*4.3.1 Chemotherapy and radiotherapy*

Radiation therapy and chemotherapy have played no significant part in the management of ameloblastoma [35]. Ameloblastoma was, together with ameloblastic carcinoma, believed to be radioresistant tumor, as older methods failed to improve outcome of the disease [53]. Nevertheless, more recent literature suggest radiotherapy may be utilized for preventing recurrence in patients with microscopic positive margins or those with inoperable disease [54]. As malignant ameloblastomas or ameloblastic carcinomas are rare, data reporting radiotherapy effects remain scarce. Kennedy et al. [53] achieved local control in 4 of 6 patients treated with radiotherapy alone or postoperatively after radical surgery. Koukourakis et al. [55] concluded that image-guided radiation therapy, intensity-modulated radiation therapy or proton beam irradiation may be beneficial in adjuvant setting after surgical treatment for local control. Results of chemotherapy are also unpredictable with a lack of research [56]. Amzerin et al. [56] used combination of doxorubicin and cisplatin in patient with recurrent ameloblastoma with lung metastases. Pain disappearance, local stabilization and lung lesions shrinkage of 30% were reported. Gall et al. [57] evaluated effectiveness of three chemotherapeutic agents (methotrexate, cyclophosphamide,

*Perspective Chapter: Ameloblastoma – Present and Future Concepts of Managing DOI: http://dx.doi.org/10.5772/intechopen.107403*

### **Figure 11.**

*Postoperative image of the patient presented in* **Figure 7***. Conservative surgery with enucleation and curettage was performed after 12 months of decompression.*

and doxorubicin) with no regression of tumor nodules in the lungs, but with major symptomatic improvements. These data suggest that chemotherapy may improve clinical symptoms in metastatic patients.

### *4.3.2 Molecular targeted therapy*

Over the past decade, novel molecular targeted therapies are evolving alongside with dramatically improved understandings of biological behavior of ameloblastoma [58]. The main identified mutations are found in MAPK and SHH signaling pathways. These include BRAF, RAS and FGFR2 genes from MAPK pathway and SMO gene from SHH signaling pathway [2, 10]. Discovery and clarification of mentioned activated molecular pathways brought out the novel potentional targeted therapies in the management of ameloblastoma.

Drugs approved by US Food and Drug Administration which are predominantly used for treatment of metastasizing, unresectable or recurrent ameloblastoma are vemurafenib, dabrafenib and trametinib [59, 60]. Initially, vemurafenib was approved for use in treatment of metastatic or surgically non-treatable melanoma, while dabrafenib and trametinib for the treatment of metastatic non-small cell lung cancer with BRAF V600E mutations. Vemurafenib and dabrafenib are BRAF inhibitors, while trametinib is MEK inhibitor [59, 60]. Although the available literature is limited with a lack of clinical research, clinical effectiveness of using molecular targeted drugs for patients with ameloblastoma was reported in several case reports [61–66]. Fernandes et al. [61] presented a case of patient with recurrent ameloblastoma with confirmed BRAF V600E mutation. Vemurafenib therapy was prescribed and complete resolution of symptoms together with continuous shrinkage of lesion evidenced on MRI scans after 11 months of therapy were reported. Furthermore, Faden et al. [62] used dabrafenib reduced to a 50% of therapy dose to treat a patient with significant medical comorbidities. MRI analysis showed a 75% reduction in tumor mass after 8 months of therapy. Both authors [61, 62] recommended single agent therapy over dual therapy in ameloblastoma patients. However, adverse reaction to vemurafenib including arthralgia, nausea and rash has been reported after 12 months of therapy [63]. Adverse effects can be controlled by decreasing the dosage without adversely

affecting outcomes of therapy. It has been found that neoadjuvant treatment with dabrafenib significantly reduces size of the primary tumor which could reduce the extent of the subsequent surgery [64]. On the other hand, Kaye et al. [65] reported a case of unresectable locally recurrent ameloblastoma of the mandible with lung metastases treated with dual targeted therapy. They used dabrafenib in combination with trametinib which resulted with significant reduction of tumor and metastases volume and utter resolution of symptoms after 20 weeks. Combination of dabrafenib and trametinib has also proven to have a significant influence resulting with complete remission in a study by Brunet et al. [66].

SMO inhibiting drugs, such as itraconazole and vismodegib, are considered less successful due to the mechanisms of resistance which disable their binding [10]. Cyclopamine is SHH signaling pathway antagonist and is more effective than SMO inhibitors [2]. However, it has ability to inhibit osteoblast proliferation and differentiation with negative effects on bone healing [67].

It is worth mentioning that matrix metalloproteinases (MMPs) have a role in local invasiveness of ameloblastoma [58]. MMPs are zinc-dependent proteinases that are important in extracellular matrix degradation and are associated with tumor growth and invasiveness [68]. MMP-2 and MMP-9 are expressed in various benign and malign tumors, including ameloblastoma. They are mainly involved in angiogenesis and tumor growth [69]. Consequently, invasion of adjacent tissues could be effectively controlled by regulation of MMPs. Still, they have a vital role in tissue remodeling and inhibition of their activity causes major side effects. Thus, further research is needed to reveal potential disease control by MMP inhibitors [58].
