Retrospective Study of Bleeding Risk with Concomitant Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor and Anticoagulation.

BACKGROUND: Patients with cancer are at higher risk for venous thromboembolism (VTE) and bleeding, in turn complicating anticoagulant therapy. An added complexity is the toxicity profile of agents used to treat certain cancers, namely the vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs), which are associated with both thromboembolism and hemorrhages. The purpose of this study was to evaluate whether patients taking concurrent VEGF TKI and therapeutic anticoagulant were at higher risk for bleeding compared with patients taking VEGF TKI alone. MATERIALS AND METHODS: This was a single-center, retrospective chart review of patients who underwent treatment with a VEGF TKI with or without anticoagulant. The primary outcome included comparison of major bleeding rates between groups. Secondary outcomes included comparison of composite major and minor bleed rates and assessment of VTE incidence and recurrence among patients treated with a VEGF TKI and VEGF TKI plus anticoagulant, respectively. RESULTS: A total of 184 and 74 patients were included in the VEGF TKI alone and VEGF TKI + anticoagulant groups, respectively. Major bleeding events occurred in 6 of 184 patients (3.3%) and 6 of 74 patients (8.1%), respectively (p = .095). Composite major and minor bleeding events occurred in 22 of 184 (13.6%) and 17 of 74 (23%), respectively (p = .026). A total of 26 of 258 patients (10.1%) experienced a VTE event while taking a VEGF TKI, and 1 of 26 (3.8%) experienced a recurrent VTE event while taking a VEGF TKI plus anticoagulant. CONCLUSION: Patients who received concomitant VEGF TKI plus anticoagulant had increased incidence of bleeding, although prospective studies are needed to further explore this association. IMPLICATIONS FOR PRACTICE: The current study showed that use of concomitant vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGF TKI) and therapeutic anticoagulation was associated with an increased risk of composite bleeding events, although at comparable rates between patients treated with VEGF TKI plus direct oral anticoagulant (DOAC) versus VEGF TKI plus non-DOAC anticoagulant. This suggests that when anticoagulation is indicated in a patient receiving a VEGF TKI, the novel DOACs may be a safe alternative to historical anticoagulants (warfarin and enoxaparin). These results fill a gap in the literature and will help guide treatment decisions for patients requiring concurrent VEGF TKI and anticoagulation.

Safety and efficacy of extended dosing intervals of denosumab in patients with solid cancers and bone metastases: a retrospective study.

AIM: More than half of patients with breast, lung, or prostate cancer who have bone metastases have evidence of skeletal-related events (SREs). Denosumab is a fully human monoclonal antibody that binds to and neutralizes receptor activator of nuclear factor kappa-B ligand (RANKL) on osteoblasts and their precursors. The United States Food and Drug Administration (FDA)-approved dose of denosumab is 120 mg every 4 weeks; however, other schedules have been used in practice for patient convenience. Evidence for the safety and efficacy of alternative dosing intervals is lacking. PATIENT & METHODS: Adult patients with solid cancers and bone metastases who received at least two doses of denosumab 120 mg were reviewed. Patients were grouped based on an average denosumab dosing interval of <5 weeks (short-interval) versus 5-11 weeks (medium-interval) versus ⩾12 weeks (long-interval). The primary outcome was the time to first SRE while on denosumab between the short- and medium-interval groups. The secondary outcomes were overall survival (OS), efficacy comparisons between the other groups, and safety events. RESULTS: There was no significant difference in median time to first SRE between the short- and medium-interval denosumab groups [33.2 versus 28.4 months, hazard ratio (HR): 1.13, 95% confidence interval (CI): 0.66-1.92, p = 0.91] or the medium- and long-interval dosing groups (28.4 versus 32.2 months, HR: 1.15, 95% CI: 0.66-2.01, p = 0.62). Median OS was not found to differ significantly between any of the groups. There were significantly more hospitalizations in the short-interval dosing group than the other groups (55.2% versus 33.8% versus 30.4%, p < 0.001). CONCLUSION: Extending denosumab dosing intervals does not appear to negatively impact time to first SRE and is associated with fewer hospitalizations in real-world patients with solid cancers and bone metastases.

Olaparib: A Novel Therapy for Metastatic Breast Cancer in Patients With a BRCA1/2 Mutation.

Breast cancer is the most frequently diagnosed cancer in women globally. Genetic mutations can increase the risk of developing breast cancer. Inherited germline mutations in BRCA1 and BRCA2 tumor suppressor genes (gBRCAm) account for 5% to 10% of breast cancer cases. The recent approval of olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in HER2-negative, metastatic breast cancer provides an additional treatment option for patients with a gBRCAm. Inhibition of PARP results in the trapping of the PARP-DNA complex at replication forks, causing single-strand breaks to become double-strand breaks (DSBs). PARP trapping and the accumulation of DSBs ultimately leads to cell apoptosis. Cells deficient in BRCA1/2 are particularly sensitive to the effects of PARP inhibition, as cells lacking these functional proteins are unable to repair DSBs, resulting in synthetic lethality. The phase III OlympiAD trial showed a progression-free survival benefit but no overall survival benefit, leading to the US Food and Drug Administration approval of olaparib. The purpose of this article is to describe current data regarding the use of olaparib in metastatic breast cancer, its role in the treatment of patients with a gBRCAm, and the clinical implications of its approval for oncology advanced practitioners.