Gliomatosis cerebri: clinical, neurochemical and neuroradiological response to temozolomide administration

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Magnetic Resonance Imaging 21 (2003) 1003–1007

Gliomatosis cerebri: clinical, neurochemical and neuroradiological response to temozolomide administration R. Lodia,*, E. Setolab, C. Tonona, P. Ambrosettoc, E. Franceschib, L. Crino`b, B. Barbirolia, P. Cortellid a

Dipartimento di Medicina Clinica e Biotecnologia Applicata “D. Campanacci” Universita` di Bologna, Italy b Divisione di Oncologia Medica, Dipartimento di Oncologia, Ospedale Bellaria, Bologna, Italy c Dipartimento Clinico di Scienze Radiologiche ed Istocitopatologiche, Universita` di Bologna, Bologna, Italy d Dipartimento di Scienze Neurologiche, Universita` di Modena, Italy

Abstract Gliomatosis cerebri is a rare form of diffusely infiltrating glioma that is typically resistant to conventional chemotherapy and radiation therapy and carries a poor prognosis. Temozolomide has shown antineoplastic activity against malignant gliomas and more recently was beneficial in one patient with gliomatosis cerebri. To make an objective assessment of the effect of long-term temozolomide administration in a patient with gliomatosis cerebri we used brain proton magnetic resonance spectroscopy and structural MRI. A 46-year-old man with gliomatosis cerebri was treated with temozolomide (200 mg/m2 per day for 5 days every 28 days). Twenty cycles of temozolomide resulted in a marked reduction in choline and scyllo-inositol content, as detected using brain proton MR spectroscopy, indicating reduced tumor cellularity and/or growth rate. Neurochemical improvements were associated with normalization of the signal intensity in most of the previously affected cerebral regions and regression of mass effect on MRI. A left pyramidal syndrome, present at the start of the treatment, disappeared. Our observation lends support to larger clinical trials evaluating the use of temozolomide to treat this brain tumor. © 2003 Elsevier Inc. All rights reserved. Keywords: Gliomatosis cerebri; Temozolomide; Proton MR spectroscopy

1. Introduction Glimatosis cerebri is a rare form [1] of diffusely infiltrating glioma involving multiple brain areas [2] with the highest incidence in the second and fifth decades [3]. Histologically, it is characterized by a diffuse proliferation of neoplastic glial cells infiltrating normal nervous tissue where destruction of myelin sheaths may be associated with only slight damage to neurons and axons [2]. No definite treatment has been proven to be effective in gliomatosis cerebri [4-9]. Proton MR spectroscopy (1H-MRS), which provides non invasive in vivo biochemical assay of tissue in selected regions of the brain, is a valuable tool in the diagnosis and management of human intracranial glioma [10,11]. A typical feature of neoplastic lesions is an increase in the choline (Cho) signal intensity which is a reliable indicator of tumor * Corresponding author. Tel.: ⫹39-051-305993; fax: ⫹39-051303962. E-mail address: [email protected] (R. Lodi). 0730-725X/03/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0730-725X(03)00214-5

metabolic activity [10]. Longitudinal studies have shown that effective treatment is associated with a decrease in choline peak whereas choline increase is an index of post therapeutic tumor recurrence and progression [12-14]. We report the second case of gliomatosis cerebri who responded to chemotherapy with temozolomide, a secondgeneration alkylating drug which has shown antineoplastic activity against malignant gliomas [15]. The effect of temozolomide administration was monitored for 20 months using MRI and quantified by proton MR spectroscopy (1H-MRS).

2. Case report and methods A 46-year-old Italian man, with a negative medical history, complained of sudden tinnitus in the left ear three months before our observation. In February 1998, he was admitted to our hospital and the general physical and neurologic examination were within normal limits. Brain MRI showed extensive areas of heterogeneous hyperintensity on T2-weighted images, affecting the cortex and white matter

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Fig. 1. Brain MR spectroscopy and imaging. A (upper panels). Proton magnetic resonance spectra (repetition time, TR ⫽ 1500 ms; echo time, TE ⫽ 136 ms) collected in the right parietal white matter before treatment and after 3, 7 and 20 courses of temozolomide. NAA ⫽ N-acetyl-aspartate, Cr ⫽ creatine, Cho ⫽ choline, s-I ⫽ scyllo-inositol, Lac ⫽ lactate. B (middle and lower panels). Axial MR T2- weighetd fast spin-echo images (TR ⫽ 4000 ms, TE ⫽ 80 ms) collected at the same time points as MR spectroscopy.

of the right temporal-parietal-occipital region. Histologic examination of a stereotaxic brain biopsy was, as it is often the case in gliomatosis cerebri, not conclusive for neoplastic process [16]. The longitudinal MRI (Fig. 1B) and clinical findings excluded other brain disorders such as leukoencephalopathy, multiple sclerosis, progressive multifocal leukoencephalopathy, ischemic changes and led to the final diagnosis of gliomatosis cerebri [2]. In March 1999, the patient presented a left pyramidal syndrome at neurologic examination, that persisted in January 2000, when he underwent the first 1H-MRS in association with MRI. In March 2000, he developed partial infrequent secondarily generalized epileptic seizures and in July, recurrent headache attacks. Phenytoin administration was then started. A second 1H-MRS/MRI study was performed in July 2000. A few days later he was admitted for severe headache, vomiting and alteration of mental status followed by coma.

Administration of high doses of steroids reversed the clinical status but not the neuroradiological picture. Therefore treatment with temozolomide (200 mg/m2 per day for 5 days, every 28 days) was started. Four milligrams of dexamethasone per day were given during the five days of temozolomide administration and every other day in between temozolomide cycles. Administration of corticosteroids was stopped after the 18th cycle of temozolomide. Combined 1H-MRS/MRI were repeated after 3, 7, 16, 20 temozolomide courses. MR spectroscopy and imaging studies were performed in a 1.5T General Electrics Medical Systems (Milwaukee, Wisconsin) Signa Horizon LX whole-body scanner using a 25 cm diameter quadrature birdcage head coil. Proton MR spectra were acquired using the PRESS single voxel localization sequence (echo time, TE ⫽ 136 ms and repetition time, TR ⫽ 1500 ms on a voxel of 2 ⫻ 2 ⫻ 2 cm). Voxels

R. Lodi et al. / Magnetic Resonance Imaging 21 (2003) 1003–1007

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Fig. 2. Brain metabolite changes with temozolamide administration. Time course changes in brain choline (Cho) (left panel) and scyllo-inositol (s-I) content (relative to creatine, Cr) (right panel) expressed as percentage of the levels measured in the first of the two pre-temozolomide 1H-MRS scans. The second 1 H-MRS pre-therapy study was performed 6 months after the first. 1H-MRS data were obtained in the right frontal (䊐) and right (}) and left (F) parietal white matter (WM).

were placed in the right parietal and frontal lobe white matter (WM) and in the left parietal lobe WM. Peak area for N-acetylaspartate (NAA) at 2.02 ppm, for creatine-phosphocreatine (Cr) at 3.03 ppm, for choline (Cho) at 3.22 and for scyllo-inositol (s-I) at 3.35 were calculated using the time domain fitting program AMARES/ MRUI (http://carbon.uab.es/mrui). Peak integral values were expressed relative to the Cr peak. Six healthy males (age range 44-48 years) were also studied. Axial MRI T2weighted fast spin-echo images (TR ⫽ 4000 ms, TE ⫽ 80 ms) were also collected at the same time points as MR spectroscopy.

3. Results Fig. 1 shows the 1H-MR spectrum collected in the right parietal white matter (WM) (A) and the axial MRI scans (B) 7 months before starting temozolomide administration. In the patient, Cho to Cr ratio was above the normal range (0.75-0.95) in the three white matter (WM) areas studied (1.10 in right parietal, 1.04 in left parietal and 1.20 in right frontal). Similarly, patient’s s-I/Cr was above the normal range (0.02-0.13) in the right (0.62) and left parietal (0.52) and right frontal WM (0.34), whereas the patient’s NAA/Cr was below the normal range (1.83-2.36) in the same brain areas (1.65, 1.53 and 1.48). MRI (Fig. 1B) showed an extensive area of hyperintensity affecting both hemispheres and compression of the right lateral ventricle with transtentorial uncal herniation compressing the right peduncle. The second 1H-MRS scan performed one week before the start of temozolomide administration showed Cho and s-I to Cr ratios further increased in most of the examined brain areas of the patient (Fig. 2) whereas NAA/Cr was unchanged (data not shown). MRI showed increased compression of the right peduncle by trans-tentorial uncal herniation

(not shown). After only three courses of temozolomide there was a substantial reduction in Cho/Cr in examined WM areas associated with a striking reduction in s-I/Cr (Fig. 1A and Fig. 2). Biochemical changes were associated with marked neuroradiological improvement with normalization of the increased signal intensity in most of the previously affected cerebral regions, and disappearance of the uncal herniation. A further reduction in Cho and s-I to Cr ratios was observed in the following 1H-MRS studies performed after 7, 16 and 20 cycles of temozolomide (Fig. 2). Cho/Cr and s-I/Cr after 20 cycles of chemotherapy were within normal range in all brain areas examined. Lactate (resonance frequency ⫽ 1.33 ppm) exhibits a typical phase reversal at 136 ms TE. We found a small though abnormal amount of lactate before temozolomide in the WM of our patient which was further increased after three cycles of the drug (Fig. 1A). After 7 cycles lactate signal was at the background level as well as after 16 and 20 cycles. Temozolomide administration did not result in any substantial change in NAA/Cr (data not shown). MRI repeated after 7, 16, and 20 (Fig. 1B) cycles showed progressive reduction of brain abnormalities. Only minor ventricular enlargements persisted, mainly in the right ventricular horn (Fig. 1B). The left pyramidal syndrome disappeared after 16 cycles of temozolomide. No side effects were reported over the period of treatment.

4. Discussion Although radiation therapy and different chemotherapy regimens have been attempted [1,6-9] the prognosis of gliomatosis cerebri is still poor. In the present follow-up study we found a sustained improvement of clinical, neurochemical and neuroradiological findings in a patient with glio-

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matosis cerebri who was treated with 20 cycles of temozolomide. Temozolomide is an orally administered second-generation imidazotetrazine prodrug that undergoes spontaneous conversion to the active alkylating agent and penetrates the blood-brain barrier [17]. It has been used in the treatment of primary malignant brain tumors including glioblastoma multiforme [18], anaplastic astrocytoma [19] and oligodendroglioma [20]. In these malignant brain tumors monotherapy with temozolomide has demonstrated a low toxicity associated with evidence of radiologic tumor regression, improved quality of life and survival [15]. In our patient, after three months of therapy, a marked MRI improvement was associated with a striking reduction in choline and scyllo-inositol peaks-both above the normal range before therapy-in all the white matter areas examined (Figs. 1 and 2). High choline peak is a 1H-MRS marker of neoplastic lesions, including gliomatosis cerebri [10]. Increased tumor cellularity and high cell membrane turnover in neoplastic tissue have been indicated as the pathologic substrate responsible for increased choline peak in tumors. Increased s-I content has often been reported in association with high choline in proliferative processes in both human [21,22] and experimental [23] gliomas. A reduction in choline and s-I peaks is hence a specific biochemical marker indicating reduced tumor cellularity and/or growth rate in our patient. Increased lactate before and after three cycles of temozolomide and its disappearance from the seventh cycle, indicates that lactate is produced by the damaged drugsensitive cells. It is tempting to speculate that this finding is early indirect evidence for the positive effect of temozolomide treatment. After 16 cycles of temozolomide administration, our patient showed disappearance of the left hemiparesis. After 20 cycles neurologic, spectroscopic and MRI improvements were sustained. Our MRS/I and clinical findings confirm, for a longer period of follow-up, the results reported by Benjelloun et al. in a patient with grade II astrocytoma gliomatosis cerebri [24]. Five months of temozolomide administration given using the same protocol as ours, resulted in disappearance of the pre-chemotherapy neurologic dysfunctions and in marked improvement on both 1H-MRS and MRI. They administered 12 cycles of temozolomide: MRI changes were sustained after ten cycles and clinical regression after twelve. Although no MRS quantitative spectral data were provided in Benjelloun’s study, the only 1H-MRS scan performed after five cycles, showed a clear reduction in the choline peak as in our patient. A reduction in s-I peak is also evident in the spectra reported by the authors [24]. In conclusion, we observed the second patient with gliomatosis cerebri responsive to temozolomide administration. Our and Benjelloun’s [24] reports call for larger clinical trials evaluating temozolomide in the treatment of gliomatosis cerebri.

Acknowledgments This work was supported by Fondazione Cassa di Risparmio in Bologna and Progetto Pluriennale di Ricerca E.F. 2000. The MR scans were performed at “Servizio di Risonanza Magnetica” Azienda Ospedaliera di Bologna S.Orsola-Malpighi.

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