Oral adverse effects of CDK4/6 inhibitors among breast cancer patients: a systematic review and meta-analysis

Background Cyclin-dependent kinase (CDK) inhibitors are widely used to treat hormone receptor-positive (HR+) breast cancer due to their efficient performance in improving survival outcomes. Although the side effects of these agents on the hematological and gastrointestinal systems have attracted significant attention, the adverse effects that have direct impacts on patients' quality of life, such as stomatitis, have not been well explored to date. Methods A systematic literature search was conducted in the PubMed, Google Scholar, European Society of Medical Oncology (ESMO), and American Society of Clinical Oncology databases. Phase 2 and 3 randomized trials on CDK4/6 inhibitors (CDK4/6Is) were identified and used in the meta-analysis based on the completeness of their safety data. Results Of the 904 records screened, 40 studies were considered relevant. Six studies were used in the meta-analysis, with a total of 2,980 patients in the safety population. The pooled relative risk (RR) and risk difference (RD) for any-grade stomatitis were 2.02 (95% CI: 1.65-2.48) and 0.10 (95% CI: 0.05-0.15), respectively. In the subgroup analysis, higher RRs were observed among patients receiving letrozole as basic endocrine therapy (ET) (8.50, 95% CI: 2.22-32.57) or palbociclib-containing regimens (2.44, 95% CI: 1.88-3.18), whereas the RDs showed no significant difference. Discussion All CDK4/6Is, especially palbociclib, could increase the risk of developing stomatitis among patients with breast cancer. Prevention and management of CDK4/6Is-related stomatitis may effectively reduce its secondary impacts. Due to the lack of individual-level data, some important personal confounding variables could not be controlled. Besides, the explanations of the secondary effects of stomatitis in this study were only based on the literature and professional knowledge. The specific quantitative impacts on patient quality of life and compliance require further questionnaire investigation. More in-depth individual-level data are needed to quantify the effect of stomatitis on patients' quality of life and treatment compliance.