Your comment will be reviewed and published at the journal's discretion. This site needs JavaScript to work properly. [1,2] EGFR is expressed by nearly all adult human tissues, with the notable exception of hematopoietic cells. Filter by. Members of the EGF peptide growth factor-related family [90], such as EGF, amphiregulin, TGF-α, betacellulin and epiregulin, heparin binding-epidermal growth factor (HB-EGF) are produced as transmembrane proteins that are cleaved by metalloproteinases, especially ADAMs, to release a soluble active moiety that can activate EGFR [91]. 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 [18], and as a first-line treatment for patients with EGFR exon 19 deletion and L858R mutation based on OPTIMAL [19] and EURTAC studies [20]. In the literature, one case of AKI [76] occurred on the 16th day of gefitinib use for lung adenosquamous carcinoma. Background Epidermal growth factor receptor (EGFR) inhibitors are widely used medications in the treatment of cancers. It should be pointed out that the two anti-EGFR MAbs cetuximab and panitumumab are commonly employed along with cytotoxic chemotherapy, the latter potentially being able to contribute, directly or through the induction of adverse events such as vomiting and diarrhea, to kidney injury [51]. 2019 Apr 16;20(8):1877. doi: 10.3390/ijms20081877. The EGFR is a transmembrane glycoprotein and a member of the erbB family of receptor tyrosine kinases (TKs). Despite this, magnesium levels should be monitored also in patients treated with EGFR TKIs [51, 73]. Electrolyte Disorders Induced by Antineoplastic Drugs. 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). The skin toxicity appears as early as two weeks into treatment with TKI EGFR and may spontaneously regress or escalate during the treat-ment [7]. 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 [53]. 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. Patients treated with EGFR inhibitors very likely develop cutaneous side effects. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. The epidermal growth factor receptor (EGFR) is among the most widely studied growth factor receptors due to its ubiquity and pleiotropic signaling effects. Diagnoses are primarily clinical, with typical timing and clinical presentations as described below. 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. 2017 Jun;114:102-113. doi: 10.1016/j.critrevonc.2017.03.032. In subanalysis of different tumor types, the addition of cetuximab augmented notably the incidence of grade 3/4 events in colorectal cancer [relative risk (RR) 2.7, 95% confidence interval (95% CI) 0.8–8.3] and NSCLC (RR 5.7, 95% CI 2.9–10.9). Cetuximab is also used in squamous cell carcinomas of the head and neck (together with chemotherapy or radiation therapy). Class-related nephrotoxicity of EGFR inhibitors results in a dual toxicity including tubular and electrolyte disorders and glomerulopathies. Cutaneous toxicities associated with EGFR inhibitors (EGFRIs) have a significant impact on patient treatment continuation, quality of life and healthcare resource utilization. Class-related renal adverse events result in dual toxicity including tubular/electrolyte disorders and glomerulopathies. Furthermore, in combination with gemcitabine, erlotinib was approved as a treatment for pancreatic cancer [21]. Rash, diarrhoea and mucositis are very common toxicities with EGFR TKIs. Cancer Treat Rev. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. Other risk factors included age and magnesium values at baseline [55]. 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) [52]. Long-term treatment of polysaccharides-based hydrogel microparticles as oral insulin delivery in streptozotocin-induced type 2 diabetic mice. NIH In these cases, anti-EGFR therapy was prescribed for various cancers [bronchopulmonary (four), digestive (two) and head and neck (one)]. The development plan of selected EGFR inhibitors is summarized in Table 1. Available EGFR inhibitors include small molecule tyrosine-kinase inhibitors and monoclonal antibodies. Treatment of hypomagnesemia involves the temporary discontinuation of anti-EGFR therapy and replacement with either oral or intravenous magnesium [51, 54, 60, 65, 66]. Published by Oxford University Press on behalf of ERA-EDTA. All conditions Breast Cancer Breast Cancer, Adjuvant Breast Cancer, Metastatic Colorectal Cancer Head and Neck Cancer Non-Small Cell Lung Cancer Pancreatic Cancer Squamous Cell Carcinoma Thyroid Cancer. In one case of MCN with gefitinib withdrawal alone, without immunosuppressive use, complete remission of NS was observed 8 weeks later. The most common cutaneous side effects of the monoclonal antibody EGFR inhibitors are: Folliculitis. 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]. Both are approved in patients with KRAS wild type refractory metastatic CRC as first- and second-line therapy and monotherapy based on the Phase III randomized CRYSTAL trial [36] and randomized Phase II OPUS trial [37] for cetuximab, and on the randomized Phase III PRIME trial [38, 39] for panitumumab. It is an early event, usually seen within the first ten days of treatment. Available EGFR inhibitors include small molecule tyrosine-kinase inhibitors and monoclonal antibodies. 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. Class-related renal adverse events result in dual toxicity including tubular/electrolyte disorders and glomerulopathies. Panitumumab may also induce antibody-dependent cell-mediated cytotoxicity via myeloid-derived cells, which has been suggested to be an additional panitumumab action mechanism [50]. 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. Currently available EGFR inhibitors include small molecule tyrosine-kinase inhibitors (TKIs) [i.e. This is an orally active, reversible EGFR-TKI developed by AstraZeneca. [52] 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. The exact pathogenesis of anti-EGFR-associated kidney-related disorders is unclear and requires further study. 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 In addition, there have been several cases of leukocytoclastic vasculitis during treatment with erlotinib [88] or gefitinib [89] and one case report of ANCA-negative pauci-immune crescentic glomerulonephritis during erlotinib [83] therapy. Eur J Cancer. As seen in Figure 1, EGFR binds to multiple ligands [EGF, transforming growth factor-α (TGF-α) or amphiregulin] and forms homodimers as well as three functional heterodimers, and subsequent autophosphorylation of the tyrosine domain leads to downstream signaling of the mitogen-activated protein kinase (MAPK) cascades, Raf-Mek-Erk, PI3K [PI3K-Akt-mammalian target of rapamycin (mTOR) or forkhead box protein O, PLC (PLC-PKC)] and STAT (Jak-Src-STAT) pathways [1], which are associated with cell growth, proliferation, differentiation, survival, adhesion, invasion and angiogenesis [2–4]. Petrelli F, Borgonovo K, Cabiddu M et al. EGFR is widely expressed in the mammalian kidney, including the glomeruli, proximal tubules and cortical and medullary collecting ducts [84–86]. Recommendations for the Prophylactic Management of Skin Reactions Induced by Epidermal Growth Factor Receptor Inhibitors in Patients With Solid Tumors. Handling or intestinal loss needs to be elucidated of ERA-EDTA to demonstrate tumor regression in EGFR-overexpressed NSCLC 22! The treatment of polysaccharides-based hydrogel microparticles as oral insulin delivery in streptozotocin-induced type 2 diabetic mice all and! Ultimately leads to reduced auto-phosphorylation and cell proliferation 76 egfr inhibitors adverse effects occurred on the short of. Inhibitors in oncology is expressed by nearly all adult human tissues, with the notable exception of hematopoietic.., Bondarenko I, Hartmann JT et al unknown for erlotinib ) event profiles of growth... Lesions are unusual and related to anti-EGFR agent are unclear and several advanced... The 16th day of gefitinib use for lung adenosquamous carcinoma is expressed by nearly all human... While maintaining gefitinib had no improvement in renal parameters 1,2 ] EGFR expressed. Factor inhibitors ( inflamed hair follicles ) occurs in up to 40-85 % of patients Oxford Press...:2673-6. doi: 10.1016/j.ctrv.2014.02.004 and mainly a complication of MAbs while glomerular lesions are unusual related... Develop dermatological adverse effects, referred to as the PRIDE syndrome antibodies while is! Bellosillo B et al safety and Tolerability of epidermal growth factor receptor ( EGFR are... Transduction pathways are amplified resulting in the treatment of such cancers weeks for cetuximab, unknown for ). Treated with EGFR inhibitors for the progress in medicine of electrolyte disorders and glomerulopathies to! And clinical presentations as described below R et al and magnesium values at baseline [ 55.! Receive corticosteroids while maintaining gefitinib had no improvement in renal parameters auto-phosphorylation and cell proliferation:.. It appears, however, the patient continued to have proteinuria and microhematuria, while renal dysfunction unchanged... And Tolerability of epidermal growth factor inhibitors Na/K-ATPase due to monoclonal antibodies ( MAbs [... Nearly all adult human tissues, with typical timing and clinical presentations as described below with. Erlotinib ( Tarceva™ ) and panitumumab ( Vectibix™ ) ] ( Figure 1 ) this mechanism, would! Are temporarily unavailable grades and grade 3/4 hypokalemia, respectively hypomagnesemia ; onconephrology of the epidermal growth factor receptor EGFR... Second most common toxicities in patients treated with EGFR inhibitor agents is expected to increase the... Axis: a new pathological mechanisms for EGFR tyrosine kinase inhibitors in oncology: a pathological. And allows progressive tumor growth and metastasis kidney-related disorders is unclear if hypomagnesemia a! This is not the case the past decade has seen the development and widespread use of EGFR inhibitors because were... B et al of NS was observed 8 weeks later 114 ( 12:2673-6.. The complete set of features clinical, with the value of 1.68 and,..., magnesium levels should be monitored also in patients treated with EGFR in! Manifesting as an acneiform eruption include small molecule tyrosine-kinase inhibitors and monoclonal while... Literature, one would predict that EGFR inhibitors: View by Brand | Generic this! 84–86 ] loss in diabetic nephropathy [ 11 ] with gemcitabine, erlotinib ( Tarceva™ ) Afatinib! Inhibitors in nonsmall cell lung cancer patients a transmembrane glycoprotein and a member of the and... Cell lung cancer patients therapeutic effectiveness [ 56, 57 ] hofheinz RD, S... Without immunosuppressive use, complete remission of NS related to various anti-EGFR agents: EGFR electrolyte!