pseudoprogression ( pspd ) and pseudoresponse ( psr ) following anticancer therapy are major areas of controversy in the management of high - grade glioma . in the era of temozolomide , discrimination of pspd and true progression of high - grade glioma after concurrent radiochemotherapy ( crt ) with conventional magnetic resonance imaging ( mri )
novel imaging modalities such as mr spectroscopy , positron emission tomography ( pet ) , and perfusion mri are showing promising results but have yet to be validated in prospective studies .
we previously reported the significance of overexpression of p53 for predicting development of pspd10 ) .
in addition to the method of interpretation for early radiologic deterioration , when to determine this is also a critical issue because it affects the clinician 's decision making regarding whether to switch to salvage therapy for recurrent disease or to continue planned adjuvant therapy .
as pspd was termed " early necrosis " in early reports , many series determined pspd at 4 weeks after treatment .
conversely , wen et al.28 ) proposed new response assessment in neuro - oncology ( rano ) working group criteria for high - grade glioma .
an increasing non - enhancing component in t2-weighted and fluid attenuated inversion recovery ( flair ) mr images was considered to be progression for patients receiving anti - angiogenic therapy with the new criteria .
they also suggested that progression can be true progression only in the cases of recurrence outside the radiation field or in pathologically confirmed cases , if radiological progression is detected within 12 weeks when pspd is most prevalent .
however , further validation would be necessary because this suggestion is not based on a clinical study that demonstrates comparable survival outcome between early true progression ( 4 weeks after treatment ; etpd ) and late true progression ( progression between 4 and 12 weeks after treatment ; ltpd ) .
if the survival difference between etpd and ltpd are significant , early progressive findings should be treated based on the assumption that the lesion would be the recurrent tumor .
psr is the concept that represents temporary radiological improvement after using an antiangiogenic agent such as bevacizumab while having progression in effect .
phase ii trials using bevacizumab and cpt-11 in recurrent malignant glioma have shown a high response rate of 63% , but this encouraging result did not lead to a significantly improved overall survival ( os)11,27 ) .
this phenomenon has been proposed to represent the effect of bevacizumab normalizing the permeability of leaky endothelium that causes edema , showing a steroid - like feature . in the present study
, we evaluated pspd following radiation therapy combined with concurrent temozolomide ( tmz ) and also assessed psr following anti - angiogenic therapy for patients with recurrent disease using criteria of the rano working group .
all data from patients diagnosed with world health organization ( who ) grade 3 or 4 glioma from march 2005 to february 2011 were retrieved from the archives of the pathologic reports .
the clinical and pathologic data of relevant patients were obtained in accordance with the protocol approved by the institutional review board .
fifty - five of sixty - two patients with high - grade glioma who received radiotherapy ( rt ) with concurrent and adjuvant tmz were included in the present study .
gross total resection was performed in 16 ( 29% ) patients , subtotal or near total resection was performed in 25 ( 45% ) patients , and stereotactic biopsy was performed in 14 ( 26% ) patients .
the median dose used for radiation therapy was 61.2 gy ( range , 59.4 - 61.2 gy ) with daily fractions of 1.8 - 2.0 gy .
forty - five patients received a total dose of 61.2 gy in 34 fractions , nine patients received 60 gy in 30 fractions , and one patient received 59.4 gy in 33 fractions .
the median time from surgery to the initiation of crt was 26 days ( range of 11 - 77 days ) .
tmz concomitant with postoperative rt was administered at 75 mg / m a day . for adjuvant tmz ,
150 - 200 mg / m was administered daily for 5 days , every 28 days . in terms of salvage therapy following recurrence ,
the surgical resection was performed for the patients who had a small progressive lesion involving non - eloquent area , and gamma knife surgery was reserved for the cases with small lesions and medically inoperable condition .
bevacizumab with or without cpt-11 was considered as a primary option for salvage therapy in all inoperable cases showing true progression .
the patients who had previous episode of intracranial hemorrhage or who were not be able to afford bevacizumab received nimustine ( acnu)/cisplatin ( cddp ) or procarbazine , lomustine , and vincristine ( pcv ) chemotherapy , or metronomic tmz . mri with gadolinium enhancement and t2/flair was performed 1 month after crt and every 3 months thereafter . when a progressive finding was present , mri was performed at 2-month intervals .
progression was defined as a more than 25% increase in the sum of the products of perpendicular diameters as in the macdonald criteria , an increase in the non - enhancing lesion in recurrent cancer with bevacizumab15 ) .
etpd and ltpd were defined as true progression found at first and second post - treatment mri with the exception of pspd , respectively .
psr was scored when progressive enhancement or a non - enhancing t2-weighted lesion was shown right after response to bevacizumab , or after discontinuation of the drug due to toxicity . in some cases , cerebral blood flow ( cbf ) , cerebral blood volume ( cbv ) values using perfusion mri , and apparent diffusion coefficient ( adc ) maps
the kaplan - meier method was used for the survival analysis to compare os between etpd and ltpd .
all data from patients diagnosed with world health organization ( who ) grade 3 or 4 glioma from march 2005 to february 2011 were retrieved from the archives of the pathologic reports .
the clinical and pathologic data of relevant patients were obtained in accordance with the protocol approved by the institutional review board .
fifty - five of sixty - two patients with high - grade glioma who received radiotherapy ( rt ) with concurrent and adjuvant tmz were included in the present study .
gross total resection was performed in 16 ( 29% ) patients , subtotal or near total resection was performed in 25 ( 45% ) patients , and stereotactic biopsy was performed in 14 ( 26% ) patients .
the median dose used for radiation therapy was 61.2 gy ( range , 59.4 - 61.2 gy ) with daily fractions of 1.8 - 2.0 gy .
forty - five patients received a total dose of 61.2 gy in 34 fractions , nine patients received 60 gy in 30 fractions , and one patient received 59.4 gy in 33 fractions .
the median time from surgery to the initiation of crt was 26 days ( range of 11 - 77 days ) .
tmz concomitant with postoperative rt was administered at 75 mg / m a day . for adjuvant tmz , 150 - 200 mg
/ m was administered daily for 5 days , every 28 days . in terms of salvage therapy following recurrence
, the surgical resection was performed for the patients who had a small progressive lesion involving non - eloquent area , and gamma knife surgery was reserved for the cases with small lesions and medically inoperable condition .
bevacizumab with or without cpt-11 was considered as a primary option for salvage therapy in all inoperable cases showing true progression .
the patients who had previous episode of intracranial hemorrhage or who were not be able to afford bevacizumab received nimustine ( acnu)/cisplatin ( cddp ) or procarbazine , lomustine , and vincristine ( pcv ) chemotherapy , or metronomic tmz .
mri with gadolinium enhancement and t2/flair was performed 1 month after crt and every 3 months thereafter . when a progressive finding was present , mri was performed at 2-month intervals .
progression was defined as a more than 25% increase in the sum of the products of perpendicular diameters as in the macdonald criteria , an increase in the non - enhancing lesion in recurrent cancer with bevacizumab15 ) .
etpd and ltpd were defined as true progression found at first and second post - treatment mri with the exception of pspd , respectively .
psr was scored when progressive enhancement or a non - enhancing t2-weighted lesion was shown right after response to bevacizumab , or after discontinuation of the drug due to toxicity . in some cases , cerebral blood flow ( cbf ) , cerebral blood volume ( cbv ) values using perfusion mri , and apparent diffusion coefficient ( adc ) maps
the kaplan - meier method was used for the survival analysis to compare os between etpd and ltpd .
all patients were treated with rt combined with concurrent and adjuvant tmz after surgical resection or stereotactic biopsy .
nine ( 24% ) of thirty - seven patients with disease progression during all treatment period and 1 case of pspd were treated with bevacizumab with or without cpt-11 .
surgical resection , gamma knife surgery , acnu / cddp , pcv chemotherapy , or metronomic tmz were also used as an option for the salvage therapy . in 13 of 55 patients
cbv , adc , or pet were undertaken , and it was insufficient number to analyze the efficiency of the techniques .
the exams only provided additional information and were not absolute means of diagnosis . at the first follow - up after crt , 21 patients ( 38% ) showed radiologic progression . and at second post - crt mri , 16 ( 29% ) of them persistently showed progression and considered as etpd .
five ( 9% ) of those patients showed progression after the first mri taken at post - treatment 4 weeks and showed improvement afterwards without specific salvage treatment with a decreasing or stable dose of dexamethasone .
these groups of patients were finally categorized as pspd . and at second post - crt mri , 7 showed new progression that was not seen in previous mri ( ltpd ) .
the follow - up time was defined as the period between surgery ( including stereotactic biopsy ) and the last follow - up day or death .
the estimated median survival was 25.6 months ( range of 3.3 - 89.7 months ) .
the os rates at 1 and 2 years were 84.8% and 59.2% , respectively . when divided into who grade iii and iv gliomas , os at 2 years were 71.4% and 53.3% , respectively ( p=0.125 ) .
1 , the os of the etpd group vs. ltpd group was 57% vs. 86% at 1 year , and oss were 30% and 51% at 2 years , respectively .
we also performed subgroup analysis in 33 patients having available data for o-6 methylguanine - dna methyltransferase ( mgmt ) methylation status .
although there was no statistically significant os difference between the patients with methylated mgmt and those with unmethylated mgmt ( p=0.178 ) , it showed trend toward better survival with mgmt methylation ( fig .
2 ) . in multivariate analysis using covariates ( recursive partitioning analysis , who grade , p53 status , mgmt methylation status and extent of resection ) , none of the factors including etpd and ltpd was related to os .
the median survivals of treatment with or without bevacizumab , were 10 and 6 months , respectively ( p=0.835 ) .
although 5 ( 50% ) of 10 patients showed a radiological response following salvage treatment with bevacizumab , the response was durable in one case and the stable state persisted for 11 months .
for one case , the mri scan showed decreased high t2 signal intensity 1 month after bevacizumab and cpt-11 , the lesion showed progression at the subsequent follow - up , and we considered this case to be pspd .
for three other cases , radiologic improvements were shown within 3 months and bevacizumab was continued until thromboembolic events in two cases and cerebral infarction in one case .
all showed rapid regrowth of the tumor immediately after discontinuation of bevacizumab on mri ( fig .
all patients were treated with rt combined with concurrent and adjuvant tmz after surgical resection or stereotactic biopsy .
nine ( 24% ) of thirty - seven patients with disease progression during all treatment period and 1 case of pspd were treated with bevacizumab with or without cpt-11 .
surgical resection , gamma knife surgery , acnu / cddp , pcv chemotherapy , or metronomic tmz were also used as an option for the salvage therapy . in 13 of 55 patients
cbv , adc , or pet were undertaken , and it was insufficient number to analyze the efficiency of the techniques .
at the first follow - up after crt , 21 patients ( 38% ) showed radiologic progression . and at second post - crt mri , 16 ( 29% ) of them persistently showed progression and considered as etpd .
five ( 9% ) of those patients showed progression after the first mri taken at post - treatment 4 weeks and showed improvement afterwards without specific salvage treatment with a decreasing or stable dose of dexamethasone .
these groups of patients were finally categorized as pspd . and at second post - crt mri , 7 showed new progression that was not seen in previous mri ( ltpd ) .
the follow - up time was defined as the period between surgery ( including stereotactic biopsy ) and the last follow - up day or death .
the estimated median survival was 25.6 months ( range of 3.3 - 89.7 months ) .
the os rates at 1 and 2 years were 84.8% and 59.2% , respectively . when divided into who grade iii and iv gliomas , os at 2 years were 71.4% and 53.3% , respectively ( p=0.125 ) .
1 , the os of the etpd group vs. ltpd group was 57% vs. 86% at 1 year , and oss were 30% and 51% at 2 years , respectively . no statistically significant difference was found between etpd and ltpd groups ( p=0.595 ) .
we also performed subgroup analysis in 33 patients having available data for o-6 methylguanine - dna methyltransferase ( mgmt ) methylation status .
although there was no statistically significant os difference between the patients with methylated mgmt and those with unmethylated mgmt ( p=0.178 ) , it showed trend toward better survival with mgmt methylation ( fig .
using covariates ( recursive partitioning analysis , who grade , p53 status , mgmt methylation status and extent of resection ) , none of the factors including etpd and ltpd was related to os .
the median survivals of treatment with or without bevacizumab , were 10 and 6 months , respectively ( p=0.835 ) .
although 5 ( 50% ) of 10 patients showed a radiological response following salvage treatment with bevacizumab , the response was durable in one case and the stable state persisted for 11 months .
for one case , the mri scan showed decreased high t2 signal intensity 1 month after bevacizumab and cpt-11 , the lesion showed progression at the subsequent follow - up , and we considered this case to be pspd .
for three other cases , radiologic improvements were shown within 3 months and bevacizumab was continued until thromboembolic events in two cases and cerebral infarction in one case .
all showed rapid regrowth of the tumor immediately after discontinuation of bevacizumab on mri ( fig .
the primary goal of this study was to evaluate the survival difference between etpd and ltpd .
thus , we could not identify a statistically significant survival difference between the two groups , indicating that it would be safe to continue planned adjuvant tmz rather than treatment for recurrence when radiologic progression appears in the first post - treatment mri .
this unique treatment strategy dealing with radiologic progression for high - grade glioma comes from the absence of a diagnostic modality providing high accuracy and resemblance between in - field recurrence and treatment response as pspd or radiation necrosis .
the mechanism of pspd which is exclusive phenomenon in high - grade glioma , is not clarified , but might be related to the nature of tumor itself .
blood tumor barrier of glioma has high expression of p - glycoprotein , a 170-kda drug efflux pump protein , which is the main component of blood brain barrier ( bbb ) and inhibits penetration23 ) . generally , glioblastoma has compromised barrier that gadolinium can penetrate and shows enhancement .
bbb breakage after rt has been well documented but the mechanism is unclear . in vitro study
showed that rt induces early transient increase in paracellular permeability while maintaining the tight junction of capillary endothelial cells6 ) .
an experimental study revealed that higher exposures of tmz in brain tumor can also attribute to breakdown of the bbb20 ) .
increased permeability of blood tumor barrier caused by rt and tmz would result in contrast enhancement due to leakage , which presents as pspd .
rano criteria were suggested to overcome the limitation of macdonald criteria and drew considerable attentions .
although it provides innovative assessment in the treatment of malignant glioma , yet several limitations were pointed out as discriminating true or false lesions in non - enhancing lesions , too simple tumor size measurement , and not reflecting any of new imaging techniques14 ) . despite current criteria as macdonald or rano , purely objective judgement of treatment response only with imaging
increased cbv / cbf and a decreased adc value do not imply progressive disease at all times , however , the decisions are made from these novel imaging modalities for most of the confusing cases .
latest imaging techniques as dynamic susceptibility contrast mri perfusion , diffusion - weighted mri , mri / pet scans using biomarker , and thallium single photon emission ct are introduced but no comparison under prospective studies have been performed2,13,29 ) .
thus , disparity sometimes in clinical judgment between oncologists and radiologists makes further treatment planning more complex and often needs to be discussed by a multidisciplinary tumor board .
for example , one patient who was considered to show pspd in our last study was confirmed to show true progression by surgery . in this case , cbv was not increased and the tumor demonstrated stabilization after 4 weeks at the second post - treatment mri , which could be considered to be pspd .
recently , vogelbaum et al.26 ) suggested that retrospective assessments of serial images to distinguish pspd form true progression and when the finding is ambiguous , the response should be called indeterminate even with rano criteria .
this shows despite the latest techniques and reorganization of the criteria they do not guarantee more reliable diagnosis or appropriate further treatment plan therefore validation should be needed .
retrospective comparative analysis among various criteria has been performed placing emphasis on the nonenhancing tumor8 ) .
the major component that we adopted from rano was the timing of decision making as well as imaging criteria .
appropriate timing is crucial in avoiding the misdiagnosis that would lead to discontinuation or initiation of the effective therapy .
also in canadian recommendations pspd can not be diagnosed until 12 weeks after the end of rt unless new lesion shows out - of - field5 ) . in the review of sanghera et al.22 ) , timing of defining pspd varied from 2 weeks to 6 months among 8 studies . considering that most of the decisions are made at 4 weeks or 6 months in performed studies , it should be confirmed that observation until 12 weeks is not related to decreased os as in the present study .
as our data showed no difference between etpd and ltpd , confirmation after serial observations would be reasonable rather than deciding early from a little information .
correlation between mgmt methylation and pspd , and association with improved os has been reported by brandes et al.1 ) . in our study , the survival graph comparing mgmt methylated / unmethylated group showed difference but not statistically significant .
may reflect increased bbb permeability , administration of bevacizumab under misdiagnosis of true progression normalizes a leaky vasculature and therefore may show a " response"25 ) .
it is highly persuasive but only a hypothesis and needs further examination in the future study . in the present study
the regression of in - field recurrence occurred 1 month after administration of the drug , and remained stable disease for 11 months .
however , as we had impression of both possibilities , true progression vs. treatment related change , we still can not rule out late pspd in this case .
counting such cases as the treatment effect may result in a falsely high response rate to an anti - angiogenic agent . as we can not perform pathologic confirmation in every suspected recurrence , pspd and psr should not be considered separately . regarding psr , conflicting views
as mentioned earlier , a strikingly high response rate and progression - free survival ( pfs ) does not result in increased os ; thus , doubt exists regarding whether bevacizumab has an antitumor effect . in a pooled analysis by norden et al.18 )
, a statistically significant increase was found in pfs of patients receiving bevacizumab ; however , os demonstrated no statistically significant difference . in the same context
bevacizumab causes adverse effects such as intracranial hemorrhage , thromboembolic events , and proteinuria7 ) . in a phase ii study of bevacizumab and cpt-11 in recurrent malignant glioma , 4 of 32 ( 13% )
patients had a thromboembolic event and two of them died of toxicity / neurologic deterioration27 ) .
. one possible advantage of bevacizumab is considered to be reduction of corticosteroid use3 ) , but paradoxically it can cause dependency on bevacizumab , which is one of the most expensive drugs . additionally , bevacizumab can cause vegf - independent mechanisms of progression in the heavily treated patients18 ) .
furthermore , as glioblastoma is known to be associated with a high risk of thromboembolism , anti - coagulation would be needed to prevent severe complication19 ) .
however , not every patient planning to be administered bevacizumab can receive prophylaxis , and thus a positive effect for survival may be countervailed .
this life - threatening toxicity can not be overlooked , and costs and benefits must be considered .
one of the limitations of the current study is showing high os than other reported data , and this may be due to censored data , as 9 of the patients were unavailable for follow - up9 ) . when recurrence was suspected , salvage treatment varied among patients because until now there is no standard chemotherapy regimen in the management of high - grade glioma .
although small - sized and retrospective in nature , the present study suggests methodology and evidence for the safety of postponed treatment of recurrent high - grade glioma until 12 weeks after termination of crt and shows clinical features of psr , raising a question about the true effect of bevacizumab .
initiating a further treatment plan after 12 weeks as recommended by rano does not lead to loss of overall survival .
additionally , in recurrent high - grade glioma , bevacizumab must be administered with caution in consideration of pspd and psr . however , mri with gadolinium enhancement alone is not sufficient to characterize tumor response or growth .
in addition to clinical correlation with adequate duration of follow - up and histopathologic validation , further studies regarding additional physiologic imaging modalities are required for accurate evaluation of tumor response .
 objectivewe evaluated pseudoprogression ( pspd ) following radiation therapy combined with concurrent temozolomide ( tmz ) , and we assessed pseudoresponse following anti - angiogenic therapy for patients with recurrent disease using the response assessment of the neuro - oncology working group.methodspatients who were pathologically confirmed as having high - grade glioma received radiotherapy with concurrent tmz followed by adjuvant tmz . 
 bevacizumab ( avastin ) with cpt-11 were used as a salvage option for cases of radiologic progression . magnetic resonance imaging ( mri ) 
 was routinely performed 1 month after concurrent radiochemotherapy ( crt ) and every 3 months thereafter . for cases treated with the bevacizumab - containing regimen for progressive disease 
 , mri was performed every 2 months.resultsof 55 patients , 21 ( 38% ) showed radiologic progression within 4 weeks after crt . of these patients , 
 16 ( 29% ) showed progression at second post - crt mri ( etpd ) and five ( 9% ) showed improvement ( pspd ) . 
 seven of thirty - four initially non - progressed patients showed progression at the second post - crt mri ( ltpd ) . 
 no difference in survival was observed between the etpd and ltpd groups ( p=0.595 ) . 
 five ( 50% ) of ten patients showed a radiological response after salvage bevacizumab therapy . 
 four of those patients exhibited rapid progression immediately after discontinuation of the drug ( drug holiday).conclusiontwelve weeks following treatment could be the optimal timing to determine pspd or true progression . 
 mri with gadolinium enhancement alone is not sufficient to characterize tumor response or growth . 
 clinical correlation with adequate follow - up duration and histopathologic validation may be helpful in discriminating pspd from true progression . 
INTRODUCTION
MATERIALS AND METHODS
Patients
Treatment
Assessment of response and statistical analysis
RESULTS
Patient characteristics
Incidence of etPD, ltPD, and PsPD
Survival outcomes
Pseudoresponse
DISCUSSION
CONCLUSION