- Email: [email protected]
Review of the prognostic factors in medulloblastoma of children and adults
Critical Reviews in Oncology/Hematology 50 (2004) 121–128
Review of the prognostic factors in medulloblastoma of children and adults Alba A. Brandes∗ , Myriam K. Paris Medical Oncology Department, University Hospital, Via Gattamelata 64, 35100 Padova, Italy Accepted 1 August 2003
Contents 1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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2.
Prognostic factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Molecular biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Stage of disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1. T-disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2. Metastatic disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3. Residual disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Performance status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Hydrocephalus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
122 122 123 123 123 124 124 124 124
3.
Recurrences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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4.
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
125 125 125 125 125
5.
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract Medulloblastoma (MB) is rare in adults, accounting for 1% of all primary tumours of the central nervous system (CNS). Based on the assumption that the disease pattern in adults is similar to that in children, adults with medulloblastoma are treated using paediatric protocols. Thanks to progress made in recent years, long-term survival is now possible, with overall ranging from 50 to 60% at 5 years and 40 to 50% at 10 years. However, effective therapy may have devastating long-term side effects, including neuro-psychic and neuro-endocrine sequelae and cognitive dysfunction, especially in young adults. Great interest has been expressed in new biological and molecular prognostic factors, which, combined with clinical variables, may allow a more satisfactory stratification of patients. © 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Medulloblastoma; Adult; Treatment; Prognostic factors; Radiotherapy; Chemotherapy; Toxicity; Review
∗
Corresponding author. Tel.: +39-049-8215-931; fax: +39-049-8215-932. E-mail address: [email protected] (A.A. Brandes).
1040-8428/$ – see front matter © 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2003.08.005
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A.A. Brandes, M.K. Paris / Critical Reviews in Oncology/Hematology 50 (2004) 121–128
1. Introduction Medulloblastoma (MB) accounts for 25% of all newly diagnosed cases of childhood primary brain tumours; in adults, the disease is much less common, comprising only 1% of primary brain tumours. The incidence of MB rose from 4 per 106 person years in 1973–1977 to 4.9 per 106 person years in 1993–1998 [1]. The prognosis and overall survival (OS) rate for patients with medulloblastoma has improved dramatically over the past three decades. Children diagnosed in the more recent period from 1985 to 1998 had a longer median survival than children diagnosed in 1973–1984 (4.9 years versus 10 years, P = 0.05) [1]. These extended survival rates can depend on several factors, including the use of mega voltage radiation therapy equipment and the inclusion of the spinal neuro-axis within the treatment field, and the administration of adjuvant chemotherapy in high-risk patients [2,3]. Future trends in the research and treatment will focus on the better identification of prognostic factors allowing the selection of patients requiring less intensive therapy [4], with a view to minimising the risk of neuropsychological, neuro-endocrinal and cognitive dysfunction [5].
2. Prognostic factor 2.1. Pathology The gross and microscopic features of medulloblastoma in children are similar to those in adults: the tumours are highly vascular and have a high growth fraction. However, in children, the tumour presents very frequently in the midline cerebellar vermis, extending into the fourth ventricle. In adults, the mass is more eccentrically located within the cerebellar hemisphere [6–9]. Frost et al. [10] report that medulloblastomas have a lateral location in 30% of cases in adults and 7% in children. Sarkar et al. [11] reported that lateral location was more common in adults (46.4%) as compared to childhood cases (10.7%). A pathogenetic theory has been proposed as the basis for different locations in the two age groups: primitive cells from which tumours arise are originally located in the midline of the roof of the fourth ventricle and only later migrate laterally [12]. Also the magnetic resonance imaging (MRI) is different between children and adults. The classic well-defined homogeneous vermian tumour with intense contrast enhancement seems to be rare in adults, whose tumours are predominantly in the cerebellar hemisphere, poorly defined and enhance less [13]. The histogenesis of primitive neuroectodermal tumour (PNET) has been controversial for more than 10 years and only recently [14] there is increased evidence that at least a subset of MB, but not PNETs, raises from external granular cell layer (EGL) of the cerebellum. Infact the occa-
sional presence of PTCH mutations and the sonic hedgehoh (SHH)/PTCH pathway, that controls cell proliferation in the EGL during embryonal development, were reported [14–16]. Gene expression profiling was able to separate a series of MBs from malignant gliomas and from atypical teratoid/rhabdoid tumour and to distinguish classic and desmoplastic MBs [15]. The new WHO classification [14] lists several variants of medulloblastoma: melanotic medulloblastoma (distinguished by the presence of melanin in the cells) and medullomyoblastoma (which shows degrees of rhabdomyoblastic differentiation) are exceedingly rare. Because of their rarity, the biological behaviour of these two variants of medulloblastoma have not been established as significantly different from that of the classic medulloblastoma. Other four medulloblastoma subtypes are described: classic, desmoplastic, extensive nodularity and large cell (LC) medulloblastoma. About 80% of MBs are not classified as variants in the WHO scheme, being regarded as classic form. Classic MBs lack the nodular/desmoplastic architectural features of desmoblastic MBs. The desmoplastic variant accounts for 15% in the paediatric population compared to 30–40% in adults [6,10,17]. In children, the disease is often limited to the posterior fossa and positive cerebrospinal fluid (CSF) and metastases outside the central nervous system (CNS) are rare. In more than 50% of cases in adults, the disease is localised in the posterior fossa; 30% have cerebrospinal fluid (CSF) involvement and 5% have metastases outside the CNS, to the bone in particular [17,18]. Large cell-anaplastic MB (LC/A) makes up only a small proportion (4%) of MBs [19,20] but emerged as a variant with specific clinical and molecular associations, which confer a poor prognosis and often show metastatic disease at presentation. Genetic alterations as aneuploidia with gain of other chromosomes, amplification of C-MYC support the hypothesis of early anaplastic progression [20–22]. The MB with extensive nodularity (MBEN) is a distinctive nodular desmoplastic variant, which was in the past called “cerebellar neuroblastoma”. It tends to arise typically in the age of first 2 years, to be localized at diagnosis, has a better outcome than other variants because represents the most differentiated form of nodular desmoplasia. The DNA is diploid and has a low labelling index [14,23]. A conclusive answer if the prognosis of desmoplastic variant is different from classic has not yet provided. Authors have reported that the desmoplastic subtype, found more frequently in adults than in children, is correlated with a better outcome, although others have found it is correlated with a poor prognosis [17,24,25]. In their univariate analysis, Frost et al. [10] found that the desmoplastic variant was not of prognostic significance, while in their multivariate analysis on 156 adult patients, Carrie et al. [6] found significantly improved 5- and 10-year
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survivals in patients with the desmoplastic variant. Eberhart et al. [21] postulated that could exist a correlation between better prognosis and increasing nodularity, while anaplasia would predict less favourable results according to the data that the variant MBEN has a better prognosis and the LC/A the worst. The authors found that the increasing grades of anaplasia were associated with progressively worse clinical outcomes. Slight anaplasia did not appear to influence the prognosis, but patients with moderate or severe anaplasia had significantly worse outcome. In log-rank analysis the anaplasia grade was able to stratify patients with respect to outcome (P = 0.03), whereas the M stage was not (P = 0.10). On the contrary, the increasing levels of nodularity was not correlated with improved survival, so, desmoplasia has not clinical significance. 2.2. Molecular biology Genetic alterations may provide additional diagnostic information and allow clinically relevant subgrouping of MBs and evidences are emerging to indicate that particular profiles correlate with biological behaviour and patient outcome. In children, the molecular basis of medulloblastoma has been analysed as a prognostic factor, but, to our knowledge, no such study is available on adults. Deletions involving the short arm of chromosome 17 are the most frequently found genetic abnormality in medulloblastoma, occurring in 40–50% of primary tumours, and several authors [26–28] observe that it is significantly correlated with a worse prognosis even if this has not been supported by others [29,30]. Nicholson et al. [31] reported loss of 17p occurs more frequently in classic than in desmoplastic variant; Eberhart et al. [30] found a strong association between MYC or MYCN amplification and loss of 17p in the anaplastic tumours and Scheurlen et al. [32] with the metastatic disease at presentation. Amplification and over expression of MYC or MYCN occurs only in 5–10% of MBs. Some studies have examined the expression of the MYC mRNA and related it to clinical outcome. Low levels of MYC expression have proved to be a strong predictor of favourable outcome [33]. Another study reported a significant correlation between MYC mRNA expression and survival, and observes that this biological characteristic is an independent predictive factor for death from disease [34]. Thus identifying MBs with MYC amplification could be important, because accumulating evidence indicates that it is associated both with the LC/A phenotype and with an aggressive clinical behaviour [19,21,26,33]. Others important molecular prognostic factors are elevated levels of ErbB-2 receptors that have been recorded in MBs [27,28] and carried a poor prognosis. A recent study [27] investigated the capacity of molecular abnormalities to increase the accuracy of disease risk-stratification above that afforded by clinical staging alone. Forty-one primary medulloblastoma tumour sam-
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ples were analysed for ErbB-2 receptor, for aberration on chromosome 17 abnormalities, and amplification of the MYC oncogene. The expression of the ErbB-2 receptor and deletion of 17p were detected in 80 and 49% of tumours, respectively. Amplification of MYC was detected in only 5% of tumours. In univariate analysis the degree of tumour resection (P = 0.007) and metastatic disease at diagnosis (P = 0.0006), expression of the ErbB-2 receptor (P = 0.003) and chromosome 17 subtype (P = 0.013) were related to survival. Combined assessment of clinical and molecular prognostic markers may allow increased accuracy of disease risk-stratification for patients with MB and could suggest the use of the anti-ErbB-2 monoclonal antibody as a potential new therapeutic approach. The prognostic significance of Trk receptor (neurotrophin3 receptor) expression by MBs has been examined in several studies and an association between over expression of TrkC receptors and a good prognosis has been demonstrated [35]: Trk mRNA and MYC mRNA were measured in a cohort of PNETs tumours and the combination of high TrkC mRNA expression and low MYC mRNA expression were present in a group of patients who were all in remission after an average period over 4 years. 2.3. Stage of disease The prognostic factors in paediatric medulloblastoma have been well studied over the past 20 years. The current consensus is that metastatic disease [17,36–40], postoperative macroscopic residual disease more than 1.5 cm2 [41], age [36,37], are the worst prognostic factors. Paediatric patients are stratified into poor risk and average risk groups. Average risk factors are defined as age >4 years, complete surgical resection and M0 stage. High-risk factors are defined as incomplete surgical resection or M1–M4 and age <4 years. Data on prognostic factors in adults are limited, because no prospective study exists and the only available data come from retrospective studies, which encompass a long period of time in which the treatment has changed a lot. 2.3.1. T-disease The use of T-stage as a prognostic factor in adults is a controversial issue. Some studies [10,17] demonstrate a favourable trend in patients with T1–T2 tumours compared to patients with T3–T4 tumours (5-year disease-free survival (DFS) 52% versus 25%; P < 0.05) in children, but recent reviews do not confirm this datum [42,43]. Invasion of the brainstem (stage T3b) has been considered a high-risk factor. However, there is little agreement on the significance of this factor [41] either in children or in adults. The International Society of Paediatric Oncology (SIOP I) study [40] reported no significant difference between the 5-year survival rate of patients with and those without brainstem involvement (41% versus 52%); this finding was confirmed by data in the review of David et al.
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[43] and in the retrospective study of Chan et al. [44]. In adults series, Carrie et al. [6], on the other hand, reported that fourth ventricular floor involvement (P = 0.00004) and brainstem involvement (P = 0.08) are correlated with a worse disease-free survival. In the group of clinical trials that evaluated the association of T stage and outcome, the children’s cancer group (CCG) found only a weak correlation [37], whereas the SIOP study found a significant survival advantage with low T stage [40]. But up to one-half of patients on previous CCG and SIOP trial did not have CSF cytology or mielography [37,40]; so the T3–T4 group was composed of both M0 and M1+ patients. When patients are completely staged and stratified there is no univariate effect of preoperative T stage on DFS. 2.3.2. Metastatic disease Patients with metastases to the subaracnoid and extraneural spaces have an unfavourable short-term prognosis [17]. In children the presence of metastatic disease has a very definite role in predicting recurrence-free survival, while T stages has not [37]. In the study of Zeltzer et al. [41] lower M stage obtained a better DFS and the difference was statistically significant (P = 0.0006). Five-year estimates of DFS for patients with MO, M1 and M2+ tumours were 70, 57 and 40%, respectively. The presence of a positive CSF cytology alone, M1 stage, was not a statistically significant factor in DFS compared with MO (P = 0.15) or M2+ stage (P = 0.103). This was possibly due to the small number of patients which M1 tumours. There was no statistical evidence of a relationship between T stage and DFS; neither T1/T2 versus T3/T4 (stratified by treatment and M stage; P > 0.4) nor T1/T2 versus T3a versus T3b comparison stratified by treatment and M stage (P > 0.6) were significant. In a study by Jenkin et al. [42], the 5-year survival for patients (80% children) in the stage M2 and M3 group was 21% compared with 78% in M0 and M1 patients (P < 0.0001). These data are comparable with those reported in all the available studies using large series staged adults, 5-year survival rates ranging from 59 to 90% for stage M0–M1 patients and from 10 to 45% for M2–M3 stage patients [9,10,37,38,43,45]. Carrie et al. [6] did not find that this factor was of prognostic value in 156 medulloblastoma patients aged more than 18 years treated between January 1975 and December 1991 in 13 French institutions, but only 95 of these patients were evaluated for extent of disease. 2.3.3. Residual disease Jenkin et al. [42], unlike other authors [9,44,46], reported that patients with local residual disease measuring <1.5 cm2 fared as well as those with complete tumour excision. In their retrospective study on 48 patients (age >16 years) treated between 1958 and 1988 at Princess Margaret Hospi-
tal, Frost et al. [10] showed that subtotal removal is predictive for posterior fossa recurrence (75% versus 44%, P < 0.04), but not for DFS. In Carrie et al.’s series of 156 patients [6], 67% of patients underwent total surgical resection, but extent of resection was not a significant prognostic factor for DFS at either univariate or multivariate analysis. Another retrospective study performed on 28 adults at the MD Anderson Cancer Centre showed that extent of resection was not prognostic for survival [47]. However, in their study on 47 adult patients, Prados et al. [9] found that subtotal resection was closely correlated with OS and DFS. 2.4. Performance status Brandes et al. [17] found that postoperative performance status (PS) was of no prognostic significance in adults. Carrie et al. [6] reported that the 5-year survival rate of patients with a PS of 2 or less was significantly greater (66%) than that of those with a PS of 3 or more (28%). The significance of PS was also confirmed by Frost et al. [10], who observed that adults with a score of 2 or less had a 5-year DFS rate of 65% versus 23% for patients with scores of 3–5. 2.5. Hydrocephalus Frost et al. [10] reported that, in adult patients, hydrocephalus, but not shunt, is correlated with DFS. In series reported on by other authors, hydrocephalus has been associated with the poorest survival [17]. The issue of whether or not ventriculoperitoneal shunts increases the risk of distant tumour dissemination was addressed by Berger et al. [48]. Five out of eight children with systemic relapse had hydrocephalus, and two of these had ventriculoperitoneal shunts. Therefore it seems that shunts, regardless of type, location, or filter insertion did not cause a predisposition to extraneural metastases. In a review of 160 cases [49] of medulloblastoma with systemic metastases (30 of them having undergone systemic shunts) shunts had probably provided the route of systemic spread in no more than 11 cases. Some authors reported individual cases of shunt related abdominal metastases [50,51] but there are not recent reviews about this characteristic as prognostic factor.
3. Recurrences The majority of all recurrences occur in the posterior fossa, alone or in combination with other sites. In adults, Chan et al. [44], found that all recurrences to the posterior fossa occur in the previous surgical bed; at multivariate analysis, complete surgical resection was predictive of improved posterior fossa control (P = 0.02) and DFS (P = 0.02) rates.
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In the adult population, 59% of all recurrences [44] occur more than 2 years after surgery, unlike in the paediatric population, in which 75% of recurrences occur within the first 2 years [17]. In the series of Abacioglu et al. [52] (30 patient >16 years) 50% of recurrences occurred after 2 years, 17% after 5 years and the posterior fossa was the most common site of relapse. Other studies on adult medulloblastoma report that late recurrences are common [6,17,25]. In particular, midline lesions are associated with earlier recurrence, whereas lateral lesions are associated with later recurrence. A long-term follow-up monitoring is important for adult medulloblastoma.
4. Treatment 4.1. Surgery Some cornerstones are now well recognised for the treatment of MB: the first step is surgery, which should be as radical as possible. As, discussed above, the extent of surgical resection is an important factor in relation to survival [40]. For this reason neurosurgeons make considerable efforts to achieve complete or near complete resection. Extensive surgery can increase the risk of reversible or permanent neurological sequelae (e.g. cerebellar mutism syndrome) that can impact the quality of survival and contribute to delay the start of the adjuvant therapy. 4.2. Radiotherapy Radiotherapy has been accepted as the most effective postoperative treatment for MB. In average risk MB the standard radiotherapy dose is 36 Gy to the craniospinal axis with a boost of 18–20 Gy to the posterior fossa (total dose 54–56 Gy). Using such dose, various studies have reported that between 40 and 70% of patients are alive and free of progression of disease 5 year from diagnosis [17]. Adults who receive >55 Gy appear to have a lower risk of recurrence than those receiving less than 52 Gy (71% versus 51% 5-year event-free survival and 71% versus 34% 10-year event-free survival) [17]. Duration of radiotherapy is found significant in predicting posterior fossa control [44,53], and freedom from relapse [53], with 5-year posterior fossa control rates of 81 and 49% for a duration of less than 48 days and 48 days or more, respectively (P = 0.06). Nevertheless, in the series reported on by Frost et al. [10] radiation doses, time interval between diagnosis and date of starting radiation, and duration of radiotherapy were not found to be of prognostic significance for DFS. In children, radiotherapy can lead to significant neurocognitive sequelae, especially in very young patients. A trial was conducted by the paediatric oncology group children’s cancer group (POG-CCG) to evaluate prospectively the effects on survival, relapse-free survival and patterns of relapse of reduced dose (23.4 Gy in 13 frac-
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tions) compared with standard dose (36 Gy in 20 fractions) neuraxis irradiation in low-stage medulloblastoma [54]. The planned interim analysis resulted in early closure of the protocol and showed that patients randomised to the reduced neuraxis treatment have increased frequency of relapse, even if at 8 years no statistical difference between the two arms of treatment has been observed (EFS 67% versus 52%, P = 0.141) [55,56]. The therapeutic gain of 36 Gy over 23.4 Gy neuraxis irradiation is at least partly offset by increased toxicity as confirmed by psychometric studies [57]. This supports the rationale for reduced-dose neuraxis radiotherapy but adding chemotherapy. Packer et al. [58] demonstrated a 79% 5 year DFS in children between 3 and 10 years old with M0 disease when treated with reduced dose radiotherapy combined with concurrent vincristine (VCR) and subsequent cisplatin/lomustine (CCNU)/VCR: these overall survival rates compare favourably to those obtained in studies using full-dose radiation therapy alone or radiation therapy plus chemotherapy. Freeman et al. [59] analysed different trials (from the North America and the four European paediatric cooperative groups) for children with medulloblastoma: the conclusion seems that in patients with average risk disease the use of chemotherapy has allowed a reduction in the dose of radiotherapy to the craniospinal axis and the combination of chemotherapy with radiotherapy appears to have brought about a significant improvement in DFS and OS in this patient population. For high-risk patients there are only preliminary data which show that these children fare better now than in the past as a consequence of the routine use of aggressive chemotherapy. 4.3. Radiosurgery A stereotactic radiosurgical boost could be effective in patients with persistent disease after craniospinal radiotherapy to improve local control and OS, even if a small number of patients were analysed in these studies [60,61]. This procedure cannot be recommended in recurrent disease where the main problem remains the control of subclinical craniospinal dissemination [62]. 4.4. Chemotherapy The CCG and the SIOP studies demonstrated the efficacy of adjuvant post-irradiation chemotherapy in children with high stage disease [38,42], but other controlled clinical trials have failed to demonstrate a similar advantage in children with low-stage disease [43,52]. There has been considerable interest in trials of pre-irradiation chemotherapy [63,64], but these studies have shown a significant incidence of relapses due to excessive delays in initiating radiation therapy and in an excessive number of patients unable to complete planned irradiation [65], even if single arm feasibility trials had generally shown reasonable tolerance and apparent
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efficacy [63,64]. Most trials reported high rates of response but a high rate of disease progression during a 3–4 months pre-irradiation chemotherapy regimen [42,63–65]. Few studies were performed randomly testing preirradiation (neoadjuvant) versus post-irradiation (adjuvant) chemotherapy. Bailey et al. [66] reported diminished disease control in low-risk cases with chemotherapy before radiotherapy in the SIOP II study. In high-risk medulloblastoma, Zeltzer et al. reported a reduction in 5-year DFS from 63 to 45% when 8–1 chemotherapy preceded radiotherapy [41]. Kortmann et al. [67] in a prospective randomised trial confirmed that adjuvant chemotherapy is significantly better than neoadjuvant especially in low risk patients. Recently, Taylor et al. [68] published the results of a large multicenter randomised trial, where the pre-radiotherapy chemotherapy increases the EFS compared with radiotherapy alone (74% versus 59.8%, P = 0.036). This is the first randomised study in which “neoadjuvant” chemotherapy has been proved to be superior to radiotherapy alone and this delay is not detrimental for survival in non-metastatic MBs. In adults no randomised studies have been performed because of the rarity of this tumour and the role of adjuvant chemotherapy is not clear: some studies have not shown a statistical improvement in DFS [6], while others have shown an improvement in DFS [17,44]. In six studies [17], adjuvant chemotherapy was given to adults with medulloblastoma (using different regimens) and the findings were inconclusive. Carrie et al. [6] observed a favourable trend but only Brandes et al. were in favour of chemotherapy [17]. Nonetheless, even in the absence of unequivocal data, it is currently thought that adjuvant chemotherapy is beneficial, at least in patients at high risk of recurrence. In our opinion, two cycles of up-front chemotherapy can be safely administered [2], and they should include cisplatin, etoposide and cyclophosphamide [17,69].
5. Conclusion Because of the small number of adult patients with this disease, no randomised studies are available and data in literature are based on retrospective analyses. Therefore, unlike in the paediatric population, it is very difficult to establish prognostic factors in adults. Most adults with medulloblastoma have been treated using paediatric protocols, even if differences concern clinical characteristics, prognostic factors and tolerance both to radiotherapy and chemotherapy exist. Additional markers other than clinical factors alone are required for the selection of patients who can be cured with less aggressive treatment and novel therapeutic approaches should be developed to improve the survival of patients with more aggressive disease. It is therefore of paramount importance to understand the molecular basis of medulloblas-
toma in adults as in children: the biological characteristics continue to be elucidated, and in recent trials have been identified as prognostic factors. Therefore, in order to improve on the treatment of medulloblastoma, an evaluation should be made of clinical, biological and pathological factors. Prospective studies must also be conducted to investigate the role of hyperfractioned radiotherapy and adjuvant chemotherapy modalities, and their timing. Due to the low incidence of this disease in adults, a multi-centre study is required for the accrual of an adequate number of patients: this would throw light upon the differences between medulloblastoma in adults and that in children, thus allowing a more reliable evaluation of prognostic factors, and facilitating the choice of appropriate therapy as was done in the past in children. Reviewers Dr. Sandrine de Ribaupierre and PD Dr. Benedict Rilliet, Service de Neurochirurgie, Centre Hospitalier Universitaire Vaudois (CHUV), Rue du Bugnon, CH-1011 Lausanne, Switzerland. PD Dr. Med. R.-D. Kortmann, Oberarzt, Klinik für Radioonkologie, Eberhard-Karls-Universität, Universitätsklinikum Tübingen, Hoppe-Seyler-Str. 3, D-72076 Tübingen, Germany. References [1] McNeil DE, Cote TR, Clegg L, Rorke LB. Incidence and trends in pediatric malignancies medulloblastoma/primitive neuroectodermal tumor: a SEER update. Surveillance epidemiology and end results. Med Pediatr Oncol 2002;39:190–4. [2] Brandes AA, Ermani M, Amistà P. The treatment of adults with medulloblastoma: a prospective study. Int J Radiat Oncol Biol Phys 2003;57(3):755–61. [3] Newton HB. Review of the molecular genetics and chemotherapeutic treatment of adult and pediatric medulloblastoma. Expert Opin Invest Drugs 2001;10:2089–104. [4] Chintagumpala M, Berg S, Blaney MS. Treatment controversies in medulloblastoma. Curr Opin Oncol 2001;13:154–9. [5] Kramer JH, Crowe AB, Larson DA, et al. Neuropsychological sequelae of medulloblastoma in adults. Int J Radiat Oncol Biol Phys 1997;38:21–6. [6] Carrie C, Lasset C, Lapetite C, et al. Multivariate analysis of prognostic factors in adult patients with medulloblastoma: retrospective study of 156 patients. Cancer 1994;2352–60. [7] Peterson K, Walker RW. Medulloblastoma/PNET in 45 adults. Neurology 1995;45:440–2. [8] Haie-Meder C, Song YP. Medulloblastoma: differences in adults and children. Int J Radiat Oncol Biol Phys 1995;32:1235–57. [9] Prados MD, Warnick RE, Wara MW, et al. Medulloblastoma in adults. Int J Radiat Oncol Biol Phys 1995;32:1145–52. [10] Frost JP, Laperriere NJ, Wong CS, et al. Medulloblastoma in adults. Int J Radiat Oncol Biol Phys 1995;32:951–7. [11] Sarkar C, Pramanik P, Karak AK, et al. Are childhood and adult medulloblastoma different? A comparative study of clinicopathological features, proliferation index and apoptotic index. J Neuroncol 2002;59:49–61. [12] Giordana MT, Cavallo P, Ditto A, et al. Is medulloblastoma the same tumour in children and adult. J Neurooncol 1997;35:169–76.
A.A. Brandes, M.K. Paris / Critical Reviews in Oncology/Hematology 50 (2004) 121–128 [13] Malheiros SM, Carrete Jr H, Stavale JN, et al. MRI of medulloblastoma in adults. Neuroradiology 2003;45:463–7. [14] Kleihues P, Louis DN, Scheitauer BW, et al. The WHO classification of tumours of the nervous system. J Neuropathol Exp Neurol 2002;61:215–25. [15] Pomeroy SL, Tamayo P, Gaasenbeek M, et al. Prediction of central nervous system embryonal tumours outcome based on gene expression. Nature 2002;415:436–42. [16] Wechsler-Reya R, Scott MP. The developmental biology of brain tumours. Annu Rev Neurosci 2001;24:385–428. [17] Brandes AA, Palmisano V, Monfardini S. Medulloblastoma in adults: clinical characteristics and treatment. Cancer Treat Rev 1999;25:3– 12. [18] Rochkind S, Blatt I, Sadeh M, Goldhammer Y. Extracranial metastases of medulloblastoma in adults: a literature review. J Neurol Neurosurg Psychiatry 1991;54:80–6. [19] Brown HG, Kepner JL, Perlman EJ, et al. Large-cell/anaplastic medulloblastomas: a pediatric oncology group study. J Neuropathol Exp Neurol 2000;59:857–65. [20] Ellison D. Classifying the medulloblastoma: insights from morphology and molecular genetics. Neuropathol Appl Neurobiol 2002;4:257–82. [21] Eberhart CG, Kepner JL, Goldthwaite PT, et al. Histopathologic grading of medulloblastoma: a pediatric oncology group study. Cancer 2002;94:552–60. [22] Leonard SR, Cai DX, Rivet DJ, et al. Large cell/anaplastic medulloblastomas and medullomyoblastomas: clinicopathological and genetic features. J Neurosurg 2001;95:82–8. [23] Giangaspero F, Perilongo G, Fondelli MP, et al. Medulloblastoma with extensive nodularity: a variant with favourable prognosis. J Neurosurg 1999;6:971–7. [24] Ildan F, Cetinalp E, Bagdatoglu H, et al. Cerebellar medulloblastoma in adults. Neurosurg Rev 1994;17:205–9. [25] Malheiros SM, Franco CM, Stavale JN, et al. Medulloblastoma in adults: a series from Brazil. J Neuroncol 2002;60:247–53. [26] Batra SK, Mc Lendon RE, Koo JS, et al. Prognostic implications of chromosome 17p deletions in human medulloblastoma. J Neurooncol 1995;24:39–45. [27] Gilbertson R, Wickramasinghe C, Hernan R, et al. Clinical and molecular stratification of disease risk in medulloblastoma. Br J Cancer 2001;85:705–12. [28] Biegel JA, Jans AJ, Raffel C, et al. Prognostic significance of chromosome 17p deletions in childhood primitive neuroectodermal tumours (medulloblastomas) of the central nervous system. Clin Cancer Res 1997;3:473–8. [29] Emadiam SM, Mc Donald JD, Gerken JC, Fults D. Correlations of chromosome 17p loss with clinical outcome in medulloblastoma. Clin Cancer Res 1996;2:1559–64. [30] Eberhart CG, Kratz JE, Schuster A, et al. Comparative genomic hybridisation detects an increased number of chromosomal alterations in large cell anaplastic medulloblastomas. Brain Pathol 2002;12:36– 44. [31] Nicholson JC, Ross FM, Kohler JA, Ellison DW. Comparative genomic hybridisation and histological variation in primitive neuroectodermal tumours. Br J Cancer 1999;80:1322–33. [32] Scheurlen WG, Schwabe GC, Joos S, et al. Molecular analysis of childhood primitive neuroectodermal tumours defines markers associated with poor clinical outcome. J Clin Oncol 1998;16:2478– 85. [33] Grotzer MA, Hogarty MD, Janss AJ, et al. MYC messenger RNA expression predicts survival outcome in childhood primitive neuroectodermal tumours/medulloblastoma. Clin Cancer Res 2001;7:2425– 33. [34] Herms J, Neidt I, Luscher B, et al. C-MYC expression in medulloblastoma and its prognostic value. Int J Cancer 2000;89:395– 402.
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[35] Grotzer MA, Janss AJ, Fung K, et al. TRKC expression predicts good clinical outcome in primitive neuroectodermal tumours. J Clin Oncol 2000;18:2027–35. [36] Albright AL, Wisoff JH, Zeltzer PM, et al. Effects of medulloblastoma resections on outcome in children: a report from the children’s cancer group. Neurosurgery 1996;38:265–71. [37] Evans AE, Jerkin RD, Sposto R, et al. The treatment of medulloblastoma. Results of a prospective randomised trial of radiation therapy with and without CCNU, vincristine and prednisone. J Neurosurg 1990;72:572–82. [38] Merchant TE, Wang MH, Haida T, et al. Medulloblastoma: long term results for patients with definitive radiation therapy during the computed tomography era. Int J Radiat Oncol Biol Phys 1996;36:29– 35. [39] Yao MS, Metita MP, Boyett JM, et al. The effect of M-stage on patterns of failure in posterior fossa primitive neuroectodermal tumors treated on CCG-921: a phase III studies in a high-risk population. Int J Radiat Oncol Biol Phys 1997;38:469–76. [40] Tait DM, Thornton Jones H, Bloom HJ, Lemerle J, Morris Jones P. Adjuvant chemotherapy for medulloblastoma. The first multicentre trial of the International Society of Paediatric Oncology SIOP I. Eur J Cancer 1990;26:464–9. [41] Zeltzer PM, Boyett JM, Finlay JL, et al. Metastasis stage, adjuvant treatment and residual tumour are prognostic factors for medulloblastoma in children: conclusion from the children’s cancer group 921 randomised phase III study. J Clin Oncol 1999;17:832–45. [42] Jenkin D, Al Shabanah MA, Henrik Shail EA, et al. Prognostic factors for medulloblastoma. Int J Radiat Oncol Biol Phys 2000;47:573– 84. [43] David KM, Casey AT, Hayward RD, et al. Medulloblastoma: is the 5-year survival rate improving? A review of 80 cases from a single institution. J Neurosurg 1997;86:13–21. [44] Chan AW, Tarbell NJ, Black PM, et al. Adult medulloblastoma: prognostic factors and patterns of relapse. Neurosurgery 2000;47:623– 32. [45] Le QT, Weil MD, Waro WM, et al. Adult medulloblastoma: an analysis of survival and prognostic factors. Cancer J Sci Am 1997;3:238– 45. [46] Cohen BJ, Packer RJ. Chemotherapy for medulloblastomas and primitive neuroectodermal tumours. J Neurooncol 1996;29:55–68. [47] Kunschner J, Kuttesch J, Hess K, Yung WK. Survival and recurrence factors in adult medulloblastoma: the M.D. Anderson Cancer Centre experience from 1978 to 1998. Neurooncology 2001;3:167–73. [48] Berger MS, Baumeister B, Geyer JR, et al. The risk of metastases from shunting in children with primary central nervous system tumours. J Neurosurg 1991;74:872–7. [49] Jamjoon ZA, Jamjoon AB, Sulaiman AH, et al. Systemic metastasis of medulloblastoma trough ventriculoperitoneal shunt: report of a case and critical analysis of the literature. Surg Neurol 1993;40:403– 10. [50] Fiorillo A, Maggi G, Martone A, et al. Shunt related abdominal metastases in an infant with medulloblastoma: long term remission by systemic chemotherapy and surgery. J Neurooncol 2001;52:273–6. [51] Carrasco Torrents R, Sancho MA, Julia V, et al. Intraabdominal metastasis of cerebellar medulloblastoma trough ventriculoperitoneal shunt. Ann Esp Pediatr 2001;54:83–5. [52] Abacioglu U, Uzel O, Sengaz M, Turkan S, Ober A. Medulloblastoma in adults: treatment results and prognostic factors. Int J Radiat Oncol Biol Phys 2002;54:855–60. [53] Paulino AC, Wen BC, Mayr NA, et al. Protracted radiotherapy treatment duration in medulloblastoma. Am J Clin Oncol 2003;26:55– 9. [54] Deutsch M, Thomas PRM, Krisher J, et al. Results of a prospective randomized trial comparing standard dose neuraxis irradiation [3600 cGy/20] with reduced neuraxis irradiation (2340 cGy/13) in patients with low stage medulloblastoma. A combined children’s cancer group pediatric oncology group study. Pediatr Neurosurg 1996;24:167–77.
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[55] Thomas PR, Deutsch M, Kepner JL, et al. Low- stage medulloblastoma: final analysis of trial comparing standard-dose with reduced dose neuraxis irradiation. J Clin Oncol 2000;18:3004–11. [56] Kun LE. Medulloblastoma-challenges in radiation therapy and the addition of chemotherapy. Int J Radiat Oncol Biol Phys 2000;46:261– 3. [57] Mulhern RK, Kepner JL, Thomas PRM, et al. Neuropsychological functioning of survivors of childhood medulloblastoma randomized to receive conventional or reduced (3600 cGy/20 versus 2340 cGy/13) dose craniospinal irradiation. A pediatric oncology group study. J Clin Oncol 1998;16:1723–8. [58] Packer RJ, Golwein J, Nicholson HS, et al. Treatment of children with medulloblastoma with reduced craniospinal radiation therapy and adjuvant chemotherapy: a children’s cancer group study. J Clin Oncol 1999;17:2127–36. [59] Freeman CR, Taylor RE, Kortmann RD, Carrie C. Radiotherapy for medulloblastoma in children: a perspective on current international clinical research effort. Med Pediatr Oncol 2002;39:99–108. [60] Patrice SJ, Tarbell NJ, Goumnerova LC, et al. Results of radiosurgery in the management of recurrent and residual medulloblastoma. Pediatr Neurosurg 1995;22:197–203. [61] Woo C, Stea B, Lulu B. The use of stereotactic radiosurgical boost in the treatment of medulloblastomas. Int J Radiat Biol Phys 1996;37: 761–4. [62] Milker-Zabel S, Zabel A, Tilmann C, et al. Results of threedimensional stereotactically-guided radiotherapy in recurrent medulloblastoma. J Neurooncol 2002;60:227–33. [63] Gentet JC, Bouffet E, Doz F, et al. Pre-irradiation chemotherapy including eight drugs in one day regimen and high dose methotrexate in childhood medulloblastoma. Results of the M7 French cooperative study. J Neurosurg 1998;82:608–14. [64] Heideman RL, Kovnan EH, Kelli SJ, et al. Pre-irradiation chemotherapy with carboplatin and etoposide in newly diagnosed embryonal paediatric CNS tumours. J Clin Oncol 1995;13:2247–54. [65] Hartsell WF, Guijar A, Heidemann RL, et al. Patterns of failure in children with medulloblastoma effect of preradiation chemotherapy. Int J Radiat Oncol Biol Phys 1997;39:15–24.
[66] Bailey CC, Gnekow A, Wellek S, et al. Prospective randomised trial of chemotherapy given before radiotherapy in childhood medulloblastoma. International Society of Paediatric Oncology (SIOP) and the German Society of Paediatric Oncology (GPO) SIOP II. Med Pediatr Oncol 1995;25:166–78. [67] Kortmann RD, Kuhl J, Timmerman B, et al. Postoperative chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomised trial HIT 91. Int J Radiat Oncol Biol Phys 2000;46:269–79. [68] Taylor RE, Bailey CC, Robinson K, et al. Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for non-metastatic medulloblastoma. The International Society of Paediatric Oncology/United Kingdom children’s cancer study group PNET-3 study. J Clin Oncol 2003;21:1581–91. [69] Zona G, de Tribolet N, Pizzolato G, Dietrich P. Etoposide-carboplatin association as emergency up-front chemotherapy in a case of lifethreatening adult medulloblastoma. J Neurooncol 1998;39:253–9.
Biography Dr. Alba A. Brandes is the coordinator of the NeuroOncology Program at the Medical Oncology Department, Padova University Hospital, Italy. Dr. Brandes graduated from the University School of Medicine, Padova, where she pursued her training and fellowship in medical oncology and in clinical immunology. She has worked extensively in medical oncology for many years especially in the clinical research on sarcomas and breast cancer. Currently her primary interest is neuro-oncology research. Dr. Brandes plays an active role in the EORTC-Brain Tumour Group trials and she is the vice-chairman and the co-coordinator of Quality Assurance Committee.
Review of the prognostic factors in medulloblastoma of children and adults Alba A. Brandes∗ , Myriam K. Paris Medical Oncology Department, University Hospital, Via Gattamelata 64, 35100 Padova, Italy Accepted 1 August 2003
Contents 1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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2.
Prognostic factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Molecular biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Stage of disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1. T-disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2. Metastatic disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3. Residual disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Performance status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Hydrocephalus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
122 122 123 123 123 124 124 124 124
3.
Recurrences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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4.
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
125 125 125 125 125
5.
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract Medulloblastoma (MB) is rare in adults, accounting for 1% of all primary tumours of the central nervous system (CNS). Based on the assumption that the disease pattern in adults is similar to that in children, adults with medulloblastoma are treated using paediatric protocols. Thanks to progress made in recent years, long-term survival is now possible, with overall ranging from 50 to 60% at 5 years and 40 to 50% at 10 years. However, effective therapy may have devastating long-term side effects, including neuro-psychic and neuro-endocrine sequelae and cognitive dysfunction, especially in young adults. Great interest has been expressed in new biological and molecular prognostic factors, which, combined with clinical variables, may allow a more satisfactory stratification of patients. © 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Medulloblastoma; Adult; Treatment; Prognostic factors; Radiotherapy; Chemotherapy; Toxicity; Review
∗
Corresponding author. Tel.: +39-049-8215-931; fax: +39-049-8215-932. E-mail address: [email protected] (A.A. Brandes).
1040-8428/$ – see front matter © 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2003.08.005
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1. Introduction Medulloblastoma (MB) accounts for 25% of all newly diagnosed cases of childhood primary brain tumours; in adults, the disease is much less common, comprising only 1% of primary brain tumours. The incidence of MB rose from 4 per 106 person years in 1973–1977 to 4.9 per 106 person years in 1993–1998 [1]. The prognosis and overall survival (OS) rate for patients with medulloblastoma has improved dramatically over the past three decades. Children diagnosed in the more recent period from 1985 to 1998 had a longer median survival than children diagnosed in 1973–1984 (4.9 years versus 10 years, P = 0.05) [1]. These extended survival rates can depend on several factors, including the use of mega voltage radiation therapy equipment and the inclusion of the spinal neuro-axis within the treatment field, and the administration of adjuvant chemotherapy in high-risk patients [2,3]. Future trends in the research and treatment will focus on the better identification of prognostic factors allowing the selection of patients requiring less intensive therapy [4], with a view to minimising the risk of neuropsychological, neuro-endocrinal and cognitive dysfunction [5].
2. Prognostic factor 2.1. Pathology The gross and microscopic features of medulloblastoma in children are similar to those in adults: the tumours are highly vascular and have a high growth fraction. However, in children, the tumour presents very frequently in the midline cerebellar vermis, extending into the fourth ventricle. In adults, the mass is more eccentrically located within the cerebellar hemisphere [6–9]. Frost et al. [10] report that medulloblastomas have a lateral location in 30% of cases in adults and 7% in children. Sarkar et al. [11] reported that lateral location was more common in adults (46.4%) as compared to childhood cases (10.7%). A pathogenetic theory has been proposed as the basis for different locations in the two age groups: primitive cells from which tumours arise are originally located in the midline of the roof of the fourth ventricle and only later migrate laterally [12]. Also the magnetic resonance imaging (MRI) is different between children and adults. The classic well-defined homogeneous vermian tumour with intense contrast enhancement seems to be rare in adults, whose tumours are predominantly in the cerebellar hemisphere, poorly defined and enhance less [13]. The histogenesis of primitive neuroectodermal tumour (PNET) has been controversial for more than 10 years and only recently [14] there is increased evidence that at least a subset of MB, but not PNETs, raises from external granular cell layer (EGL) of the cerebellum. Infact the occa-
sional presence of PTCH mutations and the sonic hedgehoh (SHH)/PTCH pathway, that controls cell proliferation in the EGL during embryonal development, were reported [14–16]. Gene expression profiling was able to separate a series of MBs from malignant gliomas and from atypical teratoid/rhabdoid tumour and to distinguish classic and desmoplastic MBs [15]. The new WHO classification [14] lists several variants of medulloblastoma: melanotic medulloblastoma (distinguished by the presence of melanin in the cells) and medullomyoblastoma (which shows degrees of rhabdomyoblastic differentiation) are exceedingly rare. Because of their rarity, the biological behaviour of these two variants of medulloblastoma have not been established as significantly different from that of the classic medulloblastoma. Other four medulloblastoma subtypes are described: classic, desmoplastic, extensive nodularity and large cell (LC) medulloblastoma. About 80% of MBs are not classified as variants in the WHO scheme, being regarded as classic form. Classic MBs lack the nodular/desmoplastic architectural features of desmoblastic MBs. The desmoplastic variant accounts for 15% in the paediatric population compared to 30–40% in adults [6,10,17]. In children, the disease is often limited to the posterior fossa and positive cerebrospinal fluid (CSF) and metastases outside the central nervous system (CNS) are rare. In more than 50% of cases in adults, the disease is localised in the posterior fossa; 30% have cerebrospinal fluid (CSF) involvement and 5% have metastases outside the CNS, to the bone in particular [17,18]. Large cell-anaplastic MB (LC/A) makes up only a small proportion (4%) of MBs [19,20] but emerged as a variant with specific clinical and molecular associations, which confer a poor prognosis and often show metastatic disease at presentation. Genetic alterations as aneuploidia with gain of other chromosomes, amplification of C-MYC support the hypothesis of early anaplastic progression [20–22]. The MB with extensive nodularity (MBEN) is a distinctive nodular desmoplastic variant, which was in the past called “cerebellar neuroblastoma”. It tends to arise typically in the age of first 2 years, to be localized at diagnosis, has a better outcome than other variants because represents the most differentiated form of nodular desmoplasia. The DNA is diploid and has a low labelling index [14,23]. A conclusive answer if the prognosis of desmoplastic variant is different from classic has not yet provided. Authors have reported that the desmoplastic subtype, found more frequently in adults than in children, is correlated with a better outcome, although others have found it is correlated with a poor prognosis [17,24,25]. In their univariate analysis, Frost et al. [10] found that the desmoplastic variant was not of prognostic significance, while in their multivariate analysis on 156 adult patients, Carrie et al. [6] found significantly improved 5- and 10-year
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survivals in patients with the desmoplastic variant. Eberhart et al. [21] postulated that could exist a correlation between better prognosis and increasing nodularity, while anaplasia would predict less favourable results according to the data that the variant MBEN has a better prognosis and the LC/A the worst. The authors found that the increasing grades of anaplasia were associated with progressively worse clinical outcomes. Slight anaplasia did not appear to influence the prognosis, but patients with moderate or severe anaplasia had significantly worse outcome. In log-rank analysis the anaplasia grade was able to stratify patients with respect to outcome (P = 0.03), whereas the M stage was not (P = 0.10). On the contrary, the increasing levels of nodularity was not correlated with improved survival, so, desmoplasia has not clinical significance. 2.2. Molecular biology Genetic alterations may provide additional diagnostic information and allow clinically relevant subgrouping of MBs and evidences are emerging to indicate that particular profiles correlate with biological behaviour and patient outcome. In children, the molecular basis of medulloblastoma has been analysed as a prognostic factor, but, to our knowledge, no such study is available on adults. Deletions involving the short arm of chromosome 17 are the most frequently found genetic abnormality in medulloblastoma, occurring in 40–50% of primary tumours, and several authors [26–28] observe that it is significantly correlated with a worse prognosis even if this has not been supported by others [29,30]. Nicholson et al. [31] reported loss of 17p occurs more frequently in classic than in desmoplastic variant; Eberhart et al. [30] found a strong association between MYC or MYCN amplification and loss of 17p in the anaplastic tumours and Scheurlen et al. [32] with the metastatic disease at presentation. Amplification and over expression of MYC or MYCN occurs only in 5–10% of MBs. Some studies have examined the expression of the MYC mRNA and related it to clinical outcome. Low levels of MYC expression have proved to be a strong predictor of favourable outcome [33]. Another study reported a significant correlation between MYC mRNA expression and survival, and observes that this biological characteristic is an independent predictive factor for death from disease [34]. Thus identifying MBs with MYC amplification could be important, because accumulating evidence indicates that it is associated both with the LC/A phenotype and with an aggressive clinical behaviour [19,21,26,33]. Others important molecular prognostic factors are elevated levels of ErbB-2 receptors that have been recorded in MBs [27,28] and carried a poor prognosis. A recent study [27] investigated the capacity of molecular abnormalities to increase the accuracy of disease risk-stratification above that afforded by clinical staging alone. Forty-one primary medulloblastoma tumour sam-
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ples were analysed for ErbB-2 receptor, for aberration on chromosome 17 abnormalities, and amplification of the MYC oncogene. The expression of the ErbB-2 receptor and deletion of 17p were detected in 80 and 49% of tumours, respectively. Amplification of MYC was detected in only 5% of tumours. In univariate analysis the degree of tumour resection (P = 0.007) and metastatic disease at diagnosis (P = 0.0006), expression of the ErbB-2 receptor (P = 0.003) and chromosome 17 subtype (P = 0.013) were related to survival. Combined assessment of clinical and molecular prognostic markers may allow increased accuracy of disease risk-stratification for patients with MB and could suggest the use of the anti-ErbB-2 monoclonal antibody as a potential new therapeutic approach. The prognostic significance of Trk receptor (neurotrophin3 receptor) expression by MBs has been examined in several studies and an association between over expression of TrkC receptors and a good prognosis has been demonstrated [35]: Trk mRNA and MYC mRNA were measured in a cohort of PNETs tumours and the combination of high TrkC mRNA expression and low MYC mRNA expression were present in a group of patients who were all in remission after an average period over 4 years. 2.3. Stage of disease The prognostic factors in paediatric medulloblastoma have been well studied over the past 20 years. The current consensus is that metastatic disease [17,36–40], postoperative macroscopic residual disease more than 1.5 cm2 [41], age [36,37], are the worst prognostic factors. Paediatric patients are stratified into poor risk and average risk groups. Average risk factors are defined as age >4 years, complete surgical resection and M0 stage. High-risk factors are defined as incomplete surgical resection or M1–M4 and age <4 years. Data on prognostic factors in adults are limited, because no prospective study exists and the only available data come from retrospective studies, which encompass a long period of time in which the treatment has changed a lot. 2.3.1. T-disease The use of T-stage as a prognostic factor in adults is a controversial issue. Some studies [10,17] demonstrate a favourable trend in patients with T1–T2 tumours compared to patients with T3–T4 tumours (5-year disease-free survival (DFS) 52% versus 25%; P < 0.05) in children, but recent reviews do not confirm this datum [42,43]. Invasion of the brainstem (stage T3b) has been considered a high-risk factor. However, there is little agreement on the significance of this factor [41] either in children or in adults. The International Society of Paediatric Oncology (SIOP I) study [40] reported no significant difference between the 5-year survival rate of patients with and those without brainstem involvement (41% versus 52%); this finding was confirmed by data in the review of David et al.
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[43] and in the retrospective study of Chan et al. [44]. In adults series, Carrie et al. [6], on the other hand, reported that fourth ventricular floor involvement (P = 0.00004) and brainstem involvement (P = 0.08) are correlated with a worse disease-free survival. In the group of clinical trials that evaluated the association of T stage and outcome, the children’s cancer group (CCG) found only a weak correlation [37], whereas the SIOP study found a significant survival advantage with low T stage [40]. But up to one-half of patients on previous CCG and SIOP trial did not have CSF cytology or mielography [37,40]; so the T3–T4 group was composed of both M0 and M1+ patients. When patients are completely staged and stratified there is no univariate effect of preoperative T stage on DFS. 2.3.2. Metastatic disease Patients with metastases to the subaracnoid and extraneural spaces have an unfavourable short-term prognosis [17]. In children the presence of metastatic disease has a very definite role in predicting recurrence-free survival, while T stages has not [37]. In the study of Zeltzer et al. [41] lower M stage obtained a better DFS and the difference was statistically significant (P = 0.0006). Five-year estimates of DFS for patients with MO, M1 and M2+ tumours were 70, 57 and 40%, respectively. The presence of a positive CSF cytology alone, M1 stage, was not a statistically significant factor in DFS compared with MO (P = 0.15) or M2+ stage (P = 0.103). This was possibly due to the small number of patients which M1 tumours. There was no statistical evidence of a relationship between T stage and DFS; neither T1/T2 versus T3/T4 (stratified by treatment and M stage; P > 0.4) nor T1/T2 versus T3a versus T3b comparison stratified by treatment and M stage (P > 0.6) were significant. In a study by Jenkin et al. [42], the 5-year survival for patients (80% children) in the stage M2 and M3 group was 21% compared with 78% in M0 and M1 patients (P < 0.0001). These data are comparable with those reported in all the available studies using large series staged adults, 5-year survival rates ranging from 59 to 90% for stage M0–M1 patients and from 10 to 45% for M2–M3 stage patients [9,10,37,38,43,45]. Carrie et al. [6] did not find that this factor was of prognostic value in 156 medulloblastoma patients aged more than 18 years treated between January 1975 and December 1991 in 13 French institutions, but only 95 of these patients were evaluated for extent of disease. 2.3.3. Residual disease Jenkin et al. [42], unlike other authors [9,44,46], reported that patients with local residual disease measuring <1.5 cm2 fared as well as those with complete tumour excision. In their retrospective study on 48 patients (age >16 years) treated between 1958 and 1988 at Princess Margaret Hospi-
tal, Frost et al. [10] showed that subtotal removal is predictive for posterior fossa recurrence (75% versus 44%, P < 0.04), but not for DFS. In Carrie et al.’s series of 156 patients [6], 67% of patients underwent total surgical resection, but extent of resection was not a significant prognostic factor for DFS at either univariate or multivariate analysis. Another retrospective study performed on 28 adults at the MD Anderson Cancer Centre showed that extent of resection was not prognostic for survival [47]. However, in their study on 47 adult patients, Prados et al. [9] found that subtotal resection was closely correlated with OS and DFS. 2.4. Performance status Brandes et al. [17] found that postoperative performance status (PS) was of no prognostic significance in adults. Carrie et al. [6] reported that the 5-year survival rate of patients with a PS of 2 or less was significantly greater (66%) than that of those with a PS of 3 or more (28%). The significance of PS was also confirmed by Frost et al. [10], who observed that adults with a score of 2 or less had a 5-year DFS rate of 65% versus 23% for patients with scores of 3–5. 2.5. Hydrocephalus Frost et al. [10] reported that, in adult patients, hydrocephalus, but not shunt, is correlated with DFS. In series reported on by other authors, hydrocephalus has been associated with the poorest survival [17]. The issue of whether or not ventriculoperitoneal shunts increases the risk of distant tumour dissemination was addressed by Berger et al. [48]. Five out of eight children with systemic relapse had hydrocephalus, and two of these had ventriculoperitoneal shunts. Therefore it seems that shunts, regardless of type, location, or filter insertion did not cause a predisposition to extraneural metastases. In a review of 160 cases [49] of medulloblastoma with systemic metastases (30 of them having undergone systemic shunts) shunts had probably provided the route of systemic spread in no more than 11 cases. Some authors reported individual cases of shunt related abdominal metastases [50,51] but there are not recent reviews about this characteristic as prognostic factor.
3. Recurrences The majority of all recurrences occur in the posterior fossa, alone or in combination with other sites. In adults, Chan et al. [44], found that all recurrences to the posterior fossa occur in the previous surgical bed; at multivariate analysis, complete surgical resection was predictive of improved posterior fossa control (P = 0.02) and DFS (P = 0.02) rates.
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In the adult population, 59% of all recurrences [44] occur more than 2 years after surgery, unlike in the paediatric population, in which 75% of recurrences occur within the first 2 years [17]. In the series of Abacioglu et al. [52] (30 patient >16 years) 50% of recurrences occurred after 2 years, 17% after 5 years and the posterior fossa was the most common site of relapse. Other studies on adult medulloblastoma report that late recurrences are common [6,17,25]. In particular, midline lesions are associated with earlier recurrence, whereas lateral lesions are associated with later recurrence. A long-term follow-up monitoring is important for adult medulloblastoma.
4. Treatment 4.1. Surgery Some cornerstones are now well recognised for the treatment of MB: the first step is surgery, which should be as radical as possible. As, discussed above, the extent of surgical resection is an important factor in relation to survival [40]. For this reason neurosurgeons make considerable efforts to achieve complete or near complete resection. Extensive surgery can increase the risk of reversible or permanent neurological sequelae (e.g. cerebellar mutism syndrome) that can impact the quality of survival and contribute to delay the start of the adjuvant therapy. 4.2. Radiotherapy Radiotherapy has been accepted as the most effective postoperative treatment for MB. In average risk MB the standard radiotherapy dose is 36 Gy to the craniospinal axis with a boost of 18–20 Gy to the posterior fossa (total dose 54–56 Gy). Using such dose, various studies have reported that between 40 and 70% of patients are alive and free of progression of disease 5 year from diagnosis [17]. Adults who receive >55 Gy appear to have a lower risk of recurrence than those receiving less than 52 Gy (71% versus 51% 5-year event-free survival and 71% versus 34% 10-year event-free survival) [17]. Duration of radiotherapy is found significant in predicting posterior fossa control [44,53], and freedom from relapse [53], with 5-year posterior fossa control rates of 81 and 49% for a duration of less than 48 days and 48 days or more, respectively (P = 0.06). Nevertheless, in the series reported on by Frost et al. [10] radiation doses, time interval between diagnosis and date of starting radiation, and duration of radiotherapy were not found to be of prognostic significance for DFS. In children, radiotherapy can lead to significant neurocognitive sequelae, especially in very young patients. A trial was conducted by the paediatric oncology group children’s cancer group (POG-CCG) to evaluate prospectively the effects on survival, relapse-free survival and patterns of relapse of reduced dose (23.4 Gy in 13 frac-
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tions) compared with standard dose (36 Gy in 20 fractions) neuraxis irradiation in low-stage medulloblastoma [54]. The planned interim analysis resulted in early closure of the protocol and showed that patients randomised to the reduced neuraxis treatment have increased frequency of relapse, even if at 8 years no statistical difference between the two arms of treatment has been observed (EFS 67% versus 52%, P = 0.141) [55,56]. The therapeutic gain of 36 Gy over 23.4 Gy neuraxis irradiation is at least partly offset by increased toxicity as confirmed by psychometric studies [57]. This supports the rationale for reduced-dose neuraxis radiotherapy but adding chemotherapy. Packer et al. [58] demonstrated a 79% 5 year DFS in children between 3 and 10 years old with M0 disease when treated with reduced dose radiotherapy combined with concurrent vincristine (VCR) and subsequent cisplatin/lomustine (CCNU)/VCR: these overall survival rates compare favourably to those obtained in studies using full-dose radiation therapy alone or radiation therapy plus chemotherapy. Freeman et al. [59] analysed different trials (from the North America and the four European paediatric cooperative groups) for children with medulloblastoma: the conclusion seems that in patients with average risk disease the use of chemotherapy has allowed a reduction in the dose of radiotherapy to the craniospinal axis and the combination of chemotherapy with radiotherapy appears to have brought about a significant improvement in DFS and OS in this patient population. For high-risk patients there are only preliminary data which show that these children fare better now than in the past as a consequence of the routine use of aggressive chemotherapy. 4.3. Radiosurgery A stereotactic radiosurgical boost could be effective in patients with persistent disease after craniospinal radiotherapy to improve local control and OS, even if a small number of patients were analysed in these studies [60,61]. This procedure cannot be recommended in recurrent disease where the main problem remains the control of subclinical craniospinal dissemination [62]. 4.4. Chemotherapy The CCG and the SIOP studies demonstrated the efficacy of adjuvant post-irradiation chemotherapy in children with high stage disease [38,42], but other controlled clinical trials have failed to demonstrate a similar advantage in children with low-stage disease [43,52]. There has been considerable interest in trials of pre-irradiation chemotherapy [63,64], but these studies have shown a significant incidence of relapses due to excessive delays in initiating radiation therapy and in an excessive number of patients unable to complete planned irradiation [65], even if single arm feasibility trials had generally shown reasonable tolerance and apparent
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efficacy [63,64]. Most trials reported high rates of response but a high rate of disease progression during a 3–4 months pre-irradiation chemotherapy regimen [42,63–65]. Few studies were performed randomly testing preirradiation (neoadjuvant) versus post-irradiation (adjuvant) chemotherapy. Bailey et al. [66] reported diminished disease control in low-risk cases with chemotherapy before radiotherapy in the SIOP II study. In high-risk medulloblastoma, Zeltzer et al. reported a reduction in 5-year DFS from 63 to 45% when 8–1 chemotherapy preceded radiotherapy [41]. Kortmann et al. [67] in a prospective randomised trial confirmed that adjuvant chemotherapy is significantly better than neoadjuvant especially in low risk patients. Recently, Taylor et al. [68] published the results of a large multicenter randomised trial, where the pre-radiotherapy chemotherapy increases the EFS compared with radiotherapy alone (74% versus 59.8%, P = 0.036). This is the first randomised study in which “neoadjuvant” chemotherapy has been proved to be superior to radiotherapy alone and this delay is not detrimental for survival in non-metastatic MBs. In adults no randomised studies have been performed because of the rarity of this tumour and the role of adjuvant chemotherapy is not clear: some studies have not shown a statistical improvement in DFS [6], while others have shown an improvement in DFS [17,44]. In six studies [17], adjuvant chemotherapy was given to adults with medulloblastoma (using different regimens) and the findings were inconclusive. Carrie et al. [6] observed a favourable trend but only Brandes et al. were in favour of chemotherapy [17]. Nonetheless, even in the absence of unequivocal data, it is currently thought that adjuvant chemotherapy is beneficial, at least in patients at high risk of recurrence. In our opinion, two cycles of up-front chemotherapy can be safely administered [2], and they should include cisplatin, etoposide and cyclophosphamide [17,69].
5. Conclusion Because of the small number of adult patients with this disease, no randomised studies are available and data in literature are based on retrospective analyses. Therefore, unlike in the paediatric population, it is very difficult to establish prognostic factors in adults. Most adults with medulloblastoma have been treated using paediatric protocols, even if differences concern clinical characteristics, prognostic factors and tolerance both to radiotherapy and chemotherapy exist. Additional markers other than clinical factors alone are required for the selection of patients who can be cured with less aggressive treatment and novel therapeutic approaches should be developed to improve the survival of patients with more aggressive disease. It is therefore of paramount importance to understand the molecular basis of medulloblas-
toma in adults as in children: the biological characteristics continue to be elucidated, and in recent trials have been identified as prognostic factors. Therefore, in order to improve on the treatment of medulloblastoma, an evaluation should be made of clinical, biological and pathological factors. Prospective studies must also be conducted to investigate the role of hyperfractioned radiotherapy and adjuvant chemotherapy modalities, and their timing. Due to the low incidence of this disease in adults, a multi-centre study is required for the accrual of an adequate number of patients: this would throw light upon the differences between medulloblastoma in adults and that in children, thus allowing a more reliable evaluation of prognostic factors, and facilitating the choice of appropriate therapy as was done in the past in children. Reviewers Dr. Sandrine de Ribaupierre and PD Dr. Benedict Rilliet, Service de Neurochirurgie, Centre Hospitalier Universitaire Vaudois (CHUV), Rue du Bugnon, CH-1011 Lausanne, Switzerland. PD Dr. Med. R.-D. Kortmann, Oberarzt, Klinik für Radioonkologie, Eberhard-Karls-Universität, Universitätsklinikum Tübingen, Hoppe-Seyler-Str. 3, D-72076 Tübingen, Germany. References [1] McNeil DE, Cote TR, Clegg L, Rorke LB. Incidence and trends in pediatric malignancies medulloblastoma/primitive neuroectodermal tumor: a SEER update. Surveillance epidemiology and end results. Med Pediatr Oncol 2002;39:190–4. [2] Brandes AA, Ermani M, Amistà P. The treatment of adults with medulloblastoma: a prospective study. Int J Radiat Oncol Biol Phys 2003;57(3):755–61. [3] Newton HB. Review of the molecular genetics and chemotherapeutic treatment of adult and pediatric medulloblastoma. Expert Opin Invest Drugs 2001;10:2089–104. [4] Chintagumpala M, Berg S, Blaney MS. Treatment controversies in medulloblastoma. Curr Opin Oncol 2001;13:154–9. [5] Kramer JH, Crowe AB, Larson DA, et al. Neuropsychological sequelae of medulloblastoma in adults. Int J Radiat Oncol Biol Phys 1997;38:21–6. [6] Carrie C, Lasset C, Lapetite C, et al. Multivariate analysis of prognostic factors in adult patients with medulloblastoma: retrospective study of 156 patients. Cancer 1994;2352–60. [7] Peterson K, Walker RW. Medulloblastoma/PNET in 45 adults. Neurology 1995;45:440–2. [8] Haie-Meder C, Song YP. Medulloblastoma: differences in adults and children. Int J Radiat Oncol Biol Phys 1995;32:1235–57. [9] Prados MD, Warnick RE, Wara MW, et al. Medulloblastoma in adults. Int J Radiat Oncol Biol Phys 1995;32:1145–52. [10] Frost JP, Laperriere NJ, Wong CS, et al. Medulloblastoma in adults. Int J Radiat Oncol Biol Phys 1995;32:951–7. [11] Sarkar C, Pramanik P, Karak AK, et al. Are childhood and adult medulloblastoma different? A comparative study of clinicopathological features, proliferation index and apoptotic index. J Neuroncol 2002;59:49–61. [12] Giordana MT, Cavallo P, Ditto A, et al. Is medulloblastoma the same tumour in children and adult. J Neurooncol 1997;35:169–76.
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Biography Dr. Alba A. Brandes is the coordinator of the NeuroOncology Program at the Medical Oncology Department, Padova University Hospital, Italy. Dr. Brandes graduated from the University School of Medicine, Padova, where she pursued her training and fellowship in medical oncology and in clinical immunology. She has worked extensively in medical oncology for many years especially in the clinical research on sarcomas and breast cancer. Currently her primary interest is neuro-oncology research. Dr. Brandes plays an active role in the EORTC-Brain Tumour Group trials and she is the vice-chairman and the co-coordinator of Quality Assurance Committee.