title: mTOR inhibitor-induced interstitial lung disease in cancer patients: Comprehensive review and a practical management algorithm.
abstract: Mammalian target of rapamycin inhibitors (mTORi) have clinically significant activity against various malignancies, such as renal cell carcinoma and breast cancer, but their use can be complicated by several toxicities. Interstitial lung disease (ILD) is an adverse event of particular importance. Mostly, mTORi-induced ILD remains asymptomatic or mildly symptomatic, but it can also lead to severe morbidity and even mortality. Therefore, careful diagnosis and management of ILD is warranted. The reported incidence of mTORi-induced ILD varies widely because of a lack of uniform diagnostic criteria and active surveillance. Because of the nonspecific clinical features, a broad differential diagnosis that includes (opportunistic) infections should be considered in case of suspicion of mTORi-induced ILD. The exact mechanism or interplay of mechanisms leading to the development of ILD remains to be defined. Suggested mechanisms are either a direct toxic effect or immune-mediated mechanisms, considering mTOR inhibitors have several effects on the immune system. The clinical course of ILD varies widely and is difficult to predict. Consequently, the discrimination between when mTOR inhibitors can be continued safely and when discontinuation is indicated is challenging. In this review, we give a comprehensive review of the incidence, clinical presentation and pathophysiology of mTORi-induced ILD in cancer patients. We present newly developed diagnostic criteria for ILD, which include clinical symptoms as well as basic pulmonary function tests and radiological abnormalities. In conjunction with these diagnostic criteria, we provide a detailed and easily applicable clinical management algorithm.
authors.affiliation: Department of Medical Oncology, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Annelieke E C A B
authors.identifier: http://orcid.org/0000-0003-2433-1915
authors.initials: AE
authors.lastname: Willemsen
authors.affiliation: Department of Pulmonology, Centre of Interstitial Lung Diseases, St. Antonius Hospital, Nieuwegein, The Netherlands.|Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jan C
authors.initials: JC
authors.lastname: Grutters
authors.affiliation: Department of Medical Oncology, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Winald R
authors.initials: WR
authors.lastname: Gerritsen
authors.affiliation: Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Nielka P
authors.initials: NP
authors.lastname: van Erp
authors.affiliation: Department of Medical Oncology, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: Carla M L
authors.initials: CM
authors.lastname: van Herpen
authors.affiliation: Department of Medical Oncology, Jeroen Bosch Hospital, 's-Hertogenbosch, The Netherlands.
authors.forename: Jolien
authors.initials: J
authors.lastname: Tol
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D019468:Disease Management; D006801:Humans; D015994:Incidence; D017563:Lung Diseases, Interstitial / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology* / Q000378:metabolism / Q000628:therapy; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy; D063868:Patient Outcome Assessment; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases
keywords: everolimus; interstitial lung disease; mTOR inhibitors; pneumonitis; toxicity