Topical 5-Fluorouracil- a Novel Therapeutic Treatment Option for the Keratocystic Odontogenic Tumour

Keratocystic odontogenic tumours (KOTs) are distinct, benign pathological entities of the jaws with potential for significant morbidity. Historically, treatment of the KOT included simple enucleation; however, this has been suboptimal due to its high recurrence rate. Enucleation alone has been shown to have recurrence rates as high as 56% with osseous resection approaching recurrence rates of 0% (Blanas et al., 2000). Application of a chemical such as Carnoy’s solution further decreased rates of recurrence but adjunctive techniques have raised concerns for increased carcinogenesis potential or permanent injury of vital structures such as the trigeminal nerve. Similarities in the molecular etiopathogenesis of basal cell carcinomas (BCCs) and KOTs allow us to postulate that KOTs may respond favorably to treatment with topical application of 5-fluorouracil (5-FU) as do superficial BCCs.

Antimetabolite drugs are chemotherapeutic agents used in the treatment of various cancers. Specifically, 5-FU incorporates into the DNA and RNA of cells, inhibiting normal biosynthetic processes, and is used in the treatment of different malignancies including: colorectal, breast, skin and head and neck cancers (Longley et al, 2003). We hypothesize that: (1) KOTs treated with enucleation, peripheral ostectomy and 5-FU have a similar or lower recurrence rate than treatment with conventional enucleation, peripheral ostectomy and application of Carnoy’s solution; (2) rates of trigeminal nerve injury are decreased when using 5-FU compared to Carnoy’s solution; and (3) KOTs are molecularly targeted by 5-FU based on immunohistochemical findings.  

A retrospective analysis of the morbidity and recurrence rates of 50 KOT patients treated with enucleation, peripheral ostectomy, and topical application of 5-FU and 50 KOT patients treated with enucleation, peripheral ostectomy and topical application of Carnoy’s solution at the University of Toronto from 2006-2014 will be studied. The research protocol is in compliance with the Committee on Human Research at the University of Toronto. Demographic information will be collected for each patient including age, sex, racial/ethnic identity, presenting symptoms, oral lesion location and tumor size. We will also perform immunostaining on 4 μm sections of formalin-fixed, paraffin-embedded KOT specimens with anti-thymidylate synthase, thymidylate phosphorylase, dihydropyrimidine dehydrogenase and p53 antibodies to provide molecular evidence of KOT susceptibility to 5-FU.  Data are reported as mean±SE. RM ANOVA, RM ANOVA-on-ranks, Wilcoxon-signed rank, Fisher exact and Pearson correlation tests will be used as appropriate (P<0.05 considered to reflect statistical significance). Preliminary results suggest there were no differences in patient demographics between the two treatment groups. The age at diagnosis was 41± 1.4 with 40% women and 60% men. All lesions were isolated to the mandible. The average size of the lesions were 37.4 mm x 31.9 mm. In the Carnoy’s group (n=5), there were 2 recurrences with a mean recurrence time of 27.5 months. In contrast, there were no recurrences in the 5-FU group (n=5). In all cases treated with Carnoy’s solution, there was transient post-operative inferior alveolar nerve paresthesia. Two of these cases resulted in permanent paresthesia; whereas only 2 cases of 5-FU-treated patients had transient paresthesia that resolved shortly thereafter.

Our preliminary findings suggest lower recurrence rates and less morbidity using topical 5-FU compared to Carnoy’s solution for treatment of KOTs. Possible advantages of topical 5-FU may include decreased morbidity, and decreased requirements for further surgical interventions. Topical 5-FU may be a novel therapeutic option for KOTs and may provide a targeted molecular approach to treatment.

References:

 

Blanas N, Freund B, Schwartz M, and Furst I. Systematic review of the treatment and prognosis of the odontogenic keratocyst. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000; 90: 553-558.

 Longley D, Harkin P, and Johnston P. 5-Fluorouracil: Mechanisms of Action and Clinical Strategies. Nature Reviews. 2003; 3: 330-338.