Early Case Series Studies and Clinical Trials With Ascorbate Only
In the early 1970s, a consecutive case series was conducted in which 50 advanced-cancer patients were treated with large doses of ascorbic acid. These patients began ascorbic acid treatment after conventional therapies were deemed unlikely to be effective. Patients received intravenous (IV) ascorbic acid (10 g/day for 10 consecutive days; some patients received higher doses), oral ascorbic acid (10 g/day), or both. The subjects exhibited a wide variety of responses to treatment, including no or minimal response, tumor regression, and tumor hemorrhage. However, the authors noted that lack of controls prevented definitive assignment of any beneficial responses to the ascorbic acid treatment. A case report published in 1975 detailed one of the patients who had experienced tumor regression. Diagnosed with reticulum cell sarcoma, the patient exhibited improvement in well-being and resolution of lung masses after being treated with ascorbic acid. When the patient's daily dose of ascorbic acid was reduced, some of signs of the disease returned; however, remission was achieved again after the patient reverted to the higher initial dose.
A larger case series of terminal cancer patients treated with ascorbate was reported in 1976. In this study, 100 terminal cancer patients (50 of whom were reported on previously) were treated with ascorbate (10 g/day for 10 days IV, then orally) and compared with 1,000 matched controls from the same hospital. The mean survival time for ascorbate-treated patients was 300 days longer than that of the matched controls.
Two studies tried to reproduce earlier results. These studies were randomized, placebo-controlled trials in which cancer patients received either 10 g oral vitamin C or placebo daily until signs of cancer progression. At the end of each study, no significant differences were noted between the two ascorbate-treated and placebo-treated groups for symptoms, performance status, or survival.
Recent Case Series Studies and Clinical Trials With Ascorbate Only
One study reported three case reports of cancer patients who received IV vitamin C as their main therapy. During vitamin C therapy, the patients used additional treatments, including vitamins, minerals, and botanicals. According to the authors, the cases were reviewed in accordance with the NCI Best Case Series guidelines. Histopathologic examination suggested poor prognoses for these patients, but they had long survival times after being treated with IV vitamin C. Vitamin C was given at doses ranging from 15 g to 65 g, initially once or twice a week for several months; two patients then received it less frequently for 1 to 4 years.
Two studies demonstrated that IV vitamin C treatment resulted in improved quality of life and decreases in cancer-related side effects in cancer patients.
Studies have shown that vitamin C can be safely administered to healthy volunteers or cancer patients at doses up to 1.5 g/kg and with screening to eliminate treating individuals with risk factors for toxicity (e.g., glucose-6-phosphate dehydrogenase deficiency, renal diseases, or urolithiasis). These studies have also found that plasma concentrations of vitamin C are higher with IV administration than with oral administration and are maintained for more than 4 hours.
Early Phase Ascorbate Trials Combined With Standard Cancer Therapies
A phase I study published in 2012 examined the safety and efficacy of combining IV ascorbate with gemcitabine and erlotinib in stage IV pancreatic cancer patients. Fourteen subjects entered the study and planned to receive IV gemcitabine (1,000 mg/m over 30 minutes, once a week for 7 weeks), oral erlotinib (100 mg daily for 8 weeks), and IV ascorbate (50 g/infusion, 75 g/infusion, or 100 g/infusion 3 times per week for 8 weeks). Minimal adverse effects were reported for ascorbic acid treatment. Five subjects received fewer than 18 of the planned 24 ascorbate infusions and thus did not have follow-up imaging to assess response. Three of those patients had clinically determined progressive disease. All of the other nine patients had repeat imaging to assess tumor size, and each met the criteria for having stable disease.
A 2013 phase I clinical study (NCT01049880) evaluated the safety of combining pharmacological ascorbate with gemcitabine in treating stage IV pancreatic cancer patients. During each 4-week cycle, patients received gemcitabine weekly for 3 weeks (1,000 mg/m over 30 minutes) and twice weekly ascorbate infusions for 4 weeks (15 g over 30 minutes during the first week, followed by weekly escalations in dose until plasma levels reached at least 350 mg/dL [20 mM]). Among nine patients, mean progression-free survival was 26 weeks and overall survival was 12 months. The combination treatment was well tolerated, and no significant adverse events were reported.
In 2014, a phase I/IIA clinical trial evaluated the toxicities of combining IV ascorbate with carboplatin and paclitaxel in stage III/IV ovarian cancer. Twenty-seven patients were randomly assigned to receive either chemotherapy alone or chemotherapy and IV vitamin C concurrently. Chemotherapy was given for 6 months, and IV vitamin C was given for 12 months. The addition of IV vitamin C was associated with reduced chemotherapy-related toxicities.
A 2015 phase I/II clinical trial of high-dose IV vitamin C (approximately 1.5 g/kg body weight) combined with various chemotherapies, depending on the specific cancer diagnosis, was conducted to do the following:
- Observe the associated adverse events.
- Assess the pharmacokinetic profiles of vitamin C and oxalic acid levels prechemotherapy- and postchemotherapy.
- Assess clinical responses.
- Assess changes in mood.
- Assess changes in quality of life.
High-dose IV vitamin C was analyzed in 14 patients and was generally well tolerated and safe, only causing minor temporary adverse effects such as increased urinary flow, thirst, nausea, vomiting and chills; some of which could be prevented. Chemotherapy administration did not affect the plasma concentration of vitamin C. Although a few patients experienced temporary stable disease, functional improvement, and increased energy, the sample size is so small that the generalizability of these results is uncertain.
In May 2019, a phase I study was published that examined the safety, pharmacokinetics, and efficacy of high-dose IV vitamin C combined with the combination chemotherapy regimens mFOLFOX6 (oxaliplatin + leucovorin + 5-fluorouracil) or FOLFIRI (leucovorin + 5-fluorouracil + irinotecan hydrochloride). This study consisted of 36 patients with metastatic colorectal cancer or gastric cancer. The main goal was to determine the maximum-tolerated dose and the recommended phase II dose of ascorbic acid with coadministration of either mFOLFOX6 or FOLFIRI. Patients received chemotherapy treatment on a 14-day cycle with vitamin C infusions occurring for 3 consecutive days for 3 hours at a time. For the dose-escalation portion of the study, ascorbic acid doses ranged from 0.2 g/kg to 1.5 g/kg. To determine the optimal administration rate of ascorbic acid, patient cohorts received infusion rates set at 0.6 g/min, 0.8 g/min, or 1 g/min. The study showed no dose-limiting toxicity for all doses and dosing rates; thus a maximum-tolerated dose was not reached, leading to a recommended phase II dose of 1.5 g/kg for ascorbic acid. Overall, no severe adverse reactions occurred, and the treatments were deemed safe and tolerable. A randomized phase III trial (NCT02969681) is being conducted to determine the clinical efficacy of ascorbic acid with mFOLFOX6 with or without bevacizumab in patients with metastatic colorectal cancer.
Trials of high-dose IV vitamin C with other drugs are ongoing. A number of studies have included small doses of IV ascorbic acid treatment (1,000 mg) with arsenic trioxide regimens, with mixed results. Refer to Table 2 for study results.
Informed by their preclinical data, researchers at the University of Iowa treated patients with non-small cell lung carcinoma (NSCLC) and glioblastoma multiforme (GBM) in two pilot clinical trials (NCT02420314 and NCT01752491). Participants in both trials were given conventional therapy plus IV vitamin C, with dosing individualized to achieve a 20 mM peak plasma concentration of ascorbate in each patient. The GBM study was a phase I design with 13 total patients. IV vitamin C was given with both radiation therapy and temozolomide and toxicity, progression-free survival, and overall survival all compared favorably to the outcomes of historical controls. The NSCLC trial was a phase II design of 14 patients with advanced cancer who received both chemotherapy and IV vitamin C (median maximum plasma concentration, 16.4 mM). The disease control and confirmed objective response rates of the study group again compared favorably with those of historical controls. Limitations of these studies included the use of historical controls and small numbers of enrolled participants.
Various trials of high-dose IV vitamin C with other drugs are ongoing. There are currently five trials being conducted by researchers at the University of Iowa; four phase II studies and one phase IB/II study. The four phase II clinical trials are investigating the efficacy of high-dose ascorbate combined with standard anticancer regimens. The studies are exploring the combination of high-dose ascorbate with standard non-small cell lung cancer therapy, including radiation therapy, carboplatin, and paclitaxel (NCT02905591); standard therapy for metastatic pancreatic adenocarcinoma, including gemcitabine and nab-paclitaxel (NCT02905578); standard therapy for localized pancreatic adenocarcinoma with gemcitabine and radiation therapy (NCT03541486); and standard therapy for glioblastoma multiforme, including temozolomide and radiation therapy (NCT02344355). Another phase IB/II trial (NCT03508726) is studying the safety and efficacy of high-dose ascorbate with preoperative radiation therapy in locally advanced soft tissue sarcoma patients.
A number of studies have included IV ascorbic acid treatment at a fixed dose of 1,000 mg with arsenic trioxide regimens, with mixed results. Researchers using this approach have suggested that the pro-oxidant properties of IV ascorbic acid may help to increase the effects of arsenic trioxide by sensitization of malignant cells to arsenic’s cytotoxic effects. The combination therapies were well tolerated and suggested beneficial effects in multiple myeloma patients, although the specific contribution of vitamin C could not be determined. However, similar combination regimens resulted in severe side effects, disease progression, and no anticancer effect in patients with refractory metastatic colorectal cancer and metastatic melanoma. Because these were not placebo-controlled trials, the extent that ascorbate contributed to the toxicity or efficacy demonstrated in these studies is unclear.