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This article is part of the 2019 Oncology Special IssueJournal of naturopathy. Read the full issue here.
Relation
Abdel-Latif MMM, Babar M, Kelleher D, Reynolds JV. A pilot study of the effects of vitamin C supplementation with neoadjuvant chemoradiotherapy on regulators of inflammation and carcinogenesis in patients with esophageal cancer. J Cancer Res Ther. 2019;15(1):185-191.
Study objective
To evaluate the effects of oral vitamin C supplementation with neoadjuvant chemoradiotherapy in esophageal adenocarcinoma on nuclear factor kappa B (NF-ΚB) and associated cytokines
Draft
Randomized 4 week trial of vitamin C but the entire treatment protocol lasted 8 weeks until surgery
Participant
Twenty patients diagnosed with esophageal carcinoma who underwent multimodal treatment
Inclusion criteria
Patients with esophageal adenocarcinoma who had samples of both the tumor and their normal esophageal tissue taken and who received external beam radiotherapy (40 Gy in 15 fractions over 3 weeks) and chemotherapy at weeks 1 and 6 (5-FU 50 mg/kg for 5 days and then cisplatin 75 mg/m2on day 7) and surgery in week 8
Exclusion criteria
Taking other nutritional supplements
Instruments
Colorimetric NF-ΚB assay, cell extract and western blot analysis and cytokine analysis
Treatment
Oral vitamin C (1,000 mg/day) for 4 weeks
Key insights
All 20 patients completed the study; 9 received oral vitamin C and 11 did not. Of the 20 patients, 4 were female, the average age was 64.5 years, 6 were smokers, 17 drank alcohol, 12 had a family history of cancer, and 13 had Barrett's adenocarcinoma.
NF-ΚB was activated in cancer tissue of all patients before treatment. Downregulation of NF-ΚB>10% was detected in 5 patients (25%), including 2 from the vitamin C group, after treatment.
NF-ΚB binds to the inhibitory IχBα and is degraded. In the 5 patients with>10% change, their tumor tissue had lower IχBα compared to normal esophageal tissue. The trend was toward a greater NF-ΚB reduction in the vitamin C group, but was not significant.
Both treatment arms had significant reductions in their cytokine profiles, with the effect being more pronounced in the vitamin C treatment arm (P<0.05).
NF-ΚBp50 and NF-ΚBp65 levels were increased in cancer tissue of all patients before treatment. Nine had lower levels after treatment, but vitamin C had no effect on these levels.
The cytokines Vascular Endothelial Growth Factor (VEGF), Interleukin (IL) 8, IL1α and IL1β were significantly increased in the tumor compared to normal tissue.
Cytokine levels were significantly reduced after treatment and this effect was greater in the vitamin C arm (P<0.05).
Practice implications
The authors chose a dose of 1,000 mg because they felt this would be an appropriate dose. However, those who use intravenous vitamin C (IVC) know that high serum levels cannot be achieved or maintained by oral treatment compared to IV treatment. First, the dose used in this study was based on the work of Levine et al. from 1999, which calculated that 200 mg would maintain adequate levels of vitamin C in the body, and secondly, on their earlier pilot study in which 1,000 mg of vitamin C per day for 4 weeks in 25 Barrett's esophagus patients revealed 8 (35%) patients with downregulation of activated NF-κB and cytokines.1.2
Administration of IVC to oncology patients does not initially raise serum levels to those of healthy patients receiving IVC, therefore repeated administration is required.
In their 2018 review article, Carr and Cook provided a comprehensive summary of the literature on IVC, including knowledge and gaps.3They note that a large proportion of cancer patients suffer from hypovitaminosis C (<23 umol/l) or overt vitamin C deficiency (<11 umol/l).3Administration of IVC to oncology patients does not initially raise serum levels to those of healthy patients receiving IVC, therefore repeated administration is required.4Cieslak and Cullen's work showed that radiation plus IVC reduced tumor growth.5Schoenfeld et al. found that additional chemotherapy increased survival rates.6In the Schoenfeld et al study of patients with glioblastoma multiforma and non-small cell lung cancer (N = 11), there was longer progression-free survival and longer average overall survival, 4 (36%) patients remained alive and 1 (9%) of the 4 had no evidence of cancer on MRI at the time of publication of the article.6
The authors of the current study noted in their discussion and conclusions that they did not achieve the success hoped for and that future studies should evaluate patients' molecular profiles and include parenteral administration of vitamin C.
restrictions
It was not clear during which 4 weeks (5 weeks in another part of the work) of their 8-week protocol the oral vitamin C was administered. The oral dose may have been too low, especially since cancer patients generally have low ascorbate levels at the time of diagnosis. The source of oral vitamin C and its verification were not reported in this publication or its previous publication.2A study using IVC might have had a better result and provided us with additional information about the effects of IVC on the different inflammatory cytokines in Barrett's esophageal adenocarcinoma.
Summary
In this small study of patients with Barrett's esophageal adenocarcinoma, an oral daily dose of 1 g of vitamin C for 4 weeks along with radiation and chemotherapy before surgery, however, there was a downregulation of NF-κB in 25% of patients, not all of whom were in the vitamin C group, and there was a significant reduction in cytokines that were in the vitamin C group was more pronounced.