This article organizes the evidence and information from 13 colorectal cancer (CRC) studies that use high dose vitamin C to improve cancer cell kill rate and reduce toxicity from chemotherapy. Each section includes the evidence summary above the research fact table.

Colorectal cancer is the third most commonly diagnosed malignancy and the fourth leading cause of cancer-related deaths in the world. Conventional chemotherapy are frequently associated with high toxicity, which often leads to the suspension of the treatment. Vitamin C therapeutic potential has been supported by a large and consistent body of evidences from pre-clinical (in vitro, in vivo) and clinical studies.

Success in Clinical Trial Leads to Large Phase III

The clinical trial included 30 patients with metastatic colorectal cancer (mCRC), of which 26 patients were tested for KRAS, NRAS and BRAF status. Among them, 10 patients carried KRAS mutations, 2 patients carried BRAF V600E mutation and 14 had wild-type RAS and BRAF.

The study combined high dose intravenous vitamin C (IVC) with chemotherapy regiments mFOLFOX6 and FOLFIRI. The majority of patients were treated with mFOLFOX6, which includes oxaliplatin, leucovorin and 5FU. FOLFIRI is comprised of irinotecan, leucovorin and 5FU. Fourteen of 30 mCRC patients received bevacizumab with chemotherapy and IVC. IVC was administered for three consecutive days during the mFOLFOX6 and FOLFIRI treatments. The researchers found that IVC combined with either chemotherapeutic agents obtained improved colorectal cancer killing effect compared to using chemo alone. The high dose of IVC was well tolerated and was shown to be safe when used with the listed chemotherapeutics. Furthermore, the study showed significantly decreased bone marrow and gastrointestinal toxic effects compared with previous trials investigating the same chemotherapeutic regimens in colorectal cancer:

• Grade ≥ 3 neutropenia (lower than normal white blood cell count) was 13.9% in this study, in contrast to approximately 30% in previous studies

• Grade 3 neurotoxicity was 2.8% in this study versus approximately 20% in prior studies

Based on the promising evidence, a Phase III study was launched to examine using IVC combined with FOLFOX as a first line therapy for mCRC patients.

Pre-Clinical Research Demonstrates Cancer Fighting Capability

 Nine pre-clinical studies have shown high dose vitamin C (VItC) can be an effective treatment for colorectal cancer (CRC) when combined with standard therapies. The first two studies in the table evaluate combining chemotherapies Irinotecan and Oxaliplatin with VitC. The researchers reported that VitC works synergistically with the chemotherapies; this means the combination of VitC with the chemo is more effective than administering chemo on it’s own. The VitC showed an ability to sensitize the colorectal cancer cells to chemo, prevent tumor growth, and improved the ability of the chemotherapy to kill cancer cells. 

German researchers also found synergies between VitC and the epigenetic therapies decitabine and azacytidine. VitC showed a proclivity to initiate apoptosis (cell death) in the colorectal cancer cells.

A biomedical group from China applied the novel approach of combining VitC with arsenic trioxide (ATO) to CRC. Again, VitC showed an ability to kill colorectal cancer cells, and improve the effect of the ATO treatment. They observed the damaging effects on the cancer cells was brought on by VitC’s ability to impose oxidative stress on the tumor; this anti-cancer mechanism of action has been shown to occur in many other cancer studies.

Vitamin C Effective Against KRAS Cancer Mutations 

The final three clinical studies involve applying VitC combination treatments to KRAS cancer mutations. KRAS mutant cancer types have been notoriously hard to target; no resoundingly effective therapies have been developed to treat it. 32% of colorectal cancers include the KRAS mutation, these studies and others have shown success using high doses of Vitamin C to kill KRAS cancer cells. 

Cetuximab is a chemotherapy used to treat colon cancer patients, but those with mutant KRAS type show resistance to the treatment. Seoul National University College of Medicine demonstrated that VitC can help cetuximab bypass this resistance to induce cancer killing effects. Tumor regression was most pronounced in subjects with high sodium-dependent vitamin C transporter 2 (SVCT-2) levels.

Researchers at the University of Texas MD Anderson Cancer Center tested a combination of high dose vitamin C with arsenic trioxide (ATO) on KRAS mutant cancer cells. They observed including VitC made the treatment be more than twice as effective as using ATO alone; the tumor weight was on average at least 70% lower than the control group. Again, the anti-cancer mechanism of action was oxidative stress.

The last pre-clinical study included contributions from Italian and US cancer research institutions. They documented that conditions that mimicked a low calorie and low sugar diet combined with high dose Vitamin C created a synergistic effect that selectively targeted KRAS-mutant cancer cells and prevented tumor progression.

Ongoing Phase II and III CRC Clinical Trials

Fudan University is completing a Phase III clinical trial with 400 metastatic colorectal cancer (mCRC) patients receiving high dose intravenous vitamin C  (IVC) with FOLFOXIRI chemotherapy protocol.

• IVC treatment days 1-3, every two weeks

• FOLFOXIRI protocol: CPT-11 concurrent with Leucovorin, followed by Oxaliplatin followed by bolus of 5FU, followed by infused 5FU over 46 hours, every 2 weeks with or without bevacizumab (every 2 weeks)

The study is expected to be completed late in 2023.

Weill Medical College (Cornell) is conducting an active Phase II trial to study the effects of IVC on three groups of mCRC patients:

1. Patients will receive IVC infusions 4 days per week 2-4 weeks prior to surgery to remove the solid tumor.

2. Patients with inoperable KRAS or BRAF mutant lung cancer who have received at least one line of standard treatment will receive high dose Vitamin C 4 days per week for 6 months

3. Patients will receive IVC for 1-3 weeks, during first week y90 radioembolization of hepatic metastases will be administered the same day as IVC therapy.

The study started in March of 2017 and is expected to be concluded June 2023.

The final Phase II trial will administer IVC concurrently with intensity-modulated radiation therapy (IMRT) to reduce the acute toxicity of chemoradiotherapy.

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