Radiotherapy for ENT cancers: the challenge of severe mucositis

Radiation-induced oral mucositis (RIOM) is one of the most critical dose-limiting toxicities in head and neck oncology, affecting 90 to 100% of patients undergoing concomitant chemo-radiotherapy. Characterized by mucosal inflammation and ulceration starting at 20 Gy, it reaches its peak severity (Grade 3+) at cumulative doses of 66-70 Gy. Beyond intense pain and dysphagia, these lesions often compromise the continuity of oncological treatment. Current standard of care (SOC), primarily based on benzydamine, remains essentially symptomatic, highlighting the need for more robust therapeutic alternatives.

Objectives and hypotheses: the Siddha integrative approach

This phase II, randomized, controlled superiority clinical trial (n=160) evaluates the efficacy of a protocol derived from Siddha medicine as an adjuvant to conventional care. The study compares a group receiving SOC alone (benzydamine mouthwash 6x/day) to an intervention group combining SOC with Siddha formulations: Thiripala Chooranam mouthwash and topical application of Gungiliya Vennai, administered three times daily.

The main hypothesis is that this integrative approach significantly reduces the proportion of severe RIOM according to the RTOG scale. The researchers also postulate a marked decrease in pain intensity (VAS score), a reduction in the use of higher-step analgesics and, in fine, a decrease in radiotherapy interruptions attributable to mucosal toxicity.

Study design and protocol

This study is designed as a phase II, randomized, controlled, superiority clinical trial with two parallel groups. The objective is to evaluate the efficacy of Siddha formulations as an adjunct to standard of care (SOC) in reducing the severity of radiation-induced oral mucositis (RIOM) in patients treated for head and neck cancers.

• Population: 160 participants in total, equally divided with 80 subjects per arm. Patients present with carcinomas of the oral cavity or oropharynx.
• Experimental groups:
  • Control Arm (SOC): Use of a benzydamine mouthwash, 6 times a day.
  • Intervention Arm: SOC combined with the Siddha regimen including Thiripala Chooranam (TPC) mouthwash and topical application of Gungiliya Vennai (GV), 3 times a day.
• Clinical evaluations: Weekly follow-up is provided by oncologists to monitor the evolution of the mucosa.
• Outcome measures: The primary endpoint is the severity of RIOM assessed via the RTOG scale. Secondary endpoints include the WHO scale for mucositis, the visual analogue scale (VAS) for pain, as well as analgesic consumption according to the WHO scale.

Preliminary data and clinical evidence

Although the phase II trial is currently ongoing (n=160), data from a preliminary case series (n=7) and previous clinical studies provide performance indicators for the Siddha protocol combining Thiripala Chooranam (TPC) mouthwash and topical application of Gungiliya Vennai (GV).

The authors also report evidence from previous studies integrated into their rationale:

• Sruthi et al. : TPC mouthwash demonstrated a significant reduction in oral pain in patients with head and neck cancers compared to chlorhexidine gluconate.
• Suresh et al. : A significantly lower incidence of intolerable mucositis was observed with TPC compared to povidone-iodine.
• Bhat et al. : Animal models have shown that the GV formulation significantly accelerated tissue regeneration and skin repair.

Dynamics of MRONJ and study objectives

The cited Indian clinical literature indicates that radiation-induced oral mucositis (RIOM) follows a precise dose-dependent progression: onset at approximately 20 Gy, extension at 30 Gy, and peak severity (Grade 3) reached at cumulative doses of 66 to 70 Gy. The current trial includes patients receiving a total dose of 55 to 72 Gy over 4 to 7 weeks.

The ongoing phase II study compares two arms (n=80 per group):

• Control Group: Standard of care (SOC) including benzydamine mouthwash (6x/day).
• Intervention Group: SOC + Siddha protocol (TPC and GV 3x/day).

The primary objective is to reduce the incidence of severe forms of RIOM, as assessed by the RTOG scale. Secondary criteria include pain reduction (minimum 2 points on the VAS scale) and the de-escalation of analgesic use according to the WHO three-step protocol.

A promising Siddha synergy to address the burden of mucositis

Preliminary data reported in this protocol suggest a potential paradigm shift in the management of radiation-induced oral mucositis (RIOM). While standard of care (SOC) remains essentially symptomatic, the integration of Thiripala Chooranam (TPC) and Gungiliya Vennai (GV) directly targets tissue regeneration. Results from a previous case series cited by the authors show a mean reduction of 5 points on the VAS scale and a two-grade improvement (WHO), figures that are clinically significant for a pathology whose severity peaks between 66 and 70 Gy. For the practitioner, such a reduction in pain and inflammation promotes therapeutic compliance and limits interruptions in oncological treatment.

Compared to alternatives such as palifermin — the only FDA-approved drug but expensive and offering only a 30% reduction in severe mucositis — this Siddha approach stands out for its accessibility and safety profile. TPC and GV act synergistically to modulate inflammation and accelerate mucosal healing, whereas conventional benzydamine mouthwashes often provide only temporary relief. Systematic intervention as soon as the critical threshold for RIOM onset is reached (approximately 20 Gy) could thus prevent escalation toward dose-limiting toxicity grades.

However, the study has the limitations inherent to a Phase II trial. With a sample of 160 participants, the statistical power to validate efficacy across all subgroups (radiotherapy alone vs. chemoradiotherapy) will need to be confirmed by the final results. Although TPC and GV formulations are traditionally used, their integration into a standard care protocol requires a rigorous long-term safety evaluation. As it stands, these data support the value of an integrative strategy: securing the mucosal barrier to ensure the continuity of curative treatment.

Summary of results

This phase II trial (n=160), currently underway, evaluates the efficacy of a Siddha protocol combining Thiripala Chooranam mouthwashes and the application of Gungiliya Vennai as an adjunct to standard benzydamine treatment. Preliminary data from a documented case series (n=7) showed a mean reduction of 5 points in pain on the VAS scale and a 2-grade improvement in mucositis on the WHO scale within 48 days.

In concrete terms, for the practitioner:

• Monitor the critical threshold: Severe radiation mucositis (Grade 3) typically peaks between 66 and 70 Gy; anticipation through rigorous mucosal care starting at 20 Gy is crucial to avoid interruptions in oncological treatment.
• Evaluate the integrative approach: The addition of phytotherapeutic formulations (Triphala) to standard anti-inflammatories could offer better tissue regeneration and a reduction in the use of level 3 analgesics.
• Target mucosal healing: Unlike benzydamine which targets inflammation, components such as Shorea robusta resin directly aim for epithelial repair.

Technical lexicon

Radiation-induced oral mucositis (RIOM): Severe inflammatory and ulcerative complication of the oral mucosa, generally occurring 5 to 7 days after the start of radio-chemotherapy in patients treated for upper aerodigestive tract cancers.

RTOG (Radiation Therapy Oncology Group) Scale: Standardized clinical grading system used to assess the severity of radiation-induced acute tissue reactions, constituting the primary endpoint in this study.

Thiripala Chooranam (TPC): Polyherbal formulation from Siddha medicine combining Terminalia chebula, Phyllanthus emblica and Terminalia bellirica, used here as a mouthwash for its anti-inflammatory and protective properties.

Gungiliya Vennai (GV): Siddha topical preparation based on Shorea robusta resin, sesame oil and coconut water, selected for its tissue regeneration and mucosal healing capabilities.

Benzydamine: Non-steroidal anti-inflammatory agent used as a mouthwash, constituting the Standard of Care in this study for the symptomatic relief of mucositis.

WHO analgesic ladder: Pain management protocol in three steps (non-opioids, weak opioids, strong opioids) used to assess the evolution of participants' medication needs.

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