Gene and Molecular Pathways of Ozone Treatment Response in Gynecological Tumor Patients With Chronic Pelvic Pain Secondary to Cancer Treatment

Official title

Gene and Molecular Pathway Characterization of the Response to Ozone Treatment in Gynecological Tumor Patients With Chronic Pelvic Pain Secondary to Radio-chemotherapy

Overview

Gynecological cancers, including those affecting the ovaries, uterus, and cervix, represent a significant health burden for women. While survival rates have improved, many women experience chronic pelvic pain secondary to cancer treatment, especially radiotherapy and chemotherapy. This treatment-induced pelvic pain can be of difficult management and significantly affects patients' quality of life. In our experience, ozone therapy has emerged as a promising complementary treatment for pain relief in patients with chronic diseases, including side effects of cancer treatment. However, the genetic and epigenetic mechanisms influencing its effectiveness have not yet been thoroughly studied. The aim of this prospective study is to analyze how ozone therapy modulates the expression of certain genes and its impact on epigenetic clocks, which could help predict pain response.

Detailed description

While survival rates of gynecological cancers have improved, many women experience chronic pelvic pain as a consequence of cancer treatment, particularly radiotherapy and chemotherapy. This persistent pain often has neuropathic characteristics, and it can be challenging to manage, negatively impacting physical and emotional well-being and quality of life.

Conventional pain management strategies for these patients often provide limited relief. In our experience, ozone therapy has emerged as a promising option for managing chronic pain in various conditions, including side effects of cancer treatment.

While the clinical benefits of ozone therapy have been observed in preliminary studies, the underlying molecular mechanisms underlying its analgesic effect remain largely unknown. Understanding how ozone therapy influences gene expression and epigenetic modifications could facilitate the identification of genes involved in the differential response to ozone therapy and a potential way for personalized strategies for pain treatment.

The aim of this prospective study is to analyze how ozone therapy modulates the expression of certain genes and its impact on epigenetic clocks, which could help predict pain response.

Primary Objectives:

In patients with gynecological tumors treated by radiotherapy/chemotherapy, To evaluate

* among patients with or without chronic pelvic pain induced by treatment. * before and after ozone treatment in those patients treated because of pelvic pain induced by radiotherapy/chemotherapy.

The potential differences in:

1. Gene expression. 2. Biological age based on epigenetic clocks:

Secondary Objectives:

Evaluate in those patients the potential relationship between gene expression and epigenetic clocks with:

1. Grade of toxicity 2. Pain score 3. Health-related quality of life, 4. Biochemical markers of oxidative stress and inflammation.

Trial Design:

This observational and prospective study will analyze data from two groups of patients with gynecological tumors treated with radiotherapy/chemotherapy:

* A group of patients with chronic pelvic pain secondary to radiotherapy-chemotherapy, submitted to our Chronic Pain Unit for compassionate/palliative ozone treatment. * A group of patients without secondary chronic pelvic pain.

Trial Population:

Adult women (≥ 18 years old) with gynecological tumors treated with radiotherapy-chemotherapy. They will be analyzed into two different groups of patients:

* A group of patients with chronic pelvic pain secondary to radiotherapy-chemotherapy, submitted to our Chronic Pain Unit for compassionate/palliative ozone treatment. * A group of patients without secondary chronic pelvic pain.

Intervention. No intervention. The management of patients will be the standard of care in our hospital.

Study Duration:

The primary completion date is planned for 14/February/2027. The study completion date is planned for 14/August/2027

Primary outcome measures

• Differences in gene expression among patients with or without chronic pelvic pain induced by radiotherapy/chemotherapy. [Time frame: At 0 week]
• Changes (from baseline) in gene expression at the end of ozone treatment. [Time frame: At 16 weeks]
• Differences in biological age based on epigenetic clocks among patients with or without chronic pelvic pain induced by radiotherapy/chemotherapy [Time frame: At 0 week.]
• Changes (from baseline) in the biological age based on epigenetic clocks, after ozone treatment [Time frame: At 16 weeks.]

Secondary outcome measures (10)

• Differences in the grade of toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) v.5.0 scale among patients with or without chronic pain induced by radiotherapy/chemotherapy [Time frame: At 0 week.]
• Changes (from baseline) in the grade of toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) v.5.0 scale, after ozone treatment. [Time frame: At 16 weeks.]
• Differences in pain score according to the visual analog scale (VAS) among patients with or without chronic pain induced by radiotherapy/chemotherapy [Time frame: At 0 week.]
• Change (from baseline) in pain score according to the visual analog scale (VAS), after ozone treatment. [Time frame: At 16 weeks.]
• Differences in "Quality of Life" (using the EQ-5D-5L questionnaire) self-perceived by patients among patients with or without chronic pain induced by radiotherapy/chemotherapy. [Time frame: At 0 week.]
• Changes (from baseline) in "Quality of Life" (using the EQ-5D-5L questionnaire) self-perceived by patients, after ozone treatment. [Time frame: At 16 weeks.]
• Differences in biochemical parameters of oxidative stress among patients with or without chronic pain induced by radiotherapy/chemotherapy. [Time frame: At 0 week.]
• Changes (from baseline) in biochemical parameters of oxidative stress, after ozone treatment. [Time frame: At 16 weeks.]
• Differences in biochemical parameters of inflammation among patients with or without chronic pain induced by radiotherapy/chemotherapy. [Time frame: At 0 week.]
• Changes (from baseline) in biochemical parameters of inflammation, after ozone treatment. [Time frame: At 16 weeks.]

Eligibility criteria

Inclusion criteria

• Adult women (>=18 years old) with gynecological tumors treated with radiotherapy-chemotherapy.
• Cancer disease is stable or in remission.
• Life expectancy > = 6 months.
• Patients included in the group of patients with pelvic pain must have a clinical, radiological, endoscopic, or histopathological diagnosis that their pain is not secondary to the oncological process.
• Patients included in the group of patients with pelvic pain must have pain for >= 3 months duration, with an intensity >= 3 on the Visual Analog Scale (VAS), or classified as toxicity >= Grade-2 of the CTCAE v.5.0 of the National Cancer Institute of the USA.
• Signed and dated informed consent specific to this study.

Exclusion criteria

• Age < 18 years old.
• Severe psychiatric disorders.
• Inability to complete the quality of life questionnaires.
• Active neoplasia requiring recent initiation (< 3 months) of systemic or local treatment.
• Life expectancy (for any reason) < 6 months.
• Failure to meet all inclusion criteria

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Case-control

Study locations

Spain · 1 center

• Hospital Universitario de Gran Canaria Dr. Negrín, (FIISC) — Las Palmas

Publications

• Tricarico G, Travagli V. The Relationship between Ozone and Human Blood in the Course of a Well-Controlled, Mild, and Transitory Oxidative Eustress. Antioxidants (Basel). 2021 Dec 4;10(12):1946. doi: 10.3390/antiox10121946. PMID 34943049
• Hidalgo-Tallon FJ, Torres-Morera LM, Baeza-Noci J, Carrillo-Izquierdo MD, Pinto-Bonilla R. Updated Review on Ozone Therapy in Pain Medicine. Front Physiol. 2022 Feb 23;13:840623. doi: 10.3389/fphys.2022.840623. eCollection 2022. PMID 35283802
• Galie M, Covi V, Tabaracci G, Malatesta M. The Role of Nrf2 in the Antioxidant Cellular Response to Medical Ozone Exposure. Int J Mol Sci. 2019 Aug 17;20(16):4009. doi: 10.3390/ijms20164009. PMID 31426459
• Clavo B, Santana-Rodriguez N, Llontop P, Gutierrez D, Ceballos D, Mendez C, Rovira G, Suarez G, Rey-Baltar D, Garcia-Cabrera L, Martinez-Sanchez G, Fiuza D. Ozone Therapy in the Management of Persistent Radiation-Induced Rectal Bleeding in Prostate Cancer Patients. Evid Based Complement Alternat Med. 2015;2015:480369. doi: 10.1155/2015/480369. Epub 2015 Aug 18. PMID 26357522
• Clavo B, Rodriguez-Esparragon F, Rodriguez-Abreu D, Martinez-Sanchez G, Llontop P, Aguiar-Bujanda D, Fernandez-Perez L, Santana-Rodriguez N. Modulation of Oxidative Stress by Ozone Therapy in the Prevention and Treatment of Chemotherapy-Induced Toxicity: Review and Prospects. Antioxidants (Basel). 2019 Nov 26;8(12):588. doi: 10.3390/antiox8120588. PMID 31779159
• Clavo B, Navarro M, Federico M, Borrelli E, Jorge IJ, Ribeiro I, Rodriguez-Melcon JI, Carames MA, Santana-Rodriguez N, Rodriguez-Esparragon F. Long-Term Results with Adjuvant Ozone Therapy in the Management of Chronic Pelvic Pain Secondary to Cancer Treatment. Pain Med. 2021 Sep 8;22(9):2138-2141. doi: 10.1093/pm/pnaa459. No abstract available. PMID 33738491
• Clavo B, Navarro M, Federico M, Borrelli E, Jorge IJ, Ribeiro I, Rodriguez-Melcon JI, Carames MA, Santana-Rodriguez N, Rodriguez-Esparragon F. Ozone Therapy in Refractory Pelvic Pain Syndromes Secondary to Cancer Treatment: A New Approach Warranting Exploration. J Palliat Med. 2021 Jan;24(1):97-102. doi: 10.1089/jpm.2019.0597. Epub 2020 May 5. PMID 32379556
• Clavo B, Rodriguez-Abreu D, Galvan S, Federico M, Martinez-Sanchez G, Ramallo-Farina Y, Antonelli C, Benitez G, Rey-Baltar D, Jorge IJ, Rodriguez-Esparragon F, Serrano-Aguilar P. Long-term improvement by ozone treatment in chronic pain secondary to chemotherapy-induced peripheral neuropathy: A preliminary report. Front Physiol. 2022 Aug 30;13:935269. doi: 10.3389/fphys.2022.935269. eCollection 202 PMID 36111149

Identifiers

NCT: NCT06816095 · 2024-192-1 · DISA'24: OA24/104 · CIGC'23/24

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗