Correspondence Continuing Education Courses For Nuclear … · 2018-12-03 · A. Benefits of Brachytherapy – Preferential Dose Deposition B. Isotopes in Brachytherapy C. Low Dose

THE UNIVERSITY OF NEW MEXICOHEALTH SCIENCES CENTER

COLLEGE OF PHARMACYALBUQUERQUE, NEW MEXICO

Correspondence Continuing Education Courses For

Nuclear Pharmacists and Nuclear Medicine Professionals

VOLUME IX, NUMBER 4

Current Advances in Prostate Brachytherapy

By:

Aldo Rolfo, B App Sci, MBA Brachytherapy Unit

Peter MacCallum Cancer InstituteEast Melbourne, Victoria

AUSTRALIA

The University of New Mexico Health Sciences Center College of Pharmacy is approved by theAmerican Council on Pharmaceutical Education as a provider of continuing pharmaceuticaleducation. Program No. 039-000-01-002-H04. 2.5 Contact Hours or .25 CEUs.

Approved for continuing Nuclear Pharmacy education by the Florida Pharmacy Association.Florida Program No. PSN2003-001.

Current Advances in ProstateBrachytherapy

By:

Aldo Rolfo, B App Sci, MBA

Coordinating Editor and Director of Pharmacy Continuing EducationWilliam B. Hladik III, MS, RPh

College of PharmacyUniversity of New Mexico Health Sciences Center

Managing EditorJulliana Newman, ELS

Wellman Publishing, Inc.Albuquerque, New Mexico

Editorial BoardGeorge H. Hinkle, MS, RPh, BCNP

Jeffrey P. Norenberg, MS, RPh, BCNPLaura L. Boles Ponto, PhD, RPh

Timothy M. Quinton, PharmD, MS, RPh, BCNP

Guest ReviewersJohn C. Roeske, PhD

Ashesh Jani, MDDepartment of Radiation and Cellular Oncology

The University of ChicagoChicago, IL

While the advice and information in this publication are believed to be true and accurate at press time, the author(s),editors, or the publisher cannot accept any legal responsibility for any errors or omissions that may be made. The

publisher makes no warranty, express or implied, with respect to the material contained herein.

Copyright 2001University of New Mexico Health Sciences Center

Pharmacy Continuing EducationAlbuquerque, New Mexico

CURRENT ADVANCES IN PROSTATE BRACHYTHERAPY

STATEMENT OF OBJECTIVES

The purpose of this continuing education lesson is to provide an overview of the role ofbrachytherapy in the management of prostate cancer. This lesson describes the benefits ofbrachytherapy when compared with other forms of treatment such as surgery and external beamradiotherapy. To develop an appreciation of the role of brachytherapy in a disease such asprostate cancer, the lesson can be considered to be in two parts.

The first part describes the etiology, physiology and pathology of prostate cancer. Thisinformation is necessary to provide the reader with knowledge vital to develop an understandingand appreciation of the rationale of brachytherapy and its application in prostate cancer.

The second part of the lesson describes brachytherapy in detail, focusing on the modalitiesavailable. The reader should be able to describe the appropriate brachytherapy modality basedon criteria such tumor stage, grade and pathology characteristics.

Specifically, this unit will address the resurgence of interest in this therapeutic modality that hasoccurred because of ongoing improvements in medical imaging, computerized treatmentplanning software, and remote afterloading technology.

Upon completion of this continuing education module, the reader should be able to:

1. Define the term “brachytherapy” and describe the principles of dose conformity anddose minimization.

2. Summarize the advances in technology which have resulted in renewed interest inbrachytherapy as a key treatment modality in prostate cancer therapy.

3. Identify the anatomy of the prostate and describe how the anatomical architectureimpacts on treatment.

4. Describe the value of diagnostic screening in brachytherapy management decisions.

5. Outline the most common isotopes used in prostate brachytherapy and describe theproperties that determine suitability for use in brachytherapy.

6. Describe other treatment modalities used for the management of prostate cancer.

7. Describe the rationale of dose rate in the management of prostate cancer.

8. Identify relevant applications for both high dose and low dose rate brachytherapy interms of tumor stage and histology.

COURSE OUTLINE

I. INTRODUCTION

II. PROSTATE BRACHYTHERAPY –

A RESURGENCE OF INTEREST

III. PROSTATE CANCER

A. Anatomy

B. Grading

C. Volume

D. Staging

E. Incidence

F. Diagnostic Screening

IV. MANAGEMENT OPTIONS

A. Surgery

B. Radical External Beam

Radiotherapy

C. Hormonal Therapies

D. Brachytherapy

V. STATE-OF-THE-ART

BRACHYTHERAPY FOR

PROSTATE CANCER

A. Benefits of Brachytherapy –

Preferential Dose Deposition

B. Isotopes in Brachytherapy

C. Low Dose Rate Permanent Seed

Brachytherapy

1. Clinical Advantages

2. Clinical Disadvantages

3. Selection Criteria for Therapeutic

Advantage – Control Vs Morbidity

4. Technique Description

5. Results

D. High Dose Rate Temporary Needle

Brachytherapy

1. Clinical Advantages

2. Clinical Disadvantages

3. Selection Criteria for Therapeutic

Advantage – Control Vs Morbidity

4. Technique Description

5. Results

VI. CONCLUSION

VII. REFERENCES

VIII. QUESTIONS

1

INTRODUCTION The discovery of radium by the Curies

in 1898 was promptly followed by its clinicalapplication in the treatment of cancer,initiating the medical discipline known todayas brachytherapy. The name “brachys,”derived from the Greek language meaningshort, implies brachytherapy occurs whensealed sources of radioactive material are usedto deliver radiation at very short distances byplacing the sources within cavities, lumens,tissues or on the surface of tumors. Thephysical benefits of this mode of treatment isthat very high doses of radiation can bedelivered directly or almost directly tomalignant tumors with a very rapid fall off ofdose to surrounding normal tissues. Thislesson describes the application ofbrachytherapy in the management of prostatecancer, which continues to be most commoncause of death in men from cancer in theUnited States.

In early prostate cancer, brachytherapycan successfully control local disease inapproximately 80% of cases and achieve 10-year survival rates similar to the resultsobtained with other forms of treatment such assurgery or external beam radiotherapy, withdecreased urinary and bowel morbidity andsexual dysfunction. Prostate brachytherapy,offered either as a sole modality therapy or inconjunction with moderate dose externalbeam radiotherapy, is challenging surgery asthe treatment of choice for localized prostatecancer. Current advances in prostatebrachytherapy are continuing to offer menwith prostate cancer excellent treatmentoutcomes in terms of improved tumor controland quality of life.

PROSTATE BRACHYTHERAPY – ARESURGENCE OF INTEREST

Prostate cancer is essentially a diseaseof elderly men. Almost half of all men over theage of 80 have evidence of prostate cancer.Unfortunately by the time most men display

symptoms of prostate cancer such as urinaryhesitancy, urgency, nocturia or impotence, it isoften too late to offer curative therapy. Withthe lifetime risk of developing prostate cancerbeing 1 in 6, attempts at early diagnosiscontinued to be the mainstay of research formany years1 .

The introduction of prostate specificantigen (PSA) and transrectal ultrasonography(TRUS) in the 1980s led to an increase in theabsolute incidence of prostate cancers and toan increase in the detection of early stagedisease2 . Renewed interest in low risk curativetherapies soon emerged, as the treatmentparadigm shifted from a palliative to curativesetting. The roles of watchful waiting(observation), radical prostatectomy(surgery), radical external beam radiotherapyand interstitial brachytherapy (where thebrachytherapy source is directly implantedinto the prostate tissue) became the topic ofactive debate across the globe.

In addition to the detection of earlystage disease, PSA also became significant indemonstrating the effectiveness of standardtherapies. As a surrogate tumor marker, PSAelevation became associated with diseaseprogression. Biochemical surveillance byPSA assays demonstrated that the standardtherapies of radical prostatectomy andexternal beam radiotherapy were not aseffective as initially thought in themanagement of more advanced disease3 . PSAsurveillance re-established the therapeuticboundaries for advanced disease, challengingclinicians to deliver more aggressive therapyin the local setting, in the belief that PSAlevels, and hence active disease, would remainunder control. Within the discipline ofexternal beam radiotherapy, PSA control andtreatment failure was associated with volumeand dose considerations. Escalating the dosewithin the tumor and reducing the irradiatedvolume of normal tissues were two concurrent

2

strategies that were identified as beingsignificant in improving tumor control4 .These strategies became significant in themanagement of both early and late stageprostate cancer.

Brachytherapy, dismissed in the early1970s as a viable treatment option, underwenta significant revival of interest in the late1980s. Concurrent developments in imagingtechnology, computer dose modeling anddelivery apparatus underpinned this interestand realized the potential to deliver higheruniform doses to the target area, whileminimizing the dose to surroundingstructures. This resurgence of interest wasevident across the world, as cliniciansattempted to provide alternatives to thestandard radical prostatectomy and radicalexternal beam radiation therapies.

By the late 1980s high and low doserate brachytherapy techniques were gainingacceptance as safe, effective and viabletreatment options for both early andadvanced disease. Both techniquesdemonstrated significant improvements incontrol with minimal acute and chronicmorbidity5 . The direct placement of theradioactive source within the tumorfacilitated precise shaping of the radiationdose around the prostate gland andsignificantly lower dose to surroundingbladder and rectal structures. Improvedtumor control and lower toxicity (sideeffects) is predicated on escalating the doseto the target area (the tumor with a smallmargin) beyond conventional levels whileminimizing the dose to adjacent normaltissue structures. This resurgence of interestin brachytherapy continues today, asclinicians attempt to improve control in bothearly and advanced stage disease through thecombined strategies of tumor dose escalationand normal tissue dose and volumeminimization.

PROSTATE CANCERThe etiology of prostate cancer is unknown,however there is a strong hereditarypredisposition. A number of genetic eventsappear to be required for the development ofclinically significant prostate cancer, althoughit is not known if other contributingenvironmental or hereditary factors exist. Inhumans, aberrant expression of the p53 geneappears to be a biomarker that may be able topredict previously undiagnosed and recurrenttumors in patients with clinically localizedprostate cancer. These data suggest that tumorsuppressor genes involved in cell cycleregulation are not only critical to thepathogenesis and progression of the cancer,but may be potential therapeutic targets.6

Several human studies have suggested a linkbetween diet and an increased risk of prostatecancer. Diets low in fat and high in soy proteinhave been previously suggested to reduce therisk of cancer. Some researchers have alsoidentified race as a significant risk factor inthe predisposition towards prostate cancer,however the data are unconvincing. It is fair tosay that the role of race as a prognostic featurein men with prostate cancer remainscontroversial7 .

AnatomyThe prostate is a male sex gland resembling awalnut in shape and weighing about 20 gm.Located immediately inferior to the bladderand anterior to the rectum, it is transversed bythe urethra (the portion of the urethra passingthough the prostate is called the prostaticurethra). The seminal vesicles lie superior andposterior to the prostate. The prostate isdivided into five histologically distinct zones8:

1. the anterior zone;2. the peripheral zone, accounting for

75% of prostatic volume and the areain which prostate cancer tends to belocalized. 70% of cancers originate inthe peripheral zone;

3

3. the central zone, where up to 20% ofcancers are noted to arise;

4. the preprostatic urethra; and 5. the transitional zone, where 10% of

cancers arise.

The functions of the prostate gland arenot well understood. It consists ofapproximately 30 to 50 tubuloalveolar glandsthat open into the prostatic urethra through 15to 30 ducts arranged in a radial pattern with astroma of fibromuscular connective tissue,blood vessels, lymphatics, and nerves. Thegland produces an acidic fluid (pH 6.5) thatconstitutes approximately 30% of seminalfluid ejaculate, containing calcium, zinc, acid,phosphatase, a clotting enzyme andprofibrinolysin.9

The natural history of prostate canceris highly variable. The majority of cancers ofthe prostate arise in the peripheral zone and donot affect the periurethral areas until thecancer has spread, explaining the lack ofsymptoms in patients in the early stages ofprostate cancer. In fact, symptoms generallydo not appear until the cancer has spreadbeyond the prostate and affected other organs,all but reducing the impact of curativetherapies. Prostatic cancers can be separatedinto cancers of acinar (which accounts for98% of all cancers of the prostate) andproximal duct origin or of distal duct origin.

It is interesting to note that the prostateitself is rarely associated with metastases fromother tumors. Prostate cancer is considered aslow growing tumor and its prognosis isrelatively good.

Tumor GradeTumor stage and tumor grade remain

the most important prognostic indicators ofprostate cancer. After a clinical diagnosis ofprostate cancer has been established, a stagingworkup must be completed to determine the

grade (degree of cellular differentiationbetween cancerous cells and normal cells) andstage (extent to which the disease is presentand has spread). Prognosis and treatment aredetermined according to the grade and stageof the cancer. Staging systems are also used todetermine the biologic potential of the cancer.In general, small tumors tend to be welldifferentiated and slow growing, whereasmost poorly differentiated tumors tend to belarger, more aggressive, and associated with apoorer prognosis. Patients with tumorsconfined to the prostate gland have a betterprognosis than do patients with tumors thathave spread beyond the prostatic capsule10 .Extracapsular spread is indicative of a moreaggressive type of tumor.

Several grading systems have beenproposed to facilitate the diagnosis of distincthistological patterns based on the degree ofcellular differentiation. Donald Gleasonintroduced the system of histopathologicalaveraging in which the final score is theaverage of two patterns. The first pattern, (x)is from the more dominant areas and thesecond (y) from the less dominant areas.11 TheGleason score is:

x + y = z.

The lowest possible score is 2,indicating a well-differentiated tumor and thehighest possible score is 10, indicating a verypoorly differentiated tumor. In general, well-differentiated tumors (Gleason grades 2 to 5)are slow growing and associated with a lowmortality rate. Patients with poorlydifferentiated tumors (Gleason grades 7 to 10)have a much higher probability of dying fromprostate cancer.12

An analysis of data pooledfrom six studies that used deferred treatmentin patients with clinically localized prostatecancer support a difference in survival basedon the level of tumor differentiation. In this

4

5

collective group of 828 men, the disease-specific survival rate at 10 years was 87% inpatients with well or moderately differentiatedtumors, whereas patients with poorlydifferentiated tumor had a 10-year disease-specific survival rate of only 34%. In thissame series, metastasis-free survival was 81%for patients with well-differentiated tumors,58% for patients with moderatelydifferentiated tumors, and 26% for patientswith poorly differentiated tumors.13

Tumor VolumeTumor volume is also an important

prognosticator. Tumors with volumes less than0.5 cc are rarely associated with extracapsularspread, whereas extracapsular spread iscommon in tumors reaching 1.0 cc or more.Seminal vesicle invasion is common in tumorsgreater than 3.0 cc. However, overt metastasesrarely occur in tumors less than 4.0 cc in size.Nodal involvement is another prognosticfactor, with the risk of dying directly related tothe extent of nodal involvement.14

Tumor StagingTumor staging is important to

determine if, and to what extent, a cancer hasspread from its point of origin. Proper stagingis critical in establishing a prognosis and inselecting an appropriate treatment protocol.Although there are several staging systems inuse, the American Joint Committee for CancerTNM (tumor, node, metastases) systemcontinues to gain favor and is the systemreferred to in this article.

T1 tumors are generally localized,with little or no presenting complaints.Detection is often incidental, followingroutine PSA screening. In general, patientswith incidentally detected prostate cancerhave a good prognosis, although overallsurvival rates at 10 years vary from 30% to85% in the literature. This variation is believedto be due to the presenting PSA, grade andvolume of the tumor, with high grade, high

volume tumors associated with a poorerprognosis. Patients with low volume diseasegenerally have a better prognosis.15

T2 tumors generally are confined toone lobe of the prostate; characterized by thepresence of moderately to poorlydifferentiated cells; and a tumor volume ofless than 1.5 cc. Patients often present withobstructed flow symptoms, however, it is notuncommon for there to be no symptoms at all.On examination the tumor can be palpated andappears on TRUS as a hypoechoic lesion. PSAis generally elevated. The overall 10-yearsurvival for patients with T2 tumors rangesbetween 34% and 71%.16, 17

T3 tumors display extension beyondthe capsule but not involving other pelvicorgans (except T3c tumors which invade theseminal vesicles). Presenting symptomsinclude acute urinary retention, pelvic painand bleeding. Detection is via examination(DRE – Digital Rectal Examination), imaging(TRUS, CT, MRI) and PSA. 10-year diseasefree survival rates have been reported toapproach 55%.18 T4 tumors extend throughthe prostate capsule and invade other pelvicorgans such as the bladder or rectum.Presenting symptoms are similar to those forT3 tumors. Survival is comparatively poor, themean survival being around 4 years.19

Survival is not impacted greatly by choice oftreatment. Treatment is palliative, to alleviatesymptoms and improve quality of life.

Incidence of Prostate CancerEach year in Australia over 12,000 men arediagnosed with prostate cancer.20 In the UnitedStates, during 1999, it is anticipated thatnearly 180,000 new cases of prostate cancerwill be identified.21 During this same year inthe United States, prostate cancer is expectedto claim the lives of 37,000 men. Death ratesfrom prostate cancer will continue to climbdue in part to the increasing proportion of

6

elderly men in society along with reducedmortality from other causes such ascirculatory and cardiac diseases.22

The incidence of prostate cancer in theUnited States continues to be highest inAfrican American men, followed by whitemen, Hispanic men, Asians and AmericanIndians. For all races, the 5-year survival rateshave climbed from 67% in the period 1974-76to 93% in 1989-94.23

Diagnostic ScreeningThe intent of screening clearly is to

detect early stage disease and thereforeattempt to alter prognosis. The three mostcommon prostate cancer screening techniquesare digital rectal examination (DRE),transrectal ultrasonography (TRUS) andprostatic specific antigen assay (PSA). Allthree techniques have contributed to theincreased survival rates described previously.

DRE is commonly used to assess thecontour, texture and symmetry of the gland.Experienced clinicians can also determine thedegree of induration of the seminal vesiclesand whether extracapsular components reachthe pelvic sidewall. In less experienced hands,the value of DRE can be suspect.24 TRUSexamination of the prostate is a valuable test inaddition to DRE. It provides informationabout the echo pattern and facilitates accurateneedle placement for core biopsies fromspecific areas (base, mid and apex) as well asany suspicious palpable or hypoechoic areas.TRUS is also used routinely in thebrachytherapy treatment process.

PSA is secreted from the acini into theducts and can be measured in the serum. PSArises more quickly with prostate cancer thanwith other causes such as ageing, infection orinflammation. PSA levels however can varysubstantially in different patients, as PSAleakage from cancerous blood vessels is highly

variable. PSA variation with tumor bulk (stage)and histological differentiation (grade) can alsobe unpredictable. Some studies suggest valuesgreater than 4ng/ml are indicative of early stagedisease (T1-T2), 10ng/ml are indicative ofnon–organ confined disease (stage T3). Levelsgreater than 20ng/ml have been associated withbone metastases (stage T4).25

The reported predictive value of PSA inscreening studies however is the topic ofongoing debate. Reported predictive accuracyrates have been demonstrated to be in the range28% to 35%.26 That is to say, only one third ofmen with elevated PSA levels (greater than4ng/ml) will be found to have prostate cancer onbiopsy and two thirds will not (false positive).False positive elevation occurs withinflammation, infection and instrumentation,and returns to normal if the gland does notcontain cancerous cells. Combining DRE withPSA increases the positive predictive value to49% if both are considered positive.27 Theaddition of TRUS examination lifts thepredictive value to over 65%.28

The question of whether mass PSAscreening improves outcome still remainsunanswered. Various clinical trials are yet toconclusively demonstrate a reduction inmortality with PSA screening. Nevertheless, theproportion of men diagnosed with metastaticdisease (stage T4) in the USA, Europe andAustralia has been steadily falling in the pastdecade,29 as more men present with T1, T2 andT3 disease. While this debate continues, thechallenge in the clinic remains to offer low riskcurative therapy to all presenting candidates, beit early stage or later stage disease.

MANAGEMENT OPTIONSPrior to determining the appropriate

treatment strategy, it is vital that a completestaging workup be undertaken. This willimpact on the protocol selected and shouldinclude:

7

1. a complete history and physicalexamination;

2. DRE;3. pathological and histological

evaluation;4. PSA, full blood workup, biochemistry

and liver function tests, and5. Imaging, comprising of chest x-ray,

bone scan, Computerized Tomography(CT) and or Magnetic ResonanceImaging (MRI) abdomen and pelvicscan and Transrectal Ultrasound(TRUS) (including core biopsies).

SurgeryRadical prostatectomy — the complete

resection of the prostate has been the currentstandard therapy for selected patients withlocalized, organ-confined disease (T1 or T2)for more than three decades. Where lifeexpectancy is considered to be greater than 15years and the Gleason score is reported as 6 orless, surgery has been the gold standard intreatment.30 However, despite ongoingtechnical advances in surgical technique,morbidity, particularly impotence andincontinence, remains a concern to cliniciansand patients.31 Complications and quality oflife considerations following surgery isassuming greater importance in the selectionof the appropriate treatment strategy.Advances in imaging, dose modeling, andtreatment apparatus in the brachytherapy fieldoffer an attractive alternative to surgery, whichoffers similar tumor control rates, butpotentially lower complications.

Radical External Beam RadiotherapyThis treatment option is usually

recommended for selected patients with organ-confined disease (T2 and T3). Many serieshave been reported for external beamradiotherapy demonstrating results comparableto both surgery and brachytherapy.32

Patients with limited extra organdisease (T3c) with a life expectancy of greater

than 10 years are also suitable for radicalexternal beam radiotherapy. Radical externalbeam radiotherapy can produce acceptableresults in these patients, particularly where thepresenting PSA is less than 15mg/ml.However, to produce similar results in patientswhere the presenting PSA is greater than15mg/ml, combined treatment strategiesinvolving hormonal therapy are required.33 Inaddition, the external beam strategy mayinvolve higher doses and larger irradiatedvolumes.34 Intensity Modulated RadiationTherapy (IMRT) and 3-DimensionalConformal Radiation Therapy (3D CRT)strategies that facilitate this dose and volumeescalation whilst limiting the dose to normalstructures have been demonstrated to produceresults in these groups of patients that arecomparable to published surgical series35 . Theopportunity to escalate the dose whileminimizing the volume of normal tissue andpotentially the incidence of complications is afeature of both IMRT and 3-D CRT that is notpossible with conventional external beamradiotherapy.

Hormonal TherapiesAs described in the previous section,

hormonal therapy is offered in combinationwith external beam radiotherapy to reduce thetumor bulk thereby limiting the volumerequiring irradiation (or implantation withbrachytherapy strategies). Numerous studieshave demonstrated a disease free survivalbenefit for T2 and T3 (in addition to the T3ctumors previously discussed).36

Hormonal therapy is also offered topatients presenting with disseminated disease(T4) and those who have failed other forms oftreatment. Prostate cancer survives under thestimulus of androgens, and cancer progressioncan be temporarily reversed by androgensuppression.37 Androgen suppression may takethe form of estrogens (tablets or injections),LHRH analogues (lutinising hormone

8

releasing hormones – injections) or bilateralorcidectomy (surgical removal of both testes).Remission during hormonal manipulation canlast on average 1-2 years. Common sideeffects include weight gain, hot flashing,osteoporosis and loss of libido.

BrachytherapyThe genesis of interstitial

brachytherapy can be traced back to 1901when Pierre Curie filled a small tube withradium and suggested to French dermatologistHenri Danlos that he insert the tube into atumor in an attempt to eradicate it. The firstrecorded prostate brachytherapy treatmentwas conducted in 1917 when Barringerinserted stainless steel radium needles throughthe perineum (trans-perineal) and into theprostate, guided by a finger in the rectum.38

.The theory, although not explicit at the time,involved moving the source of radiation closeto the target cancerous cells, and away fromsurrounding normal tissues.

These treatments continued sparinglyuntil the 1930s, when fears associated withradiation protection prevented furtherinvestigation into the use of isotopes in cancertherapy. Concurrent developments withexternal beam radiotherapy and the use ofhormonal therapies at this time furthercurtailed ongoing research into the disciplineknown as brachytherapy.39

Results from long term follow-up oflocally advanced prostate cancer, however,remained only moderate; numerousresearchers began to re-explore the potentialbenefits of brachytherapy. In 1972, Whitmoreinserted radioactive Iodine 125 sourcesdirectly into the prostate through an openpelvic surgical approach.40 Sources in the formof individual 1mm x 5mm seeds weredeposited throughout the entire gland.Whitmore postulated brachytherapy wouldoffer higher doses of radiation to the prostate

while reducing the radiation dose and henceside effects and morbidity to the bladder andrectum. Analysis of the results from theWhitmore series was extremely discouraging.Many patients returned with active disease stillpresent in the prostate despite what wasthought to be higher than conventional doses.Examination of the radiation sourcedistribution pattern within the prostatedemonstrated significant problems; mostimplants were haphazard, with the 125I seedsunevenly deposited throughout the gland.Problems with visualization and access at thetime of implantation contributed to theunacceptable loading pattern. Subsequent dosecalculations demonstrated substantial regionsof the prostate to be significantly underdosed,contributing to treatment failure. Once againbrachytherapy was relegated down the list ofpotential therapies, with surgery promoted asthe gold standard.

In 1983, Holm and colleaguesdemonstrated that transrectal ultrasonographycould be used to more accurately implant theprostate. Coupled with a trans-perineal implantapproach, radioactive 125I seeds were directedinto the prostate through the perineal regiondirectly anterior to the anus and posterior to thescrotum; the procedure was only minimalinvasive and relatively simple to perform.Using a template attached to the perineumassisted in the uniform spacing and loading ofthe seeds. Interest in interstitial seedbrachytherapy quickly developed from thework of Holm; early results demonstratedcomparable results with those achieved withsurgery, but with greater patient tolerance andpotentially lower risk of normal tissue toxicity.

STATE-OF-THE-ART BRACHYTHERAPYFOR PROSTATE CANCERThe work of Holm became the foundation forongoing interest and improvement ininterstitial prostate brachytherapy all over the

9

world. During the 1990s prostatebrachytherapy challenged surgery andradical external beam radiotherapy as anefficacious treatment option in themanagement of both early (T1/T2) andadvanced (T2/T3/T3c) stage disease. Highand low dose rate techniques developedsynchronously that shared fundamentalsimilarities built on the discovery ofresearchers such as Curie, Whitmore andHolm. Each technique provides the ability toaccurately define the implant and targetvolume, and deliver treatment in a far moreexacting and reproducible manner than themethods of the past.41

Benefits of Brachytherapy — PreferentialDose Deposition Radiation can injure cells either directly orindirectly. With direct damage, a photon ofionizing radiation causes direct injury to DNAby altering its structure. However, a photon ismore likely to indirectly damage the DNAmolecule by producing free radicals afterincidental collision with neighboring watermolecules. These free radicals ultimatelyinteract and damage the DNA molecule.42 Byensuring that these events predominantlyoccur within the tumor, the highly localizeddoses delivered using brachytherapy canminimize damage to surrounding normaltissues. Compared with radical external beam

10

radiotherapy, significant benefits should berealized as no radiation need traverse normalstructures in reaching the target region. Thebenefit of brachytherapy is realized with thispreferential delivery of dose within the tumor.

Isotopes in BrachytherapySelection of isotope is therefore essential ifdirect and indirect ionizing events are to bemaximized within the tumor or targetenvironment. Table 1 details the commonlyused isotopes in brachytherapy.

25I and 103Pd are exclusively used for low doserate (LDR) brachytherapy, whereas 192Ir isused for high dose rate (HDR) brachytherapy.Gamma sources are clearly the isotopes ofchoice in the prostate, where dose depositionof up to 0.5 cm is often required from thesource. This physical characteristic enablessources to be placed at approximately 0.5 cmto 1.0 cm intervals throughout the volume,ensuring the implantation process isrelatively efficient and minimally invasive.Using beta sources in this application wouldrequire many more sources spaced atapproximately 0.1 cm to 0.2 cm intervals.Clearly this would require excessive time andtrauma in producing a uniform source anddose pattern. Further details regarding sourceproperties and selection will be described inthe relevant low dose rate and high dose ratesections.

Low Dose Rate (LDR) Permanent SeedBrachytherapy

LDR brachytherapy implants using 125Iand 103Pd are characterized by dose rateswithin the implant field of 8cGy/hour and24cGy/hour respectively. At these dose rates,normal cells within the irradiation matrix (andbeyond) maintain continuous cell repairpotential; repairing DNA damage as it issustained. Malignant cells, however, have lesspotential to repair this damage, andtherapeutic gain is achieved by this repair-

damage phenomena at low dose rates. Theseeds, which are approximately 5mm in lengthand 1mm in diameter and encapsulated by anouter stainless steel sheath, remain in-situpermanently. With a half-life of 60 days for125I, approximately 30% of the dose isdelivered in the first 4 to 6 weeks followingimplantation.

The most common application ofLDR permanent seed brachytherapy is forearly stage (T1/T2) disease, where the implantalone is the sole therapy. Offered as analternative to both surgery and radical externalbeam radiotherapy, this monotherapy isgaining wide acceptance as being efficacious,cost effective, minimally invasive and highlyappealing to patients. For later stage disease(T2/T3/T3c), LDR brachytherapy may beoffered as an adjunct to moderate doseexternal beam therapy. This combinedapproach is capable of irradiating periprostatictissues more effectively than monotherapybrachytherapy and is able to deliver asignificantly higher intraprostatic dose than ispossible with radical external beam therapyalone44 . The addition of external beamradiotherapy is warranted on the grounds thatthe brachytherapy alone will not adequatelyirradiate the malignant tissues outside theprostate.

Clinical AdvantagesThe advantage of permanent seedbrachytherapy is largely derived from theavailability and selection of low energyisotopes. The low energy photons of reactorproduced 125I and 103Pd, 28 keV and 21 keVrespectively, are significantly attenuated intissue resulting in a favorable dose depositionpattern. The low energy effectively confinesthe high dose region to the prostate, affordinglower doses in the surrounding tissues. Asnuclear research continues, the window oftherapeutic advantage could be widened asnew isotopes are discovered.

11

These low energy photons alsofacilitate relatively simple radioprotectionpractices, requiring no elaborate shielding inthe operating room (OR). Occupationalexposure to radiation amongst medical,paramedical and nursing staff is minimal; withmonitoring and strategic rotation of staff in theOR, no staff member should exceed annualacceptable dose limits.

In terms of the procedure, there is highpatient and physician acceptance. For patients,the procedure is performed as an outpatientcase with little discomfort. For monotherapycases, this single treatment is highlyappealing. Physicians find the procedurerelatively simple to perform; the currenttechnique (to be described later) ensures lowmorbidity in the appropriately selectedpatient. When viewed with encouragingresults, monotherapy permanent seed implantsare gaining favor as the treatment of choice forselected T1 cases.45

Clinical DisadvantagesA significant disadvantage of

permanent seed brachytherapy relates to theunforgiving nature of placement errorsassociated with the low energy source. Sourceplacement errors can result in unacceptableareas of underdosage or overdosage, which areunable to be modified once the implant iscomplete. Source placement errors can occurat the time of implant or at any time thereafter.

Irregularities within the prostate ormovement of the gland during implantationcan result in source position errors. Seedmigration can occur up to one month postimplantation; initial gland swelling andsubsequent resolution can effect the positionof each individual seed. The dosimetric (dosedeposition pattern) success of the implant ishighly dependant on the prostate tissuesmaintaining the seed matrix. Thebrachytherapy technique described by

Whitmore in the 1970s failed to controllocalized prostate cancer. Radiographs ofthese implants demonstrated the widevariability of seed placement. The lack ofuniform dosimetry was associated with thetreatment failure46 . Fortunately the techniquesemployed today result in more exact implantpatterns and hence better outcomes.

The rate at which treatment isdelivered is also a significant concern withinthe brachytherapy community. Generally,radical external beam and high dose ratetemporary implants deliver the radiation atrates up to hundreds of cGy/hour. Permanentlow dose rate implants using 125I and 103Pd arecharacterized by dose rates of 8cGy/hour and24cGy/hour respectively.47 The work ofeminent radiobiologists such as Hall48 in celland animal lines suggests that dose rate mayimpact on the ability of radiation to impartcellular DNA damage. This is particularlyrelevant when the cell line is rapidly dividingas in poorly differentiated cancers.49 Thesefindings question the use of low dose rateisotopes in the treatment of high grade tumors,particularly those demonstrating high Gleasonscores. The significance of this work remainsunclear in the clinic; more research iswarranted and pending. However, mostclinicians would avoid the use of 125I in highgrade, poorly differentiated tumors, choosingto use 103Pd or high dose rate temporaryimplants. Nuclear research into isotopes withlow energy photons and higher dose rates iscontinuing.

Selection Criteria for TherapeuticAdvantage – Control Vs MorbidityThe recognition of factors that may increasecomplications from low dose ratebrachytherapy is an important aspect ofappropriate patient selection. Prostate volumeis a significant factor. In general, prostateglands that are in excess of 50 cc to 60 cc, asdetermined by TRUS, are unacceptable for

12

implantation. As the prostate increases in size,brachytherapy become technically moredifficult as uniform implantation becomescomplicated. In addition to areas ofunderdosing where tumor clonogens mayremain viable, overdosing in the central andpreprostatic urethral zones may causesignificant urethral toxicity such as strictures,fistula and obstruction.

As discussed previously, the use ofconcurrent hormonal therapies have beensuccessful in reducing prostate volume. Theuse of LHRH analogues for 3 to 4 monthscan result in a 40% volume reduction,making implantation possible.50 In thissetting, patients that may have previouslybeen considered incurable are now beingoffered state of the art brachytherapy.Clinicians need to be wary however ofreducing the volume below 20 cc, whereimplantation again becomes extremelydifficult. Ideal implant volumes are in therange of 20 cc to 50 cc.

Ensuring that tumor control ismaximized and morbidity minimized isdependant on more than volume alone; othercriteria to consider include grade, stage,Gleason score and presenting PSA. Whileresearch continues, the following guidelinescould be considered relevant in selecting theappropriate treatment strategy.51 Theseguidelines are an example of current clinicalpractice, but the author acknowledges thatvariations do occur. For example, manyclinicians use hormonal therapy in allstrategies:

Monotherapy (Low dose rate permanentimplant alone)

• Stages – T1, T2a (early stage T2disease)

• Gleason – 2 to 6• Presenting PSA – less than 10

Combined Therapy (Low dose rate permanentimplant + moderate dose external beam)

• Stages – T2b, T2c (later stage T2disease), T3

• Gleason – 7 to 10• Presenting PSA – greater than 10

Hormones and Combined Therapy (LHRH 3to 4 month + implant + external beam)

• Stages – T3c• Gleason – 7 to 10• Presenting PSA – greater than 20• Or in any case where the initial

prostate volume as determined byTRUS exceeds 50cc

Technique DescriptionLow dose rate permanent seed implant

is characterized by 3 distinct phases in theactive treatment process: pre-planning,implantation and post-implant evaluation.

Pre-planning the implant is essentialin order to maximize the therapeutic window.Most pre-planning involves either a TRUS orCT examination. These studies determine thetarget volume to be implanted, as well asvisualizing the location of surroundingrectal, bladder and urethral structures. Theimplant team uses the data from the pre-planstudy to determine the ideal seed locations aswell as calculate the dose to the rectum,bladder and urethra.

The use of sophisticated dosemodeling software enables multipleinteractive calculations to be made, allowingthe team to alter the pattern in order to achievethe ideal dose distribution. As a general guide,the following doses are set as absoluteconstraints52:

• Tumor (mean peripheral gland dose) =144Gy for 125I (monotherapy)

• Tumor (mean peripheral gland dose) =115Gy for 103Pd (monotherapy)

13

• Tumor (mean peripheral gland dose)=108Gy for 125I (combined)

• Tumor (mean peripheral gland dose)=90Gy for 103Pd (combined)

• Rectum (anterior rectal wall)= 70%-75% of tumor dose (all cases)

• Urethra (periprostatic urethra)=115%-130% of tumor dose (all cases)

Current software algorithms usesophisticated dose calculation algorithms thattake into account the source geometry, as wellas attenuation and scatter of radiation bothwithin the radioactive source and the patient.These developments have significantlyadvanced understanding and confidence inplanning the ideal implant based on all keypatient and tumor characteristics.

The implant procedure used today isderived from the approach pioneered byHolm. The procedure is routinely performedin the outpatient setting, and is well toleratedby most patients. Following spinalanesthesia, the patient is placed in thelithotomy position. Under direct transrectalultrasound guidance, the sources areimplanted into the prostate via the perineum.The sources are commonly pre-loaded intoimplant needles that allow the sources to bedeposited within the prostate as the needle iswithdrawn (see Figure 1).

Recent developments in bi-planar scanningtechnology enable the clinician to viewneedle/source placement in simultaneousaxial and sagittal planes, facilitating preciseneedle placement and identification ofsurrounding structures. Fluoroscopy andcystoscopy is also employed to ensuresources are loaded according to the pre-planmatrix. Perineal templates sutured to theperineum assist in accurate needle and sourceplacement. Between 90 and 120 sources aredeposited in the average implant. Mostprocedures are completed in less than onehour.

Post-implant evaluation occursapproximately 4 weeks following implantation.At this time prostate swelling as a result of thetrauma associated with the implant shouldhave resolved, and no further migration ofseeds should be seen. Generally, CT is usedfor this evaluation. Thin CT slices facilitateaccurate identification of each seed, which canbe difficult when the number of seeds exceeds100. The actual dose distribution throughoutthe tumor and normal tissues are generated.This final step is important in order tocorrelate clinical outcomes with the delivereddose distribution. Only by undertaking thisevaluation can ongoing refinement andprogress be achieved.

ResultsTo date, low dose rate brachytherapy

has not been subjected to prospectiverandomized trials; therefore, most data islargely retrospective and single-institutionderived. Monotherapy results generated fromthe Seattle53 experience indicates 5-year localcontrol rates of 97%, which appear equivalentto those of radical prostatectomy and radicalexternal beam radiotherapy. 10-year diseasefree survival data from the same institutionconfirms similar results to published surgicalseries.54 Morbidity such as rectal injury(bleeding, ulceration, stricture), incontinenceand impotence also appear acceptable when

Figure 1. Modern transperineal seed implantation

(Reprinted from Grimm PD, Blasko JC, Ragde H, et al.

Does brachytherapy have a role in the treatment of

prostate cancer? Hematol Oncol Clin North Am. 1996;

10:653.)

14

compared to other treatment modalities suchas surgery. Rectal injury rates as reported inthe Seattle55 series were consistently below2%. Incontinence rates in the same seriesdemonstrated an actuarial incontinence rate of48% at six years for those patients undergoingthis treatment following previous surgicaltrans-urethral resection of the prostate.Incontinence rates for those cases who had notundergone this procedure were in the order of0.5%. These data therefore impactsignificantly in the selection of patients forthis form of treatment. Potency maintenancerates vary with age; for men over the age of 70the data suggest total impotence rates of 30%and partial impotence rates of 20%.

Low dose rate permanent seedbrachytherapy is challenging other treatmentmodalities. For early stage, low volume, lowGleason score cases, monotherapy is nowrecommended as the treatment of choice bymany clinicians. In advanced disease,brachytherapy as a boost dose in a combinedregimen is offering comparable if not betteropportunities for tumor control andsignificantly lower morbidity and toxicity inthe appropriately selected patient.

High Dose Rate Temporary NeedleBrachytherapy

HDR temporary brachytherapyimplants using 192Ir are characterized by doserates in excess of 100Gy/hour. At these doserates, normal cells within the high dose region(and beyond) do not have the capacity torepair radiation damage when the total doseapproaches the clinical threshold dose fortumor control. To maximize the therapeuticwindow and exploit differential cell repairkinetics within normal and malignant cells,HDR treatments are fractionated (the totalclinical dose is divided into 3 or 4 equalfractions). Fractionation allows multiple sub-lethal doses to be delivered with a refractoryperiod of between 6 and 8 hours between

fractions. The refractory period is sufficientfor normal cells to begin to repair sub-lethaldamage before the next dose of radiation. Aspreviously described, repair in malignant cellsis not as efficient or effective, and the damagebecomes cumulative. Over the course of 3 to 4fractions, the therapeutic window is achievedas malignant cell kill exceeds that of normalcells.

The clinical application of HDRtemporary needle brachytherapy is verysimilar to that described for the LDRpermanent technique. While LDRmonotherapy is offered for early stage (T1/T2)disease, the main application for HDRtemporary brachytherapy is in the combinedand combined/hormonal approaches for laterstage disease (T2/T3/T3c). These combinedstrategies are gaining favor as cliniciansattempt to escalate the absolute dose withinthe prostate to higher levels than previouslyachievable.

Interest in high dose rate temporaryneedle brachytherapy grew from ongoingconcern and criticism associated with thesuspect dosimetry inherent in the low doserate permanent implant technique. Despiteongoing technical refinements, manyclinicians remain concerned that inadequatedose throughout the gland as a result of sourceplacement variability and migration may havean adverse clinical outcome.

Clinical AdvantagesHigh dose rate temporary needle

brachytherapy theoretically remedies theinadequacies of permanent seed implants byutilizing plan optimization functionsassociated with the stepping source dosimetryfunction. Temporary hollow needles becomethe conduit for the high activity 192Ir source (>10 Ci), which is remotely driven and loadedinto each needle. This small source,approximately 1mm in diameter and 5mm in

15

length, progresses along the needle inpredetermined steps (stepping sourcedosimetry). The treatment unit, known as aremote afterloader, advances the single highactivity source into and through eachtreatment needle according to the calculationmodel. Movement of the source within eachneedle is driven by the unit to set positions(known as dwell positions) and forpredetermined times (known as dwell times).A combination of dwell position and dwelltime within each implant needle results in ahighly conformal dose matrix. Recentdevelopments with sophisticated modelingsoftware have enabled the brachytherapy team(Radiation Oncologist, Urologist, RadiationTherapist, Physicist) to construct customizeddose distributions, cognizant of all normaltissue constraints. High dose ratebrachytherapy is delivered only after theimplant needles are in-situ and all modeling iscomplete.

The ability to plan and delivertreatment in a controlled environment hasseveral advantages over LDR seedimplantation. First, treatment planning andmodeling occurs immediately followingneedle placement; dose variation throughoutthe gland is controlled. No part of the glandneed be under or overdosed. Secondly, theoptimizing functions enable the team togenerate a unique dose distribution, whichtightly conforms to the shape of the externalprostate contour. This conformal dosedistribution minimizes dose to surroundingstructures. Thirdly, the ability to differentiallydeliver dose, such as higher doses toperipherally located bulky tumor, or lowerdoses to the central prostatic urethra makesHDR brachytherapy even moreadvantageous.56

Advances in stepping sourcetechnology not only supports the preciseplacement of the source within the implant

matrix, it also greatly reduces occupationalexposure to radiation. No source handlingoccurs with HDR brachytherapy; sourcemovement is controlled remotely, andtreatment occurs in a shielded environment.This is significantly different from thesituation with LDR permanent implants,where the sources are manually inserted andsome degree of occupational exposure toradiation occurs. Despite significantinfrastructure costs associated with buildingand capital equipment works, which canexceed millions of dollars, the benefits ofHDR remote afterloading brachytherapy interms of reduced occupational exposure toradiation are well documented.

In addition to the benefits of sourceplacement accuracy and remote afterloading,the physical property of the 192Ir sourceovercomes significant concerns regarding theeffect of dose rate on cell viability. Dose ratesin excess of 100Gy/hr with HDR treatmentsare well above the threshold described by Hallfor radiation damage repair. High Gleasonscore tumors therefore remain eminentlysuitable for a HDR approach.

Clinical DisadvantagesWhile the dose rate effect described

above can provide advantages in the clinicalsetting, clinicians must be mindful of highdose rate effects on adjacent normal tissues.The risk of damage to normal tissues is relatedto the amount of dose delivered at any onesession, the number of sessions per day andthe inter-session interval (refractory period).With LDR brachytherapy, normal tissuesimmediately adjacent to the conformal dosedistribution display some radiation repairresponses. Sub-lethal damage in these cellscan be simultaneously repaired in the presenceof ongoing irradiation. With HDRbrachytherapy this repair is not possible, sotreatment must be delivered in finitecalibrated doses which must not exceed the

16

repair threshold of normal cells. For thisreason, HDR brachytherapy must befractionated; the total dose must be deliveredin small equal fractions allowing sub-lethalrepair in normal tissues.

Single LDR permanent implantscommonly translate into approximately threeto six separate HDR treatments if tumorcontrol and normal tissue toxicity is equated.Clearly then, HDR brachytherapy becomessignificantly more labor intensive and lessappealing to patient and clinician alike. Theprospect of four repeated HDR temporaryimplant procedures could have condemnedHDR brachytherapy to an early departurefrom the clinical arena. Fortunately, ongoingclinical research in the radiobiologicalsciences indicated that multiple treatmentscould be delivered per day. Analysis of cellrepair kinetics suggested that sub-lethalrepair in normal cells in the near high doseregion should be complete within 6 hours.This theory is evident in HDR protocolstoday, where typically four HDR prostatebrachytherapy sessions are conducted overtwo consecutive days, with the intervalbetween fractions being no less than sixhours. This regimen involves only onesurgical, imaging and dose calculationprocedure and four relatively simple andquick treatments over 36 hours (needles areleft in-situ between treatments).

Selection Criteria for TherapeuticAdvantage – Control Vs Morbidity

The recognition of factors that applyfor LDR brachytherapy equally applies in theHDR brachytherapy setting; disease stage,volume, grade, Gleason score and presentingPSA readily impact on protocol design. WhileHDR monotherapy is offered by someclinicians, the overwhelming application is inthe combined strategies where biochemicalcontrol in advanced disease is thepredominant aim.

Technique DescriptionThe HDR temporary implant

technique bears many similarities to thosedescribed in the LDR section. Generallyhowever, sophisticated pre-planning is notrequired as implant quality is assured by bothhardware and software applications.

The implant phase occurs in theOperarting Room (OR), where closed-endhollow needles are introduced trans-perineally into the prostate under directultrasound control. Usually 11-18, 20cm,1.9mm diameter needles are required toadequately implant the prostate. Templatesare used to assist with accurate andexpeditious needle placement. Concurrentimaging with fluoroscopy and cystoscopyensures the prostate is adequately implanted(see figure 2).

Figure 2. Setup in the OR with the patient draped in the

litothomy position, with fluoroscopy unit and

transrectal ultrasound probe in the rectum attached to

the perineal template. (Reprinted with permission from

Nag S, Pak V, Blasko J, Grimm PD. Brachytherapy for

prostate cancer. In Nag S, ed. Principles and Practice of

Brachytherapy. Armonk, NY: Futura Publishing

Company Inc, 1997:425.)

17

Postoperative CT and or ultrasound imaging isused to identify needle positions as well as theprostate capsule, rectum, bladder and urethra(see figure 3).

Figure 3. CT Image showing trochars (black dots)

placed by TRUS guidance. (Reprinted with permission

from Rodriguez RR, Demanes J, Alteri GA. High dose

rate brachytherapy in the treatment of prostate cancer.

Hematol Oncol Clin North Am.

These data are used in the implantoptimization process, the benefits of whichhave been described. In the optimizationprocess, software algorithms perform iterativecalculations throughout the identified targetvolume, to achieve the desired dose matrix.Using stepping source technology, the systembuilds highly conformal dose patterns thatattempt to satisfy all set criteria. Typicalcriteria57 for the HDR brachytherapy phasealone includes

• Tumor (mean peripheral gland dose) =4 fractions of 4Gy to 5Gy over twoconsecutive days, minimum inter-fraction interval of 6 hours. Martinezat the William Beaumont Hospitalemploys 3 HDR fractions of 5.5Gy.58

• Rectum (anterior rectal wall)= 70-75% of tumor dose

• Urethra (periprostatic urethra)=115–130% of tumor dose

Moderate beam external beamradiotherapy either precedes or follows thebrachytherapy. Typical external beamregimens deliver between 45Gy and 50Gy in25 to 30 daily treatments. Martinez uses anexternal beam dose of 45.6Gy to complimentthe 3 HDR brachytherapy fractions.

ResultsHigh dose rate brachytherapy as a

boost in conjunction with moderate doseexternal beam radiotherapy to the prostate ischallenging conventional stand alone surgicaland radical external beam therapies. Mate59

describes comparable results to surgery forlow volume tumors presenting with initialPSAs of less than 10 ng/ml. For bulkiertumors indicated with initial PSAs of 10-20ng/ml, the results appear significantly superiorto radical external beam radiotherapy.European data confirms these results,indicating that combined HDR temporaryprostate brachytherapy is well tolerated andvery effective as a definitive treatment forprostate cancer.60

CONCLUSIONBrachytherapy is an effective

treatment for localized prostate cancer.Reducing the volume of normal tissueirradiated to a high dose permits furtherescalation of the dose within the prostate. Inthis setting, brachytherapy offers an equivalentor improved opportunity for biochemicaltumor control with a well tolerated costeffective treatment possessing a lower risk ofincontinence, impotence and rectal injury inthe appropriately selected patient.

18

REFERENCES

1. NCI Surveillance, Epidemiology andEnd Results Program, 1998.

2. Blasko JC, Ultrasound Guided LDRBrachytherapy for Prostate Cancer. In:Speiser BL and Mould RF editors.Brachytherapy for the 21st Century. TheNetherlands, 1998, 169-180.


4. Mamaghan H. Prostate cancer and PSAscreening. Australian Family PhysicianVol. 28, No.8, August 1999: 777-781.

5. Beyer DC, Ultrasound Guided LDRBrachytherapy for Prostate Cancer. In:Speiser BL and Mould RF editors. hbg.The Netherlands, 1998, 188-197.

6. Small EJ. Prostate Cancer. CurrentOpinion in Oncology 1997, 9:277-286

7. Small EJ. Prostate Cancer. CurrentOpinion in Oncology 1997, 9:277-286

8. Newman J, Rolfo A, Recent Trends inProstate Cancer and BrachytherapyTreatment. Radiation Therapist, Fall. Vol8, No 2. 1999;147-172.

9. Newman J. Epidemiology, diagnosis andtreatment of Prostate Cancer. RadiolTechnol. 1996;68:39-64.

10. Newman J. Epidemiology, diagnosisand treatment of Prostate Cancer. RadiolTechnol. 1996; 68:39-64.

11. Gleason DF. Classification of ProstaticCarcinoma. Cancer Chemotherapy Rep1966; 50:125-128.

12. Newman J. Epidemiology, diagnosis andtreatment of Prostate Cancer. RadiolTechnol. 1996;68:39-64.

13. Chodak GW, Schoenberg HW. Progressand problems in screening for carcinoma ofthe prostate. World J Surg. 1989;13:60-64.

14. Ekman P, Adolfsson J, Gronberg H. Thenatural history of prostate cancer. In:Kaisary AV et al (eds.). Textbook ofProstate Cancer: Pathology, Diagnosisand Treatment. London, England: MartinDunitz; 1999:1-6.

15. Ekman P, Adolfsson J, Gronberg H. Thenatural history of prostate cancer. In:Kaisary AV et al (eds.). Textbook ofProstate Cancer: Pathology, Diagnosisand Treatment. London, England: MartinDunitz; 1999:1-6.


17. Han, M; Walsh, P C; Partin, A W;Rodriguez, R. Ability of the 1992 and1997 American Joint Committee onCancer staging systems for prostate cancerto predict progression-free survival afterradical prostatectomy for stage T2 disease.The Journal of Urology, Volume 164,Issue 1 July 2000: 89-92

18. Petrovich Z, Lieskovsky G, LangholzB, Formenti S, Baert L, Streeter L,Skinner D. Radical prostatectomy andpostoperative irradiation in patients withpathological stage C (T3) carcinoma of theprostate. Int J Radiat Oncol Biol Phys 40,1998: 139-147.


19


21. Landis SH, Murray T, Bolden S, WingoPA. Cancer Statistics, 1999. Ca Cancer JClin. 1999; 49:8-31.

22. Boyle P, MaisonneuveP, Napalkov P.Geographical and temporal patterns ofincidence and mortality from prostatecancer. Urology. 1995;46:47-55.

23. NCI Surveillance, Epidemiology and EndResults Program, 1998.


25. Catalona WJ, Smith DS, Ratliff TL, et al.Measurement of PSA in serum as ascreening test for prostate cancer. N Engl JMed. 1991; 324: 1156-1161.

26. Catalona WJ, Ritchie JP, Ahmann FR, et al.Comparison of digital rectal examinationand serum prostate specific antigen in theearly detection of prostate cancer: resultsof a multicenter clinical trial of 6630 men.J Urol 1994; 151:1283-1290.

27. Catalona WJ, Ritchie JP, Ahmann FR, et al.Comparison of digital rectal examinationand serum prostate specific antigen in theearly detection of prostate cancer: resultsof a multicenter clinical trial of 6630 men.J Urol 1994; 151:1283-1290.

28. Mamaghan H. Prostate cancer and PSAscreening. Australian Family PhysicianVol. 28, No.8, August 1999: 777-781

29. Mettlin CJ, Murphy GP. Why is theprostate cancer death rate declining in theUnited States? Cancer 1998; 82:249-251.

30. Mamaghan H. Prostate cancer and PSAscreening. Australian Family PhysicianVol. 28, No.8, August 1999: 777-781

31. Mate TP, Gottesman JE. HighlyConformal 192Ir Afterloading ProstateBrachytherapy: Pilot Study Follow-Up.In:. Speiser BL and Mould RF editors.Brachytherapy for the 21st Century. TheNetherlands, 1998, 182-187.

32. Hanks GE. Conformal radiotherapy forprostate cancer. Ann Med 2000; 32:57-63.

33. Pilepich MV, et al. Androgen deprivationwith radiation therapy alone for locallyadvanced prostate carcinoma: arandomized comparative trial of theRTOG. Urology 1995; 45(4): 616-23.

34. Kovacs G, Galalae R, Loch T, et al. HDRBrachytherapy for Carcinoma of theProstate: German Experience. In:. SpeiserBL and Mould RF editors. Brachytherapyfor the 21st Century. The Netherlands,1998, 198-210.

35. Zelefsky MJ, Fuks Z, Hunt M, Lee HJ,Lombardi D, Ling CC et al. High doseradiation delivered by intensity modulatedconformal radiotherapy improvesoutcome of localized prostate cancer. JUrology. 2000 Sep; 166(3): 876-81.

36. Pilepich MV, et al. Androgen deprivationwith radiation therapy alone for locallyadvanced prostate carcinoma: arandomized comparative trial of theRTOG. Urology 1995; 45(4): 616-23.

37. Mameghan H. Drug therapy of prostatecancer. Curr Ther 1995; July 27-31.

38. Holm HH. The history of interstitialbrachytherapy of prostate cancer. SeminSurg Oncol 1997 Nov; 13(6): 431-437.

20

39. Newman J, Rolfo A, Recent Trends inProstate Cancer and BrachytherapyTreatment. Radiation Therapist, Fall. Vol8, No 2. 1999;147-172.

40. Whitmore WF, Hilaris B, Grabstalt H.Retropubic implantation of 125I in thetreatment of prostatic carcinoma. J Urol108:918; 1972.


42. Hall EJ. Radiation Biology for thePracticing Oncologist: Seminar Outline –Delivered in Melbourne Australia, Feb 21-23 1997.

43. Crownover RL, Wilkinson A, WeinhouseMS. The radiobiology and physics ofbrachytherapy. Hematol Oncol Clin NorthAm. 1999; 13:477-487.


45. Blasko JC, Ragde H, Luse RW, et al.Should brachytherapy be considered atherapeutic option in localized prostatecancer?. Urol Clin North Am, 1996 Nov;23(4):633-650.

46. Gottesman J, Tesh D, Weissman W. Failureof radioactive 125I to control localizedprostate cancer: a study of 41 patients. JUrol 146:1317, 1991.


48. Hall EJ. Radiation Biology for thePracticing Oncologist: Seminar Outline –Delivered in Melbourne Australia, Feb 21-23 1997.

49. Marchese MJ, Hall EJ. Encapsulated 125I inradiation oncology: II P.L.D.R. andplateau phase cell cultures. Am J ClinOncol 7:613-616, 1984.

50. Blasko JC, Ultrasound Guided LDRBrachytherapy for Prostate Cancer. In:Speiser BL and Mould RF editors.Brachytherapy for the 21

stCentury. The

Netherlands, 1998, 169-180.


52. Stock RG, Stone NN, Deyngaert JK, et al.PSA findings and biopsy results followinginteractive ultrasound guidedtransperineal brachytherapy for early stageprostate carcinoma. Cancer June1, 1999:Vol 77; No. 11.


21

54. Grimm PB, Blasko, Sylvester JE, MeierRM, Cavanagh W. 10-year biochemical(prostate specific antigen) control ofprostate cancer with 125I Brachytherapy.Int Journal Radiat Oncol Biol Phys. 2001Sep 1; 51(1):31-40.



57. HDR Treatment Policy for Carcinoma ofthe Prostate, Division of RadiationOncology, Peter MacCallum CancerInstitute, Melbourne, Australia. Sept 2001.http//www.petermac.org/treatmentpolicies

58. Martinez AA, Edmundson G, Stromberg J.Ultrasound-guided high dose rateconformal brachytherapy boost inprostate cancer: treatment description andpreliminary results of a phase I/II clinicaltrial. Int J Radiat Oncol Biol Phys. August1995, 33(1): 161-71.


60. Kovacs G, Wirth B, Bertermann H, et al.Prostate preservation by combinedexternal beam and HDR brachytherapy atnodal negative prostate cancer patients: anintermediate analysis after 10yearsexperience. Int J Radiat Oncol Biol Phys36, suppl, 198, 1996.

22

QUESTIONS1. The lifetime risk of developing

prostate cancer isa. 1 in 4.b. 1 in 6.c. 1 in 8.d. 1 in 10.

2. Brachytherapy was rediscovered as aviable treatment option for prostatecancer in the a. 1950s.b. 1970s.c. 1980s.d. 1990s.

3. Prostate brachytherapy involves theplacement of radioactive sourcesa. Around the tumor.b. Within the tumor.c. Into the circulatory system.d. Onto the perineum.

4. Brachytherapy has gained clinicalinterest becausea. The tumor is irradiated to higher

doses than is conventionally possible.b. The tumor is irradiated to higher

doses and normal tissues completelyprotected.

c. The tumor receives a uniform dose.d. The tumor is irradiated to higher

doses and normal tissue ispreferentially protected.

5. Which anatomical structure traverses theprostate?a. The prostatic urethra b. The seminal vesiclesc. The bladderd. The rectum

6. The percentage of tumors occurringwithin the peripheral zone of theprostate isa. 75%.b. 70%.c. 50%.d. 20%.

7. In general, well differentiated prostatetumors are recognized as a. Rapidly dividing with a Gleason

score of 7-10.b. Rapidly dividing with a Gleason

score of 2-5.c. Slowly dividing with a Gleason

score of 2-5.d. Slowly dividing with a Gleason

score of 7-10.

8. The reported predictive accuracy rate ofPSA screening alone is approximatelya. 10%.b. 20%.c. 30%.d. 40%.

9. When DRE is added to PSA, thepredictive accuracy rate is approximatelya. 20%.b. 30%.c. 40%.d. 50%.

10. The work of Holm in the 1980s laid thefoundation for brachytherapy todaybecause of developments witha. Transrectal ultrasound and CT

imaging.b. Better sepsis control in the operating

room.c. Discovery of the 125I isotope.d. Transperineal surgical techniques

and transrectal ultrasound.

23

11. The isotope most commonly used inLDR brachytherapy isa. 125I.b. 192Ir.c. 198AU.d. all of the above.

12. Occupational exposure to LDRbrachytherapy is a. Minimal because of the use of

shielding. b. Negligible because of remote

afterloading.c. Excessive and of concern.d. Minimal because of the use of low

energy isotopes.

13. The dose rate effect in LDRbrachytherapy is a concern becausea. Patients remain radioactive for

longer periodsb. Rapidly dividing tumor cells display

synchronous radiation damage repairc. Of questionable ability to impart

damage to rapidly dividing tumorcells

d. Normal cells are unable to repaircellar damage

14. 103Pd is used to counter the dose rateeffect becausea. the dose rate within the matrix is

higher by a factor of approximately 3.b. the average energy is lower (21KeV).c. the half life is shorter (17days).d. the prescribed dose to the implant

matrix is lower.

15. LDR monotherapy is best indicated forwhich type of prostate cancer?a. Stage T2, Gleason score = 2, PSA = 5b. Stage T1, Gleason score = 4, PSA = 10c. Stage T2, Gleason score = 6, PSA = 5d. Stage T1, Gleason score = 4, PSA = 5

16. LDR post implant evaluation isnecessary becausea. Seeds migrate and the actual dose

pattern must be calculatedb. The actual dose pattern can be

correlated with clinical findings c. Correlations lead to ongoing

technical improvementsd. All of the above

17. Interest in HDR brachytherapy grewfroma. Concern over suspect dosimetry with

LDR applications.b. Occupational exposure to radiation.c. The interest in treating later stage

disease in combination with externalbeam radiotherapy.

d. All of the above.

18. HDR brachytherapy addresses theconcerns of source placement variabilityby utilizinga. Stepping source dosimetry.b. Remote afterloading.c. Higher activity source.d. None of the above.

19. Which factors have heralded theresurgence of interest in HDR prostatebrachytherapy?a. Transrectal ultrasound, reactor

produced isotopes, MRI and CTimaging.

b. Transrectal ultrasound, perinealimplantation, dose modelingsoftware and remote afterloadinghardware.

c. Perineal implantation, higher doserate isotopes and dose modelingsoftware.

d. Transrectal ultrasound, dosemodeling software and remoteafterloading hardware.

24

20. What is the role of fractionation in HDRbrachytherapy?a. To increase the likelihood of tumor

control and greater survival.b. To enable treatments to be modified

as the tumor responds to eachradiation dose.

c. To allow normal tissues to repairsub-lethal radiation damage betweenfractions.

d. To fit in with other treatments suchas external beam radiotherapy.

21. HDR brachytherapy is predominantlyindicated as aa. Monotherapy.b. Combined therapy.c. Alternative to surgery for elderly

patients with a life expectancygreater than 10 years.

d. All of the above.

22. Rectal dose in both LDR and HDRbrachytherapy is ideally limited to 75%of the gland dose becausea. Tumor control is likely to be

acceptable as 70% of cancers occurin the peripheral zone.

b. Historical data indicates that thisdose is acceptable.

c. The risk of toxicity such as bleeding,ulceration and stricture is clinicallyacceptable.

d. Tumor control is likely to beacceptable as 20% of cancers arisein the central zone.

23. Results from monotherapy LDRbrachytherapy studies indicatea. Similar results to surgery for early

stage disease.b. Similar results to surgery for late

stage disease.c. Superior results to surgery as

toxicity is less.d. Inferior results to surgery as toxicity

is greater.

24. Results from combined HDRbrachytherapy studies indicatea. Similar results to external beam

radiotherapy (based on IMRT & 3DCRT) for early stage disease.

b. Similar results to external beamradiotherapy for later stage disease.

c. Superior results to external beamradiotherapy as toxicity is less.

d. Inferior results to external beamradiotherapy as toxicity is greater.

25. A patient presents with a T2a tumor.Analysis reveals a Gleason score of 4and presenting PSA of 8. TRUSexamination reveals a well definedhypo-echoic lesion in the peripheralaspect of a gland which measures 65ccin volume. What would be theappropriate management strategy?a. Surgeryb. LDR monotherapy brachytherapyc. HDR combined brachytherapyd. HDR or LDR combined therapy in

association with hormones

Documents

Correspondence Continuing Education Courses For Nuclear … · 2018-12-03 · A. Benefits of Brachytherapy – Preferential Dose Deposition B. Isotopes in Brachytherapy C. Low Dose