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A pro-oxidant combination of resveratrol and copper reduces chemotherapy-related non-haematological toxicities in advanced gastric cancer: results of a prospective open label phase II single-arm study (RESCU III study)

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Abstract

It has been reported that chemotherapy toxicity is primarily not due to the drugs themselves, but is caused by cell-free chromatin particles (cfChPs) that are released from chemotherapy-induced dying cells. cfChPs from dying cells are readily internalized by healthy cells, wherein they inflict dsDNA breaks and activate inflammatory cytokines. cfChPs can be deactivated by oxygen radicals that are generated upon admixing the nutraceuticals resveratrol (R) and copper (Cu). Pre-clinical studies have shown that administration of R-Cu can reduce chemotherapy toxicity via the generation of oxygen radicals which deactivate cfChPs released from chemotherapy-induced dying cells. We investigated if R-Cu would reduce toxicity of docetaxel-based multi-agent chemotherapy in advanced gastric cancer. This single-arm phase II study was designed to assess the efficacy of orally administered R-Cu in ameliorating toxic side effects, as per National Cancer Institute Common Terminology Criteria for Adverse Events v4.03, in patients with advanced gastric cancer receiving docetaxel-based multi-agent chemotherapy. The primary objective was to reduce the proportion of patients experiencing grade ≥ 3 toxicity from 90 to 70%. Between October 2019 and April 2021, 30 patients, with a median age of 54 years, were enrolled of whom 73% were male. R-Cu treatment did not reduce the overall cumulative incidence of grade ≥ 3 toxicity (77%), or of ≥ 3 haematological toxicity (73%). However, the incidence of non-haematological toxicities comprising hand-foot syndrome (N = 4), diarrhoea (N = 3) and vomiting (N = 1) were markedly reduced (13%). Median progression-free survival (PFS) was 8 months (95% CI: 5.9–10.1), and overall survival (OS) was 16 months (95% confidence interval: 6.3–28.3). A marked reduction in non-haematological toxicities was seen in patients receiving R-Cu compared to historical data without adversely affecting PFS or OS. (292).

Clinical trial information CTRI/2019/07/020289.

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Acknowledgements

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Funding

The study was supported by Department of Atomic Energy, Government of India through its grant CTCTMC to Tata Memorial Centre awarded to IM.

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Authors and Affiliations

  1. Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India

    Vikas Ostwal, Anant Ramaswamy, Prabhat Bhargava, Sujay Srinivas, Sarika Mandavkar, Deepali Chaugule & Zoya Peelay

  2. Department of Radiodiagnosis, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India

    Akshay Baheti

  3. Translational Research Lab, Tata Memorial Centre, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Homi Bhabha National Institute, Mumbai, India

    Harshali Tandel, Vishal Kumar Jadhav & Sushma Shinde

  4. Department of Clinical Pharmacology, Tata Memorial Centre, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Homi Bhabha National Institute (HBNI), Navi Mumbai, India

    Shraddha Jadhav & Vikram Gota

  5. Professor Emeritus Department of Surgical Oncology, Tata Memorial Centre, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Homi Bhabha National Institute, Kharghar, Mumbai, Navi Mumbai, 410 210, India

    Indraneel Mittra

Authors
  1. Vikas Ostwal
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  2. Anant Ramaswamy
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  12. Shraddha Jadhav
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  13. Vikram Gota
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  14. Indraneel Mittra
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Contributions

VO contributed to concept, design, data collection, patient recruitment, data analysis and manuscript finalization, PB contributed to data collection, patient recruitment, data analysis and manuscript finalization, AR contributed to data collection, patient recruitment, data analysis and manuscript finalization, SS contributed to data collection, patient recruitment, data analysis and manuscript finalization, SM contributed to data collection, data analysis and manuscript finalization, DC contributed to data analysis and manuscript finalization, ZP contributed to data collection, data analysis and manuscript finalization, AB contributed to data analysis and manuscript finalization, HT contributed to drug dispensing, data collection, data analysis and manuscript finalization, VKJ contributed to drug dispensing, data collection, data analysis and manuscript finalization, SS contributed to data collection, data analysis and manuscript finalization, SJ contributed to drug dispensing, data collection, data analysis and manuscript finalization, VG contributed to data analysis and manuscript finalization, IM contributed to concept, design, data collection, patient recruitment, data analysis and manuscript finalization.

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Correspondence to Indraneel Mittra.

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Ostwal, V., Ramaswamy, A., Bhargava, P. et al. A pro-oxidant combination of resveratrol and copper reduces chemotherapy-related non-haematological toxicities in advanced gastric cancer: results of a prospective open label phase II single-arm study (RESCU III study). Med Oncol 40, 17 (2023). https://doi.org/10.1007/s12032-022-01862-1

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