ESTRO/EAU/EORTC RECOMMENDATIONS

Summarized below are the new ESTRO/EAU/EORTC recommendations, full details of which can be found in Radiother Oncol 2000;57:315-321.

Patient selection

Patients with a good outcome in terms of biochemical disease free survival (DFS) and good functional outcome should be identified. The most significant prognostic factors for DFS are initial prostate-specific antigen (PSA), Gleason score and stage. Functional outcome is best characterised by initial prostate volume and lower urinary tract symptoms (LUTS; measured using the International Prostate Symptom Score [IPSS]). Selection criteria are shown in the following table.

Prognostic factors

PSA
PSA is a strong predictor of extra-capsular disease. Patients with PSA <10 ng/ml do well with brachytherapy alone, while those with a PSA> 20 ng/ml have high probability of biochemical failure within the first 2 years; 30-50% may, however, remain biochemically controlled. Patients with a PSA > 50 ng/ml are highly likely to have extracapsular disease and therefore not suitable candidates for radical local treatment.

Gleason score
Patients with Gleason score = 6 do well with brachytherapy alone. Those with Gleason score 7 have 50% probability of biochemical relapse within 5 years. Patients with Gleason score 6 or 7 and with a predominant grade 4 (rather than 3) have a worse prognosis. Other adjuvant therapies to be considered for patients with Gleason score 8-10.

Stage
Patients with low volume localised disease with a low risk of extra-capsular spread (T1c-T2b) do well with brachytherapy alone. T3 cases should be excluded from brachytherapy as the sole treatment. Minimal T3 may be eligible for external beam therapy (EBT) with brachytherapy as a boost to cover the extent of the known extra-capsular spread. It should be noted that many patients have disease up to 2-3 mm outside the capsule, which can still be targeted by brachytherapy.

Urinary flow
IPSS: With regard to side-effects of brachytherapy, patients with a score of 0-8 do well with a low risk of acute urinary retention (AUR) and prolonged urethritis. However, patients with an IPSS score > 20 have a 30-40% risk of these complications.

Prostate volume: Patients with a prostate volume £ 35 ml have a low risk of AUR and urinary morbidity. Patients with a prostate volume > 50-60 ml should undergo hormonal cytoreduction before brachytherapy. This will not necessarily reduce side-effects, but is necessary to achieve a satisfactory seed implant.

Pre-treatment investigations

• History and physical examination
• Digital rectal examination (DRE)
• Sexual potency and LUTS
• PSA
• Transrectal ultrasound (TRUS): evaluate extent of disease and measure prostate volume; probability of pubic arch interference
• 6-12 core TRUS guided biopsy
• Bone scan if PSA > 10 ng/ml
• Computed tomography (CT) scan and magnetic resonance imaging (MRI): relevant for staging pelvic lymph nodes only
• Pelvic phased array or endorectal MRI: in patients with adverse prognostic features to evaluate extent of the disease, especially if brachytherapy alone to be used
• Lymph node staging: in patients with poor prognostic features (risk of lymph node involvement up to 30%)
• Urodynamic studies: IPSS; Qmax, voided volume and postvoid residual urine in patients with significant symptoms.

Contraindications to permanent seed implants

• Life expectancy <5 years
• Metastatic disease
• Recent TURP with persisting large prostatic defect (difficult seed distribution, with high risk of incontinence)
• Bleeding disorders; aspirin and anticoagulants to be stopped at least 7 days before implant.
• Prostate gland > 50 ml: high risk of pubic arch interference and increased number of seeds needed. Hormonal therapy can reduce gland volume by 30%.

Other potential indications and investigational treatments

Brachytherapy as a boost after EBT
There is no evidence to indicate that this approach improves the outcome in patients with high Gleason score and high PSA.

Brachytherapy as salvage after failed EBT
Conventional doses of EBT (64-68 Gy) cannot achieve biochemical control in a high proportion of patients. If the disease remains localised within the prostate, these irradiated patients may be suitable for salvage brachytherapy. This option should be reserved for patients with a good prognosis (PSA <10 ng/ml) due to the associated risks. Seed loading should aim to reduce the dose to the urethra.

Adjuvant hormone therapy
Although frequently used in patients with PSA > 10 ng/ml and Gleason score = 7, there is no clinical trial evidence to confirm that neoadjuvant hormonal therapy improves the outcome of brachytherapy. The optimum duration of therapy is not known, but increased usage of hormonal therapy has to be balanced against side-effects, e.g. impotency. Hormonal therapy does have a role in reducing prostate volume.

Equipment and facilities

The key to achieving high quality implants is image-guided source placement. Minimum requirements are:

• TRUS with template software
• Stepping unit
• Seed planning software

Image intensifier and cystoscopy equipment are helpful. Disposables include stabilisation and implant needles.

Centre must be licensed to handle radioactive equipment and the room in which the material is handled must be specially designated for the purpose.

The clinical team
Key members include:

• Urologist
• Radiation oncologist
• Physicist
• Urologist, radiologist or radiation oncologist with ultrasound skills.

Nurses and technicians are also important to the team. It is recommended that the team participate in an established training course and attend at least one implantation procedure before starting their own programme. Post implant dosimetry is important for measuring implant quality and consequently improving technique.

Implant procedure

Pre-planning
Accurate measurement of the prostate is an essential part of planning the dose of radioactivity to be applied. It can be conducted at the same time as pre-planning. The patient is placed in the lithotomy position and 5 mm ultrasound sections taken from the base to the apex of the prostate using the stepping unit.

The urethra is placed in the middle vertical row of the template and the posterior border at the rectal interface along the first horizontal row. The coordinates on the template are used to plan the exact number and position of the seeds required to cover the target volume identified on each section.

Pre-planning can be conducted with or without anaesthetic, although it may help reproduce the patient position for treatment. The pre-plan can be done at the same time as implantation if the prostate volume is known accurately.

Implantation procedure
This is performed under general or spinal anaesthesia with the patient in the lithotomy position and TRUS and template in position. The bladder can be visualised on fluoroscopy with contrast medium inserted and the urethra on ultrasound with air-filled gel in the catheter.

It is important that the prostate position on the template is identical to the pre-planning set-up. Two or three stabilising needles will help reduce prostate movement before implantation. Implant coordinates are defined from the template, and the depth of insertion by a combination of fluoroscopy and measurement. Implant needles containing the seeds are inserted percutaneously under direct ultrasound according to the pre-plan or with interactive dosimetry in a single step procedure.

Cystoscopy may be performed after implantation to remove misplaced seeds in the urethra or bladder, although they are often voided spontaneously.

Choice of isotope

• I¹²⁵: half-life 60 days
• Pd¹⁰³: half-life 17 days

No data from randomised trials to show superiority of either isotope.

Brachytherapy dose

• I¹²⁵: 145 Gy or 95-100 Gy if used as a boost to EBT
• Pd¹⁰³: 115 Gy or 90 Gy if used as a boost to EBT

Management of side-effects
All patients develop urethritis of variable intensity and duration. Alpha blockers and non-steroidal anti-inflammatory drugs often help. Proctitis may occur in a few patients and is helped by steroid enemas. Antibiotics are frequently given after implantation, although the risk of infection is low. AUR may develop in 15% of patients either immediately or after a few days. Treatment is urethral catheterisation or suprapubic if condition persists. Transurethral resection of the prostate (TURP) should be avoided if possible, at least within the first year of implantation; transurethral incision may be adequate at that time to improve outflow.

Patient information
Written information should be supplied to the patient and the treating doctor on the pre-treatment investigations, the implant and the side-effects and treatments that may be needed.

Follow-up
Patients should be seen 4-6 weeks after implantation to check for settling of the acute reaction. Thereafter, follow-up is at 3-month intervals for the first year, 6-month intervals to 5 years and then annually. Follow-up should include history, DRE, PSA and urinary and bowel side-effects, as well as potency.

Post-implant dosimetry
Post-implant dosimetry is a useful learning tool and evidence suggests that the probability of achieving biochemical control is related to the quality of the implant. It is usually performed at 4-6 weeks when the oedema has settled and requires a post-implant CT scan to check the position of the seeds so that a full reconstruction of dose and volume can be made. The following indices of implant quality are recommended for all patients:

• Volume implanted
• Number of seeds
• Number of needles used
• Total activity implanted
• Prescribed dose
• D90: dose that covers 90% of the prostate volume
• V100: percentage of the prostate volume that has received the prescribed dose
• V150: volume that has received 50% more than the prescribed dose.

Management of relapse after brachytherapy
Biochemical failure is defined as three successive rises of PSA with at least 3 months between each, but this is not necessarily an indication for treatment. Treatment applied if PSA doubling time of less than 1 year once PSA is over 10 ng/ml. Alternatively, in this patient group, annual bone scan and surveillance may be suitable.

The mainstay of treatment for relapsed patients is hormone therapy. Other salvage treatments include: radical prostatectomy, a second implant, or EBT. All are associated with a high risk of morbidity.

Radiation protection
Dose rate at the skin surface of the two isotopes used is extremely small. Patients may sleep in the same bed as partner or be in same room as children, but it is advised that children do not sit on patient's knee for any length of time for the first 2 months after implantation. The use of condom is recommended for the first 2 to 3 ejaculations, due to the very low risk of seeds being expelled in the semen.