Choice of Radioisotopes
Radiobiologic data from the 1980’s suggested that isotope dose-rate may be an important factor for treating prostate cancer as different grades of disease with different cell doubling times may have specific sensitivities to either I-125 or Pd-103 26. Nonetheless, clinical data has been reported for both I-125 and Pd-103 regardless of tumor grade that does not indicate any difference in biochemical control 27, 28. Cha et. al. reported on the results of a matched pair analysis comparing I-125 and Pd-103 was unable to identify any difference in PSA-RFS at 5 years (Table 2) 29. Furthermore, there was no subset of patients by Gleason score or pre-treatment PSA value for which a difference between I-125 and Pd-103 was identified. As the ABS does not currently recommend the use of one isotope over the other, selection should be based on experience and individual institutional and physician preference with each available isotope.
Two approaches for permanent prostate brachytherapy have developed over the last 10 years. One utilizes a pre-plan of the prostate in the treatment position 30. The other technique utilizes an intra-operative treatment planning approach 31. Generally, each center will develop a program based on either of these two approaches so that proficiency assures excellent dosimetry in all treated patients.
When utilizing the pre-planned approach, it is important to obtain a pre-implant transrectal ultrasound of the prostate using planimetric, cross-section images at 5 mm intervals. It is important to position the patient in the lithotomy position for this test in order to mimic the required positioning in the operating room. Unfortunately, at the time of the pre-planning TRUS, it is very difficult to obtain such a high degree of lithotomy in a patient without anesthesia, therefore, limiting the pre-planned technique to a lower angle of lithotomy. Once the dimensions of the prostate are outlined, the computer program automatically calculates the volume. The physician will need to assess the pubic arch both during the TRUS study and by palpating the perineum, and if there is a question of bony interference, a pelvic CT is required to measure the pubic arch space. The TRUS images are then uploaded into a treatment planning system and the physician contours the prostate margin and the planning target volume (PTV). The PTV may include a prostate margin of 2-3 mm or may be the same as the prostate itself. The computer will develop a seed-loading plan that can then be prepared for the implant.
When using the intra-operative approach, planning can be individualized. It is generally helpful to perform a TRUS to assess the prostate volume in order to determine the total activity required to deliver the prescribed dose and allow for a certain number of sources to be ordered. Since the patient will be positioned under anesthesia in the operating room, the legs may be placed into a very high lithotomy position, rotating the pelvis up and away from the prostate gland. Pubic arch interference is rarely a problem with this technique and does not require a separate evaluation.
Role for adding External Beam Irradiation to Permanent Prostate Brachytherapy:
The reasons for combining therapy are based on the ‘statistical’ risk of having extracapsular disease associated with Gleason score, PSA and stage 32. A prostate implant only provides dose to the prostate with a 3-5 mm margin and may include just the base of the seminal vesicles 33. The ‘field’ effect of external radiation to encompass the seminal vesicles and a larger prostatic margin will potentially encompass the areas at risk for extracapsular disease not treated by the implant. Doses of 45-50.4 Gy with 75% of the prescribed implant dose are considered standard for combined therapy.
Clinical criteria recommended by the ABS for monotherapy include stage T1c and T2a, Gleason scores of 2-6 and a PSA < 10 ng/ml. Patients with stage T2b or Gleason score 8-10 or PSA > 20 ng/ml are recommended to undergo EBRT and implant 15. Nonetheless, a review of the literature is not helpful in delineating a biochemical control difference between these approaches, as many centers do not stratify their patients accordingly 34. A more important factor may be the implant quality with the addition of EBRT best reserved for those patients with an unsatisfactory implant 14.
Brachytherapy and Androgen Ablative Therapy
The role of combining neoadjuvant androgen deprivation (AD) and permanent prostate brachytherapy remains controversial. Historically, it was used to reduce the prostate volume when it exceeded 60 grams in order to facilitate brachytherapy 30. Volume reduction decreases the total isotope activity required, potentially improves implant dosimetry and decreases pelvic arch interference 35. Nonetheless, many patients are started on AD that have clinically localized disease based on prospective data from patients with advanced disease where a survival benefit has been demonstrated 36. As a result of this practice in the community, the ABS has developed guidelines on the use of AD in patients eligible for brachytherapy.
The role of AD as an adjunct therapy, either as neoadjuvant or adjuvant therapy in patients with clinically localized prostate cancer has never been shown to improve biochemical freedom from failure. There are several retrospective studies that offer differing results on this issue and currently, the ABS is unable to provide firm recommendations on the use of AD 22, 37.
In a matched pair analysis looking at the role of AD and permanent prostate brachytherapy, no difference in PSA-RFS was identified for each group or sub-group of patients 22. This contrasts with the study by Lee et. al. where differences in PSA-RFS were shown for high-risk patients who received AD 37.
Two high-dose 3D-EBT series report on the use of AD for early stage prostate cancer patients. Both studies failed to identify any advantage for the addition of AD when doses exceeded 72 Gy 38, 39. Conclusions from these series with high-dose 3D-EBT or permanent brachytherapy indicates that there may be a dose ‘threshold’ after which the addition of AD is no longer effective for patients with localized prostate cancer. With brachytherapy, the delivered dose of radiation exceeds that of external beam, therefore, this threshold dose is surpassed.
CT based dosimetry allows the visualization of the isotopes such as I-125 and Pd-103 relative to the prostate and other pelvic soft tissue structures. Because the sources often appear on more than one slice, a seed location reduction method (seed sorting) based upon nearest neighbors needs to be employed. New software algorithms have been developed to find seeds, but due to the potential for seed migration, the exact number of seeds in the prostate is required. The main difficulty with CT based evaluations is that soft tissue contrast is often poor, making it difficult to reliably contour the borders of the prostate especially at the base and the apex of the gland 40.
At the present time, CT-based evaluation of the prostate implant is the preferred choice to best satisfy the requirements of seed localization, target and normal structure delineation, and seed-target registration. The target is defined as the prostate (without margin) on the individual CT images. Care should be taken to distinguish the prostate from the peri-prostatic tissue. Several studies have noted discrepancies in volume of prostate as determined by TRUS, MRI, and CT, reflecting the difficulties in differentiating the prostate from the periprostatic musculature and venous plexus using CT 41. Normal structures of interest that can be defined by using CT include the urethra and the rectum 42.
The magnitude, dynamics, and resolution of prostate edema have obvious implications for the timing at which the dose-volume relationship is described. This can have a significant effect on dosimetry analysis with variability in dose measurements of >10% 43, 44. It appears based on various factors that the best time to assess the implant is between two and four weeks 43, 45. However, more importantly, each center should establish a set policy and follow it consistently. It may be logistically easier to obtain the CT images early following the implant compared to waiting 3-4 weeks 12, 46.
Early feedback can be used to compensate an under-dosed prostate and to improve the implantation technique. Short of participating in clinical trials, where dosimetry is independently performed, it should be understood that each center needs to correlate their own dosimetry and outcomes relative to published data, as there are too many variables to allow for true standardization at this time.