Ever since the great biochemist Linus Pauling claimed with religious fervor that high doses of vitamin C could cure everything from the common cold to cardiovascular disease and cancer, it has been the subject of confusion and controversy, primarily due to a shortage of conclusive, statistically significant data on efficacy. In a 1979 review, "Ascorbic Acid and Cancer: A Review,” Linus Pauling and his colleagues expressed their hopes that “properly designed controlled trials” would soon be conducted to “confirm or refute” their clinical findings, and that if confirmed, “ascorbate will soon become an essential part of all practical cancer treatment and cancer prevention regimens.”(1) Sadly, the trials Pauling hoped for over 40 years ago have yet to be done. Unfortunately, this playbook is well known. As with other nonpatentable therapies, vitamin C therapy exists in a limbo of unrealized (and unknown) potential. Treatments like HDvitC raise a larger question: How do clinicians make decisions about therapies that don’t have “properly designed controlled trials”? In this blog, we examine this larger question and attempt to give you an accurate picture of where high-dose vitamin C (HDvitC) currently stands as a cancer treatment.
What Is Known So Far?
Most preclinical publications of cancer therapies come with beautiful graphics that explain the therapy’s proposed mechanisms of action, showing the pathways that the treatment acts through to weaken or kill cancer cells. Most also come with promising in vitro (cells in a petri dish) studies and mouse studies demonstrating an anti-cancer effect. HDvitC is no exception. HDvitC depletes the electron carrier NADH, reducing the cell’s ability to generate ATP, which diminishes its capacity to proliferate and carry out all its pathological functions. Perhaps even more seductive is that vitamin C becomes a potent prooxidant that generates hydrogen peroxide at the correct dose, forcing cancer cells to use their precious internal antioxidant, glutathione. This prooxidant effect is what has gotten many researchers so excited about HDvitC. The delicate redox balance that cancer must maintain is a vulnerability, and many cancer therapies work by exploiting this Achilles heel. In a 2013 publication titled Oxidants, Antioxidants and the Current Incurability of Metastatic Cancers, by James Watson – a publication that the Noble Prize winner claimed was his “most important publication since the Double Helix,” he wrote, “We must focus much, much more on the wide range of metabolic and oxidative vulnerabilities that arise as consequences of the uncontrolled growth and proliferation capacities of cancer cells.”(2) This is why many researchers have become reinvigorated by the possibly of HDvitC as an adjunctive cancer therapy. Indeed, any nontoxic treatment that weakens cancer cells thus rendering them more susceptible to other oxidative therapies like chemotherapy and radiation, is an exciting prospect.
Yet we have seen this story before; exciting mechanisms of action only take you so far. As with other promising, nonpatentable cancer therapies, the efficacy data on vitamin C consists of a maddening number of preclinical animal studies and a cluster of small phase 1 trials that measure safety and tolerability, not efficacy.
In aggregate, this data points to promise yet never arrives at a conclusive measure of the therapy's true potential to treat cancer. Only a statistically significant phase 3 trial can put a tape measure to the true potential. In the graphic below, you can see there have been 57 small clinical trials with vitamin C. Most expert reviews on HDvitC agree that the only conclusion is that high-dose vitamin C is safe and well tolerated with minimal side effects, may diminish side effects from toxic treatments, reduce fatigue, and improve quality of life. Some trials suggest that HDvitC may improve outcomes; others indicate no effect.
For example, a study published in 2014 randomized 25 advanced-stage ovarian cancer patients into one group that received the standard paclitaxel/carboplatin therapy for the initial six months alone and another group that received paclitaxel/carboplatin therapy administered for six months combined with high-dose vitamin C treatment for 12 months. The study showed that overall survival improved with the addition of high-dose vitamin C therapy, and the median time for disease progression was 8.75 months longer compared to the group given chemotherapy alone.(3) Yet, the small study size did not reach statistical significance (that means that the observed effect may have been due to chance alone). Even so, the result suggests a real effect and warrants more extensive studies.
High dose vitamin C as a cancer therapy: Clinical decision making under a cloud of uncertainty.
Yogi Berra said, “'It's tough to make predictions, especially about the future.” Another famous American, Mark Twain, is attributed as saying, "There are three kinds of lies: lies, damned lies, and statistics.” Although both of these quotes are obviously glib, they nonetheless hold deep truths often encountered in medicine. Like most unpatentable therapies, the data on HDvitC is murky and inconclusive. None of us, physicians nor patients, want to live in this uncomfortable zone of foggy uncertainty. As humans, we want as much certainty as we can get. Yet, this is precisely where we find ourselves with HDvitC therapy for cancer. Unfortunately, uncertainty is the proving ground where human biases often flourish. Given the literature on HDvitC, can someone reasonably predict how effective it is as a cancer therapy? Maybe some people think they can, but the truth is: they can’t.
The massive pains taken to effectively measure a therapies effectiveness are designed to minimized human bias: randomization, blinding and placebo; all three are barriers constructed so human bias cannot creep into the results of a clinical trial. Be wary of anyone making claims based on statistical data that is not scrubbed free of human bias by well-designed and controlled trials -- never underestimate ability of people to fool themselves.
Yet, nor should we dismiss the research done so far. Clinical recommendations by physicians are almost always made with imperfect data and are always (or should be) made through the lens of a risk/ potential reward assessment. Because individual human beings interpret imperfect medical data, unsurprisingly, you will find the expected range of opinions on HDvitC: from those that dismiss it entirely because there is no “gold standard” randomized, controlled trial to those that actively promote it.
As with most things, perhaps the best approach is in the middle – not entirely dismissing it due to lack of conclusive data but being honest about the unknowns. Indeed, assessments like this are at the heart of the “practice” of medicine. A 2017 article in the New England Journal of Medicine titled Evidence for Health Decision Making — Beyond Randomized, Controlled Trials, examined this everyday dilemma faced by clinical practitioners, summarizing it this way: "There will always be an argument for more research and better data, but waiting for more data is often an implicit decision not to act or to act based on past practice rather than best available evidence. The goal must be actionable data — data that are sufficient for clinical and public health action derived openly and objectively and that enable us to say, ‘Here’s what we recommend and why.’”(4)
Here is the summary of what we know about high dose vitamin C therapy:
It is safe with minimal side-effects, however time consuming and costly at 3 infusions per week which is the common protocol (5-7 hrs. of clinic time/wk. and $600 to $1000 /wk. generally)
It may mitigate side effects from cytotoxic standard-of-care therapies like chemo and radiation.
The mechanism of action suggests that it has potential to be an adjunctive therapy that increases the outcomes of other cancer therapies.
Some small trials suggest that it may improve outcomes, yet no statistically significant conclusion has been achieved leading to standard of care adoption.
Given what is known, it seems reasonable when judged through a risk/potential reward lens, for physicians to recommend HDvitC in some cases after careful clinical assessment and review of other supportive care options.
Stay Strong and Curious,
Charles Meakin MD, MS, MHA
Travis Christofferson MS
Disclaimer: This information is not meant as direct medical advice. Readers should always review options with their local medical team. This is the sole opinion of Dr. Meakin based on a literature review at the time of the blog and may change as new evidence evolves.
1 - Cameron E, Pauling L, Leibovitz B. Ascorbic acid and Cancer: a review. Cancer Res. 1979;39(3):663–81.
2 - Watson J. Oxidants, antioxidants and the current incurability of metastatic cancers. Open Biol. 2013 Jan 8;3(1):120144. doi: 10.1098/rsob.120144. PMID: 23303309; PMCID: PMC3603456.https://geneticliteracyproject.org/2020/10/05/should-you-get-your-protein-from-plants-or-animals-short-nutrition-lessons-shows-thats-the-wrong-question/
3 - 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 Feb 5;6(222):222ra18. doi: 10.1126/scitranslmed.3007154. PMID: 24500406.
4 - Frieden TR. Evidence for Health Decision Making - Beyond Randomized, Controlled Trials. N Engl J Med. 2017 Aug 3;377(5):465-475. doi: 10.1056/NEJMra1614394. PMID: 28767357.
5 - Image 1: van der Reest, J., Gottlieb, E. Anti-cancer effects of vitamin C revisited. Cell Res 26, 269–270 (2016). https://doi.org/10.1038/cr.2016.7
6 - Image 2: Böttger, F., Vallés-Martí, A., Cahn, L. et al. High-dose intravenous vitamin C, a promising multi-targeting agent in the treatment of Cancer. J Exp Clin Cancer Res 40, 343 (2021). https://doi.org/10.1186/s13046-021-02134-y