Research
Intravenously administered vitamin C as cancer therapy: three cases
From the Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (Padayatty, Katz, Levine), and the Laboratory of Pathology, Centers for Cancer Research, National Cancer Institute (Hewitt), National Institutes of Health, Bethesda, Md.; Lady Davis Institute for Medical Research (Hoffer), McGill University, Montréal, Que.; Bio-Communications Research Institute (Riordan) (deceased), Wichita, Kan.
Correspondence to: Dr. Mark Levine, Molecular and Clinical Nutrition Section, Bldg. 10, Rm 4D52–MSC 1372, National Institutes of Health, Bethesda MD 20892–1372; MarkL@mail.nih.gov
 | Abstract |
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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) produces peak plasma concentrations of only 220 µmol/L, whereas intravenous administration of the same dose produces 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 review, 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 recent 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 cancer treatment should be reassessed.
Thirty years ago Cameron, Campbell and Pauling reported beneficial effects of high-dose vitamin C (ascorbic acid) therapy for patients with terminal cancer.1–4 Subsequent double-blind, randomized clinical trials 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.11In conventional medicine, the efficacy of treatment is proven by properly conducted clinical trials. Many treatments are still used if there is moderately good, albeit inconclusive evidence of efficacy ("clinical plausibility"), especially when treatment rationale agrees with biologic facts (conferring "biological plausibility").11 Vitamin C is an alternative 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 vitamin C was selectively toxic to cancer cells was biologically implausible.
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 administration whereas the Mayo Clinic studies used only oral administration.1,2,12–14 Recent pharmacokinetics modeling15indicates that with oral administration, even very large and frequent doses of vitamin C will increase plasma concentrations only modestly, 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,16–20and 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 cancer treatment, but to further explore the therapeutic concept. One way to increase the clinical plausibility of alternative cancer therapies is rigorous, well-documented case reporting, as laid out in the US National Cancer Institute (NCI) Best Case Series guidelines (http://www3.cancer.gov/occam/bestcase.html).23,24 Such case series might identify alternative therapies that merit further investigation.23,24
Case reports of apparent responses by malignant disease to intravenous vitamin C therapy have appeared,25–30 including those of 2 of the 3 patients presented below.25,26 However, they were reported without sufficient detail or with incomplete 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 disease who received intravenous vitamin C therapy as their only significant cancer therapy and whose clinical courses were unusually favourable. Original diagnostic material obtained before treatment with vitamin C was reviewed by pathologists at the National Institutes of Health (NIH) who were unaware of the diagnoses and treatments.
| Patient 1 |
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This case was previously reported but without long-term follow-up, without detail, and with no independent pathologic confirmation.25,26 A 51-year-old woman was found in August 1995 to have a tumour involving her left kidney. At nephrectomy in September 1995 this was shown to be a renal cell carcinoma 9 cm in diameter with thrombus extending into the renal vein. Chest radiography results were normal, and there was no evidence of metastatic disease on CT scan of the chest and abdomen. In March 1996 a CT scan of the chest indicated several new, small, rounded and well-defined soft tissue masses no larger than 5 mm in diameter; they were judged consistent with metastatic cancer. By November 1996 chest radiography revealed multiple cannonball lesions (Fig. 1).
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The patient declined conventional cancer treatment and instead chose to receive high-dose vitamin C administered intravenously at a dosage of 65 g twice per week starting in October 1996 and continuing for 10 months. She also used other alternative therapies: thymus protein extract, N-acetylcysteine, niacinamide and whole thyroid extract (Table 1). In June 1997 chest radiography results were normal except for one remaining abnormality in the left lung field, possibly a pulmonary scar (Fig. 2).
Pauling himself reportedly took at least 12,000 mg daily and raised the amount to 40,000 mg if symptoms of a cold appear [4]. In 1993, after undergoing radiation therapy for prostate cancer, Pauling said that vitamin C had delayed the cancer's onset for twenty years. This was not a testable claim. He died of the disease in August 1994.
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In October 2001 a new mass 3.5 cm in diameter in the anterior right lung was detected on radiography. A transthoracic biopsy revealed small-cell carcinoma of the lung. The patient opted for intravenous vitamin C injections. The lung mass remained constant in size in radiograpy taken in May and August 2002 but had increased to 4 cm in views taken in October 2002. In early November hyponatremia developed. Two weeks later the patient was admitted to hospital with abdominal distension and constipation. Barium studies revealed slow transit but no intestinal obstruction. Results of a CT scan of the abdomen were normal. She died shortly afterward, and no autopsy was performed. Histopathologic review of the primary renal tumour at the NIH confirmed the diagnosis of clear-cell renal carcinoma, type, nuclear grade III/IV, with the largest diameter measuring 6.5 cm. The tumour involved the renal vein and hilar perinephric fat. Pathologic review of the lung tumour biopsy specimen of October 2001 was not conducted at the NIH. Local pathologists diagnosed this specimen as indicating small-cell lung cancer and not recurrent metastatic renal cell carcinoma.
This case describes the regression of pulmonary metastatic renal cancer in a patient receiving high-dose intravenous vitamin C therapy. According to the NCI Best Case Series guidelines, the credibility of this case would be increased by biopsy proof that the multiple slowly growing bilateral cannonball lung nodules in this patient with known renal cell carcinoma were actually malignant. However, in this case, the clinical characteristics and evolution of the pulmonary lesions, in the absence of bacterial infection or other systemic disease, make any other diagnosis unlikely. The clinician attending the patient deemed a confirmatory biopsy to be unnecessary and inappropriate in this setting. A plausible alternative explanation to the conclusion that this patient's metastatic renal cell cancer responded to intravenous vitamin C therapy is that the tumours spontaneously regressed. Spontaneous regression has been reported in renal cell cancer, but it is rare, occurring in fewer than 1% of cases and typically after nephrectomy, radiation to the primary tumour or primary tumour embolization.31,32 Here, metastatic disease appeared several months after nephrectomy, rather than regressing in response to it. As well, the primary cancer was nuclear grade III/IV and involved the renal vein, factors associated with a highly unfavourable prognosis.31
Of note, more than 4 years after stopping intravenous vitamin C therapy and with the renal cell cancer in complete remission, primary small-cell lung cancer was diagnosed in this patient, who was a long-standing cigarette smoker. The second cancer did not respond to high-dose vitamin C therapy. From the clinical history it appears the tumour remained a constant size for many months and likely slowly progressed until her death about a year after diagnosis despite the resumption of intravenous vitamin C therapy.
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