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      Ozone Therapy as Adjuvant for Cancer Treatment: Is Further Research Warranted?

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          Abstract

          Introduction

          This article provides an overview of the potential use of ozone as an adjuvant during cancer treatment.

          Methods

          We summarize the findings of the most relevant publications focused on this goal, and we include our related clinical experience.

          Results

          Over several decades, prestigious journals have published in vitro studies on the capacity of ozone to induce direct damage on tumor cells and, as well, to enhance the effects of radiotherapy and chemotherapy. Indirect effects have been demonstrated in animal models: immune modulation by ozone alone and sensitizing effect of radiotherapy by concurrent ozone administration. The effects of ozone in modifying hemoglobin dissociation curve, 2,3-diphosphoglycerate levels, locoregional blood flow, and tumor hypoxia provide additional support for potential beneficial effects during cancer treatment. Unfortunately, only a few clinical studies are available. Finally, we describe some works and our experience supporting the potential role of local ozone therapy in treating delayed healing after tumor resection, to avoid delays in commencing radiotherapy and chemotherapy.

          Conclusions

          In vitro and animal studies, as well as isolated clinical reports, suggest the potential role of ozone as an adjuvant during radiotherapy and/or chemotherapy. However, further research, such as randomized clinical trials, is required to demonstrate its potential usefulness as an adjuvant therapeutic tool.

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          Most cited references85

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          Detection and characterization of tumor hypoxia using pO2 histography.

          Data from 125 studies describing the pretreatment oxygenation status as measured in the clinical setting using the computerized Eppendorf pO2 histography system have been compiled in this article. Tumor oxygenation is heterogeneous and severely compromised as compared to normal tissue. Hypoxia results from inadequate perfusion and diffusion within tumors and from a reduced O2 transport capacity in anemic patients. The development of tumor hypoxia is independent of a series of relevant tumor characteristics (e.g., clinical size, stage, histology, and grade) and various patient demographics. Overall median pO2 in cancers of the uterine cervix, head and neck, and breast is 10 mm Hg with the overall hypoxic fraction (pO2
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            Hypoxic radiosensitization: adored and ignored.

            Since observations from the beginning of the last century, it has become well established that solid tumors may contain oxygen-deficient hypoxic areas and that cells in such areas may cause tumors to become radioresistant. Identifying hypoxic cells in human tumors has improved by the help of new imaging and physiologic techniques, and a substantial amount of data indicates the presence of hypoxia in many types of human tumors, although with a considerable heterogeneity among individual tumors. Controlled clinical trials during the last 40 years have indicated that this source of radiation resistance can be eliminated or modified by normobaric or hyperbaric oxygen or by the use of nitroimidazoles as hypoxic radiation sensitizers. More recently, attention has been given to hypoxic cytotoxins, a group of drugs that selectively or preferably destroys cells in a hypoxic environment. An updated systematic review identified 10,108 patients in 86 randomized trials designed to modify tumor hypoxia in patients treated with curative attempted primary radiation therapy alone. Overall modification of tumor hypoxia significantly improved the effect of radiotherapy, with an odds ratio of 0.77 (95% CI, 0.71 to 0.86) for the outcome of locoregional control and with an associated significant overall survival benefit (odds ratio = 0.87; 95% CI, 0.80 to 0.95). No significant influence was found on the incidence of distant metastases or on the risk of radiation-related complications. Ample data exist to support a high level of evidence for the benefit of hypoxic modification. However, hypoxic modification still has no impact on general clinical practice.
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              Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck--a systematic review and meta-analysis.

              The importance of tumour hypoxia for the outcome of radiotherapy has been under investigation for decades. Numerous clinical trials modifying the hypoxic radioresistance in squamous cell carcinoma of the head and neck (HNSCC) have been conducted, but most have been inconclusive, partly due to a small number of patients in the individual trial. The present meta-analysis was, therefore, performed utilising the results from all clinical trials addressing the specific question of hypoxic modification in HNSCC undergoing curative intended primary radiotherapy alone. A systematic review of published and unpublished data identified 4805 patients with HNSCC treated in 32 randomized clinical trials, applying, normobaric oxygen or carbogen breathing (5 trials); hyperbaric oxygen (HBO) (9 trials); hypoxic radiosensitizers (17 trials) and HBO and radiosensitizer (1 trial). The trials were analysed with regard to the following endpoints: loco-regional control (32 trials), disease specific survival (30 trials), overall survival (29 trials), distant metastases (12 trials) and complications to radiotherapy (23 trials). Overall hypoxic modification of radiotherapy in head and neck cancer did result in a significant improved therapeutic benefit. This was most dominantly observed when using the direct endpoint of loco-regional control with an odds ratio (OR) of 0.71, 95% cf.l. 0.63-0.80; p<0.001), but this was almost mirrored in the disease specific survival (OR: 0.73, 95% cf.l. 0.64-0.82; p<0.001), and to a lesser extent in the overall survival (OR: 0.87, 95% cf.l. 0.77-0.98; p=0.03). The risk of distant metastases was not significantly influenced although it appears to be less in the tumours treated with hypoxic modification (OR: 0.87, 95% cf.l. 0.69-1.09; p=0.22), whereas the radiation related late complications were not influenced by the overall use of hypoxic modifications (OR: 1.00, 95% cf.l. 0.82-1.23; p=0.96). The improvement in loco-regional control was found to be independent of the type of hypoxic modification. The trials have used different fractionation schedules, including large doses per fraction, which may result in relatively more hypoxia and greater benefit. However, analysis of HNSCC trials using conventional fractionation only, showed that the significant effect of hypoxic modification was maintained. The meta-analysis thus demonstrates that there is level 1a evidence in favour of adding hypoxic modification to radiotherapy of squamous cell carcinomas of the head and neck. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Evid Based Complement Alternat Med
                Evid Based Complement Alternat Med
                ECAM
                Evidence-based Complementary and Alternative Medicine : eCAM
                Hindawi
                1741-427X
                1741-4288
                2018
                9 September 2018
                : 2018
                : 7931849
                Affiliations
                1Research Unit, Dr. Negrín University Hospital, Las Palmas, Spain
                2Radiation Oncology Department, Dr. Negrín University Hospital, Las Palmas, Spain
                3Chronic Pain Unit of the Dr. Negrín University Hospital, Las Palmas, Spain
                4Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Grupo BIOPHARM, Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain
                5Grupo de Investigación Clínica en Oncología Radioterápica (GICOR), Madrid, Spain
                6Section of Thoracic Surgery, Department of Surgery, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
                7Experimental Medicine and Surgery Unit of Hospital Gregorio Marañón and the Health Research Institute of Hospital Gregorio Marañón (IiSGM), Madrid, Spain
                8Servicio Atención Especializada, Dirección General de Programas Asistenciales, Servicio Canario de Salud, Las Palmas, Spain
                9Unidad de Ozonoterapia, Hospital Quirónsalud, Barcelona, Spain
                10University of Saint George, Italy
                11Clinicanaria Internacional, Las Palmas, Spain
                12Department of Nuclear Medicine, DIMEC Center, Clínica San Roque, Las Palmas, Spain
                Author notes

                Academic Editor: Mark Moss

                Author information
                http://orcid.org/0000-0003-2522-1064
                http://orcid.org/0000-0003-1663-3673
                Article
                10.1155/2018/7931849
                6151231
                30271455
                48c1e127-e1c7-4cb0-9547-b7edcfa7d3f0
                Copyright © 2018 Bernardino Clavo et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 April 2018
                : 9 July 2018
                Funding
                Funded by: Instituto de Salud Carlos III
                Award ID: INT07/30
                Award ID: INT07/172
                Award ID: PI 10/01485
                Funded by: Fundación Canaria de Investigación y Salud
                Award ID: PI 31/98
                Award ID: PI 2/05
                Funded by: Wilfried Fallak
                Categories
                Review Article

                Complementary & Alternative medicine
                Complementary & Alternative medicine

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