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CORRESPONDENCE
Year : 2018  |  Volume : 14  |  Issue : 10  |  Page : 789-792

Bevacizumab and stereotactic radiosurgery achieved complete response for pediatric recurrent medulloblastoma


Department of Neurosurgery, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China

Date of Web Publication24-Sep-2018

Correspondence Address:
Xiangping Fu
Department of Neurosurgery, The First Affiliated Hospital of Chinese PLA General Hospital, 51 Fucheng Road, Haidian District, Beijing
China
Prof. Zhiwen Zhang
Department of Neurosurgery, The First Affiliated Hospital of Chinese PLA General Hospital, 51 Fucheng Road, Haidian District, Beijing
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_990_15

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 > Abstract 


Recurrent medulloblastoma has a very poor prognosis in children regardless of the treatment employed. We report the case of a 3-year-old child with recurrent refractory medulloblastoma who was treated with both bevacizumab and stereotactic radiosurgery (SRS). The boy was found to harbor a tumor in the cerebral posterior fossa in November 2010. Craniotomy was performed to remove the tumor completely. Postoperative pathological examination showed desmoplastic medulloblastoma. Craniospinal radiotherapy and chemotherapy were performed. Three years later, the boy suffered from constant headache again. Magnetic resonance imaging showed seeding of medulloblastoma in the posterior fossa as four masses with diameter ranging from 2 cm to 3 cm. To avoid overdose radiation, we used SRS and anti-angiogenesis therapy. Bevacizumab was given at 10 mg/kg for four times with an interval of 1 month. Gamma Knife (Leksell Gamma Knife®, Elekta Instruments, Stockholm, Sweden) was used targeting at one lesion each time and performed for consecutive two times with bevacizumab therapy. Following this combined treatment, the lesions targeted with radiosurgery showed complete response with minimal toxicity in <1 month successively. The combined use of bevacizumab and SRS may represent a novel treatment against medulloblastoma in patients who are not surgical candidates, and should be investigated further. This is the first documented case of medulloblastoma treated with bevacizumab and SRS. Further clinical trials should be considered to evaluate the effectiveness of this strategy.

Keywords: Bevacizumab, medulloblastoma, stereotactic radiosurgery


How to cite this article:
Zhao M, Wang X, Fu X, Zhang Z. Bevacizumab and stereotactic radiosurgery achieved complete response for pediatric recurrent medulloblastoma. J Can Res Ther 2018;14, Suppl S3:789-92

How to cite this URL:
Zhao M, Wang X, Fu X, Zhang Z. Bevacizumab and stereotactic radiosurgery achieved complete response for pediatric recurrent medulloblastoma. J Can Res Ther [serial online] 2018 [cited 2020 Jun 4];14:789-92. Available from: http://www.cancerjournal.net/text.asp?2018/14/10/789/214520




 > Introduction Top


Medulloblastoma is the most common malignant primary intracranial tumor in children. To date, standard treatment for medulloblastoma includes maximal surgical resection followed by craniospinal irradiation with a boost to the original field and chemotherapy. Despite these interventions, up to 20% of children experience tumor progression or recurrence, for which no curative therapies exist.[1] Currently, there is no standard treatment for recurrent or refractory cases.

Bevacizumab (Avastin®, Genentech, San Francisco, California, USA), a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF), has shown activity in preclinical models of pediatric cancers.[2] Bevacizumab is currently approved for use in adults with colorectal cancer, renal cancer, nonsmall cell lung cancer, ovarian cancer, cervical cancer, and glioblastoma.[3] Its use in pediatric patients with medulloblastoma remains investigational. Recently, neuro-oncologists tried bevacizumab with stereotactic radiosurgery (SRS) in both malignant gliomas and brain metastatic tumors, which demonstrated this combination a safe and effective therapy.[4],[5] This may be because bevacizumab is supposed to have synergistic effects with radiotherapy in many ways.[6] To date, there have been no reports on the use of bevacizumab with SRS in medulloblastoma. We report the case of a child with recurrent medulloblastoma who was treated with a combination of bevacizumab and radiosurgery to explore its efficiency in recurrent medulloblastoma.


 > Case Report Top


A 3-year-old boy presented with complaints of headaches and nausea in December 2010. Physical examination did not reveal any positive signs. Magnetic resonance imaging (MRI) revealed a 4-cm tumor arising from the vermis in the cerebellum, which strongly compressed brainstem and actively accumulated a contrast agent, and occlusive hydrocephalus. The patient underwent craniotomy and total resection of the tumor. Postoperative MRI scan showed that the tumor was completely removed. Pathological biopsy revealed the tumor to be desmoplastic medulloblastoma. Craniospinal radiation was performed (2700 cGy/15 f/21 days, with 5600 cGy enhancement in the cerebellum), and sequential adjuvant chemotherapy was performed with cisplatin, etoposide, and cyclophosphamide for six cycles. After the radiotherapy and chemotherapy, the boy did not show any neurological deficits. Follow-up MRI was performed at an interval of 1 year.

In August 2013, the boy represented complaining of headache; subsequent MRI revealed tumor recurrence, tumor recurrence with multiple intracranial foci in the petroclival region, fourth ventricle, cerebral pontine angle (CPA), and right cerebellum [Figure 1]a1,[Figure 1]a2,[Figure 1]a3. He was transferred to our hospital for further treatment.
Figure 1: (a1–a3) Magnetic resonance imaging findings after admission in September 2013 showing multifocal tumor recurrence around the brainstem. (b1 and b2) Axial and sagittal magnetic resonance imaging 1 month following bevacizumab administration. (b3) Gamma Knife targeting the retrosellar lesion at a dose of 15.3 Gy. (c1 and c2) Magnetic resonance imaging 1 month following stereotactic radiosurgery showing disappearance of the retrosellar lesion. (c3) Following another round of bevacizumab, a second round of Gamma Knife was performed targeting the lesions in the left cerebral pontine angle (14.58 Gy) and cerebellum (14.98 Gy). (d1 and d2) Resolution of the remaining lesions was observed 1 month following the second round of radiosurgery. (d3) However, diffuse meningeal dissemination was found

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Since the boy had received craniospinal radiation and the recurrent tumors were inoperable, we used bevacizumab and SRS. Bevacizumab was administered at 10 mg/kg once a month beginning in September 2013. One month following the first round of treatment, follow-up MRI showed stable disease in all the lesions [Figure 1]b1 and [Figure 1]b2. Bevacizumab administration was continued. SRS (Leksell Gamma Knife®, Elekta Instruments, Stockholm, Sweden) was performed and targeted the retrosellar lesion at a dose of 15.3 Gy [Figure 1]b3. The brainstem dose was 1.51 Gy and external brain was 0.27 Gy [Supplement Figure 1] [Additional file 1]. Follow-up MRI was performed 1 month later, in December 2013, which revealed disappearance of the retrosellar lesion and shrinkage of the surrounding lesions [Figure 1]c1 and [Figure 1]c2.

Following these findings, bevacizumab was re-administered after Gamma Knife was preformed aiming at the lesions in the left CPA (14.58 Gy) and cerebellum (14.98 Gy) [Figure 1]c3. The brainstem dose was 1.81 Gy and external brain was 0.80 Gy [Supplement Figure 2] [Additional file 2]. The accumulated dose in organs at risk (ORA) (brainstem) and the whole external brain was 1.08 Gy and 3.3 Gy, respectively, which is safe for these organs.

In January 2014, the Gamma Knife-targeted lesions were no longer observed on MRI. At this point, complete response of the targeted lesions was found on MRI [Figure 1]d1 and [Figure 1]d2. However, diffuse meningeal tumor dissemination was observed [Figure 1]d3. The patient ceased treatment due to financial reasons and died 3 months following the second round of radiosurgery. During the course of treatment, the patient did not exhibit hypertension, hemorrhage, or hematologic toxicity. Routine blood tests did not reveal any toxic change. Radiosurgery and chemotherapy were well tolerated.


 > Discussion Top


We present a single case of recurrent medulloblastoma in a child who responded significantly to combined treatment with bevacizumab and SRS. Complete disappearance of target lesions was observed <1 month following treatment, possibly suggesting a new and efficient therapy for medulloblastoma.

The rationale for combined SRS and antiangiogenesis therapy was based on recent clinical and preclinical observations. Medulloblastoma has been found to express VEGF ligand and cognate receptors.[7] Bevacizumab, monoclonal antibody of VEGF, has been used in patients with medulloblastoma with chemotherapeutic agents.[8],[9] It provides a wide spectrum of antitumor properties with a long half-life (20 days), so we used it at an interval of 30 days. At the same time, bevacizumab and radiosurgery may have a synergistic effect and may interact in a number of different ways.[6] Primarily, bevacizumab may normalize the formation of tumor vasculature, decreasing vascular permeability and increasing tumor oxygenation while enhancing radiosensitivity. Secondly, the hypoxic tumor cells, which are not sensitive to radiation, tend to cause recurrence through molecular signaling pathways. VEGF is one of the most important molecular signaling pathways and can be blocked by bevacizumab. Finally, radiation increases the secretion of cytokines such as VEGF in tumor cells which helps promote tumor angiogenesis. Bevacizumab can block the angiogenic response and thus enhance the efficacy of radiotherapy.

In the present case, the patient received >27 Gy whole brain radiotherapy with 57 Gy enhancement in the cerebellum after the first surgery. Thus, re-irradiation would risk overdose. As SRS can deliver local doses of >10 Gy with little radiation to surrounding structures, we selected to use a combination of bevacizumab and Gamma Knife. To date, there are no reports in literature presenting the potential efficacy of this regimen. In the literature on recurrent medulloblastoma, complete response was rarely seen following treatment with bevacizumab and chemotherapy.[10],[11],[12] In the current case, all solid tumors disappeared following combined treatment with bevacizumab and Gamma Knife, presenting a possible novel method for the treatment of medulloblastoma that warrants further investigation.

Despite intensive radiotherapy and chemotherapy, metastasis to the leptomeninges represents a major challenge in the treatment of medulloblastoma.[13],[14] Patients with diffuse meningeal dissemination generally have a poor prognosis.[15] The case presented herein developed diffuse leptomeningeal metastasis in the late stages of treatment. Since the dissemination occurred after antiangiogenic agent administration, we studied the correlation between bevacizumab and tumor dissemination. In early reports, antiangiogenic agents seemed to promote cancer cell migration and invasion leading to accelerated metastasis.[16],[17] However, recent studies have shown that antiangiogenic agents can help normalize the tumor vasculature and prevent metastasis.[18],[19] In 2014, Davare et al. found that VEGF is not involved in the modulation of the migratory properties of medulloblastoma cells in vitro.[20] Therefore, we believe that bevacizumab can be safely used in the treatment against medulloblastoma; however due to the cessation of treatment in the current case, we cannot speculate as to the effectiveness of bevacizumab on disseminated metastatic tumor cells.

This case demonstrates that bevacizumab combined with SRS may be an effective treatment for medulloblastoma and a potential new therapy for patients who are not surgical candidates. Additionally, SRS is not limited by the maximum radiotherapeutic dose and can therefore be used before or after radiotherapy which makes it especially useful for recurrent tumors. If further study indicates this to be an effective therapy, it would represent another minimally invasive option for patients with medulloblastoma. Prospective clinical trials could be considered to evaluate the effectiveness of this strategy.

Financial support and sponsorship

This work was supported by research grant funds from Capital Development Fund 2014-2-5021 and Beijing Science and Technology Project Z131107002213177.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Torres CF, Rebsamen S, Silber JH, Sutton LN, Bilaniuk LT, Zimmerman RA, et al. Surveillance scanning of children with medulloblastoma. N Engl J Med 1994;330:892-5.  Back to cited text no. 1
    
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Gerber HP, Ferrara N. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res 2005;65:671-80.  Back to cited text no. 2
    
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Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349:427-34.  Back to cited text no. 3
    
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Yomo S, Hayashi M. Salvage stereotactic radiosurgery with adjuvant use of bevacizumab for heavily treated recurrent brain metastases: A preliminary report. J Neurooncol 2016;127:119-26.  Back to cited text no. 4
    
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Wang Y, Wang E, Pan L, Dai J, Zhang N, Wang X, et al. A new strategy of CyberKnife treatment system based radiosurgery followed by early use of adjuvant bevacizumab treatment for brain metastasis with extensive cerebral edema. J Neurooncol 2014;119:369-76.  Back to cited text no. 5
    
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7.
Slongo ML, Molena B, Brunati AM, Frasson M, Gardiman M, Carli M, et al. Functional VEGF and VEGF receptors are expressed in human medulloblastomas. Neuro Oncol 2007;9:384-92.  Back to cited text no. 7
    
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Aguilera D, Mazewski C, Fangusaro J, MacDonald TJ, McNall-Knapp RY, Hayes LL, et al. Response to bevacizumab, irinotecan, and temozolomide in children with relapsed medulloblastoma: A multi-institutional experience. Childs Nerv Syst 2013;29:589-96.  Back to cited text no. 8
    
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Okada K, Yamasaki K, Tanaka C, Fujisaki H, Osugi Y, Hara J. Phase I study of bevacizumab plus irinotecan in pediatric patients with recurrent/refractory solid tumors. Jpn J Clin Oncol 2013;43:1073-9.  Back to cited text no. 9
    
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Venkatramani R, Malogolowkin M, Davidson TB, May W, Sposto R, Mascarenhas L. A phase I study of vincristine, irinotecan, temozolomide and bevacizumab (vitb) in pediatric patients with relapsed solid tumors. PLoS One 2013;8:e68416.  Back to cited text no. 10
    
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Piha-Paul SA, Shin SJ, Vats T, Guha-Thakurta N, Aaron J, Rytting M, et al. Pediatric patients with refractory central nervous system tumors: Experiences of a clinical trial combining bevacizumab and temsirolimus. Anticancer Res 2014;34:1939-45.  Back to cited text no. 11
    
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Peyrl A, Chocholous M, Kieran MW, Azizi AA, Prucker C, Czech T, et al. Antiangiogenic metronomic therapy for children with recurrent embryonal brain tumors. Pediatr Blood Cancer 2012;59:511-7.  Back to cited text no. 12
    
13.
Korah MP, Esiashvili N, Mazewski CM, Hudgins RJ, Tighiouart M, Janss AJ, et al. Incidence, risks, and sequelae of posterior fossa syndrome in pediatric medulloblastoma. Int J Radiat Oncol Biol Phys 2010;77:106-12.  Back to cited text no. 13
    
14.
Dufour C, Beaugrand A, Pizer B, Micheli J, Aubelle MS, Fourcade A, et al. Metastatic medulloblastoma in childhood: Chang's classification revisited. Int J Surg Oncol 2012;2012:245385.  Back to cited text no. 14
    
15.
Bowers DC, Gargan L, Weprin BE, Mulne AF, Elterman RD, Munoz L, et al. Impact of site of tumor recurrence upon survival for children with recurrent or progressive medulloblastoma. J Neurosurg 2007;107 1 Suppl:5-10.  Back to cited text no. 15
    
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Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 2009;15:232-9.  Back to cited text no. 16
    
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Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009;15:220-31.  Back to cited text no. 17
    
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Fu Y, Hu J, Du N, Jiao S, Li F, Li X, et al. Bevacizumab plus chemotherapy versus chemotherapy alone for preventing brain metastasis derived from advanced lung cancer. J Chemother 2016;28:218-24.  Back to cited text no. 18
    
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Pishko GL, Muldoon LL, Pagel MA, Schwartz DL, Neuwelt EA. Vascular endothelial growth factor blockade alters magnetic resonance imaging biomarkers of vascular function and decreases barrier permeability in a rat model of lung cancer brain metastasis. Fluids Barriers CNS 2015;12:5.  Back to cited text no. 19
    
20.
Davare MA, Lal S, Peckham JL, Prajapati SI, Gultekin SH, Rubin BP, et al. Secreted meningeal chemokines, but not VEGFA, modulate the migratory properties of medulloblastoma cells. Biochem Biophys Res Commun 2014;450:555-60.  Back to cited text no. 20
    


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