The Egyptian Journal of Radiology and Nuclear Medicine (2013) 44, 885–891

Egyptian Society of Radiology and Nuclear Medicine

The Egyptian Journal of Radiology andNuclearMedicine

www.elsevier.com/locate/ejrnmwww.sciencedirect.com

ORIGINAL ARTICLE

Proton magnetic resonance spectroscopy

predicts concurrent chemoradiotherapy response

and time-to-progression in high-grade gliomas after

surgery

* Corresponding author. Tel.: +20 1224351806.E-mail address: lamissmohamed2@yahoo.com (L.M. sad).

Peer review under responsibility of Egyptian Society of Radiology and

Nuclear Medicine.

Production and hosting by Elsevier

0378-603X � 2013 Production and hosting by Elsevier B.V. on behalf of Egyptian Society of Radiology and Nuclear Medicine.

http://dx.doi.org/10.1016/j.ejrnm.2013.09.008

Lamiss Mohamed sad a,*, Manal Hamisa b

a Clinical Oncology Department, Tanta University, Cairo, Egyptb Radiology Department, Tanta University, Cairo, Egypt

Received 20 July 2013; accepted 14 September 2013Available online 11 October 2013

KEYWORDS

H-MRS;

Concurrent chemoradiother-

apy response;

High-grade gliomas

Abstract Introduction: Reliable early prediction response to therapy and time-to progression

(TTP) remains an important goal of High-grade glioma (HGG) research. Proton magnetic reso-

nance spectroscopy (H-MRS) has been applied with variable success in clinical application, and

we hypothesize that 1H-MRS in predictive value should perform well as a marker of TTP in

patients treated with concomitant chemoradiotherapy (CRT) after surgery

Methods: (1)H-MRS was performed before surgery on 25 patients who had undergone resection of

HGGs and fulfilled the inclusion criteria from 43 patients; then the ratios of lipid/creatine (Lip/Cr)

and myoinositol/creatine (mI/Cr) were determined in the solid tumor. CRT response was classified

as follows: complete resolution (CR), partial response (PR), stable disease (SD), and progressive

disease (PD) by comparison of pre-treatment and post-radiotherapy scans. TTP was defined at

the time to radiographic progression by MacDonald criteria. Correlation was evaluated between

the ratios of Lip/Cr, mI/Cr and treatment response, TTP. The chi-square test and Pearson correla-

tion test were used for data analyses.

Results: Multivariate analysis revealed that the prognostic value of spectroscopic variables was

independent of age, sex, WHO histologic grade, extent of surgery, and Karnofsky score (KPS).

The correlation between the ratios of lipid/Cr and TTP was significant (r = 0.894, P = 0.000),

886 L.M. sad, M. Hamisa

and between the ratios of mI/Cr and TTP was also significant (r = 0.891, P = 0.000). As predicted,

RT response correlated significantly with TTP (r = 0.59, P = 0.002): median TTP was 49.9 days

for patients with PD compared with 202.7 days for SD, 208.0 days for PR, and 234.5 days for CR.

Conclusion: The ratios of Lip/Cr and mI/Cr of the solid tumor region before surgery could provide

important information in predicting CRT response and TTP in patients with HGGs treated by con-

current chemoradiation after surgery.

� 2013 Production and hosting by Elsevier B.V. on behalf of Egyptian Society of Radiology and Nuclear

Medicine.

1. Introduction

The incidence of primary brain tumors has increased dramati-

cally over the past several decades. The term high grade gliomas(HGG), is usually used to describe HO grade III and IV tumors.Of these, glioblastomas account for 60–70%, anaplastic astrocy-

tomas for 10–15%, anaplastic oligodendrogliomas and anaplas-tic oligoastrocytomas for about 10%, while anaplasticependymoma and anaplastic gangliogliomamake up the rest (1).

Despite aggressive treatment and research for over half acentury, survival for most patients is less than 18 months (2).

Radiotherapy (RT) remains the main adjuvant treatmentafter surgical resection worldwide, despite significant morbidity

including memory impairment, personality change and cogni-tive decline in as much as two thirds of long-term survivors (3).

Trials of systemic chemotherapy provided mixed results but

overall were disappointing (4,5). However, the introduction oftemozolomide (TMZ) in the setting of newly-diagnosed GBMand anaplastic astrocytoma has made a substantial impact in

the treatment of this disease (6,7).Preliminary reports have shown that functional magnetic

resonance imaging (fMRI) techniques, such as diffusion

weighted imaging (DWI), perfusion weighted imaging (PWI),and proton magnetic resonance spectroscopy (1H-MRS), yieldstructural and metabolic information that may provide betterinsight into tumor functionality and improve the prognostic

stratification of HGG (8). Several studies have evaluated someparticular resonances of the spectrum and have found them tobe useful for predicting patient outcome in gliomas (9–11). Oh

et al. (12) found a significantly shorter median survival time forpatients with a large volume of metabolic abnormality, mea-sured by 1H-MRS. Majos et al. (13) demonstrated an inverse

correlation between resonance intensities in these regions atboth short echo time (STE) and patient survival (a high-inten-sity value of the peaks of lipid (Lip) and myo-inositol (mI) cor-

relates with low survival), and a direct correlation between mIand patient survival (a high-intensity value of the peak of mIcorrelates with high survival). However, there are no reportson the relation between the ratios of Lip/Cr or mI/Cr and

RT response, time-to-progression (TTP).The purpose of this study was to determine which of the ra-

tios, Lip/Cr or mI/creatine (Cr), was the most relevant for pre-

dicting CRT response and TTP in HGG after surgery and toanalyze the potential of 1H-MRS for discriminating patientswith good or poor prognosis.

2. Patients and treatment

A total of 43 consecutive patients with HGG who underwent

1H-MRS between April 2012 and April 2013 were enrolled forthe study. In some of the patients, the spectrum was considered

to be of poor quality and these patients were excluded. Finally,the definitive dataset of the study included 25 patients. A total of

25 patients with HGG, glioblastoma multiform (n = 19) andanaplastic astrocytoma (n= 6), who underwent subtotal or to-tal resection, were recruited to participate to test the efficacy of

1H-MRS for the assessment of concurrent chemoradiotherapyresponse. Patients with histologically confirmed HGG whohad not received any prior therapy, and who had undergoneimmediate postoperative computed tomography (CT) or MRI

within 24 h of surgery to assess the extent of resection were in-cluded. All patients were treated with fractionated RT in dailydoses of 2 Gy to a total of 56–60 Gy with concurrent timodal

50mgm daily. Patients received timodal concurrent with radio-therapy in dose of 100 mgm half an hour prior to radiotherapy.They underwent 1H-MRS at the time ofMRI before concurrent

CRT. MRI was performed at follow-up to determine CRT re-sponse 4 weeks after completion of the therapy. The patientswere subsequently assessed by their neuro-oncologist at 2-month intervals according to the local standard of care (See

Case numbers 1 and 2).

2.1. Image acquisition

Data were acquired with a 1.5 T MR imaging scanner (GE –high signa). Single-voxel 1H-MRS was performed as the lastsequence of the MR imaging examination. A volume of inter-

est (VOI) between 1.5 and 2.0 cm3 was placed for performing1H-MRS in HGG. Specifically, the VOI location and size weredetermined with the aim of positioning the largest possible

voxel within the solid brain mass, with minimal contaminationfrom the surrounding non-affected tissue or from non-enhanc-ing areas of the tumor, when possible. One spectrum was ac-quired from the VOI: STE (TR/TE, 1500/35) (Case 3).

A spectrum was considered to be of poor quality when largepeak line width, poor signal intensity-to-noise ratio, or obviousartifacts precluded precise quantification of some areas of the

spectrum.

2.2. Response assessment

Radiological assessment of response was carried out accordingto the current World Health Organization (WHO) 2000 modi-fied MacDonald criteria change in maximal perpendicular tu-

mor diameters 3 months after the conclusion of a therapeuticprotocol as follows: (14–16) complete response (CR) is definedas complete disappearance of abnormal contrast enhancementin a patient not on steroids at the time of MRI; partial response

(PR) refers to a >50% decrease in volume measure of enhanc-ing abnormality onMRI performedmore than 4 weeks after theend of therapy in a patient on a stable or decreased steroid doses;

MRI after surgery showed space occupying lesion 2x3x4cm, choline /NAA ratio=1.8; myoinostol /NAA ratio=1.8:the sum of two ratios =2.9:cholin/creatine ratio=3.2___showed marked regression of previously detected mass.

MRI----Post concurrent chemoradiotherapy showed cystic lesion by complementary MRSCholine /NAA ratio=2 ; myoinostol /NAA ratio=1.8:the sum of two ratios =3.8 ; choline/creatine ratio=1.2-------compatible with radiation necrosis

Case number 1 A 52-year-old man treated for a glioblastoma multiforme by standard fractionated RT (total dose, 60 Gy) with

concurrent chemotherapy(timodal) with no progression.

Proton magnetic resonance spectroscopy predicts concurrent chemoradiotherapy response 887

stable disease (SD) refers to no change in volume of abnormalenhancement or a change that does not meet PR or PD criteria

(<50%decrease or<25% increase) in a patient on stable or de-creased steroid dose; and progressive disease (PD) refers to a>25% increase in volume measure of enhancing abnormality

in a patient on a stable or increased steroid dose. Patients wereclassified as responders (CR and PR) or non-responders (SD

or PD) by comparison of post-treatment images to the pre-con-current chemoradiotherapy (baseline) MRI images (17). TTPwas defined as the time from diagnosis to recurrence.

Post fractionated radiotherapy with concomitant timodal ----MRI with MRS ---- choline/NAA=1.8 (more than 1.9 malignant tumor), myoinsoitol/NAA=1.1, the sum of two ratios=2.9, choline/creatine=3.2---- finding are constant with marked regression of previously detected.

Follow up after 6 months from end of concomitant chemoradiotherapy ------------- choline/NAA=1.8 (more than 1.9 malignant tumor) , myoinsoitol/NAA=1.1, the sum of two ratios=2.9, choline/creatine=0.9---- finding are constant with radiation necrosis

Case number 2 Male patient aged 42 years with anaplastic astrocytoma ——————— postoperative status ——MRI with MRS——

choline/NAAA = 2.9 (more than 1.9 malignant tumor), myoinositol/NAA = 0.2, the sum of two ratios = 3.1, choline/creatine = 2.5

—— finding are constant with residual/RECCURRENCE TUMOR.

888 L.M. sad, M. Hamisa

2.3. Statistical analysis

Prognostic variables evaluated were both clinical (age, sex,

WHO grade, Karnofsky score (KPS), and extent of surgery)

and spectroscopic (the ratios of Lip/Cr, mI/Cr). The statisticalsignificance of the differences in the ratios of Lip/Cr, mI/Cr be-

tween response groups was analyzed using c2 test. The correla-tion of ratios of Lip/Cr, mI/Cr with TTP was evaluated by

Post fractionated radiotherapy with concomitant timodal ----MRI with MRS ---- choline/NAA=2.5 (more than 1.9 malignant tumor), myoinsoitol/NAA=1.1, the sum of two ratios=2.9, choline/creatine=3.2---- finding are constant with marked progression of previously detected.

Figure A before treatment MRI with MRS ---- choline/NAAA=2.9 (more than 1.9 malignant tumor), myoinsoitol/NAA=0.2, the sum of two ratios=3.1, choline/creatine=2.5---- finding are constient with residual /RECCURRENCE TUMOR

Case 3 Representative STE spectra from PD group to RT. A 42-year-old man treated for an anaplastic astrocytoma by standard

fractionated RT (total dose, 60 Gy) with TTP of 64 days. The main significant differences are seen in the Lip and mI region.

Proton magnetic resonance spectroscopy predicts concurrent chemoradiotherapy response 889

Pearson correlation test. The association between CRT re-sponse and median TTP was evaluated with log-rank tests.

Kaplan–Meier curves were constructed by defining TTP asthe time from the initial surgical diagnosis to the time of tumorprogression. For all statistical tests, a P value less than 0.05

was considered to indicate statistical significance.

3. Results

A total of 25 patients fulfilled the inclusion criteria and wereretained in the study. Multivariate analysis revealed that theprognostic value of spectroscopic variables was independentof age, sex, WHO histologic grade, extent of surgery, and

KPS (Table 1).

The dataset of 25 patients included four groups, and the ra-tios of Lip/Cr, mI/Cr, TTP and the correlation are shown in

Table 2.The correlation between the ratios of lipid/Cr of each group

and TTP was significant (r = 0.894, P = 0.000), and that be-

tween the ratios of mI/Cr of each group and TTP was also sig-nificant (r= 0.891, P = 0.000).

As expected, CRT response correlated significantly withTTP (r= 0.590, P = 0.002). The log-rank test and Kaplan–

Meier curves revealed that patients with PD had a shortermedian TTP (49.9 days) compared with those with CR(234.5 days). TTP was also significantly longer in the PR group

(208.0 days) and SD group (202.7 days) than the PD group,but not quite as long as in the CR group. After concurrent

Table 1 Patient data and prognostic factors in 25 patients

with HGG.

Prognostic factors TTP (days)

Age

� <50 (n= 10) 183.40 (114.0–256.32)

� >50(n = 15) 143.27 (96.54–192.93)

Sex

� Male (n= 16) 171.69 (122.11–219.11)

� Female (n = 9) 137.33 (72.01–223.43)

WHO grade

� Anplastic astrocytoma (n= 6) 164.63 (115.05–217.20)

� Glioblastoma multiforme (n= 19) 144.67 (63.83–225.84)

Performance status

� 0–1(n = 14) 174.59 (117.84–269.87)

� 2 (n= 11) 134.56 (69.45–215.76)

Extent of surgery

� Partial resection (n= 19) 142.50 (85.75–193.73)

� Complete resection (n= 6) 164.63 (115.05–217.20)

890 L.M. sad, M. Hamisa

chemoradiotherapy case 1 showed radiation necrosis withMRS. case 2 showed residual or recurrrence with MRs.MRS

in case 3 showed progressive disease.

4. Discussion

It is important to identify responsive patients with HGG whocan take advantage of intensive treatments and non-responsiveones for whom conservative support treatment is a choice. His-

topathology remains the reference standard for prognosticassessment, providing an insight into the morphologic cyto-structure of the tumor (18). Nevertheless, histopathology has

its limitations in providing prognostic value, and additionalfactors have been defined for stratifying patients into diverseprognostic groups. A recursive partitioning analysis under-taken by the Radiation Therapy Oncology Group identified

four risk classes for glioblastoma based on patient age, KPS,neurologic function, mental status, and extent of surgery(19,20). These items provide a prognostic assessment based

on factors related to patient status and effectiveness of the sur-gical approach. Nevertheless, several researchers suggestedthat there might be some metabolic information in tumors that

Table 2 Results of Lip/Cr and mI/Cr in each group, and the corre

Groups NI (mean) TTP

Responsive

� CR (n= 4) Lip/Cr = 0.327 234.

� PR (n= 3) Lip/Cr = 0.351 225.

Non responsive group

� SD (n= 10) Lip/Cr = 0.4187 197.

� DP(n= 8) Lip/Cr = 0.434 49.8

Responsive group

� CR(n= 4) mI/Cr = 0.123 234.

� PR(n= 3) mI/Cr = 0.096 225.

Non responsive group

� SD(n=) mI/Cr = 0.085 197.

� DP(n=) mI/Cr = 0.073 49.8

Significant differences were found between groups.

could help in specifying the prognosis of HGG and that thisinformation could be assessed in a non-invasive way by 1H-MRS (14,20).

Our study has shown that the information provided by 1H-MRS may be of help in the prognostic assessment of patients,and we found two regions of the spectrum that have prognostic

value. The regions corresponding to lipids and mI, and thesespectroscopy points offer the opportunity to formulate ratiosbetween metabolites at STE to be used in a clinical setting.

Using ratios would have the advantage of producing a straightforward quantitative assessment of the spectrum that wouldnot require any additional normalization procedure.

Our study demonstrates that there is an inverse correlation

between ratios of lipid/Cr at STE and patient TTP, and fur-thermore, a direct correlation between ratios of mI/Cr atSTE and patient TTP.

Prior studies showed some prognostic value of the majorresonances of the spectrum, such as choline-containing com-pounds, N-acetylaspartate, creatine, lipids, and lactate

(11,12). The methodology used in our study provided theopportunity to detect differences in the area around mI, notevaluated in previous studies.

Limitations of our study include the limited number of pa-tients, and more data should be acquired. Since 1H-MRS canbe readily performed on most modern scanners in a short time,without added risk or use of contrast, this could be of signifi-

cant benefit in monitoring patients who are responding welland selecting patients who are not responding well to receiveadditional chemotherapy or supplementary stereotactic

radiation.In our study, we tried to define the relevant value of 1H-

MRS in HGG patients only with surgery and CRT for a prog-

nostic assessment. We found that the ratios of Lip/Cr, mI/Crat STE provided relevant prognostic information, and may of-fer an early marker of treatment response. This predictive va-

lue of 1H-MRS concerning TTP could be very useful forevaluating whether intensive oncologic therapy is necessaryin some patients.

Conflict of interest

No potential conflicts of intersets were disclosed.

lation among Lip/Cr, mI/Cr and TTP.

(mean) Correlation coefficient P values

50 0.894 0.000

33

00

8

0.891 0.000

50

33

00

8

Proton magnetic resonance spectroscopy predicts concurrent chemoradiotherapy response 891

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