Radiation-induced oral mucositis (RIOM) is one of the most debilitating toxicities seen in head-and-neck cancer (HNC) care. Up to 90 % of patients who receive conventionally fractionated external-beam radiotherapy (RT) combined with cisplatin develop visible ulceration, spontaneous bleeding, or severe odynophagia that compromises nutrition and speech, prolongs unplanned hospitalisation, and may even force breaks in RT that lower loco-regional tumour control. [1] Severe mucositis carries direct economic costs, but its greatest burden is personal: in meta-analyses, pain scores rise by 4–6 points on a 10-point visual analogue scale, opioid use at least doubles, and quality-of-life indices fall precipitously. [2]

Retrospective series show that the first erythematous lesions of RIOM typically appear when the cumulative mucosal dose reaches 20–30 Gy; ulceration (WHO grade ≥ 3) accelerates above 50 Gy and peaks around week five of a conventional 60–70 Gy course. Concomitant cisplatin or cetuximab, altered-fractionation schedules, and the absence of a smoking history are independent predictors of earlier, deeper ulceration. [3]

A five-phase model given by Sales et al. succinctly captures the biology of RIOM:

• Initiation: RT generates free radicals within milliseconds, directly damaging DNA in basal epithelial cells and endothelial cells and triggering a burst of mitochondrial and lysosomal reactive oxygen species (ROS).
• Primary damage response: ROS activate nuclear factor-κB (NF-κB) and other redox-sensitive pathways, setting off a transcriptional cascade dominated by TNF-α, IL-1β, IL-6, and cyclo-oxygenase-2.
• Signal amplification: Pro-inflammatory cytokines recruit macrophages and neutrophils that release further ROS and proteases, magnifying tissue injury.
• Ulceration: Frank breakdown of the epithelium exposes submucosa, creating a polymicrobial biofilm that deepens inflammation.
• Healing: When RT stops or epithelial repopulation overtakes injury, keratinocytes proliferate, angiogenesis restores vascularity, and fibroblasts remodel extracellular matrix.

Any intervention that interferes with oxidative stress, inflammatory signalling, apoptosis, or proliferative recovery can theoretically moderate one or more of these stages. [4]

Low-level laser therapy (LLLT) involves delivering non-thermal red or near-infra-red light (∼600–1060 nm) at energy densities that trigger a biological response without raising tissue temperature above 41 °C. Biophysical mechanisms of healing with LLLT are as follows:

• Mitochondrial photoreception: Cytochrome-c oxidase (CcO), the terminal enzyme of the electron-transport chain, absorbs photons strongly at 620–680 nm and 760–940  Photo-excitation accelerates electron transfer, transiently elevating proton-motive force and ATP production. [5,6]
• Redox and nitric-oxide signalling: Stochastic increases in mitochondrial ROS and nitric oxide act as second messengers, activating antioxidant defences (Nrf2/Keap1), promoting vasodilation, and modulating NF-κB to dampen excessive inflammation. [5]
• Growth-factor induction: LLLT up-regulates transforming growth factor-β, vascular endothelial growth factor, and fibroblast growth factors, enhancing re-epithelialisation, collagen deposition, and angiogenesis.
• Analgesia: LLLT, when given to a peripheral nerve, down-regulates transient-receptor-potential channels and bradykinin receptors and promotes endogenous opioid release, explaining rapid pain relief often observed within 24 
• Immunomodulation: Ex vivo and in vivo studies demonstrate reduced salivary and serum IL-6 and TNF-α after LLLT sessions during chemoradiation, aligning with clinical observations of milder erythema and smaller ulcer diameter. [4]

The biphasic (Arndt-Schulz) dose–response is critical: fluences of 1–6 J cm² generally stimulate repair, whereas doses above ≈10 J cm² may inhibit cell cycling.

Modern LLLT devices typically use:

The Multinational Association of Supportive Care in Cancer–International Society of Oral Oncology (MASCC/ISOO) 2020 update distilled thousands of publications into five “ready-for-clinic” protocols. For example, for RT-only HNC patients, it recommends 632.8 nm, 24 mW cm², 125 s per point, 3 J cm² over 12 intra-oral sites each treatment day throughout radiation. [7]

LiTEFORM trial (UK, 2022) was conducted wherein 87 adults (≥60 Gy RT) were randomised to 660 nm LLLT (75 mW, 1.5 cm², 60 s, 3 J cm², three times weekly) or sham. Mean Oral Mucositis Weekly Questionnaire scores at week 6 were found to be lower in the active arm (p = 0.03). [8] In an Indian trial, 221 patients receiving cisplatin-based chemoradiotherapy were block-randomised to He-Ne laser (632.8 nm, 3 J per point, 5 sessions/week) or sham. Severe mucositis (RTOG grade 3–4) fell from 66 % to 29 %, opioid use halved, and unscheduled RT breaks dropped from 20 % to <5 %. [2]

A 2024 meta-analysis pooled 14 RCTs (869 patients): relative risk (RR) of any mucositis from week 2 onward was 0.49–0.77 in the LLLT arms; severe mucositis fell from week 3 onward. He-Ne or InGaAlP lasers at 10–25 mW delivered the most consistent benefit. [9] Earlier reviews (2020, 30 RCTs) reported similar prophylactic efficacy with pooled RR of 0.40 for grade 3–4 oral mucositis and confirmed a shorter duration of ulcers when LLLT was started after lesions appeared. [10]

A 2025 single-blind trial treated grade 3–4 oral mucositis with 810 nm, 200 mW, 6 J cm² diode LLLT once daily for four consecutive days. Pain decreased by ≈3 points on day 4 versus diphenhydramine/antacid rinse, and ulcer size diminished significantly at one week, though the month-one difference waned. [11] Similar findings populate smaller series in stem-cell transplant cohorts, with rapid analgesia and faster epithelial closure, but a ceiling effect is seen as haematologic recovery dictates ultimate healing. To summarise, across prevention and treatment settings, the number of sessions needed to avert one case of grade ≥ 3 RIOM hovers around 5–8, while that needed to achieve clinically meaningful pain reduction is ≈3.

Safety and Oncologic Considerations

No acute or late adverse events attributable to LLLT have been reported. Concerns about tumour stimulation arise from in-vitro data showing red-light activation of pro-survival pathways in malignant cell lines; however, long-term follow-up of LLLT-treated HNC survivors has not demonstrated any local recurrence rates. [7] Contra-indications are relative and include uncontrolled diabetes when light penetration might mask infection under necrotic slough, or photosensitive porphyrias. Eye protection is mandatory for operator and patient.

To conclude, LLLT has progressed from bench curiosity to mainstream supportive-care modality over two decades. High-level evidence demonstrates that properly dosed LLLT reduces the incidence, severity, and duration of RIOM, mitigates pain, and maintains nutrition without interrupting curative RT courses. Mechanistically, it tempers the oxidative-inflammatory cascade while energising epithelial progenitors, offering a rational counter to the five-phase mucositis model.

Frequently Asked Questions

Q1. What is RIOM in head-and-neck cancer treatment?

RIOM refers to radiation-induced oral mucositis, a painful condition affecting the mouth lining during radiotherapy.

Q2. How common is oral mucositis in patients receiving RT and cisplatin?

Up to 90% of patients may develop it during treatment.

Q3. When do initial symptoms of RIOM typically appear?

Symptoms begin when the cumulative mucosal radiation dose reaches 20–30 Gy.

Q4. What role does LLLT play in RIOM management?

LLLT reduces pain, severity, and duration of mucositis without interrupting cancer treatment.

Q5. What is the working mechanism of LLLT?

LLLT works via mitochondrial stimulation, redox signalling, and growth-factor induction.

Q6. Are there any risks associated with LLLT use in cancer patients?

No acute or late side effects have been reported; eye protection is advised.

Q7. What are the recommended LLLT parameters in RT-only HNC?

Typical settings include 632.8 nm wavelength, 3 J/cm² fluence, and intra-oral application.

Q8. Is LLLT effective in Indian clinical settings?

Yes, Indian trials report significant reductions in severe mucositis and opioid use.

Q9. When is LLLT most effective — before or after mucositis starts?

It is effective in both prevention and treatment when dosed appropriately.

Q10. Does LLLT increase the risk of cancer recurrence?

Current evidence does not show any increase in local recurrence due to LLLT.

References

• Liu S, Zhao Q, Zheng Z, Liu Z, Meng L, Dong L, Jiang X. Status of Treatment and Prophylaxis for Radiation-Induced Oral Mucositis in Patients With Head and Neck Cancer. Front Oncol. 2021 Mar 18;11:642575. doi: 10.3389/fonc.2021.642575. PMID: 33816293; PMCID: PMC8013721.
• 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. Radiotherapy and Oncology. 2012 Sep 1;104(3):349-54.
• Sunaga T, Nagatani A, Fujii N, Hashimoto T, Watanabe T, Sasaki T. The association between cumulative radiation dose and the incidence of severe oral mucositis in head and neck cancers during radiotherapy. Cancer Rep (Hoboken). 2021 Apr;4(2):e1317. doi: 10.1002/cnr2.1317. Epub 2020 Dec 9. PMID: 33295153; PMCID: PMC8451373.
• Sales PV, Godói IP, Brito GA, Leitão RC, Araújo AA, Medeiros CA. Mechanisms of photobiomodulation therapy in treating and preventing antineoplastic-induced oral mucositis: a systematic review. Acta Cirúrgica Brasileira. 2025 Mar 31;40:e403125.
• El Mobadder M, Farhat F, El Mobadder W, Nammour S. Photobiomodulation Therapy in the Treatment of Oral Mucositis, Dysphagia, Oral Dryness, Taste Alteration, and Burning Mouth Sensation Due to Cancer Therapy: A Case Series. Int J Environ Res Public Health. 2019 Nov 15;16(22):4505. doi: 10.3390/ijerph16224505. PMID: 31731594; PMCID: PMC6888207.
• Cronshaw M, Parker S, Anagnostaki E, Mylona V, Lynch E, Grootveld M. Photobiomodulation and oral mucositis: a systematic review. Dentistry journal. 2020 Aug 5;8(3):87.
• Elad S, Cheng KKF, Lalla RV, Yarom N, Hong C, Logan RM, Bowen J, Gibson R, Saunders DP, Zadik Y, Ariyawardana A, Correa ME, Ranna V, Bossi P; Mucositis Guidelines Leadership Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO). MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. 2020 Oct 1;126(19):4423-4431. doi: 10.1002/cncr.33100. Epub 2020 Jul 28. Erratum in: Cancer. 2021 Oct 1;127(19):3700. doi: 10.1002/cncr.33549. PMID: 32786044; PMCID: PMC7540329.
• Nugent M, Bryant V, Butcher C, Fisher H, Gill S, Goranova R, Hiu S, Lindley L, O'Hara J, Oluboyede Y, Patterson J, Rapley T, Robinson T, Rousseau N, Ryan V, Shanmugasundaram R, Sharp L, Smith Whelan R, Stocken DD, Ternent L, Wilson J, Walker J. Photobiomodulation in the management of oral mucositis for adult head and neck cancer patients receiving irradiation: the LiTEFORM RCT. Health Technol Assess. 2022 Dec;26(46):1-172. doi: 10.3310/UWNB3375. PMID: 36484364; PMCID: PMC9761526.
• Shen B, Zhou Y, Wu D, Liu J. Efficacy of photobiomodulation therapy in the management of oral mucositis in patients with head and neck cancer: A systematic review and meta-analysis of randomized controlled trials. Head Neck. 2024 Apr;46(4):936-950. doi: 10.1002/hed.27655. Epub 2024 Jan 24. PMID: 38265122.
• Peng J, Shi Y, Wang J, Wang F, Dan H, Xu H, Zeng X. Low-level laser therapy in the prevention and treatment of oral mucositis: a systematic review and meta-analysis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2020 Oct;130(4):387-397.e9. doi: 10.1016/j.oooo.2020.05.014. Epub 2020 Jun 5. PMID: 32624448.
• Barati S, Motevasseli S, Saedi HS, Amiri P, Fekrazad R. Effectiveness of Photobiomodulation (low-level laser therapy) on treatment of oral mucositis (OM) induced by chemoradiotherapy in head and neck cancer patients. J Photochem Photobiol B. 2025 Mar;264:113115. doi: 10.1016/j.jphotobiol.2025.113115. Epub 2025 Jan 26. PMID: 39889324.

Author

Dr. Anushka Pillai (PT)

Ms. Uttara Venkatkrishnan, BPT-II semester IV