IV Vitamin C with Chemotherapy for Cisplatin-Ineligible Bladder Cancer Patients: A Forgotten Group

Purpose: Neoadjuvant cisplatin-based chemotherapy (NAC) is considered the standard of care (SOC) for patients with muscle-invasive bladder cancer (MIBC). However, approximately 50% of patients are cisplatin-ineligible (CI) and often proceed directly to surgery. We initiated a phase Ib/IIa trial to evaluate high-dose intravenous ascorbate (IVC) with gemcitabine/carboplatin (Gem/Carbo) as NAC for patients with CI-MIBC (NCT04046094). Patients and Methods: Patients with newly diagnosed CI-MIBC received a single cycle of Gem (1000 mg/m2 D1, 8)/Carbo (AUC 5 d 1) and IVC (25–125 g titrated to 350–400 mg/dL blood concentrations 2 × per week for 21 days) followed by definitive cystectomy. The primary outcome was pathological downstaging (<ypT2N0Mx) at cystectomy. Patient-reported quality of life (QOL) was assessed using the FACT-BI at enrollment, end of treatment, and 6 weeks after cystectomy. Results: Sixteen participants were enrolled, and 12 completed the protocol. The mean age was 76. Pathological downstaging was present in four patients (33%), with 3/4 patients having a pathologic complete response (pCR, ypT0N0Mx). The treatment was well tolerated. At a mean follow-up of 32.3 months (SD 18.9, range 6.6–63.8), four patients without response recurred and died of disease, and three with response had recurred, with one passing from disease. The QOL FACT-Bl did not change from baseline to the end of treatment to 6 weeks post-cystectomy. Conclusions: Neoadjuvant, single-cycle Gem/Carbo + IVC had significant activity in patients with CI-MIBC with a response rate (RR) comparable to historical outcomes of SOC therapy in this early-phase trial. Larger trials are warranted to confirm these findings and to identify biomarkers for response.