1. GENERAL INFORMATION
2. PATHOLOGY AND BIOLOGY
3. DIAGNOSIS
4. STAGING
5. PROGNOSIS
6. TREATMENT
7. LATE SEQUELAE
8. FOLLOW UP
References
Contributors


1. GENERAL INFORMATION

1.1 Incidence

Among all the childhood central nervous system tumours, medulloblastoma and other neuroectodermal tumours (International Classification of Disease for Oncology, ICD-O 9470/3–9474/3) account for 16-25% of cases (Louis 2007). The European annual incidence rate was 6.5 per million children (age 0-14 years) for the period 1988-1997, with no substantial differences between European regions. Incidence was significantly higher in boys than in girls (about 60% boys). The annual incidence rate was higher in children between 1 and 9 years of age (8 per million), slightly reduced in infants (6 per million), and it was lowest in 10-14 aged children (4 per million) (Peris-Bonet 2006).

1.2 Survival

Five year overall survival in children with diagnosis between 2000 and 2002 was 66%, and infants had the worst prognosis. There was a significant improvement of survival for children diagnosed in 2000-2002 compared to those diagnosed in 1995-1999. The risk of dying was reducedby 30% (Gatta 2009).

1.3 Risk factors

The causative factors of medulloblastoma/PNET have not been well established. Since a peak of incidence occurs during childhood, factors operating very early in life might play a key role. Birth weight has often been suggested to be a crude but easily accessible marker of prenatal exposures. Only a small proportion of birth weight is attributable to genetic influences; most of its variance is determined by nongenetic factors, such as maternal nutritional status and body weight, maternal diseases, and environmental exposures during pregnancy. Harder et al conducted a metaanalysis on the association between birth weight and risk of specific histologic types of primary brain tumors. For medulloblastoma, high birth weight was positively associated with increased risk (odds ratio = 1.27, 95% CI: 1.02, 1.60) (Thomas 2008). Recent studies have speculated on a potential infectious aetiology. A case control study in England evaluated various perinatal factors and their impact on childhood brain tumour. The Authors found that the children of mother who had a documented viral infection during pregnancy had 11-fold increased risk of malignant nervous system tumour (Fear 2001). A further large population based case-control study investigated the patterns of day care and early social contacts, as well as other markers of infectious exposure. The results showed a weak positive association between lack of social contact in the first year of life and an increased risk of developing a CNS tumor in childhood. This effect was most prominent in the primitive neuroectodermal tumor/medulloblastoma subgroup (OR 1.78, 95% CI 1.12–2.83) (Harding 2008). However, other proxy markers of infectious exposure that were analysed i.e., bedroom sharing, domestic exposure to school-age children, and birth order did not support the hypothesis of a protective effect of infectious exposure.The role of diet, both as a risk and as a protective factor, has been investigated in several studies. Among the most extensively studied hypotheses is that maternal dietary intake of N-nitroso compounds (NOC) and NOC precursors during pregnancy increases brain tumor risk in offspring. Cured meats are a major source of dietary NOC. Maternal dietary was investigated in a large international collaborative case–control study on childhood brain tumors to evaluate associations between histology-specific risk and consumption of specific food groups during pregnancy. Foods generally associated with increased risk were cured meats, eggs/dairy, and oil products; foods generally associated with decreased risk were yellow–orange vegetables, fresh fish, and grains. However, cured meat was not associated with medulloblastoma. An increased risk was found between of medulloblastoma and oil products (OR, 1.5; 95% CI, 1.0–2.2 for 4th vs. 1st quartile; p trend=0.005) (Pogoda 2009). Less recent studies reported a significant reduction in risk with folate supplementation and PNET in children (Bunin 1993; Thorne 1995). Exposure to electromagnetic fields is a potential risk factor for childhood brain tumour. Exposure to high levels of electromagnetic frequencies (EMF) at close proximity suggests an increased risk. However, these studies were performed with small patient numbers (Baldwin 2004). A large childhood cancer study, the United Kingdom (UK) Childhood Cancer Study, found no association between EMF and childhood brain tumours, specifically, after performing an extensive exposure assessment including several different types of EMF measurement (OR = 0.97, 95% CI = 0.46–2.05) (UKCCSI 1999). A recent large Canadian study (Peizhi 2009) examined the contribution of maternal occupational exposure to extremely low frequency magnetic fields (ELF-MF) shortly before and during pregnancy on the incidence of childhood brain tumours. A significantly increased risk was observed for astroglial tumours as well as for all childhood brain tumours, but no association was specifically assessed for medulloblastoma/PNET.
Several epidemiological investigations have attempted to evaluate the association between parental exposure to pesticide and childhood brain tumours, with the majority reporting positive associations (Baldwin 2004). In a recent population-based case–control study, the association between the occurrence of brain cancer in children and parental exposure to pesticides in occupa¬tional and residential settings was evaluated. The authors observed little association with PNET for any of the pesticide classes or exposure sources considered (Youn 2009). A further study, that investigated the association between the father’s hobbies and medulloblastoma/PNET (MB/PNET), found an increase risk of MB/PNET in children from the household exposures from hobbies, particularly pesticides. In multivariate analyses, a significant association was seen for lawn care with pesticides [during pregnancy: odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.0, 2.5; after birth: OR = 1.8, 95% CI: 1.2, 2.8] (Rosso 2008). Considering parental occupation, a European study found an elevated risk of PNET with parental exposure to polycyclic aromatic hydrocarbons (PAH) (OR=2.0, 95% CI=1.0-4.0) and high maternal exposure to solvent (OR=3.2, 95% CI=1.0-10.3) during the five-year period before birth (Cordier 1997).

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2. PATHOLOGY AND BIOLOGY

The 2007 WHO classification of CNS tumours recognises the classic medulloblastomas and the following four variants: desmoplastic/nodular; medulloblastoma with extensive nodularity (MBEN); anaplastic, and large cell (Giangaspero 2007). Of these variants, the anaplastic and large-cell medulloblastomas show a certain degree of overlapping and they have been grouped as large-cell/anaplastic (LCA) medulloblastomas in several studies (Gilbertson 2008). The frequency of the combined LCA form varies from 10% to 22%. Nodular/desmoplastic medulloblastoma and MBEN comprise approximately 7% and 3% of all medulloblastomas, respectively. Classic tumours constitute the remainder (McManamy 2007). Classic medulloblastoma is composed of densely packed cells with round-to-oval or carrot-shaped hyperchromatic nuclei surrounded by scanty cytoplasm. Desmoplastic/nodular medulloblastoma is avariant that contains nodular, reticulin-free zones, or ‘pale islands’ which represent zones of neuronal maturation, exhibits a reduced nuclear:cytoplasmic ratio, a fibrillary matrix and uniform cells with a neurocytic appearance. These nodules are surrounded by densely packed mitotically active cells which produce a dense intercellular reticulin-positive network of fibres. Medulloblastoma with extensive nodularity – (MBEN) occurs in infants and is associated with a good prognosis. It differs from the related nodular/desmoplastic variant by having an expanded lobular architecture, due to the fact that the reticulin-free zones become unusually elongated and rich in neuropil-like tissue. Such zones contain a population of small cells with round nuclei, which resemble the cells of a central neurocytoma and exhibit a streaming pattern. The internodular component is markedly reduced in some areas.
An interesting issue, recently clarified in the literature, is the frequency of desmoplastic variants and its correlation with age.McManamy et al reported in 2007 on the UK series (SIOP/UKCCSG PNETsIII): 315 cases > 3years and (SIOP UKCCSG CNS 9204): 35 cases < 3 years to clarify this issue. The frequency of the desmoplastic variants of 57% in patients younger than 3 years of age and 5-25% in older children was described. Garrè et al. reported similar numbers in a series of 83patients treated at a single institution: 52% in patients ≤ 3 years and 15% (9/57) in older children (Garrè 2009).
The large cell medulloblastoma is composed of monomorphic cells with large, round, vesicular nuclei, prominent nucleoli and variably abundant eosinophilic cytoplasm. Groups or sheets of these ‘large cells’ tend to mix with cells that have a different morphology characterised by marked nuclear pleomorphism and nuclear moulding The latter phenotype has been labelled ‘anaplastic’ (Figure 1).

Large cell and anaplastic medulloblastomas show considerable cytological overlap. Histological progression over time, from non-anaplastic to anaplastic types has been described in several studies, and a transition can be even observed within a single tumour, as inferred from the presence of differing degrees of cytological atypia or anaplasia in one tumour (Eberhart 2002).
Clinical data strongly indicate a favourable prognosis for the nodular/desmoplastic medulloblastoma (Rutkowski 2005), Moreover, comparing the outcome of classic and LCA medulloblastomas, a significantlyworse prognosis is evident for the LCA variant (McManamy 2003; McManamy 2007) .
Deletions of 17p and isochromosome 17q (i17q), which combines loss of 17p and gain of 17q, have long been recognized as the most common chromosomal alterations in medulloblastoma (Lo 2007). The nodular/desmoplastic and LCA variants are also associated with specific chromosomal alterations. Deletions of 9q are observed in up to 40% of desmoplastic medulloblastomas, but occur rarely in tumours of the classic variant, and amplifications of the MYCC and MYCN oncogenes occur predominantly in LCA tumours.The risk stratification of medulloblastoma may be improved by addition of biological markers such as β-catenin, c-myc and trkC (Ellison 2005; Rutkowski 2007). Two subsequent papers have in fact outlined the possibility of classifying medulloblastoma patients according to the newly known biological mechanisms, such as MYC amplification that is found in approximately 5-15% of cases, mutations in Sonic Hedgehog (SHH) pathway genes (PTCH1, SUFU) that are found in nearly 25% of medulloblastoma and in WNT pathway genes (ß-catenin, APC, AXIN) found in approximately 15% of cases. In both these papers specific genetic signatures were able to both divide medulloblastoma into five distinct subgroups (subgroups A to E) and to assign clinical risk categories to these subgroups, thus outlining the possibility of a better selection and evaluation of patients in clinical trials and supporting the development of new molecular target therapies (Thomson 2005; Kool 2008).
Tumorigenesis of medulloblastoma is strongly related to deregulation of signalling pathways involved in normal development of the cerebellum. The proliferation of granular cell precursors (GNP) is physiologically regulated by the Sonic Hedgehog (SHH) signaling pathways. SHH is secreted from Purkinje cells in the cerebellum and binds to the Patched (Ptch) receptor on GNPs, which derepresses the Smoothened (Smo) receptor and activates transcription of SHH targets, such as the Gli transcription factors (Gli1). This signaling pathway has also been implicated in the formation of medulloblastoma (Marino 2005).There is evidence suggesting that a subset of medulloblastoma cells have a stem-cell like phenotype that drives tumour growth. It has been found that cells expressing the stem-cell marker CD133, obtained from some established medulloblastoma cell lines, have a greatly increased ability to form tumour xenografts (Fan 2008).


3. DIAGNOSIS

Computerized Tomography (CT) is sometimes the first-line neuroimaging modality for patients with posterior fossa tumours because of its availability in an emergency setting. A typical feature of medulloblastoma seen with CT is a midline, homogeneous, contrast-enhancing cerebellar vermian mass. MRI is however a mandatory follow-on imaging, that should be carried out before tumour surgery. MRI features that are typical of medulloblastoma include a heterogeneous hypointense mass on T1-weighted imaging. In contrast to other CNS tumours that show T2-weighted hyperintensity compared with grey matter, medulloblastomas are intermediate between grey and white matter. Contrast enhancement of medulloblastomas is usually heterogeneous. Spinal metastases, which occur in up to 40% of patients, are most commonly seen in the lumbosacral and thoracic areas and are best seen on post-contrast T1-weighted images. In doubt ful cases they should be confirmed or excluded by axial slices. It is therefore imperative to have an MRI of the spine before starting any adjuvant treatment.Whole CNS imaging shoulde be repeated before defined phases of postoperative treatment (Buhring 2002) as a standard procedure.
Medulloblastoma can be disseminated at diagnosis, and occurs sometimes in the brain with a particular predisposition for subependymal areas of the ventricles. Other imaging modalities such as magnetic resonance spectroscopy (MRS), PET, and single photon emission computed tomography (SPECT) can be helpful to distinguish tumour recurrence from post-therapy necrosis. These imaging modalities might have substantial implications for the future directions of research into medulloblastoma. However, these evaluations are to be considered still investigational.


4. STAGING

Staging and subsequent risk stratification are crucial in the management of medulloblastoma. Current staging classification requires analysis of the cerebro-spinal-fluid (CSF) and MRI of the brain and entire spine with and without gadolinium. CSF from the lumbar region is preferred because it is a more sensitive medium than ventricular fluid for detecting disseminated disease. CSF should be obtained from the lumbar region 2 weeks postoperatively to avoid a false-positive cytology after the initial resection (Gajjar 1999).
Contraindications for lumbar puncture (increased intracranial pressure etc.) must be considered cautiously. Assessment of the CSF for disseminated disease is crucial, because up to 10% of adults and 30% of children have evidence of disseminated disease at presentation.
Traditionally, MB patients are stratified into standard and high-risk groups for therapy according to the clinical presentation, depending on the presence of metastases(M1-M4) or residual disease >1.5 cm2 according to North American stratification, as determined by early (within 24-72 hours) post-operative MRI (Packer 2003). The type of risk group for an MB patient is determined according to Chang's classification for metastases (Table 1) (Chang 1969).

Table 1. Chang classification for metastases
M0 No gross nodular or laminar subarachnoid or haematogenous metastasis
M1 Microscopic tumour cells in the cerebrospinal fluid
M2 Gross nodular or laminar seeding in the cerebellum, cerebral
subarachnoid space, or in the third or fourth ventricles
M3 Gross nodular or laminar seeding in the spinal subarachnoid space
M4 Extra-neuraxial metastasis

Patients are generally divided into risk-stratified schemes on the basis of age, the extent of residual disease, and dissemination (Figure 2).

Sixty to 70 % of patients older than 3 years are assigned to the average-risk group. High-risk patients include those in the disseminated category, and in North American trials those that have less than a gross or near-total resection, which is arbitrarily defined as 1.5 cm2 of postoperative residual disease (Figure 3).



Tumour staging will be probably implemented in forthcoming trials through integration with biological findings that have been found in retrospective series to correlate with outcome, such as proteins or genes encoding for neurotrophin-3 receptor, MYC, ErbB2,beta-catenin, survivin and p-53 (Grotzer 2001; Rutkowski2007; Ellison 2005) 40% of cases.

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5. PROGNOSIS

Today, current treatment protocols that include surgery, craniospinal irradiation, and chemotherapy have achieved 5-year overall survival rates over 70% for standard-risk patients (Packer 2003).
Until a few years ago, metastatic medulloblastoma series reported dismal results with 5-year survival around 30-50% (Evans 1990). Nowadays,intensified chemotherapy regimens (myeloablative schedules with hematopoietic support of peripheral harvested stem cells) and non-conventional radiotherapy schedules seem to have improved prognosis – with 5-year survival rates around 70% - that will need to be confirmed in further trials (Gajjar 2006 ; Gandola 2008).
Similar considerations can be applied to younger children (under 3 or 4-5-years of age at diagnosis, according to national policies) that have traditionally been treated with risk- and age adapted radiotherapy – frequently reducing total craniospinal doses - and prolonged chemotherapy schedules with the aim of reducing late sequelae especially those related to radiation treatment, and therefore reducing the risk of relapse and intensive re-treatment for around 50% of patients (Duffner 1993; Grill 2005). The most recent German experience, using systemic chemotherapy schedule combined with intraventricular methotrexate, has resulted in a 5-year progression free survival of 83% (Rutkowski 2005), thus demonstrating that a tailored use of drugs is able to replaceradiotherapy, at least in some sub-groups of patients.

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6. TREATMENT

Current and currently planned clinical trials will:
1) evaluate the feasibility of reducing both the dose of craniospinal irradiation and the volume of the posterior fossa radiotherapy boost by the modest intensification of chemotherapy in standard-risk patients;
2) determine whether intensification of chemotherapy or irradiation can improve outcome in patients with high-risk disease;
3) define molecular and biological markers that improve outcome prediction in patients with medulloblastoma and which can be incorporated for front-line stratification of newly defined risk subgroups.

6.1 Surgery

Surgical resection is a fundamental part of treatment. Depending on the location and dimensions of the tumour, an external ventricular shunt or third ventriculostomy might be needed as emergency treatment, before tumour resection, to decrease intracranial pressure secondary to fluid circulation obstruction at the foramina of Luschka, foramina of Magendie, or the aqueduct of Sylvius. About 20-30% of patients will require a permanent ventriculo-peritoneal shunt consequent to scarring of the cerebro-spinal fluid pathways. The close relationship of medulloblastoma to the fourth ventricle and sometimes brainstem is a risk for morbidity, but expert paediatric neurosurgeons are frequently able to remove the tumour gross-totally without creating major morbidity, on a type 3 level of evidence (Albright 2000). Apart from infections and mechanical complications, such as fluid leak and pseudomeningocele, direct neurosurgical manipulation can cause posterior fossa mutism syndrome (Robertson 2006). This is characterized by mutism developing 48-72 hours after resection, and is associated with severe cerebellar deficits such as dysmetria, hypotonia, paresis, and mood depression, which can last several months. It is probably secondary to disruption of reticular substance pathways.

6.2 Standard risk patients

After surgical resection, the mainstay for patients older than 3 years at diagnosis is “reduced-dose” craniospinal irradiation (CSI) with a total dose of 23.4 Gy within 40 days plus a localized boost to the posterior fossa up to a total dose of 54-55.8 Gy. This is usually combined with weekly concurrent single-drug – vincristine – and followed by a multidrug regimen that can be cisplatin, vincristine and lomustine or cisplatin, vincristine and cyclophosphamide, on a type 1 level of evidence (Packer 1990; Packer 2006). Five-year event-free survival based on this regimen is over 80%.
The “simple” regimen of craniospinal irradiation, without the addition of adjuvant chemotherapy, has in fact shown a higher number of early failures when 23.4 Gy was randomized against 36 Gy. These results were not confirmed as statistically significant at a longer follow-up but prompted the premature closure of the study and the addition of chemotherapy in subsequent trials (Thomas 2000).
Further reduction of craniospinal irradiation dose and of posterior fossa boost dimensions is currently under evaluation in a randomized COG (Children Oncology Group) study, and at present is not recommended .
Another prospective clinical trial, the HIT-SIOP PNET4 trial, conducted and recently closed in Europe, compared conformal conventionally fractionated craniospinal radiotherapy at a dose of 23.4 Gy plus boost with hyperfractionated craniospinal irradiation (2 x 1 Gy/d) at a dose of 36 Gy plus boost, followed by the same chemotherapy schedule with 8 courses of vincristine (1.5 mg/m2 for 3 doses), cisplatin (70 mg/m2) and lomustine (75 mg/m2). The aims of this randomised trial were to compare progression-free-survival and late effects after the two different radiation schedules. Hyperfractionated radiation is a technique that, at least theoretically, can achieve increased tumour cell kill with equal effects on critical normal tissues, or reduce normal tissue effects without reduction of tumour cell kill.
A French study on standard-risk medulloblastoma patients treated by hyperfractionated radiotherapy without adjuvant chemotherapy has reached a 3-year progression-free survival of 83% with a good neuro-cognitive outcome at three years of follow-up (Carrie 2005). Future trials may further evaluate the efficacy and safety of this treatment modality.

High-risk group patients. As already mentioned in the “Staging” paragraph, patients are stratified for therapy into standard and high-risk groups according to their clinical presentation, depending on the presence of metastases alone (M1-M4) or with postoperative residual disease >1.5cm2. This is based on North American stratification methods (Packer 2003). The prognosis for high-risk medulloblastoma is still unsatisfactory. Ever since the 1980’s when, whether high-risk or not, medulloblastoma has been treated with a protocol including radiation therapy and chemotherapy (vincristine and CCNU), patients had a better prognosis if they received chemotherapy (Tait 1990; Evans 1990). Chemotherapy is therefore part of adjuvant treatment in this group of patients, on a type 1 level of evidence , but optimal timing and schedule are not yet established.
A single centre study considering the use of RT followed by vincristine, cisplatin and CCNU in high-risk patients reported a survival rate of around 85% (Packer1988). In a SIOP (International Society of Pediatric Oncology) trial open from 1984 to 1989 and published with a 76-month follow-up, 27 metastatic patients treated with standard-dose RT followed by CCNU and vincristine obtained a 5-year PFS of 43% (Bailey 1995). These results were comparable to the SFOP (French Society of Pediatric Oncology) study, which treated high-risk patients with the “eight-drugs-in-one-day" chemotherapy regimen, followed by two cycles of high-dose MTX, RT and then further “eight in one” chemotherapy (Gentet 1995). The subsequent French national study confirmed the rate of response to the “sandwich” chemotherapy, but was without any significant improvement in either M1 or M2/M3 patients, who achieved a 5-year EFS of 58.8% and 43.1%, respectively (Verlooy 2006). The Children's Cancer Group 921 randomized phase III trial, open from 1986 to 1992, also proposed an “eight-in-one” chemotherapy regimen before and after RT. The 83 metastatic patients had a significantly lower PFS than the standard-risk patients (57% M1; 40% M2; 78% NED/M0, p = 0.0006) (Zeltzer 1999). In the randomized prospective multi-centre trial HIT '91, post-operative neoadjuvant chemotherapy (ifosfamide, etoposide, iv high-dose methotrexate, cisplatin and cytarabine given in two cycles) followed by craniospinal RT was compared to maintenance chemotherapy after immediate postoperative RT ("Philadelphia protocol"). The 3-year PFS for all randomized patients was 65% for M1 patients and 30% for M2-M3 patients, thus achieving a statistically significanct difference (Kortmann 2000).
More recent studies have produced encouraging results with high-dose chemotherapy and autologous stem cell transplantation. Strother et al. enrolled 19 patients with metastases for treatment with topotecan, followed by CSI and four cycles of high-dose cyclophosphamide with cisplatin and vincristine, followed by CPC reinfusion. The PFS 2 years after starting the therapy was 73.7% ± 10.5% (Strother 2001). This experience was expanded, treating a total of 42 metastatic patients, and obtaining a 5-year EFS of 66% (Gajjar 2006). A preliminary study was conducted on 9 patients with supratentorial primitive neuroectodermal tumours and metastatic medulloblastoma who were treated with high-dose cyclophosphamide with cisplatin, vincristine, etoposide and high-dose MTX for 2-3 cycles before radiotherapy. The results were interesting: 7/9 patients were tumour-free after a median follow-up of 27 months (Dhodapkar 2002). In a more recent trial, open from 1997 to 2003, 21 young patients with high-risk or disseminated medulloblastoma were enrolled for evaluation of their response rate to an intensified induction chemotherapy regimen and single myeloablative chemotherapy cycle with autologous stem-cell rescue. This was followed by RT for patients morethan six years of age, or with evidence of residual disease on completion of the induction chemotherapy if under six years old. The 3-year EFS and OS were 49% and 60%, respectively (Chi 2004).
The European phase III clinical trial SIOP/UKCCSG PNET-3 ascertained the feasibility of treating high-risk medulloblastoma with neoadjuvant CT (vincristine, cisplatin, etoposide and cyclophosphamide) followed by a standard CSI dose with a posterior fossa boost and/or a boost to metastases. The outcome was rather unsatisfactory in metastatic patients in comparison with earlier multi-institutional series, obtaining a 5-year PFS of less than 40% (Taylor 2005).
Gandola et al (Gandola 2008) have recently reported on 33 consecutive patients, treated in a semi-institutional setting, receiving postoperative methotrexate (8g/m²) plus vincristine, etoposide (2.4g/m²), cyclophosphamide (4g/m²); and carboplatin (0.8g/m²) in a 2-month schedule. Hyperfractionated accelerated radiotherapy (HART) was then delivered at a total dose to the neuraxis of 39 Gy (1.3 Gy/fraction,2 fractions/day) with a posterior fossa boost up to 60 Gy (1.5 Gy/fraction,2 fractions/day). In cases of persistent disseminated disease before HART, patients were consolidated with 2 courses of myeloablative chemotherapy and circulating progenitor cell rescue. Otherwise, they received a maintenance chemotherapy with vincristine and lomustine for one year. In this series, patients were classified as M1 (9), M2 (6), M3 (17), and M4. Twenty-two of the 32 evaluable patients responded to chemotherapy, disease was stable in 5 and progressed in 5. One septic death occurred before radiotherapy. Eight patients relapsed after a median 12 months. Fourteen of the 33 patients were consolidated after HART. With a median follow-up of 82 months, the 5-year EFS, PFS and OS were 70%, 72% and 73%, respectively. No severe clinical complications of HART have emerged so far. The authors concluded that HART with intensive postoperative chemotherapy and myeloablative chemotherapy proved to be feasible without limiting major toxicity in children with metastatic medulloblastoma.
None of these studies has so far provided more than a type 3 evidence concerning the contribution of high doses of craniospinal irradiation, possibly delivered through a hyperfractionated/accelerated modality, together with high-dose chemotherapy schedules to achieve better disease control. It is therefore desirable that wider phase 3 trials should be initiated to obtain stronger evidence. Until that time, our recommendations are to enrol these patients in controlled clinical trials, because of the dismal prognosis and the more aggressive treatment required, with accompanying acute and long-term side-effects.

6.3 Treatment for younger children

In the past, the survival of infants with medulloblastoma was inferior compared to older children. Possible reasons that may explain this observation were: delay in diagnosis, increased surgical risk, increased toxicity due to RT, under-treatment,and a potentially “more aggressive” biology. A cut-off age levelof3 years had been introduced in the mid- ‘80s because strategies to delay or omit irradiation had high priority in order to reduce unacceptable sequelae (Ries 1999; Milchaskil 2004; Duffner 2003; Garrè 2006).
The severe permanent sequelae seen in long-term survivors treated with craniospinal irradiation at a young age, with or without CT,were in fact considered unacceptable. Thus trials were performed in the USA in the 1980’s,andthen in Europe after 1985 using up-front CT in order to delay or to avoid RT. The MOPP protocol, which was a pioneering project, was used on 12 cases, 8 of whom became long-term survivors (Ater 1997).The first Paediatric Oncology baby protocol (POG1), which was the first large cooperative study that attempted to delay irradiation by using conventional CT, was followed by several American (Children’s Cancer Study Group – CCSG) and European (baby protocols of the Société Francaise D’Oncologie Pediatrique- SFOP, of the Italian Association for Pediatric Oncology-AIEOP, and German Society of Pediatric Oncology and Hematology – GPOH (HIT-SKK ’87 study) cooperative studies (Duffner 2003; Duffner 1999; Garrè 2003; Grill 2005; Rutkowski 2009). The POG1 study required children< 2 years of age to be treated with CT for 2 years, while children who were two to three years of age were treated for 1 year. Both groups were eligible for RT at the end of CT. Sixty-two cases were recruited. Event Free Survival (EFS) and overall survival (OS) at 5 yrs were 30% and 69% respectively. Radical resection was a favourable prognostic factor, as 69% of M0/T0 cases became long-term survivors (13 cases) (Duffner 1999).
The CCSG study tested the “8 in 1” protocol. After a median follow-up of 6 years,a 3 year EFS of 22% was obtained and long term survival was below 30% in M0/T0 cases (Geyer 2005). These initial studiesshowed that only a minority ofpatients with M0/T0could be cured with conventionalCT, and that thedisease could not be controlledin patients with residual tumour after surgery and/or metastases. Therefore,European and American studies intensifiedsystemic CT (POG2), while others added intraventricular CT (Germany) orhigh-dose systemic methotrexate (Italy - AIEOPSNC9501) (Garrè 2003). Standard CTin France (Baby SFOP Protocol) included alternating coursesof carboplatin/procarbazine, etoposide/cisplatin, vincristine/cyclophosphamide for 18 months. Thirty-three out of 47 MO/TO patients progressed during/after CT, but OS was 76%. The results in metastatic cases were unsatisfactory (PFS 16%), while localized failures in M0/T0 were successfully rescued by high dose CT, with or withoutre-operation, followed by focal irradiation. Neuro-psychological outcome was also reported (Grill 2005).
A German study investigated intraventricular CT in 43 patients. Although this study showed no favourable impact on metastatic disease, it achieved the best known OS and EFS in M0/T0 patients without irradiation (14/17 were cured) (Rutkowski 2005).Neuropsychological outcome was better than for cases treated with CSI (Rutkowski 2009), and about the same as cases treated with systemic chemotherapy alone, or controls. Due to the limited number of cases and special aspects of using intraventricular CT, it remains to be clarified whether these data can be reproduced in a larger international co-operative study.
The introduction of sequential HDCT for relapsed patients or“up-front” forpatients with metastases is currently being investigated in the 2nd generation studies, and high response rates have been reported (Dallorso 1999; Kalifa 1999; Garrè 2003). The French group has also demonstrated that reduced volumes of irradiation after HDCT contributed to long-term survival (Grill 2005; Kalifa 1999).Current and future studies should clarify whether these regimens can also increase the proportion of patients that may be cured without RT in the M0/T0 group, as well as in the high risk group. TheItalian AIEOPinfantpilot study, which uses HDCT followed either by conformal RT on the residual tumour or by CSI in patients with metastases, shows that 5 year EFS in the first 20 study patients has increased (70%) with respect to previous series where standard-dose schedules were adopted (Garrè 2003; Garrè 2009 ).
It is still unclear whether the subset of infants that were cured in each study had peculiar biological features that favoured survival. The HIT-SKK’92 study analyzed the impact of the histological variants and reported a high frequency of desmoplastic medulloblastoma (40%). In addition, the prognosis for desmoplastic medulloblastoma was significantly better compared with classic medulloblastoma (Rutkowski 2005). A recent single institution retrospective study reports a similar observation, confirming the high frequency of desmoplastic variants and particularly of MBEN in young ages and the high frequency of association between Gorlin Syndrome and MBEN, which was observed in 40% of cases (Garrè 2009). Further prospective cooperative studies addressing these issues should be performed.
In conclusion, the treatment of infant MB has evolved (role of RT revisited and more intensive CT adopted) during the last 10-15 years, and survival rates have been improved by modern treatment strategies; recent observations seem to show that age per se is no longer an adverse prognostic factor. This is due to the impact of reserving more intensive treatment for advanced stage disease and unfavourable histology along with the presence of favourable histological variants (in up to 50% of cases).
Many national groups recognize a role for high-dose chemotherapy in delaying or avoiding CSI as a part of multimodal treatment strategy in early childhood medulloblastoma, especially in young children with metastatic or residual disease. The efficacy of such chemotherapy intensification may allow a revised role for irradiation, which may be usedwith reduced volumes in selected groups of patients when irradiation cannot be safely delayed or avoided (i.e patients with metastases or unfavourable histology).
Future studies will clarify the prognostic relevance of desmoplasia, postoperative residual tumour and biological markers, in order to improve stratification criteria by risk-adapted treatment recommendations. An international phase III trial for young children with non-metastatic medulloblastoma, comparing survival rates and neurocognitive outcomes of different treatment strategies using standardized criteria, is under discussion within the International Society of Pediatric Oncology (SIOP).
Due to the higher frequency (28%) of cancer predisposition syndromes (mainly Gorlin Syndrome) in young patients (Garrè 2009; Amlashi 2003) with medulloblastoma, future trials should include guidelines for the identification of such conditions, and for genetic counseling to families. Due to the increased risk of secondary tumours and the frequency of naevoid basal-cell carcinomas in irradiated fields, every attempt should be made to avoid radiotherapy in infants when associated with Gorlin syndrome or infants who are at risk of showing it in subsequent years (if presenting with medulloblastoma with extensive nodularity).

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7. LATE SEQUELAE

Long-term sequelae of patients treated for medulloblastoma, including motor, sensory, endocrinological, cognitive, neuropsychological and behavioural deficits, can markedly affect their quality of life and their re-entry into school and society.

7.1 Endocrine sequelae

The occurrence of neuro-endocrine deficiencies following craniospinal irradiation for medulloblastoma is well known. Surgically induced deficiencies manifest shortly after surgery while radiation-induced damage may manifest months to years after irradiation. For this reason long-term endocrine surveillance after craniospinal irradiation is mandatory on a type 1 level of evidence (Heikens 1998).
Radiation-induced damage is currently considered a consequence of a direct neuronal rather than vascular injury to the hypothalamus on a type 3 level of evidence (Darzy 2008). Subsequently, due to the prolonged absence of rh-GH-stimulating action, pituitary function may be affected. The hypothalamus-pituitary axis has a different radiosensitivity, with the GH axis being the most radiosensitive followed by the gonadotrophin, ACTH and thyroid-stimulating hormone (TSH) axes.

GH DEFICIENCY (GHD). GHD is observed in 40-80% of survivors of medulloblastoma (Fossati 2008). Incidence of GHD depends on: age at radiotherapy, total dose delivered (>45 Gy), fields of radiotherapy, duration, fractions, and time after irradiation. The time interval after the end of treatment and chemotherapy are not determinant in causing GH deficiency. It worsens with time and frequently becomes irreversible. GHD may develop from 3 months to 5 years after the end of radiotherapy.
Growth screening of irradiated children includes on a type 1 level of evidence (Bull 2007): antropometric measurements (height, weight, BMI, lower segment and arm span, Tanner staging) every 6 months until growth complete and/or sexually mature than once a year (always refer to endocrine, or at least if height/weight 2 percentile channels, growth < 4-5cm per year and/or lack of pubertal growth spurt), nutritional evaluation (every 6 months), laboratory tests (IGF-1 -even if its role is debated-,IGF binding protein 3, bone age determination, insulin tolerance test and GH provocative tests – sleep, exercise, arginin, clonidine and levodopa).
Once diagnosed, the standard treatment of GHD consists of substitutive therapy with 0.18-0.3 mg/kg somatropin or 0.3 mg/kg somatrem, both daily as a standard option on a type 1 level of evidence.
Substitutive therapy is widely considered safe in terms of tumour recurrence and it can be started 1 year after completion of the oncological treatment with no evidence of further tumor growth (Rose 2003 ; Sklar 2002; GHRS 2000).
Three other causes of growth failure must be ruled out before starting GH replacement therapy: 1) slowing of growth during the acute phase of radiotherapy secondary to poor caloric intake, 2) poor spinal (but not limb) growth after radiation of the spine secondary to destruction of growth plates in the spine following spinal irradiation, and 3) premature closure of the epiphyses due to precocious puberty.
GONADAL ALTERATIONS. Gonadal alterations in children treated for medulloblastoma include: precocious puberty, delayed puberty and hypogonadism.
Incidence depends on: age at treatment (patients treated at younger ages are less susceptible due to sufficient follicular stores (Rutter 2007), concomitant radiochemotherapy, and radiotherapy doses. Gonadal alterations can be demonstrated after 1 year from the end of radiotherapy.
The neuro-oncological evaluation in children with possible gonadal alterations includes on a type 1 level of evidence: yearly estradiol levels assessment and pelvic ultrasonography in females, and yearly testicular volume, testosterone and β-HCG levels in males. For males and females annual height/weight assessment, LH and FSH basal and after GnRH stimulation, bone age, GH levels and Tanner stage should be monitored (Nandagopal 2008).
PRECOCIOUS PUBERTY is defined as the development of secondary sexual traits before the age of 8 years in females and 9 years in males accompanied by rapid growth in height; this alteration often coexists with GHD (and in this case if GHD is not treated the child will not benefit of the pubertal growth spurt reaching a short final height). Early detection of precocious puberty is mandatory in order to avoid a short final stature, on a type 1 level of evidence . The treatment of central precocious puberty consists in the administration of long-acting analogs of GnRH agonists, such as leuprolide acetate (1.88-3.75 mg/i.m. monthly) as a standard treatment option .
DELAYED PUBERTY must be considered when the patient does not show secondary sexual development by age of 14 for boys and 13 for girls. Replacement therapy might prove useful, and standard treatment options include: conjugated estrogen (0.3 mg) or ethynil estradiol (5-10 µg) orally daily for females and testosterone enanthate (100 mg) once in every 4 weeks for males.
OTHER DETECTABLE ALTERATIONS in survivors of pediatric medulloblastoma are: infertility and precocious menopause.Sterility is more frequent in males and it is related to alkylating agents. Before treating sexually mature boys/girls with chemotherapy or irradiation, physicians should address the possibility of infertility with patients, including fertility-preservation options and appropriate referral to reproductive specialists (Rutter 2007).
HYPOTHYROIDISM Alterated thyroid function during both craniospinal and cranial radiotherapy with central hypothyroidism after radiotherapy has been reported with a prevalence of about 6% (Anderson 2003). The role of chemotherapy in inducing thyroid damage is debated. Incidence of hypothyroidism also depends on RT fractions delivered. Hypothyroidism may contribute to growth failure and learning disabilities in survivors. Other symptoms are fatigue, weight gain, cold intolerance, constipation, dry skin, brittle hair and depressed mood. In some studies, most thyroid dysfunctions have been detected within 4 years after radiotherapy. Recommendations for annual screening, on a type 1 level of evidence , include a focused history for symptoms of hypothyroidism, height, weight, skin, hair and thyroid examination, annual bone densitometry. FT4-TSH assessment should be performed every 6 months (Nandagopal 2008). The values should be maintained in the upper half of the normal range.Thyroid hormone recommended replacement is made with oral L-thyroxine once daily orally (0.05-0.1 mg), and in case of complete thyroid failure, 4-5 µg/Kg/day for children and 2-3 µg/Kg/day for adults (Corrias 2001).
HYPERTHYROIDISM Hyperthyroidism may rarely occur after irradiation for pediatric medulloblastoma. Symptoms include: heat intolerance, tachycardia, palpitations, weight loss, emotional lability, muscular weakness and hyperphagia. Screening for hyperthyroidism consists of yearly physical examination (eyes, skin, thyroid, heart and neurologic examination) and FT3-FT4-TSH assessment (Nandagopal 2008) .
THYROID NODULES Yearly thyroid physical examination should be performed. Periodical ultrasound examination is required, and fine needle aspiration should be considered in case of suspicious nodules (Nandagopal 2008).
HYPERPROLACTINEMIA Hyperprolactinemia is a frequent finding after brain irradiation and may be due to the destruction of the hypothalamus-pituitary axis or to primary hypothyroidism. It has been described in both sexes and all age groups, but is most frequently observed in the adult females (Darzy 2008). It has only been demonstrated more than 2 years after therapy. Screening includes periodic PRL and TSH assays, and when PRL levels are higher than 50 ng/ml a pituitary MRI should be performed. The clinical features of hyperprolactinemia in females include oligomenorrhea or amenorrhea with anovulation or infertility, in males decreased libido and sexual potency with progressive hypogonadism are observed. Galactorrhea is a less frequent finding, and rare in males.
Spontaneous resolution of the hyperprolactinemia at 5-6 years after radiotherapy is a sporadic finding,more often a standard treatment with a dopamine agonists is necessary (Bromocriptine 1.25-5 mg/day orally gradually increasing the dose, or Cabergoline 0.25-1 mg/week orally).
CENTRAL ADRENAL INSUFFICIENCY ACTH deficiency is rare but potentially life threatening; in one series it has been reported in 24% of pediatric brain cancer survivors, most of whom were medulloblastoma survivors (Fossati 2008).
Symptoms include failure to thrive, anorexia, dehydratation, hypoglycemia, lethargy and unexplained hypotension. Laboratory assessments include 8:00 a.m. cortisol dosage. Given that central adrenal insufficiency has been detected in survivors many years after the completion of therapy, an 8:00 a.m. serum cortisol level should be obtained yearly until 15 years off therapy, on a type 1 level of evidence . Further endocrinological evaluations and treatment are needed if cortisol levels are< 10 µg/dl (Nandagopal 2008) .
If ACTH deficiency is suspected on clinical grounds, a test of the whole axis, such as the ITT or the metyrapone test should be performed, on a type 1 level of evidence (Toogood 2004).
OSTEOPENIA/OSTEOPOROSIS Osteopenia/Osteoporosis can be caused by both steroid therapy and craniospinal irradiation while GH deficiency does not seem to be an important factor (Anderson 2003).Bone density evaluation by DEXA or quantitative CT should be performed during follow-up, starting at 2 years after completion of cancer therapy. The patient should be referred to a specialist if osteoporosis is suspected (T score ≥ 2.5 DS or history of multiple fractures (Nandagopal 2008) .
Calcium and Vitamine D supplementation and optimisation of endocrine replacements are important as well, on a type 3 level of evidence (Krishnamoorthy 2004).
OVERWEIGHT/OBESITY, DYSLIPIDEMIA, AND METABOLIC SYNDROME Cranial RT but also the heavy metals carboplatin and cisplatin often used in medulloblastoma may cause dyslipidemia. Concurrent GH deficiency and hypothyroidism may exacerbate overweight/obesity. The survivors follow-up includes annual assessments of blood pressure and body mass index. Fasting blood glucose, serum insuline and lipidic profile should be screened every 2 years in patients who are overweight or obese, and every 5 years in normal weight patients. Other co-morbid conditions such as dylipidemia, hypertension, glucose intolerance, diabetes mellitus, hyperinsulinism, and insulin resistance should be monitored. Counseling for dietary modification, exercise, and weight loss should be given while a pharmacologic intervention should be considered in patients unresponsive to dietary and lifestyle modifications (Nandagopal 2008).
NEUROCOGNITIVE OUTCOME Many survivors of medulloblastoma treatment experience long-term cognitive, neuropsychological and academic impairments: cognitive impairments are frequent, and specific neuropsychological deficits affect the later cognitive development and the acquisition of new skills. The ultimate neurocognitive outcome is very complex and depends on a number of factors that interact in unpredictable ways. The functional neurocognitive domains that are affected the most by treatment are: attention, executive functioning, processing speed, working memory and learning, which adversely influence academic performance (Palmer 2007; Palmer 2008; Mabbot 2008). It is well established, on a type C basis, that children with medulloblastoma demonstrate declines in neurocognitive functioning and academic achievement over time. Because of deficits in these important functional domains, survivors experience declines in Intelligence Quotient (IQ) and academic achievement relative to their same-age peers. This does not mean that the cognitive growth rate is arrested or declines as in dementia, but it is reduced compared with same-age peers. Therefore, as the time since treatment increases, the gap in abilities between the survivors and the general population increases. This gap challenges some survivors in problem solving, academic achievement, independent living, and the quality of life in general.
In some children the IQ drops by as much as 3 to 4 points per year: brain calcifications, leucoencephalopathy and reductions in white matter volume correlate with these declines in neurocognitive functioning (Palmer 2007).
The late neurocognitive effects can be caused by any of the treatment modalities; the main risk factors for their onset include:
1) (Younger) Age at diagnosis and treatment. The earlier the brain damage, the worse and more generalized is the cognitive impairment. The brain damage caused by the tumour site, the presence of clinical complications and oncological treatment arrests the physiological development of brain structures and functions, affecting or halting the processes leading to new skills acquisition, with a negative domino effect on cognitive development (Mulhern 2001): there is an evidence on a type C basis;
2) Tumour site (tumour invasion of normal brain/compression of the tumour on the brain parenchyma and trauma from surgical resection). Because of their location in, or near the cerebellum, cognitive and neuropsychological difficulties may arise from the primary impact of the tumour and surgical resection due to damage to this structure. The cerebellum plays an important role in higher cognitive functions given the reciprocal connections with the frontal lobe, and there can be long-term deficits in speech, language and communication, executive function, visuospatial ability and behavioural regulation (Reeves 2006; Palmer 2008).
3) Clinical complications (hydrocephalus). Posterior cranial fossa tumours, cerebellar and pontine tumours can cause an obstruction of the 4th ventricle with ensuing hydrocephalus. This, in turn, may cause a generalized damage and nonspecific cognitive problems that add to the structural and functional damage that is specifically related to the tumour site (Hardy 2008).
4) Cranial radiation therapy (CRT). The most prominent deficits for children with brain tumours are associated with cranial radiotherapy: Patients receiving CRT are significantly more likely to have school problems than other brain tumour patients and experience a pervasive decline in knowledge acquisition. Poor intellectual outcome is associated with higher radiation doses and a larger volume as well as younger age at radiotherapy. The effects of CRT begin to clinically impact cognitive functioning at about 1 year post-treatment and show a continuing pattern of decline over time. An analysis of longitudinal changes in IQ scores over time revealed that younger patients experience an immediate decline that continued over time, while older patients experienced a delay in decline for about 2 years (Mulhern 1998; Jain 2008).
5) Sensory and motor impairments. Such deficits heavily impact on the later learning experience and the natural cognitive decline (Palmer 2007).
In general, two processes could account for the cognitive decline experienced by patients with medulloblastoma. Children who show a decline in their standardized IQ scores could be losing previously acquired information as evidenced by a decline in raw scores. They could continue otherwise to acquire new information, but at a rate slower than expected when compared with normal same-age peers, with a decline in standard scores. A slow rate of knowledge acquisition directly affects a patient’s potential academic performance, so these survivors are at great risk of losing the ability to live independent lives. School completion is highly dependent on the achievement of basic academic skills, including reading and spelling (Palmer 2007). These skills have served as important endpoints in comprehensive studies of cognitive ability following treatment for medulloblastoma (Mulhern 2005; Palmer 2007). Patients younger than 7 years show a greater impairment in reading than patients with an older age at diagnosis. While measures of intelligence and school achievements are important for understanding treatment-related changes, it is evident that changes in more basic cognitive skills such as memory, attention and processing may occur earlier in the cascade of events. In point of fact, attention and behaviour planning and organization as well as the ability to store and organize information are critical prerequisites for knowledge acquisition. It has been speculated that in children treated for medulloblastoma the inability to acquire new information and skills at a rate comparable to healthy same-age peers may be due to deficits in underlying core abilities such as memory, attention and speed of processing.
Given these issues, targeted functional assessments should be carried out periodically, on a type C basis, in order to test for cognitive problems, if any, and start specific rehabilitation together with appropriate school support.
Besides interventions aimed at reducing the neurotoxicity to the CNS, effective intervention programmes may be considered the second line of defence against the cognitive decline following treatment. An early assessment of a child’s deficits and strengths is necessary to help parents and teachers provide proper care, support and recovery from hospitalization. Generally, children who survive paediatric medulloblastoma are impaired, so they necessitate long-term multidisciplinary follow-up and treatment for psychological–emotional difficulties. The degree of impairment varies, however, between patients. Patients at heightened risk of developing specific cognitive deficits should be accurately screened to start intervention programs that can include drug therapy (Thompson 2001), cognitive therapy to enhance attention through metacognitive strategies and cognitive-behavioural strategies, along with personalized educational and support programmes (Askins 2008).
Furthermore, patients treated for medulloblastoma frequently show psychological and behavioural problems such as inadequate social competence, withdrawal, anxiety and depression that affect social adjustment and interpersonal skills. These emotional and behavioural disorders adversely influence their psychological functioning and quality of life.
Given the complexity and variability of these deficits, a range of rehabilitative services should be offered including speech and language therapy, occupational therapy, physical therapy, psychotherapy and educational remediation. Furthermore, as problems may arise at a later time, regular follow-ups are needed to monitor the children’s cognitive development and school progress.

7.2 Neurosensorial late effects

Auditory deficits are the most frequent late effects and are associated both with cochlear irradiation during boost to posterior fossa and cisplatin use (Packer 2003). Hypoacusia can be monolateral or bilateral and so severe as to require hearing aid. Audiometry is therefore constantly required during treatment and with regular follow-up examinations to provide early correction of deficits.
Visual defects relating to acuity are mainly due to intracranial hypertension while, nystagmus and diplopia may be found secondary to mass effects and tumour removal. Other defects, such as dysmetria and ataxia are frequently ameliorated by early re-education.
Orthopedic late-effects. Craniospinal irradiation can be a concomitant cause of kyphosis and of vertebral demineralization. This may also be caused by steroidal therapy, GH and gonadotropin deficits, or altered food intake. Vertebral growth is obviously altered by irradiation and not helped by growth hormone replacement (Odame 2006).
Second tumours.The use of both irradiation and chemotherapy (alkylating agents, nitrosureas, etoposide) contributes to the occurrence of secondary tumours (Goldstein 1997). Meningiomas, cavernomas and glial tumours are found in radiation fields as long as thirty years after treatment, and justify the prolongation of follow-up.
Secondary tumours due to treatment have to be distinguished from those arising in cancer predisposition syndromes like Gorlin’ and Turcot’s syndromes.

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8. FOLLOW-UP

Relapses of medulloblastoma occur and more than half of these relapses have a component of disseminated disease. Relapses occur in nearly 75% of paediatric cases within 2 years. Relapse is most commonly diagnosed by neuroimaging; occasionally, clinical progression precedes neuroimaging findings. There are no formal clinical trials that address the specific question of the frequency of MRI use for radiographic surveillance (Minn 2001).
Patients enrolled in study protocols have a formal timetable for imaging, although when a patient has completed therapy the intervals between MRI scans become arbitrary. We generally recommend imaging of the brain and spine every 3 months for the first 2 years;
later MRI of the brain should be performed every 4 months for the third year, every 6 months until the fifth year and then annually on a type C basis. Evaluation of the spineis generally required only in case of clinical suspicion.
Part of follow-up is all the clinical, radiological and biochemical examinations, together with tailored tests for neuro-functional capabilities as detailed in the “late-effects” section.

8.1 Treatment at relapse

The approach to treatment of a patient with relapsing medulloblastoma varies, and depends on a range of factors. First, the age of the patient is important when deciding to use radiation therapy, which can cause severe neurological morbidity in children younger than 3 years old and is therefore avoided at diagnosis in this age category standard-risk patients, but can be used at relapse as retrieval, combined with various chemotherapy schedules mostly with myeloablative dosages (Ridola 2007). This option, which has been used with some success, is to be considered investigational only and is not successful in older children that have already received craniospinal irradiation. In this age group, in fact, approximately 20% of patients who experience relapse after irradiation cannot be cured by salvage therapy, barring very rare exceptions (<5% of those who experience relapse) (Bouffet 1998; Massimino 2008).
In older children who have received craniospinal radiation as part of their initial therapy, re-operation, followed by focal radiation with conformal techniques or proton beam might be an option for solitary recurrences and should be considered on a case-by-case basis (Saran 2008).However, in these circumstances, the CSF must be examined before starting therapy to assess the extent of dissemination.
Trials of idarubicin, taxol, topotecan, temozolomide, and irinotecan recorded few responses with nearly all patients developing further tumour progression (Kadota 1999; Hurwitz 2001; Dreyer l 2003; Nicholson 2007; Bomgaars 2007). Another approach under investigation is the use of a low-dose chemotherapy regimen called “metronomic” therapy. Several groups have reported the feasibility of this approach for treating paediatric brain tumours in case series (Kieran 2005) although no formalised clinical trials have been done to date. The main concerns about this approach are the immediate haematological toxicities and the long-term risk of secondary malignancies. More clinical trials are needed to validate this line of therapy which is an investigational only option .
Several drugs act on tumour clonal cells, but not on tumour stem cells, which seem more resistant to multi-drug therapy. The goal of the new targeted molecular therapy will be to eliminate tumour stem cells that are present in the tumour bulk. The identification of activated signalling pathway components of stem cells may help to define new treatment strategies in aggressive tumours such as relapsed medulloblastoma (Figure 4).



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CONTRIBUTORS

Dr. Veronica Biassoni (Author)
Fondazione IRCCS "Istituto Nazionale dei Tumori" - Milan, Italy
e-mail: veronica.biassoni@istitutotumori.mi.it

Dr. Lorenza Gandola (Author)
Fondazione IRCCS "Istituto Nazionale dei Tumori" - Milan, Italy
mail: lorenza.gandola@istitutotumori.mi.it

Dr. Maria Luisa Garrè (Author)
IRCCS Giannina Gaslini - Genoa, italy

Dr. Gemma Gatta (Consultant)
Istituto Nazionale Tumori - Milan, Italy
mail: gemma.gatta@istitutotumoti.mi.it

Prof. Felice Giangaspero (Author)
Università La Sapienza and Istituto Neuromed Pozzilli - Rome, Italy

Dr. Maura Massimino (Editor and Author)
Fondazione IRCCS "Istituto Nazionale dei Tumori" - Milan, Italy
mail: maura.massimino@istitutotumori.mi.it

Dr. Geraldina Poggi (Author)
Istituto Eugenio Medea - Bosisio Parini, Italy

Prof. Stefan Rutkowski (Reviewer)
Universitätsklinikum Hamburg-Eppendorf
Klinik und Poliklinik für Pädiatrische Hämatologie und Onkologie - Hamburg, Germany
e-mail: s.rutkowski@uke.de

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