Decrease in cerebral metabolic rate of glucose after high-dose methotrexate in childhood acute lymphocytic leukemia

Decrease in Cerebral Metabolic Rate of Glucose After High-dose Methotrexate in Childhood Acute Lymphocytic Leukemia K a z u o K o m a t s u , M D * , G o r o Takada, M D * , K a z u o U e m u r a , M D ~, F u m i o Shishido, MD~, and I w a o K a n n o , PhD+

We measured changes in the regional cerebral metabolic rate of glucose (rCMRGiu) using 18F-fluorodeoxyglucose and positron emission tomography for the assessment of neurotoxicity in childhood acute lymphocytic leukemia treated with high-dose methotrexate (HD-MTX) therapy. We studied 8 children with acute lymphocytic leukemia (mean age: 9.6 years) treated with HD-MTX (200 mg/kg or 2,000 mg/M 2) therapy. CMRGlu after HD-MTX therapy was most reduced (40%) in the patient who had central nervous system leukemia and was treated with the largest total doses of both intrathecai MTX (IT-MTX) and HD-MTX. CMRGlu in the whole brain after HD-MTX therapy was reduced by an average of 21% (P < 0.05). The reductions of CMRGiu in 8 patients were correlated with total doses of both IT-MTX (r = 0.717; P < 0.05) and systemic HD-MTX (r = 0.784; P < 0.05). CMRGlu of the cerebral cortex, especially the frontal and occipital cortex, was reduced more noticeably than that of the basal ganglia and white matter. We suggest that the measurement of changes in rCMRGIu after HD-MTX therapy is useful for detecting accumulated MTX neurotoxicity. K o m a t s u K, T a k a d a G, U e m u r a K, S h i s h i d o F, K a n n o I. D e c r e a s e in c e r e b r a l m e t a b o l i c rate o f g l u c o s e after h i g h d o s e m e t h o t r e x a t e in c h i l d h o o d acute l y m p h o c y t i c leukemia. P e d i a t r Neurol 1990:6:303-6.

Introduction H i g h - d o s e m e t h o t r e x a t e ( H D - M T X ) t h e r a p y is n o w freq u e n t l y used in the treatment o f acute l y m p h o c y t i c leuk e m i a ( A L L ) and o t h e r tumors. H D - M T X t h e r a p y is used not o n l y t b r s y s t e m i c c h e m o t h e r a p y but also for p r e v e n tion of central n e r v o u s s y s t e m ( C N S ) l e u k e m i a b e c a u s e it p r o v i d e s a h i g h c o n c e n t r a t i o n o f M T X in the c e r e b r o s p i n a l fluid (CSF). P r o g n o s i s o f A L L in c h i l d h o o d has i m p r o v e d

From the *Department of Pediatrics; Akita University,: School of Medicine; +Department of Radiology and Nuclear Medicine: Research Institute tbr Brain and Blood Vessels - Akita; Akita. Japan.

r e m a r k a b l y since intrathecal M T X ( I T - M T X ) or H D - M T X t h e r a p y was c o m b i n e d with cranial irradiation for prop h y l a x i s o f C N S l e u k e m i a ; h o w e v e r , I T - M T X or s y s t e m i c H D - M T X , with or w i t h o u t cranial irradiation, c a u s e s neurotoxicity, such as acute e n c e p h a l o p a t h y or c h r o n i c leukoe n c e p h a l o p a t h y [ 1-9]. It r e m a i n s u n k n o w n w h a t m e t a b o l i c c h a n g e s o c c u r in the brain. D e t e c t i o n o f cerebral m e t a b o l i c c h a n g e s b e f o r e i r r e v e r s i b l e n e u r o t o x i c i t y o c c u r s m a y be clinically useful for p r e v e n t i n g e n c e p h a l o p a t h y . To assess the i n f l u e n c e o f H D - M T X on c e r e b r a l m e t a b olism, we m e a s u r e d the regional cerebral m e t a b o l i c rate of g l u c o s e ( r C M R G I u ) q u a n t i t a t i v e l y it~ f i f o , using 18F-fluo r o d e o x y g l u c o s e (I~;F-FDG) a n d p o s i t r o n e m i s s i o n tom o g r a p h y (PET).

Methods Eight children (mean age: 9.6 years) with ALL were studied (Table I). They were divided to standard- and high-risk groups according to age and leukocyte counts at onset of ALL. Three patients in the standard-risk group were treated with MTX 2,000 mg/M 2, wilile the 5 from the high-risk group and bone marrow (BM) relapse were treated with MTX (200 mg/kg). All of the patients were treated with IT-MTX (15 mg/M2/dose) for prophylaxis of CNS leukemia. Patient 8 was frequently treated with IT-MTX because of CNS leukemia. Six received cranial irradiation ( 1,800-2,500 cGy) lor prophylaxis of CNS leukemia. We measured rCMRGIu using I~F-FDG and PET before and after HD-MTX therapy. Total doses of MTX before PET were 11-162 gm. The first measurement of rCMRGlu was obtained 3-4 days before HDMTX therapy. Intervals between the last HD-MTX therapy and the first measurement were 7 days to 3 months. HD-MTX was administered intravenously t~r 24 hours and the second measurement was obtained within 4 hours after MTX administration. Serum sampling also was obtained to assay the MTX concentration just prior to the second measurement. We measured rCMRGIu with the PET instrument HEADTOME 1II developed at the Research Institute of Brain and Blood Vessels - A k i t a , Japan [10]. ISF-FDG was synthesized by the method described by Ido et al. till. rCMRGIu was calculated by the method described by Hutchins et al. [121 and the published rate and lumped constants by Reivich et al. [13]. For each patient, regions of interest were constructed in rCMRGIu functional images referred to radiographic computed tomographic (CT) images using un image analyzer system

Communications should be addressed to: Dn Komatsu; Department of Pediatrics; Akita University: School of Medicine; 1-1-1 Hondo; Akita 010, Japan. Received April 2, 1990; June 4, 1990.

Komatsu et al: Acute Lymphocytic Leukemia 303

Tat)le 1.

Patient clinical characteristics

Patient Number/ Age/Sex

Diagnosis

I / 15/M

High risk, bone marrov, relapse

2/6/F

High risk

3/81F

Standard risk, bone marrow relapse

4/I I/F

High risk

5/8/M

Standard risk

617/M

CNS Prophylaxis Cranial lntratheIrradiacal MTX lion Ic(;yt (mglM 2) 1,800

1,800

Total MTX

Interval Be-

Doses Before

tween Last

PET Study gm gm/M z

HD-MTX and PET Idays)

Doses of MIX During PET gm mgiM z

MTX Concertiration in Plasma During

PET (x l0 5M)

45

10

~-S

(;.I)

4.{~! (i

15

I ~,

,47

l.l

5.3~11}

45

~

180

5.1/

5.tt!~O

I

35

~.0

~.~tll~

- 2 ,)

_t 72

.o~

12

15

~0

33

1,81)0

45

~11

28

2.IJ

!3" III

t).4 1

Standard risk

1.800

45

27

28

I.~

2.000

o.58

7/5/F

Standard risk

1,8(10

45

24

28

1.6

2.~ ~t~ ~

O.(~'J

gll5/F

High risk, CNS leukemia

2,500

151)

162

100

h.{}

~; ~ t

2.32

ah

Abbreviations: CNS = Central nervous system HD = High-dose MTX = Methotrexate PET = Positron emission tomography

(Deanza IE8503). MTX concentration was assayed by the enzymauc method using an MTX assay kit (Lederle Co./. Results

M e a n r C M R G l u v a l u e s of the w h o l e b r a i n b e f o r e and after H D - M T X t h e r a p y were 7.3 + 1.5 a n d 5.8 + 0.6 i m e a n +_ S.E.) m g / 1 0 0 g m / m i n , r e s p e c t i v e l y (Table 2). T h e r e was a statistical d i f f e r e n c e b e t w e e n the 2 v a l u e s by the paired t test ( P < 0.05). C M R G I u o f the w h o l e b r a i n was r e d u c e d b y an a v e r a g e o f 21%. In P a t i e n t 8, w h o w a s treated with the l a r g e s t total d o s e s o f b o t h I T - M T X a n d s y s t e m i c H D M T X a m o n g o u r patients, r C M R G I u w a s m o s t r e d u c e d ( 4 0 % ) , T h e r e d u c t i o n s of C M R G l u in the w h o l e b r a i n were c o r r e l a t e d w i t h the total d o s e s o f b o t h I T - M T X (r = 0 . 7 1 7 / a n d H D - M T X (r = 0.784). T h e r e d u c t i o n s w e r e n o t correlated w i t h e i t h e r a single d o s e o f M T X or a n M T X c o n c e n t r a t i o n o n PET. T h e effect o f H D - M T X t h e r a p y o n r e g i o n a l C M R G I u is listed in T a b l e 3. T h e r e d u c t i o n s o f C M R G I u in the cerebral c o r t e x were g r e a t e r t h a n that in the b a s a l g a n g l i a and w h i t e matter. T h e r e w e r e s i g n i f i c a n t statistical d i f f e r e n c e s in the frontal a n d o c c i p i t a l cortex. T h e t h a l a m u s , frontal w h i t e matter, a n d c e n t r u m s e m i o v a l e w e r e n o t s i g n i f i c a n t ly affected. Discussion

W e h a d also e x p e r i m e n t e d w i t h S p r a g u e - D a w l e y rats a n d h a d m e a s u r e d r C M R G l u after H D - M T X ( 3 0 0 - 6 0 0

304 PEDIATRIC NEUROLOGY

Vol. 6 No. 5

m g / k g ) a d m i n i s t r a t i o n u s i n g J 4 C - d e o x y g l u c o s e a n d an a u t o r a d i o g r a p h i c t e c h n i q u e 115]. C o m p a r e d to the control. r C M R G I u after H D - M T X was r e d u c e d by an a v e r a g e of 30%. In c h i l d h o o d A L L . r C M R G I u after H D - M T X therapy was r e d u c e d b y an a v e r a g e o f 21 ok. M o r e o v e r . the r e d u c tions o f r C M R G l u were c o r r e l a t e d with total d o s e s o f both I T - M T X a n d H D - M T X . O u r results i n d i c a t e t h a t the m o r e total d o s e s o f b o t h I T - M T X a n d H D - M T X increase, the Table 2.

Effect of H D - M T X therapy on C M R G l u in the whole

brain

Patient Number

C M R G i u rmg/lO0 gin/rain) Before After HD-MTX HD-MTX qmean *_ S.E.I qmean ~- S.E.i

Reduclion t% l

I

5.4 L 11.3

5 -~ ~ 0.?

2

'

7.2 + 0 ~

,'U.~Ir 1).2

t~

3

5.7 r 0.2

<.2 ~ 0.2

"

.t

6,.5 _~0.3

5.3 ± 0.2

~1

.~'

-'.3 +. 0.2

<.\~ t 0.3

I',i

h

7.3 ±i).2

< "~t-(/.1

"_2

t ). 9 + (I.

il h {- {l.[

2;4

x

8.{3 + (I.2

q.2 ~ 0.2

a~'i

Mean:

- ~, + i1.~)

-:, s ! 1t.(~

2]

Table 3.

Effect of HD-MTX therapy on rCMRGlu in 8 children w i t h A L L

rCMRGlu (mg/100gin/mira Before HD-MTX

After HD-MTX

(mean _+S.E.)

(mean _+ S.E.t

P Value

7. I + 2. I

5.6 _+ (/.9

< 0.0l

Fronlal

7.5 ± 1,4

5.9 ± (I.6

< 0.01

Temporal

6.3 + 1.4

5.2 _+ 0.6

< 0.05

Parietal

7.8 + 1.5

6.2 ± 0.5

< 0.05

Occipital

6.8 _+ 1.2

5.2 _+ 0.1

< 0.01

Visual

8.6 + 1.5

6.4 _+ 0.5

< 0.01

6.6 _+ 1.5

5.3 + 0.5

< 0.05

Caudate-putamen

7.1 _+ 1.3

5.6 _+ 0.2

< 0.05

Thalamus

6. I + 1.3

4.9 + (I.4

NS

White m a t t e r

4.1 + 0.8

3.4 _+ 0.6

< 0.05

Frontal

4.1 _+ 0.5

3.6 + 0.4

NS

Temporal

4.6 + 0.9

3.7 + 0.5

< 11.(15

Occipital

4.3 + (i).6

3.4 + 0.6

< 0.01

Centare3 s e m i o v a l e

3.5 _+ 0.6

3.1 _+ 0.6

NS

Structure ('erehral cortex

Basal ,,,aHg/ia

Abbreviations: HD-MTX = High-dose methotrexate NS = Not statistically significant SE = S t a n d a r d error

more rCMRGIu after HD-MTX may decrease. We could not find any clinical neurologic abnormalities; electroencephalography was normal. Our results also indicate that the reductions of rCMRGIu after HD-MTX therapy begin to occur in patients who do not yet have any clinical neurologic abnormalities. By the measurement of the rCMRGIu changes, we detected the metabolic changes before irreversible neurotoxicity occurred in patients treated with HD-MTX therapy. These reductions were not correlated with either a single dose of MTX or MTX concentration. There was no dosedependency in reduction of CMRGlu after HD-MTX therapy in the patients or in the animal experiments. Phillips et al. reported that CMRGlu appeared to be more reduced in childhood ALL patients who received both IT-MTX and cranial irradiation than in those receiving IT-MTX alone [14]. Our results demonstrated that the reductions in rCMRGIu after HD-MTX therapy were not correlated with cranial irradiation; however, 2 patients who did not receive cranial irradiation had rather modest reductions in CMRGlu. It may indicate that cranial irradiation enhances lhe reduction of CMRGIu after HD-MTX therapy. MTX is an antimetabolic agent which interferes with folic acid metabolism, inhibiting dihydrofolate reductase,

thus suppressing DNA synthesis. The etiology of neurotoxicity caused by MTX remains unknown. It also remains unclear how MTX influences cerebral metabolism or causes neurotoxicity. Pathologic findings of leukoencephalopathy or necrosis have been reported [2,61. They may correspond to demyelination because of elevation of CSF myelin basic protein [1,3,41. From our results, the reductions of rCMRGlu alter HDMTX therapy were greater in the cerebral cortex rather than in the basal ganglia and white matter: however, the reductions of CMRGlu may not be necessarily associated with demyelination in the white matter. Recently, the relationship between methylation of arginine and phosphorylation of serine has been documented [3] which may influence membrane permeability. Reduced CMRGIu and increased brain capillary permeability were observed following HD-MTX therapy [16]. CMRGIu is calculated from the measurement of the net rote of glucose phosphorylation. We also believe that HD-MTX will reduce glucose phosphorylation and brain capillary permeability. Further PET studies are required to resolve the remaining problems. The interval between the last HD-MTX dose and the first measurement of CMRGlu was variable because of clinical limitations; the last HD-MTX dose may

K o m a t s u et al: A c u t e L y m p h o c y t i c L e u k e m i a

305

influence the first measurement of CMRGIu. A larger group of patients should be studied with the same intervals. Follow-up studies are also necessary to determine whether the reductions of CMRGlu after HD-MTX are transient or sustained. The relationship between HD-MTX and severe neurotoxicity must also be studied. We do not know how many total doses of MTX can be administered safely. In the future, we may be able to prevent irreversible neurotoxicity caused by HD-MTX therapy by determining the threshold value of HD-MTX therapy.

References [1] Packer R.I, Grossman RI, Belasco JB. High dose systemic methotrexate-associated acute neurologic dysfunction. Med Pediatr Oncol 1983;11:159-61. [2] Packer RJ, Grossman RI, Rorke LB, Sutton LN, Siegel KR. Littman P. Brain stem necrosis after preradiation high-dose metho trexate. Childs Nerv Syst 1985; 1:355-8. [3] Neijstrom E, Gabril DA, Capizzi RL. High-dose methotrexateinduced neurotoxicity associated with elevation of CSF myelin basic protein. J Clin Oncol 1985:3:593-4. 14] Mashaly R, Poisson M, Pouillart P, Gardeur D, Koziak M. Transient encephalopathy after local application of methotrexate. Neuroradiology 1985;27:449. [5] Poskitt K J, Steinbok P, Flodmark O. Methotrexate leukoencephalopathy mimicking cerebral abscess on CT brain scan. Childs Nerv Syst 1988;4:119-21. [6] Eyre JA, Gardner-Medwm D, Summerfield GP. Leukoencephalopathy after prophylactic radiation for leukemia in ataxia telangiectasia. Arch Dis Child 1988;63:1079-80.

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[71 Boogerd W. Sande J. Motile D. Acute fever and delayed leukoencephalopathy following low dose intraventricular methotrexate J Neurol Neurosurg Psychiatry 1988:51:1227-83 I81 Asada Y. Kohga S. Sumivoshl A, b,hikawa M. Nakamura H Disseminated n e c r o u z i n g encephalopathv reduced by metholrexate ahmc. Acta Pathol Jpn 1988:38:1305-12 191 Gay ('T. Bodensteinel LB. Nb, chkv R Sexattm C. R.cver,,iNe treatment-related leuk(~encephatopathy. J ('hild Ncurol t 980:4:20.8- I ~. till] K a n n o 1. Miura S. Yamamom S. c~ ,tl. Design anti evaluamm of ~ posnron emis,,lon mmograph: HEADTOME Ill J Comput 4ssb, l Tomogr 1985:0:t)31 _t) 1111 l d o 1. Warm CN. ('asclla V l:o~lv!' IS Wolt AlL Labelled 2 deoxy-i)-glucose analog~ ISF-labelled 2 dcoxy-2-fluoro-l>glucose. ? del~x)-2-fluoro I)-In[lllnOSe alld af'-2-dc~t~xv..2-fluort~-i)-Q.lucose l Labelled Comp Radiopharmaceul 1978:14:175-83 112] H u t c h i n s GD. Holden JE. Koeppc RA. llaiama JR. Gatle~. M. Nickles RJ. Alternative approach to single sc:m estlmaticw +ff cerebral glucose metabolic rate using glucose an:fl%,-,, with parlicular appl cation to ischemia. ! Cereb Blood FIov, Merab 1'984:4:35-4(I 131 Reivich M. Alavi A. Woll X. c< .:i Gluc,~sc metabolic raie kinetic model parammer determinatunl m hunmns The lumped c-ouslants and rale con,~lanls Ior I !~Pifluorode,~xyg lucost, ,l|td I !(,~de(~\ v glucose. J Ccrcb Blood Flow Melab 1985:5:!77-02 14] Phillips PC. Dhaw:m V. JardcN I(). I'halel HI'. Stl'othet St'. Roltenberg DA. Regional cerebral tc2lnt.'t_~,,c metabolism m long-term ~,tir\ ivnrs of childhood acute lymphocytk leukemia. J Cereb Blood Flow Metab lt)85:5:S {)5-6. 1151 Sokoloff L. Smith C. Biocheimcai pilnctples lbr lhe nlea,-,ure menl t~f metabolic rates it1 vlw In: Heis'~ WD. Phelps ME. cos. Positron emission tomography of lhe brain. Berlin: Springer-Vurlag, 1083: 2-18 116] Phillips PC. Dhawan V. Strothci 5( el ak Reduced cerebral gmcose metabolism and increased brain capillary permeability foil.wing hagh-dose methotrexate chemotherapy ~, positron emission tomugraphic study. Ann Neurol 1987;21:59-,53.