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Randomized placebo-controlled phase II trial of high-dose melatonin mucoadhesive oral gel for the prevention and treatment of oral mucositis in patients with head and neck cancer undergoing radiation therapy concurrent with systemic treatment

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Abstract

Purpose

The objective of this trial was to evaluate the safety and efficacy of melatonin oral gel mouthwashes in the prevention and treatment of oral mucositis (OM) in patients treated with concurrent radiation and systemic treatment for head and neck cancer.

Methods

Randomized, phase II, double-blind, placebo-controlled trial (1:1 ratio) of 3% melatonin oral gel mouthwashes vs. placebo, during IMRT (total dose ≥ 66 Gy) plus concurrent Q3W cisplatin or cetuximab. Primary endpoint: grade 3–4 OM or Severe Oral Mucositis (SOM) incidence by RTOG, NCI, and a composite RTOG-NCI scales. Secondary endpoints: SOM duration and grade 2–4 OM or Ulcerative Oral Mucositis (UOM) incidence and duration.

Results

Eighty-four patients were included in the study. Concurrent systemic treatments were cisplatin (n = 54; 64%) or cetuximab (n = 30; 36%). Compared with the placebo arm, RTOG-defined SOM incidence was numerically lower in the 3% melatonin oral gel arm (53 vs. 64%, P = 0.36). In patients treated with cisplatin, assessed by the RTOG-NCI composite scale, both SOM incidence (44 vs. 78%; P = 0.02) and median SOM duration (0 vs. 22 days; P = 0.022) were significantly reduced in the melatonin arm. Median UOM duration assessed by the RTOG-NCI scale was also significantly shorter in the melatonin arm (49 vs. 73 days; P = 0.014). Rate of adverse events and overall response rate were similar between the two arms.

Conclusions

Treatment with melatonin oral gel showed a consistent trend to lower incidence and shorter SOM duration and shorter duration of UOM. These results warrant further investigation in phase III clinical trial.

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Funding

Spherium Biomed, S.L.U. (Ferrer). Spain.

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Authors and Affiliations

Authors

Contributions

AL, RM and GE conceived the study. AL, RM, CT, PG, RB and VV contributed to study design. AL, RM, JM, JR, NF, JGM, RM, IP, ML, MGVM, LC and JG recruited patients, treated patients and collected the data. AL, RM, CT, PG, RB and VV analyzed and interpret the data. AL, RM and VV wrote the first draft of the manuscript. All authors read and contributed to the final version.

Corresponding author

Correspondence to A. Lozano.

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Conflict of interest

Pedro Grima Ph.D., Ramón Bosser Ph.D., Cristina Tarragó Ph.D. were workers at Spherium Biomed, S.L.U. (Ferrer) when this trial was designed, the patients were enrolled, and the data was analyzed. The other authors declared no conflict of interest.

Ethical approval

The study was approved by the Institutional Review Board of all the participant centers and was conducted in accordance with the Declaration of Helsinki as adopted by the World Medical Association in the Fortaleza-2013 meeting.

Informed consent

All patients provided written informed consent before starting any of the procedures of the study.

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Lozano, A., Marruecos, J., Rubió, J. et al. Randomized placebo-controlled phase II trial of high-dose melatonin mucoadhesive oral gel for the prevention and treatment of oral mucositis in patients with head and neck cancer undergoing radiation therapy concurrent with systemic treatment. Clin Transl Oncol 23, 1801–1810 (2021). https://doi.org/10.1007/s12094-021-02586-w

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  • DOI: https://doi.org/10.1007/s12094-021-02586-w

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