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Permanent Prostate Brachytherapy: Is Supplemental External-Beam Radiation Therapy Necessary?

Permanent Prostate Brachytherapy: Is Supplemental External-Beam Radiation Therapy Necessary?

Permanent prostate brachytherapy with or without supplemental therapies is a highly effective treatment for clinically localized prostate cancer, with biochemical outcomes and morbidity profiles comparing favorably with competing local modalities. However, the absence of prospective randomized brachytherapy trials evaluating the role of supplemental external-beam radiation therapy (XRT) has precluded the development of evidence-based treatment algorithms for the appropriate inclusion of such treatment. Some groups advocate supplemental XRT for all patients, but the usefulness of this technology remains largely unproven and has been questioned by recent reports of favorable biochemical outcomes following brachytherapy used alone in patients at higher risk. Given that brachytherapy can be used at high intraprostatic doses and can obtain generous periprostatic treatment margins, the use of supplemental XRT may be relegated to patients with a high risk of seminal vesicle and/or pelvic lymph node involvement. Although morbidity following brachytherapy has been acceptable, supplemental XRT has shown an adverse impact on long-term quality of life. The completion of ongoing prospective randomized trials will help define the role of XRT as a supplement to permanent prostate brachytherapy.

Prostate brachytherapy is a highly effective treatment for clinically localized prostate cancer, with biochemical outcomes and morbidity profiles comparing favorably with competing local modalities.[1-7] These favorable biochemical control rates are in part the result of intraprostatic dose escalation and therapeutic periprostatic irradiation resulting from generous periprostatic brachytherapy treatment margins and/or supplemental external-beam radiation therapy (XRT).[8-10] It has become increasingly clear that efficacy and morbidity depend on the quality of brachytherapy.[8-10] Having established that brachytherapy can eradicate cancer in a large majority of patients, investigators are focusing increasing attention on maximizing the effectiveness and efficiency of this modality.

Some investigators have advocated the liberal use of supplemental XRT based on its theoretical requirement in eradicating periprostatic cancer in patients at higher risk.[6,7] The American Brachytherapy Society has recommended that supplemental XRT be used in patients with a pretreatment prostate-specific antigen (PSA) > 10 ng/mL, a biopsy Gleason score ≥ 7, and/or bilobar, palpable disease, with brachytherapy alone reserved for patients with low-risk features (PSA ≤ 10 ng/mL, Gleason score ≤ 6, and clinical stage ≤ T2a).[11]

Development of evidence-based treatment algorithms that include supplemental XRT in patient treatment plans has been hampered by the lack of data from prospective randomized trials combining the technique with brachytherapy. In fact, this technique remains largely unproven, and recent reports of favorable biochemical outcomes following brachytherapy used alone in patients with higher-risk features have questioned its usefulness.[2,4,12,13] The ability of high-quality, monotherapeutic brachytherapy to deliver cancer-ablating intraprostatic doses with generous periprostatic treatment margins will likely obviate the need for supplemental XRT in low-, intermediate-, and selected high-risk patients.

Rationale for Supplemental XRT

When used with permanent prostate brachytherapy, supplemental XRT enhances the radiation dose to the periprostatic region and allows intraprostatic dose escalation, dose supplementation of a technically inadequate implant, and irradiation of the seminal vesicles and/or pelvic lymph nodes (Table 1). When used with high-quality brachytherapy, the value of supplemental XRT for the first three of these indications is highly suspect.

Treating Extracapsular Disease

In the absence of pelvic lymph node involvement and distant metastases, prostate cancer patients with extraprostatic extension remain curable as long as the malignant extracapsular component can be eradicated. Even among patients with clinically organ-confined prostate cancer and a PSA ≤ 10 ng/mL, as many as 50% manifest extraprostatic extension at the time of radical prostatectomy.[14] Pathologic evaluation of radical prostatectomy specimens has shown the mean extent of extraprostatic extension to be in the range of 1 to 3 mm; thus, brachytherapy treatment margins of 5 mm should encompass all sites of extracapsular extension in 99% of cases (Table 2).[15-17]

As such, the primary rationale for supplemental XRT is to increase the dose and radial extent of periprostatic irradiation for the sterilization of extraprostatic extension (Figure 1). Implant prescription radiation doses may be delivered consistently to the prostate, the periprostatic region, and the proximal seminal vesicles using appropriately placed high-activity ex-tracapsular and/or intracapsular seeds (Figure 2, Table 3).[8-10,18]

Adverse pathologic features (eg, high Gleason score, perineural invasion, and extensive tumor) in the biopsy specimen correlate with a higher likelihood of extraprostatic extension. The ability of brachytherapy to irradiate the prostate with generous treatment margins may make these adverse prognosticators less important compared with competing local treatment modalities.[1,2,4,8,19] For example, a study of hormone-naive brachy-therapy patients implanted with generous periprostatic treatment margins showed that whether or not supplemental XRT was used, the presence of perineural invasion in the biopsy specimen did not adversely affect 8-year biochemical progression-free survival.[19]

When cancer-positive prostate biopsies were stratified by pretreatment PSA level, a higher percentage predicted for a significant increase in extraprostatic extension but only a minimal increase in the involvement of either the seminal vesicles or the pelvic lymph nodes.[20] Following radical prostatectomy or three-dimensional conformal radiation therapy (3D-CRT), biopsies stratified into < 34% positive, 34%-50% positive, and > 50% positive cohorts were inversely related to biochemical outcome.[1] Although the ability of percent-positive biopsies to predict biochemical control rates following brachytherapy is statistically significant, the absolute differences when stratified into the above-mentioned percent-positive biopsy cohorts are minimal and independent of supplemental XRT use.[21] These favorable brachytherapy results may be attributed to aggressive irradiation of the extracapsular region, including the base of the seminal vesicles (Figure 2).

An aggressive locoregional approach that includes generous periprostatic brachytherapy treatment margins and delivery of therapeutic doses to the prostate gland, extracapsular region, and base of the seminal vesicles with postimplant dosimetric analyses to confirm adequate radiation dose distributions results in a high probability of biochemical success in patients with a substantial risk of extraprostatic extension, limited involvement of the seminal vesicles, and a low risk of pelvic lymph node involvement.[2,4,8-10,15-17,21]

Eradicating Intraprostatic Cancer

A second rationale for supplemental XRT is to increase intra- and extraprostatic radiation dose distributions. The precise cancer-ablating intra- and extraprostatic doses are unclear, because such doses have not been delineated definitively for gross and microscopic disease. However, available data strongly suggest that intraprostatic dose escalation secondary to the addition of supplemental XRT is unnecessary with high-quality brachytherapy.

Kollmeier and colleagues published day 30 postimplant dosimetric cutpoints for monotherapeutic intraprostatic radiation dose.[22] They concluded that a D90 (the minimum dose delivered to the "hottest" 90% of the prostate) measuring 140 Gy for iodine (I)-125 and 100 Gy for palladium (Pd)-103 represented thresholds for optimal biochemical outcome. These doses comprised 93% and 80%, respectively, of the commonly prescribed monotherapeutic doses for I-125 and Pd-103. In experienced hands, these cutpoints are routinely achievable in more than 98% of all monotherapeutic implants subjected to dosimetric analysis on the day of brachytherapy implantation.[8]

Rectifying a Technically Inadequate Implant

Technically inadequate implants result from either inadequate computer-based treatment planning or poor technique. However, the impact of implant-related edema is not an excuse for an inadequate result. While adding supplemental XRT "spackles" intraprostatic dose deficiencies, adds several millimeters to the periprostatic margin, and minimizes the clinical impact of a technically inadequate implant and/or treatment-related edema, the use of generous, planned treatment margins minimizes the effect of this fluid retention.[23]

A modified, uniform/peripheral planning philosophy results in a dose distribution that is relatively homogeneous throughout the prostate gland and extracapsular region, is least dependent on seed migration, and is relatively independent of brachytherapy-related edema.[18,23,24] With the increasing availability of intraoperative dosimetry, technically inadequate implants should be rare.[25]

Patients with probable minimal involvement of the seminal vesicles and a low risk of pelvic lymph node involvement are unlikely to benefit from supplemental XRT if they have undergone brachytherapy with treatment margins of 5 mm or larger, as determined by day 0 computed tomography (CT), and a D90 greater than the prescription dose.

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