OPINION article
Front. Surg.
Sec. Genitourinary Surgery and Interventions
This article is part of the Research TopicPerspectives in the Use of Hyaluronic Acid in Genitourinary DiseasesView all 4 articles
Hyaluronic Acid and Chondroitin Sulfate in the management of Bacillus Calmette-Guérin (BCG)- induced cystitis: What we have learned and what is still missing.
Provisionally accepted
- 1Ospedale Santa Maria alla Gruccia, Montevarchi, Italy
- 2Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
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Intravesical Bacillus Calme6e-Guérin (BCG) administra=on represents a standardized and widely accepted treatment for pa=ents with high-risk non-muscle-invasive bladder cancer (NMIBC; 1). Despite its well-established oncological efficacy, BCG ins=lla=ons may induce relevant local toxicity, mainly due to damage to the glycosaminoglycan (GAG) layer, which plays a crucial role in preserving urothelial impermeability against urinary irritants (2). Disrup=on of this protec=ve barrier, primarily composed of hyaluronic acid (HA), chondroi=n sulfate (CS), heparan sulfate, and keratan sulfate, facilitates the penetra=on of urine cons=tuents, bacteria, ions and pro-inflammatory mediators into the bladder wall, ul=mately triggering a sustained inflammatory response (3). Clinically, this results in a spectrum of adverse events ranging from mild irrita=ve symptoms to severe chemical cys==s, typically characterized by storage lower urinary symptoms (LUTS), bladder pain, burning and hematuria (4). This Opinion Ar=cle aims to provide an expert perspec=ve on the pathophysiological ra=onale and the emerging clinical evidence suppor=ng intravesical hyaluronic acid and chondroi=n sulfate for the management of BCG-induced chemical cys==s, while highligh=ng current limita=ons and unmet needs.Persistent bladder inflamma=on may lead to BCG dose reduc=on, treatment delays, or premature discon=nua=on, with a poten=al nega=ve impact on oncological outcomes (5). Consequently, preven=on and effec=ve management of BCG-related urinary toxicity should not be regarded merely as a func=onal objec=ve, but rather as an oncological priority.Preserving treatment adherence is essen=al not only to maintain pa=ents' quality of life (QoL), but also to maximize disease control and survival. Increasing awareness of this issue among clinicians represents a fundamental step toward improving daily clinical prac=ce and op=mizing BCG delivery.From this perspec=ve, proac=ve management of BCG-related urinary toxicity should be considered an integral part of the therapeu=c pathway rather than a secondary suppor=ve measure. Early interven=ons aimed at preserving urothelial integrity may contribute not only to improved symptom control, but also to sustained treatment con=nuity, thereby suppor=ng the overall effec=veness of 31 BCG immunotherapy. 32 review of the available shows that several strategies have been for the 33 management of BCG-related urinary complica=ons. However, similarly to radia=on-induced 34 chemical cys==s, no op=mal or therapeu=c has yet been clearly established. 35 Intravesical ins=lla=on of HA and CS has been proposed for more than a decade as a poten=al 36 strategy to prevent or mi=gate BCG-induced bladder toxicity, and several studies have explored this 37 approach (6). Although available evidence generally suggests a beneficial effect of HA and CS in 38 reducing urinary symptoms and improving treatment tolerability, the overall impact of these studies 39 has been limited by important methodological weaknesses, including small sample sizes, short 40 follow-up periods (ofen not exceeding one year), retrospec=ve or non-randomized design, and 41 heterogeneous treatment protocols (7). 42 Notably, despite these limita=ons, a consistent finding across published studies has been a 43 significant reduc=on in BCG-related side effects and a lower rate of treatment discon=nua=on, 44 without clinically relevant complica=ons associated with HA and CS ins=lla=on (6). However, long-45 term oncological outcomes have rarely been assessed, and robust data suppor=ng an indirect 46 benefit on cancer control through improved treatment adherence have been lacking. 47Recently, a prospec=ve randomized study including more than 100 pa=ents provided stronger 48 evidence suppor=ng the use of highly concentrated HA and CS as add-on therapy during BCG 49 immunotherapy for the management of BCG-induced chemical cys==s (8). In this study, HA and CS 50 were administered afer each BCG intravesical ins=lla=on, following a simple and reproducible 51 protocol. This approach proved to be effec=ve, safe, and well tolerated, while remaining minimally 52 =me-consuming, thus represen=ng a poten=al founda=on for the development of a standardized 53 management strategy. The significant improvement in urinary symptoms and overall treatment 54 tolerability observed in this trial supports the concept that urothelial replenishment therapy may 55 play a pragma=c role in suppor=ng pa=ents undergoing BCG immunotherapy, ul=mately enhancing 56 treatment compliance. 57These findings have been further reinforced by a recent independent commentary, which 58 underscored the poten=al clinical value of urothelial replenishment strategies to support BCG 59 tolerability and adherence (9). Importantly, intravesical GAG therapy demonstrated a favorable 60 safety profile, with no evidence of systemic adverse effects or impairment of BCG efficacy, although 61 further long-term data are s=ll warranted. In conclusion, evidence accumulated over the last decade suggests that failure to prevent or 63 adequately manage BCG-related urinary toxicity represents both a func=onal and oncological risk 64 that remains underes=mated in everyday clinical prac=ce. Effec=ve strategies to reduce BCG-65 associated complica=ons do exist, and an ini=al standardized protocol supported by prospec=ve 66 randomized data has now been proposed. The next crucial step will be the valida=on of these 67 findings through larger, mul=center studies with extended oncological follow-up, which may 68 ul=mately lead to a paradigm shif in the suppor=ve management of pa=ents receiving intravesical 69 BCG therapy. In this context, a more proac=ve and structured approach to the preven=on of BCG-70 related bladder toxicity appears increasingly jus=fied. Early iden=fica=on of pa=ents at higher risk 71 of intolerance, together with the =mely adop=on of urothelial protec=ve strategies, may represent 72 a key step toward individualized suppor=ve care during BCG immunotherapy. From a broader 73 perspec=ve, integra=ng symptom control into oncological treatment pathways may help bridge the 74 tradi=onal gap between efficacy and tolerability, ul=mately aligning func=onal preserva=on with 75 long-term cancer outcomes. This evolving body of evidence supports the concept that op=mizing 76 bladder tolerability during BCG therapy should be regarded as an integral component of high-quality 77 oncological care, rather than a purely suppor=ve interven=on. 78 Further valida=on through large, mul=center studies with standardized protocols and long-term 79 oncological follow-up is warranted to confirm the clinical and oncological impact of urothelial 80 replenishment strategies during BCG immunotherapy. 81 82 83
Keywords: BCG-induced cystitis, chondroitin sulfate, Hyaluronic Acid, Non-muscle-invasive bladder cancer, Urothelial protection
Received: 07 Jan 2026; Accepted: 06 Feb 2026.
Copyright: © 2026 Gubbiotti, Rosadi, Giommoni, Bigazzi and Rubilotta. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Marilena Gubbiotti
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