Clinical Practice Recommendations for the Prevention and Management of Intravesical Therapy–Associated Adverse Events

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Abstract

Context

Although intravesical therapy is an integral part of the management of non-muscle invasive bladder cancer (NMIBC), both intravesical chemotherapy and bacillus Calmette-Guérin (BCG) have potential side effects that may lead to treatment cessation and incomplete treatment courses.

Objective

To provide evidence-based strategies for the prevention and management of intravesical therapy–associated adverse events.

Evidence acquisition

A committee of international leaders in bladder cancer management, known as the International Bladder Cancer Group (IBCG), was convened in October 2006 to review current literature surrounding adverse events associated with intravesical therapy. Following the inaugural meeting in October 2006, the IBCG met on three subsequent occasions to exchange ideas and to develop practical recommendations for the prevention and management of these adverse events.

Evidence synthesis

The IBCG provided an overview of adverse events associated with BCG and intravesical chemotherapy as well as practical recommendations for the prevention and management of these side effects based on current evidence.

Conclusions

Cystitis and hematuria are side effects common to both chemotherapy and BCG. Other rare complications common to both intravesical therapies include contracted bladder and ureteral obstructions. BCG-specific adverse events include granulomatous prostatitis, epididymo-orchitis, systemic BCG reactions, and allergic reactions, while side effects specific to intravesical chemotherapy include contact dermatitis, bladder calcifications, and myelosuppression. The keys to management of these adverse events are education, prevention, and awareness. Preventive strategies include instructing health care professionals about proper catheterisation techniques and instilling BCG at least 2 wk following a TURBT; if catheterisation is traumatic or the patient has a urinary tract infection, BCG instillations should be deferred for 1 wk. Furthermore, the use of prophylactic ofloxacin 200 mg given twice after BCG instillations appears to be a simple and practical method of improving BCG tolerability while maintaining its efficacy. BCG dose reduction may also be a reasonable option, particularly for those patients known to be intolerant to standard-dose BCG.

Introduction

Intravesical therapy is an integral part of the management of non-muscle invasive bladder cancer (NMIBC). Both intravesical chemotherapy and bacillus Calmette-Guérin (BCG) have potential side effects which can be described as local or systemic. Local side effects are common for both therapies and can lead to treatment cessation and incomplete treatment, resulting in suboptimal outcomes. BCG-related adverse events can be treated successfully in most patients, even those patients with serious side effects [1]. The keys to management of these adverse events are education, prevention, and awareness. Furthermore, it should be noted that BCG-associated side effects are generally seen during induction and during the first 6 mo of maintenance BCG [1], [2]. During further maintenance, BCG-related adverse events do not significantly increase, and instillations are generally well tolerated [1].

This article summarizes the local and systemic side effects associated with intravesical therapy and presents the International Bladder Cancer Group's (IBCG) recommendations for the effective management of these adverse events based on currently available evidence. Strategies for the prevention of BCG-related adverse events, such as education, dose reductions, and the use of ofloxacin are also reviewed.

Section snippets

Local side effects common to both intravesical chemotherapy and bacillus Calmette-Guérin

Cystitis and hematuria are the most common local side effects of intravesical therapy, but they usually resolve 48 h after instillation. More severe, but less common, are local adverse events that include contracted bladder and ureteral obstruction.

Local side effects specifically associated with bacillus Calmette-Guérin

More severe local side effects associated with BCG therapy include granulomatous prostatitis and epididymo-orchitis.

Contact dermatitis

Contact dermatitis has been reported in up to 19% of patients treated with intravesical mitomycin C [4] and often leads to eczema-like desquamation of the skin on the palms, soles, perineum, chest, and face [17]. A case of penile gangrene resulting from contact dermatitis following intravesical administration of mitomycin C has recently been reported. The gangrene required penectomy 3 mo after the instillation [18].

Careful cleansing of the hands after drug-handling and cleansing of the genitals

Systemic side effects associated with bacillus Calmette-Guérin

Systemic side effects are less frequent than local side effects but are more likely to be severe. The most common systemic side effects associated with BCG therapy are general malaise, fever, myalgia, and nausea. Low-grade fever has been shown to develop in about 30.5% of BCG-treated patients, while fever greater than 39 °C has been reported in 5–20%. These side effects generally resolve within 48 h with or without the use of antipyretics as symptomatic treatment; however, persistent high-grade

Myelosuppression

Although rare, myelosuppression has been noted in patients treated with mitomycin C [22], [23] and may result from the use of high-concentration instillations into a bladder that has recently been traumatized [4].

The management of myelosuppression involves cessation of intravesical chemotherapy and monitoring of white blood cell (WBC) count.

The International Bladder Cancer Group's recommendations for the management of intravesical therapy–associated adverse events

The IBCG's recommendations for the management of intravesical therapy–associated adverse events are summarized in Table 1. This table also includes the following World Health Organization grading of toxic drug effects, which can be used as a guide for determining when intravesical therapy may be contraindicated [7]:

  • Grade 1: Moderate and <48 h (usually require no modification of intravesical therapy)

  • Grade 2: Severe and/or >48 h (usually require suspension of instillations until resolution of

Strategies for the prevention of bacillus Calmette-Guérin–associated adverse events

Strategies that may help prevent BCG-associated adverse events include education, dose reductions, and the use of ofloxacin. Other strategies that have been proposed but not reviewed in this section include concomitant use of isoniazid, decreasing the dwell time of BCG, and the addition of other immune-modulators.

The International Bladder Cancer Group's recommendations for the prevention of bacillus Calmette-Guérin–associated adverse events

Based on the review of potential strategies for the prevention of BCG-associated adverse events, the IBCG has proposed the following recommendations:

  • Instill BCG after a minimum of 2 wk following a TURBT.

  • Teach proper catheterisation techniques to administering health care professionals.

  • Defer BCG instillations for 1 wk if catheterisation is traumatic.

  • If gross hematuria is present, delay BCG until this has resolved.

  • If the patient has a UTI, then defer BCG for 1 wk until resolution of the UTI with

References (28)

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