Pancreatic ductal adenocarcinoma (PDAC) is now the 3rd leading cause of cancer death in the US and extends at an increasing rate of 0.5% per year. A plethora of literature has shown that 80-85% of patients present with unresectable disease at diagnosis; of those who are resected, roughly 75% will develop metastatic disease. Overall survival (OS) rates currently reported for patients with five years of follow-up are only 12% in this disease stage, with an even more dismal figure, less than 3%, among patients found to have already disseminated disease at the time of diagnosis.
Research on the side effects of immunotherapy in advanced stages of other cancers appears to be very optimistic. However, immunotherapy works very poorly in the case of PDAC due to certain inherent features of the disease. Hence, there is a need to find alternative treatment modes and test them for their effectiveness.
Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have poor 5-year survival. Pharmacological ascorbate (P-AscH-, high dose, intravenous, vitamin C) has shown promise as an adjunct to chemotherapy. We hypothesized adding P-AscH- to gemcitabine and nab-paclitaxel would increase survival in patients with metastatic PDAC.
A recent study published in Redox Biology and researchers evaluated pharmacological ascorbate (P-AscH-, high dose, intravenous, vitamin C), gemcitabine, and nab-paclitaxel for metastatic pancreatic cancer.
Patients diagnosed with stage IV pancreatic cancer were randomized in a 1:1 ratio to either gemcitabine and nab-paclitaxel only (SOC, control) or SOC with the addition of intravenous P-AscH-, 75 g three times weekly (ASC, investigational). The primary outcome being measured was overall survival while secondary objectives included determining progression-free survival and incidence of adverse event occurrence. Exploratory measures included are health-related quality of life and patient-reported outcomes for common oncologic symptoms. The sample size included thirty-six participants, out of which 34 underwent the assigned study treatment. All analyses were based on data frozen on December 11, 2023.
The application of high doses of P-AscH- via intravenous administration altered the serum ascorbate levels from micromolar to millimolar concentration. The addition of P-AscH- to the regimen of gemcitabine + nab-paclitaxel (ASC) reached an overall survival of 16 months against 8.3 months with gemcitabine + nab-paclitaxel (SOC) (HR = 0.46; 90% CI 0.23, 0.92; p = 0.030). The median progression-free survival was 6.2 (ASC) versus 3.9 months (SOC) (HR = 0.43; 90% CI 0.20, 0.92; p = 0.029). The addition of P-AscH- did not negatively affect the quality of life nor did it raise the occurrence or intensity of the adverse effects. Adverse events were in keeping with those foreseen due to concurrent administration of gemcitabine and nab-paclitaxel therapy. The severe adverse event rates were lower in the ASC arm and the occurrences of grade 3 and 4 hematologic toxicity (anemia, neutropenia, thrombocytopenia, and leukopenia) were lesser in the ASC population over SOC (1.1 vs. 1.6).
This phase 2 study involving P-AscH- suggests both an improvement in OS and quality of life in patients with advanced pancreatic ductal adenocarcinoma (PDAC). Nevertheless, the advantages are mitigated by the amount of time that is required to treat these patients. Patients are treated with this regimen three times weekly with a 2-h infusion; this does not count the travel to the hospital or the waiting time in queue. Finally, this randomized study showed that the addition of P-AscH- to a regimen consisting of gemcitabine plus nabpaclitaxel improved the OS and PFS, without increased hematological toxicity.
The quality of life measured with the EORTC QLQ-C30 was similar in both treatment arms, with no evident treatment-associated deterioration. Such randomized, actively controlled trials, though hampered by small sample and lack of diversity, yield important data on effect size necessary for the planning of a phase 3 trial looking at the effectiveness of P-AscH in patients with metastatic pancreatic cancer, as well as its applicability to a broader patient population. It also helps in saying that P-AscH– helps enhance the tolerability of cytotoxic chemotherapy.
Reference: Bodeker KL, Smith BJ, Berg DJ, et al. A randomized trial of pharmacological ascorbate, gemcitabine, and nab-paclitaxel for metastatic pancreatic cancer. Redox Biol. 2024;77:103375. doi: 10.1016/j.redox.2024.103375
