A single-center retrospective safety analysis of cyclin-dependent kinase 4/6 inhibitors concurrent with radiation therapy in metastatic breast cancer patients

Abstract

Cyclin dependent kinases 4/6 (CDK4/6) inhibitors gained an essential role in the treatment of metastatic breast cancer. Nevertheless, data regarding their use in combination with radiotherapy are still scarce. We performed a retrospective preliminary analysis of breast cancer patients treated at our Center with palliative radiation therapy and concurrent CDK4/6 inhibitors. Toxicities were measured according to CTCAE 4.0, local response according to RECIST 1.1 or PERCIST 1.0 and pain control using verbal numeric scale. 18 patients (32 treated sites) were identified; 50% received palbociclib, 33.3% ribociclib and 16.7% abemacliclib. Acute non-hematologic toxicity was fair, with the only exception of a patient who developed G3 ileitis. During 3 months following RT, 61.1% of patients developed G 3-4 neutropenia; nevertheless no patient required permanent suspension of treatment. Pain control was complete in 88.2% of patients three months after radiotherapy; 94.4% of patients achieved and maintained local control of disease. Radiotherapy concomitant to CDK4/6 inhibitors is feasible and characterized by a fair toxicity profile, with isolated episodes of high-grade reversible intestinal toxicity. Rate of G 3-4 neutropenia was comparable with that measured for CDK4/6 inhibitors alone. Promising results were reported in terms of pain relief and local control of disease. Selective cyclin dependent kinases 4/6 (CDK4/6) inhibitors block tumor suppressor retinoblastoma protein phosphorylation, preventing the transition of cancer cells from G1 to S phase with consequent inhibition of cell cycle and proliferation 1. To date, three CDK4/6 inhibitors are approved against hormone receptor positive, human epidermal growth factor receptor 2 negative metastatic or advanced breast cancer in combination with aromatase inhibitors or fulvestrant both in first and subsequent lines of therapy. After different phase III trials 2-7 reporting significant improvements in response rate and progression free survival, palbociclib was the

Oligometastatic Breast Cancer: How to Manage It?

“…Although the results of these trials are limited by the small number of the sample, the clinical and radiological outcomes are promising. Future studies with a larger population and a longer follow-up will validate these results [64,77].…”

Unexpected toxicity of CDK4/6 inhibitor palbociclib and radiotherapy

“…22,23 Furthermore, hypofractionated radiotherapy is often applied showing several cases of G3 skin and gastrointestinal toxicity. [13][14][15][16][17][18] However, the nature and limited size of these studies, including our study, make it difficult to reliably predict the absolute risk of increased toxicity.…”

“…13,14 Two retrospective studies show that the combination is generally safe, but the authors also report a G3 ileitis in one patient (10 Â 3 Gy) and G3 skin toxicity in two patients (radiation dose not mentioned). 15,16 Grade 3 esophagitis is described in two case reports (30 Â 2 Gy and 5 Â 4 Gy), combined with G3 dermatitis in one patient. 17,18 Also, a conference abstract reports unexpected pronounced pulmonary fibrosis and radiation pneumonitis.…”

RB expression confers sensitivity to CDK4/6 inhibitor–mediated radiosensitization across breast cancer subtypes

“…Taken together, our results suggest that CDK4/6 inhibition + RT is a promising strategy to decrease recurrence and increase local disease control across ER+ and TNBC and that RB may be a potential biomarker for efficacy. Concerns about the safety of concurrent CDK4/6 inhibition and RT remain, and to date, small studies exploring outcomes in patients with MBC receiving palliative radiation and CDK4/6 inhibitor therapy have conflicting results regarding toxicity, depending on the dose/fractionation of radiation and the regions targeted in the metastatic setting (visceral organs) (61)(62)(63)(64). Reassuringly, no studies to date have demonstrated more pronounced side effects of CDK4/6 inhibitors, such as cytopenias and skin desquamation, in women receiving concurrent therapy to the breast or axillary regions.…”

“…Concerns about the safety of concurrent CDK4/6i and RT remain, and to date, small studies exploring outcomes in patients with metastatic breast cancer receiving palliative radiation and CDK4/6 inhibitor therapy have conflicting results regarding toxicity, depending on the dose/fractionation of radiation and the regions targeted in the metastatic setting (visceral organs; refs. 61 – 64 ). Reassuringly, to our knowledge, no studies to date have demonstrated more pronounced side effects of CDK4/6 inhibitors, such as cytopenias and skin desquamation, in women receiving concurrent therapy to the breast or axillary regions.…”