, Santiago Uribe-Lewis1, Jennifer Uribe1 and Stephen Langley1
Department of Urology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK
Prostate brachytherapy is a very effective radiation-based treatment for localised prostate cancer. The aim is to deliver a high therapeutic dose of radiation to the prostate while minimising radiation exposure to the surrounding organs and thus limiting toxicity. Modern imaging techniques allow precise targeting of the prostate tissue and limit exposure to normal tissue. Prostate brachytherapy delivers the radiation dose directly into the target tissue without traversing skin and other structures, unlike external beam radiotherapy (EBRT). This targeted access is achieved by a template and image-guided approach delivered percutaneously through the perineum (Fig. 10.1).
Low dose rate brachytherapy patient set-up
There are two types of brachytherapy: low dose-rate (LDR) and high dose-rate (HDR). LDR brachytherapy (LDR-BT) involves the permanent implantation of radioactive seeds through rigid needles into the prostate. The seeds release radiation over time at a rate < 2 Gy/h1. HDR brachytherapy (HDR-BT) delivers radiation by means of a radioactive source passing through catheters temporarily inserted into the prostate at a rate of ≥12 Gy/h .
Initially LDR-BT brachytherapy was delivered through an open suprapubic approach . Modern prostate brachytherapy was developed in Seattle in the 1980s when transrectal ultrasound (TRUS) probes enabled better visualisation of the prostate, improving the accuracy of the treatment and delivery of radiation by means of template-guided perineal access; the “Seattle” technique required two stages often performed under spinal or general anaesthetic . The first stage involved a planning TRUS of the prostate from which the number of seeds was calculated and the seeds ordered from the manufacturer. The second stage, typically several weeks later, involved the implantation of the seeds into the prostate using the co-ordinates previously calculated. One of the limitations of this treatment was the need for two separate stages, as on occasions the prostate shape or volume could change, especially if the patient had high-risk cancer and was also being treated by hormone therapy or EBRT. The original technique did not allow for the dose to be monitored and optimised during the procedure, known as real-time planning. There have been a number of technical approaches and modifications of LDR-BT over the years seeking to improve clinical outcomes, dose delivery and distribution, convenience and optimisation of resources [3, 4]. The clinical team normally includes a radiation oncologist, a urologist and a radiation physicist.
The first remotely controlled afterloaders to deliver HDR-BT were developed in the 1960s. The use of these machines eliminated staff exposure to high activity radionuclides and made possible the use of sources such as Iridium-192 (192Ir). The radioprotection and regulatory infrastructure required for HDR-BT is considerable compared to that of LDR-BT.
Low Dose-Rate Brachytherapy Procedure
LDR-BT involves permanent implantation of small titanium seeds (4.5 mm long × 0.8 mm diameter) containing the radionuclide Iodine-125 (125I), Palladium-103 (103Pd) or Cesium-131 (131Cs). The half-life of 125I, the most commonly used isotope, is approximately 60 days. Usually between 60 and 100 iodine seeds are implanted to cover the prostate with a prescription dose of 145 Gy for monotherapy and 110 Gy when combined with EBRT. The majority of the biologically effective radiation from isotope decay is released in the first 3 months, although the effect on the prostate tissue and thereby the PSA response, occurs over a number of years. Seeds for implantation are available as either loose seeds or seeds embedded in bio-absorbable stranding material. The loose seeds enable more flexible positioning, but have a higher risk of migration both within and away from the gland. Stranded seeds are prevented from migration by the stranding material for the first weeks post-implant and then by a prostate tissue capsule [5, 6]. Stranded seeds also enable extension of the dose outside the prostate capsule in order to encompass extraprostatic extension .
The dosimetry planning and dose delivery is evaluated according to several parameters, most importantly the V100 (percentage of the prostate volume receiving 100% of the prescribed dose) and D90 (radiation dose, in Gy, received by 90% of the prostate). The dose received by both urethra and rectum is also analysed to minimise toxicity. Post-implant dosimetry values have been correlated to long-term clinical outcomes, which is a unique feature of LDR-BT [8, 9].
The most recent technique, 4D Brachytherapy , allows the procedure to be performed in a single real-time planning procedure that lasts about 45 min. This approach requires a prior outpatient clinic-based TRUS to assess five key measurements of the prostate, which are used to calculate the number of seeds required for that specific patient using a web-based nomogram. The technique uses a combination of stranded seeds implanted around the periphery of the prostate (thus avoiding migration) followed by loose seeds implanted in the centre of the gland; as the seeds are implanted the treatment planning computer programme updates the dosimetry in real time to optimise dose coverage . To evaluate the dose delivered and implant quality, patients have a post-implant CT scan immediately after the procedure. The procedure is usually performed as a day case, recovery time is short and normal activities resumed within a few days in most cases.
Post-brachytherapy follow-up involves serial PSA measurements. The downward trend of PSA values is gradual and may take between 1 and 5 years before PSA reaches its lowest level, called the PSA nadir. A biochemical recurrence of cancer is usually defined as a rise in PSA that greater than 2 ng/ml above the nadir.
After LDR-BT approximately 20% of patients experience a PSA bounce. This is a transient increase in PSA typically 1.5–2 years after the implant. The exact cause of this phenomenon is unknown, but it seems to be more common in larger glands and younger patients. Awareness of this phenomenon is important as it can be confounded with biochemical recurrence and therefore patients should be monitored closely, but mainly reassured.
Rising PSA values should trigger investigations such as template biopsy, multiparametric MRI or a PET-CT scan, to ascertain whether there is a local or distant recurrence.
In the immediate post-operative period, patients should be aware of the most common side effects of BT due to prostate oedema and subsequently, radiation effects which may develop from 2 to 6 weeks after implantation:
Haematuria for 1–2 weeks
Haematospermia for up to a month
Bruising and pain in the perineum
Dysuria, urinary urgency, frequency and nocturia
Urinary retention requiring catheterisation (1.5–11%), due to swelling of the prostate; risk may be reduced by giving an alpha-blocker for the first few weeks after the treatment.
More rarely seeds may migrate into the bladder, which need to be removed by cystoscopy. Loose seeds can migrate into blood vessels and usually to the lung. For this reason the use of stranded seeds in the periphery of the prostate is commonly preferred .
EBRT is known to cause a small increase in the risk of secondary malignancies typically after 10 years of treatment. In prostate EBRT there is increased risk of bladder and rectal cancer by 1.9- and 2.2-fold, respectively, although the overall risk is still low. No consistent finding of an increased cancer risk has been identified in patients treated with LDR-BT, presumably due to better targeting of the radiation and relative sparing of the adjacent tissues .
Clinical Indications for LDR-BT
When considering the indications for prostate brachytherapy there are both oncological and urological factors to assess.
Patients suitable for LDR-BT monotherapy typically have either low or low-intermediate risk prostate cancer and usually treated with a LDR-BT implant to 145 Gy. Those presenting with high-intermediate or high-risk disease are usually treated with brachytherapy in combination with androgen deprivation therapy (ADT) or ADT with a short course of EBRT respectively . Cancer up to stage cT3a may be treated with combination treatment of hormone therapy (starting 3 months before treatment and usually continuing for at least 3 months post-implant), EBRT (45 Gy) and LDR-BT (110 Gy). Patients presenting with cT3b disease involving the seminal vesicle are not ideally suited to LDR-BT as accurate placement of the seeds with the vesicles is not possible. ADT may also be used neo-adjuvantly to reduce the size of larger prostates (60–80 cm3).
To minimise the most common post-brachytherapy side effect, a temporary worsening in urinary obstructive and irritative symptoms (but not incontinence), patients should have a pre-treatment International Prostate Symptom Score (IPSS) below 15, an un-obstructed flow rate and effective emptying of the bladder. Patients with small obstructive prostates may safely have a limited TURP ~3 months pre-treatment, to improve their symptoms and reduce post-treatment side effects . Patients with prostate glands larger than 60 cm3 may be difficult to implant as the pubic arch of the pelvis may prevent access of the needles into the antero-lateral part of the gland. In patients with glands between 60–80 cm3 adequate size reduction to permit implantation is usually achieved with 3 month of neo-adjuvant ADT.
Inflammatory bowel disease
International Prostate Symptom Score (IPSS) >15
Prostate volume > 60 cm3
Life expectancy of less than 10 years.
Absence of rectum precluding use of TRUS probe
Unacceptable operative risk
Poor anatomy that could lead to a suboptimal implant (e.g. a large or poorly healed defect from transurethral resection of the prostate (TURP), large median lobe, large gland size)
Pathologically positive lymph nodes
Significant obstructive uropathy
Numerous studies have demonstrated excellent clinical results for patients treated by LDR-BT . The Prostate Cancer Results Study Group was created to evaluate the comparative effectiveness of prostate cancer treatments . The study outcomes suggested that, in terms of biochemical-free progression, brachytherapy provides superior outcome in patients with low-risk disease. For intermediate-risk disease, the combination of EBRT and brachytherapy appears equivalent to brachytherapy alone. For high-risk patients, combination therapies involving EBRT and brachytherapy with or without ADT appear superior to more localised treatments such LDR-BT alone, surgery alone or EBRT.
As part of a recent UK Health Technology Assessment by Ramsay et al.  a meta-analysis was conducted that included over 26,000 patients. The 5-year follow-up rate of biochemical failure was lower for brachytherapy (7%) than for EBRT (13%; OR 0.46, 95% CI 0.32 to 0.67) or RP (11%; OR 0.35, 95% CI 0.21–0.56).
There is strong evidence to support the use of LDR-BR in multimodality treatment of intermediate- and high-risk PCA. The ASCENDE- RT randomised trial reported on an analysis of survival endpoints comparing LDR-BT boost to a dose-escalated EBRT boost for high- and intermediate-risk prostate cancer . Compared to 78 Gy EBRT, men randomized to LDR-BT boost were twice as likely to be free of biochemical failure at 6.5 years median follow-up. The 9-year BCRF was 83% in the LDR-BT cohort compared to 63% with EBRT boost.
These results mirror those achievable with radical prostatectomy (RP) in low risk groups and better than RP in intermediate and high risk groups [16, 19, 20]. In most mature radical prostatectomy series there is a need for post-operative EBRT in 20–30% of patients with positive surgical margins or at high risk of recurrence. By contrast, in the authors’ experience of over 3500 patients treated with LDR-BT, <1% require subsequent radical prostatectomy as the risk of recurrence within the prostate alone is rare.