Risk of mucocutaneous toxicities in patients with solid tumors treated with everolimus; a systematic review and meta-analysis

Abstract

Background: We performed a systematic review and meta-analysis of mucocutaneous toxicities associated with the use of everolimus in solid tumors. Patients and methods: Eligible studies included randomized Phase II and III trials of patients with solid tumors on everolimus; describing events of stomatitis, skin rash, pruritus and mouth ulceration. Results: Our search strategy yielded 380 potentially relevant citations on everolimus from Pubmed/Medline, CENTRAL Cochrane registry and American Society of Clinical Oncology meeting library. After exclusion of ineligible studies, a total of 10 clinical trials were considered eligible for the meta-analysis, including eight Phase III trials and two Phase II trials. The relative risk of all-grade stomatitis, skin rash, pruritus and mouth ulceration were 3.86(95% CI: 2.23–6.68; p < 0.001); 3.49(95% CI: 2.39–5.08; p < 0.0001); 2.85(95% CI: 2.04–3.97; p = 0.0001); 3.31 (95% CI: 1.46–7.50; p = 0.004); respectively. Exploratory subgroup analysis showed no effect of tumor types or treatment regimen on the relative risk of the relevant adverse events. Conclusion: Our meta-analysis has demonstrated that everolimus is associated with a significantly increased risk of all-grade stomatitis, skin rash, and pruritus and mouth ulceration. Clinicians should be aware of these risks and perform early clinical assessment and intervene accordingly.

Keywords::

• everolimus
• meta-analysis
• pruritus
• skin rash
• stomatitis

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

 Background

• Everolimus is a rapamycin derivative that inhibits the mTOR pathway by acting on mTOR complex-1.

• Currently, the US FDA has approved everolimus for patients with metastatic renal cell carcinoma, advanced pancreatic neuroendocrine tumors and advanced hormone receptor positive breast cancer, in addition to its use in tuberous sclerosis-related malignancies.

• mTOR inhibitors, including everolimus, have been linked to a unique spectrum of adverse events, most notably including mucocutaneous adverse events.

• In this review, the authors performed a systematic review and meta-analysis of mucocutaneous toxicities associated with everolimus.

 Methodology

• Eligible studies included randomized Phase II and III trials of patients with solid tumors on everolimus, describing events of skin stomatitis, skin rash and pruritus and mouth ulceration.

 Results

• After proper selection of the studies, a total of 10 randomized clinical trials were considered eligible for the meta-analysis.

• Patients treated with everolimus had a significantly increased risk of all-grade mucocutaneous toxicities (including stomatitis, skin rash and pruritus and mouth ulceration).

• Subgroup analyses showed there was no effect of tumor types or treatment regimen.

• Clinicians should be aware of these risks and perform regular mucocutaneous monitoring.