Intravesical instillation with mitomycin C and bacillus Calmette-Guérin in non-muscle-invasive bladder cancer (2026)

11. Complications and side effects

11.1 Catheter associated bacteriuria

Insertion of a catheter outside an operating theatre is a risk factor for developing bacteriuria [19]. Aseptic technique must be used when inserting the catheter before instillation. To minimise the risk of cross-infection, healthcare professionals must be constantly aware of their hand hygiene [50].

11.2 Side effects of MMC

The high molecular weight of MMC results in low absorption, therefore, it does not usually cause systemic toxicity. Local toxicity, however, is more common, resulting in chemical cystitis, allergic rash and palmar or genital desquamation from contact dermatitis [62].

11.2.1 Local side effects: chemical cystitis

Administration of cytotoxic chemotherapy into the bladder can induce an array of irritative voiding symptoms. Most of the adverse effects occur during the first six months of therapy [81]. These side effects can be treated symptomatically:

• dysuria
• frequency
• urgency
• suprapubic discomfort
• gross haematuria
• pelvic pain

These symptoms are referred to collectively as ‘chemical cystitis’ [79, 82-87]. The incidence of chemical cystitis is ~10%, and the prevalence of symptoms is 1-25% [79].

Other severe local side effects of intravesical chemotherapy [79, 83, 84, 88, 89] include transmural and extravesical fat necrosis and bladder wall ulceration and calcification.

11.2.2 Systemic side effects

Intravesical chemotherapy can cause skin toxicity, both through direct contact and systemic exposure following absorption through the bladder epithelium. An estimated 9% of patients develop some type of cutaneous side effect. Common manifestations of skin reactions include a generalised rash, along with dermatitis of the hands and feet or genitalia. Other reported symptoms include eruptions of the face, trunk or chest; vulvar dermatitis; and palpable purpura of the lower extremities [79, 83, 85, 90, 91].

11.2.3 Long-term complications

Benign chronic ulcers at the resection site have been described and are attributed to the effect of impaired healing from chemotherapy. Calcification, fibrosis, reduced bladder volume and reduced bladder compliance are less common [79, 83, 86, 87, 92, 93].

11.2.4 How to reduce the risk of side effects of MMC

Minimise systemic absorption: one of the first factors to be considered is the risk of drug absorption, which may result in systemic toxicity. Although some factors that affect drug absorption may be under the control of the operating surgeon (such as surgical technique and depth of resection), others are strictly related to the physical properties of the drug. Such properties include molecular weight, concentration and liphophilicity. Other factors that may increase absorption include drug dwell time and bladder wall integrity [79].

Reduce discomfort during instillation: other strategies to help reduce discomfort during treatment include ensuring that the bladder is empty before drug instillation and ensuring meticulous haemostasis at the end of resection to prevent accumulation of blood clots that may occlude the catheter and exacerbate the symptoms [79]. A novel technique has been proposed to improve patient comfort during intravesical instillation of MMC. Some of the pain associated with perioperative instillation results from the rigid resistance of a clamped catheter, and it is proposed to maintain the chemotherapeutic agent in the bladder without clamping. By elevating the urine bag 1m above the supine patient, MMC can be retained in the bladder by hydrostatic pressure [79, 94].

Prevent necrosis and ulceration: the most important method to reduce the incidence of necrosis and ulceration is to establish haemostasis after tumour resection and perform intraoperative cystography if there is any suspicion of bladder injury [79].

11.2.5 How to manage side effects of MMC

Intraperitoneal extravasation: initial management comprises immediate evacuation of the drug, followed by confirmation by cystography. Exploratory laparotomy is required to confirm evacuation of the drug and repair of the defect [79, 95].

Extraperitoneal extravasation: management involves catheter drainage, but it is also essential to carry out imaging to evaluate fluid collection, abscess formation, fistula formation or bowel obstruction. Fluid collections should be drained, and culture-directed antibiotics should be initiated [79, 95].

Chemical cystitis: symptoms are usually self-limiting and require no further treatment in the perioperative setting. Agents such as phenazopyridine and anticholinergics can be used in difficult cases. Powdered opium and belladonna alkaloid suppositories can also be used during instillation to provide relief of bladder spams and discomfort, and to help with retention of the intravesical agent [79].

Skin toxicity: It is important to differentiate between local skin toxicity and systemic allergic or hypersensitivity reactions, as management and the need for medical review may differ. In most cases, cutaneous side effects resolve after removal of the causative agent. Antihistamines and corticosteroids are useful for those who develop generalised urticaria [79, 90].

Myelosuppression: management is usually supportive. Blood products can be given in severe cases of myelosuppression, but the incidence of severe myelosuppression is low [79].

Table 7. Side effects of MCC and their recommended nursing interventions [79, 90, 95]

11.3 Common side effects of BCG

Intravesical BCG is associated with more side effects compared to intravesical chemotherapy [14]. The most common side effects of BCG treatment are increased urinary frequency, dysuria, urgency and flu-like symptoms. These effects are reported in > 90% of patients receiving therapy [96]. In four of five studies with toxicity data, BCG-associated cystitis was significantly more frequent than MMC-associated cystitis (53.8% versus 39.2%) [97]. In a study by EORTC, 20% of patients treated for three years with BCG stopped treatment due to local or systemic side effects [98]. However, serious side effects are encountered in < 5% of patients and can be treated effectively in almost all cases [14]. Maintenance therapy is not associated with an increased risk of side effects compared with induction [14]. Major complications can appear after systemic absorption of BCG. Contraindications to intravesical instillation of BCG should therefore be respected [14]. The most common side effects of BCG and their management strategies are presented in Table 8, which is reproduced with permission from the EAU Guidelines on Non-Muscle-Invasive Bladder Cancer [14]. Table 9 presents rare local and systemic side effects.

Table 8. Management options for side effects associated with intravesical BCG [99-102]

* Persistent severe cystitis symptoms associated with BCG use have a high risk of underlying a complicated UTI (even in the absence of a positive culture) and thus no restriction applies to the empirical use of quinolones by the EMA’s Pharmacovigilance Risk Assessment Committee (see also Section 3.7 Complicated UTI and Section

3.7.4.1 Choice of antimicrobials of the EAU Guidelines on Urological Infections 2025 [19, 103].

Table 9. Rare local and systemic side effects

11.4 How to reduce the risk of side effects of BCG

In two studies, a sequential administration of 40mg of hyaluronic acid reduced local side effects of BCG [140]. Another study suggested the use of Adelmidrol in combination with hyaluronic acid (intravesical instillations with a medical device combining Adelmidrol 2% + hyaluronic acid 0.1%) [141]. Further studies are needed.

The use of intravesical instillations of hyaluronic acid (HA 1.6%) and chondroitin sulfate (CS 2%) may be considered in patients with symptoms of BCG-induced chemical cystitis or at risk of developing it, in order to reduce bladder-related symptoms (e.g., frequency, urgency, pelvic pain) and to improve adherence to BCG therapy. Two clinical studies support this approach: A retrospective observational study [142] showed a sustained improvement in urinary symptoms in patients with BCG-induced chemical cystitis refractory to first-line treatments, after eight weekly instillations of HA + CS, with no adverse events reported. A prospective, multicenter, non-randomised controlled study [143] demonstrated that sequential administration of HA + CS after each BCG instillation during the maintenance phase significantly reduced bladder pain, lower urinary tract symptoms (LUTS), and therapy dropout rates compared to a control group receiving BCG alone. Further randomised controlled trials are warranted to define standardised treatment protocols and assess long-term efficacy and safety.

Three RCTs showed reduced side effects by administering different quinolones in conjunction with the BCG instillations [144-146]. The latter, involving the use of two doses of levofloxacin (at 6 and 12 hours after first voiding) in conjunction with each BCG instillation, reduced the proportion of patients with high-grade side effects, both local (pollakiuria) and systemic (fever), without improving the completion rate of the maintenance regimen or the risk of severe BCG-related adverse events [144].

11.5 How to manage side effects of BCG

Patients should be informed about potential side effects and involved in discussions about symptom management, treatment continuation, and any necessary adjustments to their regimen.

Management of side effects after BCG should reflect their type and grade (Table 8) [110].

No significant differences in toxicity are detected according to dose (one-third dose versus full dose) or duration (1 year versus 3 years) of BCG treatment. Neither reducing the dose nor shortening the duration of maintenance decreased the percentage of patients who stopped treatment because of side effects [147, 148]. One study reported less toxicity in patients who were treated with one-third dose of BCG for three consecutive weeks every six months [148]. The EORTC did not find any difference in toxicity between one-third and full-dose BCG, but one-third dose BCG was associated with a higher recurrence rate, especially when it was given only for one year [98]. To manage and monitor all side-effects, nurses can use the validated questionnaire “Bladder Instillation Therapy Form (BITF)” [149]. See Appendix 3.