New perspectives in the treatment of adult medulloblastoma in the era of molecular oncology

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Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx

New perspectives in the treatment of adult medulloblastoma in the era of molecular oncology Alba A. Brandes a,∗ , Marco Bartolotti a , Gianluca Marucci b , Claudio Ghimenton c , Raffaele Agati d , Antonio Fioravanti e , Maurizio Mascarin f , Lorenzo Volpin g , Franco Ammannati h , Barbara Masotto i , Marina Paola Gardiman j , Dario De Biase k , Giovanni Tallini k , Girolamo Crisi l , Stefania Bartolini a , Enrico Franceschi a a

Department of Medical Oncology, Bellaria-Maggiore Hospitals, Azienda USL – IRCCS Institute of Neurological Sciences, Bologna, Italy b Department of Biomedical and NeuroMotor Sciences (DiBiNeM), University, of Bologna, Section of Pathology, M. Malpighi, Bellaria Hospital, Bologna, Italy c Pathology Department, Verona Hospital, Verona, Italy d Department of Neuroradiology, Bellaria-Maggiore Hospitals, Azienda USL – IRCCS Institute of Neurological Sciences, Bologna, Italy e Department of Neurosurgery, Bellaria Hospital – IRCCS Institute of Neurological Sciences, Azienda USL, Bologna, Italy f Department of Radiotherapy Unit, CRO, Aviano, Italy g Department of Neuroscience and Neurosurgery, San Bortolo Hospital, Vicenza, Italy h Department of Neurosurgery I, Careggi University Hospital, Firenze, Italy i Section of Neurosurgery, Department of Neuroscience, University of Verona, Verona, Italy j Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University Hospital, Padova, Italy k Department of Medicine (DIMES) – Anatomic Pathology Unit, Bellaria Hospital, University of Bologna, Bologna, Italy l Department of Neuroradiology, Parma University Hospital, Parma, Italy Accepted 23 December 2014

Contents 1. 2. 3. 4. 5.

6.

7.

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Histopathology and biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical and radiological presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular subgroups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. WNT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. SHH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Group 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Group 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other molecular alterations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Notch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. BMP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Epigenetic alterations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Neurosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.1. Average risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.2. High risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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∗ Corresponding author at: Department of Medical Oncology, Bellaria-Maggiore Hospitals, Azienda USL – IRCCS Institute of Neurological Sciences, Via Altura 3, 40139 Bologna, Italy. Tel.: +39 051 6225697; fax: +39 051 6225057. E-mail address: [email protected] (A.A. Brandes).

http://dx.doi.org/10.1016/j.critrevonc.2014.12.016 1040-8428/© 2014 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Brandes AA, et al. New perspectives in the treatment of adult medulloblastoma in the era of molecular oncology. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2014.12.016

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7.3.

8.

Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.1. Average risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.2. High risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4. Recurrent disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.1. Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.2. Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.3. Systemic treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5. Targeting stem cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6. Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interests statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract Medulloblastoma is the most common central nervous system tumor in children, while it is extremely rare in adults. Multimodal treatment involving surgery, radiotherapy and chemotherapy can improve the prognosis of this disease, and recent advances in molecular biology have allowed the identification of molecular subgroups (WNT, SHH, Groups 3 and 4), each of which have different cytogenetic, mutational and gene expression signatures, demographics, histology and prognosis. The present review focuses on the state of the art for adult medulloblastoma treatment and on novel molecular advances and their future implications in the treatment of this disease. © 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Medulloblastoma; Adults; Treatment; SHH; WNT

1. Introduction Medulloblastoma, a malignant, invasive, embryonal tumor of the cerebellum with a preferential manifestation in children and a marked tendency to cerebro-spinal fluid (CSF) metastatization [1], is found in 15–30% of all childhood primary tumors of the central nervous system (CNS). About 70% of the cases occur in patients under 15 years of age, the incidence peak being 3–6 years [2]. In adults, medulloblastoma is much less frequent, accounting for less than 3% of primary CNS tumors. A recent US registry analysis from the Surveillance, Epidemiology, and End-Results (SEER) database [3] found that the incidence of medulloblastoma was 1.5 cases per million in the general population, children being ten times more likely to develop the disease than adults (6.0 vs. 0.6 cases per million). Males are 1.58 times more likely than females to be diagnosed with medulloblastoma during childhood, but this difference is not maintained in adulthood [3].

produces cerebellar granule cells. These cell groups are related to different molecular subtypes of medulloblastoma: it widely known that VZ cells give origin to the wingless (WNT) subtype, while sonic hedgehog (SHH) medulloblastomas derive from EGL cells [4]. The latest 2007 WHO classification [1] of CNS describes five histopathological subtypes of medulloblastoma: classic (80% of all medulloblastomas in children, 70% in adults), desmoplastic (15% in children, 30–40% in adults), anaplastic (10–20%), large-cells (2–4%), and extensive nodularity (3%). Differences between children and adults have been found for histological subgroups, which are of prognostic significance: desmoplastic and nodular subtypes are associated with a better prognosis in children <5 years of age whereas anaplastic and large-cells are associated with poor prognosis in all age patients [5]. Medulloblastoma, typically having a median localization in children, is more commonly lateral in adults [6].

2. Histopathology and biology

3. Clinical and radiological presentation

The exact cellular origin of medulloblastoma is a matter of debate. It has been suggested that the disease might arise from two distinct embryonal cell groups: cells from the ventricular zone (VZ), which differentiate into Purkinje cells, basket cells, and other glial and neuronal cells of the cerebellum, and cells from the external germinal layer (EGL) that

Because medulloblastoma arises in the posterior fossa, a frequent complication is hydrocephalus due to the compression of ventricle IV, with a consequent increase in intracranial pressure. Common symptoms are vertigo, vomiting, ataxia and headache. Patients with a tumor localized in the mid-cerebellum may have symptoms (nystagmus,

Please cite this article in press as: Brandes AA, et al. New perspectives in the treatment of adult medulloblastoma in the era of molecular oncology. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2014.12.016

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Table 1 Chang’s staging system. T stage T1

T2 T3a

T3b T4 M stage M0 M1 M2 M3 M4

Tumor less than 3 cm in diameter and limited to the classic midline position in the vermis, the roof of the fourth ventricle, and less frequently to the cerebellar hemispheres Tumor greater than 3 cm and invading one adjacent structure or partially filling fourth ventricle Tumor further invading two adjacent structures or completely filling the fourth ventricle with extension into the aqueduct of Sylvius, foramen of Magendie, or foramen of Luschka, thus producing marked internal hydrocephalus Tumor arising from floor of fourth ventricle and filling fourth ventricle Tumor spread through aqueduct of Sylvius to involve third ventricle, midbrain, or down into upper cervical cord No gross subarachnoid or hematogenous metastasis Microscopic tumor cells found in CSF Gross nodular seeding in cerebellum, cerebral subarachnoid space, or in third or fourth ventricles Gross nodular seeding in spinal subarachnoid space Extraneuraxial metastasis

diplopia, hearing loss, seventh cranial palsies) that are related to compression of the cranial nerves. If the medulloblastoma spreads to the spine, peripheral neurological deficits may be present. At MRI medulloblastoma typically appears within the posterior fossa in the form of tumor masses, which are usually iso- to hypointense on T1-weighted (T1-W) images. The T2 signal varies, ranging from hyperintense to hypointense. Contrast enhancement, usually present, can vary in degree and extent. Other typical features are increased signals on diffusion-weighted images (DWI) and a decreased apparent diffusion coefficient (ADC), which may help in differentiating from other posterior fossa tumors, such as pilocytic astrocytoma and ependymoma [7].

4. Staging Correct staging, crucial for a reliable risk stratification of patients, influences the therapeutic approach. Metastatic spread has higher incidence in children than adults (13% vs. 8%) [8,9] and typically follows CSF and leptomeningeal dissemination along the spinal cord. The cerebellum and brain are the most common sites of metastases in conjunction with spinal diffusion. Atypical metastatic sites are bones, which are the most common extra-CNS sites (80%) for both children and adults, followed by the lung (in adults) and liver (children). The time interval between diagnosis of the primary and detection of metastases is usually shorter in children than adults (20 months vs. 36 months) [6]. Patients are usually divided into average and high-risk groups, according to Chang’s classification and based on findings at [10] (Table 1). Staging examinations of fundamental importance are brain/spinal contrast enhanced MRI, performed both before and after (48 h) surgery, and CSF cytology, performed

3

after MRI. If CSF is positive, this investigation should be repeated 20 days after surgery in order to rule out any false positive findings. Patients are considered average risk when they present neither metastases nor residual disease after surgery (residual disease being defined as >1.5 cm2 ), and have favorable histology (i.e. other than large cells/anaplastic histology). High-risk patients have metastases, and/or residual disease >1.5 cm2 and/or large cells/anaplastic histology. Although the above-mentioned prognostic factors are widely accepted and used in clinical practice, the impact of metastases and residual disease on outcome is a matter of debate due to contradictory results obtained in different trials. Chan et al. [11] reported a 5-year progression free survival (PFS) rate of 47% and 59% in patients with and without metastatic dissemination, respectively. Brandes at al. reported a 5-year PFS of 61% vs. 78% in metastatic and nonmetastatic patients, respectively [12]. Similar data were also found previously by Carrie et al. [9]. The prognostic value of M1 disease is an open question: it is not clear whether CSF dissemination has an outcome similar to that of M0 or metastatic disease. At present, M1 disease is considered high-risk and should be treated accordingly. Data on residual disease are also contradictory. Chan et al. [11] found a 5-year PFS rate of 86% for patients without residual tumor, against 27% for patients with residual tumor. On the other hand, Brandes et al. found that residual disease had no significant impact [12].

5. Molecular subgroups One of the most important advances in the knowledge of medulloblastoma is the discovery of molecular patterns allowing the division of medulloblastomas into distinct molecular subgroups with different cytogenetic, mutational and gene expression signatures, as well as different demographics, histology and prognosis. A number of studies have been performed to improve on the identification of a variable number of subgroups [13–16]. There are two well characterized subgroups of medulloblastoma with peculiar pathways: WNT and SHH. The remaining groups have been labeled as non-WNT/SHH, and their numbers vary in different studies. A recent consensus [17] established that medulloblastoma can be divided into four main molecular subgroups: WNT, SHH, group 3 and group 4. 5.1. WNT The least common medulloblastomas, WNT account for 10% of all medulloblastomas (15% in adults) [18]. Typically they occur in children over three years of age, are rarely found in adults with medulloblastoma, are equally distributed between males and females, have a classic histology, and are rarely metastatic; their prognosis is best in children, with 5-year survival rates of >95%, whereas in adults the

Please cite this article in press as: Brandes AA, et al. New perspectives in the treatment of adult medulloblastoma in the era of molecular oncology. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2014.12.016

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5-year survival rate is 80%. This subgroup is characterized by enhanced WNT-beta catenin pathway activation. Catenin beta 1 gene mutation (CTNNB1) is the most common genetic alteration in this subgroup (present in 90% of the cases). The mutation and abnormal activation of Ctnnb1 leads to an enhanced activation of MYC and MYCN oncogenes, with a subsequent increase in cellular proliferation [19]. Other frequently altered genes are DDX3X (50%), SMARCA4 (26%), MLL2 (12%) and TP53 (12%). Genetic signatures of the subgroup are typically loss of chromosome 6q and 17p [20]. Given its better prognosis, this subgroup of patients is considered for de-escalated therapeutic protocols in order to minimize any long-term adverse events. 5.2. SHH The SHH subgroup, consisting of 30% of all patients with medulloblastoma, mainly comprises adults (60%) [18], and infants, this form being rarer in children aged ≥3 years. The prognosis is intermediate for both age groups, the 5-year survival rate being in the region of 70%. Almost every histological subtype is present in this group, but desmoplastic and nodular forms are almost exclusive to the SHH subgroup. Metastatization is uncommon, its distribution being equivalent in both sexes. The most commonly found genetic mutations are PTCH1 (28%) or suppression of the fused homologue (SUFU). Other frequently mutated genes are: TP53 (13%), MLL2 (13%), MYCN (8%), LDB1 (7%), GLI2 (5%). Deletions of chromosomes 9q, 10q, 6q and CDK6 amplification are also frequent [21]. SHH, a transmembrane protein, activates another transmembrane protein, the smoothened receptor (Smo). This event activates two transcription factors, Gli1 and Gli2, and arrests the transcription repressor Gli3. These factors induce cell proliferation via the overexpression of MYCN oncogene and cyclins Ccnd 1 and 2. Within this pathway Ptch1 acts as a Smo inhibitor. Mutations of this protein, the most frequent molecular alterations in this subgroup, lead to the constitutional activation of SHH pathway [22]. A recent study [23] demonstrated that the presence of TP53 mutations in SHH medulloblastoma allows a further prognostic stratification, this mutation being associated with a poorer survival. TP53 can also be mutated in WNT tumors, but in this subgroup it does not seem to be of prognostic significance. This subgroup, probably the most widely studied, has the greatest dramatic clinical implications: since SHH pathway inhibitors (specifically Smo inhibitors) have been proven to be effective, they are currently being evaluated in phase III trials (NCT01708174). 5.3. Group 3 This group, which has the worst prognosis with 5-year survival rates of 40 to 50% [21], makes up 25% of the diagnoses, the condition occuring in children and infants, with a predominance in males (2:1). It has rarely been described in adults

(<2%) [24]. The tendency to metastatization is high (45%), and the most commonly found genetic alteration is protooncogene MYC mutation/amplification (16.7%). This group is characterized by an elevated genomic instability with frequent chromosome 1p gains, 10q and 5q loss and the presence of isochromosome 17 [21]. 5.4. Group 4 Group 4 is the largest subgroup of all, accounting for 35% of all medulloblastomas [21]. The condition occurs in adults (20–25% of all adult medulloblastomas) and children (35%), the latter having better prognosis than adults. Overall, the prognosis is intermediate, with an overall survival rate of 75%. Metastases occur in 35–40% of cases. Almost all cases have classic or large-cells histology. The incidence in males is three times higher than in female. MYCN and CDK6 amplifications are the most commonly found genetic alterations in this group [21].

6. Other molecular alterations Alterations of different proteins and pathways, described in medulloblastoma and currently being evaluated as potential therapeutic targets, can occur in any of the above molecular subgroups. 6.1. Notch The notch pathway seems to be involved in medulloblastoma proliferation: during embryonal development, Notch2 signaling induces proliferation of GCP (precursors of the cerebellar granule cell, one of the cells in which medulloblastoma originates), via the up-regulation of the Hes1 transcription factor. Furthermore, Notch2 activation induces BMP suppression and an increase in Atoh1/Math1 expression [22]. However, the results of a phase I/II study evaluating the efficacy of the gamma-secretase/notch pathway inhibitor RO4929097 on various tumors, including recurrent childhood medulloblastoma (NCT01088763) are not yet available. 6.2. BMP Bmp family is a group of negative regulator proteins that act, during cerebellum development, as inhibitors of SHHinduced GCP proliferation. Involved in this process are Bmp2 and Bmp4, which also plays a role in inducing the differentiation of GCPs [25,26]. In preclinical models it has been found that BMPs inhibit medulloblastoma proliferation [26], thus suggesting that molecules functioning as BMP agonists might be effective in the treatment of medulloblastoma [27].

Please cite this article in press as: Brandes AA, et al. New perspectives in the treatment of adult medulloblastoma in the era of molecular oncology. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2014.12.016

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6.3. Epigenetic alterations Epigenetic alterations, mostly involving histone modifiers, have been widely described in medulloblastomas, and are under evaluation as a potential therapeutic target. Truncating mutations of histone methyltransferases MLL2 and MLL3 have been found in WNT, group3 and 4 medulloblastomas [28–30], whereas mutations of histone demethylases KDM6A and ZMYM have been identified in Group 3 and 4 [30,31]. Overexpression of H3K27me3 methyltransferase and (polycomb repressive complex 2 (PRC2 complex) component enhancer of zeste homolog 2 (EZH2) has been found in some medulloblastomas [32]. At present, different agents targeting these proteins have been developed and are currently under evaluation for medulloblastoma, in particular: histone deacetylase vorinostat, valproic acid and romidepsin and inhibitors of EZH2 (NCT01076530, NCT00867178, NCT01861990, NCT00053963, NCT01897571).

5

The dose-response relationship is well established. Berry et al. [39] described a disease free survival (DFS) of 77% at 10 years when radiation doses to the posterior fossa exceeded 52 Gy. Hubbard et al. [35] described a 91% 5-year disease control rate with doses of >54 Gy, against 33% for doses of <54 Gy.

7.2. Radiotherapy

7.2.1. Average risk Radiotherapy is burdened by important toxicities, especially in young children, whose neurological and intellectual development can be compromised by it. Efforts have therefore been made to reduce irradiation dose whenever possible in pediatric patients. Packer et al. [40] reported positive results their trial in which children with non-metastatic medulloblastoma (no metastases or positive CSF) were treated with postoperative, reduced-dose craniospinal radiation therapy (23.4 Gy in13 fractions) plus a boost to the posterior fossa (31.8 Gy in 17 fractions) with concomitant vincristine and adjuvant lomustine, vincristine, and cisplatin. In this study, the PFS rate was 86% at 3 years and 79% at 5 years, these percentages being comparable to those obtained with full-dose radiotherapy [40]. In a study by Packer et al. [41], 421 patients with non-metastatic medulloblastoma (no metastases or positive CSF and residual disease <1.5 cm2 ) were treated with reduced craniospinal irradiation (23.4 Gy/13 fractions) with a posterior fossa boost of 32.4 Gy/17 fractions and the same chemotherapy as in the previous study by Packer et al. EFS at 5 years was 81% and OS, 86%. Adverse events, in particular hematologic toxicity and infections, were more predominant in the cyclophosphamide regimen. Following these results, this approach has become widely used in various institutions for the treatment of average risk children, with a preference for the lomustine based scheme, due to the better tolerance and its efficacy, which is similar to that achieved with the cyclophosphamide regimen [40]. Adult patients with average risk medulloblastoma are usually treated with post-operative radiation therapy only, as the use of chemotherapy in this subset of patients is still controversial and the hematological toxicity greater; data available on this aspect are reported in small retrospective studies [42] and one prospective trial [43].

Since surgery alone is associated with a high incidence of recurrence [35,36], complementary therapy is needed if medulloblastoma is to be treated with a curative intent. The cornerstone of medulloblastoma treatment is post-operative radiotherapy, for both patients with average and those with high-risk disease. Radiotherapy should start within the fifth postoperative week, as it has been demonstrated that delay is associated with worse local control and an impaired prognosis [37]. Furthermore, time to completion of RT has been demonstrated to be important in terms of prognosis, as delays and interruptions may have a negative impact on event free survival (EFS) [38].

7.2.2. High risk Standard radiotherapy for high-risk patients is craniospinal irradiation (36 Gy/20 fractions with posterior fossa boost of 19.8 Gy/11 fractions), patients with spinal metastatic dissemination requiring higher spinal irradiation doses (39.6 Gy/22 fractions). Chemotherapy is part of the treatment for high-risk patients but, to date, there is no consensus on regimens, doses, and timing of the chemotherapy in either pediatric or adult settings. In children, different schedules have been used in clinical trials and, at present, no one is considered standard. In adult patients, the preferred chemotherapeutic regimens are cisplatin or carboplatin and etoposide with or without

7. Treatment 7.1. Neurosurgery As the extent of resection (total or near total), the first therapeutic approach, is of prognostic significance, the most radical possible excision should be undertaken [33] by experienced surgeons for optimal outcome with a standard risk of complications. In the presence of hydrocephalus, it might be necessary to relieve intracranial pressure with ventriculoperitoneal shunt or third ventriculostomy before proceeding with the surgical tumor resection. Ventriculostomy is often undertaken prior to resection in order to spare the patient ventriculoperitoneal shunt placement [34]. Surgical resection can be complicated by hemorrhage, meningitis, cervical instability and posterior fossa syndrome (swallowing difficulties, mutism, truncal ataxia and emotional instability.

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cyclophosphamide, widely used on the basis of the results of the prospective study by Brandes et al. [12]. The exact timing of chemotherapy in adults (before or after radiotherapy) is still matter of debate. New radiotherapy techniques are under evaluation in order to reduce side effects from the treatment. Intensity modulated radiotherapy (IMRT) [44] and helical tomotherapy [45] have been evaluated, but only in a small series of patients for which results were disappointing. Tomotherapy does seem to be favorable in terms of target volume coverage, dose homogeneity, and reduction of dose to non-target tissues, but concerns have been raised regarding longer radiation beamon times that could lead to higher whole-body isodoses due to intra-fraction motion. Increased whole-body doses could increase the risk of radiation-induced tumors, especially in children. Proton therapy allows the delivery of high therapeutic dose within the target area, with lower non-target tissues irradiation than for standard and three-dimensional conformational therapy [46,47]. Normal-tissue dose sparing has been achieved with IMRT and proton treatment of the posterior fossa and spinal column. For example, in the study by St. Clair et al., the dose to 90% of the cochlea was reduced from 101.2% of the prescribed dose with conventional X-rays to 2.4% with protons. Similarly, the dose to 50% of the heart volume was reduced from 72.2% with conventional X-rays to 0.5% with protons [46]. In their study, Merchant et al. [47] created models to compare the effects of proton therapy vs. photon therapy in medulloblastoma and other brain tumors. These models showed that proton therapy could lead to a reduction in hearing impairment (less cochlear dose distribution) and slower cognitive and IQ decline over time. Also, reduced doses to the hypothalamic–pituitary axis may decrease the incidence of hypopituitarism. 7.3. Chemotherapy 7.3.1. Average risk The role of chemotherapy in the treatment of medulloblastoma has long been debated, both in the pediatric and the adult setting. In average-risk children, the use of chemotherapy was established after the results of trials that showed it prolonged EFS and OS. The PNET-3 [38] trial compared pre-radiation chemotherapy (alternating vincristine-etoposide-carboplatin and vincristine-etoposide-cyclophosphamide) followed by radiotherapy with radiotherapy alone in children with nonmetastatic disease (M1 patients were allowed), and found that EFS was significantly improved by chemotherapy and RT (78.5% at 3 years and 74.2% at 5 years compared with 64.8% at 3 years and 59.8% at 5 years), whereas no statistically significant difference was found between the two regimans for OS. At multivariate analysis it was found that chemotherapy (P = 0.0248) and time to complete RT (P = 0.01) affected EFS. In the German HIT91 trial [48], patients were randomized to receive neoadjuvant chemotherapy before radiotherapy (investigational arm) with ifosfamide, etoposide, intravenous high-dose methotrexate,

cisplatin, and cytarabine given in two cycles. In the standard arm, patients received immediate postoperative radiotherapy, with concomitant vincristine followed by eight cycles of maintenance chemotherapy consisting of cisplatin, lomustine, and vincristine. Relapse free survival was better in the post-RT group (78% vs. 65%), as was OS, with a 10-year OS rate of 91% vs. 62% in M0 patients and 70% vs. 34% in M1 patients. Following these results and those from the trial by Packer et al. [41], which showed that a RT dose reduction was feasible with concomitant vincristine and adjuvant chemotherapy (lomustine, cisplatin, vincristine), cytotoxic therapy became a standard practice in the treatment of children with medulloblastoma on a type 1 level of evidence. At present, the mainstay for patients older than 3 years and younger than 18 years of age is reduced dose RT (23.4 Gy/13 fractions) with posterior fossa boost of 32.4 Gy/17 fractions and concomitant vincristine administration with subsequent adjuvant chemotherapy (lomustine, cisplatin, vincristine), up to 8 cycles. The role of chemotherapy in adults with average riskdisease is still matter of debate. Given the rarity of the disease in the adult population, data on treatment derive mostly from retrospective, small series, and randomized studies are complicated to perform (Table 2). In the one available prospective study [43], in which patients were treated with radiotherapy (only if they were average risk) and with pre and post radiotherapy chemotherapy (if they were high risk), patients with average risk disease treated with RT alone had a 5-year PFS of 76%, compared with 61% of high risk patients treated with additional chemotherapy. Updated data after a follow up of 7.6 years showed no difference between the PFS and OS of average risk patients treated with RT only (54.8 Gy in 30 fractions) and high-risk patients treated with chemotherapy and RT (5 years PFS 80% vs. 69%; 5 years OS 80% vs. 73%). Results from a large retrospective analysis by Padovani et al. [42], showed that there was no difference between patients with average risk medulloblastoma treated with radiotherapy alone and that of those treated with radiotherapy in association with adjuvant chemotherapy (P = 0.7); in this retrospective study, the Authors collected data from 253 adult patients in order to analyze prognostic factors, and found, in the group of standard risk patients (n = 123), no significant difference between the 56% of patients treated with axial doses of ≥34 Gy and that of patients treated with craniospinal doses <34 Gy in combination with chemotherapy (46%) (P = 0.7). However, chemotherapeutic regimens were not homogeneous, as data were collected during a prolonged period from different centers. For average risk patients only fourth ventricular floor involvement (P = 0.035) and posterior fossa radiation dose <50 Gy 8 (P = 0.004) were significantly associated with a worse prognosis at a multivariate analysis. Current treatment for adult patients with average risk medulloblastoma, craniospinal irradiation (36 Gy in 20 fractions + posterior fossa boost − 18/19.8 Gy in 10–11 fractions), is followed by a 5-year PFS of >75%. Adjuvant

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Table 2 Studies with adjuvant chemotherapy on adult patients. Study

No. patients

Treatment

5-yr OS

Bloom 1990 [86]

47

RT RT → CT (in 1971–1981)

1952–1963: 38% 1964–1981: 59% 1971–1981: 76%

Prados 1995 [85]

47

RT → CT (in 32pts)

AR: 81% HR: 54%

Frost 1995 [8]

48

RT (only 1 pt treated with CT)

62%

Chan 2000 [11] Louis 2002

32 24

RT → CT (in 24 pts) RT → CT (in 6 pts)

83% 82%

RT → CT (in 143 pts)

AR: 77% HR: 65%

RT CT → RT → CT

AR: 80% HR: 73%

RT → CT

4 yr OS: 89%

Padovani 2007 [42] Brandes 2003 & 2007 [12] Friedrich 2012 [51]

253 10 AR 26 HR 70 (non metastatic)

Abbreviations: RT, radiotherapy; CT, chemotherapy; DEC, cisplatin, etoposide, cyclophosphamide; CDDP, cisplatin; CCNU, lomustine; PFS, progression-free survival; OS, overall survival; EFS, event-free serviva; AR, average risk; HR, high risk.

chemotherapy could be evaluated in higher risk histology (large cells/anaplastic). 7.3.2. High risk In general, it is accepted that the addition of chemotherapy to radiotherapy in high-risk patients improves the outcome. Nevertheless, data available are insufficient and questions remain open, especially regarding timing, dose and schedule of chemotherapy. The majority of trials undertaken demonstrate that the prognosis is dismal for this subgroup of patients. As described below, most of the trials showed that metastatic patients had a PFS of 20–40% and a 5-years survival rate of 20–30%. The CCSG trial [49] found that patients with metastatic disease had a 5-year EFS of 46% when treated with chemotherapy and radiotherapy, compared with zero for patients treated with chemotherapy alone. The study randomized 233 patients with medulloblastoma to receive RT alone or RT followed by adjuvant chemotherapy with CCNU, vincristine and prednisone. The EFS of non-metastatic patients was unchanged (EFS 51% for RT alone and 61% for RT and chemotherapy, P = 0.27), whereas patients with metastasis benefited from this chemotherapeutic regimen. In the HIT91 [48] study, 137 patients were randomized to receive pre-RT chemotherapy (ifosfamide, etoposide, high-dose methotrexate, cisplatin and cytarabine for 2 cycles) or concomitant vincristine and maintenance post-RT chemotherapy with cisplatin, CCNU and vincristine for 8 cycles. In patients with metastatic disease, maintenance chemotherapy was followed by a 5-year PFS rate of 30% and an OS of 30%. In their series, Chan et al. [11] reported a 5-year PFS rate of 45% with chemotherapy and radiotherapy. Prados et al. [50] treated 27 medulloblastoma patients (24 of which with high-risk disease) with chemotherapy plus radiotherapy.

One cycle of chemotherapy was given prior to, and for 6 cycles following, radiotherapy. Chemotherapy consisted of procarbazine, 6-thioguanine, dibromodulcitol, CCNU and vincristine. Hydroxyurea was given concomitant with RT. Fifteen patients had M1 or higher stage; these patients had a 5-year PFS and OS of 20% and 40%, respectively. Brandes et al. [43] achieved a PFS rate at 5 years of 45% in the group of adult patients with high-risk disease treated with cisplatin, etoposide, cyclophosphamide before and after radiotherapy. Updated results [12] showed that this group of patients had 5-year PFS rate of 69% and 5-year OS rate of 75%, similar to those patients with average risk disease treated with radiotherapy alone. Whether to treat adult patients with pre-RT or post-RT chemotherapy is still a matter of debate. In general, chemotherapy administered before cranio-spinal irradiation (CSI) is better tolerated, because after radiotherapy the incidence of hematological and neurological toxicity is higher. In the study by Friedrich et al. [51], in which adult patients were treated according to the HIT 2000 protocol (CCNU, vincristine and cisplatin for 8 cycles after radiotherapy), the incidence of grade ≥3 hematotoxicity was 58% and grade 2–3 neurotoxicity was 69%. Half the patients enrolled managed to receive all the 8 cycles and most of the patients experienced delays and required dose reductions. Another aspect is that in the studies that compared pre-RT with post-RT chemotherapy [48,52], the outcome of the patients who received CT before RT was not inferior to that obtained in patients treated with post-RT chemotherapy. Furthermore, in the study by Brandes et al. [12] no patients treated with pre-RT chemotherapy had disease progression during chemotherapy. Adult patients have been frequently treated with cisplatin, etoposide and cyclophosphamide or with cisplatinor carboplatin plus etoposide [12].

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7.4. Recurrent disease At present there is no standard treatment for recurrent disease. Depending on the site and the extent of relapse, different therapeutic options can be considered. 7.4.1. Surgery Re-resection is recommended if the patient is a suitable candidate for surgery and in the presence of local, resectable relapses [53,54]. No data from randomized trials comparing re-resection with other therapeutic approaches data are available. Nevertheless, data in literature have shown a prolongation of survival in patients re-resected for recurrence [55]. 7.4.2. Radiotherapy Radiotherapy, in particular stereotactic radiotherapy or radiosurgery, might be a therapeutic option in cases of recurrence with single, small lesions. Results from a small series of patients showed a control rate of 89% with these techniques, with survival rates of 65% at 1 year, 25% at 3 years and 17% at 5 years. The risks of re-irradiation have been described in literature, various authors reporting high rates of cumulative toxicity, in particular radionecrosis [56,57]. 7.4.3. Systemic treatments Systemic treatments are considered in cases of multifocal relapse. There are few data regarding the different agents and schemes used, as no clinical trials have been performed in order to test the efficacy and superiority of one treatment over another; data available generally derive from case reports and single institution experiences. In general, patients can be treated with platinum-etoposide containing regimens if the time to recurrence is long enough (>6 months) from first treatment. In literature there are reports of the activity of regimens such as CVP (cisplatin-cyclophosphamide-etoposide) or MOPP (methotrexate, procarbazine, vincristine, prednisone) [58], temozolomide and bevacizumab [59] or temozolomide alone [60]. Another approach is high-dose chemotherapy (HDCT) with stem cells transplantation. Most of the data in literature [61–65] derive from single case reports and small series and show prolongation of survival. Only one trial included a comparison group and reported an OS of 3.47 years with HDCT against 2 years following conventional chemotherapy [66]. Out of 66 patients reported in these publications, 7 died of toxicity. Therefore, this therapeutic option should be limited to a small group of selected patients and performed only in centers with expertise in the management of medulloblastoma and HDCT. Novel biological agents are under evaluation for the treatment of recurrent medulloblastoma. The most developed and promising agents are inhibitors of the hedgehog pathways, in particular Smo inhibitors, such as vismodegib and LDE225 (sonidegib). Vismodegib, which was active in one patient with bone metastases from medulloblastoma [67] and showed

a degree of activity in patients of the SHH subgroup in a phase I trial [68], is currently under evaluation in a phase II trial in adult patients (NCT00939484). LDE225 demonstrated efficacy in patients with solid tumors in a phase I trial [69] and is currently under evaluation in a phase II (NCT01125800) and a phase III trial (NCT01708174), in which the hedgehog pathway is being explored using a 5gene signature assay; a strong association between activation of this pathway and tumor response has been observed in patients with medulloblastoma. Therefore, the ongoing phase III trial is testing LDE225 on patients with the activated hedgehog pathway only. As it is known that these agents are effective in patients harboring Smo mutations (about 10% of all medulloblastomas), these agents can be offered to a small subset of patients. It should also be borne in mind that their activity is limited in time, and mechanisms of resistance have already been described. In particular, a mutation of Smo (SMO-D473H) that has no effect on HH signaling and induces loss of interaction between vismodegib and Smo has been identified [70]. Upregulation of Gli2, was found to be an important alternative mechanism that confers resistance against Smo antagonists [71,72]. IGF1R-PI3K target genes were overexpressed in NVP-LDE225 – resistant cells, suggesting that an up-regulation of this pathway may contribute to the development of resistance [72]. 7.5. Targeting stem cells It has been suggested that medulloblastoma cells have similar features to neural stem cells. Indeed, many of the pathways present in medulloblastoma, such as WNT, SHH and NOTCH, are also involved in the embryonal development of the neural tissue, and active in neural stem cells [4]. It has also been suggested that only a fraction of medulloblastoma cells have a stem-like phenotype, and it has been demonstrated that some cells can be maintained as neurospheres with the same techniques used to grow non-tumoral stem cells [73,74]. Furthermore, a fraction of medulloblastoma cells express stem-cell marker CD133 [75,76]. Stem cells, which usually have a high rate of proliferation, contribute to tumor growth and are known to be particularly resistant to common therapeutic agents. Targeting stem cells has always been an appealing issue in oncology. Some molecular targeted drugs are under development to target medulloblastoma stem-cell pathways, such as inhibitors of the hedgehog pathway and Notch. Hedgehog inhibitorsbove show some activity against medulloblastoma; nevertheless, it is unclear whether these drugs also affect medulloblastoma stem cells. In preclinical models, Notch inhibitors induce a marked reduction of CD133 cells in medulloblastoma cell lines [77]. Another proposed therapeutic approach is to target the stem cell niche, the micro-environment composed of supportive cells, extracellular matrix and factors required for the support and growth of stem cells. It is believed that, by disrupting this environment, stem cells will be eliminated. In preclinical models [78], it was found that CD133 medulloblastoma cells were

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localized in the proximity of endothelial cells and small vessels. This raises the hypothesis that anti-angiogenic treatment could be beneficial in targeting medulloblastoma stem cells [4]. 7.6. Immunotherapy Immunotherapy is another therapeutic approach that has been considered for the treatment of medulloblastoma. The target antigens that have been identified are cancer testis antigens (CTAs), MAGE and GAGE proteins [79,80]. MAGE-4 expression has been found in 50% of medulloblastomas, MAGE-A in 62% and GAGE in 84% [79]. MAGE antigens, already successfully targeted in other tumor types [81,82], are a promising targets for immunotherapy in patients with medulloblastoma. Other possible immunotherapeutic approaches are vaccinations against EGFRvIII in combination with GM-CSF, which have already been tested in other brain tumors [83], and intrathecal infusion of lymphokine activated killer (LAK) cells. This last therapeutic strategy was tested on 8 patients with the achievement of complete responses in 3 patients for up to 20 months [84]. Unfortunately, these results have not been replicated in the successive studies.

8. Conclusions Over the past 20 years, the outcome of patients with medulloblastoma has improved, thanks to the use of chemotherapy and improvement in radiotherapy techniques, which have enabled a reduction in the incidence of late iatrogenic sequelae. Major steps forward in the treatment of medulloblastoma are the advances made in molecular sequencing and the classification of the disease into molecular subgroups. The different molecular types of medulloblastoma have their peculiarities in terms of prognosis, clinical presentation and molecular targets. By identifying molecular subgroups of medulloblastoma it will become possible to modify the therapeutic options for specific patients. The current management protocols do not yet consider these molecular groups as a key factor in management, protocols still relying exclusively on clinical features. One of the main questions is how to incorporate molecular biology findings into the decision making process for the treatment of medulloblastoma. Division into molecular subgroups might become a useful tool for the risk stratification the patients, enabling the decision to be made as to whether to offer a more or less aggressive treatment based on the expected prognosis. For example, WNT tumors have an excellent outcome and could be treated less aggressively (reduced RT doses, avoidance of chemotherapy). Furthermore, the identification of specific molecular alterations should lead to the development of targeted agents, such as Smo inhibitors for SHH tumors. It thus seems reasonable to forsee that the integration of standard treatments

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(chemotherapy and RT) and targeted agents will become a therapeutic option for SHH medulloblastomas. The ongoing phase II trial (NCT01878617) well exemplifies treatment selection according to molecular stratification: the amount of radiation therapy and type of chemotherapy administered will be determined by the patient’s treatment stratum, based on the tumor’s molecular subgroup assignment and the clinical risk. Patients will be subdivided according to the molecular subgroups will be WNT, SHH and Non-WNT/Non-SHH, and then assigned to a clinical risk group (low, standard, intermediate, or high) based on the assessment of radiological staging, histology and chromosomal abnormalities. Patients with low-risk WNT tumors will undergo reduced dose craniospinal irradiation, while high-risk patients will be treated with standard RT and 4 cycles of cisplatin, vincristine and cyclophosphamide. SHH patients will receive standard treatments followed by maintenance therapy with vismodegib. After undergoing RT and chemotherapy, non-WNT/non-SHH patients with high-risk disease will be given maintenance treatment with pemetrexed and gemcitabine [87]. In conclusion, the discovery of molecular subgroups has generated a numerous hypotheses for tailoring of treatment, and most of the tailored treatments suggested are already under evalutation. The results of ongoing studies are awaited in order to understand whether the adaptation of therapies to the molecular subgroups could lead to an improvement in the outcome of the disease. Further molecular characterization will allow the identification of novel targeted therapies and will help improve the reliability of risk stratification for patients. It is therefore hoped that a more personalized approach to this disease will be achieved, and patients with a good prognosis will be spared the side effects of intensive treatments, while new and intensified therapeutic approaches could be modeled for high-risk patients in order to improve their survival.

Conflict of interests statement The authors declare that they have no conflict of interests.

Reviewers Prof. Rolf Dieter Kortmann, Universität Leipzig, Klinik und Poliklinik für Strahlentherapie und Radioonkologie, Stepanstrasse 9A, D-04103 Leipzig, Germany. Prof. Andreas F. Hottinger, CHUV University Hospital, Department of Clinical Neurosciences & Oncology, Department of Clinical Neurosciences & Oncology, BH 08/635, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland.

Please cite this article in press as: Brandes AA, et al. New perspectives in the treatment of adult medulloblastoma in the era of molecular oncology. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2014.12.016

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Prof. Roger Stupp, UniversitaetsSpital Zuerich, Cancer Center & Department of Oncology, Rämistrasse 100, CH8091 Zurich, Switzerland.

Acknowledgement The authors express their gratitude to GICNO (Gruppo Italiano Cooperativo di Neuro-Oncologia) for supporting and funding the research.

References [1] Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007;114:97–109. [2] Peris-Bonet R, Martinez-Garcia C, Lacour B, et al. Childhood central nervous system tumours – incidence and survival in Europe (1978–1997): report from Automated Childhood Cancer Information System project. Eur J Cancer 2006;42:2064–80. [3] Smoll NR, Drummond KJ. The incidence of medulloblastomas and primitive neurectodermal tumours in adults and children. J Clin Neurosci 2012;19:1541–4. [4] Fan X, Eberhart CG. Medulloblastoma stem cells. J Clin Oncol 2008;26:2821–7. [5] Rutkowski S, von Hoff K, Emser A, et al. Survival and prognostic factors of early childhood medulloblastoma: an international metaanalysis. J Clin Oncol 2010;28:4961–8. [6] Brandes AA, Franceschi E, Tosoni A, et al. Adult neuroectodermal tumors of posterior fossa (medulloblastoma) and of supratentorial sites (stPNET). Crit Rev Oncol Hematol 2009;71:165–79. [7] Eran A, Ozturk A, Aygun N, Izbudak I. Medulloblastoma: atypical CT and MRI findings in children. Pediatr Radiol 2010;40(7):1254–62. [8] Frost PJ, Laperriere NJ, Wong CS, Milosevic MF, Simpson WJ, Pintilie M. Medulloblastoma in adults. Int J Radiat Oncol Biol Phys 1995;32:951–7. [9] Carrie C, Lasset C, Alapetite C, et al. Multivariate analysis of prognostic factors in adult patients with medulloblastoma. Retrospective study of 156 patients. Cancer 1994;74:2352–60. [10] Chang CH, Housepian EM, Herbert Jr C. An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas. Radiology 1969;93:1351–9. [11] Chan AW, Tarbell NJ, Black PM, et al. Adult medulloblastoma: prognostic factors and patterns of relapse. Neurosurgery 2000;47:623–31 [discussion 31–32]. [12] Brandes AA, Franceschi E, Tosoni A, Blatt V, Ermani M. Long-term results of a prospective study on the treatment of medulloblastoma in adults. Cancer 2007;110:2035–41. [13] Thompson MC, Fuller C, Hogg TL, et al. Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 2006;24:1924–31. [14] Kool M, Koster J, Bunt J, et al. Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS ONE 2008;3:e3088. [15] Cho YJ, Tsherniak A, Tamayo P, et al. Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol 2011;29:1424–30. [16] Northcott PA, Korshunov A, Witt H, et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 2011;29:1408–14. [17] Taylor MD, Northcott PA, Korshunov A, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 2012;123:465–72.

[18] Remke M, Hielscher T, Northcott PA, et al. Adult medulloblastoma comprises three major molecular variants. J Clin Oncol 2011;29:2717–23. [19] Kongkham PN, Northcott PA, Croul SE, Smith CA, Taylor MD, Rutka JT. The SFRP family of WNT inhibitors function as novel tumor suppressor genes epigenetically silenced in medulloblastoma. Oncogene 2010;29:3017–24. [20] Ramaswamy V, Northcott PA, Taylor MD. FISH and chips: the recipe for improved prognostication and outcomes for children with medulloblastoma. Cancer Genet 2011;204:577–88. [21] Northcott PA, Jones DT, Kool M, et al. Medulloblastomics: the end of the beginning. Nat Rev Cancer 2012;12:818–34. [22] Hatten ME, Roussel MF. Development and cancer of the cerebellum. Trends Neurosci 2011;34:134–42. [23] Zhukova N, Ramaswamy V, Remke M, et al. Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J Clin Oncol 2013;31:2927–35. [24] Shonka N, Brandes AA, De Groot JF. Adult medulloblastoma, from spongioblastoma cerebelli to the present day: a review of treatment and the integration of molecular markers. Oncology (Williston Park) 2012;26:1083–91. [25] Rios I, Alvarez-Rodriguez R, Marti E, Pons S. Bmp2 antagonizes sonic hedgehog-mediated proliferation of cerebellar granule neurones through Smad5 signalling. Development 2004;131:3159–68. [26] Zhao H, Ayrault O, Zindy F, Kim JH, Roussel MF. Post-transcriptional down-regulation of Atoh1/Math1 by bone morphogenic proteins suppresses medulloblastoma development. Genes Dev 2008;22: 722–7. [27] Merve A, Dubuc AM, Zhang X, et al. Polycomb group gene BMI1 controls invasion of medulloblastoma cells and inhibits BMP-regulated cell adhesion. Acta Neuropathol Commun 2014;2:10. [28] Dubuc AM, Remke M, Korshunov A, et al. Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma. Acta Neuropathol 2013;125:373–84. [29] Parsons DW, Li M, Zhang X, et al. The genetic landscape of the childhood cancer medulloblastoma. Science 2011;331:435–9. [30] Robinson G, Parker M, Kranenburg TA, et al. Novel mutations target distinct subgroups of medulloblastoma. Nature 2012;488:43–8. [31] Lee MG, Wynder C, Cooch N, Shiekhattar R. An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 2005;437:432–5. [32] Bunt J, Hasselt NA, Zwijnenburg DA, Koster J, Versteeg R, Kool M. OTX2 sustains a bivalent-like state of OTX2-bound promoters in medulloblastoma by maintaining their H3K27me3 levels. Acta Neuropathol 2013;125:385–94. [33] Albright AL, Wisoff JH, Zeltzer PM, Boyett JM, Rorke LB, Stanley P. Effects of medulloblastoma resections on outcome in children: a report from the Children’s Cancer Group. Neurosurgery 1996;38:265–71. [34] Bartlett F, Kortmann R, Saran F. Medulloblastoma. Clin Oncol (R Coll Radiol) 2013;25:36–45. [35] Hubbard JL, Scheithauer BW, Kispert DB, Carpenter SM, Wick MR, Laws Jr ER. Adult cerebellar medulloblastomas: the pathological, radiographic, and clinical disease spectrum. J Neurosurg 1989;70:536–44. [36] Ferrante L, Mastronardi L, Celli P, Acqui M, Cervoni L, Fortuna A. Medulloblastoma in adulthood. J Neurosurg Sci 1991;35:23–30. [37] Abacioglu U, Uzel O, Sengoz M, Turkan S, Ober A. Medulloblastoma in adults: treatment results and prognostic factors. Int J Radiat Oncol Biol Phys 2002;54:855–60. [38] Taylor RE, Bailey CC, Robinson K, et al. Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: the International Society of Paediatric Oncology/United Kingdom Children’s Cancer Study Group PNET-3 study. J Clin Oncol 2003;21:1581–91. [39] Berry MP, Jenkin RD, Keen CW, Nair BD, Simpson WJ. Radiation treatment for medulloblastoma. A 21-year review. J Neurosurg 1981;55:43–51.

Please cite this article in press as: Brandes AA, et al. New perspectives in the treatment of adult medulloblastoma in the era of molecular oncology. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2014.12.016

ONCH-1925; No. of Pages 12

ARTICLE IN PRESS A.A. Brandes et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx

[40] Packer RJ, Goldwein J, Nicholson HS, et al. Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: a Children’s Cancer Group study. J Clin Oncol 1999;17:2127–36. [41] Packer RJ, Gajjar A, Vezina G, et al. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 2006;24:4202–8. [42] Padovani L, Sunyach MP, Perol D, et al. Common strategy for adult and pediatric medulloblastoma: a multicenter series of 253 adults. Int J Radiat Oncol Biol Phys 2007;68:433–40. [43] Brandes AA, Ermani M, Amista P, et al. The treatment of adults with medulloblastoma: a prospective study. Int J Radiat Oncol Biol Phys 2003;57:755–61. [44] Breen SL, Kehagioglou P, Usher C, Plowman PN. A comparison of conventional, conformal and intensity-modulated coplanar radiotherapy plans for posterior fossa treatment. Br J Radiol 2004;77:768–74. [45] Sharma DS, Gupta T, Jalali R, Master Z, Phurailatpam RD, Sarin R. High-precision radiotherapy for craniospinal irradiation: evaluation of three-dimensional conformal radiotherapy, intensity-modulated radiation therapy and helical TomoTherapy. Br J Radiol 2009;82:1000–9. [46] St Clair WH, Adams JA, Bues M, et al. Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma. Int J Radiat Oncol Biol Phys 2004;58:727–34. [47] Merchant TE, Hua CH, Shukla H, Ying X, Nill S, Oelfke U. Proton versus photon radiotherapy for common pediatric brain tumors: comparison of models of dose characteristics and their relationship to cognitive function. Pediatr Blood Cancer 2008;51:110–7. [48] Kortmann RD, Kuhl J, Timmermann B, et al. Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT ‘91. Int J Radiat Oncol Biol Phys 2000;46:269–79. [49] Evans AE, Jenkin RD, Sposto R, et al. The treatment of medulloblastoma. Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and prednisone. J Neurosurg 1990;72:572–82. [50] Prados MD, Wara W, Edwards MS, et al. Treatment of high-risk medulloblastoma and other primitive neuroectodermal tumors with reduced dose craniospinal radiation therapy and multi-agent nitrosourea-based chemotherapy. Pediatr Neurosurg 1996;25:174–81. [51] Friedrich C, von Bueren AO, von Hoff K, et al. Treatment of adult nonmetastatic medulloblastoma patients according to the paediatric HIT 2000 protocol: a prospective observational multicentre study. Eur J Cancer 2013;49:893–903. [52] Tarbell NJ, Friedman H, Polkinghorn WR, et al. High-risk medulloblastoma: a pediatric oncology group randomized trial of chemotherapy before or after radiation therapy (POG 9031). J Clin Oncol 2013;31:2936–41. [53] Network NCC. Clinical practice guidelines in oncology: central nervous system cancers. Version 1.2013; 2013. www.nccn.org/ professionals/physician gls/f guidelines.asp#site [54] Services AH. Clinical practice guidelines, cancer care: medulloblastoma; 2010. www.albertahealthservices.ca/hp/if-hp-cancer-guidecns008-medulloblastoma.pdf [55] Balter-Seri J, Mor C, Shuper A, Zaizov R, Cohen IJ. Cure of recurrent medulloblastoma: the contribution of surgical resection at relapse. Cancer 1997;79:1241–7. [56] Bauman GS, Sneed PK, Wara WM, et al. Reirradiation of primary CNS tumors. Int J Radiat Oncol Biol Phys 1996;36:433–41. [57] Tokuuye K, Akine Y, Sumi M, et al. Reirradiation of brain and skull base tumors with fractionated stereotactic radiotherapy. Int J Radiat Oncol Biol Phys 1998;40:1151–5. [58] Kunschner LJ, Kuttesch J, Hess K, Yung WK. Survival and recurrence factors in adult medulloblastoma: the M.D. Anderson Cancer Center experience from 1978 to 1998. Neuro Oncol 2001;3:167–73. [59] Privitera G, Acquaviva G, Ettorre GC, Spatola C. Antiangiogenic therapy in the treatment of recurrent medulloblastoma in the

[60] [61]

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75] [76] [77]

[78] [79]

[80] [81]

11

adult: case report and review of the literature. J Oncol 2009;2009: 247873. Durando X, Thivat E, Gilliot O, et al. Temozolomide treatment of an adult with a relapsing medulloblastoma. Cancer Invest 2007;25:470–5. Dunkel IJ, Gardner SL, Garvin Jr JH, Goldman S, Shi W, Finlay JL. High-dose carboplatin, thiotepa, and etoposide with autologous stem cell rescue for patients with previously irradiated recurrent medulloblastoma. Neuro Oncol 2010;12:297–303. Zia MI, Forsyth P, Chaudhry A, Russell J, Stewart DA. Possible benefits of high-dose chemotherapy and autologous stem cell transplantation for adults with recurrent medulloblastoma. Bone Marrow Transplant 2002;30:565–9. Dunkel IJ, Boyett JM, Yates A, et al. High-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue for patients with recurrent medulloblastoma. Children’s Cancer Group. J Clin Oncol 1998;16:222–8. Abrey LE, Rosenblum MK, Papadopoulos E, Childs BH, Finlay JL. High dose chemotherapy with autologous stem cell rescue in adults with malignant primary brain tumors. J Neurooncol 1999;44:147–53. Graham ML, Herndon 2nd JE, Casey JR, et al. High-dose chemotherapy with autologous stem-cell rescue in patients with recurrent and high-risk pediatric brain tumors. J Clin Oncol 1997;15:1814–23. Gill P, Litzow M, Buckner J, et al. High-dose chemotherapy with autologous stem cell transplantation in adults with recurrent embryonal tumors of the central nervous system. Cancer 2008;112:1805–11. Asklund T, Henriksson R, Axelsson J, et al. Early and persisting response to vismodegib in a patient with bone metastasizing medulloblastoma. Acta Oncol 2013;52:862–6. Gajjar A, Stewart CF, Ellison DW, et al. Phase I study of vismodegib in children with recurrent or refractory medulloblastoma: a pediatric brain tumor consortium study. Clin Cancer Res 2013;19:6305–12. Rodon J, Tawbi HA, Thomas AL, et al. A phase 1, multicenter, open-label, first-in-human, dose-escalation study of the oral hedgehog inhibitor sonidegib (LDE225) in patients with advanced solid tumors. Clin Cancer Res 2014. Yauch RL, Dijkgraaf GJ, Alicke B, et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 2009;326:572–4. Dijkgraaf GJ, Alicke B, Weinmann L, et al. Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer Res 2011;71: 435–44. Buonamici S, Williams J, Morrissey M, et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med 2010;2:51ra70. Hemmati HD, Nakano I, Lazareff JA, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci U S A 2003;100:15178–83. Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 2004;64:7011–21. Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003;63:5821–8. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature 2004;432:396–401. Fan X, Matsui W, Khaki L, et al. Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 2006;66:7445–52. Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells. Cancer Cell 2007;11:69–82. Kasuga C, Nakahara Y, Ueda S, et al. Expression of MAGE and GAGE genes in medulloblastoma and modulation of resistance to chemotherapy. Laboratory investigation. J Neurosurg Pediatr 2008;1:305–13. Oba-Shinjo SM, Caballero OL, Jungbluth AA, et al. Cancer-testis (CT) antigen expression in medulloblastoma. Cancer Immun 2008;8:7. Kim SH, Castro F, Gonzalez D, Maciag PC, Paterson Y, Gravekamp C. Mage-b vaccine delivered by recombinant Listeria monocytogenes

Please cite this article in press as: Brandes AA, et al. New perspectives in the treatment of adult medulloblastoma in the era of molecular oncology. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2014.12.016

ONCH-1925; No. of Pages 12

12

[82]

[83] [84]

[85]

[86]

[87]

ARTICLE IN PRESS A.A. Brandes et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx

is highly effective against breast cancer metastases. Br J Cancer 2008;99:741–9. Atanackovic D, Altorki NK, Stockert E, et al. Vaccine-induced CD4+ T cell responses to MAGE-3 protein in lung cancer patients. J Immunol 2004;172:3289–96. Kim W, Liau LM. Dendritic cell vaccines for brain tumors. Neurosurg Clin N Am 2010;21:139–57. Okamoto Y, Shimizu K, Tamura K, et al. An adoptive immunotherapy of patients with medulloblastoma by lymphokine-activated killer cells (LAK). Acta Neurochir (Wien) 1988;94:47–52. Prados MD, Warnick RE, Wara WM, Larson DA, Lamborn K, Wilson CB. Medulloblastoma in adults. Int J Radiat Oncol Biol Phys 1995;32:1145–52. Bloom HJ, Bessel EM. Medulloblastoma in adults: a review of 47 patients treated between 1952 and 1981. Int J Radiat Oncol Biol Phys 1990;18:763–72. Morfouace M, Shelat A, Jacus M, et al. Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma. Cancer Cell 2014;25(April (4)):516–29.

Biographies

Antonio Fioravanti is a neuro-surgeon at the Department of Neurosurgery, Bellaria Hospital – IRCCS Institute of Neurological Sciences, Azienda USL, Bologna, Italy. Maurizio Mascarin is a radiotherapist at the Department of Radiotherapy Unit, CRO, Aviano, Italy. Lorenzo Volpin is the Head of the Department of Neuroscience and Neurosurgery, San Bortolo Hospital, Vicenza, Italy. Franco Ammannati is the Head of the Department of Neurosurgery I, Careggi University Hospital, Firenze, Italy. Barbara Masotto is a neurosurgeon in the Section of Neurosurgery, Department of Neuroscience, University of Verona, Verona, Italy. Marina Paola Gardiman is a pathologist at the Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University Hospital, Padova, Italy.

Alba Brandes is the Head of Medical Oncology Department, Bellaria-Maggiore, Azienda USL, Bologna, Italy.

Dario De Biase is a molecular biologist at the Department of Medicine (DIMES) – Anatomic Pathology Unit, Bellaria Hospital, University of Bologna, Bologna, Italy.

Marco Bartolotti is an oncologist in Medical Oncology Department, Bellaria-Maggiore, Azienda USL, Bologna, Italy, and involved in brain tumor treatment and clinical research.

Giovanni Tallini is a pathologist of the Department of Medicine (DIMES) – Anatomic Pathology Unit, Bellaria Hospital, University of Bologna, Bologna, Italy.

Gianluca Marucci is a pathologist in the Department of Biomedical and NeuroMotor Sciences (DiBiNeM), University, of Bologna, Section of Pathology, M. Malpighi, Bellaria Hospital, Bologna, Italy. Claudio Ghimenton is a pathologist in the Pathology Department, Verona Hospital, Verona, Italy. Raffaele Agati is a neuro-radiologist Department of Neuroradiology, Bellaria-Maggiore Hospitals, Azienda USL – IRCCS Institute of Neurological Sciences, Bologna, Italy.

Girolamo Crisi is the Head of the Department of Neuroradiology, Parma University Hospital, Parma, Italy. Stefania Bartolini is a biologist and data-manager in Medical Oncology Department, Bellaria-Maggiore, Azienda USL, Bologna, Italy. Enrico Franceschi is an oncologist in Medical Oncology Department, Bellaria-Maggiore, Azienda USL, Bologna, Italy, and involved in brain tumor treatment and clinical research.

Please cite this article in press as: Brandes AA, et al. New perspectives in the treatment of adult medulloblastoma in the era of molecular oncology. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2014.12.016