Management of Radiation Therapy Oncology Group grade 4 urinary adverse events after radiotherapy for prostate cancer

Transcription

1 Management of Radiation Therapy Oncology Group grade 4 urinary adverse events after radiotherapy for prostate cancer Erik N. Mayer, Jonathan D. Tward, Mitchell Bassett, Sara M. Lenherr, James M. Hotaling, William O. Brant, William T. Lowrance and Jeremy B. Myers Department of Surgery, Center for Reconstructive Urology and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA Objective To describe the management of Radiation Therapy Oncology Group (RTOG) grade 4 urinary adverse events (UAEs) after radiotherapy (RT) for prostate cancer (PCa). Methods We conducted a single-centre retrospective review, over a 6-year period ( ), to identify men with RTOG grade 4 UAEs after RT for PCa. RT was classified as combined therapy (radical prostatectomy [RP] followed by external beam radiotherapy [EBRT], EBRT + low-dose-rate [LDR] brachytherapy, EBRT + high-dose-rate [HDR] brachytherapy or other combinations of RT) or monotherapy RT. UAEs were classified as outlet (urethral stricture, bladder neck contracture, prostate necrosis, or recto-urethral fistula) or bladder (contraction, necrosis, fistula, ureteric stricture or haemorrhage) UAEs. Results We identified 73 men with a mean age of 73 years. Of these, 44 (60%) received combined therapy, consisting of RP + EBRT (n = 19), HDR brachytherapy + EBRT (n = 19), LDR brachytherapy + EBRT (n = 5), and other combined RT (n = 1). Twenty-nine (40%) patients had monotherapy consisting of EBRT (n = 4), HDR brachytherapy (n = 11), LDR brachytherapy (n = 12), or proton beam therapy (n = 2). UAEs were isolated to the bladder in six men (8%), the outlet in 52 men (71%), and to both in 15 men (21%). UAE management included: conservative in 21 (29%), indwelling catheters in 12 (16%), reconstructive in 19 (26%), and urinary diversion (UD) in 23 men (32%). Reconstruction included: ureteric (n = 4), recto-urethral fistula repair (n = 2), and posterior urethroplasty (n =13), of which 14/16 surgeries (88%) with follow-up >90 days were successful. Conclusions Although the incidence of RTOG grade 4 UAEs after PCa radiation treatment is not well defined, their associated morbidity is significant, and approximately one third of patients with these high-grade complications require UD. Conversely, only about a quarter of patients can be managed with conservative strategies or local surgeries. Reconstruction is successful in selected patients. Keywords radiation, prostate cancer, complications, management, treatment Introduction Radiotherapy (RT) can be used as a primary mode of treatment for localized prostate cancer (PCa), either as monotherapy or in combined therapies. Combined therapy includes RT administration after radical prostatectomy (RP), either as adjuvant therapy, as salvage therapy, or when different forms of RT are used together, such as external beam radiotherapy (EBRT) combined with brachytherapy [1]. The estimated number of new patients diagnosed with PCa in the USA in 2015 was > , and the prevalence is estimated to be ~2.8 million men [2]. PCa has high survivorship and, as a result, there are numerous men who have received RT in the USA. Unfortunately, because of its direct and indirect toxicity on cellular architecture, radiation may induce damage to surrounding non-cancerous tissue [3]. In the case of PCa and pelvic RT, this damage has the potential to cause genitourinary injury because of the proximity of important urinary structures to the prostate. Although debated, for most clinically localized PCa, longterm survival is similar for patients undergoing RP and RT [4,5] and, for this reason, understanding the morbidity of BJU Int 2017; 119: BJU International doi: /bju wileyonlinelibrary.com published by John Wiley & Sons Ltd on behalf of BJU International. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

2 Management of RTOG grade 4 urinary complications after radiotherapy these treatments is essential for patients to make informed decisions. Previous studies reporting genitourinary toxicity after RT have, by and large, been limited by relatively short-term follow-up (<5 years) [6 8]. These short-term studies show that severe urinary adverse events (UAEs), defined as Radiation Therapy Oncology Group (RTOG) grades 3, 4 or 5, are rare [3,7,9]. Unfortunately RT injury accumulates over time and severe complications can arise many years later [10]. The management of the severe delayed UAEs from RT have not been well characterized, nor has the burden of these complications on patients. Previous studies which focus on surgical management of long-term adverse RT events often focus on a sub-population of patients such as those with a fistula or bony complications in the pelvis [11 15], rather than on the spectrum of problems which can occur. In the present study, we report our experience in the management of RTOG grade 4 UAEs after RT and describe a management algorithm. We hypothesized that these RT injuries would be associated with high morbidity, but reconstructive surgery would be feasible in selected patients. Methods Study Population A single-centre, retrospective chart review was performed in men with RTOG grade 4 UAEs referred to our reconstructive urology programme between 2010 and 2015 after previous treatment for PCa with RT. These men came from a vast geographical area in the west and sometimes other parts of the USA; for this reason, we were not able to determine the incidence of high-grade complications among men after RT for PCa. We excluded men who presented with incontinence or erectile dysfunction and then developed complications from treatment, such as erosion of an artificial urinary sphincter and subsequent urethral stricture causing obstruction. This type of progression could appear to be a grade 4 RTOG UAE if it were not recognized that the complication, at least in part, arose from the treatment of incontinence rather than solely from RT. A total of 80 men met the initial inclusion criteria. Seven were excluded because of a lack of information about RT treatment (n = 2), preexisting urological disease not necessarily related to RT (n = 2), or development of complications after primary treatment for incontinence or erectile function (n = 3). Primary chart review was conducted on the remaining 73 men, including initial PCa treatment, RT-related UAEs, UAE management, and outcomes after management. Original information on the patient s PCa was rarely available, such as Gleason grade, PSA at diagnosis or tumour stage, since the treatment was often carried out years before and at other facilities. Current PCa status was classified as: no evidence of disease; local recurrent; or metastatic. The Phoenix criteria were used to define PCa recurrence, but in many cases the men could only tell us that they had a low PSA concentration and that none of their physicians were concerned about recurrence. These men underwent a PSA test and if the value was low and similar to the values in their record (if the value was available), they were classified as having no evidence of PCa. Definitions of Radiation Treatment and Urinary Adverse Events We classified RT as either combined or monotherapy. Patients were deemed to have had combined therapy if they underwent RP with adjuvant or salvage RT or if they received some combination of different RT techniques, such as brachytherapy and EBRT. There were four distinct RT types: EBRT; low-dose-rate (LDR) brachytherapy; high-dose-rate (HDR) brachytherapy; and proton beam therapy. Cryoablation and high-intensity focused ultrasonography may have been used in conjunction with RT in select patients, but were not used as criteria for classification. The role of neoadjuvant, concurrent and adjuvant androgen deprivation therapy as a possible contributor to morbidity was not evaluated. We graded UAEs according to RTOG criteria, which grade UAEs on a scale of 0 5. Grade 0 denotes no complications and grade 5 indicates death. The scale is further divided into acute and chronic, with each category giving specific examples of UAEs. We used a composite of the acute and chronic scales, and defined RTOG grade 4 as: haematuria requiring transfusion; severe haemorrhagic cystitis; bladder contraction of <100 ml; necrosis; ulceration; and acute bladder obstruction not secondary to clot passage. In addition, we included ureteric stenosis as a grade 4 UAE as this involves obstruction of the urinary tract, although this situation is not addressed directly in the RTOG grading descriptions. We further defined UAEs according to the location of their urinary tract involvement; they were classified as either outlet-related (urethral stricture, bladder neck contracture, prostate necrosis and recto-urethral fistula) or bladder-related (contraction, necrosis, bladder fistula, ureteric stricture, severe haemorrhage). Classification of Management Patients were separated into different management categories. These categories included: (i) conservative management (selfdilatation via intermittent catheterization and local surgeries, including: direct vision internal urethrotomy, transurethral resection/incision of the prostate and placement of artificial urinary sphincter); (ii) permanent indwelling catheter (suprapubic tube [SPT] or Foley catheter), (iii) reconstruction (ureteric reconstruction, recto-urethral fistula repair and posterior urethroplasty), and (iv) urinary diversion (UD; BJU International published by John Wiley & Sons Ltd on behalf of BJU International 701

3 Mayer et al. urinary conduit [ileal or colon] or continent catheterizable pouch). For the purposes of comparison between groups, patients were classified into each of these categories based on the most invasive management method they underwent, even if they had previously undergone one of the other interventions. The invasiveness of management from most invasive to least was: UD, reconstruction, indwelling catheter, and conservative/local therapy. We recorded the use of hyperbaric oxygen therapy (HBOT) and gracilis muscle flap as adjunctive treatments. Other Variables and Follow-Up The Charlson comorbidity index, adjusted for age, was used to assess preoperative patient health [16]. Modified Clavien Dindo postoperative complications grading was used [17] and grade 3 5 complications were recorded. The postoperative period was defined as <6 weeks for complications grade 3 and 4 and <12 weeks for grade 5 (death). We excluded patients from management outcome analysis who had <90 days of follow-up. In the reconstruction group, surgical success was defined by freedom from additional surgeries/ procedures or from reliance on indwelling catheter, intermittent catheterization, or UD. Follow-up for those managed conservatively or with local therapy was defined as time from presentation to our reconstructive urology clinic. Follow-up for those who were treated with an indwelling catheter, reconstruction or UD was defined as time from surgical intervention. Statistics We used simple descriptive statistics and analysed differences in baseline characteristics according to management category using Fisher s exact test for categorical variables and one-way ANOVA for continuous variables. We performed post hoc testing for variables where the main effect was statistically significant (an a level of P = 0.05) and controlled for multiple comparisons using Tukey s honest significant differences test for continuous variables and Bonferroni-corrected pairwise technique for categorical variables. We analysed differences in readmission rate and postoperative Clavien Dindo complications of grade 3 among the indwelling catheter, reconstruction and UD groups using Fisher s exact test. All statistical analyses were performed using SAS (SAS Institute, Cary, NC, USA), with two-sided P values <0.05 taken to indicate statistical significance. Results Patient Characteristics Table 1 shows the descriptive statistics for the cohort according to management technique. We identified 73 men, with a mean (range) age of 73 (59 92) years. The median (range) Charlson comorbidity index score for the entire cohort was 3 (1 10) and the median (range) time from RT to presentation at our reconstructive centre was 8 (0 17) years. Sixty-nine men (95%) had no evidence of PCa at time of presentation. Of the four men with known recurrent PCa, three had local recurrence and one had metastatic disease. Forty-four men (60%) received combined therapy and 29 (40%) had monotherapy. Combined therapy consisted of RP + EBRT (n = 19), HDR brachytherapy + EBRT (n = 19), LDR brachytherapy + EBRT (n = 5), and other dual RT (n = 1). The other dual RT consisted of proton beam therapy with high-intensity focused ultrasonography 2 years later. One man who received HDR brachytherapy + EBRT also underwent subsequent cryoablation. Men who underwent monotherapy received LDR brachytherapy (n = 12), HDR brachytherapy (n = 11), EBRT (n = 4), or proton beam therapy (n = 2). RTOG grade 4 UAEs were isolated to the bladder in six men (8%), to the outlet in 52 men (71%), and occurred in both in 15 men (21%). The majority of outlet problems were obstructive, which most commonly arose from urethral stricture in 53 men (73%), and less commonly from prostate necrosis, or bladder neck contracture. Other specific UAEs included 13 men with urinary tract fistulae (18%). Men had a mean (range) of 3 (0 12) procedures before final management at our centre. Commonly reported procedures before final surgical intervention included 36 direct visual internal urethrotomies (DVIUs), 23 TURPs, or 21 SPT placements. At least one attempt at direct visual internal urethrotomy (DVIU) as an initial management strategy was carried out in 13/18 men (72%) who went on to undergo reconstruction and 9/23 men (39%) who went on to undergo UD. The rate of previous TURP and SPT placement was significantly different among management approaches (P < 0.05); however, after controlling for multiple comparisons, only the rate of previous SPT placement in men who had received conservative/local treatment vs reconstruction remained significant (P = 0.006). Overall Management The men were managed (Fig. 1) with conservative/local treatment in 21 (29%) cases, indwelling catheters in 11 (15%), reconstruction in 18 (25%), and UD in 23 (32%, 14 urinary conduits, nine catheterizable pouch). Men treated with indwelling catheters were significantly older at presentation (mean age years) compared with those who were treated conservatively (P = 0.004). Men managed with reconstruction had a significantly higher Charlson comorbidity index score (mean 5 1.9) compared with men who were managed conservatively (mean = 3 1.1; P < 0.004). HBOT was used in 31 men (44%) and gracilis muscle flap in 15 men (21%) as adjunctive therapy. The rates of post-intervention Clavien Dindo grade 3 complications 702 BJU International published by John Wiley & Sons Ltd on behalf of BJU International

4 Management of RTOG grade 4 urinary complications after radiotherapy Table 1 Patient characteristics by most invasive management method. All Conservative/local treatment Indwelling catheter Reconstructive Diversion P Total patients Age at RT, years, mean (range) 66 (47 80) 62 (47 74)* 69 (54 79)* 66 (59 78) 67 (53 80) Age at presentation, years, mean (range) 73 (59 92) 71 (59 89)* 79 (63 92)* 73 (63 79) 74 (66 85) Time from RT to presentation, years, median (range) 8 (0 17) 10 (1 17) 9 (3 15) 7 (1 14) 8 (0 15) BMI, kg/m 2, mean (range) 28 (18 42) 30 (23 42) 27 (19 33) 28 (18 38) 27 (20 38) CCI, mean (range) 4 (1 10) 3 (1 5)* 3 (2 5) 5 (2 10)* 4 (2 10) Type of RT, n (%) Monotherapy 29 (40) EBRT 4 (5) 0 (0) 1 (9) 1 (6) 2 (9) LDR brachytherapy 11 (15) 5 (24) 0 (0) 5 (28) 1 (4) HDR brachytherapy 12 (16) 5 (24) 2 (18) 2 (11) 3 (13) Proton 2 (3) 1 (5) 0 (0) 0 (0) 1 (4) Combination therapy 44 (60) RP + EBRT 19 (26) 5 (24) 3 (27) 4 (22) 7 (30) LDR + EBRT 5 (7) 2 (10) 0 (0) 2 (11) 1 (4) HDR brachytherapy + EBRT 19 (26) 2 (10) 5 (45) 4 (22) 8 (35) Other Combination RT 1 (1) 1 (5) 0 (0) 0 (0) 0 (0) Procedures prior to final management No. of procedures prior to final management, mean (range) 3 (0 12) 2 (0 5) 2 (0 11) 2 (1 9) 3 (0 12) TURP 23 (32) 8 (38) 4 (36) 1 (6) 10 (43) DVIU 36 (49) 10 (48) 4 (36) 13 (72) 9 (39) SPT 21 (29) 1 (5)* 3 (27) 8 (44)* 9 (39) Follow-up since presentation, months, mean (range) 19 (0 63) 14 (0 58) 13 (0 59) 17 (2 49) 27 (2 63) Follow-up since intervention, months, mean (range) 16 (0 61) 6(4 59) 14 (0 48) 21 (1 61) Location, n (%) Bladder 6 (8) 0 (0) 0 (0) 3 (17) 3 (13) <0.001 Outlet 52 (71) 20 (95) 10 (91) 13 (72) 9 (39) Bladder + Outlet 15 (21) 1 (5) 1 (9) 2 (11) 11 (48) Specific UAEs Fistula 13 (18) 1 (5) 2 (18) 4 (22) 6 (26) Stricture 53 (73) 16 (76) 10 (91) 15 (83) 12 (52) RT, radiation therapy; BMI, body mass index; CCI, Charlson comorbidity index; EBRT, external beam radiation therapy, LDR, low-dose rate; HDR, high-dose rate; DVIU, direct visual internal urethrotomy; SPT, suprapubic tube. *Denotes which groups differed from one another by Tukey s honest significant differences test or by Bonferroni pairwise comparison technique; Not significant after controlling for multiple comparisons using a Bonferroni-corrected pairwise technique. according to procedure were 13%, 7% and 43% for indwelling catheter, reconstruction and UD, respectively, although these differences did not reach significance (P = 0.051). Similarly, the differences in readmission rate were similar at 13, 13% and 38% for indwelling catheter, reconstruction and UD, respectively (P = 0.224). Conservative Management Group Conservative management therapies (n = 21) included: none (29%, n = 6); DVIU (14%, n = 3); artificial urinary sphincter placement (29%, n = 6); transurethral incision of bladder neck (14%, n = 3); and intermittent catheterization (33%, n = 7) to keep strictures open. We did not record complications associated with conservative management. Indwelling Catheter Group In many cases a trial of SPT was attempted. Out of 28 men who presented with indwelling catheters or had them placed during the course of their care, only 12 were managed ultimately in this manner (11 men within the group and one additional man for whom reconstruction failed, also leaving him with a permanent indwelling catheter). SPT placement was used in 8/19 men (42%) who ultimately went on to undergo reconstruction and in 9/23 patients (40%) who ultimately went on to undergo UD. Surgical complications were very low in this group, and consisted of one Clavien Dindo grade 5 complication (death), which occurred within 3 months of SPT placement for urethral stricture, and which led to Fournier s gangrene. Reconstructive Surgery Group A total of 19 men had reconstruction, but in one man reconstruction failed and he progressed to UD; this man s case is described in the present study, but for the purpose of comparison between the groups he was analysed in the UD group. Among the 19 men undergoing reconstructive surgery, four ureteric repairs for pelvic ureteric strictures (22%), two recto-urethral fistula repairs (6%), and 13 posterior urethroplasties (68%) were performed. Sixteen men had BJU International published by John Wiley & Sons Ltd on behalf of BJU International 703

5 Mayer et al. Fig. 1 Management of Radiation Therapy Oncology Group (RTOG) Grade 4 urinary adverse events (UAEs). SPT, suprapubic tube; CIC, clean intermittent catheterization; DVIU, direct visual internal urethrotomy; TUIBN, transurethral incision of the bladder neck; AUS, artificial urinary sphincter. 1 Patients undergoing conservative management may have undergone multiple treatment types and therefore more than 21 treatments are accounted for (e.g. DVIU + CIC). 2 After failed reconstructive posterior urethroplasty, one man was treated with urinary diversion and one with a permanent SPT. 73 RTOG Grade 4 UAEs 1 Conservative Management (21) Foley catheter or SPT (12) Reconstruction (19) Urinary Diversion (23) CIC (7) DVIU (3) Ureteral (4) Urinary conduit (14) TUIBN (3) AUS Placement (6) Recto-Urethral Fistula Repair (2) Catheterizable colon pouch (9) No Intervention (6) 1 Failure Posterior urethroplasty (13) 2 1 Failure follow-up 3 months (mean [range] 16 [3 48] months). Surgical success was achieved in 14/16 men (88%). The two surgical failures were treated with a permanent SPT and a continent catheterizable UD, respectively. The latter case was also included in the outcomes analysis after UD. In the reconstructive group as a whole, 14 men (73%) had a gracilis muscle flap and 14 (73%) also received HBOT before surgery. Subsequent artificial urinary sphincter placement was performed in five men (26%). There was only one man with a grade 3 Clavien Dindo complication in this group at 90 days of follow-up: a man who developed a seroma in his leg, after gracilis muscle flap, requiring drainage (grade 3a). Urinary Diversion Group Within the UD group, 14 men (78%) had creation of a urinary conduit and nine had a continent catheterizable (Indiana) pouch (22%). Fourteen of the men in the UD group (62%) also underwent concurrent simple cystectomy. Eighteen men (78%) had 3 months of follow-up and did not die postoperatively (mean [range] follow-up 25 [3 61] months). Of these men, 13 (72%) did not require additional surgical interventions during follow-up. The UD group as a whole had the most serious surgical complications. Clavien Dindo complications grade 3 after UD occurred in nine men (43%), including grade 3 in five, grade 4 in two and grade 5 (death) in three. The deaths all occurred in the urinary conduit group; one man died from sepsis complicated by longstanding pre-existing severe liver failure arising from a history of cholangiocarcinoma, one from a delayed presentation of rectal injury for which he elected to forgo operative treatment, and one from postoperative haemorrhage. There were eight readmissions (38%) within 6 weeks of UD. Discussion In the current literature, the reported incidence of high-grade UAEs after RT is low, but these studies are often limited because they are from single institutions and have inadequate follow-up to capture long-term RT-related complications [18,19]. Studies of administrative data such as Surveillance Epidemiology and End Results (SEER)-Medicare show a much greater incidence of high-grade UAEs, but are limited in their ability to quantify the health-related impact of highgrade RT-related UAEs [10,20]. The surgical management of high-grade RT-related UAEs has generally been addressed in sub-set populations, such as rectourethral fistula or bony 704 BJU International published by John Wiley & Sons Ltd on behalf of BJU International

6 Management of RTOG grade 4 urinary complications after radiotherapy complications in the pelvis [11 15]. While we are unable to address the true incidence of such UAEs, the present study is unique in examining the spectrum of problems and management solutions among a series of men presenting with RTOG grade 4 RT UAEs resulting from PCa therapy. Multiple factors influence the likelihood of developing a RT-related UAE. Time from therapy [21], age of the patient, previous TURP [22], type of RT [10] and dosage [19] are some of the previously investigated risk factors associated with incidence of RT-related complications in genitourinary cancer. In multiple studies, dose escalation in RT results in improved disease-free recurrence for PCa [23,24], but also increases the risk of high-grade urinary toxicities [19,25 27]. Similarly, analysis of high-grade UAEs from SEER-Medicare data showed that combined therapy, including RP and RT, had higher rates of complications after 10 years compared with monotherapy [10]. In the present cohort, both time since RT and combined therapy appear to have contributed to the development of severe complications. The cumulative effects of time on injury are illustrated by the long median latency period from RT to presentation at our centre (8 years). This observation reinforces that UAEs often arise remotely from the original RT treatment and emphasizes the limitations in much of the RT literature, where studies often have much shorter follow-up. In addition, the majority of our cohort (60%) had undergone combined therapy. In SEER-Medicare data, only 19% of men treated with RT received combined therapy. The higher rate of combined therapy in the present series compared with that in the SEER-Medicare data suggests that greater radiation dosages were implicated in the observed high-grade toxicities among our cohort; however, we do not know the number of men treated within our referral area with combined therapy compared with monotherapy RT. Urethral strictures comprised a large portion of the morbidity in the present cohort, with (88%) of men having outlet problems alone or in combination with bladder problems. Jarosek et al. [10] also concluded that BOO (urethral stricture or bladder neck contracture) was the most common late UAE, occurring in % of patients receiving differing forms of RT for PCa. In treating these strictures, Sullivan et al. [28] found that urethral strictures after RT could be adequately treated with either optical urethrotomy or dilatation. This seems quite improbable, however, because recent publications have shown that even in non-radiated and presumably better-quality tissue, the likelihood of cure with DVIU is <10% [29]. It is well established that dilatation and DVIU carry a higher failure rate than urethroplasty [30,31]. In the present cohort, most men failed to achieve symptomatic relief with these measures (DVIU or dilatation) and were seeking more definitive therapy. We found an 88% success rate for posterior urethroplasty in highly selected patients without prostate necrosis and minimal bladder pathology. Our success rate was similar to that of other published series of urethroplasty in patients post-rt, which range from 70% to 90% [32 35]. We liberally used HBOT (44%) in the hope of improving tissue quality as well as wrapping all of the urethral anastomoses in a gracilis muscle flap. There is a lack of mature data on these interventions, but we have found them to be helpful. Given the overall urethroplasty success rate, despite the RT damage, urethroplasty should be considered early after stricture presentation in appropriate cases without prostate necrosis and significant bladder pathology. Additionally, repeated attempts at DVIU or dilatation can add to stricture complexity, increasing the difficulty of curative urethroplasty [36]. An additional striking finding in our patient cohort was the high number of men who underwent RT after RP (43% of men receiving combined therapy). The extensive use of RT after RP is in part based on a perception among some clinicians that there are very few complications of this therapy. For instance, in a prospective, randomized controlled trial of postoperative RT vs surveillance after RP (n = 1 005), Bolla et al. [37] found that late adverse events were more frequent in the radiation group, but reported no grade 4 toxicities. In fact, the study reported that the 10-year cumulative incidence of grade 3 genitourinary toxicity was only 5.3% (95% CI ). Another study from the Southwest Oncology Group reported that men treated with RT postoperatively had a better quality of life over time than those who were observed after RP alone. We cannot discern the frequency of RTOG grade 4 UAEs in our cohort because of the observational study design and our inability to determine the overall number of men treated with RT, but it would appear that high-grade UAEs are just as bad in men treated with surgery and postoperative RT as with dualtherapy RT. The most invasive treatment option, UD (catheterizable colon [Indiana] pouch or urinary conduit) with or without simple cystectomy, had the highest morbidity and mortality of any management group (Clavien Dindo grade 3 complications in 39%, and death in 13%). We reserve this option for men for whom no other treatments are feasible (because of the condition of the urethra/bladder) or who have failed conservative management such as an SPT. UD was felt to be the last resort and was used only in cases where there truly did not seem to be other viable treatment choices, such as continuing SPT drainage. Despite this conservative strategy, we needed to perform UD in almost one-third of our patient group. This fact highlights the severity of the RT UAEs. Two other groups recently described similar reasons for diversion after radiation for PCa including fistula, end-stage bladder, devastated outlet, and a combination of bladder and outlet problems [38,39]. BJU International published by John Wiley & Sons Ltd on behalf of BJU International 705

7 Mayer et al. We follow a general management algorithm for men who present with radiation-related UAEs (Fig. 2). This starts with full evaluation of the urinary system. In some cases, this involves examination under anaesthesia and DVIU to allow assessment of the viability of the urethra, necrosis within the prostate or bladder, and the bladder volume. We feel that repairable defects are those where the stenosis is short (i.e. 1 4 cm), there is no necrosis in the areas of a potential anastomosis, such as the bladder neck, and the bladder has an adequate capacity so the patient would have a good functional result if reconstruction were successful. If there is a possibility of conservative management, such as SPT placement, this is pursued. Common scenarios in men treated conservatively are a man who is able to live with his voiding symptoms, or is able to pass a catheter daily to keep the radiated stricture open. Patients undergo reconstruction if they have minimal necrosis, adequate bladder volume, do not tolerate or want a SPT, and are felt to have reasonable surgical risks based on their age and underlying comorbidities. When patients are not good candidates for reconstruction because of age, comorbidities or the extent of RT injury, they undergo a trial of a SPT. Ultimately only ~15% of our cohort was managed with SPT and, in fact, only 42% of men where this strategy was attempted ended up tolerating a SPT in the long term. Typical problems that move patients to UD or reconstruction (if feasible) are sepsis episodes, intractable pain, dissatisfaction and haematuria. The present study has several important limitations. First, it was retrospective in nature and the men were referred for management of their RTOG Grade 4 UAEs to a tertiary referral centre. As a result, we could not determine the Fig. 2 Management algorithm for Radiation Therapy Oncology Group (RTOG) grade 4 urinary adverse events (UAEs). HBOT, hyperbaric oxygen therapy. RTOG Grade 4 Complications 1. Full physical examination 2. Examination under anaesthesia, DVIU, SPT if needed 1. Repairable defect OR 2. Symptoms manageable with local therapies 3. Can tolerate surgery HBOT if possible 1. Extensive necrosis 2. Lengthy strictures 3. Severe bladder contraction 4. Unrepairable pathology, too elderly/severe comorbidities Conservative (CIC, AUS, periodic DVIU) Reconstruction, consider gracilis flap for urethral pathology Indwelling Catheter FAIL Urinary Diversion FAIL FAIL FAIL 706 BJU International published by John Wiley & Sons Ltd on behalf of BJU International

8 Management of RTOG grade 4 urinary complications after radiotherapy incidence of these events. Likewise, we cannot draw any firm conclusions about the morbidity of RT UAEs in a wider patient population with PCa, which might actually be very low. Second, only a few men underwent their initial RT at our institution and so we were unable to determine the exact dose of radiation received or the EBRT technique used (threedimensional, conformal or intensity-modulated, or whether image guidance was used), but just the timing and the type of radiation. Original data on tumour stage, PSA level and Gleason grade were also missing for most of the men, and the severity of the PCa could have a bearing on subsequent complications. In addition, we made no assessment of the use of androgen deprivation therapy, which certainly could have influenced complications. Third, this study represents a crosssectional snapshot of men who were on a spectrum of disease progression and management approaches. It is quite possible that many men we chose to treat conservatively will go on to further invasive treatments. Likewise, many additional complications and surgical failures may occur over time in men who underwent reconstructive surgery or UD. Finally, this was a small and heterogeneous study population in which each man received personalized management unique to their disease course and psychosocial characteristics using shared-decision making. We can therefore only make generalized observations of these cases. These limitations notwithstanding, the present study shows that the impact of RT-related UAEs is often severe and debilitating, and can result in multiple procedures and interventions. In conclusion, Grade 4 RTOG UAEs arising from PCa treatment carry significant morbidity. Up to one-third of patients require UD to manage these events. Conversely, only about a quarter of patients can be managed with conservative strategies or local surgeries. In highly selected patients reconstructive surgery can be successful. HBOT and gracilis muscle flap creation are frequently used in the course of reconstruction and may be useful adjuncts to surgical care. From the time of initial presentation, patients need to be counselled that these are difficult, complex problems, cure may not be possible, and careful management with long-term close follow-up and multiple therapies are necessary. Although most patients may not be entirely cured of their complication, symptomatic control with the aim of improved quality of life is a reasonable goal through guided management. Acknowledgements The surgical management of four patients undergoing ureteric reconstruction was recently described by the authors in a case series published in Urology Case Reports [40]. Conflict of Interest The authors whose names are listed above certify that neither they nor their institutions at any time received payment or services from a third party (government, commercial, private foundation, etc.) for any aspect of the submitted work (including but not limited to grants, data monitoring board, study design, manuscript preparation, statistical analysis, etc.). The authors have no financial relationships (regardless of amount) with any entities in the bio-medical arena that could be perceived to influence, or that give the appearance of potentially influencing, what was written in the submitted work. The authors have no patents, whether planned, pending or issued, broadly relevant to the work. There are no other relationships or activities that readers could perceive to have influenced, or that give the appearance of potentially influencing, what was written in the submitted work. References 1 Thompson IM Jr, Tangen CM, Paradelo J et al. 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