Reliable Cancer Therapies

Samenvatting

Deze informatie is samengesteld door Reliable Cancer Therapies en is gebaseerd op de professionele informatie. Laatste update: februari 2011

Vitamine C is een voor mensen essentiële vitamine die voorkomt in alle fruit en groente. Door de manier waarop vitamine C geabsorbeerd wordt in het lichaam, is het noodzakelijk om de vitamine intraveneus toe te dienen om hoge concentraties vitamine C te bereiken en te behouden. Er wordt beweerd dat intraveneuze hoge dosissen vitamine C gebruikt kunnen worden om het volgende te bereiken: 1. De dood van kankercellen, maar niet die van normale cellen. 2. Verhoogde levenskwaliteit. 3. Bescherming van normale weefsels voor de giftigheid van chemotherapie. 4. De versterking van de effecten van conventionele chemotherapie en radiotherapie. Er zijn echter nog geen gerandomiseerde, gecontroleerde studies uitgevoerd om deze claims te beoordelen. Er is beperkt bewijs dat hoge dosissen intraveneuze vitamine C de levenskwaliteit van patiënten met een geavanceerde kanker zou kunnen verbeteren. Hoewel intraveneuze hoge dosissen vitamine C veilig is, met slechts beperkt neveneffecten, kan het de therapeutische effecten van conventionele kankerbehandelingen verminderen. 
 

Wat is het?

Vitamine C, ook gekend als L-ascorbinezuur of sodium-L-ascorbaat, is een essentieel voedingsbestanddeel om gezond te blijven. Het is oplosbaar in water en door de antioxiderende eigenschappen speelt het een belangrijke rol bij een aantal vitale biologische processen, zoals de functie van het immuunsysteem. Een acuut gebrek aan vitamine C leidt tot scheurbuik, een ziekte die mogelijk dodelijk is.

Toediening en dosering

Vitamine C kan op verschillende manieren toegediend worden. Deze samenvatting bespreekt enkel de intraveneuze toediening van hoge dosissen vitamine C (>0.5 g/kg lichaamsgewicht). Er is op dit moment geen consensus over de aanbevolen minimale efficiënte hoeveelheid intraveneuze vitamine C. Er is echter één fase-I-studie die heeft aangeraden drie maal per week 1.5 gram intraveneuze vitamine C per kilo lichaamsgewicht te geven. Normaal begint de behandeling met een lagere dosis en wordt deze geleidelijk aan verhoogd tot het beoogde niveau in de afwezigheid van neveneffecten.

Geschiedenis/werkzaamheidclaims

Vroege studies over de antikanker-effecten van hoge dosissen orale vitamine C waren vruchteloos, aangezien het tot de jaren ’90 niet geweten was dat de concentratie vitamine C in het plasma en in weefsel strikt gecontroleerd wordt door absorptie in de darmen, opeenstapeling in weefsels, en reabsorptie en excretie door de nieren. Hierdoor was het onmogelijk om de concentratie in weefsels en plasma te verhogen eens de dagelijkse orale inname van vitamine C 200 mg overschreed. Intraveneuze vitamine C, echter, kan gebruikt worden om farmacologische hoeveelheden vitamine C-concentratie in bloed en weefsels te bereiken. Er wordt beweerd dat intraveneuze hoge dosissen vitamine C de dood van kankercellen kan veroorzaken, maar niet die van normale cellen, de levenskwaliteit kan verbeteren en conventionele chemotherapie of radiotherapie kan versterken.

Werkingsmechanisme

Bij minimaal efficiënte (fysiologische) dosissen is vitamine C een antioxidant die reactieve zuurstofverbindingen deactiveren. Bij hogere dosissen wordt vitamine C echter een pro-oxidans. Het genereert dan namelijk hoge reactieve mineralen, zoals waterstofperoxide, die celschade veroorzaken. Er is gesuggereerd dat intraveneuze hoge dosissen vitamine C antikanker-activiteit uitoefent omdat het waterstofperoxide naar kankercellen kan brengen en zo selectief de dood van kankercellen kan teweegbrengen. Van normale cellen is gebleken dat ze niet aangetast worden door therapeutische concentraties vitamine C (tot 20 mM). Orale dosissen vitamine C kunnen geen waterstofperoxide genereren.

Werkt het?

Klinische studies

Op het moment van dit schrijven waren er nog geen gerandomiseerde gecontroleerde studies uitgevoerd om het antikanker-potentieel van hoge dosissen intraveneuze vitamine C te beoordelen. Er zijn echter enkele fase-I-klinische studies uitgevoerd om de mogelijke antikanker-effecten van hoge dosissen intraveneuze vitamine C te onderzoeken. Eén studie met 24 terminale kankerpatiënten in een laat stadium toonde aan dat intraveneuze vitamine C minimale en bovendien lichte neveneffecten met zich meebracht. Slechts bij één patiënt had de ziekte zich gestabiliseerd aan het einde van het onderzoek. Een ander onderzoek met 24 patiënten met gevorderde kankers of leukemie of lymfomen toonde ook aan dat de behandeling veilig is, maar geen antikanker-effecten heeft. Een ander onderzoek met 39 terminale kankerpatiënten die 10 mg vitamine C intraveneus kregen toegediend met een interval van drie dagen, gecombineerd met een dagelijkse orale inname van vier gram gedurende één week, toonde tot op zekere hoogte een paar subjectieve verbeteringen, maar opnieuw geen objectieve respons.

Er zijn een paar case series en anekdotische rapporten over het gebruik van hoge dosissen intraveneuze vitamine C voor de behandeling van kanker. De meeste van deze studies hebben echter te leiden onder onvolledige gegevens door inadequate follow-up-beoordelingen, gebrek aan microscopische bevestiging of bevestiging uit het laboratorium, gebruik van andere concurrerende of conventionele therapieën, en andere veelvoorkomende methodologische zwaktes die met case reports worden geassocieerd.

Veilig?

Neveneffecten

Vitamine C is in wezen niet giftig. Neveneffecten die met hoge dosissen intraveneuze vitamine C-infusies worden geassocieerd zijn over het algemeen mild en kunnen voorkomen worden door vloeistoffen te drinken voor en tijdens de infusie.
 

Contra-indicaties

Vitamine C is gecontra-indiceerd bij patiënten met glucose-6-fosfaat-dehydrogenase-deficiëntie. Patiënten met deze erfelijke ziekte die hoge dosissen vitamine C nemen lopen het risico op hemolyse (de afbraak van rode bloedcellen). Vitamine C is ook gecontra-indiceerd bij patiënten met een verminderde nierfunctie of bij patiënten die in het verleden nierstenen hebben gehad. Levensbedreigende bloedingen zijn geassocieerd met de snelle dood van tumorcellen als resultaat van intraveneuze toediening van vitamine C.

Interacties

Omdat vitamine C antioxiderende eigenschappen heeft, is het mogelijk dat hoge dosissen intraveneuze vitamine C conventionele kankerbehandelingen ten kwade kunnen beïnvloeden, waardoor deze minder efficiënt kunnen worden.

Samenvatting

This information was compiled and reviewed by the CAM-Cancer consortium. Last Updated: February 2011

Physiological concentrations of vitamin C (L-ascorbate or L-ascorbic acid) in the body are controlled through intestinal absorption, tissue accumulation, and renal reabsorption and excretion. Therefore, intravenous administration is used to achieve pharmacologic doses.

In the context of cancer, high-dose intravenous vitamin C (> 0.5 g per kg body weight) is claimed to have several effects: a) cytotoxicity for cancer cells, but not for normal tissue, b) improved quality of life for cancer patients, c) protection of normal tissues from toxicity caused by chemotherapy, and d) reinforcement of the action of radiation and some types of chemotherapy.

To date, no randomized controlled clinical trial with high-dose intravenous vitamin C has been published. A limited number of Phase I clinical trials confirm the non-toxic character of the treatment, and give some indications that the treatment may improve quality of life, but do not suggest distinct anti-cancer effects. Several case reports argue for a positive effect on survival time, even reporting cancer remission, and improved quality of life.

High-dose vitamin C is essentially non-toxic. Reported side-effects are minor if patients are adequately screened for renal disease and glucose 6-phosphate dehydrogenase deficiency, and when doses are gradually increased with careful monitoring of the patient. Vitamin C might reduce the therapeutic response to conventional anti-cancer therapy.

Wat is het?

Scientific name(s)/brand name(s)/common name(s)

Vitamin C is also known as L-ascorbic acid or as sodium L-ascorbate.

Application and dosage

Vitamin C can be administered via several routes including orally. This article only discusses the intravenous administration of high doses of vitamin C (> 0.5 g per kg body weight).
A Phase I dose-finding study in 24 cancer patients recommends the use of 1.5 g intravenous vitamin C per kg body weight three times weekly in further clinical research.(1) It is advised to start treatment with a lower dose, and, if no adverse events are observed, to gradually increase doses to their final level.(1-2)
Ascorbic acid solutions for clinical infusion might be unstable over time.(3-5)
There is no consistent information available as to which clinical dose would be needed to yield an anti-cancer effect.(6) The above-mentioned dose of 1.5 g per kg body weight was only found to be safe and to be capable to achieve plasma ascorbic acid concentrations of more than 10 mM for several hours in patients with normal renal function.

History / claims of efficacy

Vitamin C was isolated by Szent-Györgyi in 1928.(7) The vitamin plays a key role in several biological functions including the biosynthesis of collagen and L-carnitine, cholesterol metabolism, cytochrome P-450 activity, and neurotransmitter synthesis. Vitamin C is also essential for the efficient functioning of the immune system. Moreover, it is a major water-soluble anti-oxidant quenching potentially damaging free radicals resulting from metabolic respiration. Acute lack of vitamin C leads to scurvy, a disease marked by connective tissue damage and blood vessel fragility eventually resulting in death.
Soon after its isolation, methods for vitamin C synthesis were developed and the molecule became widely available. Over the years, a wealth of case reports, anecdotal accounts and pilot studies, all reporting some degree of clinical benefit conferred by supplemental vitamin C in cancer, were published.(8) Two controlled retrospective studies (using 10 g vitamin C per day, intravenous and oral) published by Cameron and Pauling further substantiated these claims.(9-10) As the latter studies lacked randomization and were retrospective, the US National Cancer Institute (NCI) sponsored two randomized, placebo-controlled, double-blind trials to evaluate the effect of high-dose vitamin C on symptoms and survival of patients with advanced cancer;(11-12) but Creagan and Moertel, who used 10 g oral vitamin C per day, did not find a therapeutic benefit in the treatment of cancer. Hence, the use of vitamin C in cancer therapy was abandoned by mainstream oncologists in the 1980s.(13-14)
In the late 1990s new insights started to emerge from research not related to the treatment of cancer, determining pharmacokinetics and physiology of vitamin C.(15-17) It was found that vitamin C concentrations in plasma and tissues were tightly controlled through intestinal absorption, tissue accumulation, and renal reabsorption and excretion.(18) As a result, it was impossible to increase plasma and tissue concentrations once daily oral intake of vitamin C exceeded 200 mg. However, intravenous administration bypassed this tight control until equilibrium was restored through renal excretion. In a study involving 17 healthy volunteers it was found that oral administration of the maximum tolerated dose of 3 g every 4 hours resulted in peak plasma concentrations of 0.22 mM, while an intravenous vitamin C dose of 50 g produced a peak plasma concentration of 13.4 mM.(19) Comparable results were found in cancer patients.(1,20-21)
Hence, the route of administration is critical in achieving pharmacologic concentrations of vitamin C, urging the reevaluation of vitamin C in cancer treatment.(22)

Mechanism(s) of action

Originally, the mechanisms of the putative anti-cancer effects of vitamin C were not well understood and several hypotheses were put forward.(8,23) Based on the resemblance between the widespread stromal changes observed in scurvy and the local stromal changes seen in cancer, the latter was postulated to be a collagen disease following vitamin C deficiency. Later on, it was hypothesized that vitamin C was required for the protective encapsulation of tumors, and that vitamin C could inhibit hyaluronidase thereby preventing cancer from spreading. Moreover, a role of hydrogen peroxide generated inside cancer cells during metabolic oxidation of vitamin C was presumed. However, none of these hypotheses were supported by convincing experimental data.
At the normal low physiological concentrations, vitamin C is an anti-oxidant that inactivates reactive oxygen species.(24) However, at high concentrations it was found to become a pro-oxidant generating oxidative species, i.e. extracellular hydrogen peroxide, that are lethal to cancer cells.(25) In these in vitro experiments, pharmacologic concentrations of vitamin C (up to 20 mM) using 1-hour incubations to mimic clinical intravenous use killed cells originating from several cancers by apoptosis, pyknosis, and necrosis, whereas physiologic concentrations (0.1 mM) did not. Normal cells were unaffected by both concentrations of vitamin C. At higher pharmacologic concentrations, vitamin C reacts with redox-active transition metal ions such as cupric or ferric ions, presumably bound to extracellular proteins, which in turn readily react with oxygen to form hydrogen peroxide.(26) In vitro findings were confirmed in rats and mice, where virtually the same cancer-killing hydrogen peroxide concentrations were found in extracellular fluid, but not in blood, after intravenous administration of high-dose vitamin C.(27-29) Oral doses did not result in generation of hydrogen peroxide. It was proposed that extracellular hydrogen peroxide diffuses into cancer cells and mediates toxicity by ATP depletion, thereby causing cell death. Moreover, hydrogen peroxide toxicity compromises membranes, glucose metabolism, and DNA integrity. In normal cells hydrogen peroxide is readily neutralized by antioxidant enzymes like catalase, gluthatione peroxidase, and superoxide dismutase, while antioxidant enzyme levels are low or imbalanced in most human cancers.(30) Thus, intravenous high-dose vitamin C may serve as a prodrug for the formation of hydrogen peroxide resulting in the death of cancer cells.
Daily high-dose intravenous vitamin C significantly decreased the volume of tumors in mice by 41-53% for diverse aggressive cancer types.(28) Inhibition of tumor growth was also found in other mouse models of human cancers,(31-32) and human cancer cell lines.(29)

Prevalence of use

Although use of high-dose intravenous vitamin C was abandoned by mainstream oncologists, complementary and alternative medicine practitioners continue to use it (as can be seen on the internet

Werkt het?

Clinical trials

Recent findings on the mechanism of action and pharmacokinetics of high-dose intravenous vitamin C triggered a renewed interest in its application as an anti-cancer agent. Therefore, several Phase I clinical trials were initiated and the results of a few have already been published.
Riordan et al. conducted a pilot clinical study in 24 late-stage terminal cancer patients.(33) Patients received 0.15 to 0.71 g intravenous vitamin C per kg body weight per day for up to eight weeks as their sole treatment. Adverse events were minor and the effect on indicators of renal function and blood parameters was minimal; two patients discontinued intravenous vitamin C. Though efficacy was not an expected result in this trial, one patient had stabilized disease during the trial and continued treatment for 48 weeks. Noteworthy, applied doses of vitamin C were low and plasma concentrations did not exceed 3.8 mM.
Hoffer et al. performed a dose-finding Phase I and pharmacokinetics study in 24 patients with advanced cancer or hematologic malignancy refractory to standard therapy.(1) Patients received 0.4 to 1.5 g intravenous vitamin C per kg body weight three times weekly for up to 30 weeks as only treatment. Plasma concentrations of above 10 mM were sustained for several hours after infusion. High-dose intravenous vitamin C was found to be safe and free of important toxicity in appropriately screened patients. Patients receiving 0.6 g or more of vitamin C per kg body weight maintained physical quality of life throughout the trial, while patients receiving the lowest dose experienced deterioration. This observation is noteworthy as the latter dose is the closest to the one that is infused in most published studies. No patient experienced an objective anti-cancer response.
Yeom et al. investigated health-related quality of life after intravenous administration of high-dose vitamin C in 39 terminal cancer patients.(34) All patients received 10 g vitamin C intravenously with a 3-day interval combined with a daily oral intake of 4 g for a week. After administration of vitamin C, patients reported significantly higher scores for physical, role, emotional, and cognitive function, and significantly lower scores for fatigue, nausea/vomiting, pain, and appetite loss; the other function and symptom scales were not significantly changed. Unfortunately, this study did not contain a placebo-treated group and therefore it is not certain that the observed improvement in quality of life was indeed due to the vitamin C treatment.
Overall, the published Phase I clinical trials provided evidence for the non-toxic character of intravenous high-dose vitamin C, and offered limited evidence for improved quality of life, but did not indicate tumor response.

Case series/studies

Over the years, intravenous high-dose vitamin C in the treatment of cancer has been described in many case reports.
In 1974, Cameron and Campbell reported 50 cases at the Vale of Leven hospital (Loch Lomondside, UK) where advanced cancer patients without further conventional treatment options received intravenous and/or oral doses (5 to 45 g per day, indefinitely) of vitamin C as their only treatment.(35) Three patients were reported to experience cytostasis, five had tumor regression, while tumor hemorrhage and necrosis was observed in four cases. Overall, there was an improvement in patients’ quality of life and no major side effects were seen. However, it is important to note that some of the patients who experienced a positive effect on tumor growth did not receive intravenous vitamin C, while the treatment period was short and the 10-g dosage was rather low for those receiving intravenous doses, compared to more recent studies assessing optimal dosage.
Riordan et al. published case reports for patients with metastasized adenocarcinoma of the kidney (36), metastasized pancreas cancer,(37) metastasized breast cancer,(38) metastasized renal cell carcinoma of the kidney,(39) metastasized stage IV colorectal carcinoma,(40) metastasized carcinoma of the pancreas,(40) and two cases of non-Hodgkin’s lymphoma.(40) Vitamin C infusions, as sole treatment or combined with conventional therapy, were generally started at 15 g twice weekly and increased to 30 to 100 g twice weekly for long periods of time. In all but one case, complete remission was observed. Overall, results indicated lack of toxicity.
Drisko et al. described two cases of advanced epithelial ovarian cancer.(41) Both patients were first treated with chemotherapy and oral antioxidants, after which 60 g intravenous vitamin C was administered twice weekly for one patient in combination with consolidation paclitaxel chemotherapy. Both patients were disease-free three years after diagnosis. No toxicity was found.
A problem with case studies is that many cases are reported without sufficient detail, with incomplete follow-up for evaluation, and without objective pathological confirmation, which makes it difficult to judge their value. Therefore, Padayatty et al. applied the NCI Best Case Series guidelines to three well-documented cases of advanced cancers (metastasized kidney cancer, bladder cancer, and non-Hodgkin’s lymphoma), which were confirmed by histopathologic review.(42) Two of these cases had been reported previously.(39-40) Patients received 15-65 g intravenous vitamin C twice weekly for at least two months, and lower treatment frequencies thereafter, as their only significant cancer therapy. In all three cases, remission of cancer was observed.
Noteworthy, for all the successful case reports, alternative explanations for cancer remission are possible, e.g. spontaneous remission or remission due to the therapy received before intravenous vitamin C was initiated. Moreover, a general weakness of case reports is that they omit the number of patients having received high-dose intravenous vitamin C without any effect.

Retrospective studies

As there was no possibility to judge increased survival time in the 50 cases originally described by Cameron and Campbell,(35) Cameron and Pauling performed two controlled retrospective studies comparing 100 terminal cancer patients receiving 10 g vitamin C per day (intravenously for about 10 days and orally thereafter, or only oral) with 1,000 historical control patients suffering from similar disease that had not received vitamin C.(9-10) The treated groups of 100 patients were partly the same in both studies and partly overlapped with the 50 patients described earlier.(35) A 4-fold increased average survival time was found. Also in a database analysis comparing 294 incurable cancer patients that had received vitamin C (10 g per day intravenously for about 10 days, orally thereafter, or orally for the whole treatment period) with 1532 that did not, vitamin-C-supplemented patients were found to have about 2-fold longer survival.(43)
For all these studies, the study designs were criticized as they were not randomized nor placebo controlled. Again it should be noted that not all patients were treated with intravenous vitamin C, that the treatment period with intravenous vitamin C was only about 10 days, and that the dose was rather low.

Veilig?

Reported/possible adverse events (frequency, severity)

Vitamin C itself is essentially non-toxic. In general, adverse events after high-dose intravenous vitamin C were mild,(1,33) and consistent with side effects occurring due to rapid infusion of any high-osmolarity solution, and were preventable by drinking fluids before and during the infusion.(1)

Existing contraindications

Patients with glucose 6-phosphate dehydrogenase deficiency were found to be at risk to experience hemolysis (breakdown of red blood cells) following administration of high doses of vitamin C.(44-45) Therefore patients should be screened for this metabolic deficiency before initiation of therapy.
Oxalic acid is an end product of metabolic oxidation of vitamin C. Oxalate nephropathy has been reported after administration of intravenous vitamin C in subjects with renal dysfunction.(46-48) However, in people with normal renal function, only about 2% of large doses intravenous vitamin C (1.5 g per kg body weight) was found in the urine as oxalic acid 6 hours after infusion.(49) Hence in this population, the risk of oxalate crystallization in the kidney was not increased, in particular since calcium oxalate stones develop over months to years. Therefore, research results conclude that high-dose intravenous vitamin C is contraindicated in people with renal dysfunction, and a history of kidney stones should be reviewed.
Another concern is life-threatening bleeding (hemorrhage) and rapid necrosis of tumors.(50) Authors therefore advised gradual increase of intravenous vitamin C whilst monitoring the patient.

Reported/possible interactions with other drugs/herbs/therapies

As vitamin C at physiological concentrations has antioxidant properties, it is conceivable that it may attenuate the anti-cancer activity of therapies generating increased reactive oxygen species, e.g. radiation and some chemotherapeutics.
Several studies on interactions of vitamin C and anti-cancer therapies have been performed, both in vitro and in vivo.(51-53) Vitamin C was found to reinforce the action of radiation and several chemotherapeutics, while it has no influence or even diminishes the effects of other chemotherapeutics. In this respect, the results of Heaney et al. are worth mentioning.(54) When comparing the therapeutic efficacy of a range of anticancer agents in cell lines and tumor-bearing mice with and without pretreatment with dehydroascorbic acid (the oxidized form of vitamin C), it was found that the latter caused a dose-dependent reduction of cytotoxicity. The mechanism of action was suggested to be related with inhibition of chemotherapy-induced mitochondrial membrane depolarization, rather than interference with the reactive oxygen species generated by the tested anti-cancer drugs. Also, several studies showed that vitamin C could abrogate the effects of bortezomib when taken simultaneously.(55)
It is important to note that the observed effects of vitamin C on the efficacy of conventional anti-cancer therapies might depend on the used in vitro or in vivo test system and the specific cancer, and the relevance with respect to the clinical application of intravenous high-dose vitamin C is sometimes doubtful.
In conclusion, negative interactions may occur when adding vitamin C to conventional anti-cancer therapy, making the conventional therapy less potent.

References

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Intraveneuze hoge dosis vitamine C

Vitamine C