C You Later Cancer
Big Disclaimer: I am not a doctor, and this is not medical advice. Also, what I am writing about is not FDA approved. Take from that what you will.
Vitamin C (L-ascorbic acid: a water-soluble vitamin that we must get from dietary sources) is kind of like a Swiss Army Knife when it comes to its role in the body. Vitamin C is necessary for the synthesis of collagen (the most abundant protein in our body and an imperative part of connective tissue; 1,2), the synthesis of L-Carnitine (a protein involved in fatty acid oxidation, 1,2), protein metabolism (1,2), is a physiological antioxidant (3), and helps to regenerate vitamin E (a fat-soluble vitamin and antioxidant; 4). And maybe, if you keep your finger on the pulse of Alternative Medicine, you may have heard that Vitamin C is effective at treating cancer. This is a pretty controversial claim…but is there any truth to this?
Well, we can look back to the 1970s to find the origins of these claims. Drs. Ewan Cameron and Linus Pauling both retrospectively published case reports of advanced stage cancer patients benefiting from 10g/day of Vitamin C (5–7). Case reports are great, but in science we like to see more. Specifically, we like to see double-blind, randomized controlled trials (considered the gold standard). So that is exactly what Mayo Clinic doctors did. They used the same 10g/day dose of Vitamin C but found no benefit compared to the placebo. When a randomized controlled trial, especially one from the Mayo Clinic, shows no effect for Vitamin C in cancer…that is pretty much a death sentence. Thus, oral Vitamin C was nixed as a potential anti-cancer agent (8–10).
Fortunately for us, several researchers would not settle for this claim, frankly because something about the pharmacokinetic data struck them as peculiar. So, over the last 25 years, researchers at the NIH and across the globe have tried to figure out the perplexing case of Vitamin C and its potential role in cancer.
In brief, when you take Vitamin C orally, your body tightly regulates the amount that will be absorbed and subsequently found in circulation in your plasma (thanks to limited gastrointestinal absorption, saturated tissue transporters, and renal reabsorption and excretion). Roughly 70–90% of Vitamin C is absorbed at intakes between 30–180 mg/day, but when you take doses above 1g/day orally, absorption plummets to below 50%, and any unmetabolized Vitamin C will be excreted via urine (4). We also have data showing that mean peak plasma Vitamin C concentrations can be reached with 1.25g/day of oral Vitamin C. This produces a concentration of 135 micromol/L (4). With oral administration, pharmacokinetic modeling predicts that plasma concentrations could reach 220 micromol/L if one takes 3g of Vitamin C every 4 hours, but this has never been tested in humans (35). So, we can just keep a ballpark of 135–220 micromol/L in the back of our minds with regards to oral administration.
Well, it turns out that when you administer Vitamin C intravenously (IV), that tight regulation can be bypassed (because you inject straight into the vein), and plasma Vitamin C concentrations can reach all the way up to 26,000 micromol/L (11,12). What’s more, is that at these supraphysiologic concentrations, Vitamin C acts a pro-oxidant to form Hydrogen Peroxide in the extracellular space (13–17). Based on animal models, we know that this hydrogen peroxide has anti-cancer properties like chemotherapy, can synergize with traditional chemotherapy (18–21), and selectively kills cancer cells while sparing healthy cells (27–29). IV Vitamin C has a multitude of effects that could explain its effectiveness in treating cancer (Figure 1). I spent roughly 2 weeks combing through the literature and created this infographic for a laboratory presentation and would like to share it with my audience:
With this realization, we can look back at the Cameron/Pauling case reports and the Mayo Clinic Randomized Control Trial. It turns out that Cameron/Pauling used both oral and IV administration of Vitamin C, but the Mayo Clinic only used oral administration. Now, while we cannot definitively say that Cameron/Pauling saw positive results because of intravenous administration (because these were retrospective case reports), we can conclude that the Mayo Clinic saw no positive results because they used oral Vitamin C, thus producing plasma concentrations 70–80-fold lower than what is needed to produce the cancer destroying hydrogen peroxide!
So, what kind of clinical data do we have in humans? Well, for IV Vitamin C to hit the mainstream, we need positive results from a Phase III Clinical Trial, and subsequent FDA approval. We are not quite at that stage yet, but in recent years there have been a handful of early phase trials and case reports.
Early phase clinical trials demonstrate that IV Vitamin C at 1g/kg over 90–120 minutes, 2–3x a week is well tolerated, may enhance chemo sensitivity, and decrease chemotherapy related side effects (15,17,19, 22–26; Figure 2).
A recent 2018 case report outlines the use of IV Vitamin C in a patient diagnosed with Stage 4 Pancreatic Ductal Cancer (5-year survival rate is 6%; 30). The patient sought out a different approach to care, after traditional care was ineffective. The patient exclusively received IV Vitamin C (75–125 g per day, 2–3x per week), and survived 4 years post-diagnosis (31). There are other similar case reports to this one in the literature (nothing magical, but extended life w/ diagnosis and improved quality of life).
There are also currently 11 IV Vitamin C cancer clinical trials that are still recruiting patients (34). More data is on the way (Search “IV Vitamin C + Cancer +Recruiting on www.ClinicalTrials.gov)!
So, what was the point with all this? I think it is fair to say that there is a plethora of data showing the effectiveness of IV Vitamin C in treating cancer. In fact, with the 11 clinical trials still recruiting, we should be pushing towards a Phase 3 trial soon. The problem with mainstream medicine is that we are so tied to the data (for a good reason). We want to follow the data and let it talk. However, science is not some static creature, it is fluid and ever-changing. If the data changes, then shouldn’t our opinion on the topic change as well? Isn’t that supposed to be the essence of science and medicine? We now have data that invalidates the Mayo Clinic trial, so maybe it is time to remove the taboo around using IV Vitamin C to treat cancer.
I am in no way suggesting you seek out IV Vitamin C therapy if you or a loved one has cancer, it is merely another tool in the toolbox. Although traditional medicine is still wavering, many alternative medicine doctors use this tool if it is of interest to you. You have the data at your fingerprints, so it is up to you to strike up a dialogue with your physician if this interests you. However, there are a few conditions that may preclude you from receiving IV Vit C. These include Kidney disease, G6P Deficiency, and hemochromatosis, so please keep these conditions in mind.
If I were a betting man, I would bet that IV Vitamin C becomes a mainstay treatment option for various cancers in the next 25 years. What do you think?
1. Li Y, Schellhorn HE. New developments and novel therapeutic perspectives for vitamin C. J Nutr 2007;137:2171–84.
2. Carr AC, Frei B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr 1999;69:1086–107.
3. Frei B, England L, Ames BN. Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci U S A 1989;86:6377–81.
4. Jacob RA, Sotoudeh G. Vitamin C function and status in chronic disease. Nutr Clin Care 2002;5:66–74.
5. Cameron E, and Campbell A (1974). The orthomolecular treatment of cancer. II. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer. Chemico-biological interactions 9, 285–315
6. Cameron E, and Pauling L (1976). Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proceedings of the National Academy of Sciences of the United States of America 73, 3685–3689.
7. Cameron E, and Pauling L (1978). Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer. Proceedings of the National Academy of Sciences of the United States of America 75, 4538–4542.
8. Creagan ET, Moertel CG, O’Fallon JR, Schutt AJ, O’Connell MJ, Rubin J, and Frytak S (1979). Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial. N Engl J Med 301, 687–690.
9. Moertel CG, Fleming TR, Creagan ET, Rubin J, O’Connell MJ, and Ames MM (1985). 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, 137–141.
10. Wittes RE (1985). Vitamin C and cancer. N Engl J Med 312, 178–179
11. Padayatty SJ, Riordan HD, Hewitt SM, Katz A, Hoffer LJ, Levine M. Intravenously administered vitamin C as cancer therapy: three cases. CMAJ 2006;174:937–42.
12. Hoffer LJ, Levine M, Assouline S, Melnychuk D, Padayatty SJ, Rosadiuk K, et al. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol 2008;19:1969–74.
13. Chen Q, Espey MG, Sun AY, Pooput C, Kirk KL, Krishna MC, Khosh DB, Drisko J, and Levine M (2008). Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proceedings of the National Academy of Sciences of the United States of America 105, 11105–11109.
14. Hoffer LJ, Levine M, Assouline S, Melnychuk D, Padayatty SJ, Rosadiuk K, Rousseau C, Robitaille L, and Miller WH Jr. (2008). Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Annals of oncology : official journal of the European Society for Medical Oncology 19, 1969–1974.
15. Monti DA, Mitchell E, Bazzan AJ, Littman S, Zabrecky G, Yeo CJ, Pillai MV, Newberg AB, Deshmukh S, and Levine M (2012). Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. PloS one 7, e29794.
16. Padayatty SJ, Sun AY, Chen Q, Espey MG, Drisko J, and Levine M (2010). Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PloS one 5, e11414.
17. Welsh JL, Wagner BA, van’t Erve TJ, Zehr PS, Berg DJ, Halfdanarson TR, Yee NS, Bodeker KL, Du J, Roberts LJ 2nd, et al. (2013). Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. Cancer chemotherapy and pharmacology 71, 765–775.
18. Espey MG, Chen P, Chalmers B, Drisko J, Sun AY, Levine M, and Chen Q (2011). Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer. Free radical biology & medicine 50, 1610–1619.
19. Ma Y, Chapman J, Levine M, Polireddy K, Drisko J, and Chen Q (2014). High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Science translational medicine 6, 222ra218.
20. Serrano OK, Parrow NL, Violet PC, Yang J, Zornjak J, Basseville A, and Levine M (2015). Antitumor effect of pharmacologic ascorbate in the B16 murine melanoma model. Free radical biology & medicine 87, 193–203.
21. Xia J, Xu H, Zhang X, Allamargot C, Coleman KL, Nessler R, Frech I, Tricot G, and Zhan F (2017). Multiple Myeloma Tumor Cells are Selectively Killed by Pharmacologically-dosed Ascorbic Acid. EBioMedicine 18, 41–49.
22. Carr AC, Vissers MC, and Cook JS (2014). The effect of intravenous vitamin C on cancer- and chemotherapy-related fatigue and quality of life. Frontiers in oncology 4, 283.
23. Hoffer LJ, Robitaille L, Zakarian R, Melnychuk D, Kavan P, Agulnik J, Cohen V, Small D, and Miller WH Jr. (2015). High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: a phase I-II clinical trial. PloS one 10, e0120228.
24. Shim EH, Livi CB, Rakheja D, Tan J, Benson D, Parekh V, Kho EY, Ghosh AP, Kirkman R, Velu S, et al. (2014). L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer. Cancer discovery 4, 1290–1298.
25. Schoenfeld JD, Sibenaller ZA, Mapuskar KA, Wagner BA, Cramer-Morales KL, Furqan M, Sandhu S, Carlisle TL, Smith MC, Abu Hejleh T, et al. (2017). O2- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer cell 31, 487–500.e488
26. Stephenson CM, Levin RD, Spector T, and Lis CG (2013). Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer chemotherapy and pharmacology 72, 139–146
27. Chen Q, Espey MG, Sun AY, Pooput C, Kirk KL, Krishna MC, 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 2008;105:11105–9.
28. Chen Q, Espey MG, Krishna MC, Mitchell JB, Corpe CP, Buettner GR, 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 2005;102:13604–9.
29. Chen Q, Espey MG, Sun AY, Lee JH, Krishna MC, Shacter E, et al. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci U S A 2007;104:8749–54
30. Siegel R, Miller K, Jemal A. Cancer statistics 2015. CA Cancer J Clin 2015; 65:5–29.
31. Drisko JA, Serrano OK, Spruce LR, Chen Q, Levine M. Treatment of pancreatic cancer with intravenous vitamin C: a case report. Anticancer Drugs. 2018;29(4):373–379. doi:10.1097/CAD.0000000000000603
32. PLOS ONE: Phase I Evaluation of Intravenous Ascorbic Acid in Combination with Gemcitabine and Erlotinib in Patients with Metastatic Pancreatic Cancer
33. 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/patient/vitamin-c-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389507]
34. Search of: Intravenous Vitamin C | Recruiting Studies | Cancer — List Results — ClinicalTrials.gov