epidermal growth factor receptor 
 ( egfr ) , a member of the erbb family of receptor tyrosine kinases , is a cell 
 surface molecule whose activation leads to an intracellular signaling cascade 
 affecting invasion , apoptosis , and angiogenesis [ 1 , 2 ] . members of the efgr 
 family receptors ( erb1/efgr , erb2/her2 , erb3/her3 , and erb4/her4 ) are composed of 
 extracellular ligand binding domains . when ligands bind to these domains , 
 receptor dimerization and autophosphorylation of intracellular tyrosine kinase 
 domains occur . autophosphorylation activates the downstream signaling pathways 
 ras , raf , mitogen - activated protein kinase ( mapk ) , phosphatidylinositol 
 3-kinase ( pl3k ) , akt , and the signal transduction and activator of 
 transcription ( stat ) pathways . this downstream signaling leads to activation of 
 cell growth , proliferation , and survival of cells [ 3 , 4 ] . binding of the egfr 
 by inhibitors leads to a disruption in proliferation resulting in apoptosis . immunological effects , such as cell - dependent cytotoxicity ( cdc ) and 
 antibody - dependent cell - mediated cytotoxicity ( adcc ) , also contribute to their mechanism 
 of action . drugs targeting egfr in malignancies 
 were initially developed in the 1980s , which lead to the development of 
 anti - egfr monoclonal antibodies and small molecule egfr tyrosine kinase 
 inhibitors ( tkis ) [ 69 ] . egfr is overexpressed in many solid tumors and this 
 over expression correlates to advanced stage and a worse prognosis . in the 
 last few years , numerous clinical trials have proven the clinical efficacy of 
 egfr - targeted therapies in the management of several cancers , including breast , 
 colon , pancreas , head and neck , renal , gastrointestinal stromal tumors ( gists ) , 
 and lung carcinomas . since these agents are now commonly used , clinical 
 presentation of associated toxicities and their management are important to 
 recognize . therefore , this review discusses commonly used efgr inhibitors 
 currently approved by the us food and drug administration ( fda ) . a summary of 
 clinical data in support of these agents and commonly encountered toxicities 
 and management are discussed . erlotinib is an oral agent that 
 reversibly binds to the intracellular tyrosine kinase domain of the her1/egfr 
 thus blocking phosphorylation and inhibiting signal transduction . initially studied in nonsmall cell lung cancer ( nsclc ) , phase ii data showed a 
 response rate ( rr ) of 12% in patients previously treated with platinum - based 
 chemotherapy [ 12 , 13 ] . the national cancer institute of canada clinical trials 
 group ( ncicctg ) then developed a phase iii trial comparing erlotinib to placebo 
 in patients with advanced nsclc who had prior failure of first- or second - line 
 chemotherapy . this study showed that erlotinib when compared to placebo had a 
 higher overall ( o)rr , median duration of response , progression - free survival 
 ( pfs ) , and overall survival ( os ) ( table 1 ) . there was also a greater reduction 
 in cancer - related pain , cough , and dyspnea as well as improvement in physical 
 function in those treated with erlotinib . as a result , erlotinib is a 
 useful treatment option presently utilized in the management of nsclc . in 
 another large phase iii randomized trial of previously untreated advanced 
 nsclc , the results were not as favorable and showed no difference in 
 orr or os . egfr gene mutations are being investigated as a predictor of 
 efficacy with erlotinib in nsclc . recently presented at the american society of 
 clinical oncology ( asco ) annual meeting , a phase ii trial of erlotinib in 
 previously untreated nsclc patients with mutations of the tyrosine kinase 
 domain of egfr was evaluated . in this trial , 37 of 297 tumors screened had 
 mutations in the tyrosine kinase domain ( 25 with exon 19 deletion , 11 with 
 l858r mutation ) . responses occurred in 100% of exon 19 deletions and in 75% of 
 those with the l858r mutation . this led to an ncic trial 
 comparing gemcitabine in combination with erlotinib or placebo in patients with 
 locally advanced or metastatic pancreatic adenocarcinomas . this trial showed a 
 minimal but statistically significant increase in os favoring the 
 gemcitabine / erlotinib combination . although statistically significant , the 
 absolute increase in median survival was only 2 weeks . gefitinib , an orally bioavailable 
 egfr tki , was the first targeted drug to be approved for nsclc . the iressa dose 
 evaluation in adjuvant lung cancer ( ideal1 and ideal2 ) trials were phase ii 
 nonrandomized studies investigating the efficacy of gefitinib monotherapy in 
 nsclc patients previously treated with a platinum agent [ 17 , 18 ] . based on 
 objective responses , stable disease , and symptomatic improvement , the iressa survival 
 evaluation in lung cancer ( isel ) trial , a phase iii randomized study , evaluated 
 gefitinib versus placebo in previously treated nsclc . although there was a 
 significantly higher response rate seen with gefitinib , the study did not show 
 a significant difference in os . as a result , the fda restricted the use of 
 gefitinib to patients enrolled in clinical trials or deriving benefit from 
 ongoing treatment . other randomized phase iii trials , assessing gefitinib given 
 concurrently with chemotherapy as well as gefitinib maintenance did not show 
 improvements in os [ 2022 ] . recently , the 33rd european 
 society for medical oncology congress released results of a large - scale 
 randomized phase iii trial ( iressa pan - asia study [ ipass ] ) . in 1,217 patients , the study compared gefitinib monotherapy to carboplatin / paclitaxel 
 ( c / p ) in chemonaive never- or light - exsmokers with advanced nsclc with 
 adenocarcinoma histology ( table 2 ) . gefitinib was superior in pfs , orr , 
 toxicity , and quality of life ( qol ) compared to combination chemotherapy . pfs was longer for gefitinib than c / p in egfr mutation 
 positive patients and longer with c / p in mutation - negative patients . cetuximab is a chimeric monoclonal 
 igg1 antibody that binds to the egfr subsequently blocking phosphorylation of 
 the receptor . cetuximab , initially approved for the treatment of 
 metastatic colon cancer , has made a significant difference in the management of 
 patients with this disease . a phase iii trial comparing cetuximab monotherapy 
 to best supportive care ( bsc ) showed improved os and qol in patients with 
 colorectal cancer who had previously failed or had contraindications to 
 fluoropyrimidine- , irinotecan- , and oxaliplatin - based therapies ( table 2 ) . 
 a subsequent randomized phase iii trial compared cetuximab monotherapy to 
 cetuximab plus irinotecan in refractory metastatic colorectal cancer ( mcrc ) . this study was reserved for patients who had documented disease progression on 
 a prestudy irinotecan regimen . the combination therapy arm showed 
 significantly improved orr , median time to progression ( ttp ) , and disease 
 control . another similar randomized phase iii trial evaluated irinotecan 
 monotherapy to cetuximab plus irinotecan in patients with mcrc previously 
 failing oxaliplatin and/or a fluoropyrimidine who were irinotecan nave . the 
 combination therapy arm yielded improved orr , pfs , and qol , but similar os to 
 the cetuximab - only treated patients . this lack of os difference may have been 
 due to posttrial therapy since a large number of patients assigned to 
 irinotecan eventually received cetuximab . most recently , the combination 
 of irinotecan and 5-fluorouracil ( folfiri ) with or without cetuximab in the 
 first - line treatment of mcrc was evaluated . the combination of egfr and vascular 
 endothelial growth factor-(vegf- ) targeted agents was also evaluated in a randomized 
 phase iii study of capecitabine / oxaliplatin ( capox ) plus bevacizumab with or 
 without cetuximab in mcrc . unfortunately , the combination chemotherapy , 
 bevacizumab , and cetuximab resulted in a significant decrease in pfs compared 
 to bevacizumab and capox alone with no difference in os . therefore , it was 
 concluded that cetuximab and bevacizumab should not be used concomitantly with 
 chemotherapy . at last year 's asco annual meeting , 
 data revealed that kras gene mutation conferred resistance to treatment with 
 cetuximab and panitunimab . in contrast ,  wild - type  or normal kras mutation 
 status was found to be a predictive marker for cetuximab and panitumumab 
 efficacy . in a retrospective analysis of 5-fluorouracil / leucovorin / oxaliplatin 
 ( folfox ) in combination with cetuximab , kras wild - type status was found to be 
 associated with a significantly higher orr and longer pfs when compared to 
 mutant kras in egfr - positive patients . similarly , when egfr - positive 
 patients with untreated mcrc were treated with folfiri with or without 
 cetuximab , kras mutational status was predictive of response ; wild - type kras 
 was associated with improved orr and prolonged pfs . based on these studies as 
 well as data with panitumumab , kras testing and verification of wild - type status 
 are now required before treatment with these agents in colorectal cancer 
 [ 2931 ] . egfr is also   upregulated in squamous 
 cell carcinoma ( scc ) of the head and neck . initial phase ii data 
 revealed activity of single agent cetuximab in recurrent and/or metastatic scc 
 of the head and neck in those failing to respond to platinum - based therapy . as 
 a single agent , the rr was 13% with a disease control rate of 46% . the combination 
 of cetuximab with chemotherapy has also been found to be effective . platinum - based chemotherapy , fluorouracil , with or without cetuximab as 
 first - line treatment of metastatic or recurrent scc of the head and neck showed 
 that the cetuximab combination yielded a higher orr and os . a similar 
 phase iii trial was conducted addressing pfs with cisplatin monotherapy versus 
 cisplatin with cetuximab in patients with recurrent and/or metastatic scc of 
 the head and neck . this study did not show a significant difference in 
 pfs or os ; however , there was a significant difference in rr favoring the 
 cetuximab / cisplatin arm . cetuximab with radiotherapy versus radiotherapy alone 
 was also studied in a separate phase iii trial . the addition of cetuximab to 
 radiotherapy significantly prolonged pfs , median os , and duration of 
 locoregional control in patients with locoregionally advanced head and neck 
 cancer . in pancreatic adenocarcinoma cetuximab with 
 gemcitabine or gemcitabine alone was evaluated in a large multi - institutional 
 phase iii trial in pancreatic adenocarcinoma . the addition of cetuximab did not 
 significantly improve orr , pfs , or os [ 3638 ] . at the plenary session of asco 2008 , 
 data was released on the treatment of nsclc with cetuximab in combination with 
 cisplatin / vinorelbine ( cv ) compared to cv alone . cetuximab plus cv 
 demonstrated an os advantage . a modest survival benefit of one - to - two month(s ) this was the first trial to demonstrate an os advantage 
 of an egfr - targeted agent in combination with platinum - based chemotherapy in 
 nsclc . egfr gene copy number detected by 
 fluorescent in situ hybridization ( fish ) has been shown to be useful in 
 selecting nsclc patients for treatment with cetuximab . patients with advanced - stage nsclc were enrolled into a phase ii trial evaluating sequential or 
 concurrent chemotherapy ( carboplatin plus paclitaxel ) with cetuximab . the orr , 
 disease control rate , pfs , and os were significantly higher in the 
 fish - positive versus fish - negative patients . further investigation on the 
 accuracy of fish - positive egfr status is needed to evaluate its prognostic 
 value in nsclc . in contrast to cetuximab , panitumumab 
 is the first fully human egfr monoclonal antibody . it is an immunoglobulin 
 ( ig)g2 antibody that binds to the extracellular portion of the egfr thus 
 inhibiting phosphorylation and activation of the intracellular kinases . efficacy of panitumumab has been evaluated in egfr - expressing metastatic 
 colorectal adenocarcinomas with disease progression following oxaliplatin , 
 irinotecan , and fluropyrimidine - containing chemotherapy regimens . an initial 
 phase ii multicenter trial included patients with progressive mcrc treated with 
 panitumumab monotherapy ; patients were stratified into two groups based on   egfr 
 staining intensity . as a single agent , panitumumab response and disease 
 stabilization efficacy 
 was evaluated in patients with 1% or greater egfr tumor staining by ihc and 
 disease progression while on or within 6 months of the most recent 
 chemotherapy . panitumumab yielded a significant reduction in pfs when compared 
 to bsc ; however , there was no significant difference in os ( table 3 ) . patients in the bsc arm were subsequently allowed to crossover to the 
 panitumumab arm if disease progression was documented during the study . the 
 crossover patient population yielded comparable results with prolonged pfs 
 after panitumumab treatment . this has led to the approval of panitumumab 
 for treatment of egfr - positive , metastatic colorectal carcinoma with disease 
 progression following chemotherapy . as mentioned earlier , wild - type kras 
 is required for panitumumab efficacy in patients with mcrc . the combination of egfr- and 
 vegf - targeting antibodies was also found to lack benefit in the case of 
 panitumumab . in the panitumumab advanced colorectal cancer evaluation ( pacce ) study , patients with untreated mcrc were randomized to folfox or folfiri based 
 on investigator or patient choice . the combination of 
 folfox / panitumumab / bevacizumab resulted in higher mortality compared to 
 folfox / bevacizumab alone . based on the results of the interim analysis , the study 
 was stopped and panitumumab was discontinued in both the folfox and folfiri 
 arms . similar to cetuximab , this trial with panitumumab argues against the 
 combined use of these agents with bevacizumab in mcrc . sorafenib is a novel multikinase 
 inhibitor with antiangiogenic and proapoptotic activity targeting egfr as well as multiple kinases including raff / mapk - erk kinase , vegfr-2 , vegfr-3 , and pdgfr- 
 . it is approved for use in the treatment of renal cell carcinoma ( rcc ) and 
 hepatocellular carcinoma ( hcc ) . rcc is characterized by the loss of 
 the von hippel landau ( vhl ) gene , which leads to dysregulation of the vegfr , 
 pdgfr- , transforming growth factor - alpha ( tgf- )  , egfr , and raf pathways promoting 
 angiogenesis , lymphangiogenesis , tumor cell growth , and survival . membranous and/or cytoplasmic 
 egfr immunostaining in rcc was present in 123 of 132 ( 93% ) primary and 49 of 53 
 ( 92% ) metastatic samples with extensive immunoreactivity present in 83% of 
 primary and 74% of metastatic tumors . in previously treated patients with 
 metastatic rcc , the activity of sorafenib was demonstrated in two randomized 
 trials . in the largest of these studies , a randomized phase iii trial of 
 metastatic cytokine refractory rcc , significant response and improvement in pfs 
 was demonstrated ( table 4 ) . at asco 2007 , there was no statistically significant improvement in os ; survival 
 benefit was likely obscured since one half of the patients originally assigned 
 to placebo had switched to sorafenib . egfr is frequently expressed in human 
 hepatoma cells ; in fact , egf is one of the mitogens required for the growth of 
 hepatoma cells . at the asco meeting in 2007 , the sorafenib hcc assessment randomized protocol 
 ( sharp ) trial was a large phase iii double - blind placebo - controlled study 
 evaluating the efficacy of sorafenib versus bsc in patients with advanced hcc 
 who had not received previous chemotherapy . patients receiving sorafenib had a 
 three - month median survival benefit compared to placebo . importantly , sorafenib was 
 the first active treatment that has been proven to confer a survival benefit 
 and to show promise as a standard treatment for advanced hcc . in another 
 phase iii randomized trial of sorafenib in asia - pacific patients with hcc , 
 results mirrored those of the sharp trial . despite asia - pacific patients having 
 more advanced disease based on the eastern cooperative oncology group 
 performance status ( ecog ps ) , a significant os advantage with sorafenib was 
 confirmed . a north american phase ii randomized trial of doxorubicin with 
 sorafenib versus doxorubicin with placebo in 96 child - pugh a patients was 
 published in abstract form and presented at the 2007 european cancer 
 organization conference ( ecco ) . median ttp was two months longer in the 
 combination arm , but did not reach statistical significance . however , os was 
 significantly longer for the combination of sorafenib / doxorubicin compared to 
 the doxorubicin only arm ( 13.7 vs. 6.5 mo ) . sorafenib has also recently 
 demonstrated significant activity in the treatment of iodine - refractory thyroid 
 carcinoma . in a phase ii trial of 30 subjects , most of the patients ( 80% ) 
 showed a clinical benefit from this agent . ninety - five percent of individuals 
 with available thyroglobulin levels showed a rapid response in thyroglobulin 
 levels with a mean decrease of 70% . these results represent a significant 
 advance in both response and pfs over studies in the past utilizing 
 chemotherapy . like sorafenib , sunitinib is an oral small 
 molecule tki that inhibits cellular signaling by targeting egfr , vegfr , pdgfr- , 
 fetal liver tyrosine kinase receptor ( flt-3 ) , and c - kit , a stem cell factor 
 receptor . this ultimately targets both angiogenesis and tumor cell 
 proliferation causing tumor shrinkage and cell death . sunitinib is currently 
 approved for the treatment of rcc as well as   gastrointestinal stromal tumors   gists . like rcc , egfr expression 
 in gists had been validated in a recent article in which tissue microarray 
 samples of 33 gists were surveyed by ihc . the antitumor activity of sunitinib 
 was initially shown in two phase ii trials of metastatic rcc patients who had 
 failed previous cytokine therapy [ 54 , 55 ] . this led to a large phase iii trial 
 comparing sunitinib to interferon - alpha ( ifn- ) as first - line therapy ( table 5 ) . sunitinib showed superior activity in orr and in pfs , including patients 
 with good , intermediate , and poor risk features . furthermore , os was 
 significantly longer in the sunitinib arm , despite significant patient crossover 
 from the ifn- arm to sunitinib . sunitinib has also shown significant 
 activity in metastatic and/or unresectable gist following imatinib failure . in 
 a phase iii randomized trial comparing sunitinib to placebo in imatinib 
 refractory gist patients , time to tumor progression and pfs was 4-fold longer 
 in patients on sunitinib compared to placebo ; partial response ( pr ) and stable 
 disease ( sd ) were also significantly longer in the sunitinib arm . patients in 
 the placebo arm were subsequently allowed to crossover to the sunitinib arm if 
 disease progression was documented during the study . activation and overexpression of 
 oncogenes encoding trans - membrane receptor tyrosine kinases of the egfr family , 
 including egfr ( erbb1 ) and her2/neu ( erbb2 ) , play an important role in the 
 development of breast cancer . lapatinib is an orally active 
 4-anilinoquinazoline tki of both her2/neu ( erbb2 ) and egfr ( erbb1 ) . it inhibits 
 the autophosphorylation sites on the receptors , thereby blocking the downstream 
 signaling pathways of her2 and egfr . lapatinib has shown activity for the 
 treatment of advanced her2/neu positive metastatic breast cancer refractory to 
 trastuzumab ( table 6 ) . unlike trastuzumab , lapatinib seems to have activity 
 against brain metastases [ 5961 ] . primary and secondary resistances have been 
 seen in patients with her2-positive breast cancers who had been treated with 
 trastuzumab both in the metastatic and adjuvant settings 
 [ 53 , 6265 ] . potential 
 mechanisms of resistance may be related to signaling through other receptors 
 such as egfr or igfr-1 . lapatinib , being a small molecule tki , interacts 
 with intercellular domains and does not require full receptor activity . in a 
 phase iii study of her2-positive advanced or metastatic breast cancer 
 refractory to anthracyclines , taxanes , and trastuzumab , lapatinib plus 
 capecitabine showed a significant advantage over capecitabine monotherapy with 
 respect to orr and pfs with a nonsignificant trend toward longer os . in 
 another phase iii randomized trial , the combination of paclitaxel with lapatinib 
 compared to paclitaxel monotherapy in patients with her2-positive cancer was 
 evaluated . the 
 study showed a statistically significant advantage in orr and ttp , but not in 
 os . only 91 of 580 patients were her2-positive on central testing , with 
 retrospective analysis revealing benefit limited to fish - positive or ihc 3 + 
 tumors . egfr is expressed on nearly all 
 normal cells , particularly those of epithelial origin such as skin , liver , and 
 gastrointestinal tract , but not on hematopoietic cells . as a consequence , the most commonly encountered toxic effects from these agents are rash and 
 diarrhea . along with other toxicities , recognition and management of associated 
 adverse effects with anti - egfr agents will result in improved clinical 
 outcomes , patient compliance , and qol . when egf was initially discovered , it 
 was named for its ability to increase growth and keratinization of skin 
 epithelium . egfr was found to be expressed in the human skin within 
 keratinocytes , the follicular epithelium , sweat and sebaceous glands , and in 
 capillaries of the dermis [ 7073 ] . for this reason , the most common 
 toxicity of egfr - targeted agents involves the skin and adnexal structures 
 resulting in a rash and less commonly nail toxicity . egfr is expressed on hair follicles 
 and sebaceous glands and the binding of this receptor by inhibitors leads to a 
 disruption in proliferation , resulting in an immunological reaction with skin 
 inflammation , folliculitis , and rash [ 72 , 73 ] . the most commonly seen skin 
 reaction with efgr inhibitors is a follicular acneiform eruption , also termed 
 acne - like rash or folliculitis . egfr - associated rash differs from acne in that 
 there are no comedones or blackheads . the incidence of an acneiform - like skin 
 rash has been reported to occur in about 85% of cetuximab - treated patients 
 [ 74 , 75 ] . this is mainly located on the face ( nose , cheeks , nasolabial folds , chin , 
 forehead , and in a perioral distribution ) . the rash tends to improve over 
 time even with continued use and does resolve fully after cessation of therapy . 
 in 35% of patients , dry itchy skin of the arms and legs can occur , which can 
 potentially become secondarily infected by staphylococcus aureus or herpes 
 simplex infection . there have been numerous studies 
 showing a direct correlation between   the severity of a rash with response and os . in fact , the   greatest benefit in survival of cetuximab - treated patients is seen 
 in those with a grade 3 rash [ 27 , 75 , 76 ] . the degree of skin toxicity has been 
 classified by the national cancer institute common toxicity criteria version 
 3.0 ( table 7 ) . prospective trials are needed to further investigate the 
 correlation between anti - egfr therapy and rash to elucidate the validity and 
 clinical implications of this association . recommendations in the management of 
 egfr - associated rash have been limited by the lack of clinical trials 
 evaluating rash therapies ( table 8) . this has led to treatment recommendations based   on 
 the clinical experience of dermatologists and oncologists familiar with 
 egfr - associated rash . in general , preventive measures are essential and include 
 avoidance of soaps , limiting shower time , use of lukewarm water , and liberal 
 use of skin moisturizers and emollients . beneficial topical treatment 
 approaches for a grade 1 rash include the use of antibiotic agents 
 ( metronidazole , erythromycin , and clindamycin lotion ) as well as local 
 corticosteroid cream if an extensive inflammatory component is present . for 
 grade 2 reactions , anti - inflammatory oral antibiotics ( minocycline or 
 doxycycline ) should be used since secondary infections are common . in the event 
 of a grade 3 rash , oral corticosteroids and antibiotics should be utilized and 
 egfr - targeted therapy should be held until the acute inflammatory phase has 
 resolved [ 77 , 78 ] . rash and hand - foot syndrome , 
 characterized by redness , ulceration , and dysesthesia of the palms and soles , 
 are the most common adverse events associated with sorafenib and sunitinib . 
 hand - foot syndrome associated with these agents occurs in 2030% of patients , 
 with less than 10% experiencing grade 3 or higher toxicity . it rapidly resolves 
 with drug discontinuation and topical emollients and moisturizers are used to 
 prevent and diminish toxicity . other associated adverse events seen with 
 sorafenib and sunitinib include diarrhea , hypertension , fatigue , and 
 hematologic cytopenias [ 79 , 80 ] . anti - egfr therapy can also result in 
 nail toxicity , which can occur in 1015% of patients after 48 weeks of 
 therapy . it can progress into a paronychia like cracking reaction , a painful 
 and difficult to treat side effect . since egfr signaling plays a vital role 
 in the initiation of hair growth , interruption of egfr signaling can result in 
 disorganized hair follicles leading to follicular necrosis and alopecia 
 [ 81 , 82 ] . nimotuzumab , which is marketed under the name 
 of biomabegfr , is a recombinant 
 humanized igg1 monoclonal antibody targeting egfr . it has been approved for scc 
 of the head and neck and glioma in a number of countries . in the clinical 
 trials thus far , nimotuzumab has not been associated with skin toxicity . the use of oral anti - egfr tkis has 
 been found to be strongly associated with gastrointestinal toxicities including 
 diarrhea and hepatotoxicity . the pathophysiology of anti - egfr - induced diarrhea 
 is thought to result from excessive chloride secretion inducing a secretory 
 diarrhea . in large randomized trials , oral tkis erlotinib and lapatinib 
 have been found to cause diarrhea in 4060% of patients with approximately 10% 
 experiencing grade 3 or 4 toxicity [ 11 , 14 ] . the reported incidence of diarrhea 
 associated with sorafenib and sunitinib has been 2040% [ 79 , 81 ] . diarrhea 
 induced by oral tkis can be managed by lowering the dose and rarely involves 
 treatment interruption . hepatic toxicity with asymptomatic 
 elevations of transaminases and hyperbilirubinemia is commonly associated with 
 oral tkis . the mechanism of action is thought to be direct targeting of 
 hepatocytes that overexpress egfr with potential induction of chronic hepatitis 
 with active necrosis . the overall incidence of hepatotoxicity with oral 
 anti - egfr tkis has been reported at around 10% ( 2% grade 2 or 3 ) [ 11 , 14 , 79 , 80 ] . 
 these compounds can be continued with mild hyperbilirubinemia and should be 
 discontinued with grade 3 or 4 toxicity . interstitial lung disease related to 
 gefitinib therapy has been well reported , with a worldwide incidence estimated 
 at 1% [ 85 , 86 ] . in a small series from japan , the incidence of ild in 112 four deaths occurred , 
 all being in current or former smokers , with pre - existing pulmonary fibrosis 
 being a significant risk factor . the adverse pulmonary effects of erlotinib are 
 less well known , but cases of fatal ild have been reported [ 88 , 89 ] . a phase 3b 
 trial has been initiated to examine the efficacy and safety of erlotinib in advanced 
 nsclc with disease progression after chemotherapy . from a total of 229 
 patients , one ( 0.4% ) interstitial lung disease - like event it is clear that cardiotoxicity with tkis is not a    class effect ,  
 since it does not occur with all known agents . sunitinib caused a decline in 
 left ventricular ejection fraction ( lvef ) below 50% in 11% of the patients 
 . in a phase iii trial comparing sunitinib to ifn- , 10% of patients had 
 declines in lvef after a median duration treatment of 6 months . sorafenib 
 has induced acute coronary syndromes , including myocardial infarction . in the 
 rcc study comparing sorafenib to placebo , 2.9% of sorafenib - treated patients 
 had a myocardial infarction , compared to 0.4% in placebo - treated patients . the cardiac toxicity of lapatinib was analyzed in 3.558 patients treated in 18 
 phase i  iii clinical trials ; 598 received prior anthracyclines and 759 had been 
 given trastuzumab in the past . lapatinib was associated with a decline in 
 lvef in 1.6% of patients ( 58 of 3,558 ) . the mean lvef decrease was 18.7% and 
 was mostly asymptomatic ( 1.4% asymptomatic and 0.2% symptomatic ) . of the seven 
 with symptomatic lvef decrease , cardiotoxicity resolved in all but one patient . allergic and anaphylactoid reactions are associated with cetuximab and , less often , panitumumab administration 
 [ 26 , 75 ] . severe reactions are observed in approximately 3% of patients 
 following cetuximab administration , with a fatal outcome in 0.1% of patients 
 [ 93 , 94 ] . up to 90% of severe reactions associated with cetuximab the decision to rechallenge or 
 discontinue treatment after a reaction occurs depends on the severity of the 
 reaction . in the case of anaphylactic reactions , mild - to - moderate hypersensitivity reactions can be managed 
 by temporary infusion interruption and resuming at a slower infusion rate . hypersentivity reactions to cetuximab 
 might correlate with the development of specific antihuman ige antibodies . 
 on the contrary , the incidence of hypersensitivity reactions with panitumumab in multiple trials 
 has been approximately 3% , with severe reactions accounting for approximately 
 1% . the successful use of panitumumab after severe hypersensitivity 
 reactions to cetuximab has been reported , but requires further investigation 
 . therapeutic agents in clinical 
 practice targeting the egfr pathway have made great advances in the treatment 
 of malignancy . egfr activation is associated with proliferation , 
 antiapoptosis , and metastatic spread , making this pathway a compelling target . numerous large clinical trials have shown clinical evidence of anticancer 
 activity with these new agents resulting in improved tumor response and 
 patients ' survival . several other anti - egfr agents are in development , giving 
 hope to future advances in therapy . an awareness and proper management of 
 associated toxicities can increase patient compliance , qol , and overall 
 treatment success . ongoing and future research will expand the applications of 
 anti - egfr therapy , elucidate optimal combinations and sequences , discover 
 pathways of resistance , and continue to benefit cancer patients .
epidermal growth factor receptor ( egfr ) is a cell surface molecule and member of the erbb family of receptor tyrosine kinases . 
 its activation leads to proliferation , antiapoptosis , and metastatic spread , making inhibition of this pathway a compelling target . in recent years , 
 an increasing number of clinical trials in the management of solid malignancies have become available indicating the clinical efficacy of anti - egfr monoclonal antibodies and oral small molecule tyrosine kinase inhibitors ( tkis ) . 
 this review addresses frequently used egfr inhibitors , summarizes clinical efficacy data of these new therapeutic agents , and discusses their associated toxicity and management .