Prevention and treatment options for mTOR inhibitor-associated stomatitis
Inhibitors of mammalian target of rapamycin (mTOR) are approved for treatment of various advanced solid tumors (renal cell carcinoma, neuroendocrine tumors, breast cancer). mTOR inhibitor-associated stomatitis (mIAS), a frequent, early-onset side effect of this drug class, can be dose limiting and diminish patient quality of life. This systematic review describes clinical presentation and pathophysiology of mIAS and reviews its prevention and treatment. Published literature on mTOR inhibitors and their side effects, and their prevention and treatment were reviewed. Preventative and management strategies under evaluation in clinical trials were also reviewed. The majority of patients develop a mild form of stomatitis that does not interfere with treatment of their disease. A minority of patients can develop moderate to severe mIAS that can be managed with treatment modification or discontinuation, but these approaches may have an impact on disease outcome. mIAS is a relatively recent phenomenon, so evidence-based preventive and therapeutic measures are not yet available – although under active investigation – and current management is based largely on collective experience with chemotherapy- or radiation-induced oral mucositis and aphthous ulcers. Expert opinion and clinical experience from managing oral mucositis and apthous ulcers suggest that management of mIAS should focus on three major approaches: prevention, early aggressive treatment, and, when needed, more aggressive pain management. Early recognition and diagnosis of mIAS facilitate early intervention to limit potential sequelae of mIAS and minimize the need for mTOR inhibitor dose reduction and interruption. Funding for manuscript development was provided by Novartis Pharmaceuticals Corporation.
Accepted for publication February 17, 2017
Correspondence Kavitha J Ramchandran, MD; kavitha@stanford.edu
Disclosures The authors report no disclosures/conflicts of interest.
Citation JCSO 2017;15(2):74-81
©2017 Frontline Medical Communications
doi https://doi.org/10.12788/jcso.0335
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Therapeutic measures for patients with mIAS
Therapeutic measures for mIAS are based largely on experience with chemotherapy- or radiation-induced oral mucositis or recurrent aphthous ulcers (Table 3) and vary in part by the severity of lesions. Treatments for mild mIAS aim to ameliorate symptoms (eg, topical analgesics for pain), protect the oral mucosa (eg, mucoadhesive gels or viscous solutions that coat the oral cavity), prevent potential sequelae (eg, prophylactic antibiotics to avoid secondary infections), and reduce inflammation/immune response (eg, steroid-based mouth rinses, topical steroids, or topical anti-inflammatory agents). Treatments for mild mIAS are generally local rather than systemic.
Treatment options for moderate to severe mIAS include systemic approaches that generally carry increased risk of AEs and, therefore, should be reserved for patients with multiple lesions, uncontrolled or poorly controlled pain, or greatly diminished oral food intake (Table 3).41 When mIAS cannot be controlled with the interventions described, the dose of the mTOR inhibitor can be reduced with the recognition that dose modification of anticancer therapy may affect disease outcomes.29 The experience of reduction or interruption of treatment with everolimus in the BOLERO-2 trial as a strategy for management of AEs is discussed in a recent review.29 Prescribing information for both temsirolimus and everolimus specify that grade 3 AEs be treated with temporary dose interruption, and with resolution (temsirolimus: grade ≤2; everolimus: grade ≤1), treatment may be resumed at lower doses (temsirolimus: reduce by 5 mg/week; no lower than 15 mg/week; everolimus: reduce by half the previously administered dose).3,4 Grade 4 events due to treatment with temsirolimus may also be treated with dose interruption/reduction; the everolimus prescribing information advises treatment discontinuation for grade 4 stomatitis.
Summary and discussion
mTOR inhibitors can be effective treatments for patients with advanced cancer, specifically for advanced RCC, advanced pNET, and HR+, HER2-negative advanced breast cancer. Although mIAS may occur in many patients, it is usually grade 1 or 2 in severity. mIAS has an early onset, usually within the first 2 weeks of treatment16,19,42 and a relatively rapid resolution, usually within 3 weeks.16,19 Thus, most cases of mIAS are self-limiting.
,The relatively recent emergence of mIAS poses short-term challenges regarding diagnosis, assessment, prevention, and treatment. Several clinical studies are underway to evaluate a range of interventions for their preventive and therapeutic efficacy in mIAS. Furthermore, our growing understanding of the underlying pathophysiology of mIAS can guide how mIAS is managed and what interventions patients receive.
Although mIAS is believed to differ from chemotherapy- or radiation-induced oral mucositis and aphthous ulcers, much can be learned from the treatment of both of these. Several strategies have been proposed to limit the occurrence of mIAS (Table 3). First, establish an oral care protocol. Educate patients who are initiating treatment with an mTOR inhibitor on implementation of the oral care protocol and emphasize adherence. Second, educate patients on the symptoms and timing of mIAS. Patients may hesitate to report mild symptoms or assume they are innocuous, so be clear that reporting all symptoms is important to allow timely clinical evaluation. Early recognition of mIAS facilitates early intervention and can prevent dose modification and interruption. Third, implement the preventive and treatment measures described. Many of the preventive measures can be incorporated into an oral care protocol.
The advent of mTOR inhibitors has clinically benefited many patients with cancer. Although side effects, like mIAS, may develop during treatment, they should not be considered insurmountable. Through education, vigilance, and aggressive management, health care providers and patients can work together to help patients maintain their quality of life while continuing to optimally address their disease.
Acknowledgment
The authors thank Anna Lau, PhD, and Patricia Segarini, PhD, of Percolation Communications LLC, for their editorial assistance. Funding for manuscript development was provided by Novartis Pharmaceuticals Corp.
