Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach

Review Article

Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach


E. Klimant, MD*, H. Wright, ND, D. Rubin, ND, D. Seely, ND MSc, M. Markman, MD§


doi: http://dx.doi.org/10.3747/co.25.3790


ABSTRACT

This article reviews intravenous vitamin C (IV C) in cancer care and offers a rational approach to enable medical oncologists and integrative practitioners to safely provide IV C combined with oral vitamin C to patients. The use of IV C is a safe supportive intervention to decrease inflammation in the patient and to improve symptoms related to antioxidant deficiency, disease processes, and side effects of standard cancer treatments. A proposed rationale, together with relevant clinical safety considerations for the application of IV C in oncologic supportive care, is provided.

KEYWORDS: Vitamin C deficiency, intravenous vitamin C, ascorbate, supportive care, quality of life

INTRODUCTION

Historically, Cameron and Campbell1 and Cameron and Pauling2 investigated oral and intravenous vitamin C (IV C) treatment in patients with advanced malignancy. Phase i trials in which IV C doses of 75–220 g (up to 1.5 g/kg or 110 mg/m2) were given to patients with advanced malignancies alone and in combination with chemotherapy demonstrated both safety and tolerability, providing some reduction in symptoms, but did not allow for conclusions to be drawn about tumour response or overall treatment efficacy38.

Extensive literature demonstrates that cancer patients experience vitamin C deficiency correlated with reduced oral intake, inflammation, infection, disease processes, and treatments such as radiation, chemotherapy, and surgery929. Studies report reductions in inflammatory markers and suggest some improvement in symptoms, with a possible benefit in quality of life (qol) when IV C alone or in combination with oral vitamin C is used in oncologic care3034.

We propose a pragmatic approach for the administration of IV and oral vitamin C as a supportive therapy, including recommendations to ensure safety before and after chemotherapy. In the post-adjuvant and advanced incurable settings, IV C with radiation treatment is not discussed.

METHODS

Using the ovid platform in medline, a scoping review was conducted current to October 2016 to address these questions:

  • ■ What are the pharmacokinetics of IV C and how would administration affect cancer patients?

  • ■ Do cancer patients, compared with healthy subjects, experience vitamin C deficiency?

  • ■ Is it safe to administer IV C to cancer patients during and after chemotherapy? Does IV C have the potential to improve qol?

Overall, the literature to date has not supported the efficacy of IV C as monotherapy in anticancer treatment, and our research questions therefore did not address that topic. Instead, we set out to address the potential value of vitamin C in supportive care. To be included in the review, studies had to be conducted in humans, to be published in English, and to provide information about the safety of IV C in malignant conditions, about any reductions in side effects or cancer-related symptoms, or about the effect for qol. We included controlled, uncontrolled, and nonrandomized studies. We excluded studies assessing oral ascorbate only and included those that assessed IV C or IV C combined with oral vitamin C administration.

The first search used key terms relevant to pharmacokinetics in cancer patients (“ascorbate metabolism,” “renal clearance of vitamin C,” “vitamin C and kidney function”). It resulted in the selection of eight studies for their reporting about the storage, use, and clearance of vitamin C.

A second search for “vitamin C blood levels in cancer patients” and “vitamin C deficiency in cancer patients” used key search terms (“plasma vitamin C,” “antioxidant status,” “serum antioxidant levels”) in combination with “cancer.” Articles about vitamin C deficiency were included if they reported vitamin C plasma levels in humans, tumour type, stage of disease, and comparisons with healthy control subjects. All others were excluded. The search identified 142 records for screening, of which 14 are included in the present report (Tables i and ii).

TABLE I Vitamin C blood levels in healthy subjects

 

TABLE II Vitamin C blood levels in cancer patientsa

 

A third search pertaining to the safety of IV C use in cancer patients identified 147 records for screening. The search strategy used key word searches according to population (“cancer,” “oncology,” “neoplasm,” “malignancy”) and intervention (“ascorbic acid,” “ascorbate,” “vitamin C,” “intravenous vitamin C,” “IVC”). Of the 147 records screened, 138 were selected for extraction. Of the 138 records extracted, 24 were related to human studies in patients receiving I VC and are reported on in this paper: 1 randomized controlled trial, 6 controlled trials, 7 uncontrolled trials, 6 observational studies, and 4 case-based reports.

Our scoping review did not include articles pertaining to use of IV C during radiation therapy.

RESULTS

Vitamin C: Oral and IV Pharmacokinetics

Vitamin C (ascorbic acid or ascorbate) is required for the biosynthesis of collagen, l-carnitine, and some neurotransmitters37,38. Humans have a mutated gene encoding for ascorbate biosynthesis, making vitamin C an essential nutrient to prevent deficiency leading to disease37,39,40. Vitamin C increases the intestinal absorption of non-heme iron from dietary sources and is involved in the metabolism of tyrosine and in the maximization of activity for the hormones cholecystokinin, oxytocin, vasopressin, and alpha-melanotropin37. Vitamin C deficiency interferes with collagen synthesis, catecholamine formation, prostaglandin metabolism, and cellular immunity37.

The total human body store of vitamin C can range between 300 mg (at severe depletion such as scurvy) and 2 g14,38. The bioavailability of vitamin C is moderated by intestinal absorption, tissue stores, renal resorption, renal excretion, and the health status of the individual9,15,26,34,41. Ascorbate is transported by sodium-dependent transporters Slc23a1 and Slc23a2 in the small intestine and proximal renal tubule42,43. The normal range for ascorbate in human blood plasma is 0.70–1.4 mg/dL (40–80 μmol/L)44. Oral consumption of vitamin C creates maximal serum levels of 1.3–4.0 mg/dL (73.8–227.1 μmol/L)4449; IV C can increase concentrations to more than 350 mg/dL or 20–49 mmol/L5,7,44. The unit conversion for reporting vitamin C levels is 1 mg/dL = 56.78 μmol/L50.

In a study of advanced cancer patients who were administered 15 g IV C over a period of 30 minutes, average vitamin C levels before and after IV C were 0.6 ± 0.1 mg/dL and 57.0 ± 6.0 mg/dL respectively15. Table iii illustrates the relationship of IV C dose to plasma level in several studies. Above steady-state blood levels, IV C is rapidly cleared by the renal system, proportional to concentration4,45,47,52,53.

TABLE III Relationship of intravenous vitamin C (IV C) dose with plasma vitamin C level

 

Duconge et al.54 reported the saturation point of renal tubular resorption for vitamin C to be 70 μmol/L. Graumlich et al.41 described the saturation point at the proximal renal tubule as Vmax 126 mg/h, after which clearance of vitamin C approaches the glomerular filtration rate. Compared with healthy subjects, cancer patients excrete less vitamin C from all intake sources, including IV C15,17,41,48,49,53. Estimates for the clearance time of IV C range from 30 minutes to 2 hours4,7,41,49,54.

Vitamin C Deficiency and Oxidative Stress

Vitamin C deficiency is reported to occur more frequently in patients with chronic disease and major depression and in hospitalized patients, postsurgical patients, and smokers18,2023,2527,29,5561. Tables i and ii summarize vitamin C blood levels measured in cancer patients and in healthy control subjects, reporting lower levels for cancer patients with advanced-stage compared with early disease.

Hypovitaminosis C is described as depletion at less than 0.5 mg/dL and as deficiency at less than 0.2 mg/dL18. A diagnosis of hypovitaminosis C is established by clinical findings and low serum ascorbic acid level18,23,24,62. Fasting vitamin C blood levels are reported to best represent body stores24. Scurvy occurs within 1–3 months of depletion and is diagnosed by vitamin C levels less than 0.2 mg/dL62. Symptoms of vitamin C deficiency include fatigue, myalgia, weakness, poor wound healing, follicular hyperkeratosis, perifollicular hemorrhages, ecchymoses, xeroses, and lower extremity edema14,18,62. Gingival swelling, oral hemorrhage, pain in the back and joints, hemorrhage into the soft tissue and joints, syncope, and sudden death can also occur with persistent deficiency18,62.

Cancer patients experience increased oxidative stress and inflammation11,15,34,51,60,6365 known to increase utilization of ascorbate. That increase in utilization correlates with low vitamin C blood levels in patient populations913,1723,25,28,29,34,35,58,59,65,66. Vitamin C is consumed during inflammation as it reduces free radical activity. When an antioxidant destroys a free radical, the antioxidant itself becomes oxidized. Antioxidant resources must therefore constantly be restored in the body. When inflammation consumes vitamin C such that stores become low, the kidneys slow excretion so that vitamin C from dietary consumption can be retained. However, decreased excretion might not be well compensated oral intake during high levels of inflammation. In cancer patients, IV C has been shown to decrease inflammation through suppression of cox-2 and nuclear factor κB15,34. Mikirova et al.34 reported that advanced cancer patients receiving doses of 7.5–50 g IV C showed reductions in C-reactive protein; interleukins 1α, 2, and 8; tumour necrosis factor α; and eotaxin. In a study of 193 patients, inflammatory markers were comparatively higher and vitamin C levels were lower in those with metastatic compared with localized tumours15. Although increased oxidative stress might contribute to vitamin C deficiency independent of dietary intake11,35,57,59,67, cancer patients with impaired oral intake or a history of surgery or radiation affecting absorptive surfaces might also experience hypovitaminosis C9. Several studies reported that micronutrient deficiencies, including for vitamin C, are not corrected by total parenteral nutrition; hence, IV C could be useful to consider as supportive care21,29,66.

Factors associated with vitamin C deficiency include the metabolic state of the malignancy and its effects on host metabolism, the catabolic effects of antineoplastic therapy, and the physiologic stresses of disease processes9. Studies combining oral and IV C show safety, decreased inflammation, and repletion of vitamin C levels1,2,31. Thus, clinicians might find it useful, depending on individual factors, to consider a regimen of both oral and IV C in supportive care.

IV C and QOL

Clinical trials using IV C in cancer patients conducted by Hoffer et al.4, Stephenson et al.7, and Ma et al.8 collected qol data, but did not report a statistically significant benefit. Yeom et al.31, Vollbracht et al.30, Takahashi et al.33, and Carr et al.32 investigated the effect of IV C on qol for cancer patients, reporting a benefit for that outcome.

Yeom and colleagues31 conducted a prospective study of 39 patients with metastatic cancer, providing 10 g IV C twice (with a 3-day interval between doses), together with 4 g oral ascorbate daily for 1 week and reported a significant improvement in qol. Drawbacks of the study were the small sample size, the short duration of the study, and the lack of a control group.

The observational retrospective study conducted by Vollbracht and colleagues30 evaluated breast cancer patients (stages iiaiiib) attending 15 treatment centres. Their comparison of 53 patients treated with 7.5 g IV C weekly for 4 weeks, plus standard therapy (surgery, chemotherapy, radiation, and hormonal treatment) and 72 control subjects matched for age, stage, and type of treatment found that appetite, fatigue, depression, and sleep disorders during and after adjuvant therapy were significantly improved in the group receiving IV C plus standard treatment. Compared with the control subjects, patients receiving IV C also had significantly better mean Eastern Cooperative Oncology Group performance status scores during adjuvant treatment and after 6 months had elapsed. Tolerability for IV C administration during adjuvant chemotherapy was reported to be excellent (86.8%) and good (13.2%) for those receiving IV C before and after treatment, and no significant interactions between vitamin C therapy and adjuvant therapy were observed during the study. One major limitation of the study was its lack of randomization and the potential expectation bias that could have been introduced. The study also did not report survival outcomes.

The prospective interventional study by Takahashi et al.33 investigated health-related qol in 60 patients with newly diagnosed advanced cancer, including those undergoing chemotherapy, who received doses of 12.5–100 g IV C given at a rate of 0.5–1.0 g per minute twice weekly for 4 weeks in addition to oral vitamin C doses of 2–4 g daily. Findings from the study included significant decreases in fatigue, insomnia, and constipation after 2 weeks, and a reduction in pain after 4 weeks. The 30-question Core Quality of Life Questionnaire from the European Organisation for Research and Treatment of Cancer was completed before IV C treatment and after 2 and 4 weeks of twice-weekly IV C, daily oral vitamin C, and standard-of-care therapy. Clinical Global Impression of Change assessments were conducted throughout the study by physicians. Significant improvements in physical, emotional, and social functioning were reported after 2 weeks of treatment, and improvement in cognitive function was reported after 4 weeks. The baseline mean global health status score of 44.6 improved to 61.4 after 4 weeks of IV and oral ascorbate given in addition to standard treatment. No adverse events were reported. Although the study lacked a control group, the results suggest that administration of vitamin C can improve qol, including a reduction in fatigue, for cancer patients. It is notable that, during the study period, 55.0% of the patients were receiving concomitant chemotherapy. The authors proposed that vitamin C might have improved qol by relieving fatigue and other symptoms caused by a state of chronic vitamin C deficiency in combination with inflammatory processes. Despite design flaws and lack of a control group, the study provided valuable data about the safety of vitamin C and improvement in qol outcomes.

Safety of IV C

Phase i studies of IV C alone and in combination with chemotherapy have reported excellent safety profiles18,33. A survey of providers who used IV C for 9328 patients reported an adverse event rate of 1.0%68. Reported side effects of IV C used in clinical trials include nausea, dizziness, dry mouth, perspiration, and weakness6,7. Suggestions for prevention of side effects include giving plenty of oral fluids before and during treatment35,7.

Conditions for which screening is recommended for all dosage levels of IV C include glucose 6 phosphate dehydrogenase (g6pd) deficiency, iron and copper storage diseases, renal failure, history of kidney stones or oxaluria, and pregnancy or lactation. Doses of IV C greater than 75 g or those leading to blood concentrations exceeding 10 mmol/L might be contraindicated for patients with renal failure, history of oxalosis, anuria, dehydration, severe pulmonary edema, or low cardiac output; use of lower doses of IV C could be appropriate at the discretion of the clinician4. Clinical trials providing IV C to cancer patients reported oxaluria that uneventfully returned to baseline4,69.

Caution is advised for the use of IV C in cancer patients with end-stage renal failure predisposed to oxaluria70,71. In contrast, two studies in patients with chronic renal failure undergoing frequent hemodialysis found that, alone and in combination with erythropoietin, single applications of IV C (0.3 g and 0.5 g) are a safe way to mobilize iron stores and to increase hemoglobin levels in patients with functional anemia72,73. Several case reports have pointed to vitamin C intake as a possible cause of kidney stones and renal failure3,74,75; however, prospective trials have not supported the association76,77. Several case reports suggest vitamin C can cause hemolytic events in patients in whom g6pd is deficient; hence, testing for g6pd deficiency before IV C administration is warranted78,79. High serum concentrations of ascorbate in the presence of g6pd deficiency have the potential to cause a red blood cell hemolytic crisis80,81. Levels of g6pd can also be higher after hemolytic episodes or transfusion of red blood cells, which might mask deficiency, and therefore testing 8–12 weeks after transfusion is recommended80,81. Normal g6pd levels range from 4.6 U/g hemoglobin to 13.5 U/g hemoglobin80.

DISCUSSION

Our review shows that vitamin C depletion might occur more readily in patients with cancer because of lack of oral intake, decreased bioavailability, increased tissue utilization, and increased oxidative stress. Inflammation attributable to disease processes, standard anticancer treatments, and vitamin C deficiency can cause symptoms that might be ameliorated by IV C. Review of the data suggests that a combination of oral vitamin C and IV C as supportive care is safe, and hence we provide a rational approach for administration in cancer patients as supportive care during, for example, the post-adjuvant or the incurable advanced setting.

Because of theoretical concerns about the administration of intravenous antioxidant treatment during curative chemotherapy and any possible reduction in treatment efficacy, we recommend an approach that allows for clearance of IV C before chemotherapy administration. Giving 5–25 g IV C over a period of 30–120 minutes is safe for cancer-affected adults of any sex and body mass to decrease inflammation, allow for optimal repletion of the body’s antioxidant stores, and possibly support qol. In addition, 500–4000 mg oral vitamin C daily is safe during the intervals between IV C treatments and could support continued oral repletion, as observed in studies combining oral and IV C in adults with cancer1,2,31.

Temporary or long-term barriers to oral repletion during cancer treatment make IV C a plausible consideration in oncology care. Slower infusion times as described in Table iv could allow for maximal incorporation of vitamin C into the body’s antioxidant stores. Symptoms correlated with deficiency such as fatigue, myalgia, arthralgia, and nonspecific anemia present an opportunity to consider whether IV C could potentially be used to reduce symptoms and support health. Such an approach could be beneficial if coordinated with cancer treatments of noncurative intent, in which the goal is to support the patient, prevent interruptions to standard treatment, and possibly improve qol. Vitamin C could also be considered for potential activity in the tumour microenvironment, which contains inflammatory proteins such as vascular endothelial growth factor, interleukin 8, and other cytokines that favour malignant processes34,8285. Vitamin C might also take part in stromal activity to decrease the hospitality of the stroma to the malignant entity83.

TABLE IV Suggested intravenous vitamin C doses, infusion times, and osmolarity

 

Doses of IV C greater than 15 g given over a period of 30 or fewer minutes have been found in vitro and in vivo to have a pro-oxidative effect8688 when blood concentrations exceed 3–4 mm/L86,8890. Preclinical studies that demonstrate plasma concentrations greater than 10 mmol/L and an antitumour effect86,90 propose that a pro-oxidative effect is created by the generation of hydrogen peroxide (H2O2) and ascorbyl radicals in the extracellular space44,54,91. Mikirova et al.65 reported that single doses of 15–25 g IV C increase the total antioxidant capacity of the blood and that single IV C doses greater than 25 g decrease total antioxidant capacity. Figure 1 depicts those findings. Mikirova and colleagues also reported that IV C doses of 15–25 g create no pro-oxidant effect on plasma lipids and proteins. Although studies providing IV C at more than 30 g have been conducted [achieving blood levels of 20–30 mm/L (400 mg/dL)], human data reporting clinical benefit are lacking. A case report by Mikirova et al.92 describes a child who at 14 months was diagnosed with neurofibroma and optic pathway tumours. The child received treatment with carboplatin and vincristine for 1 year, after which disease progression continued. At 4 months after chemotherapy completion, the child began treatment with IV C (7–15 g weekly). After 30 months of IV C, magnetic resonance imaging demonstrated a significant reduction of the tumours and disease stability over time. The patient experienced no complications from IV C and continued receiving IV C up to age 5, when the case was published.

 


 

FIGURE 1 At doses less than 25 g, intravenous vitamin C maximally adds to the antioxidant value of blood plasma. Reprinted, with permission, from Mikirova et al., 200765.

Vitamin C is stored and used by the body in varying amounts depending on disease status. Human studies indicate that IV C is rapidly cleared by the kidneys and that blood levels return to steady state within several hours after administration4,7,41. Increasing the IV C dose without extending the infusion time can drive plasma levels to peak, creating a differential gradient and driving ascorbate into the tissue space, theoretically stimulating pro-oxidant behaviour. We hypothesize that there are no absolute low and high doses of IV C, but rather “low-dose behaviour” and “high-dose behaviour,” which we identify as functions of the administered dose, the infusion time, and the disease status of the individual. We postulate that high-dose behaviour might yield pro-oxidative effects and could potentially be created with IV C given at higher doses over shorter infusion times. Those effects are further discussed in a systematic review by Fritz et al.93. High-dose behaviour requires the infusion of larger volumes of fluid in hyperosmolar concentrations, which can create side effects in patients as previously described. In contrast, low-dose behaviour potentially increases total antioxidant capacity, requires less fluid volume for administration, and can be given at near physiologic osmolarity, maximizing exposure to tissue stores and obviating the side effects described in the studies using high-dose behaviour. Based on the 2007 study by Mikirova and colleagues15, we identify the optimal gram doses of IV C to be between 5 g and 25 g. Based on that postulate and pharmacokinetic data4,44,46,54, we propose a defined infusion time between 30 minutes and 2 hours to allow for optimal repletion of antioxidant stores and potential benefit for inflammation and symptoms, thus improving qol.

In a randomized phase i/iia pilot study in 27 patients with stages iii and iv ovarian cancer8, one group was treated with carboplatin–paclitaxel and IV C, and another group was treated with carboplatin–paclitaxel only. The authors, Ma et al., reported a statistically significant decrease in grades 1 and 2 toxicities in the IV C treatment group based on the U.S. National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 3. Although the sample size was too small to analyze for antitumour effect, the reported reduction in chemotherapy-related side effects with the addition of IV C is promising.

A possible criticism of our proposed approach is the potential for a placebo effect. Another potential criticism is the question of whether antioxidant vitamin C would interfere with pro-oxidative therapies such as chemotherapy. A further criticism could be the lack of outcomes data for the combination of IV C with conventional therapies. However, in the noncurative clinical setting, we propose that patients with a potentially increased need for vitamin C and those with presumed deficiencies could benefit from IV C and oral vitamin C to optimize homeostasis though anti-inflammatory support, potentially resulting in symptom reduction and improved qol. We propose giving 5–25 g IV C away from or before chemotherapy (followed by a 30- to 60-minute break to allow for clearance of additional vitamin C by the kidney and to normalize blood levels before chemotherapy administration).

In a systematic review of IV C and oral vitamin C given to cancer patients, the authors (Jacobs et al.73) concluded that most of the relevant studies have failed to report an antitumour effect, and that the studies thus far report a possible qol benefit for patients, including effects on symptoms such as fatigue, pain, and insomnia. In a review of vitamin C and cancer-related fatigue conducted by Carr et al.32, the authors noted that some other types of standard treatments for cancer-related fatigue are prescribed despite limited evidence for efficacy.

The systematic review by Jacobs et al. suggests that the time required for vitamin C infusion is a possible issue for patients. In our experience, patients receiving IV C for 1- to 2-hour infusions once or twice weekly are willing to use this relatively low-cost but time-intensive therapy because of the perceived benefits. We recommend that clear information be provided to patients that the effects of adding IV C to chemotherapy are unknown with respect to overall efficacy and that vitamin C could potentially decrease treatment efficacy despite any positive effect on symptoms (Table v). If the decision is made to provide IV C in supportive care, we recommend that it be given before chemotherapy, followed by a 30- to 60-minute break, or that it be given 12–72 hours after chemotherapy with attention to the half-life and clearance of the chemotherapy. Table v illustrates doses, osmolarity, and infusion times for the safe administration of IV C according to the proposed rational approach. Caution is recommended to minimize any potential interaction between chemotherapy and excess circulating vitamin C. We propose to combine IV C and oral vitamin C in a continuous manner to prevent deficiencies that could lead to side effects and reduced qol. In the supportive care setting, IV C given 1–3 times per week for 1–4 months in combination with oral vitamin C—for example, during post-adjuvant treatment—could improve or prevent deficiency, promote wound healing, lessen inflammation, improve qol or performance status, and potentially lessen the side effects of systemic treatment. Our rational approach to safely providing IV C is presented in Table v.

TABLE V Rational approach for using intravenous (IV) and oral vitamin C in the supportive care of cancer patients

 

CONCLUSIONS

In doses up to 25 g, IV C can safely be used to treat presumptive ascorbate deficiency based on symptoms and could favourably affect clinical parameters such as inflammation, fatigue, and qol. Using a rational, evidence-based approach such as that presented in Table v, clinicians can safely provide IV C as supportive care to patients with cancer.

The potential synergy of IV C with chemotherapy or radiation treatment, and the effect on overall outcomes, including survival, of a combined treatment approach, warrant further study. Studies that have already explored the effects of IV C in supportive care have design flaws such as small sample sizes and lack of a control group; thus, future studies could add a placebo control in a parallel-arm or crossover design. Studies that include blood biomarkers are also needed. How long any potential effect of an individual IV C treatment lasts is unknown. Studies designed to test that factor could be useful in creating evidence-based guidelines for optimal or sustained improvement in qol. Studies measuring vitamin C status before and during standard-of-care treatment could elucidate whether ongoing or intermittent deficiencies exist and whether such deficiencies could be related to symptoms that affect qol. Additional research is needed to study the roles of IV C and oral ascorbate with respect to dose, metabolic clearance, and infusion time. The role of target vitamin C plasma levels in relation to objective treatment response in humans requires further investigation as well. Although caution is warranted with respect to the use of IV C with surgery, chemotherapy, and radiation in the curative setting, vitamin C is a low-cost, safe therapy for the supportive care setting that might be an effective tool for improved supportive care.

ACKNOWLEDGMENTS

The authors thank Alexandra Louden nd, the Salish Cancer Center (http://salishcancercenter.com) in Salish, WA, U.S.A.; the Ottawa Integrative Cancer Centre (http://OICC.ca) in Ottawa, ON; Naturopathic Specialists, llc, (http://listenandcare.com) in Scottsdale, AZ, U.S.A.; and Cancer Treatment Centers of America’s Eastern Regional Medical Center (http://cancercenter.com) in Philadelphia, PA, U.S.A. for their collaboration.

CONFLICT OF INTEREST DISCLOSURES

We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.

AUTHOR AFFILIATIONS

*Salish Cancer Center, Fife, WA, U.S.A.;,
Naturopathic Specialists, Scottsdale, AZ, U.S.A.;,
Department of Research and Clinical Epidemiology, Ottawa Integrative Cancer Centre, Ottawa, ON;,
§Department of Medical Oncology, Cancer Treatment Centers of America, Philadelphia, PA, U.S.A..

REFERENCES

1. Cameron E, Campbell A. The orthomolecular treatment of cancer. ii. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer. Chem Biol Interact 1974;9:285–315.
cross-ref  pubmed  

2. Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A 1978;75:4538–42.
cross-ref  pubmed  pmc  

3. Riordan HD, Casciari JJ, González MJ, et al. A pilot clinical study of continuous intravenous ascorbate in terminal cancer patients. P R Health Sci J 2005;24:269–76.

4. Hoffer LJ, Levine M, Assouline S, et al. Phase i clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol 2008;19:1969–74. [Erratum in: Ann Oncol 2008;19:2095]
cross-ref  pubmed  

5. Monti DA, Mitchell E, Bazzan AJ, 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:e29794.
cross-ref  

6. Welsh JL, Wagner BA, van’t Erve TJ, et al. Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (pacman): results from a phase i clinical trial. Cancer Chemother Pharmacol 2013;71:765–75.
cross-ref  pubmed  pmc  

7. Stephenson CM, Levin RD, Spector T, Lis CG. Phase i clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemother Pharmacol 2013;72:139–46.
cross-ref  pmc  

8. Ma Y, Chapman J, Levine M, Polireddy K, Drisko J, Chen Q. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci Transl Med 2014;6:222ra18.
cross-ref  pubmed  

9. Hoffman FA. Micronutrient requirements of cancer patients. Cancer 1985;55(suppl):295–300.
cross-ref  pubmed  

10. Mayland CR, Bennett MI, Allan K. Vitamin C deficiency in cancer patients. Palliat Med 2005;19:17–20.
cross-ref  pubmed  

11. Mahdavi R, Faramarzi E, Seyedrezazadeh E, Mohammad-Zadeh M, Pourmoghaddam M. Evaluation of oxidative stress, antioxidant status and serum vitamin C levels in cancer patients. Biol Trace Elem Res 2009;130:1–6.
cross-ref  pubmed  

12. Ramaswamy G, Krishnamoorthy L. Serum carotene, vitamin A, and vitamin C levels in breast cancer and cancer of the uterine cervix. Nutr Cancer 1996;25:173–7.
cross-ref  pubmed  

13. Torun M, Yardim S, Gönenç A, Sargin H, Menevşe A, Símşek B. Serum beta-carotene, vitamin E, vitamin C and malondi-aldehyde levels in several types of cancer. J Clin Pharm Ther 1995;20:259–63.
cross-ref  pubmed  

14. Fain O, Mathieu E, Thomas M. Scurvy in patients with cancer. BMJ 1998;316:1661–2.
cross-ref  pubmed  pmc  

15. Mikirova N, Casciari J, Riordan N, Hunninghake R. Clinical experience with intravenous administration of ascorbic acid: achievable levels in blood for different states of inflammation and disease in cancer patients. J Transl Med 2013;11:191.
cross-ref  pubmed  pmc  

16. Alexandrescu DT, Dasanu CA, Kauffman CL. Acute scurvy during treatment with interleukin-2. Clin Exp Dermatol 2009;34:811–14.
cross-ref  

17. Bodansky O, Wroblewski F, Markardt B. Concentrations of ascorbic acid in plasma and white blood cells of patients with cancer and noncancerous chronic disease. Cancer 1952;5:678–84.
cross-ref  pubmed  

18. Fain O, Pariés J, Jacquart B, et al. Hypovitaminosis C in hospitalized patients. Eur J Intern Med 2003;14:419–25.
cross-ref  pubmed  

19. Gupta A, Bhatt ML, Misra MK. Lipid peroxidation and antioxidant status in head and neck squamous cell carcinoma patients. Oxid Med Cell Longev 2009;2:68–72.
cross-ref  pmc  

20. Gan R, Eintracht S, Hoffer LJ. Vitamin C deficiency in a university teaching hospital. J Am Coll Nutr 2008;27:428–33.
cross-ref  pubmed  

21. Schorah CJ, Downing C, Piripitsi A, et al. Total vitamin C, ascorbic acid, and dehydroascorbic acid concentrations in plasma of critically ill patients. Am J Clin Nutr 1996;63:760–5.
cross-ref  pubmed  

22. Anthony HM, Schorah CJ. Severe hypovitaminosis C in lung-cancer patients: the utilization of vitamin C in surgical repair and lymphocyte-related host resistance. Br J Cancer 1982;46:354–67.
cross-ref  pubmed  pmc  

23. Fain O. Vitamin C [French]. Rev Prat 2013;63:1091–6.
pubmed  

24. Mayne S. Antioxidant nutrients and chronic disease: use of biomarkers of exposure and oxidative stress status in epidemiologic research. J Nutr 2003;133(suppl 3):933S–40S.
cross-ref  pubmed  

25. Emri S, Kilickap S, Kadilar C, Halil MG, Akay H, Besler T. Serum levels of alpha-tocopherol, vitamin C, beta-carotene, and retinol in malignant pleural mesothelioma. Asian Pac J Cancer Prev 2012;13:3025–9.
cross-ref  pubmed  

26. Khanzode SS, Khanzode SD, Dakhale GN. Serum and plasma concentration of oxidant and antioxidants in patients of Helicobacter pylori gastritis and its correlation with gastric cancer. Cancer Lett 2003;195:27–31.
cross-ref  pubmed  

27. Mehdi WA, Zainulabdeen JA, Mehde AA. Investigation of the antioxidant status in multiple myeloma patients: effects of therapy. Asian Pac J Cancer Prev 2013;14:3663–7.
cross-ref  pubmed  

28. Romney SL, Basu J, Vermund S, Palan PR, Duttagupta C. Plasma reduced and total ascorbic acid in human uterine cervix dysplasia and cancer. Ann N Y Acad Sci 1987;498:132–43.
cross-ref  

29. Jonas CR, Puckett AB, Jones DP, et al. Plasma antioxidant status after high-dose chemotherapy: a randomized trial of parenteral nutrition in bone marrow transplantation patients. Am J Clin Nutr 2000;72:181–9.
cross-ref  pubmed  

30. 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;25:983–90.
pubmed  

31. Yeom CH, Jung GC, Song KJ. Changes of terminal cancer patients’ health-related quality of life after high dose vitamin C administration. J Korean Med Sci 2007;22:7–11.
cross-ref  pubmed  pmc  

32. Carr AC, Vissers MD, Cook JS. The effect of intravenous vitamin C on cancer- and chemotherapy-related fatigue and quality of life. Front Oncol 2014;4:283.
cross-ref  pubmed  pmc  

33. Takahashi H, Mizuno H, Yanagisawa A. High-dose intravenous vitamin C improves quality of life in cancer patients. Personalized Medicine Universe 2012;1:49–53.
cross-ref  

34. Mikirova N, Casciari J, Rogers A, Taylor P. Effect of high-dose intravenous vitamin C on inflammation in cancer patients. J Transl Med 2012;10:189.
cross-ref  pubmed  pmc  

35. Schectman G, Byrd JC, Gruchow HW. The influence of smoking on vitamin C status in adults. Am J Public Health 1989;79:158–62.
cross-ref  pubmed  pmc  

36. Suh SY, Bae WK, Ahn HY, Choi SE, Jung GC, Yeom CH. Intravenous vitamin C administration reduces fatigue in office workers: a double-blind randomized controlled trial. Nutr J 2012;11:7.
cross-ref  pubmed  pmc  

37. Gropper SA, Smith JL, Carr TP. Advanced Nutrition and Human Metabolism. 7th ed. Boston, MA: Cengage Learning; 2009.

38. United States, Department of Health and Human Services, National Institutes of Health, Office of Dietary Supplements (ods). Vitamin C: Fact Sheet for Health professionals [Web resource]. Bethesda, MD: ods; 2017. [Current version available at: https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/; cited 15 November 2017]

39. Lachapelle MY, Drouin G. Inactivation dates of the human and guinea pig vitamin C genes. Genetica 2011;139:199–207.
cross-ref  

40. Mandl J, Szarka A, Bánhegyi G. Vitamin C: update on physiology and pharmacology. Br J Pharmacol 2009;157:1097–110.
cross-ref  pubmed  pmc  

41. Graumlich JF, Ludden TM, Conry-Cantilena C, Cantilena LR Jr, Wang Y, Levine M. Pharmacokinetic model of ascorbic acid in healthy male volunteers during depletion and repletion. Pharm Res 1997;14:1133–9.
cross-ref  pubmed  

42. Du J, Cullen JJ, Buettner GR. Ascorbic acid: chemistry, biology and the treatment of cancer. Biochim Biophys Acta 2012;1826:443–57.
pubmed  pmc  

43. Corpe CP, Tu H, Eck P, et al. Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. J Clin Invest 2010;120:1069–83.
cross-ref  pubmed  pmc  

44. Padayatty SJ, Sun H, Wang Y, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med 2004;140:533–7.
cross-ref  pubmed  

45. Oreopoulos DG, Lindeman RD, Vanderjagt DJ, Tzamaloukas AH, Bhagavan HN, Garry PJ. Renal excretion of ascorbic acid: effect of age and sex. J Am Coll Nutr 1993;12:537–42.
cross-ref  pubmed  

46. Levine M, Conry-Cantilena C, Wang Y, et al. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci U S A 1996;93:3704–9.
cross-ref  pubmed  pmc  

47. Levine M, Padayatty S, Espey M. Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries. Adv Nutr 2011;2:78–88.
cross-ref  pmc  

48. Benke KK. Modeling ascorbic acid level in plasma and its dependence on absorbed dose. J Aust Coll Nutr Env Med 1999;18:11–12.

49. Hickey DS, Roberts HJ, Cathcart RF. Dynamic flow: a new model for ascorbate. J Orthomol Med 2005;20:237–44.

50. United States, Department of Health and Human Services, National Institutes of Health, National Center for Biotechnology Information (ncbi). PubChem Compound Database: Ascorbic acid [Web resource (CID=54670067)]. Bethesda, MD: ncbi; n.d. [Available at: https://pubchem.ncbi.nlm.nih.gov/compound/54670067; cited 12 January 2016]

51. Drisko JA, Chapman J, Hunter VJ. The use of antioxidants with first-line chemotherapy in two cases of ovarian cancer. J Am Coll Nutr 2003;22:118–23.
cross-ref  pubmed  

52. Friedman GJ, Sherry S, Ralli EP. The mechanism of the excretion of vitamin C by the human kidney at low and normal plasma levels of ascorbic acid. J Clin Invest 1940;19:685–9.
cross-ref  pubmed  pmc  

53. Spellberg MA, Keeton RW. Excretion of ascorbic acid in relation to saturation and utilization with some diagnostic implications. Arch Intern Med 1939;63:1095–116.
cross-ref  

54. 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. P R Health Sci J 2008;27:7–19.
pubmed  

55. Gałecki P, Szemraj J, Bieşkiewicz M, Florkowski A, Gałecka E. Lipid peroxidation and antioxidant protection in patients during acute depressive episodes and in remission after fluoxetine treatment. Pharmacol Rep 2009;61:436–47.
cross-ref  

56. Richardson TI, Ball L, Rosenfeld T. Will an orange a day keep the doctor away? Postgrad Med J 2002;78:292–4.
cross-ref  pubmed  pmc  

57. Alberg A. The influence of cigarette smoking on circulating concentrations of antioxidant micronutrients. Toxicology 2002;180:121–37.
cross-ref  

58. Berger MM, Baines M, Raffoul W, et al. Trace element supplementation after major burns modulates antioxidant status and clinical course by way of increased tissue trace element concentrations. Am J Clin Nutr 2007;85:1293–300.
cross-ref  pubmed  

59. Pelletier O. Smoking and vitamin C levels in humans. Am J Clin Nutr 1968;21:1259–67.
cross-ref  pubmed  

60. Moore MM, Chua W, Charles KA, Clarke SJ. Inflammation and cancer: causes and consequences. Clin Pharmacol Ther 2010;87:504–8.
cross-ref  pubmed  

61. Jacob RA, Sotoudeh G. Vitamin C function and status in chronic disease. Nutr Clin Care 2002;5:66–74.
cross-ref  pubmed  

62. World Health Organization (who), United Nations High Commissioner for Refugees. Scurvy and its Prevention and Control in Major Emergencies. Geneva, Switzerland: who; 1999.

63. Wallace JM. Nutritional and botanical modulation of the inflammatory cascade—eicosanoids, cyclooxygenases and lipoxygenases—as an adjunct in cancer therapy. Integr Cancer Ther 2002;1:7–37.

64. Mcmillan DC. Systemic inflammation, nutritional status and survival in patients with cancer. Curr Opin Clin Nutr Metab Care 2009;12:223–6.
cross-ref  pubmed  

65. Mikirova NA, Jackson JA, Riordan NH. The effect of high dose IV vitamin C on plasma antioxidant capacity and level of oxidative stress in cancer patients and healthy subjects. J Orthomol Med 2007;22:153–60.

66. Luo M, Fernandez-Estivariz C, Jones DP, et al. Depletion of plasma antioxidants in surgical intensive care unit patients requiring parenteral feeding: effects of parenteral nutrition with or without alanyl-glutamine dipeptide supplementation. Nutrition 2008;24:37–44.
cross-ref  

67. Petroianu A, Alberti LR. Effect of oral supplementation of vitamin C on intestinal anastomotic resistance. Rev Col Bras Cir 2011;38:54–8.
cross-ref  pubmed  

68. 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:e11414.
cross-ref  pubmed  pmc  

69. Robitaille L, Mamer OA, Miller WH Jr, et al. Oxalic acid excretion after intravenous ascorbic acid administration. Metabolism 2009;58:263–9.
cross-ref  pubmed  pmc  

70. McAllister CJ, Scowden EB, Dewberry FL, Richman A. Renal failure secondary to massive infusion of vitamin C. JAMA 1984;252:1684.
cross-ref  pubmed  

71. Canavese C, Petrarulo M, Massarenti P, et al. Long-term, lowdose, intravenous vitamin C leads to plasma calcium oxalate supersaturation in hemodialysis patients. Am J Kidney Dis 2005;45:540–9.
cross-ref  pubmed  

72. Shahrbanoo K, Taziki O. Effect of intravenous ascorbic acid in hemodialysis patients with anemia and hyperferritinemia. Saudi J Kidney Dis Transpl 2008;19:933–6.
pubmed  

73. Jacobs C. Intravenous vitamin C can improve anemia in erythropoietin-hyporesponsive hemodialysis patients. Nat Clin Pract Nephrol 2006;2:552–3.
cross-ref  pubmed  

74. Auer BL, Auer D, Rodgers AL. Relative hyperoxaluria, crystalluria and haematuria after megadose ingestion of vitamin C. Eur J Clin Invest 1998;28:695–700.
cross-ref  pubmed  

75. 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;118:561–3.
cross-ref  pubmed  

76. Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Intake of vitamins B6 and C and the risk of kidney stones in women. J Am Soc Nephrol 1999;10:840–5.
pubmed  

77. Gerster H. No contribution of ascorbic acid to renal calcium oxalate stones. Ann Nutr Metab 1997;41:269–82.
cross-ref  pubmed  

78. Mehta JB, Singhal SB, Mehta BC. Ascorbic-acid-induced haemolysis in g-6-pd deficiency. Lancet 1990;336:944.
cross-ref  

79. Rees DC, Kelsey H, Richards JD. Acute haemolysis induced by high dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency. BMJ 1993;306:841–2.
cross-ref  pubmed  pmc  

80. Braunstein EM. Glucose 6-phosphate dehydrogenase deficiency. In: Lichtin AE, ed. Merck Manual: Professional Edition. 19th online ed. Kenilworth, NJ: Merck Sharp and Dohme Corp; 2018. [Available at: http://www.merckmanuals.com/professional/hematology_and_oncology/anemias_caused_by_hemolysis/glucose-6-phosphate_dehydrogenase_g6pd_deficiency.html; cited 8 January 2016]

81. Glucose-6-phosphate dehydrogenase deficiency. who Working Group. Bull World Health Organ 1989;67:601–11.

82. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74.
cross-ref  pubmed  

83. Clementz AG, Harris A. Collagen xv: exploring its structure and role within the tumor microenvironment. Mol Cancer Res 2013;11:1481–6.
cross-ref  pubmed  pmc  

84. Bowie AG, O’Neill LA. Vitamin C inhibits nf-kappa b activation by tnf via the activation of p38 mitogen-activated protein kinase. J Immunol 2000;165:7180–8.
cross-ref  pubmed  

85. Cárcamo JM, Pedraza A, Bórquez-Ojeda O, Zhang B, Sanchez R, Golde DW. Vitamin C is a kinase inhibitor: dehydroascorbic acid inhibits IκBα kinase β. Mol Cell Biol 2004;24:6645–52.
cross-ref  

86. Chen Q, Espey MG, Sun AY, et al. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci U S A 2008;105:11105–9.
cross-ref  pubmed  pmc  

87. Casciari JJ, Riordan HD, Miranda-Massari JR, Gonzalez MJ. Effects of high dose ascorbate administration on L-10 tumor growth in guinea pigs. P R Health Sci J 2005;24:145–50.
pubmed  

88. Verrax J, Calderon PB. Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoural effects. Free Radic Biol Med 2009;47:32–40.
cross-ref  pubmed  

89. Espey MG, Chen P, Chalmers B, et al. Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer. Free Radic Biol Med 2011;50:1610–19.
cross-ref  pubmed  pmc  

90. Chen Q, Espey MG, Sun AY, et al. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci U S A 2007;104:8749–54.
cross-ref  pubmed  pmc  

91. Wefers H, Sies H. The protection by ascorbate and glutathi-one against microsomal lipid peroxidation is dependent on vitamin E. Eur J Biochem 1988;174:353–7.
cross-ref  pubmed  

92. Mikirova N, Hunnunghake R, Scimeca RC, et al. High-dose intravenous vitamin C treatment of a child with neurofibromatosis type 1 and optic pathway glioma: a case report. Am J Case Rep 2016;17:774–81.
cross-ref  pubmed  pmc  

93. Fritz H, Flower G, Weeks L, et al. Intravenous vitamin C and cancer: a systematic review. Integr Cancer Ther 2014;13:280–300.
cross-ref  pubmed  


Correspondence to: Heather Wright, Naturopathic Specialists, 7331 E. Osborne Drive, Scottsdale, Arizona 85251 U.S.A. E-mail: H.Wright.ND@gmail.com

(Return to Top)



Current Oncology, VOLUME 25, NUMBER 2, April 2018








Copyright © 2018 Multimed Inc.
ISSN: 1198-0052 (Print) ISSN: 1718-7729 (Online)