Symptomatic reduction in free testosterone levels secondary to crizotinib use in male cancer patients

Abstract

Background: Crizotinib is a tyrosine kinase inhibitor active against ALK, MET, and ROS1. We previously reported that crizotinib decreases testosterone in male patients. The detailed etiology of the effect, its symptomatic significance, and the effectiveness of subsequent testosterone replacement have not been previously reported.

Methods: Male cancer patients treated with crizotinib had total testosterone levels measured and results compared with non-crizotinib-treated patients. Albumin, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), and/or luteinizing hormone (LH) were tracked longitudinally. A subset of patients had free testosterone levels measured and a hypogonadal screening questionnaire administered. Patients receiving subsequent testosterone supplementation were assessed for symptomatic improvement.

Results: Mean total testosterone levels were -25% below the lower limit of normal (LLN) in 32 crizotinib-treated patients (27 of 32 patients below LLN, 84%) compared with +29% above LLN in 19 non-crizotinib-treated patients (6 of 19 below LLN, 32%), P = .0012. Levels of albumin and SHBG (which both bind testosterone) declined rapidly with crizotinib, but so did FSH, LH, and free testosterone, suggesting a centrally mediated, true hypogonadal effect. Mean free testosterone levels were -17% below LLN (19 of 25 patients below LLN, 76%). Eighty-four percent (16 of 19) with low free levels, and 79% (19/24) with low total levels had symptoms of androgen deficiency. Five of 9 patients (55%) with low testosterone given testosterone supplementation had improvement in symptoms, coincident with increases in testosterone above LLN.

Conclusions: Symptoms of androgen deficiency and free or total/free testosterone levels should be tracked in male patients on crizotinib with consideration of testosterone replacement as appropriate.

Figure 1

Total testosterone levels in crizotinib treated and non-crizotinib treated patients in relation to lower limit of normal (LLN) of assay used. NCTG non-crizotinib treated group; CTG2 crizotinib treated group 2; CTG 1 crizotinib treated group 1.

Figure 2

Free testosterone levels in crizotinib treated patients relative to lower limit of normal of assay used

Figure 3

Correlation of each individual’s total testosterone relative to lower limit of normal of assay used to free testosterone relative to lower limit of normal of assay used. Total and free testosterone assessed on same occasion in each patient.

Figure 4

Dynamic assessment of sex hormones and testosterone binding proteins in three patients commenced on crizotinib showing decrease in total, free testosterone relative to baseline measurement, as well as rapid decreases in LH and FSH, albumin and sex hormone binding globulin.