(i)Rationale/ gaps in existing knowledge,: Oral cancer, one of the top three common cancers in India is usually preceded by Oral potentially malignant disorders in nearly two thirds of the cases like Oral leukoplakia. OL has a high prevalence and malignant transformation rates(0.13% - 40.8%). There are no universal protocols for management in OL ranging from preventive, conservative, medical and surgical interventions. They all have limitations and high recurrence rates requiring regular follow up.
(ii)Novelty: Removal of pathological lesions are believed to reduce the risk of malignant transformation in OL. Surgical methods are associated with morbidity and high recurrence rates. Non -invasive methods (like Photodynamic therapy) that can remove the abnormal lesions would be preferred as they are cheaper, convenient, safe with less morbidity and better patient acceptability. They also have the advantage of repeatability with minimum morbidity and damage to adjacent normal tissues. Non -invasive medical management involves topical application of retinoids which are associated with systemic toxicity, recurrence and development of resistance.
(iii)Objectives,
Primary objective:
To compare the effect of 2.5% Toluidine blue mediated topical photodynamic therapy and topical calcipotriol (0.005%) on clinical response after completion of treatment at 4 weeks from baseline during management of Oral leukoplakia
Secondary objectives:
To compare the effect of 2.5% Toluidine blue mediated topical photodynamic therapy with topical Calcipotriol (0.005%) on lesion size, lesion roughness/ whiteness, and oral health quality of life after completion of treatment at 4 weeks and 12 weeks from baseline during management of Oral leukoplakia To compare the effect of 2.5% Toluidine blue mediated topical photodynamic therapy with topical Calcipotriol (0.005%) on salivary molecular markers ( IL6, TNF-α, PCNA, Survivin and VEGF) after completion of treatment at 4 weeks from baseline To compare the adverse events, time to complete response and recurrence rates between the two groups
(iv)Methods,: An open label randomized clinical trial where Group A (n=83) will receive 4 sessions of Toludine blue mediated photodynamic therapy (Fluence 15J/cm2); GroupB (n=83) will receive twice daily tropical application of Calcipotriol (0.005%) over a period of 4 weeks. The clinical response, lesion thickness/ whiteness, lesion size /area, OHIP-14 scores, adverse events and recurrence rates will be compared with baseline at 4 weeks and 12 weeks after completion of therapy. Sterile PVA ophthalmic sponges will be used to evaluate molecular markers ( IL6, TNF-α, PCNA, Survivin VEGF) from treatment site of lesion at baseline and 4 weeks after completion of treatment by ELISA. The data will be analyzed statistically using Intention to treat and as per protocol analysis at significance levels of p\<0.05.
(v)Expected outcome.: The study will validate and verify the effectiveness of the TB mediated PDT protocol in the management of OL as compared to other non invasive method of topical Calcipotriol in terms of clinical response ( complete/ partial/ none), lesion thickness/ whiteness, lesion size and it's effect on oral health quality of life. Adverse events if any and recurrence rates or malignant transformation rates will also help in assessment of safety of the protocol. The molecular markers will help to monitor and determine prognosis of the lessons following treatment.
All diagnosed cases of Oral Leukoplakia with size ≥ 2 cm2 (Van der Waal classification ≥ L2) reporting to the department of OMR, CDER and willing to participate in the study will be included
Subjects clinically and histologically diagnosed as Oral Leukoplakia.
Subjects > 18 years of age.
Subjects willing to participate in the study and to complete the treatment sessions.
History of any topical and/or systemic therapy for Oral Leukoplakia other than general management in last 2 months.
Subjects with current or past history of malignancy.
Subjects with any lesion suspicious of malignancy requiring biopsy.
Subjects with severe dysplasia and carcinoma in situ on biopsy of oral lesion
Parallel
Non-invasive Photo Dynamic Therapy using LED of wavelength ranging from 630-660nm( Fluence 15 J/cm2) as light source and 2.5% TB as photosensitizer
Other interventionChoice of LED light source instead of morecommonly used lasers and 2.5% Toludine blue as photosensitizer for photodynamic therapy instead of 5ALA in Oral leukoplakia
Topical application of Calcipotriol ointment 0.005% twice a day for 4 weeks along with preventive and conventional therapy
DrugTopical retinoids have been more commonly used in oral leukoplakia and are associated with relapses, toxicity and photosensitivity
Conventional non-invasive management : All subjects in the two groups will receive the same standard conventional non- invasive management advised for OL as per current scientific evidence
Other interventionBoth Groups A and b will receive conventional non-invasive management as per current scientific evidence
Clinical response: Number of patients with Complete response/ Partial response/ No response/ alteration in clinical pattern
a. Clinical response(Chen et al 2021)(42): 1. complete remission of the lesion clinically evaluated; Complete Response CR 2. partial reduction of at least 20% in the total diameter of the lesion; Partial response PR 3. reduction of the lesion by less than 20% in diameter; No Response NR 4. alteration in the clinical pattern of the lesion (homogeneous and non- homogeneous).
Lesion size
(bidimensional measurement in cm and area in cm2 ) using Image J software
Lesion roughness/ whiteness: Number of patients with total resolution/ Moderate resolution/ Minimal change/ No visible change
Lesion roughness/ whiteness score (Femanio et al 2001)(68): 0: Total resolution of lesions 1. Moderate resolution= reduction of consistency with leveling of the lesion 2. Minimal change= reduction of consistency without leveling of the lesion 3. No visible change
Oral Health quality of Life: Number of patients with OHIP-14 scores 0-8
Assessment of oral health quality of life using Oral Health Impact Profile -14 questionnaire: (Score 0-8)
Concentration of salivary molecular markers ( IL6, TNF-α, PCNA, Survivin and VEGF)
Estimation of concentration of salivary molecular markers ( IL6, TNF-α, PCNA, Survivin and VEGF) by ELISA after completion of treatment at 4 weeks from baseline
time to complete response
The time required from baseline for complete response in both groups
Oral pain/ burning sensation scores 0-10
Oral pain/ burning sensation assessment using The numeric rating scale (NRS) from 0-10
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Dr. Shalini Gupta
Lead sponsor
All India Institute of Medical Sciences
Sponsor institution
All India Institute of Medical Sciences
Collaborator
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