Description
Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin. Through intravenous high-dose application of vitamin C, plasma concentrations of up to 25mM can be achieved. At these concentrations, high-dose intravenous vitamin C (HDIVC) promotes the formation of free radicals and has a pro-oxidant effect. These concentrations cannot be reached with oral intake due to the tightly regulated bioavailability of vitamin C.
Efficacy
Antitumour therapy
The results of two randomised controlled trials (RCTs) and a small pilot study suggest (partly in subgroup analyses) that HDIVC administered in addition to chemotherapy could have an antineoplastic effect in patients with advanced ovarian cancer, acute myeloid leukaemia of advanced age (>60y.), metastatic colorectal cancer of advanced age (>55y.) and, independent of age, with RAS mutation (moderate-high certainty evidence).
Supportive and palliative therapy
The results from two RCTs are not conclusive. The most recent and largest RCT concludes that HDIVC cannot alleviate cancer-related or therapy-associated side effects in patients with metastatic colorectal carcinoma (high certainty), while a small pilot RCT suggests that HDIVC in addition to chemotherapy can reduce mild side effects (CTCAE 1-2) in patients with ovarian cancer but has no influence on higher-grade side effects (CTCAE 3+) (low-certainty evidence).
Safety
HDIVC is generally well tolerated. Caution is advised in patients with impaired renal function and glucose-6-phosphate dehydrogenase deficiency.
Citation
Ali Behzad, Janine Ziemann, Markus Horneber, CAM Cancer Collaboration. Vitamin C (intravenous high-dose) [online document], Feb 28, 2023.
Document history
Latest update in February 2023.
Next update due in February 2026.
Description and background
Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin that can only be stored in small quantities in the body. Since the human organism cannot produce it itself due to the lack of the enzyme L-gulonolactone oxidase, vitamin C must be taken in through the diet (Padayatty 2016, Maeda 2000). According to the Office of Dietary Supplements at the US National Institutes of Health the recommended dietary allowance for vitamin C for adults aged 19 and over is 90mg for men, 75mg for women, 85mg for pregnant and 120mg for lactating women. Foods with a high vitamin C content are all types of cabbage and citrus fruits as well as sea buckthorn berries, rosehip and parsley.
The scientific name L-ascorbic acid is derived from the scorbutic disease caused by vitamin C deficiency ("antiscorbutic acid"). For commercial use, vitamin C is primarily produced synthetically but the effects do not differ between the synthetic and natural forms.
In physiological concentrations (<100µM), ascorbic acid is important in biochemical processes primarily as an electron donor and therefore has an antioxidant effect. It also plays a role in iron metabolism and is an important co-factor of enzymes in diverse biological processes such as collagen and carnitine biosynthesis, demethylation of proteins, DNA and RNA (Buettner 1993, Lane 2014, Kuiper 2014).
In the late 1990s, it was discovered that parenteral administration of vitamin C from 0.5-1g/kg body weight per day can achieve concentrations up to 25mM, which cannot be achieved through oral intake due to limited bioavailability. The path of administration of vitamin C is therefore crucial for obtaining of pharmacological concentrations.
Ingredients and quality requirements
Vitamin C products are mainly based on the pure substance L-ascorbic acid. According to the specifications of the European Pharmacopoeia, quality of the raw material is characterised by low contamination with impurities such as (heavy) metals, oxalic acid, inorganic components or additional substances, so that the purity ranges between 99 and 100.5 %. Alternatively, some medicinal products also use the salt sodium ascorbate, which ideally consists of 99-101 % of the pure substance according to pharmaceutical quality requirements.
Alleged indications
Apart from substitution in deficiency states, there are no established indications for HDIVC. Nevertheless, its use in complementary and alternative medicine is widespread (Padayatty 2010). In clinical studies in oncology, its application in tumour therapy and supportive therapy have been explored (Zasowska-Nowak 2021).
Further investigation of the antitumour efficacy of orally applied vitamin C was abandoned after two randomised controlled trials (Creagan 1979, Moertel 1985) showed no improvement in survival rates.
Administration and dosage
In cancer patients, HDIVC has been administered in clinical trials as a bolus infusion 1-3 times per week in a dose of 0.5-1.5 g vitamin C per kg body weight, often concomitantly with drug therapy. (Hoffer 2008, Stephenson 2013, Wang 2022). One provider of vitamin C infusions recommends that due to a lack of clinical data, the administration should be delayed an interval of at least 24-hour before planned chemotherapy and then only after 3-4 half-lives of the chemotherapeutic agent. (Pascoe 2022). For better tolerability, some clinical trials begin with a lower dose (e. g. 20% of the target dose) and gradually increase the dose if well tolerated. A pharmacologically effective dose (>20mM) as reported in the studies ranges from 50-100g (Riordan 2003, Hoffer 2008).
To ensure solubility and osmolarity, studies in line with the study by Hoffer et al. (Hoffer 2015) have used about 20ml of a carrier solution (usually sodium chloride 0.9%) per 1g of vitamin C, i. e. 300-1800ml of carrier solution have been used for administrations between 15-140g of vitamin C. The infusion rate is between 0.5-1g/minute, which means that an infusion of 100g takes about 100-200 minutes (Hoffer 2015). The stability of ascorbic acid solutions for infusion purposes is limited in time, so that the administration should be applied no later than 2-4 hours after preparation. (Allwood 1998, Lavoie 2004).
Preparations for parenteral administration are available without prescription in pharmacies.
Mechanisms of actions
Only studies of pharmacological effects relating to clinical applications in oncology are presented below.
Although the mechanism of action of HDIVC is fundamentally different from that of orally ingested vitamin C, bolus administration leads to normal plasma and tissue levels that are cleared over a half-life of 8-20 days (Nauman 2018). In many studies, the next dose is administered before the end of this time, so that it can be assumed that normal vitamin C levels are maintained in the plasma. Patients with cancer are more likely to have low plasma vitamin C levels than healthy subjects (Mayland 2005, Shenoy 2017). The severity of the deficiency correlates with the severity of the cancer (Ramaswamy 1996, Khanzode 2004) and is inversely correlated to the survival prognosis (Mayland 2005). Effects via replenishment of vitamin C stores are therefore also conceivable.
HDIVC is an electron donor for oxygen and extra- and intracellular catalytic metals such as iron or copper, which in their reduced form favour the formation of oxygen free radicals (reactive oxygen species = ROS). The reaction with oxygen produces H2O2. (Ngo 2019).
Since malignant cells often have an increased labile iron pool, a greater amount of iron storage (Ngo 2019) and lack antioxidant enzymes such as catalase and gluthathione peroxidase (Macan 2019), it is assumed that cancer cells are selectively damaged while healthy cells have protective mechanisms. The good clinical tolerability supports this assumption, even if the mechanism has not yet been fully understood (Zasowska-Nowak 2021, Ngo 2019).
Three randomised intervention trials (RCTs) of HDIVC in tumour therapy are available (Wang 2022; Zhao 2018; Ma 2014). Wang 2022 (n=442) investigated the effect of HDIVC on tumour response, overall survival, progression-free survival and side effects according to CTCAE; Zhao 2018 (n=73) the effect on 3-year survival and remission rates and Ma 2014 (n=29) the effect on 5-year survival and progression-free survival, tumour response and side effects of chemotherapy according CTCAE.
Furthermore, results are available from three systematic reviews that include a large number of non-controlled or early phase studies in addition to the RCT by Ma 2014 (Fritz 2014, Jacobs 2014, Nauman 2018). While Fritz 2014 included studies exclusively on HDIVC, the conclusions of Jacobs 2014 are based on various administrations of vitamin C including oral administration and low-dose administration. Nauman 2018 also summarised both low-dose and HDIVC in their conclusion. Overall, these reviews concluded that no firm conclusions could be made due to the low certainty of the results of the studies and that the partially positive results need to be confirmed in larger, rigorous studies to allow a conclusive assessment.
Description of included studies
Antitumor treatment
In a randomised, multicentre phase III trial (n=442), Wang et al investigated the efficacy of HDIVC administered in addition to chemotherapy with FOLFOX+/bevacizumab on PFS as measured by radiological response (RECIST) in patients with metastatic colorectal cancer (mCRC). (Wang 2022) The intervention group received an additional 1.5 g/kg body weight of vitamin C intravenously on days 1-3 of chemotherapy. The cycle was repeated every 2 weeks and ended after a maximum of 12 cycles. Compared to the control group, there were no significant differences in progression-free survival (PFS), objective response rate (ORR) and overall survival (OS), only a trend in PFS (8.6 vs 8.3 months; P = 0.1). In the subgroup with RAS mutation and in older patients >55 years, the PFS prolongation was significant compared to the control group (9.2 vs 7.8 months; P=0.01 and 9.2 vs 8.1, respectively; P not shown). In the subgroup with RAS mutation, there was also a trend towards improved overall survival (20.2 vs. 16.8 months; p=0.2), but again no significant difference in ORR (43 vs 42%, p=0.8). Since the vitamin C infusion was administered only once every fortnight and ended after 6 months, i.e. before the majority of disease progression had occurred, the authors believe that "the true effect of HDIVC in mCRC may be underestimated". No significant differences in the number and severity of physician-assessed adverse events after CTCAE 4.0, such as blood count changes, electrolyte shifts, gastrointestinal side effects, elevation of liver or kidney function parameters were observed. An expected attenuation of effect based on basic pharmacological considerations and cell culture results, was not confirmed here; there were even indications of an enhanced effect.
In an RCT, Zhao et al. investigated the efficacy of intravenous vitamin C on remission rates and overall survival in 73 patients aged 60 years and over with AML. (Zhao 2018) All patients received DCAG (decitabine 15mg/m² day 1-5 and G-CSF 300µg day 0-9, 10mg/m² cytarabine q12h day 3-9 and 8mg/m² aclarubicin) and the intervention group received additional vitamin C 50-80mg/kg day 0-9. A primary endpoint was not stated. In the intervention group, the authors reported a significantly higher rate of complete remission after the first induction and a trend of higher complete remission rates after the second induction. It was not stated whether these were cytological or molecular remissions. The authors also reported significantly higher 3-year survival in the vitamin C group at 15.3 vs 9.3 months (low-certainty evidence).
In a small pilot RCT, Ma et al. evaluated the efficacy of HDIVC on adverse events and 5-year survival in 27 patients with advanced ovarian cancer. (Ma 2014) Patients in both groups received paclitaxel/carboplatin as chemotherapeutic agents; the intervention group also received 75-100g of intravenous vitamin C twice weekly for 12 weeks. The starting dose was 15g and increased to 75-100g with a target plasma level of 350-400mg/dl (20-23mM). The study was too small to statistically confirm the potential efficacy of HDIVC. The authors reported a trend for improvement in 5-year survival (no numerical data provided). Progression-free survival was 25.5 months in the experimental group vs. 16.75 months in the control group (low-certainty evidence).
Two controlled trials HDIVC, one using a combination treatment and the other a retrospective matched-group design, are not included in the above-mentioned reviews due to their publication date.
A phase II RCT (n=97) used a combination treatment of HDIVC and additional modulated electrohyperthermia (Ou 2020) in addition to best supportive care (BSC) in advanced, therapy-refractory non-small cell lung cancer (NSCLC). The control groups received BSC alone. The authors report significant improvements of progression-free survival (PFS), overall survival (OS) and quality of life; however, no conclusions about the specific effects of HDIVC in this combination treatment can be made.
A retrospective study evaluated the efficacy of HDIVC administered in addition to chemotherapy with gemcitabine and carboplatin (70 patients) compared to a matched group with chemotherapy alone (53 patients) in patients with triple-negative breast carcinoma. (Qu 2020) The authors reported a significant prolongation in PFS (7 vs. 4.5 months; P <0.05) and OS (27 vs. 18 months; p < 0.05).
Supportive and palliative care
The RCT by Wang et al. (Wang 2022) investigated the efficacy of HDIVC on adverse events after CTCAE 4.0. The authors reported that HDIVC had no clear effect on the rate and severity of reported physician-assessed adverse events after CTCAE 4.0, such as blood count changes, electrolyte shifts, gastrointestinal adverse events, elevation of liver or renal function parameters (high-certainty evidence).
The above-mentioned pilot RCT of (Ma 2014) also investigated the efficacy of HDIVC on adverse events after CTCAE 3.0. The authors evaluated the impact of the intervention on physician-assessed adverse events of chemotherapy and reported a significantly lower incidence of grade 1/2 adverse events (low-certainty evidence).
Adverse effects
Adverse events following the administration of HDIVC are minor and correspond to the side effects to be expected with rapid infusion of highly osmolar solutions. They can be avoided by drinking fluids before and during infusion. (Riordan 2005, Hoffer 2008, Padayatty 2010). In patients with heart failure, volume overload is possible for a short time due to the hyper-osmolar solution, but HDIVC has an osmodiuretic effect, so that weight gain or volume overload during the interval is unlikely. A temporary polyuria in the first 24 h after infusion is possible (Hoffer 2015 ).
Also in the largest RCT to date with 442 patients (Wang 2022), the physician-assessed side effects after CTCAE in patients who received HDIVC (1-1.5g/kg body weight) in addition to chemotherapy with FOLFOX (+/- bevacizumab) for metastatic colorectal carcinoma were comparable to those of the control group. A phase 1 study assessed, the safety of administering HDIVC (≥25g; ≥20mM) 3x/week in addition to radiochemotherapy (temozolomide 75mg/m2/day, 1.8Gy/day) in 11 patients with glioblastoma. (Allen 2019) There were no dose-limiting toxicities (up to 87.5g HDIVC) and no increased cancer-related or treatment-associated adverse events (CTCAE 4.03) compared to the historically expected comparison.
In patients with glucose-6-phosphate dehydrogenase deficiency, the administration of HDIVC can lead to haemolysis. (Campbell 1975, Rees 1993). This risk is particularly present at doses >59g (Marik 2019). Therefore, patients should be screened for this before starting therapy. Oxalic acid is an end product of the metabolic oxidation of vitamin C. Oxalate nephropathy has been reported following intravenous administration of vitamin C in impaired renal function. (Mc Allister 1984, Lawton 1985, Wong 1994) However, the risk of intrarenal crystallisation of oxalate is not increased in normal renal function. (Robitaille 2009).
Contraindications
Impaired renal function or glucose-6-phosphate dehydrogenase deficiency is a relative contraindication.
Interactions
Previous clinical studies on pharmacokinetic interactions refer to the oral intake of ascorbic acid (Williams 1983, Gordi 2003, Slain 2005, Gonzalez 1995, van Heeswijk 2005). The results do not suggest a clinically relevant influence on drug metabolism. Since vitamin C is a co-factor in many biochemical processes, activates liver enzymes and HDIVC achieves higher plasma levels, pharmacokinetic interactions cannot be ruled out.
Evidence of adverse effects by vitamin C in cell models related to antineoplastic therapy (Subramani 2014, Heaney 2008) and have not been further investigated clinically. (Subramani 2014, Heaney 2008). Although an attenuation of radiotherapy and many chemotherapeutic agents by radical inactivation would be expected, a large number of preclinical studies also suggest supportive antitumour effects through the use of HDIVC (Böttger 2021).
In the largest RCT to date with 442 patients in patients with mCRC and a therapy with FOLFOX (+/- bevacizumab), HDIVC had no negative influence on the effectiveness of chemotherapy, although it was administered on the same day and the two following days. (Wang 2022) Findings from subgroups even suggest increased efficacy. Similar results were reported by the authors of the two other controlled intervention trials (Ma 2014, Zhao 2018).
In summary, there is evidence from some of the controlled intervention studies that HDIVC does not lead to an attenuation of efficacy but to an enhancement of efficacy of antineoplastic therapy.
In the case of oral administration, sufficient dosing intervals should be observed when taking drugs at the same time (e.g. multikinase inhibitors) in order to prevent complex formation and resorptive disorders, for example.
Miscellaneous/warnings
Individuals who are on continuous plasma glucose monitoring because of diabetes mellitus may report incorrectly high glucose values after receiving HDIVC. In order to avoid insulin-induced hypoglycaemia they should be advised accordingly.
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