our institutional review board approved our retrospective study with a waiver of informed consent ; written informed consent was acquired for the use of ct scans for all the patients . we acquired the patients ' data from the prospective phase ii clinical trial of bevacizumab as a salvage treatment for nsclc , which was conducted at our institution during the period from may 2006 to july 2009 . a total of 21 patients with metastatic or recurrent nsclc and who were treated with bevacizumab ( at a dose of 15 mg / kg on day 1 ) combined with cytotoxic chemotherapeutic agents ( gemcitabine 1000 mg / m iv on days 1 and 8 , and cisplatin 70 mg / m iv on day 1 ) , were selected for this study . we excluded those patients ( n = 2 ) who had not undergone post - treatment ct at our institution , or those ( n = 3 ) who had no measurable disease on the pre - treatment ct . ultimately , 16 patients ( m : f = 11:5 ; median age , 57 years ) were enrolled in this study . the median follow - up time was 7.9 months ( range , 0.9 - 32.6 months ) . the initial ct scans were performed within two weeks before starting chemotherapy , and the follow - up ct scans were conducted after two cycles of chemotherapy . for all the patients , the ct studies were obtained with a 64-detector ( lightspeed vct xt , ge healthcare , wi ) row scanner and using the helical technique ( 125 ma , 120 kvp , a beam width of 10 - 20 mm , a beam pitch of 1.375 - 1.5 ) . the scans covered from the lung apices to the level of the middle portion of both kidneys . scanning was started 90 seconds after the intravenous injection of contrast medium ( a total of 80 ml of iomeron 300 [ iomeprol ] ; bracco ; milan , italy ) . the contrast medium was infused at a rate of 3 ml / s and by using a power injector ( mct plus ; medrad ; pittsburgh , pa ) . for the mediastinal window images , the image data was reconstructed with a soft - tissue algorithm , and for lung window images , the data was reconstructed with a bone algorithm . the reconstructed images were directly interfaced with a picture archiving and communication systems ( pacs ) ( pathspeed or centricity 2.0 ; ge healthcare , mt . prospect , il ) , which displayed all the image data on two monitors ( a 1536  2048 matrix , an 8-bit viewable gray scale and 60-ft - lambert luminescence ) . both the mediastinal ( width : 400 hu , level : 20 hu ) and lung ( width : 1500 hu , level : -700 hu ) window images were viewed on these monitors . two chest radiologists ( both with five years of ct interpretation experience ) and who were blinded to the clinical details and outcomes independently evaluated the ct images . the size of the target lesion was measured on the initial and follow - up ct scans at the level of the lesion equator ( the longest diameter on the largest target lesion image plane ) . they recorded the changes in the size of the target lesion before and after the therapy once with including both the solid and ggo components ( on lung window images ) of the lesion ( [ recist guidelines version 1.1 ] , designated as recist ) and then at the other time with including only the solid component on the mediastinal window images of the lesion ( designated as recistsolid ) ( 6 ) ( fig . each target lesion was classified as being either cavitated or not cavitated . in a cavitary lesion , only the soft - tissue wall thickness , except the cavitary area , was measured as the tumor size ( designated as the alternative measurement ) , that is , we subtracted the cavity diameter ( zero if no cavity was present ) from the longest diameter of the target lesion ( 3 ) ( fig . each measurement was performed on the same image plane . as for the attenuation measurements , the mean ct attenuation value of each target lesion was measured in hus by drawing a region of interest covering as large an area as possible ( at least two thirds of the longest diameter ) in the solid portion of the target lesion . the attenuation measurements were performed for the evaluation of the percentage changes in the mean lesion attenuation or the contrast enhancement changes before and after treatment ( designated as the combined criteria for evaluating both the changes of the tumor size and attenuation based on choi 's criteria ) ( table 1 ) . if a lesion had a small solid portion , then a region of interest of a 5 mm area was not applicable to measure the attenuation ( e.g. , a very thin cavitary wall in a cavitary lesion or a very small tumor after the treatment ) , and we were not able to measure the attenuation values of such a lesion . all the other details regarding the definitions for the designation of response and the assessment of non - target lesions for the three different assessment methods were identical to the recist version 1.1 . first , response assessment was performed by using the recist version 1.1 ( 2 ) . second , the tumor response was evaluated according to recist with covering only the solid component of the target lesions ( recistsolid ) . third , an alternative response assessment ( the alternative method ) was used to measure the tumor response and particularly in the cavitary lesions ; we calculate the changes of the target lesion with including only the soft - tissue wall thickness component and we excluded the air component of cavitary change ( subtracting the cavity diameter from the longest diameter of the cancer mass ) ( 3 ) . finally , the combined criteria ( table 1 ) were applied for tumor response evaluation ( 4 ) , for which both the size and attenuation changes on the enhanced scans before and after treatment were computed for each target lesion . following independent interpretations by the two readers , discordant reports were jointly reviewed by the two readers and one third reader ( with seven years of ct interpretation experience ) , and a final consensus decision was reached . after treatment , the patients were followed up at two month intervals with chest and abdominal ct scans to identify any disease progression . the patients were also observed for survival until death or until the last contact if still alive . the patients were classified as patients with a complete response ( cr ) , partial response ( pr ) , stable disease ( sd ) or progressive disease ( pd ) after treatment . the good responders were deemed as the patients with a cr or pr , and the good overall responders were deemed as the patients showing a cr , pr or sd on the follow - up ct . statistical analyses were performed with spss software ( spss for windows , version 15.0 , 2006 ; spss , chicago , il ) , and significance was set at p values < 0.05 . disease pfs was defined as the time from the starting date of treatment until the time point of patient progression ( as shown by radiologic [ ct ] and clinical examination ) or death from the disease . for the patients who had no evidence of progressive disease , the absence of disease progression was ascertained at the date of the last follow - up examination . we determined how much the response assessment would be altered if we applied the three different assessment evaluation methods instead of the recist method . to evaluate the capability of recist , recistsolid , the alternative method and the combined criteria to predict the patient prognosis , the pfss were compared between the responders ( cr , pr , sd and pd ) or between the good and poor responders or between the good and poor overall responders according to the four different measurement methods . the interobserver agreement between the two radiologists was assessed by calculating the k value for response according to each response criterion . our institutional review board approved our retrospective study with a waiver of informed consent ; written informed consent was acquired for the use of ct scans for all the patients . we acquired the patients ' data from the prospective phase ii clinical trial of bevacizumab as a salvage treatment for nsclc , which was conducted at our institution during the period from may 2006 to july 2009 . a total of 21 patients with metastatic or recurrent nsclc and who were treated with bevacizumab ( at a dose of 15 mg / kg on day 1 ) combined with cytotoxic chemotherapeutic agents ( gemcitabine 1000 mg / m iv on days 1 and 8 , and cisplatin 70 mg / m iv on day 1 ) , were selected for this study . we excluded those patients ( n = 2 ) who had not undergone post - treatment ct at our institution , or those ( n = 3 ) who had no measurable disease on the pre - treatment ct . ultimately , 16 patients ( m : f = 11:5 ; median age , 57 years ) were enrolled in this study . the median follow - up time was 7.9 months ( range , 0.9 - 32.6 months ) . the initial ct scans were performed within two weeks before starting chemotherapy , and the follow - up ct scans were conducted after two cycles of chemotherapy . for all the patients , the ct studies were obtained with a 64-detector ( lightspeed vct xt , ge healthcare , wi ) row scanner and using the helical technique ( 125 ma , 120 kvp , a beam width of 10 - 20 mm , a beam pitch of 1.375 - 1.5 ) . the scans covered from the lung apices to the level of the middle portion of both kidneys . scanning was started 90 seconds after the intravenous injection of contrast medium ( a total of 80 ml of iomeron 300 [ iomeprol ] ; bracco ; milan , italy ) . the contrast medium was infused at a rate of 3 ml / s and by using a power injector ( mct plus ; medrad ; pittsburgh , pa ) . the image data was reconstructed with a 2.5-mm section thickness . for the mediastinal window images , the image data was reconstructed with a soft - tissue algorithm , and for lung window images , the data was reconstructed with a bone algorithm . the reconstructed images were directly interfaced with a picture archiving and communication systems ( pacs ) ( pathspeed or centricity 2.0 ; ge healthcare , mt . prospect , il ) , which displayed all the image data on two monitors ( a 1536  2048 matrix , an 8-bit viewable gray scale and 60-ft - lambert luminescence ) . both the mediastinal ( width : 400 hu , level : 20 hu ) and lung ( width : 1500 hu , level : -700 hu ) window images were viewed on these monitors . two chest radiologists ( both with five years of ct interpretation experience ) and who were blinded to the clinical details and outcomes independently evaluated the ct images . the size of the target lesion was measured on the initial and follow - up ct scans at the level of the lesion equator ( the longest diameter on the largest target lesion image plane ) . they recorded the changes in the size of the target lesion before and after the therapy once with including both the solid and ggo components ( on lung window images ) of the lesion ( [ recist guidelines version 1.1 ] , designated as recist ) and then at the other time with including only the solid component on the mediastinal window images of the lesion ( designated as recistsolid ) ( 6 ) ( fig . each target lesion was classified as being either cavitated or not cavitated . in a cavitary lesion , only the soft - tissue wall thickness , except the cavitary area , was measured as the tumor size ( designated as the alternative measurement ) , that is , we subtracted the cavity diameter ( zero if no cavity was present ) from the longest diameter of the target lesion ( 3 ) ( fig . each measurement was performed on the same image plane . as for the attenuation measurements , the mean ct attenuation value of each target lesion was measured in hus by drawing a region of interest covering as large an area as possible ( at least two thirds of the longest diameter ) in the solid portion of the target lesion . the attenuation measurements were performed for the evaluation of the percentage changes in the mean lesion attenuation or the contrast enhancement changes before and after treatment ( designated as the combined criteria for evaluating both the changes of the tumor size and attenuation based on choi 's criteria ) ( table 1 ) . if a lesion had a small solid portion , then a region of interest of a 5 mm area was not applicable to measure the attenuation ( e.g. , a very thin cavitary wall in a cavitary lesion or a very small tumor after the treatment ) , and we were not able to measure the attenuation values of such a lesion . in these conditions , all the other details regarding the definitions for the designation of response and the assessment of non - target lesions for the three different assessment methods were identical to the recist version 1.1 . first , response assessment was performed by using the recist version 1.1 ( 2 ) . second , the tumor response was evaluated according to recist with covering only the solid component of the target lesions ( recistsolid ) . third , an alternative response assessment ( the alternative method ) was used to measure the tumor response and particularly in the cavitary lesions ; we calculate the changes of the target lesion with including only the soft - tissue wall thickness component and we excluded the air component of cavitary change ( subtracting the cavity diameter from the longest diameter of the cancer mass ) ( 3 ) . finally , the combined criteria ( table 1 ) were applied for tumor response evaluation ( 4 ) , for which both the size and attenuation changes on the enhanced scans before and after treatment were computed for each target lesion . following independent interpretations by the two readers , discordant reports were jointly reviewed by the two readers and one third reader ( with seven years of ct interpretation experience ) , and a final consensus decision was reached . after treatment , the patients were followed up at two month intervals with chest and abdominal ct scans to identify any disease progression . the patients were also observed for survival until death or until the last contact if still alive . the patients were classified as patients with a complete response ( cr ) , partial response ( pr ) , stable disease ( sd ) or progressive disease ( pd ) after treatment . the good responders were deemed as the patients with a cr or pr , and the good overall responders were deemed as the patients showing a cr , pr or sd on the follow - up ct . statistical analyses were performed with spss software ( spss for windows , version 15.0 , 2006 ; spss , chicago , il ) , and significance was set at p values < 0.05 . disease pfs was defined as the time from the starting date of treatment until the time point of patient progression ( as shown by radiologic [ ct ] and clinical examination ) or death from the disease . for the patients who had no evidence of progressive disease , the absence of disease progression was ascertained at the date of the last follow - up examination . we determined how much the response assessment would be altered if we applied the three different assessment evaluation methods instead of the recist method . to evaluate the capability of recist , recistsolid , the alternative method and the combined criteria to predict the patient prognosis , the pfss were compared between the responders ( cr , pr , sd and pd ) or between the good and poor responders or between the good and poor overall responders according to the four different measurement methods . the interobserver agreement between the two radiologists was assessed by calculating the k value for response according to each response criterion . the details of the response designations by using the four different assessment methods for each patient are summarized in table 2 . five patients in the trial of bevacizumab - containing chemotherapy were found to have cavitation within lesions after treatment . marked cavitation ( to the degree that there was no residual solid component ) within the lesions occurred in two patients ( fig . 2 ) . of the 16 patients , six recist poor responders would have achieved a designation of pr by the combined criteria . in the case of the alternative method , of the same six patients , the overall response rates ( orrs , the patients showing a cr , pr or sd ) according to recist , recistsolid , the alternative method and the combined criteria were 81% , 88% , 81% , and 81% , respectively . the confirmed response rates ( rrs , the patients showing a cr or pr with the condition of response confirmation ) were 19% , 19% , 50% and 56% , respectively . although no significant difference was observed for the pfs among the three ( pr , sd and pd ) response groups to vascular inhibitor therapy , the alternative method showed the biggest stratifying power among the three groups for the prediction of pfs ( p = 0.07 ) ( fig . 3 ) . for the prognosis between the good ( cr or pr ) and poor responders , the alternative method again showed the biggest stratifying power among the three groups for the prediction of pfs ( p = 0.09 ) , yet there is no statistically significance ( fig . the recist and the alternative method showed a significant difference for the prognosis between the good ( cr , pr , or sd ) and poor overall responders ( p = 0.02 ) ( fig . the interobserver agreements between the two radiologists for the recist and the newly devised criteria that reflected morphologic changes were all good ( table 3 ) . the interobserver agreement for the alternative method was the best (  = 0.79 , 95% ci : 0.52 - 1.00 ) , whereas that for the combined criteria was the worst (  = 0.68 , 95% ci : 0.36 - 0.99 ) . the details of the response designations by using the four different assessment methods for each patient are summarized in table 2 . five patients in the trial of bevacizumab - containing chemotherapy were found to have cavitation within lesions after treatment . marked cavitation ( to the degree that there was no residual solid component ) within the lesions occurred in two patients ( fig . 2 ) . of the 16 patients , six recist poor responders would have achieved a designation of pr by the combined criteria . in the case of the alternative method , of the same six patients , the overall response rates ( orrs , the patients showing a cr , pr or sd ) according to recist , recistsolid , the alternative method and the combined criteria were 81% , 88% , 81% , and 81% , respectively . the confirmed response rates ( rrs , the patients showing a cr or pr with the condition of response confirmation ) were 19% , 19% , 50% and 56% , respectively . although no significant difference was observed for the pfs among the three ( pr , sd and pd ) response groups to vascular inhibitor therapy , the alternative method showed the biggest stratifying power among the three groups for the prediction of pfs ( p = 0.07 ) ( fig . 3 ) . for the prognosis between the good ( cr or pr ) and poor responders , the alternative method again showed the biggest stratifying power among the three groups for the prediction of pfs ( p = 0.09 ) , yet there is no statistically significance ( fig . the recist and the alternative method showed a significant difference for the prognosis between the good ( cr , pr , or sd ) and poor overall responders ( p = 0.02 ) ( fig . 5 ) . the interobserver agreements between the two radiologists for the recist and the newly devised criteria that reflected morphologic changes were all good ( table 3 ) . the interobserver agreement for the alternative method was the best (  = 0.79 , 95% ci : 0.52 - 1.00 ) , whereas that for the combined criteria was the worst (  = 0.68 , 95% ci : 0.36 - 0.99 ) . evaluating a pr on an imaging study of solid tumors is not easy ( 7 - 9 ) . molecular - targeted treatment has given rise to a different antitumor effect from that of cytotoxic therapy and so this may highlight the limitations of using the size criteria alone for the assessment of a tumor response to the target agent ( 5 ) . furthermore , the response to bevacizumab , which has an antiangiogenic mechanism of action , may be inadequately assessed by the traditional size - based radiologic criteria ( recist 1.0 or recist 1.1 ) , which were designed for assessing the reduction of the tumor volume following the administration of cytotoxic agents . we present here three novel ct criteria that reflect the morphologic findings for predicting the response to bevacizumab - containing chemotherapy in patients with nsclc . these criteria were reproducible , as was shown by the good interobserver agreement for the assessment of tumor response between the two independent radiologists . cavitation within a tumor may be a kind of tumor response to cancer therapy , and especially to vegf receptor inhibitor therapy . thus , the response evaluation can be improved by incorporating cavitation into the volume assessment for target lesions and this may change important outcome - measurement parameters . in our study , five patients were found to have cavitation in lesions after treatment with bevacizumab therapy . in the case of figure 2 , the entire solid component was changed into an air - filled thin - walled cystic lesion . however , the tumor response was assessed as sd according to the traditional recist method . the combined criteria reflect the change of tumor enhancement and this helped confirm that recist significantly underestimated the tumor response . the decreased attenuation values of the target lesions on ct after cancer therapy histopathologically correspond to an area of tumor necrosis or cystic degeneration . comparing the results of figures 4 and 5 , the discrepancies among the response rates and overall response rates were mostly attributable to the different definition of pr between the traditional recist 1.1 and the combined criteria . in the combined criteria , the lower - level cut - off value ( from 30% in recist 1.1 to 10% in the combined criteria ) for a pr in terms of a decreased tumor size these five patients were in the same overall good response group both according to the recist 1.1 and the combined criteria ( fig . 5 ) , yet they were reclassified into the good response group according to the combined criteria from the poor response group according to the recist 1.1 ( fig . this reclassification better reflects the recently changed concept of sd ; achieving sd has been identified as a potential surrogate end point for an improved clinical outcome for epidermal growth factor receptor - tyrosine kinase inhibitors ( egfr - tki ) therapy . currently , durable modest regression or prolonged sd achieved by these agents is viewed as evidence of antitumor activity ( 9 ) . the recent studies that assessed tumors ' responses to antiangiogenic agents with using ct or mri have focused on tumor perfusion ( 10 , 11 ) . however , the degree of tumor enhancement has been consistently assessed because of variations in the scanning techniques . the choi criteria can be simply and efficiently applied to response evaluation in daily practice , whereas the tumor perfusion evaluation method , despite that it is a sophisticated and accurate method , it requires repeated scans over time and this may impose a potential radiation hazard on patients who are undergoing ct perfusion evaluation ( 4 ) . the extent of ground - glass opacity in a peripheral lung cancer and especially in an adenocarcinoma ( a partly solid nodule on ct scans ) may be a prognosis determinant ( 6 ) . however , the extent of ggo within a partly solid lung cancer does not vary much even after effective chemotherapy . only the solid component within a partly solid nodule may show a response to cancer therapy , as is shown in figure 1 . therefore , the measurement of changes in the solid component in the partly solid peripheral lung cancers may reflect accurately the tumor response to chemotherapy . even though our results using the recistsolid method did not show a significant result for the prediction of pfs during bevacizumab therapy , this might have been caused by too small a number of patients who had a partly solid peripheral lung cancer . when assessing a peripheral lung cancer response to anticancer therapy , recist 1.0 or recist 1.1 do not elaborate on the image viewing methods and specifically on whether we should use the lung or mediastinal window images of ct scans ( 1 , 2 ) . thoracic radiologists conventionally measure the tumor size on the lung window images ( including both the ggo and solid components in a partly solid tumor ) . yet as mentioned above , only the solid component may show a response to anticancer therapy . thus , the mediastinal window images may be more appropriate in the assessment of tumor response , and particularly in peripheral lung cancers ( partly solid nodules ) . first , our study was a retrospective study ( although the patients were enrolled in a prospective trial ) . thus , our results may not represent the overall results and they can not be to freely generalized . third , the applicability of these criteria should be tested with other biologic agents other than bevacizumab for treating nsclc . in conclusion , the response outcome evaluations using three different ct response criteria reflecting tumor cavitation , the ggo component and the attenuation changes in nsclc patients treated with bevacizumab showed different results from that with using the traditional recist method . our results indicate that assessing the morphologic characteristics , not to mention measuring the tumor size , may reflect the more detailed changes within tumors with this therapy and so give clinically useful response information as a noninvasive surrogate marker for predicting the prognosis . further studies with a large number of nsclc patients are needed for developing new response evaluation methods that combine and integrate the changes of the morphologic and size characteristics of target lesions .
objectivewe wanted to compare the efficacy of the new ct response evaluation criteria for predicting the tumor progression - free survival ( pfs ) with that of recist 1.1 in non - small cell lung cancer ( nsclc ) patients who were treated with bevacizumab.materials and methodssixteen patients ( m : f = 11:5 ; median age , 57 years ) treated with bevacizumab and combined cytotoxic chemotherapeutic agents were selected for a retrospective analysis . 
 the tumor response was assessed by four different methods , namely , by using recist 1.1 ( recist ) , recist but measuring only the solid component of tumor ( recistsolid ) , the alternative method reflecting tumor cavitation ( the alternative method ) and the combined criteria ( the combined criteria ) that evaluated both the changes of tumor size and attenuation . to evaluate the capabilities of the different measurement methods to predict the patient prognosis , 
 the pfs were compared , using the log rank test , among the responder groups ( complete response [ cr ] , partial response [ pr ] , stable disease [ sd ] and progressive disease [ pd ] ) in terms of the four different methods.resultsthe overall ( cr , pr or sd ) response rates according to recist , recistsolid , the alternative method and the combined criteria were 81% , 88% , 81% and 85% , respectively . 
 the confirmed response rates ( cr or pr ) were 19% , 19% , 50% and 54% , respectively . 
 although statistically not significant , the alternative method showed the biggest difference for predicting pfs among the three response groups ( pr , sd and pd ) ( p = 0.07 ) . 
 recist and the alternative method showed a significant difference for predicting the prognosis between the good ( pr or sd ) and poor overall responders ( p = 0.02).conclusionthe response outcome evaluations using the three different ct response criteria that reflect tumor cavitation , the ground - glass opacity component and the attenuation changes in nsclc patients treated with bevacizumab showed different results from that with using the traditional recist method .