Intravenous Vitamin C for Cancer Therapy – Identifying the Current Gaps in Our Knowledge

August 2018
Anitra C. Carr, and John Cook

 

Abstract

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? Does IVC interfere with chemotherapy or radiotherapy? Does IVC decrease the toxic side effects of chemotherapy and improve quality of life? What are the relevant mechanisms of action of IVC? What are the optimal doses, frequency, and duration of IVC therapy? Researchers have made massive strides over the last 20 years and have addressed many of these important aspects, such as the best route for administration, safety, interactions with chemotherapy, quality of life, and potential mechanisms of action. However, we still do not know the answers to a number of fundamental questions around best clinical practice, such as how much, how often and for how long to administer IVC to oncology patients. These questions point the way forward for both basic research and future clinical trials.

 

Introduction

Over the years, numerous epidemiological studies have highlighted a decreased incidence of cancer and improved survival in patients with higher dietary intakes of vitamin C or higher plasma levels of the vitamin (Carr and Frei, 1999b; Harris et al., 2014). Although vitamin C is often considered a good marker of fruit and vegetable intake (Block et al., 2001), the vitamin has essential functions within the body, including integral roles in various anti-cancer mechanisms (Du et al., 2012). Because of the pleiotropic functions of vitamin C, optimizing its levels in the body through diet and supplementation is likely to be of benefit to oncology patients. In support of this premise, studies in a vitamin C-requiring mouse model indicate that oral vitamin C supplementation of these animals can impair the development of tumors and can also increase the rejection rate of implanted tumor cells (Campbell et al., 2016a; Cha et al., 2016). This suggests an important role for vitamin C in host defense against cancer.

Treatment of cancer, in contrast, is thought to require much higher doses of vitamin C than normal dietary intakes (Parrow et al., 2013). In fact, high dose intravenous vitamin C (IVC) has been administered by physicians for many decades as a complementary and alternative therapy for oncology patients (Padayatty et al., 2010). This practice has continued despite significant controversy in the field as a result of two high profile Mayo Clinic trials carried out in the late 1970s which debunked the initially encouraging findings of Cameron and Pauling (1976, 1978; Creagan et al., 1979; Moertel et al., 1985). Due to the paucity of a strong evidence base for informing appropriate clinical practice, there are significant inconsistencies in administration of IVC therapy to oncology patients (Padayatty et al., 2010). These include huge variability in the dose, frequency, and duration of vitamin C administration.

Research in the 1990s highlighting the important differences between oral and IVC pharmacokinetics resulted in a surge of new research in the IVC field with numerous in vitro, preclinical and clinical studies being undertaken (Parrow et al., 2013; Fritz et al., 2014). The in vitro studies have provided useful insights into potential mechanisms of action and pre-clinical studies have indicated promising efficacy of IVC, however, clinical studies have so far been limited primarily to Phase I safety and pharmacokinetic trials (Du et al., 2012; Parrow et al., 2013). As a result of study design issues with many of the earlier clinical trials there remains controversy as to the efficacy of IVC in the treatment of cancer (Wilson et al., 2014). Many of these trials recruited terminal or end-stage patients, for whom any sort of treatment is unlikely to have an effect, and they often recruited cohorts with mixed cancers, which may respond differentially to IVC depending on the underlying mechanisms involved.

In this review, we pose a series of questions, both clinically relevant and patient centered, related to IVC use in cancer therapy in order to identify the current gaps in our knowledge. Although many of these questions have been adequately addressed, some require further research in order to provide the essential data required to inform good clinical practice.

Conclusion

• Do oncology patients have compromised vitamin C status? Yes, studies consistently show that patients with cancer have lower mean circulating vitamin C levels than healthy volunteers. These patients also exhibit higher rates of hypovitaminosis C and deficiency. Furthermore, chemotherapy can impact negatively on the vitamin C status of oncology patients. Because of vitamin C’s supportive functions in the body, increasing the vitamin C status of oncology patients is likely to be of benefit.

• Is IV the optimal route for vitamin C administration? Yes, IV administration of vitamin C can provide significantly higher peak plasma concentrations because it bypasses the regulated intestinal uptake of oral vitamin C. These higher concentrations are believed to be required for some of the proposed anti-cancer mechanisms of vitamin C and may also enhance diffusion of the vitamin into the hypoxic core of solid tumors.

• Is IVC safe? Yes, IVC is remarkably safe, considering the massive (>75 g) doses that are often administered. However, there are several currently known situations where caution is warranted. These include patients with impaired renal function due to their inability to adequately clear high IVC doses from circulation, and patients with G6PD deficiency due to inability to detoxify oxidative stress generated by high dose IVC administration. Caution is also required for patients requiring regular glucose monitoring due to the potential for IVC to interfere with point-of-care glucose monitors.

• Does IVC interfere with chemotherapy or radiotherapy? Clinical trials indicate that IVC does not adversely interfere with chemotherapy and pre-clinical studies indicate that it may in fact act synergistically in combination with different chemotherapeutic agents. There is as yet limited research around interference with radiotherapy, with conflicting results likely due to the timing of the interventions.

• Does IVC decrease the toxic side effects of chemotherapy and improve quality of life? Both pre-clinical and clinical studies indicate that IVC can decrease the off-target toxicity of chemotherapeutic agents, likely through its antioxidant and anti-inflammatory activities, without affecting the anti-cancer activities of the chemotherapeutic agents. The reduction in specific chemotherapy-related side-effects results in an overall improvement in the health-related quality of life of oncology patients.

• What are the relevant mechanisms of action of IVC? A number of plausible anti-cancer mechanisms have been proposed, such as indirect generation of hydrogen peroxide, enzyme cofactor activities (e.g., collagen synthesis, HIF hypoxic response regulation, TET and JHDM epigenetic regulation), as well as antioxidant and anti-inflammatory functions. Different cancers likely respond differently to IVC therapy depending upon their underlying mechanisms. Thus, future work should focus on tailoring IVC regimens to specific cancers or cancer subtypes, e.g., hematological cancers that are driven specifically by TET mutations may respond more readily to IVC therapy.

• What are the optimal doses, frequency, and duration of IVC therapy? Although these are the most relevant questions clinically, there is still little consensus as to how much, how often and for how long to administer IVC to oncology patients. The different proposed mechanisms of action provide some insight into dosing, with higher doses (>50 g/d) being required for some anti-cancer mechanisms, and lower doses (≤10 g/d) being sufficient for decreasing symptoms and improving quality of life. Pre-clinical studies indicate that more frequent dosing exhibits enhanced efficacy.

However, depending on the underlying mechanisms involved, it is possible that anti-tumor activity may require long term treatment and follow-up, e.g., over years rather than just the few weeks or months of most clinical trials. It is unlikely that future large scale IVC RCTs will be carried out due to the prohibitive costs. Nevertheless, smaller scale studies, if well designed, have the potential to contribute relevant and translatable findings to inform good clinical practice.