Esophageal Cancer: Treatment with Radiation, Oral Vitamin C, Chemotherapy and the Effects on Inflammatory Markers

This article is part of the 2019 Oncology Special Issue of Natural Medicine Journal. Read the full issue here. 

Reference

Abdel-Latif MMM, Babar M, Kelleher D, Reynolds JV. A pilot study of the impact of Vitamin C supplementation with neoadjuvant chemoradiation on regulators of inflammation and carcinogenesis in esophageal cancer patients. J Cancer Res Ther. 2019;15(1):185-191.

Study Objective

To assess the effects of oral vitamin C supplementation with neoadjuvant chemoradiation in esophageal adenocarcinoma on the nuclear factor-kappa B (NF-ΚB) and associated cytokines

Design

Randomized 4-week trial of vitamin C, but the entire treatment protocol was 8 weeks until surgery

Participants

Twenty patients diagnosed with esophageal carcinoma who were undergoing multimodal treatment

Inclusion Criteria

Patients with adenocarcinoma of the esophagus who had samples collected from both the tumor and their normal esophageal tissue and received external beam radiotherapy (40 Gy in 15 fractions over 3 weeks), as well as chemotherapy in weeks 1 and 6 (5-FU 50 mg/kg for 5 days and then cisplatin 75 mg/m² on day 7) and surgery during week 8

Exclusion Criteria

Taking other nutritional supplements

Instruments

Colorimetric NF-ΚB assay, cell extracts and Western blot analysis, and cytokine analysis

Treatment

Oral vitamin C (1,000 mg/day) for 4 weeks

Key Findings

All 20 patients completed the trial; 9 received the oral vitamin C and 11 did not. Of the 20 patients, 4 were female, median age was 64.5 years old, 6 were smokers, 17 drank alcohol, 12 had a family history of cancer, and 13 had Barrett adenocarcinoma.

NF-ΚB was activated in the cancer tissue of all patients before treatment. Down-regulation of NF-ΚB >10% was noted in 5 patients (25%), including 2 from the vitamin C group, post-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 for greater NF-ΚB reduction in the vitamin C group, but it was not significant.

Both treatment arms had a significant reduction in their cytokine profiles, with the effect more pronounced in the vitamin C treatment arm (P<0.05).

NF-ΚBp50 and NF-ΚBp65 levels were elevated in the cancer tissue of all patients before treatment. Nine had lower levels post treatment, but vitamin C had no effect on these levels.

Cytokines vascular endothelial growth factor (VEGF), interleukin (IL) 8, IL1α, and IL1β were significantly elevated 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 it would provide an adequate dose. However, those who use intravenous vitamin C (IVC) know that high serum levels cannot be achieved or maintained from oral treatment compared to IV treatment. The dose used in this study was based first on the 1999 paper by Levine et al that calculated 200 mg would maintain an adequate level of vitamin C in the body, and second on their prior pilot study in which 1,000 mg/d of vitamin C for 4 weeks in 25 Barrett esophagus patients yielded 8 (35%) patients with down-regulation of activated NF-KB and cytokines.^1,2

The administration of IVC to oncology patients does not initially raise serum levels to those of healthy patients receiving IVC, which is why repeated dosing is needed.

In their 2018 review paper, Carr and Cook provided a comprehensive summary of the literature on IVC, including both knowledge and gaps.³ They note that a large proportion of cancer patients present with hypovitaminosis C (<23 umol/L) or frank vitamin C deficiency (<11 umol/L).³ The administration of IVC to oncology patients does not initially raise serum levels to those of healthy patients receiving IVC, which is why repeated dosing is needed.⁴ Work by Cieslak and Cullen showed that radiation plus IVC decreased tumor growth.⁵ Schoenfeld et al found that the addition of chemotherapy increased survival rates.⁶ In the Schoenfeld et al trial involving patients with glioblastoma multiforma and non-small cell lung carcinoma (N=11), there was longer progression-free survival and longer average overall survival, 4 (36%) subjects remained alive, and 1 (9%) of the 4 showed no evidence of cancer on MRI when the paper was published.⁶

The authors of the current study noted in their discussion and conclusions that they did not achieve the success they had hoped for and that future studies should evaluate patient molecular profiles and involve parenteral administration of vitamin C.

Limitations

It was not clear in which 4 weeks (5 weeks in another part of the paper) of their 8-week protocol the oral vitamin C was given. The oral dose may have been too low, especially since patients with cancer are generally low in ascorbate at the time of diagnosis. The source of oral vitamin C and its verification were not stated in this paper or their previous paper.² A trial using IVC may have had a better outcome and given us additional information on the effects of IVC on the various inflammatory cytokines in Barrett esophageal adenocarcinoma.

Summary

In this small trial of patients with Barrett esophageal adenocarcinoma, an oral daily dose of 1 g vitamin C for 4 weeks, along with radiotherapy and chemotherapy prior to surgery, there was a down-regulation of NF-KB in 25% of patients, but not all were in the vitamin C group, and there was a significant reduction in cytokines that was more pronounced in the vitamin C group.