Prostate International 9 (2021) 48e53 Contents lists available at ScienceDirect Prostate International journal homepage: https://www.journals.elsevier.com/prostate-international Research Article Radiation-induced haemorrhagic cystitis after prostate cancer radiotherapy: factors associated to hospitalization and treatment strategies Francesco Sanguedolce a, *, Gemma Sancho Pardo b, Asier Mercade  Sanchez a, ~ a Lucena , Francesca Pisano , Julio Caldero Josep Balan a a  n Cortez , Angelo Territo a, a a Jordi Huguet Perez , Josep Gaya Sopen ~ a , Cristina Esquina Lopez c, Alberto Breda a, a a Joan Palou Redorta a Department of Urology, Fundacio Puigvert, Autonomous University of Barcelona, Spain b Department of Radiation Oncology, Hospital Sant Pau i de la Santa Creu, Autonomous University of Barcelona, Spain c Research Institute-Statistics Section, Vall d'Hebron Hospital, Barcelona, Spain a r t i c l e i n f o a b s t r a c t Article history: Background: Late onset of radiation-induced haemorrhagic cystitis (RHC) after radiation therapy (RT) Received 29 March 2020 for prostate cancer (PCa) may present or evolve severely, requiring hospitalization with invasive in- Received in revised form terventions. In the present study, we have analysed the prevalence and risk factors associated with the 31 May 2020 onset of RHC. Accepted 27 July 2020 Methods: From January 2002 to May 2017, 1421 patients undertook RT for PCa as a primary, adjuvant, or Available online 11 August 2020 salvage treatment option. RHC presented in 5.6% (n ¼ 80) of the patients; the diagnosis was based on clinical and endoscopic characteristics. Variables in observation included patients, tumours, and RT- Keywords: Prostate neoplasm dosimetry characteristics. Patients with a previous history of bladder cancer were excluded. Univariate Radiotherapy (Student t/Chi square) and uni-/multivariate Cox regression analysis were performed; the events and Hospitalization time-points were hospitalization and time-to-event, respectively. Hematuria Results: There were 80 patients with a mean age at RT of 70.1 years (SD 6.4), mean time lag to RHC of Cystitis 43.9 months (SD 37.5). Median Emergency attendance was two and three times for patients without/with Risk factors hospitalization, respectively. There were in total 64 admissions with invasive treatment required in 26/36 (72.2%) of the patients hospitalised, including transurethral fulguration in 22 and radical cystectomy in 5. Patients at higher risk of hospitalization were those undertaking antiplatelet/anticoagulant treatment (HR:3.30; CI 95%:1.53e3.30; p ¼ 0.002) and those treated with salvage RT with higher bladder volume receiving >70 Gy (bladder V70) (HR:1.03; CI 95%:1.01e1.05; p ¼ 0.027). At receiving operating charac- teristic analysis, the cutoff for bladder V70 was 29%. Conclusion: Nearly half of patients presenting RHC may require invasive treatment including cys- tectomy. Risk factors associated with hospitalization are patients undertaking antiplatelet/coagulant treatment and bladder V70 > 29% in salvage RT patients. © 2020 Asian Pacific Prostate Society. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction Radiotherapy (RT) is one of the treatment options available for * Corresponding author. C/Cartagena 340-350, 08025, Barcelona, Spain. E-mail addresses: fsangue@hotmail.com (F. Sanguedolce), GSancho@santpau.cat patients affected by prostate cancer (PCa); it is indicated for pri- (G. Sancho Pardo), amercade@fundacio-puigvert.es (A. Mercade  Sanchez), jbalana@ mary treatment, in an adjuvant regime, or in the setting of salvage fundacio-puigvert.es (J. Balan ~ a Lucena), francescapisano85@gmail.com (F. Pisano), treatment after biochemical recurrence postradical prostatectomy jfcalderon@fundacio-puigvert.es (J.C. Cortez), territoangelo86@gmail.com [1,2]. However, adverse events may occur acutely or during follow- (A. Territo), jhuguet@fundacio-puigvert.es (J. Huguet Perez), jmgaya@fundacio- ~ a), CrisE4@hotmail.com (C. Esquina Lopez), albbred@ up due to toxic effects on the gastrointestinal (GI) and/or of the puigvert.es (J. Gaya Sopen hotmail.com (A. Breda), jpalou@fundacio-puigvert.es (J. Palou Redorta). genitourinary (GU) systems. https://doi.org/10.1016/j.prnil.2020.07.006 p2287-8882 e2287-903X/© 2020 Asian Pacific Prostate Society. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). F. Sanguedolce et al. / Radiation-induced hemorrhagic cystitis 49 Radiation-induced cystitis (RC) includes bladder toxicities of Table 1 Grade 2 according to the Radiation Therapy Oncology Inclusion/exclusion criteria Group (RTOG) classification and refers to different degrees of low Inclusion criteria urinary tract symptoms (LUTS) and haematuria [3]. Patients with diagnosis of prostate cancer Incidences of RC reported in literature range between 2% and Patients treated with radiotherapy for primary tumour, or in adjuvant/salvage regime after radical prostatectomy 59% of patients treated for pelvic cancers: this wide range may be Patients with visible/gross haematuria and endoscopic characteristics due to the heterogeneity of definitions adopted in literature, which of radiation-induced haemorrhagic cystitis (RHC) according to predefined may include acute and/or late toxicities, or even all types of RC criteria [8] (including bladder loss capacity, LUTS, etc.) or just the subgroup of Exclusion criteria the radiation-induced haemorrhagic cystitis (RHC) [4,5]. Patients with past medical history of bladder cancer Diagnosis of bladder cancer within 6 months from the diagnosis of RHC The RHC is among the most threatening RT complications as it Suspicious or positive urine cytology may account for a significant proportion of urological emergency Patients with radiation therapy (RT) for other diseases (A&E) admissions and/or hospitalization [6]. Treatment options Patients presenting RHC with RT performed in other centres involve a variety of approaches depending on the severity of the haematuria, including conservative managements like hydration and/or bladder irrigation up to the endoscopic fulguration or even number of hospital admissions, and treatment for RHC. The bladder cystectomy. V70 parameter was chosen according to the findings of Schaake RHC can develop from 6 months to as long as 20 years after RT, et al and measured on the outer layer of the bladder wall [9]. with a mean latent time of 35 months [7]. For patients requiring hospitalization, continuous bladder irri- In the present study, we report the prevalence of RHC in a sin- gation, transurethral fulguration (TUF) of the bladder and cys- gle-centre cohort of patients who received RT for PCa (either as tectomy were the treatment modalities adopted according to the primary or as adjuvant/salvage treatment), the types of manage- gravity and/or persistency of haematuria. TUF was performed with ment undertaken, and the risk factors associated with low-energy monopolar setting (50 Hz) in the bleeding spots and hospitalization. areas with telangiectasia [10]. Bladder instillations with hyaluronic acid (HA) and hyperbaric oxygen therapy (HBOT) were planned 2. Patients and methods after haematuria remission (either with or without hospitalization) to prevent recurrence, in an ambulatory regime. A cohort of 1421 patients that underwent RT for PCa in a single Statistical analysis included descriptive statistics of the variables center was retrospectively analysed from January in observation (standard deviation, median and interquartile 2002dcorresponding to the local establishment of the three- rangedIQRd25e75), univariate (Student t and Chi square), and dimensional conformal external beam RT (EBRT) with high en- uni-/multivariate Cox regression analysis performed to assess risk ergy linear accelerator dto May 2017. We included patients that factors for hospitalization. Relevant cutoff values were calculated received RT as a primary treatment, in adjuvant regime or as a by means of the Receiving Operating Characteristic (ROC) curve salvage option in case of biochemical recurrence after radical analysis. Tests significance level was set at P values <0.05 (R Sta- prostatectomy. tistical Software). The diagnosis of RHC was based on the combination of visible haematuria requiring admission to A&E not related to urinary tract infection, and of cystoscopic findings; diagnostic criteria on this 3. Results latter regard included the absence of bladder lesions and/or stones as well as the presence of pale mucosa, diffused telangiectasia and/ After screening for the inclusion/exclusion criteria, a total of 80 or petechiae, or even ulcerations, as described and standardised by PCa patients treated with RT presented RHC in the period in Fajardo in 1978 [8]. Moreover, urine cytology was always per- observation, corresponding to the 5.6% of the overall cohort of RT formed to further rule out bladder urothelial carcinoma in situ patients, and were included in the analysis. Half of the patients (CIS): in case of suspicious or positive findings, random bladder undertook primary RT, and another half received salvage RT; no biopsies and CT scan were performed. patient in the final cohort underwent adjuvant RT. Patients with a history of bladder cancer (BCa) were excluded, as The median follow-up of the patients was 36 months (IQR: well as patients diagnosed of BCa within 6 months from the diag- 18.75e49.25). Most of the patients harbored intermediate (40%) nosis of RHC (see Table 1 with inclusion/exclusion criteria). In pa- and high risk (33.75%) PCa according to the National Comprehen- tients with later diagnosis of BCa, the RHC follow-up was sive Cancer Network risk stratification [2]. In 97.5% of the cases, a discontinued at the date of the latest control prior to the BCa three-dimensional conformal RT was undertaken, with a median diagnosis. For the remainder of the patients, follow-up was counted fractionation of 1.8 Gy. The demographics of patients are detailed in until the latest outpatient clinic visit or the date of death. Table 2. The primary endpoint consisted of the identification of factors Out of 80 patients (55%; Group 1), 44 attended A&E at our associated with Grade 3 RTOG bladder toxicity requiring hospi- institution because of intermittent haematuria that remitted either talization; secondary endpoint included a descriptive narration of spontaneously with hydration or temporal catheterization with/ the treatments undertaken as well as their efficacy and morbidity. without bladder wash-out; median times of A&E attendance was 2 Events and time-points consisted of hospitalization (yes vs. no) and (IQR 1e4). time-to-event, respectively. Patients not requiring hospitalization Only one patient in this subgroup of patients received HA in- were labeled as Group 1, those who needed hospital admission stillations, completing the induction course (1-weekly 6) with no were identified as Group 2. maintenance instillation performed. Among the variables taken into account for analysis, there were Hospitalization was needed in the remainder 36 patients (45%; patient's comorbidities, antiplatelet/coagulant therapy, age at the Group 2), due to persisting haematuria requiring continuous time of RT, indication of RT, fraction dose, percentage bladder vol- bladder irrigation and/or urgent endoscopic bladder clot washout ume receiving 70 Gy (bladder V70), mean bladder dose, acute in the theater; median A&E attendance prior to hospitalization was bladder toxicity during RT, number of emergency room attendance, three times (IQR: 1e6) because of haematuria, dysuric symptoms 50 Prostate International 9 (2021) 48e53 Table 2 Patients’ demographics. Total sample Group 1 (no hospital admission) Group 2 (hospital admission) P N ¼ 80 N ¼ 44 N ¼ 36 Age at the RT (SD) 70.1 (6.4) 68.8 (6.5) 71.4 (6.1) 0.067 Diabetes mellitus (SD) 24 (30%) 11 (25%) 13 (36.1%) 0.646 Hypertension (SD) 53 (66.25%) 25 (56.8%) 28 (77.7%) 0.354 Anticoagulant or/and antiplatelet treatment 20 (25%) 5 (11.3%) 15 (41.6%) 0.012 NCCN prostate cancer risk group - Very low risk 4 0 4 0.011 - Low risk 4 0 4 - Intermediate risk 32 20 12 - High risk 27 15 12 - Very high risk 10 8 2 - N/A 3 1 2 Indication for RT - Primary 40 (50%) 18 (40.9%) 22 (61.1%) 0.150 - Adjuvant 0 0 0 - Salvage 40 (50%) 26 (59.1%) 14 (38.9%) Type of RT - Brachytherapy 1 0 1 0.45 - 3D CRT 1 43 35 - IMRT/IGMT 1 1 0 Fractionation-Gy (median) 1.8 1.8 1.8 0.972 RT of lymph nodes  Yes 68 (85.0%) 38 (86.3%) 30 (83.3%) 0.175  No 12 (15.0%) 6 (13.7%) 6 (16.7%) GU acute toxicities (during RT) - Visible/gross haematuria 1 (1.25%) 1 (2.7%) 0 (0%) 0.980 - Acute urine retention 1 (1.25%) 1 (2.7%) 0 (0%) 0.980 - Urinary tract infection 1 (1.25%) 1 (2.7%) 0 (0%) 0.980 - Dysuria 77 (96.25%) 41 (93.2%) 36 (100.0%) 0.714 Hormonal treatment 38 (47/5%) 19 (43.18%) 19 (52.7%) 0.928 Mean bladder dose (Gy) 60.5 (9.7) 61.4 (9.3) 59.6 (10.1) 0.432 Mean bladder V70 (%) 35.0 (27.8) 32.4 (26.8) 37.8 (28.8) 0.395 Time from RT to cystitis, months 43.9 (37.5) 42.3 (35.1) 45.7 (40.3) 0.682 RT, radiotherapy; SD, standard deviation; NCCN, National Comprehensive Cancer Network; 3D CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy; IGRT, imaging-guided radiotherapy; Gy, gray. and/or catheter tamponade for clots. Nearly half of these patients Bladder urothelial cancer was detected in five patients during (n ¼ 15/36; 41.66%) were hospitalised for more than once (IQR: the follow-up, after >6 months from the diagnosis of RHC, with one 2e3). There were in total 64 hospital admissions, with 26 patients patient requiring radical cystectomy in the follow-up. (72.2% of Group 2) requiring invasive procedures in theatre and Radical cystectomy was also performed in further five RHC pa- with a mean hospital stay of 7 days (IQR: 4e11.75). tients as a result of severe haematuria not responding to conser- The treatment modalities undertaken are summarised in vative management (n ¼ 3) and of remittent RHC in a low-volume Table 3. All patients were admitted with continuous bladder irri- bladder capacity associated to severe dysuria (n ¼ 1). All these gations. TUF was commonly performed (n ¼ 22, 61.1%) with six and patients experienced a range of complication: two patients expe- two patients needing a second and a third TUF during the follow- rienced Grade II (ileus requiring parenteral nutrition), two patients up, respectively. Ambulatory consolidative treatment was per- had a Grade IIIb (ileal anastomosis leakage at 8 days post-op, and formed in seven patients, six with HA instillations (median of 6 ileal conduit fistula at 60 days post-op, both requiring surgical in- instillations), and one with HBOT. Only one of these patients pro- terventions), and one developed a Grade IV (sepsis requiring gressed to refractory haematuria requiring cystectomy. intensive care unit management) according to the modified Clav- Blood transfusions were needed in 38.9% of Group 2 patients ieneDindo classification for postoperative complications [11]. One with a median of 2 units transfused per patient (IQR: 2e5.5), of these patients eventually died 6 months after surgery for the including all the admissions recorded. complications of pseudomembranous colitis that required total colectomy. At univariate analysis, clinical variables associated to the Table 3 admission to the hospital were time from RT to diagnosis of HRC Treatments undertaken in patients hospitalised. (HR:0.91; CI 95%:0.88e0.98; p ¼ 0.041) and anticoagulant treat- Treatment N (%) ment (HR:2.89; CI 95%:1.40e3.38; p ¼ 0.030). Bladder catheter þ washout 36/36 (100%) At multivariate Cox regression analysis (see Table 4), anticoag- TUF (þ second or third repeated TUF) 22/36 (61.1%) (þ6 þ 2) ulant/antiplatelet treatment and bladder V70 in the setting of Cystectomy 6a)/36 (16.6) salvage RT patients were found to be the only variables significantly Blood transfusion 14/36 (38.9) associated to the events (HR:3.30; CI 95%:1.53e3.30; p ¼ 0.002, Consolidation treatment: -HA bladder instillation 6/36 (16.6) HR:1.03; CI 95%:1.01e1.05; p ¼ 0.027, respectively). At ROC, the -HBOT 1/36 (2.7) cutoff value for the bladder V70 was 29%. A sensitive analysis was performed by removing from the Cox TUF, transurethral fulguration; HA, hyaluronic acid; HBOT, hyperbaric oxygen therapy. regression analysis patients with BCa detected in follow-up, and no a) Includes one patient undertaking radical cystectomy for bladder cancer. difference of the outcomes was observed. F. Sanguedolce et al. / Radiation-induced hemorrhagic cystitis 51 Table 4 pelvic RT, it may account for a significant proportion of A&E Multivariate Cox model analysis. admission for urological causes. Recently, an Australian study re- Adjusted model p ported a 7.2% of RT patients admitted from A&E for RT complica- tions (90% after prostate RT), with RHC accounting for more than HR CI 95% half of the cases; similarly, two-thirds of the RT complications Time from RT to RHC 0.96 0.92e1.01 0.072 required surgical intervention, with bladder TUF for RHC being the Antiplatelet/anticoagulant treatment 10.9 4.23e10-7 <0.001 Age at the onset of RHC 1.09 0.98e1.22 0.110 most common one [6]. Our study is in line with these latter figures, Bladder v70 in salvage RT patients 1.03 1.01e1.05 0.027 with a prevalence of 5.6% of prostate RT patients experiencing HRC, Type of RT (primary vs. salvage) 1.15 0.55e1.35 0.650 and a median of three attendances per patient to our A&E; nearly RT, radiotherapy; RHC, radiation-induced haemorrhagic cystitis. half of these patients required hospitalization, requiring a variety of low urinary tract manipulations. Factors associated with the development of RHC have been investigated in few studies with modern series of EBRT patients; 4. Discussion although Martinez-Ribas et al could find a relationship with the anticoagulant/antiplatelet therapy at univariate analysis, in both RHC has been shown to be a serious late adverse event of RT: publications the authors failed to identify at multivariate analysis although reported rates range from 5% to 10% of patients with prior statistically significant variables associated to RHC [5]. Gross haematuria in pt with past medical history of RT Urothelial cancer workup Posive: treatment of Negave: Urothelial cancer management of RHC RTOG ≤2: outpaent RTOG ≥3: hospital management admission Self-liming Unfavourable Remission of Refractory haematuria prognosc favours* haematuria haematuria Discharge to GP care HA or HBOT Transurethral coagulaon Remission of Refractory haematuria haematuria Unfavourable prognostic favours*: -Anticoagulant/antiplatelet therapy Embolizaon or radical cystectomy -Bladder V70 >29% Figure 1. Diagnostic and therapeutic pathway for patients presenting gross haematuria with past medical history of prostate radiotherapy. 52 Prostate International 9 (2021) 48e53 To identify patients at higher risk for hospital admission and AS a result of our outcomes, we have established a protocol to invasive management, we looked at factors associated with hos- undertake appropriate actions in an attempt to reduce the risk of pital admission, finding at multivariate analysis the anticoagulant/ progression of RHC after the first presentation of haematuria; we antiplatelet therapy and bladder V70 in the subgroup of salvage RT strongly believe that its application can be generalised although patients as factors significantly associated to the events. This latter further studies might be needed (see Fig. 1). finding is consistent with a recent publication regarding a cohort of Our study has some limitations: it is a retrospective study, and salvage RT patients after radical prostatectomy biochemical failure relevant confounding factors (like selection bias) may be present. where the relevant dosimetric parameter was associated with a We have not weighted our findings against the rest of the RT cohort significantly higher risk to develop a Grade >2 late genitourinary during the study period; however, the study design intentionally toxicity (HR 1.05, CI 95%: 1.02e1.08. p ¼ 0.001) [12]. The association involved only the patients with diagnosis of RHC as the primary of anticoagulant/antiplatelet therapy with a severe degree of RHC is endpoint consisted in identifying factors associated with bladder very much intuitive as it is likely the result of the induced bleeding toxicity requiring hospitalisation and invasive treatment. diathesis on an affected urothelium. On the other hand, the role of Also, we were unable to measure how the patients' quality of life bladder V70 in patients receiving salvage RT after radical prosta- was affected, as no patients’ reported outcomes tools were used tectomy could be multifactorial: from one side, the treatment of the due the retrospective nature of the study; however, it is reasonable surgical field expose to a direct effect of the radiations to the to estimate that with several admissions to A&E, eventual bladder; moreover, it must be noted that some of these patients hospitalization ± the relevant invasive manoeuvres, patients with may suffer a certain degree of incontinence (for surgery or aging) RHC have a severely impaired quality of life. which might prevent them in keeping a full bladder during the RT Finally, we believe that on the basis of this study's outcomes sessions being this latter described as a protector to GU and GI future trials could be undertaken with better patients' selection and toxicity [13]. appropriate planning of treatment strategies. While bladder washout and TUF are established first-line treatments, HA and HBOT are treatment options usually adopted 5. Conclusion as consolidation therapy to prevent the recurrence of haematuria after the resolution of an acute episode [14] [15]. RHC is a fearsome late complication of prostate RT even in the In our series, all patients were initially managed with bladder modern era of RT. Antiplatelet/anticoagulant therapy and bladder washout (either at A&E or as inpatients) and TUF was necessary for V70 > 29% are the factors associated with the need of patients’ nearly two-thirds of patients requiring hospitalization, with six of hospitalization. A variety of treatment options are available, them undertaking multiple TUF and four patients (plus further two although they are associated to an impairment of quality of life and patients with metachronous BCa) ending up with radical severe risk of complications. Prophylactic measures in patients at cystectomy. higher risks of severe RHC may prevent the progression of the Eight patients, one of the non-hospitalised group and seven of disease, but further investigations are needed. the hospitalised group, received a consolidation therapy, with only one nonresponding to the treatment and requiring finally a radical Conflicts of interest cystectomy. Most of these patients received HA (n ¼ 7) as HBOT was logistically difficult to get access to. Although HBOT has been more None. extensively investigated, the intravesical instillation of HA (þ/ chondroitin sulfatedCS-) in the setting of pelvic radiation cystitis is Abbreviations a more recent therapeutic option: Gacci et al found a significant improvement in patients who developed severe LUTS after prostate RT radiotherapy RT in a cohort of 80 patients undergoing intravesical instillation of PCa prostate cancer HA þ CS [16]. In a head-to-head comparison, 36 RHC patients were GU genitourinary randomly assigned to receive either HBOT or HA, and no differences GI gastrointestinal in efficacy were recorded at all the time-points, suggesting that RC radiation-induced cystitis both therapies are equally effective [17]. RTOG Radiation Therapy Oncology Group Cystoprostatectomy is the last resort for RHC refractory to all RHC radiation-induced haemorrhagic cystitis the conservatory treatment options as it is strongly associated A&E accident and emergency department with severe comorbidities and with a higher risk of intra-/post- EBRT external beam radiotherapy operative mortality: in our cohort, three out of five patients (60%) BCa bladder cancer undergoing cystectomy with final histology of actinic cystitis Bladder V70 percentage of bladder volume irradiated with 70 Gray experienced severe complications (ClavieneDindo Grade 3), and TUF transurethral fulguration one patient died as a result of later complications of the surgery at HA hyaluronic acid 6-month post-op. These results are consistent with the outcomes HBOT hyperbaric oxygen therapy published by Linder et al with 42% of severe complication rate and 16% of mortality rate, respectively, within 90 days from surgery Support/financial disclosures [18]. Our findings may help practitioners in identifying those RHC None. patients at higher risk to eventually prompt prophylactic measures. An emerging option is the glycosaminoglycan replenishment References therapy for patients experiencing acute bladder toxicity during pelvic RT: one pilot study showed a benefit of the instillation of 1. Mottet NBJ, Briers E, Bolla M, Bourke L, Cornford P, De Santis M, et al, members chondroitin sulfate in a small cohort of 20 female symptomatic of the EAU e ESTRO e ESUR eSIOG Prostate Cancer Guidelines Panel. EAU e patients receiving pelvic RT; a further randomised controlled trial ESTRO e ESUR e SIOG Guidelines on Prostate Cancer. The Netherlands: EAU Guidelines Office. 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