Magnetic resonance imaging-guided functional anatomy approach to prostate brachytherapy

Brachytherapy

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MRI-guided functional anatomy approach to prostate brachytherapy Payal D. Soni1, Alejandro Berlin2, Aradhana M. Venkatesan3, Patrick W. McLaughlin1,* 1 Department of Radiation Oncology, University of Michigan, Ann Arbor, MI Department of Radiation Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada 3 Section of Abdominal Imaging, Department of Diagnostic Radiology, MD Anderson Cancer Center, Houston, TX 2

ABSTRACT

PURPOSE: To provide an MRI based functional anatomy guide to prostate brachytherapy. METHODS AND MATERIALS: We performed a narrative review of periprostatic functional anatomy and the significance of this anatomy in prostate brachytherapy treatment planning. RESULTS: MRI has improved delineation of gross tumor and critical periprostatic structures that have been implicated in toxicity. Furthermore, MRI has revealed the significant anatomic variants and the dynamic nature of these structures that can have significant implications for treatment planning and dosimetry. CONCLUSIONS: The MRI-based functional anatomy approach to prostate brachytherapy takes into account extent of disease, its relation to the patient’s individual anatomy, and functional baseline to optimize the therapeutic ratio of prostate cancer treatment. Ó 2016 Published by Elsevier Inc. on behalf of American Brachytherapy Society.

Keywords:

Functional anatomy; Prostate; Prostate cancer; Brachytherapy; MRI

Introduction There are over 3 million prostate cancer survivors in the United States, with the 15-year survival rate of prostate cancer reaching 95% (1). Therefore, the goal of prostate cancer treatment must emphasize preservation of quality of life just as much as cure. Brachytherapy is a highly effective and economical treatment for prostate cancer (2e10). The highly conformal nature of brachytherapy treatments allows for significant dose escalation to areas of disease while minimizing dose to vulnerable regional anatomy that is critical to daily functions and quality of life. The true potential of brachytherapy is becoming clearer as MRI plays a larger role in prostate cancer management. There are profound limitations to traditional CT-based postimplant dosimetry (11, 12). The prostate boundaries are obscured, the actual tumor is not defined, and critical adjacent structures merge with and are commonly included in the ‘‘prostate’’ contour, leaving patients at risk of Received 10 October 2016; received in revised form 17 November 2016; accepted 18 November 2016. Conflicts of interest: None. * Corresponding author. Department of Radiation Oncology, University of Michigan, Assarian Cancer Center, 47601 Grand River Avenue, Novi, MI 48374. Tel.: 248-465-4300; fax: 248-465-5471. E-mail address: [email protected] (P.W. McLaughlin).

treatment failure and urinary, bowel, and sexual dysfunction. Functional outcomes after prostate brachytherapy typically fall on a spectrum that ranges from complete preservation of function, to bothersome symptoms which may be transient or controlled with medication, to severe reversible complications which have significant morbidity and may require invasive remedies, and finally to severe irreversible complications which can be life-altering events. Although the majority of severe complications are reversible as demonstrated in brachytherapy trials with longterm followup (13e15), it is difficult to accept even a small number of severe irreversible complications given the impact they have on a patient’s quality of life, in the context of a frequently curable or indolent disease course such as early-stage prostate cancer. The MRI functional anatomy approach replaces CT with MRI-based preimplant and postimplant planning that can improve tumor and functional anatomy delineation, improve implant quality, and ultimately shift the goal of treatment from avoiding complications to preserving function. MRI-based postimplant dosimetry has already defined the mechanism responsible for many severe complications. For example, MRI has clearly identified dose delivery below the prostate apex which contributes nothing to cure and has been implicated in complications such as stricture and rectal-urethral fistula, demonstrating the need for further technical refinement. Vessel-sparing

1538-4721/$ - see front matter Ó 2016 Published by Elsevier Inc. on behalf of American Brachytherapy Society. http://dx.doi.org/10.1016/j.brachy.2016.11.009

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radiation is one example in which the MRI-based functional anatomy approach has demonstrated an unprecedented level of sexual function preservation, with further improvement likely as other candidate targets are defined (16). Functional anatomy is an umbrella term for a wide variety of anatomic categories impacting brachytherapy practice and outcomes (Table 1). Functional anatomy includes mobile (17e19) and immobile (20e22) adjacent structures

Table 1 Anatomic categories 1) Functional anatomy a) Mobile (dynamic) i) Bladder neck ii) Genitourinary diaphragm iii) External sphincter iv) Rectourethralis v) Seminal vesicle vi) Levator ani vii) Rectum, lower rectal segment, and anal sphincter b) Immobile i) Neurovascular elements ii) Internal and accessory pudendal arteries iii) Corpus cavernosa iv) Penile bulb v) Dorsal vascular complex vi) Verumontanum vii) Ejaculatory ducts viii) Prostatic and membranous urethra 2) Variant anatomy a) Bladder neck i) Intact ii) Expanded iii) Effacement (intrabladder extension) iv) Asymmetric intrabladder extension (median lobe) b) External sphincter i) Apex to penile bulb length ii) Intraprostate extension c) Neurovascular elements i) Bundle configuration ii) Plexus configuration 3) Implant anatomy (probe effects) i) Potential space (bound by rectum, apex, and GU diaphragm) ii) Prostate rotation iii) Asymmetric swelling iv) Rectourethralis extension 4) Postimplant dynamic anatomy i) Rectourethralis recoil (potential space obliteration) ii) Bladder neck iii) Levator ani and GU diaphragm 5) Tumor anatomy (mpMRI) a) Peripheral zone and: i) Extraprostatic extension ii) Seminal vesicle involvement iii) GU diaphragm extension iv) Anterior extension b) Transition zone and: i) Absence of bladder neck involvement ii) Bladder neck involvement iii) Intrabladder extension iv) Urethra involvement mpMRI 5 multiparametric MRI.

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that play a role in genitourinary, gastrointestinal, and sexual function. One cannot surmise functional status of an active tissue from anatomic configuration alone. For example, an extremely enlarged prostate does not reliably predict urinary obstructive symptoms (23), just as a small prostate does not guarantee normal urination. Furthermore, most common functions adjacent to the prostate are not single tissue dependent but rather are coordinated and carefully sequenced activations of several structures. Variant anatomy is the recognition of the wide diversity in functional anatomic structures and the variable capacities to dose limit some of these variants (24e26). Implant anatomy refers to the profound effect that probe placement has on adjacent anatomic relationships and the potential for misinterpretation of implant quality with the probe in place (27). Postimplant dynamic anatomy refers to the active motion of the prostate and adjacent musculature, and their ability to impact seed position after an implant has been completed (28). Finally, tumor anatomy as defined by multiparametric MRI (mpMRI) may define the actual tumor grade and location within the prostate (peripheral zone or transition zone) and beyond the prostate (29). To achieve a balance in functional and disease-specific outcomes, it is important to properly define the target volumes and the functional anatomy at risk. Superimposing tumor distribution obtained from mpMRI over individual functional anatomy (best seen on T2-weighted MRIs) will reveal opportunities to achieve cure while protecting quality of life. Herein, we review all relevant anatomic categories by region (base, mid, and apex) and discuss the implications for treatment planning and the unique implant and dosimetric challenges to consider to enhance the therapeutic index of brachytherapy for prostate cancer.

Brachytherapy challenge at the base The bladder neck and seminal vesicles are two key structures in close proximity to the base of the prostate that play important roles in urinary and sexual function, respectively. The prostate base is comprised purely of transition zone, a region at low risk of harboring prostate cancer in most patients. Using MRI to identify patients with no evidence of disease at the base can allow for de-escalation of dose in this region to reduce urinary and sexual dysfunction after prostate brachytherapy. Most acute urinary toxicity, whether obstructive or irritative, can be attributed to dose at the base. Mobile functional anatomy The point of connection between the bladder and the prostate base is a highly active region in the adult male. There is still significant controversy over the true structure of the bladder neck and its mechanism of action (18, 30, 31). Increasing evidence from pathologic and radiographic studies

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shows that the neck is comprised of a complex arrangement of muscular fibers with some traversing around the proximal urethra, some extending along the urethra within the base of the prostate and others extending along the anterior aspect of the prostate contributing to the anterior fibromuscular stroma (32). This intricate array perhaps explains how the uniform contraction of all these fibers can lead to the synchronized occurrence of two contradicting actions: bladder contraction and proximal urethral sphincter opening. These dynamic structures epitomize the dyad of the functional anatomy challenge. Implantation of the bladder neck can not only lead to disruption of urinary function, but can also lead to seed displacements affecting the quality of the implant and final dose distribution. Maximum dose to bladder neck has shown to predict for acute and late urinary toxicity (19), and therefore, avoiding high doses to the bladder neck from seeds within or immediately adjacent to this structure is critical in preserving urinary function. When utilizing stranded seeds, implantation of the bladder neck musculature can cause seeds to migrate during the urinary cycle. Multiple prior studies comparing postimplant dosimetry on the day of implant vs. 14e30 days postimplant have demonstrated significant changes in dose distribution. One of the common patterns of change noted is the cranial migration of strands and subsequently of the dose distribution relative to the prostate (28, 33). Figure 1 demonstrates how the bladder rises during the urinary cycle (34) and can potentially drag a strand of seeds superiorly through the prostate, consequently increasing the dose to the bladder neck region and leaving the apex under dosed. In cases where full dose coverage of the prostate base is critical, one may consider implanting loose seeds with a Mick applicator or preloaded needles in this region to avoid migration of stranded seeds. Hybrid strand plus loose seed techniques have been defined to take advantage of both technologies (35). Variant anatomy To avoid implanting the bladder neck, one must evaluate the configuration of this structure preoperatively and establish the extent of tumor involvement at the base to

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determine the feasibility of sparing this region. Over the course of decades, the prostate transition zone commonly enlarges and expands the distinct circular bladder neck opening. In extreme cases, this prostatic enlargement can extend through the bladder neck and project into the bladder lumen (36). If this hypertrophy is asymmetric, a dominant median lobe may be visualized. These variations have been previously classified by Dess et al. (26) (Fig. 2). A treatment strategy supported by MRI guidance in which only the peripheral zone is treated has been successfully tested in low-risk patients (37, 38). However, in higher risk patients, aggressive peripheral zone tumors may infiltrate and extend into the transition zone (Fig. 3). MRI can clarify such gross tumor involvement and help determine which patients need aggressive dose coverage at the base and bladder neck region due to the presence of gross disease. Tumor localization using pathologic and MRI characterization should be used to identify those patients without prostate base involvement, in whom the bladder neck can be protected from implant-related trauma and radiation dose without jeopardizing tumor control probability. Preimplant lower urinary tract symptoms are a predictor of worse toxicity after brachytherapy (15, 39). Although MRI can clearly depict the extreme variation in hypertrophy and bladder neck distortion, it is difficult to predict urinary dysfunction from MRI. Some patients with no prostate hypertrophy and a distinct bladder neck experience profound obstructive symptoms, and some men with overarching median lobes have no urinary symptoms. A thorough review of baseline urinary function is necessary before considering radiation options as methods of optimizing urinary function are often available. A complete evaluation includes understanding the patient’s symptom pattern, visualizing the anatomic configuration of the bladder neck and in most cases obtaining uroflowmetry and postvoid residual (PVR) measurements. Asynchrony of bladder contraction and urethral opening can result in obstructive or irritative dysfunction, two different syndromes that both present with increased urinary frequency (40). Obstructive dysfunction is characterized by incomplete and frequent emptying, whereas irritative dysfunction involves frequent emptying due to

Fig. 1. Migration of stranded seeds during micturition. (Yellow: bladder neck; gray: strand of seeds; blue: prostate; pink: levator ani; light blue: external sphincter.) (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

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Fig. 2. Dess Classification of Bladder Neck Variants (a) bladder neck intact; (b) bladder neck expansion; (c) bladder neck effacement with prostate protruding into bladder lumen; (d) median lobe (yellow line 5 bladder neck; yellow arrow 5 median lobe). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

urgency. Nonetheless, it is often difficult to discern from history if frequency is due to obstruction and incomplete emptying or irritation and incomplete filling (Fig. 4). A PVR can clarify this conundrum and help determine the appropriate management strategy. A high PVR is an indication of obstructive dysfunction. Additionally, peak flow rate can be obtained to better characterize obstructive physiology because a patient may accomplish full urinary emptying with a slow stream and still be prone to difficulties during or after radiation. Indeed, peak flow rate has been demonstrated to be a better predictor of a postradiation urinary toxicity than the PVR volume (41). There are several ways of optimizing urinary function before radiation treatment. Prior study has shown that if transurethral resection of the prostate (TURP) is necessary to address obstruction, surgical outcomes are better if performed prior as opposed to after radiation (42). A limited TURP such as removal of median lobe only (Fig. 5a) or a so-called ‘‘golf tee’’ TURP (Fig. 5b) with a partial transitional zone resection may leave sufficient tissue for anchoring brachytherapy seeds/catheters. These procedures

are preferred over a full excavation of the transition zone to the verumontanum (veru) typical of a classical TURP (43). Over several years, even after a classical TURP, the prostate can grow to fill in the defect (Fig. 5c). Two common interventions that may obviate the need for a TURP include alpha adrenergic inhibitors and androgen deprivation therapy. It is worth noting that dramatic downsizing of the prostate following androgen deprivation therapy may not improve urinary dysfunction; therefore, urinary function must be independently ascertained regardless of the magnitude in morphological changes. In addition to obstructive and irritative dysfunction following an implant, many men suffer from loss of ejaculate after prostate brachytherapy. A subset of men with preserved erectile function and climax are extremely bothered by loss of ejaculate. This is a multifactorial process resulting from the use of alpha adrenergic inhibitors, loss of seminal vesicle function, damage to the ejaculatory ducts, and treatment effects on glandular epithelium. Retrograde ejaculation is a well-known side effect associated with alpha adrenergic inhibitors (44). Preserving

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Fig. 3. Sagittal T2-weighted images (a) and axial dynamic contrast-enhanced images (b) of the prostate demonstrate transition zone tumor extending into the bladder lumen and infiltrating bladder wall (red dashed line 5 tumor; B 5 bladder; PZ 5 peripheral zone). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

bladder neck function, as discussed earlier, may preclude the need for long-term alpha adrenergic inhibitors and help alleviate this phenomenon. The concept of limiting the extent of seminal vesicle treatment is a matter of unresolved controversy in the current literature. One study based on postprostatectomy findings suggests that in low- and intermediate-risk patients, only the proximal 2 cm of the seminal vesicles are at risk of involvement and the remaining distal tissue can be spared (45). Conversely, other studies have suggested that the entire seminal vesicles are at risk (46). In the current era of MRI staging, direct tumor and seminal vesicle visualization should replace estimating the chance and degree of seminal vesicle involvement by risk group. Accurate imaging of the seminal vesicle requires sexual abstinence to assure seminal vesicle filling. Provided there is no involvement of the seminal vesicle on MRI, significant glandular function can be preserved.

Immobile functional anatomy Damage to the ejaculatory ducts is a significant contributor to loss of ejaculatory fluid after brachytherapy. The ejaculatory ducts are not routinely visible in their collapsed state. However, the duct entry point at the medial base and the termination point at the veru can be seen. This course of the ejaculatory ducts can thus be spared using peripheral loading techniques and MRI guidance. A component of the ejaculate comes from the prostate gland proper. The only possible strategy to preserve prostate secretion is partial prostate radiation, an emerging but still experimental practice.

Brachytherapy challenge at the apex The apex is comprised purely of peripheral zone tissue and is therefore at high risk for tumor involvement. On CT-based treatment planning, there is a tendency to

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Fig. 4. Subtypes of urinary dysfunction.

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Fig. 5. Sagittal T2-weighted MRIs demonstrating changes of median lobectomy (a), median lobectomy with limited ‘‘golf tee’’ TURP (b), and regrowth of prostate defect 12 years postclassic TURP (c) (yellow arrow 5 median lobe presurgery and postsurgery; yellow lines 5 golf tee TURP defect; green dashed line 5 prostate contour). TURP 5 transurethral resection of the prostate. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

overestimate imaging and er, there are tures around

the prostate apex (11) due to suboptimal concern for under dosing disease. Howevseveral critical functional anatomic strucand within the apex. Accurate definition

of the apex and awareness of anatomical changes in this region induced by the ultrasound probe is extremely important in reducing the risk of severe irreversible complications.

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Mobile functional anatomy The levator ani (LA) is comprised of three different muscles that are arranged in a funnel-like shape to create the majority of the genitourinary diaphragm (GUD), the cranial layer of the pelvic floor. The LA supports the pelvic structures. The medial fibers of the LA (i.e., puborectalis) in men partly attach to the inferior aspect of the prostate (34). The LA changes from a concave configuration above the prostate apex to a convex arrangement below the apex. This distinct anatomy is important in defining the prostatic apex for treatment planning. Contraction of the LA is implicated in several pelvic functions including micturition and defecation (47). As the LA contracts, the organs within the pelvis including the prostate are lifted up (17, 48). Similar to the bladder neck, the dynamics of the pelvic floor have dual implications for prostate brachytherapy. Seed implantation within the GUD can compromise these pelvic functions. Furthermore, in permanent implants using stranded seeds, the strands may migrate as the LA contracts if they are embedded in the LA (Fig. 6). This downward migration of the strands not only disrupts the dose distribution within the prostate, but increases dose to the external urethral sphincter (EUS), rectum, and other subapical structures (28). Carefully placing stranded seeds within the prostate and seminal vesicles while avoiding placement in active muscle allows the advantage of stranded seeds to be achieved without the liability of migration. If adequate coverage is not achieved with this approach, then a hybrid stranded and loose seeds configuration can be considered. Variant anatomy As the urethra exits the prostate, it traverses through the LA via the urogenital hiatus. This portion of the urethra is surrounded by smooth and skeletal muscle which acts as the EUS. Normal micturition is initiated by complete relaxation of the EUS. Recent anatomic studies (16, 24, 49) have demonstrated that both smooth and skeletal muscle components of the urethral sphincter may project within the prostate toward the veru. In the past, the EUS was considered to be entirely external. These recent data underscore the

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importance of careful treatment planning to avoid dysfunction and strictures within the prostate in patients with extensive intraprostatic extension of the EUS. T2-weighted MRIs can clearly depict the degree of sphincter extension within the prostate (Fig. 7), the tumor, and the spatial relationship between them. Considering that not all apical tissue is necessarily involved with tumor, in some cases, a balance of dose intensification where necessary while avoiding high dose to the sphincter seems warranted. The risk of damage to the EUS is likely related to both dose and length of contiguous involvement. Prior studies have demonstrated that high doses to the MRI-defined EUS predict worse urinary function (50). Given the intraprostatic extension of the EUS at the apex, it is essential to define the actual apex and to avoid including the GUD and the remainder of the EUS in the radiation plan. The T2-weighted coronal view most clearly depicts the apex, and this reconstruction is subjected to the least interobserver variability (51). When possible, allowing 1 cm between the urethra and seed placement will avoid high dose to the sphincter at the apex. Immobile functional anatomy The termination of the neurovascular elements at the apex is varied. Typically, the elements converge at the 5 and 7 o’clock position and proceed through the GUD before situating in the 2 and 10 o’clock position. These terminal branch cavernosal nerves are not visible on MRI but proceed alongside the EUS. After reaching the penile bulb, they spread over the surface of the corpus cavernosa (CC) (16). In some patients, the nerve bundle is distinct and separable from the prostate and can be dose limited (25). Accurate definition of the prostate apex is again important to avoid high dose to the small caliber cavernosal nerves traveling along the EUS. The internal pudendal artery (IPA) and CC are terminal components of the erectile complex, and avoidance of these structures has yielded the highest reported rate of erection preservation (16). Although the IPA and CC can be distant from the prostate in some men, overestimating the apex of the prostate can approximate the high dose region to these structures. Similarly, although these structures are below

Fig. 6. Migration of stranded seeds as a result of levator ani contraction and prostate elevation (blue: prostate; gray: strand of seeds; pink: levator ani; light blue: external urethral sphincter). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

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Fig. 7. Coronal T2-weighted MRI demonstrating variable intraprostatic extension of the external sphincter. TZ 5 transition zone; PZ 5 peripheral zone; PB 5 penile bulb; cm 5 centimeter.

the ‘‘region of interest’’ during brachytherapy implant, needle trajectory can lead to trauma and swelling that can explain commonly observed acute transient erectile dysfunction postbrachytherapy. The majority of the IPA can be defined by a noncontrast time-of-flight sequence, but this fails to define the final extent of the IPA connection to the CC (52). dynamic contrast enhanced sequences better define the full extent of the IPA and termination at the CC. The CC and the proximal muscle (crura) are clearly visible on T2-weighted MRI (16). Clear relationships of trauma and/or dose to these structures and preservation of erectile function have not been firmly established, but available data suggest that extremely high doses to these structures are associated with high rates of erectile dysfunction (53, 54). Given the rapid dose fall off with brachytherapy, avoiding low-dose-rate (LDR) seeds or high-dose-rate (HDR) dwell positions within these structures should allow dose restriction and function preservation. The accessory pudendal artery (APA) is well defined in the surgical literature, and techniques to define and spare this vessel have resulted in improved preservation of erectile function postprostatectomy (21). It is estimated to be present in 15e25% of men (55). There are multiple variants, the most common of which is a branch of the IPA coursing to the prostate surface near the apex and passing through the region of the dorsal venous plexus through the GUD to the CC. Given the proximity of this vessel to the prostate, sparing of an APA would not be possible with external beam radiotherapy as the vessel courses through the planning target volume. In combination therapy, extremely high doses to the APA could be avoided by

placing seeds or catheters slightly more centrally within the prostate rather than loading the prostate peripherally. At present, the significance of the APA may be in defining the mechanism of ED rather than providing an avenue for preservation. The dorsal venous plexus is another periprostatic structure that may play a secondary role in the maintenance of erections. Preserved erectile function requires adequate arterial supply for engorgement as well as venous occlusion for maintenance of an erection. One defined mechanism of erectile dysfunction is venous leak rather than arterial insufficiency. In the past, ligation of the dorsal venous plexus was a remedy for venous leak. In some men, the termination of the IPA and the dorsal venous plexus are both close to the prostate apex and within a usual highdose region. Significant changes have been demonstrated in erectile hemodynamics after radiation therapy, both arterial and venous in nature, with up to 85% of patients who developed erectile dysfunction after radiation therapy found to have venous leak (56). Approximately 50% of these venous leaks are from the crura; however, for the other 50%, there may be a role in sparing the dorsal venous plexus. The dorsal venous plexus has broad anatomic variability. In some men, the volume of the dorsal venous plexus is as large as two-thirds the prostate volume and often can be unwittingly included in CT-defined prostate contours. Using MRI to distinguish the dorsal venous plexus from the prostate can help to spare this tissue. Recent surgical reports have described the presence of arterial tissue within the dorsal venous plexus and have proposed renaming this structure the dorsal vascular complex

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(57). The origin and role of this arterial tissue is yet to be determined, but it may play a role in erectile function and further supports sparing this region.

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benefit of leaving the probe in place during HDR brachytherapy treatments, to limit rectal dose during treatment delivery (60).

Implant anatomy: Probe effects The rectourethralis is a muscle that arises from the anterior rectal wall and attaches to the perineal body or EUS just below the apex of the prostate (58). It plays a role in recoil of the recto-anal flexure after probe-based brachytherapy procedures. Probe placement causes a straightening of the recto-anal flexure and pulls the rectum away from the GUD, stretching the rectourethralis into an ‘‘open’’ position. This creates the illusion of a space between the rectum and the prostate on ultrasound, especially when the probe is in a downward-tilt and/or at a distance from the gland as is often the case for implant procedures. One sequelae of this complex dynamic is that seeds placed in the posterior row adjacent to the rectum may seem distant from the rectum on ultrasound but on postimplant imaging are found to be immediately adjacent, delivering high dose to the rectum (27) (Fig. 8). There are three components to this phenomenon. First, swelling may occur during the procedure which may represent a change in the density of the prostate tissue. This tissue will be compressible when the rectum recoils. Second, the prostate position is flexed by the probe and rotates back in position after probe removal. Finally, the rectourethralis approximates the rectum and GUD bringing the posterior row of seeds closer to the rectal surface than intended (59). Three potential solutions include placing the posterior row needles early in the procedure before swelling, placing the posterior row needles slightly anterior to the ideal position, or implanting the posterior row needles an entire row anterior and using beveled needles to steer seeds to the ideal posterior position at the base. Any of these strategies can avoid unintended high rectal dose. A benefit of understanding the probe effect is the potential

Brachytherapy challenge at midgland Defining the middle of the prostate gland is clearer than the apex and base regions. This is due to a clear fat plane surrounding the midgland, unlike at the base where the prostate merges with the adjacent soft tissue of bladder muscle and the apex where it merges with the GUD. Disagreement in defining the midgland occurs due to anterior fascial variation (11). Challenges at the level of the midgland include (1) distinguishing prostate from fascia for treatment planning and postimplant dosimetry, (2) presence of anterior T3 disease, that is, not palpable on examination and not routinely biopsied, (3) anatomic variability of neurovascular elements, and (4) the veru and its potential role in painful or decreased ejaculation. Variant anatomy Fascia surrounding the lateral and anterior prostate creates a potential space clearly visible on MRI and ultrasound (US), but poorly defined on CT (11). This space may contain the dorsal venous plexus near the apex but may seem empty at midgland. However, this potential space is not universal; therefore, no assumptions can be made without clear imaging. Although an expansive space is visible in 1 patient, hypertrophy completely fills and obliterates the space in another (Fig. 9). Knowledge of this variation defined on MRI can inform US-based contours in the OR. Postimplant dosimetry using CT often leads to mistaking the anterior fascia as an under dosed region of the prostate. MRI clarifies this and allows more accurate postimplant dosimetry (Fig. 10) (11). Although the fascia

Fig. 8. Dynamic distance between rectum and rectal row of seeds (a) preimplant sagittal view demonstrating natural relationship between prostate and rectum, (b) intraoperative sagittal view with rectal probe in place demonstrating anterior rotation of prostate, straightening of rectum, and resulting space between prostate apex and rectum, and (c) postimplant sagittal view after rectal probe has been removed demonstrating recoil of rectum bringing together rectal row seeds and rectal surface (yellow triangle 5 temporary space). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

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Fig. 9. Sagittal T2-weighted MRIs demonstrating variations in anterior prostate anatomy (red 5 anterior fascia; blue 5 dorsal venous plexus [DVP]; green 5 prostate; orange 5 external urethral sphincter) (a) anterior fascia with DVP, (b) anterior fascia without DVP, and (c) enlarged prostate obliterating anterior space. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

is a potential space opposite to the peripheral zone biopsies at midgland, anterior T3 disease can project into this space. This area is not palpable on clinical examination, not typically sampled with standard transrectal ultrasound (TRUS)

eguided biopsies, and may not be visible on US. Anterior disease may only be discovered by mpMRI pretreatment (61) and may harbor aggressive disease that needs to be accounted for on brachytherapy treatment planning (62).

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Fig. 10. T2-weighted axial MRIs demonstrating how MRI-based prostate contours differ from CT-based prostate contours. (a) T2-weighted axial MRI slice through midprostate gland, (b) T2-weighted axial MRI slice through prostate apex (blue: dorsal venous plexus, green: MRI-based prostate contour, yellow: CT-based prostate contour, orange dots: true prostate edge). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

The variation in neurovascular anatomy is most apparent at midgland. Liss et al. (25) presented a series in which the greatest circumferential spread of nerve elements along the prostate surface occurs at midgland. In approximately 40% of patients, the nerve elements form an ill-defined plexus spread over the lateral surface of the prostate. In over 50%, the nerves form a bundle in the classic posterolateral location. In less than 5%, no nerve elements are apparent. Such variation in anatomy nullifies previous doseresponse analyses that assumed a classic configuration (dorsolateral bundles) (63, 64). In a subset of patients, the nerve bundle is clearly defined and separate from the prostate, enabling dose restriction during planning and implantation. For patients with the plexus pattern, peripherally loaded LDR implants may result in high dose to the nerve

elements. Moving the seeds just inside the capsule may avoid extreme doses to the nerve elements at the expense of slightly higher urethral doses. This requires further study. Immobile functional anatomy The veru (i.e., seminal colliculus) is the expansion in the urethra at midgland through which the ejaculate (semen) passes. Two common maladies related to the veru are retrograde ejaculation due to TUR or alpha blockers discussed previously, and painful ejaculation experienced in a minority of men postbrachytherapy (65). At present, the etiology is unclear, but extremely high dose to this region may cause inflammation (acute) or narrowing (chronic) with

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Fig. 11. Sample case. (a) Tumor defined on axial ADC map. (b) Tumor defined on axial DWI. (c) Tumor defined on axial T2WI. (d) Prostate biopsy map. (e) Coronal tumor map. (f) Axial tumor map (green 5 prostate, red 5 GTV, orange 5 HR-CTV, yellow 5 LR-CTV). (g) 3D tumor map. (h) 3D functional anatomy map. (i) Overlaying tumor and functional anatomy map. SV 5 seminal vesicles; NVB 5 neurovascular bundle; IPA 5 internal pudendal artery; EUS 5 external urethral sphincter; PB 5 penile bulb; CC 5 corpus cavernosa; ADC 5 apparent diffusion coefficient; DWI 5 diffusion weighted image; T2WI 5 T2-weighted image; GTV 5 gross tumor volume; HR-CTV 5 high risk clinical target volume; LR-CTV 5 low risk clinical target volume; R 5 right; L 5 left; H 5 head; F 5 foot. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

associated pain. The veru and the ejaculatory ducts are visible on MRI and CT. Peripheral loading may decrease the likelihood of high dose to this region and limit this complications. Practical implications of MRI anatomy in clinical decision-making A spectrum of approaches has been developed to exploit the information obtained from MRI. There is heightened interest in more conformal prostate cancer radiation that focuses on targeting actual tumor defined by mpMRI rather than the whole organ (66), acknowledging that the latter represents a faulty surrogate of disease given that cancer is neither defined by nor confined to the prostate

boundaries. Some have postulated partial gland irradiation, and others have explored focused radiation in which the whole prostate gland is treated, but only the area of disease is dose escalated. When necessary, the whole prostate can be dose escalated using a combination of brachytherapy and external beam which allows more control over dose distribution and allows better sparing of periprostatic tissues. The feasibility of these approaches and the ability to achieve adequate tumor coverage while reducing dose to organs at risk has been well demonstrated (66, 67). Although the concern for multifocal disease in the prostate and the risk of failure in the underdosed parts of the prostate exists, the literature suggests that the dominant lesion likely drives prognosis (68, 69). Areas of high disease burden at diagnosis correlate with areas of local failure

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Table 2 Planning directive for the case presented demonstrating treatment priorities within the prostate and organs at risk (OAR) that can be spared Targets

Definition

Coverage goals

Priority

GTV HR-CTV LR-CTV Prostate

Positive on T2WI, DWI, ADC map Positive for $ GS 7 on biopsy but not visualized on MRI Positive for GS 6 on biopsy Negative on biopsy and MRI

D90 5 100% D90 O 90% D90 O 90% D90 O 90%

2 2 3 3

OAR

Gross tumor involvement

At risk for tumor involvement

Goals

Priority

SV Bladder neck EUS NVB APA IPA CC Crura PB

No No Yes No N/A No No No No

Likely (given base involved) Unlikely (given TZ not involved) Yes Unlikely N/A Unlikely Unlikely Unlikely Unlikely

Treat proximally ALARA ALARA ALARA N/A ALARA ALARA ALARA ALARA

2 1 3 1 N/A 1 1 1 1

GTV 5 gross tumor volume; HR-CTV 5 high risk clinical target volume; LR-CTV 5 low risk clinical target volume; SV 5 seminal vesicles; EUS 5 external urethral sphincter; NVB 5 neurovascular bundles; APA 5 accessory pudendal artery; IPA 5 internal pudendal artery; CC 5 corpus cavernosa; PB 5 penile bulb; T2WI 5 T2-weighted image; ADC 5 apparent diffusion coefficient; DWI 5 diffusion weighted image; GS 5 Gleason score; TZ 5 transition zone.

after curative-intent radiotherapy (70, 71). Indeed, some have further suggested that only patients with an MRIidentifiable lesion should undergo diagnostic biopsies, regardless of screening prostate-specific antigen levels, based on the premise that disease that is not visible on MRI is unlikely to be clinically significant (72). Additionally, the ability to salvage failures in areas of the prostate that were not initially treated has been demonstrated (73, 74). The optimal approach to prostate radiation in the era of mpMRI guidance remains an area of active and evolving research, with normal tissue and organ function preservation becoming outcomes of paramount importance. In this review, we have presented a functional anatomy-based approach to prostate brachytherapy. This approach employs differential prioritization within the prostate based on tumor location and individual patient anatomy. Integrating functional anatomy and tumor anatomy A patient with an elevated prostate-specific antigen of 4.5 ng/mL undergoes a 12 core TRUS-guided prostate biopsy revealing adenocarcinoma in 5/12 cores involving the left base, midgland and apex, and right midgland (Fig. 11). The patient subsequently undergoes an mpMRI that demonstrates a PIRADS 5 lesion, likely high-grade disease, at the left anterior apex. Given the anterior location of this lesion, it had not been identified on clinical examination or sampled during the TRUS-guided biopsy. Given the burden of disease at the apex, surgical treatment would leave him at high risk of a positive margin (75). Furthermore, as seen in Fig. 11, the patient has a short EUS. With surgical treatment, his personal risk of incontinence would be significant (76). He chooses to proceed with radiation. To plan his radiation treatment, a gross tumor volume was defined using information from the T2-weighted

images, diffusion-weighted images, and apparent diffusion coefficient map. A high-risk clinical target volume was defined by encompassing prostate regions found to be positive for Gleason score (GS) 7 disease or higher on biopsy but diffusion negative on MRI. A low-risk clinical target volume was defined to include areas found to be positive for GS 6 disease on biopsy but negative on MRI. All functional anatomic structures including the prostate were defined on the MRI. This patient is noted to have GS 7 disease at the base on biopsy and gross disease extending to the intraprostatic EUS on MRI. Given base involvement, microscopic extension to the seminal vesicle is a consideration. The fact that no extension is apparent on MRI allows the majority of the seminal vesicle to be spared. Given proximity of diffusion positive, aggressive disease adjacent to the EUS, it becomes important to prioritize disease coverage over EUS sparing. However, with precise definition of the apex, dose can be restricted to the extraprostatic EUS, IPA, penile bulb, crura, and CC. Furthermore, given that there is no transition zone involvement, dose can be restricted to the bladder neck. Table 2 summarizes the brachytherapy planning goals and priorities considered for this patient. To establish priorities, it is important to distinguish those structures that are clearly separate from the prostate (i.e., extraprostatic EUS, IPA, penile bulb, CC) from those within the prostate but separate from gross disease, and those within the prostate and involved by gross disease. Such a modulated plan is likely to result in a heterogeneous dose distribution within the prostate. The goal of such a plan is to localize hot spots within areas of disease identified on MRI and to drive cold spots toward areas that are unlikely to harbor disease to protect functional tissues. Some critical structures within the prostate (i.e., APA, nerve plexus, intraprostatic EUS) may only be spared using partial prostate radiation, a method currently being studied.

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In some instances in which adequate coverage of the whole prostate is necessary, the implant dose can be integrated as background dose for the external beam Intensity Modulated Radiation Therapy calculation to supplement low-dose regions, provide dose margin, and provide dose to structures at risk not sufficiently covered by brachytherapy (77). The concepts of this article apply both to LDR and to the rapidly emerging HDR brachytherapy modalities. Particularly in HDR brachytherapy, implant and/or planning can be MRI based, and dwell time optimization is performed after positioning of the catheters. Therefore, resultant dose distributions may better reflect the actual dose, with less susceptibility to misplacements or migrations (78, 79). Some have demonstrated the risk of ‘‘cold spots’’ and catheter migration with HDR therapy and have shown that a significant number of local failures may be ‘‘geographical misses’’ occurring in areas of under dosed disease (80). Unlike LDR implants, in which underdosed regions are objectively apparent by postimplant seed distribution, allowing for correction if external beam radiation is sequenced after the implant, cold areas from an HDR implant are more difficult to define because no clear tracking of intended vs. actual catheter position is possible. However, catheter migration was a technical challenge with multifraction HDR and is less of a concern in single fraction treatments. Studies have suggested better prostate coverage, conformity, and sparing of surrounding organs at risk with HDR compared to LDR implants (81). At this time, no superior clinical outcomes have been objectively demonstrated in any risk group with HDR compared to LDR; however, these findings certainly nurture the importance of novel concepts for normal function preservation. Better target and anatomic delineation with MRI-based implants may help to minimize these technical challenges and further optimize disease control and functional preservation with both HDR and LDR treatments. Conclusion Conventional prostate radiation has involved homogenous treatment to the entire prostate gland. This is due to the inability to visualize subglandular anatomy and in situ prostate cancers on CT and US imaging and due to concern of microscopic disease throughout the rest of the prostate gland. With mpMRI, improved delineation of gross tumor, aggressive tumor, extraprostatic extension and vulnerable functional anatomical structures, prostate radiation in general, and brachytherapy in particular, can challenge these paradigms and redefine treatment strategies to improve cure and quality of life for prostate cancer survivors. The presented approach to curative-intent radiation therapy has shown great strides in other disease sites. In head and neck malignancies, xerostomia and dysphagia were once expected and accepted toxicities in a majority of patients undergoing definitive chemotherapy and radiation. However, with better imaging and improved radiation techniques, the

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structures responsible for these maladies were recognized and could be spared in those patients with limited disease (82, 83). Herein, we suggest a parallel approach for prostate cancer. With a better understanding of tumor probability within the prostate, differential biological characterization of distinct intraprostatic tumor foci, intraprostatic and periprostatic structures at risk, rational decisions can be made to dose de-escalate in the vicinity of key functional tissues without compromising or even intensifying selective coverage of the clinical target volume. In summary, we provide mounting evidence and propose a novel approach for prostate cancer brachytherapy that could improve the therapeutic index of prostate radiation, in the current era of advanced brachytherapy planning and delivery, MRI-based characterization and guidance, and treatment personalization strategies. References [1] Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin 2016;66:271e289. [2] Hoskin PJ, Rojas AM, Bownes PJ, et al. Randomised trial of external beam radiotherapy alone or combined with high-dose-rate brachytherapy boost for localised prostate cancer. Radiother Oncol 2012;103:217e222. [3] Sathya JR, Davis IR, Julian JA, et al. Randomized trial comparing iridium implant plus external-beam radiation therapy with external-beam radiation therapy alone in node-negative locally advanced cancer of the prostate. J Clin Oncol 2005;23:1192e1199. [4] Morris WJ, Tyldesley S, Rodda S, et al. *ASCENDE-RT: An analysis of survial endpoints for a randomized trial comparing a lowdose-rate brachytherapy boost to a dose-escalated external beam boost for high- and intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys 2016;. http://dx.doi.org/10.1016/j.ijrobp.2016.11. 026. [5] Hayes JH, Ollendorf DA, Pearson SD, et al. Observation versus initial treatment for men with localized, low-risk prostate cancer: A cost-effectiveness analysis. Ann Intern Med 2013;158:853e860. [6] Spratt DE, Zumsteg ZS, Ghadjar P, et al. Comparison of high-dose (86.4 Gy) IMRT vs combined brachytherapy plus IMRT for intermediate-risk prostate cancer. BJU Int 2014;114:360e367. [7] Liss AL, Abu-Isa EI, Jawad MS, et al. Combination therapy improves prostate cancer survival for patients with potentially lethal prostate cancer: The impact of Gleason pattern 5. Brachytherapy 2015;14:502e510. [8] Shilkrut M, Merrick GS, McLaughlin PW, et al. The addition of low-dose-rate brachytherapy and androgen-deprivation therapy decreases biochemical failure and prostate cancer death compared with dose-escalated external-beam radiation therapy for high-risk prostate cancer. Cancer 2013;119:681e690. [9] Shilkrut M, McLaughlin PW, Merrick GS, et al. Treatment outcomes in very high-risk prostate cancer treated by dose-escalated and combined-modality radiation therapy. Am J Clin Oncol 2016; 39:181e188. [10] Grimm P, Billiet I, Bostwick D, et al. Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group. BJU Int 2012;109 Suppl 1:22e29. [11] McLaughlin PW, Evans C, Feng M, et al. Radiographic and anatomic basis for prostate contouring errors and methods to improve prostate contouring accuracy. Int J Radiat Oncol Biol Phys 2010;76:369e378.

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[12] Dubois DF, Prestidge BR, Hotchkiss LA, et al. Intraobserver and interobserver variability of MR imaging- and CT-derived prostate volumes after transperineal interstitial permanent prostate brachytherapy. Radiology 1998;207:785e789. [13] Rodda S, Tyldesley S, Morris W. GU and GI toxicity in ASCENDERT*: A multicentre randomized trial of dose-escalated radiation for prostate cancer. Radiother Oncol 2015;115:S22eS23. [14] Leong N, Pai HH, Morris WJ, et al. Rectal ulcers and rectoprostatic fistulas after (125)I low dose rate prostate brachytherapy. J Urol 2016;195:1811e1816. [15] Keyes M, Miller S, Pickles T, et al. Late urinary side effects 10 years after low-dose-rate prostate brachytherapy: Population-based results from a multiphysician practice treating with a standardized protocol and uniform dosimetric goals. Int J Radiat Oncol Biol Phys 2014;90:570e578. [16] Lee JY, Spratt DE, Liss AL, et al. Vessel-sparing radiation and functional anatomy-based preservation for erectile function after prostate radiotherapy. Lancet Oncol 2016;17:e198ee208. [17] Mikuma N, Tamagawa M, Morita K, et al. Magnetic resonance imaging of the male pelvic floor: The anatomical configuration and dynamic movement in healthy men. Neurourol Urodyn 1998; 17:591e597. [18] Hocaoglu Y, Herrmann K, Walther S, et al. Contraction of the anterior prostate is required for the initiation of micturition. BJU Int 2013;111:1117e1123. [19] Hathout L, Folkert MR, Kollmeier MA, et al. Dose to the bladder neck is the most important predictor for acute and late toxicity after low-dose-rate prostate brachytherapy: Implications for establishing new dose constraints for treatment planning. Int J Radiat Oncol Biol Phys 2014;90:312e319. [20] Kaul S, Savera A, Badani K, et al. Functional outcomes and oncological efficacy of Vattikuti Institute prostatectomy with Veil of Aphrodite nerve-sparing: An analysis of 154 consecutive patients. BJU Int 2006;97:467e472. [21] Rogers CG, Trock BP, Walsh PC. Preservation of accessory pudendal arteries during radical retropubic prostatectomy: Surgical technique and results. Urology 2004;64:148e151. [22] Hindson BR, Millar JL, Matheson B. Urethral strictures following high-dose-rate brachytherapy for prostate cancer: Analysis of risk factors. Brachytherapy 2013;12:50e55. [23] Agrawal CS, Chalise PR, Bhandari BB. Correlation of prostate volume with international prostate symptom score and quality of life in men with benign prostatic hyperplasia. Nepal Med Coll J 2008;10: 104e107. [24] Liss A, Murgic J, Evans C, et al. Variation in external sphincter extension within and beyond the prostate: Implications from MRIbased post implant segmental dosimetry. Brachytherapy 2013;12: S33. [25] Liss A, Zhou J, Evans C, et al. Anatomic variability of the neurovascular elements defined by MRI. Brachytherapy 2014;13:S42eS43. [26] Dess R, Evans CA, Narayana V, et al. Bladder neck variants: MRI versus ultrasound definition. Brachytherapy 2016;15:S195e S196. [27] Soni PD, Yao B, Evans C, et al. The brachytherapy ‘‘Bermuda triangle’’: A potential space with important implications for LDR and HDR prostate brachytherapy. Brachytherapy 2016;15:S175eS176. [28] McLaughlin P, Narayana V, Pan C, et al. Comparison of day 0 and day 14 dosimetry for permanent prostate implants using stranded seeds. Int J Radiat Oncol Biol Phys 2006;64:144e150. [29] Wibmer A, Verma S, Vargas HA. Role of MRI in the risk assessment of primary prostate cancer. Top Magn Reson Imaging 2016; 25:133e138. [30] Watanabe H, Takahashi S, Ukimura O. Urethra actively opens from the very beginning of micturition: A new concept of urethral function. Int J Urol 2014;21:208e211. [31] Nishio K, Soh S, Syukuya T, et al. Role of male pelvic floor muscles and anterior fibromuscular stroma in males on a(1)-blocker

[32]

[33]

[34] [35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44] [45]

[46]

[47]

[48] [49]

[50]

[51]

-

(2016)

-

treatment: A magnetic resonance imaging study. Int J Urol 2014; 21:724e727. Li XM, Yang H, Li DQ, et al. Muscular structure at the male bladder outlet examined with successive celloidin-embedded slices. Urology 2015;85:629e635. Usmani N, Chng N, Spadinger I, et al. Lack of significant intraprostatic migration of stranded iodine-125 sources in prostate brachytherapy implants. Brachytherapy 2011;10:275e285. Shah AP, Mevcha A, Wilby D, et al. Continence and micturition: An anatomical basis. Clin Anat 2014;27:1275e1283. Langley SE, Laing RW. 4D Brachytherapy, a novel real-time prostate brachytherapy technique using stranded and loose seeds. BJU Int 2012;109 Suppl 1:1e6. Lebdai S, Ammi M, Bigot P, et al. Clinical impact of the intravesical prostatic protrusion: A review by the LUTS committee of the French Urological Association. Prog Urol 2014;24:313e318. D’Amico AV, Davis A, Vargas SO, et al. Defining the implant treatment volume for patients with low risk prostate cancer: Does the anterior base need to be treated? Int J Radiat Oncol Biol Phys 1999;43:587e590. Nguyen PL, Chen MH, Zhang Y, et al. Updated results of magnetic resonance imaging guided partial prostate brachytherapy for favorable risk prostate cancer: Implications for focal therapy. J Urol 2012;188:1151e1156. Teishima J, Iwamoto H, Miyamoto K, et al. Impact of pre-implant lower urinary tract symptoms on postoperative urinary morbidity after permanent prostate brachytherapy. Int J Urol 2012;19:1083e 1089. Sadananda P, Vahabi B, Drake MJ. Bladder outlet physiology in the context of lower urinary tract dysfunction. Neurourol Urodyn 2011; 30:708e713. Martens C, Pond G, Webster D, et al. Relationship of the International Prostate Symptom score with urinary flow studies, and catheterization rates following 125I prostate brachytherapy. Brachytherapy 2006;5:9e13. Merrick GS, Butler WM, Wallner KE, et al. Effect of transurethral resection on urinary quality of life after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2004;58:81e88. Brousil P, Hussain M, Lynch M, et al. Modified transurethral resection of the prostate (TURP) for men with moderate lower urinary tract symptoms (LUTS) before brachytherapy is safe and feasible. BJU Int 2015;115:580e586. Samplaski MK, Nangia AK. Adverse effects of common medications on male fertility. Nat Rev Urol 2015;12:401e413. Kestin L, Goldstein N, Vicini F, et al. Treatment of prostate cancer with radiotherapy: Should the entire seminal vesicles be included in the clinical target volume? Int J Radiat Oncol Biol Phys 2002;54: 686e697. Kristiansen A, Wiklund F, Wiklund P, et al. Prognostic significance of patterns of seminal vesicle invasion in prostate cancer. Histopathology 2013;62:1049e1056. Shafik A, El-Sibai O. Effect of levator ani muscle contraction on urethrovesical and anorectal pressures and role of the muscle in urination and defecation. Urology 2001;58:193e197. Andrews EW. Infrapubic section for prostatectomy. J Am Med Assoc 1902;39:955e959. McLaughlin PW, Narayana V, Meirovitz A, et al. Vessel-sparing prostate radiotherapy: Dose limitation to critical erectile vascular structures (internal pudendal artery and corpus cavernosum) defined by MRI. Int J Radiat Oncol Biol Phys 2005;61:20e31. Register SP, Kudchadker RJ, Levy LB, et al. An MRI-based dosee response analysis of urinary sphincter dose and urinary morbidity after brachytherapy for prostate cancer in a phase II prospective trial. Brachytherapy 2013;12:210e216. Rasch C, Barillot I, Remeijer P, et al. Definition of the prostate in CT and MRI: A multi-observer study. Int J Radiat Oncol Biol Phys 1999;43:57e66.

P.D. Soni et al. / Brachytherapy [52] Gillan C, Kirilova A, Landon A, et al. Radiation dose to the internal pudendal arteries from permanent-seed prostate brachytherapy as determined by time-of-flight MR angiography. Int J Radiat Oncol Biol Phys 2006;65:688e693. [53] Merrick GS, Butler WM, Wallner KE, et al. The importance of radiation doses to the penile bulb vs. crura in the development of postbrachytherapy erectile dysfunction. Int J Radiat Oncol Biol Phys 2002;54:1055e1062. [54] Merrick GS, Butler WM, Wallner KE, et al. Erectile function after prostate brachytherapy. Int J Radiat Oncol Biol Phys 2005;62:437e 447. [55] Benoit G, Droupy S, Quillard J, et al. Supra and infralevator neurovascular pathways to the penile corpora cavernosa. J Anat 1999;195: 605e615. [56] Mulhall J, Ahmed A, Parker M, et al. The hemodynamics of erectile dysfunction following external beam radiation for prostate cancer. J Sex Med 2005;2:432e437. [57] Power NE, Silberstein JL, Kulkarni GS, et al. The dorsal venous complex (DVC): Dorsal venous or dorsal vasculature complex? Santorini’s plexus revisited. BJU Int 2011;108:930e932. [58] Soga H, Takenaka A, Murakami G, et al. Topographical relationship between urethral rhabdosphincter and rectourethralis muscle: A better understanding of the apical dissection and the posterior stitches in radical prostatectomy. Int J Urol 2008;15:729e732. [59] Soni PD, Berlin A, Yao B, et al. The Brachytherapy Bermuda Triangle: Probe influence on pelvic anatomy in prostate implants. Manuscript in progress. [60] Rylander S, Buus S, Bentzen L, et al. The influence of a rectal ultrasound probe on the separation between prostate and rectum in high-dose-rate brachytherapy. Brachytherapy 2015;14: 711e717. [61] Moosavi B, Flood TA, Al-Dandan O, et al. Multiparametric MRI of the anterior prostate gland: Clinical-radiological-histopathological correlation. Clin Radiol 2016;71:405e417. [62] Lawrentschuk N, Haider MA, Daljeet N, et al. ‘Prostatic evasive anterior tumours’: The role of magnetic resonance imaging. BJU Int 2010;105:1231e1236. [63] Goldstein I, Feldman MI, Deckers PJ, et al. Radiation-associated impotence. A clinical study of its mechanism. JAMA 1984;251: 903e910. [64] Merrick GS, Butler WM, Dorsey AT, et al. A comparison of radiation dose to the neurovascular bundles in men with and without prostate brachytherapy-induced erectile dysfunction. Int J Radiat Oncol Biol Phys 2000;48:1069e1074. [65] Huyghe E, Delannes M, Wagner F, et al. Ejaculatory function after permanent 125I prostate brachytherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2009;74:126e132. [66] Jereczek-Fossa BA, Ciardo D, Petralia G, et al. Primary focal prostate radiotherapy: Do all patients really need whole-prostate irradiation? Crit Rev Oncol Hematol 2016;105:100e111. [67] Peach MS, Trifiletti DM, Libby B. Systematic review of focal prostate brachytherapy and the future implementation of image-guided

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75] [76]

[77]

[78]

[79]

[80]

[81]

[82]

[83]

-

(2016)

-

17

prostate HDR brachytherapy using MR-ultrasound fusion. Prostate Cancer 2016;2016:4754031. Arora R, Koch MO, Eble JN, et al. Heterogeneity of Gleason grade in multifocal adenocarcinoma of the prostate. Cancer 2004;100: 2362e2366. Noguchi M, Stamey TA, McNeal JE, et al. Prognostic factors for multifocal prostate cancer in radical prostatectomy specimens: Lack of significance of secondary cancers. J Urol 2003;170:459e463. Arrayeh E, Westphalen AC, Kurhanewicz J, et al. Does local recurrence of prostate cancer after radiation therapy occur at the site of primary tumor? Results of a longitudinal MRI and MRSI study. Int J Radiat Oncol Biol Phys 2012;82:e787ee793. Chopra S, Toi A, Taback N, et al. Pathological predictors for site of local recurrence after radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2012;82:e441ee448. Klotz L, Emberton M. Management of low risk prostate canceractive surveillance and focal therapy. Nat Rev Clin Oncol 2014; 11:324e334. Banerjee R, Park SJ, Anderson E, et al. From whole gland to hemigland to ultra-focal high-dose-rate prostate brachytherapy: A dosimetric analysis. Brachytherapy 2015;14:366e372. Kamrava M, Chung MP, Kayode O, et al. Focal high-dose-rate brachytherapy: A dosimetric comparison of hemigland vs. conventional whole-gland treatment. Brachytherapy 2013;12:434e441. Meeks JJ, Eastham JA. Radical prostatectomy: Positive surgical margins matter. Urol Oncol 2013;31:974e979. Tienza A, Hevia M, Benito A, et al. MRI factors to predict urinary incontinence after retropubic/laparoscopic radical prostatectomy. Int Urol Nephrol 2015;47:1343e1349. Soto DE, McLaughlin PW. Combined permanent implant and external-beam radiation therapy for prostate cancer. Semin Radiat Oncol 2008;18:23e34. Menard C, Susil RC, Choyke P, et al. MRI-guided HDR prostate brachytherapy in standard 1.5T scanner. Int J Radiat Oncol Biol Phys 2004;59:1414e1423. Murgic J, Chung P, Berlin A, et al. Lessons learned using an MRIonly workflow during high-dose-rate brachytherapy for prostate cancer. Brachytherapy 2016;15:147e155. Roberts SA, Miralbell R, Zubizarreta EH, et al. A modelled comparison of prostate cancer control rates after high-dose-rate brachytherapy (3145 multicentre patients) combined with, or in contrast to, external-beam radiotherapy. Radiother Oncol 2014;111:114e119. Wang Y, Sankreacha R, Al-Hebshi A, et al. Comparative study of dosimetry between high-dose-rate and permanent prostate implant brachytherapies in patients with prostate adenocarcinoma. Brachytherapy 2006;5:251e255. Eisbruch A, Schwartz M, Rasch C, et al. Dysphagia and aspiration after chemoradiotherapy for head-and-neck cancer: Which anatomic structures are affected and can they be spared by IMRT? Int J Radiat Oncol Biol Phys 2004;60:1425e1439. Wang X, Eisbruch A. IMRT for head and neck cancer: Reducing xerostomia and dysphagia. J Radiat Res 2016;57 Suppl 1:i69ei75.