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Intravenous Vitamin C Sensitizes Pancreatic Cancer to Radiation Therapy.

A landmark paper on using intravenous vitamin C concurrently (IVC) with chemotherapy and radiation treatments for pancreatic cancer was published in December 2018. This paper summarizes a series of studies conducted by senior author Joseph Cullen at the University of Iowa and colleagues. (1) There were three parts to this research by Cullen's team:

1. In vitro vitamin C treatment increased toxicity of radiation therapy to pancreatic cancer cells more than radiation therapy alone. Secondly IVC plus radiation damaged healthy jejunal cells less than radiation alone. This suggests that the combination may increase anti-tumor effect while protecting healthy cells.

2. In mice who grew pancreatic tumors and received radiation treatment, they tested intraperitoneal injection of vitamin C and looked at the impact on nearby jejunal tissues compared with control mice who received radiation alone and found that the mice treated with vitamin C had less damage to nearby jejunal tissue demonstrated by reduced villous blunting, loss of crypt cells, and collagen deposition. It was found that radiation created heavy damage to mitochondrial structures in jejunal epithelial cells, which was partially inhibited by ascorbate treatment.

3. In the human clinical trial, they evaluated the safety and potential efficacy of IVC combined with radiation treatment and gemcitabine chemotherapy for patients with locally advanced pancreatic cancer compared to matched historical controls who received gemcitabine and radiation but not IVC. The study also assessed the maximal tolerated dose (MTD) of IVC in participants.

In the human study, IVC was administered during radiation therapy while participants received ongoing treatment with gemcitabine. Fifteen subjects were enrolled in the experimental group, and 19 subjects were selected from the records of the hospital to be used as historical comparators. Blinding and randomization were not described. All the patients in the study received similar gemcitabine and radiation therapy. All of the patients had pancreatic adenocarcinoma. Patients initially received one test dose of 15 g IVC before proceeding to the dose cohort of 50 grams of IVC, which was given daily, while gemcitabine was given weekly for six weeks and radiation was given via 25-28 treatments for a total of 50 Gy. Interestingly, this is the first study to actively infuse IVC during radiation 'beam on' time. For this, patients were started on IVC in the infusion area then transported to the radiation area for their treatment and then they returned to the infusion area to complete the drip.

The IVC doses for each patient were escalated from 50 grams to 75 grams and then to 100 grams in a two-stage design for participants who tolerated it well without dose limiting toxicity, defined as vomiting resulting in hypokalemia, febrile neutropenia, intra-abdominal hemorrhage, or severe weight loss. Serious adverse events related to the IVC were also considered a dose-limiting toxicity.

Of the sixteen patients enrolled in the study, two withdrew and fourteen patients completed the study. In the ascorbate group there were eight females, and six males with a median age of 59. In the comparator group there were six females, and 13 males with a median age of 63. All the participants in the IVC treatment group had received prior chemotherapy while only two of the control group had. More people in the control group had higher performance scores, fewer smoked, and more were diagnosed with earlier stage disease and node negative disease than those in the treatment group. Thus, the comparator group could have had an advantage and possibly be expected to have better outcomes compared to those patients in the IVC treatment group.

While the stated primary purpose of this study was to assess the safety and toxicity of the combination of IVC, gemcitabine, and radiation treatment, our attention is drawn to the secondary objectives, which were to ascertain a maximum tolerated dose of vitamin C and to understand any effect the combined treatment had on patient prognosis. Though the study was not powered to prospectively assess differences in survival, the investigators hypothesized that the patients receiving treatment with IVC would be no worse off than those receiving the chemoradiation alone. The median overall survival of the 14 patients receiving IVC-gemcitabine-radiation was reported to be 21.7 months. The authors compared this to 12.7 months in the University of Iowa's institutional average for patients receiving the same treatment without IVC, however did not report survival data for the 19 historical comparator subjects selected. Also, these survival values did not meet statistical significance (p=0.08). The median overall survival of the treatment group as reported is better than n=74 patients in the E4201 trial, which compared outcomes of locally advanced pancreatic patients receiving gemcitabine with or without radiation therapy reporting statistically significant survival benefit for the combined approach. (2) In terms of progression-free survival (PFS) in the Cullen study, the IVC-treated group median was reported to be 13.7 months, which the authors compared to the University of Iowa's institutionally treated median of 4.6 months and was also compared to subjects in the ECOG-E4201 trial (11.1 months).

Three adverse effects were attributed to IVC: dry mouth, thirst, and transient blood pressure elevations. One patient had a grade 3 transient blood pressure elevation due to hypovolemia and withdrew. Another patient withdrew due to chronic back pain attributed to prolonged sitting during the IVC infusion and radiation. One of the patients in the IVC treatment group receiving the 100 g dose experienced transient hypertension resolving within 30 minutes after infusion. A second participant at the 100 g dose level, who did not have a baseline history of hypertension, developed post-infusion hypertension that did not resolve within 30 minutes post infusion. This was considered possibly a dose-limiting toxicity of IVC, and the patient resumed the study in the 75 g dose cohort without further complication.

Other adverse events included anemia, leukopenia, decreased lymphocyte count, decreased ANC, and decreased platelet counts, which were all consistent with known effects from gemcitabine and radiation therapy.

Hemoglobin levels remained stable in the IVC patients but fell significantly in 13 out of the 19 'controls' (p<0.01). Oxidative injury assessed via plasma [F.sub.2]-lsoprostane levels showed a significant decrease in the IVC-treated patients (p=0.02) but did not change in controls (p=0.88). Further, one in 13 patients in the IVC group (7%) had grade 3 anemia whereas six subjects (18%) in the comparator group had grade 3 or 4 anemia.

Two subjects in the treatment group became resectable following trial completion (both were initially borderline resectable) and were alive at follow-up 44 and 35 months from diagnosis.

Plasma vitamin C levels in the treatment group averaged 15 mM at the 50 gram/day dose (n=17, 95% CI 13-17 mM), 20 mM for the 75 g dose (n=37, 95% CI 9-21 mM) and 20 mM for the 100 g dose (n=32, 95% CI 19-22mM). Increasing the daily dose of vitamin C above 75 g/day did not significantly increase plasma levels. As has been determined in other studies, the maximum tolerated dose of IVC was found to be 100 grams per infusion with 75 g selected as a recommended dose for future phase II trials. Six participants entered the 75 g dose cohort receiving IVC over 120 minutes, and five moved up to the 100 g dose cohort receiving IVC over 180 minutes.

Cullen and his research team at the University of Iowa are working to assess the effect of adding vitamin C to treatment in several other cancer types. In addition to pancreatic cancer, they are running research trials on lung cancer and glioblastoma. A $9.7 million grant from the National Cancer Institute is helping fund their research. (3)

Cullen's phase I pancreatic clinical trial adds further confirmation that IVC is safe and well tolerated in humans when given alone or in combination with chemotherapy. (4-7) The unique and exciting part of this study is that chemotherapy and radiation were combined with daily IVC in 50-100 g doses, which appears to be safe in patients with resectable pancreatic cancer. This study's protocol is also unique in that the vitamin C was infused during the actual radiation treatment.

The protocol used in Cullen's study reflects an overall change in treatment strategy that's occurred over the last few years. For pancreatic cancer patients not initially eligible for surgery, a combination of chemotherapy and radiation is now thought to improve survival and the chances of becoming resectable. More research on IVC, gemcitabine, and radiation--while safe--will still have a way to go before oncology teams would potentially implement this approach. Larger well-designed studies are needed.

Of the two patients in the Cullen study who went on to get surgery, both had received FOLFIRINOX as first line treatment that had been discontinued due to progression of disease before they entered the Cullen trial.

Although most people think of vitamin C as an antioxidant, the mechanism of action against cancer is thought to be pro-oxidant. We think vitamin C action varies with concentration. At blood concentrations obtained through IV administration, vitamin C can increase generation of hydrogen peroxide in the tissue space, where a pro-oxidant effect is thought to trigger apoptosis in cancer cells that are deficient in catalase (which protects normal cells such as red blood cells from damage by hydrogen peroxide). Thus, the strategy used in the Cullen study is of particular interest as the anti-cancer effect of radiotherapy is also understood to be pro-oxidant and the combination of IVC and radiation may have either additive or synergistic pro-oxidant actions as seen in the vitro and vivo portions of Cullen's study as well as in other studies.

Regarding plasma levels of ascorbate, the authors selected the study doses based on pre-clinical and human data reporting synergy between gemcitabine and IVC in doses sufficient to generate high millimolar plasma concentrations (10-15 mM) predicted to have anti-tumor effect.

The plasma ascorbate levels for the 50 g dose level averaged 15 mM (n=17, 95% CI 13-17), significantly lower than seen at the higher doses of 75 g and 100 g (p<0.05). The take-home for the clinician is that doses of 50-100 g are safe. Cullen's study also confirmed that dosing by weight in kilograms allows predictable plasma concentrations but tells us that a cap at 75 g might make sense for future studies as higher doses do not raise plasma levels further.

A sweet spot may exist at this 75 g dose between potential benefit and risk of adverse events. The main thing though was that higher doses were not associated with increased plasma levels.

In patients with advanced disease and poor performance status where a top priority is to support quality of life and do no harm, I recommend lower doses, 30 -50 g. While higher doses are reported safe, the side effects associated with high osmolarity fluids and high total fluid volume could be cause for concern.

If vitamin C is given to boost quality of life or replete suspected vitamin C or antioxidant deficiency, these lower dose IVC infusions could make sense as supportive care; giving 20-30 g at intervals of every few days or weekly might be helpful.

This study provided IVC infusions during radiation treatment for a total of 50 to 50.4 Gray in 25-28 fractions, meaning IVC was given every day for up to 28 days. In terms of performance status, 11 out of 14 patients in this study who received IVC plus chemoradiation had Karnofsky scores that remained stable, while two increased, one decreased, and there were two patients who withdrew from the study. The average Karnofsky score for participants was reported to be 86 [+ or -]2 (SEM). This is good; 80-100 is the top tier for performance status.

The mild adverse events reported by Cullen et al are similar to those reported in other studies and are typical to what is seen in clinical practice: thirst, dry mouth, and transient blood pressure and/or urinary changes resolving soon after infusion completion. It is not uncommon to also see dizziness, hypotension, urinary urgency, chills, and/or cramping pains. While there are reports of hypotension in the literature, Cullen et al report they did not observe this symptom. Instead they report that five participants experienced transient blood pressure elevations at least once in the course of the study which resolved within 30 minutes after IVC treatment. One patient was admitted for what ultimately turned out to be esophageal spasm yet subsequently completed the trial in the 75 g dose cohort without further issue.

Normally we expect that patients receiving chemotherapy and radiation treatment will develop anemia to the degree that it impacts quality of life and may disrupt treatment. The Cullen study reports that hemoglobin levels in the experimental group remained stable (p=0.44). In contrast the controls were reported to have significant decreases in hemoglobin over the course of treatment (p<0.01). In non-oncology settings, several studies report low doses of IVC may elevate hemoglobin in anemia. (89) In a study of 40 patients on hemodialysis, it was found that IVC given as 3 g twice weekly was equally effective as erythropoietin in raising hemoglobin (p=0.076). (10)

This new strategy of treating patients with chemo and radiation prior to surgery is the subject of a series of recent studies that will encourage oncologists to change the routine.

The results of this study are extremely encouraging. Two participants out of 14 became eligible for surgery, underwent resection, and at 44 months and 35 months post diagnosis were without evidence of recurrence.

Previous studies providing IVC to oncology patients have reported benefit to quality of life and reduction in side effects of standard cancer treatment approaches. (11-14) The studies have been small and with considerable heterogeneity. Some of the drawbacks of the studies on intravenous vitamin C are use of historical controls or lack of controls, lack of randomization and/or control groups, participants with primarily advanced incurable disease, and lack of power to analyze overall survival.

Possible vitamin C deficiency isn't talked about much in the IVC clinical trials. People with cancer and smokers have higher levels of inflammation and vitamin C deficiency when compared to healthy volunteers or non-smokers. Antioxidant and anti-inflammatory effects of IVC have been reported in oncology and non-oncology trials. (15) The difficult question that often arises is, how does an antioxidant like vitamin C interact with pro-oxidant cancer treatments? One of the reasons this study by Cullen is so important is that it suggests vitamin C can potentially act synergistically with pro-oxidant therapies such as chemotherapy and radiation to add anti-tumor effect while also acting as an antioxidant protecting the surrounding tissue.

To start to look at this further in humans, Cullen measured plasma [F.sub.2]-Isoprostanes as a marker of systemic lipid peroxidation or oxidative stress. These levels dropped significantly in those who received IVC but not in the comparator group.

More patients in the IVC group also actually completed treatment, meaning they received all of their prescribed chemo and radiation rather than having dose reductions or stopping treatment. This is something I believe happens more often in patients receiving integrated cancer care. With lower side effects, less damage to peripheral tissues, and improved overall outcomes, the people using integrative therapies may actually be more adherent to standard cancer treatment regimens and this may support better outcomes overall. Specifically, in this Cullen trial, 14 subjects were enrolled to receive the combined therapy, and eight (57%) received GEM as prescribed in six cycles with all 14 (100%) receiving the prescribed radiation dose. This is a better rate of therapy completion than typically seen. For example, in the ECOG 2011 study, only 29% of patients completed all cycles of chemotherapy and almost a quarter did not complete radiation therapy. (16)

As a clinician, I advocate for the use of intravenous vitamin C as a reasonable and rational approach for supportive care in integrative oncology and consider doses between 15 g and 75 g on an individual basis finding them to be well tolerated by people who have been carefully screened. (17) Many naturopathic doctors have experience with the safe delivery of IVC to oncology patients and thus make excellent points of referral and coordination for patients seeking integrative care with this modality. The Oncology Association of Naturopathic Physicians (https://oncanp.org/about-oncanp/) is the specialty organization of naturopathic oncology providers. Members have expertise in integrative cancer treatment coordinating natural therapies with standard oncology care.

References

(1.) Alexander MS, et al. Pharmacologic Ascorbate Reduces Radiation-Induced Normal Tissue Toxicity and Enhances Tumor Radiosensitization in Pancreatic Cancer. Cancer Res. 2018 Dec 15;78(24):6838-6851.

(2.) Loehrer PJ, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011;29(31):4105-12.

(3.) https://cbs2iowa.com/news/local/ui-researchers-say-vitamin-c-is-enhancing-some-cancer-treatments

(4.) Monti DA, et al. Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. PLoS One. 2012;7:e29794.

(5.) Welsh JL, et al. Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. Cancer Chemother Pharmacol. 2013;71:765-75.

(6.) Ma Y, et al. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci Transl Med. 2014;6:222ral8.

(7.) Vollbracht C, et al. Intravenous vitamin C administration improves quality of life in breast cancer patients during chemo-/radiotherapy and aftercare: results of a retrospective, multicentre, epidemiological cohort study in Germany. In Vivo. 2011;25:983-90.

(8.) Shahrbanoo K, Taziki 0. Effect of intravenous ascorbic acid in hemodialysis patients with anemia and hyperferritinemia. Saudi J Kidney Dis Transpl 2008;19:933-6.

(9.) Jacobs C. Intravenous vitamin C can improve anemia in erythropoietin-hyporesponsive hemodialysis patients. Nat Clin Pract Nephrol 2006;2:552-3.

(10.) Sedighi 0, et al. (2013). Comparative Study of Intravenous Iron Versus Intravenous Ascorbic Acid for Treatment of Functional Iron Deficiency in Patients Under Hemodialysis: A Randomized Clinical Trial. Nephro-urology monthly. 2013;5:913-917.

(11.) Yeom CH, Jung GC, Song KJ. Changes of terminal cancer patients' health-related quality of life after high dose vitamin C administration. J Korean Med Sci. 2007;22:7-11.

(12.) Vollbracht C, et al. Intravenous vitamin C administration improves quality of life in breast cancer patients during chemo-/radiotherapy and aftercare: results of a retrospective, multicentre, epidemiological cohort study in Germany. In Vivo. 2011;25:983-90.

(13.) Takahashi H, Mizuno H, Yanagisawa A. High-dose intravenous vitamin C improves quality of life in cancer patients. Personalized Medicine Universe. 2012;1:49-53.

(14.) Carr AC, Vissers MD, Cook JS. The effect of intravenous vitamin C on cancer- and chemotherapy-related fatigue and quality of life, front Oncol. 2014;4:283.

(15.) Mikirova N, et al. Effect of high-dose intravenous vitamin C on inflammation in cancer patients. J Transl Med. 2012;10:189.

(16.) Loehrer PJ, Sr., et at. Locally Advanced, Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology. 2016;34(22):2654-68.

(17.) Klimant E, et al. Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach. Curr Oncol. 2018 Apr; 25(2): 139-148.

by Heather Wright, ND, FABNO

Heather Wright is a naturopathic doctor with 12 years of experience working in hospital-based integrative oncology teams. Dr. Wright graduated from Bastyr University in 2005 after completing post-baccalaureate pre-medical studies at Tufts and Northeastern Universities. Dr. Wright has special expertise in pancreatic cancer and has co-authored and conducted clinical trials as well as participated in consortium work in the field of pancreatic cancer.

Dr. Wright is currently president of the Oncology Association of Naturopathic Physicians (OncANP.org) and serves as research director for KNOWoncology. org, a knowledge translation project summarizing human level data in integrative oncology. Dr. Wright sees clients at CAMAcenter.com in Philadelphia, Pennsylvania, and also uses teleconsultation services.
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Author:Wright, Heather
Publication:Townsend Letter
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Geographic Code:1USA
Date:Jun 1, 2019
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