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High-Dose Vitamin C (PDQ®)

Health Professional Version

.

Published online: October 13, 2020.

Created: .

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of high-dose vitamin C in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is reviewed regularly and updated as necessary by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Overview

This cancer information summary provides an overview of the use of high-dose vitamin C (also known as ascorbate or L-ascorbic acid) as a treatment for people with cancer. This summary includes a brief history of early clinical trials of high-dose vitamin C; reviews of laboratory, animal, and human studies; and current clinical trials.

This summary contains the following key information:

Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.

Reference citations in some PDQ cancer information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the National Cancer Institute.

General Information

Vitamin C is an essential nutrient that has redox functions, is a cofactor for several enzymes, and plays an important role in the synthesis of collagen.[1] A severe deficiency in vitamin C results in scurvy, which is associated with malaise, lethargy, easy bruising, and spontaneous bleeding.[2] One of the effects of scurvy is a change in collagen structure to a thinner consistency. Normal consistency is achieved with administration of vitamin C.

In the mid-20th century, a study hypothesized that cancer may be related to changes in connective tissue, which may be a consequence of vitamin C deficiency.[3] A review of evidence published in 1974 suggested that high-dose ascorbic acid may increase host resistance and be a potential cancer therapy.[4]

Vitamin C is synthesized from D-glucose or D-galactose by many plants and animals. However, humans lack the enzyme L-gulonolactone oxidase required for ascorbic acid synthesis and must obtain vitamin C through food or supplements.[1]

References

  1. Naidu KA: Vitamin C in human health and disease is still a mystery? An overview. Nutr J 2: 7, 2003. [PMC free article: PMC201008] [PubMed: 14498993]
  2. Padayatty S, Espey MG, Levine M: Vitamin C. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. New York, NY: Informa Healthcare, 2010, pp 821-31.
  3. McCORMICK WJ: Cancer: a collagen disease, secondary to a nutritional deficiency. Arch Pediatr 76 (4): 166-71, 1959. [PubMed: 13638066]
  4. Cameron E, Pauling L: The orthomolecular treatment of cancer. I. The role of ascorbic acid in host resistance. Chem Biol Interact 9 (4): 273-83, 1974. [PubMed: 4609626]

History

The earliest experience of using high-dose vitamin C (intravenous [IV] and oral) for cancer treatment was by a Scottish surgeon, Ewan Cameron, and his colleague, Allan Campbell, in the 1970s.[1] This work led to a collaboration between Cameron and the Nobel Prize–winning chemist Linus Pauling, further promoting the potential of vitamin C therapy in cancer management.[2,3] As a result, two clinical trials of oral vitamin C were conducted in the late 1970s and early 1980s.[4,5]

(Refer to the Human Studies section of this summary for more information about these early studies.)

Pharmacokinetic studies later revealed substantial differences in the maximum achieved blood concentrations of vitamin C based on the route of administration. When vitamin C is taken orally, plasma concentrations of the vitamin are tightly controlled, with a peak achievable concentration less than 300 µM. However, this tight control is bypassed with IV administration of the vitamin, resulting in very high levels of vitamin C plasma concentration (i.e., levels up to 20 mM).[6,7] Further research suggests that pharmacologic concentrations of ascorbate, such as those achieved with IV administration, may result in cell death in many cancer cell lines.[8]

Health care practitioners attending complementary and alternative medicine conferences in 2006 and 2008 were surveyed about usage of high-dose IV vitamin C in patients. Of the 199 total respondents, 172 had administered vitamin C to patients. In general, IV vitamin C was commonly used to treat infections, cancer, and fatigue.[9]

References

  1. Cameron E, Campbell A: The orthomolecular treatment of cancer. II. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer. Chem Biol Interact 9 (4): 285-315, 1974. [PubMed: 4430016]
  2. Cameron E, Pauling L: Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A 73 (10): 3685-9, 1976. [PMC free article: PMC431183] [PubMed: 1068480]
  3. Cameron E, Pauling L: Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A 75 (9): 4538-42, 1978. [PMC free article: PMC336151] [PubMed: 279931]
  4. Creagan ET, Moertel CG, O'Fallon JR, et al.: Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial. N Engl J Med 301 (13): 687-90, 1979. [PubMed: 384241]
  5. Moertel CG, Fleming TR, Creagan ET, et al.: High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison. N Engl J Med 312 (3): 137-41, 1985. [PubMed: 3880867]
  6. Padayatty SJ, Sun H, Wang Y, et al.: Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med 140 (7): 533-7, 2004. [PubMed: 15068981]
  7. Hoffer LJ, Levine M, Assouline S, et al.: Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol 19 (11): 1969-74, 2008. [PubMed: 18544557]
  8. Verrax J, Calderon PB: Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects. Free Radic Biol Med 47 (1): 32-40, 2009. [PubMed: 19254759]
  9. Padayatty SJ, Sun AY, Chen Q, et al.: Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS One 5 (7): e11414, 2010. [PMC free article: PMC2898816] [PubMed: 20628650]

Laboratory/Animal/Preclinical Studies

In Vitro Studies

Numerous studies have demonstrated that pharmacological doses of ascorbic acid (0.1–100 mM) decrease cell proliferation in a variety of cancer cell lines.[1-5] Specifically, decreases in cell proliferation after ascorbic acid treatment have been reported for prostate,[6] pancreatic,[7,8] hepatocellular,[9] colon,[10] mesothelioma,[11] and neuroblastoma [12] cell lines.

The potential mechanisms through which treatment with high-dose ascorbic acid may exert its effects on cancer cells have been extensively investigated. Several studies have demonstrated that the in vitro direct cytotoxic effect of ascorbic acid on various types of cancer cells is mediated through a chemical reaction that generates hydrogen peroxide.[1,7,13,14] Treating colon cancer cells with 2 mM to 3 mM of ascorbic acid resulted in downregulation of specificity protein (Sp) transcription factors, iron metabolism disruption, and Sp-regulated genes involved in cancer progression.[10,15] One study suggested that ascorbate-mediated prostate cancer cell death may occur through activation of an autophagy pathway.[6] Data from a 2018 study demonstrated that labile iron and hydrogen peroxide play important roles in the mechanisms of selective toxicity of ascorbate and induction of oxidative DNA damage/cancer cell death.[16] Another in vitro study found that ascorbic acid killed colorectal cancer cells with KRAS or BRAF mutations by inhibiting the enzyme glyceraldehyde 3-phosphate dehydrogenase.[17]

Differences in chemosensitivity to ascorbate treatment in breast cancer cell lines may depend on expression of the sodium-dependent vitamin C transporter 2 (SVCT-2).[18]

Research has suggested that pharmacological doses of ascorbic acid enhance the effects of the following:

Findings from one study reported in 2012 suggested that high-dose ascorbate increases radiosensitivity of glioblastoma multiforme cells, resulting in more cell death than from radiation alone.[21]

However, not all studies combining vitamin C with chemotherapy have shown improved outcomes. Treating leukemia and lymphoma cells with dehydroascorbic acid (the oxidized form of vitamin C that increases levels of intracellular ascorbic acid) reduced the cytotoxic effects of various antineoplastic agents tested, including doxorubicin, methotrexate, and cisplatin (relative reductions in cytotoxicity ranged from 30% to 70%).[22] In another study, multiple myeloma cells were treated with bortezomib and/or plasma obtained from healthy volunteers who had taken vitamin C supplements. Cells treated with a combination of bortezomib and volunteers’ plasma exhibited lower cytotoxicity than did cells treated with bortezomib alone.[23]

Animal Studies

Using N-acetylcysteine and vitamin C, researchers showed in 2007 that these compounds, both thought to act predominantly as antioxidants, may have antitumorigenic actions in vivo by decreasing levels of hypoxia-inducible factor-1, a transcription factor that targets vascular endothelial growth factor and plays a role in angiogenesis.[24]

Studies have demonstrated tumor growth inhibition after treatment with pharmacological ascorbate in animal models with the following:

The effects of high-dose ascorbic acid in combination with standard treatments on tumors have been investigated. In a mouse model of pancreatic cancer, the combination of gemcitabine (30 or 60 mg/kg every 4 days) and ascorbate (4 g/kg daily) resulted in greater decreases in tumor volume and weight, compared with gemcitabine treatment alone.[8] A study of mouse models of ovarian cancer found that ascorbate enhanced the tumor inhibitory effect of carboplatin and paclitaxel, first-line chemotherapy used in ovarian cancer.[27] One study working with xenograft models of non-small cell lung cancer and glioblastoma multiforme showed that the combination of chemotherapy (carboplatin for lung cancer and temozolomide for glioblastoma), radiation therapy, and pharmacologic ascorbate (4 g/kg/d) intraperitoneal injection resulted in prolonged survival compared with just the combination of chemotherapy and radiation therapy.[15]

A study explored the efficacy of high-dose ascorbate with gemcitabine or radiation treatment in a mouse sarcoma xenograft model. Treatment involved intraperitoneally administered doses of ascorbate (4 g/kg) combined with gemcitabine (60 mg/kg) or radiation therapy (12 Gy in 2 fractions). Compared with the control group, the combination treatments produced significantly greater inhibition of tumor growth, greater survival rate, and no increase in toxicity, suggesting cancer cell selective toxicity.[16]

There have also been reports of animal studies in which vitamin C has interfered with the anticancer activity of various drugs. In a study reported in 2008, administration of dehydroascorbic acid to lymphoma-xenograft mice prior to doxorubicin treatment resulted in significantly larger tumors than did treatment with doxorubicin alone.[22] Notably, this study used dehydroascorbate, the oxidized form of vitamin C that is known to be transported actively into cells and then reduced to vitamin C. Treating multiple myeloma xenograft mice with a combination of oral vitamin C and bortezomib resulted in significantly greater tumor volume than did treatment with bortezomib alone.[23] This increase in tumor volume was caused by a chemical reaction that occurs in the gastrointestinal tract but does not appear to be relevant to intravenous administration.

References

  1. Chen P, Stone J, Sullivan G, et al.: Anti-cancer effect of pharmacologic ascorbate and its interaction with supplementary parenteral glutathione in preclinical cancer models. Free Radic Biol Med 51 (3): 681-7, 2011. [PubMed: 21672627]
  2. Chen Q, Espey MG, Krishna MC, et al.: Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci U S A 102 (38): 13604-9, 2005. [PMC free article: PMC1224653] [PubMed: 16157892]
  3. Verrax J, Calderon PB: Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects. Free Radic Biol Med 47 (1): 32-40, 2009. [PubMed: 19254759]
  4. Chen Q, Espey MG, Sun AY, et al.: Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci U S A 105 (32): 11105-9, 2008. [PMC free article: PMC2516281] [PubMed: 18678913]
  5. Frömberg A, Gutsch D, Schulze D, et al.: Ascorbate exerts anti-proliferative effects through cell cycle inhibition and sensitizes tumor cells towards cytostatic drugs. Cancer Chemother Pharmacol 67 (5): 1157-66, 2011. [PMC free article: PMC3082037] [PubMed: 20694726]
  6. Chen P, Yu J, Chalmers B, et al.: Pharmacological ascorbate induces cytotoxicity in prostate cancer cells through ATP depletion and induction of autophagy. Anticancer Drugs 23 (4): 437-44, 2012. [PubMed: 22205155]
  7. Du J, Martin SM, Levine M, et al.: Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. Clin Cancer Res 16 (2): 509-20, 2010. [PMC free article: PMC2807999] [PubMed: 20068072]
  8. Espey MG, Chen P, Chalmers B, et al.: Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer. Free Radic Biol Med 50 (11): 1610-9, 2011. [PMC free article: PMC3482496] [PubMed: 21402145]
  9. Lin ZY, Chuang WL: Pharmacologic concentrations of ascorbic acid cause diverse influence on differential expressions of angiogenic chemokine genes in different hepatocellular carcinoma cell lines. Biomed Pharmacother 64 (5): 348-51, 2010. [PubMed: 19932582]
  10. Pathi SS, Lei P, Sreevalsan S, et al.: Pharmacologic doses of ascorbic acid repress specificity protein (Sp) transcription factors and Sp-regulated genes in colon cancer cells. Nutr Cancer 63 (7): 1133-42, 2011. [PMC free article: PMC3359146] [PubMed: 21919647]
  11. Takemura Y, Satoh M, Satoh K, et al.: High dose of ascorbic acid induces cell death in mesothelioma cells. Biochem Biophys Res Commun 394 (2): 249-53, 2010. [PubMed: 20171954]
  12. Hardaway CM, Badisa RB, Soliman KF: Effect of ascorbic acid and hydrogen peroxide on mouse neuroblastoma cells. Mol Med Report 5 (6): 1449-52, 2012. [PMC free article: PMC3327822] [PubMed: 22469841]
  13. Du J, Cullen JJ, Buettner GR: Ascorbic acid: chemistry, biology and the treatment of cancer. Biochim Biophys Acta 1826 (2): 443-57, 2012. [PMC free article: PMC3608474] [PubMed: 22728050]
  14. Levine M, Padayatty SJ, Espey MG: Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries. Adv Nutr 2 (2): 78-88, 2011. [PMC free article: PMC3065766] [PubMed: 22332036]
  15. Schoenfeld JD, Sibenaller ZA, Mapuskar KA, et al.: O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer Cell 32 (2): 268, 2017. [PubMed: 28810149]
  16. Schoenfeld JD, Sibenaller ZA, Mapuskar KA, et al.: Redox active metals and H2O2 mediate the increased efficacy of pharmacological ascorbate in combination with gemcitabine or radiation in pre-clinical sarcoma models. Redox Biol 14: 417-422, 2018. [PMC free article: PMC5651553] [PubMed: 29069637]
  17. Yun J, Mullarky E, Lu C, et al.: Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350 (6266): 1391-6, 2015. [PMC free article: PMC4778961] [PubMed: 26541605]
  18. Hong SW, Lee SH, Moon JH, et al.: SVCT-2 in breast cancer acts as an indicator for L-ascorbate treatment. Oncogene 32 (12): 1508-17, 2013. [PubMed: 22665050]
  19. Ong PS, Chan SY, Ho PC: Differential augmentative effects of buthionine sulfoximine and ascorbic acid in As2O3-induced ovarian cancer cell death: oxidative stress-independent and -dependent cytotoxic potentiation. Int J Oncol 38 (6): 1731-9, 2011. [PubMed: 21455570]
  20. Martinotti S, Ranzato E, Burlando B: In vitro screening of synergistic ascorbate-drug combinations for the treatment of malignant mesothelioma. Toxicol In Vitro 25 (8): 1568-74, 2011. [PubMed: 21645609]
  21. Herst PM, Broadley KW, Harper JL, et al.: Pharmacological concentrations of ascorbate radiosensitize glioblastoma multiforme primary cells by increasing oxidative DNA damage and inhibiting G2/M arrest. Free Radic Biol Med 52 (8): 1486-93, 2012. [PubMed: 22342518]
  22. Heaney ML, Gardner JR, Karasavvas N, et al.: Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer Res 68 (19): 8031-8, 2008. [PMC free article: PMC3695824] [PubMed: 18829561]
  23. Perrone G, Hideshima T, Ikeda H, et al.: Ascorbic acid inhibits antitumor activity of bortezomib in vivo. Leukemia 23 (9): 1679-86, 2009. [PubMed: 19369963]
  24. Gao P, Zhang H, Dinavahi R, et al.: HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell 12 (3): 230-8, 2007. [PMC free article: PMC2084208] [PubMed: 17785204]
  25. Pollard HB, Levine MA, Eidelman O, et al.: Pharmacological ascorbic acid suppresses syngeneic tumor growth and metastases in hormone-refractory prostate cancer. In Vivo 24 (3): 249-55, 2010 May-Jun. [PMC free article: PMC9718485] [PubMed: 20554995]
  26. Yeom CH, Lee G, Park JH, et al.: High dose concentration administration of ascorbic acid inhibits tumor growth in BALB/C mice implanted with sarcoma 180 cancer cells via the restriction of angiogenesis. J Transl Med 7: 70, 2009. [PMC free article: PMC2732919] [PubMed: 19671184]
  27. Ma Y, Chapman J, Levine M, et al.: High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci Transl Med 6 (222): 222ra18, 2014. [PubMed: 24500406]

Human/Clinical Studies

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.[1] 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 the following:

However, the authors noted that lack of controls prevented definitive assignment of any beneficial responses to the ascorbic acid treatment.[1] A case report published in 1975 detailed one of the patients who had experienced tumor regression.[2] 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) [1] 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.[3,4]

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.[5,6]

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.[7] 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.

One study demonstrated that IV vitamin C treatment resulted in improved quality of life and a decrease in cancer-related side effects in cancer patients.[8]

A single-arm pilot study of weekly infusions of 60 g of ascorbic acid for 9 weeks in castration-resistant prostate cancer patients failed to observe a reduction in serum prostate-specific antigen or a decrease in tumor regression.[9]

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.[10,11]

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/m2 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.[12]

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/m2 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.[13]

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.[14]

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:[15]

  • 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.[15]

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 + fluorouracil) or FOLFIRI (leucovorin + 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.[16]

Table 1. Clinical Studies of Ascorbate with Chemotherapya

Type of StudyCondition Treated/DoseNo. of Patients: Enrolled; Treated; Placebo or No Treatment ControlbResultsConcurrent Therapy UsedLevel of Evidence Scorec
Phase I, open label trial [12]Metastatic stage IV pancreatic cancer; 50 g/infusion, 75 g/infusion, or 100 g/infusion 3x/wk for 8 wk14; 14 (9 analyzed); noneAscorbic acid was well tolerated with gemcitabine and erlotinibGemcitabine, erlotinib2Dii
Phase I, open label trial [13]Stage IV pancreatic adenocarcinoma; 15 g/wk until the plasma level reached at least 350 mg/dL (20 mM) 15; 11 (9 completed); noneAscorbate acid was well tolerated with gemcitabineGemcitabine2Dii
Pilot phase I/IIA trial [14]Stage III/IV ovarian cancer; up to 75 or 100 g 2x/wk for 12 mo 27; 14 (chemotherapy), 13 (chemotherapy and intravenous vitamin C); noneAscorbate acid added to carboplatin and paclitaxel therapy reduced chemotherapy-related toxicitiesCarboplatin, paclitaxel2C

No. = number of patients.

aRefer to text and the NCI Dictionary of Cancer Terms for additional information and definition of terms.

bNumber of patients treated plus number of patient controls may not equal number of patients enrolled; number of patients enrolled equals number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated equals number of enrolled patients who were given the treatment being studied AND for whom results were reported.

cFor information about levels of evidence analysis and an explanation of the level of evidence scores, refer to Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.

Trials of high-dose IV vitamin C with other drugs are ongoing.[12,14] 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.

Table 2. Clinical Studies of Ascorbate in Arsenic Trioxide-Containing Regimensa

Type of Study Condition Treated/DoseNo. of Patients: Enrolled; Treated; Placebo or No Treatment ControlbResultsConcurrent Therapy Used Level of Evidence Scorec
RCT [17]Multiple myeloma; 1,000 mg48; arm 1 (N = 16), arm 2 (N = 17), arm 3 (N = 15); noneThe addition of arsenic trioxide and ascorbic acid to high-dose melphalan was reported safe and well toleratedMelphalan1iiDii
Phase II, open label [18]Relapsed or refractory multiple myeloma; 1,000 mg20; 20; noneClinical efficacy and tolerability with arsenic trioxide, dexamethasone, and ascorbic acid was reported Dexamethasone3Dii
Phase I/II, open label [19]Relapsed or refractory multiple myeloma; 1,000 mg22; 22; noneArsenic trioxide, bortezomib, and ascorbic acid was well tolerated with signs of clinical efficacy Bortezomib3Dii
Phase II [20]Relapsed or refractory multiple myeloma; 1,000 mg65; 65; noneMelphalan, arsenic trioxide, and ascorbic acid was effective and well tolerated Melphalan3Dii
Phase II [21]Refractory metastatic colorectal carcinoma; 1,000 mg5; 5; nonePatients developed moderate to severe toxic side effects without clinical responseNone3Dii
Phase II, open label [22]Metastatic melanoma; 1,000 mg 11; 10; nonePatients developed toxic side effects without clinical responseTemozolomide 3Dii

N = number of patients; RCT = randomized controlled trial.

aRefer to text and the NCI Dictionary of Cancer Terms for additional information and definition of terms.

bNumber of patients treated plus number of patient controls may not equal number of patients enrolled; number of patients enrolled equals number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated equals number of enrolled patients who were given the treatment being studied AND for whom results were reported.

cFor information about levels of evidence analysis and an explanation of the level of evidence scores, refer to Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.

Informed by their preclinical data,[18] 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).[23] 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 the following:

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.[24] 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.[17-20] However, similar combination regimens resulted in severe side effects, disease progression, and no anticancer effect in patients with refractory metastatic colorectal cancer [21] and metastatic melanoma.[22] Because these were not placebo-controlled trials, the extent that ascorbate contributed to the toxicity or efficacy demonstrated in these studies is unclear.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

  1. Cameron E, Campbell A: The orthomolecular treatment of cancer. II. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer. Chem Biol Interact 9 (4): 285-315, 1974. [PubMed: 4430016]
  2. Cameron E, Campbell A, Jack T: The orthomolecular treatment of cancer. III. Reticulum cell sarcoma: double complete regression induced by high-dose ascorbic acid therapy. Chem Biol Interact 11 (5): 387-93, 1975. [PubMed: 1104207]
  3. Cameron E, Pauling L: Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A 73 (10): 3685-9, 1976. [PMC free article: PMC431183] [PubMed: 1068480]
  4. Cameron E, Pauling L: Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A 75 (9): 4538-42, 1978. [PMC free article: PMC336151] [PubMed: 279931]
  5. Creagan ET, Moertel CG, O'Fallon JR, et al.: Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial. N Engl J Med 301 (13): 687-90, 1979. [PubMed: 384241]
  6. Moertel CG, Fleming TR, Creagan ET, et al.: High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison. N Engl J Med 312 (3): 137-41, 1985. [PubMed: 3880867]
  7. Padayatty SJ, Riordan HD, Hewitt SM, et al.: Intravenously administered vitamin C as cancer therapy: three cases. CMAJ 174 (7): 937-42, 2006. [PMC free article: PMC1405876] [PubMed: 16567755]
  8. Yeom CH, Jung GC, Song KJ: Changes of terminal cancer patients' health-related quality of life after high dose vitamin C administration. J Korean Med Sci 22 (1): 7-11, 2007. [PMC free article: PMC2693571] [PubMed: 17297243]
  9. Nielsen TK, Højgaard M, Andersen JT, et al.: Weekly ascorbic acid infusion in castration-resistant prostate cancer patients: a single-arm phase II trial. Transl Androl Urol 6 (3): 517-528, 2017. [PMC free article: PMC5503969] [PubMed: 28725594]
  10. Padayatty SJ, Sun H, Wang Y, et al.: Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med 140 (7): 533-7, 2004. [PubMed: 15068981]
  11. Hoffer LJ, Levine M, Assouline S, et al.: Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol 19 (11): 1969-74, 2008. [PubMed: 18544557]
  12. 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 7 (1): e29794, 2012. [PMC free article: PMC3260161] [PubMed: 22272248]
  13. Welsh JL, Wagner BA, van't Erve TJ, et al.: Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. Cancer Chemother Pharmacol 71 (3): 765-75, 2013. [PMC free article: PMC3587047] [PubMed: 23381814]
  14. Ma Y, Chapman J, Levine M, et al.: High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci Transl Med 6 (222): 222ra18, 2014. [PubMed: 24500406]
  15. Hoffer LJ, Robitaille L, Zakarian R, et al.: High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: a phase I-II clinical trial. PLoS One 10 (4): e0120228, 2015. [PMC free article: PMC4388666] [PubMed: 25848948]
  16. Wang F, He MM, Wang ZX, et al.: Phase I study of high-dose ascorbic acid with mFOLFOX6 or FOLFIRI in patients with metastatic colorectal cancer or gastric cancer. BMC Cancer 19 (1): 460, 2019. [PMC free article: PMC6524297] [PubMed: 31096937]
  17. Qazilbash MH, Saliba RM, Nieto Y, et al.: Arsenic trioxide with ascorbic acid and high-dose melphalan: results of a phase II randomized trial. Biol Blood Marrow Transplant 14 (12): 1401-7, 2008. [PMC free article: PMC4112362] [PubMed: 19041063]
  18. Abou-Jawde RM, Reed J, Kelly M, et al.: Efficacy and safety results with the combination therapy of arsenic trioxide, dexamethasone, and ascorbic acid in multiple myeloma patients: a phase 2 trial. Med Oncol 23 (2): 263-72, 2006. [PubMed: 16720927]
  19. Berenson JR, Matous J, Swift RA, et al.: A phase I/II study of arsenic trioxide/bortezomib/ascorbic acid combination therapy for the treatment of relapsed or refractory multiple myeloma. Clin Cancer Res 13 (6): 1762-8, 2007. [PubMed: 17363530]
  20. Berenson JR, Boccia R, Siegel D, et al.: Efficacy and safety of melphalan, arsenic trioxide and ascorbic acid combination therapy in patients with relapsed or refractory multiple myeloma: a prospective, multicentre, phase II, single-arm study. Br J Haematol 135 (2): 174-83, 2006. [PubMed: 17010047]
  21. Subbarayan PR, Lima M, Ardalan B: Arsenic trioxide/ascorbic acid therapy in patients with refractory metastatic colorectal carcinoma: a clinical experience. Acta Oncol 46 (4): 557-61, 2007. [PubMed: 17497326]
  22. Bael TE, Peterson BL, Gollob JA: Phase II trial of arsenic trioxide and ascorbic acid with temozolomide in patients with metastatic melanoma with or without central nervous system metastases. Melanoma Res 18 (2): 147-51, 2008. [PubMed: 18337652]
  23. Schoenfeld JD, Sibenaller ZA, Mapuskar KA, et al.: O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer Cell 32 (2): 268, 2017. [PubMed: 28810149]
  24. Campbell RA, Sanchez E, Steinberg JA, et al.: Antimyeloma effects of arsenic trioxide are enhanced by melphalan, bortezomib and ascorbic acid. Br J Haematol 138 (4): 467-78, 2007. [PubMed: 17587338]

Adverse Effects

Intravenous (IV) high-dose ascorbic acid has been generally well tolerated in clinical trials.[1-8] Renal failure after ascorbic acid treatment has been reported in patients with preexisting renal disorders.[9] One study reported fluid overload related to ascorbic acid infusion, but this may be caused by the delivery method and not the product.[10]

Case reports have indicated that patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency should not receive high doses of vitamin C because of the risk of developing hemolysis.[11-13]

Vitamin C may increase bioavailability of iron, and high doses of the vitamin are not recommended for patients with hemochromatosis.[14]

Drug Interactions

When administered in high doses, vitamin C may result in adverse interactions with some anticancer agents. These interactions have primarily been detected in preclinical studies. A 2013 phase I clinical study evaluated the safety of combining high-dose IV ascorbate with gemcitabine in stage IV pancreatic cancer patients. The combination therapy was well tolerated by patients, and no significant adverse events were reported.[15]

In vitro and in vivo animal studies have suggested that combining oral vitamin C with bortezomib interferes with the drug’s ability to act as a proteasome inhibitor and blocks bortezomib-initiated apoptosis.[16-18] This interference occurred even with the oral administration of vitamin C (40 mg/kg/day) to animals. Studies in cell culture and performed by adding blood plasma from healthy volunteers given oral vitamin C (1 g/day) also showed a significant decrease in bortezomib’s growth inhibitory effect on multiple myeloma cells. Another study found similar results. Plasma from healthy volunteers who took 1 g of oral vitamin C per day was shown to decrease bortezomib growth inhibition in multiple myeloma cells and to block its inhibitory effect on 20S proteasome activity.[18] However, a study that utilized mice harboring human prostate cancer cell xenografts failed to find any significant effect of oral vitamin C (40 mg/kg/day or 500 mg/kg/day) on the tumor growth inhibitory action of bortezomib.[19]

Several studies have been performed to assess the potential synergistic or inhibitory action of vitamin C on certain chemotherapy drugs, with variable results. A series of studies in cell culture and in animals bearing tumors has shown that when given at high concentrations or dosages, dehydroascorbic acid (an oxidized form of vitamin C) can interfere with the cytotoxic effects of several chemotherapy drugs.[20] However, dehydroascorbic acid is generally present only at low concentrations in dietary supplements and fresh foods.

References

  1. Padayatty SJ, Sun H, Wang Y, et al.: Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med 140 (7): 533-7, 2004. [PubMed: 15068981]
  2. Hoffer LJ, Levine M, Assouline S, et al.: Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol 19 (11): 1969-74, 2008. [PubMed: 18544557]
  3. Chen Q, Espey MG, Sun AY, et al.: Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci U S A 105 (32): 11105-9, 2008. [PMC free article: PMC2516281] [PubMed: 18678913]
  4. 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 7 (1): e29794, 2012. [PMC free article: PMC3260161] [PubMed: 22272248]
  5. Abou-Jawde RM, Reed J, Kelly M, et al.: Efficacy and safety results with the combination therapy of arsenic trioxide, dexamethasone, and ascorbic acid in multiple myeloma patients: a phase 2 trial. Med Oncol 23 (2): 263-72, 2006. [PubMed: 16720927]
  6. Berenson JR, Matous J, Swift RA, et al.: A phase I/II study of arsenic trioxide/bortezomib/ascorbic acid combination therapy for the treatment of relapsed or refractory multiple myeloma. Clin Cancer Res 13 (6): 1762-8, 2007. [PubMed: 17363530]
  7. Qazilbash MH, Saliba RM, Nieto Y, et al.: Arsenic trioxide with ascorbic acid and high-dose melphalan: results of a phase II randomized trial. Biol Blood Marrow Transplant 14 (12): 1401-7, 2008. [PMC free article: PMC4112362] [PubMed: 19041063]
  8. Ma Y, Chapman J, Levine M, et al.: High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci Transl Med 6 (222): 222ra18, 2014. [PubMed: 24500406]
  9. Padayatty SJ, Sun AY, Chen Q, et al.: Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS One 5 (7): e11414, 2010. [PMC free article: PMC2898816] [PubMed: 20628650]
  10. Nielsen TK, Højgaard M, Andersen JT, et al.: Weekly ascorbic acid infusion in castration-resistant prostate cancer patients: a single-arm phase II trial. Transl Androl Urol 6 (3): 517-528, 2017. [PMC free article: PMC5503969] [PubMed: 28725594]
  11. Campbell GD, Steinberg MH, Bower JD: Letter: Ascorbic acid-induced hemolysis in G-6-PD deficiency. Ann Intern Med 82 (6): 810, 1975. [PubMed: 1138591]
  12. Mehta JB, Singhal SB, Mehta BC: Ascorbic-acid-induced haemolysis in G-6-PD deficiency. Lancet 336 (8720): 944, 1990. [PubMed: 1976956]
  13. Rees DC, Kelsey H, Richards JD: Acute haemolysis induced by high dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency. BMJ 306 (6881): 841-2, 1993. [PMC free article: PMC1677333] [PubMed: 8490379]
  14. Barton JC, McDonnell SM, Adams PC, et al.: Management of hemochromatosis. Hemochromatosis Management Working Group. Ann Intern Med 129 (11): 932-9, 1998. [PubMed: 9867745]
  15. Welsh JL, Wagner BA, van't Erve TJ, et al.: Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. Cancer Chemother Pharmacol 71 (3): 765-75, 2013. [PMC free article: PMC3587047] [PubMed: 23381814]
  16. Zou W, Yue P, Lin N, et al.: Vitamin C inactivates the proteasome inhibitor PS-341 in human cancer cells. Clin Cancer Res 12 (1): 273-80, 2006. [PubMed: 16397052]
  17. Llobet D, Eritja N, Encinas M, et al.: Antioxidants block proteasome inhibitor function in endometrial carcinoma cells. Anticancer Drugs 19 (2): 115-24, 2008. [PubMed: 18176107]
  18. Perrone G, Hideshima T, Ikeda H, et al.: Ascorbic acid inhibits antitumor activity of bortezomib in vivo. Leukemia 23 (9): 1679-86, 2009. [PubMed: 19369963]
  19. Bannerman B, Xu L, Jones M, et al.: Preclinical evaluation of the antitumor activity of bortezomib in combination with vitamin C or with epigallocatechin gallate, a component of green tea. Cancer Chemother Pharmacol 68 (5): 1145-54, 2011. [PMC free article: PMC3215871] [PubMed: 21400028]
  20. Heaney ML, Gardner JR, Karasavvas N, et al.: Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer Res 68 (19): 8031-8, 2008. [PMC free article: PMC3695824] [PubMed: 18829561]

Changes to This Summary (10/13/2020)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Human/Clinical Studies

Added text to state that a single-arm pilot study of weekly infusions of 60 g of ascorbic acid for 9 weeks in castration-resistant prostate cancer patients failed to observe a reduction in serum prostate-specific antigen or a decrease in tumor regression (cited Nielsen et al. as reference 9).

Adverse Effects

Added text to state that one study reported fluid overload related to ascorbic acid infusion, but this may be caused by the delivery method and not the product (cited Nielsen et al. as reference 10).

This summary is written and maintained by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of high-dose vitamin C in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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This summary is reviewed regularly and updated as necessary by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ High-Dose Vitamin C. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/cam/hp/vitamin-c-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389504]

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