Common Uses in Cancer Care
IVC is most commonly prescribed to improve quality of life, to slow cancer progression and to reduce cancer-treatment related symptoms, for example fatigue, nausea and lack of appetite. The administration of IVC results in far higher serum levels of vitamin C than oral administration of an identical dose. IV infusion may raise serum levels of vitamin C 70-fold compared to those that may be achieved through oral dosing alone. IV administration bypasses the gastrointestinal controls within the body that prevent the absorption of vitamin C when taken orally. Only the IV route of administration has been documented to achieve sufficient serum levels to observe an anticancer effect.
Mechanism of Action:
A) H2O2 Production: Administration of IVC has been shown to cause measurable increases in extracellular H2O2, which has been shown to cause cell death in numerous cancer cell lines by necrosis while leaving normal human cells unharmed.
B) Pro-oxidant effect: Despite vitamin C’s known action as an antioxidant when taken orally, the high serum concentrations of vitamin C that result from IV administration lead to the generation of free radicals in the extracellular fluid, causing the infused vitamin C to behave as a pro-oxidant compound in vivo. The actions of a pro-oxidant are the opposite to an antioxidant in that the pro- oxidant will generate free radicals, rather than quench them.
Clinical Evidence Related to Quality of life
The clinical trials that have been published have included only patients with advanced disease. These studies have assessed the impact of IVC on quality of life. In one trial, quality of life remained stable while quality of life improved in another. Breast cancer patients who used IVC in combination with standard care demonstrated improved quality of life as compared to those who used standard care only. These results are notable, as quality of life would otherwise be expected to decrease in this population of patients with advanced disease.
Clinical Evidence Related to Slow Cancer Progression
IVC is not considered a curative therapy for cancer, however, a handful of well-documented case reports suggest that treatment with IVC is associated with tumour regression and remission, and unexpectedly long survival times. These outcomes are supported by animal studies conducted using high doses of vitamin C obtainable by IV infusion that demonstrate reduced tumour size and decreased tumour growth rate. Similarly, in vitro evidence demonstrates sensitivity of a number of cell lines to treatment with vitamin C.
IVC IN COMBINATION WITH STANDARD CARE
Recent clinical studies have examined the combination of IVC with concurrent chemotherapy based on hypotheses that IVC may reduce the toxicity of standard treatment, improve treatment response, or both. In one study that included women with breast cancer, cancer-related symptoms and treatment side effects were reduced in those women who were treated with IVC. In a separate trial conducted in women with ovarian cancer, women who received IVC treatment reported fewer side effects and a trend towards benefit in disease-related outcomes. Other therapies used in these trials included epirubicin, cyclophosphamide, methotrexate, fluorouracil, paclitaxel and cisplatin.
A recent trial included people newly diagnosed with stage IV pancreatic cancer who were treated with IVC in combination with gemcitabine and erlotinib as first line treatment. Eight of the 9 patients who completed the trial had a reduction in the size of their primary tumour and tumour size was stable in the ninth patient. These results are not typical for treatment with either gemcitabine or gemcitabine plus erlotinib alone.
Animal and cell-line studies suggest a synergistic effect when some chemotherapeutic agents are combined with pharmacologic doses of vitamin C. Published evidence appears to support concurrent use of IVC with: gemcitabine (20), carboplatin (21), cisplatin (3, 22, 23), etoposide (3), 5-fluorouracil (3, 22, 24), epirubicin (24), doxorubicin (3, 16, 23), paclitaxel (3, 23), docetaxel (24), and irinotecan (24). In these studies, the combination of IVC plus chemotherapy was related to increased tumour inhibition and decreased tumour growth rate as compared to either IVC or chemotherapy alone.
PCNM and Ottawa Integrative Cancer Clinic have prepared this information to share results and review the research evidence related to IVC within cancer patient care. Every effort is made to ensure the information is accurate at the time it is published. Prior to using a new therapy or product, always consult a licensed health care provider. This information should not be interpreted as medical advice nor should it replace the advice of a qualified health care provider.
1. Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Annals of internal medicine. 2004;140(7):533-7. Epub 2004/04/08.
2. 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. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(21):8749-54. Epub 2007/05/16.
3. Verrax J, Calderon PB. Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects. Free radical biology & medicine. 2009;47(1):32-40. Epub 2009/03/04.
4. 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. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(38):13604-9. Epub 2005/09/15.
5. Duconge J, Miranda-Massari JR, Gonzalez MJ, Jackson JA, Warnock W, Riordan NH. Pharmacokinetics of vitamin C: insights into the oral and intravenous administration of ascorbate. Puerto Rico health sciences journal. 2008;27(1):7-19. Epub 2008/05/03.
6. Robitaille L, Mamer OA, Miller WH, Jr., Levine M, Assouline S, Melnychuk D, et al. Oxalic acid excretion after intravenous ascorbic acid administration. Metabolism: clinical and experimental. 2009;58(2):263-9. Epub 2009/01/22.
7. Lee YJ, Shacter E. Oxidative stress inhibits apoptosis in human lymphoma cells. The Journal of biological chemistry. 1999;274(28):19792-8. Epub 1999/07/03.
8. 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. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(32):11105-9. Epub 2008/08/06.
9. Padayatty SJ, Katz A, Wang Y, Eck P, Kwon O, Lee JH, et al. Vitamin C as an antioxidant: evaluation of its role in disease prevention. Journal of the American College of Nutrition. 2003;22(1):18- 35. Epub 2003/02/06.
10. 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. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2008;19(11):1969-74. Epub 2008/06/12.
11. Yeom CH, Jung GC, Song KJ. Changes of terminal cancer patients’ health-related quality of life after high dose vitamin C administration. Journal of Korean medical science. 2007;22(1):7-11. Epub 2007/02/14.
12. Vollbracht C, Schneider B, Leendert V, Weiss G, Auerbach L, Beuth J. Intravenous vitamin C administration improves quality of life in breast cancer patients during chemo-/radiotherapy and aftercare: results of a retrospective, multicentre, epidemiological cohort study in Germany. In vivo. 2011;25(6):983-90. Epub 2011/10/25.
13. Drisko JA, Chapman J, Hunter VJ. The use of antioxidants with first-line chemotherapy in two cases of ovarian cancer. Journal of the American College of Nutrition. 2003;22(2):118-23. Epub 2003/04/04.
14. Padayatty SJ, Riordan HD, Hewitt SM, Katz A, Hoffer LJ, Levine M. Intravenously administered vitamin C as cancer therapy: three cases. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne. 2006;174(7):937-42. Epub 2006/03/29.
15. Chen P, Yu J, Chalmers B, Drisko J, Yang J, Li B, et al. Pharmacological ascorbate induces cytotoxicity in prostate cancer cells through ATP depletion and induction of autophagy. Anti-cancer drugs. 2012;23(4):437-44. Epub 2011/12/30.
16. Casciari JJ, Riordan NH, Schmidt TL, Meng XL, Jackson JA, Riordan HD. Cytotoxicity of ascorbate, lipoic acid, and other antioxidants in hollow fibre in vitro tumours. British journal of cancer. 2001;84(11):1544-50. Epub 2001/06/01.
17. Du J, Martin SM, Levine M, Wagner BA, Buettner GR, Wang SH, et al. Mechanisms of ascorbate- induced cytotoxicity in pancreatic cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010;16(2):509-20. Epub 2010/01/14.
18. Sullivan G, Chen Q, Chen P, Chapman J, Levine M, Drisko J. Prospective Randomized Phase I/IIa Pilot Trial to Assess Safety and Benefit Administering High-Dose Intravenous Ascorbate in Combination with Chemotherapy in Newly Diagnosed Advanced Stage III or Stage IV Ovarian Cancer. 8th Annual Conference of the Society for Integrative Oncology; November 9-12, 2011; Cleveland, Ohio 2011.
19. Monti DA, Mitchell E, Bazzan AJ, Littman S, Zabrecky G, Yeo CJ, et al. 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. Epub 2012/01/25.
20. Chen P, Chalmers B, Drisko J, Chen Q. Pharmacologic Ascorbate Synergizes with Gemcitabine in Pre-Clinical Models of Pancreatic Cancer 8th Annual Conference of the Society for Integrative Oncology; November 9-12, 2011; Cleveland, Ohio2011.
21. Ma Y, Drisko J, Polireddy K, Chen Q. Synergistic Effects of Ascorbate with Carboplatin against Human Ovarian Cancer In Vitro and In Vivo 8th Annual Conference of the Society for Integrative Oncology; November 9-12, 2011; Cleveland, Ohio2011.
22. Abdel-Latif MM, Raouf AA, Sabra K, Kelleher D, Reynolds JV. Vitamin C enhances chemosensitization of esophageal cancer cells in vitro. Journal of chemotherapy. 2005;17(5):539-49. Epub 2005/12/06.
23. Kurbacher CM, Wagner U, Kolster B, Andreotti PE, Krebs D, Bruckner HW. Ascorbic acid (vitamin C) improves the antineoplastic activity of doxorubicin, cisplatin, and paclitaxel in human breast carcinoma cells in vitro. Cancer letters. 1996;103(2):183-9. Epub 1996/06/05.
24. Fromberg A, Gutsch D, Schulze D, Vollbracht C, Weiss G, Czubayko F, et al. Ascorbate exerts anti- proliferative effects through cell cycle inhibition and sensitizes tumor cells towards cytostatic drugs. Cancer chemotherapy and pharmacology. 2011;67(5):1157-66. Epub 2010/08/10.
25. Heaney ML, Gardner JR, Karasavvas N, Golde DW, Scheinberg DA, Smith EA, et al. Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer research. 2008;68(19):8031-8. Epub 2008/10/03.
26. Drisko J. Intravenous Vitamin C and Other IV Therapies in Cancer Care. Confronting Cancer as a Chronic Disease: Primary Care Takes a 360-degree May 20-23, 2010; San Diego, California2010.
27. Levine M, Espey MG, Chen Q. Losing and finding a way at C: new promise for pharmacologic ascorbate in cancer treatment. Free radical biology & medicine. 2009;47(1):27-9. Epub 2009/04/14.
28. Chen P, Stone J, Sullivan G, Drisko JA, Chen Q. Anti-cancer effect of pharmacologic ascorbate and its interaction with supplementary parenteral glutathione in preclinical cancer models. Free radical biology & medicine. 2011;51(3):681-7. Epub 2011/06/16.
29. Riordan HD, Casciari JJ, Gonzalez MJ, Riordan NH, Miranda-Massari JR, Taylor P, et al. A pilot clinical study of continuous intravenous ascorbate in terminal cancer patients. Puerto Rico health sciences journal. 2005;24(4):269-76. Epub 2006/03/31.
30. Padayatty SJ, Sun AY, Chen Q, Espey MG, Drisko J, Levine M. Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PloS one. 2010;5(7):e11414. Epub 2010/07/16.
31. Auer BL, Auer D, Rodgers AL. Relative hyperoxaluria, crystalluria and haematuria after megadose ingestion of vitamin C. European journal of clinical investigation. 1998;28(9):695-700. Epub 1998/10/10. 32. Mashour S, Turner JF, Jr., Merrell R. Acute renal failure, oxalosis, and vitamin C supplementation: a case report and review of the literature. Chest. 2000;118(2):561-3. Epub 2000/08/11.
33. Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of the intake of vitamins C and B6, and the risk of kidney stones in men. The Journal of urology. 1996;155(6):1847-51. Epub 1996/06/01.
34. Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Intake of vitamins B6 and C and the risk of kidney stones in women. Journal of the American Society of Nephrology : JASN. 1999;10(4):840-5. Epub 1999/04/15.
35. Canavese C, Petrarulo M, Massarenti P, Berutti S, Fenoglio R, Pauletto D, et al. Long-term, low- dose, intravenous vitamin C leads to plasma calcium oxalate supersaturation in hemodialysis patients. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2005;45(3):540-9. Epub 2005/03/09.
36. McAllister CJ, Scowden EB, Dewberry FL, Richman A. Renal failure secondary to massive infusion of vitamin C. JAMA : the journal of the American Medical Association. 1984;252(13):1684. Epub 1984/10/05.
37. Lawton JM, Conway LT, Crosson JT, Smith CL, Abraham PA. Acute oxalate nephropathy after massive ascorbic acid administration. Archives of internal medicine. 1985;145(5):950-1. Epub 1985/05/01.
38. Riordan HD, Jackson JA, Riordan NH, Schultz M. High-dose intravenous vitamin C in the treatment of a patient with renal cell carcinoma of the kidney. Journal of Orthomolecular Medicine. 1998;13:72-3.
39. Campbell GD, Jr., Steinberg MH, Bower JD. Letter: Ascorbic acid-induced hemolysis in G-6-PD deficiency. Annals of internal medicine. 1975;82(6):810. Epub 1975/06/11.
40. Rees DC, Kelsey H, Richards JD. Acute haemolysis induced by high dose ascorbic acid in glucose- 6-phosphate dehydrogenase deficiency. Bmj. 1993;306(6881):841-2. Epub 1993/03/27.
41. Barton JC, McDonnell SM, Adams PC, Brissot P, Powell LW, Edwards CQ, et al. Management of hemochromatosis. Hemochromatosis Management Working Group. Annals of internal medicine. 1998;129(11):932-9. Epub 1998/12/29.
42. Shahrbanoo K, Taziki O. Effect of intravenous ascorbic acid in hemodialysis patients with anemia and hyperferritinemia. Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia. 2008;19(6):933-6. Epub 2008/11/01.