Elsevier

European Journal of Pharmaceutical Sciences

Volume 109, 15 November 2017, Pages 412-418
European Journal of Pharmaceutical Sciences

The safety and pharmacokinetics of high dose intravenous ascorbic acid synergy with modulated electrohyperthermia in Chinese patients with stage III-IV non-small cell lung cancer

https://doi.org/10.1016/j.ejps.2017.08.011 Get rights and content

Abstract

Ascorbic acid (AA) infusion and modulated electrohyperthermia (mEHT) are widely used by integrative cancer practitioners for many years. However, there are no safety and pharmacokinetics data in Chinese cancer patients. We carried out a clinical trial to evaluate the safety and pharmacokinetics of those methods in patients with stage III-IV non-small cell lung cancer (NSCLC). Blood ascorbic acid in the fasting state was obtained from 35 NSCLC patients; selecting from them 15 patients with stage III-IV entered the phase I study. They were randomized allocated into 3 groups, and received doses 1.0, 1.2, 1.5 g/kg AA infusions. Participants in the first group received intravenous AA (IVAA) when mEHT was finished, in the second group IVAA was administered simultaneously with mEHT and in the third group IVAA was applied first, and followed with mEHT. Pharmacokinetic profiles were obtained when they received solely IVAA and when IVAA in combination with mEHT. The process was applied 3 times a week (every other day, weekend days off) for 4 weeks. We found that fasting plasma AA levels were significantly correlated with stage of the disease. Peak concentration of AA was significantly higher in the simultaneous treatments than in other combinations with mEHT or in solely IVAA-managed groups. IVAA synergy with simultaneous mEHT is safe and the concomitant application significantly increases the plasma AA level for NSCLC patients.

Graphical abstract

Pharmacokinetic plots of each treatment in the six groups by increasing dosage. Junwen Ou, Xinyu Zhu, et al.

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Introduction

Lung cancer is the most common cancer type and the leading cause of cancer mortality in China, accounting for 19.59% of all newly diagnosed cancer cases (Chen et al., 2015). Nearly 80% of lung cancers are non-small cell lung cancer (NSCLC). The majority of patients diagnosed with advanced NSCLC are not suitable for surgery. Chemotherapy and tyrosine kinase inhibitors (TKIs) are the first recommendations for these patients. However, side effects including diarrhea, neuropathy, neutropenia, skin reaction, and weight loss are frequently accompanied by chemotherapy and TKIs, which are the major reasons for patients stopping treatments.

Ascorbic acid (AA) infusion and modulated electrohyperthermia (mEHT) are widely used by integrative and complementary cancer practitioners for many years. High-doses ascorbic acid infusion means the use of ascorbate, administered IV, to achieve plasma levels of ascorbate on the order of 100–1000 times that of healthy nutritional levels (Welsh et al., 2013). A Phase I study showed the safety of high dose AA (Kawada et al., 2014), and the safety of mEHT has also been shown for most heat-sensitive organs, such as the brain (Wismeth et al., 2010). High dose AA might have a prophylactic effect against lung cancer, as suggested by a meta-analysis (Luo et al., 2014) of 18 articles, including 21 studies involving 8938 lung cancer cases. Estimates based on dose-response analysis (Luo et al., 2014) show a risk reduction in lung cancer by 7% for every 100 mg/day increase in the intake of AA. The refractory cases may also be re-sensitized by AA (Chiang et al., 1994). The high dose intravenous AA (IVAA) produces high blood-plasma concentrations that could be 70- to 100-fold higher than the maximally tolerated oral doses (Creagan et al., 1979). Only IVAA produces high plasma and urine concentrations of ascorbates (Padayatty et al., 2004). The expected peak of 60 g IVAA administration is about 25 mmol/L in the plasma at tmax  90 min (Duconge et al., 2008).

Laboratory studies (Chen et al., 2008) showed that pharmacological concentrations achieved by high-dose AA have redox properties and can decrease cell proliferation in lung cancer cell lines. Different studies have reported the anticancer mechanisms induced by IVAA, which include apoptosis (Carosio et al., 2007), DNA damage and ATP depletion (Ma et al., 2014), and cell cycle arrest (Chen et al., 2005). Human studies (Hoffer et al., 2008, Riordan et al., 2005, Stephenson et al., 2013) indicated that high-dose IVAA infusions are safe and well tolerated, and can modulate inflammation, improving outcomes for cancer patients (Mikirova et al., 2013). Clinical studies (Ma et al., 2014, Monti et al., 2012, Welsh et al., 2013) have suggested that large doses of IVAA can increase its efficacy or reduce toxic side effects from chemo drugs when used in synergy with chemotherapy. The action of AA was a mystery for a long time (Naidu, 2003) due to its declared anti-oxidant effects, but it also shows pro-oxidant behavior as well (Podmore et al., 1998, Putchala et al., 2013). Its real action depends on the physiological conditions and plasma-concentration (Carr and Frei, 1999).

Synergy of hyperthermia with high-dose AA has been shown in vitro (Saitoh et al., 2015), expecting the same clinical results. mEHT has long been used in clinical practice for various malignant diseases (Baronzio et al., 2014). It is based on the modulated electric field effect, which works in synergy with heat (Andocs et al., 2009). The key advantage of this method is the nano-range energy liberation instead of overall heating of the target (Andocs et al., 2015). It is a descendant of hyperthermia initially based on nano-thermal but not temperature-dependent effects of electromagnetic fields and special fractal modulation, whose effect could exceed the effect of the overall heating, the macroscopic temperature elevation, by 3–4 times (Szasz, 2012). mEHT does not require homogenous hyperthermia-range temperatures in the tumor; it selects the malignant cells by heterogenic heating.

Previous hyperthermia studies showed the benefits of hyperthermia applied complementary to chemo and radio-therapies (Falk and Issels, 2001). A previous study indicated the linear increase in the cytotoxic effect of alkylating agents (e.g. ifosfamide) and the platinum chemo drugs when temperatures are elevated from 37 °C to over 40.5 °C (Hildebrandt et al., 2002). The hyperthermia method mEHT has shown its capability for NSCLC in clinical studies (Szasz, 2014). Consequently, the treatment could be performed safely without invasive thermal control. These facts motivated our team to conduct a Phase I clinical trial to evaluate the safety and pharmacokinetics of high dose intravenous ascorbic acid synergy with mEHT in patients with NSCLC.

Section snippets

Study population & eligibility criteria

Patients were required to have histologically confirmed non-small cell lung cancer, diagnosed with primary lung cancer, stage III and IV. Patients were progression after radio and/or chemotherapy, or fail to respond to other conventional therapies. When they receive IVAA and mEHT, patients cannot simultaneously receive anticancer therapies during treatment period (for almost 2 months). Patients who can tolerate the above treatments and with the ECOG performance status of 0 to 2 were enrolled

Results

The characteristics of the participants are collected in Table 1. Thirty-five NSCLC patients were studied in a preparative study. Thirty participants received prior conventional anticancer therapies, with 18 experiencing severe adverse events leading to cessation of those treatments. Blood ascorbic acid in the fasting state was obtained from all 35 participants. 15 patients with stage III-IV satisfied the inclusion and exclusion criteria, and those entered the treatment phases of the present

Discussion

Our data from the preparation of the study with a larger number of patients (n = 35) show that tumor burden can affect fasting plasma AA level. Fasting plasma AA was significantly correlated with the stage of disease. The lower the level of plasma AA, the more advanced stage of the disease. In comparison with healthy people, fasting plasma AA was significantly lower in stage III-IV NSCLC patients. Cancer cells produce a significant amount of reactive oxygen species (Sundaresan et al., 1996),

Conclusion

The goals of this trial were to evaluate the safety, tolerability and pharmacokinetics of high dose intravenous AA synergies in mEHT patients with stage III-IV NSCLC, and to identify the best pattern of intravenous AA synergies with mEHT for a phase II study to monitor the maintenance or improvement in quality of life by using QLQ-C30. AA concentrations safely reached a peak concentration and only mild adverse events were observed in this study. There was one patient who suffered severe

Abbreviations

    AA

    Ascorbic acid

    mEHT

    modulated electrohyperthermia

    NSCLC

    non-small cell lung cancer

    TKIs

    tyrosine kinase inhibitors

    IVAA

    intravenous AA

    G6PD

    Glucose-6-phosphate dehydrogenase deficiency

    DLT

    dose-limiting toxicity

    QLQ-C30

    Quality of Life Questionnaire

    QoL

    quality of life

Ethical approval and consent to participate

The protocol and consent form were approved by the Ethics Committee of the Clifford Hospital. Approval code: 2/2015-10

Informed consent was obtained from all participants. There was no identifying information relating to participants.

Availability of data and materials

All data generated and analyzed during this study are included in this published article and in its supplementary data files.

Competing interests

The authors declare that they have no competing interests.

Funding

Clifford L.K. Pang Funding, China. Funding number: 2016-01.

Trial registration

ClinicalTrials.gov , NCT02655913 , Registration date: 7th Jan, 2016. Date of enrolment of the first participant to the trial: 17th Jan, 2016. No changes to the methodology occurred following trial commencement. We confirmed that all methods were performed in accordance with the approved guidelines and regulations. We report and present data according to the CONSORT statement.

Author contributions

JO designed the whole protocol, enrolled the patients, and wrote the manuscript text; XYZ followed up with the patients, analyzed the samples and collected data; YL and JW applied mEHT treatment on participants; CZ and XG randomized the patients, XTZ and TZ analyzed the data; HZ and XW monitored the status of the participants. CP gave suggestions of full text writing. All authors reviewed the manuscript.

Acknowledgements

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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