E URO PE A N U ROL O GY OP E N S C I E NC E 2 6 ( 20 21 ) 45 – 54 available at www.sciencedirect.com journal homepage: www.eu-openscience.europeanurology.com Voiding Dysfunction Multicentre International Study for the Prevention with iAluRil of Radio-induced Cystitis (MISTIC): A Randomised Controlled Study Juan Palou Redorta a,b, Francesco Sanguedolce a,b, Gemma Sancho Pardo a,b, Martin Romancik c, Gianni Vittori d, Andrea Minervini d, Fabrizio Di Maida d, Richard Lunik e,f, Renzo Colombo g, Vincenzo Serretta h, Bülent Çetinel i, Vittorio Bini j, Davide Corradengo k, Massimo Lazzeri l,* a b Fundació Puigvert, Autonomous University of Barcelona, Barcelona, Spain; Hospital Sant Pau i de la Santa Creu, Autonomous University of Barcelona, Barcelona, Spain; c Department of Urology, St. Cyril and Methodius Hospital, Bratislava, Slovakia; d Department of Urology, University of Florence, Careggi Hospital, Firenze, Italy; e Department of Urology, Fakultná nemocnica s poliklinikou Prešov, Prešov, Slovakia; f Remedium Clinic, Bardejov, Slovakia; g Vita h Salute San Raffaele University and Urological Research Institute, San Raffaele Hospital, Milan, Italy; Department of Urology, Azienda Ospedaliera i Universitaria Policlinico Paolo Giaccone, Palermo, Italy; Department of Urology, Cerrahpaa Medical School, Istanbul University, Istanbul, Turkey; j Department of Medicine, University of Perugia, Perugia, Italy; k Ospedale Policlinico San Martino IRCCS, Genova, Italy; l IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Milan, Italy Article info Abstract Article history: Background: Radiation-induced cystitis is a common side effect of radiotherapy Accepted January 29, 2021 (RT) to the pelvic area. Hyaluronic acid (HA) and chondroitin sulfate (CS) are components of the urothelial mucosa and positive results have been obtained for Associate Editor: intravesical HA/CS instillations for the treatment of urinary tract infections and Guillaume Ploussard bladder pain syndrome. HA/CS may also have a protective effect against RT bladder toxicity. Keywords: Objective: To investigate whether HA and CS protect the urothelium during RT, Prostate cancer alleviate lower urinary tract symptoms, and improve quality of life. Radiotherapy Design, setting, and participants: This multicentre randomised controlled trial was Cystitis conducted across seven centres in four countries. Male patients aged 18 yr Hyaluronic acid scheduled to undergo primary intensity-modulated radiotherapy for localised Chondroitin sulfate prostate cancer were enrolled. Questionnaries Intervention: Patients were randomised to intravesical HA/CS plus an oral formu- Quality of life lation of curcumin, quercetin, HA, and CS (group A) or no treatment (group B). Lower urinary tract symptoms Outcome measurements and statistical analysis: The primary endpoint was abso- lute changes from baseline to follow-up in urinary domain scores for the Expanded Prostate Cancer Index Composite (EPIC), the International Consultation on Incon- tinence Questionnaire-Male Lower Urinary Tract Symptoms (ICIQ-MLUTS), and the EuroQol Group EQ-5D-5L questionnaire. Data analysis for efficacy and safety out- comes was performed using an intention-to-treat (ITT) approach; the ITT popula- tion was defined as all randomised patients. * Corresponding author. Department of Urology, Humanitas Clinical and Research Center, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano MI, Italy. Tel. +39 028224 4553; Fax: +39 02 8224 8224. E-mail address: massimo.lazzeri@humanitas.it (M. Lazzeri). http://dx.doi.org/10.1016/j.euros.2021.01.016 2666-1683/© 2021 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 46 EUROPEAN UROLOGY OPEN SCIENCE 26 (2021) 45–54 Results and limitations: Of 57 patients screened, 49 were enrolled and randomly assigned to either active treatment (group A, n = 25) or the control (group B, n = 24). Three patients in the control group withdrew after randomisation. Changes from baseline to 12 mo were worse in the control group for subtotal scores for urinary symptoms and impact of symptoms on quality of life and for the total score (p = 0.05, p = 0.003, and p = 0.008, respectively). There was a significant time  group interaction in favour of active treatment for the incontinence symptom score (p = 0.011) and bother score (p = 0.017). The absence of a sham procedure and/or placebo is the main limitation. Conclusions: Our results suggest that intravesical HA/CS in combination with an oral formulation may reduce urinary symptoms and improve QoL at short-term (1 yr) follow-up. Patient summary: We investigated whether hyaluronic acid (HA) and chondroitin sulfate (CS) have a protective effect against the bladder toxicity of radiotherapy for prostate cancer. HA/CS used for weekly bladder irrigation for 6 wk and given orally with curcumin and quercetin for 12 wk reduced urinary incontinence symptoms and bother measured at 1-year follow-up. This may hold promise as a preventive treatment if the results are confirmed in further trials. © 2021 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY-NC-ND license (http://creati- vecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction and proposed several questions that remained to be addressed through further research [11]. Acute and late radiation-induced cystitis is a common side Several clinical studies have shown the efficacy of effect occurring in up to 25% of patients during and after intravesical instillation of high concentrations of sodium pelvic organ cancer treatment with radiotherapy (RT) hyaluronate and sodium CS in protecting the urothelium in [1]. Radiation-induced bladder toxicity is characterised by different settings [12–15]. Considering the positive results early acute inflammation, sometimes haemorrhagic, that obtained for intravesical HA and CS instillation for the resolves in many patients, and late fibrosis with filling/ treatment of bladder diseases such as urinary tract voiding dysfunction that can occur months or years later. infections and bladder pain syndrome, which symptomati- The acute and late clinical complaints of patients often cally resemble radiation-induced cystitis, we reasoned that resemble those for acute or chronic cystitis, such as bladder protection of the urothelium by HA and CS during RT could pain syndrome, and some patients may also experience represent a preventive strategy capable of alleviating the gross haematuria, which further impacts quality of life consequences, hence avoiding or improving the symptoms (QoL) and may require invasive treatment [1–3]. of radiation-induced cystitis and improving QoL. Therefore, Ionising radiation impacts cells, tissues, and pelvic we tested the hypothesis that intravesical HA/CS (iAluRil) organs of the body via different mechanisms and effects. plus an oral formulation of HA, CS, curcumin, and quercetin In in vivo animal models, irradiated bladders exhibit (iAluRil Soft Gels) may prevent acute and late radiation- oedema, inflammatory cell infiltrate, blood vessel dilation induced cystitis and improve quality of life. and urothelial loss, and exhibit fibrosis and disruption of the urothelial barrier [4]. The urothelial barrier consists of a 2. Patients and methods protective mucin layer that contains negatively charged glycosaminoglycans, the main components of which are 2.1. Study design hyaluronic acid (HA) and chondroitin sulfate (CS) [5]. RT may impair the function of the urothelium because of This was an investigator-initiated, European, unblinded, randomised fibrosis and nerve changes in bladder tissue, leading to an controlled trial (active vs no additional treatment) conducted in seven acute local inflammatory response and chronic lower centres in four countries (Italy, Slovakia, Spain, Turkey) in a selected urinary tract symptoms (LUTS), whether or not associated population of men with prostate cancer who underwent RT: the with gross haematuria and pain [6,7]. Multicentre International Study for the Prevention with iAluRil of Radio- Several strategies have been used to treat radiation- induced Cystitis (MISTIC). The study was approved by the medical research ethics board of each induced cystitis [3,8,9]. However, with the possible excep- participating centre and was conducted in compliance with the tion of modest effects with hyperbaric oxygen, most of these International Conference on Harmonization/Good Clinical Practice treatments have failed to demonstrate optimal and long- guidelines, national laws, applicable regulatory requirements, and the term efficacy [1,10]. In 2019, the International Consultation ethical principles of the Declaration of Helsinki. Specifically, the study on Incontinence Research Society identified gaps in the was approved by the Ethics Committees of Universidad Autónoma de knowledge on effects of radiation on the lower urinary tract Barcelona, Università Vita-Salute San Raffaele, Ospedali Careggi, the E UROP E AN U RO LO GY OP E N SCI ENCE 2 6 (2 021 ) 45 –5 4 47 University of Palermo, St. Cyril and Methodius University Hospital, Incontinence Questionnaire-Male Lower Urinary Tract Symptoms (ICIQ- Fakultná nemocnica s poliklinikou Prešov, and Istanbul University. The MLUTS) score, and the EuroQol Group EQ-5D-5L questionnaire score. The overall protocol is available on ClinicalTrial.gov (NCT03493997) and secondary outcome was the rate of patients who stopped treatment with follows the CONSORT guidelines. intravesical or oral iAluRil because of intolerance or adverse events. Tolerability endpoints included the discontinuation rate, significant 2.2. Participants deviation from the study treatment protocol for Group A, and safety, defined as drug-related adverse reactions. Male patients aged 18 yr who were scheduled to undergo primary intensity-modulated radiotherapy (IMRT) for localised prostate cancer 2.6. Statistical analysis were enrolled. All patients provided written informed consent. The participants did not enter the trial if any of the following applied: female; To calculate the sample size, the EPIC questionnaire was fixed as the life expectancy of <24 mo; radiologically confirmed metastasis; reference and a power analysis was conducted to determine the number documented urethral strictures; ongoing chemotherapy; previous of participants needed to detect an absolute change of 15 points in the brachytherapy; history of chemoradiotherapy for prostate cancer; EPIC urinary domain total score between the first and last visit, given a previous treatment with bacillus Calmette-Guérin; postvoid residual standard deviation of 20 and correlation of 0.500 between observations volume >200 ml; bladder calculi; neurogenic bladder; lower urinary for the same subject. A sample size of 21 subjects for each group achieved tract infection; unstable cardiovascular disease/congestive heart failure; 80% power to detect this difference at a 0.05 significance level (PASS current nitrate or anticoagulant use; clinically significant hepatobiliary version 11.0.7; NCSS, Kaysville, UT, USA). Data analyses for both efficacy or renal disease; history of significant central nervous system injuries and safety outcomes were performed using an intention-to-treat (ITT) within 6 mo; and any other significant disease or disorder that, in the approach; the ITT population was defined as all randomised patients. opinion of the investigator, might either put the participant at risk The Shapiro-Wilk test was used to assess the variables followed a because of participation in the trial or influence the result of the trial or normal distribution. The Mann-Whitney U test and Wilcoxon signed- the participant’s ability to participate in the trial. rank test were used for comparisons of independent and paired data, respectively. Frequencies of qualitative variables were analysed using the 2.3. Randomisation and masking x2 test with Yates’ continuity correction or Fisher’s exact test. Comparisons within and between groups over time were analysed The randomisation (1:1) was carried out according to a predefined, using a mixed-model repeated-measures analysis of variance (RM- centre-specific randomisation list prepared using validated software ANOVA), Mauchly’s test of sphericity, and Levene’s test for equality of (Random Allocation Software version 1.0.0; https://doi.org/10.1186/ variances were used to exclude any possible violation of ANOVA 1471-2288-4-26) by the appointed personnel. Treatment was not assumptions. Time (variable value at baseline and at each follow-up visit) masked. and group (therapy arms) were considered as within-subjects and between-subject factors, respectively, with five time levels and two group levels. Time  group interactions were also evaluated. All 2.4. Procedures statistical analysis was performed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). In all analyses, a two-sided p value <0.05 was All patients received external beam RT (EBRT) for prostate cancer, considered statistically significant. delivered as IMRT using moderate hypofractionation with a simulta- neous integrated boost, guided by fiducial intraprostatic markers according to the European Organisation for Research and Treatment 3. Results of Cancer guidelines for primary prostate cancer RT, and lasting for 6 wk [16]. After completion of screening (visit 1), eligible patients were Of 57 patients screened between January 2017 and Decem- randomly assigned at a 1:1 ratio to receive either active treatment (group ber 2019, seven did not agree to participate and one opted A) or standard care (group B). Patients in group A received a sterile for radical prostatectomy; finally, 49 were eligible for solution containing sodium hyaluronate 1.6%, 800 mg/50 ml and sodium inclusion. After completion of baseline assessments (visit chondroitin sulfate 2%, 1 g/50 ml (HA-SC; iAluRil Prefill; IBSA, Lodi, Italy) 1), 25 patients were randomly assigned to group A and 24 to via weekly intravesical instillation for 6 wk, plus an oral soft-gel formulation (iAluRil Soft Gels; IBSA) containing 200 mg of CS, 20 mg of the control group (group B; Fig. 1). HA, 200 mg of quercetin, and 100 mg of curcumin, one capsule twice a Patient demographics and disease characteristics were day for 12 wk. Intravesical HA/SC was instilled in the 24 h before every RT similar in both groups (Table 1). The two groups were also weekly session. Patients in group B did not receive any intravesical or oral well balanced with regard to the RT received; there were no treatment. All other treatments were allowed except those mentioned in significant differences in the number of sessions, RT doses, the exclusion criteria. or other RT parameters (Table 2). Patients in both groups were followed up and assessed at 4 wk after Two patients in group B withdrew consent after the first instillation (during the RT treatment period; visit 2); at 6 wk (at randomisation, and one in group B was diagnosed with a the end of the RT period; visit 3); at 12 wk (6 wk after the end of RT; visit new cancer and was ruled out. No patients withdrew from 4); and 1 yr after RT initiation (visit 5). During the planning of treatment, the study because of catheter discomfort, and none regimen and average dose to the whole bladder was recorded to assess the impact of EBRT on urinary symptoms. discontinued oral therapy because of side effects. All of the patients were evaluated after 1 yr. 2.5. Outcomes There were no significant differences in EPIC urinary domain scores between the groups at baseline. When single The primary outcome was the absolute change from baseline to follow- items were considered, scores at 12 mo for EPIC item 5 up in the Expanded Prostate Cancer Index Composite (EPIC) urinary (p = 0.012) and item 7 (p = 0.033) were significantly higher single and overall domain score, the International Consultation on in group A than in group B. In group B, a significant 48 EUROPEAN UROLOGY OPEN SCIENCE 26 (2021) 45–54 Fig. 1 – Flowchart of patient inclusion in the trial. reduction was observed between baseline and last follow- There were no statistically significant differences at up for item 1 (p = 0.021), item 6 (p = 0.005), and item 7 baseline for overall ICIQ-MLUTS scores evaluating male (p = 0.009). The subtotal scores for the two main categories LUTS and impact on QoL (Table 4). (urinary symptoms, items 1–5; and impact of symptoms on In group A, a statistically significant increase was observed QoL, items 6–7) and for the total score (items 1–7) were between baseline and last follow-up for the total score significantly lower at 12 mo than at baseline in group B (p = 0.019) and voiding symptom score (p = 0.007), while a (p = 0.05, p = 0.003, and p = 0.008, respectively). Changes in significant increase was observed for the total score QoL items from baseline to the 12 mo significantly differed (p = 0.008), incontinence symptoms score (p = 0.004), and between groups A and B for item 6 (p = 0.002), item 7 bother score (p < 0.0001) in group B. Comparison of changes (p = 0.016), the subtotal score for items 6–7 (p = 0.003), and in incontinence score and bother score from baseline to last the overall score for items 1–7 (p = 0.006). All data are follow-up between the two groups revealed that the change reported in Table 3. in score was significantly greater (worse condition) in group B RM-ANOVA revealed statistically significant within- (p = 0.004 and p < 0.0001, respectively). RM-ANOVA showed group factors over time for all questionnaire sections and a statistically significant higher score over time for group B a significant time  group interaction for the items 6–7 versus A for total score (p < 0.0001), incontinence symptoms subscore and the total score (items 1–7), with lower values score (p = 0.002), and bother score (p = 0.001). There was a in group B than in group A (Fig. 2). significant time  group interaction for the incontinence Table 1 – Baseline characteristicsa Group A (n = 25) Group B (n = 24) p value Median age, yr (IQR) 67 (64.5–75.5) 71 (68.5–74.5) 0.508 Median body mass index, kg/m2 (IQR) 26.1 (25.2–28.9) 27.4 (25.6–30.9) 0.242 Median Charlson comorbidity index (IQR) 4 (4–4) 3 (2.5–5) 0.625 Smokers, n (%) 6 (24) 7 (29) 0.754 Positive DRE, n (%) 18 (72) 16 (76) 0.999 Median PSA, ng/ml (IQR) 12.3 (7.7–24.3) 10 (7.5–13.5) 0.168 Median Gleason score (IQR) 7 (7–8) 7 (7–8) 0.289 Median number of total cores, n (IQR) 12 (12–12) 12 (12–14) 0.217 Median number of positive cores, n (IQR) 4 (3–8) 3 (2–4) 0.055 Median percentage positive cores, % (IQR) 25 (17–71) 21 (13–27) 0.272 DRE = digital rectal examination; IQR = interquartile range; PSA = prostate-specific antigen. a Group A: intravesical sodium hyaluronate/sodium chondroitin sulfate plus oral chondroitin sulphate, hyaluronic acid, quercetin, and curcumin. Group B: no intravesical or oral treatment. E UROP E AN U RO LO GY OP E N SCI ENCE 2 6 (2 021 ) 45 –5 4 49 Table 2 – Radiotherapy treatment parameters Group A (n = 25) Group B (n = 24) p value Median number of sessions (interquartile range) 36 (29–36) 36 (30–37) 0.470 Median dose, Gy (interquartile range) Prostate 72 (71–72) 72 (71–74) 0.432 Seminal vesicles 65 (56–65) 65 (65–67) 0.170 Lymph nodes 45 (45–49) 46 (45–48) 0.724 Bladder 44 (36–46) 44 (32–47) 0.941 Table 3 – Results for the urinary domain of the Expanded Prostate Cancer Index Compositea Item Group A WG p value Group B WG p value BG p value MD BG (95% CI) Visit 1 (baseline) Number of patients 25 21 1. Over the past 4 weeks, how often have you leaked urine? 84  29.7 76.2  34.9 0.426 2. Over the past 4 weeks, how often have you urinated 100  0 100  0 1.000 blood? 3. Over the past 4 weeks, how often have you had pain or 96  9.4 94  17.5 0.930 burning with urination? 4. Which of the following best describes your urinary control 77.5  20.9 79.5  26.8 0.516 during the last 4 weeks? 5. How many pads or adult diapers per day did you usually 96  14.7 88.9  26.5 0.266 use to control leakage during the last 4 weeks? Total for items 1–5 90.7  10.5 87.7  13.5 0.727 6. How big a problem, if any, has each of the following been 79.7  15.8 82.7  16.4 0.431 for you during the last 4 weeks? 7. Overall, how big a problem has your urinary function been 77  19 76.2  20.1 0.981 for you during the last 4 weeks? Total for items 6–7 79.3  15.3 81.8  16.6 0.492 Total for items 1–7 84  11 84.3  13.5 0.604 Visit 5 Number of patients 23 21 1. Over the past 4 weeks, how often have you leaked urine? 77.2  30.1 64.3  37.6 0.247 2. Over the past 4 weeks, how often have you urinated 98.9  5.2 94  13.5 0.124 blood? 3. Over the past 4 weeks, how often have you had pain or 96.7  8.6 86.9  23.2 0.46 burning with urination? 4. Which of the following best describes your urinary control 78.4  19 70  20.9 0.178 during the last 4 weeks? 5. How many pads or adult diapers per day did you usually 98.6  6.9 79.4  34.1 0.012 use to control leakage during the last 4 weeks? Total for items 1–5 90  7.7 78.9  20.7 0.096 6. How big a problem, if any, has each of the following been 83.7  9.3 71.4  25.9 0.228 for you during the last 4 weeks? 7. Overall, how big a problem has your urinary function been 79.3  16.3 63.1  26.9 0.033 for you during the last 4 weeks? Total for items 6–7 83.1  9.1 70.2  25.7 0.157 Total for items 1–7 85.9  7.7 73.9  22.6 0.126 Change from baseline to visit 5 1. Over the past 4 weeks, how often have you leaked urine? 9.8  21 0.034 11.9  21.8 0.021 0.665 2.1 ( 10.9 to 15.1) 2. Over the past 4 weeks, how often have you urinated 1.1  5.2 0.317 6  13.5 0.059 0.124 4.9 ( 1.2 to 11) blood? 3. Over the past 4 weeks, how often have you had pain or 1.1  9.2 0.564 7.1  26.4 0.230 0.144 8.2 ( 3.6 to 20) burning with urination? 4. Which of the following best describes your urinary control 1.4  15.7 0.655 9.5  23.9 0.150 0.107 8.1 ( 7.7 to 23.8) during the last 4 weeks? 5. How many pads or adult diapers per day did you usually 00 1 9.5  23.9 0.084 0.070 9.5 ( 0.5 to 19.6) use to control leakage during the last 4 weeks? Total for items 1–5 2.2  6.4 0.776 8.8  18.5 0.050 0.209 6.6 ( 1.7 to 14.8) 6. How big a problem, if any, has each of the following been 2.2  10.9 0.138 11.3  15.8 0.005 0.002 13.5 (3.3–22.9) for you during the last 4 weeks? 7. Overall, how big a problem has your urinary function been 0  13.1 1 13.1 18.7 0.009 0.016 13.1 (3.3–22.8) for you during the last 4 weeks? Total for items 6–7 1.9  10.5 0.819 11.6  15.5 0.003 0.003 13.5 (5.4–21.4)) Total for items 1–7 0.1 7.1 0.592 10.4  16 0.008 0.006 10.5 (3.2–18) BW = between groups; CI = confidence interval; MD = mean difference; WG = within-group. a Score results are presented as mean  standard deviation. 50 EUROPEAN UROLOGY OPEN SCIENCE 26 (2021) 45–54 Fig. 2 – Repeated-measures analysis of variance for the urinary domain of the Expanded Prostate Cancer Index Composite (EPIC). Data are presented as mean  standard deviation. Table 4 – Results for the International Consultation on Incontinence Questionnaire-Male Lower Urinary Tract Symptoms Group A WG p value Group B WG p value BG p value MD BG (95% CI) Visit 1 (baseline) Number of patients 25 21 Total score 15.6  5.7 15.1 7.6 0.921 Voiding symptoms score 5.9  4.3 6.6  4.3 0.542 Incontinence symptoms score 6.4  3.0 5.5  3.3 0.385 Bother score 16.6  13.9 16.1 16.4 0.635 Visit 5 Number of patients 24 21 Total score 17.9  6.5 20.4  8 0.202 Voiding symptoms score 7.6  4.7 7.4  4.3 0.982 Incontinence symptoms score 6.3  3.4 9.3  4.9 0.017 Bother score 13.5  9.5 27.4  24.6 0.099 Change from visit 1 to visit 5 Total score 2.3  3.8 0.019 5.2  7.9 0.008 0.391 2.9 ( 6.7 to 0.7) Voiding symptoms score 1.7  3.1 0.007 0.8  4.1 0.270 0.280 0.9 ( 1.3 to 3) Incontinence symptoms score 0.1  2.2 0.877 3.8  5.0 0.004 0.004 3.9 ( 6.1 to 1.6) Bother score 1.6  6.7 0.19 11.3  15.4 <0.0001 <0.0001 12.9 ( 19.9 to 5.9) BW = between groups; CI = confidence interval; MD = mean difference; WG = within-group. a Score results are presented as mean  standard deviation. symptoms score (p = 0.011) and bother score (p = 0.017), with three patients. There were no serious (grade 3–4) drug- higher scores in group B than in A (Fig. 3). related adverse events or treatment-related withdrawals. There were no significant differences between the groups in overall EQ-5D-5L scores at baseline. Group A 4. Discussion had a significantly higher score for the Health today item at 12 mo when compared to group B (p = 0.028). These data are To the best of our knowledge, MISTIC is the first unblinded summarised in Table 5. randomised controlled trial (active treatment vs no RM-ANOVA revealed a statistically significant within- treatment in addition to RT) on the prevention of subjects factor over time (p = 0.039) and a significant time  radiation-induced cystitis assessing a broad range of group interaction (p < 0.0001), with a higher score in group urinary symptoms and QoL using specific questionnaires. A than in B for the Health today domain only (Fig. 4). Although new precision medicine RT modalities aim to Intravesical treatment was very well tolerated, as personalise RT based on individual radiosensitivity, the substantiated by full compliance for all patients, who number of patients affected by acute and late radiation retained the intravesical solution in the bladder for at least cystitis is still relatively high and remains a challenge for 30 min without any distress. Overall, there were seven mild- health care systems [11]. Available options at present include to-moderate (grade 1–2) drug-related adverse events, different drugs for acute cystitis (anti-inflammatory, anti- including haematuria, nausea, and urticaria reported by biotics, analgesics, antimuscarinics), bladder irrigation (with E UROP E AN U RO LO GY OP E N SCI ENCE 2 6 (2 021 ) 45 –5 4 51 Fig. 3 – Repeated-measures analysis of variance for the International Consultation on Incontinence Questionnaire-(ICIQ) Male Lower Urinary Tract Symptoms. Data are presented as mean  standard deviation. saline or specific solutions such as alum, silver nitrate, oral treatment concurrently with RT initiation and contin- formalin, HA, and HA/CS), coagulation or selective embolisa- ued the oral treatment for 12 wk. The aim was to protect the tion of bleeding vessels, and hyperbaric oxygen therapy for patient from acute radiation-induced bladder injuries and chronic conditions [3,9]. These modalities are not always to prevent a negative outcome over time by consolidating successful, and radical cystectomy is the only remaining the protection of the urothelium. option for severe chronic intractable radiation cystitis. A limited number of single-centre, nonrandomised, and Only a few studies have tried to investigate a preventive underpowered studies assessed the use of intravesical HA/ strategy and timing of the intervention. Some have shown SC for the treatment of radiation-induced cystitis, although that a shorter time from RT to treatment may positively this treatment has been extensively investigated for improve patient outcomes, supporting the need for early recurrent urinary tract infection and LUTS [18,19]. In a treatment to alleviate or prevent urinary symptoms [17]. In study of 23 consecutive patients with symptomatic cystitis the current study, we started intravesical instillation and after external RT for prostate cancer, Gacci et al [20] 52 EUROPEAN UROLOGY OPEN SCIENCE 26 (2021) 45–54 Table 5 – Results for the EuroQol Group EQ-5D-5L questionnairea Group A WG p value Group B WG p value BG p value MD BG (95% CI) Visit 1 (baseline) Number of patients 25 21 Index score 0.858  0.09 0.843  0.15 0.578 Health today score 74  13.6 77.6  11 0.510 Visit 5 Number of patients 24 21 Index score 0.857  0.1 0.802  0.16 0.177 Health today score 79.8  9.8 70  15.9 0.028 Change from visit 1 to visit 5 Index score 0.001  0.04 0.972 0.041  0.15 0.266 0.190 0.04 ( 0.02 to 0.1) Health today score 4.8  8.1 0.05 7.6  13.1 0.021 0.002 12.4 (5.9–18.9) BW = between groups; CI = confidence interval; MD = mean difference; WG = within-group. a Score results are presented as mean  standard deviation. Fig. 4 – Repeated-measures analysis of variance for the EuroQol Group EQ-5D-5L questionnaire. Data are presented as mean  standard deviation. observed a significant impact on nocturnal voiding fre- literature for the use of dietary supplements to treat quency on logistic regression analysis (Interstitial Cystitis radiation-induced urinary symptoms, but it is limited to a Symptoms Index Q3: r = 0.293, p = 0.011 and r = 0.970, number of single-centre and underpowered studies. It is p < 0.001). In our series we considered urinary symptoms, thought that dietary supplements can have an impact not only nocturia, as well as QoL, using specific tools to on mild to moderately severe acute radiation-induced investigate changes from baseline to 12 mo. The results for cystitis. Products containing flavonoids, anthocyanins, and all questionnaires showed an improvement in QoL and proanthocyanidins with strong antioxidant and anti- symptoms in patients who received the active treatment inflammatory characteristics may protect the urothelium (group A). from free radical damage. Campbell et al [21] investigated In the current study we combined intravesical HA/CS, a the effects of cranberry juice, which contains flavonoids, well-documented treatment for LUTS, with a similar oral and other antioxidant and anti-inflammatory agents on preparation containing HA/CS and two dietary supple- acute radiation cystitis in patients with prostate cancer. ments. To the best of our knowledge, this is the first trial to Unfortunately, they did not find any statistically significant combine the two formulations. There is a rationale in the difference in cystitis severity between the group using E UROP E AN U RO LO GY OP E N SCI ENCE 2 6 (2 021 ) 45 –5 4 53 cranberry juice and the control juice group. On the contrary, accordance with previous experience with intravesical Bonetta et al [22] reported a significant decrease in cystitis HA/CS for the treatment of urinary tract infections or symptoms among 370 prostate cancer patients taking painful bladder syndrome, no evidence-based schedule standardised cranberry capsules during RT for prostate exists for the dietary supplement. No data are reported on carcinoma. However, the study was not randomised and the the use of medical treatment for LUTS (eg, anticholiner- study design appeared to be poor. Hamilton and co-workers gics, analgesics, hyperbaric oxygen) or the number of [23] carried out a double-blind placebo-controlled, under- readmissions for lower urinary tract complications (eg, powered pilot study in 41 prostate cancer patients who took haematuria). Furthermore, many patients who undergo cranberry capsules (containing 72 mg of proanthocyani- pelvic RT also have symptoms from adjacent organs, such dins) or placebo during RT treatment and for 2 wk after as the rectum and genitalia. We did not investigate these treatment completion. They observed a small but statisti- scenarios in our series and we recognise the need for cally significant decrease in the incidence of pain/burning future studies to address these important aspects. The and nocturia and an improvement in urinary flow strength non-negligible rate of patients presenting with pre- [23]. These results were not confirmed in a recent large existing LUTS related to benign prostate hyperplasia in multicentre, double-blind, randomised, placebo-controlled our series might represent a confounding bias. However, clinical trial in which patients were instructed to take two this potential bias is balanced by the randomisation. cranberry capsules every day during RT and for 2 wk after Finally, our observations stopped after 1 yr and we have no treatment [24]. The severity of acute radiation cystitis was long-term follow-up data. investigated using the modified Radiation Therapy Oncolo- gy Group grading system, the validated O’Leary Interstitial 5. Conclusions Cystitis Symptom and Problem Scale, and the novel Radiation-Induced Cystitis Assessment Scale. Contrary to In conclusion, our study shows a beneficial effect of expectations, the study failed to show that cranberry intravesical HA-SC plus the oral combination of curcumin, capsules were superior to placebo with respect to pain/ quercetin, HA, and CS for prevention of acute and radiation- burning, nocturia, and strength of urinary flow. induced cystitis. Although the improvement in symptoms Curcumin, the main natural polyphenol found in the was maintained after 1 yr, our findings do not allow any rhizome of Curcuma longa, has a benefit in inflammatory conclusions regarding the intermediate- and long-term conditions because of its antioxidant effects [25]. Combina- effects of oral and intravesical preparations on the risk of tion with quercetin, a flavonoid found in fruits and late radiation-induced cystitis. vegetables that has unique anti-inflammatory properties, improves the intestinal absorption and bioavailability of Author contributions: Massimo Lazzeri had full access to all the data in curcumin [26,27]. In addition, experimental evidence the study and takes responsibility for the integrity of the data and the suggests that the combination has a role as a potential accuracy of the data analysis. radioprotective factor [28]. Saadipoor et al [29] conducted a Study concept and design: Lazzeri. randomised, double-blind, placebo-controlled phase 2 trial Acquisition of data: Sanguedolce, Palou Redorta, Romancik, Lunik, Vittori, of nanocurcumin in prostate cancer patients undergoing RT. Di Maida, Colombo, Serretta, Çetinel. Sixty-four patients with prostate cancer were randomised Analysis and interpretation of data: Sanguedolce, Palou Redorta, Lazzeri. to receive oral nanocurcumin (120 mg/d) or placebo 3 d Drafting of the manuscript: Lazzeri, Corradengo. before and during the course of RT. No significant between- Critical revision of the manuscript for important intellectual content: Palou group difference in radiation-induced cystitis was observed. Redorta, Minervini. Fersino et al [30] performed a randomised controlled trial in Statistical analysis: Bini. 40 patients who were randomised (1:1) to receive RT alone Obtaining funding: None. or RT combined with iAluRil Soft Gels. The authors used the Administrative, technical, or material support: None. International Prostate Symptom Score (IPSS) questionnaire Supervision: Palou Redorta. Other: None. to investigate clinical outcomes. Although the IPSS is not designed to capture the specific study population, iAluRil Financial disclosures: Massimo Lazzeri certifies that all conflicts of Soft Gels appeared to have a beneficial role in reducing interest, including specific financial interests and relationships and genitourinary toxicity. In our study, we used a combination affiliations relevant to the subject matter or materials discussed in the of intravesical HA/CS and an oral preparation containing HA, manuscript (eg, employment/affiliation, grants or funding, consultan- CS, curcumin, and quercetin, and assessed outcomes using a cies, honoraria, stock ownership or options, expert testimony, royalties, specific questionnaire for the study cohort (ie, EPIC). The or patents filed, received, or pending), are the following: None. concordance between the three different questionnaires Funding/Support and role of the sponsor: This study was supported by and the randomised study design support a high level of the TETI Association. The sponsor played no direct role in the study. evidence from our findings. The study has some limitations. The lack of a placebo Acknowledgments: The authors thank Ray Hill, an independent medical writer, who provided technical and English language editing and journal and/or sham strategy group is the major drawback of styling support. the present RCT. Unfortunately, choice of the dose and duration for oral treatment was purely empirical. Data sharing statement: Data will be available through a specific Although the intravesical schedule was modulated in repository with publication. 54 EUROPEAN UROLOGY OPEN SCIENCE 26 (2021) 45–54 References [17] Oscarsson N, Muller B, Rosen A, et al. Radiation-induced cystitis treated with hyperbaric oxygen therapy (RICH-ART): a randomised, [1] Bennett MH, Feldmeier J, Hampson NB, et al. Hyperbaric oxygen controlled, phase 2–3 trial. Lancet Oncol 2019;20:1602–14. therapy for late radiation tissue injury. Cochrane Database Syst Rev [18] Ciani O, Arendsen E, Romancik M, et al. Intravesical administration of 2016;2016:CD005005. combined hyaluronic acid (HA) and chondroitin sulfate (CS) for the [2] Nordling J. Bladder pain syndrome/interstitial cystitis. Update in treatment of female recurrent urinary tract infections: a European Europe. Int J Urol 2014;21(Suppl 1):A1–11. multicentre nested case-control study. BMJ Open 2016;6:e009669. [3] Smit SG, Heyns CF. Management of radiation cystitis. Nat Rev Urol [19] Cervigni M, Sommariva M, Tenaglia R, et al. A randomized, open- 2010;7:206–14. label, multicenter study of the efficacy and safety of intravesical [4] Zwaans BM, Krueger S, Bartolone SN, et al. Modeling of hyaluronic acid and chondroitin sulfate versus dimethyl sulfoxide in chronic radiation-induced cystitis in mice. Adv Radiat Oncol women with bladder pain syndrome/interstitial cystitis. Neurourol 2016;1:333–43. Urodyn 2017;36:1178–86. [5] Buckley MS, Washington S, Laurent C, et al. Characterization and [20] Gacci M, Saleh O, Giannessi C, et al. Sodium hyaluronate and immunohistochemical localization of the glycoconjugates of the chondroitin sulfate replenishment therapy can improve nocturia rabbit bladder mucosa. Arch Biochem Biophys 1996;330:163–73. in men with post-radiation cystitis: results of a prospective pilot [6] Giglio D, Podmolikova L, Tobin G. Changes in the neuronal control of study. BMC Urol 2015;15:65. the urinary bladder in a model of radiation cystitis. J Pharmacol Exp [21] Campbell G, Pickles T, D’Yachkova Y. A randomised trial of cranberry Ther 2018;365:327–35. versus apple juice in the management of urinary symptoms during [7] McDonnell BM, Buchanan PJ, Prise KM, et al. Acute radiation external beam radiation therapy for prostate cancer. Clin Oncol impacts contractility of guinea-pig bladder strips affecting muco- 2003;15:322–8. sal-detrusor interactions. PLoS One 2018;13:e0193923. [22] Bonetta A, Di Pierro F. Enteric-coated, highly standardized cranberry [8] Denton AS, Clarke NW, Maher EJ. Non-surgical interventions for extract reduces risk of UTIs and urinary symptoms during radiother- late radiation cystitis in patients who have received radical radio- apy for prostate carcinoma. Cancer Manag Res 2012;4:281–6. therapy to the pelvis. Cochrane Database Syst Rev 2002;2002: [23] Hamilton K, Bennett NC, Purdie G, et al. Standardized cranberry CD001773. capsules for radiation cystitis in prostate cancer patients in New [9] Pascoe C, Duncan C, Lamb BW, et al. Current management of Zealand: a randomized double blinded, placebo controlled pilot radiation cystitis: a review and practical guide to clinical manage- study. Support Care Cancer 2015;23:95–102. ment. BJU Int 2019;123:585–94. [24] Herst PM, Aumata A, Sword V, et al. Cranberry capsules are not [10] Villeirs L, Tailly T, Ost P, et al. Hyperbaric oxygen therapy for superior to placebo capsules in managing acute non-haemorrhagic radiation cystitis after pelvic radiotherapy: systematic review of radiation cystitis in prostate cancer patients: a phase III double the recent literature. Int J Urol 2020;27:98–107. blinded randomised placebo controlled clinical trial. Radiother [11] Bosch R, McCloskey K, Bahl A, et al. Can radiation-induced lower Oncol 2020;149:117–23. urinary tract disease be ameliorated in patients treated for pelvic [25] Sahebkar A, Serban M-C, Ursoniu S, et al. Effect of curcuminoids on organ cancer: ICI-RS 2019? Neurourol Urodyn 2020;39(Suppl 3): oxidative stress: a systematic review and meta-analysis of random- S148–55. ized controlled trials. J Funct Foods 2015;18:898–909. [12] Damiano R, Quarto G, Bava I, et al. Prevention of recurrent urinary [26] Li Y, Yao J, Han C, et al. Quercetin, inflammation and immunity. tract infections by intravesical administration of hyaluronic acid Nutrients 2016;8:167. and chondroitin sulphate: a placebo-controlled randomised trial. [27] Grill AE, Koniar B, Panyam J. Co-delivery of natural metabolic Eur Urol 2011;59:645–51. inhibitors in a self-microemulsifying drug delivery system for [13] De Vita D, Giordano S. Effectiveness of intravesical hyaluronic acid/ improved oral bioavailability of curcumin. Drug Deliv Transl Res chondroitin sulfate in recurrent bacterial cystitis: a randomized 2014;4:344–52. study. Int Urogynecol J 2012;23:1707–13. [28] Liang PS, Haff RP, Ovchinnikova I, et al. Curcumin and quercetin as [14] Scarneciu I, Bungau S, Lupu AM, et al. Efficacy of instillation treatment potential radioprotectors and/or radiosensitizers for X-ray-based with hyaluronic acid in relieving symptoms in patients with BPS/IC sterilization of male navel orangeworm larvae. Sci Rep 2019;9:2016. and uncomplicated recurrent urinary tract infections – long-term [29] Saadipoor A, Razzaghdoust A, Simforoosh N, et al. Randomized, results of a multicenter study. Eur J Pharm Sci 2019;139:105067. double-blind, placebo-controlled phase II trial of nanocurcumin in [15] Stellavato A, Pirozzi AVA, Diana P, et al. Hyaluronic acid and chon- prostate cancer patients undergoing radiotherapy. Phytother Res droitin sulfate, alone or in combination, efficiently counteract in- 2019;33:370–8. duced bladder cell damage and inflammation. PLoS One 2019;14: [30] Fersino S, Fiorentino A, Giaj Levra N, et al. Impact of Ialuril Soft Gels e0218475. in reducing urinary toxicity during radical hypofractionated radio- [16] Boehmer D, Maingon P, Poortmans P, et al. Guidelines for primary therapy in prostate cancer: a preliminary experience. Minerva Urol radiotherapy of patients with prostate cancer. Radiother Oncol Nefrol 2016;68:9–13. 2006;79:259–69.