Consensus Meeting "Prostate Brachytherapy" 2005
Neubauer S., Derakhshani P., Spira G.
Brachytherapy is a form of radiation therapy in which a radiation source is placed either within or in close proximity to the tissue. In low dose prostate brachytherapy, radionuclide sources are permanently implanted into the prostate gland, in high-dose rate brachytherapy the source is temporarily introduced into the prostate and removed after radiation treatment.
Developments in transrectal ultrasound, the use of a transperineal approach instead of retropubic implantation and the enormous advances in planning software renewed the interest in prostate brachytherapy and led to an increasing use worldwide.
Physical advantages of brachytherapy result from the fact that radioactive sources are located within the target volume; thus, the distance radiation has to travel through tissue to reach its target is minimised. Prostate tumors can be treated without radiating the skin or other dose-limiting organs. A second advantage is attributable to the “inverse square” law. The intensity of radiation decreases proportionally to the inverse of the square of the distance between source and target. Because of this exponential attenuation of radiation intensity, the dose decreases at a much greater rate near the radioactive source compared to external radiation techniques. With judicious source placement very high doses can be delivered to the tumor, and a minimum dose given to adjacent normal structures.
Several studies have shown the importance of physician experience for adequate dose delivery. At least 100 initial treatments and approximately 40-60 annual procedures will be necessary for every team to achieve high and reproducible implant quality.
Modern prostate brachytherapy technique
In 1981, Holm in Denmark developed a transperineal implant method using transrectal ultrasound (TRUS) . TRUS was used to guide percutaneous delivery of radioisotopes, achieving uniform seed distribution in the prostate and eliminating the guesswork previously used to guide the seeds in place. This formed the basis of the transperineal technique that today is used in brachytherapy, whether it is permanent or temporary, high-dose rate (HDR), or low-dose rate (LDR) brachytherapy.
The aim of permanent seed implants (PSI) is to deliver a tumoricidal dose to the entire prostate gland. The seeds employed may contain either the radio-isotope iodine125 or palladium103. The seeds are introduced into the prostate gland by means of template-guided needles transperineally under transrectal ultrasound guidance. Dose planning software permits rapid planning of the seed position and dose profiles around the prostate capsule to ensure that an adequate dose is achieved around the periphery of the gland together with a suitable margin. At the same time calculations are made to assure that adjacent organs receive as little dose as possible in order to limit side effects. Implant techniques vary from preloaded needles to afterloading the seeds once the needles are introduced into the gland. Stranded seeds are used preferably over loose seeds to prevent seed migration and improve post implant dosimetry.
At present most centres use an intraoperative technique, where planning and execution of the implant are done in a single session. A report from The American Brachytherapy Society in 2000 recognised the following variations Preplanning: Creation of a plan a few days or weeks before the implant procedure.
Intra-Operative Planning: Treatment planning in the operating theatre; the patient and TRUS probe
are not moved during the time between the volume study and seed insertion procedure.
Intra-Operative Preplanning: Creation of a plan in the operating theatre just before the implant procedure, with immediate execution of the plan.
Interactive Planning: Stepwise refinement of the treatment plan using computerised dose calculations derived from image-base needle position feedback.
Dynamic Dose Calculation: Constant updating of calculations of dose distribution using continuous deposited seed position feedback.
After the seeds are implanted, a post implant dosimetry is performed as a quality control measure to ensure that the dose delivered to the gland has been sufficient. The influence on treatment efficacy of the technical modifications described above remains unclear at present.
In temporary prostate implants (TPI), afterloading needles are placed under ultrasound guidance into the prostate. A dose calculation based on ultrasound or CT-scan images is performed. The radioactive sources are loaded into the needles according to the treatment plan only for the duration of the procedure. Optimized inverse planning provides greater flexibility for delivering individual dose distributions. A remote afterloading unit under robotic control is used to deliver treatments. This minimizes the radiation exposure to medical staff. A single radioactive source is moved along the afterloading needles. After the target dose is delivered, the source and the needles are removed. Recently intraoperative realtime planning has also been introduced to TPI.37 The possibility of realtime-modification in conjunction with ultrasound-based image acquisition in 1 mm slices enhances implant quality possibly leading to improved clinical results in the future.
Patient selection for brachytherapy
Prostate brachytherapy is a multidisciplinary technique. Patient selection involves issues that relate to both urology and radiation oncology. The most commonly used risk stratification criteria appear in table 1. In accordance with the recommendations of the American Brachytherapy Society and the EAU/ESTRO/EORTC , patients with low risk prostate cancer may be treated with PSI alone. There are a number of studies that have shown good results with PSI alone or combined with external beam radiotherapy (EBRT) in patients with intermediate risk disease. An RTOG study, now closed, randomised patients with intermediate risk disease to implant alone or implant combined with external beam radiotherapy, the results although pending should help to clarify the optimal treatment strategies for these patients.
For high risk patients the role of brachytherapy is less certain. Patients with two or more adverse risk factors (PSA > 10 ng/ml, Gleason score > 6 or > T2a disease) are frequently treated with EBRT for 5 weeks before or after the implant. Despite these general guidelines, some experts believe that as long as an adequate margin is applied to the target volume there is no need for EBRT, whereas others routinely recommend the use of external beam in combination with brachytherapy.
For PSI prostate size is optimal below 50 ml to avoid pubic arch interference. In experienced hands, larger prostates up to 70 ml volume can safely be treated if pubic arch interference is ruled out and IPSS is below 15. Volume reduction with an LHRH analogue may be indicated, if the pubic arch is narrow , however these patients have been shown to have a higher incidence of post implant retention and irritative symptoms . Patients must be able to flex their hips to 90º, have a pre-treatment IPSS of <15, a maximum urinary flow rate above 10 ml/s and should be clinically or urodynamically unobstructed , . Prior transurethral resection of the prostate (TURP) is a relative contraindication to PSI, especially if there is a large or irregular resection defect or continence is marginal. Time interval between TURP and seed implant should be at least 6 months to avoid substantial urinary morbidity , . With strict patient selection, PSI can be safely performed in patients after TURP.
As temporary implants do not cause prolonged radiation, urinary morbidity in general is lower in patients at risk (prior TURP, large prostate volume, high IPSS) . Therefore patients not suitable for permanent implants in terms of urinary tract status may be candidates for a temporary implant instead.
Permanent Seed Implant Monotherapy
Long term results have been reported in the literature by many centres around the world. The first to publish 10 year results were the Seattle group in 1998 . This series was comprised of the first cohort of patients ever treated with modern brachytherapy techniques. Risk stratification in patient selection was not well understood at the time. Of 152 patients in the series, 64% were treated with implant alone. Thirty six percent, who were deemed at higher risk, were treated with a combination of implant (Iodine125 or Palladium103) and external beam radiotherapy. Biochemical disease free survival (PSA < 0.5 ng/ml) at 10 years was 64%. The effect of the learning curve for the technique and the treatment in general could be appreciated when in 2001, the same group published results for low risk patients treated two years on1. There was a significant improvement in the results, 87% of patients treated had biochemical disease free survival (PSA 0.2 ng/ml) at ten years follow up.
Other centres, both in America and Europe, have produced similar long term results as shown in tables 2 and 3.
Combined Permanent Seed Implant and EBRT
There are a number of publications on long-term follow-up of patients with intermediate and high risk prostate cancer treated with PSI. Most authors advocate combined treatment with EBRT, although some authors reported similar results with PSI monotherapy 14, 15, 16, . To date it remains unclear whether high risk tumors can be treated with PSI alone or need combined treatment. At present it seems reasonable to treat patients with intermediate risk tumors with PSI monotherapy in selected cases.
Stock el al31 treated 132 high-risk patients (Gleason score 8-10, PSA level >20 ng/ml, Stage T2c-T3 or positive seminal vesicle biopsy or two or more of the following: Gleason score 7, PSA level >10-20 ng/ml, or Stage T2b) with combined hormonal therapy (9 months), permanent radioactive seed brachytherapy, and external beam radiation. The actuarial overall freedom from PSA failure rate was 86% at 5 years. (97% /85% /76% for Gleason <6/ 7/ 8-10).
Merrick et al reported on 46 consecutive T1c-T2b (1997 AJCC) patients with Gleason score 8 and 9 prostate cancer with a median follow-up of 58 months treated with Pd-103 and supplemental external beam radiation therapy (45 Gy). The utilization of hormonal therapy for 6 months or less resulted in a statistically not significant improvement in biochemical outcome (92.3% versus 81.8%, P = 0.393).
Critz et al 12 treated 1.469 men (T1,T2,Nx,M0) with PSI followed by external irradiation with a median follow-up of 6 years. The overall 10-year disease-free survival rate (PSA < 0.2 ng/ml) was 83%. Median time to recurrence was 30 months (range 3 months to 8 years) and 24% of recurrences were after 5-year follow-up. 10-year DFS for low, intermediate and high risk group was 93%, 80% and 61%, respectively (p <0.0001). Pre-treatment PSA, Gleason score and percent