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Bevacizumab as salvage therapy for progressive brain stem gliomas
Clinical Neurology and Neurosurgery 115 (2013) 165–169
Contents lists available at SciVerse ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Bevacizumab as salvage therapy for progressive brain stem gliomas T. Reithmeier a,∗ , W.O. Contreras Lopez a , T.S. Spehl b , T. Nguyen c , I. Mader c , G. Nikkhah a , M.O. Pinsker a a
Department of Neurosurgery, Division of Stereotactic and Functional Neurosurgery, University Medical Center Freiburg, Breisacher Str. 64, 79106 Freiburg im Breisgau, Germany Department of Nuclear Medicine, University Medical Center Freiburg, Breisacher Str. 64, 79106 Freiburg im Breisgau, Germany c Department of Neuroradiology, University Medical Center Freiburg, Breisacher Str. 64, 79106 Freiburg im Breisgau, Germany b
a r t i c l e
i n f o
Article history: Received 13 March 2012 Received in revised form 17 April 2012 Accepted 30 April 2012 Available online 29 May 2012 Keywords: Brain stem glioma Bevacizumab Positron emission tomography
a b s t r a c t Objective: There is no standard of care for patients with progredient brain stem gliomas. Therefore, we report about clinical, radiological and metabolic response to anti-angiogenic treatment with bevacizumab in a series of 3 patients with gliomas involving the brain stem. Patients and methods: Three patients with histologically confirmed gliomas involving the brain stem were treated with bevacizumab for tumor progression. The clinical data, histopathological findings as well as MRI and PET follow up examinations during bevacizumab therapy were retrospectively analyzed. Results: The histopathological diagnosis revealed an anaplastic astrocytoma WHO grade III in two patients and an astrocytoma WHO grade II in 1 patients with clinical and neuroradiological signs of malignization. One patient is still progression-free 97 weeks after initiation of bevacizumab therapy. Mean progressionfree survival and overall survival for the other two patients after initiation of bevacizumab therapy was 34.5 weeks and 43.5 weeks. During bevacizumab therapy mean KPS improved from 60 to 80 and mean dosage of daily dexamathasone was reduced from 7.3 mg to 1.3 mg. MRI showed a decrease of T2 weighted hyperintense lesions in all patients and a decrease of contrast enhancement in two patients. 18 F-FET-PET showed a decrease of tracer uptake in all cases (mean maximum decrease: 25%). Conclusion: In this series treatment of progressive gliomas involving the brain stem with bevacizumab resulted in an improved clinical condition of the patients as well as a reduction of the T2 weighted lesions and reduced amino acid uptake in the tumor area. It therefore may represent a therapeutic salvage option for this type of tumor. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Adult brain stem gliomas are a rare tumor entity accounting for 1.5–2.5% of all intracranial tumors. Therapeutic options for intrinsic brain stem gliomas are limited, mainly consisting of radiotherapy with an undefined role of chemotherapy and no standard of care for patient with recurrent brain stem tumors. Recently two case reports about successful treatment of a progressive diffuse brain stem glioma with bevacizumab with or without irinotecan have been published [1,2]. Therefore we retrospectively analyzed a series of three patients with histological confirmed gliomas involving the brain stem treated with bevacizumab alone as a salvage therapy and report here the clinical, radiological and metabolic findings. 2. Patients and methods We performed a retrospective review of the MS ACCESS database of our department and identified three patients with the
∗ Corresponding author. Tel.: +49 0761 270 93210; fax: +49 0 761 270 50100. E-mail address: [email protected] (T. Reithmeier). 0303-8467/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2012.04.027
histopathologically confirmed diagnosis of a glioma with involvement of the brain stem who were treated with bevacizumab as a salvage therapy for tumor progression. The positive experience with bevacizumab therapy in one of these patients was already published as a case report by the author [2]. The patients’ records, histopathological findings and the radiological and metabolic follow-up examinations during bevacizumab therapy were reexamined. There were two female and one male patient with a mean age of 36 years (range: 32–39 years) at first diagnosis of a glioma. Initial symptoms consisted of gait disturbance, headache, progressive eye deviation, nausea and dizziness. Mean duration from start of symptoms until diagnosis was 6 months (range: 3–9 months). Initial MRI evaluation with T1 weighted sequences after gadolinium and T2 weighted sequences showed a lesion with involvement of the brain stem in all cases. Histopathological diagnosis was confirmed by frame based stereotactic serial biopsy and revealed an anaplastic astrocytoma grade III in two patients (one patient with a primary grade III tumor, one patient showed upgrading from a grade II to a grade III tumor after a second stereotactic biopsy) and an astrocytoma grade II in 1 patient. Treatment before initiation of anti-angiogenic therapy with bevacizumab consisted of interstitial radiosurgery, external fractionated radiation therapy
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T. Reithmeier et al. / Clinical Neurology and Neurosurgery 115 (2013) 165–169
Table 1 Summary of therapeutic procedures for patients with progressive brain stem gliomas.
Operative procedure Stereotactic biopsy Chemotherapy Temozolomide (5/23) Temozolomide (7/7) CCNU BCNU Bevacizumab Radiation therapy Interstitial radiosurgery External beam radiation
Case 1
Case 2
Case 3
Yes
Yes
Yes
No 1 cycle No No 32 cycles
Yes 4 cycles No 1 cycle 7 cycles
Yes 3 cycles 1 cycle No 8 cycles
No Yes
Yes Yes
No Yes
and various chemotherapies (for details see Table 1). Bevacizumab in a dosage of 10 mg/kg was administered as salvage therapy biweekly and intravenously under antiallergic prophylaxis. A complete blood count was obtained weekly. Urinanalysis, evaluation of cardiovascular parameters and a cranial CT or MRI examination to rule out intratumoral bleeding were performed every 2 weeks before administration of bevacizumab. Treatment was suspended in grade 3 or greater hematologic or non-hematologic toxicity or in detection of tumor bleeding. 3. Case 1 The first patient was a 32-year old female with 6 months of nausea and dizziness symptoms. MRI examination showed a homogeneous T2 hyperintense lesion in the medulla oblongata with no contrast enhancement. A stereotactic biopsy was performed with the histological finding of an astrocytoma (WHO II) and initial treatment consisted of external fractionated radiotherapy with 54 Gy. Four months later the patient was admitted to our department due to clinical deterioration with progressive gait ataxia, diplopia and nausea. MRI reevaluation showed a new contrastenhancing lesion in the medulla oblongata, compatible with a progressive disease and malignization. 18 F-FET-PET revealed strong amino acid uptake (tumor-to-brain uptake ratio: 3.7), consistent with vital tumor tissue. Chemotherapy according to the intensified temozolomide scheme (1 week on/1 week off) was initiated. After the second cycle the patient further deteriorated clinically with dysphagia, diplopia and progressive gait disturbances (KPS 50; dexamethasone: 12 mg/day). Radiological examination by MRI showed a diffuse contrast enhancement of the lower brain stem and anti-angiogenic with bevacizumab was started. 4. Case 2 A 36-year old female patient presented with 3 months of intermittent gait disturbance and headache. MRI examination showed a diffuse, non-contrast-enhancing mass in the left cerebellar peduncle with infiltration of the brain stem. A stereotactic biopsy was performed with the histological finding of a low-grade glioma WHO II. Regarding the young age of the patient and the clear delineation of the tumor no external radiation was planned and it was decided to perform a stereotactic implantation of two iodine-125 seeds for interstitial radiosurgery. Radiological and clinical tumor progression was documented 20 months later with increased tumor volume on the MRI, increased amino acid uptake in 11 C-MET-PET (tumor-to-brain uptake ratio of 1.7) and right hemiparesis. A new stereotactic biopsy was performed and showed tumor upgrading to malignant astrocytoma WHO grade III. Recidive therapy consisted of external fractionated radiotherapy with 60 Gy and temozolomide chemotherapy according to the 5/23 schedule. Further progression of the
disease 6 months later was treated with three cycles of the intensified temozolomide scheme after the 7/7-schedule and afterwards with one cycle of BCNU chemotherapy (80 mg/m2 intravenously on 3 days). Further tumor progress occurred 3 months later with bilateral pontomesencephalic infiltration, compression of the brain stem structures and cystic transformation of the cerebellar tumor. The patient presented with a Karnofsky performance index (KPI) of 80% and a daily dexamethasone dosage of 4 mg and received then treatment with bevacizumab. 5. Case 3 The third case was a 39-year old male patient with a 1 year progressive eye deviation and 6 months unsteady gait. MRI showed a contrast-enhancing lesion in the pontine tegmentum on both sides with extension to the quadrigeminal plate, pons and cerebellum (Fig. 1). Stereotactic biopsy of the tumor revealed an anaplastic astrocytoma WHO grade III and the patient was treated with external fractionated radiotherapy (54 Gy). The patient remained progression free for 4 months, after which there was an increase in the tumor size in the brain stem and associated clinical deterioration with facial paresis and a double vision. 18 F-FET-PET ruled out pseudoprogression and showed vital tumor tissue with a tumorto-brain uptake ratio of 2.3. Chemotherapy with temozolomide according to 5/23-day scheme was started and was switched to the intensified temozolomide schema due to tumor progression for 3 cycles and thereafter to CCNU chemotherapy for one cycle. After further clinical and radiological tumor progress with a decrease of KPI to 70 and a daily dexamethasone dosage of 6 mg, bevacizumab therapy was initiated. 6. Results 6.1. Clinical course One patient is still alive and progression free for a period of 97 weeks after initiation of bevacizumab therapy. This patient had initially the diagnosis of a diffuse astrocytoma grade II which showed clinical, radiological and metabolic signs of malignization before administration of bevacizumab. The two other patients died during the observation period and mean progression free and overall survival from start of bevacizumab was 34.5 weeks and 43.5 weeks. Mean total overall survival from time point of first diagnosis for these two patients was 42.5 months. Mean KPS improved from 60 at the start of bevacizumab therapy to 80 during bevacizumab therapy and mean dosage of daily dexamethasone was reduced from 7.3 mg to 1.3 mg. Adverse events during bevacizumab therapy included gastric ulcer, dizziness, low potassium, soft tissue abscess, pulmonary infection and urinary tract infection. No signs of relevant intracranial hemorrhage, hematologic toxicity, cardiovascular abnormalities or nephrotic syndrome could be detected as a consequence of antiangiogenic therapy. 6.2. Radiological and metabolic imaging (see Figs. 1, 2.1, 2.2) MRI follow-up at 4 weeks after initiation of bevacizumab therapy showed a decrease of the T2-weighted hyperintense lesion in all patients. T1-weighted images after intravenous contrast administration showed a decrease of contrast enhancement in two patients (cases 1 and 3). In the patient which is still alive (case 1), there is no evidence of radiological progression in followup MRI up to the latest MRI. In PET imaging, the tumor-to-brain uptake ratio (TBR) of 18 F-FET-PET decreased by >30% after initiation of bevacizumab therapy (from 3.7 to 2.5) and has remained stable in follow-up PET Scans (ranging from 2.7 to 2.8). In a recent
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Fig. 1. Time course of 18 F-FET-uptake in patient 1; (A) initial PET-scan with a TBR of 3.7, (B) after start of bevacizumab therapy, TBR decreased to 2.5, (C–F) TBR remains stable between 2.7 and 2.8 over >1 year, while visible tumor mass does not grow in the follow-up PET-scans (PET-scans A–C, E–F were performed on a Siemens ECAT EXACT 922/47 Scanner, Scan D was performed on a Philips Gemini TrueFlight 64 PET/CT Scanner).
publication [12], a >10% decrease in TBR has been proposed as a sign of treatment response in supratentorial glioma after radiochemotherapy consistent with improved outcome, which is supported by the favorable outcome of the patient presented here. In the other patients (cases 2 and 3) MRI findings remained stable in follow-up MRIs for a period of 35 and 39 weeks after initiation of bevacizumab therapy, respectively. PET imaging in these patients showed an initial decrease of tumor-to-brain uptake ratio of > 25% and 17% respectively, suggesting a treatment response and TBR remained stable over the course of the follow-up scans in case 3 (TBR 1.9). In case 2 a decrease of amino acid-uptake after initiation of bevacizumab therapy was detected (TBR decreased from 2.7 to 2.0), whereas the size of the area showing increased amino aciduptake appeared to grow slightly in visual inspection. The amino acid-uptake in the follow-up scan 2 months later showed then a clear increase in uptake of >10% in the aforementioned areas (TBR 2.4). The results of PET imaging are summarized in Table 2.
Table 2 Amino acid uptake as measured by 18 F-FET-PET, bold print = after initiation of bevacizumab therapy. Case 1
Case 2
Case 3
Date
Ratio
Date
Ratio
Date
Ratio
11 01 04 07 01 06
3.7 2.5 2.7 2.8 2.8 2.7
04 2010 12 2010 02 2011
2.7 2.0 2.4
12 05 03 07
2.3 2.3 1.9 1.9
2009 2010 2010 2010 2011 2011
2009 2010 2011 2011
7. Discussion According to the actual literature adult brain stem gliomas are subdivided into four distinct categories with regard to their clinical and radiological patterns [3]. Adult diffuse intrinsic low-grade brain stem gliomas with an onset in the third decade of life and a radiological pattern of diffuse pontomedullary tumor infiltration without contrast enhancement. Therapy consists mainly of radiation therapy and anaplastic transformation occurred in 27% of patients after a long period of stable disease. Overall median survival time of this group is 7.3 years. The second group consists of adult malignant brain stem gliomas with patients older than 40 years: MRI shows contrast enhancement and signs of necrosis and this type of tumor is highly resistant to radiation therapy resulting in a median survival time of 11.2 months. Another group are focal tectal brain stem gliomas which have a good prognosis after optional resection and radiation. Finally there is a heterogeneous group of brain stem tumors which cannot be classified in one of the previous mentioned categories. While the cornerstone of therapy at time of diagnosis is radiation therapy with or without chemotherapy patients are treated with various chemotherapeutic protocols at tumor progression. These include BCNU [1,2-bis(2-chloroethyl)1-nitrosourea], BCNU-procarbazine, CCNU [1-(2-chloroethyl)-3cyclohexyl-1-nitrosourea]-procarbazine-vincristine (PCV), carboplatin, carboplatin-VP16, carboplatin-VP16-ifosfamid, ifosfamid, procarbazine-VP16, temozolomide, CCNU, vincristine, irinotecan, cisplatin and temozolomide, ACNU and procarbazine. Effectiveness of these protocols were limited: Guillamo [3] reported a radiological response rate of 7% 3 months after onset of chemotherapy and clinical improvement lasting longer than 6 months in 15% of
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T. Reithmeier et al. / Clinical Neurology and Neurosurgery 115 (2013) 165–169
Fig. 2. (2.1) (Patient 3): MRI before Bevacizumab: (a) axial T1w after Gd; (b) sagittal T1w after Gd; (c) coronal FLAIR sequence. (2.2) (Patient 3): MRI after the 3rd cycle of Bevacizumab: (a) axial T1w after Gd; (b) sagittal T1w after Gd; (c) coronal FLAIR sequence.
patients and Samlaggi [4] described a temporary clinical and radiological stabilization in 22% of patients after chemotherapy. Therefore, new therapeutic approaches are needed to improve the prognosis of patients with progressive brain stem gliomas. Recent research and therapy strategies have focused on understanding the mechanisms leading to the origin of tumor angiogenesis to develop new approaches that effectively block angiogenesis and promote tumor regression [5] and anti-angiogenetic strategies with bevacizumab, a targeted molecule against vascular endothelial growth factor (VEGF) has been intensively studied in recurrent glioblastoma [6]. These studies showed, that bevacizumab seems to suppress the enhancing tumor recurrence more effectively than the non-enhancing infiltrative tumor [7] and while anti-angiogenic therapy improves PFS, it may not prolong overall survival in patients with recurrent malignant glioma [8]. This reduction of contrast enhancing tumor area is based on the reduction of vascular permeability by VEGF blocking agents and described in the literature as “pseudo-response” [9]. Therefore newer imaging techniques such as PET, MR spectroscopy, and perfusion- and diffusion-weighted images should be used for a more reliable assessment of tumor activity during anti-angiogenic treatment [10]. Other studies have demonstrated that bevacizumab improved survival, but it was unclear if it increased the invasiveness of the tumor [11]. In contrast to the reported experiences in the literature with various chemotherapeutic treatment regimes for progressive brain stem gliomas and the experience with bevacizumab in recurrent glioblastomas we observed a clinical and radiological response to bevacizumab therapy in all cases, supported by a decrease in amino acid uptake of at least >15% in all 3 patients as shown in 18 F-FET-PET [12]. The radiological response in MRI did not only affected the contrast enhancing tumor but also the tumor expansion in T2 weighted images with no signs of increased invasiveness
in all patients. The decrease of tumor size in T2 weighted images as well as the decrease of amino acid uptake in combination with a marked reduction of daily dexamethasone intake indicates antitumor activity of bevacizumab instead of a pseudoresponse in this series. In one patient, contrary to MRI, PET imaging found a slightly increasing tumor volume with a subsequent increase in TBR in a follow-up scan, thus a possible change in invasiveness in this case remains to be discussed. Another notable side effect of antiangiogenic therapy with bevacizumab was the dramatic reduction of the daily dexamethasone dosage, preventing patients from corticoid induced side effects like Cushing syndrome. With regard to the classification of Guillamo one patient in our series can be classified as malignant brain stem glioma, the other two patients had the initial diagnosis of a low grade brain stem glioma, one patient with the classical radiological appearance of a T2 weighted hyperintense lesion in the medulla oblongata and one patient with an initially hypointense lesion of the cerebellar peduncle and adjacent brain stem. In both patients secondary malignization before initiation of bevacizumab therapy was suspected, which was proven by stereotactic re-biopsy in one patient and which was assumed by clinical course, metabolic and radiological imaging in the other patient. However this patient is still alive with an almost complete radiological response and a residual, but not increasing amino acid uptake in PET-imaging. Therefore, pseudoprogression after radiation therapy instead of a true tumor malignization has also to be considered. Dynamic PET imaging techniques have shown promising results in the primary grading of gliomas, but these experiences cannot be simple conferred to progressive or recurrent gliomas as therapy induced effects on amino acid uptake and distribution have also to be considered [13,14]. This raises the question for the need of stereotactic rebiopsy before initiating bevacizumab therapy, as – although antiangiogenic treatment is usually well
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tolerated – life-threatening complications such as thromboembolism, hemorrhage, and gastrointestinal perforation can occur [15]. Further studies are needed to evaluate the effect of bevacizumab in brain stem gliomas as well as the value of functional imaging with PET in the diagnosis of pseudoprogression. 8. Conclusion In this series treatment of progressive gliomas involving the brain stem with bevacizumab resulted in an improved clinical condition of the patients as well as decrease of the T2-weighted hyperintense lesions and reduced amino acid uptake in the tumor area. It therefore may represent a therapeutic salvage option for this type of tumor. References [1] Torcuator R, Zuniga R, Loutfi R, Mikkelsen T. Bevacizumab and irinotecan treatment for progressive diffuse brainstem glioma: case report. Journal of Neuro-Oncology 2009;93:409–12. [2] Reithmeier T, Rottenburger C, Doostkam S, Pinsker MO, Trippel M, Bosche B, et al. Treatment of progressive brain stem glioma with bevacizumab: radiological, metabolic and histopathological aspects. Central European Neurosurgery November 2, 2011 [Epub ahead of print]. [3] Guillamo JS, Monjour A, Taillandier L, Devaux B, Varlet P, Haie-Meder C, et al. Brainstem gliomas in adults: prognostic factors and classification. Brain 2001;124:2528–39. [4] Salmaggi A, Fariselli L, Milanesi I, Lamperti E, Silvani A, Bizzi A, et al. Natural history and management of brainstem gliomas in adults. A retrospective Italian study. Journal of Neurology 2008;255:171–7. [5] Kargiotis O, Rao JS, Kyritsis AP. Mechanisms of angiogenesis in gliomas. Journal of Neuro-Oncology 2006;78:281–93.
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[6] Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. Journal of Clinical Oncology 2009;27:740–5. [7] Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, et al. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 2009;70:779–87. [8] Norden AD, Drappatz J, Muzikansky A, David K, Gerard M, McNamara MB, et al. An exploratory survival analysis of anti-angiogenic therapy forrecurrent malignant glioma. Journal of Neuro-Oncology 2009;92:149– 55. [9] Yamasaki F, Kurisu K, Aoki T, Yamanaka M, Kajiwara Y, Watanabe Y, et al. Advantages of high b-value diffusion-weighted imaging to diagnose pseudo-response in patients with recurrent glioma after bevacizumab treatment. European Journal of Radiology November 17, 2011 [Epub ahead of print]. [10] Wen PY, Macdonald Dr, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al. Update response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. Journal of Clinical Oncology 2010;28:1963–72. [11] Narayana A, Kelly P, Golfinos J, Parker E, Johnson G, Knopp E, et al. Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: impact on local control and patient survival. Journal of Neurosurgery 2009;110:173–80. [12] Piroth MD, Pinkawa M, Holy R, Klotz J, Nussen S, Stoffels G, et al. Prognostic value of early [18 F]fluoroethyltyrosine positron emission tomography after radiochemotherapy in glioblastoma multiforme. International Journal of Radiation Oncology, Biology, Physics 2011;80:176–84. [13] Mehrkens JH, Pöpperl G, Rachinger W, Herms J, Seelos K, Tatsch K, et al. The positive predictive value of O-(2-[18 F]fluoroethyl)-l-tyrosine (FET) PET in the diagnosis of a glioma recurrence after multimodal treatment. Journal of NeuroOncology 2008;88:27–35. [14] Pöpperl G, Kreth FW, Mehrkens JH, Herms J, Seelos K, Koch W, et al. for the evaluation of untreated gliomas: correlation of FET uptake and uptake kinetics with tumour grading. European Journal of Nuclear Medicine and Molecular Imaging 2007;34:1933–42. [15] Norden AD, Drappatz J, Ciampa AS, Doherty L, LaFrankie DC, Kesari S, et al. Colon perforation during antiangiogenic therapy for malignant glioma. NeuroOncology 2009;11:92–5.
Contents lists available at SciVerse ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Bevacizumab as salvage therapy for progressive brain stem gliomas T. Reithmeier a,∗ , W.O. Contreras Lopez a , T.S. Spehl b , T. Nguyen c , I. Mader c , G. Nikkhah a , M.O. Pinsker a a
Department of Neurosurgery, Division of Stereotactic and Functional Neurosurgery, University Medical Center Freiburg, Breisacher Str. 64, 79106 Freiburg im Breisgau, Germany Department of Nuclear Medicine, University Medical Center Freiburg, Breisacher Str. 64, 79106 Freiburg im Breisgau, Germany c Department of Neuroradiology, University Medical Center Freiburg, Breisacher Str. 64, 79106 Freiburg im Breisgau, Germany b
a r t i c l e
i n f o
Article history: Received 13 March 2012 Received in revised form 17 April 2012 Accepted 30 April 2012 Available online 29 May 2012 Keywords: Brain stem glioma Bevacizumab Positron emission tomography
a b s t r a c t Objective: There is no standard of care for patients with progredient brain stem gliomas. Therefore, we report about clinical, radiological and metabolic response to anti-angiogenic treatment with bevacizumab in a series of 3 patients with gliomas involving the brain stem. Patients and methods: Three patients with histologically confirmed gliomas involving the brain stem were treated with bevacizumab for tumor progression. The clinical data, histopathological findings as well as MRI and PET follow up examinations during bevacizumab therapy were retrospectively analyzed. Results: The histopathological diagnosis revealed an anaplastic astrocytoma WHO grade III in two patients and an astrocytoma WHO grade II in 1 patients with clinical and neuroradiological signs of malignization. One patient is still progression-free 97 weeks after initiation of bevacizumab therapy. Mean progressionfree survival and overall survival for the other two patients after initiation of bevacizumab therapy was 34.5 weeks and 43.5 weeks. During bevacizumab therapy mean KPS improved from 60 to 80 and mean dosage of daily dexamathasone was reduced from 7.3 mg to 1.3 mg. MRI showed a decrease of T2 weighted hyperintense lesions in all patients and a decrease of contrast enhancement in two patients. 18 F-FET-PET showed a decrease of tracer uptake in all cases (mean maximum decrease: 25%). Conclusion: In this series treatment of progressive gliomas involving the brain stem with bevacizumab resulted in an improved clinical condition of the patients as well as a reduction of the T2 weighted lesions and reduced amino acid uptake in the tumor area. It therefore may represent a therapeutic salvage option for this type of tumor. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Adult brain stem gliomas are a rare tumor entity accounting for 1.5–2.5% of all intracranial tumors. Therapeutic options for intrinsic brain stem gliomas are limited, mainly consisting of radiotherapy with an undefined role of chemotherapy and no standard of care for patient with recurrent brain stem tumors. Recently two case reports about successful treatment of a progressive diffuse brain stem glioma with bevacizumab with or without irinotecan have been published [1,2]. Therefore we retrospectively analyzed a series of three patients with histological confirmed gliomas involving the brain stem treated with bevacizumab alone as a salvage therapy and report here the clinical, radiological and metabolic findings. 2. Patients and methods We performed a retrospective review of the MS ACCESS database of our department and identified three patients with the
∗ Corresponding author. Tel.: +49 0761 270 93210; fax: +49 0 761 270 50100. E-mail address: [email protected] (T. Reithmeier). 0303-8467/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2012.04.027
histopathologically confirmed diagnosis of a glioma with involvement of the brain stem who were treated with bevacizumab as a salvage therapy for tumor progression. The positive experience with bevacizumab therapy in one of these patients was already published as a case report by the author [2]. The patients’ records, histopathological findings and the radiological and metabolic follow-up examinations during bevacizumab therapy were reexamined. There were two female and one male patient with a mean age of 36 years (range: 32–39 years) at first diagnosis of a glioma. Initial symptoms consisted of gait disturbance, headache, progressive eye deviation, nausea and dizziness. Mean duration from start of symptoms until diagnosis was 6 months (range: 3–9 months). Initial MRI evaluation with T1 weighted sequences after gadolinium and T2 weighted sequences showed a lesion with involvement of the brain stem in all cases. Histopathological diagnosis was confirmed by frame based stereotactic serial biopsy and revealed an anaplastic astrocytoma grade III in two patients (one patient with a primary grade III tumor, one patient showed upgrading from a grade II to a grade III tumor after a second stereotactic biopsy) and an astrocytoma grade II in 1 patient. Treatment before initiation of anti-angiogenic therapy with bevacizumab consisted of interstitial radiosurgery, external fractionated radiation therapy
166
T. Reithmeier et al. / Clinical Neurology and Neurosurgery 115 (2013) 165–169
Table 1 Summary of therapeutic procedures for patients with progressive brain stem gliomas.
Operative procedure Stereotactic biopsy Chemotherapy Temozolomide (5/23) Temozolomide (7/7) CCNU BCNU Bevacizumab Radiation therapy Interstitial radiosurgery External beam radiation
Case 1
Case 2
Case 3
Yes
Yes
Yes
No 1 cycle No No 32 cycles
Yes 4 cycles No 1 cycle 7 cycles
Yes 3 cycles 1 cycle No 8 cycles
No Yes
Yes Yes
No Yes
and various chemotherapies (for details see Table 1). Bevacizumab in a dosage of 10 mg/kg was administered as salvage therapy biweekly and intravenously under antiallergic prophylaxis. A complete blood count was obtained weekly. Urinanalysis, evaluation of cardiovascular parameters and a cranial CT or MRI examination to rule out intratumoral bleeding were performed every 2 weeks before administration of bevacizumab. Treatment was suspended in grade 3 or greater hematologic or non-hematologic toxicity or in detection of tumor bleeding. 3. Case 1 The first patient was a 32-year old female with 6 months of nausea and dizziness symptoms. MRI examination showed a homogeneous T2 hyperintense lesion in the medulla oblongata with no contrast enhancement. A stereotactic biopsy was performed with the histological finding of an astrocytoma (WHO II) and initial treatment consisted of external fractionated radiotherapy with 54 Gy. Four months later the patient was admitted to our department due to clinical deterioration with progressive gait ataxia, diplopia and nausea. MRI reevaluation showed a new contrastenhancing lesion in the medulla oblongata, compatible with a progressive disease and malignization. 18 F-FET-PET revealed strong amino acid uptake (tumor-to-brain uptake ratio: 3.7), consistent with vital tumor tissue. Chemotherapy according to the intensified temozolomide scheme (1 week on/1 week off) was initiated. After the second cycle the patient further deteriorated clinically with dysphagia, diplopia and progressive gait disturbances (KPS 50; dexamethasone: 12 mg/day). Radiological examination by MRI showed a diffuse contrast enhancement of the lower brain stem and anti-angiogenic with bevacizumab was started. 4. Case 2 A 36-year old female patient presented with 3 months of intermittent gait disturbance and headache. MRI examination showed a diffuse, non-contrast-enhancing mass in the left cerebellar peduncle with infiltration of the brain stem. A stereotactic biopsy was performed with the histological finding of a low-grade glioma WHO II. Regarding the young age of the patient and the clear delineation of the tumor no external radiation was planned and it was decided to perform a stereotactic implantation of two iodine-125 seeds for interstitial radiosurgery. Radiological and clinical tumor progression was documented 20 months later with increased tumor volume on the MRI, increased amino acid uptake in 11 C-MET-PET (tumor-to-brain uptake ratio of 1.7) and right hemiparesis. A new stereotactic biopsy was performed and showed tumor upgrading to malignant astrocytoma WHO grade III. Recidive therapy consisted of external fractionated radiotherapy with 60 Gy and temozolomide chemotherapy according to the 5/23 schedule. Further progression of the
disease 6 months later was treated with three cycles of the intensified temozolomide scheme after the 7/7-schedule and afterwards with one cycle of BCNU chemotherapy (80 mg/m2 intravenously on 3 days). Further tumor progress occurred 3 months later with bilateral pontomesencephalic infiltration, compression of the brain stem structures and cystic transformation of the cerebellar tumor. The patient presented with a Karnofsky performance index (KPI) of 80% and a daily dexamethasone dosage of 4 mg and received then treatment with bevacizumab. 5. Case 3 The third case was a 39-year old male patient with a 1 year progressive eye deviation and 6 months unsteady gait. MRI showed a contrast-enhancing lesion in the pontine tegmentum on both sides with extension to the quadrigeminal plate, pons and cerebellum (Fig. 1). Stereotactic biopsy of the tumor revealed an anaplastic astrocytoma WHO grade III and the patient was treated with external fractionated radiotherapy (54 Gy). The patient remained progression free for 4 months, after which there was an increase in the tumor size in the brain stem and associated clinical deterioration with facial paresis and a double vision. 18 F-FET-PET ruled out pseudoprogression and showed vital tumor tissue with a tumorto-brain uptake ratio of 2.3. Chemotherapy with temozolomide according to 5/23-day scheme was started and was switched to the intensified temozolomide schema due to tumor progression for 3 cycles and thereafter to CCNU chemotherapy for one cycle. After further clinical and radiological tumor progress with a decrease of KPI to 70 and a daily dexamethasone dosage of 6 mg, bevacizumab therapy was initiated. 6. Results 6.1. Clinical course One patient is still alive and progression free for a period of 97 weeks after initiation of bevacizumab therapy. This patient had initially the diagnosis of a diffuse astrocytoma grade II which showed clinical, radiological and metabolic signs of malignization before administration of bevacizumab. The two other patients died during the observation period and mean progression free and overall survival from start of bevacizumab was 34.5 weeks and 43.5 weeks. Mean total overall survival from time point of first diagnosis for these two patients was 42.5 months. Mean KPS improved from 60 at the start of bevacizumab therapy to 80 during bevacizumab therapy and mean dosage of daily dexamethasone was reduced from 7.3 mg to 1.3 mg. Adverse events during bevacizumab therapy included gastric ulcer, dizziness, low potassium, soft tissue abscess, pulmonary infection and urinary tract infection. No signs of relevant intracranial hemorrhage, hematologic toxicity, cardiovascular abnormalities or nephrotic syndrome could be detected as a consequence of antiangiogenic therapy. 6.2. Radiological and metabolic imaging (see Figs. 1, 2.1, 2.2) MRI follow-up at 4 weeks after initiation of bevacizumab therapy showed a decrease of the T2-weighted hyperintense lesion in all patients. T1-weighted images after intravenous contrast administration showed a decrease of contrast enhancement in two patients (cases 1 and 3). In the patient which is still alive (case 1), there is no evidence of radiological progression in followup MRI up to the latest MRI. In PET imaging, the tumor-to-brain uptake ratio (TBR) of 18 F-FET-PET decreased by >30% after initiation of bevacizumab therapy (from 3.7 to 2.5) and has remained stable in follow-up PET Scans (ranging from 2.7 to 2.8). In a recent
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Fig. 1. Time course of 18 F-FET-uptake in patient 1; (A) initial PET-scan with a TBR of 3.7, (B) after start of bevacizumab therapy, TBR decreased to 2.5, (C–F) TBR remains stable between 2.7 and 2.8 over >1 year, while visible tumor mass does not grow in the follow-up PET-scans (PET-scans A–C, E–F were performed on a Siemens ECAT EXACT 922/47 Scanner, Scan D was performed on a Philips Gemini TrueFlight 64 PET/CT Scanner).
publication [12], a >10% decrease in TBR has been proposed as a sign of treatment response in supratentorial glioma after radiochemotherapy consistent with improved outcome, which is supported by the favorable outcome of the patient presented here. In the other patients (cases 2 and 3) MRI findings remained stable in follow-up MRIs for a period of 35 and 39 weeks after initiation of bevacizumab therapy, respectively. PET imaging in these patients showed an initial decrease of tumor-to-brain uptake ratio of > 25% and 17% respectively, suggesting a treatment response and TBR remained stable over the course of the follow-up scans in case 3 (TBR 1.9). In case 2 a decrease of amino acid-uptake after initiation of bevacizumab therapy was detected (TBR decreased from 2.7 to 2.0), whereas the size of the area showing increased amino aciduptake appeared to grow slightly in visual inspection. The amino acid-uptake in the follow-up scan 2 months later showed then a clear increase in uptake of >10% in the aforementioned areas (TBR 2.4). The results of PET imaging are summarized in Table 2.
Table 2 Amino acid uptake as measured by 18 F-FET-PET, bold print = after initiation of bevacizumab therapy. Case 1
Case 2
Case 3
Date
Ratio
Date
Ratio
Date
Ratio
11 01 04 07 01 06
3.7 2.5 2.7 2.8 2.8 2.7
04 2010 12 2010 02 2011
2.7 2.0 2.4
12 05 03 07
2.3 2.3 1.9 1.9
2009 2010 2010 2010 2011 2011
2009 2010 2011 2011
7. Discussion According to the actual literature adult brain stem gliomas are subdivided into four distinct categories with regard to their clinical and radiological patterns [3]. Adult diffuse intrinsic low-grade brain stem gliomas with an onset in the third decade of life and a radiological pattern of diffuse pontomedullary tumor infiltration without contrast enhancement. Therapy consists mainly of radiation therapy and anaplastic transformation occurred in 27% of patients after a long period of stable disease. Overall median survival time of this group is 7.3 years. The second group consists of adult malignant brain stem gliomas with patients older than 40 years: MRI shows contrast enhancement and signs of necrosis and this type of tumor is highly resistant to radiation therapy resulting in a median survival time of 11.2 months. Another group are focal tectal brain stem gliomas which have a good prognosis after optional resection and radiation. Finally there is a heterogeneous group of brain stem tumors which cannot be classified in one of the previous mentioned categories. While the cornerstone of therapy at time of diagnosis is radiation therapy with or without chemotherapy patients are treated with various chemotherapeutic protocols at tumor progression. These include BCNU [1,2-bis(2-chloroethyl)1-nitrosourea], BCNU-procarbazine, CCNU [1-(2-chloroethyl)-3cyclohexyl-1-nitrosourea]-procarbazine-vincristine (PCV), carboplatin, carboplatin-VP16, carboplatin-VP16-ifosfamid, ifosfamid, procarbazine-VP16, temozolomide, CCNU, vincristine, irinotecan, cisplatin and temozolomide, ACNU and procarbazine. Effectiveness of these protocols were limited: Guillamo [3] reported a radiological response rate of 7% 3 months after onset of chemotherapy and clinical improvement lasting longer than 6 months in 15% of
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Fig. 2. (2.1) (Patient 3): MRI before Bevacizumab: (a) axial T1w after Gd; (b) sagittal T1w after Gd; (c) coronal FLAIR sequence. (2.2) (Patient 3): MRI after the 3rd cycle of Bevacizumab: (a) axial T1w after Gd; (b) sagittal T1w after Gd; (c) coronal FLAIR sequence.
patients and Samlaggi [4] described a temporary clinical and radiological stabilization in 22% of patients after chemotherapy. Therefore, new therapeutic approaches are needed to improve the prognosis of patients with progressive brain stem gliomas. Recent research and therapy strategies have focused on understanding the mechanisms leading to the origin of tumor angiogenesis to develop new approaches that effectively block angiogenesis and promote tumor regression [5] and anti-angiogenetic strategies with bevacizumab, a targeted molecule against vascular endothelial growth factor (VEGF) has been intensively studied in recurrent glioblastoma [6]. These studies showed, that bevacizumab seems to suppress the enhancing tumor recurrence more effectively than the non-enhancing infiltrative tumor [7] and while anti-angiogenic therapy improves PFS, it may not prolong overall survival in patients with recurrent malignant glioma [8]. This reduction of contrast enhancing tumor area is based on the reduction of vascular permeability by VEGF blocking agents and described in the literature as “pseudo-response” [9]. Therefore newer imaging techniques such as PET, MR spectroscopy, and perfusion- and diffusion-weighted images should be used for a more reliable assessment of tumor activity during anti-angiogenic treatment [10]. Other studies have demonstrated that bevacizumab improved survival, but it was unclear if it increased the invasiveness of the tumor [11]. In contrast to the reported experiences in the literature with various chemotherapeutic treatment regimes for progressive brain stem gliomas and the experience with bevacizumab in recurrent glioblastomas we observed a clinical and radiological response to bevacizumab therapy in all cases, supported by a decrease in amino acid uptake of at least >15% in all 3 patients as shown in 18 F-FET-PET [12]. The radiological response in MRI did not only affected the contrast enhancing tumor but also the tumor expansion in T2 weighted images with no signs of increased invasiveness
in all patients. The decrease of tumor size in T2 weighted images as well as the decrease of amino acid uptake in combination with a marked reduction of daily dexamethasone intake indicates antitumor activity of bevacizumab instead of a pseudoresponse in this series. In one patient, contrary to MRI, PET imaging found a slightly increasing tumor volume with a subsequent increase in TBR in a follow-up scan, thus a possible change in invasiveness in this case remains to be discussed. Another notable side effect of antiangiogenic therapy with bevacizumab was the dramatic reduction of the daily dexamethasone dosage, preventing patients from corticoid induced side effects like Cushing syndrome. With regard to the classification of Guillamo one patient in our series can be classified as malignant brain stem glioma, the other two patients had the initial diagnosis of a low grade brain stem glioma, one patient with the classical radiological appearance of a T2 weighted hyperintense lesion in the medulla oblongata and one patient with an initially hypointense lesion of the cerebellar peduncle and adjacent brain stem. In both patients secondary malignization before initiation of bevacizumab therapy was suspected, which was proven by stereotactic re-biopsy in one patient and which was assumed by clinical course, metabolic and radiological imaging in the other patient. However this patient is still alive with an almost complete radiological response and a residual, but not increasing amino acid uptake in PET-imaging. Therefore, pseudoprogression after radiation therapy instead of a true tumor malignization has also to be considered. Dynamic PET imaging techniques have shown promising results in the primary grading of gliomas, but these experiences cannot be simple conferred to progressive or recurrent gliomas as therapy induced effects on amino acid uptake and distribution have also to be considered [13,14]. This raises the question for the need of stereotactic rebiopsy before initiating bevacizumab therapy, as – although antiangiogenic treatment is usually well
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tolerated – life-threatening complications such as thromboembolism, hemorrhage, and gastrointestinal perforation can occur [15]. Further studies are needed to evaluate the effect of bevacizumab in brain stem gliomas as well as the value of functional imaging with PET in the diagnosis of pseudoprogression. 8. Conclusion In this series treatment of progressive gliomas involving the brain stem with bevacizumab resulted in an improved clinical condition of the patients as well as decrease of the T2-weighted hyperintense lesions and reduced amino acid uptake in the tumor area. It therefore may represent a therapeutic salvage option for this type of tumor. References [1] Torcuator R, Zuniga R, Loutfi R, Mikkelsen T. Bevacizumab and irinotecan treatment for progressive diffuse brainstem glioma: case report. Journal of Neuro-Oncology 2009;93:409–12. [2] Reithmeier T, Rottenburger C, Doostkam S, Pinsker MO, Trippel M, Bosche B, et al. Treatment of progressive brain stem glioma with bevacizumab: radiological, metabolic and histopathological aspects. Central European Neurosurgery November 2, 2011 [Epub ahead of print]. [3] Guillamo JS, Monjour A, Taillandier L, Devaux B, Varlet P, Haie-Meder C, et al. Brainstem gliomas in adults: prognostic factors and classification. Brain 2001;124:2528–39. [4] Salmaggi A, Fariselli L, Milanesi I, Lamperti E, Silvani A, Bizzi A, et al. Natural history and management of brainstem gliomas in adults. A retrospective Italian study. Journal of Neurology 2008;255:171–7. [5] Kargiotis O, Rao JS, Kyritsis AP. Mechanisms of angiogenesis in gliomas. Journal of Neuro-Oncology 2006;78:281–93.
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