Photobiomodulation in the management of oral mucositis for adult head and neck cancer patients receiving irradiation: the LiTEFORM RCT
Authors: Nugent Michael , Bryant Valerie , Butcher Chrissie , Fisher Holly , Gill Sean , Goranova Rebecca , Hiu Shaun , Lindley Lyndsay , O’Hara James , Oluboyede Yemi , Patterson Joanne , Rapley Tim , Robinson Tomos , Rousseau Nikki , Ryan Vicky , Shanmugasundaram Ramkumar , Sharp Linda , Smith Whelan Ruby , Stocken Deborah D , Ternent Laura , Wilson Janet , Walker Jenn 
Published: December 2022

Background
Oral mucositis is a debilitating and painful complication of head and neck cancer irradiation that is characterised by inflammation of the mucous membranes, erythema and ulceration. Oral mucositis affects 6000 head and neck cancer patients per year in England and Wales. Current treatments have not proven to be effective. International studies suggest that low-level laser therapy may be an effective treatment.

Objectives
To assess the clinical effectiveness and cost-effectiveness of low-level laser therapy in the management of oral mucositis in head and neck cancer irradiation. To identify barriers to and facilitators of implementing low-level laser therapy in routine care.

Design
Placebo-controlled, individually randomised, multicentre Phase III superiority trial, with an internal pilot and health economic and qualitative process evaluations. The participants, outcome assessors and therapists were blinded.

Setting
Nine NHS head and neck cancer sites in England and Wales.

Participants
A total of 87 out of 380 participants were recruited who were aged ≥ 18 years and were undergoing head and neck cancer irradiation with ≥ 60 Gy.

Intervention
Random allocation (1 : 1 ratio) to either low-level laser therapy or sham low-level laser therapy three times per week for the duration of irradiation. The diode laser had the following specifications: wavelength 660 nm, power output 75 mW, beam area 1.5 cm2, irradiance 50 mW/cm2, exposure time 60 seconds and fluence 3 J/cm2. There were 20–30 spots per session. Sham low-level laser therapy was delivered in an identical manner.

Main outcome measure
The mean Oral Mucositis Weekly Questionnaire-Head and Neck Cancer score at 6 weeks following the start of irradiation. Higher scores indicate a worse outcome.

Results
A total of 231 patients were screened and, of these, 87 were randomised (low-level laser therapy arm, n = 44; sham arm, n = 43). The mean age was 59.4 years (standard deviation 8.8 years) and 69 participants (79%) were male. The mean Oral Mucositis Weekly Questionnaire-Head and Neck Cancer score at 6 weeks was 33.2 (standard deviation 10) in the low-level laser therapy arm and 27.4 (standard deviation 13.8) in the sham arm.

Limitations
The trial lacked statistical power because it did not meet the recruitment target. Staff and patients willingly participated in the trial and worked hard to make the LiTEFORM trial succeed. However, the task of introducing, embedding and sustaining new low-level laser therapy services into a complex care pathway proved challenging. Sites could deliver low-level laser therapy to only a small number of patients at a time. The administration of low-level laser therapy was viewed as straightforward, but also time-consuming and sometimes uncomfortable for both patients and staff, particularly those staff who were not used to working in a patient’s mouth.

Conclusions
This trial had a robust design but lacked power to be definitive. Low-level laser therapy is relatively inexpensive. In contrast with previous trials, some patients found low-level laser therapy sessions to be difficult. The duration of low-level laser therapy sessions is, therefore, an important consideration. Clinicians experienced in oral cavity work most readily adapt to delivering low-level laser therapy, although other allied health professionals can be trained. Blinding the clinicians delivering low-level laser therapy is feasible. There are important human resource, real estate and logistical considerations for those setting up low-level laser therapy services.

Future work
Further well-designed randomised controlled trials investigating low-level laser therapy in head and neck cancer irradiation are needed, with similar powered recruitment targets but addressing the recruitment challenges and logistical findings from this research.

Trial registration
This trial is registered as ISRCTN14224600.

Funding
This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 46. See the NIHR Journals Library website for further project information.