ON-LINE APPENDIX

ON-LINE APPENDIXSearch Strategies

PubMed((“Brain Neoplasms”[MeSH Terms] OR “Glioma”[MeSH

Terms] OR glioma* OR (glioblastoma* OR “glioblastoma multi-

forme”) OR (astrocytoma* OR “anaplastic astrocytoma”) OR

(oligodendrocytoma* OR “anaplastic oligodendrocytoma”) OR

(brain AND (tumor* OR tumour*)) OR (neuroectodermal AND

(tumor* OR tumour*)) OR ependymoma* OR oligodendrogli-

oma*)) AND (“Tomography, Emission-Computed”[MeSH

Terms] OR (positron AND emission AND tomograph*) OR pet)

AND “humans”[MeSH Terms]

Scopus(TITLE-ABS-KEY (glioma*) OR TITLE-ABS-KEY (glioblas-

toma*) OR TITLE-ABS-KEY (glioblastoma PRE/0 multiforme)

OR TITLE-ABS-KEY (astrocytoma*) OR TITLE-ABS-KEY (ana-

plastic PRE/0 astrocytoma) OR TITLE-ABS-KEY (oligodendro-

cytoma*) OR TITLE-ABS-KEY (anaplastic PRE/0 oligodendrocy-

toma) OR TITLE-ABS-KEY (brain tumo*r*) OR TITLE-ABS-

KEY (neuroectodermal PRE/0 tumo*r*) OR TITLE-ABS-KEY

(ependymoma*) OR TITLE-ABS-KEY (oligodendroglioma*)

AND TITLE-ABS-KEY (positron PRE/0 emission PRE/0 tomo-

graph*) OR TITLE-ABS-KEY (pet).

PUBLICATIONS EXCLUDED AFTER FULL-TEXTSCREENINGRelevant but<10 Patients (n� 7)

1. Lichy MP, Bachert P, Henze M, et al. Monitoring individual re-sponse to brain-tumor chemotherapy: proton MR spectroscopy ina patient with recurrent glioma after stereotactic radiation therapy.Neuroradiology 2004;46:126 –29

2. Pruim J, Willemsen AT, Molenaar WM et al. Brain tumors: L-[1-C-11]tyrosine PET for visualization and quantification of proteinsynthesis rate. Radiology 1995;197:221–26

3. Kim EE, Chung SK, Haynie TP et al. Differentiation of residual orrecurrent tumors from posttreatment changes with F-18 FDG PET.Radiographics 1992;12:269 –79

4. Di Chiro G, Oldfield E, Wright DC, et al. Cerebral necrosis afterradiation therapy and/or intra-arterial chemotherapy for braintumor: PET and neuropathologic studies. AJR Am J Roentgenol1988;150:189 –97

5. Glantz MJ, Hoffman JM, Coleman RE et al. Identification of earlyrecurrence of primary central nervous system tumors by [18F]fluo-rodeoxyglucose positron emission tomography. Ann Neurol 1991;29:347–55

6. Ogawa T, Kanno I, Shishido F et al. Clinical value of PET with 18F-fluorodeoxyglucose and L-methyl-11C-methionine for diagnosisof recurrent brain tumor and radiation injury. Acta Radiol 1991;32:197–202

7. Chao ST, Suh JH, Raja S, et al. The sensitivity and specificity of FDGPET in distinguishing recurrent brain tumor from radionecrosis inpatients treated with stereotactic radiosurgery. Int J Cancer 2001;96:191–97

Partially Eligible but Pertinent Data Not Extractable (n�6)

8. Yamane T, Sakamoto S, Senda M. Clinical impact of (11)C-methio-nine PET on expected management of patients with brain neo-plasm. Eur J Nucl Med Mol Imaging 2010;37:685–90

9. Chen W, Silverman DH, Delaloye S, et al. 18F-FDOPA PET imagingof brain tumors: comparison study with 18F-FDG PET and evalua-tion of diagnostic accuracy. J Nucl Med 2006;47:904 –11

10. Henze M, Mohammed A, Schlemmer HP et al. PET and SPECT fordetection of tumor progression in irradiated low-gradeastrocytoma: a receiver-operating-characteristic analysis. J NuclMed 2004;45:579 – 86

11. Wang SX, Boethius J, Ericson K. FDG-PET on irradiated braintumor: ten years’ summary. Acta Radiol 2006;47:85–90

12. Deshmukh A, Scott JA, Palmer EL, et al. Impact of fluorodeoxyglu-cose positron emission tomography on the clinical management ofpatients with glioma. Clin Nucl Med 1996;21:720 –25

13. Maldonado A, Alfonso JM, Ossola G, et al. The role of PET-FDG inresolving diagnostic doubt: recurrence versus radionecrosis in braintumors: experience in 94 patients. Riv Neuroradiol 2003;16:887–90

All Recurrent Cases (n� 4)14. Hubner KF, Thie JA, Smith GT, et al. Positron emission tomography

(PET) with 1-aminocyclobutane-1-[(11)C]carboxylic acid (1-[(11)C]-ACBC) for detecting recurrent brain tumors. Clin PositronImaging 1998;1:165–73

15. Ishikawa M, Kikuchi H, Miyatake S, et al. Glucose consumption inrecurrent gliomas. Neurosurgery 1993;33:28 –33

16. Yamamoto Y, Wong TZ, Turkington TG, et al. 3�-deoxy-3�-[F-18]fluorothymidine positron emission tomography in patientswith recurrent glioblastoma multiforme: comparison with Gd-DTPA enhanced MR imaging. Mol Imaging Biol 2006;8:340 – 47

17. Grosu AL, Astner ST, Riedel E, et al. An interindividual comparisonof O-(2- [(18)F]fluoroethyl)-L-tyrosine (FET)- and L-[methyl-(11)C]methionine (MET)-PET in patients with brain gliomas andmetastases. Int J Radiat Oncol Biol Phys 2011;81:1049 –58

Irrelevant (n� 5)18. Weber WA, Wester HJ, Grosu AL et al. O-(2-[18F]fluoroethyl)-L-

tyrosine and L-[methyl-11C]methionine uptake in brain tumors:initial results of a comparative study. Eur J Nucl Med 2000;27:542– 49

19. Blasberg RG, Roelcke U, Weinreich R et al. Imaging brain tumorproliferative activity with [124I]iododeoxyuridine. Cancer Res2000;60:624 –35

20. Willemsen AT, van WA, Paans AM et al. In vivo protein synthesisrate determination in primary or recurrent brain tumors by usingL-[1–11C]-tyrosine and PET. J Nucl Med 1995;36:411–19

21. Pirotte B, Goldman S, David P et al. Stereotactic brain biopsyguided by positron emission tomography (PET) with [F-18]fluo-rodeoxyglucose and [C-11]methionine. Acta Neurochir Suppl1997;68:133–38

22. Ledezma CJ, Chen W, Sai V, et al. 18F-FDOPA PET/MR imagingfusion in patients with primary/recurrent gliomas: initial experi-ence. Eur J Radiol 2009;71:242– 48

Not a Dedicated PET Scanner (n� 1)23. Stokkel M, Stevens H, Taphoorn M, et al. Differentiation between

recurrent brain tumor and postradiation necrosis: the value of201Tl SPET versus 18F-FDG PET by using a dual-headed coinci-dence camera–a pilot study. Nucl Med Commun 1999;20:411–17

AJNR Am J Neuroradiol : www.ajnr.org E1

ON-LINE FIG 1. Sensitivity and specificity of PET for differentiating glioma recurrence from treatment-induced necrosis (for both low- andhigh-grade gliomas [A] and high-grade glioma only [B]). Squares (proportional to the number of patients) represent the point estimates ofsensitivity and specificity; extending lines represent the 95% confidence interval (CI) of each estimate; and n/n denotes true-positive casesdivided by recurrent cases for sensitivity, and true-negative cases divided by nonrecurrent cases for specificity. BPA indicates 18F-boronophe-nylalanine; V, visual assessment.a tumor-to-cortex ratio.b tumor-to-white matter ratio.

E2 AJNR www.ajnr.org

ON-LINE FIG 2. Subgroup and sensitivity analyses of sensitivity and specificity. Squares (proportional to the number of patients) representpoint estimates of sensitivity and specificity; extending lines represent the 95% confidence interval of each estimate. QA indicates, quantitativeassessment; VA, visual assessment; Q*, “Q-star” statistic, a global summary of the ROC curve (see text for details).a Sensitivity analyses preferring quantitative assessment for 18F-FDG PET and visual assessment for 11C-MET PET (see text for details).b Sensitivity analyses preferring the optimal cutoff threshold for defining positive and negative scans by receiver operating characteristicanalysis (see text for details).


ON-LINE FIG 3. Comparative accuracy of PET for differentiating recurrent glioma from treatment-induced necrosis. Comparisons amongdifferent PET tracers for both high- and low-grade glioma histology (A) and high-grade glioma only (B), between 18F-FDG PET and other imagingmodalities for any glioma histology (C) and high-grade glioma (D), and between 11C-MET PET and other imaging modalities for both high- andlow-grade glioma histology (E) and high-grade glioma only (F). Closed and open symbols, respectively, indicate PET and comparator imagingmodalities. Dashed lines connect estimates for pairs of different PET tracers in (eg, 18F-FDG-PET versus 11C-MET) or of PET and a comparatorimaging test (eg, 18F-FDG-PET versus Tl-SPECT) compared in a study. Closed circle (black), square (red), triangle (green), and diamond (blue),respectively, indicate PETwith FDG,MET, FET, and FLT.Open circle (green) and square (blue), respectively, indicate SPECT andMR imaging–basednovel imaging.


ON-LINETABLE1:Studycharacteristicsofpositron-emissiontomographytodifferentiaterecurrencefromtreatment-relatednecrosisintreatedglioma

Study

Country

Study

Period

(yr)

Patient

(No.)Institution

(No.)

Design

Clinical

Context

Indication

Tracer

Comparator

Imaging

Tests

Prior

Imaging

Tests

MedianTime

(fromDx/Tx)

toImaging

(range)(mo)

Reference

Standard

Median

Follow-Up

afterPET

(range)(mo)

Anygrades

Janusetal199316

US

ND

501

RetrospectiveND

Suspectedrecurrence,

radiationnecrosis,or

othersbyMRI

FDG

None

EnhancedMRI11(1–208)

Bxorclinical

follow-up

12(5–27)a

Kahnetal199417

US

ND

171

Prospective

ND

Suspectedrecurrenceby

deterioratingclinical

courseorchangeinMRI

orCT

FDG

Tl-SPECT

EnhancedMRI

orCT

33(6–120)(Dx)Bxorclinical

follow-up

12(1–32)

Nelsonetal199718

US

1994–1995

191

RetrospectiveND


MRI

FDG

None

EnhancedMRIND

Clinicalfollow-up

only

8(2–22)

Riccietal199819

US

1993–1995

311

RetrospectiveND

Suspectedrecurrenceor

radiationnecrosisby

symptomsandMRI

FDG

None

EnhancedMRIND

Bxonly

NA

Sonodaetal199820

Japan

ND

101

RetrospectiveND

Highlysuggestiveof

recurrencebyMRI

MET

Tl-SPECT

MRI

ND

Bx/surgeryor

clinicalfollow-

upfor3mo

ND

Baderetal199921

Germany

ND

301

Prospective

ND

Suspectedrecurrence

FDG

IMT-SPECT

ND

24(6–144)(Tx)Bxonly

NA

Thompsonetal19922

US

ND

151

RetrospectiveND

Suspectedprogressionor

necrosisbyCTorMRI

FDG

None

MRIorCT

37b(7–90)(Tx)Bxonly

NA

Belohláveketal200223

Czech

ND

291

RetrospectiveND

Suspectedrecurrence

FDG

None

EnhancedMRIND(4–64)

�Tx)Bxorclinical

follow-up

ND(12–28)

Pöpperletal200424

Germany

ND

531

RetrospectivePost1st-and

2nd-line

Suspectedrecurrence

FET

None

MRIorCT

36(4–180)(Dx)Bxorclinical

follow-upfor

2mobyMRI

Mean34

(16–69)c

VanLaereetal200525

Belgium

1997–2000

301

RetrospectivePost1st-lineTodifferentiatetumor

recurrencefrom

radiationnecrosis

FDG,METNone

MRIorCT

48(1–216)

Survival/deathat

lastfollow-up15

Rachingeretal200526

Germany

2001–2003

361

RetrospectiveND


progression

FET

Noned

MRI

ND

Bxorclinical

follow-up

9(5–18)e

8(4–20)f

Gómez-Ríoetal200827

Spain

2002–2005

761

Prospective

Post1st-lineSuspectedrecurrenceby

clinicalsymptomsand

MRIg

FDG

Tl-SPECT

MRI

ND

Bxorclinical

follow-uph

31(9–48)

Mehrkensetal200828

Germany

2003–2004

311

Prospective

ND


progressionbyMRI

FET

None

EnhancedMRIND

Bxand/orclinical

follow-up

24(10–32)

Terakawaetal200829

Japan

1995–2006

261

RetrospectiveND


radiationnecrosisby

clinicalsymptomsand

MRI

MET

None

MRIorCT

36(Tx)

Bxorclinical

follow-up

�6

mobyMRI

ND

Nakajimaetal200930

Japan

1995–2008

181

RetrospectiveND


radiationnecrosis

MET

MRS

MRI

15(4–80)(Tx)

Bxorclinical

follow-up

�6

mobyMRI

67b

Spenceetal200940

US

ND

191

RetrospectiveND

Todifferentiatetumor

recurrencefrom

radiationnecrosis

FDG,FLT

None

EnhancedMRI24(2–120)(Tx)Bxorclinical

follow-upby

MRI

14(3–56)

Jeongetal201031

SouthKorea

2003–2009

321

RetrospectiveND


MRI

FLT,FET

None

EnhancedMRI13b(1–114)(Tx)Bxorclinical

follow-upby

MRI

ND

Ozsunaretal201032

US

ND

301

RetrospectiveND


necrosisbyMRI

FDG

MRI-DSCE-CBV,

MRI-ASL

MRI

�6moe

Bxorclinical

follow-up

�12

mo

ND

Pratetal201033

Spain

ND

261

RetrospectiveND

Suspectedrecurrence,

histologicupgrading,or

radiationnecrosisbyMRI

FDG

MRS,pMRI

EnhancedMRIND

Bxorclinical

follow-up

�5

mobyMRI

5.6b,c

14.7b,c

Santraetal201241

India

2006–2008

901

Prospective

ND

Clinicalsuspicionof

recurrence

FDG

None

None

ND

Bxorclinical

follow-up

�6

mobyimaging

ND continued


ON-LINETABLE1,continued

Study

Country

Study

Period

(yr)

Patient

(No.)Institution

(No.)

Design

Clinical

Context

Indication

Tracer

Comparator

Imaging

Tests

Prior

Imaging

Tests

MedianTime

(fromDx/Tx)

toImaging

(range)(mo)

Reference

Standard

Median

Follow-Up

afterPET

(range)(mo)

High-gradeonly

Valketal198834

US

ND

321

RetrospectiveND

Worseningofsymptoms

orCTfindings

FDG

None

CT

11(3–27)(Tx)

Bxorclinical

follow-up

8(2–37)

VanTasseletal199535

US

1988–1992

101

RetrospectivePost1st-lineNewenhancing

parenchymallesions

byMRI

FDG

None

EnhancedMRIorCTND

Bxonly

NA

Tsuyuguchietal200436Japan

ND

111

RetrospectivePost1st-lineSuspectedrecurrenceor

necrosis

MET

None

MRI

7Bxorclinical

follow-up

�5

mobyMRI

7(5–12)

Miyashitaetal200837

Japan

2002–2006

101

RetrospectivePost1st-and

2nd-line


progressionbyMRI

BPA

None

EnhancedMRIl

ND

Bxorclinical

follow-upby

MRIl

ND

Dandoisetal201038

Belgium

ND

281

RetrospectiveND


necrosis

MET

pMRI

EnhancedMRI,FLAIR

MRI,DWI

ND

Bxorclinical

follow-up

includingPET

13b(3–40)

Kimetal201039

SouthKorea

2001–2007

101

RetrospectivePost1st-lineNewlyenhancedlesions

byMRI,without

clinicalevidenceof

recurrence

FDG,MET

pMRI

MRI

ND

Bxorclinical

follow-up

�12

mo

6.5(6–10)i

28(18–50)c

Note:—ASLindicatesarterialspin-labeling;DSCE,dynamicsusceptibilitycontrast-enhanced;BPA,18F-boronophenylalanine;pMRI

�perfusionMRimaging;Bx,biopsy;Dx,diagnosis;IMT,123I-alpha-methyl-tyrosine;NA,notapplicable;ND,nodata;Tx,

therapy.

aOnlylivingpatients.

bMean.

cNonrecurrentpatients.

dConventionalMRIwascompared.

ePatientsfollowedupwithoutbiopsy.

fBiopsiedpatients.

gTheMacdonaldCriteria(MacdonaldD,CascinoT,ScholdSJ,etal:ResponsecriteriaforphaseIIstudiesofsupratentorialmalignantglioma.JClinOncol1990;8:1277–80)wereused.

hStablediseaserequirednochangesbyMRI

�3monthsforhigh-gradegliomaand

�6monthsforlow-gradeglioma.

i Aftercompletionofprotonbeamtherapy.

j Recurrentpatients.

kPreviouslyperformedBPA-PETwasalsoused.

l StablediseaserequirednochangesbyMRIfor�4months.


ON-LINETABLE2:Patientandtherapycharacteristicsofstudiesofpositron-emissiontomographytodifferentiaterecurrencefromtreatment-relatednecrosisintreatedglioma

Study

Patient

(No.)

Median

Age(yr)

Male

(%)

Histology

(%)

Tumor

Location(%)

Treatment(%)

Useof

TMZ(%)

Anygrades

Janusetal199316

5039(15–66)

64LG:20;HG:80

ND

LG:Surg

�RTx

�Cx(40),Surg

�RTx(40),RTx

�Cx(10),

Surgalone(10);HG:Surg

�RTx

�Cx(73),Surg

�RTx(15),

RTx

�Cx(8),RTxalone(3),none(3)

0

Kahnetal199417

1738(26–57)

52a

LG:29;HG:71

ND

ND

0Nelsonetal199718

1947(26–70)

68LG:16;HG:84

ND

LG:RTx(34)HG:RTx(88)

0Riccietal199819

2846b(27–70)a

55a

LG:25;HG:75

ND

HG/LG:Surg

�RTx

�Cx

0Sonodaetal199820

1036(21–68)

60LG:50;HG:50

ND

HG/LG:Surg

�RTx

�Cx(90),RTx

�Cx(10)

0Baderetal199921

3050(32–70)

73LG:40;HG:60

ND

HG/LG:Surg,RTx,orSurg

�RTx

0Thompsonetal19922

1552b(25–72)

ND

ND

ND

HG/LG:RTx

�Cx(93),RTxalone(7)

0Belohláveketal200223

29ND(17–65)

72LG:10;HG:90

ND

ND

0Pöpperletal200424

53ND

53LG:19;HG:81

ND

HG/LG:Surg(83),RTx(94),CTx(40),IRS(13),RIT(17)

0VanLaereetal200525

3040(11–69)

70LG:50;HG:50

Supratentorium:93;

infratentorium:7

LG:Surg

�RTx(47),RTx(20),Cx(20),Surg

�RTx

�Cx(7),

RTx

�Cx(7);HG:Surg

�RTx(73),RTx(20),RTx

�Cx(7)

ND

Rachingeretal200526

3645b(26–75)a

51a

LG:24;HG:76c

ND

HG/LG:“conventional”

�RITorpaclitaxel

0Gómez-Ríoetal200827

7648b

�16d

57LG:42;HG:58

ND

HG/LG:Surg

�RTx

0Mehrkensetal200828

3146b(29–65)

55LG:55;HG:45

Supratentorium:100

LG:IRS(69),Surg(50),RTx(50),Cx(31);HG:Surg

�RTx(100),

Cx(43),IRS(14),RIT(7),IPDT(7)

ND

Terakawaetal200829

2654(14–83)a

60a

LG:23;HG:77

ND

HG/LG:RTx

�SRS

0Nakajimaetal200930

1845b(14–67)

67LG:22;HG:78

ND

HG/LG:RTx

�Cx(100)

ND

Spenceetal200940

1946(19–67)

68LG:16;HG:84

Supratentorium:100

LG:RT(33),lRT

�Cx(67);HG:RT(13),RTx

�Cxincluding

TMZ(87)

74

Jeongetal201031

26ND

58LG:15;HG:85

Lobar:69;deep:19;

multicentric:4

GBM:Surg

�RTx

�TMZ(100);anaplastictumors:

Surg

�RTx

�BCNU(100);LG:Surgalone(100)

42

Ozsunaretal201032

3247b(32–68)

38LG:31;HG:69

ND

LG:Surg(10),Surg

�Cx(30),Surg

�Cx

�RTx(60);HG:

Surg(14),Surg

�Cx(23),Surg

�Cx

�RTx(50),

Surg

�RTx(14)

ND

Pratetal201033

3042b(20–69)

73LG:23;HG:77

ND

LG/HG:Surg

�RTx

�PBRT

�Cx(100)

ND

Santraetal201241

9037b(12–68)

73LG:40;HG:60

Supratentorium:94;

infratentorium:6

LG/HG:Surg

�RTx(53),Surg

�RTx

�Cx(38),Surgor

RTx(9)

ND

High-gradeonly

Valketal198834

32ND

ND

HG:100

ND

HG:Surg/Bx

�RTx

�Cx(75),Surg/Bx

�RTx(25)

0VanTasseletal199535

10ND

ND

HG:100

ND

HG:RTx

�Cx(100)

0Tsuyuguchietal200436

1135(23–62)

72HG:100

Supratentorium:91;

infratentorium:9

HG:Surg

�RTx

�SRS

�Cx(100)

0

Miyashitaetal200837

10ND

ND

HG:100

ND

HG:Surg

�RTx

�BNCT(100)

0Dandoisetal201038

2851b(25–74)

57HG:100

ND

HG:RTx

�TMZ(18),Surg

�RTx

�TMZ(82)

100

Kimetal201039

1046b(31–66)

80HG:100

Supratentorium:90;

infratentorium:10

HG:Surg

�RTx(100),PCV(20),ACNU

�CDDP(20),

TMZ(50)

50

Note:—ACNUindicatesnimustine;BCNU,carmustine;BNCT,boronneutroncapturetherapy;CDDP,cisplatin;Cx,chemotherapy;GBM,glioblastomamultiforme;HG,high-grade;IPDT,interstitialphotodynamictherapy;IRS,interstitialradiosurgery;

LG,low-grade;ND,nodata;PBRT,protonbeamradiationtherapy;PCV,procarbazine,lomustine,vincristine;RIT,radioimmunotherapy;RTx,radiationtherapy;Surg,surgery;TMZ,temozolomide;Bx,biopsy;SRS,stereotacticradiosurgery.

aWholeincludedpatients,someofwhomhadirrelevanthistologies.

bMean.

cWholeincludedpatients,someofwhomwereevaluatedwithPETforanirrelevantpurpose.

dSD.


ON-LINETABLE3:PETcharacteristicsofstudiesofpositron-emissiontomographytodifferentiaterecurrencefromtreatment-relatednecrosisintreatedglioma

Study

PET

Tracer

TypeofPET

Scanner

Model(Maker)

Preparation

(Time,hr)

Administered

PETTracer

Activity

(MBq)

Timeof

Scanning

afterInjection

(min)

ScanTime

(min)

Attenuation

Correction

Image

Reconstruction

Method

Anygrades

Janusetal199316

FDG

PETcamera

Posicam6.5(Positron,Westmont,

Illinois)

ND

185–370

ND

�20

Performed

ND

Kahnetal199417

FDG

PETcamera

GE-4096plusPETsystem(GEMS,

Milwaukee,Wisconsin)

Fasting(4)

370

045

Performed

ND

Nelsonetal199718

FDG

PETcamera

ECATExactHR(Siemens,Erlangen,

Germany)

ND

370

4030

Performed

ND

Riccietal199819

FDG

PETcamera

GE-4096(GEMS)

ND

370

3025

Performed

FBP

Sonodaetal199820

MET

PETcamera

PT931(CTI,Largo,Maryland)

ND

111–555

3010

Performed

ND

Baderetal199921

FDG

PETcamera

ECATPart1(CTI/Siemens)

Fasting(�12)

200

ND

ND

Performed

FBP

Thompsonetal19922

FDG

ND

ND

ND

ND

ND

ND

ND

ND


FDG

PETcamera

ECATExactHR(Siemens)

Fasting(6)

3a35–40

15Performed

OSEM

Pöpperletal200424

FET

PETcamera

ECATExactHR�(Siemens)

Fasting(�6)

180

3030

Performed

FBP

VanLaereetal200525

FDG,MET

PETcamera

ECATExactHR(Siemens)

Fasting(�12)

150(FDG),

220(MET)

30(FDG),20–40(MET)

20(FDG),20(MET)

Performed

FBP

Rachingeretal200526

FET

PETcamera


Fasting(�6)

180

060

Performed

FBP


FDG

PETcamera

ECATExact47(Siemens)

Fasting(6)b

185

45ND

ND

OSEM

Mehrkensetal200828

FET

PETcamera


Fasting(�6)

180

060

Performed

FBP

Terakawaetal200829

MET

PETcamera

HeadtomeIV(Shimadzu)

Fasting(ND)

6a20

10Performed

ND

Nakajimaetal200930

MET

PETcamera

HeadtomeV(Shimadzu)

ND

200–550

2010

Performed

FBP

Spenceetal200940

FDG,FLT

PETcamera

GEAdvancedPETtomography

(GEMS)

Fasting(FDG)

3.7a(FDG),

2.7a(FLT)

75(FDG),0(FLT)

15(FDG),90–120(FLT)

Performed

ND

Jeongetal201031

FLT,FET

PETcamera,

PET/CTc

ECATExactHR�(Siemens),

Biograph6PET/CTscanner

(Siemens)

ND

370

3020(PET),10(PET/CT)

Performed

OSEM

Ozsunaretal201032

FDG

PETcamera

PC-384orPC-4096(Scanditronix,

Uppsala,Sweden)

ND

185–370

045minutes

Performed

FBP

Pratetal201033

FDG

ND

ND

ND

ND

ND

ND

ND

ND

Santraetal201241

FDG

PET/CT

Biograph2PET/CTscanner

(Siemens)

Fasting(4)

370

45–60

6–10

Performed

OSEM

High-gradeonly

Valketal198834

FDG,82 Rb

PETcamera

Donner280-CrystalPositronRing

(LawrenceBerkeleyLaboratory,

Berkley,California)

ND

370(FDG),

555(82 Rb)

0(FDG),0(82 Rb)

45(FDG),5(82 Rb)

Performed

ND

VanTasseletal199535

FDG

ND

ND

ND

185–370

ND

ND

ND

ND

Tsuyuguchietal200436

MET

PETcamera

HeadtomeIV(Shimadzu)

Fasting(4)

370

2010

Performed

ND

Miyashitaetal200837

BPA

PETcamera

HeadtomeIII(Shimadzu)

3.7–5.55a

060

ND

ND

Dandoisetal201038

MET

PETcamera

HR961(CTI/Siemens)

ND

740

1520

Performed

FBP

Kimetal201039

FDG,MET

PETcamera

ECATExact47(Siemens)

Fasting(6)

370–555(FDG),

550–740(MET)

40(FDG),10(MET)

20(FDG),20(MET)

Performed

ND

Note:—BPAindicates18F-boronophenylalanine;FBP,filteredback-projection;ND,nodata;OSEM,orderedsubsetexpectationmaximization;GEMS,GEHealthcare;82 Rb,rubidium-82.

aAdministeredactivityperkilogramofbodyweight.

bFastingbloodglucose

�120mg/dLwasrequiredforinclusion.

cFiveof32patientswereevaluatedwithPET/CT.


ON-LINETABLE4:Diagnosticcriteriaofpositron-emissiontomographytodifferentiaterecurrencefromtreatment-relatednecrosisintreatedglioma

Study

PETDrug

Method

VisualAssessment

Quantitative

Assessment,

CutoffValue

Referent

Baseline

Scan

No.of

Interpreters

Experience

ofInterpreters

PositiveCriteria

NegativeCriteria

Anygrades

Janusetal199316

FDG

Visualassessment

Increaseinactivityrelativetothe

contralateralhemisphereor

adjacentareasuggestiveof

tumorprogression

Decreasedactivity

–ND

2ND

Kahnetal199417

FDG

Visualassessmentusingagradingscalea

IncreasedFDGuptakerelativetothe

immediatelyadjacenttissue

Markedlyreducedor

absentFDGuptake

–ND

3Experiencednuclear

medicinespecialists

Nelsonetal199718

FDG

Visualassessmentusingagradingscaleb

ND

ND

–ND

ND

Experienced(�15year)

interpreters

Riccietal199819

FDG

Visualassessmentusingagradingscalec

Hypermetabolicrelativeto

contralateralwhitematter

grade2or3c

Activitylessthanor

equaltowhite

mattergrade0or1c

–ND

ND

CAQcertified

neuroradilogist

Sonodaetal199820

MET

Visualassessment,quantitative

assessmentusingtumor-to-normal

graymatterratio(T/N)d

Increaseduptake

Normalordecreased

uptake

ND

ND

ND

ND

Baderetal199921

FDG

Visualassessment

ND

ND

–ND

�2

ND

Thompsonetal19922

FDG

ND

ND

ND

–ND

ND

ND


FDG

Visualassessment

Clearlyapparentfocalaccumulation

ofFDG

Nofocallyenhanced

activity

–ND

ND

ND

Pöpperletal200424

FET

QuantitativeassessmentusingSUVmax,

quantitativeassessmentusing

SUVmax/backgroundratioe

––

2.2(SUVmax),2.0(SUVmax/BG)

ND

ND

ND

VanLaereetal200525

FDG,MET

Quantitativeassessmentusingtumor

tocontralateralcorticalbackground

uptakeratio

––

0.8(FDG),2.2(MET)

ND

2ND

Rachingeretal200526

FET

QuantitativeassessmentusingSUVmax

––

2.2

ND

ND

ND

Gómez-Ríoetal200827FDG

Visualassessment

Unexplainablemetabolicactivity,

increasedFDGuptakelesionrelative

toimmediatelyadjacenttissueor

closestadjacentwhitematterin

oneormoretransaxialsections

ND

–ND

ND

ND

Mehrkensetal200828

FET

QuantitativeassessmentusingSUVmax/

backgroundratioe

––

2.0

ND

ND

ND

Terakawaetal200829

MET



SUVmean,quantitativeassessment

usinglesiontonormaltissueratio

(L/N)maxf ,quantitative

assessmentusingL/Nmeanf

––

1.58(L/Nmean)

ND

2Experiencednuclear

medicineradiologists

Nakajimaetal200930

MET

Quantitativeassessmentusingtumor

tonormalgraymatterratio(T/N)

––

2.0

ND

ND

ND

Spenceetal200940

FDG,FLT

Visualassessmentusingagradingscale,


SUVmean,SUVmax;tumortonormal

cortex(T/C)orwhitematterratio

(T/WM)(FDGonly);andkinetic

model(FLTonly)

ND

ND

ND

ND

2Experiencednuclear

medicinespecialists

Jeongetal201031

FLT, FET


quantitativeassessmentusinglesion

tonormalratio(LNR)g

––

Anygrades:0.44(SUVmax,FLT),

1.66(SUVmax,FET);3.0(LNR,FLT),

2.18(LNR,FET),HGG:0.8(SUVmax,

FLT),1.66(SUVmax,FET);3.0

(LNR,FLT),2.46(LNR,FET)

ND

ND

ND

Ozsunaretal201032

FDG

Visualassessment

ND

ND

–ND

2Board-certified

neuroradiologists

Pratetal201033

FDG

Semiquantitativeassessmentcomparing

pathologicimageswiththoseon

thecontralateralsideh

ND

ND

–ND

ND

ND

continued


ON-LINETABLE4,continued

Study

PETDrug

Method

VisualAssessment

Quantitative

Assessment,

CutoffValue

Referent

Baseline

Scan

No.of

Interpreters

Experience

ofInterpreters

PositiveCriteria

NegativeCriteria

Santraetal201241

FDG

Visualassessment

AdefinitelesiononCTimages

(hypermetabolic/iso-metabolic/

hypometaboliconPETimages)oran

increasedfocalFDGuptakewithout

anyclearlydiscerniblelesiononCT

ND

–ND

2Experiencednuclear

medicinephysicians

High-gradeonly

Valketal198834

FDG

Visualassessment

Activitygreaterthanorequaltothat

oftheadjacentbrain

Activitylessthan

thatoftheadjacent

brain

–ND

2ND

VanTasseletal199535

FDG

Visualassessment

Hypermetabolictumor

ND

–ND

ND

ND


MET

Visualassessment,quantitativeassessment

usingSUVmean,quantitativeassessment

usingtumorlesiontonormalratio

(Tmean/Nmean)i

ND

ND

ND

ND

2Experiencednuclear

medicinephysicians

Miyashitaetal200837

BPA

Quantitativeassessmentusinglesionto

normalratio(L/N)j

––

2Performed

partially

ND

ND

Dandoisetal201038

MET

Visualassessment

ND

ND

–ND

ND

Nuclearmedicine

physicians

Kimetal201039

FDG,MET

Visualassessment,quantitativeassessment

usinglesiontoreferencearearatio

(Lmax/Rmax)k

ND

ND

1.45(FDG),2.64(MET)ND

ND

ND

Note:—BPAindicates18F-boronophenylalanine;CAQ,certificateofaddedqualification;ND,nodata;SUV,standarduptakevalue;Lmax,maximumuptakeintumorlesion;R/max,maximumuptakeinreferencearea;LNR,lesiontonormalratio;Tmean,

meanuptakeintumorlesion;Nmean,meanuptakeinnormalbrain;T/N,tumortonormal;BG,background;SUVmax,maximumstandardizeduptakevalue;SUVmean,meanstandardizeduptakevalue;T/WM,tumortowhitematterratio;HGG,high-grade

glioma.

aGrade1�totallyabsent,grade2

�slightlylessuptakethansurroundingarea,grade3

�sameuptakeassurroundingarea,grade4

�slightlytomoderatelyincreaseduptakecomparedwithsurroundingarea,grade5

�markedlyincreaseduptake.

bGrade0

�intensitylessthanthatofwhitematter,grade1�intensitysimilartothatofwhitematter,grade2

�intensitybetweenwhitematterandgraymatter,grade3

�intensitysimilartograymatter,grade4

�intensityhigherthangraymatter.

cGrade0

�noapplicablemetabolicuptake,grade1�similartonormalcontralateralwhitematter,grade2

�betweencontralateralwhitematterandgraymatter,grade3

�equaltoorovergraymatter.

dDifferentialabsorptionratiodefinedastheproductoftissueradioactivityandthepatient’sbodyweightdividedbytheadministeredradioactivityofMETwasusedtoestimateT/Nratio.

eBackground(BG)wasdefinedasthemeanuptakeof70%and80%ofisocontourregionsmirroredtothecontralateral(ie,non-tumor-bearing)hemisphere.

fL/NmeanwasdefinedastheSUVmeanofthelesiondividedbytheSUVmeanofthecontralateralnormalfrontal-lobegraymatter.L/NmaxwasdefinedastheSUVmaxofthelesiondividedbytheSUVmeanofthecontralateralnormalfrontal-lobe

graymatter.

gNormalbrainparenchyma,usuallyinthecontralateralnormalfrontalcerebralcortexwasusedasthereference.

hVisualassessment(inferred).

i Normalgraymatterinthecontralateralfrontallobewasusedasthereference.

j Normalbrainareainthecontralateralbrainlobewasusedasthereference.

kCorrespondingareainthecontralateralbrainlobewasusedasthereference.


ON-LINETABLE5:Qualityassessmentofincludedstudies

Study

12

34

56

78

910

1112

1314

Spectrum

Bias

Inclusion

CriteriaReference

Standard

Partial

Verification

Bias

Differential

Verification

Bias

Incorporation

Bias

Index

TestReference

Standard

Test

Review

Bias

Diagnosis

Review

Bias

Treatment

ParadoxClinical

Data

Uninterpretable

orIntermediate

Results

Withdrawal

Anygrades

Janusetal199316

NY

YY

UY

YY

YU

NY

NN

Kahnetal199417

NY

YY

UY

YY

YY

UY

YN

Nelsonetal199718

NU

NY

UU

YN

UU

UY

YN

Riccietal199819

NY

NN

YY

YY

UU

UY

YY

Sonodaetal199820

NU

YY

UU

YY

UU

UU

NN

Baderetal199921

YU

NY

YY

YY

UU

YU

YN

Thompsonetal19922

NY

NN

YY

NY

UU

UU

NN


NU

UY

UU

YN

YU

UN

YN

Pöpperletal200424

NU

YY

UY

YY

UU

UU

NN

VanLaereetal200525

NU

UY

UU

YN

UU

UU

NY

Rachingeretal200526

NU

YY

YY

YY

UY

UU

NN


YY

YY

UY

YY

UU

UY

NN

Mehrkensetal200828

YY

YY

UY

YY

UY

UY

NN

Terakawaetal200829

NY

YY

UY

YY

UU

YY

NY

Nakajimaetal200930

NU

UY

UU

YN

UU

UY

NN

Spenceetal200940

NY

YY

UY

YY

UU

YU

YN

Jeongetal201031

NY

YY

UY

YY

UU

UY

NN

Ozsunaretal201032

NY

YY

UU

YY

UY

UU

NN

Pratetal201033

NY

YY

UY

NY

UU

UU

NN

Santraetal201241

YY

YY

UY

YY

YU

UN

NN

High-gradeonly

Valketal198834

NY

YY

UU

YY

UU

NU

NN

VanTasseletal199535

NY

NN

YY

NY

UU

UU

NY


NU

YY

UU

YY

UU

UU

NN

Miyashitaetal200837

NU

YY

UY

YY

UU

UY

NN

Dandoisetal201038

NU

NY

UN

YN

UN

YU

NN

Kimetal201039

NY

YY

UY

YY

UU

UY

NN

Note:—Yindicatesyes(relevantinformationreportedorbiasavoided);N,no(relevantinformationnotreportedorbiasnotavoided);U,unclear(insufficientreportingoravoidanceofbiasunclear).


Documents

ON-LINE APPENDIX