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Intravenously administered vitamin C as cancer therapy: three cases. CMAJ 2006;174(7):937-42

Riordan HD et al. A pilot clinicla study of continuous intravenous ascorbate in terminal cancer patients. PR Health Sci J. Dec 2005;24(4):269-76

Mikirova N, Casciari J, Rogers A, Taylor P. Effect of high dose intravenous vitamin C on inflammation in cancer patients

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Chen Q et al. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues. PNAS. Sept 20 2005;102(38):13604-13609

http://lpi.oregonstate.edu/mic/vitamins/vitamin-C – Linus Pauling Institute – newsletter and review studies  of benefit of Vitamin C Therapy

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Intravenously administered vitamin C as cancer therapy: three cases

Abstract

Early clinical studies showed that high-dose vitamin C, given by intravenous and oral routes, may improve symptoms and prolong life in patients with terminal cancer. Double-blind placebo-controlled studies of oral vitamin C therapy showed no benefit. Recent evidence shows that oral administration of the maximum tolerated dose of vitamin C (18 g/d) pro- duces peak plasma concentrations of only 220 μmol/L, whereas intravenous administration of the same dose pro- duces plasma concentrations about 25-fold higher. Larger doses (50–100 g) given intravenously may result in plasma concentrations of about 14 000 μmol/L. At concentrations above 1000 μmol/L, vitamin C is toxic to some cancer cells but not to normal cells in vitro. We found 3 well-documented cases of advanced cancers, confirmed by histopathologic re- view, where patients had unexpectedly long survival times after receiving high-dose intravenous vitamin C therapy. We examined clinical details of each case in accordance with National Cancer Institute (NCI) Best Case Series guidelines. Tumour pathology was verified by pathologists at the NCI who were unaware of diagnosis or treatment. In light of re- cent clinical pharmacokinetic findings and in vitro evidence of anti-tumour mechanisms, these case reports indicate that the role of high-dose intravenous vitamin C therapy in can- cer treatment should be reassessed.

CMAJ 2006;174(7):937-42

Thirty years ago Cameron, Campbell and Pauling re- ported beneficial effects of high-dose vitamin C (ascorbic acid) therapy for patients with terminal cancer.1–4 Subsequent double-blind, randomized clinical tri- als at the Mayo Clinic failed to show any benefit,5,6 and the role of vitamin C in cancer treatment was discarded by mainstream oncologists.7,8 Vitamin C continues, however, to be used as an alternative cancer therapy.9,10

A key distinction between conventional, science-based medicine and alternative therapy is the presence or absence of scientific plausibility.11 In conventional medicine, the efficacy of treatment is proven by properly conducted clinical trials. Many treatments are still used if there is moderately good, al- beit inconclusive evidence of efficacy (“clinical plausibility”),

especially when treatment rationale agrees with biologic facts (conferring “biological plausibility”).11 Vitamin C is an alter- native cancer therapy because the results obtained in original studies that suggested clinical benefit were not confirmed by controlled clinical trials, and the notion that high-dose vita- min C was selectively toxic to cancer cells was biologically im- plausible.

New information is available pertaining to biological plausibility. Although similar doses of vitamin C were used in the Cameron–Pauling and Mayo Clinic studies, the Cameron–Pauling studies combined intravenous and oral adminis-tration whereas the Mayo Clinic studies used only oral administration.1,2,12–14 Recent pharmacokinetics modeling15 indicates that with oral administration, even very large and frequent doses of vitamin C will increase plasma concentrations onlymodestly, from 70 μmol/L to a maximum of 220 μmol/L whereas intravenous administration raises plasma concentrations as high as 14 000 μmol/L. Concentrations of 1000–5000 μmol/L are selectively cytotoxic to tumour cells in vitro,16–20 and emerging evidence indicates that ascorbic acid at concentrations achieved only by the intravenous route may function as a pro-drug for hydrogen peroxide delivery to tissues.20 The in vitro biologic evidence and clinical pharmacokinetics data confer biological plausibility to the notion that vitamin C could affect cancer biology and may explain in part the negative results of the Mayo Clinic trials.13,15,21,22 Thus, sufficient evidence has accumulated, not to use vitamin C as cancetreatment, but to further explore the therapeutic concept. Oneway to increase the clinical plausibility of alternative cancetherapies is rigorous, well-documented case reporting, as laid out in the US National Cancer Institute (NCI) Best Case Series

Case reports of apparent responses by malignant disease to intravenous vitamin C therapy have appeared, includ ing those of 2 of the 3 patients presented below.25,26 However, they were reported without sufficient detail or with incom plete follow-up for evaluation and without conforming to NCI Best Case Series guidelines. They also lacked objective pathologic confirmation, which is a pillar of NCI guidelines. In this article, we use NCI Best Case Series guidelines to report 3 cases of patients with usually progressive malignant

guidelines (http://www3.cancer.gov/occam/bestcase.html). Such case series might identify alternative therapies that merit further investigation.23,24

CMAJ • March 28, 2006 • 174(7) | 937

© 2006 CMA Media Inc. or its licensors

DOI:10.1503/cmaj.050346

CMAJ • March 28, 2006 • 174(7) | 938

The overall plausibility of ascorbic acid administered intra- venously as a cancer therapy is enhanced by recent insights into clinical pharmacokinetics and in vitro cancer-specific cy- totoxicity of vitamin C.15–20 Pharmacokinetics data show that orally administered vitamin C results in tightly controlled plasma and cell concentrations. Subjects consuming 200–300 mg per day of vitamin C in 5 or more daily servings of fruits and vegetables have fasting steady state plasma con- centrations of about 70–80 μmol/L.40,41 Even with maximally tolerated oral doses of 3 g every 4 hours, peak plasma con- centrations are estimated to not exceed 220 μmol/L.15 Intra- venous administration of vitamin C bypasses tight control for several hours, until homeostasis is restored by renal excre- tion. Depending on the dose and infusion rate, peak plasma concentrations obtained intravenously are estimated to reach 14 000 μmol/L, and concentrations above 2000 μmol/L may persist for several hours. Emerging in vitro data show that ex- tracellular ascorbic acid selectively kills some cancer but no normal cells by generating hydrogen peroxide.20 Death is me- diated exclusively by extracellular ascorbate, at pharmaco- logic concentrations that can be achieved only by intravenous administration. Vitamin C may serve as a pro-drug for hydrogen peroxide delivery to extravascular tissues, but without the presence of hydrogen peroxide in blood. These data are consistent with clinical pharmacokinetics of vitamin C administered intravenously.