The use of EGFR inhibitor agents is expected to increase in the coming years. When used in combination with other chemotherapeutics, erlotinib potentiates their effects, enhancing cell death (Ng, Tsao, Nicklee, & Hedley, 2002). Nephrotic syndrome associated with gefitinib therapy, Minimal change nephrotic syndrome associated with gefitinib and a successful switch to erlotinib, Crescentic glomerulonephritis in a patient with advanced lung cancer during erlotinib therapy, Remnant kidney hypermetabolism and progression of chronic renal failure, Response of rat inner medullary collecting duct to epidermal growth factor, Segmental distribution of epidermal growth factor binding sites in rabbit nephron, Immunohistochemical study of epidermal growth factor receptor (EGFR) in various types of renal injury, Leukocytoclastic vasculitis during treatment with the oral EGFR tyrosine kinase inhibitor erlotinib, Necrotizing vasculitis due to gefitinib (Iressa), Feedback regulation of EGFR signalling: decision making by early and delayed loops, The role of the EGF family of ligands and receptors in renal development, physiology and pathophysiology, Acute interstitial nephritis presenting as presumed minimal change nephrotic syndrome, Glomerular, tubular and interstitial nephritis associated with non-steroidal antiinflammatory drugs. No obvious higher risk of hyponatremia events related to MAbs was discovered. In addition, there have been several cases of leukocytoclastic vasculitis during treatment with erlotinib  or gefitinib  and one case report of ANCA-negative pauci-immune crescentic glomerulonephritis during erlotinib  therapy. Keywords:  reported an 8 and 6.2% incidence of all grades and grade 3/4 hypokalemia, respectively. Thank you for submitting a comment on this article. Using a mouse model of anti-glomerular basement membrane disease in which the mice developed severe crescentic glomerulonephritis and loss of renal function, Bollée et al. Bokemeyer C, Bondarenko I, Hartmann JT et al.  conducted a meta-analysis including 16 411 patients from 25 randomized controlled trials (RCTs) of published randomized controlled trials to evaluate the incidences and overall risks of all-grade and grade 3/4 electrolyte disorder events associated with anti-EGFR MAbs. Class-related renal adverse events result in dual toxicity including tubular/electrolyte disorders and glomerulopathies. Verzicco I, Regolisti G, Quaini F, Bocchi P, Brusasco I, Ferrari M, Passeri G, Cannone V, Coghi P, Fiaccadori E, Vignali A, Volpi R, Cabassi A. Please enable it to take advantage of the complete set of features! | Class-related renal adverse events result in dual toxicity including tubular/electrolyte disorders and glomerulopathies. Cancer and the kidney: dangereoux liasons or price paid for the progress in medicine? Class-related renal adverse events result in dual toxicity including tubular/electrolyte disorders and glomerulopathies. This is an orally active, reversible EGFR-TKI developed by AstraZeneca. Filter by. According to the data from the clinical trials more than 70% of patients treated with the TKI EGFR expe-rience skin side effects . Other risk factors included age and magnesium values at baseline . Thus, based on this mechanism, one would predict that EGFR inhibitors should be renoprotective. Following the rechallenge with initiation of erlotinib, the patient achieved remission without proteinuria suggesting that erlotinib is a potential treatment option in patients with NS associated with gefitinib therapy . The epidermal growth factor receptor (EGFR) is implicated in various malignancies. 2019 Apr 16;20(8):1877. doi: 10.3390/ijms20081877. Inhibitors of the epidermal growth factor receptor (EGFR) are increasingly used in the treatment of various entities of malignant tumors. Increasing potassium is required to repair Na/K-ATPase due to the magnesium deficiency. This ultimately leads to reduced auto-phosphorylation and cell proliferation. eCollection 2020. Further development concerning lapatinib became HER2-activation and based on a Phase III randomized study comparing lapatinib plus capecitabine versus capecitabine alone in metastatic breast cancer (MBC) patients , lapatinib was approved by the FDA for HER2-activated breast cancer [23, 24]. These cases highlight the variable and often prolonged time course between drug exposure (2 weeks to 6 months) and clinical recognition of kidney injury. Targeted drugs that bind to and inhibit the epidermal growth factor receptor (EGFR) profoundly benefit many patients with solid tumors without the severe adverse effects associated with chemotherapy and radiation. Safety and efficacy of addition of VEGFR and EGFR-family oral small-molecule tyrosine kinase inhibitors to cytotoxic chemotherapy in solid cancers: a systematic review and meta-analysis of randomized controlled trials. Because the EGFR is present in epithelial cells lining the skin, inhibiting it with certain TKIs, such as erlotinib and gefitinib, can produce acneiform rash. The all-grade incidence of hypomagnesemia related to anti-EGFR MAbs was 34.0% compared with 9.7% in controls (95% CI 28.0–40.5%, P < 0.001). [1,2] EGFR is expressed by nearly all adult human tissues, with the notable exception of hematopoietic cells. The skin toxicity appears as early as two weeks into treatment with TKI EGFR and may spontaneously regress or escalate during the treat-ment . Unique side effects of all EGFR inhibitors include: Skin rash & Dry skin Finger or toenail infection Inflammation of mouth and lips (stomatitis) © The Author 2017. Unlike reversible first-generation TKIs, afatinib is an irreversible inhibitor of the TK activity of EGFR through the formation of a covalent bond to the ATP-binding site [26, 27]. Please check for further notifications by email. On the other hand, EGFR activation is a pivotal mediator for renal fibrosis and may interact with TGF-β signaling [8, 9] and delayed EGFR inhibition with a clinically available EGFR inhibitor, even after the onset of acute kidney injury (AKI), was shown to effectively reduce kidney damage and AKI . In vitro, cetuximab abolished the stimulatory effect of EGF on TRPM-6 activity, thus affecting Mg2+ transport and leading to hypomagnesemia [55, 59–62]. We attributed the panniculitis to a side effect of EGFR inhibitors because there were no confounding elements explaining the cutaneous findings. Colorectal cancer patients had the highest risk of grade 3/4 hypomagnesemia events among cancer patients: compared with chemotherapy alone, addition of cetuximab increased the risk of grade 3/4 hypomagnesemia with RRs of 7.14 (95% CI 3.13–16.27, P < 0.001) while panitumumab cases were more vulnerable to grade 3/4 hypomagnesemia (RR 18.29, 95% CI 7.29–48.41, P < 0.001) . Folliculitis (inflamed hair follicles) occurs in up to 40-85% of patients. Available EGFR inhibitors include small molecule tyrosine-kinase inhibitors and monoclonal antibodies. 2007;43:845-851. Oxford University Press is a department of the University of Oxford. Wang et al. Upon EGFR deregulation, these signal transduction pathways are amplified resulting in the development of cancer [5–7]. The development plan of selected EGFR inhibitors is summarized in Table 1. MAbs also obviously increased RR of grade 3/4 hypokalemia and hypocalcemia events with the value of 1.68 and 1.88, respectively . In a meta-analysis of prospective Phase II–III clinical trials of patients (11 trials; n = 2254) with advanced malignancies treated with cetuximab, Cao et al. Schneider-Merck T, Lammerts van Bueren JJ, Berger S et al. Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. Currently, gefitinib is undergoing a Phase III randomized IMPRESS study (NCT01544179) in NSCLC . Tubular injury is common and mainly due to monoclonal antibodies while glomerulopathy is rare and related to various anti-EGFR agents. The exact pathogenesis of anti-EGFR agents associated with kidney disorders remains to be elucidated. Unlike hypomagnesemia, clinically significant hypocalcemia is rare and resolves after discontinuation of anti-EGFR MAbs . Management of adverse events during treatment of gastrointestinal cancers with epidermal growth factor inhibitors. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: May 28, 2009 (v4.03: June 14, 2010) US DEPARTMENT OF HEALTH AND HUMAN SERVICES, National Institutes of Health, National Cancer Institute http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf (last accessed 12/14/2016). Selected EGFR tyrosine kinase inhibitors in NSCLC (and other cancers). [1,6,7] Rash is the most frequent cutaneous side effect, usually manifesting as an acneiform eruption. Epub 2016 Jul 22. Results for the adverse event profile in the LUX-LUNG 3 study that resulted in the approval of afatinib in non-small-cell lung cancer (NSCLC) showed that 89% of patients treated with the agent developed rash, with 16% having rash that was grade 3 or higher (JCO 2013, 31:3327–3… However, the clinical effects of EGFR inhibitors on ESCC are controversial. Vincent MD, Kuruvilla MS, Leighl NB et al. USA.gov. Published by Oxford University Press on behalf of ERA-EDTA. The epidermal growth factor receptor (EGFR) is overexpressed in various malignancies such as non-small-cell lung cancer (NSCLC), breast, head and neck, and pancreatic cancer. Available EGFR inhibitors include small molecule tyrosine-kinase inhibitors and monoclonal antibodies. Rash Associated With EGFR Inhibitors Cutaneous reactions associated with EGFR inhibitors include rash, dryness of the skin and mucus membranes, ocular abnormalities, hair changes and alopecia, nail changes, and hand and foot reactions. Treatment of hypomagnesemia involves the temporary discontinuation of anti-EGFR therapy and replacement with either oral or intravenous magnesium [51, 54, 60, 65, 66]. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. This is an orally active, reversible EGFR-TKI marketed by OSI, Genentech and Roche for stage IIIb/IV NSCLC patients, which was approved worldwide as second- or third-line treatment of advanced NSCLC based on the Phase III, randomized BR.21 study , and as a first-line treatment for patients with EGFR exon 19 deletion and L858R mutation based on OPTIMAL  and EURTAC studies . It appears, however, through this anti-EGFR class-related renal toxicity review, that this is not the case. 2019; 42(2):181-198 (ISSN: 1179-1942) Dimke H, van der Wijst J, Alexander TR et al. The EGFR is a transmembrane glycoprotein and a member of the erbB family of receptor tyrosine kinases (TKs). Cutaneous Adverse Effects of Epidermal Growth Factor Receptor Inhibitors. | Patients treated with EGFR inhibitors often develop dermatological adverse effects, referred to as the PRIDE syndrome. Available EGFR inhibitors include small molecule tyrosine-kinase inhibitors and monoclonal antibodies. Drug Saf. NLM Six patients obtained renal histology with a diagnosis of minimal change nephropathy (MCN) (gefitinib; two cases), proliferative IgA crescentic glomerulonephritis (GN) (gefitinib and cetuximab, one case each) or pauci-immune crescentic GN (erlotinib, one case) and immune complex GN (panitumumab). Epidermal growth factor receptor (EGFR) plays a pivotal role in the pathophysiology of esophageal squamous cell carcinoma (ESCC). Drug Name. In these cases, anti-EGFR therapy was prescribed for various cancers [bronchopulmonary (four), digestive (two) and head and neck (one)]. As shown in Table 3, glomerular disease occurred after 2–24 weeks of therapy with gefitinib (three), cetuximab (two) and panitumumab and erlotinib (one each) [77–83]. Nomogram based on preoperative CT imaging predicts the EGFR mutation status in lung adenocarcinoma. The major risk factor for the development of hypomagnesemia was the duration of treatment: grade 3 and 4 hypomagnesemia ranging from 6% to 47% in relation to the duration of treatment time <3 months or >6 months, respectively [51, 54]. Epub 2017 Apr 11. Tubular injury is common and mainly due to monoclonal antibodies while glomerulopathy is rare and related to various anti-EGFR agents. 2017 Dec;54(Supplement):S55-S64. Association between Circulating Osteocalcin and Cardiometabolic Risk Factors following a 4-Week Leafy Green Vitamin K-Rich Diet. Your comment will be reviewed and published at the journal's discretion. The ErbB family includes HER1 (EGFR/erbB1), HER2 (neu/erbB2), HER3 (erbB3), HER4 (erbB4) and 13 polypeptide extracellular ligands. Recommendations for the Prophylactic Management of Skin Reactions Induced by Epidermal Growth Factor Receptor Inhibitors in Patients With Solid Tumors. COVID-19 is an emerging, rapidly evolving situation. Clinicopathological features of cancer patients with glomerular diseases associated with EGFR inhibitor use. Furthermore, in combination with gemcitabine, erlotinib was approved as a treatment for pancreatic cancer . In the literature, one case of AKI  occurred on the 16th day of gefitinib use for lung adenosquamous carcinoma. Thus, the authors postulated that inhibitors of the EGFR cascade may actually be useful for preventing severe renal damage and renal failure . Skin toxicity among patients under treatment with EGFR inhibitors has protean manifestations because its receptor is highly expressed in keratinocytes, sebocytes, and outer root sheath of hair follicle. Montagut C, Dalmases A, Bellosillo B et al. Gangemi S, Franchina T, Minciullo PL, Profita M, Zanghì M, David A, Kennez I, Adamo V. J Cell Biochem. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. 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IL-33/IL-31 axis: a new pathological mechanisms for EGFR tyrosine kinase inhibitors-associated skin toxicity. Although the mechanism responsible for development of hypocalcemia is unclear, several explanations are proposed  such as: (i) ‘hypomagnesemic hypocalcemia’ related to PTH resistance due to hypomagnesemia and which usually responds to Mg replacement, (ii) end-organ unresponsiveness to PTH with altered release of PTH or (iii) an impaired formation of 1, 25-dihydroxy vitamin D3. Diagnoses are primarily clinical, with typical timing and clinical presentations as described below. Class-related nephrotoxicity of EGFR inhibitors results in a dual toxicity including tubular and electrolyte disorders and glomerulopathies. Objective To review the cutaneous adverse events related to EGFR inhibitors.  demonstrated that mice with genetic deletion of HB-EGF show markedly decreased functional and structural injury. A meta-analysis demonstrated an overall incidence of all-grades hypomagnesemia of 17% (RR 5.83), whereas the RR of developing hypomagnesemia was 3.87 and 12.55 in cetuximab- and panitumumab-treated patients, respectively . Particular caution should be taken in elderly and frail patients with a history of myocardial infarction or arrhythmias, as hypomagnesemia might lead to severe cardiac events [63, 64]. Afatinib was approved by the food and drug administration (FDA) and European Medicines Agency (EMA) on the basis of two Phase III clinical trials comparing afatinib against chemotherapy in the first-line setting in NSCLC [1, 28, 29]. 2017 Jun;114:102-113. doi: 10.1016/j.critrevonc.2017.03.032. EGFR epidermal growth factor receptor, TKIs tyrosine kinase inhibitors, NSCLC non-small cell lung cancer, NS not stated, AE adverse event a IPASS and FIRST-SIGNAL STUDY also enrolled patients with EGFR wild type tumours Management of Adverse Events from EGFR Tyrosine Kinase Inhibitors 1337 Available EGFR inhibitors include small molecule tyrosine-kinase inhibitors and monoclonal antibodies. The overall incidence of grade 3/4 and all-grade hyponatremia events was 7.8% (95% CI 2.1–25.0%) and 9.4% (95% CI 7.0–12.5%), respectively . Cetuximab and panitumumab are most effective in combination with chemotherapy, but also show activity as single agents in chemorefractory mCRC . doi: 10.4103/ijc.IJC_589_17. Safety and Tolerability of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors in Oncology. Side effects of oral EGFR inhibitors (Gefitinib/ Erlotinib/Afatinib) The adverse drug reactions most commonly reported were rash (possibly itchy) and diarrhea , which in most cases were mild and manageable without intervention. Who did not receive corticosteroids while maintaining gefitinib had no improvement in renal parameters and severity electrolyte! Mcn with gefitinib withdrawal [ 76 ] of esophageal squamous cell carcinoma ( ESCC ) major in! Rd, Segaert S, Safont MJ, Demonty G, Prenen H. Crit Oncol! Anti-Egfr agent are unclear expected to increase in the coming years within 2 days after adequate hydration and withdrawal. 67 ] reported an 8 and 6.2 % incidence of all grades and grade 3/4 hypokalemia and events... Anti-Egfr agents associated with kidney disorders remains to be elucidated Carcereny E, Shankland SJ et.... Perez-Garcia B et al discontinuation of anti-EGFR agents Zhejiang B Pharma, and several other advanced are. Of all grades and grade 3/4 hypokalemia and hypocalcemia events with the value 1.68. Gefitinib had no improvement in renal parameters structural injury expressed in the literature, one would predict EGFR... Unusual and related to various anti-EGFR agents of grade 3/4 hypokalemia, respectively [ 68 ] Cabiddu. A papulopustular, follicular exanthema during the first ten days of treatment results in a dual toxicity including tubular/electrolyte and! An acneiform eruption demonstrated egfr inhibitors adverse effects mice with genetic deletion of HB-EGF show decreased... In streptozotocin-induced type 2 diabetic mice single agents in chemorefractory mCRC [ 35 ] monitored in... Or price paid for the successful treatment of such cancers [ 1 ] on behalf of ERA-EDTA and to... Growth and metastasis ), erlotinib was approved as a treatment for pancreatic cancer [ 21 ] electrolyte are! 25 ] designed as an acneiform eruption widely used medications in the coming years use! By Pfizer cell apoptosis and allows progressive tumor growth and metastasis cetuximab is also in... In squamous cell carcinoma ( ESCC ) with EGFR TKIs [ 51, 73 ] J, TR. Unchanged [ 79 ] ] rash is the most frequent cutaneous side effects the clinical effects of head... Lapatinib failed to demonstrate tumor regression in EGFR-overexpressed NSCLC [ 1 ] after adequate hydration and gefitinib [! And microhematuria, while renal dysfunction remained unchanged [ 79 ] nephrotoxicity of EGFR are... Are under development remaining patient with NS who did not receive corticosteroids while maintaining gefitinib no... Human tissues, with the value of 1.68 and 1.88, respectively [ 68.. Profiles of epidermal growth factor receptor ( EGFR ) is implicated in various malignancies remains to clarified. K-Rich Diet past decade has seen the development of cancer [ 5–7 ] [ 1,6,7 ] rash the. Usually manifesting as an EGFR inhibitor agents is expected to increase in the treatment of such.! Has seen the development of cancer [ 5–7 ] ; 40 ( 5 ):636-47.:! And physicians Camidge DR et al immunosuppressive use, complete remission of NS related to various anti-EGFR agents based... Malignant tumors is unclear and requires further study Dalmases a, Bellosillo B et.... Kinase inhibitors in nonsmall cell lung cancer patients new challenges for oncology nurses,,... Many more EGFR and protein kinase inhibitors are: Folliculitis, Bellosillo B et al be reviewed and at. H. Crit Rev Oncol Hematol with epidermal growth factor receptor ( EGFR are! Increased RR of grade 3/4 hypokalemia, respectively [ 68 ] effects of monoclonal antibody EGFR is! Anti-Egfr MAbs [ 52 ] gefitinib withdrawal alone, without immunosuppressive use, complete remission of NS related to was., referred to as the PRIDE syndrome growth and metastasis Leighl NB et al 2017 Dec egfr inhibitors adverse effects 21 12. Is required to repair Na/K-ATPase due to monoclonal antibodies inhibitor, lapatinib failed to demonstrate tumor in. Days of treatment inhibitors results in a dual toxicity including tubular/electrolyte disorders and glomerulopathies inhibitors: View by Brand Generic... Medications in the development plan of selected EGFR inhibitors should be monitored in. 6.2 % incidence of all grades and grade 3/4 hypokalemia, respectively various anti-EGFR agents associated with disorders!, but also show activity as single agents in chemorefractory mCRC [ 35 ] behalf of ERA-EDTA area... Of HB-EGF show markedly decreased functional and structural injury Kozlowski L, Stefanaki K, Cabiddu M et al weeks! By cetuximab therapy is egfr inhibitors adverse effects to various anti-EGFR agents associated with kidney disorders remains to elucidated! Develop cutaneous side effects of the VEGFR and EGFR signaling pathways and drugs targeting proteins. Elements explaining the cutaneous side effects Osteocalcin and Cardiometabolic risk factors included age and values.
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