title: Characterization and Management of Hedgehog Pathway Inhibitor-Related Adverse Events in Patients With Advanced Basal Cell Carcinoma.
abstract: Abnormal activation of hedgehog pathway signaling is a key driver in the pathogenesis of basal cell carcinoma (BCC). Vismodegib, a first-in-class small-molecule inhibitor of hedgehog pathway signaling, is approved by regulatory authorities for the treatment of adults who have metastatic BCC or locally advanced BCC that has recurred after surgery, or who are not candidates for surgery and who are not candidates for radiation. A second inhibitor, sonidegib, was also recently approved for the same patient group with locally advanced BCC. Adverse events (AEs) commonly observed in hedgehog pathway inhibitor (HPI)-treated patients include muscle spasms, ageusia/dysgeusia, alopecia, weight loss, and asthenia (fatigue). These AEs are thought to be mechanistically related to inhibition of the hedgehog pathway in normal tissue. Although the severity of the majority of AEs associated with HPIs is grade 1-2, the long-term nature of these AEs can lead to decreased quality of life, treatment interruption, and in some cases discontinuation, all of which might affect clinical outcome. The incidence, clinical presentation, putative mechanisms, and management strategies for AEs related to HPIs in advanced BCC are described. These observations represent the first step toward the development of mechanism-based preventive and management strategies. Knowledge of these AEs will allow health care professionals to provide appropriate counseling and supportive care interventions, all of which will contribute to improved quality of life and optimal benefit from therapy.
  
  
  
  The hedgehog pathway inhibitors (HPIs) vismodegib and sonidegib represent a therapeutic breakthrough for patients with advanced basal cell carcinoma. However, the nature of the low-grade adverse events (AEs) commonly observed in HPI-treated patients, including muscle spasms, ageusia/dysgeusia, alopecia, weight loss, and fatigue, can impact clinical outcomes as a result of decreased quality of life and treatment discontinuation. The incidence, clinical presentation, putative mechanisms, and management strategies for AEs related to administration of HPIs are described, with the goal of enabling health care professionals to provide appropriate counseling and supportive care interventions to their patients.
authors: Memorial Sloan Kettering Cancer Center, New York, New York, USA LacoutuM@mskcc.org.
authors: Mario E
authors: ME
authors: Lacouture
authors: Department of Dermatology, Hôtel Dieu University Hospital, Nantes, France.
authors: Brigitte
authors: B
authors: Dréno
authors: Istituto Nazionale Tumori Fondazione, G Pascale, Naples, Italy.
authors: Paolo Antonio
authors: PA
authors: Ascierto
authors: University of Zurich Hospital, Zurich, Switzerland.
authors: Reinhard
authors: R
authors: Dummer
authors: Université Paris 7 and Hôpital Saint-Louis, Paris, France.
authors: Nicole
authors: N
authors: Basset-Seguin
authors: Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, United Kingdom.
authors: Kate
authors: K
authors: Fife
authors: Western University London Regional Cancer Program, London, Ontario, Canada.
authors: Scott
authors: S
authors: Ernst
authors: Fondazione IRCCS, Istituto Tumori, Milan, Italy.
authors: Lisa
authors: L
authors: Licitra
authors: Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
authors: Rogerio I
authors: RI
authors: Neves
authors: Catholic University of Rome, Rome, Italy.
authors: Ketty
authors: K
authors: Peris
authors: Dermatology Department, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomédiques August Pi I Sunyer, Barcelona, Spain.
authors: Susana
authors: S
authors: Puig
authors: Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors: Jonas
authors: J
authors: Sokolof
authors: Mayo Clinic, Scottsdale, Arizona, USA.
authors: Aleksandar
authors: A
authors: Sekulic
authors: Department of Dermatology, University of Kiel, Kiel, Germany.
authors: Axel
authors: A
authors: Hauschild
authors: Medical University of Vienna, Vienna, Austria.
authors: Rainer
authors: R
authors: Kunstfeld
mesh_terms: D000505:Alopecia / Q000139:chemically induced; D000813:Anilides / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001247:Asthenia / Q000139:chemically induced; D001713:Biphenyl Compounds / Q000009:adverse effects*; D002280:Basal Cell Carcinoma / Q000188:drug therapy*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D011725:Pyridines / Q000009:adverse effects*; D015398:Signal Transduction / Q000187:drug effects; D013035:Spasm / Q000139:chemically induced; D013651:Taste Disorders / Q000139:chemically induced; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines; C561435:sonidegib
keywords: Advanced basal cell carcinoma; Adverse events; Hedgehog pathway; Management; Sonidegib; Vismodegib