Photodynamic therapy in treatment of squamous cell carcinoma of oral cavity with chlorine e6 photosensitizer with long-term follow up

Photodynamic therapy is an effective method for treating superficial forms of malignant neoplasms, characterized by a minimal risk of damage to normal tissues. In this study, we presented our experience of treating cancer of the oral mucosa using photodynamic therapy, and analyzed the immediate and long-term results of treatment. 38 patients with squamous cell carcinoma of oral cavity mucosa, with a depth of invasion no more than 7 mm, were included in the study. All patients underwent photodynamic therapy with chlorine e6 based photosensitizer. Photosensitizers were administered intravenously 3 hours before irradiation, at a dosage of 1 mg/kg of the patient’s weight. Photodynamic therapy was performed with the following parameters: P – 1.0 W, Ps – 0.31 W/cm2, E – 300 J/cm2. The area of one irradiation field ranged 1.0-2.0 cm2. Treatment effect was evaluated by RECIST 1.1. Overall survival, cancer-specific survival, and disease-free survival were calculated using Kaplan-Meier curves. Evaluation of adverse events was made by .TCAE 5.0 criteria. At 35 (92.1%) out of 38 cases, complete regression was observed after photodynamic therapy. Among them in 3 out of 35 patients relapse was diagnosed in 11.5 to 43.2 months. The total number of patients who didn’t respond to treatment was 6 (15.8%). Follow-up period was 4.2-87.3 months. (mean 42.9). 34 (89.5%) out of 38 patients are alive, 1 (2.6%) died from progression, and three died from other causes. The 5-year overall survival rate was 82.1%, cancer-specific survival rate was 97.0%, and disease-free survival rate was 81.1%. Among the factors significantly (p < 0.05) influencing relapse-free survival: depth of invasion < 5 mm (p – 0.013) and the presence of leukoplakia (p – 0.007). When assessing cancer-specific survival, factors worsening the prognosis were: age >70 years (p – 0.034) and the presence of leukoplakia (p – 0.007). Photodynamic therapy is an alternative treatment method of oral cancer superficial lesions, in case of proper assessment of primary lesion and in case of possibility of full irradiation of the tumor. Moreover, after using photodynamic therapy, the underlying connective-muscular structures are preserved, which promotes rapid healing with minimal scarring, the functions of the affected organ remain intact, and cosmetic defects do not form.

1. Kaprin A.D., Starinsky V.V., Shakhzadova A.O. Clinical recommendations of the Association of Oncologists of Russia. Malignant neoplasms of the oral cavity, 2020, pp. 18-19

2. Cooper J.S., Zhang Q., Pajak T.F., et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int. J. Radiat. Oncol. Biol. Phys, 2012, vol. 84(5), pp. 1198-205.

3. Kansy K., Mueller A.A., Mücke T., et al. A worldwide comparison of the management of T1 and T2 anterior floor of the mouth and tongue squamous cell carcinoma Extent of surgical resection and reconstructive measures. J. Craniomaxillofac Surg, 2017, vol. 45(12), pp. 2097-2104.

4. Ochoa E., Larson A.R., Han M., et al. Patient-Reported Quality of Life After Resection With Primary Closure for Oral Tongue Carcinoma. Laryngoscope, 2021, vol. 131(2), pp. 312-318.

5. Biazevic M.G., Antunes J.L., Togni J., et al. Immediate impact of primary surgery on health-related quality of life of hospitalized patients with oral and oropharyngeal cancer. J. Oral Maxillofac Surg, 2008, vol. 66, pp. 1343-1350.

6. Chandu A., Smith A.C., Rogers S.N. Health-related quality of life in oral cancer: a review. J Oral Maxillofac Surg, 2006, vol. 64, pp. 495502.

7. Shah J.P., Gil Z. Current concepts in management of oral cancer – Surgery. Oral Oncol, 2009, vol. 45, pp. 394-401.

8. Agarwal P., Upadhyay R., Agarwal A. Radiotherapy complications and their possible management in the head and neck region. Indian J Dent Res, 2012, vol. 23(6), pp. 843.

9. de Visscher S.A., Melchers L.J., Dijkstra P.U., et al. mTHPC-mediated photodynamic therapy of early stage oral squamous cell carcinoma: a comparison to surgical treatment. Ann Surg Oncol, 2013, vol. 20(9), pp. 3076-3082.

10. Toratani S., Tani R., Kanda T., et al. Photodynamic therapy using Photofrin and excimer dye laser treatment for superficial oral squamous cell carcinomas with long-term follow up. Photodiagnosis Photodyn Ther, 2016, vol. 14, pp. 104-110.

11. Ibarra A.M.C., Cecatto R.B., Motta L.J., et al. Photodynamic therapy for squamous cell carcinoma of the head and neck: narrative review focusing on photosensitizers. Lasers Med Sci, 2022, vol. 37(3), pp. 1441-1470.

12. Cerrati E.W., Nguyen S.A., Farrar J.D., Lentsch EJ. The efficacy of photodynamic therapy in the treatment of oral squamous cell carcinoma: a meta-analysis. Ear Nose Throat J, 2015, vol. 94(2), pp. 72-79.

13. Karakullukcu B., Stoker S.D., Wildeman A.P., et al. A matched cohort comparison of mTHPC-mediated photodynamic therapy and trans-oral surgery of early stage oral cavity squamous cell cancer. Eur Arch Otorhinolaryngol, 2013, vol. 270(3), pp. 1093-1097.

14. Panaseykin Y.A., Kapinus V.N., Filonenko E.V., et al. Photodynamic therapy treatment of oral cavity cancer in patients with comorbidities. Biomedical Photonics, 2022, Vol. 11(4), pp. 19-24.

15. Panaseykin Y.A., Filonenko E.V., Sevrukov F.E., et al. Possibilities of photodynamic therapy in the treatment of malignant tumors of the oral cavity. Biomedical Photonics, 2021, vol. 10(3), pp. 32-38.

16. Kapinus V. N., Kaplan M. A., Yaroslavtseva-Isaeva E. V., and coauthors A. Application of chlorin E6-photodynamic therapy of basal cell skin cancer. Research and Practice in Medicine, 2021, vol. 8(4), pp. 33-43.

17. Gondivkar S.M., Gadbail A.R., Choudhary M.G., et al. Photodynamic treatment outcomes of potentially-malignant lesions and malignancies of the head and neck region: A systematic review. J Investig Clin Dent, 2018, pp. 9-10.

18. Kapinus V. N., Kaplan M.A., Yaroslavtseva-Isayeva E. V., et al Photodynamic therapy for head and neck basal cell skin cancer with additional interstitial laser irradiation. Biomedical Photonics, 2018, vol. 6, pp. 20-26.

19. Shevchenko O.V., Korshunova O.V., Plekhova N.G. Study of the cytotoxic effect of a molecular conjugate based on chloride e6. Medical and pharmaceutical journal “Pulse”, 2022, vol. 24(11), pp. 18-22.

20. Senge M.O., Brandt J.C., Temoporfin (Foscan®, 5,10,15,20-tetra(mhydroxyphenyl)chlorin)--a second-generation photosensitizer. Photochem Photobiol, 2011, vol. 87(6), pp. 1240-1296.

21. Copper M.P., Triesscheijn M., Tan I.B., et al. Photodynamic therapy in the treatment of multiple primary tumors in the head and neck, located to the oral cavity and oropharynx. Clin Otolaryngol, 2007, vol. 32, pp. 185-189.

22. Hopper C. Photodynamic therapy: a clinical reality in the treatment of cancer. Lancet Oncol, 2000, vol. 1, pp. 212-219.

23. Lin J., Guangcheng N., Tingting D., et al. Photodynamic Therapy for Oral Squamous Cell Carcinoma: A Systematic Review and MetaAnalysis. International Journal of Photoenergy, 2021, pp. 1-14.

24. Brierley J. D., Gospodarowicz M. K., Wittekind C. TNM Classification of malignant tumor. Eighth Edition, 2017, pp. 36-39.

25. Grant W.E., Speight P.M., Hopper C., et al. Photodynamic therapy: an effective, but non-selective treatment for superficial cancers of the oral cavity. Int. J. Cancer, 1997, vol. 71, pp. 937-942.

26. Hopper C., Kübler A., Lewis H., et al. mTHPC-mediatedphotodynamic therapy for early oral squamous cell carcinoma. Int. J. Cancer, 2004, pp. 138-146.

27. Luryi A.L., Chen M.M., Mehra S., et al. Treatmentfactor associated with survival in early-stage oral cavity cancer. Analysis of 6830 cases from the National Cancer Date Base. JAMA Otolaryngol. Head NeckSurg, 2015, vol. 141, pp. 593-598.

28. Umeda M., Komatubara H., Ojima Y., et al. A comparison of brachytherapy and surgery for treatment of stage I-II squamous cell carcinoma of the tongue. Int. J. Oral Maxillofac. Surg, 2005, vol. 34, pp. 739-744.

29. Gluckman J.L., Hematoporphyrin photodynamic therapy: is there truly a future in head and neck oncology? Reflection on a 5-years’ experience. Laryngoscope, 1991, vol. 101, pp. 36-42.

30. Biel M.A., Photodynamic therapy and the treatment of head and neck neoplasia. Laryngoscope, 1996, vol.108, pp. 1259-1268.

31. Slaughter D., Southwick W., Smejkal W., Field cancerization in oral stratifiedsquamous epithelium: clinical implications multicentric origin. Cancer, 1953, pp. 963-968.

32. de Visscher J.G.A.M., van der Meij E.H. Witte afwijking van het mondslijmvlies: leukoplakie [White lesions of the oral mucosa: leukoplakia]. Ned Tijdschr Tandheelkd, 2023, vol. 130(5), pp. 232236.

33. Pass H.I., Photodynamic therapy in oncology: mechanisms and clinical use. J. Natl. Cancer Inst, 1993, vol. 85, pp. 443-456.

34. Grant W.E., Hopper C., Speight P.M., et al. Photodynamictherapy of malignant and premalignant lesions in patients with ‘fieldcancerization’ of the oral cavity. J. Laryngol. Otol, 1993, vol. 107, pp. 1140-1145.

35. Chadha R., Jain D.V.S., Aggarwal A. et al. Binding constants of inclusion complexes of nitroimidazoles with βcyclodextrins in the absence and presence of PVP. Thermochim. Acta, 2007, vol. 459, pp. 111-115.

36. Douillard S., Olivier D., Patrice T. In vitro and in vivo evaluation of Radachlorin(R) sensitizer for photodynamic therapy. Photochem. Photobio. Sci., 2009, vol. 8(3), pp. 405-13.

37. Chan Thi Hai Yen, Ramenskaya G.V., Oborotova N.A. Photosensitizers of the chlorine series in PDT of tumors. Russian Biotherapeutic Journal, 2009, vol. 4.

38. Moan J., Berg K., Kvam E., et al. Intracellular Localization of Photosensitizers, In Ciba Foundation Symposium 146. Photosensitizing Compounds: Their Chemistry, Biology and Clinical Use (eds G. Bock and S. Harnett), 1989, pp. 95-111.

39. Agostinis P., Berg K., Cengel K.A., et al. Photodynamic therapy of cancer: An update. CA: A Cancer Journal for Clinicians, 2011, vol. 61, № 4, pp. 250-281.

40. Mosaddad S.A., Mahootchi P., Rastegar Z., et al. Photodynamic Therapy in Oral Cancer: A Narrative Review. Photobiomodul Photomed Laser Surg., 2023, vol. 41(6), pp. 248-264.