oncology practice has dramatically changed in the last ten to fifteen years ( 1 ) . genomic assessment of tumors has become commonplace , and there has been a paradigm shift toward the use of targeted therapies directed against the specific molecular drivers of tumors in individual patients where possible . this personalized approach to cancer treatment has profoundly altered patient management , in terms of the available treatment armamentarium , logical sequencing of agents , and optimized use of the targeted therapies to maximize survival and limit toxicities . at many timepoints along the care continuum , imaging interpretation plays a critical role , especially in terms of assessment of patients ' response to molecular targeted therapy ( mtt ) or lack thereof , and in detection of disease and treatment - related complications . as oncology care becomes increasingly diverse and complex , it is a challenge to remain up - to - date on the state of the art and standards within the field . for example , there are now seven vascular endothelial growth factor ( vegf)-targeted agents approved for use in advanced or metastatic renal cell carcinoma ( rcc ) by the united states food and drug administration ( fda ) , two of which were approved in the last six months . innovations in genomic characterization of cancer , targeted drug discoveries and new approvals occur continuously , and it is difficult to keep abreast of changes directly impacting cancer patients treated in both academic and community practices . to fully integrate into the multidisciplinary team and provide best care for patients , radiologists must communicate with oncologists using a common language . therefore , we must be familiar with routinely employed mtts and the range of imaging findings associated with their use . the radiologist may be the first provider to suggest an atypical response pattern or a subclinical toxicity , which can significantly alter study interpretation and contribute to patient management . the purpose of this review is to provide a summary of the commonly used mtts relevant to imaging interpretation , including the rationale of the various anti - angiogenic and non - anti - angiogenic treatments , indications for use , response assessment methods and characteristic toxicities . immune checkpoint blocker agents will not be addressed in this report since these represent a separate class of targeted immune therapies covered separately in this special issue . folkman ( 2 ) described the link between solid tumor growth and neovascularization in 1971 , and he proposed the term  anti - angiogenesis ,  referring to  the prevention of new vessel sprouts from penetrating into an early tumor implant  as a means of cancer treatment . since that time , it has been shown that a number of cancers , including colon , renal and lung , are associated with increased vegf expression , and that vegf expression levels have prognostic significance in many instances ( 3456 ) . a number of anti - angiogenic agents , also known as vegf - targeted agents , have since become fda - approved , and have been shown to prolong progression - free and overall survival in various malignancies . there are multiple subtypes of vegf ( a , b , c , d , and placental growth factor ) and multiple vegf - receptor ( vegfr ) tyrosine kinases ( vegfr 1 , 2 , and 3 ) , and antiangiogenic drugs may target one or more specific circulating vegf subtypes or vegfr . the first angiogenesis inhibitor to be approved by the fda , bevacizumab ( avastin ; genentech inc . , south san francisco , ca , usa ) , is a recombinant , humanized monoclonal antibody to circulating vegf - a . approved indications for use of bevacizumab include , but are not limited to : metastatic colorectal cancer , unresectable or metastatic non - squamous , non - small cell lung cancer , metastatic rcc , recurrrent glioma , recurrent or metastatic cervical cancer , as well as platinum - resistant ovarian or primary peritoneal cancer , often in combination with chemotherapy ( 789101112 ) . , bridgewater , nj and tarrytown , ny , usa ) is an agent which also binds vegf , representing a humanized recombinant fusion protein comprised of portions of the extracellular domains of vegf receptors fused to the fc portion of human immunoglobulin g1 ( 13 ) . ziv - aflibercept is approved for use in metatstatic colorectal cancer in combination with 5-fluorouracil , leucovorin , and irinotecan following treatment with an oxaliplatin - based regimen ( 14 ) . small molecule inhibitors of receptor tyrosine kinases inhibit ( tki ) the vegf - receptor and other transmembrane kinases , and include sunitinib ( sutent ; pfizer , new york , ny , usa ) , sorafenib ( nexavar ; bayer pharmaceuticals corporation , wayne , nj and onyx pharmaceuticals inc . , emeryville , ca , usa ) , pazopanib ( votrient ; glaxosmithkline , middlesex , united kingdom ) and others ( 15 ) . tkis are approved in a variety of malignancies , including metastatic rcc , hepatocellular carcinoma and gastrointestinal stromal tumor , amongst others ( 161718 ) . since anti - angiogenic agents exert their effects via distinct mechanisms of action , it follows that response patterns differ from those seen with traditional cytotoxic therapies ( fig . tumor stabilization has been acknowledged as an endpoint of treatment ( 19 ) . according to the response evaluation criteria in solid tumors ( recist ) , which was developed during the age of cytotoxic chemotherapy , a 30% decrease in the sum long axis diameter of target lesions is required for partial response ( 20 ) . in the era of anti - angiogenic targeted therapy , response rates according to recist are sometimes low , ranging from 1040% in rcc trials , for example ( 917 ) . a rather large number of rcc patients achieve a best response of  stable disease  on treatment , a heterogeneous categorization including patients who may or may not experience prolonged progression free survival ( 21 ) . several drugs have gained fda - approval for indications on the basis of prolonged progression - free survival or  clinical benefit  in treated patients . kerbel and folkman ( 22 ) acknowledged the challenges in determining the most reliable end points indicative of therapeutic efficacy in anti - angiogenic treatments . many investigators have examined a variety of alternative response criteria , aimed at optimizing response assessment in drug and cancer - specific treatment settings ( 23 ) . for example , the response assessment in neuro - oncology ( rano ) criteria have been developed to assess high grade gliomas treated with anti - angiogenic agents , and to address limitations of the previously used macdonald criteria , including underestimation of non - enhancing tumor and overestimation of response related to changes in enhancement ( 24 ) . similarly , computed tomography ( ct)-based morphologic criteria have been developed to address morphologic changes in liver metastases which correlate with pathologic changes and overall survival in patients with metastatic colorectal cancer treated with bevacizumab - containing regimens ( fig . changes of cavitation have been incorporated into modified recist ( mrecist ) assessment of non - small - cell lung cancer treated with an anti - angiogenic agent ( 26 ) . in the setting of hepatocellular carcinoma treated with sorafenib , adjustments to recist include measurement of the arterially enhancing components of tumors in mrecist and other changes in irregular tumors using response evaluation criteria in cancer of the liver ( fig . a variety of alternative assessment methods have been tested to better differentiate responders and non - responders to anti - angiogenic treatments , including choi criteria , morphology , attenuation , size and structure criteria , and alternate tumor shrinkage thresholds ( 21293031 ) . anti - angiogenic or vegf - targeted therapies are associated with several treatment - specific complications of which radiologists must be aware , since imaging manifestations of the drug toxicity may occur before a patient develops symptoms . some of the most important , potentially life - threatening adverse events associated with anti - angiogenic therapy are bowel perforation , pneumatosis and/or tumor bowel fistula , which may have subtle or overt imaging appearances ( fig . 4 ) . while these events are infrequent , occurring in 1.7% of 1442 patients treated with bevacizumab according to one report ( 32 ) , prompt detection is important , as pneumatosis and perforation are often managed conservatively via discontinuation of therapy and supportive care . the radiologist may be the first provider to encounter these toxicities , as 70.8% of cancer patients with pneumatosis and/or bowel perforation were asymptomatic in one study ( 33 ) . other potential abdominal complications in anti - angiogenic treatment include colitis , cholecystitis , pancreatitis and hepatic steatosis ( 34 ) . hemorrhage , thrombosis and hypertension are other potential toxicities related to vegf - targeted therapy . hemorrhage is reported in up to 30% of patients with various cancers treated with bevacizumab , severe in fewer than 5% of patients ( 35 ) . while common presentations include epistaxis , gastrointestinal bleeding and hemoptysis , it is particularly relevant for radiologists to be cognizant of potential intratumoral hemorrhage , which can result in increased size of metastases and lead to erroneous interpretation of progression ( pseudoprogression ) . a clue to potential pseudoprogression is development of fluid - fluid levels in metastases , and mri is a helpful problem solving tool to detect hemorrhagic ( t1-hyperintense ) contents in challenging cases . arterial thromboembolic events are increased in patients treated with vegf - targeted therapies , with overall relative risk of 1.46 in bevacizumab treated patients and 3.03 in sunitinib or sorafenib treated patients , compared to controls ( 3637 ) . risk of venous thromboembolic events in this setting is considered controversial , with increased risk in one meta - analysis and no increased risk in another ( 3839 ) . hypertension is another adverse effect and potential biomarker in patients treated with anti - angiogenic agents , since improved response rates and survival parameters have been documented in patients who develop hypertension on treatment ( 40 ) . posterior reversible encephalopathy syndrome is a rare complication of anti - angiogenic therapy ( 41 ) . when reporting imaging studies of patients treated with anti - angiogenic or vegf - targeted therapy , it is important for the radiologist to pay close attention to the study indication ( including disease and specific therapy ) , to use appropriate cancer - specific and/or treatment - specific response criteria when available , to consider the possibility of an atypical response , and to evaluate for known toxicities of the treatment regimen on imaging . reporting of cancer imaging studies can be facilitated by the use of cancer imaging radiology report templates ( 42 ) . for example , in a patient with metastatic colon cancer to liver treated with a bevacizumab - containing regimen , it is relevant to consider response according to ct - based morphologic criteria . atypical response patterns should be considered , including potential increased size but decreased density / greater homogeneity in liver metastases , and/or apparent new lesions which could have been isodense at baseline ( 43 ) . in difficult cases , correlation may be made with tumor markers ( e.g. , carcinoembryonic antigen ) and patient 's performance status through discussion with the referring oncologist . in addition , it is important to scrutinize the imaging study for treatment related complications and toxicities , such as pneumatosis , thromboembolism and hepatic steatosis . as reviewed , anti - angiogenic agents are approved for use in a variety of malignancies . also during the last decade , multiple other mtts have been developed to target molecular pathways other than / in addition to the vegf - axis . many of these are approved for use in cancer - specific treatment settings , with or without associated documentation of a cancer 's driver mutation via fda - approved genetic tests . using lung , renal and breast cancer as representative examples , several commonly used mtts will be discussed , including an overview of their treatment rationale , expected response patterns and imaging manifestations of toxicity . epidermal growth factor receptor ( egfr ) tyrosine kinase is a protein involved in cell proliferation , apoptosis , angiogenesis and invasion , overexpressed in non - small - cell lung cancer ( 44 ) . activating mutations in the egfr - tyrosine kinase domain have been documented in approximately 10% of non - small cell lung cancer patients of north american / western european descent and 2550% of non - small cell lung cancer patients of asian descent ( 45 ) . presence of an activating mutation in egfr has been associated with dramatic response to targeted egfr tki gefitinib ( iressa ; astrazeneca , pharmaceuticals , wilmington , de , usa ) and erlotinib ( tarceva ; genentech , south san francisco , ca , usa ) ( fig . this discovery , reported in 2004 , was a major advance in the lung cancer treatment paradigm ; prior to this , all patients with advanced non - small cell lung cancer were treated with a platinum - based chemotherapy regimen . in the new era , patient 's tumors are prospectively tested for sensitizing mutations amenable to targeted treatments such as egfr tkis . clinical features associated with the sensitizing mutations and responsiveness to egfr tkis include asian descent , female sex and never smoker status . another genomically characterized lung cancer involves anaplastic lymphoma kinase ( alk ) rearrangement , occurring in 27% of non - small - cell lung cancer patients ( 49 ) . in this setting , the echinoderm microtubule - associated protein - like 4 ( emf4 ) gene clinical features associated with alk rearranged lung cancer include young age and never to light smoking history . patients with alk rearrangements are highly sensitive to alk inhibitors such as crizotinib ( xalkori ; pfizer , new york , ny , usa ) and ceritinib ( zykadia ; novartis , east hanover , nj , usa ) ( fig . 6 ) ( 4950 ) . in lung cancer patients with selected driver mutations , for example , response rates to egfr tkis are reportedly 5575% in the first line setting , and median progression free survival is on the order of 9 months ( 515253 ) . similarly , the phase iii overall response rate to crizotinib was 65% and median progression free survival approximately 8 months ( 54 ) . conventional size based response criteria ( such as recist ) are typically employed in these settings , which capture response in many cases , though other methods of assessment including ct tumor volumetry have been proposed ( 55 ) . as many patients demonstrate dramatic tumor shrinkage , the nadir target lesion diameter may be quite small and modest increases in diameter upon acquired resistance ( for example , via acquired t790 m mutation or another mechanism in egfr mutant patients ) may represent recist disease progression ( 23 ) . if targeted therapy is withdrawn , a flare phenomenon can occur , with dramatic increase in tumor burden upon withdrawal of the targeted agent ( fig . many in the field realize the clinical benefit to continuing egfr - targeted therapy beyond recist progression in some patients , either alone or in combination with chemotherapy . alternative criteria are sought to objectively differentiate patients with slow progression amenable to targeted agent continuation from those without treatment benefit ( 5758 ) . tumor volume models to define tumor growth have been investigated in this regard ( 59 ) . the appropriate time to initiate a treatment change will become even more complicated as therapies targeted to resistance mechanisms become available . for example , osimertinib ( tagrisso ; astrazenecae , pharmaceuticals , wilmington , de , usa ) was approved for patients with acquired egfr t790 m mutation - positive metastatic non - small cell lung cancer in november 2015 ( 60 ) . when reporting imaging studies of patients with genomically characterized lung cancer , it is often helpful for the radiologist to know the specific mutation and targeted therapy . furthermore , it may be useful to know the date of the baseline scan , the tumor burden at baseline , as well as have an awareness of the nadir tumor burden , if reached . familiarity with the treatment course and the expected time of resistance development may help to detect subtle changes in tumor size and shape indicative of early resistance . it is also important to assess such patients for radiologic evidence of drug toxicity , including pneumonitis in those treated with egfr tki or alk inhibitors . four patterns of pneumonitis have been associated with egfr tki according to one report , including : 1 ) nonspecific area of groundglass attenuation , 2 ) multifocal airspace consolidation , 3 ) patchy ground - glass attenuation accompanied by interlobar septal thickening , and 4 ) extensive bilateral ground - glass attenuation or airspace consolidation with traction bronchiectasis ( 61 ) . pattern a was the most common in this study , involving 44% of 70 patients with gefitinib - related lung disease , while pattern d was associated with the highest mortality , involving 75% of patients in this category . in phase iii clinical trials of erlotinib and crizotinib , interstitial lung disease / pneumonitis resulted in 5 deaths ( 1% ) and 2 deaths ( ~1% ) in the treatment groups , respectively ( 5462 ) . radiologists should also be aware of other potential imaging manifestions of egfr tki toxicity , including diarrhea / colitis , pneumatosis and periportal edema related to hepatic failure ( 63 ) . diarrhea / colitis is commonly reported , evidenced by fluid filled colon , dilation , wall thickening and/or mesenteric hyperemia ( 63 ) . in contrast , pneumatosis and periportal edema related to hepatic failure are rare events ( 63 ) . it is worthwhile to mention that each of the egfr tkis toxicities can be seen in patients treated with these agents in other cancer settings ( e.g. , erlotinib treatment of pancreatic cancer ; cetuximab ( erbitux ; bristol - myers squibb , new york , ny , usa ) treatment of advanced squamous cell carcinoma of the head and neck ) ( 6465 ) . development of complex renal cysts has been associated with crizotinib therapy , and cysts regress when therapy is discontinued ( 66 ) . rapid onset hypogonadism with low testosterone has also been reported with crizotinib therapy ( fig . a drug - based imaging toxicity checklist or template may assist radiologists in reporting pertinent findings ( 42 ) . in rcc , the vegf - axis is a common therapeutic target due to inactivation of the von hippel lindau gene in the majority of clear cell rccs , leading to accumulation of hypoxia inducible factor and overexpression of vegf . however , the phosphatidylinositol-3-kinase - akt - mammalian target of rapamycin ( mtor ) pathway is another active intracellular molecular signaling pathway in rcc amenable to targeted treatment . mtor is a serine / threonine kinase , and its activation ultimately promotes protein synthesis and cell survival ( 6869 ) . everolimus ( afinitor ; novartis , east hanover , nj , usa ) and temsirolimus ( torisel pfizer , new york , ny , usa ) are inhibitors of mtor approved in metastatic rcc ( 7071 ) . both agents were associated with modest response rates ranging from 19% in phase iii trials , though progression free survival was prolonged by both agents and overall survival prolonged by the latter ( 7071 ) . everolimus is also approved for use in subependymal giant cell astrocytoma , advanced hormone receptor  positive human epidermal growth factor receptor 2 ( her2)-negative breast cancer , and pancreatic neuroendocrine tumors . clinical trials of everolimus in waldenstrom 's macroglobulinemia have been reported , with promising results ( 72 ) . given the high prevalence of stable disease according to recist in rcc patients treated with mtor inhibitors , alternative criteria have been sought to better differentiate responders and non - responders . according to an analysis of phase iii study data in everolimus - treated patients , a reduction of greater than 5% in the sum long diameter measurements of target lesions predicted benefit in progression free survival better than partial response ( 30% reduction ) ( 73 ) . however , it is possible that 5% reduction in the sum long diameter measurements of target lesions is within the range of measurement variability , therefore , the clinical utility of this threshold is questionable ( 74 ) . modified choi criteria have been applied to rcc patients treated with everolimus , and modified choi assessments in three dimensions enabled identification of patients with progression free survival benefit from everolimus according to one study ( 75 ) . given the limitations and the complexity of these alternative criteria , response assessment remains largely according to recist in this clinical setting . radiographic evidence of pneumonitis occurs in up to a third of patients , represented by ground - glass opacities and consolidation ( fig . ( 76 ) , 31% of patients with radiographic evidence of pneumonitis were symptomatic ( with cough , shortness of breath and/or oxygen requirement ) , highlighting the important role of the radiologist in detecting early / asymptomatic lung toxicity . pneumonitis has been proposed as a marker of therapeutic benefit , since patients in one report with imaging evidence of pneumonitis more frequently demonstrated stable disease according to recist than those without pneumonitis ( 77 ) . in patients with other malignancies treated with mtor inhibitors , as many as 58% of patients with waldenstrom 's macroglobulinemia demonstrated imaging findings of pneumonitis , while 21% of patients with pancreatic neuroendocrine tumors did , most commonly manifesting as cryptogenic organizing pneumonia and non - specific interstitial pneumonia patterns ( 7980 ) . cholecystitis , pancreatitis and enteritis are less commonly seen mtor toxicities on imaging ( 818283 ) . while molecular targeted therapies are commonly employed in a variety of advanced / metastatic cancers , targeted treatment in breast cancer may be applied in neoadjuvant and adjuvant settings , as well as in advanced / metastatic disease . according to the national comprehensive cancer network ( nccn ) clinical practice guidelines in oncology , adjuvant therapy is recommended in patients with tumors greater than 1 cm or with lymph node involvement ( 84 ) . traditional cytotoxic chemotherapies including taxanes and anthracyclines are commonly used in first line treatment ( 84 ) . in addition to stage , hormone receptor status and her2 status are also important factors influencing treatment , and hormonal and/or targeted agents are part of the armamentarium . these are amenable to treatment with hormonal agents , including selective estrogen receptor modulators ( serms ) , like tamoxifen , and/or aromatase inhibitors ( ais ) , including anastrozole , letrozole , exemestane . serms act by an anti - estrogenic effect in the breast tissue and ais reduce conversion of androgens to estrogens , the latter commonly used in post - menopausal patients . given their relative safety profile , adjuvant hormonal therapy may be continued for 510 years after diagnosis . in metastatic disease , hormonal agents may be used in the first line setting in the absence of rapidly progressing visceral metastases , in light of the preferable side effect profiles of these drugs compared to cytotoxic chemotherapy . hormonal agents may be used alone or in combination with other agents , including mtts ( fig . for example , in february 2015 , the cyclin dependent kinase ( cdk ) inhibitor palbociclib ( ibrance ; pfizer ) was approved in combination with letrozole for initial treatment of advanced hormone receptor positive , her2 negative breast cancer in postmenopausal patients ( 85 ) . palbociclib is a small molecule inhibitor of cdk4 and 6 , which blocks progression of cells from the g1 into s phase of the cell cycle , resulting in growth arrest . in the phase ii study of letrozole plus palbociclib compared to letrozole alone , median progression free survival was doubled in patients treated with combination therapy ( 20.2 months vs. 10.2 months , p = 0.0004 ) and partial response rates were higher among patients with measurable disease treated with combination therapy ( 54% vs. 39% , p = 0.047 ) ( 85 ) . in february 2016 , palbociclib was approved in combination with fulvestrant , a complete estrogen receptor antagonist , for postmenopausal patients with hormone receptor positive , her2 negative advanced breast cancer after progression on endocrine therapy ( 86 ) . the mtor inhibitor everolimus is also approved in combination with exemestane for patients with advanced , hormone receptor positive , her2 negative breast cancer who have progressed on letrozole or anastrozole ( 87 ) . response to the combination of hormonal agents and mtts is typically assessed according to recist criteria in breast cancer . for example , in the case of serm or tamoxifen use , proestrogenic effects are observed in the uterus , including benign entities ( endometrial polyps , hyperplasia , adenomyosis , and fibroids ) and malignant disease ( endometrial carcinoma , and sarcoma ) ( 88 ) . human epidermal growth factor receptor 2 positive breast cancer represents up to 20% of breast cancer cases . positive breast cancers overexpress her2 , also known as erbb2 , a receptor tyrosine kinase involved in cell growth and proliferation . positivity is a biomarker of disease aggressiveness but is also predictive of responsiveness to her2 targeted treatments . , south san francisco , ca , usa ) is a monoclonal antibody targeted to her2 used in adjuvant and metastatic breast cancer treatment of her2 positive tumors , often in combination with other drugs ( 90 ) . toxicities associated with trastuzumab therapy include cardiotoxicity which may be identified on echocardiogram or on multiple - gated acquisition scan . pertuzumab ( perjeta ; genentech inc . ) is another her2 targeted therapy , aimed at inhibiting her2 dimerization . it is approved in combination with trastuzumab and docetaxel in the neoadjuvant and metastatic settings ( 91 ) . other targeted therapies are fda - approved for patients who have progressed on trastuzumab - containing regimens . in 2007 , the dual her2/egfr inhibitor lapatinib ( tykerb ; glaxosmithkline , middlesex , united kingdom ) was approved in her2 overexpressing breast cancer in combination with capecitabine in patients who have progressed on prior therapy containing trastuzumab ( 92 ) . in 2010 , lapatinib was approved in combination with letrozole in hormone receptor positive , her2 positive disease . lapatinib is a small molecule which may penetrate the blood brain barrier , an important feature in her2 positive disease , since one third or more patients with metastatic her2 positive breast cancer develop brain metastases ( 93 ) . in 2013 , the drug - antibody conjugate known as tdm-1 or ado - trastuzumab emtansine ( kadcyla ; genentech inc . ) was approved for patients with her2 positive disease after progression on trastuzumab and a taxane , separately or in combination ( 94 ) . in this therapy , dm-1 is an antimicrotubule agent which is linked to trastuzumab for selective delivery into cancer cells . response assessment is according to recist in the various her2 targeted treatments in breast cancer . epidermal growth factor receptor ( egfr ) tyrosine kinase is a protein involved in cell proliferation , apoptosis , angiogenesis and invasion , overexpressed in non - small - cell lung cancer ( 44 ) . activating mutations in the egfr - tyrosine kinase domain have been documented in approximately 10% of non - small cell lung cancer patients of north american / western european descent and 2550% of non - small cell lung cancer patients of asian descent ( 45 ) . presence of an activating mutation in egfr has been associated with dramatic response to targeted egfr tki gefitinib ( iressa ; astrazeneca , pharmaceuticals , wilmington , de , usa ) and erlotinib ( tarceva ; genentech , south san francisco , ca , usa ) ( fig . this discovery , reported in 2004 , was a major advance in the lung cancer treatment paradigm ; prior to this , all patients with advanced non - small cell lung cancer were treated with a platinum - based chemotherapy regimen . in the new era , patient 's tumors are prospectively tested for sensitizing mutations amenable to targeted treatments such as egfr tkis . clinical features associated with the sensitizing mutations and responsiveness to egfr tkis include asian descent , female sex and never smoker status . another genomically characterized lung cancer involves anaplastic lymphoma kinase ( alk ) rearrangement , occurring in 27% of non - small - cell lung cancer patients ( 49 ) . in this setting , the echinoderm microtubule - associated protein - like 4 ( emf4 ) gene clinical features associated with alk rearranged lung cancer include young age and never to light smoking history . patients with alk rearrangements are highly sensitive to alk inhibitors such as crizotinib ( xalkori ; pfizer , new york , ny , usa ) and ceritinib ( zykadia ; novartis , east hanover , nj , usa ) ( fig . for example , response rates to egfr tkis are reportedly 5575% in the first line setting , and median progression free survival is on the order of 9 months ( 515253 ) . similarly , the phase iii overall response rate to crizotinib was 65% and median progression free survival approximately 8 months ( 54 ) . conventional size based response criteria ( such as recist ) are typically employed in these settings , which capture response in many cases , though other methods of assessment including ct tumor volumetry have been proposed ( 55 ) . as many patients demonstrate dramatic tumor shrinkage , the nadir target lesion diameter may be quite small and modest increases in diameter upon acquired resistance ( for example , via acquired t790 m mutation or another mechanism in egfr mutant patients ) may represent recist disease progression ( 23 ) . if targeted therapy is withdrawn , a flare phenomenon can occur , with dramatic increase in tumor burden upon withdrawal of the targeted agent ( fig . many in the field realize the clinical benefit to continuing egfr - targeted therapy beyond recist progression in some patients , either alone or in combination with chemotherapy . alternative criteria are sought to objectively differentiate patients with slow progression amenable to targeted agent continuation from those without treatment benefit ( 5758 ) . tumor volume models to define tumor growth have been investigated in this regard ( 59 ) . the appropriate time to initiate a treatment change will become even more complicated as therapies targeted to resistance mechanisms become available . for example , osimertinib ( tagrisso ; astrazenecae , pharmaceuticals , wilmington , de , usa ) was approved for patients with acquired egfr t790 m mutation - positive metastatic non - small cell lung cancer in november 2015 ( 60 ) . when reporting imaging studies of patients with genomically characterized lung cancer , it is often helpful for the radiologist to know the specific mutation and targeted therapy . furthermore , it may be useful to know the date of the baseline scan , the tumor burden at baseline , as well as have an awareness of the nadir tumor burden , if reached . familiarity with the treatment course and the expected time of resistance development may help to detect subtle changes in tumor size and shape indicative of early resistance . it is also important to assess such patients for radiologic evidence of drug toxicity , including pneumonitis in those treated with egfr tki or alk inhibitors . four patterns of pneumonitis have been associated with egfr tki according to one report , including : 1 ) nonspecific area of groundglass attenuation , 2 ) multifocal airspace consolidation , 3 ) patchy ground - glass attenuation accompanied by interlobar septal thickening , and 4 ) extensive bilateral ground - glass attenuation or airspace consolidation with traction bronchiectasis ( 61 ) . pattern a was the most common in this study , involving 44% of 70 patients with gefitinib - related lung disease , while pattern d was associated with the highest mortality , involving 75% of patients in this category . in phase iii clinical trials of erlotinib and crizotinib , interstitial lung disease / pneumonitis resulted in 5 deaths ( 1% ) and 2 deaths ( ~1% ) in the treatment groups , respectively ( 5462 ) . radiologists should also be aware of other potential imaging manifestions of egfr tki toxicity , including diarrhea / colitis , pneumatosis and periportal edema related to hepatic failure ( 63 ) . diarrhea / colitis is commonly reported , evidenced by fluid filled colon , dilation , wall thickening and/or mesenteric hyperemia ( 63 ) . in contrast , pneumatosis and periportal edema related to hepatic failure are rare events ( 63 ) . it is worthwhile to mention that each of the egfr tkis toxicities can be seen in patients treated with these agents in other cancer settings ( e.g. , erlotinib treatment of pancreatic cancer ; cetuximab ( erbitux ; bristol - myers squibb , new york , ny , usa ) treatment of advanced squamous cell carcinoma of the head and neck ) ( 6465 ) . development of complex renal cysts has been associated with crizotinib therapy , and cysts regress when therapy is discontinued ( 66 ) . rapid onset hypogonadism with low testosterone has also been reported with crizotinib therapy ( fig . a drug - based imaging toxicity checklist or template may assist radiologists in reporting pertinent findings ( 42 ) . in rcc , the vegf - axis is a common therapeutic target due to inactivation of the von hippel lindau gene in the majority of clear cell rccs , leading to accumulation of hypoxia inducible factor and overexpression of vegf . however , the phosphatidylinositol-3-kinase - akt - mammalian target of rapamycin ( mtor ) pathway is another active intracellular molecular signaling pathway in rcc amenable to targeted treatment . mtor is a serine / threonine kinase , and its activation ultimately promotes protein synthesis and cell survival ( 6869 ) . everolimus ( afinitor ; novartis , east hanover , nj , usa ) and temsirolimus ( torisel pfizer , new york , ny , usa ) are inhibitors of mtor approved in metastatic rcc ( 7071 ) . both agents were associated with modest response rates ranging from 19% in phase iii trials , though progression free survival was prolonged by both agents and overall survival prolonged by the latter ( 7071 ) . everolimus is also approved for use in subependymal giant cell astrocytoma , advanced hormone receptor  positive human epidermal growth factor receptor 2 ( her2)-negative breast cancer , and pancreatic neuroendocrine tumors . clinical trials of everolimus in waldenstrom 's macroglobulinemia have been reported , with promising results ( 72 ) . given the high prevalence of stable disease according to recist in rcc patients treated with mtor inhibitors , alternative criteria have been sought to better differentiate responders and non - responders . according to an analysis of phase iii study data in everolimus - treated patients , a reduction of greater than 5% in the sum long diameter measurements of target lesions predicted benefit in progression free survival better than partial response ( 30% reduction ) ( 73 ) . however , it is possible that 5% reduction in the sum long diameter measurements of target lesions is within the range of measurement variability , therefore , the clinical utility of this threshold is questionable ( 74 ) . modified choi criteria have been applied to rcc patients treated with everolimus , and modified choi assessments in three dimensions enabled identification of patients with progression free survival benefit from everolimus according to one study ( 75 ) . given the limitations and the complexity of these alternative criteria , response assessment remains largely according to recist in this clinical setting . radiographic evidence of pneumonitis occurs in up to a third of patients , represented by ground - glass opacities and consolidation ( fig . ( 76 ) , 31% of patients with radiographic evidence of pneumonitis were symptomatic ( with cough , shortness of breath and/or oxygen requirement ) , highlighting the important role of the radiologist in detecting early / asymptomatic lung toxicity . pneumonitis has been proposed as a marker of therapeutic benefit , since patients in one report with imaging evidence of pneumonitis more frequently demonstrated stable disease according to recist than those without pneumonitis ( 77 ) . in patients with other malignancies treated with mtor inhibitors , as many as 58% of patients with waldenstrom 's macroglobulinemia demonstrated imaging findings of pneumonitis , while 21% of patients with pancreatic neuroendocrine tumors did , most commonly manifesting as cryptogenic organizing pneumonia and non - specific interstitial pneumonia patterns ( 7980 ) . cholecystitis , pancreatitis and enteritis are less commonly seen mtor toxicities on imaging ( 818283 ) . while molecular targeted therapies are commonly employed in a variety of advanced / metastatic cancers , targeted treatment in breast cancer may be applied in neoadjuvant and adjuvant settings , as well as in advanced / metastatic disease . according to the national comprehensive cancer network ( nccn ) clinical practice guidelines in oncology , adjuvant therapy is recommended in patients with tumors greater than 1 cm or with lymph node involvement ( 84 ) . traditional cytotoxic chemotherapies including taxanes and anthracyclines are commonly used in first line treatment ( 84 ) . in addition to stage , hormone receptor status and her2 status are also important factors influencing treatment , and hormonal and/or targeted agents are part of the armamentarium . these are amenable to treatment with hormonal agents , including selective estrogen receptor modulators ( serms ) , like tamoxifen , and/or aromatase inhibitors ( ais ) , including anastrozole , letrozole , exemestane . serms act by an anti - estrogenic effect in the breast tissue and ais reduce conversion of androgens to estrogens , the latter commonly used in post - menopausal patients . given their relative safety profile , adjuvant hormonal therapy may be continued for 510 years after diagnosis . in metastatic disease , hormonal agents may be used in the first line setting in the absence of rapidly progressing visceral metastases , in light of the preferable side effect profiles of these drugs compared to cytotoxic chemotherapy . hormonal agents may be used alone or in combination with other agents , including mtts ( fig . for example , in february 2015 , the cyclin dependent kinase ( cdk ) inhibitor palbociclib ( ibrance ; pfizer ) was approved in combination with letrozole for initial treatment of advanced hormone receptor positive , her2 negative breast cancer in postmenopausal patients ( 85 ) . palbociclib is a small molecule inhibitor of cdk4 and 6 , which blocks progression of cells from the g1 into s phase of the cell cycle , resulting in growth arrest . in the phase ii study of letrozole plus palbociclib compared to letrozole alone , median progression free survival was doubled in patients treated with combination therapy ( 20.2 months vs. 10.2 months , p = 0.0004 ) and partial response rates were higher among patients with measurable disease treated with combination therapy ( 54% vs. 39% , p = 0.047 ) ( 85 ) . in february 2016 , palbociclib was approved in combination with fulvestrant , a complete estrogen receptor antagonist , for postmenopausal patients with hormone receptor positive , her2 negative advanced breast cancer after progression on endocrine therapy ( 86 ) . the mtor inhibitor everolimus is also approved in combination with exemestane for patients with advanced , hormone receptor positive , her2 negative breast cancer who have progressed on letrozole or anastrozole ( 87 ) . response to the combination of hormonal agents and mtts is typically assessed according to recist criteria in breast cancer . for example , in the case of serm or tamoxifen use , proestrogenic effects are observed in the uterus , including benign entities ( endometrial polyps , hyperplasia , adenomyosis , and fibroids ) and malignant disease ( endometrial carcinoma , and sarcoma ) ( 88 ) . . human epidermal growth factor receptor 2 positive breast cancer represents up to 20% of breast cancer cases . her2 positive breast cancers overexpress her2 , also known as erbb2 , a receptor tyrosine kinase involved in cell growth and proliferation . positivity is a biomarker of disease aggressiveness but is also predictive of responsiveness to her2 targeted treatments . , south san francisco , ca , usa ) is a monoclonal antibody targeted to her2 used in adjuvant and metastatic breast cancer treatment of her2 positive tumors , often in combination with other drugs ( 90 ) . toxicities associated with trastuzumab therapy include cardiotoxicity which may be identified on echocardiogram or on multiple - gated acquisition scan . pertuzumab ( perjeta ; genentech inc . ) is another her2 targeted therapy , aimed at inhibiting her2 dimerization . it is approved in combination with trastuzumab and docetaxel in the neoadjuvant and metastatic settings ( 91 ) . other targeted therapies are fda - approved for patients who have progressed on trastuzumab - containing regimens . in 2007 , the dual her2/egfr inhibitor lapatinib ( tykerb ; glaxosmithkline , middlesex , united kingdom ) was approved in her2 overexpressing breast cancer in combination with capecitabine in patients who have progressed on prior therapy containing trastuzumab ( 92 ) . in 2010 , lapatinib was approved in combination with letrozole in hormone receptor positive , her2 positive disease . lapatinib is a small molecule which may penetrate the blood brain barrier , an important feature in her2 positive disease , since one third or more patients with metastatic her2 positive breast cancer develop brain metastases ( 93 ) . in 2013 , the drug - antibody conjugate known as tdm-1 or ado - trastuzumab emtansine ( kadcyla ; genentech inc . ) was approved for patients with her2 positive disease after progression on trastuzumab and a taxane , separately or in combination ( 94 ) . in this therapy , dm-1 is an antimicrotubule agent which is linked to trastuzumab for selective delivery into cancer cells . response assessment is according to recist in the various her2 targeted treatments in breast cancer . interpretation of imaging studies in oncology patients has become progressively more complex in the context of evolving genomic cancer characterization and increasing number and types of therapies available to patients . radiologists should be familiar with anti - angiogenic treatments and the wide variety of non - anti - angiogenic molecular targeted therapies associated with typical and atypical patterns of tumor response , resistance , growth and toxicity . it is a formidable task to keep abreast of developments in oncology , but it is necessary to provide optimal diagnoses , render appropriate response assessments , and identify important drug toxicities which may impact patient management .
oncology is a rapidly evolving field with a shift toward personalized cancer treatment . the use of therapies targeted to the molecular features of individual tumors and the tumor microenvironment has become much more common . in this review , 
 anti - angiogenic and other molecular targeted therapies are discussed , with a focus on typical and atypical response patterns and imaging manifestations of drug toxicities .