Vicini and colleagues present an informative, compelling review of both past and recent clinical investigations of the use of brachytherapy in patients with prostate cancer, particularly those with locally advanced disease. The tables presented at the conclusion of the article provide an excellent resource to compare, albeit loosely, some of the more important published results related to modern radiotherapeutic management of prostate cancer.
Renewed interest in brachytherapy as part of a multimodality approach for locally advanced disease stems from many factors but can be attributed primarily to the dismal biochemical cure rates reported with standard external-beam radiotherapy alone. Other factors responsible for this renaissance include: suboptimal results with permanent interstitial implantation alone in patients with unfavorable prognostic factors; promising dose-escalation trials with three-dimensional (3D) external-beam radiation therapy, and rapid advances in quality ultrasound imaging and computer software. Although few prospective trials exist, recent pub-lished experiences using brachytherapy have helped identify basic guidelines worth considering in the management of both favorable- and unfavorable-risk diseases.
Adverse Tumor-Related Prognostic Factors
First, excellent biochemical cure rates have been reported in patients with favorable prognostic features (prostate-specific antigen [PSA] < 10 ng/mL, Gleason < 7, stage < T2b) using either transperineal permanent implantation or computed tomography (CT)assisted implantation, palladium-103 or iodine-125 isotopes, different seed distribution patterns, and pretreatment or real-time planning.[1-5] Over follow-up periods ranging from 5 to 9 years, cure rates are comparable to those achieved with surgery or 3D external-beam radiation.
Despite the lack of randomized trials, available data with transperineal permanent implantation or CT-assisted implantation as single-modality therapy have helped identify adverse tumor-related variables (Gleason ³ 7; PSA > 10 ng/mL, stage > T2b) for which seed implantation alone is insufficient and should be discouraged.[1-3] As Vicini et al note, other tumor- and treatment-related factors may have independent significance and must be factored into treatment decisions; however, these factors have not been tested in a prospective fashion.
Second, both historical and recent data demonstrate both a dose-response relationship and a dose-volume relationship with interstitial implantation alone that has important implications for the management of locally advanced disease. Stock et al performed CT-based 3D dosimetric evaluation in 134 patients with T1/T2 prostate cancer implanted with iodine-125 transperineal permanent implantation alone, using TG43 guidelines.[7,8] Dose delivered to the gland was defined as the D90 (dose delivered to 90% of the prostate tissue as defined by CT). Dose was the most important variable determining outcome in multivariate analysis, particularly for patients presenting with PSA > 10 ng/mL. The 4-year freedom from biochemical failure rates for patients with D90 < 140 Gy and D90 > 140 Gy were 51% vs 100%, respectively. Post-treatment biopsies were negative in 64% vs 100% of these patients, respectively.
Zelefsky et al reported a similar dose-response relationship in a review of the iodine-125 retropubic implant experience from Memorial Sloan-Kettering Cancer Center. Both Zelefsky et al and Hanks et al have also reported stronger dose-response relationships for patients with PSA > 10 ng/mL treated with 3D external-beam radiation therapy alone.[6,10]
Need for QOL Data
Similar to the evolution in treatment for Hodgkins disease, the continued improvements in treatment outcome with brachytherapy will make it imperative to perform detailed quality-of-life (QOL) assessments and treatment cost-analyses. Little comparative QOL and acute or late morbidity information exists among the various treatment approaches that the patient can use to make an informed decision.
Zelefsky et al retrospectively compared patients treated with either 3D external-beam radiation or CT-assisted implantation at Memorial Sloan-Kettering Cancer Center. They concluded that despite equivalent cure rates (88% vs 82% respectively) at 5 years, the incidence of protracted grade 2 urinary symptoms among patients followed more than 1 year was significantly higher in patients treated with CT-assisted implantation than in those given 3D external-beam radiotherapy (31% vs 8%). According to the authors, potential factors responsible for this difference included higher average urethral doses with transperineal permanent implantation, higher seed activity, and a nonperipheral-based seed placement approach. In contrast, using transperineal permanent implantation with a peripheral loading arrangement and real time dosimetry, Terk et al reported grade 2-3 genitourinary (GU) toxicity comparable to the Memorial 3D external-beam therapy experience.
It seems reasonable to employ the same strategy of androgen blockade combined with brachytherapy for locally advanced disease based on published experiences suggesting a local control and survival benefit with external-beam radiation therapy.[13,14] With the increasing use of androgen ablative therapy in conjunction with transperineal permanent implantation or transperineal permanent implantation/external-beam radiation, the rates of potency preservation will most certainly decline.[15-17]
No published data exist to show a benefit to androgen blockade combined with brachytherapy, despite increasing use of this approach in the oncologic community for favorable-risk patients. Androgen blockade with brachytherapy may also be unnecessary in subsets of patients with only one poor prognostic variable. Knowledge of this information would be valuable for patients who want to preserve potency. In addition, recent reports with longer follow-up also suggest underestimation of erectile dysfunction with transperineal permanent implantation without androgen blockade.
Several issues that remain unresolved, and in need of further investigation, include: (1) the effects of androgen ablation combined with brachytherapy on local control, biochemical control and quality of life; (2) the efficacy, morbidity, and cost of alternative radioactive sources (palladium-103 vs iodine-125)[2,5]; (3) the optimal dose and dose-volume distribution with transperineal permanent implantation either alone or as a boost; and (4) the optimal PSA nadir after transperineal permanent implantation.[18,19] In recent publications focusing on implantation as either unimodality or bimodality therapy, Storey et al and Critz et al suggest that a PSA nadir of < 0.5 ng/mL may be a more sensitive indicator of true ultimate biochemical cure then a PSA nadir of < 1 ng/mL.[18,19] Investigators using brachytherapy should consider the consensus guidelines recommended by the American Society of Therapeutic Radiology and Oncology when comparing and reporting PSA outcome until further rospective comparative studies are initiated. Several reports cited by Vicini et al use PSA nadir levels ³ 1.5 ng/mL to define success; such nadir levels may be inadequate and make comparisons difficult.
3D Brachytherapy Combined With External-Beam Radiation Therapy
Brachytherapy is arguably the ultimate in 3D conformal treatment, with potential advantages over 3D external-beam radiation therapy alone. Among patients with unfavorable prognostic features, brachytherapy as a boost, combined with external-beam radiation (with or without androgen blockade) has become an accepted standard approach in nonacademic centers as a means of increasing dose intensity, decreasing overall treatment time, and decreasing dose to normal structures. As Vicini et al point out, this combined approach has shown considerable promise in achieving significantly improved biochemical cure rates, as compared with standard external-beam radiation, even with short follow-up and deserves investigation in a cooperative group setting (eg, American Brachytherapy Society).
Both permanent and temporary interstitial boosts appear to offer equivalent results, as well as superior outcomes, compared with external-beam radiation therapy alone or transperineal permanent implantation alone for locally advanced disease, and yet many questions remain to be answered. Several experiences pointed out by Vicini et al emphasize this point.
Dattoli et al combined low dose pelvic external-beam radiation (41 Gy) with palladium-104 for locally advanced, high-risk patients. The majority of patients did not receive hormonal therapy. The actuarial freedom from biochemical failure rate (defined as PSA < 1.0 ng/mL) at 3 years was 79%. Although not prospectively studied, the rate of potency preservation was 77%, and grade 2 or higher GU side effects were minimal. Singh et al recently reviewed the Memorial experience with androgen ablation, 3D external-beam radiation to the prostate only (54 Gy), and palladium-103 for a similar cohort of unfavorable risk patients. The 2-year actuarial PSA relapse-free survival rate was 96%.
Role of HDR Procedures
Mate et al have reported 5-year data using conformal high-dose-rate (HDR) temporary implantation with a single procedure delivering four fractions, and pelvic external-beam radiation (50 Gy) without hormonal therapy. The PSA actuarial relapse-free survival rates were 84% for PSA < 20 ng/mL and 50% for PSA > 20 ng/mL, with a 7% urethral stricture rate. In a dose-escalation trial, Stromberg et al reported similar results with a more unfavorable group of patients using two to three separate HDR procedures combined with concurrent external-beam radiation to the pelvis (46 Gy). However, the PSA end point measured was > 1.5 ng/mL, GU morbidity was higher, and follow-up was shorter. Hopefully, the ongoing Radiation Therapy Oncology Group trial will determine the relative benefits of pelvic vs local treatment and the optimal timing of androgen blockade, which, in turn, will help us to customize therapy for different subsets of patients.
Our group is prospectively studying transperineal HDR brachytherapy. We agree with Vicini et al that this boost technique has potential advantages over permanent seeds. We initially explored this method due to the logistical nightmare of ordering radioactive sources, as well as the cost. On-site HDR eliminated this problem. Also, the afterloading dosimetry reduces the need to perform a geometrically perfect implant, and allows us to preferentially spare the urethra and rectum. Real-time 3D dosimetry is intriguing and obviates the need for postimplant CT scanning and labor-intensive afterloading dosimetry. The real-time 3D dosimetric plan could be used for subsequent doses within a single hospital stay and eliminate the need for second and third implants. This would potentially reduce repeat trauma, cost, and morbidity.
We perform one interstitial implant and deliver three fractions (5.5 Gy) over 2 days. We have observed minimal movement of the catheters over the course of the hospital stay. We have been surprised by the lack of significant GU and gastrointestinal (GI) symptoms. Prior transurethral resection of the prostate, urinary obstructive symptoms, or large or small glandular volume may preclude permanent implantation. However, in our experience, HDR appears to be a viable alternative for these patients.
This article demonstrates the reemergence of brachytherapy as a viable 3D treatment option. Vicini et al emphasize the need for careful selection of patients for brachytherapy when used as either single- or combined-modality therapy. Patient selection should be based on multiple tumor- and patient-related factors, and on prospective data comparing the effects of these various approaches on QOL variables, as well as their costs and morbidities.
Physician expertise and experience are major factors that contribute to the success or failure of brachytherapy approaches, and thus the patient should be highly selective in that regard. Brachytherapy will continue to thrive in the treatment of prostate cancer as advances in technology lead to decreased morbidity.