Irreversible ototoxicity associated with the use of erlotinib in a patient with pancreatic cancer

Koutras, Angelos; Mastronikolis, Nicholas; Evans, TR Jeffry; Papadeas, E.; Makatsoris, Thomas; Kalofonos, Haralabos P.

doi:10.1080/02841860802213328

Cited by 9 publications

(6 citation statements)

References 9 publications

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“…Although other potential endpoints in such trials are of great interest, and may have a place as secondary endpoints in trials, we argue here, based on our initial experience with small numbers of patients as well as published studies on NF2 and VS, that a standardized assessment of these two endpoints should be included routinely in trials of antitumor drugs in NF2. We do not here systematically address certain other important aspects of phase II trial design, such as entry criteria (including definitions of NF2 and of VS in the absence of histological diagnosis), choice of trial design (e.g., singlearm, randomized with active or placebo comparator arm [30, 31], crossover [32], or randomized discontinuation [30, 33]), measuring responses in non-VS lesions such as meningiomas or other schwannomas, toxicities that should be monitored with special significance in NF2 such as ototoxicity [34] and corneal keratopathy (to which patients with trigeminal lesions may be especially susceptible) [35], or the “go/no go” choice of what level of response justifies proceeding to phase III trials for a specific agent [36]. …”

Section: Introductionmentioning

confidence: 99%

Suggested response criteria for phase II antitumor drug studies for neurofibromatosis type 2 related vestibular schwannoma

Plotkin

Halpin

Blakeley³

et al. 2009

J Neurooncol

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Neurofibromatosis type 2 (NF2) is a tumor suppressor gene syndrome characterized by multiple schwannomas, especially vestibular schwannomas (VS), and meningiomas. Anticancer drug trials are now being explored, but there are no standardized endpoints in NF2. We review the challenges of NF2 clinical trials and suggest possible response criteria for use in initial phase II studies. We suggest two main response criteria in such trials. Objective radiographic response is defined as a durable 20% or greater reduction in VS volume based on postcontrast T1-weighted MRI images collected with 3 mm or finer cuts through the internal auditory canal. Hearing response is defined as a statistically significant improvement in word recognition scores using 50-word recorded lists in audiology. A possible composite endpoint incorporating both radiographic response and hearing response is outlined. We emphasize pitfalls in response assessment and suggest guidelines to minimize misinterpretations of response. We also identify research goals in NF2 to facilitate future trial conduct, such as identifying the expectations for time to tumor progression and time to measurable hearing loss in untreated NF2-related VS, and the relation of both endpoints to patient prognostic factors (such as age, baseline tumor volume, and measures of disease severity). These data would facilitate future use of endpoints based on stability of tumor size and hearing, which might be more appropriate for testing certain drugs. We encourage adoption of standardized endpoints early in the development of phase II trials for this population to facilitate comparison of results across trials of different agents.

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Section: Introductionmentioning

confidence: 99%

Suggested response criteria for phase II antitumor drug studies for neurofibromatosis type 2 related vestibular schwannoma

Plotkin

Halpin

Blakeley³

et al. 2009

J Neurooncol

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“…After a 400 mg/day dose of imatinib was administered for five days, bilateral hearing loss developed [6] . In addition to this, sensorineural hearing loss due to erlotinib was reported in a patient [12] .…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Lapatinib and Trastuzumab for Ototoxic Effects

Eryılmaz

Demirci²,

Günel³

et al. 2016

Int Adv Otol

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Original Article INTRODUCTIONTrastuzumab (Herceptin®; Genentech, California, San Francisco, USA) is used for treating human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Trastuzumab is a humanized recombinant monoclonal antibody that acts on the extracellular portion of the HER2 protein [1] . Lapatinib (Tykerb®; Glaxo-Smith Kline) is a tyrosine kinase inhibitor that suppresses epidermal growth factor 1 (EGF-1) and intracellular phosphorylation of the HER-2/neu receptor. In studies with trastuzumab, cardiotoxicity is stated as the most common side effect [2] . The known side effects of lapatinib are the reduction of the left ventricular ejection fraction, interstitial lung disease/pneumonitis, dizziness, fatigue, severe diarrhea, dry cough, white sores in the mouth or lips, nosebleeds, nausea, stomach pain, jaundice, loss of appetite, aspartate aminotransferase (AST) changes, alanine aminotransferase (ALT) changes, and hematological changes [3,4] . To our knowledge, the ototoxicity of these chemotherapeutic agents has not yet been studied. The aim of this study is to identify whether these agents are ototoxic in rats and to determine the dose dependency of the ototoxicity. MATERIALS and METHODSThe study was approved by the Animal Experiments Ethical Committee of Adnan Menderes University (64583101/2013/038). A total of 48 male rats aged 4-8 months were randomly divided into six groups. All rats were subjected to distortion product otoacoustic emissions (DPOAE) on the first day after being anesthetized with ketamine/xylazine. Group 1 (control group) received Evaluation of Lapatinib and Trastuzumab for Ototoxic EffectsOBJECTIVE: Trastuzumab and lapatinib are widely used chemotherapeutic agents. Our aim in this study was to assess the possible ototoxicity of these chemotherapeutic agents. MATERIALS and METHODS:Forty-eight rats were divided into six groups: Group 1 (control, n=8) received intraperitoneal saline for 7 days. Group 2 (n=8) and Group 3 (n=8) received 10 mg/kg and 30 mg/kg single doses of intraperitoneal trastuzumab, respectively. Lapatinib was administered by oral gavage to Group 4 (n=8) at 100 mg/kg/day and to group 5 (n=8) at 300 mg/kg/day for 7 days. Group 6 (n=8) received only one dose of 10 mg/kg intraperitoneal trastuzumab; subsequently, Group 6 received one dose of lapatinib at 100 mg/kg/day by oral gavage for 7 days. Before any medication was administered, distortion product emissions (DPOAE) were obtained. DPOAE tests were performed again on the rats on day 7, after which the mastoid bullas were harvested. The apoptosis degree was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) procedure. RESULTS:The lapatinib 300 and lapatinib+trastuzumab groups (p=0.008 and p=0.001, respectively) were significantly different from the control group according to the spiral ganglion TUNEL. Apoptosis in the organ of corti was statistically different compared with the control group in the lapatinib 100, lapatinib 300, and lapatinib+trastuzu...

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“…After treatment with first generation RTK inhibitors, 50% of patients have a secondary missense T790 mutation resulting in acquired resistance due to steric hindrance with a bulkier methionine (Pao et al, 2005, Shepherd et al, 2005, Engelman and Janne, 2008, Sequist et al, 2011, Majem and Pallares, 2013). Although no preclinical studies of their ototoxicity, one clinical case was reported with erlotinib ototoxicity (Koutras et al, 2008). The success of this first generation inhibitors coupled with the known acquired resistance has resulted in a need for new RTK inhibitor therapies with more sustained effects than gefitinib and erlotinib (Han et al, 2008, Butts et al, 2010, Mukherjea et al, 2011, Allen et al, 2012, Yang et al, 2013, Agustoni et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Canertinib induces ototoxicity in three preclinical models

Tang

Qian

et al. 2015

Hearing Research

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Neuregulin-1 (NRG1) ligand and its epidermal growth factor receptor (EGFR)/ERBB family regulate normal cellular proliferation and differentiation in many tissues including the cochlea. Aberrant NRG1 and ERBB signaling cause significant hearing impairment in mice. Dysregulation of the same signaling pathway in humans is involved in certain types of cancers such as breast cancer or non-small cell lung cancer (NSCLC). A new irreversible pan-ERBB inhibitor, canertinib, has been tested in clinical trials for the treatment of refractory NSCLC. Its possible ototoxicity was unknown. In this study, a significant dose-dependent canertinib ototoxicity was observed in a zebrafish model. Canertinib ototoxicity was further confirmed in two mouse models with different genetic backgrounds. The data strongly suggested an evolutionally preserved ERBB molecular mechanism underlying canertinib ototoxicity. Thus, these results imply that clinical monitoring of hearing loss should be considered for clinical testing of canertinib or other pan-ERBB inhibitors.

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Irreversible ototoxicity associated with the use of erlotinib in a patient with pancreatic cancer

Cited by 9 publications

References 9 publications

Suggested response criteria for phase II antitumor drug studies for neurofibromatosis type 2 related vestibular schwannoma

Suggested response criteria for phase II antitumor drug studies for neurofibromatosis type 2 related vestibular schwannoma

Evaluation of Lapatinib and Trastuzumab for Ototoxic Effects

Canertinib induces ototoxicity in three preclinical models

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