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Stomatitis And Everolimus: A Review Of Current Literature On 8,201 Patients
Authors Arena C , Troiano G , Zhurakivska K , Nocini R , Lo Muzio L
Received 30 November 2018
Accepted for publication 23 January 2019
Published 14 November 2019 Volume 2019:12 Pages 9669—9683
DOI https://doi.org/10.2147/OTT.S195121
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Prof. Dr. Takuya Aoki
Claudia Arena,1 Giuseppe Troiano,1 Khrystyna Zhurakivska,1 Riccardo Nocini,2 Lorenzo Lo Muzio1,3
1Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy; 2Section of Otolaryngology, Department of Surgical Sciences, Dentistry, Gynecology, and Pediatrics, University of Verona, Verona, Italy; 3C.I.N.B.O. (Consorzio Interuniversitario Nazionale per la Bio-Oncologia), Chieti, Italy
Correspondence: Lorenzo Lo Muzio
Clinica Odontoiatrica, Università degli Studi di Foggia, 50 Via Rovelli, Foggia 71122, Italy
Tel +39 0881 588 090
Fax +39 0881 588081
Email [email protected]
Background: Oral toxicities, such as mucositis and stomatitis, are some of the most significant and unavoidable side effects associated with anticancer therapies. In past decades, research has focused on newer targeted agents with the aim of decreasing the rates of side effects on healthy cells. Unfortunately, even targeted anticancer therapies show significant rates of toxicity on healthy tissue. mTOR inhibitors display some adverse events, such as hyperglycemia, hyperlipidemia, hypophosphatemia, hematologic toxicities, and mucocutaneous eruption, but the most important are still stomatitis and skin rash, which are often dose-limiting side effects.
Aim: This review was performed to answer the question “What is the incidence of stomatitis in patients treated with everolimus?"
Methods: We conducted a systematic search on the PubMed and Medline online databases using a combination of MESH terms and free text: “everolimus” (MESH) AND “side effects” OR “toxicities” OR “adverse events”. Only studies fulfilling the following inclusion criteria were considered eligible for inclusion in this study: performed on human subjects, reporting on the use of everolimus (even if in combination with other drugs or ionizing radiation), written in the English language, and reporting the incidence of side effects.
Results: The analysis of literature revealed that the overall incidence of stomatitis after treatment with everolimus was 42.6% (3,493) and that of stomatitis grade G1/2 84.02% (2,935), while G3/4 was 15.97% (558).
Conclusion: Results of the analysis showed that the incidence of stomatitis of grade 1 or 2 is higher than grade 3 or 4. However, it must be taken into account that it is not possible to say if side effects are entirely due to everolimus therapy or combinations with other drugs.
Keywords: stomatitis, everolimus, mucositis, targeted therapy, oral medicine, oral pathology
Introduction
Conventional anticancer therapy does not distinguish between normal and cancer cells. The damage inflicted on normal tissue have thus hampered this therapy.1 The introduction of targeted-therapy molecules targeting specific enzymes, growth-factor receptors, and signal transducers has lowered the incidence of side effects,2 significantly influencing patient quality of life and survival rates.2mTOR is a therapeutic target for both solid and hematologic malignancies. It is part of a pathway that regulates protein biosynthesis, cell growth, and cell-cycle progression. Moreover, mTOR is the downstream effector of the PI3K–Akt–mTOR pathway, which regulates cell growth and metabolism and is involved in multiple processes.1,3–5
Rapamycin and its analogues form the first generation of mTOR inhibitors. The action of these molecules is targeting a 289 kDa serine/threonine-protein kinase that is a component of the big family of PI3Ks. Rapamycin and its analogues work by inhibiting the activity of mTORC1 through binding to FKBP12 and the establishment of a ternary complex with mTOR.6Actually, there are three available mTOR inhibitors: everolimus, temsirolimus, and ridaforolimus. Everolimus is currently used for the treatment of advanced hormone receptor–positive HER2-negative breast cancer together with exemestane, renal-cell carcinoma after failure of therapies based on sunitinib or sorafenib, progressive neuroendocrine tumors of pancreatic origin, in combination with exemestane, and subependymal giant-cell astrocytoma.
These drugs have a different spectrum of side effects compared to conventional chemotherapy. Common side effects are anemia, fatigue, hyperglycemia, hyperlipidemia, stomatitis, rash, and thrombocytopenia.5,7 The terms “oral mucositis” and “stomatitis” are both used to describe inflammation and ulceration of the oral mucosal lining due to chemotherapy or ionizing radiation. However, stomatitis associated with mTOR inhibitors should be considered a separate entity this often being designated as mTOR inhibitor–associated stomatitis (mIAS).8,9 Mouth lesions present as superficial, ovoid, well-demarcated singular or multiple ulcers with a grayish white pseudomembrane. Their size often does not exceed 0.5 cm in diameter. Lesions typically involve the nonkeratinized mucosa, like the inner aspect of the lips, the ventral and lateral surfaces of the tongue, and the soft palate. Ulcers generally develop in 5 days and usually heal spontaneously in 1 week, most frequently in the first cycle of mTOR-inhibitor therapy.10
Methods
This review was performed to answer to the question “Which is the rate of incidence of stomatitis in patients treated with everolimus?” A systematic search on the online databases PubMed and Medline was conducted using a combination of MESH terms and free-text words: “everolimus” (MESH) AND “side effects” OR “toxicities” OR “adverse events”. The authors included in this study only reports that fulfilled certain criteria: performed on human subjects, everolimus alone or in combination with other drugs/ionizing radiation, written in the English language, and providing incidence of side effects. No restrictions were applied on year of publication. Reviews, case reports, and studies in vitro or performed on animal models were excluded. Information collected comprised name of first author, year, title, number of patients enrolled, and number and grade of events recorded. In addition, data were independently extracted by two authors (CA and LLM) and checked in a joint session.
Results
Our literature search yielded 1,019 potentially relevant studies. After elimination of duplicates, titles and abstracts of 912 potentially relevant studies were screened. Of these, 731 were not considered because they did not meet the inclusion criteria. A total of 181 studies were read in full text. Of these, only 100 reported on stomatitis or oral mucositis, and 30 were excluded due to lack of data (Figure 1). Results howed that the overall incidence of stomatitis after treatment with everolimus was 42.6% (3,493), stomatitis grade G12 84.02% (2,935), and G34 15.97% (558, Table 1).
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Table 1 Papers About Everolimus And Stomatitis |
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Figure 1 Flowchart showing the process of paper selection used in this review. |
Discussion
Targeted therapy includes those drugs that selectively inhibit a target that is mutated in malignant tissue, aiming to achieve preferential localization in the region of disease and thus an increase in local concentration. In particular, mTOR inhibitors work as signal-transduction inhibitors. Rapamycin, also named sirolimus, was the first mTOR inhibitor approved. It is an antiungal agent produced by Streptomyces hygroscopicus with immunosuppressive properties.11 However, sirolimus has been show to have poor pharmacokinetic characteristics, and research has focused on the synthesis of analogues of rapamycin more suitable to therapy, such as everolimus, temsirolimus, and ridaforolimus. These molecules differ from sirolimus in their C-40-O positions, resulting in disparate pharmacokinetic and pharmacodynamic profiles.12 This class of drugs is typically used for the treatment of solid tumors, such as renal-cell carcinoma, breast cancer, pancreatic neuroendocrine tumors, and tuberous sclerosis complex.13–17
Unlike results obtained from reviews about mucositis caused by conventional chemotherapy, in which mucositis is often severe and the most debilitating effect for patients,18 our analysis showed that the incidence of stomatitis of grade 1 or 2 is higher than that of grade 3 or 4. These results are consistent with our previous work.19 However, it must be taken into account that it is not possible to say if side effects are entirely due to everolimus therapy or combination with other drugs. Moreover, not all the papers included in this review specified the exact therapeutic regimen. mIAS generally sets in within a few weeks of initiating everolimus therapy. Grade 3 or 4 lesions may lead to dose interruption or reduction. Interfering with patientfood intake and diminishing quality of life, this kind of toxicity may cause treatment discontinuation or interruption.20
mIAS is often evaluated using common scales employed in the evaluation of conventional oral mucositis (OMAS, 1999; NCI-CTCAE 2006, 2010). However, its clinical appearance tends to differ from conventional mucositis. A more specific mIAS scale was set by Boers-Doets and Lalla. According to this scale, lesions are evaluated depending on their duration, eg, a grade 3 lesion is an ulceration lasting >7 days.21 Management of mIAS is still widely based on education of patients on oral hygiene measures, diet modifications, and pain management.9,22 Treatments used are often based on “magic” mouthwash, composed of lidocaine gel 2% × 30 g, doxycycline suspension 50 mg/5mL × 60 mL, and sucralfate oral suspension 1,000 mg/5 mL dissolved in sodium chloride 0.9% × 2,000 mL used for 3–15 days,23 a sodium bicarbonate–based mouthwash combined with oral fluconazole,24 or a combination of dexamethasone solution 0.5 mg/mL and miconazole 2% gel.25 Another treatment is based on a combination of topical anesthetics, a magic mouthwash (composed of lidocaine, aluminum hydroxide, magnesium hydroxide, dimethicone suspension, diphenhydramine, equal parts) clobetasol gel 0.05%, dexamethasone 0.1 mg/mL, triamcinolone paste, intralesional triamcinolone, and systemic prednisone (1 mg/kg for 7 days). Management of mIAS nowadays is based on education of patients on oral hygiene measures, diet modifications, and pain management.9 Rugo et al showed evidence of the efficacy of a prophylactic use of dexamethasone mouthwash in patients treated with everolimus plus exemestane for advanced or metastatic breast cancer.26 The mouthwash was administered in combination with a prophylactic topical antifungal agent to prevent potential fungal infection.26 It still cannot be determined which lesions will self-limit and which will reduce quality of life, leading to malnutrition and dose reduction in medically necessary treatment.
Disclosure
The authors report no conflicts of interest in this work
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