Prostate Brachytherapy

D Ash, DM Bottomley and BM Carey Yorkshire Regional Centre for Cancer Treatment, Cookridge Hospital, Leeds, LS16 6QB

In recent years there has been an increase in the number of centres, especially in the USA, using prostate brachytherapy as a means of treating localised prostate cancer. Several centres now have medium term follow up data of large numbers of patients treated with this technique suggesting that outcome in terms of tumour control may be comparable to patients treated surgically. This review summarises results from different brachytherapy series and outlines some of the possible advantages of this technique compared with current conventional treatments for localised prostate cancer.

Keywords: prostate cancer; brachytherapy

Introduction New techniques of brachytherapy Like many apparently new developments prostate brachy- In 1981 Holm and Gammelgaard4 described the technique therapy was ®rst attempted many years ago; ®rst by of transrectal ultrasound with template guidance that Pasteau and Degrais1 in 1910 using radium needles and allowed accurate positioning of needles within the pros- then by Flocks et al2 in 1930 with radioactive gold. tate. This was ®rst developed for guided needle biopsy Prostate brachytherapy experienced a renaissance in the but it soon became apparent that similar techniques could early 1970s when the technique of open retropubic Iodine be used to guide radioactive sources accurately into the 125 seed implantation was developed at the Memorial prostate and that this could be done percutaneously Hospital in New York.3 The technique appeared to offer under ultrasound control.5 This has formed the basis of an effective and convenient alternative to radical prosta- new techniques in brachytherapy. This is performed as a tectomy but by the late 1980s had been largely aban- two-stage procedure. The ®rst stage is to use transrectal doned. It is important to analyse the reasons for this ultrasound to de®ne the prostate volume and use the failure because there are valuable lessons to be learned information from the template co-ordinates to plan the when reviewing newly introduced techniques. The main number and position of radioactive sources required to reason for failure was that the manual placement of deliver a homogeneous dose of radiation to the prostate. iodine seeds by the open retropubic technique was dif®- At the second stage the sources are inserted into their cult to perform so that seed placement was frequently pre-planned position in the prostate using a template. suboptimal and resulted in signi®cant hot spots and cold Needles are inserted through the perineal skin as a closed spots within the prostate gland. The problem was com- procedure. pounded by the fact that the early techniques for deter- It is possible to plan the implant from CT data but this mining the distribution and dose of Iodine 125 seeds was tends to over-estimate the volume and can result in more relatively crude and did not have the advantage of sources being placed near the rectal wall with a conse- modern computer algorithms to determine accurately quent increased risk of radiation proctitis. dose distribution. Follow up of patients implanted by The total dose of radiation delivered to the prostate the retropubic technique not only showed morbidity as a and the distribution of dose is determined by a compu- result of inadvertent hot spots but also recurrences which terised software programme. A variety of different pro- became more apparent when regular PSA testing became grammes are available depending on the type of isotope available. There was also a signi®cant contribution to and regime of treatment to be used. morbidity from the open retropubic surgery required for There are essentially two forms of brachytherapy seed placement. In those cases where a satisfactory which are as follows. implant was achieved the results were good but, because it was so dif®cult to ensure the achievement of satisfactory seed placement, the technique was correctly and Permanent implants understandably abandoned. This is the commonest form of prostate brachytherapy Correspondence: Dr D Ash. and several thousand patients have been treated to date. Received 11 September 1997; revised 5 January 1998; accepted For permanent implantation the sources are left within 4 February 1998 the prostate and deliver their radiation over several Prostate brachytherapy D Ash et al

186 weeks or months. Iodine 125 has a half life of 60 d and it is the space of 2 or 3 d or done in two separate applica- usual to prescribe a minimum peripheral dose of 160 Gy tions. With modern afterloading techniques radiation to a volume which includes the prostate capsule plus a 2 exposure is not a problem but because source tubes or 3 mm margin. This means that 80 Gy is delivered in the have to remain within the prostate for the duration of ®rst 60 d and the remainder at decreasing dose rates over the implantation and exit through the perineum they the next 4 ± 6 months. Palladium 103 has a half life of 17 d cannot be tolerated for more than a day or two and it is which is 3 ± 4 times as fast as that of Iodine 125. Palladium usually necessary with these techniques to give most is used by some centres for high Gleason grade tumours of the treatment with fractionated external beam which are thought to be proliferating faster than low radiation and to use brachytherapy as a localised grade ones. There is as yet, however, little data either boost to the prostate. This signi®cantly increases both on the proliferation rate of human prostate cancer or good the duration and cost of the treatment. evidence of improved ef®cacy. Because of the higher dose rate which is more biologically effective a dose rate correction is made for Palladium 103 so that instead of 160 Gy the minimum peripheral dose is reduced to 115 Gy. Indications for and contra-indications to Iodine 125 has an energy of 27±35 KV and Palladium 20 ± 23 KV. The low energy means that there is not much brachytherapy penetration into tissue and this combined with the inverse For Iodine 125 and Paladium 103 permanent seed square law results in the dose falling to less than 50% of implants the selection criteria are similar to selection for the minimum peripheral dose within a few millimetres. radical prostatectomy. Patients who are deemed un®t This therefore provides a signi®cant advantage in terms for prostatectomy may, however, be suitable for brachy- of reduction of dose to adjacent critical structures such as therapy. the rectum and neurovascular bundles but is equally a Selection criteria are broadly as follows: limitation in dealing with disease more than 3 or 4 mm outside the prostate capsule. life expectancy greater than 10 y Successful prostate brachytherapy requires consider- histologically con®rmed adenocarcinoma of prostate able team work and there is a steep learning curve both disease con®ned within the prostate capsule, namely, for implant dosimetry and seed implantation before T1±T2C as con®rmed by transrectal ultrasound and/or acceptable dose coverage is achieved in most patients. endorectal MRI scanning This is in some way similar to the learning curve for no evidence of metastatic disease radical prostatectomy which should successively reduce no TURP the complications and the risk of pathologically positive prostate volume less than 50 cc (for larger prostates resection margins. Both procedures should be done in hormonal manipulation with LHRH analogues Æ centres with specialised expertise. androgen blockers for three months will reduce the The main advantage of permanent implantation is that prostate volume to less than 50 cc). the treatment is completed in a single application which PSA less than 50. The cut off level of 50 is higher than can often be done as an out-patient procedure or with a usually accepted for surgery and will almost certainly single overnight stay in hospital. The disadvantage is the include a proportion of patients whose disease has need to handle live radioactive sources. The radiation extended through the prostate capsule or distantly energy of the sources, however, is so low that exposure to even though diagnostic imaging tests are normal. other persons is negligible with straightforward radiation Results, however, show that a 5 y PSA relapse free protection procedures. survival of 30±40% can still be achieved in such patients and it may be reasonable because of the low morbidity of the procedure to accept patients for brachytherapy rather than external beam radiation. This is, however, Removable implants still an area of controversy. Source carrying needles or tubes are placed in the prostate Staging biopsies may be performed under ultrasound and can be afterloaded with a radioactive source that is control where there is a high risk of extra-capsular then removed on completion of treatment. There are two involvement as predicted by PSA, Gleason grade and potential ways of delivering treatment. stage. Where extra-capsular spread is con®rmed external beam radiotherapy and/or a rigid needle afterloading 1. Continuous Low Dose Rate (LDR) implant is recommended. The source carriers are loaded with low activity For permanent seed implants which deliver a very high iridium wire which delivers a continuous low dose dose of radiation to the urethra patients who have had a rate for the duration of the implant. previous TURP should be excluded because there is a 2. High Dose Rate Implants (HDR) high risk of developing incontinence in this group of With high dose rate treatments a high activity source is patients. The same is not, however, such a problem with used to deliver a pulse of radiation to the prostate. patients treated using other techniques where the central Because larger doses of radiation given at a high dose dose is less. rate are poorly tolerated it is necessary to fractionate For removable implants using rigid source carriers it is treatment with HDR techniques and it is common to possible to extend the indications to T3 carcinomas deliver 4±6 fractions of treatment either separated over because the sources can be held in position outside the Prostate brachytherapy D Ash et al 187 Table 1 Clinical and PSA response following transrectal ultrasound guided I125/Pd103 prostate implant

Series No. of patients Stages Treatment Clinical disease free (%) PSA control (%) Follow (y)

7 a Wallner et al 62 T1b±T2b I 125 90 83 3 8 b Kaye et al 45 T1±T2 I 125 Ð 98 2 9 c Porter et al 97 T1b±T2b Pd 103 95 86 4 10 c Blasko et al 197 T1b±T2b I 125 95 93 5 11 a Stock et al 97 T1b±T2b I 125/Pd 103 Ð 76 2 12 b Beyer and Priestley 465 T1±T2 I 125/Pd 103 83 79 5 aProgression free. bPSA < 4.0. c PSA < 1.0. prostate capsule. This is dif®cult to achieve with seed Beyer and Priestly12 and Blasko et al17 is that between 4 implants which are thus con®ned to T1 and T2 cases. and 8% of patients require minor surgical procedures such as catheterisation or cystoscopy in the post operation period. Proctitis occurs in less than 2% of patients receiv- ing seed implant as the sole treatment. Incontinence Results of brachytherapy occurred in 0±1% of patients in these series when no When evaluating results of any treatment for prostate previous TURP had been performed. cancer it is important to have adequate information on the Where TURP has been performed the incontinence rate distribution of prognostic factors within the population is up to 50%. However, there has been a recent report of 19 patients having had previous TURP, only one of whom treated and for results to include information on survival, 18 local control, incidence of metastases and PSA relapse free developed stress incontinence following seed implant. survival. This low rate of incontinence was attributed to distribut- ing the radioactive seeds at some distance from the The largest body of mature data is from centres who 7,8 have treated T1 and T2 tumours with iodine seed implan- urethra. Early series reported maintenance of potency 7±12 in 81% and 75% of previously potent patients after 2±3 y tation and these are summarised in Table 1. 17 These series show encouraging results in terms of the respectively. Blasko et al reported that 85% of under 70s number of patients who remain clinically disease free at and 50% of over 70s remained potent 3 y after prostate follow up of up to 5 y. PSA control at 2±5 y for the brachytherapy. different series ranges from 76±98%. In all these series it is clear that pre-treatment factors, notably baseline PSA, Gleason grade and clinical stage, are strong predictors of Advantages of radioactive iodine seed subsequent outcome, as would be expected. For higher risk localised prostate cancer, for example, brachytherapy over surgery and external Gleason grade greater than or equal to 7 and/or high beam radiotherapy initial PSA, some centres combine external beam radiation with radioactive seed implant. One series has reported on 73 high risk patients treated with external 1. Convenience beam radiotherapy and a Pd103 boost. These patients had Patients having single modality iodine seed implanta- three year freedom from biochemical failure of 79% at 3 y tion can often have this as an out patient procedure or and, where the PSA was initially less than 15 ng/ml, 87% with a single overnight stay in hospital. The majority were biochemically free of disease.13 At the Northwest are back at work or have resumed normal activity Hospital in Seattle 232 patients have been treated by within a week of their implant. combining external beam radiotherapy with a permanent 2. Cost radioactive seed implant between 1986 and 1994. At 5 y The relative costs of the three procedures depend on 79% of patients showed freedom from biochemical failure the health care system in which they are delivered. The with a disease free survival of 80%.10 best data comes from American Health Insurance With regard to removable implants the published providers.19 These have shown that iodine seed series contains small groups of patients ranging from implants are 25% cheaper than external beam radio- 21±36.14±16 These small series have combined high dose therapy and 50% cheaper than radical surgery. These rate prostate brachytherapy with external beam radio- costings only include the direct costs and do not therapy. Local control after short follow up periods include the added indirect costs to the patients which ranged from 76 ±92%. may be related to the costs of attending for daily radiotherapy and those related to prolonged periods away from work. 3. Low morbidity Complications The low incidence of incontinence, rectal complications and high preservation of potency compare well with Patients commonly experience obstructive and irritative surgical and external beam radiotherapy series. urinary symptoms following prostate brachytherapy. Late 4. Applicability complications appear to be low and the experience of Brachytherapy can be used in patients who are not ®t Prostate brachytherapy D Ash et al 188 for radical surgery and can also be used for patients References who are not suitable for radical external beam radiation because of problems relating to the presence of 1 Pasteau O, Degrais P. De L'emploi du radium dans le traitement bowel within the radiation ®elds, particularly in des cancers de la prostate. J Urol Med Chir 1913; 4: 341±366. patients with in¯ammatory bowel disease. 2 Flocks RH, Kerr HD, Elkins HB, Culp D. Treatment of carcinoma of the prostate by interstitial radiation with radioactive gold-198; 5. Effectiveness a preliminary report. J Urol 1952; 68: 510 ±522. In terms of PSA freedom from progression, prostate 3 Whitmore WF, Hilaris BS Grabstald H. Retropubic implantation brachytherapy results appear equivalent to those of of Iodine 125 in the treatment of prostatic cancer. JUrol1972; 108: radical prostatectomy when strati®ed by initial 918 ±920. PSA.20,21 Freedom from PSA progression appears infer- 4 Holm HH, Gammelgaard J. Utrasonically guided precise needle ior for patients treated with external beam radiother- placement in the prostate and seminal vesicles. J Urol 1981; 125: 385 ±387. apy compared to prostate brachytherapy. However 5 Holm HH, Juul N, Pedersen JF. Transperineal 125 Iodine seed these series did include patients with T3 prostate implantation in prostatic cancer guided by transrectal ultrasono- cancer.22,23 graphy. J Urol 1983; 130: 283±286. 6 Partin AW et al. Re: the use of prostate speci®c antigen, clinical stage and Gleason score to predict pathological stage in men with localised prostate cancer. JUrol199; 151(1): 172±173. Can the results of treatment with 7 Wallner K et al. Short-term freedom from disease progression after I-125 prostate implantation. Int J Radiat Oncol Biol Phys 1994; different techniques be reasonably 30: 405 ±409. 8 Kaye KW, Olson DJ, Payne JT. Detailed preliminary analysis of compared? 125-Iodine implantation for localised prostate cancer using per- cutaneous approach. JUrol1995; 153: 1020 ±1025. There are unfortunately no large randomised trials com- 9 Porter AT et al. Brachytherapy for prostate cancer. Cancer J Clin paring different treatments for localised prostate cancer or 1995; 45: 165±178. treatment v a watch and wait policy. There are, however, 10 Blasko JC, Grimm PD, Ragde H. Prostate speci®c antigen based many observational studies of different treatments but disease control following ultrasound-guided I-125 implantation care is needed when analysing these in view of possible for Stage T1/T2 prostatic carcinoma. J Urol 1995; 154: 1096 ±1097. confounding factors that will affect outcome. 11 Stock RG et al. Prostate speci®c antigen ®ndings and biopsy results following interactive ultrasound guided transperineal (a) Patient selection factors brachytherapy for early stage prostate carcinoma. Cancer 1996; The most important are the age of the patient at 77(11): 2386 ±2392. 12 Beyer DC, Priestley JB. Biochemical disease-free survival follow- treatment, general ®tness and the presence of other ing I-125 prostate implantation. Int J Radiat Oncol Biol Phys 1997; co-morbidities. In general, surgical series contain 37(3): 559±563. younger patients with fewer coexisting medical 13 Dattoli M et al. 103Pd brachytherapy and external beam irradia- problems as compared to series of non-surgical treat- tion for clinically localised, high-risk prostate carcinoma. Int J ment. Radiat Oncol Biol Phys 1996; 35(5): 875±879. (b) Tumour factors 14 Stromberg J et al. Ultrasound-guided high dose rate conformal brachytherapy boost in prostate cancer: treatment description Patients need to be matched for the major prognostic and preliminary results of a phase 1/11 clinical trial. Int J factors which are Gleason grade, initial PSA and Radiat Oncol Biol Phys 1995; 33(1): 161±171. tumour stage and the presence or absence of positive 15 Prestidge BR et al. Ultrasound guided placement of transperineal pelvic nodes. Surgical series tend to exclude patients prostatic afterloading catheters. Int J Radiat Oncol Biol Phys 1994; who are found to have positive nodes at laparotomy 28: 263 ±266. but this is rarely the case for series of patients treated 16 Reddy EK et al. Iridium-192 template therapy for localised by external beam radiation or brachytherapy. Surgery prostate cancer. Endo-Hyperthermia 1994; 10: 125±129. 17 Blasko JC, Grimm PD, Ragde H. Brachytherapy and organ also tends to select patients with lower initial PSA. preservation in the management of carcinoma of the prostate. (c) Outcome analysis Sem Radiat Oncol 1993; 3(4): 240±249. When comparing results of treatment the same out- 18 Wallner K. Low risk of urinary incontinence following come indices should be used and should include prostate brachytherapy in patients with a prior transurethral overall survival, local recurrence rates, metastasis prostate resection. Int J Radiat Oncol Biol Phys 1997; 37(3): 565±569. rate, PSA relapse free survival, complications, mor- 19 Blasko JC. Personal communication 1996; 20 Partin AW et al. Serum PSA after anatomic radical prostatectomy. bidity and patient derived quality of life data. The John Hopkinson experience after ten years. Urol Clin 1993; 20: 713 ±725. 21 Kupelian P et al. Correlation of clinical and pathological factors Conclusions with rising prostate-speci®c antigen pro®les after radical prostatectomy alone for clinically localised prostate cancer. Urology Where it has been possible to control for confounding 1996; 48: 249±260. factors brachytherapy appears to perform at least as well 22 Zietman AL. Radical radiation therapy in the management of as either surgery or external beam radiotherapy. Because prostatic adenocarcinomas: the initial prostate speci®c antigen value as a predictor of treatment outcome. J Urol 1994; 151: of its side effect pro®le, convenience and cost, brachy- 640±645. therapy should therefore be made available as an option 23 Zagars ZK. Prostate-speci®c antigen and radiation therapy for for patients with localised carcinoma of the prostate clinically localised prostate cancer. Int J Radiat Oncol Biol Phys where local treatment is deemed appropriate. 1995; 32: 293±306.