ALTERNATIVE CANCER SOLUTION

 Vitamin C and Cancer Research

Discussion
These cases were analyzed in accordance with the NCI's Best Case Series process, which reports and interprets apparent responses to alternative therapies.23,24 Apart from its implications regarding vitamin C, this article illustrates the use of the Best Case Series approach in assessing the clinical plausibility of novel therapies. None of these case histories provides definitive proof that intravenous vitamin C therapy was responsible for the patient's unusually favourable clinical course. It is often difficult to prove definitively that a given treatment is responsible for a specific clinical outcome. When the treatment is unorthodox, alternative explanations, even if highly unlikely, tend to be preferred.38,39 However, although they do not provide grounds for advocating intravenous vitamin C therapy as a cancer treatment, these cases increase the clinical plausibility of the notion that vitamin C administered intravenously might have effects on cancer under certain circumstances.

The overall plausibility of ascorbic acid administered intravenously as a cancer therapy is enhanced by recent insights into clinical pharmacokinetics and in vitro cancer-specific cytotoxicity 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 concentrations of about 70–80 µmol/L.40,41 Even with maximally tolerated oral doses of 3 g every 4 hours, peak plasma concentrations are estimated to not exceed 220 µmol/L.15Intravenous administration of vitamin C bypasses tight control for several hours, until homeostasis is restored by renal excretion. 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 extracellular ascorbic acid selectively kills some cancer but no normal cells by generating hydrogen peroxide.20 Death is mediated exclusively by extracellular ascorbate, at pharmacologic 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.15Of note, only a minority of cancer patients reported by Cameron and colleagues responded to intravenous and oral vitamin C therapy,1–4and not all cancer cells were killed by ascorbic acid in vitro.20 Further basic investigation of pharmacologic vitamin C concentrations in mediating cell death will facilitate discovery of the mechanisms responsible for sensitivity and resistance in vitro and in vivo. On the basis of emerging clinical and in vitro data, early-phase clinical trials of intravenous vitamin C therapy alone and in combination with conventional chemotherapy are currently in the planning and execution phase, including a formal phase I trial in progress at McGill University.

The cases reported here do not prove that vitamin C induced the favourable outcomes observed. These patients received other alternative medicine therapies. Spontaneous remission of some tumours may occur rarely, although the 3 cancers reported here are dissimilar. Accretion of more cases meeting NCI Best Case Series guidelines may indicate whether vitamin C or other factors contribute to such remissions.

It is likely that high vitamin C intakes have low toxicity, except under certain conditions.45,46 Intravascular hemolysis was reported after massive vitamin C administration in people with glucose-6-phosphate dehydrogenase deficiency.46Administration of high-dose vitamin C to patients with systemic iron overload may increase iron absorption and represents a contraindication.46,47Ascorbic acid is metabolized to oxalate, and 2 cases of acute oxalate nephropathy were reported in patients with pre-existing renal insufficiency given massive intravenous doses of vitamin C.48,49Therefore, patients with renal insufficiency or renal failure, or who are undergoing dialysis, should not receive high doses of vitamin C.46 It is controversial whether high-dose vitamin C use is associated with oxalate kidney stones, and patients with hyperoxaluria or a prior history of oxalate kidney stones have a relative contraindication to high-dose vitamin C.46Rare cases of acute tumour hemorrhage and necrosis were reported in patients with advanced cancer within a few days of starting high-dose intravenous vitamin C therapy, although this was not independently verified by pathologic review.1,50 Although tumour hemorrhage suggests an anticancer potential for ascorbate, there is the potential for risk to some patients.

The cases reported here are of tumours confirmed by histopathologic examination to have poor prognosis but that instead had long clinical remissions. Most previous case reports lacked independent pathologic confirmation of the tumour and did not follow the NCI Best Case Series guidelines, which makes their interpretation difficult. Recent findings show that only high-dose intravenous, but not oral, vitamin C therapy results in very high plasma vitamin C concentrations (e.g., 14 000 µmol/L). At these concentrations, the vitamin is toxic to some cancer cells, possibly because at these concentrations the vitamin is a pro-drug for hydrogen peroxide formation in extracellular fluid. Accumulated data confer some degree of biological and clinical plausibility to the notion that high-dose intravenous vitamin C therapy may have anti-tumour effects in certain cancers. When all available data are considered, further clinical study as to safety and efficacy of intravenous vitamin C is warranted.

 

Footnotes
Editor's take.

Intravenous administration of the maximum tolerated dose of vitamin C produces plasma levels 25 times that achieved when the same dose is administered orally. At high plasma concentrations vitamin C is toxic to some cancer cells but not to normal cells in vitro.

Using the National Cancer Institute Best Case Series guidelines, the authors reviewed 3 cases of advanced cancer where patients had unexpectedly long survival times after receiving high-dose intravenous vitamin C therapy.

Implications for practice: In a setting of biological plausibility and clinical plausibility, further research into vitamin C as a treatment for cancer is warranted.