File Name: intravenous vitamin c and cancer a systematic review .zip
- Intravenous Vitamin C for Cancer Therapy – Identifying the Current Gaps in Our Knowledge
- Intravenous ascorbic acid
- Pilot trial of high-dose vitamin C in critically ill COVID-19 patients
- Systematic Review of Intravenous Ascorbate in Cancer Clinical Trials
Many cancer patients on intensive chemotherapy lack vitamin C.
Vitamin C is an antioxidant that may scavenge reactive oxygen species preventing DNA damage and other effects important in cancer transformation. Dietary vitamin C from natural sources is taken with other compounds affecting its bioavailability and biological effects. High pharmacological doses of vitamin C may induce prooxidant effects, detrimental for cancer cells. An oxidized form of vitamin C, dehydroascorbate, is transported through glucose transporters, and cancer cells switch from oxidative phosphorylation to glycolysis in energy production so an excess of vitamin C may limit glucose transport and ATP production resulting in energetic crisis and cell death. Vitamin C may change the metabolomic and epigenetic profiles of cancer cells, and activation of ten-eleven translocation TET proteins and downregulation of pluripotency factors by the vitamin may eradicate cancer stem cells.
Intravenous Vitamin C for Cancer Therapy – Identifying the Current Gaps in Our Knowledge
Many cancer patients on intensive chemotherapy lack vitamin C. Vitamin C stimulates the production and activation of immune cells, so perhaps supplementation could be used to improve the immunity in those patients.
This review assesses the effectiveness and safety of vitamin C administration in cancer. A total of 19 trials were included.
In only 4 trials randomization was used to determine if patients received vitamin C or a placebo. The result of this review does not prove that there is a clinically relevant positive effect of vitamin C supplementation in cancer patients in general on the overall survival, clinical status, quality of life QOL and performance status PS , since the quality of the studies published is low. Interventions and patient groups are very diverse, hence an effect in some patient groups is possible.
There seems to be a better effect with intravenous than oral administration. Nevertheless, treatment with vitamin C is safe with minimal side effects. Thereby, we think it is safe to examine the effects of vitamin C on specific groups of patients in a randomized controlled setting. Vitamin C is an essential micronutrient, that plays an important role in numerous physiological processes in the human body. Unlike most mammals, humans lack the ability to generate endogenous vitamin C due to a mutation in the GULO gene and are thereby completely dependent on dietary intake.
The biological efficacy of vitamin C depends on its redox abilities and it functions as a cofactor in many enzymatic reactions. In physiological concentrations, it also functions as an antioxidant. By the s, Nobel Price winner Linus Pauling had already developed a strategy to use intravenous IV vitamin C in cancer patients [ 1 , 2 ].
He treated patients with advanced cancer with high doses of vitamin C and reported a positive effect on survival. However, these studies have been methodologically criticized on several aspects such as data collection and data analysis. This resulted in a limited use of vitamin C in cancer patients. Other studies performed afterwards could also not reproduce these results; however, opposed to the intravenous use of vitamin C by Pauling et al, in most of these studies, oral vitamin C supplementation was used [ 3 ].
Pharmacokinetic studies show that the way of administration makes a big difference as peak plasma vitamin C concentrations after intravenous administration are much higher up to fold than after oral intake [ 4 ]. There are multiple hypotheses about the way vitamin C has anti-tumor effects. An important possible mechanism of action is that in pharmacological concentrations especially after intravenous use vitamin C functions as a pro-oxidant and stimulates the formation of hydrogen peroxide.
This hydrogen peroxide can create reactive oxygen species ROS , that directly have cytotoxic activity on cancer cells [ 5 ]. Another important hypothesis is that vitamin C can create important epigenetic changes due to its effect on 2-oxoglutarate-dependent dioxygenases, like histone and DNA demethylases [ 6 ]. In preclinical studies investigators also show that vitamin C can have a synergetic effect with some types of chemo- and immunotherapy [ 7 , 8 , 9 , 10 , 11 ].
This could be the result of low dietary intake of these patients or of an increased need for vitamin C in tumor cells or in immune cells. In extension of our results, other researchers observed that low vitamin C plasma levels in patients with various types of advanced cancer were associated with worse survival [ 16 ].
Boosting their immune system with vitamin C to hasten immune recovery and thereby prevent infectious complications is attractive, since vitamin C is cheap and generally available. However, since some vitamins have been shown to promote cancer development, we were interested in the effects of vitamin C on cancer progression and its safety. To this end, we conducted a systematic review of the literature on vitamin C administration in cancer patients. We focused on administration route, efficacy and on the side-effects in combination with or without other cancer treatment.
The aim of this review is to assess the effectiveness of vitamin C in the treatment of cancer, with or without adjuvant standard anti-cancer treatment like chemotherapy and radiotherapy. An attempt was also made to quantify toxicity and side effects of vitamin C and the findings were considered in the discussion to determine the risk—benefit ratio of the treatment.
This systematic review was written conform the PRISMA statement for reporting systematic reviews of studies that evaluate health care interventions [ 17 ]. Studies on the effect of vitamin C administration in cancer patients after diagnosis were included. All study designs were allowed except for Phase I trials and case reports, since there was a lack of extensive randomized controlled trials RCTs but the quality of the studies was weighted during analysis and discussion.
Language was restricted to English. Studies on the effect of clinical vitamin C administration, as mono-therapy or in combination with other standard cancer treatment regimes. The dose and mode of delivery were considered in subgroup analyses.
Primary outcome measure was overall survival. Secondary outcome measures were progression-free survival, tumor response, response rate, disease-free survival, adverse effects, quality of life QOL , clinical response and performance status PS.
The last search was run on the 11th of March The complete search strategy is shown in Supplementary File S1. Bibliographies of identified articles were also reviewed and searched manually for additional references. Assessment of eligibility of the articles for inclusion in this review was performed and peer reviewed by two of the authors. The identified articles were screened on title and abstract in agreement with the inclusion and exclusion criteria by E. Lookermans E. Subsequent full text assessment resulted in the final study selection.
Data were collected by E. For each included study, information was extracted regarding the methods of the study aim, study design, number of groups , the participants number of patients, patient description, geographic location, methods of recruitment, inclusion criteria for participation, exclusion criteria for participation, age, gender the intervention vitamin C treatment, dose, schedule, mode of delivery, additional treatment, previous cancer treatments received, setting and the outcomes and comparison groups primary outcome measures, secondary outcome measures, method of assessing outcome measures, method of follow-up for non-respondents, outcome assessment, length of follow-up, frequency, relevant adverse events.
Discrepancies in the data extraction were resolved through discussion. The quality of all eligible studies was assessed independently by two authors E. These tools were used to make judgments about the extent of bias that may be present in each of the studies and to rate the information in each component of the paper Supplementary File S2.
An additional article was found through article references, bringing the total number of records suitable for further evaluation to After removal of duplicates there were articles left for investigation.
By scanning the title and abstract of these records, records were excluded because they clearly did not match the inclusion criteria mostly it were preclinical studies. Thirty-eight articles were evaluated on their full text. Of these articles, 19 records were excluded based on the inclusion criteria. In most of these articles, vitamin C supplementation was not the primary intervention, but combined with other experimental treatments, like other vitamins or arsenic trioxide.
This resulted in 19 records being included for qualitative synthesis Figure 1. The study characteristics of the 19 articles selected for this review are described in Table 1. All studies described different individual patients except the 2 studies by the same authors. In both of these studies, patients with terminal cancer which were treated with IVC were compared to similar control patients. The second study 10 of the original studied patients were replaced since there were not enough suitable control patients, but 90 patients and most of the controls were identical to the first study [ 1 , 23 ].
Most trials included patients with a variety of cancer types, and most of the time patients were in a terminal or advanced stage. In only 6 studies a specific cancer type was treated: 2 times breast cancer, 1 ovarian cancer, 1 colorectal cancer, 1 prostate cancer and 1 acute myeloid leukemia. All trials included both sexes, except for the studies on breast cancer and ovarian cancer that logically treated only women and the study on prostate cancer that logically treated only men.
The average age of the participants was approximately 60 years. In 8 studies, vitamin C was given intravenously IV , all in different doses and time intervals [ 22 , 25 , 26 , 27 , 28 , 33 , 35 , 37 ]. In 8 studies intravenous vitamin C IVC was given followed by or in combination with oral vitamin C supplementation [ 1 , 2 , 23 , 24 , 30 , 31 , 34 , 36 ]. In 3 studies vitamin C supplementation was only prescribed orally [ 3 , 29 , 32 ]. In 7 studies, conventional anti-cancer treatment was given in addition to the administration of vitamin C [ 22 , 24 , 25 , 27 , 34 , 35 , 37 ].
In 6 studies, this was not specifically documented, but it seems unlikely that patients had concomitant treatments [ 3 , 26 , 28 , 30 , 32 , 36 ] and in 6 articles it was written that no additional treatment was given at the time of the intervention with vitamin C [ 1 , 2 , 23 , 29 , 31 , 33 ]. In 4 articles, the researchers described that patients received conventional cancer therapy prior to participation [ 2 , 31 , 32 , 35 ], 13 articles report no information of previous treatments [ 1 , 3 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 30 , 33 , 34 , 36 ] and in 2 studies patients received no prior treatment [ 29 , 37 ].
Ten articles discuss the effect of vitamin C on overall survival [ 1 , 3 , 23 , 24 , 26 , 27 , 29 , 30 , 32 , 37 ], 9 articles the effect on clinical response in general [ 2 , 25 , 26 , 28 , 29 , 30 , 31 , 33 , 37 ], 7 on QOL and PS [ 3 , 26 , 30 , 31 , 34 , 35 , 36 ] and 14 articles report on the safety and toxicity of vitamin C treatment [ 2 , 3 , 22 , 25 , 26 , 27 , 29 , 30 , 31 , 33 , 34 , 35 , 36 , 37 ].
Figure 2 presents the bias risk assessment as percentages across all RCTs. Supplementary File S3 shows a summary of the risk of bias assessment of each item for each included RCT. Risk is presented percentages across all included RCTs. In all RCTs, the selection process and the randomization process were not clearly described.
It was therefore impossible to make a statement about the selection bias in the studies. Two of the 4 studies were blinded. There was a low risk of detection bias since the main outcome in the RCTs was overall survival. There did not seem to be other forms of bias in the selected RCTs.
The ROBINS-I tool, used for the non-randomized comparative studies, showed moderate to high risk of bias for the majority of the comparative studies as seen in Table 2. The Effective Public Health Practice Project tool, used for the non-randomized non-comparative studies, showed moderate to weak quality of the majority of non-comparative studies as seen in Table 3.
Although certain studies used broad selection criteria, selection bias is hard to avoid without randomization. Risk-of —bias assessment of comparative studies. Quality assessment of non-comparative studies. Judgment for quality of the studies based on the Effective Public Health Practice Project tool for each included non-comparative study strong, moderate, weak.
Results of the individual studies are summarized in Table 1. Ten of the included studies measured overall survival in vitamin C treated patients [ 1 , 3 , 23 , 24 , 26 , 27 , 29 , 30 , 32 , 37 ] Table 1. All studies compared their results with those obtained with a control group. In three studies, no effect of vitamin C on survival time was observed [ 3 , 29 , 32 ]. Two of those studies were RCTs.
In 7 studies, the researchers found a positive effect of vitamin C on survival time [ 1 , 23 , 24 , 26 , 27 , 30 , 37 ], two of those studies were RCTs. One of these RCTs was done in acute myeloid leukemia in a small group of patients treated with a hypomethylating agent decitabine that in vitro has a synergistic effect on vitamin C on TET2 expression, apoptosis and proliferation of tumor cells. Patients received a relatively low dose of vitamin C intravenous and median overall survival increased with 6 months [ 37 ].
In the other RCT, the overall survival also trended toward improvement with vitamin C addition to standard chemotherapy for ovarian cancer, but since the patient groups were very small the increase in median overall survival was not significant [ 27 ]. All studies in which researchers suggested a positive effect of vitamin C on survival time, supplementation was administered intravenously, with [ 1 , 23 , 24 , 30 ] or without [ 26 , 27 , 37 ] oral supplementation.
Intravenous ascorbic acid
Intravenous Ascorbic Acid also known as vitamin C or L-ascorbic acid , is a type of therapy that delivers soluble ascorbic acid directly into the bloodstream, either administered via injection or infusion. Intravenous ascorbic acid is used as a dietary supplement for nutritional deficiencies and also, as complementary therapy to cancer treatments. The use of intravenous ascorbic acid as a cancer treatment or co-treatment has been a controversial topic since the emergence of misleading data in the s. In patients suffering from malnutrition or malabsorption , intravenous ascorbic acid can be used to treat deficiency. For people who are receiving all of their nutrient requirements via total parenteral nutrition there are vitamin products that include ascorbic acid. High doses of ascorbic acid administered by intravenous infusion have been shown to increase the absorption of iron. High dosages of ascorbic acid such as those used in intravenous therapy have been reported to cause some intestinal discomfort, diarrhoea, as well as increased gas and urination.
Vitamin C ascorbate, ascorbic acid is a major water-soluble antioxidant that also increases extracellular collagen production and is important for proper immune cell functioning Hoffman, ; Cameron, et al. It also plays key roles in L-carnitine synthesis, cholesterol metabolism, cytochrome P activity, and neurotransmitter synthesis Geeraert, IVC use has increased recently among integrative and orthomolecular medicine practitioners: a survey of roughly practitioners conducted between and indicated that roughly ten thousand patients received IVC, at an average dose of 0. While IVC may have a variety of possible applications, such as combating infections Padayatty, et al. Also, since cancer patients are often depleted of vitamin C Hoffman, ; Riordan, et al.
Pilot trial of high-dose vitamin C in critically ill COVID-19 patients
Vitamin C L-ascorbic acid is a potent reducing agent, meaning that it readily donates electrons to recipient molecules Figure 1. Vitamin C is the primary water-soluble, non-enzymatic antioxidant in plasma and tissues. Even in small amounts, vitamin C can protect indispensable molecules in the body, such as proteins , lipids fats , carbohydrates , and nucleic acids DNA and RNA , from damage by free radicals and reactive oxygen species ROS that are generated during normal metabolism , by active immune cells, and through exposure to toxins and pollutants e.
Metrics details. Few specific medications have been proven effective for the treatment of patients with severe coronavirus disease COVID This randomized, controlled, clinical trial was performed at 3 hospitals in Hubei, China. Only 56 critical COVID patients were ultimately recruited due to the early control of the outbreak. Patients with ARDS and systemic complications require critical care and lead to a higher risk of death [ 4 , 5 , 6 ].
Vitamin C, also known as ascorbic acid, is an essential nutrient, widely recognized for its antioxidant properties. These properties arise from its potent redox potential due to its capacity to donate electrons to oxidized molecules. Even in small quantities vitamin C can protect critical molecules in the body such as proteins, lipids, carbohydrates, and nucleic acids DNA and RNA from damage by reactive oxygen species, which are generated during normal metabolism, by active immune cells, and through exposure to toxins and pollutants e.
Systematic Review of Intravenous Ascorbate in Cancer Clinical Trials
The use of intravenous vitamin C IVC for cancer therapy has long been an area of intense controversy. Despite this, high dose IVC has been administered for decades by complementary health care practitioners and physicians, with little evidence base resulting in inconsistent clinical practice. In this review we pose a series of questions of relevance to both researchers and clinicians, and also patients themselves, in order to identify current gaps in our knowledge. These questions include: Do oncology patients have compromised vitamin C status? Is intravenous the optimal route of vitamin C administration? Is IVC safe?
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