An Open Label Study Comparing Photobiomodulation Therapy to Cryotherapy in Patients at High Risk for Drug-Induced Oral Mucositis
Authors: Nakov Philipp , Lando Ruth , Schroeder Torsten , Jost Lasse , Miarka Lauritz , Baden David , Baden Cornelia , Kakavand Nassim , Restrepo-Salamaca Enrique , Kloth Alina , Albici Anca Maria , Kramp Laura Jane , Brachaczek Felix , Feuerborn Julia , Haack Carsten , Schmalz Claudia , Busch Stephanie , Stoelzel Friedrich , Baldus Claudia D , Fransecky Lars 
Published: December 2023

Background and rationale
Oral mucositis (OM) is one of the most common side effects of chemotherapy and may lead to weight loss and increased risk for infection ultimately impairing overall survival.
Evaluated options for mucositis prophylaxis in patients receiving a high-dose chemotherapy include oral cryotherapy (CT) and photobiomodulation therapy (PBMT) using laser diodes to reduce incidence and severity of OM. However, standards of mucositis prophylaxis in German hospitals differ substantially. While CT has been standard of care in melphalan treated patients, the German guidelines for supportive oncology do not recommend the use of PBMT for patients receiving high-dose chemotherapy. Several clinical trials have demonstrated the beneficial effect of PBMT, however, no randomized clinical trials (RCT) exist to compare the efficacy of oral CT versus PBMT.
Study design
This is a single-center, open-label, randomized, two-arm interventional trial to evaluate the efficacy of PBMT and CT as prophylaxis of OM in patients with hematological malignancies receiving high-dose chemotherapy as part of a conditioning regimen prior to hematopoietic cell transplantation (HCT) or high-dose methotrexate (MTX, defined as ≥ 500 mg/m 2). Randomization will occur 1:1, stratified according to conditioning regimen/chemotherapy protocol. The primary endpoint of the trial is rate of severe OM as assessed by the world health organization (WHO) OM grading scale grade 3 or higher. Key secondary endpoints include duration of OM, patient reported pain, total parenteral nutrition, opioid usage, weight loss, length of in-patient stay and overall survival.
Eligible patients randomized to receive PBMT will undergo daily laser therapy at 4 J/cm² of the oral mucosal areas most frequently affected by OM, starting on the first day of the administration of chemotherapy, until neutrophil engraftment or resolution of OM, whatever occurs first. Eligible patients randomized to oral CT will receive ice chips (IC) made from filtered tap water or flavored ice popsicles on days of chemotherapy infusions only, starting 5 min prior to chemotherapy until 30 min after the end of infusion.
Patients ≥ 18 years of age, receiving therapies with high potential to induce OM, including the conditioning regimen high-dose melphalan, carmustine/etoposide/cytarabine/melphalan (BEAM), thiotepa/etoposide/cytarabine/melphalan (TEAM), fludarabine/thiotepa/melphalan (FTM) and fludarabine/melphalan (FM) or chemotherapy protocols with high-dose MTX, are included in this trial.
The trial tests the null hypothesis (H 0) that the observed rate of severe OM with PBMT and CT prophylaxis are equal versus the alternative hypothesis (H 1) that the observed rate of severe OM differs between CT and PBMT. We estimate a rate of severe OM of 45 % in our trial population (H 0).
With a power of 80 %, a type 1 error rate of 5 %, and an expected difference in severe OM rate of 30 % considered relevant between both arms, with an expected dropout rate of 5 %, n = 86 patients should participate in the study to ensure discrimination of H 0 and H 1.
Conclusion
This study aims to compare PBMT and CT with regard to their effectiveness in the prevention of severe OM in a randomized trial for the first time. Our objective is to provide data that may guide the development of a standardized OM prophylaxis for patients undergoing high-dose chemotherapy. At the time of abstract submission, 8 patients have been randomized in the study.
Acknowledgments
This is an independent academic trial conducted under the sponsor role of the University Cancer Center Schleswig-Holstein, Germany. This study is conducted in compliance with the protocol, Good Clinical Practice (GCP), all applicable regulatory requirements and the ethical principles of the Declaration of Helsinki.