March 9, 2016

High-Dose Intravenous Vitamin C in Cancer Care

Phase I-II clinical trial looks at intravenous vitamin C combined with chemo
A new intravenous vitamin C (IVC) clinical trial—and a call for physicians providing IVC to report cases of exceptional responses to help better focus future studies.


Hoffer LJ, Robitaille L, Zakarian R, et al. High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: a phase I-II clinical trial. PLoS ONE. 2015;10(4):e0120228. 

Study Objectives

The study aimed to 
  1. determine the safety and tolerability of 1.5 g/kg intravenous vitamin C (IVC) over 90-120 minutes given 2-3 times per week to cancer patients during the course of chemotherapy including documentation of side effects and toxicity;
  2. determine pharmacokinetics by measuring plasma vitamin C and urinary oxalic acid before, during, and after treatment with IVC and chemotherapy; 
  3. identify any cancer types and treatments that might be favorable to combine with IVC if possible; and
  4. measure quality of life (QoL) and mood monthly throughout the study.


Single dose Phase IIA pilot study 


Oncology patients ages 47 to 76 were referred from within a medical university–affiliated cancer center and were eligible if they had an Eastern Co-operative Oncology Group (ECOG) status 0-1, a CT and staging workup within the 4 weeks of the first IVC treatment on protocol, normal red blood cell glucose 6 phosphate dehydrogenase (G6PD) activity, serum creatinine ≤175 µmol/L, and the judgment of their treating oncologist that standard of care or off-label cytotoxic chemotherapy offered less than a 33% likelihood of an objective clinical response. The study evaluated 31 people, enrolled 16, analyzed 12, and described 14 (7 males, 7 females).

Study Parameters Assessed

CT scan of chest, abdomen, and pelvis performed 4 weeks before treatment and approximately every second chemotherapy cycle with assessment for any response using Response Evaluation Criteria in Solid Tumors (RECIST 1.0).
  • The following were measured at study entry and every 4 weeks:
  • Tumor markers
  • Complete blood count (CBC)
  • Metabolic panel
  • C-reactive protein (CRP)
  • Physical exam
  • Coagulation profile
The following were measured at baseline, at 2 weeks, and then monthly:
  • Functional Assessment of Cancer Therapy-General (FACT-G) quality of life questionnaire scores; range from 1 to 108
  • Profile Mood States-B questionnaire giving Total Mood disturbance score; range from -20 to 100
Less than 7 days prior to first chemotherapy dose, plasma vitamin C levels and urinary oxalic acid were measured during and after the administration of 0.6 g/kg IVC given over 90 minutes. The same was performed again 3 days after chemotherapy administration.
Adverse events were evaluated using National Cancer Institute clinical criteria 3.0.

Primary Outcome Measures

Safety and tolerability of 1.5 g/kg IVC given concurrent to chemotherapy regimens (although not given on the same day) in a heterogeneous advanced disease cancer population via descriptive analysis using quality of life and mood questionnaires and individual case synopsis.

Pre- and post-chemotherapy pharmacokinetics of IVC in humans with advanced cancer via measurement of plasma IVC and urinary oxalate levels before, during, and after treatment. 

Key Findings

IVC was nontoxic for all participants. Side effects of thirst and increased urinary flow were common symptoms during all IVC infusions. Other side effects included nausea and vomiting, unpleasant fluttering sensation, chills, headaches, and a rumbling feeling in the abdomen. One patient experienced increased lower extremity edema. One patient reported a mentally hazy feeling on the day after infusion.
Mean baseline plasma vitamin C concentrations changed from 66.4±74.9 µmol/L before IVC and chemotherapy was initiated to 131.6±102.0 µmol/L after treatment (P<0.031). Total urinary excretion profiles before chemotherapy was initiated (149±49.3) were higher than after (133±40.0), suggesting a short-term tissue retention of vitamin C after chemotherapy (P<0.099) with no significant increase in total urinary oxalic acid excretion (P<0.850).
Three patients with different types of cancer experienced unexpected transient stable disease, increased energy, and functional improvement.

Practice Implications

Pilot studies should provide a clear list of aims and objectives within a formal framework to encourage methodological rigor, produce a work that is scientifically valid and publishable, and lead to higher-quality RCTs.1
For our purposes as integrative providers, we hope that an IVC pilot will help us focus efforts and find key reasons larger studies should move forward. In vitro and preclinical data report IVC to have pro-oxidative and antitumor effects.2-4 Human clinical trials have not found clear-cut antitumor response but have achieved high blood millimolar concentrations of ascorbate in humans (10+ mmol/L) similar to in vitro (5 mmol/L) and preclinical models (10 mmol/L) that have demonstrated antitumor effects. At this point human IVC clinical trials collectively suggest that improved quality of life and reduction in symptoms of disease and/or side effects of cancer treatment may be attributed to treatment with IVC. 5-9
Although this pilot study is based on a non-statistically representative population, and therefore is limited in practice implications, it does raise some points to consider.
This study is one of a growing body of studies finding safety and tolerability of IVC in patients with advanced disease receiving standard chemotherapy regimens. 9-14 The study describes 14 cases of people with different tumor types (6 colorectal, 2 lung, 1 cervical, 1 breast, 1 ovarian, 1 bladder, 1 tonsil, 1 biliary) who receive IVC 2-3 times weekly during treatment with chemotherapy regimens where the oncologist determines there’s less than 33% chance the chemo may have efficacy. 
The first author of this study published another important Phase I pilot study in 2008 that reported IVC is safe and well-tolerated in humans with advanced malignancy and established a safe and tolerated dose of 1.5 g/kg given 3 times weekly.11 The 2008 Hoffer study also described that patients receiving 1.5 g/kg excreted a mean 81.3±18.8 mg of oxalic acid (during and over the 6 h after infusion) before returning to baseline. Oxalic acid excretion normally ranges from 10 to 60 mg/24 h. Thus it was determined that a transient rise with subsequent return to normal shortly after IVC was not a threat to patients with normal kidney function. The study also found that patients reliably excreted 25% of the vitamin C during the infusions and established that time-blood plasma vitamin C concentration were relative and predictable according to dose of IVC.
The current study continues this work. The dose and frequency of IVC given is 1.5 g/kg administered 2-3 times weekly, though in this study it is given to patients receiving concurrent chemotherapy (not on the same day). It also reproduces similar, statistically analyzed minimal and transient rise in oxalic acid excretion during and after IVC, as well as a reduction in total ascorbate excreted after chemotherapy. It is plausible to consider that during pro-oxidant therapies, antioxidant blood levels may decrease. Body stores of vitamin C may be in flux, hence less may be excreted. Other investigators have conducted studies reporting that when given the same doses of IVC, patients with metastatic disease excrete less ascorbate compared to those with local disease.15 This phenomenon has been well-documented in other disease and chronic inflammatory states, as well as in smokers.16-18 It is thought that the higher state of inflammation in metastatic disease states consumes more antioxidants. That said, there is much concern over whether antioxidant vitamin C interferes with chemotherapy. Conventional oncology providers caution that in patients with known curative potential from conventional means, the addition of IVC therapy is an unknown and poses an undefined risk of interfering with the benefits of treatment until outcome studies prove otherwise. This is certainly something to further explore in well-designed studies. Most of the high-dose IVC studies to date, including the Hoffer 2015 study and others referenced previously, are designed to test safety and benefits with advanced disease (eg, improving quality of life, stabilizing disease trajectory, lessening side effects of conventional therapies).
One interesting component of this study is that the authors report 2 cases of hypovitaminosis C out of 14 cases evaluated during enrollment. The odds of this occurring in cancer patients compared to the general population are higher. One observational study found 6 cases of scurvy in 3,723 consecutive patients treated for noncancerous conditions in a hospital emergency room; 6 cases of scurvy were found in 219 patients with cancer who were consecutively treated during the same timeframe.19 Informed clinicians should watch for signs and symptoms of hypovitaminosis and nutrient deficiency in patients with cancer. These symptoms may be commingled with signs of disease processes and side effects of standard antineoplastic treatments.
Cancer patients are known to have hypovitaminosis more frequently than healthy populations19-24, for a variety of reasons, such as physiologic stresses associated with disease processes, impaired oral intake, a history of surgery or radiation affecting absorptive digestive surfaces, and the catabolic effects of antineoplastic therapy. 
Patients in this study also reported side effects of IVC—some of which the authors attribute to the high osmolarity and cooler than ambient temperature and/or sodium load of the IVC infusate. The authors state some of the side effects were reduced or eliminated with slowing the rate of the IVC infusion, reducing the total IVC dose, and/or letting the infusion solution come to room temperature before administration. It’s also notable that this study used sterile water and vitamin C for infusion vs sterile water, vitamin C, plus mineral additives. 
Hoffer reports that adverse events or side effects may occur for patients using IVC unless safeguards and the above mitigating procedures are used. Appropriate screening as part of the methodology of this study includes G6PD testing of each patient prior to IVC administration and assuring adequate kidney function, since vitamin C is primarily cleared by the renal system. No further screening for safety with IVC is discussed in the methods section of the paper. However, other investigators have listed potential contraindications or exclusions in methodology such as serum glucose >300 mg/dL, hypercalcemia or hyper-oxaluria, metal storage diseases, and iron overload. This study reiterated the previous caution that finger stick glucose could be falsely abnormal and should be avoided for 12 hours after IVC.8
This study adds to the safety literature on IVC in cancer care. It also provides objective, concise descriptive summaries of 14 cases of people with advanced cancer who received IVC adjunctive to standard of care chemotherapy. In a way, this brings forward the work of Cameron and Pauling, who reported on the treatment of advanced stage cancer patients who did not have the option of salvage therapies at that time period and were reported to have had improved quality of life and survival with use of IVC and oral vitamin C.25-26
Though this prospective study by Hoffer et al is considered more methodologically rigorous in our current paradigm, the number of cases is too small to get an idea of what IVC might offer for patients in the day-to-day difficulties of managing disease and standard of care treatment. This study and the 14 case synopses, in which 3 people are reported to have longer than anticipated periods of stable disease deemed unlikely to result from chemotherapy alone, seems to convey rather more side effects from IVC with equal weighting to any benefits. In fact the study reports some rather significant-sounding side effects from high-dose IVC, as well as beneficial effects reported by patients. The QoL and mood questionnaires did not report any trends. 
Hoffer relates that “despite its biological and clinical plausibility, [IVC] is ignored by conventional cancer investigators and funding agencies” and suggests that there may be value in an individual case-centered evaluation strategy such as “discovery in clinical practice,” which has been advocated as a means to discovering new indications for conventional drug therapies. The authors state that integrative cancer therapists prescribe IVC widely without collectively reporting clinical data that is normally gathered as important in cancer drug development. 
Hoffer concludes “if carried out in sufficient numbers, simple studies like this could identify specific clusters of cancer type, IVC, and chemotherapy regimens in which unexpectedly beneficial outcomes or exceptional responses occur frequently enough to justify focused clinical trials.” This brings to mind the work being done in gynecologic cancers by Jeanne Drisko et al as was reported in the Ma 2014 study previously referenced. In my experience in working primarily with pancreatic cancer patients for several years in an integrative cancer hospital in which patients routinely received IVC as part of their care, this population is also of interest for further exploration in well-designed clinical trials. Perhaps IVC could be used adjunctively earlier in diagnosis and with first- and second-line regimens to test whether IVC combined with chemotherapy can improve survival outcomes vs standard therapies alone.
Many of us have seen through clinical experience that IVC appears to help quality of life and/or improve tolerability of standard chemotherapy regimens. Some of our patients have significant alteration in disease status and unusually favorable results when receiving IVC therapy alone or in addition to standard of care cancer treatment. If we can work to document cases like these via case reports or series and do the hard work of designing small clinical trials to test its benefits, as Hoffer’s 2015 IVC study advocates, we’ll improve our ability to learn about IVC and other therapies while helping create a new paradigm of integrative cancer care. 

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