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Minimizing prostate brachytherapy-related morbidity
REVIEW
MINIMIZING PROSTATE BRACHYTHERAPYRELATED MORBIDITY GREGORY S. MERRICK, KENT E. WALLNER,
A
fter permanent prostate brachytherapy with or without supplemental external beam radiotherapy (EBRT), most studies have reported favorable long-term biochemical outcomes for patients with low, intermediate, and high-risk features.1 These findings result in part from dose escalation and the ability to treat the periprostatic region aggressively.2– 4 With the assimilation of brachytherapy into conventional cancer care, a rapidly expanding body of literature is available regarding therapy-related morbidity.5– 8 With the highly demarcated therapeutic geography of brachytherapy, even minor differences in source placement philosophies could lead to significant differences in cancer eradication and radiation-related morbidities. Similarly, with the intense inflammatory reaction that results from prostate brachytherapy, it seems logical that patient management policies could have a substantial effect on postimplant morbidities. With maturation of the brachytherapy literature, it has become increasingly apparent that efficacy and morbidity are highly dependent on implant quality, with substantial differences in the reported incidence and clinical course of radiation-related morbidity.9 –13 After analyzing our own data and the data of others, it appears that many of the conflicts are likely related to technical differences in treatment planning, in the implantation process itself, or in variations in patient management philosophies. Accordingly, we have summarized the patient selection factors, technical factors, and management strategies that appear to affect morbidity subThis study was funded in part by unrestricted educational grants from Theragenics and Amersham Health. G. S. Merrick is a study investigator funded in part by Theragenics and Amersham Health. From the Schiffler Cancer Center, Wheeling Hospital; Wheeling Jesuit University, Wheeling, West Virginia; and Puget Sound Health Care System Department of Veterans Affairs, Seattle, Washington Reprint requests: Gregory S. Merrick, M.D., Schiffler Cancer Center, Wheeling Hospital, 1 Medical Park, Wheeling, WV 26003-6300 Submitted: March 28, 2003, accepted (with revisions): May 12, 2003
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© 2003 ELSEVIER INC. ALL RIGHTS RESERVED
AND
WAYNE M. BUTLER
stantially. In addition, the presumed importance of some patient selection criteria and dosimetric parameters has recently been questioned. Elucidation and widespread adoption of evidencesupported planning philosophies, intraoperative techniques, and medical management should further improve outcomes. URINARY MORBIDITY Many investigators have studied the role of the International Prostate Symptom Score (IPSS) in patient selection, with varied conclusions.14,15 After brachytherapy, almost all patients develop urinary irritative/obstructive symptoms, with 2% to 32% of patients developing acute urinary retention.14 –17 However, only approximately 2% of patients require a urinary catheter for longer than 1 week.14 The potential relationship between the preimplant IPSS and the subsequent development of urinary retention has been evaluated with mixed results.14,15 In a prospective study at the University of Washington, little correlation was reported between the preimplant IPSS and acute urinary retention or long-term urinary function.16,18 In addition, urodynamic studies, postvoid residual urine volume, maximal flow rate, or preimplant cystourethroscopy did not predict for postimplant urinary retention.16,18 Currently, no reliable preimplant criteria are available to predict which patients will develop prolonged urinary retention. Urinary morbidity in the immediate postimplant setting has been well documented, with the preimplant IPSS correlating with the duration of postimplant obstructive symptoms.14,15,19,20 Alpha-blockers are widely used to ameliorate brachytherapy-related urinary morbidity, and the timing of their initiation may substantially influence their effect.14,19 Following a policy of prophylactic and prolonged medication use, Merrick and colleagues14 reported that the IPSS peaked 2 weeks after implantation with either palladium-103 or iodine-125 and returned to preimplant values at a median of 6 weeks. In contrast, without the use of prophylactic alpha-blockers, a timeline of approxUROLOGY 62: 786 –792, 2003 • 0090-4295/03/$30.00 doi:10.1016/S0090-4295(03)00558-2
FIGURE 1. Mean difference between antecedent patient IPSS and subsequent IPSS plotted for questionnaire intervals. Two curves stratify alpha-blocker use into prophylactic and therapeutic outcomes.
imately 12 months was reported for the IPSS to return to baseline.20 In a large multi-institutional study, prophylactic alpha-blockers resulted in a return of the IPSS to baseline significantly faster than in patients not receiving alpha-blockers or receiving them after substantial exacerbation of urinary symptoms19 (Fig. 1). However, the incidence of prolonged urinary catheter dependency (longer than 3 days) and the need for postimplant surgical intervention were not affected by alpha-blocker use.19 The initiation of alpha-blockers 2 to 3 weeks before implantation with continuation at least until the IPSS normalizes maximizes their beneficial effect. In addition, the results from a prospective randomized trial comparing palladium-103 with iodine-125 have reported a significantly faster resolution of IPSS in the palladium-103 arm.21 Dysuria is common after brachytherapy.22 The ability of alpha-blockers to relax alpha-adrenergic receptors in the bladder neck and prostate gland improves urinary flow and reduces the symptoms of prostatitis. In patients receiving prophylactic and prolonged alpha-blockers, the incidence of dysuria peaked at 52% 1 month after implantation.22 Although dysuria is a relatively common event during the first few years after brachytherapy, only rarely is it severe in frequency or intensity. Although no difference in preimplant IPSS was noted in patients with or without dysuria, patients with brachytherapy-related dysuria displayed greater postimplant IPSSs. The isotope used, supplemental EBRT, and hormonal status did not contribute to dysuria. Preliminary results of a double-blind pilot study of tamsulosin versus placebo for patients with chronic nonbacterial prostatitis revealed a benefit to treatment with tamUROLOGY 62 (5), 2003
sulosin.23 The utility of alpha-blockers in such patients may be translatable to brachytherapy-related dysuria and is currently being evaluated in an ongoing prospective randomized trial.21 In addition, anti-inflammatory agents and the avoidance of bladder irritants (i.e., caffeine, alcohol) may alleviate the intensity and frequency of treatment-related dysuria. Prostate size has been considered a relative contraindication to brachytherapy even though gland size has inconsistently been associated with increased morbidity.8,13,14 The transition zone (TZ) has been correlated with brachytherapy-related obstructive symptoms.17,24 The TZ index (TZ index ⫽ transition zone volume divided by prostate gland volume) correlated with the time to IPSS normalization, maximal increase in IPSS, and the subsequent need for postimplant surgical intervention.24 In patients undergoing postimplant transurethral resection of the prostate or transurethral incision of the prostate (TURP/TUIP), the TZ index was 0.34 versus 0.23 in those patients not requiring surgical intervention (P ⫽ 0.016). Thomas and colleagues17 reported that the TZ volume was the most important predictor of acute urinary retention after magnetic resonance-guided prostate brachytherapy. The TZ index may have greater predictive power for prolonged urinary dysfunction and the need for subsequent surgical intervention than any other single parameter and potentially could replace more simplistic patient selection factors such as ultrasound prostate volume. The vast majority of patients with prolonged urinary retention will eventually spontaneously urinate without surgical intervention. In the unlikely scenario that postimplant TURP/TUIP is necessary, it should be delayed as long as possible. Stone and Stock25 have recommended preservation of the bladder neck at the 5 and 7-o’clock positions to maintain sufficient prostatic urethral blood supply and minimize the risk of post-TURP/TUIP incontinence. Minimal cautery should be used to prevent late urethral ischemic damage.25 It has been suggested that a safe minimal time to perform TURP/TUIP is 6 months for iodine-125 and 2 months for palladium-103.25 In our practice, we have strongly discouraged surgical intervention for at least the first 12 months after brachytherapy. Using the Expanded Prostate Cancer Index Composite (EPIC), Merrick and colleagues8,26 reported urinary incontinence scores of 89.4 in brachytherapy patients without TURP and 79.3 in patients with preimplant TURP, but only 63.7 in patients with postimplant TURP (EPIC scores range from 0 to 100, with higher scores indicative of better function). 787
Dexamethasone has been widely used to reduce brachytherapy-related edema, improve urinary function, and reduce acute urinary retention. However, in a controlled study, the prophylactic use of dexamethasone did not affect short-term urinary catheter dependency or IPSS resolution.27 In contrast, low-dose prednisone (5 to 10 mg daily) is effective in ameliorating brachytherapy-induced dysuria (unpublished data). Wallner and colleagues28 reported an association between urinary morbidity and urethral doses greater than 250% minimal peripheral dose (mPD). In contemporary series, however, urethral doses have not correlated with urinary morbidity, probably because of sophisticated treatment planning with urethral sparing, which limits the urethral dose to 100% to 140% mPD, regardless of prostate size.2 Although urethral doses greater than 150% mPD should be minimized, underdosage (less than 100% mPD) should be avoided. Leibovich et al.29 reported the mean distance from the urethra to the nearest foci of cancer to be 3 mm, with 17% of all prostate cancers abutting the urethra. The significance of dose homogeneity within the prostate gland has been an area of concern, but a recent study reported no significant difference in IPSS resolution on the basis of the volume of the gland receiving 100%, 200%, or 300% of the prescribed dose.30 Although details of optimal urethral doses have yet to be elucidated, the average postimplant urethral doses should be limited to 140% mPD or less. Although supplemental EBRT and hormonal therapy are often used in brachytherapy patients, their influence on long-term urinary function has not been completely discerned. Supplemental EBRT results in an increased trend for late hematuria.31 A prospective randomized trial reported that 22% and 9% of patients receiving and not receiving, respectively, supplemental EBRT developed late but self-limited brachytherapy-related hematuria.31 In a study of long-term urinary function using the urinary domain of EPIC, supplemental EBRT adversely affected the urinary function and incontinence domains, but did not alter the irritation/obstruction or bother domains.8 Of multiple clinical, treatment, and dosimetric parameters, the use of tobacco most strongly predicted for adverse quality-of-life outcomes. In addition, former smokers had a quality-of-life outcome intermediate between those who had never smoked and current smokers.8 Conflicting results have been reported concerning a potential relationship between postimplant urinary retention and the use of neoadjuvant hormonal therapy.13–15,19 However, the largest of these studies, which consisted of 714 consecutive patients, reported that hormonal manipulation did not ad788
FIGURE 2. Dose to bulbomembranous urethra as percentage of mPD versus distance inferior to prostatic apex. Overall mean dose for stricture patients, 97.6% of mPD, differed significantly from that for control patients, 81.8% of mPD (P ⫽ 0.031). Reprinted with permission from Merrick GS, Butler WM, Tollenaar BG, et al: The dosimetry of prostate brachytherapy-induced urethral strictures. Int J Radiat Oncol Biol Phys 52: 461–468, 2002.
versely affect catheter dependency, IPSS normalization, or the need for postbrachytherapy surgical intervention. In contrast, hormonal therapy of longer than 6 months’ duration resulted in deleterious changes in the EPIC subscores of function and irritation/obstruction, with a trend for poorer bother and postimplant IPSS.8 Taken together, the data suggest that supplemental EBRT and/or hormonal therapy increase urinary morbidity and, as such, should be deleted from the treatment plan when possible. Patients should also be strongly counseled regarding cessation of cigarette smoking. The reported 5-year actuarial risk of urethral strictures ranges from 5% to 12% and appears to be directly related to overimplantation of the periapical region.10 Strictures typically involve the bulbomembranous urethra and are usually easily managed with dilation. Day 0 computed tomography (CT)-based dosimetry demonstrated that radiation doses to the bulbomembranous urethra were significantly greater in patients with strictures than those without10 (Fig. 2). With careful attention to implant technique, including extensive use of the sagittal plane for deposition of the seeds, it is possible to implant the apex with a 5-mm margin without “drawing” seeds into the region of the bulbomembranous urethra. Hormonal therapy of longer than 6 months’ duration increased the likelihood of urethral strictures.10 An enlarging body of data shows that brachytherapy-related urinary morbidity can be lessened UROLOGY 62 (5), 2003
TABLE I. Clinical and treatment parameters associated with increased urinary morbidity, rectal morbidity, and erectile dysfunction after prostate brachytherapy Implicated Factors Urinary morbidity Elevated preimplant IPSS Delayed use of alpha-blockers Large transition zone index Greater radiation dose to prostatic and bulbomembranous urethra Lack of careful attention to placement of periapical seeds Use of supplemental EBRT Hormonal therapy ⬎6-mo duration Choice of isotope Status of tobacco consumption Rectal morbidity Radiation dose Supplemental EBRT Constipation Failure to use biplanar ultrasonography with various frequencies Choice of isotope Erectile dysfunction Radiation dose to proximal penis Supplemental EBRT Hormonal therapy Radiation doses to prostate gland Lack of careful attention to placement of periapical seeds Patient age Diabetes Preimplant erectile function Lack of penile “physical therapy” KEY: IPSS ⫽ International Prostate Symptom Score; EBRT ⫽ external beam radiotherapy.
with refinements in patient selection, medical intervention, and intraoperative techniques. Prophylactic and prolonged usage of alpha-blockers, evaluation of the TZ, minimizing the volume of the urethra receiving more than 140% mPD, careful attention to the placement of periapical seeds, judicious use of supplemental EBRT and hormonal therapy, and the cessation of cigarette smoking are currently recognized to play a role in morbidity minimization (Table I). RECTAL MORBIDITY Rectal complications consist primarily of mild, self-limited proctitis and have consistently been correlated with the rectal dose.11,32–34 The onset of bleeding peaks at 8 months with an incidence of 4% to 12% and usually resolves spontaneously.32,35 Snyder and colleagues11 reported grade 2 proctitis to be volume dependent for a given dose, with no UROLOGY 62 (5), 2003
cases developing more than 36 months after implantation. Using day 30 CT-based dosimetry, Snyder et al.11 reported an 8% rate of grade 2 proctitis when less than 1.8 cm3 of rectum was exposed to 160 Gy after iodine-125 monotherapy, and the risk increased to approximately 25% when more than 1.8 cm3 of rectum was exposed.11 With day 0 CTbased dosimetry, Merrick and colleagues32 previously reported self-limited proctitis with radiation point doses to the anterior rectal mucosa of 85%. Recommendations included limiting the anterior maximal mucosal dose to 120% mPD and limiting the length of the rectal mucosa receiving 100% and 120% mPD to 10 mm and 5 mm, respectively.32 In a subsequent randomized trial, the minimal dose received by 5% of the rectum best correlated with brachytherapy-related rectal dysfunction (day 0 dosimetry).33 To compare rectal doses between series, the timing of the postimplant CT scan must be documented. Waterman and Dicker36 reported that the minimal dose that encompassed 10% of the surface area of the rectum increased on average by 68% from day 0 through day 30.36 Intraoperatively, careful attention to implant technique and ultrasound anatomy will reduce the dose to the anterior rectal wall and minimize bowel dysfunction. Extensive use of both transverse and sagittal images to confirm appropriate needle placement and the use of multiple ultrasound frequencies helps ensure proper seed placement. Higher transducer frequencies result in clearer definition of anatomy closer to the probe. Posterior row needle placements performed with the 7.5MHz setting help ensure that needles are placed just within the posterior prostatic capsule and not in the rectal wall. All other rows are imaged with the 5.0-MHz frequency. Rectal ulceration and fistula formation have occasionally been reported.37 Although the dose has been correlated with rectal bleeding, Howard and colleagues37 found no correlation between rectal dose and the development of fistula, with the conclusion that severe complications may occur in an unpredictable manner typically unrelated to known clinical, treatment, or dosimetric parameters. In a case report, constipation significantly increased the radiation dose to the rectum.38 Although no studies to date have correlated constipation with rectal toxicity, postimplant attention to bowel habits for two half-lives of the implanted isotope may minimize rectal distension and decrease the dose to the anterior rectal wall. Multiple studies have failed to reveal a correlation between prostate size and rectal complications.34 Bowel function assessments by patient-administered questionnaires, including the Rectal Function Assessment Score and the modified Radiation Therapy Oncology Group toxicity scale, illustrate 789
that long-term dysfunction after brachytherapy is relatively uncommon.7,33,34 Merrick and colleagues34 noted that only 12% of patients reported their bowel function to be worse after implantation. The number of preimplant bowel movements, history of tobacco consumption, median rectal dose, and addition of supplemental EBRT resulted in deterioration in bowel habits.34 For patients receiving high-dose three-dimensional conformal external beam RT, Jackson et al.39 reported an independent association with larger percent volumes exposed to intermediate doses (approximately 46 Gy) and the development of rectal bleeding. They hypothesized that a “large surrounding region of intermediate dose may interfere with the ability to repair the effects of a central high dose region.” This may also explain the deleterious effect of supplemental EBRT in some brachytherapy series. After three-dimensional conformal external beam RT, the use of hormonal therapy increased grade 2-4 late rectal toxicity (30.3% versus 14.1%)40 and potentially could have a similar effect on brachytherapy-related morbidity. However, using the Rectal Function Assessment Score instrument with a median follow-up of 66 months, hormonal therapy did not influence brachytherapyrelated bowel function.41 Preliminary results from an ongoing prospective randomized trial comparing palladium-103 with iodine-125 have reported a trend for greater rectal morbidity with iodine-125 without grade 3 or 4 events.21 In summary, brachytherapy-related bowel morbidity can be minimized with meticulous implant technique to minimize the radiation dose to the anterior rectal wall, careful attention to postimplant bowel habits, and the judicious use of supplemental EBRT (Table I). The potential effect of isotope requires additional investigation. ERECTILE DYSFUNCTION The penile erectile bodies (the paired corpora cavernosa and midline corpora spongiosum) represent a potential candidate for site-specific radiation doses related to erectile dysfunction (ED).12 Although ED is likely a multifactorial process, an increasing body of data implicating excessive radiation doses to the proximal penis is available.12 ED appears to be technique related and should be minimized by careful attention to source placement. With day 0 CT-based dosimetric evaluation, the radiation dose delivered to 50% of the bulb of the penis was less than 50 Gy and the dose delivered to 95% of the bulb of the penis was less than 20 Gy for most patients who maintained potency, and for the vast majority of men who became impotent the doses exceeded these values.12 Excessive radiation doses to the bulb of the penis are a result of poor 790
planning and/or poor intraoperative techniques. Recommendations to maximize potency preservation include limiting the penile bulb radiation dose delivered to 50% of the bulb of the penis to less than 40% mPD and the crura to less than 28% mPD.12 Refinements in implant technique, including preplanning and intraoperative seed placement, with use of the sagittal plane for the deposition of the apical/periapical seeds results in lower radiation doses to the proximal penis, with potential improvement in potency preservation. Radiation doses to the neurovascular bundles (NVBs) and the development of brachytherapy-induced ED have been evaluated in retrospective and prospective studies.42,43 Although initial reports (median follow-up of 37 months) have not demonstrated any relationship between NVB doses and treatment-induced ED,42 it is possible that with longer follow-up, NVB doses may be found to contribute to brachytherapy-related ED. On the basis of the available data, however, it is not rational to recommend NVB-sparing brachytherapy, particularly, because the NVB lies so close to the frequently biopsy-positive peripheral zone of the prostate. From a clinical perspective, potency preservation after brachytherapy is most closely related to preimplant erectile function.44,45 However, the addition of supplemental EBRT,44,46 radiation doses to the prostate gland,45 patient age,44 and diabetes44 may exacerbate brachytherapy-induced ED. The role of neoadjuvant hormonal therapy in potency preservation has been mixed,44 – 46 and choice of isotope appears unrelated.44,45 Radiation-related ED typically responds well to sildenafil.47 A lack of erectile activity may be deleterious to erectile function, and, as such, patients should be encouraged to develop regular erections with or without sexual relations. This recommendation is based on the concept of cavernosal oxygenation. In the absence of routine penile erections, the corporal smooth muscle experiences chronic hypoxia with resultant loss of elasticity and distensibility, which may lead to a venous leak. On the basis of the premise that erections enhance tissue oxygenation and suppress smooth muscle fibrosis, therapy to enhance nocturnal erections (nighttime “physical therapy” for the penis) might have a therapeutic benefit.48 Montorsi et al.49 demonstrated that sildenafil and not placebo taken at bedtime produced a significant improvement in nocturnal erectile activity. This concept of nighttime “physical therapy” could potentially reduce brachytherapy-induced ED. In summary, although the etiology of brachytherapy-induced ED is likely multifactorial, the available data strongly support the proximal penis as an important site-specific structure. Suboptimal seed UROLOGY 62 (5), 2003
placement (either owing to poor planning and/or poor implementation) of periapical radiation sources results in excessive radiation doses to the bulb of the penis. Refinements in implant technique should result in lower radiation doses to the proximal penis and increased rates of potency preservation. In addition, more judicious use of supplemental EBRT and hormonal therapy may enhance potency preservation (Table I). CONCLUSIONS It is increasingly apparent that the efficacy and morbidity of brachytherapy is dependent on patient selection, implant quality, and medical management. Additional refinement and promulgation of these evidence-based strategies should enhance outcomes with a reduced incidence of treatmentrelated morbidity. REFERENCES 1. Merrick GS, Wallner KE, and Butler WM: Permanent interstitial brachytherapy in the management of carcinoma of the prostate gland. J Urol 169: 1643–1652, 2003. 2. Merrick GS, Butler WM, Dorsey AT, et al: The effect of prostate size and isotope selection on dosimetric quality following permanent seed implantation. Tech Urol 7: 233–240, 2001. 3. Merrick GS, Butler WM, Wallner KE, et al: Extracapsular radiation dose distribution following permanent prostate brachytherapy. Am J Clin Oncol (in press). 4. Merrick GS, Butler WM, Galbreath RW, et al: The relationship between percent positive biopsies and biochemical outcome following permanent interstitial brachytherapy for clinically organ-confined carcinoma of the prostate gland. Int J Radiat Oncol Biol Phys 52: 664 –673, 2002. 5. Lee WR, Hall MC, McQuellon RP, et al: A prospective quality-of-life study in men with clinically localized prostate carcinoma treated with radical prostatectomy, external beam radiotherapy, or interstitial brachytherapy. Int J Radiat Oncol Biol Phys 51: 614 –623, 2001. 6. Wei JT, Dunn RL, Sandler HM, et al: Comprehensive comparison of health-related quality of life after contemporary therapies for localized prostate cancer. J Clin Oncol 20: 557– 566, 2002. 7. Talcott JA, Clark JA, Stark PC, et al: Long-term treatment related complications of brachytherapy for early prostate cancer: a survey of patients previously treated. J Urol 166: 494 –499, 2001. 8. Merrick GS, Butler WM, Wallner KE, et al: Long-term urinary quality of life following permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 56: 454 – 461, 2003. 9. Stock RG, Stone NN, Tabert A, et al: A dose-response study for I-125 prostate implants. Int J Radiat Oncol Biol Phys 41: 101–108, 1998. 10. Merrick GS, Butler WM, Tollenaar BG, et al: The dosimetry of prostate brachytherapy-induced urethral strictures. Int J Radiat Oncol Biol Phys 52: 461–468, 2002. 11. Snyder KM, Stock RG, Hong SM, et al: Defining the risk of developing grade 2 proctitis following 125I prostate brachytherapy using a rectal dose-volume histogram analysis. Int J Radiat Oncol Biol Phys 50: 335–341, 2001. 12. 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 54: 1055–1062, 2002. UROLOGY 62 (5), 2003
13. Crook J, McLean M, Catton C, et al: Factors influencing risk of acute urinary retention after TRUS-guided permanent prostate seed implantation. Int J Radiat Oncol Biol Phys 52: 453–460, 2002. 14. Merrick GS, Butler WM, Lief JH, et al: Temporal resolution of urinary morbidity following prostate brachytherapy. Int J Radiat Oncol Biol Phys 47: 121–128, 2000. 15. Terk MD, Stock RG, Stone NN: Identification of patients at increased risk for prolonged urinary retention following radioactive seed implantation of the prostate. J Urol 160: 1379 –1382, 1998. 16. Landis P, Wallner K, Locke J, et al: Late urinary function after prostate brachytherapy. Brachytherapy 1: 21–26, 2002. 17. Thomas MD, Cormack R, Tempany CM, et al: Identifying the predictors of acute urinary retention following magnetic-resonance-guided prostate brachytherapy. Int J Radiat Oncol Biol Phys 47: 905–908, 2000. 18. Gray G, Wallner K, Roof J, et al: Cystourethroscopic findings before and after prostate brachytherapy. Tech Urol 6: 109 –111, 2000. 19. Merrick GS, Butler WM, Wallner KE, et al: Prophylactic versus therapeutic alpha blockers following permanent prostate brachytherapy. Urology 60: 650 –655, 2002. 20. Desai J, Stock RG, Stone NN, et al: Acute urinary morbidity following I-125 interstitial implantation of the prostate gland. Radiat Oncol Invest 6: 135–141, 1998. 21. Wallner K, Merrick G, True L, et al: I-125 versus Pd103 for low-risk prostate cancer: morbidity outcomes from a prospective randomized multicenter trial. Cancer J Sci Am 8: 67–73, 2002. 22. Merrick GS, Butler WM, Wallner KE, et al: Dysuria following permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 55: 979 –985, 2003. 23. Narayan P, McKay J, and Doyle C: A six-week doubleblind pilot study of tamsulosin versus placebo in patients with chronic non-bacterial prostatitis/chronic pelvic pain. J Urol 167(suppl): 24, 2002. 24. Merrick GS, Butler WM, Galbreath RW, et al: The relationship between the transition zone index of the prostate gland and urinary morbidity after brachytherapy. Urology 57: 524 –529, 2001. 25. Stone NN, and Stock RG: Complications following permanent prostate brachytherapy. Eur Urol 41: 427–433, 2002. 26. Merrick GS, Butler WM, Wallner KE, et al: The effect of transurethral resection on urinary quality of life following permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys (in press). 27. Merrick GS, Butler WM, Dorsey AT, et al: Influence of prophylactic dexamethasone on edema following prostate brachytherapy. Tech Urol 6: 117–122, 2000. 28. Wallner K, Roy J, and Harrison L: Dosimetry guidelines to minimize urethral and rectal morbidity following transperineal I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 32: 465–471, 1995. 29. Leibovich BC, Blute ML, Bostwick DG, et al: Proximity of prostate cancer to the urethra: implications for minimally invasive ablative therapies. Urology 56: 726 –729, 2000. 30. Jones S, Wallner K, Merrick G, et al: Clinical correlates of high intraprostatic brachytherapy dose volumes. Int J Radiat Oncol Biol Phys 53: 328 –333, 2002. 31. Barker J, Wallner K, and Merrick G: Hematuria after prostate brachytherapy. Urology 61: 408 –411, 2003. 32. Merrick GS, Butler WM, Dorsey AT, et al: Rectal dosimetric analysis following prostate brachytherapy. Int J Radiat Oncol Biol Phys 43: 1021–1027, 1999. 33. Merrick GS, Butler WM, Wallner KE, et al: Rectal function following brachytherapy: results of two prospective randomized trials. Brachytherapy (in press). 791
34. Merrick GS, Butler WM, Wallner KE, et al: Late rectal function following prostate brachytherapy. Int J Radiat Oncol Biol Phys 57: 42– 48, 2003. 35. Gelblum DY, and Potters L: Rectal complications associated with transperineal interstitial brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys 48: 119 –124, 2000. 36. Waterman FM, and Dicker AP: Effect of post-implant edema on rectal dose in prostate brachytherapy. Int J Radiat Oncol Biol Phys 45: 571–576, 1999. 37. Howard A, Wallner K, Han B, et al: Clinical course and dosimetry of rectal fistulas after prostate brachytherapy. J Brachyther Int 17: 37–42, 2001. 38. Merrick GS, Butler WM, Dorsey AT, et al: The effect of constipation on rectal dosimetry following prostate brachytherapy. Med Dosim 25: 237–241, 2000. 39. Jackson A, Skwarchuk MW, Zelefsky MJ, et al: Late rectal bleeding after conformal radiotherapy of prostate cancer (II): volume effects and dose-volume histograms. Int J Radiat Oncol Biol Phys 49: 685–698, 2001. 40. Sanguineti G, Agostinelli S, Foppiano P, et al: Adjuvant androgen deprivation impacts late rectal toxicity after conformal radiotherapy of prostate carcinoma. Br J Cancer 86: 1843– 1847, 2002. 41. Merrick GS, Butler WM, Wallner KE, et al: The influence of hormonal therapy on late rectal function following permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys (in press).
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42. 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 46: 1069 –1074, 2000. 43. Merrick GS, Wallner K, Butler WM, et al: Short-term sexual function after prostate brachytherapy. Int J Cancer (Radiat Oncol Invest) 96: 313–319, 2001. 44. Merrick GS, Butler WM, Galbreath RW, et al: Erectile function after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 52: 893–902, 2002. 45. Stock RG, Kao J, and Stone NN: Penile erectile function after permanent radioactive seed implantation for treatment of prostate cancer. J Urol 165: 436 –439, 2001. 46. Potters L, Torre T, Fearn PA, et al: Potency after permanent prostate brachytherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 50: 1235–1242, 2001. 47. Merrick GS, Butler WM, Lief JH, et al: The efficacy of sildenafil citrate in prostate brachytherapy patients with erectile dysfunction. Urology 53: 1112–1116, 1999. 48. McCullough AR: Prevention and management of erectile dysfunction following radical prostatectomy. Urol Clin North Am 28: 613–627, 2001. 49. Montorsi F, Maga T, Strambi LF, et al: Sildenafil taken at bedtime significantly increases nocturnal erections: results of a placebo-controlled study. Urology 56: 906 –911, 2000.
UROLOGY 62 (5), 2003
MINIMIZING PROSTATE BRACHYTHERAPYRELATED MORBIDITY GREGORY S. MERRICK, KENT E. WALLNER,
A
fter permanent prostate brachytherapy with or without supplemental external beam radiotherapy (EBRT), most studies have reported favorable long-term biochemical outcomes for patients with low, intermediate, and high-risk features.1 These findings result in part from dose escalation and the ability to treat the periprostatic region aggressively.2– 4 With the assimilation of brachytherapy into conventional cancer care, a rapidly expanding body of literature is available regarding therapy-related morbidity.5– 8 With the highly demarcated therapeutic geography of brachytherapy, even minor differences in source placement philosophies could lead to significant differences in cancer eradication and radiation-related morbidities. Similarly, with the intense inflammatory reaction that results from prostate brachytherapy, it seems logical that patient management policies could have a substantial effect on postimplant morbidities. With maturation of the brachytherapy literature, it has become increasingly apparent that efficacy and morbidity are highly dependent on implant quality, with substantial differences in the reported incidence and clinical course of radiation-related morbidity.9 –13 After analyzing our own data and the data of others, it appears that many of the conflicts are likely related to technical differences in treatment planning, in the implantation process itself, or in variations in patient management philosophies. Accordingly, we have summarized the patient selection factors, technical factors, and management strategies that appear to affect morbidity subThis study was funded in part by unrestricted educational grants from Theragenics and Amersham Health. G. S. Merrick is a study investigator funded in part by Theragenics and Amersham Health. From the Schiffler Cancer Center, Wheeling Hospital; Wheeling Jesuit University, Wheeling, West Virginia; and Puget Sound Health Care System Department of Veterans Affairs, Seattle, Washington Reprint requests: Gregory S. Merrick, M.D., Schiffler Cancer Center, Wheeling Hospital, 1 Medical Park, Wheeling, WV 26003-6300 Submitted: March 28, 2003, accepted (with revisions): May 12, 2003
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© 2003 ELSEVIER INC. ALL RIGHTS RESERVED
AND
WAYNE M. BUTLER
stantially. In addition, the presumed importance of some patient selection criteria and dosimetric parameters has recently been questioned. Elucidation and widespread adoption of evidencesupported planning philosophies, intraoperative techniques, and medical management should further improve outcomes. URINARY MORBIDITY Many investigators have studied the role of the International Prostate Symptom Score (IPSS) in patient selection, with varied conclusions.14,15 After brachytherapy, almost all patients develop urinary irritative/obstructive symptoms, with 2% to 32% of patients developing acute urinary retention.14 –17 However, only approximately 2% of patients require a urinary catheter for longer than 1 week.14 The potential relationship between the preimplant IPSS and the subsequent development of urinary retention has been evaluated with mixed results.14,15 In a prospective study at the University of Washington, little correlation was reported between the preimplant IPSS and acute urinary retention or long-term urinary function.16,18 In addition, urodynamic studies, postvoid residual urine volume, maximal flow rate, or preimplant cystourethroscopy did not predict for postimplant urinary retention.16,18 Currently, no reliable preimplant criteria are available to predict which patients will develop prolonged urinary retention. Urinary morbidity in the immediate postimplant setting has been well documented, with the preimplant IPSS correlating with the duration of postimplant obstructive symptoms.14,15,19,20 Alpha-blockers are widely used to ameliorate brachytherapy-related urinary morbidity, and the timing of their initiation may substantially influence their effect.14,19 Following a policy of prophylactic and prolonged medication use, Merrick and colleagues14 reported that the IPSS peaked 2 weeks after implantation with either palladium-103 or iodine-125 and returned to preimplant values at a median of 6 weeks. In contrast, without the use of prophylactic alpha-blockers, a timeline of approxUROLOGY 62: 786 –792, 2003 • 0090-4295/03/$30.00 doi:10.1016/S0090-4295(03)00558-2
FIGURE 1. Mean difference between antecedent patient IPSS and subsequent IPSS plotted for questionnaire intervals. Two curves stratify alpha-blocker use into prophylactic and therapeutic outcomes.
imately 12 months was reported for the IPSS to return to baseline.20 In a large multi-institutional study, prophylactic alpha-blockers resulted in a return of the IPSS to baseline significantly faster than in patients not receiving alpha-blockers or receiving them after substantial exacerbation of urinary symptoms19 (Fig. 1). However, the incidence of prolonged urinary catheter dependency (longer than 3 days) and the need for postimplant surgical intervention were not affected by alpha-blocker use.19 The initiation of alpha-blockers 2 to 3 weeks before implantation with continuation at least until the IPSS normalizes maximizes their beneficial effect. In addition, the results from a prospective randomized trial comparing palladium-103 with iodine-125 have reported a significantly faster resolution of IPSS in the palladium-103 arm.21 Dysuria is common after brachytherapy.22 The ability of alpha-blockers to relax alpha-adrenergic receptors in the bladder neck and prostate gland improves urinary flow and reduces the symptoms of prostatitis. In patients receiving prophylactic and prolonged alpha-blockers, the incidence of dysuria peaked at 52% 1 month after implantation.22 Although dysuria is a relatively common event during the first few years after brachytherapy, only rarely is it severe in frequency or intensity. Although no difference in preimplant IPSS was noted in patients with or without dysuria, patients with brachytherapy-related dysuria displayed greater postimplant IPSSs. The isotope used, supplemental EBRT, and hormonal status did not contribute to dysuria. Preliminary results of a double-blind pilot study of tamsulosin versus placebo for patients with chronic nonbacterial prostatitis revealed a benefit to treatment with tamUROLOGY 62 (5), 2003
sulosin.23 The utility of alpha-blockers in such patients may be translatable to brachytherapy-related dysuria and is currently being evaluated in an ongoing prospective randomized trial.21 In addition, anti-inflammatory agents and the avoidance of bladder irritants (i.e., caffeine, alcohol) may alleviate the intensity and frequency of treatment-related dysuria. Prostate size has been considered a relative contraindication to brachytherapy even though gland size has inconsistently been associated with increased morbidity.8,13,14 The transition zone (TZ) has been correlated with brachytherapy-related obstructive symptoms.17,24 The TZ index (TZ index ⫽ transition zone volume divided by prostate gland volume) correlated with the time to IPSS normalization, maximal increase in IPSS, and the subsequent need for postimplant surgical intervention.24 In patients undergoing postimplant transurethral resection of the prostate or transurethral incision of the prostate (TURP/TUIP), the TZ index was 0.34 versus 0.23 in those patients not requiring surgical intervention (P ⫽ 0.016). Thomas and colleagues17 reported that the TZ volume was the most important predictor of acute urinary retention after magnetic resonance-guided prostate brachytherapy. The TZ index may have greater predictive power for prolonged urinary dysfunction and the need for subsequent surgical intervention than any other single parameter and potentially could replace more simplistic patient selection factors such as ultrasound prostate volume. The vast majority of patients with prolonged urinary retention will eventually spontaneously urinate without surgical intervention. In the unlikely scenario that postimplant TURP/TUIP is necessary, it should be delayed as long as possible. Stone and Stock25 have recommended preservation of the bladder neck at the 5 and 7-o’clock positions to maintain sufficient prostatic urethral blood supply and minimize the risk of post-TURP/TUIP incontinence. Minimal cautery should be used to prevent late urethral ischemic damage.25 It has been suggested that a safe minimal time to perform TURP/TUIP is 6 months for iodine-125 and 2 months for palladium-103.25 In our practice, we have strongly discouraged surgical intervention for at least the first 12 months after brachytherapy. Using the Expanded Prostate Cancer Index Composite (EPIC), Merrick and colleagues8,26 reported urinary incontinence scores of 89.4 in brachytherapy patients without TURP and 79.3 in patients with preimplant TURP, but only 63.7 in patients with postimplant TURP (EPIC scores range from 0 to 100, with higher scores indicative of better function). 787
Dexamethasone has been widely used to reduce brachytherapy-related edema, improve urinary function, and reduce acute urinary retention. However, in a controlled study, the prophylactic use of dexamethasone did not affect short-term urinary catheter dependency or IPSS resolution.27 In contrast, low-dose prednisone (5 to 10 mg daily) is effective in ameliorating brachytherapy-induced dysuria (unpublished data). Wallner and colleagues28 reported an association between urinary morbidity and urethral doses greater than 250% minimal peripheral dose (mPD). In contemporary series, however, urethral doses have not correlated with urinary morbidity, probably because of sophisticated treatment planning with urethral sparing, which limits the urethral dose to 100% to 140% mPD, regardless of prostate size.2 Although urethral doses greater than 150% mPD should be minimized, underdosage (less than 100% mPD) should be avoided. Leibovich et al.29 reported the mean distance from the urethra to the nearest foci of cancer to be 3 mm, with 17% of all prostate cancers abutting the urethra. The significance of dose homogeneity within the prostate gland has been an area of concern, but a recent study reported no significant difference in IPSS resolution on the basis of the volume of the gland receiving 100%, 200%, or 300% of the prescribed dose.30 Although details of optimal urethral doses have yet to be elucidated, the average postimplant urethral doses should be limited to 140% mPD or less. Although supplemental EBRT and hormonal therapy are often used in brachytherapy patients, their influence on long-term urinary function has not been completely discerned. Supplemental EBRT results in an increased trend for late hematuria.31 A prospective randomized trial reported that 22% and 9% of patients receiving and not receiving, respectively, supplemental EBRT developed late but self-limited brachytherapy-related hematuria.31 In a study of long-term urinary function using the urinary domain of EPIC, supplemental EBRT adversely affected the urinary function and incontinence domains, but did not alter the irritation/obstruction or bother domains.8 Of multiple clinical, treatment, and dosimetric parameters, the use of tobacco most strongly predicted for adverse quality-of-life outcomes. In addition, former smokers had a quality-of-life outcome intermediate between those who had never smoked and current smokers.8 Conflicting results have been reported concerning a potential relationship between postimplant urinary retention and the use of neoadjuvant hormonal therapy.13–15,19 However, the largest of these studies, which consisted of 714 consecutive patients, reported that hormonal manipulation did not ad788
FIGURE 2. Dose to bulbomembranous urethra as percentage of mPD versus distance inferior to prostatic apex. Overall mean dose for stricture patients, 97.6% of mPD, differed significantly from that for control patients, 81.8% of mPD (P ⫽ 0.031). Reprinted with permission from Merrick GS, Butler WM, Tollenaar BG, et al: The dosimetry of prostate brachytherapy-induced urethral strictures. Int J Radiat Oncol Biol Phys 52: 461–468, 2002.
versely affect catheter dependency, IPSS normalization, or the need for postbrachytherapy surgical intervention. In contrast, hormonal therapy of longer than 6 months’ duration resulted in deleterious changes in the EPIC subscores of function and irritation/obstruction, with a trend for poorer bother and postimplant IPSS.8 Taken together, the data suggest that supplemental EBRT and/or hormonal therapy increase urinary morbidity and, as such, should be deleted from the treatment plan when possible. Patients should also be strongly counseled regarding cessation of cigarette smoking. The reported 5-year actuarial risk of urethral strictures ranges from 5% to 12% and appears to be directly related to overimplantation of the periapical region.10 Strictures typically involve the bulbomembranous urethra and are usually easily managed with dilation. Day 0 computed tomography (CT)-based dosimetry demonstrated that radiation doses to the bulbomembranous urethra were significantly greater in patients with strictures than those without10 (Fig. 2). With careful attention to implant technique, including extensive use of the sagittal plane for deposition of the seeds, it is possible to implant the apex with a 5-mm margin without “drawing” seeds into the region of the bulbomembranous urethra. Hormonal therapy of longer than 6 months’ duration increased the likelihood of urethral strictures.10 An enlarging body of data shows that brachytherapy-related urinary morbidity can be lessened UROLOGY 62 (5), 2003
TABLE I. Clinical and treatment parameters associated with increased urinary morbidity, rectal morbidity, and erectile dysfunction after prostate brachytherapy Implicated Factors Urinary morbidity Elevated preimplant IPSS Delayed use of alpha-blockers Large transition zone index Greater radiation dose to prostatic and bulbomembranous urethra Lack of careful attention to placement of periapical seeds Use of supplemental EBRT Hormonal therapy ⬎6-mo duration Choice of isotope Status of tobacco consumption Rectal morbidity Radiation dose Supplemental EBRT Constipation Failure to use biplanar ultrasonography with various frequencies Choice of isotope Erectile dysfunction Radiation dose to proximal penis Supplemental EBRT Hormonal therapy Radiation doses to prostate gland Lack of careful attention to placement of periapical seeds Patient age Diabetes Preimplant erectile function Lack of penile “physical therapy” KEY: IPSS ⫽ International Prostate Symptom Score; EBRT ⫽ external beam radiotherapy.
with refinements in patient selection, medical intervention, and intraoperative techniques. Prophylactic and prolonged usage of alpha-blockers, evaluation of the TZ, minimizing the volume of the urethra receiving more than 140% mPD, careful attention to the placement of periapical seeds, judicious use of supplemental EBRT and hormonal therapy, and the cessation of cigarette smoking are currently recognized to play a role in morbidity minimization (Table I). RECTAL MORBIDITY Rectal complications consist primarily of mild, self-limited proctitis and have consistently been correlated with the rectal dose.11,32–34 The onset of bleeding peaks at 8 months with an incidence of 4% to 12% and usually resolves spontaneously.32,35 Snyder and colleagues11 reported grade 2 proctitis to be volume dependent for a given dose, with no UROLOGY 62 (5), 2003
cases developing more than 36 months after implantation. Using day 30 CT-based dosimetry, Snyder et al.11 reported an 8% rate of grade 2 proctitis when less than 1.8 cm3 of rectum was exposed to 160 Gy after iodine-125 monotherapy, and the risk increased to approximately 25% when more than 1.8 cm3 of rectum was exposed.11 With day 0 CTbased dosimetry, Merrick and colleagues32 previously reported self-limited proctitis with radiation point doses to the anterior rectal mucosa of 85%. Recommendations included limiting the anterior maximal mucosal dose to 120% mPD and limiting the length of the rectal mucosa receiving 100% and 120% mPD to 10 mm and 5 mm, respectively.32 In a subsequent randomized trial, the minimal dose received by 5% of the rectum best correlated with brachytherapy-related rectal dysfunction (day 0 dosimetry).33 To compare rectal doses between series, the timing of the postimplant CT scan must be documented. Waterman and Dicker36 reported that the minimal dose that encompassed 10% of the surface area of the rectum increased on average by 68% from day 0 through day 30.36 Intraoperatively, careful attention to implant technique and ultrasound anatomy will reduce the dose to the anterior rectal wall and minimize bowel dysfunction. Extensive use of both transverse and sagittal images to confirm appropriate needle placement and the use of multiple ultrasound frequencies helps ensure proper seed placement. Higher transducer frequencies result in clearer definition of anatomy closer to the probe. Posterior row needle placements performed with the 7.5MHz setting help ensure that needles are placed just within the posterior prostatic capsule and not in the rectal wall. All other rows are imaged with the 5.0-MHz frequency. Rectal ulceration and fistula formation have occasionally been reported.37 Although the dose has been correlated with rectal bleeding, Howard and colleagues37 found no correlation between rectal dose and the development of fistula, with the conclusion that severe complications may occur in an unpredictable manner typically unrelated to known clinical, treatment, or dosimetric parameters. In a case report, constipation significantly increased the radiation dose to the rectum.38 Although no studies to date have correlated constipation with rectal toxicity, postimplant attention to bowel habits for two half-lives of the implanted isotope may minimize rectal distension and decrease the dose to the anterior rectal wall. Multiple studies have failed to reveal a correlation between prostate size and rectal complications.34 Bowel function assessments by patient-administered questionnaires, including the Rectal Function Assessment Score and the modified Radiation Therapy Oncology Group toxicity scale, illustrate 789
that long-term dysfunction after brachytherapy is relatively uncommon.7,33,34 Merrick and colleagues34 noted that only 12% of patients reported their bowel function to be worse after implantation. The number of preimplant bowel movements, history of tobacco consumption, median rectal dose, and addition of supplemental EBRT resulted in deterioration in bowel habits.34 For patients receiving high-dose three-dimensional conformal external beam RT, Jackson et al.39 reported an independent association with larger percent volumes exposed to intermediate doses (approximately 46 Gy) and the development of rectal bleeding. They hypothesized that a “large surrounding region of intermediate dose may interfere with the ability to repair the effects of a central high dose region.” This may also explain the deleterious effect of supplemental EBRT in some brachytherapy series. After three-dimensional conformal external beam RT, the use of hormonal therapy increased grade 2-4 late rectal toxicity (30.3% versus 14.1%)40 and potentially could have a similar effect on brachytherapy-related morbidity. However, using the Rectal Function Assessment Score instrument with a median follow-up of 66 months, hormonal therapy did not influence brachytherapyrelated bowel function.41 Preliminary results from an ongoing prospective randomized trial comparing palladium-103 with iodine-125 have reported a trend for greater rectal morbidity with iodine-125 without grade 3 or 4 events.21 In summary, brachytherapy-related bowel morbidity can be minimized with meticulous implant technique to minimize the radiation dose to the anterior rectal wall, careful attention to postimplant bowel habits, and the judicious use of supplemental EBRT (Table I). The potential effect of isotope requires additional investigation. ERECTILE DYSFUNCTION The penile erectile bodies (the paired corpora cavernosa and midline corpora spongiosum) represent a potential candidate for site-specific radiation doses related to erectile dysfunction (ED).12 Although ED is likely a multifactorial process, an increasing body of data implicating excessive radiation doses to the proximal penis is available.12 ED appears to be technique related and should be minimized by careful attention to source placement. With day 0 CT-based dosimetric evaluation, the radiation dose delivered to 50% of the bulb of the penis was less than 50 Gy and the dose delivered to 95% of the bulb of the penis was less than 20 Gy for most patients who maintained potency, and for the vast majority of men who became impotent the doses exceeded these values.12 Excessive radiation doses to the bulb of the penis are a result of poor 790
planning and/or poor intraoperative techniques. Recommendations to maximize potency preservation include limiting the penile bulb radiation dose delivered to 50% of the bulb of the penis to less than 40% mPD and the crura to less than 28% mPD.12 Refinements in implant technique, including preplanning and intraoperative seed placement, with use of the sagittal plane for the deposition of the apical/periapical seeds results in lower radiation doses to the proximal penis, with potential improvement in potency preservation. Radiation doses to the neurovascular bundles (NVBs) and the development of brachytherapy-induced ED have been evaluated in retrospective and prospective studies.42,43 Although initial reports (median follow-up of 37 months) have not demonstrated any relationship between NVB doses and treatment-induced ED,42 it is possible that with longer follow-up, NVB doses may be found to contribute to brachytherapy-related ED. On the basis of the available data, however, it is not rational to recommend NVB-sparing brachytherapy, particularly, because the NVB lies so close to the frequently biopsy-positive peripheral zone of the prostate. From a clinical perspective, potency preservation after brachytherapy is most closely related to preimplant erectile function.44,45 However, the addition of supplemental EBRT,44,46 radiation doses to the prostate gland,45 patient age,44 and diabetes44 may exacerbate brachytherapy-induced ED. The role of neoadjuvant hormonal therapy in potency preservation has been mixed,44 – 46 and choice of isotope appears unrelated.44,45 Radiation-related ED typically responds well to sildenafil.47 A lack of erectile activity may be deleterious to erectile function, and, as such, patients should be encouraged to develop regular erections with or without sexual relations. This recommendation is based on the concept of cavernosal oxygenation. In the absence of routine penile erections, the corporal smooth muscle experiences chronic hypoxia with resultant loss of elasticity and distensibility, which may lead to a venous leak. On the basis of the premise that erections enhance tissue oxygenation and suppress smooth muscle fibrosis, therapy to enhance nocturnal erections (nighttime “physical therapy” for the penis) might have a therapeutic benefit.48 Montorsi et al.49 demonstrated that sildenafil and not placebo taken at bedtime produced a significant improvement in nocturnal erectile activity. This concept of nighttime “physical therapy” could potentially reduce brachytherapy-induced ED. In summary, although the etiology of brachytherapy-induced ED is likely multifactorial, the available data strongly support the proximal penis as an important site-specific structure. Suboptimal seed UROLOGY 62 (5), 2003
placement (either owing to poor planning and/or poor implementation) of periapical radiation sources results in excessive radiation doses to the bulb of the penis. Refinements in implant technique should result in lower radiation doses to the proximal penis and increased rates of potency preservation. In addition, more judicious use of supplemental EBRT and hormonal therapy may enhance potency preservation (Table I). CONCLUSIONS It is increasingly apparent that the efficacy and morbidity of brachytherapy is dependent on patient selection, implant quality, and medical management. Additional refinement and promulgation of these evidence-based strategies should enhance outcomes with a reduced incidence of treatmentrelated morbidity. REFERENCES 1. Merrick GS, Wallner KE, and Butler WM: Permanent interstitial brachytherapy in the management of carcinoma of the prostate gland. J Urol 169: 1643–1652, 2003. 2. Merrick GS, Butler WM, Dorsey AT, et al: The effect of prostate size and isotope selection on dosimetric quality following permanent seed implantation. Tech Urol 7: 233–240, 2001. 3. Merrick GS, Butler WM, Wallner KE, et al: Extracapsular radiation dose distribution following permanent prostate brachytherapy. Am J Clin Oncol (in press). 4. Merrick GS, Butler WM, Galbreath RW, et al: The relationship between percent positive biopsies and biochemical outcome following permanent interstitial brachytherapy for clinically organ-confined carcinoma of the prostate gland. Int J Radiat Oncol Biol Phys 52: 664 –673, 2002. 5. Lee WR, Hall MC, McQuellon RP, et al: A prospective quality-of-life study in men with clinically localized prostate carcinoma treated with radical prostatectomy, external beam radiotherapy, or interstitial brachytherapy. Int J Radiat Oncol Biol Phys 51: 614 –623, 2001. 6. Wei JT, Dunn RL, Sandler HM, et al: Comprehensive comparison of health-related quality of life after contemporary therapies for localized prostate cancer. J Clin Oncol 20: 557– 566, 2002. 7. Talcott JA, Clark JA, Stark PC, et al: Long-term treatment related complications of brachytherapy for early prostate cancer: a survey of patients previously treated. J Urol 166: 494 –499, 2001. 8. Merrick GS, Butler WM, Wallner KE, et al: Long-term urinary quality of life following permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 56: 454 – 461, 2003. 9. Stock RG, Stone NN, Tabert A, et al: A dose-response study for I-125 prostate implants. Int J Radiat Oncol Biol Phys 41: 101–108, 1998. 10. Merrick GS, Butler WM, Tollenaar BG, et al: The dosimetry of prostate brachytherapy-induced urethral strictures. Int J Radiat Oncol Biol Phys 52: 461–468, 2002. 11. Snyder KM, Stock RG, Hong SM, et al: Defining the risk of developing grade 2 proctitis following 125I prostate brachytherapy using a rectal dose-volume histogram analysis. Int J Radiat Oncol Biol Phys 50: 335–341, 2001. 12. 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 54: 1055–1062, 2002. UROLOGY 62 (5), 2003
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34. Merrick GS, Butler WM, Wallner KE, et al: Late rectal function following prostate brachytherapy. Int J Radiat Oncol Biol Phys 57: 42– 48, 2003. 35. Gelblum DY, and Potters L: Rectal complications associated with transperineal interstitial brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys 48: 119 –124, 2000. 36. Waterman FM, and Dicker AP: Effect of post-implant edema on rectal dose in prostate brachytherapy. Int J Radiat Oncol Biol Phys 45: 571–576, 1999. 37. Howard A, Wallner K, Han B, et al: Clinical course and dosimetry of rectal fistulas after prostate brachytherapy. J Brachyther Int 17: 37–42, 2001. 38. Merrick GS, Butler WM, Dorsey AT, et al: The effect of constipation on rectal dosimetry following prostate brachytherapy. Med Dosim 25: 237–241, 2000. 39. Jackson A, Skwarchuk MW, Zelefsky MJ, et al: Late rectal bleeding after conformal radiotherapy of prostate cancer (II): volume effects and dose-volume histograms. Int J Radiat Oncol Biol Phys 49: 685–698, 2001. 40. Sanguineti G, Agostinelli S, Foppiano P, et al: Adjuvant androgen deprivation impacts late rectal toxicity after conformal radiotherapy of prostate carcinoma. Br J Cancer 86: 1843– 1847, 2002. 41. Merrick GS, Butler WM, Wallner KE, et al: The influence of hormonal therapy on late rectal function following permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys (in press).
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42. 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 46: 1069 –1074, 2000. 43. Merrick GS, Wallner K, Butler WM, et al: Short-term sexual function after prostate brachytherapy. Int J Cancer (Radiat Oncol Invest) 96: 313–319, 2001. 44. Merrick GS, Butler WM, Galbreath RW, et al: Erectile function after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 52: 893–902, 2002. 45. Stock RG, Kao J, and Stone NN: Penile erectile function after permanent radioactive seed implantation for treatment of prostate cancer. J Urol 165: 436 –439, 2001. 46. Potters L, Torre T, Fearn PA, et al: Potency after permanent prostate brachytherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 50: 1235–1242, 2001. 47. Merrick GS, Butler WM, Lief JH, et al: The efficacy of sildenafil citrate in prostate brachytherapy patients with erectile dysfunction. Urology 53: 1112–1116, 1999. 48. McCullough AR: Prevention and management of erectile dysfunction following radical prostatectomy. Urol Clin North Am 28: 613–627, 2001. 49. Montorsi F, Maga T, Strambi LF, et al: Sildenafil taken at bedtime significantly increases nocturnal erections: results of a placebo-controlled study. Urology 56: 906 –911, 2000.
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