- Vitamin C (L-ascorbate or L-ascorbic acid) has been used in the treatment of cancer patients. Intravenous administration of vitamin C is used to attain pharmacologic concentrations.
- Anti-cancer activity of high intravenous doses of vitamin C has not been confirmed in clinical trials.
- There is limited evidence indicating that high-dose intravenous vitamin C might improve the quality of life of patients with advanced cancers.
- High intravenous doses of vitamin C are generally safe, causing only minor side effects, but are contraindicated in people with renal disease or glucose 6-phosphate dehydrogenase deficiency. They may interact with conventional anti-cancer therapies.
Physiological concentrations of vitamin C (L-ascorbate or L-ascorbic acid) in the body are controlled through intestinal absorption, tissue accumulation, and renal reabsorption and excretion. Therefore, intravenous administration is used to achieve pharmacologic doses.
In the context of cancer, high-dose intravenous vitamin C (> 0.5 g per kg body weight) is claimed to have several effects: a) cytotoxicity for cancer cells, but not for normal tissue, b) improved quality of life for cancer patients, c) protection of normal tissues from toxicity caused by chemotherapy, and d) reinforcement of the action of radiation and some types of chemotherapy.
A limited number of Phase I clinical trials, including only one controlled trial, confirm the non-toxic character of the treatment, and give some indications that the treatment may improve quality of life, but do not suggest distinct anti-cancer effects. Several case reports argue for a positive effect on survival time, even reporting cancer remission, and improved quality of life.
High-dose vitamin C is essentially non-toxic. Reported side-effects are minor if patients are adequately screened for renal disease and glucose 6-phosphate dehydrogenase deficiency, and when doses are gradually increased with careful monitoring of the patient. Vitamin C might reduce the therapeutic response to some conventional anti-cancer therapies, but may act synergistic with other conventional therapies.
Luc Geeraert, CAM Cancer Consortium. Vitamin C (intravenous high-dose) [online document], July 9, 2014.
Most recent update and revision in July 2014 by Luc Geeraert.
Fully updated and revised in October 2012 by Luc Geeraert.
Summary first published in February 2011, authored by Luc Geeraert.
Description / Names
Vitamin C is also known as L-ascorbic acid or as sodium L-ascorbate.
Ingredients / Components
The richest natural sources of vitamin C are fruits and vegetables, and a balanced diet usually meets the daily requirements. Vitamin C is sold as a nutritional supplement in a variety of forms.
Application and dosage
Vitamin C can be administered via several routes including orally. This article only discusses the intravenous administration of high doses of vitamin C (> 0.5 g per kg body weight).
Phase I dose-finding studies in cancer patients recommend the use of 1.5 g to 2 g intravenous vitamin C per kg body weight three to four times per week1,2. In further clinical research it is advised to start treatment with a lower dose, and, if no adverse events are observed, to gradually increase doses to their final level1,3.
Ascorbic acid solutions for clinical infusion might be unstable over time4-6.
There is no consistent information available as to which clinical dose would be needed to yield an anti-cancer effect7. The above-mentioned dose of 1.5 g per kg body weight was only found to be safe and to be capable to achieve plasma ascorbic acid concentrations of more than 10 mM for several hours in patients with normal renal function1.
History / Claims of efficacy
Vitamin C was isolated by Szent-Györgyi in 19288. The vitamin plays a key role in several biological functions including the biosynthesis of collagen. It is a major water-soluble reducing agent and anti-oxidant, quenching potentially damaging free radicals resulting from metabolic respiration. Acute lack of vitamin C leads to scurvy, a disease marked by connective tissue damage and blood vessel fragility eventually resulting in death9.
Soon after its isolation, methods for vitamin C synthesis were developed and the molecule became widely available. Over the years, a wealth of case reports, anecdotal accounts and pilot studies, all reporting some degree of clinical benefit conferred by supplemental vitamin C in cancer, were published10. Two controlled retrospective studies (using 10 g vitamin C per day, intravenous and oral) by Cameron and Pauling further substantiated these claims11,12. As the latter studies lacked randomization and were retrospective, the US National Cancer Institute (NCI) sponsored two randomized, placebo-controlled, double-blind trials to evaluate the effect of high-dose vitamin C on symptoms and survival of patients with advanced cancer13,14; but Creagan and Moertel, who used 10 g oral (not intravenous) vitamin C per day, did not find a therapeutic benefit in the treatment of cancer. Hence, the use of vitamin C in cancer therapy was abandoned by mainstream oncologists in the 1980s15,16.
In the late 1990s, it was found that vitamin C concentrations in plasma and tissues were tightly controlled through intestinal absorption, tissue accumulation, and renal reabsorption and excretion17-20. As a result, it was impossible to increase plasma and tissue concentrations once oral intake of vitamin C exceeded 200 mg per day. However, intravenous administration bypassed this tight control until equilibrium was restored through renal excretion. In healthy volunteers, oral administration of the maximum tolerated dose of 3 g every 4 hours resulted in peak plasma concentrations of 0.22 mM, while an intravenous vitamin C dose of 50 g produced a peak plasma concentration of 13.4 mM21. Comparable results were found in cancer patients1,22,23.
Mechanisms of action / Alleged indications
At the normal low physiological concentrations (0.1 mM), vitamin C is an anti-oxidant that inactivates reactive oxygen species25. However, at high pharmacologic concentrations (up to 20 mM) it was found to become a pro-oxidant generating oxidative species, i.e. extracellular hydrogen peroxide, which is lethal to cancer cells26,27. Normal cells were unaffected by both concentrations of vitamin C. In vitro findings were confirmed in rats and mice, where virtually the same cancer-killing hydrogen peroxide concentrations were found in extracellular fluid, but not in blood, after intravenous administration of high-dose vitamin C; oral doses did not result in generation of hydrogen peroxide28-30. It was proposed that extracellular hydrogen peroxide diffuses into cancer cells and mediates toxicity by ATP depletion, thereby causing cell death. Moreover, hydrogen peroxide toxicity compromises membranes, glucose metabolism, and DNA integrity. In normal cells hydrogen peroxide is readily neutralized by antioxidant enzymes like catalase, glutathione peroxidase, and superoxide dismutase, while levels of these antioxidant enzymes are low or imbalanced in most human cancers31.
Daily high-dose intravenous vitamin C significantly decreased the volume of tumours in mice by 41-53% for diverse aggressive cancer types29. Inhibition of tumour growth was also found in other mouse models of human cancers and in human cancer cell lines9,30,32-34.
Prevalence of use / providers
Although use of high-dose intravenous vitamin C was abandoned by mainstream oncologists, the compound is in wide use by complementary and alternative medicine practitioners35.
Cost and expenditure
Vitamin C infusions, to be applied by a medical practitioner, are widely available at moderate cost (around $150.00 per infusion in a clinic).
Recent findings on the mechanism of action and pharmacokinetics of high-dose intravenous vitamin C triggered a renewed interest in its application as an anti-cancer agent. Therefore, several Phase I clinical trials were initiated and the results of one controlled and six uncontrolled trials have been published. Also, eight case studies and five retrospective studies have been reported. Several clinical trials are underway36.
While the case series and retrospective studies gave some indications for efficacy, the published clinical trials did not indicate tumour response. Overall, evidence for the non-toxic character of intravenous high-dose vitamin C, limited evidence for improved quality of life, and some suggestion of synergism with certain conventional therapy was offered.
Study details can be found in Table 1.
Controlled clinical trials
Only one controlled clinical trial has been published. In this Phase I/IIa randomized controlled clinical trial, Ma et al. randomized 27 patients with newly diagnosed stage III/IV ovarian cancer to receive either conventional paclitaxel/carboplatin therapy alone (control group), or combined with intravenous vitamin C (treatment group)37. Addition of intravenous high-dose vitamin C was found to reduce toxicities associated with chemotherapy.
Cameron et al. performed three controlled retrospective studies comparing terminal cancer patients receiving vitamin C with historical control patients that had not received vitamin C, and found increased survival times in the vitamin-C-treated groups11,12,50. The study designs were criticized as they were not randomized nor placebo controlled. Moreover, some patients were treated with oral vitamin C, the treatment period with intravenous vitamin C was only about 10 days, and the doses were rather low.
Vollbracht et al. evaluated intravenous vitamin C administration in the first postoperative year of women with breast cancer, in an epidemiological retrospective cohort study, and found that vitamin C resulted in a significant reduction of complaints induced by the disease and chemo- or radiotherapy. Vitamin C was well-tolerated and had no effect on tumour status after 6 or 12 months51.
Uncontrolled clinical trials
Intravenous vitamin C was well-tolerated in a pilot clinical study in 24 late-stage terminal cancer patients, and one patient had stabilized disease during the trial38. Noteworthy, applied doses of vitamin C were low.Several aspects of health-related quality of life were improved after administration of intravenous high-dose vitamin C to 39 terminal cancer patients: i.e., significantly higher scores for physical, role, emotional, and cognitive function, and significantly lower scores for fatigue, nausea/vomiting, pain, and appetite loss39.
In a dose-finding Phase I and pharmacokinetics study in 24 patients with advanced cancer or hematologic malignancy refractory to standard therapy, high-dose intravenous vitamin C was found to be safe and free of important toxicity. Patients receiving 0.6 g or more of vitamin C per kg body weight maintained physical quality of life throughout the trial. No patient experienced an objective anti-cancer response1.
The combination of intravenous vitamin C with standard treatment of gemcitabine and erlotinib was tested in an open-label, dose-escalating Phase I trial in 14 patients with metastatic pancreatic cancer40. Nine subjects completed the study of which seven patients experienced stable disease. No increased toxicity was revealed with the addition of vitamin C to gemcitabine and erlotinib.
In a Phase I dose-escalation trial in 17 patients with advanced solid tumours not responding to standard therapy, pharmacokinetics of high-dose intravenous vitamin C were determined2. Vitamin C was generally well tolerated and no objective antitumour responses were observed. The authors recommend a dose of 70 to 80 g/m2 (i.e., around 2 g per kg body weight) for future studies.
In a Phase I clinical trial in nine patients with biopsy-proven stage IV pancreatic adenocarcinoma, the concurrent administration of high-dose intravenous vitamin C with gemcitabine was well-tolerated and a suggestion of improved efficacy by vitamin C addition was found41.
Analysis of a database from 45 patients with different cancers treated with high-dose intravenous vitamin C by Mikirova et al. taught that this treatment affected levels of C-reactive protein and pro-inflammation cytokines, supporting the hypothesis that inflammation in cancer patients may be reduced by high-dose intravenous vitamin C52.
Several case reports on the treatment of advanced cancer patients with high-dose intravenous vitamin C have been published42-49. Vitamin C infusions were either used as sole treatment or combined with conventional therapy. Overall, the results indicated lack of toxicity. Also, in several cases tumour regression or even complete remission was observed.
Noteworthy, for all the successful case reports, alternative explanations for cancer remission are possible, e.g. spontaneous remission or remission due to the therapy received before intravenous vitamin C was initiated. Moreover, a general weakness of case reports is that they omit the number of patients having received high-dose intravenous vitamin C without any effect.
Vitamin C itself is essentially non-toxic. In general, adverse events after high-dose intravenous vitamin C were mild, and consistent with side effects occurring due to rapid infusion of any high-osmolarity solution, and were preventable by drinking fluids before and during the infusion1,35,38.
Patients with glucose 6-phosphate dehydrogenase deficiency were found to be at risk to experience haemolysis (breakdown of red blood cells) following administration of high doses of vitamin C53,54. Therefore patients should be screened for this metabolic deficiency before initiation of therapy.
Oxalic acid is an end product of metabolic oxidation of vitamin C. Oxalate nephropathy has been reported after administration of intravenous vitamin C in subjects with renal dysfunction55-57. However, in people with normal renal function, the risk of oxalate crystallization in the kidney was not increased58. Therefore, high-dose intravenous vitamin C is contraindicated in people with renal dysfunction, and a history of kidney stones should be reviewed.
Another concern is life-threatening bleeding (haemorrhage) and rapid necrosis of tumours59. Authors therefore advised gradual increase of intravenous vitamin C whilst monitoring the patient.
As vitamin C at physiological concentrations has antioxidant properties, it is conceivable that it may attenuate the anti-cancer activity of therapies generating increased reactive oxygen species, e.g. radiation and some chemotherapeutics.
Several studies on interactions of vitamin C and anti-cancer therapies have been performed, both in vitro and in vivo36-37,60-68. Vitamin C was found to reinforce the action of radiation and several chemotherapeutics, while it has no influence or even diminishes the effects of other chemotherapeutics. In this respect, the results of Heaney et al. are worth mentioning69. When comparing the therapeutic efficacy of a range of anticancer agents in cell lines and tumour-bearing mice with and without pretreatment with dehydroascorbic acid (the oxidized form of vitamin C), it was found that the latter caused a dose-dependent reduction of cytotoxicity; however, later studies questioned the relevance of these findings when using pharmacological concentrations of vitamin C63. Also, several studies showed that vitamin C could abrogate the effects of bortezomib when taken simultaneously70.
In conclusion, negative interactions may occur when adding vitamin C to conventional anti-cancer therapy, making the conventional therapy less potent.
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