Efficacy of early intravesical instillation of hyaluronic acid after transurethral resection of non-muscle-invasive bladder cancers: An open-label, prospective, single-center, randomized, controlled and parallel-group pilot study

Abstract

Background: Lower urinary tract symptoms (LUTS) and pain are clinically relevant problems after transurethral resection (TURBT) of nonmuscle-invasive bladder cancer. Although intravesical instillation of hyaluronic acid has already been proven to be a valid treatment for storage LUTS and pain in patients with inflammatory bladder syndrome, its efficacy in patients who undergo TURBT is unknown. This study aimed to present the results of a prospective, randomized, controlled, clinical pilot study on the safety and clinical performance of HydealCyst (Fidia Farmaceutici S.p.A., Italy), a device formulated to provide progressive, long-lasting intravesical release of hyaluronic acid.

Materials and methods: Adults diagnosed with nonmuscle-invasive bladder cancer and scheduled for TURBT were included and underwent 4 visits up to 25 days after TURBT. Of the 47 patients who completed the investigation, 25 participants received 2 postoperative intravesical instillations with HydealCyst. The efficacy of HydealCyst on storage LUTS, pain, urinary symptoms, and patients’ quality of life was evaluated using validated questionnaires.

Results: Although the overall LUTS were similar in the 2 experimental groups, lower micturition frequency and fewer daytime micturitions were observed in patients treated with HydealCyst. These patients also showed a significant reduction in pain (p = 0.03) 3 days after catheter removal and better quality of life at the end of the study. The device was well tolerated, with no treatment-emergent adverse events of severe intensity.

Conclusion: The results from this pilot study indicate a clinically meaningful improvement of symptoms after 2 instillations of HydealCyst, supporting this intervention as a potentially effective treatment for LUTS and pain after TURBT.

Keywords

Transurethral resection / Lower urinary tract symptoms / Nonmuscle invasive bladder cancer / Hyaluronic acid / Pain / Quality of life

Acknowledgments

The authors would like to thank Nadia Lo Iacono and Francesca Bernuzzi, who worked as study coordinators; Laura Monzani, the head nurse; and Maria Vittoria Fantacci, the case manager.

Statement of ethics

This study was approved by the Ethics Committee IRCCS Istituto Clinico Humanitas (authorization number 2559) and performed in accordance with the Declaration of Helsinki, ISO (EN) 14155, and ICH-Good Clinical Practice and Regulation (EU) 2017/745. All patients signed an informed consent form before participation. This study was also registered on ClinicalTrials.gov (ID: NCT06069453).

Conflicts of interest statement

The authors declare that they have no conflicts of interest.

Funding source

This study was funded by Fidia Farmaceutici S.p.A.

Author contributions

PC, RH, and ML: Concept and study design; PC, RH, NMB, GL, AS, VF, MP, AB, RP, LP, SZ, PA, AU, and ML: Methods and experimental work; PC and ML: Results analysis and conclusions, manuscript preparation.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

[1] McDonough RC 3rd, Ryan ST. Diagnosis and management of lower urinary tract dysfunction. Surg Clin North Am 2016; 96(3):441-452.

[2] Kamei J, Fujimura T. Urinary tract infection in patients with lower urinary tract dysfunction. J Infect Chemother 2023; 29(8):744-748.

[3] Abreu-Mendes P, Silva J, Cruz F. Pharmacology of the lower urinary tract: Update on LUTS treatment. Ther Adv Urol 2020;12:175628722092242.

[4] Di Bello F, Napolitano L, Abate M, et al. Nocturia and obstructive sleep apnea syndrome: A systematic review. Sleep Med Rev 2023;69:101787.

[5] Abrams P, Cardozo L, Fall M, et al. Standardisation Sub-committee of the International Continence Society. The standardisation of terminology of lower urinary tract function: Report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002; 21(2):167-178.

[6] Munno GM, La Verde M, Lettieri D, et al. Pelvic organ prolapse syndrome and lower urinary tract symptom update: What’s new? Healthcare (Basel) 2023; 11(10):1513.

[7] Digesu GA, Tailor V, Bhide AA, Khullar V. The role of bladder instillation in the treatment of bladder pain syndrome: Is intravesical treatment an effective option for patients with bladder pain as well as LUTS? Int Urogynecol J 2020; 31(7):1387-1392.

[8] Teoh JYC, Kamat AM, Black PC, Grivas P, Shariat SF, Babjuk M. Recurrence mechanisms of non-muscle-invasive bladder cancer—A clinical perspective. Nat Rev Urol 2022; 19(5):280-294.

[9] Babjuk M, Burger M, Capoun O, et al. European Association of Urology Guidelines on non-muscle-invasive bladder cancer (Ta, T1, and carcinoma in situ). Eur Urol 2022; 81(1):75-94.

[10] Martinez Rodriguez RH, Buisan Rueda O, Ibarz L. Bladder cancer: Present and future. Med Clin (Barc) 2017; 149(10):449-455.

[11] Horňák J, Brisuda A, Babjuk M. Transurethral resection of bladder cancer with or without fluorescence. Curr Opin Urol 2023; 33(2):152-156.

[12] Li M, Toniolo J, Nandurkar R, et al. Continuous bladder irrigation after transurethral resection of non‐muscle invasive bladder cancer for prevention of tumour recurrence: A systematic review. ANZ J Surg 2021; 91(12):2592-2598.

[13] Chou R, Selph S, Buckley DI, et al. Intravesical therapy for the treatment of nonmuscle invasive bladder cancer: A systematic review and meta-analysis. J Urol 2017; 197(5):1189-1199.

[14] Chuang YC, Weng SF, Hsu YW, Huang CLC, Wu MP. Increased risks of healthcare-seeking behaviors of anxiety, depression and insomnia among patients with bladder pain syndrome/interstitial cystitis: A nationwide population-based study. Int Urol Nephrol 2015; 47(2):275-281.

[15] Hung MJ, Tsai CP, Lin YH, Huang WC, Chen GD, Shen PS. Hyaluronic acid improves pain symptoms more than bladder storage symptoms in women with interstitial cystitis. Taiwan J Obstet Gynecol 2019; 58(3):417-422.

[16] Barry MJ, Fowler FJ Jr, O’Leary MP, et al. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 1992; 148(5):1549-57; discussion 1564.

[17] Donovan JL, Peters TJ, Abrams P, Brookes ST, de aa Rosette JJ, Schäfer W. Scoring the short form ICSmaleSF questionnaire. International Continence Society. J Urol 2000; 164(6):1948-1955.

[18] Brookes ST, Donovan JL, Wright M, Jackson S, Abrams P. A scored form of the Bristol Female Lower Urinary Tract Symptoms questionnaire: Data from a randomized controlled trial of surgery for women with stress incontinence. Am J Obstet Gynecol 2004; 191(1):73-82.

[19] Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011; 20(10):1727-1736.

[20] Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: A multi-country study. Qual Life Res 2013; 22(7):1717-1727.

[21] Gakis G, Efstathiou J, Lerner SP, et al. International Consultation on Urologic Disease-European Association of Urology Consultation on Bladder Cancer 2012. ICUD-EAU International Consultation on Bladder Cancer 2012: Radical cystectomy and bladder preservation for muscle-invasive urothelial carcinoma of the bladder. Eur Urol 2013; 63(1):45-57.

[22] Ruggeri M, Pavan M, Soato M, et al. Synergy of hydeal-D^® and hyaluronic acid for protecting and restoring urothelium: In vitro characterization. Pharmaceutics 2021; 13(9):1450.

[23] Porru D, Leva F, Parmigiani A, et al. Impact of intravesical hyaluronic acid and chondroitin sulfate on bladder pain syndrome/interstitial cystitis. Int Urogynecol J 2012; 23(9):1193-1199.

[24] Riedl CR, Engelhardt PF, Daha KL, Morakis N, Pflüger H. Hyaluronan treatment of interstitial cystitis/painful bladder syndrome. Int Urogynecol J Pelvic Floor Dysfunct 2008; 19(5):717-721.

[25] Sharma H. Statistical significance or clinical significance? A researcher’s dilemma for appropriate interpretation of research results. Saudi J Anaesth 2021; 15(4):431-434.

[26] Chamie K, Ballon-Landa E, Bassett JC, et al. Quality of diagnostic staging in patients with bladder cancer: A process-outcomes link. Cancer 2015; 121(3):379-385.

[27] Kim LHC, Patel MI. Transurethral resection of bladder tumour (TURBT). Transl Androl Urol 2020; 9(6):3056-3072.

[28] Han S, Dong K, Shen M, et al. Observation and mechanism study of bladder wound healing after transurethral holmium laser resection of bladder tumor. Lasers Med Sci 2019; 34(6):1217-1227.

[29] Yassin A, Alwani M, Al-Zoubi RM, et al. Voiding function improves under long-term testosterone treatment (TTh) in hypogonadal men, independent of prostate size. Int Urol Nephrol 2023; 55(7):1649-1658.

[30] Campoccia D, Doherty P, Radice M, Brun P, Abatangelo G, Williams DF. Semisynthetic resorbable materials from hyaluronan esterification. Biomaterials 1998; 19(23):2101-2127.