Optimizing pharmacokinetics of intravesical chemotherapy for bladder cancer

Abstract

Non-muscle-invasive bladder cancer (NMIBC) remains one of the most common malignancies and is associated with considerable treatment costs. Patients with intermediate-risk or high-risk disease can be treated with intravesical BCG, but many of these patients will experience tumour recurrence, despite adequate treatment. Standard of care in these patients is radical cystectomy with urinary diversion, but this approach is associated with considerable morbidity and lifestyle modification. As an alternative, perioperative intravesical chemotherapy is recommended for low-risk papillary NMIBC, and induction intravesical chemotherapy is an option for patients with intermediate-risk NMIBC and BCG-unresponsive NMIBC. However, poor pharmaceutical absorption and drug washout during normal voiding can limit sustained drug concentrations in the urothelium, which reduces efficacy, and small-molecule chemotherapeutic agents can be absorbed through the urothelium into the bloodstream, leading to systemic adverse effects. Several novel drug delivery methods — including hyperthermia, mechanical sustained released devices and nanoparticle drug conjugation — have been developed to overcome these limitations. These novel methods have the potential to be combined with established chemotherapeutic agents to change the paradigm of NMIBC treatment.Intravesical chemotherapy is a mainstay of treatment for non-muscle-invasive bladder cancer; however, the biology of the bladder means that intravesical therapy is limited by washout of the agent during voiding and systemic effects caused by absorption through the bladder wall. In this Review, the authors consider novel approaches to improving the pharmacokinetics of intravesical chemotherapy, such as chemohyperthermia, sustained release devices, and nanoparticle conjugation.Key pointsIntravesical chemotherapy has historically been used as a single-dose treatment after transurethral resection of the bladder tumour to prevent recurrence and in clinical trials for patients with bacillus Calmette–Guérin (BCG) failure.The clinical effect of intravesical chemotherapy is limited by rapid clearance of agents during voiding and by physiological drug uptake into the bladder wall.Novel mechanical and chemical drug delivery methods have been developed to overcome these physiological limitations.Nanoparticle-based intravesical drug delivery has shown promising results in increasing penetration, bladder wall retention and the clinical response to chemotherapeutic agents in murine models.DNA damage response gene mutations in resected tumours are a potential biomarker to select those patients who would most benefit from novel drug delivery methods.