20 Prostate Cancer

SECOND EDITION

The GEC ESTRO Handbook of Brachytherapy

PART II: CLINICAL PRACTICE Urogenital Tract 20 Prostate Cancer Peter Hoskin, György Kovacs, Marco van Vulpen, Dimos Baltas

Editors Erik Van Limbergen Richard Pötter

Peter Hoskin Dimos Baltas

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THE GEC ESTRO HANDBOOK OF BRACHYTHERAPY | Part II: Clinical Practice Version 1 - 01/12/2014

20 Prostate Cancer

Peter Hoskin, György Kovacs, Marco van Vulpen, Dimos Baltas

1. Summary 2. Introduction

3 3 4 5 5 6 7 8

9. Treatment planning

10 10 13 14 16 18 18

10. Dose, dose rate, fractionation

3. Anatomical Topography

11. Monitoring

4. Pathology 5. Work Up

12. Results

13. Adverse side effects 14. Key messages

6. Indications and Contraindications

7. Target Volume 8. Technique

15. References

1. SUMMARY

indolent and therefore not clinically significant. The recent PIV- OT trial [2] demonstrated in men with localized prostate cancer that radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. However, subgroup analy- ses did reveal that radical prostatectomy improved all cause mor- tality for patients with a PSA >10 ng/ml and there was a trend for improved all cause survival for intermediate and high risk patients [2]. This study suggests that overtreatment occurs for patients with low risk prostate cancer. Due to the psychological burden of the disease, many patients prefer treatment and will accept potential toxicity. In recent years, there have been signifi- cant improvements in the management of localized prostate can- cer using brachytherapy, external beam radiotherapy or surgery but the optimal treatment remains undefined. In the absence of prospective clinical trials, survival and biochemical control data are difficult to assess and quality of life issues have consequent- ly gained increasing importance in the choice of interventional therapy for individual patients. Brachytherapy has the potential advantages of convenience, effectiveness, and relatively low mor- bidity. has been established in low, intermediate and high risk dis- ease in combination with external beam radiotherapy. HDR brachytherapy alone in prostate cancer is gaining ground with increasing evidence for its efficacy in all risk groups. Recognised side effects include acute urinary outflow symp- toms with a 5-10% incidence of short term catheterization, erectile dysfunction in around 30% and late urethral strictures in 5-8%. Compared to radical prostatectomy brachytherapy results suggest lower incidences of urinary symptoms and erectile dysfunction and compared to external beam radio- therapy very low bowel toxicity and no incidence of second malignancies. New developments in prostate brachytherapy include its use in salvage treatment following relapse in patients who re- ceived prior radiotherapy and focal brachytherapy either as an integrated boost to subvolumes within the CTV or as true focal therapy of localized tumour within the gland.

2. INTRODUCTION Prostate cancer is a disease of ageing men being rare under the age of 45 years but with an incidence which rises with age, post mortem series showing malignant changes in up to 100% of men over 80 [1]. It is more common in urban than rural communi- ties; it has been related to a high fat and meat diet and is more common in married men than never married men. The risk is increased up to three fold in men with a first degree relative hav- ing prostate cancer and there is a five fold risk in carriers of the BRCA-2 gene. Other genetic changes have been identified asso- ciated with prostate cancer of which the most common is meth- ylation of the promoter GSTP1 involved in carcinogen detoxifi- cation. The overall incidence of prostate cancer is rising, partly attributed to an ageing population and increased measurement of PSA levels in asymptomatic men, despite the absence of good evidence to support screening. Especially favourable risk prostate cancer is common in elderly men in developed countries. These cancers are often biologically Brachytherapy is now established as an effective treatment for prostate cancer alongside radical prostatectomy and exter- nal beam radiotherapy. The ultrasound guided transperineal approach has been developed to combine real time imaging of the implantation with one step dosimetry ensuring con- sistently high standards of implant quality which is related to outcome. Brachytherapy has the physical advantage of being able to concentrate a high radiation dose in the target with high conformality minimizing doses to organs at risk. HDR brachytherapy delivered in large doses per fraction also ex- ploits the low alpha beta ratio of prostate cancer delivering very high equi-effective doses in excess of 100Gy (EQD2). Low dose rate permanent implants give best outcomes with low and intermediate risk prostate cancer and in combina- tion with external beam radiotherapy are effective for high risk disease. HDR temporary afterloading brachytherapy

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3. ANATOMICAL TOPOGRAPHY

The prostate surrounds the urethra from the bladder base to its apex, which is near to the external sphincter. It is composed of four regions, the peripheral zones, central zone, transitional zones and anterior fibro muscular stroma zone as shown in fig- ure 21.1. Structures reviewed in the literature all include prostate zonal anatomy (transition zone, peripheral zone, central zone). The central zone surrounds the ejaculatory ducts; the anterior fi- bro muscular stroma is an anterior band of fibro muscular tissue contiguous with the bladder muscle and the external sphincter. The seminal vesicles arise from the superolateral aspects of the gland, and extend posterior to the gland wrapping around the rectum. The normal gland volume is 20 to 30 cm 3 but in mid- dle age benign prostatic hypertrophy (BPH) will develop and the gland volume will slowly increase. BPH typically affects the median transition zone which can cause a compression of the surrounding prostate structures and extending superiorly will indent the bladder base where parts of the bladder muscle converge and merge with the inner longitudinal muscle of the internal preprostatic sphincter. The bladder, bladder neck and internal sphincter are continuous and therefore no demarcation line is visible. This has a very important role in brachytherapy planning, since too high dose in this region may cause sphincter function problems due to late fibrosis. The important anatomical relations of the prostate gland in brachytherapy are to the urethra and rectum. The urethra passes through the gland from the bladder base typically moving at first inferiorly and then looping anteriorly to enter the base of the pe- nis through the urogenital diaphragm. This is illustrated in figure 21.2 which is taken from a transrectal ultrasound volume study using aerated gel to identify the urethra. The external sphincter surrounds the urogenital diaphragm and is easily seen with MR tomography. The cross sectional profile of the urethra also varies along its length. When catheterised it appears a uniform circular tube but in fact it is a crescentic shape expanding as it passes through the gland to the veru montanum where the prostatic ducts enter and then reducing in size as it approaches the uro- genital diaphragm. The rectum lies immediately posterior to the prostate along its entire length. The distance between the pos- terior capsule and anterior rectal wall varies and is a critical di- mension when planning prostate brachytherapy. The rectal wall thickens inferiorly as it becomes the anal canal and approaches the internal anal sphincter. There are three major vascular and neural pathways around the prostate. The first is located posterolaterally and includes the neurovascular bundles (NVB) and courses over the lateral rectal surface and then posteriorly and laterally adjacent to the seminal vesicle and superior prostate. The second pathway is inferolateral and has no contact with the prostate. The anteroinferior pathway is the third, consisting of the dorsal venous plexus coursing over the anterior prostate from the inferior direction. The majority of tumours start in the peripheral zones of the prostate in the posterior and lateral regions, however close his- tological examination of prostatectomy specimens often shows scattered foci of tumour throughout the gland and transurethral resection specimens suggest that up to 85% of cancers will be found in the periurethral region also. The issue of prognostic rel- evance of the zonal anatomy has been reviewed [3]. This identi- fied 64% of cancer involvement only in the peripheral zone and

Fig 21.1: Zonal anatomy of prostate

Fig 21.2: TRUS showing urethral anatomy

8% only transitional zone tumours. Of the remaining 28% of the patients with involvement in both the peripheral and transition- al zones, one third had dominant involvement of the peripheral zone and two thirds of the transitional zone, so the study con- firms the frequent transitional zone involvement in early tumour stages. As the tumour grows it extends into and through the loose cap- sule of fibrous connective tissue, which surrounds the prostate (extracapsular extension-ECE). This may also spread into the seminal vesicles and into adjacent pelvic nodes. This pattern of local extension is reflected in the T staging classification shown in table 21.1. The probability of finding disease outside the pros- tate capsule based on prostatectomy specimens can be related to clinical stage, PSA and Gleason grade as shown in table 21.2. This is an important consideration when evaluating a patient for brachytherapy; those with a high risk of ECE are considered unsuitable for permanent LDR seed brachytherapy and the risk of ECE and seminal vesicle invasion may be taken into account when designing the clinical target volume (CTV) for HDR brachytherapy.

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Table 21.1: T STAGE according to the TNM staging system

Table 21.2: Indications for LDR brachytherapy (ESTRO/EAU/EORTC recommenda- tions 2000 [9])

T STAGE ACCORDING TO THE TNM STAGING SYSTEM

RECOM- MENDED DOWELL

INVESTIGA- TIONAL DO POORLY

OPTIONAL FAIR

4. PATHOLOGY The vast majority of adult prostate malignancies are adenocar- cinomas; other types including transitional cell cancer, duct- al acinar tumour, lymphoma and sarcoma are not suitable for treatment with brachytherapy. Adenocarcinomas are described by their differentiation, using the Gleason grading system. Grade 1 is the most well differentiated and Grade 5 the most poorly differentiated. Tumours are often heterogeneous and it is usual to give a combined score for the two most common appearanc- es, which varies from 2 (1+1) to 10(5+5) In practice today few cancers are graded Gleason 1 or 2 and the lowest grade prostate cancer Is given a score of 3+3=6.. The scoring has a good corre- lation with outcome; low grade tumours with a Gleason score of 6 have excellent cancer specific survival with low probability of metastases whereas Gleason scores of 8 to 10 have a higher prob- ability of developing metastases within a few years of diagnosis. There is also a premalignant entity recognised in the prostate gland which is termed Prostatic Intraepithelial Neoplasia (PIN). This is characterised by malignant cytology but lack of invasion. Unlike other sites such as the bladder and cervix the natural his- tory of PIN is not as well defined; it is thought likely that many cases do eventually progress to invasive prostatic cancer but management is usually by continued surveillance and repeat bi- opsies rather than radical ablative techniques in the absence of invasive components. It is important to realise biopsies are generally performed in a random systematic way, currently 12 core biopsies are consid- ered appropriate [4]. Further, biopsy Gleason score seems to T1: Tumour impalpable detected incidentally. • T1a: Cancer is found incidentally during a TURP in no more than 5% of the tissue removed. • T1b: Cancer is found during a TURP but is in more than 5% of the tissue removed. • T1c: Cancer is found by needle biopsy that was done because of an increased PSA. T2: Palpable on digital rectal exam (DRE) confined to the prostate gland. • T2a: The cancer is in one half or less of only one side of the prostate. • T2b: The cancer is in more than half of only one side of the prostate. • T2c: The cancer is in both sides of the prostate. T3: The cancer is outside the prostate • T3a: The cancer extends through the prostate capsule but not to the seminal vesicles. • T3b: The cancer has spread to the seminal vesicles. T4: The cancer has grown into adjacent tissue such as the urethral sphincter the rectum, the bladder, and/or the pelvic sidewall.

PSA (ng/ml) Gleason score

<10 5-6

10-20

>20 8-10

7

Stage IPSS

T1c-T2a

T2b-T2c

T3

0-8

9-19

>20

Prostate volume (ml)

<40

40-60

>60

Q

(ml.s- 1 )

>15

10-15

<10

max

Residual volume (ml)

>200

TURP

±

±

+

have a poor agreement with prostatectomy Gleason scores, where Gleason 5-6 undergrading occurs in 35%, Gleason 8-10 overgrading in 35% (n=1670) [5]. MRI is another option to eval- uate the GTV location particularly in the anterior gland which might not be detected by biopsies although still it is insufficient to detect all cancers, especially lower grade Gleason 6 tumours. It cannot be used without pathology [6].

5. WORK UP

Prostate cancer is a disease of ageing men and is rarely seen un- der the age of 45 years. Clinical presentation of localised disease may arise in one of two ways: 1) Asymptomatic men who have a PSA blood test either as part of a general health check or at their request as a screening measure, particularly where there is a close family history. 2) Symptoms of prostatic dysfunction. This will most common- ly be due to prostatic enlargement causing urinary outflow symptoms of frequency, urgency and nocturia. Other events may include haematuria, haematospermia and erectile dys- function. Outside the scope of this chapter, other less fortunate patients will present with symptoms of metastatic disease, typically bone metastases. Clinical evaluation should include: 1) A full medical history including comorbidities and evaluation of fitness for brachytherapy. 2) Objective measure of urinary function; the International Prostate Symptom Score (IPSS) is the most common scale used. 3) Objective measure of erectile function; the International Erectile Function Score (IEFS) is one example. 4) Digital Rectal Examination (DRE) to define clinical T stage. Blood tests should include serum PSA alongside a more general evaluation of the patient. There is controversy around the role

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of measuring free and bound PSA ratios; an excess of free PSA over bound is more usually associated with malignancy. Uri- nary PCA3 (Prostate Cancer Gene 3) is a new test now available which is said to have greater specificity for prostate cancer than PSA; it may have a role in screening but for evaluation prior to brachytherapy there is no data to evaluate its role above PSA for selection and prediction of outcome. Diagnosis will usually be confirmed by transrectal ultrasound guided biopsies of the gland. Typically extensive sampling from all four sextants will be undertaken to ensure adequate sam- pling of the gland. However this may miss anterior sections of the gland. Increasingly image guided transperineal biopsy tech- niques are being used to target areas shown to be likely sites of tumour after imaging; these techniques also enable accurate mapping of the cancer throughout the gland. The biopsy samples should be examined by an experienced prostate pathologist; as a minimum the Gleason grade for each biopsy and the presence of perineural invasion should be reported. On transrectal ultrasound malignant tumours of the prostate cause usually hypoechogenity compared to normal prostate tis- sues. The normal prostate has a homogenous echoic structure but large tumours sometimes contain echogenic regions. The dimensions in young men are typically 45 mm in the transverse plane, 35 mm cranio-caudal and 30 mm dorso-ventral with a volume of 18-23 cc. Usually it is easy to define the prostatic part of the urethra, the muscles of the internal sphincter as well the periurethral stroma. They are less echogenic compared to the covering peripheral part of the prostate. In the sagittal planes the ejaculatory ducts and the ampullae of the vas deferens are also readily identified. Hyperplastic adenomas are located most frequently in the tran- sitional zone, seldom in the central zone – but almost never in the periphery of the prostate. On the other hand, 70-80% of ma- lignant tumours origin in the peripheral zone and later can infil- trate the surrounding areas. In regions with cancer involvement the zonal anatomy as well the borders of the prostate are less sharp and areas of cancer infiltration are visible as hypoechoic regions. Following histological confirmation of prostate cancer all pa- tients should have pelvic imaging to refine the clinical stage of the tumour and identify those with gross ECE or seminal vesicle invasion. MRI is vastly superior to CT for this and multi-para- metric MR including T1, T2, dynamic contract enhanced (DCE) and diffusion weighted (DWI) is now considered the gold stand- ard [6]. The role of an isotope bone scan in low risk patients is controversial; the likelihood of bone metastases when the PSA is below 10 and Gleason score is 7 or less is <1% and there is no justification for a bone scan; but as the PSA rises above 10 and in patients with a Gleason score of 8-10 an isotope bone scan should also be undertaken. Where the results of screening with isotope bone scan and MR are equivocal choline PET may have a role in evaluating metastatic disease but is of no value in staging the primary tumour. Conventionally prostate cancer is classified into three risk groups; low, intermediate and high. Several classifications have been described all using serum PSA, Gleason score and T stage. The D’Amico classification is the most widely accepted and shown below:

Low risk: PSA<20ng/ml Gleason 3+3=6 Stage T1, T2a or T2b Intermediate risk: One of the above criteria not met High risk: Two or more of the above criteria not met

6. INDICATIONS AND CONTRAINDICATIONS

6.1 Indications for brachytherapy Selection of patients for brachytherapy will be based upon a number of factors, taking into account the competing options for localised prostate cancer which include active surveillance, radical prostatectomy, external beam radiotherapy and minimal intervention techniques for focal disease using high frequency ultrasound (HIFU) or cryotherapy. In many situations where there is low risk disease the outcomes of treatment in terms of biochemical disease control and survival will be no different and the decision is therefore based on competing morbidities and pa- tient preference. In more advanced disease where prostatectomy is less likely to achieve complete surgical clearance and active surveillance is not indicated then the role of brachytherapy may be in combination with external beam radiotherapy to achieve dose escalation. The indications for the two different brachytherapy techniques, permanent LDR seed brachytherapy and temporary HDR after- loading brachytherapy are different and are discussed below: Permanent LDR seed brachytherapy The indications for LDR prostate brachytherapy have been de- scribed by several guidelines [7][8][9][10]. Patients should have a life expectancy of at least ten years, since in these patients it is not expected that they will die within this period of their pros- tate cancer. The disease should be localised within the prostate capsule, ie stage T1 and T2 and should have low risk factors for ECE according to the Partin tables [11] and there should be no evidence of metastases. The patient should be carefully clinical- ly assessed with regard to possible interference from the pubic arch at implantation and the risks of acute retention after seed implantation. Especially large median lobes are considered a risk [12]. Cytoreduction with androgen deprivation is an option where these risks are considered significant. The relative indica- tions for a seed implant defined in the ESTRO/EAU guidelines [9] are shown in table 21.2: Tumour characteristics: The most significant prognostic features are the presenting PSA, Gleason score and stage. • Low risk patients with a PSA of less than 10, a Gleason score of 6 or less and stage T1C to T2A should do well with brachyther- apy alone. • Patients with a PSA of 10 to 20, a Gleason score of 7 and stage T2B to T2C are at intermediate risk and may also be considered for seed brachytherapy. • High risk patients with a PSA of more than 20, a Gleason score of more than 7 and/or T3 disease do less well and other treat- ments or additional adjuvant therapy may be indicated. Patient characteristics: Patients should be fit enough for a brachytherapy procedure. Functional outcome is related to prostate size, IPSS and history

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HDR afterloading brachytherapy: Monotherapy Currently there is limited mature clinical data from using HDR monotherapy in the literature. The current data suggests HDR monotherapy may have advantages compared to other forms of therapy [16]; however, the results of ongoing studies are awaited. The current literature suggests it may be considered in all risk groups of prostate cancer including high risk disease. HDR monotherapy has also been advocated as a potential sal- vage treatment for local failures after seed implantation, surgery, primary hormonal-, or external beam treatments. In locally recurrent prostate cancer in case of technical eligibility salvage HDR or LDR implantations may be performed but again there is only very limited experience in the literature [16] and this should only be considered by experienced teams within defined protocols. The recommendations of the GEC ESTRO guidelines [17] are shown in table 21.3. Pulsed Dose Rate (PDR) afterloading brachytherapy There is currently limited experience in the use of PDR brachytherapy for prostate cancer. In principle the same indica- tions and contraindications as for HDR brachytherapy will apply. 6.2 Adjuvant hormone therapy Adjuvant hormone therapy has been shown to be of benefit when given with external beam radiation for locally advanced prostate cancer but this has not yet been demonstrated after brachythera- py. The main indication for hormone therapy in relation to LDR brachytherapy is prior to the procedure to reduce the volume of the gland before implantation [18]. When brachytherapy is used as a boost in combination with ex- ternal radiation, it is common practice to prescribe hormonal deprivation for intermediate and high risk patients where there is best evidence for a positive interaction [19]. LDR seed brachytherapy The volume to be treated includes the whole prostate within the confines of the capsule plus a 2 to 3 mm margin. Although the prostate is best visualised with MRI, the volume is usually de- fined by transrectal ultrasound with the patient in the treatment lithotomy position to determine the prostate volume. HDR afterloading brachytherapy Unlike seed brachytherapy for HDR brachytherapy the CTV will be defined after insertion of the needles or catheters. The defi- nition of the HDR CTV is the same as for LDR seeds to include the prostate capsule with a 2mm margin. This will be further extended if there is extracapsular or seminal vesicle disease to include those areas also. A subvolume (CTV2) which includes the peripheral zone of the prostate and maybe other areas in the prostate or periprostatic areas which are involved by the tumour may also be defined as a CTV 3 [17]. Functional imaging in- cluding Doppler sonography, dynamic contrast enhanced CT or MR, MR Spectroscopy or choline PET may be incorporated to enable planning of biological subvolumes which will be desig- 7. TARGET VOLUME

Table 21.3: Indications for HDR brachytherapy combined with external beam radio- therapy

Inclusion criteria Stages T1b–T3b Any Gleason score Any PSA level

Exclusion criteria TURP within 3-6 months Maximum urinary flow rate (Qmax)< 10 ml/sec IPSS > 20 Pubic arch interference Lithotomy position or anaesthesia not possible Rectal fistula

of TURP. Patients with benign prostatic hypertrophy and a large gland volume of greater than 50-60 cm 3 but otherwise suitable, can be downsized with three to six months of neo-adjuvant hor- mone therapy. The volume reduction in general will be between 30 and 50%, hence very large volumes will be excluded unless there is clearly no evidence of pubic arch interference for im- plant. Patients with IPSS <10 will do well after seed implantation, those with IPSS 10-20, have a higher chance of acute retention and patients with IPSS >20 should be offered another treatment modality. Urodynamic studies can further help to select patients who are at high risk for retention. Patients with a history of TURP still can have LDR brachytherapy, but a period of 6 to 12 months to allow for healing should be given. MRI or ultrasound should be used to assess the tissue deficit and where there is a large cav- ity brachytherapy may be contraindicated. This is currently un- der evaluation and new planning protocols to accommodate the TURP cavity have been described [13]. Recent TURP before or after seed implantation is associated with a higher than usual risk for incontinence. HDR afterloading brachytherapy The most common application of HDR afterloading is as a boost in conjunction with external beam therapy, however there is in- creasing interest in its use as monotherapy also. HDR afterloading brachytherapy: Boost High dose radiotherapy alone achieves good rates of biochem- ical control and cure in locally advanced prostate cancer with acceptable levels of acute- and late radiation toxicities [13]. Comparing treatment results of ultra-high-dose IMRT alone to IMRT combined with HDR brachytherapy, the combined treat- ment schedule resulted in improved PSA disease free survival. The greatest advantage of EBRT combined with brachytherapy boost seems to be seen in intermediate-, and high-risk groups of patients [14][15]. Combined external beam radiation and temporary brachyther- apy boost is also effective in low-risk cases but LDR brachyther- apy as monotherapy is as good. Comparing LDR (permanent seed) brachytherapy to HDR (temporary) brachytherapy as a boost complementary to external beam radiation there may also be additional advantages in economics and quality assurance in favour of temporary brachytherapy.

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are different from that of the catheter; whilst this is an acceptable estimate when radiation exposure is completed with the catheter in situ, as in HDR brachytherapy, it will not represent the urethra during prolonged exposure after LDR seed insertion [20]. Bladder base and penile bulb may also be outlined for reporting but at present there is not sufficient evidence to define dose con- straints for these structures. CTV and PTV Whilst previously the CTV was considered to be the same as the PTV it is now recognised that there are a number of uncer- tainties which are not accounted for in definition of the CTV ranging from 5% for HDR to 11% for LDR [21]. These relate to physical parameters such as image definition and registration, catheter reconstruction and source positioning and also changes in the patient with prostatic and periprostatic oedema, varia- tion in bladder filling and bowel position which should be taken into account when planning treatment. This will vary from pa- tient to patient and is also dependent on technique. There will be less uncertainty during HDR, particularly when undertaken as a single step procedure with radiation delivery immediately after implantation in contrast to LDR when radiation delivery occurs over several months. No specific recommendations for this effect can be made; usually the addition of 2-3mm beyond the capsule to define the CTV is considered adequate to account for this but if this is considered the margin required to include all microscopic disease then a further expansion of 2-3mm should be considered for the PTV. Pre-implant preparation: 1. The rectum is cleared with an enema before implantation. Lax- atives may also be given in the preceding days. 2. Evaluation for anaesthetic is required. In some centres spinal anaesthesia will be used whilst others prefer general anaesthe- sia. 3. Where there is an element of outflow obstruction the use of an alpha blocking drug may improve flow both before and after implant. The patient is catheterised to drain the bladder during the treat- ment and to visualise the urethra. It may also be helpful to place air filled gel in the catheter or urethra so that it is more clearly visible on ultrasonography. The transrectal ultrasound probe is inserted and attached to a stepping unit and template (Fig 21.4) as for the volume study (see below). Traditionally image acquisi- tion is by stepping in 5.0 mm Intervals from base to apex of the gland.. Modern devices and planning systems now allow higher resolution with up to 1mm continuous movement of the probe without stepping and with rotational volume acquisitions. In this way a higher accuracy in volume definition and needle place- ment can be achieved. Implant procedure The patient is placed in the dorsal lithotomy position. 8. TECHNIQUE

a. MR image showing CTV 1 (entire prostate); CTV2 (peripheral zone) and CTV 3 (GTV boost)

CTV 1

CTV 2

CTV 3

b. CT image showing CTV 1 (entire prostate); CTV2 (peripheral zone) and CTV 3 (GTV boost)

Fig 21.3: CTV subvolumes for HDR brachytherapy

nated CTV2, CTV3 etc. as in the GEC ESTRO guidelines [17] and shown in Figure 21.3.

Organs at risk The critical organs, urethra and rectum, will also be outlined. The urethra will be defined by the visible intraurethral catheter which remains in situ throughout the procedure; when ultra- sound is used visibility may be enhanced using aerated sterile ultrasound gel. The natural shape and dimensions of the urethra

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a. TRUS, stepper unit showing cradle for ultrasound in position and template holder

Cradle

Template holder

Control wheel for forward and backward movement of cradle

Fig 21.5: TRUS for LDR implant Urethra is placed along row D and the inferior border is within row 1

In the past the volume study was done separately and followed later by the actual implantation, the so called preplanning. A dis- advantage of this technique is the difference in position of the patient, the volume study in this setting often being performed without anaesthesia unlike the implant procedure. One advan- tage of preplanning is to test for pubic arch interference and to exclude those patients with a large volume for whom antiandro- gen cytoreduction is indicated. It also enables the precise num- ber of seeds required to be calculated and is essential if preloaded needles are to be ordered. In most centres today preplanning has been replaced by a ‘one- step’ procedure with the volume study done on the treatment table under anaesthesia directly before the insertion of the nee- dles.This eliminates positional errors, but takes more time in the operating room. Improved implant dosimetry over the conven- tional ‘two stage’ approach has been demonstrated which could translate into improved biochemical control [22][23]. Interactive planning is a further development in which the plan- ning process is performed real time during the insertion of the needles. This is usually based on a preplan and as the needles are placed in position their precise location is mapped with adjust- ments made in the plan as the implant progresses to optimise the actual distribution achieved. The distance from the outer wall of the bladder base to template is determined. This is used as a reference for retraction of the nee- dle tip from the base. The radioactive seeds are inserted through 20 cm long 18 gauge needles. These can either be preloaded or afterloaded once correctly positioned within the prostate. The planned loading pattern indicates the X and Y co-ordinates of each needle, the number of seeds in each needle and the re- traction of each needle tip from the reference base plane for the location of each seed (the Z co-ordinate).

b. Ultrasound positioned on cradle being passed per rectum in preparation for implant

Fig 21.4

8.1 Permanent implants Since intra-operative planning is the most widely used technique and the preplanning technique is not much different, only this technique is described here. To reduce prostate movement during the procedure two or three stabilising needles may be inserted; A volume study is performed in which transverse images of the prostate are taken every 5 mm from base to apex. Superimposed on the ultrasound image is a template matrix. The volume is de- fined on each ultrasound slice (Fig 21.5) and the images are en- tered into a dedicated treatment planning system to determine the exact number and position of seeds required to deliver the prescribed minimal peripheral dose to the margins of the tar- get volume. With many systems 3D images can be acquired for delineation of the prostate contour, resulting in a more accurate prostate volume.

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It is usual to start implantation with the anterior needles in or- der to minimise ultrasound interference during the course of the implant. Each needle is inserted into the preplanned co-ordinate and advanced until it is visible in the ultrasound plane, which is set to define the depth (Z co-ordinate). An alternative way of defining the needle position is by sagital imaging with the ultra- sound probe. With pre-loaded needles, the seeds are immediately deposited in the prostate. With an afterloading technique, either all needles or each row by row is placed in position before the seeds are deposited. The afterloaded seeds can be single seeds as with a Mick applicator or the FIRST system or stranded or linked seeds which are connected to reduce the possibility of seed migration and loss during voiding [24]. There is no firm evidence to show better results with one technique or the other, although one study has shown an advantage with no seed migration seen after the use of stranded seeds [25]. Once the implant has been completed the coverage of the pros- tate can be checked both by ultrasonography and fluoroscopy. With fluoroscopy the number of seeds can be counted to ensure all seeds can be accounted for before leaving the implant area. Cystoscopy can be performed at the end of the implant to re- move any loose seeds. This is not absolutely necessary as it is a rare event and they will usually pass spontaneously and most centres no longer include cystoscopy. The bladder catheter can be removed at the end of the procedure although after spinal anaesthesia it may be preferred to retain it until sensation has returned.. 8.2 Temporary HDR implants Temporary brachytherapy uses implanted applicators (catheters or needles) which are then loaded using the remote control af- terloader. This may be given before or after a course of external beam therapy with no evidence to suggest one approach is better than the other or as monotherapy within a clinical protocol. The principles of transrectal ultrasound pre-planning and needle placement under ultrasound guidance are similar to those used for permanent seed implants [26]. The patient is set up with the TRUS in position and using a stepping frame with a template; the urethral plane is defined along the central row which is then avoided when inserting catheters. The distance between the low- est row of sources and the rectum should be maximised and the this lowest row of catheters should if required cover the semi- nal vesicles. In the majority of techniques rigid needles or plastic catheters are used which are maintained in position by a perineal template. The usual principle of applicator placement to cover the CTV uniformly is achieved by placing applicators at approxi- mately 1cm spacing around the periphery of the gland with a sec- ond inner core to provide dose to the central gland. As with LDR seed implants the periurethral zone will be kept free of seeds. If the seminal vesicles are to be included in the implant then it is important when setting the patient up to ensure that the base row of the template includes these structures. Free hand implanted catheters with the template removed may be used by experienced teams to maximise seminal vesicle and peripheral cover. The first possible source dwell position lies some millimetres from the catheter tip and therefore the tip of the catheters needs

to be pushed well up to the bladder base to make sure that the base of the prostate is adequately covered. This can be monitored by cystoscopy which will demonstrate tenting of the bladder mucosa as the tip of the catheter reaches the base. Others rec- ommend that the catheters pass through the bladder base com- pletely to ensure adequate coverage of the base of the prostate. On completion of the implant imaging is required to define the CTV and the source positions within the catheters. In cases where plastic needles are used, the obturators used for needle insertion and guidance have to be removed prior to final image acquisition for the treatment planning. Imaging may use TRUS with the patient still anaesthetised in the operating room and in lithotomy position [17, 26] or CT/MR following transfer after recovery from the anaesthetic. This data will then be used for the treatment planning process to optimise the dwell positions of the source within the catheters so that the dose to the urethra and rectum can be minimised while at the same time ensuring adequate cover of the tumour with a boost to sites of macroscop- ic disease if they are identified. When multiple fractions are delivered through a single implant the tip of the catheters may move in relation to the bladder base between fractions and it is important that there is a means of ensuring accurate catheter position based on re-imaging before each fraction employing good quality assurance procedures [27]. This may be avoided by using catheters with anchoring wings [28]. After completing the treatment, the needles and any in-vivo dosimetry devices can be removed. This is usually atraumatic with any superficial bleeding readily controlled by a short pe- riod of compression. The urethral catheter can also be removed although occasionally where the catheters are advanced to the bladder base bruising may result in haematuria which requires an additional period of bladder irrigation. Pulsed Dose Rate (PDR) afterloading brachy- therapy The technique for PDR brachytherapy is the same as for HDR brachytherapy using the same range of applicators and afterload- ing equipment.

9. TREATMENT PLANNING 10. DOSE, DOSE RATE, FRACTIONATION

LDR permanent implants Permanent seed implants can be performed either with Io- dine-125, Palladium-103 or Caesiun-131. The half-life of iodine is 59.49 days, 16.991 days for palladium and 9.689 days for cae- sium. Palladium and iodine emit photons of very low energy ra- diation (21 to 28 keV), where caesium emits photons of slightly higher energy (29 to 34 keV) so that radiation protection is eas- ily achieved [29][30]. Palladium and caesium are not popular in Europe, and the vast majority of implants are with iodine seeds. Typical initial seed strengths used for permanent prostate im- plants are in the range of 0.5-1.0 U (0.4-0.8 mCi) for Iodine-125,

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THE GEC ESTRO HANDBOOK OF BRACHYTHERAPY | Part II: Clinical Practice Version 1 - 01/12/2014

145 Gy isodose In yellow

PTV in lilac

urethra

Seed position

Rectal wall

Fig 21.6: Map of needle positions for LDR based on the standard template design with rows designated by letters along the x axis and numbers up the y axis: There are several clinical implantation rules. Place the needles inside the prostate contour and start from the upper rows due to scatter of the needles at ultrasound. Usually 1cm spacing is used on rows and columns and treatment is performed using a checkerboard pattern. The needles should avoid the urethra (red area). There should be no needles in the column including the urethra (red area).

Fig 21.7: LDR dose distribution for 145Gy I125

Table 21.4: Dose volume parameters for LDR brachytherapy

DOSE-VOLUME PARAMETER

DOSE RECOMMENDA- TION 145Gy (100%) for Io- dine-125

PRE-PLAN

POST-PLAN

VOI

Prescription

Yes

yes

V

Yes Yes Yes Yes Yes No No Yes Yes No

yes yes yes yes yes yes yes yes yes yes

≥ 95% ≥ 100% ≤ 50% ≤100% < 200Gy

PTV

100

D

90

V

150

D

2cm³

D

0.1cm³

OAR: Rectum

V V

--- ---

100

150

D D

< 150% < 130%

10

OAR: prostatic urethra

30

D

---

5

and 1.4-2.2 U (1.1-1.7 mCi) for Palladium-103 and 1.6-2.2 U (2.5-3.4 mCi). U is the unit for air kerma strength, 1U = 1 cGy cm² h -1 . Due to the much higher initial dose rate (typically 7 cGy.h-1 for Iodine-125 versus 21 cGy.h -1 for Palladium-103 and more than 30 cGy.h-1 for Caesium-131) and the much shorter half-life, the prescribed dose for caesium is 115 Gy, for palladium is 125 Gy, while for iodine the usual dose at the periphery of the planning target volume is 145 Gy (Fig 21.7) using the AAPM TG43 for- malism. Ninety percent of the treatment dose is delivered within 197 days for iodine, within 56 days for palladium and 32 days for caesium. Technically, the implantation procedure is identical for all three isotopes. According to ESTRO recommendations [31] there is a set of dose-volume parameters for both PTV and OARs which have to be reported and considered for both pre-planning and post-plan-

ning procedures. Table 21.4 summarizes those parameters and the corresponding recommended dose limits [31]. In practice in order to avoid very high dose volumes (above 150% of the prescription dose) the number of seeds in the cen- tre of the PTV is reduced achieving thus a modified peripheral loading pattern (Fig 21.6, Fig 21.7). However, adequate cover- age of base and apex prostate region is mandatory and this can be achieved by placing an inner ring of applicators and loading them only at the base and apex. It is recommended that post implant dosimetry for iodine-125 implants is performed based on cross sectional imaging at 4-6 weeks after implantation [31], although some centres have rec- ommended that post plan dosimetry should be undertaken at 24 hours post implant (32). In the case of palladium-103 implants an optimal imaging time is considered to be 16 days after im- plantation [33].

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Table 21.5: Physical and equi-effective dose values (EQD2) for LDR brachytherapy.

RADIONUCLIDE

INDICES

Iodine-125

Palladium-103 Caesium 131

Prescription Dose (Gy) EQD2 (Gy)

145.0

125.0

115.0

66.2

68.3

58.0-68.7

The radiobiological values for those calculations are taken by the AAPM Report (Table I in Nath et al . [33]): a=0.15 Gy−1, ß=0.05 Gy−2, a/ß =3.0 Gy, Tp=42 days, and repair half-time of 0.27 h. Initial dose rates were 7cGy/h, 21cGy/h and 30cGy/h for 125 I, 103 Pd and 131 Cs sources, respectively.

CT is the usual imaging modality for post-planning due to its wide availability and the excellent resolution for identifying and reconstructing the implanted sources in addition to reasonable soft tissue contrast in the pelvic region. CT imaging is not as re- liable as MRI for prostate and other normal tissue delineation. On the other hand multiple scans are required with MRI for op- timal viewing of tissue and sources. In general, CT overestimates the prostate volume [34]. CT based post-planning should use an axial, 2-3 mm, contiguous image series. When MR imaging is considered for prostate and relevant anatomy delineation a T2 weighted 3mm contiguous image series should be acquired. [31] [33]. Table 21.5 offers representative values for Biological Effective Dose (EQD0=BED) and Biological Equivalent Dose (EQD2) to be delivered in 2Gy fractions assuming homogeneous dose dis- tribution at the corresponding prescribed dose using the formal- ism and parameters as described in [33] for iodine, palladium and caesium sources. HDR temporary implants In contrast to LDR permanent implants where the treatment dose is accumulated over several weeks or months depending on the half-life of the radionuclide used, in HDR temporary im- plants the treatment dose is delivered in fractions each of 10-15 minutes duration (comparable to the dose rate in external beam radiotherapy). Iridium-192 high strength sources (40,3 kU or 10Ci) are the gold standard and are in use with HDR afterload- ers for temporary implants. Some use a Co60 source rather than iridium which having a much longer half-life requires source changes far less often; dosimetry from the two isotopes is com- parable. Ultrasound (US) based implantation guided by the clinical ex- perience of the team is followed by either US-based or CT-based planning and treatment delivery. Currently commercial systems are available allowing an intraoperative 3D-US pre-planning and 3D US-based planning for the final treatment delivery. With such technology patient transfers from implantation to imaging and then to treatment room can be avoided and the whole proce- dure can be realized within an implantation room with adequate shielding for iridium-192 HDR treatments [17], [26]. This ena- bles a total procedure duration comparable to that achieved with permanent seeds implants of 1-2 hours. The current GEC ESTRO recommendations define the CTV as the entire prostate gland defined by the capsule in case of T1 and

Figure 21.8 demonstrates an example of dose distribution and DVHs for a CT-based HDR prostate implant.

Figure 21.9 demonstrates an example of dose distribution and DVHs for a 3D-US-based HDR prostate implant.

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THE GEC ESTRO HANDBOOK OF BRACHYTHERAPY | Part II: Clinical Practice Version 1 - 01/12/2014

T2-disease and extended to include any extracapsular or seminal vesicle extension in T3 disease. Other subvolumes containing areas of macroscopic tumour defined on imaging or template bi- opsies may also be defined and will be designated CTV2 CTV 3 etc. The planning target volume is defined by the CTV1 incorpo- rating a margin for uncertainties typically of 3mm constrained to the bladder base and anterior rectal wall. This can be defined using ultrasound as shown in figure 21.8, CT as shown in figure 21.9, or MRI. The influence of prostate-water-rectal-displacement-kit (PWDK) on the catheter, prostate gland and rectum geometry and do- simetry has been investigated [35]. PWDK enables individual adjustments of water filling for achieving adequate US-image quality and to enable a better accessibility of the prostate gland at its dorsal extend via needles inserted through the template holes. In order to reduce the dose to rectum after the final image ac- quisition and planning either the water in the PWDK is emptied or the whole US-probe is removed. Even when 18-20 metallic needles have been inserted there is a movement of the prostate (probably decompression of the dorsal region) independently of the needles. The needles remain in place but the decompres- sion of dorsal prostate results in increased distance of the dor- sal border from the most dorsally implanted needles. This effect is expected to be most pronounced when the probe as whole is removed and will result in a reduction in the rectal dose.,with uncertainties over the dose delivered and DVH-based values for both CTVs/PTV and rectum itself. The 4D study results for 3D-transrectal ultrasound based treatment planning and treat- ment with unchanged patient positioning and the ultrasound probe remaining in rectum during delivery has demonstrated that under those stable conditions a stability of anatomy and im- plant of such high as 1.0 mm can be achieved during the whole period from planning to delivery [36]. The ESTRO/AAPM re- port [37] shows that under those conditions a total dosimetric uncertainty in the treatment delivery of up to 5% (for k=1) can occur. When treatment planning is based on US, then real-time in- traoperative planning technology utilizing 3D-US offers the best possible workaround for defining target volumes e.g. pros- tate gland (CTV 1) in the presence of needles. More advanced US-imaging technology can help in overcoming partly the diffi- culties of identifying the ventral gland border. There is some potential for biological planning with the use of Doppler sonography or matching of TRUS + MR spectroscopy, functional CT or MR images or 11C-choline PET. Usually, by the use of inhomogeneous dose distributions, about 20-40 % of the CTV1 volume can receive at least double the prescribed dose due to the high inhomogeneity of the dose distribution, this may be exploited in focal therapy. The planning aim doses and the dose prescription for HDR brachytherapy [17] are not fixed after external beam delivering a dose of 45-46Gy in 23-25 fractions. A single dose of 15Gy for CTV1 is increasingly being adopted. However, alternatives in- clude 15Gy in 3 fractions or 11-22Gy in 2 fractions. When HDR is used as monotherapy the following planning aim doses have been recommended: 34-38Gy in 4 fractions, 31-33Gy in 3 frac- tions or 26Gy in 2 fractions [17] Focal prostate brachytherapy Improved imaging using multifocal MR and choline PET to-

gether with transperineal template biopsies now enables the dis- tribution of cancer within the prostate to be defined with some accuracy. Based on this there is increasing interest in focal brachytherapy for low-risk localized prostate cancer rather than conventional whole gland brachytherapy [37][38]. In practice this may take two forms: i) Whole gland treatment with a focal boost to defined dominant lesions, now termed ‘focussed’ treatment ii) Focal therapy to the dominant lesion(s) alone. This may take the form of hemi-gland treatment covering the half gland containing tumour or true focal treatment to the dominant lesion alone. Patient selection and implant technique will be as described above except that for focal implants a CTV 2 will be defined and with LDR a greater concentration of seeds implanted in that area and for HDR additional catheters or needles will be required. So far, focal primary treatment seems safe and feasible, but no long term follow up has been described yet [37]. It is therefore cur- rently an experimental approach and cannot be recommended outside a clinical trial. There are some existing interdisciplinary/ international consensus meeting results and review publications advising enrolling criteria for such prospective investigations [37][39][40]. Patients can be discharged from hospital the same or the follow- ing day after completion of seed implantation and HDR treat- ment delivery. Before the patient leaves the hospital he receives instructions for radiation safety and how to manage voiding problems. Many centres prescribe an alpha-blocker to enhance the urine flow and a week of prophylactic antibiotics. Following HDR brachytherapy there are no radioprotection is- sues however after seed brachytherapy, whilst the dose outside the patient is very low and within radiation safety limits it is usu- al to recommend that for the first two months after implant chil- dren do not sit on the lap of the patient. Occasionally loose seeds migrate through the urethra and these should be picked up using a long handled tool such as a spoon and disposed of through the patient’s sanitary disposal system. For men who resume sexual activity condom use is recommended for the first two months to prevent transfer of seeds to their partner, again a very unlikely event. Cremation can cause contamination of the crematorium and liberate radioactive material into the atmosphere; it is usu- ally therefore recommended that this is not undertaken in the first two years after seed implantation. Written information re- garding the sources, radiation strength, date of implantation and contact numbers should be given to the patient for him to carry with him. After seed brachytherapy patients will usually return at 4 to 6 weeks for post implant dosimetry and clinical review. Subse- quent follow up appointments should be made at least 6 monthly in the first year and annually thereafter. Long term follow up is 11. MONITORING