Total Lesion Glycolysis Determined per RECIST 11 CriteriaPredicts Survival in EGFR Mutation-Negative Patients
With Advanced Lung Adenocarcinoma
Tsung-Ying Ho MD Pai-Chien Chou MD PhDdagger Cheng-Ta Yang MDdagger
Ngan-Ming Tsang MD PhDDagger and Tzu-Chen Yen MD PhD
Objective The aim of this retrospective study was to investigate the clinical im-pact of 18F-FDG PET in patients with advanced lung adenocarcinoma stratifiedaccording to the epidermal growth factor receptor (EGFR) mutation statusPatients and Methods A total of 56 patients with advanced lung adenocarci-noma were included in the study Thirty-one patients (55) were EGFRmutation-positive whereas the remaining 25 (45) participants tested negativefor EGFR mutations All of the patients underwent 18F-FDG PETCT for pre-treatment planning The main outcome measure was overall survival (OS) at24 months The following 18F-FDG PETCT-derived variables were tested fortheir associations with OS main tumor SUVmax main tumor total lesion glycol-ysis and target lesions TLG determined per RECIST (Response EvaluationCriteria In Solid Tumors) 11 criteria (TLGRECIST) We also investigated theclinical characteristics in relation to OS and EGFR mutation statusResults In EGFR mutation-positive patients neither the clinical characteristicsnor 18F-FDG PETCT-derived parameters were significantly associated withOS In contrast univariate analysis identified male sex a positive history ofsmoking and TLGRECIST greater than or equal to 412 g as adverse prognosticfactors for OS in EGFR mutation-negative patients After adjustment for poten-tial confounders in multivariate analysis TLGRECIST was the sole independentpredictor of OS in this subgroupConclusions TLG determined per RECIST 11 criteria is an independent predic-tor of OS in EGFR mutation-negative patients with advanced lung adenocarci-noma Further studies are needed to investigate whether this parameter may bea promising tool for stratifying such patients for risk-adapted therapies
Key Words lung cancer adenocarcinoma epidermal growth factor receptormutations 18F-FDG PET total lesion glycolysis RECIST 11
(Clin Nucl Med 201540 e295ndashe299)
L ung cancer remains a leading cause of cancer-related mortalityworldwide It is not only the most commonly diagnosed but
also ranked first in terms of cause of cancer deaths globally1 Inaddition the majority of lung cancer patients are diagnosed at ad-vanced stage2 The main prognostic factors in lung cancer includeclinical variables and the presence of epidermal growth factor receptor(EGFR) mutations3 Importantly the prevalence of EGFR mutations isethnicity dependent with a higher proportion in Asian (514) thanin whites (137)45
To date little is known about the prognostic significanceof 18F-FDG PETCT-derived variables in relation to EGFR muta-tions among patients with lung cancer We therefore designed this
Received for publication June 12 2014 revision accepted January 26 2015From the Departments of Nuclear Medicine and Molecular Imaging Center
daggerThoracic Medicine and DaggerRadiation Oncology Chang Gung Memorial Hos-pital at Linkou Taoyuan Taiwan Republic of China
Drs Tsung-Ying Ho and Pai-Chien Chou contributed equally to this workConflicts of interest and sources of funding none declaredReprints Tzu-Chen Yen MD PhD Department of Nuclear Medicine and Molecular
Imaging Center Chang Gung Memorial Hospital at Linkou No 5 Fu-Hsing StKwei-Shan Taoyuan Taiwan Republic of China E-mail yentc1110gmailcom
Copyright copy 2015 Wolters Kluwer Health Inc All rights reservedISSN 0363-9762154006ndashe295
Clinical Nuclear Medicine bull Volume 40 Number 6 June 2015
Copyright copy 2015 Wolters Kluwer H
retrospective study to investigate the clinical impact of 18F-FDG PET-derived parameters in patients with advanced (ge stage IIIB) lung adeno-carcinoma stratified according to the EGFR mutation status
PATIENTS AND METHODS
PatientsA total of 56 patients with histology-proven lung adenocarci-
noma in advanced stage (ge stage IIIB) were included in the studyThirty-one patients (55) were EGFR mutation-positive whereas theremaining 25 (45) participants tested negative for EGFR mutationsAll of the participants were followed up for at least 24 months or cen-sored at the date of the last follow-up Staging was performed usingthe Seventh Edition of the American Joint Committee on Cancer Stag-ing System published in 2010 Each patients stage was determined bythe consensus reached in our tumor board conference The study proto-col was approved by the institutional review board of the Chang GungMemorial Hospital (IRB 102-2413B)
18F-FDG PETCT ImagingAll 18F-FDG PETCT scans were performed on either Discovery
ST 16 PETCT scanner (GE Healthcare Milwaukee Wis) or SiemensBiograph mCT PETCT scanner (Siemens Healthcare Molecular Im-aging Hoffman Estates Ill) After 6 hours of fasting patients wereinjected intravenously with 370 to 444MBq (10ndash12mCi) 18F-FDG Pa-tients were scanned at 50minutes from the mid thigh to the skull vertexCT data were used for both attenuation correction and fusion withattenuation-corrected PET images Images were reconstructed using or-dered subsets expectation maximization (4 iterations and 10 subsets)All PET CT and PETCT images were displayed in axial coronaland sagittal views PET data were also displayed in a rotating MIPTwo nuclear medicine physicians independently reviewed all PETimaging results Abnormal 18F-FDG uptake was defined as focalincreased activity higher than the background activity Regions of in-terest were measured over lesions visible on PET images The SUVwas calculated according to the following formula SUV = radioactivityconcentration in tissue [becquerelgram](injected dose [becquerel]patient weight [gram])
EGFR Mutation AnalysisExons 18 to 21 of the EGFR gene were amplified and subjected
to direct sequencing as previously described6
Lesion Analysis per RECIST 11 CriteriaThe following lesions were selected using the RECIST (Re-
sponse Evaluation Criteria In Solid Tumors) 11 criteria pulmonarymain tumor with longest diameter greater than or equal to 10 mmlymph nodes with longest diameter greater than or equal to 15 mmin short axis and solid metastatic lesions with longest diametergreater than or equal to 10 mm All measurable lesions up to a maxi-mum of 5 lesions per patient and 2 lesions per organ were included inthe analysis7
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TABLE 1 General Characteristics of the Study Patients (n = 56)
Variable n ()
Age y
ge63 28 (50)
lt63 28 (50)
Sex
Male 33 (59)
Female 23 (41)
History of smoking
Yes 23 (41)
No 33 (59)
EGFR mutations
Yes 31 (55)
No 25 (45)
SUVmax main tumor
ge12 28 (50)
lt12 28 (50)
TLGMT g
ge170 28 (50)
lt170 28 (50)
TLGRECIST g
ge342 28 (50)
lt342 28 (50)
M status
M0 7 (12)
M1a 6 (11)
M1b 43 (77)
Radiotherapy
Yes 33 (59)
No 23 (41)
TLGRECIST sum of TLG values of lesions selected per RECIST 11 criteria
FIGURE 1 ROC curve analysis for identifying the optimal cutoff valumutation-negative patients The optimal cutoff points were identifiedthe sum of sensitivity and specificity were maximal The parenthesesmeasured values under the cutoff value out of the total number of paTLGRECIST in EGFR mutation-negative patients were 118 g and 412 g
Ho et al Clinical Nuclear Medicine bull Volume 40 Number 6 June 2015
e296 wwwnuclearmedcom
Copyright copy 2015 Wolters Kluwer H
Total Lesion GlycolysisThe metabolic tumor volume (MTV) was measured from
attenuation-corrected 18F-FDGPETCT fusion images A segmentationalgorithm implemented in the TrueD software (Siemens Healthcare)was used for tumor segmentation The boundaries were drawn to in-clude all of the lesions identified using the RECIST 11 criteria on axial18F-FDG PETCT images Lesion contours were delineated automati-cally by a threshold SUV of 25 All voxels presenting SUV intensitygreater than 25 within the contouring margin were incorporated to de-fine the MTV The mean SUV valuewithin each volume of interest wasacquired simultaneously Total lesion glycolysis (TLG) was then calcu-lated according to the following formula TLG = mean SUV MTVThe main tumor total lesion glycolysis (TLGMT) was defined as TLGfrom the largest primary pulmonary lesion Finally TLGRECISTwas cal-culated as the sum of all TLG values of the lesions selected using theRECIST 11 criteria
Data AnalysisThe main outcome measure was overall survival (OS) at
24 months 18F-FDG PET-derived parameters were expressed as con-tinuous variables and univariate Cox proportional hazards regressionanalysis was used to identify their associations with OS Receiver oper-ating characteristic curves were used to determine the optimal cutoffvalues that maximized the sum of sensitivity and specificity Kaplan-Meier survival estimates compared with the log-rank test were usedin the univariate analysis Multivariate Cox regression models wereconstructed to identify the independent predictors of OS Two-tailedP values less than 005 were considered statistically significant
RESULTS
Patient CharacteristicsBetween November 2007 and May 2012 a total of 56 patients
(33 men and 23 women median age 63 years) with advanced (ge stageIIIB) lung adenocarcinoma were included in the study The generalcharacteristics of the study participants are reported in Table 1
es of 18F-FDG PETCT-derived parameters in EGFRby determining the values where the area under the curve andunder each cutoff value indicate the number of patients withtients per group The optimal cutoff values for TLGMT andrespectively
copy 2015 Wolters Kluwer Health Inc All rights reserved
ealth Inc All rights reserved
TABLE 2 Univariate and Multivariate Analyses of OS in EGFRMutation-Negative Patients
Univariate Analysis Multivariate Analysis
Parameter n vs n OS (months plusmn SD) P HR (95 CI) P
Age y ge63 vs lt 63 14 vs 11 150 plusmn 33 vs 127 plusmn 29 0487
Sex M vs F 19 vs 6 105 plusmn 21 vs 243 plusmn 40 0022 613 (077-4867) 0087
History of smoking Yes vs no 14 vs 11 94 plusmn 22 vs 198 plusmn 35 0022 267 (066-1082) 0168
M1b M1b vs non-M1b 18 vs 7 133 plusmn 29 vs 156 plusmn 27 0749
TLGMT g ge118 vs lt 118 19 vs 6 126 plusmn 25 vs 180 plusmn 40 0315
TLGRECIST g ge412 vs lt 412 18 vs 7 100 plusmn 20 vs 247 plusmn 44 0006 872 (120-6322) 0032
Radiotherapy Yes vs no 17 vs 8 130 plusmn 28 vs 157 plusmn 37 0490
Use of TKIs Yes vs no 17 vs 8 159 plusmn 29 vs 89 plusmn 22 0201
M Male F Female TLGRECIST sum of TLG values of lesions selected per RECIST 11 criteria TKIs tyrosine kinase inhibitors
Clinical Nuclear Medicine bull Volume 40 Number 6 June 2015 TLG Determined per RECIST 11 Criteria
Survival AnalysisInformation on age sex history of smoking SUVmax of the
main tumor TLGMT TLGRECIST M1 status radiotherapy EGFRmu-tation status and use of tyrosine kinase inhibitors was available for allparticipants Thirty-one patients (55) were EGFRmutation positivewhereas the remaining 25 participants (45) tested negative forEGFR mutations The mean OS of patients who were positive forEGFR mutations was marginally higher than that of patients whotested negative (215 plusmn 26 months vs 141 plusmn 23 months respectivelyP = 0057) Among EGFR mutation-positive patients no associationsbetween 18F-FDG PET-derived parameters and OS were identified inunivariate Cox regression analysis By contrast TLGRECIST was sig-nificantly associated with OS in EGFR mutation-negative patients(P = 0041) Similarly TLGMT showed a marginally significant asso-ciation with OS in patients without EGFR mutations (P = 0054)Receiver operating characteristic curve analysis was then performedto identify the optimal cutoff values for TLGRECIST and TLGMTFigure 1 shows the identified optimal cutoff points (412 g and 118 gfor TLGRECIST and TLGMT respectively) and their correspondingsensitivity specificity and areas under the ROC curve Such valueswere used for subsequent survival analyses
Among EGFR mutation-positive patients Kaplan-Meier esti-mates failed to identify significant associations of OS with clinical var-iables (eg age sex history of smoking M1 status and radiotherapy)However there were significant univariate associations of OS withsex history of smoking and TLGRECIST in EGFR mutation-negativepatients (Table 2) After allowance for potential confounders in multi-variate Cox regression analysis a TLGRECIST greater than or equal to412 g was identified as the only independent predictor of OS in EGFRmutation-negative patients (hazards ratio [HR] 872 95 confidenceinterval [CI] 120ndash6322 P = 0032) whereas male sex showed a mar-ginally significant association (HR 613 95 CI 077ndash4867 P =0087 Table 2) As expected Kaplan-Meier plots for OS were sig-nificantly different in EGFR mutation-negative patients who had aTLGRECIST greater than or equal to 412 g versus TLGRECIST less than412 g (Fig 2) However no such association was seen for EGFRmutation-positive patients (Fig 3)
FIGURE 2 Kaplan-Meier curves for OS according to TLGRECIST inEGFRmutation-negative patients In EGFRmutation-negativepatients subjects with a TLGRECIST greater than or equal to 412 gshowed a shorter OS than those with a TLGRECIST less than412 g (100 plusmn 20 vs 247 plusmn 44 months respectively P = 0006)
DISCUSSIONThe results of the present study demonstrate that TLGRECIST is
an independent predictor of OS in EGFR mutation-negative patientswith advanced lung adenocarcinoma Specifically significantly shorterOS time characterized EGFR mutation-negative patients who had aTLGRECIST greater than or equal to 412 g However neither the clinical
copy 2015 Wolters Kluwer Health Inc All rights reserved
Copyright copy 2015 Wolters Kluwer H
characteristics nor 18F-FDG PETCT-derived parameters were signifi-cantly associated with OS in EGFR mutation-positive patients
The results obtained in our EGFR mutation-negative patientsare generally in line with those of previous studies demonstratingthe prognostic significance of whole-body TLG in non-Asian patientsundergoing nonsurgical treatment for advanced nonndashsmall cell lungcancer89 However it should be noted that the prognostic significanceof TLGRECIST found in our study was limited to patients withoutEGFR mutations The low frequency of EGFR mutations in whites5
may explain the comparable findings Notably our data also suggestthat TLGRECIST may reliably reflect the whole-body metabolic tumorburden Because EGFR mutation-positive lung cancer cases are com-mon in Asia (sim50 of all patients) we stratified our study populationaccording to the EGFR mutation status Our results indicated thatEGFR mutation-positive patients had marginally better OS than thosewithout EGFR mutations The lack of statistical significance may beexplained by the smaller sample size as compared with previous stud-ies3 Among EGFR mutation-positive patients neither clinical vari-ables nor 18 F-FDG PETCT-derived parameters were found to be
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FIGURE 3 TLGRECIST in relation toOS in patients with advanced lung adenocarcinoma stratified according to the EGFRmutation statusEGFRmutation-negative patients with a TLGRECIST greater than or equal to 412 g had poor OS In contrast TLGRECIST did not predictOS in EGFRmutation-positive patients
Ho et al Clinical Nuclear Medicine bull Volume 40 Number 6 June 2015
significantly associated with OS These results suggest that genetics isthe most important prognostic determinant of OS in patients bearingEGFR mutations
The National Comprehensive Cancer Network guidelines rec-ommend that patients with advanced (ge stage IIIB) lung cancer shouldbe treated with nonsurgical approaches10 In this context the baselinetumor metabolic burden (as measured byMTVand TLG of the main tu-mor) is considered an important predictor of progression-free survivaland OS rates in patients with advanced nonndashsmall cell lung cancertreated with chemotherapy11 In our study we have used TLGRECIST
as an expression of total metabolic tumor burden by selecting lesionsper RECIST 11 criteria and summing up TLG values of selected le-sions In other words we used TLG and the RECIST 11 criteria insteadof MTV and the PET Response Evaluation Criteria in Solid Tumors(PERCIST) criteria respectively Notably TLG is considered to reflectthe primarymetabolic tumor burdenmore closely thanMTV1213More-over the RECIST 11 criteria currently represent the standard by whichthe efficacy of therapeutic agents is determined among patients withsystemic diseases14 In contrast the clinical usefulness of the PERCIST10 criteria may be limited for geographical areas characterized by ahigh incidence of hepatitis (such as Taiwan) because PERCIST 10 re-lies on FDG uptake of liver as its reference tissue value15 An importantfinding of this study is that the prognostic significance of 18F-FDGPETin patients with advanced lung adenocarcinomawas found to be depen-dent on the EGFR mutation status Moreover we demonstrate for thefirst time that TLG determined per RECIST 11 criteria predicts sur-vival in this group of patients Compared with the sum of TLG valuesfrom all measurable lesions TLGRECIST from a maximum of 5 selectedlesions is compatible with the widely accepted RECIST 11 criteria andcan be more practical to perform
Our findings should be interpreted in the context of some limita-tions First our report has a retrospective nature and represents onlya single-center experience Most patients did not undergo follow-up
e298 wwwnuclearmedcom
Copyright copy 2015 Wolters Kluwer H
18F-FDG PET scans and longitudinal changes in TLGRECIST valueswere not examined in relation to treatment response Further prospec-tive studies are needed to investigate whether this parameter may be apromising tool for stratifying patients with advanced lung cancer forrisk-adapted therapies
These limitations notwithstanding our current data demonstratethat TLGRECIST is an independent predictor of OS in EGFR mutation-negative patients with advanced lung adenocarcinoma In contrast18F-FDG PETCT-derived parameters did not predict OS in EGFRmutation-positive patients
REFERENCES
1 Cancer IAfRo GLOBOCAN 2012 estimated cancer incidence mortality andprevalence worldwide in 2012 World Health Organization Available at httpglobocaniarc frPagesfact_sheets_cancer aspx Accessed May 28 2014
2 Youlden DR Cramb SM Baade PD The international epidemiology of lungcancer geographical distribution and secular trends J Thorac Oncol 20083819ndash831
3 Kobayashi K Hagiwara K Epidermal growth factor receptor (EGFR) mutationand personalized therapy in advanced nonsmall cell lung cancer (NSCLC) TargetOncol 2013827ndash33
4 Shi Y Au JS Thongprasert S et al A prospective molecular epidemiology studyof EGFRmutations inAsian patientswith advanced nonndashsmall-cell lung cancer ofadenocarcinoma histology (PIONEER) J Thorac Oncol 20149154ndash162
5 Bauml J Mick R Zhang Y et al Frequency of EGFR and KRASmutations in pa-tients with non small cell lung cancer by racial background do disparities existLung Cancer 201381347ndash353
6 Hsieh MH Fang YF Chang WC et al Complex mutation patterns of epidermalgrowth factor receptor gene associated with variable responses to gefitinib treat-ment in patients with non-small cell lung cancer Lung Cancer 200653311ndash322
7 Nishino M Jagannathan JP Ramaiya NH et al Revised RECIST guideline ver-sion 11 What oncologists want to know and what radiologists need to knowAJR Am J Roentgenol 2010195281ndash289
8 Olivier A Petyt G Cortot A et al Higher predictive value of tumour and node[18 F]-FDG PET metabolic volume and TLG in advanced lung cancer under che-motherapy Nucl Med Commun 201435908ndash915
copy 2015 Wolters Kluwer Health Inc All rights reserved
ealth Inc All rights reserved
Clinical Nuclear Medicine bull Volume 40 Number 6 June 2015 TLG Determined per RECIST 11 Criteria
9 Liao S Penney BCWroblewskiK et al Prognostic value ofmetabolic tumor bur-den on 18F-FDG PET in nonsurgical patients with non-small cell lung cancerEur J Nucl Med Mol Imaging 20123927ndash38
10 Ettinger DS AW Borghaei H Chang AC NCCN Clinical Practice Guidelines inOncology NonndashSmall Cell Lung Cancer Version 3 Fort Washington PA Na-tional Comprehensive Cancer Network Clinical Guidelines in Oncology 2014
11 Zaizen Y Azuma K Kurata S et al Prognostic significance of total lesion glycol-ysis in patientswith advanced nonndashsmall cell lung cancer receiving chemotherapyEur J Radiol 2012814179ndash4184
12 Arslan N Tuncel M Kuzhan O et al Evaluation of outcome prediction and dis-ease extension by quantitative 2-deoxy-2-[18F] fluoro-D-glucose with positron
copy 2015 Wolters Kluwer Health Inc All rights reserved
Copyright copy 2015 Wolters Kluwer H
emission tomography in patients with small cell lung cancer Ann Nucl Med201125406ndash413
13 Chan SC Chang JT Lin CY et al Clinical utility of 18F-FDG PET parameters inpatients with advanced nasopharyngeal carcinoma predictive role for differentsurvival endpoints and impact on prognostic stratification Nucl Med Commun201132989ndash996
14 Wahl RL Jacene H Kasamon Y et al From RECIST to PERCIST evolvingconsiderations for PET response criteria in solid tumors J Nucl Med 200950(Suppl 1)122Sndash150S
15 Beasley RP Hwang LY Lin CC et al Incidence of hepatitis B virus infections inpreschool children in Taiwan J Infect Dis 1982146198ndash204
wwwnuclearmedcom e299
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TABLE 1 General Characteristics of the Study Patients (n = 56)
Variable n ()
Age y
ge63 28 (50)
lt63 28 (50)
Sex
Male 33 (59)
Female 23 (41)
History of smoking
Yes 23 (41)
No 33 (59)
EGFR mutations
Yes 31 (55)
No 25 (45)
SUVmax main tumor
ge12 28 (50)
lt12 28 (50)
TLGMT g
ge170 28 (50)
lt170 28 (50)
TLGRECIST g
ge342 28 (50)
lt342 28 (50)
M status
M0 7 (12)
M1a 6 (11)
M1b 43 (77)
Radiotherapy
Yes 33 (59)
No 23 (41)
TLGRECIST sum of TLG values of lesions selected per RECIST 11 criteria
FIGURE 1 ROC curve analysis for identifying the optimal cutoff valumutation-negative patients The optimal cutoff points were identifiedthe sum of sensitivity and specificity were maximal The parenthesesmeasured values under the cutoff value out of the total number of paTLGRECIST in EGFR mutation-negative patients were 118 g and 412 g
Ho et al Clinical Nuclear Medicine bull Volume 40 Number 6 June 2015
e296 wwwnuclearmedcom
Copyright copy 2015 Wolters Kluwer H
Total Lesion GlycolysisThe metabolic tumor volume (MTV) was measured from
attenuation-corrected 18F-FDGPETCT fusion images A segmentationalgorithm implemented in the TrueD software (Siemens Healthcare)was used for tumor segmentation The boundaries were drawn to in-clude all of the lesions identified using the RECIST 11 criteria on axial18F-FDG PETCT images Lesion contours were delineated automati-cally by a threshold SUV of 25 All voxels presenting SUV intensitygreater than 25 within the contouring margin were incorporated to de-fine the MTV The mean SUV valuewithin each volume of interest wasacquired simultaneously Total lesion glycolysis (TLG) was then calcu-lated according to the following formula TLG = mean SUV MTVThe main tumor total lesion glycolysis (TLGMT) was defined as TLGfrom the largest primary pulmonary lesion Finally TLGRECISTwas cal-culated as the sum of all TLG values of the lesions selected using theRECIST 11 criteria
Data AnalysisThe main outcome measure was overall survival (OS) at
24 months 18F-FDG PET-derived parameters were expressed as con-tinuous variables and univariate Cox proportional hazards regressionanalysis was used to identify their associations with OS Receiver oper-ating characteristic curves were used to determine the optimal cutoffvalues that maximized the sum of sensitivity and specificity Kaplan-Meier survival estimates compared with the log-rank test were usedin the univariate analysis Multivariate Cox regression models wereconstructed to identify the independent predictors of OS Two-tailedP values less than 005 were considered statistically significant
RESULTS
Patient CharacteristicsBetween November 2007 and May 2012 a total of 56 patients
(33 men and 23 women median age 63 years) with advanced (ge stageIIIB) lung adenocarcinoma were included in the study The generalcharacteristics of the study participants are reported in Table 1
es of 18F-FDG PETCT-derived parameters in EGFRby determining the values where the area under the curve andunder each cutoff value indicate the number of patients withtients per group The optimal cutoff values for TLGMT andrespectively
copy 2015 Wolters Kluwer Health Inc All rights reserved
ealth Inc All rights reserved
TABLE 2 Univariate and Multivariate Analyses of OS in EGFRMutation-Negative Patients
Univariate Analysis Multivariate Analysis
Parameter n vs n OS (months plusmn SD) P HR (95 CI) P
Age y ge63 vs lt 63 14 vs 11 150 plusmn 33 vs 127 plusmn 29 0487
Sex M vs F 19 vs 6 105 plusmn 21 vs 243 plusmn 40 0022 613 (077-4867) 0087
History of smoking Yes vs no 14 vs 11 94 plusmn 22 vs 198 plusmn 35 0022 267 (066-1082) 0168
M1b M1b vs non-M1b 18 vs 7 133 plusmn 29 vs 156 plusmn 27 0749
TLGMT g ge118 vs lt 118 19 vs 6 126 plusmn 25 vs 180 plusmn 40 0315
TLGRECIST g ge412 vs lt 412 18 vs 7 100 plusmn 20 vs 247 plusmn 44 0006 872 (120-6322) 0032
Radiotherapy Yes vs no 17 vs 8 130 plusmn 28 vs 157 plusmn 37 0490
Use of TKIs Yes vs no 17 vs 8 159 plusmn 29 vs 89 plusmn 22 0201
M Male F Female TLGRECIST sum of TLG values of lesions selected per RECIST 11 criteria TKIs tyrosine kinase inhibitors
Clinical Nuclear Medicine bull Volume 40 Number 6 June 2015 TLG Determined per RECIST 11 Criteria
Survival AnalysisInformation on age sex history of smoking SUVmax of the
main tumor TLGMT TLGRECIST M1 status radiotherapy EGFRmu-tation status and use of tyrosine kinase inhibitors was available for allparticipants Thirty-one patients (55) were EGFRmutation positivewhereas the remaining 25 participants (45) tested negative forEGFR mutations The mean OS of patients who were positive forEGFR mutations was marginally higher than that of patients whotested negative (215 plusmn 26 months vs 141 plusmn 23 months respectivelyP = 0057) Among EGFR mutation-positive patients no associationsbetween 18F-FDG PET-derived parameters and OS were identified inunivariate Cox regression analysis By contrast TLGRECIST was sig-nificantly associated with OS in EGFR mutation-negative patients(P = 0041) Similarly TLGMT showed a marginally significant asso-ciation with OS in patients without EGFR mutations (P = 0054)Receiver operating characteristic curve analysis was then performedto identify the optimal cutoff values for TLGRECIST and TLGMTFigure 1 shows the identified optimal cutoff points (412 g and 118 gfor TLGRECIST and TLGMT respectively) and their correspondingsensitivity specificity and areas under the ROC curve Such valueswere used for subsequent survival analyses
Among EGFR mutation-positive patients Kaplan-Meier esti-mates failed to identify significant associations of OS with clinical var-iables (eg age sex history of smoking M1 status and radiotherapy)However there were significant univariate associations of OS withsex history of smoking and TLGRECIST in EGFR mutation-negativepatients (Table 2) After allowance for potential confounders in multi-variate Cox regression analysis a TLGRECIST greater than or equal to412 g was identified as the only independent predictor of OS in EGFRmutation-negative patients (hazards ratio [HR] 872 95 confidenceinterval [CI] 120ndash6322 P = 0032) whereas male sex showed a mar-ginally significant association (HR 613 95 CI 077ndash4867 P =0087 Table 2) As expected Kaplan-Meier plots for OS were sig-nificantly different in EGFR mutation-negative patients who had aTLGRECIST greater than or equal to 412 g versus TLGRECIST less than412 g (Fig 2) However no such association was seen for EGFRmutation-positive patients (Fig 3)
FIGURE 2 Kaplan-Meier curves for OS according to TLGRECIST inEGFRmutation-negative patients In EGFRmutation-negativepatients subjects with a TLGRECIST greater than or equal to 412 gshowed a shorter OS than those with a TLGRECIST less than412 g (100 plusmn 20 vs 247 plusmn 44 months respectively P = 0006)
DISCUSSIONThe results of the present study demonstrate that TLGRECIST is
an independent predictor of OS in EGFR mutation-negative patientswith advanced lung adenocarcinoma Specifically significantly shorterOS time characterized EGFR mutation-negative patients who had aTLGRECIST greater than or equal to 412 g However neither the clinical
copy 2015 Wolters Kluwer Health Inc All rights reserved
Copyright copy 2015 Wolters Kluwer H
characteristics nor 18F-FDG PETCT-derived parameters were signifi-cantly associated with OS in EGFR mutation-positive patients
The results obtained in our EGFR mutation-negative patientsare generally in line with those of previous studies demonstratingthe prognostic significance of whole-body TLG in non-Asian patientsundergoing nonsurgical treatment for advanced nonndashsmall cell lungcancer89 However it should be noted that the prognostic significanceof TLGRECIST found in our study was limited to patients withoutEGFR mutations The low frequency of EGFR mutations in whites5
may explain the comparable findings Notably our data also suggestthat TLGRECIST may reliably reflect the whole-body metabolic tumorburden Because EGFR mutation-positive lung cancer cases are com-mon in Asia (sim50 of all patients) we stratified our study populationaccording to the EGFR mutation status Our results indicated thatEGFR mutation-positive patients had marginally better OS than thosewithout EGFR mutations The lack of statistical significance may beexplained by the smaller sample size as compared with previous stud-ies3 Among EGFR mutation-positive patients neither clinical vari-ables nor 18 F-FDG PETCT-derived parameters were found to be
wwwnuclearmedcom e297
ealth Inc All rights reserved
FIGURE 3 TLGRECIST in relation toOS in patients with advanced lung adenocarcinoma stratified according to the EGFRmutation statusEGFRmutation-negative patients with a TLGRECIST greater than or equal to 412 g had poor OS In contrast TLGRECIST did not predictOS in EGFRmutation-positive patients
Ho et al Clinical Nuclear Medicine bull Volume 40 Number 6 June 2015
significantly associated with OS These results suggest that genetics isthe most important prognostic determinant of OS in patients bearingEGFR mutations
The National Comprehensive Cancer Network guidelines rec-ommend that patients with advanced (ge stage IIIB) lung cancer shouldbe treated with nonsurgical approaches10 In this context the baselinetumor metabolic burden (as measured byMTVand TLG of the main tu-mor) is considered an important predictor of progression-free survivaland OS rates in patients with advanced nonndashsmall cell lung cancertreated with chemotherapy11 In our study we have used TLGRECIST
as an expression of total metabolic tumor burden by selecting lesionsper RECIST 11 criteria and summing up TLG values of selected le-sions In other words we used TLG and the RECIST 11 criteria insteadof MTV and the PET Response Evaluation Criteria in Solid Tumors(PERCIST) criteria respectively Notably TLG is considered to reflectthe primarymetabolic tumor burdenmore closely thanMTV1213More-over the RECIST 11 criteria currently represent the standard by whichthe efficacy of therapeutic agents is determined among patients withsystemic diseases14 In contrast the clinical usefulness of the PERCIST10 criteria may be limited for geographical areas characterized by ahigh incidence of hepatitis (such as Taiwan) because PERCIST 10 re-lies on FDG uptake of liver as its reference tissue value15 An importantfinding of this study is that the prognostic significance of 18F-FDGPETin patients with advanced lung adenocarcinomawas found to be depen-dent on the EGFR mutation status Moreover we demonstrate for thefirst time that TLG determined per RECIST 11 criteria predicts sur-vival in this group of patients Compared with the sum of TLG valuesfrom all measurable lesions TLGRECIST from a maximum of 5 selectedlesions is compatible with the widely accepted RECIST 11 criteria andcan be more practical to perform
Our findings should be interpreted in the context of some limita-tions First our report has a retrospective nature and represents onlya single-center experience Most patients did not undergo follow-up
e298 wwwnuclearmedcom
Copyright copy 2015 Wolters Kluwer H
18F-FDG PET scans and longitudinal changes in TLGRECIST valueswere not examined in relation to treatment response Further prospec-tive studies are needed to investigate whether this parameter may be apromising tool for stratifying patients with advanced lung cancer forrisk-adapted therapies
These limitations notwithstanding our current data demonstratethat TLGRECIST is an independent predictor of OS in EGFR mutation-negative patients with advanced lung adenocarcinoma In contrast18F-FDG PETCT-derived parameters did not predict OS in EGFRmutation-positive patients
REFERENCES
1 Cancer IAfRo GLOBOCAN 2012 estimated cancer incidence mortality andprevalence worldwide in 2012 World Health Organization Available at httpglobocaniarc frPagesfact_sheets_cancer aspx Accessed May 28 2014
2 Youlden DR Cramb SM Baade PD The international epidemiology of lungcancer geographical distribution and secular trends J Thorac Oncol 20083819ndash831
3 Kobayashi K Hagiwara K Epidermal growth factor receptor (EGFR) mutationand personalized therapy in advanced nonsmall cell lung cancer (NSCLC) TargetOncol 2013827ndash33
4 Shi Y Au JS Thongprasert S et al A prospective molecular epidemiology studyof EGFRmutations inAsian patientswith advanced nonndashsmall-cell lung cancer ofadenocarcinoma histology (PIONEER) J Thorac Oncol 20149154ndash162
5 Bauml J Mick R Zhang Y et al Frequency of EGFR and KRASmutations in pa-tients with non small cell lung cancer by racial background do disparities existLung Cancer 201381347ndash353
6 Hsieh MH Fang YF Chang WC et al Complex mutation patterns of epidermalgrowth factor receptor gene associated with variable responses to gefitinib treat-ment in patients with non-small cell lung cancer Lung Cancer 200653311ndash322
7 Nishino M Jagannathan JP Ramaiya NH et al Revised RECIST guideline ver-sion 11 What oncologists want to know and what radiologists need to knowAJR Am J Roentgenol 2010195281ndash289
8 Olivier A Petyt G Cortot A et al Higher predictive value of tumour and node[18 F]-FDG PET metabolic volume and TLG in advanced lung cancer under che-motherapy Nucl Med Commun 201435908ndash915
copy 2015 Wolters Kluwer Health Inc All rights reserved
ealth Inc All rights reserved
Clinical Nuclear Medicine bull Volume 40 Number 6 June 2015 TLG Determined per RECIST 11 Criteria
9 Liao S Penney BCWroblewskiK et al Prognostic value ofmetabolic tumor bur-den on 18F-FDG PET in nonsurgical patients with non-small cell lung cancerEur J Nucl Med Mol Imaging 20123927ndash38
10 Ettinger DS AW Borghaei H Chang AC NCCN Clinical Practice Guidelines inOncology NonndashSmall Cell Lung Cancer Version 3 Fort Washington PA Na-tional Comprehensive Cancer Network Clinical Guidelines in Oncology 2014
11 Zaizen Y Azuma K Kurata S et al Prognostic significance of total lesion glycol-ysis in patientswith advanced nonndashsmall cell lung cancer receiving chemotherapyEur J Radiol 2012814179ndash4184
12 Arslan N Tuncel M Kuzhan O et al Evaluation of outcome prediction and dis-ease extension by quantitative 2-deoxy-2-[18F] fluoro-D-glucose with positron
copy 2015 Wolters Kluwer Health Inc All rights reserved
Copyright copy 2015 Wolters Kluwer H
emission tomography in patients with small cell lung cancer Ann Nucl Med201125406ndash413
13 Chan SC Chang JT Lin CY et al Clinical utility of 18F-FDG PET parameters inpatients with advanced nasopharyngeal carcinoma predictive role for differentsurvival endpoints and impact on prognostic stratification Nucl Med Commun201132989ndash996
14 Wahl RL Jacene H Kasamon Y et al From RECIST to PERCIST evolvingconsiderations for PET response criteria in solid tumors J Nucl Med 200950(Suppl 1)122Sndash150S
15 Beasley RP Hwang LY Lin CC et al Incidence of hepatitis B virus infections inpreschool children in Taiwan J Infect Dis 1982146198ndash204
wwwnuclearmedcom e299
ealth Inc All rights reserved
TABLE 2 Univariate and Multivariate Analyses of OS in EGFRMutation-Negative Patients
Univariate Analysis Multivariate Analysis
Parameter n vs n OS (months plusmn SD) P HR (95 CI) P
Age y ge63 vs lt 63 14 vs 11 150 plusmn 33 vs 127 plusmn 29 0487
Sex M vs F 19 vs 6 105 plusmn 21 vs 243 plusmn 40 0022 613 (077-4867) 0087
History of smoking Yes vs no 14 vs 11 94 plusmn 22 vs 198 plusmn 35 0022 267 (066-1082) 0168
M1b M1b vs non-M1b 18 vs 7 133 plusmn 29 vs 156 plusmn 27 0749
TLGMT g ge118 vs lt 118 19 vs 6 126 plusmn 25 vs 180 plusmn 40 0315
TLGRECIST g ge412 vs lt 412 18 vs 7 100 plusmn 20 vs 247 plusmn 44 0006 872 (120-6322) 0032
Radiotherapy Yes vs no 17 vs 8 130 plusmn 28 vs 157 plusmn 37 0490
Use of TKIs Yes vs no 17 vs 8 159 plusmn 29 vs 89 plusmn 22 0201
M Male F Female TLGRECIST sum of TLG values of lesions selected per RECIST 11 criteria TKIs tyrosine kinase inhibitors
Clinical Nuclear Medicine bull Volume 40 Number 6 June 2015 TLG Determined per RECIST 11 Criteria
Survival AnalysisInformation on age sex history of smoking SUVmax of the
main tumor TLGMT TLGRECIST M1 status radiotherapy EGFRmu-tation status and use of tyrosine kinase inhibitors was available for allparticipants Thirty-one patients (55) were EGFRmutation positivewhereas the remaining 25 participants (45) tested negative forEGFR mutations The mean OS of patients who were positive forEGFR mutations was marginally higher than that of patients whotested negative (215 plusmn 26 months vs 141 plusmn 23 months respectivelyP = 0057) Among EGFR mutation-positive patients no associationsbetween 18F-FDG PET-derived parameters and OS were identified inunivariate Cox regression analysis By contrast TLGRECIST was sig-nificantly associated with OS in EGFR mutation-negative patients(P = 0041) Similarly TLGMT showed a marginally significant asso-ciation with OS in patients without EGFR mutations (P = 0054)Receiver operating characteristic curve analysis was then performedto identify the optimal cutoff values for TLGRECIST and TLGMTFigure 1 shows the identified optimal cutoff points (412 g and 118 gfor TLGRECIST and TLGMT respectively) and their correspondingsensitivity specificity and areas under the ROC curve Such valueswere used for subsequent survival analyses
Among EGFR mutation-positive patients Kaplan-Meier esti-mates failed to identify significant associations of OS with clinical var-iables (eg age sex history of smoking M1 status and radiotherapy)However there were significant univariate associations of OS withsex history of smoking and TLGRECIST in EGFR mutation-negativepatients (Table 2) After allowance for potential confounders in multi-variate Cox regression analysis a TLGRECIST greater than or equal to412 g was identified as the only independent predictor of OS in EGFRmutation-negative patients (hazards ratio [HR] 872 95 confidenceinterval [CI] 120ndash6322 P = 0032) whereas male sex showed a mar-ginally significant association (HR 613 95 CI 077ndash4867 P =0087 Table 2) As expected Kaplan-Meier plots for OS were sig-nificantly different in EGFR mutation-negative patients who had aTLGRECIST greater than or equal to 412 g versus TLGRECIST less than412 g (Fig 2) However no such association was seen for EGFRmutation-positive patients (Fig 3)
FIGURE 2 Kaplan-Meier curves for OS according to TLGRECIST inEGFRmutation-negative patients In EGFRmutation-negativepatients subjects with a TLGRECIST greater than or equal to 412 gshowed a shorter OS than those with a TLGRECIST less than412 g (100 plusmn 20 vs 247 plusmn 44 months respectively P = 0006)
DISCUSSIONThe results of the present study demonstrate that TLGRECIST is
an independent predictor of OS in EGFR mutation-negative patientswith advanced lung adenocarcinoma Specifically significantly shorterOS time characterized EGFR mutation-negative patients who had aTLGRECIST greater than or equal to 412 g However neither the clinical
copy 2015 Wolters Kluwer Health Inc All rights reserved
Copyright copy 2015 Wolters Kluwer H
characteristics nor 18F-FDG PETCT-derived parameters were signifi-cantly associated with OS in EGFR mutation-positive patients
The results obtained in our EGFR mutation-negative patientsare generally in line with those of previous studies demonstratingthe prognostic significance of whole-body TLG in non-Asian patientsundergoing nonsurgical treatment for advanced nonndashsmall cell lungcancer89 However it should be noted that the prognostic significanceof TLGRECIST found in our study was limited to patients withoutEGFR mutations The low frequency of EGFR mutations in whites5
may explain the comparable findings Notably our data also suggestthat TLGRECIST may reliably reflect the whole-body metabolic tumorburden Because EGFR mutation-positive lung cancer cases are com-mon in Asia (sim50 of all patients) we stratified our study populationaccording to the EGFR mutation status Our results indicated thatEGFR mutation-positive patients had marginally better OS than thosewithout EGFR mutations The lack of statistical significance may beexplained by the smaller sample size as compared with previous stud-ies3 Among EGFR mutation-positive patients neither clinical vari-ables nor 18 F-FDG PETCT-derived parameters were found to be
wwwnuclearmedcom e297
ealth Inc All rights reserved
FIGURE 3 TLGRECIST in relation toOS in patients with advanced lung adenocarcinoma stratified according to the EGFRmutation statusEGFRmutation-negative patients with a TLGRECIST greater than or equal to 412 g had poor OS In contrast TLGRECIST did not predictOS in EGFRmutation-positive patients
Ho et al Clinical Nuclear Medicine bull Volume 40 Number 6 June 2015
significantly associated with OS These results suggest that genetics isthe most important prognostic determinant of OS in patients bearingEGFR mutations
The National Comprehensive Cancer Network guidelines rec-ommend that patients with advanced (ge stage IIIB) lung cancer shouldbe treated with nonsurgical approaches10 In this context the baselinetumor metabolic burden (as measured byMTVand TLG of the main tu-mor) is considered an important predictor of progression-free survivaland OS rates in patients with advanced nonndashsmall cell lung cancertreated with chemotherapy11 In our study we have used TLGRECIST
as an expression of total metabolic tumor burden by selecting lesionsper RECIST 11 criteria and summing up TLG values of selected le-sions In other words we used TLG and the RECIST 11 criteria insteadof MTV and the PET Response Evaluation Criteria in Solid Tumors(PERCIST) criteria respectively Notably TLG is considered to reflectthe primarymetabolic tumor burdenmore closely thanMTV1213More-over the RECIST 11 criteria currently represent the standard by whichthe efficacy of therapeutic agents is determined among patients withsystemic diseases14 In contrast the clinical usefulness of the PERCIST10 criteria may be limited for geographical areas characterized by ahigh incidence of hepatitis (such as Taiwan) because PERCIST 10 re-lies on FDG uptake of liver as its reference tissue value15 An importantfinding of this study is that the prognostic significance of 18F-FDGPETin patients with advanced lung adenocarcinomawas found to be depen-dent on the EGFR mutation status Moreover we demonstrate for thefirst time that TLG determined per RECIST 11 criteria predicts sur-vival in this group of patients Compared with the sum of TLG valuesfrom all measurable lesions TLGRECIST from a maximum of 5 selectedlesions is compatible with the widely accepted RECIST 11 criteria andcan be more practical to perform
Our findings should be interpreted in the context of some limita-tions First our report has a retrospective nature and represents onlya single-center experience Most patients did not undergo follow-up
e298 wwwnuclearmedcom
Copyright copy 2015 Wolters Kluwer H
18F-FDG PET scans and longitudinal changes in TLGRECIST valueswere not examined in relation to treatment response Further prospec-tive studies are needed to investigate whether this parameter may be apromising tool for stratifying patients with advanced lung cancer forrisk-adapted therapies
These limitations notwithstanding our current data demonstratethat TLGRECIST is an independent predictor of OS in EGFR mutation-negative patients with advanced lung adenocarcinoma In contrast18F-FDG PETCT-derived parameters did not predict OS in EGFRmutation-positive patients
REFERENCES
1 Cancer IAfRo GLOBOCAN 2012 estimated cancer incidence mortality andprevalence worldwide in 2012 World Health Organization Available at httpglobocaniarc frPagesfact_sheets_cancer aspx Accessed May 28 2014
2 Youlden DR Cramb SM Baade PD The international epidemiology of lungcancer geographical distribution and secular trends J Thorac Oncol 20083819ndash831
3 Kobayashi K Hagiwara K Epidermal growth factor receptor (EGFR) mutationand personalized therapy in advanced nonsmall cell lung cancer (NSCLC) TargetOncol 2013827ndash33
4 Shi Y Au JS Thongprasert S et al A prospective molecular epidemiology studyof EGFRmutations inAsian patientswith advanced nonndashsmall-cell lung cancer ofadenocarcinoma histology (PIONEER) J Thorac Oncol 20149154ndash162
5 Bauml J Mick R Zhang Y et al Frequency of EGFR and KRASmutations in pa-tients with non small cell lung cancer by racial background do disparities existLung Cancer 201381347ndash353
6 Hsieh MH Fang YF Chang WC et al Complex mutation patterns of epidermalgrowth factor receptor gene associated with variable responses to gefitinib treat-ment in patients with non-small cell lung cancer Lung Cancer 200653311ndash322
7 Nishino M Jagannathan JP Ramaiya NH et al Revised RECIST guideline ver-sion 11 What oncologists want to know and what radiologists need to knowAJR Am J Roentgenol 2010195281ndash289
8 Olivier A Petyt G Cortot A et al Higher predictive value of tumour and node[18 F]-FDG PET metabolic volume and TLG in advanced lung cancer under che-motherapy Nucl Med Commun 201435908ndash915
copy 2015 Wolters Kluwer Health Inc All rights reserved
ealth Inc All rights reserved
Clinical Nuclear Medicine bull Volume 40 Number 6 June 2015 TLG Determined per RECIST 11 Criteria
9 Liao S Penney BCWroblewskiK et al Prognostic value ofmetabolic tumor bur-den on 18F-FDG PET in nonsurgical patients with non-small cell lung cancerEur J Nucl Med Mol Imaging 20123927ndash38
10 Ettinger DS AW Borghaei H Chang AC NCCN Clinical Practice Guidelines inOncology NonndashSmall Cell Lung Cancer Version 3 Fort Washington PA Na-tional Comprehensive Cancer Network Clinical Guidelines in Oncology 2014
11 Zaizen Y Azuma K Kurata S et al Prognostic significance of total lesion glycol-ysis in patientswith advanced nonndashsmall cell lung cancer receiving chemotherapyEur J Radiol 2012814179ndash4184
12 Arslan N Tuncel M Kuzhan O et al Evaluation of outcome prediction and dis-ease extension by quantitative 2-deoxy-2-[18F] fluoro-D-glucose with positron
copy 2015 Wolters Kluwer Health Inc All rights reserved
Copyright copy 2015 Wolters Kluwer H
emission tomography in patients with small cell lung cancer Ann Nucl Med201125406ndash413
13 Chan SC Chang JT Lin CY et al Clinical utility of 18F-FDG PET parameters inpatients with advanced nasopharyngeal carcinoma predictive role for differentsurvival endpoints and impact on prognostic stratification Nucl Med Commun201132989ndash996
14 Wahl RL Jacene H Kasamon Y et al From RECIST to PERCIST evolvingconsiderations for PET response criteria in solid tumors J Nucl Med 200950(Suppl 1)122Sndash150S
15 Beasley RP Hwang LY Lin CC et al Incidence of hepatitis B virus infections inpreschool children in Taiwan J Infect Dis 1982146198ndash204
wwwnuclearmedcom e299
ealth Inc All rights reserved
FIGURE 3 TLGRECIST in relation toOS in patients with advanced lung adenocarcinoma stratified according to the EGFRmutation statusEGFRmutation-negative patients with a TLGRECIST greater than or equal to 412 g had poor OS In contrast TLGRECIST did not predictOS in EGFRmutation-positive patients
Ho et al Clinical Nuclear Medicine bull Volume 40 Number 6 June 2015
significantly associated with OS These results suggest that genetics isthe most important prognostic determinant of OS in patients bearingEGFR mutations
The National Comprehensive Cancer Network guidelines rec-ommend that patients with advanced (ge stage IIIB) lung cancer shouldbe treated with nonsurgical approaches10 In this context the baselinetumor metabolic burden (as measured byMTVand TLG of the main tu-mor) is considered an important predictor of progression-free survivaland OS rates in patients with advanced nonndashsmall cell lung cancertreated with chemotherapy11 In our study we have used TLGRECIST
as an expression of total metabolic tumor burden by selecting lesionsper RECIST 11 criteria and summing up TLG values of selected le-sions In other words we used TLG and the RECIST 11 criteria insteadof MTV and the PET Response Evaluation Criteria in Solid Tumors(PERCIST) criteria respectively Notably TLG is considered to reflectthe primarymetabolic tumor burdenmore closely thanMTV1213More-over the RECIST 11 criteria currently represent the standard by whichthe efficacy of therapeutic agents is determined among patients withsystemic diseases14 In contrast the clinical usefulness of the PERCIST10 criteria may be limited for geographical areas characterized by ahigh incidence of hepatitis (such as Taiwan) because PERCIST 10 re-lies on FDG uptake of liver as its reference tissue value15 An importantfinding of this study is that the prognostic significance of 18F-FDGPETin patients with advanced lung adenocarcinomawas found to be depen-dent on the EGFR mutation status Moreover we demonstrate for thefirst time that TLG determined per RECIST 11 criteria predicts sur-vival in this group of patients Compared with the sum of TLG valuesfrom all measurable lesions TLGRECIST from a maximum of 5 selectedlesions is compatible with the widely accepted RECIST 11 criteria andcan be more practical to perform
Our findings should be interpreted in the context of some limita-tions First our report has a retrospective nature and represents onlya single-center experience Most patients did not undergo follow-up
e298 wwwnuclearmedcom
Copyright copy 2015 Wolters Kluwer H
18F-FDG PET scans and longitudinal changes in TLGRECIST valueswere not examined in relation to treatment response Further prospec-tive studies are needed to investigate whether this parameter may be apromising tool for stratifying patients with advanced lung cancer forrisk-adapted therapies
These limitations notwithstanding our current data demonstratethat TLGRECIST is an independent predictor of OS in EGFR mutation-negative patients with advanced lung adenocarcinoma In contrast18F-FDG PETCT-derived parameters did not predict OS in EGFRmutation-positive patients
REFERENCES
1 Cancer IAfRo GLOBOCAN 2012 estimated cancer incidence mortality andprevalence worldwide in 2012 World Health Organization Available at httpglobocaniarc frPagesfact_sheets_cancer aspx Accessed May 28 2014
2 Youlden DR Cramb SM Baade PD The international epidemiology of lungcancer geographical distribution and secular trends J Thorac Oncol 20083819ndash831
3 Kobayashi K Hagiwara K Epidermal growth factor receptor (EGFR) mutationand personalized therapy in advanced nonsmall cell lung cancer (NSCLC) TargetOncol 2013827ndash33
4 Shi Y Au JS Thongprasert S et al A prospective molecular epidemiology studyof EGFRmutations inAsian patientswith advanced nonndashsmall-cell lung cancer ofadenocarcinoma histology (PIONEER) J Thorac Oncol 20149154ndash162
5 Bauml J Mick R Zhang Y et al Frequency of EGFR and KRASmutations in pa-tients with non small cell lung cancer by racial background do disparities existLung Cancer 201381347ndash353
6 Hsieh MH Fang YF Chang WC et al Complex mutation patterns of epidermalgrowth factor receptor gene associated with variable responses to gefitinib treat-ment in patients with non-small cell lung cancer Lung Cancer 200653311ndash322
7 Nishino M Jagannathan JP Ramaiya NH et al Revised RECIST guideline ver-sion 11 What oncologists want to know and what radiologists need to knowAJR Am J Roentgenol 2010195281ndash289
8 Olivier A Petyt G Cortot A et al Higher predictive value of tumour and node[18 F]-FDG PET metabolic volume and TLG in advanced lung cancer under che-motherapy Nucl Med Commun 201435908ndash915
copy 2015 Wolters Kluwer Health Inc All rights reserved
ealth Inc All rights reserved
Clinical Nuclear Medicine bull Volume 40 Number 6 June 2015 TLG Determined per RECIST 11 Criteria
9 Liao S Penney BCWroblewskiK et al Prognostic value ofmetabolic tumor bur-den on 18F-FDG PET in nonsurgical patients with non-small cell lung cancerEur J Nucl Med Mol Imaging 20123927ndash38
10 Ettinger DS AW Borghaei H Chang AC NCCN Clinical Practice Guidelines inOncology NonndashSmall Cell Lung Cancer Version 3 Fort Washington PA Na-tional Comprehensive Cancer Network Clinical Guidelines in Oncology 2014
11 Zaizen Y Azuma K Kurata S et al Prognostic significance of total lesion glycol-ysis in patientswith advanced nonndashsmall cell lung cancer receiving chemotherapyEur J Radiol 2012814179ndash4184
12 Arslan N Tuncel M Kuzhan O et al Evaluation of outcome prediction and dis-ease extension by quantitative 2-deoxy-2-[18F] fluoro-D-glucose with positron
copy 2015 Wolters Kluwer Health Inc All rights reserved
Copyright copy 2015 Wolters Kluwer H
emission tomography in patients with small cell lung cancer Ann Nucl Med201125406ndash413
13 Chan SC Chang JT Lin CY et al Clinical utility of 18F-FDG PET parameters inpatients with advanced nasopharyngeal carcinoma predictive role for differentsurvival endpoints and impact on prognostic stratification Nucl Med Commun201132989ndash996
14 Wahl RL Jacene H Kasamon Y et al From RECIST to PERCIST evolvingconsiderations for PET response criteria in solid tumors J Nucl Med 200950(Suppl 1)122Sndash150S
15 Beasley RP Hwang LY Lin CC et al Incidence of hepatitis B virus infections inpreschool children in Taiwan J Infect Dis 1982146198ndash204
wwwnuclearmedcom e299
ealth Inc All rights reserved
Clinical Nuclear Medicine bull Volume 40 Number 6 June 2015 TLG Determined per RECIST 11 Criteria
9 Liao S Penney BCWroblewskiK et al Prognostic value ofmetabolic tumor bur-den on 18F-FDG PET in nonsurgical patients with non-small cell lung cancerEur J Nucl Med Mol Imaging 20123927ndash38
10 Ettinger DS AW Borghaei H Chang AC NCCN Clinical Practice Guidelines inOncology NonndashSmall Cell Lung Cancer Version 3 Fort Washington PA Na-tional Comprehensive Cancer Network Clinical Guidelines in Oncology 2014
11 Zaizen Y Azuma K Kurata S et al Prognostic significance of total lesion glycol-ysis in patientswith advanced nonndashsmall cell lung cancer receiving chemotherapyEur J Radiol 2012814179ndash4184
12 Arslan N Tuncel M Kuzhan O et al Evaluation of outcome prediction and dis-ease extension by quantitative 2-deoxy-2-[18F] fluoro-D-glucose with positron
copy 2015 Wolters Kluwer Health Inc All rights reserved
Copyright copy 2015 Wolters Kluwer H
emission tomography in patients with small cell lung cancer Ann Nucl Med201125406ndash413
13 Chan SC Chang JT Lin CY et al Clinical utility of 18F-FDG PET parameters inpatients with advanced nasopharyngeal carcinoma predictive role for differentsurvival endpoints and impact on prognostic stratification Nucl Med Commun201132989ndash996
14 Wahl RL Jacene H Kasamon Y et al From RECIST to PERCIST evolvingconsiderations for PET response criteria in solid tumors J Nucl Med 200950(Suppl 1)122Sndash150S
15 Beasley RP Hwang LY Lin CC et al Incidence of hepatitis B virus infections inpreschool children in Taiwan J Infect Dis 1982146198ndash204
