Brachytherapy is performed by directly inserting radioactive sources into the prostate gland and is an important treatment option for appropriately selected men with prostate adenocarcinoma. Brachytherapy provides highly conformal radiotherapy and delivers tumoricidal doses that exceed those administered with external beam radiation therapy. There is a significant body of literature supporting the excellent long-term oncologic and safety outcomes achieved when brachytherapy is used for men in all risk categories of nonmetastatic prostate cancer. This article highlights some important considerations and published outcomes that relate to brachytherapy and its role in the treatment of prostate cancer.
Key points
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Brachytherapy is an important tool for radiation oncologists in the curative management of men with all risk categories of localized prostate cancer.
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By delivering radiation directly to the prostate gland via implantation, brachytherapy allows clinicians to deliver significant radiation dose escalation while minimizing doses to nearby normal tissues.
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Both low dose rate and high dose rate brachytherapy have published long-term data supporting their use for the treatment of prostate cancer.
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The long-term safety and tolerability of brachytherapy has been reported in multiple trials and series.
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Outcomes with brachytherapy compare favorably with other definitive treatment modalities.
Introduction
In 2016, there will be an estimated 180,890 men with a new diagnosis of prostate cancer, of whom approximately 80% will have localized disease, with an estimated 26,120 prostate-cancer specific deaths. Prostate cancer is the second leading cause of cancer-related death among men in the United States. For men diagnosed with nonmetastatic prostate cancer who pursue an active treatment approach, the National Comprehensive Cancer Network (NCCN) guidelines currently recommend radical prostatectomy and radiation therapy as appropriate definitive local therapy modalities. Both treatments have long been considered equivalent in cancer outcomes for the treatment of prostate cancer, an assertion that has been confirmed in a recently published randomized trial for low-risk patients. Among radiation therapy strategies, brachytherapy is an important treatment option with compelling data supporting its use for appropriately selected men with any NCCN risk category of nonmetastatic prostate cancer.
The term brachytherapy is derived from the Greek term “brachy,” which means “short,” and generally is used to describe a variety of therapeutic techniques using radioactive sources placed into or near tissues. The French physicians Pasteau and Degrais published the first description of prostate brachytherapy in 1914, which was performed using radium inserted through a catheter placed in the urethra. The first use of interstitial radioactive needle implantation, a technique more akin to modern methods, was published in 1917 by Benjamin Barringer, who was Chief of Urology at Memorial Hospital in New York. During the ensuing century, the technique and use of prostate brachytherapy has evolved to make it a safe and highly effective treatment modality for prostate cancer.
Introduction
In 2016, there will be an estimated 180,890 men with a new diagnosis of prostate cancer, of whom approximately 80% will have localized disease, with an estimated 26,120 prostate-cancer specific deaths. Prostate cancer is the second leading cause of cancer-related death among men in the United States. For men diagnosed with nonmetastatic prostate cancer who pursue an active treatment approach, the National Comprehensive Cancer Network (NCCN) guidelines currently recommend radical prostatectomy and radiation therapy as appropriate definitive local therapy modalities. Both treatments have long been considered equivalent in cancer outcomes for the treatment of prostate cancer, an assertion that has been confirmed in a recently published randomized trial for low-risk patients. Among radiation therapy strategies, brachytherapy is an important treatment option with compelling data supporting its use for appropriately selected men with any NCCN risk category of nonmetastatic prostate cancer.
The term brachytherapy is derived from the Greek term “brachy,” which means “short,” and generally is used to describe a variety of therapeutic techniques using radioactive sources placed into or near tissues. The French physicians Pasteau and Degrais published the first description of prostate brachytherapy in 1914, which was performed using radium inserted through a catheter placed in the urethra. The first use of interstitial radioactive needle implantation, a technique more akin to modern methods, was published in 1917 by Benjamin Barringer, who was Chief of Urology at Memorial Hospital in New York. During the ensuing century, the technique and use of prostate brachytherapy has evolved to make it a safe and highly effective treatment modality for prostate cancer.
The rationale for brachytherapy in the management of prostate cancer
Prostate cancer represents a favorable clinical scenario for the use of brachytherapy. The anatomic location of the prostate gland renders it relatively accessible for percutaneous placement of brachytherapy catheters. Incorporation of transrectal ultrasound imaging at the time of the brachytherapy procedure for visualization of the prostate gland and nearby anatomy allows accurate needle or catheter placement, which is vital for optimal radioactive source localization.
Brachytherapy allows a number of potential advantages over external beam radiation therapy (EBRT) delivered using either high-energy photons or protons. The most commonly used radioactive sources for modern prostate brachytherapy emit relatively low-energy (20–400 keV) photons that are typically absorbed by the surrounding tissues within a few centimeters. Megavoltage photons, which are standard for modern EBRT, have significantly greater energy than those used in brachytherapy applications. As such, photons from EBRT sources deposit energy over greater distances beyond their target before being attenuated fully. This physical property, along with the fact that EBRT inherently requires an entrance dose (ie, dose delivered on the pathway to the radiation target), results in a greater integral dose exposure to the normal tissue in proximity to the prostate. Although modern radiation techniques, such as intensity modulated radiation therapy (IMRT), have improved EBRT dose delivery, the dose concentration in the target allowed by brachytherapy is superior. Fig. 1 shows a comparison of the relative dose distribution achieved treating the prostate with high dose rate (HDR) brachytherapy (see Fig. 1 A) and IMRT (see Fig. 1 B). This image clearly demonstrates the ability of brachytherapy to limit both higher dose exposure to the rectum and low dose level exposure to the surrounding soft tissues. Proton beam therapy has physical characteristics that can decrease deposition of low to medium dose radiation compared with photon-based treatments. However, even a state-of-the art proton beam treatment plan (see Fig. 1 C) does not achieve the conformity provided by brachytherapy. Detailed dosimetric analyses have confirmed the superiority of brachytherapy treatments for decreasing radiation dose to the bladder and rectum compared with either IMRT or proton beam therapy with modern treatment regimens and technologies.
An additional point to consider is the ability of brachytherapy to provide dose-escalated treatment. Randomized studies have shown that improved clinical outcomes are associated with increased EBRT dose delivery to the prostate. With its favorable dosimetric conformality, brachytherapy allows clinicians to deliver radiation doses to the prostate far exceeding those able to be safely administered with external beam techniques. Most patients treated with modern EBRT receive a dose of approximately 74 to 80 Gy to the prostate, whereas commonly used brachytherapy prescription doses deliver a biological effective dose that is 1.5 to 3.0 times greater. Large brachytherapy treatment series have demonstrated the treatment with an increased biological effective dose is associated with improved disease control outcomes. Furthermore, by placing radioactive sources directly within the target tissue, brachytherapy creates focal “hot spots” or regions of dose more than 2-fold greater than the prescription level (see Fig. 1 A). Owing to their restricted location within the prostate, these areas of dose heterogeneity may confer improved cancer control rates without significantly affecting toxicity.
Prostate brachytherapy technical factors
Early applications of prostate brachytherapy were typically performed with placement of radioactive sources under visual guidance or by palpation, using a retropubic approach requiring open laparotomy for access. However, widespread adoption of this technique was hindered by the need for an open surgical procedure, suboptimal radiation dose coverage, and concerns related to radiation safety.
Modern prostate brachytherapy is almost exclusively performed by insertion of radioactive sources by way of transperineally implanted hollow catheters or needles with real-time image guidance ( Fig. 2 ). Most prostate brachytherapy procedures are performed as a same-day surgical procedure using either general anesthesia or spinal anesthesia with intravenous sedation. The number of needles required is variable and is influenced by prostate size, patient pelvic anatomy, and physics of the particular radioisotope used. Typically, 14 to 22 needles are used. The majority of implants are performed with transrectal ultrasound guidance, which allows excellent visualization of the prostate and brachytherapy needles. A Foley catheter is usually placed during the procedure to assist with identification of the urethra. A template with needle guidance holes at regular intervals is commonly placed on the perineum to assist with the identification, spacing, and securing of catheters. The positions of the template’s needle holes are registered and projected onto the ultrasound electronic display screen to guide and coregister the needle localization. The location and pattern for the placement of the interstitial needles and radiation sources into the prostate can be determined before the actual procedure using existing transrectal ultrasound images to optimize radiation dose delivery in a method known as “preplanning.” Conversely, needles can be inserted in a templated arrangement at the time of the procedure and modern computer-based treatment planning software can then be used to determine the optimal distribution of radiation sources to allow real-time planning. Real-time planning allows clinicians to account for differences in prostate volume or position at the time of the procedure and may improve clinical outcomes compared with preplanning. However, real-time planning typically prolongs the duration of the procedure compared with preplanning. After the implant is complete, the needles are removed and the patient is discharged after appropriate recovery from anesthesia. After the procedure, specific dosimetric parameters that quantify the dose to the prostate and nearby organs at risk (ie, urethra, bladder, and rectum) are recorded as a means to measure the quality of the implant and subsequent risk of toxicity.
Categories of prostate brachytherapy
Low Dose Rate Brachytherapy
Prostate brachytherapy techniques are often broadly categorized according to the physical properties of the radiation sources being used. Low dose rate (LDR) brachytherapy is used to describe treatments delivered by radioactive sources with dose rates of less than 2 Gy per hour. Modern transperineal implanted LDR brachytherapy, also known as permanent prostate brachytherapy, has been used for more than 30 years and is estimated to have been performed on more than 250,000 patients in the United States. Although a number of different radioactive isotopes have been used for LDR brachytherapy, the 3 most commonly used and commercially available sources, their physical properties, and typical prescription doses are shown in Table 1 . With an introduction year of 1965, 125 I has a longer clinical track record than either palladium-103 ( 103 Pd, 1986) or cesium-131 ( 131 Cs, 2004). Given the similar average energies of these 3 radionuclides, they possess comparable relative dose distributions and photon attenuation properties. The relatively shorter half-lives of 103 Pd and 131 Cs result in more rapid radiation dose rate delivery for these isotopes compared with 125 I. Both 103 Pd and 131 Cs offer a theoretic radiobiological advantage for improving tumor control, but do require lower prescription doses. However, multiple studies, including 1 randomized trial, have demonstrated no significant difference in patient clinical outcomes when comparing implants performed with either 125 I or 103 Pd. The current American Brachytherapy Society (ABS) and American Society for Radiation Oncology/American College of Radiology guidelines for permanent prostate brachytherapy provide recommendations relating to the use of either 125 I or 103 Pd for management of prostate cancer, with no preference given for either radionuclide. Given the growing experience with 131 Cs, its routine use has also gained acceptance among brachytherapy clinicians.
| Radionuclide | Half-Life (d) | Average Energy (keV) | Prescription Dose Range (Gy; Monotherapy) | Prescription Dose Range (Gy; Combined with EBRT) |
|---|---|---|---|---|
| Iodine-125 ( 125 I) | 59.4 | 28.4 | 140–160 | 108–110 |
| Palladium-103 ( 103 Pd) | 17.0 | 20.7 | 110–125 | 90–100 |
| Cesium-131 ( 131 Cs) | 9.7 | 30.4 | 115 | 80–85 |
Patient selection is an important consideration for delivery of LDR prostate brachytherapy. The ABS consensus guidelines provide a thorough overview of patient-specific factors that should be evaluated when determining candidacy for permanent prostate brachytherapy. As with any active treatment strategy being considered, all patients should have a recent biopsy (within <12 months from treatment) confirming prostate adenocarcinoma with Gleason score grading, a pretreatment serum prostate-specific antigen, physical examination including a digital rectal examination to determine tumor classification (T stage), and a thorough clinical history documenting pertinent past medical/surgical history. Table 2 lists both absolute and relative contraindications for LDR prostate brachytherapy according to the ABS consensus guidelines, which are similar to the recommendations published in other professional group guidelines for brachytherapy. Both obstructive and irritative lower urinary symptoms before implantation are an important factor to evaluate before proceeding with LDR brachytherapy. A number of publications have shown that patients with elevated International Prostate Symptom Scores before treatment are at greater risk of developing urinary retention or increased toxicity after permanent prostate brachytherapy. Patients who present with potentially prohibitive lower urinary tract symptoms at baseline can be treated with either medical (ie, alpha blockers) or surgical (transurethral resection of the prostate [TURP]) interventions with hopes to improve symptoms and render the risk of subsequent brachytherapy acceptable. However, medical treatments are generally preferred and TURP is generally reserved in the preimplant setting for men with large median lobes. Furthermore, although large TURP defects are considered a contraindication to permanent prostate brachytherapy owing to concerns regarding limitations in seed placement resulting in inadequate dosimetry, there are number of reports detailing excellent outcomes when brachytherapy is used in patients with previous TURP. Nevertheless, some studies still suggest an increased risk of urinary incontinence in the setting of prior TURP. Thus, careful patient evaluation with a detailed urinary function evaluation, volumetric imaging, and cystoscopy can be helpful in determining whether a TURP defect is prohibitory. Adequate placement of brachytherapy needles can be limited further by pubic arch interference related to individual pelvic anatomy, patient positioning at the time of procedure and prostate size. Generally, for men with prostate gland volumes of greater than 60 cm 3 , prebrachytherapy androgen deprivation therapy (ADT) with both luteinizing hormone-releasing hormone agonists and antiandrogens is recommended to mitigate pubic arch interference. A 4-month course of ADT will result in an average prostate volume reduction of 30%. Ultimately, the decision to proceed with LDR prostate brachytherapy should be undertaken after careful review of each patient and only after obtaining informed consent. The factors that determine brachytherapy candidacy often vary between individual physicians and are often guided by practitioner experience, skill, and training.
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High Dose Rate Brachytherapy
Modern HDR prostate brachytherapy, defined as treatment using a radionuclide with a calculated delivery rate of 12 Gy or greater per hour, emerged in the early 1990s as a novel and promising tool for the treatment of prostate cancer. Unlike LDR brachytherapy sources, which remain permanently implanted into the prostate, HDR sources are inserted temporarily into hollow needle catheters before being removed. Depending on the strength of the source being used and the dose prescribed, the radiation treatment is often delivered in 15 to 30 minutes. Nearly all modern prostate HDR brachytherapy treatments are performed using the radionuclide iridium-192 ( 192 Ir). 192 Ir has a half-life of 73.8 days and emits photons with an average energy of 380 keV, primarily via beta minus decay. Commercially available 192 Ir sources are typically small (eg, ∼5 mm in length and <1 mm in diameter) and are normally housed within a shielded robotic afterloader that also serves as the control mechanism for their deployment to and retrieval from catheters. One advantage provided by HDR brachytherapy is that a single source can be used for multiple treatments, across multiple tumor types such as breast and gynecologic malignancies, during its 90- to 120-day practical lifetime. Whereas the use of a remotely controlled radionuclide source delivery afterloader results in essentially no radiation exposure to staff with HDR brachytherapy, the absolute advantage in exposure over manually loaded LDR brachytherapy is insignificant. HDR brachytherapy does typically require more capital equipment costs upfront than LDR brachytherapy given the need to obtain an afterloader and remote control panel. Furthermore, the recurring costs of replacing the 192 Ir source multiple times per year must be justified by adequate clinical volume. An additional consideration for HDR brachytherapy is the need for significantly greater room and storage area shielding than is required for most LDR sources.
Patient selection criteria for consideration of prostate HDR brachytherapy are very similar to those for LDR prostate brachytherapy. ABS consensus guidelines are available for HDR prostate brachytherapy and list absolute contraindications of preexisting rectal fistula, medically unsuited for anesthesia, and no proof of other major malignancy. According to the European Society for Therapeutic Radiology and Oncology, additional factors that should be evaluated on an individual patient basis to determine candidacy for HDR prostate brachytherapy include prior pelvic radiation or surgery, inflammatory bowel disease, previous urethral procedures, urinary function, and prostate volume.
Consideration of brachytherapy according to prostate cancer risk group stratification
Although the American Joint Commission Cancer staging guidelines have long been used to stage prostate cancer patients for prognostic and treatment considerations based on pathologic and radiographic findings, risk group stratification has emerged as a means to use clinically available data for classification of newly diagnosed patients. A number of organizations, including the American Urologic Association, European Association of Urology, NCCN, and European Society for Medical Oncology have published risk group stratification parameters that divide patient into either low-, intermediate-, or high-risk categories based on clinical tumor classification (T stage), pretreatment prostate-specific antigen levels, and Gleason Score grade. Both the ABS and European Society for Therapeutic Radiology and Oncology consensus guidelines for LDR and HDR brachytherapy provide guidance with regard to the appropriateness of brachytherapy for men with prostate cancer according to their clinical risk group. However, these guidelines do also caution that recommendations are limited by a lack of level I evidence guiding patient selection. It should be emphasized that the existing literature reporting clinical outcomes for prostate brachytherapy are primarily institutional reports with heterogeneous inclusion criteria and methodologies.
In men with low-risk disease, there is universal consensus that brachytherapy alone is an excellent treatment modality for men undergoing LDR brachytherapy and those not pursuing active surveillance. In patients with intermediate risk factors, there remains differing perspectives whether brachytherapy is suitable as a stand-alone treatment, or should only be considered when used in combination with EBRT or ADT. This concern stems from the fact that certain patients with intermediate-risk prostate cancer will likely harbor clinically occult tumor extraprostatic disease, such as extraprostatic extension, seminal vesicle invasion, or lymph node metastases, which may be treated inadequately with brachytherapy alone. Detailed reviews of pathologic prostatectomy specimens has shown that radial extension of extraprostatic tumor rarely exceeds 5 mm, and thus should be adequately treated by brachytherapy treatments incorporating an appropriate planning margin. Some studies have suggested that patients with more concerning intermediate risk factors, often termed “unfavorable intermediate risk,” have a poorer prognosis when treated with brachytherapy alone. However, the addition of supplemental EBRT in intermediate-risk prostate cancer has not yet been proven to improve outcomes. Further study is needed to elucidate if there are subsets of intermediate risk patients that derive benefit from the addition other treatment modalities to brachytherapy for definitive management. Men with high-risk prostate cancer have the poorest prognosis and seem to benefit from the use of multimodality therapy given their risk of non–organ-confined disease. Thus, brachytherapy is only recommended as a boost to EBRT for these patients. However, the importance of brachytherapy as a means to provide dose escalation and improve local control in high-risk prostate cancer should not be discounted, because its incorporation in multimodal therapy has been shown to improve outcomes compared with EBRT or surgery-based strategies.
Clinical Outcomes of Prostate Cancer
Brachytherapy alone
Table 3 lists the pertinent details and clinical outcomes from selected published studies of both LDR and HDR monotherapy for the treatment of men with prostate cancer. These data clearly demonstrate that long-term prostate-specific antigen control exceeding 82% can be expected with the use of brachytherapy alone for men with low-risk prostate cancer, whereas biochemical control rates of 70% to 89% are typical in men with intermediate-risk disease. These outcomes compare very favorably to those seen in similar patients enrolled on contemporary studies assessing treatment with EBRT or radical prostatectomy.
| Study | Years of Treatment | Number of Patients | Risk Group (%) | Dose Prescription | Biochemical Control (%) | ||||
|---|---|---|---|---|---|---|---|---|---|
| Low | Intermediate | High | Low | Intermediate | High | ||||
| Low dose rate brachytherapy | |||||||||
| Kittel et al, 2015 | 1996–2007 | 1989 | 61 | 30 | 5 | 144 Gy ( 125 I) | 87 (10 y) | 79 (10 y) | 68 (5 y) |
| Funk et al, 2015 | 1998–2013 | 966 | 71 | 29 | — | 145 Gy ( 125 I) | 90 (10 y) | 74 (10 y) | — |
| Tran et al, 2013 | 2003–2007 | 615 | — | 100 | — | 145 Gy ( 125 I) | — | 89 (5 y) | — |
| Sylvester et al, 2011 | 1988–1992 | 215 | 74 | 21 | 5 | 144 Gy ( 125 I) | 86 (15 y) | 80 (15 y) | 62 (15 y) |
| Henry et al, 2010 | 1995–2004 | 1298 | 44 | 33 | 14 | 145 Gy ( 125 I) | 86 (10 y) | 77 (10 y) | 61 (10 y) |
| Zelefsky et al, 2007 | 1988–1998 | 2693 | 55 | 40 | 5 | 144 Gy ( 125 I), 130 Gy ( 103 Pd) | 82 (8 y) | 70 (8 y) | 48 (8 y) |
| Guedea et al, 2006 | 1998–2003 | 1050 | 64 | 28 | 6 | 145 Gy ( 125 I) | 93 (3 y) | 88 (3 y) | 80 (3 y) |
| Grimm et al, 2001 | 1988–1990 | 126 | 77 | 23 | — | 145 Gy ( 125 I) | 87 (10 y) | 79 (10 y) | — |
| Blasko et al, 2000 | 1988–1995 | 230 | 45 | 46 | 9 | 115 Gy ( 103 Pd) | 94 (5 y) | 82 (5 y) | 65 (5 y) |
| High dose rate brachytherapy | |||||||||
| Yoshioka et al, 2016 | 1995–2012 | 190 | — | 42 | 58 | 45.5–54 Gy in 7–9 fractions | — | 91 (8 y) | 77 (8 y) |
| Jawad et al, 2016 | 1999–2013 | 494 | 68 | 32 | — | 24–38 Gy in 2–4 fractions | 97 (5 y) | 88 (5 y) | — |
| Hauswald et al, 2016 | 1996–2009 | 448 | 64 | 36 | — | 42–43.5 Gy in 6 fractions | 99 (10 y) | 95 (10 y) | — |
| Zamboglou et al, 2013 | 2002–2009 | 718 | 55 | 25 | 20 | 34.5–38 Gy in 3–4 fractions | 95 (5 y) | 93 (5 y) | 93 (5 y) |
| Rogers et al, 2012 | 2001–2011 | 248 | — | 100 | — | 39 Gy in 6 fractions | — | 94 (5 y) | — |
| Hoskin et al, 2012 | 2003–2009 | 197 | 4 | 52 | 44 | 26–36 Gy in 2–4 fractions | — | 99 (3 y) | 91 (3 y) |
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