Hemodialysis no reason to withhold everolimus

Abstract

Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR) was reported to have anti-tumor activity in neuroendocrine tumors (NET) in phase III studies [1, 2]. These studies excluded patients with major comorbidities. This is not reflecting common practice. Particularly in NETs, often diagnosed in middle-aged or elderly patients, multiple comorbid conditions can coexist [3]. This can pose a challenge in the systemic treatment for a NET. One of the possible comorbidities is renal insufficiency. In Von Hippel–Lindau disease, a disease that predisposes to NET, even up to 25 % of patients develop terminal renal failure due to surgery for renal cell carcinoma. We have treated a 76-year-old lady suffering from a terminal renal insufficiency requiring hemodialysis with everolimus. She had a serotonin producing to the liver metastasized grade 1 ileac carcinoid. The patient had clinical and radiologic progressive disease with diarrhea while on treatment with a somatostatin analog. Comorbidity precluded treatment with interferon or radioactive lutetium. Therefore, treatment with everolimus was considered. Everolimus is in 98 % metabolised by the liver and excreted in the bile and only 2 % is eliminated in the urine [4]. No information is available on everolimus treatment in solid tumor patients on hemodialysis. Given its elimination profile and availability of an everolimus blood level assay, we decided that it was worth to start everolimus in this patient with terminal renal failure. Everolimus was started, under controlled conditions, at 50 % of the starting dose in the phase 3 NET trials, namely 5 mg orally once daily. After 3 weeks, she experienced no side effects and diarrhea was reduced. Whole blood everolimus concentrations at steady state were measured with liquid chromatography–mass spectrometry at two different times to rule out unexpected toxic accumulation. Whole blood everolimus levels were 4.4 and 6.5 lg/l before and 3.3 and 5.8 lg/l after hemodialysis. These values do not exceed the levels measured in solid tumor patients using 5 mg everolimus with normal renal function [5]. After 6 weeks of use, an ongoing decrease in diarrhea and fatigue and a decrease in chromagranin A occurred. Liver metastases were stable on ultrasound of the liver. The dose was increased to 10 mg daily and everolimus blood levels after 1 week did not exceed the previously reported blood values in patients using 10 mg. The patient is currently on everolimus treatment for 9 months without adverse effects. In conclusion, everolimus at a dose of 5–10 mg orally once daily can be used in patients with end-stage renal disease requiring hemodialysis in the treatment for solid tumors. Our findings confirm the recent report about two patients on hemodialysis. Here, hemodialysis did also not influence everolimus blood concentrations in renal cell cancer patients using 10 mg everolimus orally once daily [6]. These findings can help translating the treatment of a selected study population to clinical practice. This is of relevance given the growing number of indications for everolimus, including since recently postmenopausal estrogen positive advanced breast cancer [7]. J. M. van Rooijen (&) E. G. E. de Vries Department of Medical Oncology, University Medical Center Groningen, P.O. Box 30001, Groningen, The Netherlands e-mail: j.m.van.rooijen@umcg.nl