Risk of hematological toxicities in patients with advanced breast cancer treated with everolimus: A meta-analysis of phase 3 randomized controlled trials.

Abstract

e13087 Background: Aberrant signaling through the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway was shown to involve in endocrine and trastuzumab resistance in breast cancer. Everolimus (E) is an oral mTOR inhibitor and showed clinical benefit in these population with noteworthy safety concerns. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of hematological toxicities. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through January 2018 were queried. Phase 3 RCTs that mention hematological toxicities as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Random effects model was applied. Results: Three phase 3 RCTs with a total of 1992 patients with advanced breast cancer were eligible for analysis. Studies compared E+ paclitaxel(P) + herceptin(H) vs P+H, E+ exemestane(Ex) vs Ex, E+ vinorelbine(V)+ H vs V+H. The RR of all-grade side effects were as follows: anemia, 2.07 (95% CI: 1.45-2.96, p < 0.001); neutropenia, 1.30 (95% CI: 0.97-1.73, p = 0.07); leukopenia, 1.27 (95% CI: 1.06-1.52, p = 0.009); thrombocytopenia, 6.19 (95% CI: 3.25-11.77, p < 0.001); and febrile neutropenia (FN), 4.27 (95% CI: 2.33-7.85, p < 0.001). The RR of high-grade side effects were as follows: anemia, 3.55 (95% CI: 2.33-5.42, p < 0.001); neutropenia, 1.36 (95% CI: 0.92-2.00, p = 0.11); leukopenia, 1.31 (95% CI: 1.04-1.63, p = 0.01); thrombocytopenia, 5.49 (95% CI: 1.82-16.54, p = 0.002); and FN, 4.33 (95% CI: 2.30-8.18, p < 0.001). Conclusions: Our meta-analysis demonstrated that patients on everolimus experienced a significant increase in all grades of anemia, leukopenia and thrombocytopenia. Everolimus-based regimens also contributed to a significant increase in all grades of FN with a relative risk of 4.33 for grade 3 and 4 FN. FN remains a major cause of morbidity, mortality and drug dosing inconsistencies among patients with cancer and proper supportive care is required.