Hyperthermic Intravesical Chemotherapy as a Bladder-Sparing Alternative to BCG in the Management of Non-Muscle-Invasive Bladder Cancer: A Systematic Review of Oncological Outcomes in the Era of BCG Shortage

Background/Objectives: The ongoing Bacillus Calmette–Guérin (BCG) shortage, treatment intolerance, and BCG-unresponsive disease necessitate bladder-sparing alternatives for non-muscle-invasive bladder cancer (NMIBC). We reviewed the clinical evidence for hyperthermic intravesical chemotherapy (HIVEC). Methods: PubMed and PubMed Central were searched from inception to 15 March 2026 (updated 10 July 2026) for primary studies of device-assisted HIVEC in NMIBC. Studies reporting recurrence-free survival (RFS), progression, response, or safety were eligible. Records were screened and data extracted independently in duplicate, and risk of bias was assessed with RoB 2 (randomised trials), ROBINS-I (non-randomised comparative studies), and the Newcastle–Ottawa Scale (single-arm and registry cohorts). Outcomes were synthesised narratively within pre-specified clinical strata, with carcinoma in situ (CIS) analysed separately from papillary-only disease. Results: Twenty-four studies (>3600 patients), including seven randomised trials and a large multinational registry, were included. In BCG-naive or mixed-risk populations, 12-month RFS generally ranged from 78% to 98% and 24-month RFS from 57% to 88%; progression was uncommon. In BCG-unresponsive or BCG-failure disease, 24-month RFS was typically 40–60%, with poorer control in carcinoma in situ. Comparative studies mostly reported no statistically significant difference in RFS or progression versus BCG, but these analyses were predominantly retrospective or underpowered, and the single randomised signal favouring HIVEC over BCG was confined to a per-protocol analysis. Two randomised trials against non-heated mitomycin C (HIVEC-1 and HIVEC-II) found no recurrence benefit from hyperthermia, whereas an earlier randomised trial of radiofrequency thermochemotherapy reported a large long-term advantage over mitomycin C alone. Severe adverse events were infrequent, including approximately 2% in the largest series. Conclusions: HIVEC appears to be a tolerable bladder-sparing option in selected intermediate- and high-risk NMIBC. The available evidence is compatible with, but does not establish, equivalence or non-inferiority to BCG, because most comparative data are non-randomised, underpowered, and at moderate-to-serious risk of bias. Disease control after BCG failure is clinically meaningful but less durable, particularly in CIS. Adequately powered randomised trials reporting intention-to-treat outcomes are needed.