High-dose Intravenous Vitamin C in Clinical Trials

High-dose Intravenous Vitamin C in Clinical Trials

High-dose Intravenous Vitamin C in Clinical Trials


Cancer and Ascorbic Acid

Millions of individuals are affected by cancer, one of the major causes of mortality in the globe. There are many drugs and treatments such as chemotherapy, and radiotherapy used for the treatment of cancer. Ascorbic acid (vitamin C) is a natural antioxidant which is present in citrus fruits. Vitamin C plays many vital functions in the human body. Here, we will explain the part of intravenous injected Vit C in the shrinkage of the tumor with a strictly regulated diet plan. The data presented here is collected from Clinicaltrials.gov and all completed studies with its outcome are included here.

Vitamin C

Humans require vitamin C as a micronutrient because they lack the enzyme needed to synthesise it. Although it is only one of many dietary antioxidants, ascorbic acid has high antioxidant potential. Vitamin C was once thought to be a cancer preventative in the 1950s, but in the 1970, Linus Pauling and Ewan Cameron claimed that it may potentially have a therapeutic impact by citing an improvement in survival rates for patients with cancer in advanced stages after receiving high-dose IV Vit C. However, several later randomized controlled studies (RCTs) using large doses of oral Vit C were unable to show a similar benefit, raising questions about the treatment efficacy

Intravenous Ascorbic Acid

More recent literature studies has revealed that oral Vit C treatment limits the rate of absorption from the stomach, making intravenous or intraperitoneal administration the only way to attain high plasma concentrations of vitamin C. Human plasma concentrations of high-dose IV Vit C are about 200 times greater than those attained with Vit C treatment orally. Therefore, high-dose Vit C treatments administered orally and intravenously must be viewed as separate therapeutic modalities.

Invitro and In vivo Studies

Vitamin C has demonstrated strong anticancerous effects in tissue culture experiments and animal models, including lethal effects in some cancer cell lines at uM to mM concentrations. Clinical investigations have demonstrated that IV and oral vitamin C doses may lessen symptoms and survival in cancer patients who are near the end of their lives. Recent placebo-controlled studies (double-blind) have demonstrated that giving patients with cancer vitamin C orally had no positive effects. On the other hand, IV Vit C delivery increases plasma concentrations to maximum 14 mM/L, and it has been discovered that values between 1 and 5 mM/L are specifically cytotoxic in invitro conditions to tumor cells.

Clinical Trials Data

In another phase 1 clinical trial, Stephenson et al. used IV Vit C as monotherapy for the patients with solid tumors that were showing resistance to conventional therapies and examined pharmacokinetics, tolerability, safety, and high dose of Vit C. After commencing at 30 grams per m2 in the first stage, ascorbic acid was infused intravenously (i.v.) in five cohorts of three patients for 4 weeks, 1 gram per minute, for 4 consecutive days each week. The dose was raised to 20 g/m2 for the optimization of maximum tolerated dose. According to this study’s findings, Vit C was well tolerated and produced up to 49 mM Vit C in the blood of the patient when supplied intravenously for 4 days in a row each week for 4 weeks. Future research should use a dosage of 70–80 g/m2 [1].

Von Hoff et al. used a 3 + 3 design in phase 2 clinical study to increase the amount of ascorbic acid (AA). Stage IV metastatic pancreatic cancer (MPC), an ECOG score of 0 to 1, and detectable disease are requirements for eligibility. Some researchers have combined the use of gemcitabine (G), cisplatin (C), and protein-bound paclitaxel (PP) to treat MPC. However, AA is also employed in this research experiment in addition to these medications. AA doses range between 25-56 gm/m2. After all the molecular and proteome analysis it was seen that MPC patient’s recovery rate was high in the case of combined treatment with AA and there were obvious signs of tumor shrinkage [2].

One of the deadliest tumors with poorly accepted treatments is pancreatic cancer. Because of its minimal toxicity, high-dose intravenous ascorbate (IVC) is becoming more popular as a treatment for this illness. To better understand how IVC and gemcitabine interact pharmacologically in the treatment of MPC, researchers carried out a phase 1 and 2 trials. IV Vit C is used along with gemcitabine. In-vitro analysis showed that this combination has successfully inhibited tumor growth and metastasis. The results are also validated in a mouse model. In the clinical trial, comparable results were seen. When taken as a whole, these data demonstrated a pharmacological ascorbate’s anti-cancer action with minimum toxicity, and they gave designers of bigger definitive trials design direction to examine the effectiveness of IVC in treating advanced pancreatic cancer [3].

It was believed that cancer treatment with chemotherapy off label is 33% effective. In a phase 1 and 2 trials by John Hoffer et al. tested pharmacokinetics, tolerance, and efficiency of IV Vit C with chemotherapy. In this study researchers focused on pre and post Vit C chemotherapy and pharmacokinetic profiles of oxalic acid in which they recorded mood, quality of life, clinical responses in case of IV Vit C infusions.There were fourteen patients signed up. Although some patients suffered brief side effects during or after IVC infusions, IVC was usually well tolerated and safe. This chemotherapy results in an increase in vitamin C tissue uptake but not in oxalic acid excretion in the urine. A combined approach to treat tumors is effective with IV vitamin C [4].

In a phase 1 clinical trial study, patients of metastatic pancreatic cancer (stage 4) were recruited. They were treated with IV Vit C along with gemcitabine and erlotinib with an 8-week cycle. From the total 9 out of 14 students successfully completed the trails with 15 less serious and 8 major adverse effects caused due to erlotinib or gemcitabine. In this study, the tumor size was reduced, the plasma concentration of the Vitamin C was increased, more uptake of AA into the cells was seen and there were signs of improvements in the patients with combined chemotherapy with IV vitamin C [5].

Because high doses of vitamin C are thought to increase antioxidant capacity and restore plasma vitamin C concentrations, they may help lessen the harmful effects of chemotherapy. Additionally, there is in vitro evidence that suggests vitamin C may lessen the doxorubicin-induced cardiac toxicity, which is thought to be connected to the peroxidation of cardiac lipids, without sacrificing effectiveness [6].



  1. Stephenson CM, Levin RD, Spector T, Lis CG. Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemother Pharmacol. 2013 Jul;72(1):139-46. DOI: 10.1007/s00280-013-2179-9. Epub 2013 May 14. PMID: 23670640; PMCID: PMC3691494.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691494/

  1. Von Hoff, D. D., & Jameson, G. (2020). A phase Ib/II trial of high dose ascorbic acid (AA)+ paclitaxel protein bound (PP)+ cisplatin (C)+ gemcitabine (G) with digital spatial profiling (DSP) in patients (pts) with metastatic pancreatic cancer (MPC). European Journal of Cancer, 138, S55.

Link: https://www.ejcancer.com/article/S0959-8049(20)31224-7/fulltext

  1. Polireddy K, Dong R, Reed G, Yu J, Chen P, Williamson S, Violet PC, Pessetto Z, Godwin AK, Fan F, Levine M, Drisko JA, Chen Q. High Dose Parenteral Ascorbate Inhibited Pancreatic Cancer Growth and Metastasis: Mechanisms and a Phase I/IIa study. Sci Rep. 2017 Dec 7;7(1):17188. doi: 10.1038/s41598-017-17568-8. PMID: 29215048; PMCID: PMC5719364.

Link: https://pubmed.ncbi.nlm.nih.gov/29215048/

  1. Hoffer LJ, Robitaille L, Zakarian R, Melnychuk D, Kavan P, Agulnik J, Cohen V, Small D, Miller WH Jr. High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: a phase I-II clinical trial. PLoS One. 2015 Apr 7;10(4): e0120228. doi: 10.1371/journal.pone.0120228. PMID: 25848948; PMCID: PMC4388666.

Link: https://pubmed.ncbi.nlm.nih.gov/25848948/

  1. Monti DA, Mitchell E, Bazzan AJ, Littman S, Zabrecky G, Yeo CJ, Pillai MV, Newberg AB, Deshmukh S, Levine M. 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. Epub 2012 Jan 17. PMID: 22272248; PMCID: PMC3260161.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260161/

  1. Shimpo, K., Nagatsu, T., Yamada, K., Sato, T., Niimi, H., Shamoto, M., … & Fujita, K. (1991). Ascorbic acid and adriamycin toxicity. The American journal of clinical nutrition, 54(6), 1298S-1301S.

Link: https://academic.oup.com/ajcn/article-abstract/54/6/1298S/4715243


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