Topical 5-Fluorouracil in the treatment of OKC

Usage of 5-Fluorouracil in OKC management

1. GOOD MORNING

2. Topical 5-fluorouracil application in management of odontogenic keratocysts Parveen Akhter Lone (Dr)a,∗, Nisar Ahmed Wani (Dr)b, Zubair Ahmed Janbaz (Dr)c, Mehnaz Bibi (Dr)c, Amit Kour (Dr)c a Indira Gandhi Government Dental College Amphalla Jammu Affiliated to University of Jammu, India b Consultant Pediatric Radio Diagnosis GB Pant Hospital Srinagar Kashmir Affiliated to University of Kashmir, India c House Surgeon OMFS, IGGDC, Jammu, India Journal of Oral Biology and Craniofacial Research 10 (2020) 404–406

3. CONTENTS INTRODUCTION 01 MATERIALS & METHODS 02 RESULTS 03 DISCUSSION 04 CONCLUSION 05 REFERENCES 07 LITERATURE REVIEW 06

4. INTRODUCTION

5. Odontogenic keratocysts (OKC) is an aggressive cystic lesion of jaw arising from dental lamina, with high growth and recurrence rates. First described by Philipson in 1956. Clinical Features: Swelling, pain, facial asymmetry, infection, paraesthesia Radiographic Features: multilocular or unilocular radiolucent lesion Incidence : 1.8 and 21.5% of odontogenic cysts. Age predilection :7 yrs – 83 yrs ; Peal incidence: 10-30 yrs Gender Predilection : Male to females – 16:1; dominance in males Site predilection : ramus and angle of the mandible Management: Medical management Enucleation & curettage Surgical management: Peripheral ostectomy to aggressive resection combinations I NTRODUCT I ON

6. 5-FLUROURACIL 5-FU is an antimetabolite drug, used in treatment Basal cell carcinoma (BCC), and various other cancers. It is an established treatment for actinic keratosis. It inhibits thymidylate synthetase an enzyme required for DNA synthesis thus causing cell death.

7. 5-FLUROURACIL and its mechanism of action Action of THYMIDYLATE SYNTHETASE DeoxyUridine MonoPhosphate -DUMP -----------  DeoxyThymidine Monophosphate-DTMP This DTMP is required for synthesis of DNA 5-Fluorouracil causes scarcity of this DTMP leading to thymine less death of rapidly dividing cancer cells Methylation by Thymidylate synthase

8. To determine the efficacy of 5- FU in OKC because of its similarities to BCC in molecular etiopathogenesis. AIM

9. MATERIALS AND METHODS

10. Department of Oral & Maxillofacial Surgery LOCATION 27 Patients SAMPLE Last 7 years from the date of publication STUDY PERIOD 2-9 Years FOLLOW UP PERIOD

11. RESULTS

12. DEMOGRAPHICS OF OKC

13. COMPARISION BETWEEN GROUPS

14. DISCUSSION

15. The name keratocyst was first introduced in 1950. The classification underwent many changes from 1950 to 2017, and as per WHO organization in 2005, it was renamed from OKC to keratocystic odontogenic tumour (KCOT) due to its aggressive potential. According to these classification there are two subtypes of OKC, the orthokeratinized and the parakeratinized . In 2007, KCOT was again reclassified as odontogenic keratocysts (OKC).

16. TREATMENT OPTIONS Enucleation Marsupilization Curettage Peripheral ostectomy,Adjunctive solution application Segmental resection. TREATMENT GOALS Minimize morbidity Maintain vitality of surrounding structures and Reduce the possible chances of recurrence The treatment modality depends upon the size of lesion, location, proximity of lesion to vital structures like inferior alveolar nerve, maxillary sinus & nasal cavity

17. Enucelation – 56% recurrence Carnoy’s solution – Decreased rate of recurrence but carcinogenic potential of chloroform in the original CS, a modified CS is used instead. And this modified CS increased the rate of recurrence to 66%. Resection – Most aggressive treatment but high morbidity – for least recurrence, approximate 5mm margin of healthy bone is to be resected – because of this high morbidity, not accepted as a routine treatment and is limited to only most severe cases. Over the past few years – attention to new procedures in the treatment of OKC – as simple and as successful possible. One such therapeutic agents – 5FLUROURACIL – antimetabolite that is used in different malignant diseases like BCC for topical application.

18. Leddehroff in 2017 proposed a targeted approach based on the understanding of molecular genetics of OKC. OKC has been reported to develop through protein patched Homolog (PTCH) gene mutation like that in Basel cell carcinomas (BCC) PTCH causing smoothened (SMO) activation and sonic Hedgehog (SHH) signals resulting in neoplastic changes Ledderhof NJ, Caminiti MF, Bradley G, Lam DK. Topical 5-fluorouracil is a novel Targeted therapy for the keratocystic odontogenic tumour. J Oral Maxillofac Surg. 2017;75(3):514–524.

19. Study by Rui et al. in 2014 showed that SHH signal pathway antagonism may be an effective way to target OKC molecularly through suppression of SHH transcription factor and SMO inhibition. This SMO gene alteration play an important role in OKC development. Rui Z, Li-Ying P, Jia-Fei Q, et al. Smoothened gene alterations in keratocystic odontogenic tumors . Head Face Med. 2014;10:1. Balamurugan Rajendran . 5 fluorouracil: trend setter in the management of odontogenic keratocyst . J Case Stud Cl Trials. 2019;1(1). Balamurugan in 2019 also reported 5-FU as a trend setter treatment modality in OKC.

20. Majority of studies – OKC treated with modified CS – neurosensory deficit even after following 3 min application protocol by Frerich et al. SEP – SOMATOSENSORY EVOKED POTENTIALS Frerich B, Cornelius C, Weitholter H. Critical time of exposure of the rabbit inferior Alveolar nerve to Carnoy's solution. J Oral Maxillofac Surg. 1994;52:599–606

21. Till date no study has shown adverse effects of direct application of 5-FU on major blood vessels. Twice weekly application of topical 5% 5FU – 4 weeks after medial maxillectomy , sphenoethmoidectomy for ethmoidal adenocarcinoma showed no adverse effects on infraorbital nerve or remaining sinus mucosa

22. 5-FU has been considered more useful in treatment of OKC than carnoy solution due to its short operating time, availability, technical simplicity, reduced morbidity, low cost, with low or no recurrence, thereby decreasing the need for a second surgery. CONCLUSION

23. LITERATURE REVIEW

24. Pogrel M A.Treatment of Keratocysts . The case for Decompression and Marsupialisation. J Oral and Maxillofac Surg 2005;63:1667-73. The cryotherapy devitalizes organic tissue beyond the visible margin of the lesion but leaves the inorganic bony framework intact. In this way, any adjacent daughter cells or cyst remnants will be destroyed.

25. Bredell M, Rordorf T, Kroiss S, Rücker M, Zweifel DF, Rostetter C, Denosumab as a treatment alternative for central giant cell granuloma: a long-term retrospective cohort study, Journal of Oral and Maxillofacial Surgery 2017; 1-24

26. Denosumab is a fully human immunoglobulin G2 monoclonal antibody with high affinity and specificity for human RANKL. Denosumab is an effective agent for minimizing bone loss associated with certain cancer treatments. Narayanan P. Denosumab : A comprehensive review. South Asian J Cancer 2013;2:272-7.

27. Ledderhof NJ, Caminiti MF, Bradley G, Lam DK. Topical 5-fluorouracil is a novel Targeted therapy for the keratocystic odontogenic tumour. J Oral Maxillofac Surg. 2017;75(3):514–524.

28. Heikinheimo K, Kurppa K J, Alineus K. Novel targets for the treatment of Ameloblastoma . Journal of Dental Research 2015, Vol. 94(2) 237– 240

29. REFERENCES

30. Ledderhof NJ, Caminiti MF, Bradley G, Lam DK. Topical 5-fluorouracil is a novel Targeted therapy for the keratocystic odontogenic tumour. J Oral Maxillofac Surg. 2017;75(3):514–524. Rui Z, Li-Ying P, Jia-Fei Q, et al. Smoothened gene alterations in keratocystic odontogenic tumors . Head Face Med. 2014;10:1. Balamurugan Rajendran . 5 fluorouracil: trend setter in the management of odontogenic keratocyst . J Case Stud Cl Trials. 2019;1(1). Heikinheimo K, Kurppa K J, Alineus K. Novel targets for the treatment of Ameloblastoma . Journal of Dental Research 2015, Vol. 94(2) 237– 240 Pogrel M A.Treatment of Keratocysts . The case for Decompression and Marsupialisation. J Oral and Maxillofac Surg 2005;63:1667-73. Narayanan P. Denosumab : A comprehensive review. South Asian J Cancer 2013;2:272-7. Bredell M, Rordorf T, Kroiss S, Rücker M, Zweifel DF, Rostetter C, Denosumab as a treatment alternative for central giant cell granuloma: a long-term retrospective cohort study, Journal of Oral and Maxillofacial Surgery 2017; 1-24 Frerich B, Cornelius C, Weitholter H. Critical time of exposure of the rabbit inferior Alveolar nerve to Carnoy's solution. J Oral Maxillofac Surg. 1994;52:599–606

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