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Asia-Pacific Journal of Clinical Oncology 2014; 10: 2237

doi: 10.1111/ajco.12173

REVIEW ARTICLE

Review of high-dose intravenous vitamin C as

an anticancer agent
Michelle K WILSON,1* Bruce C BAGULEY,2 Clare WALL,2 Michael B JAMESON3 and
Michael P FINDLAY2
1

Auckland City Hospital, 2University of Auckland, Auckland and 3Waikato Hospital, Hamilton, New Zealand

Abstract
In the 1970s, Pauling and Cameron reported increased survival of patients with advanced cancer treated
with high-dose intravenous (IV) vitamin C (L-ascorbate, ascorbic acid). These studies were criticized for
their retrospective nature and lack of standardization of key prognostic factors including performance
status. Subsequently, several well-designed randomized controlled trials failed to demonstrate a significant
survival benefit, although these trials used high-dose oral vitamin C. Marked differences are now recognized in the pharmacokinetics of vitamin C with oral and IV administration, opening the issue of therapeutic efficacy to question. In vitro evidence suggests that vitamin C functions at low concentrations as
an antioxidant but may have pro-oxidant activity at high concentrations. The mechanism of its prooxidant action is not fully understood, and both intra- and extracellular mechanisms that generate hydrogen peroxide have been proposed. It remains to be proven whether vitamin C-induced reactive oxygen
species occur in vivo and, if so, whether this will translate to a clinical benefit. Current clinical evidence
for a therapeutic effect of high-dose IV vitamin C is ambiguous, being based on case series. The interpretation and validation of these studies is hindered by limited correlation of plasma vitamin C concentrations with response. The methodology exists to determine if there is a role for high-dose IV vitamin C
in the treatment of cancer, but the limited understanding of its pharmacodynamic properties makes this
challenging. Currently, the use of high-dose IV vitamin C cannot be recommended outside of a clinical
trial.
Key words: cancer, pro-oxidant, vitamin C.

INTRODUCTION
Vitamin C is an essential micronutrient for humans, who
lack the enzyme required for its synthesis. Vitamin C is
well known for its antioxidant activity although it is only
one of a large variety of dietary antioxidants. In the

Correspondence: Dr Michelle K Wilson MBChB, Auckland

City Hospital, 85 Park Road, Grafton, Private Bag 92019,
Auckland 1023, New Zealand.
Email: michelle.wilson@uhn.ca
*Present address: Princess Margaret Hospital, Toronto,
Canada.
Conflict of interest: none
Accepted for publication 25 November 2013.

2014 Wiley Publishing Asia Pty Ltd

1950s, vitamin C was originally hypothesized to be protective against cancer,1,2 but in the 1970s, Ewan Cameron
and Linus Pauling suggested that it also had a therapeutic
effect, reporting increased survival of patients with
advanced cancer following high-dose IV vitamin C treatment.3 In contrast, several subsequent randomized controlled trials (RCTs) of high-dose oral vitamin C failed to
demonstrate a similar benefits,46 opening the issue of
therapeutic effectiveness to controversy.
More recent studies showed that high plasma concentrations of vitamin C can only be achieved if vitamin C
is administered intravenously or intraperitoneally as the
rate of absorption from the gut is limited with oral
administration.7,8 Plasma concentrations in humans following high-dose IV vitamin C are approximately 200

23

High-dose IV vitamin C as anticancer agent

times higher than those achieved following oral administration.8 High-dose oral and high-dose IV vitamin C
treatment therefore have to be considered as distinct
therapeutic approaches.
The purpose of this review is to survey the literature
to analyze the antitumor effects of vitamin C in both
human and animal studies in terms of the dose and
achieved plasma vitamin C concentrations. In analyzing
the effects of vitamin C in rodent models, it must be
noted that rodents synthesize their own vitamin C and
therapeutic effects are limited to high plasma vitamin
C. The five questions this review will address are therefore (i) Does vitamin C (at high plasma concentrations)
have antitumor activity in rodent systems? (ii) If so, how
does vitamin C potentially exert its antitumor activity?
(iii) Does vitamin C (at high plasma concentrations)
have clinical antitumor activity? (iv) Is vitamin C safe
alone and in conjunction with chemotherapy? and (v) If
the answer is not clear, how can the issue of therapeutic
efficacy be addressed in the future?

DOES VITAMIN C (AT HIGH PLASMA

CONCENTRATIONS) HAVE
ANTITUMOR ACTIVITY IN
RODENT SYSTEMS?
Despite a large amount of preclinical in vitro data on the
effects of vitamin C on tumor cells, there are few reports
on the antitumor activity of high-dose vitamin C in
xenografts of human tumors in immunodeficient mice, a
well-characterized method of predicting potential antitumor activity in humans (Appendix I). Chen et al. demonstrated that vitamin C (4 g/kg intraperitoneal [IP]
once or twice daily) reduced tumor growth and weight
by 4153% using ovarian (Ovcar5), pancreatic
(PAN01) and glioblastoma (9 L) tumor cell lines in
mice.9 The effective plasma concentration that decreased
survival by 50% (EC50) was less than 10 mM in 75% of
the tumor cells tested, but in contrast cytotoxicity was
not evident in normal cells at ascorbate concentrations
exceeding 20 mM. The lack of any complete response
led them to propose that the role for vitamin C may be
as an adjunct alongside chemotherapy. Similar results
have been shown in mesothelioma cell lines.10 In keeping
with this premise, Espey et al. demonstrated that
vitamin C (4 g/kg) inhibited the growth rate of PAN02
pancreatic tumors by approximately 40%, and also augmented the effect of concurrently administered gemcitabine (30 mg/kg).11 This dose of vitamin C in rodents is
equivalent to 1.5 g/kg in humans.12

Asia-Pac J Clin Oncol 2014; 10: 2237

HOW DOES VITAMIN C POTENTIALLY

EXERT ITS ANTITUMOR ACTIVITY?
One of the issues with the use of high-dose IV vitamin C
is the lack of understanding of its potential mechanism of
action. Although initial theories centered on modification
of biological responses, more recent research has concentrated on the importance of both extracellular and intracellular effects of vitamin C. McCormick postulated that
vitamin C protected against cancer by increasing collagen
synthesis.1 Cameron and Pauling later hypothesized that
the association between vitamin C and hyaluronidase
activity was key. They speculated that a high intake of
vitamin C increased the biosynthesis of a physiological
inhibitor of hyaluronidase (PHI) and subsequently
reduced the invasiveness of proliferative disease.13
Experimental studies, while demonstrating that scorbutic
guinea pigs have higher levels of PHI compared with
those receiving oral vitamin C, failed to show a link
between PHI levels and the amount of vitamin C given.14
High-dose oral vitamin C has been shown to be a
potent immunomodulator, enhancing the activity of
natural killer (NK) cells in vivo.15 NK cells are thought
to be important in immune surveillance, preventing
growth and dissemination of tumor cells.16 Heuser and
Vojdani demonstrated that vitamin C caused an increase
not only in NK activity but also B- and T-cell activity in
patients previously exposed to a toxic chemical.17 Both
these studies used oral vitamin C. Other studies have
found evidence to the contrary so while it is a potential
mechanism, this remains unproven.18

Extracellular mechanisms for

vitamin C action
Studies by Chen et al. established that high doses of
vitamin C in mice (IV or IP) generated significant extracellular concentrations of hydrogen peroxide (H202).19
H202 is central to a diverse range of physiological
responses pivotal to disease progression, including
angiogenesis, and oxidative stress.20 They hypothesized
that the presence of a catalyst such as ferric ion within
the extracellular matrix of tumors could oxidize vitamin
C to ascorbate radicals, which then could then donate
electrons to oxygen to form superoxide radicals (O2)
(Fig. 1). This would be converted by superoxide dismutase to the potentially tumoricidal peroxide ion.19
Because peroxide is rapidly converted to oxygen in
blood, the accumulation of peroxide would occur only
in tissues. The identity of the catalyst was not elucidated
but a later study suggested that it could be the metalloprotein ferritin, which is secreted by some tumor cells.22

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MK Wilson et al.

Extracellular ascorbate

Neutrophil

Metalloprotein
complex

BH4

Intracellular mechanisms for

vitamin C action

e
O2

O2

NADPH oxidase
O2

O2
Superoxide
dismutase

H2O2

The selective cancer cell death may be explained by the

different mechanisms of ATP generation with cancer
cells primarily using anaerobic generation and normal
cells aerobic generation. It remains uncertain whether
this in vitro and in vivo data will translate into clinical
benefit.

H2O2

Figure 1 Extracellular mechanism of action of high-dose

intravenous vitamin C. Legend: Two possible mechanisms for
the generation of extracellular hydrogen peroxide (H2O2) in
response to ascorbate. In the first, as shown on the left-hand
side, molecular oxygen is reduced to superoxide by a molecular
complex of ascorbate and an as yet uncharacterized metalloprotein catalyst (such as ferritin).9 In the second, as shown on
the right-hand side, ascorbate is first taken up by a cell such as
a neutrophil, either directly by an ascorbate transporter or
indirectly as dehydroascorbate by the glucose transporter. Here
it stabilizes tetrahydrobiopterin (BH4), preventing its degradation and leading to activation of the enzyme nicotinamide
adenine dinucleotide phosphate (NADPH) oxidase, which
reduces molecular oxygen to superoxide.21 In each case, peroxide is generated subsequently by the enzyme superoxide
dismutase.

Extracellular peroxide, depending on concentration, can

have a cytotoxic effect.
Chen et al. demonstrated that high (pharmacologic)
but not low (physiological) concentrations of vitamin C
killed cancer but not normal cells, with cell death dependent on extracellular vitamin C concentrations.9,19,23
H202 generation displayed a linear relationship with the
formation of the vitamin C radical.23 The pattern of cell
death changed from apoptosis to pyknosis/necrosis as
vitamin C concentrations increased, in keeping with
H202-mediated cell death.23 When H202 scavengers
were employed they were protective against cell death.23
H202 generated by vitamin C oxidation and exogenously added H202 produced cell death curves that
were indistinguishable.23
Chen et al. did not demonstrate a lower level of antioxidant enzymes (catalase, superoxide dismutase and
glutathione peroxidase) in malignant cells to explain the
selective death of cancer cells.23 Instead they theorized
that H202 diffuses into sensitive cancer cells and causes
toxicity by adenosine triphosphate (ATP) depletion.19

2014 Wiley Publishing Asia Pty Ltd

Vitamin C is taken into cells by sodium-dependent

vitamin C transporter 1 (SVCT1) and SVCT2 sodiumdependent transporters that are members of the SLC23
family.24 The oxidized form of vitamin C, dehydroascorbate, can also be taken up by the glucose transporter
(GLUT) and reduced in the cell to ascorbate.25 Macrophages and vascular endothelial cells can express high
levels of SCVT2 and thus concentrate vitamin C to a
high millimolar degree.26,27
High intracellular vitamin C concentrations are proposed to inhibit hypoxia-inducible factor (HIF)-1
activation. HIF plays an important role in determining
patterns of gene expression in cancer and is another
potential target of vitamin C action. HIF-1 is broken
down by hydroxylases, which require iron and ascorbic
acid as cofactors.28 Vitamin C deficiency has been shown
in vitro to compromise hydroxylation of HIF and upregulate HIF-1.29,30 HIF-1 overexpression promotes tumor
progression through angiogenesis, confers resistance
to chemotherapy and radiotherapy, and carries a poor
prognosis.29,31,32
Vitamin C levels have been studied in patients with
endometrial cancer, demonstrating significantly lower
levels of vitamin C in high-grade tumors compared with
paired normal tissue.33 Markers of HIF-1 activation
(HIF-1 protein, GLUT-I and BCL 2/adenovirus E1B)
were elevated in samples with low vitamin C levels, in
keeping with the theory that low tissue vitamin C concentrations upregulate the HIF-1 pathway. There was
also an inverse correlation between vascular endothelial
growth factor levels and vitamin C concentrations.
Similar findings have been demonstrated in gliomas.32
Genetic approaches and small-molecule inhibitors targeting HIF-1 have proven effective at decreasing resistance to chemotherapeutics in a number of different
cancers.34,35 A study using vitamin C with a recombinant
adenovirus-associated virus (rAAV) vector bearing
small-interfering RNA targeting HIF-1 (rAAV-siHIF)
in pancreatic tumors in athymic mice found that vitamin
C could inhibit expression of HIF-1 protein but not
messenger RNA expression.36 It inhibited the growth in
early and middle stages of disease but not advanced

Asia-Pac J Clin Oncol 2014; 10: 2237

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High-dose IV vitamin C as anticancer agent

stages. The lack of blood supply in advanced stages is

thought to compromise the delivery of vitamin C to the
tumor.36

DOES VITAMIN C (AT HIGH PLASMA

CONCENTRATIONS) HAVE CLINICAL
ANTITUMOR ACTIVITY?
In 1974 Cameron and Campbell published the first clinical trial suggesting the therapeutic role for vitamin C in
cancer.37 Fifty patients with no further conventional
treatment options were treated with IV and oral vitamin
C (20% receiving oral only). Of five tumor regressions
described, one occurred in a patient with ovarian cancer
who had extensive pelvic disease at initial diagnostic
laparotomy, which was not present at autopsy.
However, this did not seem to prolong survival with the
patient dying on day 33. Two other patients reported to
have regression had no histological diagnoses of incurable disease. One of these patients diagnosed with
advanced pancreatic cancer at laparotomy was found to

have chronic pancreatitis on autopsy. A further patient

with lymphoma had evidence of remission while on
vitamin C, which recurred once treatment stopped.
Remission was again achieved on restarting vitamin C.38
Another 48% of patients reported a subjective improvement quantified by a reduction in analgesic use and need
for paracentesis.37 However, with no control group, a
placebo effect for these symptomatic improvements
cannot be excluded.
Cameron and Pauling then published two historically
controlled trials, each comparing 100 patients treated
with high-dose vitamin C, with 1000 controls matched
by age, sex, tumor site and histological features
(Fig. 2).3,39 Both trials found a significant prolongation
of mean survival (210 vs 50 days and 293 vs 39 days,
respectively).3,39 However, neither of these trials was
standardized by two critical prognostic factors: performance status and stage.4,40 The consistency of determination of untreatability is also controversial in the
initial trial: 20% of the control group died within a few
days of being deemed untreatable compared with none

400
350

Average survival (days)

300
250
200
150
100
50
0
Cameron
and Pauling
1976 +

Cameron
and Pauling
1978 +

Murata,
Mortshige
1982 *
(Kamioka
Kozan)

Murata,
Mortshige
1982 ++ **
(Fukuoka)

Cameron
and
Campbell
1991 +

Creagan
1979 ++ ^

Tschetter
1983 ++ ^

Moertel
1985 ^

Figure 2 Clinical studies of high-dose vitamin C in cancer. Summary of survival results from published studies on high-dose
vitamin C administration to patients with cancer. Control patients are shown in yellow and patients treated with vitamin C in blue.
The bars on the left-hand side represent trials with intravenous administration and those on the right with oral administration.
+Reported mean survival. ++Reported median survival. Randomized controlled trials. *Compared nil versus low versus high-dose
vitamin C using combination of oral and intravenous (IV) dosing. **Compared low versus high-dose vitamin C using combination
of oral and IV dosing.

Asia-Pac J Clin Oncol 2014; 10: 2237

2014 Wiley Publishing Asia Pty Ltd

26

in the treatment group. The latter trial retrospectively

analyzed the time from first hospital admission to date
of untreatability (>1 year in 27% of patients in the
treatment group and 23% in control group not statistically significant) to address this concern.
The Mayo Clinic conducted three RCTs to examine
the efficacy of vitamin C (Fig. 2), none of which showed
a definitive benefit in terms of survival or quality of
life.46 They compared 10 g of vitamin C administered
orally versus placebo. The initial trial used patients
unsuitable for further systemic therapy either because of
progression during treatment or because their general
condition precluded further treatment.4 These negative
results were refuted due to concerns that, if vitamin C
acts by improving host resistance, prior treatment would
obscure any benefit.41,42 All but nine patients had had
previous treatment compared with only 4 of the 100
patients in the initial Cameron and Pauling trial.42
The second RCT was conducted in 100 cytotoxicnaive patients with colorectal cancer.5 None of the 38
patients with measurable disease demonstrated disease
response.5 This trial was criticized as it was limited to
patients with colorectal cancer and it was questioned
whether negative results in this tumor group were
transferable to other primary sites.5,40 However, 20% of
the patients in the initial Cameron and Pauling trial
had colorectal cancer and they demonstrated similar
survival benefit to other tumor subtypes.3,39 Subsequently, 144 patients with predominantly lung and
colorectal primaries were studied. They described an
initial benefit in overall well-being but this was lost by
6 weeks.6
The results from these RCTs led to the current
opinion among oncologists that high-dose vitamin C is
ineffective. However, it is now recognized that vitamin C
pharmacokinetics differ significantly with oral and IV
dosing.8 Plasma vitamin C concentrations were not measured in any of these trials.
Around this time two further trials published similar
results to the historical trials, demonstrating prolongation of survival times and improvement in quality of life
(Fig. 2).43,44 Cameron and Campbell published the only
trial that measured plasma levels in association with
survival time and demonstrated a linear relationship
between dose and IV plasma vitamin C levels.43 Levels
above 3 mg/dL (0.17 mM) were reported as desirable
but this concentration based on recent literature appears
too low to exert a pro-oxidant effect.43 Treatment was
not randomized and was dependent on clinician preference, creating the potential for selection bias. Again
there was no stratification by performance status.

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MK Wilson et al.

Since this time case series and reports have continued

to raise interest in a therapeutic role for high-dose
Vitamin C, but there has been limited correlation with
plasma vitamin C concentrations.38,4549 Riordan et al.
and Padayatty et al. published the largest of these series
with seven45 and three patients, respectively.46 These
series cover a spectrum of malignancies but there is
significant overlap, with many of these cases published
repeatedly.37,38,4547 Padayatty et al. reported on three
patients with renal cell cancer (RCC), non-Hodgkin
lymphoma (NHL) and bladder cancer, in keeping with
the guidelines of the US National Cancer Institute Best
Case Series Program.46 Two of these patients were also
included in the Riordan series et al.45
All of these patients used IV vitamin C either with
standard therapy or alongside other alternative therapies, making it impossible to definitively assign clinical
benefit to vitamin C. They described positive results
with either improved health status or slowed disease
progression but with no control group this is inconclusive. RCC is a malignancy that has a variable natural
history and one that rarely can undergo spontaneous
regression (although usually following nephrectomy,
which was not the case in this report).50 The latter two
cases reported received standard therapy with radiation
and surgery, respectively. All of these cases had the slim
potential for long-term remission with these therapies.51
Interestingly, the case of NHL did have nodal relapse
confirmed histologically that appeared to regress with
vitamin C. There were no plasma vitamin C concentrations measured to help establish a doseresponse relationship. There was often a lack of histological diagnosis
in the case of recurrent or metastatic disease. In view of
these factors, they do not provide definitive evidence of
a beneficial or detrimental role for IV vitamin C.
Drisko et al. published a case series of two patients
with advanced stage IIIc ovarian cancer treated with
chemotherapy and IV vitamin C (60 g twice weekly).49
Both these patients had optimal surgical debulking, a
key prognostic determinant of patient outcome.52 These
patients were reported to demonstrate prolonged survival with both patients alive over 3 years out from
diagnosis. Treated stage IIIc ovarian cancer has a 5-year
survival rate of around 30%.53 The survival for these
patients consequently may be explained by optimal conventional therapy. However, neither of these patients
had subsequent chemotherapy over this time.
A recent retrospective multicenter epidemiological
cohort study examined the effect of IV vitamin C (7.5 g
weekly) on quality of life during adjuvant chemotherapy
and radiotherapy and aftercare in patients with breast

Asia-Pac J Clin Oncol 2014; 10: 2237

27

High-dose IV vitamin C as anticancer agent

cancer.54 Mean intensity scores in patients treated with

vitamin C during adjuvant therapy were improved (0.25
vs 0.4, P = 0.013), but the absolute difference was small
and unlikely to be of clinical significance (score of 0
representing no symptoms and 1 representing mild complaints). They showed a mean Eastern Cooperative
Oncology Group performance status during adjuvant
therapy of 1.596 in the study group and 2.067 in the
control (P = 0.002). Tumor status was reported to be
stable at 6 and 12 months; however, longer follow-up is
necessary to evaluate the effect on survival and relapse,
two critical outcomes of adjuvant therapy.
In palliative patients, improvement in quality of life is
an important component of care and a key end point.55
Yeom et al. investigated the effect of IV vitamin C (10 g
twice a day for 3 days) on quality of life in 39 palliative
patients.56 They demonstrated a significant improvement in quality of life with higher scores for physical,
emotional and cognitive function and lower scores for
fatigue, nausea and vomiting, pain and appetite loss
(both P < 0.005) in a single assessment 1 week posttreatment.56 Although these results are suggestive of a
benefit, with no control group a placebo effect cannot be
excluded. The duration of benefit was also not assessed.
Cameron hypothesized palliative patients experience
a strong reverse placebo effect because of previous
treatment failures that counterbalance placebo and
anticipation effects.3,39 This has not been described in
the literature elsewhere.

Clinical pharmacokinetics
Vitamin C has different functions at physiological and
pharmacological plasma concentrations. Oral vitamin C
administration is associated with tightly controlled
plasma concentrations regulated by the pharmacokinetic principles of bioavailability and clearance.7 Saturation of bioavailability mechanisms occurs at oral
doses of 400 mg daily equating to blood levels of
60100 M.8 IV dosing bypasses this tight control,
achieving plasma concentrations up to 20 mM.7,8
In vitro evidence suggests plasma concentrations of
10 mM are necessary for an antitumor effect and this
appears achievable clinically only with IV administration.8 Padayatty et al. postulated that the vitamin C-free
radical species, ascorbyl radical, forms only when
human plasma concentrations are greater than 10 mM
and that it is this radical or its unpaired electron that
induces oxidative damage in cancer cells.8
Casciari et al. published a trial to determine the dose
necessary to achieve this level in humans.57 In a single
patient with colon cancer, they found that a dose of 60 g

Asia-Pac J Clin Oncol 2014; 10: 2237

but not 30 g was effective at attaining this. A recent

phase I trial of 24 patients demonstrated that IV vitamin
C to a dose level of 1.5 g/kg three times per week was
safe and achieved plasma concentrations >10 mM for
several hours.58 While average follow-up was only 10
weeks, this trial did not demonstrate objective tumor
response at these levels.58 Riordan et al. published a
series of 24 patients treated with IV vitamin C 150 mg/
kg/day and 710 mg/kg/day.59 The mean plasma level was
1.1 mM (below the expected therapeutic target). They
did not demonstrate a correlation between dose and
plasma concentration. The reason for this is unclear.
Other factors such as critical illness, renal function and
chemotherapy regimens may alter plasma vitamin C
concentrations and affect the plasma concentration necessary for cytotoxicity.58

IS VITAMIN C SAFE ALONE AND IN

CONJUNCTION WITH CHEMOTHERAPY
AND RADIOTHERAPY?
Vitamin C is generally regarded as an innocuous compound with a favorable therapeutic index (Table 1).
While many centers have used high doses, there is
limited published data around the safety at these doses.
Cases of acute hemolysis in patients with underlying
glucose-6-phosphate dehydrogenase (G6PD) deficiency
have been reported in patients treated with high-dose

Table 1

Side effects of intravenous vitamin C

Major side effects

Glucose-6-phosphate deficiency
Renal stones particularly oxalate stones
Tumor acceleration
Minor side effects
Dyspepsia, nausea and altered bowel habit
Increase iron absorption
Raise urinary uric acid levels and excretion of calcium and
iron60
Fluid overload caution in patients with ascites, heart
failure
Interfere with routine laboratory parameters B12, glucose
and fecal occult blood
Side effects falsely attributed to vitamin C60,61
Mutagenicity
Rebound scurvy
Infertility
Hypoglycemia
Destruction of vitamin B12

Absolute contraindication to intravenous vitamin C. Important in

patients with hemochromatosis.

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MK Wilson et al.

vitamin C with at least one fatality described.62,63 All

patients should be screened for G6PD deficiency prior to
starting vitamin C therapy.62
Caution should also be taken in patients with a
history of renal stones.60 Acute obstructive renal failure
secondary to oxalate stones has been reported in a
patient with underlying renal impairment.64 The effect of
vitamin C on oxalate excretion is controversial with
some believing excessive ingestion of AA increases the
formation of oxalate stones.60
In patients with widespread and rapidly proliferating
tumors, vitamin C has been reported to cause tumor
acceleration and precipitate tumor hemorrhage and
necrosis.37,65 The initial Cameron and Campbell trial
described four patients in this category.37 Potentially, this
could also be explained by the natural history of the
underlying cancer.
Dyspepsia, nausea and altered bowel habit are the
most frequently reported side effects, particularly following oral administration.59,60 High doses of oral
vitamin C have been shown to affect iron absorption
and interfere with many routine laboratory parameters.59,60 In patients with congestive heart failure and
ascites, the high fluid intake associated with administration may exacerbate their condition.60

5-fluorouracil (5FU), sodium d-ascorbate and radiation.75 Contrary to this, Witenberg et al. demonstrated a
reduction in apoptosis from ionizing radiation in myeloid
leukemia cells treated with dehydroascorbic acid.76
This sensitizing effect is postulated to be due to the
increased H202 generation secondary to vitamin C
administration. However, vitamin C may also result in
a reduction in HIF-1, which in xenograft models has
been shown to be associated with heightened radiation
sensitivity.77 In keeping with this theory, putative
small-molecule inhibitors of HIF-1 have demonstrated
enhanced tumor responsiveness to radiation in vitro,
supporting the use of this as a target in association with
conventional therapies.78
High-dose vitamin C is also postulated to reduce the
toxicity of chemotherapy because of restoration of
plasma vitamin C concentrations and thus antioxidant
capacity.54 In vitro evidence has also suggested that
vitamin C may reduce the cardiac toxicity associated
with doxorubicin without compromising efficacy, postulated to be related to peroxidation of cardiac lipids.79

Role of vitamin C in combination with

chemotherapy and radiation

There are a number of trials underway in both the phase

I and II setting (Table 2). Although the methodology
exists for investigating the role of high-dose vitamin C in
cancer therapy, it is hindered by uncertainties including
the target population and markers and predictors of
response. The inconsistency and current level of evidence to support a clear scientific rationale also makes
the likelihood of funding for the necessary research
problematic.
The ready availability and accessibility of IV vitamin
C to patients makes a true placebo-controlled trial difficult, with crossover likely to be a major confounding
factor. Comparison of high-dose oral versus high-dose
IV vitamin C (at least 1.5 g/kg three times per week as
used in phase I trials) may address this, that is, low
plasma concentration versus high (Table 3). A third
placebo-controlled arm could be added.
The target population remains unclear. There is no
clear cancer type or phase of care defined for the role of
vitamin C. In view of this, vitamin C could be trialed as an
isolated treatment in patients who have exhausted conventional treatments. An alternative approach would be
to use vitamin C in patients on observation such as those
with asymptomatic biochemical progression of ovarian
or prostate cancer, asymptomatic pulmonary metastases

The literature reports that 3095% of patients with

cancer try unconventional therapies, with the majority
using these as adjuncts to their standard care with the
intention to improve their quality of life and symptom
control.6668 Despite this wide use, it remains unclear
whether the concurrent use of antioxidants with chemotherapy and radiotherapy is beneficial or detrimental.69
Because of the paucity of clinical trial evaluation, the
evidence to date is mostly derived from in vitro and in
vivo data, and observational records. There are no published RCTs examining high-dose IV vitamin C in conjunction with chemotherapy or radiotherapy, making it
difficult to definitively assess safety and efficacy.
Vitamin C has been studied in combination with a
number of cytotoxic agents in vitro and in vivo with
conflicting outcomes on efficacy11,7072 (see Appendix II).
It is theorized that vitamin C may sensitize refractory
cancers to radiotherapy and chemotherapy.11,7073 Koch
and Biaglow studied dehydroascorbic acid alongside
radiation in hypoxic Ehrlich cells in ascites in vivo,
demonstrating increased inhibition of cell growth with
half the radiation dose.74 Similar findings were found in
neuroblastoma and glioma cell lines treated with

2014 Wiley Publishing Asia Pty Ltd

HOW CAN THE ISSUE OF

THERAPEUTIC EFFICACY BE
ADDRESSED IN THE FUTURE?

Asia-Pac J Clin Oncol 2014; 10: 2237

Asia-Pac J Clin Oncol 2014; 10: 2237

III

II

II

II

Levin
NCT00441207

Hoffer et al.
NCT01050621

Mikines
NCT01080352

Monti
NCT00626444

Edman
NCT00954525

Drisko

Safety of oral antioxidants and IV

vitamin C during gyn cancer care

IV vitamin C in combination with

standard chemotherapy for pancreatic
cancer

Pilot trial of IV vitamin C in refractory

non-Hodgkin lymphoma (NHL)

Evaluation of cytotoxicity and genetic

changes of high-dose IV vitamin C
infusions in castration-resistant
metastatic human prostate cancer

Phases III clinical trial of combination

conventional cytotoxic chemotherapy
and IV vitamin C in patients with
advanced cancer or hematological
malignancy for whom cytotoxic
chemotherapy alone is only
marginally effective

A phase I study of high-dose IV vitamin

C treatment in patients with solid
tumors

Title

PSA change after 1220 weekly treatments.

Changes in bone metastases and markers of bone
activity (bone-specific ALP, PINP, NTX).
Pharmacokinetics in elderly cancer patients.

20 g IV vitamin C weekly

Oral and IV vitamin C two to

three times per week
(individual doses not
specified)

50, 75 or 100 g IV vitamin C

three times per week

Evaluate safety of adding high-dose Antioxidants to

chemotherapy in the treatment of gynecologic
malignancies (uterine, cervical or epithelial
ovarian).
Evaluate tumor response rates in patients with
gynecologic malignancies treated with antioxidants
to include IV and oral ascorbic acid, IV
glutathione, oral mixed carotenoids, mixed
tocopherols and vitamin A.

Evaluate safety and tolerability of IV vitamin C and

tumor shrinkage.

Evaluate safety and tolerability of IV vitamin C and

tumor shrinkage.

Evaluate safety and tolerability of IV vitamin C when

administered alongside cytotoxic therapies.
To assess tumor response.
To assess effect on quality of life.
Determine the effect of chemotherapy on
pharmacokinetics of IV vitamin C.

Dose escalation beginning with

0.9 g/kg escalating to 1.5 g/kg
IV two to three times per
week, bracketing
chemotherapy

IV vitamin C to achieve plasma

level of 300350 mg/dL given
three times per week

Evaluate safety and tolerability of IV vitamin C.

Observe evidence of tumor response to vitamin C
and compare the level of fatigue, pain control,
quality of life before and after vitamin C.

Objectives

Not specified

Dose of vitamin C

ALP, alkaline phosphatase; IV, intravenous; NTX, N-terminal telopeptide; PINP, procollagen type I N-terminal propeptide; PSA, prostate-specific antigen.

Phase

Current clinical trials

Investigator

Table 2

High-dose IV vitamin C as anticancer agent

29

2014 Wiley Publishing Asia Pty Ltd

30

Table 3

MK Wilson et al.

Design of potential clinical trial

Factors to be considered

Recommendations

Population

1.
2.
3.
4.

Palliative patients with no further chemotherapeutic options

Alongside chemotherapy in refractory disease ideal to use alongside one specific agent
One tumor subtype on observation alone, for example, good prognosis renal cell cancer
Across tumor subtypes based on initial data from Cameron trial

Trial arms

1. Comparison of oral high-dose (low plasma concentration) vitamin C versus IV high-dose

(high plasma concentration) vitamin C
2. Three arm trial with placebo versus oral high-dose vitamin C versus IV high-dose vitamin C
3. Placebo versus high-dose IV vitamin C
4. Similar arms as described above alongside chemotherapy or radiotherapy

Pharmacokinetics

1. Baseline and on-treatment assessment of plasma vitamin C levels

2. If alongside chemotherapy, pharmacokinetic studies of the chemotherapeutic agent

Markers of response

1. Pre- and posttreatment biopsy if easily obtainable tissue

2. Catalase genotype evaluation as subgroup analysis to determine if there is a potential target
population with increased efficacy
3. CT/MRI to assess response timing of imaging remains controversial
4. PET-CT scan to assess tumor metabolic activity pre- and posttreatment

End points

1. Assessment of tumor response

2. Progression-free and overall survival
3. Quality of life assessment

Addition of vitamin C alongside chemotherapy or radiation treatment has a number of ethical concerns because of the potential for both a beneficial
or detrimental interaction. Vitamin C could be studied in a population who have developed chemoresistance and have no further treatment options.
CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography.

in good prognosis RCC or indolent low-grade NHL.

Regardless of the population used, patient safety remains
paramount. All patients should have a G6PD screen and
caution should be exercised in patients with a history of
renal stones.
Baseline and on-treatment vitamin C levels should
be assessed and used to titrate dose to achieve a concentration of at least 10 mM based on in vitro data.8
This would help improve knowledge on the pharmacokinetic properties of vitamin C and help establish a
doseresponse relationship.
Based on experience gained from chemotherapeutic
agents, further delineation of the mechanism of action
may identify a target population with higher response
rates. If vitamin C acts via H2O2 formation, populationbased differences in the genotype and phenotype of catalase expression and activity may be relevant.80 Those
with low levels of catalase activity may be more sensitive
to the effect and toxicity of high-dose vitamin C. Assessment of this in a clinical trial would help determine if
this theoretical sensitivity translates to clinical response.
It remains uncertain whether the use of vitamin C in
conjunction with chemotherapy and radiotherapy has a
beneficial or detrimental interaction. Trials using vitamin
C alongside chemotherapy need to include analyses of the
pharmacokinetic properties of both vitamin C and the

2014 Wiley Publishing Asia Pty Ltd

chemotherapeutic agent. In vitro and in vivo data suggest

vitamin C may overcome chemoresistance and improve
chemosensitivity.11,7073 This has been demonstrated in
vivo in pancreatic cancer cell lines in combination with
gemcitabine, making this a potential population to start
with.11
Biopsies pre- and post treatment may help identify
predictors and markers of response. This has not been
performed in the trials to date. Method and timing
of assessment of tumor response is hindered by our
limited understanding of the mechanism of action
and lack of specific biomarkers. Improvement of our
translational knowledge is critical for future research.
Fluorodeoxyglucose-positron emission tomography
could be used as a surrogate marker of response by
assessing the effect of high-dose vitamin C on tumor
metabolism. There is evidence to support the use of
PET to assess response to other modalities such as
chemotherapy and chemoradiation.81

CONCLUSION
Although the rates of utilization of vitamin C therapy
remain uncertain, its popularity has increased over
the years since the first suggestion of its chemotherapeutic activity in the 1970s. Although there is

Asia-Pac J Clin Oncol 2014; 10: 2237

High-dose IV vitamin C as anticancer agent

currently no definitive evidence that IV vitamin C

improves quality of life, progression-free or overall survival, the published RCT data do not negate potential
benefit based on an improved understanding of vitamin C
pharmacokinetics.
The pharmacokinetic properties of IV and oral vitamin
C are critical in interpreting the data to date. Based on in
vitro data, it is now recognized that the plasma levels
necessary for cytotoxicity requires IV dosing. However, a
phase I trial of 24 patients did not demonstrate objective
responses despite using IV doses of up to 1.5 g/kg.58
Vitamin C is well known for its antioxidant activity,
but it is the proposed pro-oxidant activity at high concentrations that remains controversial. This situation
is perpetuated by the lack of a defined mechanism of
action. While intracellular and extracellular generation
of H2O2 is the most common theory, clarification of this
and determination whether this will translate to a clinical benefit is critical in future research.
Although high-dose IV vitamin C appears relatively
innocuous given alone, it does have the potential to
cause harm in patients with G6PD deficiency and previous renal stones. It remains uncertain whether vitamin C
is clinically safe when given alongside chemotherapy
and radiotherapy.
Despite 40 years of research since the initial reports
on high-dose IV vitamin C, its use remains controversial.
The methodology exists to determine if high-dose IV
vitamin C does have an anticancer effect, but the ability
to design and conduct studies is impaired by the lack of
a consistent scientific rationale, the ready availability
and the use of this agent by practitioners already convinced by current evidence. This makes a placebocontrolled trial difficult.
There are highly polarized views on the use of highdose vitamin C for cancer treatment, with passionate
advocates balanced by passionate critics. This is a key
reason for why carefully controlled clinical trials, rather
than a review of the literature, are needed to obtain a
clear view of this field.

ACKNOWLEDGMENT
No funding for this project.

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Asia-Pac J Clin Oncol 2014; 10: 2237

Mouse

82

Ehrlich ascites carcinoma and

leukemia cells
Hepatocellular carcinoma,
bladder, breast, prostate and
cervix
Hormone-refractory prostate
cancer
Human leukemic, preleukemic
and myeloma

Asia-Pac J Clin Oncol 2014; 10: 2237

Takemura et al.10

Human
Mouse and human
Human

Du et al.90
Espey et al.11
Sestili et al.91

Pancreatic
Promyelocytic

Ascorbate concentration
020 mM
Ascorbate 4 g/kg
Ascorbate concentration
300 M

Ascorbate 4 g/kg

Ascorbate concentration 10 nM
to 1 mM

Ascorbate concentration
501000 M

L-ascorbic acid 0.20.5 mM

Neuroblastoma (NB) doses of 4 g/kg in rodents are proposed to be equivalent to 1.5 g/kg in humans.

Human

Chen et al.9

Human

Human

Ovarian, pancreatic and

glioblastoma
Pancreatic

Neuroectodermal cell lines

De Laurenzi et al.89
Neuroblastoma and melanoma

Mesothelioma

Mouse and human

Human
Mouse and human

Human

Park and Kimler85

Leukemic cells
Park et al.86
Leung et al.87
Lymphoid neoplasm,
lymphocytic leukemia, acute
lymphoblastic leukemia,
epidermoid carcinoma,
fibrosarcoma
Melanoma
Bram et al.88

Ascorbate 4 g/kg

Mouse

Pollard et al.84

Inhibits cell growth but no

effect on normal fibroblasts
Decrease tumor growth rate

Results

H202-mediated cytotoxicity

Proposed mechanism of action

Inhibited tumor growth and

prolonged survival
Inhibited tumor growth
Potentiate cell death

Slower growth at low

concentrations in NB cells
(10100 nM). Increased cell
death at 1 mM in both
melanoma and NB cells
Inhibit cell growth

Dose-dependent reduction in
cell viability

Twofold to 10-fold more

sensitive to ascorbate

H202-mediated cytotoxicity
Similar mechanism to H202 as reversed with
catalase

H202-mediated cytotoxicity

H202-mediated cytotoxicity

Vitamin C essential for melanin biosynthesis and

preferentially incorporated into melanoma
tissue.
H202-mediated cytotoxicity
Production of reactive oxygen species
particularly H202 accompanied by disruption
of mitochondria structure
Induces programmed cell death with DNA
fragmentation likely related to H202 formation

Inhibit tumor growth by

Not discussed
approximately 50%
Multistep model with oxidation reduction
L-ascorbic acid minimum
Both enhancement and
and/or electron transfers that may finally lead
effective dose of 0.03 mM
suppression of growth.
to free radical scavenging and cell protection
Consistent effect within
or to generation of free radicals and cell death
individual cell lines
L-ascorbic acid 0.3 mM
Suppress in vitro growth
Sodium ascorbate, d-isoascorbic Cytotoxic to malignant cell lines Complex likely deplete amino acids essential
acid
but not nonmalignant cells
for cell growth; induce chromosomal
aberrations; production of H202

Ascorbate concentration 50 M
to 33 mM

Vitamin C 0.4 g/kg and B12

Dose or target ascorbate

concentration

Verrax and Calderon83 Mouse and human

Poydock

Type human/animal

Author

Cell lines

Data in Cell Lines

APPENDIX I

High-dose IV vitamin C as anticancer agent

35

2014 Wiley Publishing Asia Pty Ltd

 2014 Wiley Publishing Asia Pty Ltd

Breast

Preclinical in vitro
positive results
Breast carcinoma
Endometrial
adenocarcinoma Oral
epidermoid carcinoma
Breast cancer
Colon fibroblast
Melanoma
Pancreatic cancer
Skin fibroblast

Preclinical in vitro
negative results
Leukemia
Lymphoma

Type of cancer

Human cell lines

Human cell lines

Human cell lines

Casciari et al.57

Kurbacher et al.71

Cell lines and murine

xenografts

Setting

Noto et al.93

Heaney et al.92

Author

Studies of Chemotherapy with Vitamin C

APPENDIX II

Doxorubicin

Doxorubicin
Cisplatin
Paclitaxel

1 M or 100 M

Doxorubicin
Cisplatin
Methotrexate
Vincristine
Imatinib

Chemotherapy

Ascorbic acid 10 mM for

2 days

Vitamin C 1 M to
10 mM
Vitamin K3 10105 nM

0 and 18 mM

Dose or concentration
of vitamin C

Potentiate cell death at high

levels. Additive effect at high
levels with doxorubicin but at
levels that may not be
clinically feasible.
At low doses reduced benefit of
doxorubicin.
No clear synergistic role with
vitamin K3
Synergism with doxorubicin
Partly synergistic with cisplatin
and paclitaxel

Effective in combination but

higher doses needed for less
effect for individual vitamins

Detrimental results

Results

Formation of oxyradicals in use

with doxorubicin and
cisplatin.
Possible action mediated via
p-glycoprotein.
Dose-related phenomenon low
doses with doxorubicin, with
the highest concentrations
necessary in conjunction with
cisplatin

Mediated through H202

production

Used dehydroascorbic acid

36
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Asia-Pac J Clin Oncol 2014; 10: 2237

Asia-Pac J Clin Oncol 2014; 10: 2237

Human cell lines
Human cell lines

Mouse cell lines

Grad et al.70
Song et al.72

Prasad et al.95

Abdel-Latif
et al.96

Multiple myeloma

Nonsmall-cell lung cancer

Neuroblastoma

Esophageal

Mouse model
Mouse model

Kassouf et al.98

Qazilbash et al.99

Urothelial

Clinical trials
Multiple myeloma

Vincristine

25 g/mL

Vitamin C 1000 mg IV
for 5 days

Vitamin C 23 g/L
Vitamin K3 0.23 g/L

Vitamin C 1 g/kg
Vitamin K3 10 mg/kg
Vitamin C 4 g/kg

Ascorbate concentration
50 M to 33 mM

20 mM

L-ascorbic acid at
500 g/mL (2.53 mM)
and sodium
d-isoascorbate

Potentiate by reducing resistance

Potentiate benefit

Potentiate

Potentiates

Potentiates in combination but

not alone
Potentiates in combination with
activity alone
Potentiates in combination

Potentiate in combination

Melphalan arsenicNeutral longer follow-up

and ascorbic acid necessary

Gemcitabine

Gemcitabine

Etoposide
Cisplatin
5FU
Doxorubicin
Paclitaxel
Vincristine

5-Fluorouracil (5FU)Potentiate 5FU, irradiation,

Bleomycin, Prostaglandin E1,
X-irradiation
Sodium butyrate.
Bleomycin
Prostaglandin E1 No effect on vincristine,
6-thioguanine, CCNU.
Sodium butyrate
Reduced cytotoxicity of DTIC
Vincristine
and methotrexate
6-thioguanine
CCNU
Methotrexate
DTIC
Cisplatin
Potentiate
5FU

Arsenic

0 and 100 M

500 M

Cisplatin
Etoposide
Adriamycin
Bleomycin
Arsenic

0.1 M to 10 mM

AP-1, activator protein 1; CCNU, lomustine; DTIC, dacarbazine; GSH, glutathione; IV, intravenous; NF-B, nuclear factor B.

Phase II (n = 48)

Mouse model

Taper and
Roberfroid97
Espey et al.11

Pancreatic

Mouse model

Verrax and
Calderon83

Preclinical in vivo
positive results
Bladder
Breast
Cervix
Hepatocarcinoma,
Prostate
Liver ascites

Mouse cell lines

Dai et al.94

Lymphoma

Human cell lines

Human cell lines

Reddy et al.73

Cervical

Increased apoptosis

Through H202 production

Through H202 production

H202-mediated cytotoxicity

Inhibit translocation of NF-B

and AP-1

Deplete GSH and increase H202

death
Deplete GSH and increase H202
death
Speculated to be due to
modification of cell
membrane
Multiple mechanisms of action:
inhibition of catalase leading to
accumulation of H202 and
subsequent cell death

Down regulates AP-1 and

stabilizes p53

High-dose IV vitamin C as anticancer agent

37

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