High Dose Rate Brachytherapy(HDR BT) in Organ Confined Prostate Cancer

Review Article

HIGH DOSE RATE BRACHYTHERAPY(HDR BT) IN ORGAN CONFINED PROSTATE CANCER P Mahadev, L S Ravishankar, P G G Kurup,V Murali, Jayraj and Bhagyam Department of Radiation Oncology,Urology,Medical Physics,Radiology, Apollo Speciality Hospital, 21, Greams Lane, Chennai 600 006, India. Brachytherapy is one of the curative treatment for early stage prostate cancer.HDR BT has normally been used in combination with external beam radiotherapy.There has been considerable interest in the recent years in HDR BT as monotherapy. HDR BT was started at Apollo Speciality Hospital,Chennai in April 2006. This article briefly describes and compares the treatment alternatives of surgery, external beam radiation, and brachytherapy for prostate cancer and highlights the advantages of HDR brachytherapy Keywords: Prostate cancer; Radiotherapy; Brachytherapy; High-dose-rate; Monotherapy

THE number of early prostate cancers detected in India has been gradually increasing and as per some of the tumor registries prostate cancer is now sixth in incidence rate among men in India. Possible reasons could be the increased longevity of the population and increased awareness leading to consult a doctor at an earlier stage. Prostate cancer screening is not yet very popular in India and hence the reported incidence may actually be higher. Treatment options for organ confined prostate cancer include:

deciding the optimal treatment.

(a) Watchful waiting,

Intermediate Risk

(b) Radical prostatectomy, (c) External beam irradiation-3D Conformal Radiotherapy (3D CRT, Intensity Modulated, Radiotherapy (IMRT), Image guided Radiotherapy (IGRT) (d) Brachytherapy-LDR (low dose rate), HDR (high dose rate) (e) Hormonal manipulation with or without Radiotherapy. This article briefly describes and compares the treatment alternatives of surgery, external beam radiation, and brachytherapy for prostate cancer and highlights the advantages of HDR brachytherapy. Surgery and Radiotherapy give equally good results in early prostate cancer. Among these modalities, Brachytherapy is probably the most conformal treatment with high rates of local control with good patient compliance, low morbidity and cost effective. Prostate cancer patients are normally categorized into low risk, intermediate risk and high risk category for Apollo Medicine, Vol. 5, No. 3, September 2008

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Low Risk PSA less than 10, and Gleason score less than or equal to 6 (3 + 3), and Tumor stage T2b or less (tumor on one side of gland, or not felt)

PSA 10 to 19.9, or Gleason 7, or Stage T2c (tumor felt or seen on both sides of gland) High Risk PSA 20.0 or higher, or Gleason 8 to 10, or Stage T3a or worse (tumor felt extending beyond prostate) SURGERY Radical prostatectomy is surgery designed to remove cancer in the prostate and seminal vesicles. It may be performed through a conventional surgical incision or with a robotic device that uses small scopes inserted through the abdominal wall (robotic prostatectomy). Surgery is associated with significant risks of urinary incontinence and erectile dysfunction. Nerve-sparing operations reduce the incidence erectile dysfunction, but they should be performed only when there is a high probability that this approach will not compromise complete tumor removal.

Review Article

EXTERNAL BEAM RADIATION THERAPY As the name indicates, external beam radiation involves the delivery of radiation from outside the body into the prostate. Standard external-beam linear accelerator therapy has historically been given with doses of 65-70 Gy with limited success. The advent of computer-assisted threedimensional treatment planning, however, made it possible to deliver higher and more effective doses (75-78 Gy) to the prostate but with higher rectal doses and, consequently, more rectal complications. A further technology refinement called intensity-modulated radiation therapy (IMRT) and later on Image guideded radiotherapy(IGRT) was subsequently developed to modulate the intensity of the beam and improve control of the target shape. Therefore, IMRT can selectively deliver higher radiation doses to the prostate and give lower doses to the bladder and rectum. Proton external beam radiation is another form of advanced external beam technology with precise targeting of the prostate cancer5. The problems with highly targeted external-beam radiation, however, are (i) variable day-today targeting accuracy due to patient set-up and organ motion, (ii) deposition of radiation into normal tissue before it gets to the target, and (iii) the fact that none of the externalbeam delivery systems have achieved the same high tumor dose, or offer as fine a level of dose distribution control within the prostate as brachytherapy. BRACHYTHERAPY

rate (HDR) temporary brachytherapy (Fig. 1). Both techniques are used either in conjunction with external beam radiotherapy or as monotherapy. However, 192 Ir HDR brachytherapy is usually used to deliver a boost to external beam radiotherapy while 125I seed implants are more commonly used as single modality treatment, restricting its application to early stage prostate cancer Permanent seed implants involve placing under ultrasound guidance, approximately 100 radioactive seeds into the prostate gland. They give off their radiation at a low dose rate over several weeks or months, the seeds remaining in the prostate gland permanently. There are four basic steps to HDR brachytherapy (Fig. 2). They are (i) image-guided applicator insertion, (ii) image acquisition of the completed implant (simulation) (Fig. 3), (iii) dose distribution calculations (computerized dosimetry), and (iv) treatment delivery. It involves placing very tiny plastic catheters into the prostate gland under transrectal ultrasound guidance, and then giving a series of radiation treatments (3 to 6, usually over 36 hours) through these catheters after CT based treatment planning (Fig. 4). The catheters are then easily pulled out, and no radiactive material is left in the prostate gland. A computer-controlled machine pushes a single highly radioactive iridium seed into the catheters one by one. Because the computer can control how long this single seed remains in each of the catheters, the radiation dose in different regions of the

Brachytherapy is a potentially curative treatment for prostate cancer. With brachytherapy, most of the radiation dose is delivered to the target and not the surrounding organs because the dose from a source of radiation within the prostate decreases very rapidly (i.e the inverse square law). The result is high tumor control and low complication rates There are two major methods of prostate brachytherapy, permanent seed implantation and high dose

Fig.2. HDR Catheters

Fig.1. Permanent seed 155

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Fig. 3. Illustration of the implant catheters entering the perineum going into the prostate and seminal vesicles

Fig. 4.

CT cross section of the pelvis with implant catheter positions in the prostate and the radiation isodose curves covering the target

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prostate can be easily controlled and optimised. We can give the tumor a higher dose, and we can ensure that the (urethra) and rectum receive a lower dose. This ability to modify the dose after the needles are placed(optimization) is one of the main advantages of HDR brachytherapy over permanent seed implants. With the technological advancement in ultrasound equipment, fixing devices, ultrasound probe carriers, treatment planning systems and the availability of a variety of source configurations, brachytherapy in experienced hands is the treatment of choice of many physicians and even more importantly patients for early prostate cancers. 125-I or 103-Pd low-dose-rate brachytherapy has become a standard treatment option for early prostate cancer. On the other hand, for locally advanced cases, the debate about the role of such brachytherapy is still ongoing. There is as yet no evidence to confirm that combining external beam irradiation (EBI) and such brachytherapy improves outcome [1,2]. The optimal treatment for non metastatic locally advanced prostate cancer is still evolving.For intermediate and high risk category patients, a combination of hormones and Radiotherapy is usually prescribed. HDR brachytherapy can be used as a sole modality of treatment (monotherapy) or is more commonly used as a boost in combination with external beam radiotherapy.A number of studies have been published using HDR as a boost to external radiotherapy [3,4]. Over the past few years there has been considerable interest in HDR brachytherapy as monotherapy and a few studies have been published with excellent results. With HDR monotherapy, a 3-year local control, overall survival and PSA failure free rates have been reported as 100, 97 and 83% with 111 patients with a media FU of 27 months, range 5-119 months [5]. The corresponding 5 year rates are 97, 92 and 70%.Other monotherapy studies have showed similar favourable results [6-8]. ADVANTAGES OF SEEDS Considerable clinical experience has accumulated within the last 15 years with 125 I seed therapy whereas 103 Pd or 131 Cs seed therapy is relatively new. On the other side it is only within the last 5 years that HDR monotherapy has been initiated. Hence it is still too early for a comparison of clinical outcomes. Both the techniques are similar with regards to the use of trans rectal ultrasound. However with post implant dosimetry and optimization methods with a single source, HDR dosimetry is more flexible and accurate. Seeds are very often used without external beam radiation. HDR, on the other hand, is usually combined with 4 - 5 weeks of external beam. A seed implant is cheaper than

HDR + external beam. HDR monotherapy is relatively a new approach.The published results for seeds are generally very good for early stage cancers, with implants done in major institutions with a lot of experience. An excellent seed implant will be similar to an HDR implant in terms of conformality (how well the prescribed radiation dose matches the prostate). BENEFITS OF HDR OVER PERMANENT SEEDS HDR can be used for tiny glands (10cc) as well as big glands (100cc+), following a TURP, and even for treating recurrences after seeds. HDR is probably the most precise way to give radiation to the prostate: more conformal than seeds, protons, IMRT, or 3D EBRT.HDR catheters can be easily placed in the extracapsular tissues and seminal vesicles. This allows HDR to treat stage 3 prostate cancer. Once the HDR catheters are placed, the computer can control the amount of radiation given to each catheter, correcting for catheters that are too close together, too far apart, or too close to the urethra or rectum. This helps prevent radiation hot spots and cold spots, which may occur with permanent seed implants if the seeds are injected too close together or too far apart. The HDR dose can be “sculpted” in the prostate, boosting the dose to the tumor if its location is known, and giving less to the urine passage (urethra) and rectum. By adjusting the radiation dose in each catheter we can put the radiation where we need it. Permanent seeds are irreversible. Once a permanent seed is placed, it cannot be moved, removed, or adjusted in any way, short of doing surgery. HDR catheters can be turned off, advanced, retracted, removed, or added. An HDR implant may even be aborted after the catheters have been placed. Permanent seeds must be ordered in advance, which may cause delays and is more expensive. Permanent seeds can migrate through the bloodstream to the lung, or can be urinated out. There are usually restrictions placed on small children or pregnant women coming close for a time period after having a permanent seed implant because of the radioactivity being released by the seeds. With HDR, no radioactivity is left following the treatments. Recent studies theorize that prostate cancer cells may respond better to the large fraction sizes of HDR, versus the slow release of radiation from permanent seeds. Generally the urinary complications reported are higher with seed implants. Grills [9] reported decreased acute rates of grade 1-3 dysuria with HDR monotherapy (36%) against 67% ( P <0.001) for 103 Pd seed implant. They also noted a reduction in urinary frequency 92% vs. 54% for HDR and LDR techniques (P <0.001). Though urethral stricture of 8% was reported for the HDR group against 3% for LDR group ( P=0.177), 3-year actuarial impotence rate was only 16% in the HDR group, against 45% for the LDR group.

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The clinical results cannot be reliably compared as the HDR patients are generally in the higher risk group with increased PSA and advanced staging.

2. Nag S, Beyer D, Friedland J, et al. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999;44:789-799.

Once the HDR unit is installed, the total cost including source changes can be shared with all HDR treatments. However, the cost of seeds varying in number from 80 to 120, will have to be charged to individual patients.

3. Borghede G, Hedelin H, Holmang S, et al. Combined treatment with temporary short-term high dose rate iridium-192 brachytherapy and external beam radiotherapy for irradiation of localized prostatic carcinoma. Radiother Oncol 1997; 44: 237-244.

At the Apollo Speciality Hospital , we started doing HDR brachytherapy in 2005 April and have done about 25 applications with favorable results till now. Long term results are awaited. In conclusion, recent findings seem to indicate that HDR brachytherapy (HDR-BT) is becoming increasingly important in prostate radiotherapy, and HDR-BT alone without EBI is a promising modality. Studies prove that HDRBT without EBI is feasible and its toxicity acceptable. Short-term tumor control was promising, even for locally advanced cases. HDR brachytherapy for prostate cancer can be delivered more conformally and safely with reduction in overall cost. Patients tolerate the technique very well. Results of long-term follow-up need to be awaited, however, one can expect them to be quite favorable for this modality. In fact, the trend in USA indicates an increased rate in the use of HDR brachytherapy relative to seed implants (Nissar Syed, Personal communication 2006). REFERENCES 1. Ash D, Flynn A, Battermann J, et al. ESTRO/EAU/EORTC recommendations on permanent seed implantation for localized prostate cancer. Radiother Oncol 2000;57:315321.

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4. Demanes DJ, Rodriguez RR, Altieri GA. High dose rate prostate brachytherapy: The California endocurietherapy (CET) method. Radiother Oncol 2000;57:289-296. 5. Yoshioka Y, Konishi K, Oh RJ, Sumida I, Yamazaki H, Nakamura S, et al . High-dose-rate brachytherapy without external beam irradiation for locally advanced prostate cancer. Radiother Oncol 2006;80:62-68. 6. R. Mark, G. Vallabhan, P. Anderson, T. Neumann, R. Akins, M. Nair. Interstitial high dose rate (HDR) brachytherapy + IMRT vs. HDR monotherapy for early stage prostate cancer. Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. 2005: 23,(16S) 4718. 7. Hoskin, P. Bownes, L. Bryant, P Ostler. HDR Monotherapy Brachytherapy for Localised Prostate Cancer. Clinical Oncology ,19 (3), S7-S7 P . 8. High Dose Rate Monotherapy for Prostate Cancer Early Result : D Jeffrey Demanes, M D, Gillian Altieri, C M D David Brandt, M A, Lionel Schour, M D, Marie-Claire Barnaba, MSN-NP, Pat Skoolisariyaporn MS. Presented at American Society for Therapeutic Radiology and Oncology (ASTRO) Conference October 2005. 9. Grills IS, Martinez AA, Hollander M, Huang R, Goldman K, Chen PY, et al . High dose rate brachytherapy as prostate cancer monotherapy reduces toxicity compared to low dose rate palladium seeds. J Urol 2004;171:1098-1104.