Annelieke E C A B Willemsen1, Lioe-Fee de Geus-Oei2,3, Maaike de Boer4, Jolien Tol5, Yvonne Kamm6, Paul C de Jong7, Marianne A Jonker8, Allert H Vos9, Willem Grootjans2, Johannes W B de Groot10, Sasja F Mulder1, Erik H J G Aarntzen11, Winald R Gerritsen1, Carla M L van Herpen1, Nielka P van Erp12. 1. Department of Medical Oncology, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, the Netherlands. 2. Department of Radiology, Leiden University Medical Center (LUMC), Leiden, the Netherlands. 3. Biomedical Photonic Imaging Group, MIRA Institute, University of Twente, Enschede, the Netherlands. 4. Division of Medical Oncology, Department of Internal Medicine, GROW-School of Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands. 5. Department of Medical Oncology, Jeroen Bosch Hospital, 's-Hertogenbosch, the Netherlands. 6. Department of Medical Oncology, Maasziekenhuis Pantein, Boxmeer, the Netherlands. 7. Department of Medical Oncology, St. Antonius Ziekenhuis, Utrecht, the Netherlands. 8. Department for Health Evidence, Radboud university medical center, Nijmegen, the Netherlands. 9. Department of Medical Oncology, Bernhoven Ziekenhuis, Uden, the Netherlands. 10. Isala Oncology Center, Zwolle, the Netherlands. 11. Department of Radiology and Nuclear Medicine, Radboud university medical center, Nijmegen, the Netherlands. 12. Department of Pharmacy, Radboud Institute for Health Sciences, Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands. Nielka.vanerp@radboudumc.nl.
Abstract
BACKGROUND: Treating breast cancer patients with everolimus and exemestane can be challenging due to toxicity and suboptimal treatment responses. OBJECTIVE: We investigated whether everolimus exposure and early metabolic response are predictors for toxicity and effectiveness in these patients. PATIENTS AND METHODS: We performed pharmacokinetic assessments 14 and 35 days after starting treatment. [18F]fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) was performed at baseline, and 14 and 35 days after the start of the therapy. We recorded toxicity, defined as dose interventions within 3 months, and progression-free survival (PFS). RESULTS: Among 44 evaluable patients, the geometric mean (GM) Ctrough was higher in patients with toxicity compared to patients without (17.4 versus 12.3 μg/L (p = 0.02)). The optimal cut-off value to predict toxicity was Ctrough > 19.2 μg/L. GM Ctrough of patients with and without progressive disease (PD) within 3 months was not significantly different (12.0 versus 15.2 μg/L (p = 0.118)). In 28 evaluable patients, PD within 3 months could best be predicted using the percentage decrease in peak standardized uptake value normalized by lean body mass of the lesion with highest FDG uptake (SULpeak high) at day 14. Patients with <11% versus >11% decrease in SULpeak high at day 14 had a median PFS of 90 days versus 411 days, respectively (p = 0.0013) and more frequently had PD within 3 months: 70 vs 11%, respectively. CONCLUSIONS: Our results show that everolimus toxicity is related to everolimus Ctrough. No relation was observed between everolimus exposure and treatment effectiveness. An early FDG-PET can identify patients at high risk of nonresponse. These results warrant further validation. Clinicaltrials.gov identifier: NCT01948960.
BACKGROUND: Treating breast cancerpatients with everolimus and exemestane can be challenging due to toxicity and suboptimal treatment responses. OBJECTIVE: We investigated whether everolimus exposure and early metabolic response are predictors for toxicity and effectiveness in these patients. PATIENTS AND METHODS: We performed pharmacokinetic assessments 14 and 35 days after starting treatment. [18F]fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) was performed at baseline, and 14 and 35 days after the start of the therapy. We recorded toxicity, defined as dose interventions within 3 months, and progression-free survival (PFS). RESULTS: Among 44 evaluable patients, the geometric mean (GM) Ctrough was higher in patients with toxicity compared to patients without (17.4 versus 12.3 μg/L (p = 0.02)). The optimal cut-off value to predict toxicity was Ctrough > 19.2 μg/L. GM Ctrough of patients with and without progressive disease (PD) within 3 months was not significantly different (12.0 versus 15.2 μg/L (p = 0.118)). In 28 evaluable patients, PD within 3 months could best be predicted using the percentage decrease in peak standardized uptake value normalized by lean body mass of the lesion with highest FDG uptake (SULpeak high) at day 14. Patients with <11% versus >11% decrease in SULpeak high at day 14 had a median PFS of 90 days versus 411 days, respectively (p = 0.0013) and more frequently had PD within 3 months: 70 vs 11%, respectively. CONCLUSIONS: Our results show that everolimustoxicity is related to everolimus Ctrough. No relation was observed between everolimus exposure and treatment effectiveness. An early FDG-PET can identify patients at high risk of nonresponse. These results warrant further validation. Clinicaltrials.gov identifier: NCT01948960.
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