1 Introduction

  • The goal of brachytherapy is to deliver ablative doses of radiation directly to a tumor with relative sparing of surrounding normal tissues by placing the radioactive source in close proximity to the tumor.

  • High dose rate (HDR) brachytherapy is the use of radioactive isotopes to deliver radiation dose at a rate ≥20 cGy/min (12 Gy/h, usually much higher) [1]. It is performed by temporarily inserting a radioactive source through catheters that are directly inserted in a tumor via a remote afterloader. The total dose is delivered over the course of one or several fractions—either as a single implant or multiple implants.

  • In prostate cancer, HDR brachytherapy is commonly used as monotherapy in men with low and favorable intermediate risk prostate cancer, as a boost when combined with external beam radiation therapy (EBRT) for men with unfavorable intermediate or high risk prostate cancer, or as salvage local therapy in men with local recurrence after prior curative-intent radiotherapy [2].

  • Biochemical and clinical outcomes with HDR brachytherapy are similar to those seen with surgery and EBRT [3,4,5,6,7].

  • In this chapter, we will discuss the history and rationale for prostate HDR brachytherapy, key anatomy, optimal patient selection, implantation and treatment delivery considerations, treatment-related toxicity, and patient follow-up considerations.

2 History of Prostate HDR Brachytherapy

  • Prostate HDR was pioneered in the late 1980s and early 1990s as a boost treatment to EBRT in men with intermediate and high-risk prostate cancer at multiple centers across the world [8,9,10]. These regimens used 2–4 fractions delivered using 1–2 implants.

  • Following the encouraging outcomes seen with HDR boost, HDR as monotherapy was pioneered at Osaka University, Japan, in the mid-1990s. This initial regimen consisted of one implant and a subsequent 5-day hospitalization. Patients received 48 Gy in 8 fractions or 54 Gy in 9 fractions delivered twice daily >6 h apart [11]. Around this time, 4 and 6 fraction regimens were also developed [12,13,14].

  • Like other forms of prostate cancer radiation therapy, there has been a trend toward the use of more hypofractionated regimens for monotherapy and boost treatment delivery. Current regimens are delivered using 1–2 implants (delivering 1–2 fractions per implant) as outpatient procedures.

  • Initial prostate HDR brachytherapy strategies employed ultrasound or CT-based treatment planning, but MRI has become increasingly available for contouring and treatment planning.

  • Salvage local therapy for locally radiorecurrent disease after initial curative-intent radiation represents the most novel role of prostate HDR brachytherapy and is actively being studied.

3 Rationale for Prostate HDR Brachytherapy

  • The initial rationale for the use of HDR brachytherapy was to overcome the variability of dosimetry seen with low dose rate (LDR) brachytherapy due to seed displacement/misplacement. Given the relatively fixed nature of the catheters and the post-implantation plan optimization, the radiation dose could be reliably delivered according to the treatment plan. Additionally, the rapid complete dose delivery of HDR was hypothesized to offer a radiobiologic advantage in the setting of prostate cancer, which has a low alpha/beta ratio.

  • Both LDR and HDR brachytherapy have dosimetric advantages over EBRT. Comparative series suggest more consistent dosimetry with HDR compared to LDR [15, 16]. A dosimetric comparison from a randomized trial demonstrated improved urethral and rectal dosimetry with HDR [17] compared to LDR. Additionally, HDR may allow for improved coverage of extracapsular extension and seminal vesicle involvement compared to LDR [18].

  • Retrospective comparisons suggest similar biochemical control with LDR and fractionated HDR but less severe urinary and bowel toxicity and similar or decreased sexual toxicity with HDR [13, 19, 20].

  • A small Phase II randomized pilot study of 31 patients developed through CHU de Quebec-Universite Laval compared definitive single fraction HDR with LDR. HDR demonstrated less severe detriment and more rapid resolution in International Prostate Symptom Score (IPSS). Additionally, the HDR group had improved IPSS and Expanded Prostate Cancer Index Composite (EPIC)-26 urinary incontinence scores compared to the LDR group in the first year [21]. However, as discussed below, single fraction HDR may not be the optimal form of HDR monotherapy due to a higher risk of recurrence compared to fractionated HDR.

  • Several trials are ongoing comparing definitive HDR and LDR brachytherapy (NCT02692105, NCT02960087, NCT03426748, NCT02628041, NCT02960087).

  • Disadvantages to HDR include:

    • Compared to EBRT, HDR requires a surgical procedure. In fact, depending on the regimen that is used, multiple implantation surgical procedures may be required, which increases the risk of complications from anesthesia and the implant procedures themselves (e.g., infection). This contrasts with LDR, which requires only a single implant procedure. However, the current NCCN guideline-endorsed HDR regimens are 13.5 Gy × 2 fractions as monotherapy and 15 Gy × 1 as a boost, decreasing the number of treatments/implants [2].

    • Compared to LDR, there are higher initial capital costs (i.e., to purchase the remote-afterloader system and building a shielded room). However, this can be mitigated by the ability to use the remote-afterloader system and shielded room for many patients with various malignancies.

    • From a staffing perspective, HDR typically requires more time and resources than LDR.

4 Pertinent Anatomy for Prostate HDR Brachytherapy

  • Comprehensive understanding of the key anatomic structures and their appearance on the various imaging modalities is critical to deliver safe and effective HDR brachytherapy. Similar to other forms of radiation therapy, these include the urethra, rectum, bladder neck, neurovascular tissue, external urethral sphincter, and penile bulb. Similar to LDR brachytherapy, the pubic arch, formed by the inferior rami and pubis, should be identified as it may lead to interference during the transperineal implantation procedure, although this is typically a lesser concern than with LDR.

  • The brachytherapist must have comfort with identifying and delineating these anatomic structures prior to the implant, intraoperatively during the implantation and during treatment planning in the axial and sagittal dimensions.

  • Pre-operative MRI is particularly helpful in preparing and strategizing for the implant in several ways:

    • It can identify sites of gross extracapsular extension (ECE) and seminal vesicle involvement (SVI), which can be incorporated into the overall treatment plan and implant procedure and brachytherapy treatment.

    • MRI can aid in identifying a prominent median lobe.

    • MRI can better identify anteriorly located tumors which may require modification of the brachytherapy implant approach for appropriate coverage.

    • Some centers are incorporating preoperative MRI or an MRI during the implantation or treatment planning into the workflow to better delineate the boundaries of the prostate, particularly at the apex in order to spare the external urethral sphincter, which may be associated with urinary toxicity.

    • Some institutions are using gross tumor noted on MRI to create a focal simultaneous integrated boost [22].

  • Please refer to Chap. 2 for a detailed discussion about functional and imaging anatomy relevant for prostate cancer radiotherapy. Chapter 5 also discusses the use of MRI with LDR brachytherapy in detail. We discuss the use of MRI for treatment planning with HDR brachytherapy as follows.

5 Patient Selection

  • The American Brachytherapy Society has consensus guidelines that can be used as a tool for patient selection [23].

  • Table 6.1 describes selection criteria for HDR brachytherapy.

  • It is important to note that many of the criteria used to select for HDR brachytherapy are extrapolated from those used for LDR brachytherapy. We discuss some of these considerations in Table 6.1.

Table 6.1 Selection criteria for prostate HDR brachytherapy
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6 Pre-operative Assessments and Procedures

  • Patients should be counseled about the risk and benefits of treatment and alternatives to HDR brachytherapy.

  • Staging work-up should be completed according to NCCN guidelines [2].

  • As discussed above, preoperative MRI can help with implant/treatment planning.

  • A volume study can be conducted prior to the implant procedure. The volume study is critical for LDR brachytherapy when pre-implant treatment planning methods are used but is less critical for HDR. In the setting of HDR, it may help direct needle placement or identify anatomic concerns that may make the implant technically difficult or impossible (i.e., pubic arch interference, large gland size, large median lobe, excessive calcifications). Many clinicians choose to omit the volume study for prostate HDR brachytherapy.

  • The brachytherapist should work with the patient’s care team (i.e., primary care physician and/or cardiologist) and anesthesia team to obtain preoperative clearance for the selected form of anesthesia and the implant procedure.

  • Anticoagulation should be held prior to the surgical procedure based on recommendations from the provider(s) managing the anticoagulation. Each case is unique and requires clinical judgment in determining the duration. Antiplatelet therapy can be held as well, but the incremental risk of bleeding is relatively low.

  • Some centers use tamsulosin prophylactically beginning ~1 week prior to the implant to help with acute urinary symptoms from the implant procedure and treatment. Similarly, some centers use prophylactic phospodiesterase inhibitors to prevent erectile dysfunction. However, there are no data available that suggest these practices effectively reduce the risk of toxicity in these domains, and some centers choose not to use prophylactic medications.

  • Fleets enemas can be used the night prior to the procedure and morning of the procedure to improve visualization of the prostate under transrectal ultrasound.

7 Operative Procedure

  • Preoperative antibiotics can be delivered in the operating room. Intravenous cefazoloin × 1 prior to the procedure is a common choice for this purpose. For patients with an allergy, a single dose of clindamycin can be used.

  • The patient is then placed under anesthesia. Many centers use general anesthesia, while other centers use a spinal block or epidural anesthesia. For centers with CT or MRI-based post-implant planning, a spinal nerve block or spinal epidural can limit discomfort with adjustments and potentially reduce the risk of displacement. However, the recovery of lower extremity neurologic function after the procedure may take some time and delay discharge if only a single fraction is being delivered. A spinal epidural may offer more durable pain control for patients who are being admitted overnight for multiple fractions. Ultimately, local workflow and unique patient considerations should be used to determine the optimal form of anesthesia.

  • Positioning:

    • Place the patient into the dorsal lithotomy position. The goal is to begin the implant with the knees and hips at 90° flexion using stirrups. Caution should be taken in patients with arthritic conditions and one can consider positioning such patients while awake when possible.

    • Ensure that the patient is in the center of the table laterally, and there is no roll or yaw translational rotation.

  • Scrub, prep, and drape procedural area including lower abdomen, inner thighs, perineum, penis. Ensure adequate sterilization, visualization, and access for implantation to the transperineal region posterior to the pubic arch to the anus. However, brachytherapy is not a sterile procedure.

  • Insert Foley catheter into the urethra. There is no agreed upon ideal Foley size. ABS guidelines recommend using the smallest gauge catheter [23]. This minimizes distortion of the urethra, which may be particularly important for smaller glands. A 12F catheter can be used for this purpose. Another option used at multiple centers is the use of a 16F catheter. The Foley bulb can be filled with diluted contrast (i.e., 1 cc isovue and 6 cc sterile water) to help with subsequent treatment planning if using CT-based planning.

  • Fill the bladder in order to allow appropriate visualization of the bladder neck. 120 cc normal saline is a common choice.

  • Immobilize the scrotum and penis out of the perineal implant field. A sterile adhesive surgical drape can be used, or a wet surgical towel tucked into the inguinal folds to elevate the scrotum away from the perineum.

  • Place the transrectal ultrasound into the anus and visualize the prostate in the axial and sagittal dimensions.

    • Evaluate the prostate size and dimensions and ensure the posterior aspect of the prostate is parallel to the ultrasound probe and the urethra is as midline as anatomically possible on axial ultrasound over the course of the prostate.

    • Evaluate for any unexpected anatomy.

    • Evaluate the rectal wall anatomy (i.e., thickened rectal wall, anterior protrusion of the rectum near the prostate apex that must be avoided with the implant).

    • Assess for a large median lobe.

    • Follow the urethral trajectory to plan for any special considerations during the implant for a deviating urethra within the prostate.

  • Some institutions, particularly those using CT-based planning, place fiducial markers at the base and/or apex to help with target delineation as well as to confirm no displacement of the implant at the time of treatment. This can be placed using a transperineal approach.

  • For centers using ultrasound-based planning, a stepper-based system with a grid template is typically used. This fixed set up (similar to the LDR setup) allows for intraoperative treatment planning. Other institutions use a technique in which a mobile perineal template is held against the perineum to guide and space the catheters. Finally, other institutions use no template at all for catheter placement but use putty to immobilize the catheters at the end of the procedure. The free hand and mobile template techniques allow for more freedom to change the angles of catheter insertion to allow for implanting larger glands and in patients with more narrow pubic arches.

  • Brachytherapy catheter placement

    • Progression from anterior to posterior is commonly done to avoid ultrasound artifact from catheters already in place.

    • When placing the catheters, always “follow” the catheters as you place them with the ultrasound through the perineum, into the subcutaneous tissues inferior to the prostate, past the bulbar urethra, into the prostate, and up to the bladder neck. This allows the brachytherapist to avoid trauma to critical structures such as the urethra and rectum.

    • Be very cautious when placing the medial catheters in the area of the bulbar urethra to avoid urethral perforation. If a catheter appears to perforate the urethra at any time, remove it and replace it.

    • Visualize the positioning of the catheters in axial and sagittal dimensions to ensure appropriate placement.

    • As more catheters are placed, the prostate tends to be deflected superiorly from the pressure. Continuously ensure that all previously placed catheters remain at the optimal depth and the template is tight against the skin.

    • Be cautious to avoid anterior rectal protrusion near the apex when placing the posterior catheters. Posterior pressure on the TRUS probe can help displace this.

    • The goal is to have catheters 0.7–1 cm apart and distributed throughout the prostate (and proximal seminal vesicles if determined to be at risk). Figures 6.1 and 6.2 depict an example of appropriate catheter placement on CT and MRI, respectively.

    • During placement, take any ECE or SVI identified on pre-operative or intraoperative imaging into consideration to ensure adequate coverage.

    • If a rectal spacer is planned to be used, this can be placed after completion of catheter placement to avoid artifact from the spacer making visualization difficult, as well as to avoid perforation of the spacer with catheters. If multiple implant procedures are indicated, rectal spacer placement may make subsequent procedures difficult (inability to clearly see the prostate on ultrasound).

  • There can be displacement of the catheters when the patient’s legs are brought down to the supine position at the end of the procedure. To assess this, the legs can be brought down past flexion with the ultrasound still in place. Additionally, if cystoscopy or fluoroscopy are being used post-treatment, these can be performed with the legs down as well. The catheters can be adjusted based on any changes noted during these evaluations.

  • Upon completion of the implant, if using post-implant planning and treatment delivery (i.e., CT or MRI-based planning), the template is sutured to the skin to minimize the risk of displacement with movement. At least a suture in all four corners of the implant should be used. Suturing to the skin is not necessary if the patient will not be moved for these later aspects of treatment (i.e., if intraoperative ultrasound-based planning is used).

  • Some institutions perform a secondary imaging modality to confirm appropriate placement of catheters (i.e., fluoroscopy). Alternatively, cystoscopy can be performed in collaboration with our urology colleagues after all the catheters are placed. During cystoscopy, one can evaluate for any urethral perforation as well as ensure the catheters are at the optimal depth at the bladder neck. A sign that the catheters are at the appropriate depth is evidence of bladder mucosal “tenting” without perforation at the bladder neck on cystoscopy. This is seen by retro-flexing the cystoscope.

  • At centers with intraoperative treatment planning and delivery workflows, these occur in the OR and then implant is removed.

  • At centers with post-operative treatment planning. The patient is awoken from anesthesia with the catheters still in place for post-anesthesia recovery and subsequent treatment planning and delivery.

Fig. 6.1
figure 1

Catheter placement at seminal vesicles, prostate base, mid and distal gland on CT

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Fig. 6.2
figure 2

Catheter placement at seminal vesicles, prostate base, mid and distal gland on MRI

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8 Treatment Planning

  • There are two primary treatment planning approaches for prostate HDR brachytherapy:

    • Ultrasound-based planning (intraoperative planning).

    • CT-based planning (post-implant planning).

  • Both treatment planning approaches have advantages and disadvantages and are discussed in detail below.

  • Ultrasound-based planning [46]

    • Technique: At the conclusion of the implant, there is an immediate transition to the planning process. TRUS images are obtained and critical structures (prostate, urethra, bladder wall, and rectal wall) are contoured (similar to the delineation defined below). Catheters are reconstructed, and anatomy-based inverse planning is used to generate an optimized plan. The afterloader is connected to the respected catheters and treatment delivered with the TRUS probe in place. After treatment delivery, the catheters are removed, the anesthesia is reversed, and the patient is transferred to post-anesthesia recovery. The entire process takes about 60–120 min.

    • Advantages: Intraoperative planning allows minimization of anatomic changes from edema and real-time imaging during planning. There is no/limited patient transfer, which minimizes the risk of catheter displacement. This also allows for efficient utilization of time and resources. Finally, TRUS provides excellent soft tissue delineation for prostate contouring.

    • Disadvantages: Ultrasound-based intraoperative planning is best done with all steps in the same room. This necessitates either an OR with appropriate shielding, or anesthesia delivery in an HDR suite. This process also relies on high quality ultrasound imaging, which may be difficult to obtain in patients with calcifications, or other artifacts. Finally, it can be difficult to identify the prostate apex on ultrasound [47, 48].

  • CT-based planning

    • Technique: At the conclusion of the implant, the catheters/template are fixed to the perineum and the patient proceeds to post-anesthesia recovery.

    • After completion of post-anesthesia recovery, the patient undergoes CT simulation in the supine position to obtain the image dataset for planning. 1.5–2 mm image slices are obtained from above the bladder to below the template. During CT, the bladder is typically filled with dilute contrast to visualize the bladder neck (2 cc isovue and 28 cc normal saline is an option to allow contrast between the Foley bulb, prostate, and filled bladder). Additionally, ensure that the Foley bulb is pulled down to the bladder neck to aid in treatment planning.

      • There are several aspects for the brachytherapist to review at the time of CT simulation. If the brachytherapy catheters are advanced too cranially (i.e., into the bladder) or are too shallow, adjustments can be made to ensure optimal depth. Confirmation of appropriate spacing between catheters (~0.7–1 cm), avoidance of the urethra and rectum, and adequate coverage of the prostate and seminal vesicles are also important to assess during CT simulation.

      • Upon completion of any adjustments, the catheters should be marked with a pen/marker to be able to assess for movement prior to the subsequent treatment delivery.

      • Of note, both plastic and metal catheters are available for implantation. Plastic catheters cause less CT artifact than metal catheters and can allow for easier target and normal tissue delineation.

    • The catheters are then digitized by the medical physicist on the CT and the target and organs at risk (OARs) are delineated by the physician (discussed below).

    • Treatment planning is performed using inverse planning. There are resources to help improve treatment planning efficiency [15].

    • Advantages: CT-based planning minimizes OR procedure time, which may be important for centers that do not have a brachytherapy suite and utilize the general OR resources.

    • Disadvantages: With ultrasound-based planning, the patient can undergo implantation, treatment planning, treatment, and removal while under anesthesia. With CT-based planning, most workflows require the patient to wake up with the catheters in place and the patient remains awake during treatment planning and delivery and catheter removal. This can lead to more pain from the patient’s perspective (although this can be managed with pain medications or spinal nerve block) and makes for a longer treatment day. As part of this, extra resources are needed in the clinic (nursing staff, availability on the CT simulator). Additionally, the soft tissues of the prostate can be difficult to identify on CT due to the catheters, particularly the apex. A major disadvantage is that there could be implant displacement due to patient transfers from surgical table to CT sim to treatment table. This risk requires multiple imaging studies to exclude, and if it occurs, it requires multiple potential readjustments to correct.

  • MRI-based Planning

    • Some institutions have transitioned to using MRI-based planning. This can be performed either with a MRI simulator or separate T2 MRI after implant and CT simulation to help with target delineation. The improved visualization of the prostate, rectum, and bladder neck allow for more precise target and OAR delineation. The clinical target volume (CTV) contents remain the same. One can consider the same or smaller planning target volume (PTV) margins due to improved target delineation compared to CT alone. Several series have compared CT and MRI-based planning and demonstrated that MRI-based planning is associated with a smaller target volume and improved OAR doses [49, 50].

    • An example of catheter distribution seen on MRI is shown in Fig. 6.2.

    • Figure 6.3 displays a comparison in prostate visualization utilizing CT imaging and MRI imaging.

  • An example of the finalized HDR brachytherapy treatment plan performed with MRI imaging is shown in Fig. 6.4.

Fig. 6.3
figure 3

Implanted catheters visualized via CT (left) vs. MRI (right) demonstrating enhanced soft tissue visualization and prostate delineation with MRI

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Fig. 6.4
figure 4

Catheter placement at prostate mid-gland on MRI with isodose lines (in % of prescription dose of 13.5 Gy)

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9 Target and Organ at Risk Delineation

  • There is no consensus regarding CTV, PTV, or treatment margins.

    • The CTV is typically the prostate with or without the seminal vesicles. All areas of extracapsular extension and seminal vesicle invasion should be encompassed in the CTV.

    • The role and optimal PTV expansion are unknown. In the EBRT setting, the PTV is used for set-up uncertainties, which are less of an issue with HDR. At many institutions, the CTV = PTV. At other institutions, an asymmetric expansion of 0–5 mm is added to the CTV, limiting expansions in the area of OARs (i.e., rectum and bladder neck).

  • The knowledge about the patient’s anatomy and the relative anatomic placement of the catheters during the implant should be used in target delineation.

  • The rectum, urethra, and bladder should be contoured as OARs.

  • The preoperative MRI can be fused to aid in target delineation. However, due to displacement and distortion of the normal prostate position from the implant, the fusion can be difficult. It can be used side by side to help guide target delineation when helpful, particularly in cases where a clear GTV is identified (i.e., when a tumor can be visualized on MRI).

  • An example of catheter distribution seen on CT is shown in Fig. 6.1.

10 Treatment Delivery Using the Remote Afterloading System

  • The patient is treated in a shielded room with the afterloader. In the setting of intraoperative planning and treatment delivery, this is conducted in a shielded OR. Other centers do this in a shielded room in the radiation oncology department.

  • The remote afterloading system is connected to the catheters with appropriate quality assurance (including but not limited to): double-check of catheter and remote–afterloader connections, and visual inspection of template and catheters. Some centers conduct fluoroscopy to confirm the appropriate positioning of the catheters has been maintained if the patient has been moved. Treatment is delivered under physicist and physician supervision.

  • If only a single fraction is to be delivered after the implant, then the patient moves on to catheter removal and discharge as below. If the patient is to receive multiple fractions with the same implant, these should be delivered a minimum of 6 h apart. At some centers, 2 fractions are delivered the same day. Other centers require overnight admissions if the 2 fractions will be delivered on separate days or more than 2 fractions are planned. In this scenario, the inpatient team must be educated on the importance of minimizing the risk of catheter displacement, and the positioning should be assessed prior to each treatment.

  • Upon completion of the brachytherapy fraction(s) to be delivered with the implant, catheters are removed with appropriate analgesia (e.g., at Loyola IV dilaudid is used) and hemostasis ensured.

  • Then, the bladder is typically filled and the Foley is removed. Following spontaneous voiding (approximately how much the bladder was filled with), the patient is sent home.

  • Some institutions discharge patients with prophylactic medications (e.g., tamsulosin), antibiotics (e.g., 3 days of ciprofloxacin), and/or an anti-inflammatory medication (e.g., 2 weeks of naproxen). However, like the discussion about prophylactic medications above, other centers do not prescribe these medications, and there are no data demonstrating the need or efficacy of this practice. Opioid pain medications are not usually required.

11 Dose and Fractionation Considerations

  • There have been many different dose/fractionations used with prostate HDR, both as monotherapy and as a boost. There is no current consensus on the ideal dose/fractionation, but most institutions are moving toward the more hypofractionated regimens (i.e., 13.5 Gy × 2 for monotherapy, 15 Gy × 1 as a boost).

  • Monotherapy dose/fractionation options:

    • A randomized trial compared 13.5 Gy × 2 vs. 19 Gy × 1 as monotherapy and demonstrated inferior biochemical and local control with single fraction HDR. Therefore, single fraction HDR for monotherapy should be avoided [51].

    • Monotherapy Dose/fractionations supported by guidelines include [2, 23]

      • 34 Gy in 4 fractions

      • 36–38 Gy in 4 fractions

      • 31.5 Gy in 3 fractions

      • 26–27 Gy in 2 fractions

      • Current NCCN Guidelines recommend [2]:

        • 27 Gy in 2 fractions

        • 34 Gy in 4 fractions

    • Interfraction interval:

      • Fractions delivered BID as part of the same implant should be delivered ≥6 h apart.

      • Fractions delivered as separate implants are usually delivered 1–2 weeks apart. The duration between implants does not appear to be associated with toxicity [52].

  • Boost dose/fractionations supported by guidelines include [2, 23]:

    • 15 Gy in 3 fractions

    • 11–22 Gy in 2 fractions

    • 12–15 Gy in 1 fraction

    • Current NCCN guidelines recommend [2]:

      • 15 Gy in 1 fraction

      • 21.5 Gy in 2 fractions

  • HDR Sequencing with EBRT: HDR boost can be delivered before, during, or after external beam radiotherapy. There are no strong data demonstrating any clinical impact to sequencing.

    • The THEPCA trial (NCT02618161) was a trial that compared HDR before EBRT with HDR after EBRT, but the results are not yet available [53].

    • A common method is to deliver the HDR boost ~2 weeks prior to EBRT in order to manage brachytherapy-related toxicity during EBRT as well as place fiducial markers.

  • EBRT Dose: Typically, 45–50.4 Gy in 25–28 fractions is used. A hypofractionated option is 37.5 Gy in 15 fractions [54]. Studies are ongoing testing ultra-hypofractionated supplemental EBRT doses (i.e., 5 Gy × 5) (NCT04236752). Depending on the risk of pelvic nodal involvement, the pelvic lymph nodes can be included.

  • Dose Constraints

    • Given the significant heterogeneity in dose/fractionation schedules used in prostate HDR brachytherapy, no consensus guidelines currently exist for DVH planning goals. Consequently, there is variability among institutions in regard to the planning goals.

    • Several studies have suggested that larger volumes of the urethra receiving higher doses are correlated with increased genitourinary toxicity [55,56,57].

    • The GEC/ESTRO consensus guidelines provide constraints based on the EQD2 (Table 6.2) [54].

    • Examples of planning goals used in RTOG, the Sunnybrook and the CHU de Quebec-Universite Laval Randomized Trials are listed in Table 6.2 [21, 51, 58, 59].

Table 6.2 HDR brachytherapy planning goals from GEC/ESTRO and Key prospective trials
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12 Toxicity

  • In general, acute and late toxicities from prostate HDR brachytherapy are similar to other forms of radiation therapy in nature and frequency. The exceptions to this are the risks of the operative implant procedure.

  • It is frequent for patients receiving monotherapy to have very limited subjective acute toxicities after the first implant, but a significant increase after the second implant.

  • The risk of acute urinary retention after the implantation procedure is ~5% [51, 60,61,62]. This usually occurs either immediately or within a few days of the implant procedure. It can be managed with a temporary catheter placement until acute inflammation resolves. In this scenario, we frequently add a 5-alpha reductase inhibitor and a steroid to the tamsulosin to help reduce acute inflammation that is contributing to the obstruction.

  • Acute hematuria occurs in ~2% of patients [51, 60,61,62]. This can be managed with temporary urinary catheter placement. In rare severe cases, hospitalization may be indicated as well as continuous bladder irrigation.

  • Dysuria and other obstructive symptoms are common, with reported rates ranging from 20% to 60% [60,61,62]. Management with tamsulosin, naproxen, or phenazopyridine are good first options.

  • After approximately 1-month, patients begin noticing improvement in acute urinary toxicities, with most patients returning to baseline ~2 months after treatment [21]. However, it can take upwards of 12 months for patients to have their urinary function return to baseline [63].

  • Late genitourinary toxicities include persistent obstructive/irritative urinary symptoms. Late grade 2 GU toxicity occurs in 10–40% of patients [60,61,62]. Tamsulosin can be continued for obstructive urinary symptoms as needed. In refractory cases, a 5-alpha reductase inhibitor can be considered, and thereafter referral to an urologist for potential surgical options if still bothersome. Late cystitis can lead to irritative symptoms or hematuria. Irritative urinary symptoms can be managed with anticholinergics or phenazopyridine.

  • Severe, late, grade 3 urinary toxicities are rare, occurring in <5% of cases [60,61,62]. Gross hematuria should prompt referral to a urologist. Late strictures are rare and should prompt referral to a urologist.

  • Acute and chronic GI toxicity are rare with reported rates of <5% [51, 52, 60,61,62,63]. Steroid suppositories can be used for acute or chronic proctitis. Severe proctitis is extremely rare. However, if it occurs, consider hyperbaric oxygen, silver nitrate/formaldehyde cauterization, or partial colectomy if refractory.

  • Erectile Dysfunction is common, occurring in up to 50% of patients, either acutely due to the trauma from catheter placement or chronically due to radiation-related neurovascular late effects [51, 52, 63]. A phosphodiesterase inhibitor can be used with escalation to a penile pump, penile injection therapy, intraprostatic phosphodiesterase inhibitor therapy as needed.

13 Follow-Up

  • A short-term follow-up (2–4 weeks) post-implant assessment may be useful to assess for significant post-implant acute toxicity and treat it appropriately.

  • Standardized patient and physician reported toxicities tools, including IPSS, EPIC Quality of life forms, and CTCAE can be utilized at each follow-up to standardize treatment-related toxicity assessment and management.

  • PSA levels should be taken at regular intervals after treatment to assess biochemical control.

    • PSA bounce occurs in ~25–40% of patients and typically occurs 12–30 months post treatment [64, 65].

    • There is no definite long-term correlation between PSA bounce and biochemical control with HDR [64].

  • The PSA kinetics post-HDR are relatively dynamic. The PSA nadir + 2 ng/ml definition of biochemical failure is used for HDR brachytherapy, although many argue that it may not be sensitive after brachytherapy due to the ablative nature of treatment, and may not be specific due to the relatively variable PSA kinetics within the first several years post-HDR. Continually rising PSA levels that approach, meet, or exceed the nadir + 2 ng/ml definition of biochemical recurrence should be evaluated via diagnostic imaging with bone scan, MRI, and/or novel molecular imaging (i.e., fluciclovine, choline, or PSMA PET/CT).

14 Salvage Prostate HDR Brachytherapy for Local Recurrence After Curative-Intent Radiotherapy

  • Salvage local therapy is an option for select patients with biopsy-proven local recurrences after prior curative-intent radiotherapy [66].

  • NCCN provides general guidelines for selection of patients for salvage local therapy.

    • Candidates include those with biopsy-proven, local-only recurrent disease who have no nodal or metastatic disease on restaging imaging and no significant morbidity from prior radiotherapy [2].

  • Both LDR [67,68,69,70,71,72,73,74,75,76,77] and HDR [77,78,79,80,81,82,83,84,85] brachytherapy have been used in the treatment of local recurrence of prostate cancer after either EBRT or brachytherapy.

  • Data describing outcomes with salvage HDR brachytherapy are primarily retrospective. A single phase II trial has reported results with 5-year biochemical relapse-free, distant metastases-free and cause-specific survival of 68.5%, 81.5%, and 90.3% respectively, and with 1 patient developing grade 3 GU toxicity and no grade 3 GI and no grade 4 toxicities [85].

  • Pre-salvage brachytherapy MRI can delineate the area of recurrence for brachytherapy planning [86].

  • When possible, novel molecular imaging (e.g., fluciclovine PET scan) should be performed to rule-out patients for distant metastatic disease [87].

  • Use of rectal spacer may be considered to reduce rectal dose from re-irradiation [88, 89].

  • There is no standard dose/fractionation for salvage HDR. Some reported regimens include 8 Gy × 4 fractions, 6 Gy × 6 fractions, and 10–13.5 Gy × 2 [79, 80, 82, 83, 85, 89].

  • Some institutions target the whole gland, while others perform focal salvage brachytherapy.

  • Focal salvage brachytherapy:

    • In the setting of focally recurrent prostate cancer, often the recurrent disease is not detected in all parts of the prostate gland.

    • Focal brachytherapy to the specific area of disease recurrence may allow recurrent disease control while minimizing toxicity by avoiding repeat irradiation to the entire gland [90, 91].

    • New imaging techniques such as multiparametric MRI, saturation biopsies, and novel molecular PET imaging may allow better detection of specific disease location within the gland [87].

    • There have been a few phase I/II trials as well as retrospective studies investigating focal HDR brachytherapy [91,92,93,94,95,96,97]. Murgic et al. in a prospective trial of 15 patients with locally recurrent prostate cancer after EBRT delivered 27 Gy divided in 2 implants to CTV defined as quadrant of prostate with MRI-visible recurrent lesion, showing 3-year PSA failure-free rate of 61%, 1 patient with grade 3 GU toxicity and no changes in EPIC composite bowel or urinary scores [91].

15 Conclusions

  • Prostate HDR brachytherapy remains an effective component of prostate cancer care as a method of optimal conformal dose-escalation.

  • There are a variety of clinical scenarios in which HDR brachytherapy is an appropriate treatment option, including in the definitive setting as monotherapy or in combination with androgen deprivation therapy and/or EBRT, as well as in the salvage setting for local recurrence after prior curative-intent radiotherapy.

  • In each of these settings, appropriate patient selection and attention to treatment preparation, technique, and planning are crucial to the delivery of successful brachytherapy.