Permanent Prostate Brachytherapy: Lessons Learned, Lessons to Learn

Introduction

Localized prostate cancer may be treated with permanent isotope implants, used either as monotherapy or combined with external-beam irradiation as curative therapy. Permanent source brachytherapy has evolved from a surgically based retropubic technique to today’s closed, ultrasound-guided, interstitial transperineal approach using either iodine-125 (¹²⁵I) or palladium-103 (¹⁰³Pd).

The therapeutic goal in patients with localized prostate cancer is to achieve local control and disease-free survival, defined as prostate-specific antigen (PSA) relapse-free survival. Therefore, prostate brachytherapy is a therapeutic alternative to three-dimensional high-dose external-beam radiation or radical prostatectomy for patients with localized prostate cancer.

Recent data with follow-up of 9 and 10 years confirm that transperineal implantation offers excellent PSA relapse-free survival rates,[1,2] however, as with any treatment modality, there is considerable variation in how brachytherapy is being performed. A recent review of prostate brachytherapy series confirms that there is no consistency in the implant technique used or how the data are reported.[3] To help standardize this procedure, the American Brachytherapy Society has published clinical and dosimetric guidelines, which, when adhered to, will provide uniform treatment parameters and methods for reporting data.[4,5] This article describes current state-of-the-art permanent prostate brachytherapy.

Retropubic ¹²⁵I Brachytherapy: Lessons Learned

Experience with retropubic ¹²⁵I brachytherapy as monotherapy was gained between 1970 and approximately 1988. Thus, these data were obtained prior to the PSA era, and both the staging and grading systems used are now considered to be obsolete. In addition, the definitions of local control and treatment success at that time differ considerably from today’s more stringent American Society for Therapeutic Radiology (ASTRO) consensus definitions using consecutive PSA values.[6] The clinical definition of “local control” varied considerably in publications from that era, but grade and stage were consistently identified as significant predictors of local control.

For early-stage, low-grade tumors, local control rates reported at the time for retropubic prostate brachytherapy were similar to those for external-beam irradiation.[7] In patients with disease of higher grade and stage, the outcomes with prostate brachytherapy were inferior to those achieved with external-beam radiation therapy.[8] Nonetheless, much information can be extrapolated from these series, which can provide guidance for the current technique of transperineal prostate brachytherapy.

Dose-Response or Implant Quality

An advantage of brachytherapy is its ability to provide a prescribed conformal radiation dose to a defined target volume. Postimplant dosimetry can be performed as a means of measuring the dose-response, or quality of the implant. However, the technology of the time did not permit accurate delineation of the prostate volume relative to the implanted volume, and, therefore, these early series did not provide clear-cut dose-response data. Several series that attempted to analyze the dose delivered by an implant confirmed that local control is a function of dose. Inferior local control rates were associated with doses to the prostate below 100 to 140 Gy.[9-12]

A recent analysis of 110 patients from the original Yale series of retropubic brachytherapy was carried out using modern, three-dimensional CT-based dosimetric parameters; this analysis provides new insights into the retropubic experience.[13] Several dosimetric parameters were evaluated to determine cutoff points that statistically separated the parameters according to local recurrence-free survival. This analysis demonstrated a twofold increase in 10-year recurrence-free survival between the favorable and unfavorable dosimetry parameters. More importantly, a comparison of Yale’s “inadequate” implants identified a group of patients with local control rates similar to those of other series from this era that reported poor outcomes.[7,14]

One of the main reasons for poor implant dosimetry during this time period was inadequate imaging technology for the volume-averaging technique of determining ¹²⁵I activity. Other factors include a poor delivery system, resulting in the bunching together of individual seeds centrally within the prostate; poor patient selection; and differences in technique among institutions and physicians.[8]

Conclusions From the Retropubic ¹²⁵I Experience

Although these variables cannot be evaluated readily from published data from the retropubic era, certain conclusions can be drawn from this experience. First, implant dosimetry, reported either as implant quality or delivered dose, clearly has an impact on local control. Second, stage and tumor grade also affect local control and disease-free survival rates. An understanding of the retropubic data within this context provided the foundation for the evolution of prostate brachytherapy in the late 1980s and ’90s.

Transperineal Permanent Isotope Brachytherapy

With the advent of the transrectal ultrasound probe as a means for visualizing the prostate, Holm et al developed the transperineal approach to prostate brachytherapy.[15] This closed technique allows for placement of needles into the prostate, guided by real-time ultrasound imaging, while the patient is in the lithotomy position. The isotope is then introduced through the needles directly into the prostate.

In the United States, Drs. Blasko and Ragde from Seattle pioneered this approach to brachytherapy in the early 1990s.[16] A conceptually similar approach using computed tomographic (CT) scans instead of ultrasonography was developed at Memorial Sloan-Kettering Cancer Center (MSKCC) around the same time.[17] In the intervening 10 years, the number of patients treated with ultrasound-guided transperineal interstitial permanent prostate brachytherapy (TIPPB) has grown exponentially; an estimated 35,000 implants were performed in 1999.[5]

Some believe that TIPPB with advanced biplane-transrectal ultrasonography, perineal guidance systems, treatment planning computers, and postimplant CT scanning has enhanced our ability to perform an “adequate” implant. As such, permanent brachytherapy yields associated biochemical control rates that are comparable to those of radical prostatectomy or high-dose three-dimensional external-beam irradiation in appropriately selected patients. However, an American Brachytherapy Society review of the practices of physicians who perform prostate brachytherapy uncovered tremendous variation in indications, technique, treatment regimens, and dosimetry.[4]

The main areas of controversy include the selection of patients for monotherapy or combined therapy with external-beam irradiation, the role of neoadjuvant androgen deprivation, the selection of ¹²⁵I or ¹⁰³Pd, the type of preimplant planning and technique, and the type and timing of postimplant dosimetry.

Despite these controversies, several published studies have assessed outcomes following TIPPB at institutions reporting biochemical control rates (Table 1). According to these studies, 4- to 10-year biochemical control rates range from 63% to 92%.[1,2,18-26] Because of differences among the studies with respect to patient characteristics, median follow-up, and the methods of defining outcomes, a meta-analysis of these data cannot be performed.

Potters et al reported risk-profile outcomes of a cohort of 717 patients treated with TIPPB. Patients were grouped based on a pretreatment PSA £ 10 ng/mL and Gleason score £ 6.[22] Patients who met both criteria were classified as a favorable-risk group (N = 303) and had a 93% 5-year PSA relapse-free survival rate (ASTRO definition[6]; see Figure 1). Individuals who fulfilled one criterion were considered at intermediate risk (N = 268), with a 5-year PSA relapse-free survival of 77%. Those who did not satisfy either criterion were classified as unfavorable risk (N = 146) and had a 62% 5-year PSA relapse-free survival rate.

Using identical risk definitions and a modification of the ASTRO definition of PSA relapse-free survival (two consecutive rises), Blasko et al reported outcomes in 230 patients treated with ¹⁰³Pd monotherapy.[1] Favorable-risk patients had a 94% 5-year PSA relapse-free survival rate, while the intermediate- and unfavorable-risk patients had PSA relapse-free survival rates of 82% and 65%, respectively (P = .04; see Table 2).

Prestidge et al have reported that biochemical control rates correlate with postbrachytherapy biopsy rates. Their data indicate a close correlation between PSA control and biopsy results, with 80% of biopsied patients having a negative result.[27] However, the significance of a negative or positive postimplant biopsy result remains controversial.

Currently, a multi-institutional trial is underway, with strict reporting methodology, to assess TIPPB in early-stage prostate cancer. In addition, the Radiation Therapy Oncology Group (RTOG) is conducting a feasibility trial of this modality, also with strict quality control parameters. Until prospective data become available, variations in treatment techniques for TIPPB will appear in the literature.