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.

Seminal Vesicle/Pelvic Lymph Node Involvement

The ability of prostate brachytherapy to successfully sterilize the prostate gland and periprostatic region may relegate the use of supplemental XRT to patients at high risk of seminal vesicle and/or pelvic lymph node involvement. In a large, comprehensive study, Kestin and colleagues reported that only 1% of low-risk patients but 27% of high-risk patients (PSA > 20 ng/mL and/or Gleason score ≥ 7) had seminal vesicle involvement.[26] When all patients were included, only 7% had such involvement beyond 1.0 cm, and 1% had involvement beyond 2.0 cm. Of patients with seminal vesicle involvement, 51% had extension more than 1.0 cm beyond the prostate/seminal-vesicle junction, and 6% had such extension beyond 2.0 cm.[26]

The proximal 6 to 10 mm of the seminal vesicles can be successfully implanted with high radiation doses.[9,27] With generous periprostatic seed placement, a D90 of approximately 100% of the prescribed dose is routinely delivered to the proximal 10 mm of the seminal vesicles. Beyond 12 mm, however, the radiation dose decreases rapidly (Figures 2 and 3). Thus, brachytherapy seminal vesicle radiation dose distributions are inadequate for a substantial minority of patients. Patients at high risk of seminal vesicle involvement probably require the addition of supplemental XRT. Moreover, in patients with seminal vesicle involvement, the customary supplemental XRT doses of 45 Gy may be inadequate to eradicate the malignant extension, and implantation of the proximal seminal vesicles may be of therapeutic benefit.

Supplemental XRT may also benefit patients with a significant risk of pelvic lymph node involvement.[28] Kestin and colleagues reported that among prostate cancer patients with seminal vesicle involvement, 64% also had pelvic lymph node involvement.[26] In a randomized, prospective clinical trial, Roach and colleagues demonstrated that neoadjuvant androgen deprivation with pelvic radiotherapy given to patients with a 15% or greater incidence of pelvic lymph node involvement maximized disease-free survival, suggesting a synergistic effect between the two modalities.[28]

Because of the steep dose gradients inherent to brachytherapy, patients at significant risk for seminal vesicle and/or pelvic lymph node involvement are likely to benefit from supplemental XRT.

Brachytherapy Planning and the Need for Supplemental XRT

Favorable brachytherapy results have been obtained with a variety of planning and intraoperative techniques-and the role of supplemental XRT depends, to some extent, on the definition of target volume (ie, prostate only vs prostate with periprostatic margin). Unfortunately, there is no consensus as to what the optimal target volume is, and the opinions of highly experienced brachytherapists vary substantially.[29]

In programs using generous preplanned treatment margins, the planning target volume (ie, the prostate gland with a periprostatic margin) is determined by a 3- to 8-mm enlargement of each ultrasound slice.[8,9,24] This margin is based on pathologic measures of the probability of microscopic extraprostatic extension [15-17] as well as on estimates that seed placement uncertainty is approximately 5 mm longitudinally and 3 mm in transverse directions.[30] Our approach places approximately 35% of seeds in selected periprostatic locations, with a long-term fixity (persistence) exceeding 98% for Pd-103 Theraseed (Theragenics, Norcross, Ga) or I-125 RapidStrand (Oncura, Plymouth Meeting, Pa).[18,24]

Using this approach, CT-based dosimetry performed on the day of the implant has demonstrated mean postimplant treatment margins of 6.5 mm at the 100% isodose line (Table 3).[9] The 100% isodose margin exceeded 6 mm at all locations except the bladder neck and the prostatorectal interface (Figure 2). These dosimetric margins were accomplished without increased urinary, rectal, or sexual toxicity, compared with brachytherapy techniques that do not use generous periprostatic treatment margins.[3]

Differences in Treatment Margins

Treatment margins may vary markedly between patients with comparable dosimetric parameters. In a prospective, randomized trial, dosimetric results from the day of implantation showed that brachytherapy margins outperformed other dosimetric parameters in predicting biochemical progression-free survival.[10] If implants are designed and executed with generous periprostatic margins, the determination of postimplant prostate volume as shown by CT does not significantly influence the traditionally assessed dosimetric parameters-ie, volume of the gland receiving 100%, 150%, and 200% of the prescription dose, and D90.[23] In addition, brachytherapy plans that consider the prostate with margins minimize any dosimetric differences between the I-125 and Pd-103.[8]

Biochemical progression-free survival is related directly to radiation dose.[22] Since the radiation dose decreases by up to 20 Gy/mm at the periphery of the target volume,[31] the use of treatment planning margins further increases the confidence that a therapeutic radiation dose will be consistently delivered to the periprostatic region. Because the vast majority of prostate cancer cases are intraprostatic,[32] the control of extraprostatic cancer may be assumed to be at least as good as the intraprostatic component if the radiation doses delivered to the intra- and extraprostatic sites are comparable. This finding may partially explain the fact that supplemental XRT may not improve biochemical outcome for low-, intermediate-, or even selected high-risk patients.[2,4]

Does Supplemental XRT Improve Biochemical Progression-Free Survival?

Low-Risk Features

In contemporary series, brachytherapy alone for patients with low-risk features (PSA ≤ 10 ng/mL, Gleason score ≤ 6, and clinical stage = T1c or T2a, per 2002 American Joint Committee on Cancer [AJCC] staging)[33] has produced high rates of biochemical control, with no apparent improvement when supplemental XRT was added. Biochemical progression-free survival rates of 87% to 98% have been reported.[2,4,5,34,35]

Grimm and colleagues reported the presence of a learning curve, demonstrating significant differences in biochemical progression-free survival among low-risk patients stratified into 1986-1987 vs 1988-1989 cohorts (Figure 4).[5] This information likely explains the poorer results of the earliest Seattle experience, in which patients who received supplemental XRT in conjunction with brachytherapy had improved biochemical control rates despite poorer prognosticators.[36,37] When data are stratified in terms of pretreatment PSA levels, biochemical progression-free survival for high-quality brachytherapy alone vs brachytherapy plus supplemental XRT are virtually superimposable.[2,4-6]

Intermediate-Risk Features

Similar to low-risk patients, those with intermediate-risk features (PSA ≥ 10 ng/mL or Gleason score ≥ 7 or clinical stage ≥ T2c, per the 2002 AJCC)[33] can achieve high rates of biochemical control with high-quality monotherapeutic brachytherapy. Blasko and colleagues reported a 9-year freedom-from-biochemical-progression rate of 82%, with a plateau on the curve for a Pd-103 monotherapeutic approach.[4] The addition of supplemental XRT to brachytherapy, however, did not improve 5-year biochemical outcome (84% vs 85%).[38]

In a more contemporary series, Merrick and colleagues reported an 8-year, biochemical progression-free survival rate of 95% when brachytherapy alone was used in hormone-naive, intermediate-risk patients, with a median posttreatment PSA level < 0.1 ng/mL.[2,39] Interestingly, Potters and colleagues demonstrated no benefit when supplemental XRT was administered to intermediate-risk patients.[35] Taken together, these data show no evidence of biochemical advantage when supplemental external-beam radiation is used in hormone-naive, intermediate-risk brachytherapy patients.[2,4,35,38,39]

High-Risk Features

High-risk patients (with at least two of the following risk factors: PSA ≥ 10 ng/mL, Gleason score ≥ 7, clinical stage ≥ T2c, per the 2002 AJCC)[33] have generally fared poorly with external-beam radiation alone, exhibiting apparent cure rates of < 50%. Early reports of brachytherapy used with supplemental external-beam radiation were surprisingly favorable and led to the widespread use of supplemental XRT.[6,7]

For example, Dattoli and colleagues reported a 79% 10-year biochemical progression-free survival (PSA ≤ 0.2 ng/mL) for patients receiving supplemental XRT followed by a Pd-103 boost, with a plateau on the biochemical freedom-from-failure curves within 3 years of implantation.[7] For hormone-naive, high-risk patients undergoing brachytherapy and supplemental XRT, Merrick and colleagues demonstrated an approximate 80% 8-year freedom-from-biochemical-failure rate, with a median posttreatment PSA < 0.1 ng/mL.[2,40]

The favorable cure rates reported following administration of brachytherapy and supplemental XRT were quickly interpreted as evidence that the latter was essential to the treatment scheme. However, some studies with brachytherapy alone have shown similar, highly favorable results for high-risk patients. For example, Lee et al stratified high-risk brachytherapy patients undergoing brachytherapy without supplemental XRT into two groups: One received "low-dose" therapy (day 30 D90 dose < 140 Gy for I-125 and < 100 Gy for Pd-103), and the other received "high-dose" implants. The high-dose arm exhibited an 80% 5-year freedom from biochemical failure.[13] In addition, in the early Seattle experience, Blasko and colleagues reported a 65% 9-year freedom-from-biochemical-progression rate using Pd-103 alone in patients with a pretreatment PSA > 20 ng/mL.[4]

Conflicting Opinions on Supplemental XRT

Almost all studies of intermediate- and high-risk brachytherapy patients receiving supplemental XRT have reported favorable biochemical outcomes. However, the biochemical control rates for intermediate- and high-risk patients given monotherapeutic brachytherapy remain controversial (Figure 5). We attribute some of the discrepancies to differences in preplanning and/or intraoperative technique.

Some initial reports described remarkably poor outcomes for intermediate- and high-risk patients treated with brachytherapy alone. For instance, Brachman and colleagues reported 5-year, biochemical, progression-free survival rates of 53% for patients with a pretreatment PSA of 10 to 20 ng/mL and 28% for those with a Gleason score of 7 following brachytherapy alone.[41] In other research, following Pd-103 monotherapy, D’Amico and colleagues projected a 5-year biochemical control rate of 35% for intermediate-risk patients and 0% for high-risk patients.[42] In addition, Kwok et al reported a 5-year freedom-from-biochemical-progression rate of 24% for high-risk patients receiving I-125 brachytherapy only.[43]

These poor outcomes were interpreted by some to be evidence that brachytherapy alone was unsuitable for patients with higher-risk features. However, these outcomes most likely resulted from poor technique rather than the inadequacy of brachytherapy per se. None of these three monotherapeutic studies used extracapsular seeds or evaluated postimplant dosimetric outcomes. In fairness to these early authors, technology for the calculation of postimplant dosimetry was not always available.

Cancer eradication in monotherapeutic intermediate- and high-risk brachytherapy patients likely requires meticulous technique, generous periprostatic treatment margins, postimplant dosimetric confirmation of adequate radiation dose distributions, minimal involvement of the seminal vesicles, and a low risk of pelvic lymph node involvement.[9,22,24] In the absence of any of these criteria, the use of supplemental XRT may be mandatory for durable biochemical control.

Morbidity

In addition to rapidly accumulating data suggesting that supplemental external-beam irradiation is not needed to maximize brachytherapy cure rates for most patients, there is increasing evidence that supplemental XRT increases brachytherapy-related urinary, rectal, and sexual morbidity.

Urinary Function

Using the patient-administered urinary domain of the Expanded Prostate Cancer Index Composite (EPIC), Merrick et al reported that supplemental XRT adversely affected long-term urinary quality of life, including the urinary function and incontinence domains.[44] Supplemental external-beam irradiation also increased the risk of late hematuria and bulbomembranous urethral strictures.[3,45]

Rectal Function

Supplemental XRT has been reported to result in minimal, but detectable, long-term bowel dysfunction in some, but not all, studies.[3,46,47] These equivocal results partially result from the method of data collection and the quality-of-life instrument used. Nevertheless, they emphasize the rare nature of severe rectal complications following modern brachytherapy.

Erectile Dysfunction

Radiation dose to the proximal penis has been implicated in the development of radiation-induced erectile dysfunction.[48] In early studies, supplemental external-beam radiation reportedly increased the incidence of brachytherapy-induced erectile dysfunction, with a decrease in the 6-year actuarial rate of potency preservation (as determined by the International Index of Erectile Function) from 52% to 26%.[3,48] However, some of this negative effect on erectile function may be due to injudicious treatment delivery, as supplemental XRT did not affect erectile function in a prospective, randomized trial using treatment-planning techniques to minimize the dose to the proximal penis.[49] Fortunately, most cases of brachytherapy-induced erectile dysfunction respond favorably to erectogenic medications.[50]

Cost

Treatment that cures prostate cancer is the most economic in the long term, and the expense of supplemental XRT pales in comparison to the cost of treating persistent cancer. However, superfluous use of supplemental external-beam radiation substantially increases treatment costs unnecessarily.

At the Schiffler Cancer Center, the addition of 45 Gy given via 3D-CRT over 5 weeks to brachytherapy increases the cost by approximately 60% compared to monotherapy (Figure 6). However, the use of intensity-modulated beam radiation increases the cost by almost threefold. Thus, in both the absence of quality clinical evidence of a benefit for supplemental XRT and the presence of an increasing body of data that shows the technique to increase morbidity, supplemental external-beam radiation should be reserved for patients who are most likely to benefit from it.

Ongoing Prospective Randomized Clinical Trials

The issue of supplemental external-beam radiation will eventually be resolved. Given the disconnect between superficially logical rationales for its use and clinical evidence that it is not beneficial in most patients, several research teams are currently performing prospective randomized clinical trials to evaluate its benefit.

To investigate the most appropriate dose of supplemental XRT in prostate cancer patients with higher-risk features who are receiving Pd-103 brachytherapy, investigators at the University of Washington, the Puget Sound Veteran's Administration Hospital, and the Schiffler Cancer Center randomized patients in this population to 44 vs 20 Gy of supplemental external-beam radiation (Figure 7). A preliminary analysis showed no difference in biochemical outcome between the groups, suggesting that the dose of XRT can be safely reduced.[51]

The absence of differences in biochemical control rates with a lowered external-beam radiation dose strongly suggests that the technique is not necessary. As such, a second-generation, prospective, randomized trial for patients with high-risk features is randomizing patients to the aforementioned 20-Gy arm vs treatment with monotherapeutic Pd-103 (Figure 8). The Radiation Therapy Oncology Group (RTOG) is also evaluating the role of supplemental external-beam radiation (at 45 Gy) in treating patients with intermediate-risk features (Figure 9). Results from these latter two trials should be available by 2010.

Conclusions

Generous brachytherapy treatment margins appear to obviate the need for supplemental XRT in low-, intermediate-, and selected high-risk brachytherapy patients. In the absence of clinical data based on administration of high-quality brachytherapy, the use of supplemental beam should be limited to patients at significant risk of seminal vesicle or pelvic lymph node involvement.

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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