrounding prostatebrachytherapy are important in selecting patients whoare likely to have minimal post-implant symptoms.Patients should ideally have glands less than 60cc insize to avoid pubic arch interference, although thiscan occur with smaller glands and needs to be assessedat the time of the planning scan. In patients whoseglands are between 60cc and 75cc, a three-monthcourse of hormone deprivation via an luteinisinghormone releasing hormone (LHRH) analogue willusually allow sufficient volume reduction to permit anadequate implant. Such patients, however, tend tohave an increased risk of temporary retention andurinary morbidity. Patients must be able to flex theirhips to 90°, have few pre-treatment lower urinarytract symptoms, (IPSS <15) and should beurodynamically unobstructed.

S umma r y

Brachytherapy appears highly effective in thetreatment of localised prostate cancer and theseresults have been reproduced across America as wellas within Europe. A number of quality of life surveyshave suggested that optimum quality of life isobtained with brachytherapy both in terms of urinaryand sexual parameters. With many patients treated bybrachytherapy in a day-case setting and being able toreturn to work within a few days, the advantages ofbrachytherapy are readily apparent. As with everytreatment in medicine, however, case selection iscritical in brachytherapy to ensure satisfied patientswith a low morbidity and high chance of cure. ■

A version of this article containing references and additionaltables can be found in the Reference Section on the websitesupporting this briefing (www.touchoncologicaldisease.com).

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