title: 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.
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Weickhardt
authors.forename: Robert C
authors.initials: RC
authors.lastname: Doebele
authors.forename: W Thomas
authors.initials: WT
authors.lastname: Purcell
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bunn
authors.forename: Ana B
authors.initials: AB
authors.lastname: Oton
authors.forename: Micol S
authors.initials: MS
authors.lastname: Rothman
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Wierman
authors.forename: Tony
authors.initials: T
authors.lastname: Mok
authors.forename: Sanjay
authors.initials: S
authors.lastname: Popat
authors.forename: Julie
authors.initials: J
authors.lastname: Bauman
authors.forename: Jorge
authors.initials: J
authors.lastname: Nieva
authors.forename: Silvia
authors.initials: S
authors.lastname: Novello
authors.forename: Sai-Hong Ignatius
authors.initials: SH
authors.lastname: Ou
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000097:blood*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D015179:Colorectal Neoplasms / Q000188:drug therapy; D000077547:Crizotinib; D005640:Follicle Stimulating Hormone / Q000097:blood; D006801:Humans; D007006:Hypogonadism / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis; D008175:Lung Neoplasms / Q000188:drug therapy; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects*; D012709:Serum Albumin / Q000378:metabolism; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism; D011795:Surveys and Questionnaires; D013739:Testosterone / Q000097:blood*
chemical_list: D000728:Androgens; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D012709:Serum Albumin; D012738:Sex Hormone-Binding Globulin; D013739:Testosterone; D000077547:Crizotinib; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone