HIGH DOSE INTRAVENOUS VITAMIN C AS ADJUNCTIVE THERAPY TO CHEMO AND RADIATION

Several epidemiological studies conducted over the years have described that individuals with high consumption of vitamin C or with elevated levels of vitamin C in their plasma have demonstrated a decline in the occurrence of cancer and a better survival rate is also observed in cancer patients (1,2). A good intake of vegetables and fruits is often marked by vitamin C (3) but this vitamin performs an important part in many essential body functions including its involvement in many anti-cancer mechanisms (4). Due to vitamin C’s function to act on a single gene to affect multiple traits in humans, beneficial outcomes can be obtained for cancer patients when the concentration of vitamin C is optimized in the body through supplementation and diet.

Many studies in animals indicate that the development of tumors in animals was impaired because of vitamin C supplements given orally (5,6) explaining the consequences of vitamin C providing defense against the formation of cancer. However, when it comes to the usage of vitamin C to manage cancer, higher doses than normal dietary consumption of vitamin C are required (7). As a matter of fact, physicians have delivered high doses of IV vitamin C as a substitutive and complementary remedy for cancer patients for many years (8).

USE OF VITAMIN C AND CONTROVERSY IN CHEMOTHERAPY

Concerns have been raised about the role of vitamin C in chemotherapy because of vitamin C’s anti-oxidant nature that it would collect in tumors (9) and the effectiveness of the chemotherapy could be compromised (10). This notion was reinforced by the work of Heaney and colleagues that dehydroascorbic acid was used as pre-treatment, and in-vitro tumor cells and xenografts in mice showed resistance to numerous anticancer agents (11). This was then brought into question whether the conditions under which Heaney and colleagues conducted experiments were biochemically or clinically appropriate among other problems considering they used dehydroascorbic acid instead of using ascorbic acid, another name for vitamin C (12).

It is imperative to take notice that the purpose of delivering IV vitamin C is to obtain millimolar concentrations of vitamin C intra-tumor, and therefore, collection of vitamin C in the tumor can bear beneficial outcomes. Several laboratory studies indicated that when vitamin C is delivered in high concentrations, it does not render irradiation or chemotherapy ineffective. Instead, it improves efficacy in some circumstances (12–18). Numerous meta-analyses based on clinical research on vitamin C and cancer also supported the above that vitamin C is given as an antioxidant supplement, it does not hinder the toxic effect of chemotherapeutic agents (19,20).

USE OF HIGH-DOSE VITAMIN C IN COMBINATION THERAPY

Several past researches have observed the impact of high-dose vitamin C as a pro-oxidant adjunctive agent in radiotherapy and chemotherapy. Moreover, other combination therapies along with vitamin C are also thoroughly investigated.

Use of Vitamin C in Pre-Clinical Studies as an Adjunctive to Radiation and Chemotherapy

In preclinical studies, the administration of high-dose vitamin C along with several chemotherapeutic agents has been reported to enhance their effectivity in numerous sorts of cancer cells either by improving the effectiveness of treatment or often in a collaborative manner. These chemotherapeutic agents include cisplatin (15,21–27), carboplatin (22,28), 5-FU (17,22,29), temozolomide (30,31), chlorambucil (32), and gemcitabine (12,33–35). A 2020 study conducted in vivo in oral squamous carcinoma observed that when cisplatin is administered along with a high dose of vitamin C i.e. 4-gram vitamin C per kg body weight intraperitoneal for two times a day, the therapeutic impact of cisplatin was increased (21). A study conducted in 2017 in mice for pancreatic cancer reported that when gemcitabine is used along with the same 4-gram dose of vitamin C, a noteworthy inhibition in the progress of the cancer was observed in mice in contrast to the control group and the group that was only treated with gemcitabine (33).

Another promising observation that was brought forward was that during chemo-radiation or radiotherapy of cancer models in preclinical studies, vitamin C functions as a radio-sensitizer specifically targeting cancer cells in comparison to healthy cells (22,30,34,36–43). The study conducted by Schoenfeld and colleagues is a notable example in which a combination therapy of cisplatin with vitamin C was used for Non-Small Cell Lung Cancer and standard temozolomide was used for Glioblastoma along with radiation and vitamin C. Schoenfeld and colleagues studied the effects in cell line models, conducted in vivo research and also a phase I/II clinical trial. The overall rate of survival was increased in mice when a high dose of vitamin C was administered along with radio-chemotherapy using 5 mg per kg body weight of carboplatin (30). This indicates that vitamin C increased the radio-sensitizing of these hard-to-treat tumors of Non-Small Cell Lung Cancer and Glioblastoma to contemporary treatment therapies. Comparable outcomes were observed by O’Leary and colleagues in gastric cancer. A high dose of vitamin C was used by them along with 15mg per kg body weight of carboplatin, and 10mg per kg body weight of paclitaxel and radiation (22).

Use of Vitamin C in Clinical Studies as an Adjunctive to Radiation and Chemotherapy

Two clinical studies conducted very initially reported that with the usage of IV vitamin C, the survival rate of cancer patients increased beyond expectations (44,45). Padayatti and colleagues reported a case of a 51-year-old female patient suffering from renal cell carcinoma that has also metastasized into the lung. The patient declined chemotherapy and opted to get IV injections of vitamin C starting at a dose of 15 mg. After two weeks, the quantity was taken up to 65 grams. The patient continued receiving the same amount of dose for ten months. Except for vitamin C, no other treatment through chemotherapy or radiation was given to the patient. Out of eight masses present in the lungs, seven of them resolved and the patient did not show any sign of regression for four years (46).

A 2014 clinical trial was conducted based on the preclinical results of ovarian cancer inhibition because of combination therapy of vitamin C and conventional chemotherapeutic drugs paclitaxel, and carboplatin through its synergistic effect. The clinical trial assessed the effectiveness and harmfulness of the treatment regimen in patients who were suffering from stage three and four ovarian cancer. Participants were divided randomly into two groups. In one group, patients received standard therapy with carboplatin/paclitaxel for initial six months. In the second group, patients received a combination therapy in which carboplatin/paclitaxel was given for initial six months with concomitant treatment with vitamin C for twelve months. The analysis showed that the overall survival rate improved and the median disease progression time was 8.75 months longer when vitamin C was given along with standard treatment with chemotherapy in comparison to chemotherapy alone (28). In two phase one non-randomized clinical studies, it was observed that the size of the primary tumor decreased, performance status increased and the overall median survival rate was noted to be 182 days and thirteen months in patients suffering from metastatic pancreatic cancer when gemcitabine/erlotinib and gemcitabine respectively was used in them in combination with intravenous vitamin C (47,48).

Based on results obtained from in vitro research related to improvement in arsenic trioxide’s activity due to vitamin C against multiple myeloma showing drug resistance, a phase one clinical trial was carried out to determine the impact and toxicity of this combination therapy in patients suffering from stage IIIA relapsed or refractory multiple myeloma. The trial observed that the working of arsenic trioxide inside the body did not alter and the toxicity was also acceptable when arsenic trioxide was given for five days a week followed by vitamin C for five continuous weeks and this was followed by a resting period of two weeks (49). Something similar was also noted in patients suffering from resistant multiple myeloma treated with combination therapy of standard treatment along with vitamin C. Two more clinical trials were conducted in which patients were treated with dexamethasone, arsenic trioxide, and IV vitamin C. The response rate was noted to be 6% and 30% while the median survival was found to be 11 months and 962 days and the survival without any disease progression was found to be 4 months and 316 days, respectively (50,51).

Berenson and colleagues conducted a phase I/II clinical trial with bortezomib, arsenic trioxide, and vitamin C as a combination therapy and found that the objective response rate of the study was 27%. The overall survival rate was 74% in patients while the survival free of progression was 34%. The median survival period free of any disease progression was found to be five months in patients with relapsed/refractory multiple myeloma (52). In a clinical report, a case was presented in which complete remission was observed in patients suffering from stage four colorectal carcinoma after receiving combination therapy of 5FU/Leucovorin with hundred grams of intravenous vitamin C every week. In the same report, another case reported that disease progression was halted in patients suffering from low-grade metastatic pancreatic mucinous carcinoma after the chemotherapy combined with intravenous vitamin C (53).

The data obtained from these clinical trials look promising and provide reliable evidence for the administration of intravenous vitamin C in high doses as an effective anti-cancer treatment.

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