Stomatitis and VEGFR-Tyrosine Kinase Inhibitors (VR-TKIs): A Review of Current Literature in 4369 Patients.

Background
Multitargeted tyrosine kinase inhibitors (TKIs) represent a new class of target-specific antineoplastic agents. These agents show some specific adverse events such as fatigue/asthenia, anorexia/loss of appetite, dysgeusia, diarrhea/abdominal pain, hypothyroidism, hypertension, myelosuppression, and stomatitis.


Materials and Methods
A systematic search was performed on PubMed online database using a combination of MESH terms and free text words, "sunitinib" OR "sorafenib" OR "axitinib" OR "cabozantinib" OR "pazopanib" OR "regorafenib" OR "nintedanib" OR "vatalanib" combined through the use of Boolean operator AND with the key words "stomatitis" OR "mucositis," (i) on human subjects, (ii) written in the English language, and (iii) reporting about the incidence of stomatitis or oral mucositis.


Results
The incidence of stomatitis of any grade was 35.2% for sunitinib, 20.52% for sorafenib, 20.63% for axitinib, and 34.21% for cabozantinib. All the agents showed high rates of low-grade stomatitis (G1-G2), while the onset of severe stomatitis (G3-G4) was very low.


Conclusions
Analysis of the reports with patients treated with sunitinib, sorafenib, axitinib, and cabozantinib showed a clear prevalence of stomatitis grade 1 or grade 2. These data differ from those of patients treated with conventional chemotherapy in which mucositis is predominantly of grade 3 or grade 4.


Introduction
Traditional treatment of malignancies with chemotherapeutic agents often causes the damage of normal healthy cells [1]. Toxicities of the oral cavity, such as mucositis and stomatitis, are some of the most significant and unavoidable side effects associated with cancer treatment [2]. Oral toxicities have a huge impact on the patient with cancer and are a common cause of dose delays and interruptions of cancer therapy [3]. The terms "oral mucositis" and "stomatitis" are often used interchangeably to indicate oral complications of anticancer therapy, but they do not refer to the same process (Parkhill, 2013). Oral mucositis is a Medical Subject Headings term that describes inflammation of oral mucosa due to chemotherapeutic agents or ionizing radiation. Stomatitis is a less specific term used to describe any inflammatory condition of oral tissue. For such reason in the last decades, newer targeted agents have been developed, aiming to decrease the rates of side effects on healthy cells.

Materials and Methods
The following review was performed to answer to the following question: "which is the rate of incidence of oral stomatitis in patients treated with VEGF TKIs?" A systematic search was performed on the PubMed online database using a combination of MESH terms and free text words, "sunitinib" (free text) OR "sorafenib" (free text) OR "axitinib" (free text) OR "cabozantinib" (free text) OR "pazopanib" (free text) OR "regorafenib" (free text) OR "nintedanib" (free text) OR "vatalanib" (free text) combined through the use of Boolean operator AND with the key words "stomatitis" (MESH) OR "mucositis" (MESH), (i) performed on human subjects, (ii) reporting about the use of an mTOR inhibitor, (iii) written in the English language, and (iv) reporting about the incidence of stomatitis or oral mucositis.
Case reports and studies on animal model were excluded from this study. No restrictions were applied to the year of publication.
For each study, the following records were extracted: name of the first author, year of publication, number of patients enrolled, type of disease treated, number of events recorded, and grade of the events reported. To simplify the process of data extraction, an ad hoc extraction sheet was used. In addition, data were independently extracted by two authors (Lorenzo Lo Muzio and Claudia Arena) and checked in a joint session.

Bibliographic Research.
Titles and abstract of 358 potentially relevant studies were screened; of these, 311 studies were excluded because they did not meet the inclusion criteria ( Figure 1). The full texts of 47 studies were read. Of the included studies, 28 referred to sunitinib use, 16 to sorafenib, 4 to axitinib, and 2 to cabozantinib. Of these, 5 referred to both sunitinib and sorafenib and 2 referred to both axitinib and sorafenib.

Analysis of Data.
For sunitinib, 28 studies were analyzed (Table 1). A total of 2.596 patients were treated with sunitinib. The overall incidence of stomatitis of any grade with treatment was 35.2% (914 patients). Studies reported data about grade of stomatitis for 2068 patients and 739 cases were grade 1/2 (35.73%) and 90 were grade 3/4 (5.35%).
For sorafenib, 16 studies were analyzed ( Table 2). A total of 1218 patients were treated with sorafenib. The overall incidence of stomatitis of any grade with treatment was 20.52% (250 patients). Studies reported data about grade of stomatitis for 830 patients and 174 cases were grade 1/2 (20.96%) and 19 were grade 3/4 (2.28%).

Discussion
Targeted therapy is a kind of chemotherapy that inhibits a molecular target which is abnormally expressed in malignancy.         This method allows reaching a preferential localization of a drug in the region of disease, thus achieving an increase in local concentration. VEGFR TKI drugs work by inhibiting neoangiogenesis in the tumor. The cloning of vascular endothelial growth factor in 1989 was a major step in understanding of tumor angiogenesis. Angiogenesis inhibitors are a class of drugs that include monoclonal antibodies and tyrosine kinase inhibitors.
In this review, we focused on oral side effects provoked by tyrosine kinase inhibitors. Small molecule inhibitors of VEGFR2 were first reported in 1996. This type of therapy is based on the fact that tumor cells can obtain the necessary oxygen and nutrients for survival by passive diffusion for tumor size <1-2 mm, but angiogenesis is necessary for tumor growth beyond the size of 100-300 cells [68]. The mRNAs for both VEGFR1 and VEGFR2 are reported to be upregulated in tumor-associated endothelial cells in comparison to the vasculature of the surrounding normal tissue. Moreover, recent studies highlighted that VEGF and VEGFR-1 and VEGFR-2 not only drive tumor angiogenesis but also directly stimulate tumor growth and the formation of metastases [69].
The main oral side effects reported in the studies include nonspecific stomatitis, dysgeusia, and xerostomia. These toxicities may occur alone or in combination.
Results of analysis of the literature showed that the incidence rate of overall stomatitis is higher in patients treated with sunitinib (40.08%) compared to sorafenib (22.55%), axitinib (20.63%), and cabozantinib (34.21%). Although it was not possible to carry out an accurate analysis of stomatitis by grade, it can be noted that most of the studies included in the review showed a high rate of minor stomatitis (G1-G2), while the onset of severe stomatitis (G3-G4) was lower. Indeed, in patients treated with sunitinib, the rate of incidence of low-grade stomatitis was 35.73%, while the rate of incidence of high-grade stomatitis was 5.35%; in patients treated with sorafenib, the rate of incidence of low-grade stomatitis was 18.67%, while the rate of incidence of highgrade stomatitis was 2.28%; in patients treated with axitinib, the rate of incidence of low-grade stomatitis was 17.91%, while the incidence of high-grade stomatitis was 2.72%; in patients treated with cabozantinib, the rate of incidence of low-grade stomatitis was 29.82%, while the rate of incidence of high-grade stomatitis was 4.38%. These results differ from those reported in literature about mucositis provoked by conventional chemotherapy in which mucositis is often a severe and dose-limiting toxicity.
The stomatitis caused by this kind of targeted therapy presents as a diffuse mucosal hypersensitivity/dysesthesia which can be associated with moderate erythema or inflammation of the oral mucosa. The symptoms appear in the first week of treatment and then gradually disappear [67,89]. The literature reports that sunitinib and sorafenib may cause linear lingual ulcers of the nonkeratinized mucosa. Other typical oral side effects caused by treatment with VEGFR TKI are dysgeusia reported after treatment with cabozantinib and sunitinib and benign migratory glossitis which can be moderately painful and usually does not require any treatment modification or specific local treatment [90].
The changes in vascular permeability caused by the inhibition of VEGF can also induce mucocutaneous bleeding [91] and a delay in wound healing. Moreover, an oral screening for patients should be considered before undergoing therapy with antiangiogenic treatment. Treatment with tyrosine kinase inhibitors should end at least 1 week before oral surgery.

Conclusion
In conclusion, the targeted therapy has not kept the initial promises, as it determines several side effects, even if it is often lower than traditional chemotherapy. Regarding the BioMed Research International 13 oral cavity, the main side effect remains stomatitis, present in 20-30% of patients. The major advantage is that stomatitis is predominantly grade 1-2 in patients treated with targeted therapy while the effects of conventional chemotherapy are predominantly grades 3 and 4.