Low-level laser therapy in treatment of chemoradiotherapy-induced mucositis in head and neck cancer: results of a randomised, triple blind, multicentre phase III trial

Florence Legouté, René-Jean Bensadoun, Valérie Seegers, Yoann Pointreau, Delphine Caron, Philippe Lang, Alain Prévost, Laurent Martin, Ulrike Schick, Benjamin Morvant, Olivier Capitain, Gilles Calais, Eric Jadaud, Florence Legouté, René-Jean Bensadoun, Valérie Seegers, Yoann Pointreau, Delphine Caron, Philippe Lang, Alain Prévost, Laurent Martin, Ulrike Schick, Benjamin Morvant, Olivier Capitain, Gilles Calais, Eric Jadaud

Abstract

Background: Low-level laser therapy (LLLT) also called Photobiomodulation therapy (PBMT) could reduce oral mucositis (OM) incidence and severity in head and neck cancer patients treated by chemoradiotherapy, however randomised data about efficacy and safety are missing with curative dose 4 J/cm2.

Methods: This phase III trial was conducted in patients with oral cavity, or oro/hypopharyngeal cancers (stage III or IV). Patients were treated by lasertherapy on OM lesions grade ≥ 2 (4 J/cm2 or placebo), during chemoradiotherapy and until recovery. Severity of OM (incidence and duration of grades ≥3) was used as primary endpoint and blindly assessed.

Results: Among 97 randomised patients, 83 patients (85.6%) could be assessed finally (erroneous inclusions, chemoradiotherapy interruptions) and 32 patients had no lasertherapy because of unreachable OM lesions. Randomisation and population characteristics (sex ratio, age, chemoradiotherapy procedures, toxicities incidence) were still comparable between the two LLLT/PBMT groups. An acute OM (grade ≥ 3) was observed in 41 patients (49.4%): 23 patients (54.8%) of the active laser group versus 18 (43.9%) in the control group (modified intend to treat, p = 0.32). Median time before occurrence of OM ≥ grade 3 in half of the patients was 8 weeks in active laser group (vs. 9 weeks in control group). However, 95% of patients exhibited a very good tolerance of LLLT/PBMT.

Conclusions: This study assessed LLLT/PBMT according to the Multinational Association of Supportive care in Cancer recommendations but lacked power. LLLT/PBMT was well tolerated with a good safety profile, which promotes its use in clinical routine for severe OM treatment.

Trial registration: ClinicalTrials.gov Identifier: NCT01772706 .

Title: Laser Mucite ORL: Effectiveness of Laser Therapy for Mucositis Induced by a Radio-chemotherapy in Head and Neck Cancer (LaserMucite). Study Start Date: October 2008. Primary Completion Date: October 2016. Responsible Party: Institut de Cancérologie de l'Ouest - Paul Papin. Principal Investigator: Eric Jadaud, M.D., Institut de Cancérologie de l'Ouest - Paul Papin.

Funding: French Ministry of Health, French national funding scheme (PHRC 2008).

Keywords: Chemoradiotherapy; Head and neck cancer; Lasertherapy; Oral mucositis; Supportive care.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flowchart. CRT: Chemoradiotherapy, LLLT: Low-Level Laser Therapy, OM: Oral Mucositis, Reasons of exclusion: - Patients without complete chemoradiotherapy, - Patients with exclusion criteria. Randomisation was still well balanced despite the exclusion of 14 patients. Only 51 patients were treated by lasertherapy (active or inactive): no imbalance was observed between the LLLT groups
Fig. 2
Fig. 2
a: Time to first occurrence of OM grade ≥ 3 – Modified intention to treat analysis. b: Time to first occurrence of OM grade ≥ 3 – Per protocol analysis. Arm A: active Lasertherapy arm - Arm B: control placebo, arm (Laser-off treatment), OM: Oral mucositis
Fig. 3
Fig. 3
Pain assesment – at the first and at the last lasertherapy session - Per protocol analysis. Arm A: active Lasertherapy arm - Arm B: control placebo arm (Laser-off treatment), VAS: Visual Analogue Scale: A numeric pain rating scale was used (0: ‘No pain’ to 10: ‘Worst pain possible’)

References

    1. Elting LS, Keefe DM, Sonis ST, Garden AS, Spijkervet FKL, Barasch A, et al. Patient-reported measurements of oral mucositis in head and neck cancer patients treated with radiotherapy with or without chemotherapy: demonstration of increased frequency, severity, resistance to palliation, and impact on quality of life. Cancer. 2008;113(10):2704–2713. doi: 10.1002/cncr.23898.
    1. Raber-Durlacher JE, Elad S, Barasch A. Oral mucositis. Oral Oncol. 2010;46(6):452–456. doi: 10.1016/j.oraloncology.2010.03.012.
    1. Elting LS, Cooksley CD, Chambers MS, Garden AS. Risk, outcomes, and costs of radiation-induced Oral mucositis among patients with head-and-neck malignancies. Int J Radiat Oncol. 2007;68(4):1110–1120. doi: 10.1016/j.ijrobp.2007.01.053.
    1. Jadaud E, Bensadoun R. Low-level laser therapy: a standard of supportive care for cancer therapy-induced oral mucositis in head and neck cancer patients? Laser Ther. 2012;21(4):297–303. doi: 10.5978/islsm.12-RE-01.
    1. Trotti A, Bellm LA, Epstein JB, Frame D, Fuchs HJ, Gwede CK, et al. Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother Oncol. 2003;66(3):253–262. doi: 10.1016/S0167-8140(02)00404-8.
    1. Van den Bogaert W, Van der Leest A, Rijnders A, Delaere P, Thames H, van der Schueren E. Does tumor control decrease by prolonging overall treatment time or interrupting treatment in laryngeal cancer? Radiother Oncol. 1995;36(3):177–182. doi: 10.1016/0167-8140(95)01597-A.
    1. Antunes HS, Herchenhorn D, Small IA, Araújo CMM, Viégas CMP, Cabral E, et al. Phase III trial of low-level laser therapy to prevent oral mucositis in head and neck cancer patients treated with concurrent chemoradiation. Radiother Oncol J Eur Soc Ther Radiol Oncol. 2013;109(2):297–302. doi: 10.1016/j.radonc.2013.08.010.
    1. Antunes HS, de AAM, Bouzas LF da S, Adão CAE, Pinheiro CT, Mayhe R, et al. Low-power laser in the prevention of induced oral mucositis in bone marrow transplantation patients: a randomized trial. Blood. 2007;109(5):2250–2255. doi: 10.1182/blood-2006-07-035022.
    1. Carvalho PA, Jaguar GC, Pellizzon AC, Prado JD, Lopes RN, Alves FA. Evaluation of low-level laser therapy in the prevention and treatment of radiation-induced mucositis: a double-blind randomized study in head and neck cancer patients. Oral Oncol. 2011;47(12):1176–1181. doi: 10.1016/j.oraloncology.2011.08.021.
    1. Cowen D, Tardieu C, Schubert M, Peterson D, Resbeut M, Faucher C, et al. Low energy Helium-Neon laser in the prevention of oral mucositis in patients undergoing bone marrow transplant: results of a double blind randomized trial. Int J Radiat Oncol Biol Phys. 1997;38(4):697–703. doi: 10.1016/S0360-3016(97)00076-X.
    1. Gautam AP, Fernandes DJ, Vidyasagar MS, Maiya AG, Vadhiraja BM. Low level laser therapy for concurrent chemoradiotherapy induced oral mucositis in head and neck cancer patients – a triple blinded randomized controlled trial. Radiother Oncol. 2012;104(3):349–354. doi: 10.1016/j.radonc.2012.06.011.
    1. Genot-Klastersky MT, Klastersky J, Awada F, Awada A, Crombez P, Martinez MD, et al. The use of low-energy laser (LEL) for the prevention of chemotherapy- and/or radiotherapy-induced oral mucositis in cancer patients: results from two prospective studies. Support Care Cancer. 2008;16(12):1381–1387. doi: 10.1007/s00520-008-0439-8.
    1. Kuhn A, Porto FA, Miraglia P, Brunetto AL. Low-level infrared laser therapy in chemotherapy-induced Oral mucositis: a randomized placebo-controlled trial in children. J Pediatr Hematol Oncol. 2009;31(1):33–37. doi: 10.1097/MPH.0b013e318192cb8e.
    1. de LAG, Antequera R, Peres MPS de M, Snitcosky IML, Federico MHH, Villar RC. Efficacy of low-level laser therapy and aluminum hydroxide in patients with chemotherapy and radiotherapy-induced oral mucositis. Braz Dent J. 2010;21(3):186–192. doi: 10.1590/S0103-64402010000300002.
    1. Schubert MM, Eduardo FP, Guthrie KA, Franquin J-C. Bensadoun R-JJ, Migliorati CA, et al. a phase III randomized double-blind placebo-controlled clinical trial to determine the efficacy of low level laser therapy for the prevention of oral mucositis in patients undergoing hematopoietic cell transplantation. Support care Cancer off J Multinatl Assoc. Support Care Cancer. 2007;15(10):1145–1154. doi: 10.1007/s00520-007-0238-7.
    1. Zanin T, Zanin F, Carvalhosa AA, Castro PH de S, Pacheco MT, Zanin ICJ, et al. Use of 660-nm diode laser in the prevention and treatment of human oral mucositis induced by radiotherapy and chemotherapy. Photomed Laser Surg. 2010;28(2):233–237. doi: 10.1089/pho.2008.2242.
    1. Bensadoun R-J, Nair RG. Low-level laser therapy in the prevention and treatment of cancer therapy-induced mucositis: 2012 state of the art based on literature review and meta-analysis. Curr Opin Oncol. 2012;24(4):363–370. doi: 10.1097/CCO.0b013e328352eaa3.
    1. Jenkins PA, Carroll JD. How to report low-level laser therapy (LLLT)/Photomedicine dose and beam parameters in clinical and laboratory studies. Photomed Laser Surg. 2011;29(12):785–787. doi: 10.1089/pho.2011.9895.
    1. Grégoire V, Levendag P, Ang KK, Bernier J, Braaksma M, Budach V, et al. CT-based delineation of lymph node levels and related CTVs in the node-negative neck: DAHANCA, EORTC, GORTEC, NCIC,RTOG consensus guidelines. Radiother Oncol. 2003;69(3):227–236. doi: 10.1016/j.radonc.2003.09.011.
    1. MASCC ISOO. Recommandations MASCC/ISOO de bonnes pratiques cliniques basées Sur des preuves pour les mucites induites par Une thérapie anticancéreuse. In: ©multinational Association of Supportive Care in Cancer (MASCC) and the International Society of Oral Oncology (ISOO) all rights reserved worldwide • publication/adaptation of these guidelines in any form requires prior permission from the MASCC/ISOO mucositis study group • supportive care makes excellent Cancer care possible • pg 7. 2014.
    1. Zecha JAEM, Raber-Durlacher JE, Nair RG, Epstein JB, Elad S, Hamblin MR, et al. Low-level laser therapy/photobiomodulation in the management of side effects of chemoradiation therapy in head and neck cancer: part 2: proposed applications and treatment protocols. Support Care Cancer. 2016;24(6):2793–2805. doi: 10.1007/s00520-016-3153-y.
    1. Migliorati C, Hewson I, Lalla RV, Antunes HS, Estilo CL, Hodgson B, et al. Systematic review of laser and other light therapy for the management of oral mucositis in cancer patients. Support Care Cancer Off J Multinatl Assoc Support Care Cancer. 2013;21(1):333–341.
    1. Sonis ST, Hashemi S, Epstein JB, Nair RG, Raber-Durlacher JE. Could the biological robustness of low level laser therapy (Photobiomodulation) impact its use in the management of mucositis in head and neck cancer patients. Oral Oncol. 2016;54:7–14. doi: 10.1016/j.oraloncology.2016.01.005.
    1. Hamblin MR, Nelson ST, Strahan JR. Photobiomodulation and Cancer: What Is the Truth? Photomed Laser Surg. 2018;36(5):241–245. doi: 10.1089/pho.2017.4401.
    1. De Sanctis V, Bossi P, Sanguineti G, Trippa F, Ferrari D, Bacigalupo A, et al. Mucositis in head and neck cancer patients treated with radiotherapy and systemic therapies: literature review and consensus statements. Crit Rev Oncol Hematol. 2016;100:147–166. doi: 10.1016/j.critrevonc.2016.01.010.
    1. Simões A, Eduardo FP, Luiz AC, Campos L, Sá PHRN, Cristófaro M, et al. Laser phototherapy as topical prophylaxis against head and neck cancer radiotherapy-induced oral mucositis: comparison between low and high/low power lasers. Lasers Surg Med. 2009;41(4):264–270. doi: 10.1002/lsm.20758.
    1. Arbabi-Kalati F, Arbabi-Kalati F, Moridi T. Evaluation of the effect of low level laser on prevention of chemotherapy-induced mucositis. Acta Med Iran. 2013;51(3):157–162.
    1. Gautam AP, Fernandes DJ, Vidyasagar MS, Maiya AG, Nigudgi S. Effect of low-level laser therapy on patient reported measures of oral mucositis and quality of life in head and neck cancer patients receiving chemoradiotherapy--a randomized controlled trial. Support Care Cancer Off J Multinatl Assoc Support Care Cancer. 2013;21(5):1421–1428.
    1. Gouvêa de Lima A, Villar RC, de Castro G, Antequera R, Gil E, Rosalmeida MC, et al. Oral mucositis prevention by low-level laser therapy in head-and-neck cancer patients undergoing concurrent chemoradiotherapy: a phase III randomized study. Int J Radiat Oncol Biol Phys. 2012;82(1):270–275. doi: 10.1016/j.ijrobp.2010.10.012.
    1. Duchosal S. Tolérance muqueuse et laser de basse énergie : la délégation aux manipulateurs en radiothérapie est-elle possible ? Cancer Radiothérapie. 2015;19(6–7):548–551. doi: 10.1016/j.canrad.2015.07.018.
    1. Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010;11(1):21–28. doi: 10.1016/S1470-2045(09)70311-0.
    1. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567–578. doi: 10.1056/NEJMoa053422.
    1. Mesía R, Rivera F, Kawecki A, Rottey S, Hitt R, Kienzer H, et al. Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol Off J Eur Soc Med Oncol. 2010;21(10):1967–1973. doi: 10.1093/annonc/mdq077.
    1. Walsh L, Gillham C, Dunne M, Fraser I, Hollywood D, Armstrong J, et al. Toxicity of cetuximab versus cisplatin concurrent with radiotherapy in locally advanced head and neck squamous cell cancer (LAHNSCC) Radiother Oncol J Eur Soc Ther Radiol Oncol. 2011;98(1):38–41. doi: 10.1016/j.radonc.2010.11.009.
    1. Sonis ST. Pathobiology of mucositis. Semin Oncol Nurs. 2004;20(1):11–15. doi: 10.1053/j.soncn.2003.10.003.
    1. Stokman MA, Sonis ST, Dijkstra PU, Burgerhof JGM, Spijkervet FKL. Assessment of oral mucositis in clinical trials: impact of training on evaluators in a multi-centre trial. Eur J Cancer. 2005;41(12):1735–1738. doi: 10.1016/j.ejca.2005.04.030.
    1. Epstein JB, Beaumont JL, Gwede CK, Murphy B, Garden AS, Meredith R, et al. Longitudinal evaluation of the oral mucositis weekly questionnaire-head and neck cancer, a patient-reported outcomes questionnaire. Cancer. 2007;109(9):1914–1922. doi: 10.1002/cncr.22620.
    1. Stiff PJ, Erder H, Bensinger WI, Emmanouilides C, Gentile T, Isitt J, et al. Reliability and validity of a patient self-administered daily questionnaire to assess impact of oral mucositis (OM) on pain and daily functioning in patients undergoing autologous hematopoietic stem cell transplantation (HSCT) Bone Marrow Transplant. 2006;37(4):393–401. doi: 10.1038/sj.bmt.1705250.
    1. Münstedt K, Momm F, Hübner J. Honey in the management of side effects of radiotherapy- or radio/chemotherapy-induced oral mucositis. A systematic review. Complement Ther Clin Pract. 2019;34:145–152. doi: 10.1016/j.ctcp.2018.11.016.

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