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Childhood Medulloblastoma – 2015

UPDATED DECEMBER 2015

1. General information

1.1 What is the disease and how is it treated?

What is Medulloblastoma?
Medulloblastoma is a cancer that develops in the cerebellum, the lower, rear part of the brain, which is responsible for movement, balance, and coordination, and for some cognitive functions; it affects mostly children.

What are the causes of the disease?
The exact causes are not known, but, as Medulloblastoma occurs mainly during childhood, a key role is suspected for agents operating very early in life or during maternal pregnancy, such as toxic chemicals, some foods, or infections.

Is it a frequent disease?
No, it is not. Although it is the most common malignant brain tumour in childhood, it is nonetheless a rare cancer, affecting about 7 per million children (0-14 years old) per year.

How is it treated?
Treatment is based on surgery to remove as much cancer tissue as possible, followed in older children and adults by radiotherapy and chemotherapy; in young children, radiotherapy is usually delayed or avoided.

2. What is it, how does it occur, how is it diagnosed?

2.1 What is Medulloblastoma?

Medulloblastoma is a cancer of the central nervous system (CNS) that develops in the cerebellum, the lower, rear part of the brain, which is responsible for movement, balance, and coordination. It affects mostly children.
The 2007 World Health Organization classification of CNS tumours recognizes classic Medulloblastoma and the following four histological variants, defined according to the microscopic appearance of cancer tissue:

  • nodular/desmoplastic Medulloblastoma;
  • Medulloblastoma with extensive nodularity (MBEN);
  • large-cell Medulloblastoma;
  • anaplastic Medulloblastoma.

Of these variants, large-cell and anaplastic Medulloblastomas show a number of similarities and are often grouped as large-cell/anaplastic (LC/A) Medulloblastomas. Progression over time, from non-anaplastic to anaplastic types, has been described in several studies, and a transition can even be observed within a single tumour.
The LC/A variant comprises from 10% to 22% of all Medulloblastomas; the nodular/desmoplastic variant accounts for approximately 7%, while the MBEN variant accounts for 3%. Classic tumours constitute the remainder.
Clinical data strongly indicate a favourable prognosis for nodular/desmoplastic Medulloblastoma. Medulloblastoma with extensive nodularity (MBEN) occurs in infants and has a good prognosis, too. The LC/A variant has a significantly worse outcome compared to classic Medulloblastoma.
In recent years, genetic studies have made it possible to distinguish different kinds of Medulloblastoma – called molecular groups – having distinct gene mutations and different prospects of cure. Examining the tumour tissue with specific exams, the doctor can distinguish what kind of Medulloblastoma a patient has. According to genetic analysis, four groups of Medulloblastoma are presently recognized:

  • wingless (WNT);
  • sonic hedgehog (SHH);
  • Group 3;
  • Group 4 (see Figure 2 in the Professional area).
2.1.1 WNT (wingless) Medulloblastoma

This is the least common group of Medulloblastomas, accounting for 11% of all cases. WNT Medulloblastomas can occur at all ages, but predominantly affect older children, with a peak incidence in the 10-12 year age group, and are rarely observed in infants. Females are more affected than males, unlike in the other subgroups.
Regarding the histological variant, the majority of WNT Medulloblastomas are of the classic type; rare examples of the LC/A type have been documented, but this does not seem to affect prognosis.
Compared to other groups, metastatic diffusion is much lower. Prognosis in this group is the best of all four molecular groups, with survival rates around 95%-100%. The reasons for improved survival is not known, but could be due to increased tumour sensitivity to radiotherapy. Also, the presence or absence of TP53 gene mutations, which often influence prognosis, does not seem to affect the excellent prognosis of this group.

2.1.2 SHH (sonic hedgehog) Medulloblastoma

SHH and the related genes play a key role in normal cerebellar development, where they induce proliferation of immature neuronal cells in the developing cerebellum and other tissues.
The SHH subgroup accounts for about 30% of all Medulloblastomas. It occurs mostly in infants (younger than 3 years) and adults (older than 16 years), while it is less frequent in patients who are 3-16 years old. Males and females are almost equally affected, although there is a slight male predominance among infants.
Histology is most often of the nodular/desmoplastic type; nodular/desmoplastic and MBEN types are almost exclusively found in this group. The remaining cases are either of classic or LC/A histology.
Overall, patients in this group have an intermediate prognosis, with a 5-year overall survival of approximately 75% when treated with standard therapy. However, the prognosis is worse if genetic analysis finds certain specific gene mutations, or if the tumour tissue is of the anaplastic variant (see above), or if metastases are already present at diagnosis (which occurs in about 17% of cases).

2.1.3 Group 3 Medulloblastoma

Group 3 Medulloblastoma accounts for about 25%-28% of cases. It is exclusively found in children, with a male predominance, and has a high incidence of metastatic disease at diagnosis and is frequently of the LC/A histological variant.
Little is known about gene mutations that promote the disease. The genome in Group 3 Medulloblastoma is highly unstable and frequent chromosomal anomalies are found, including unusual ones.
Unfortunately, this subgroup has the worst prognosis amongst all, with a 5-year survival of less than 50%. Certain gene mutations or the presence of metastasis confer an even worse prognosis in this group.
Preliminary studies, conducted on isolated cells or animals, have shown that these tumours seem to be sensitive to novel drugs, which in future could lead to better treatment.

2.1.4 Group 4 Medulloblastoma

Group 4 is the most common molecular group of Medulloblastomas, accounting for about 35% of cases. This tumour type can affect all ages, but it is rare in infants. There is a significant male predominance, as males are affected three times more than females. Regarding the tissue type, the vast majority of Group 4 Medulloblastomas are of classic histology, although cases of LC/A have been observed. The gene mutations and disease processes underlying Group 4 Medulloblastoma are not well understood.
Patients in this group have an intermediate prognosis with conventional therapy. Some chromosome anomalies (loss of chromosome 11 and presence of i17q) confer an excellent prognosis even in patients who have metastasis.

2.1.5 Disease stats

Medulloblastoma belongs to a group of tumours whose cells have a similar appearance, called primitive neuroectodermal tumours (PNETs), which usually form in the brain or spinal cord in children or young adults, and account for 45% of all central nervous system cancers in children. Their European annual incidence rate was 6.8 per million children (0-14 years old) for the period 2000-2007, with higher rates in Southern and Central Europe. Medulloblastoma affects about 40% more boys than girls. It mostly affects children between 1 and 9 years of age (almost 8 per million children of this age are diagnosed with the disease each year); it is less frequent in infants (6 per million), and even less in 10- to 14-year-old children (4 per million). A rise in incidence was recorded for Medulloblastoma during the period 1978-1997, by 1.3% on average.

2.2 Risk factors

The peak of incidence of Medulloblastoma/PNET occurs during childhood; therefore, agents operating very early in life, such as harmful substances or infections, might play a key role.
Birth weight is often considered as a rough but easy indicator of prenatal exposure to such agents, and studies showed that children with high birth weight run a slightly (27%) increased risk of Medulloblastoma.
Several studies have speculated that some infections may increase or decrease the risk of Medulloblastoma. For example, an English study found that the children of mothers who had a viral infection during pregnancy had an 11-fold increased risk of nervous system cancer. Another large study tried to understand whether Medulloblastoma is more or less frequent in children who have more or less contact with other people during their first year of life (i.e., are more or less exposed to infections).
Children who had no social contact with other infants in the first year of life displayed an increased (78%) risk of developing a Medulloblastoma, suggesting a protective effect of some childhood infections; however, other markers of infectious exposure (i.e., bedroom sharing, domestic exposure to school-age children, and birth order) did not show any relationship with Medulloblastoma, so it is still uncertain if there is any real link.
Even diet has been investigated in several studies, both as a risk and a protective factor. One of the most extensively studied hypotheses is that maternal dietary intake of N-nitroso compounds (NOC) during pregnancy, mainly from cured meats, increases brain tumour risk in offspring.
A large international study on maternal diet during pregnancy and childhood brain tumours found that eating cured meats, eggs, dairy, and oil products during pregnancy seems to increase risk, while yellow-orange vegetables, fresh fish, and grains seem to decrease it. However, these results can be applied to childhood brain tumours in general and not specifically to Medulloblastoma; cured meat did not increase the risk of Medulloblastoma, while an increased risk of Medulloblastoma was found for oil products.
A large Canadian study examined the role of maternal occupational exposure to extremely low frequency magnetic fields shortly before and during pregnancy. An increased risk was observed for all childhood brain tumours, but not specifically for Medulloblastoma/PNET.
Several investigations evaluated whether childhood brain tumours are more frequent when parents are more exposed to pesticides, and most studies concluded that they are. Regarding specifically Medulloblastoma/PNET, both paternal and maternal exposure in the years before and after birth to agents such as pesticides and other chemicals, at work and at home (e.g., in lawn care), appeared to increase the risk in most studies, though not in all.
Finally, some genetic disorders (i.e., Gorlin syndrome, Turcot syndrome, Li-Fraumeni syndrome) are associated with an increased risk of Medulloblastoma.

2.3 What are the symptoms?

The symptoms of Medulloblastoma are caused by pressure exerted by the tumour on the brain and on cranial nerves, and by blockage of normal circulation of cerebrospinal fluid due to tumour growth.
The early symptoms are often non-specific; they include drowsiness, irritability, headaches, loss of appetite, and morning vomiting.
With tumour growth, and increase of fluid build-up and brain pressure (especially on the cerebellum, which controls balance and movement), symptoms increase and new symptoms may appear. They include morning headaches, nausea, vomiting, lethargy, often accompanied by dizziness and problems with walking, balance, and coordination. Patients can also present eye problems (such as diplopia, dilated pupils or unusual eye movements, face muscle weakness, neck stiffness, a tilt of the head, loss of feeling in part of the face, or problems with taste or hearing.
In infants, symptoms can be less evident. First symptoms may include increased head size and irritability, followed by intermittent vomiting, weight loss or failure to grow, a bulging of the soft spot of the head (fontanel), and inability to move the eyes upward.

2.4 Diagnosis

Medulloblastoma is one of the brain tumours that can develop in the posterior fossa, the bottom area of the skull. So it has to be distinguished from other tumours located in the same area, which include cerebellar astrocytoma, ependymoma, brainstem glioma, and atypical theratoid/rhabdoid tumour.
Diagnosis is based on medical history and physical examination, followed by imaging tests. If the first serious cancer symptom is a sudden crisis and the patient is taken to an emergency unit, Computed Tomography (CT) is sometimes the first-line neuroimaging exam, because it is usually available in the emergency setting.
However the best brain imaging exam to diagnose a posterior fossa tumour is magnetic resonance imaging (MRI), to be performed before tumour surgery.
Also, as up to 40% of patients can have metastases in the spinal cord, after surgery it is imperative to have an MRI of the spine before starting any adjuvant treatment. Whole brain and spinal cord imaging will be repeated before subsequent phases of postoperative treatment to check how the disease is progressing or regressing.
Other imaging exams (called magnetic resonance spectroscopy or MRS, PET, and single photon emission computed tomography or SPECT) might help to distinguish if anomalies seen in brain images are a tumour recurrence or simply a spot of dead brain tissue due to treatment. However, the use of these imaging techniques is still investigational.

3. How is Medulloblastoma treated?

3.1 General information

Tumours of the posterior fossa are usually treated by surgery to remove as much cancer tissue as possible, followed (in older children and adults) by radiotherapy and chemotherapy.
New treatment approaches are in development, aimed at both improving survival and reducing treatment damages; for instance, doctors are trying to use less irradiation to reduce side effects in some patients who may be at lower risk of disease recurrence; or increasing chemotherapy or irradiation to improve survival in patients with high-risk disease, according to newly-defined criteria that are also being explored. Currently, these experimental treatments are offered only to participants in a few studies called clinical trials, held in specialized centres.

3.2 Surgery

Surgical removal of the tumour is a fundamental part of treatment. Depending on where the tumour is placed inside the brain and its dimensions, an emergency treatment might be needed before removing it, to decrease pressure caused by cerebrospinal fluid build-up due to obstruction of its circulation. This treatment may be an external ventricular shunt or ventriculostomy. About 20%-30% of patients will require a permanent ventriculo-peritoneal shunt even after tumour removal, consequent to scarring and obstruction of the cerebrospinal fluid pathways.
As Medulloblastoma may grow near important brain areas, the surgeon might damage these areas and cause further brain injuries, but expert paediatric neurosurgeons are frequently able to totally remove the gross tumour without creating major problems. In some patients, however, total tumour removal without serious brain damage is impossible and some visible tumour remains after surgery.
Possible complications may include infections; mechanical problems such as cerebrospinal fluid leak and pseudomeningocele; and a syndrome called posterior fossa mutism. This is characterized by mutism developing 2-3 days after surgery, and it is associated with severe cerebellar deficits such as dysmetria, hypotonia, paresis, and mood depression, which can last several months.
After surgery, an MRI, usually performed within 48 hours, can assess if all the visible tumour tissue was removed (though microscopic tumour cells may have infiltrated nearby tissue or spread to other parts of the brain and spinal cord).

3.3 Standard risk patients

Patients are subdivided for treatment into standard and high-risk groups, depending on whether they have metastases or postoperative residual tumours. Standard risk patients are those with no cancer cells in the cerebrospinal fluid, absence of observable metastases, and little or no residual tumour after surgery (for details, see below Section 4 «Stages of Medulloblastoma»).
After surgery, the mainstay for patients older than 3 years at diagnosis is radiotherapy: a lower dose of radiation is administered to the whole head and spine (craniospinal irradiation) to destroy tumour cells that may have spread from the initial tumour site, and a higher dose is administered to the area where the tumour was (the posterior fossa).
This is usually combined with a chemotherapy that begins with a single-drug (vincristine) and is followed by a multidrug regimen that can be cisplatin, vincristine, and lomustine (CCNU); or cisplatin, vincristine, and cyclophosphamide. With this treatment, over 80% of patients survive at least five years with no cancer recurrence nor any other major complication due to cancer (event-free survival).
In recent years, CT and MRI scans have been increasingly used to decide exactly how to perform the irradiation.
Two clinical trials (the International Society of Paediatric Oncology PNET 5 study, and a study by the Children’s Oncology Group) are evaluating whether a further reduction of irradiation is possible in selected subgroups of patients to reduce side effects without decreasing efficacy.
An already completed European study (the HIT-SIOP PNET4 trial), tried to establish whether a different way of administering radiation (hyperfractionated radiotherapy, in which the total dose of radiation is divided into small doses given more frequently over the same number of weeks) gave better results than the conventional schedule. But the study showed no difference between the two approaches, so the conventional radiotherapy schedule is still used.

3.4 High-risk group patients

High-risk patients are those with cancer cells in the cerebrospinal fluid, visible metastases (macrometastases), or large residual tumour after surgery (for details, see below Section 4 «Stages of Medulloblastoma»). The prognosis for these patients is still unsatisfactory.
Ever since the 1980s, when Medulloblastoma, whether high-risk or not, has been treated with radiation therapy and chemotherapy, patients have had a better outcome if they received chemotherapy, too. Chemotherapy is, therefore, part of adjuvant treatment in this group of patients, but optimal timing and schedule have not yet been established. Some patients are treated with regimens similar to standard-risk patients. Others may receive stronger treatments with more drugs, such as what is known as the eight-drugs-in-one-day regimen, which administer several drugs in a short time, because different kinds of cancer cells are usually present within an individual tumour and they may be more sensitive to different drugs, and because some drugs are more powerful when used in combination. Radiotherapy may be added in several sessions both before and after chemotherapy.
More recent studies have produced encouraging results with high-dose chemotherapy and autologous stem cell transplantation.
However, no regimen was shown to be clearly better than others. For example, some studies showed that a strong regimen with high-dose radiotherapy and high-dose chemotherapy might achieve better results, but the evidence is still weak. So, doctors are still not sure whether this regimen is preferable in high-risk patients and more studies are needed.
Until studies obtain stronger evidence, our recommendations are that high-risk patients should enrol in controlled clinical trials, because of the unsatisfactory prognosis and the more aggressive treatment required, with accompanying acute and long-term side effects.

3.5 Treatment for younger children

Infants have either SHH tumours, which typically have a better prognosis, or group 3 tumours, which frequently have a poor prognosis (see Section 2.1 «What is Medulloblastoma?»).
In the past, the survival of infants with Medulloblastoma was inferior compared to older children. Possible reasons were delay in diagnosis, increased surgical risk, increased toxicity due to radiotherapy, the use of too weak a treatment, and a potentially more aggressive disease.
So in the mid-1980s it was decided to use different treatments in children younger than 3 years, delaying or omitting irradiation to reduce unacceptable side effects, as the severe permanent damages seen in long-term survivors treated with craniospinal irradiation at a young age, with or without chemotherapy, were considered unacceptable. Thus, trials were performed in the USA and Europe, using chemotherapy as a first treatment in order to delay or avoid radiotherapy.
The initial studies showed that only a minority of patients with limited disease could be cured with conventional chemotherapy. Therefore, European and American studies tried different chemotherapy regimens, such as higher doses of drugs, or different drugs, or injection of drugs directly into the cerebrospinal fluid (intraventricular chemotherapy) and not into the blood, with various successful outcomes.
A recent combined analysis of all these infant studies conducted in the United States, Germany, France, Italy, and the United Kingdom between 1987 and 2004 evaluated outcomes of 270 children less than 5 years of age treated with different strategies. Eight-year event-free survival and overall survival were significantly better for infants with nodular/desmoplastic Medulloblastoma (55% and 76%, respectively) as compared to those with classic (27% and 42%, respectively) or anaplastic tumours (14% and 14%, respectively). Similarly, infants without metastases whose tumour had been completely removed had a significantly better outcome compared to those with incomplete removal and/or metastases. So, it appears that nodular/desmoplastic Medulloblastoma in young children is associated with a better outcome irrespective of the therapeutic approach used; further studies addressing these issues should be performed.
In conclusion, during the last 10-15 years, the treatment of infant Medulloblastoma has evolved (role of radiotherapy has been revisited to reduce its side effects, and more intensive chemotherapy has been adopted), and survival rates have been improved. Recent observations seem to show that, with these new treatments, young children do not necessarily have a worse prognosis anymore, thanks to the use of more intensive treatment only for patients with advanced disease and unfavourable histology, and because up to 50% of infants have a favourable histological variant such as nodular/desmoplastic Medulloblastoma.
A new international trial for young children with non-metastatic Medulloblastoma is under discussion within the International Society of Paediatric Oncology (SIOP).

3.6 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 radiotherapy, which can cause severe neurological damages in children younger than 3 years and is therefore avoided at diagnosis in these young standard-risk patients, but can be used at relapse, combined with various chemotherapy schedules. However, this option is still investigational.
In addition, radiotherapy is not successful in older children that have already received craniospinal irradiation. In older children who received craniospinal irradiation as part of their initial therapy, re-operation to remove the recurring tumour, followed by irradiation limited to the tumour area, might be an option if tumour recurs in a single site and should be considered on a case-by-case basis.
Even chemotherapy can be used to treat recurring tumour. A number of regimens were tried, but gave poor results, while a promising approach under investigation is a chemotherapy regimen called “metronomic” therapy, which uses repetitive, low doses. This regimen poses some concerns, such as its immediate damage to blood-forming cells (with problems such as low levels of red blood cells or white blood cells or platelets), and the increased risk of new tumours in the long term, but nonetheless it is giving promising preliminary results and a clinical trial is ongoing in Europe to confirm its validity.
In a subgroup of patients with specific gene mutations, a class of drugs (Smoothened inhibitors) that target these mutations was evaluated, but gave poor results. Even when patients respond to treatment, the benefits are transient, because the cancer becomes resistant to the drugs. It is, therefore, unlikely that these drugs are likely to provide sustained benefit by themselves.

4. Stages of Medulloblastoma

Staging of a disease is the determination of distinct phases in its course, to help decide what exams and treatment the patient should undergo.
Staging and subsequent classification of the patient as standard-risk or high-risk are crucial in the management of Medulloblastoma.
Current staging classification requires magnetic resonance imaging (MRI) of the brain and entire spine with and without gadolinium, and analysis of the cerebrospinal fluid to look for cancer cells that have spread. This is crucial, because up to 10% of adults and 30% of children have evidence of disseminated disease when Medulloblastoma is discovered. Cerebrospinal fluid obtained 2 weeks after surgery from the lumbar region is preferred, because it is more sensitive than ventricular fluid for detecting disseminated cancer cells. However, in patients with certain conditions (such as increased pressure inside the skull) lumbar puncture may be contraindicated.
Traditionally, according to the North American classification, Medulloblastoma patients are classified into standard and high-risk groups for therapy, depending on the presence of metastases or large residual cancer tissue after surgery, as determined by MRI performed early after surgery (within 2-3 days). The presence of metastases is evaluated on a scale from M0 to M4 according to Chang’s classification.

Table 1. Chang classification for metastases.
M0 No detectable metastasis in the brain and spinal cord nor in the blood
M1  Microscopic tumour cells are found in the cerebrospinal fluid
M2  The tumour spreads within the brain beyond its initial site
M3  The tumour spreads to the spinal cord
M4  The tumour spreads to other tissues beyond the brain and the spinal cord

Patients are generally divided into risk groups on the basis of their age, the extent of residual disease, and dissemination (see Figure 4 in the Professional Area).
Children older than 3 years are classified as standard risk patients if they have no cancer cells found in the cerebrospinal fluid, no observable metastases, and little or no residual tumour after surgery; 60% to 70% of patients older than 3 years are assigned to this group.
High-risk patients include people with cancer cells found in the cerebrospinal fluid or with metastases, and patients who have an incomplete tumour removal (arbitrarily defined as 1.5 cm2 of residual cancer tissue after surgery).
Other elements may contribute to assess the risk, such as the histological variant (LC/A have a poorer outcome compared to classic or desmoplastic tumours; see Section 2.1 «What is Medulloblastoma?»). Further factors, such as certain gene mutations, are proving to have a role in determining the outcome and will be better evaluated in forthcoming clinical trials.

5. Prognosis

5.1 General information

Prognosis indicates the likelihood that treatment will be successful. It is a statistical measure obtained from different studies that observe the progress of the disease in a high number of patients. It is important to remember that these statistics merely provide an indication: no doctor is able to predict exactly what the outcome of treatment in an individual patient will be, nor how long the patient will live, as prognosis depends on several factors, in relation with the individual patient.

5.2 Prognosis of Medulloblastoma

In European children with a Medulloblastoma diagnosed in the period 2000-2007, 1-, 3-, and 5-year survival figures were 81%, 63%, and 56%, respectively. Prognosis was worst for infants, with a 5-year survival of 33%; slightly better for children aged 1-4 years (47%); and significantly better (67%) for children aged 5-14 years.
Survival improved significantly during the end of the Nineties, then remained stable during the period 1999-2007. Standard care treatment for children older than 3 years resulted in an overall cure rate of approximately 70%-75%. Outcome varied across European countries, suggesting difficulty to access to effective treatment and/or reach timely and correct diagnosis in some areas; 5-year survival was better in Northern Europe (64%) and lowest in Eastern Europe (53%).
Until a few years ago, patients with metastases had dismal outcomes, with 5-year survival around 30%-50%. Nowadays, intensified chemotherapy regimens and non-conventional radiotherapy schedules seem to have improved prognosis, with 5-year survival rates around 70%, which will need to be confirmed in further trials.
Similar improvements have been obtained for younger children (under 3 or 4-5 years of age at diagnosis, depending on national policies), treated with risk- and age-adapted radiotherapy (frequently reducing total doses) and prolonged chemotherapy schedules to reduce late consequences and the risk of relapse. The most recent experience, carried out in Germany, resulted in a 5-year progression free survival of 83%.

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6. What to do after treatment

6.1 Late sequelae

Long-term consequences of patients treated for Medulloblastoma, including motor, sensory, hormonal, cognitive, neuropsychological, and behavioural deficits, can markedly affect their quality of life and their re-entry into school and society.
Prognosis of the risk posed by Medulloblastoma to an individual patient – by combining information from genetic anomalies (see above, Section 2.1 «What is Medulloblastoma?») and clinical risk factors, such as age and tumour staging – allows for therapy intensification in high-risk children to improve survival, and reduction of treatment in children with low-risk disease to avoid the significant complications of therapy.
While the first studies mainly focused on how to improve survival, the quality of subsequent life is now becoming a crucial issue and future trials should put reducing long-term consequences among the goals of treatment.
For example, a recent study in standard-risk Medulloblastoma patients in seven Countries (PNET4) checked if hyperfractionated radiotherapy improves the quality of long-term survival compared to standard radiotherapy. However, the conclusions are not clear-cut: hyperfractionated treatment shows both advantages and disadvantages, but without overall differences in health status, behaviour, or quality of life, and many uncertainties still remain.

6.1.1 Endocrine sequelae

After treatment for Medulloblastoma, several neuroendocrine deficiencies may occur, because of damages during surgery and because of irradiation. Surgically induced deficiencies manifest shortly after surgery, while radiation-induced damage may manifest months to years after irradiation. For this reason, after craniospinal irradiation it is necessary to keep checking endocrine functions for a long time.
Two brain centres, the hypothalamus and the pituitary gland, produce hormones that control the activity of many tissues in the body, including several hormone-producing glands. Radiation may damage the hypothalamus, and over time the anomalous activity of the hypothalamus may damage the pituitary gland, so eventually several organs controlled by these two centres may be affected. Production of different hormones in the hypothalamus and the pituitary gland is affected differently by treatment: the growth hormone (GH) is the most sensitive, followed by the gonadotropins, ACTH, and thyroid-stimulating hormone (TSH). Here below, the details about each hormone.

Growth hormone deficiency (GHD). The growth hormone (GH) stimulates the growth of bone and cartilage in children and teens, and controls several body processes in people of all ages, such as protein production and the use of fat. GHD is observed in 40%-80% of survivors of Medulloblastoma. The risk to develop GHD depends on: age at radiotherapy, total dose delivered, irradiated areas, duration of radiotherapy, how doses are fractioned, and time after irradiation. GHD may develop from 3 months to 5 years after the end of radiotherapy; once started, it worsens over time, and frequently becomes irreversible.

To detect GHD, irradiated children have to undergo the following: anthropometric measurements (height, weight, body mass index – BMI), lower segment and arm span, Tanner staging every 6 months until growth is complete or they are sexually mature, then once a year; nutritional evaluation (every 6 months); and laboratory tests including IGF-1 (even though its role is debated), IGF binding protein 3, bone age determination, insulin tolerance test and GH provocative tests.
Once diagnosed, the standard treatment of GHD consists in substitutive therapy with drugs that replace the missing hormone, such as somatropin (0.18-0.3 mg/kg) or somatrem (0.3 mg/kg), both daily as a standard option. Substitutive therapy can be started 1 year after the completion of the oncological treatment; even if growth hormone stimulates cell multiplication, it has been shown that this treatment is safe and does not promote further tumour growth.
Three other causes of growth failure must be ruled out before starting GH replacement therapy:

  1. slowing of growth during radiotherapy due to poor caloric intake;
  2. poor spinal (but not limb) growth after irradiation of the spine, caused by destruction of growth plates in the spine by radiation;
  3. premature end of bone growth due to precocious puberty.

Gonadotropins and gonadal alterations. Gonadotropins are hormones produced in the pituitary gland that control gamete and sex hormone production by the gonads (testes in males and ovaries in females). The two major gonadotropins are the luteinizing hormone (LH) and follicle stimulating hormone (FSH), produced by the pituitary gland. Children treated for Medulloblastoma may suffer impairments of gonad functions due to altered gonadotropin production, with consequences such as precocious puberty, delayed puberty (see below), or hypogonadism
Gonadal alterations can be seen 1 year after the end of radiotherapy. The risk depends on: age at treatment (patients treated at younger ages are less susceptible), concomitant use of radiotherapy and chemotherapy, and radiotherapy doses.
Children with possible gonadal alterations should undergo checks yearly, including: estradiol levels assessment and pelvic ultrasonography in females; yearly testicular volume, testosterone and β-HCG levels in males; in both sexes annual height/weight assessment, LH and FSH, both basal and after GnRH stimulation, bone age, GH levels, and Tanner stage should be monitored.

Precocious puberty is defined as the development of secondary sexual traits (such as breasts in girls and beard in boys) before the age of 8 years in females and 9 years in males, accompanied by rapid growth in height. This alteration is caused by the premature production of gonadotropins and often coexists with GHD (in this case, if GHD is not treated, the child will not benefit from the normal pubertal growth spurt, reaching a short final height). Early detection of precocious puberty is mandatory in order to avoid a short final stature. The standard treatment consists in drugs that suppress improper production of gonadotropins (long-acting analogues of GnRH agonists, such as leuprolide acetate 1.88-3.75 mg/i.m. monthly).

Delayed puberty must be considered when the patient does not develop secondary sexual traits (such as breasts in girls and beard in boys) by age 14 for boys and 13 for girls. Replacement therapy with sex hormones might prove useful, and standard treatment options include: conjugated oestrogen (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 paediatric Medulloblastoma are infertility and precocious menopause. Sterility is more frequent in males and is due to some chemotherapy drugs (known as 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.

Hypothyroidism. A decreased thyroid function during and after radiotherapy appears in about 6% of patients treated for Medulloblastoma. Chemotherapy could also contribute to thyroid damage, but this is still debated. 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. Annual screening should include a focused history for symptoms of hypothyroidism, height, weight, skin, hair, and thyroid examination, and annual bone densitometry. An assessment of thyroid-related hormones (FT4 and TSH) should be performed every 6 months. The values should be maintained in the upper half of the normal range. If the values are low, recommended treatment is thyroid hormone replacement with 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).

Hyperthyroidism. Rarely, an overactive thyroid, producing too much hormone, may occur after irradiation for paediatric 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.

Thyroid nodules. Thyroid nodules are lumps that form inside one’s thyroid; usually they do not cause symptoms or problems, but in a few cases they may be cancerous. To detect nodules, yearly thyroid physical examination and periodical ultrasound examination should be performed, and a biopsy should be considered if suspicious nodules are found.

Hyperprolactinaemia is a frequent finding after brain irradiation. It occurs in both sexes and all age groups, but is most frequent in adult females. It only appears more than 2 years after therapy. Screening includes periodic prolactin and TSH assays; when prolactin levels are higher than 50 ng/ml, pituitary magnetic resonance imaging should be performed. In females, hyperprolactinaemia causes oligomenorrhea or amenorrhea with lack of ovulation or infertility; in males, it causes decreased libido and reduced sexual potency with progressive hypogonadism. Galactorrhea is a less frequent finding, and rare in males.
Sometimes, hyperprolactinaemia disappears spontaneously 5-6 years after radiotherapy, but, more often, treatment is necessary. The standard treatment is with a dopamine agonist (Bromocriptine 1.25-5 mg/day orally, gradually increasing the dose, or Cabergoline 0.25-1 mg/week orally).
Central adrenal insufficiency is a deficiency of the ACTH hormone produced by the pituitary gland, which controls release of another hormone, cortisol, by the adrenal glands. It is rare, but potentially life threatening. Symptoms include failure to thrive, anorexia, dehydration, hypoglycaemia, lethargy, and unexplained hypotension.
The insufficiency has been detected in survivors many years after the completion of therapy, so a cortisol dosage should be performed yearly until 15 years off therapy. Further endocrinological evaluations and treatment are needed if cortisol levels are below 10 µg/dl.
If ACTH deficiency is suspected because of symptoms, a test of the whole hypothalamus-pituitary-adrenal glands functioning should be performed (such as an insulin tolerance test or metyrapone test).

Osteopoenia/osteoporosis can be caused by both steroid therapy and craniospinal irradiation, while GH deficiency does not seem to be an important factor. Bone density evaluation should be performed during follow-up, starting 2 years after completion of cancer therapy. The patient should be referred to a specialist if osteoporosis is suspected. Calcium and vitamin D supplementation and optimisation of endocrine replacements seem to be important as well.

Overweight/obesity, dyslipidemia, and metabolic syndrome. Cranial irradiation or the drugs carboplatin and cisplatin, often used in Medulloblastoma chemotherapy, may cause dyslipidemia. GH deficiency and hypothyroidism may exacerbate overweight/obesity. Survivor follow-up includes annual assessments of blood pressure and body mass index. Fasting blood glucose, serum insulin, and lipid profile should be screened every 2 years in patients who are overweight or obese, and every 5 years in normal weight patients. Other conditions such as hypertension, glucose intolerance, diabetes mellitus, hyperinsulinism, and insulin resistance should be monitored in these patients. They should receive counselling for dietary modification, exercise, and weight loss, while a pharmacologic intervention should be considered in patients unresponsive to dietary and lifestyle modifications.

Neurocognitive outcome. Neurocognitive functions are cognitive abilities closely linked to the function of particular brain areas or networks. Many survivors of Medulloblastoma treatment experience long-term cognitive, neuropsychological, and academic impairments. In survivors, 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 neurocognitive domains most affected by treatment are attention, executive functioning, processing speed, working memory, and learning, which adversely influence academic performance. It is well established that children with Medulloblastoma demonstrate declines in neurocognitive functioning and academic achievement over time. Because of these deficits, 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 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.
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 some brain structures and functions, affecting or halting the processes leading to new skill acquisition, with a negative domino effect on cognitive development;
  2. tumour site: tumour invasion of the normal brain, compression of the tumour on the brain, 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, and long-term deficits can appear in speech, language and communication, executive function, visuospatial ability, and the ability to regulate one’s behaviour;
  3. clinical complications, such as hydrocephalus. Tumours in this area can cause an obstruction of the cerebrospinal fluid circulation with ensuing hydrocephalus; in turn, this may cause generalized damage and cognitive problems added to the specific damage in the tumour site;
  4. cranial radiation therapy. The most prominent deficits for children with brain tumours are associated with cranial radiotherapy. Patients irradiated in the head are significantly more likely to have school problems than non-irradiated brain tumour patients, and experience a pervasive decline in knowledge acquisition. Poor intellectual outcome is associated with higher radiation doses and a larger irradiated region, as well as younger age at radiotherapy. The effects of cranial irradiation begin to show visible impacts on cognitive functioning at about 1 year post-treatment and the decline continues over time. In a study, younger patients experienced an immediate decline that continued over time, while in older patients the decline began about 2 years after treatment;
  5. sensory and motor impairments: such deficits heavily impact on patients’ later learning experience and natural cognitive decline.

Two processes could account for the cognitive decline experienced by patients with Medulloblastoma. Children who show a decline in their IQ scores could be losing previously acquired information, or they could acquire new information at a rate that is slower than normal same-age peers. A slow rate of knowledge acquisition directly affects potential academic performance, including basic academic skills such as reading and spelling, crucial for school completion, so these survivors are at great risk of losing the ability to live independent lives. These basic skills have served as important endpoints in comprehensive studies of cognitive ability following treatment for Medulloblastoma. Patients younger than 7 years show a greater impairment in reading than patients older at diagnosis.
Impairments in measures of intelligence and school achievements may be the consequences of changes in more basic cognitive skills, such as memory, attention, and processing, which may occur earlier in the cascade of events; in fact, attention, behaviour planning, organisation, and the ability to store and organize information are critical prerequisites for knowledge acquisition.
Given these issues, functional assessments should be carried out periodically to test for cognitive problems and, if necessary, start specific rehabilitation with appropriate school support. An early assessment of a child’s deficits and strengths is necessary to help parents and teachers provide proper care, support, and recovery from hospitalisation. Long-term multidisciplinary follow-up and treatment for psychological and emotional difficulties should follow. As the degree of impairment varies between patients, children at heightened risk of developing specific cognitive deficits should be accurately screened to start intervention programs, which can include drug therapy, cognitive therapy to enhance attention, and cognitive-behavioural strategies, along with personalized educational and support programmes.
Furthermore, survivors frequently show psychological and behavioural problems, such as inadequate social competence, withdrawal, anxiety, and depression, which affect social life and interpersonal skills, undermining 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. As problems may arise at a later time, regular follow-ups are needed to monitor the children’s cognitive development and school progress, as well.

6.1.2 Late sensorineural effects

Auditory deficits are the most frequent late effects and are associated both with cochlear irradiation during radiotherapy and use of the drug cisplatin in chemotherapy. The deficit can affect only one ear or both and be so severe as to require hearing aid. Audiometry is, therefore, constantly required during and after treatment, with regular follow-up examinations to provide early correction of deficits.
Visual defects may include reduced visual acuity, nystagmus and diplopia. Other defects, such as dysmetria and ataxia, are frequently ameliorated by early re-education.

6.1.3 Orthopaedic late-effects

Craniospinal irradiation can alter vertebral growth, causing kyphosis and vertebral demineralisation. This may also be caused by steroidal therapy, deficits of growth hormone or gonadotropin, or altered food intake.

6.1.4 Second tumours

Both irradiation and chemotherapy may cause new tumours. Several kinds of brain tumours (meningiomas, cavernomas, and glial tumours) may show in the irradiated area even thirty years after treatment, justifying the prolongation of follow-up.
New tumours due to treatment have to be distinguished from those arising because the patient has a syndrome that predisposes to cancer, such as Gorlin’s and Turcot’s syndromes.

6.2 Follow-up

Medulloblastoma can recur, most often within 2 years, and more than half of relapses include metastases. Relapse is most commonly diagnosed with brain and spine imaging; occasionally, clinical symptoms are seen before neuroimaging findings.
There are no studies showing how frequently magnetic resonance imaging should be repeated. Imaging of the brain and spine is generally recommended every 3 months for the first 2 years. Later, imaging of the brain should be performed every 4 months for the third year, every 6 months until the fifth year, and then annually. Evaluation of the spine is generally required only in case of clinical suspicion.
All the clinical, radiological, and biochemical examinations and neuro-functional tests detailed above (in Section 6.1 «Late sequelae») contribute to follow-up for second cancers.

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7. What to ask doctors

Here is a list of questions that you might wish to ask your doctor or any specialists you may consult. To avoid unnecessary concern, it is useful to ask about any doubts you might have, no matter how small they may appear.

General questions

• What leaflets, books, or websites could I read to learn more about Medulloblastoma?
• Is there a patient association or online support group I could contact?
• How will the disease and treatments interfere with school and playing?
• Should my child pay special attention to activities such as playing or sports?
• Do you have special advice regarding nutrition?
• Is there any contraindication regarding vaccinations?
• Does Medulloblastoma run in families? Are my other children at risk of getting Medulloblastoma?
• How can I help my child to remain serene?
• Can you refer me for counselling?

Diagnosis and exams

• What type of brain tumour is it?
• What tests are you going to do?
• What are you looking for?
• How long will the exam take?
• Will the child be asleep?
• Are CT or MRI dangerous because of radiation exposure?
• Is lumbar puncture painful? Is it performed under general or local anaesthesia?
• How long will it take to confirm diagnosis?

Treatment

• Do I need a highly specialized centre for my child?
• Are the histology and molecular groups of the tumour favourable or unfavourable?
• What is the cancer stage, and what does it mean?
• What type of treatment is needed?
• Is there any choice of treatments?
• What is the outlook for cure?
• What are the options if the first therapy does not work?
• Should my child participate in a clinical trial? If so, in what trial?
• What are the risks and benefits of the treatments?
• How long will treatment last? Where will it be done?
• Will treatment reduce symptoms and discomfort?
• What are the possible side effects of therapy? Will my child lose his/her hair, or have nausea and vomiting?
• How can I help to reduce the side effects?
• During treatment, should I take special precautions or change some habits?
• Which supportive therapy is suggested during treatment?
• How will treatment affect my child?
• What late effects could treatments have?
• Will treatment affect my child’s growth, school achievements, future sex life, or ability to have children?
• Could Medulloblastoma recur?
• Will I pay for treatment? What is it likely to cost?