Vitamin C Increases Chemotherapy Responses in Cisplatin-Ineligible Patients With Muscle-Invasive Bladder Cancer

John A. Taylor, III, MD, MS

Treatment with gemcitabine and carboplatin (GCa) may be more successful if it is co-administered with intravenous (IV) vitamin C for patients with locally advanced muscle invasive bladder cancer , according to findings presented at the 2022 American Urological Association Annual Meeting.

Overall, investigators observed a 30% rate of pathological downstaging (n = 4) among patients who underwent simultaneous treatment with GCa and IV vitamin C, which met the continuation criteria for a stage 2 study. Furthermore, among those who experienced a pathological response, 25% achieved a complete response. No treatment related adverse events were reported.

Of those 12 patients who underwent simultaneous treatment with gemcitabine and carboplatin plus IV vitamin C, 11 underwent cystectomy following treatment, and 1 patient is pending surgery.

The standard of care for patients with locally advanced disease is neoadjuvant cisplatin-based chemotherapy. However, this treatment strategy is not appropriate for all patients; an estimated 40% to 50% of patients have either renal insufficiency, hearing loss, or poor performance status and are therefore ineligible for cisplatin.

The GCa regimen has demonstrated limited success as an alternative treatment for these patients. However, many patients progress directly to cystectomy without realizing the potential survival effect associated with neoadjuvant chemotherapy.

In other models, the IV administration of vitamin C has been found to safely and feasibly enhance outcomes with chemotherapy. For example, a phase 1 trial (NCT00954525) which assessed vitamin C in conjunction with gemcitabine, or gemcitabine plus erlotinib (Tarceva), elicited unexpected stable disease and prolonged survival in patients with advanced pancreatic cancer.² The regimen was also reported to have good tolerability.

Similarly, a phase 1/2a trial (NCT00772798) not only reported that vitamin C substantially decreased grade 1/2 toxicities in patients with ovarian cancer who were receiving paclitaxel plus carboplatin, but also showed that the combination resulted in prolonged median progression-free survival (PFS). The difference in median PFS between those who did and did not receive IV vitamin C was 25.5 months vs 16.75 months, respectively.³

Treatment with gemcitabine and carboplatin (GCa) may be more successful if it is co-administered with intravenous (IV) vitamin C for patients with locally advanced muscle invasive bladder cancer , according to findings presented at the 2022 American Urological Association Annual Meeting.

This first-stage analysis (NCT04046094) enrolled 16 and ultimately treated 12 patients with muscle-invasive bladder cancer who were at least 18 years old.⁴ To be eligible, patients needed to have an ECOG performance status between 0 and 2, as well as adequate organ and marrow functions. Women of child-bearing potential and men whose partners had child-bearing potential needed to consent of prespecified forms of birth control.

Patients were ineligible for enrollment if they were enrolled in any other clinical trials, were currently or anticipating undergoing another investigational agent during the course of the study, diagnosed with any psychiatric or social illness which would inhibit their ability to comply with study requirements, pregnant or breast feeding, had a histology of pure adenocarcinoma, pure squamous cell carcinoma, or pure small cell carcinoma in a TURBT sample, had an uncontrolled or intercurrent illness, or had any prior systematic chemotherapy—not including prior intravesical therapy—or prior radiation to the urinary bladder.

In addition, current tobacco product consumption, as well as a history of glucose-6-phosphate dehydrogenase (G6PD) deficiency, were criteria for exclusion.

Treatment consisted of a single cycle of GCa and IV vitamin C titrated to peak plasms concentration of 350 to 400 mg/dL (~20 mM) for 21 days followed by cystectomy. Patients underwent cystectomy about 4 to 6 weeks following treatment initiation.

Following therapy, patients were followed in accordance with National Comprehensive Cancer Network guidelines. This consisted of standard-of-care bloodwork, physical exams, and imaging studies until either progression or death. Quality of life is being evaluated by Functional Assessment of Cancer Therapy-Bladder (FACT-Bl).

At a mean follow-up of 10.8 months, 3 patients had experienced a recurrence, and 2 patients had died. FACT-BI analysis and clinical follow-up is still ongoing and will be reported at study completion.

References

1. Taylor J, Parikh R, Chen Q, et al. Interim analysis NCT04046094: IV vitamin C with chemotherapy for cisplatin ineligible bladder cancer patients (CI-MIBC). Presented at: 2022 American Urological Association Annual Meeting; New Orleans, LA; May 13-16, 2022. Abstract LBA01-09. https://bit.ly/3FPQ99n
2. Monti DA, Mitchell E, Bazzan AJ, et al. Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. PLoS One. 2012;7(1):e29794. doi:10.1371/journal.pone.0029794
3. Ma Y, Chapman J, Levine M, Polireddy K, Drisko J, Chen Q. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci Transl Med. 2014;6(222):222ra18. doi:10.1126/scitranslmed.3007154
4. Intravenous (IV) vitamin C with chemotherapy for cisplatin ineligible bladder cancer patients. ClinicalTrials.gov. Updated May 4, 2021. Accessed May 15, 2022. https://clinicaltrials.gov/ct2/show/NCT0404609