Relapsed Medulloblastoma

Surveillance scanning is very important after therapy since it can detect

most recurrences prior to the onset of symptoms. Studies have shown
some improvement of survival in relapsed patients using high-dose
carboplatin, thiotepa and etoposide followed by autologous stem cell
rescue (Table 21-6), with salvage rates up to 30%
BRAIN STEM TUMORS
Brain stem gliomas comprise 15-20% of all childhood CNS tumors. Th all
childhood tumors. The median age at presentation is 6-7 years of age. Fifty
percent of the patients present with cranial nerve and long tract signs.
The majority of patients have diffuse, infiltrating pontine tumors,
sometimes with an exophytic component. These are typically WHO grades
II-IV gliomas with 1-year and 2-year survival rates of <10-20%. A subset of
patients have focal lesions that are usually grade I tumors and have 2-year
survival rates of about 60% or greater. Localized brainstem tumors may also
be PNETS. While sensitivity to chemotherapy as well as radiation is
common, prognosis remains poor, at around 10% 2-year survival.
Surgery
Surgical resection is not usually possible because of the proximity to
vital structures, limited room for expansion and swelling and possible
damage to medullary structures. There is no apparent benefit from a
surgical biopsy when the imaging and clinical picture are indicative of a
diffuse infiltrating pontine glioma. For focal tumors (nontectal),
complete resection may be safe and may not require any further
therapy.Partial resection of exophytic tumors will establish the
diagnosis and reduce the obstructing mass within the fourth ventricle.
If hydrocephalus is present, a CSF diversion should be performed
Radiotherapy
Limited field radiation is standard palliative care in patients with
infiltrative pontine gliomas. A tumor dose of approximately 5,400 cGy is
standard. The treatment field should include the extent of the defined
tumor and a 2-cm margin around the tumor. In irradiating these
tumors, precaution should be taken to minimize brain stem edema,
especially in patients who have not been shunted. The use of high-dose
steroids is valuable during treatment and may be required throughout
the treatment period. Children with diffusely infiltrating pontine
gliomas often initially respond to radiation therapy but progressive
disease is usually seen within 8-12 months. Timing of radiation for
partially resected focal
Radiotherapy
• lesions is unclear. It is not known whether immediate adjuvant
therapy is superior to observation and therapy only at the time of
progression
Chemotherapy
The use of combination chemotherapy after radiotherapy has not
improved the disease-free survival in brain stem tumors. Until some
chemotherapeutic regimen confirms a survival advantage in newly
diagnosed patients, chemotherapy currently plays a palliative role
Prognosis
The overall prognosis for brain stem tumors is poor. Most centers
report a 5-20% 2.vers survival rate when high doses of irradiation are
employed. Children with diffusal infiltrating pontine gliomas often
respond initially to radiation therapy but progressive disease is usually
seen within 8-12 months. Improved survival is seen in focal low-grade
brain stem astrocytomas especially those seen in patients with NF-1
and those in the tectalarea
EPENDYMOMAS
Fifty percent of all ependymomas occur during childhood and
adolescence and they constitute approximately 9% of all primary
childhood CNS tumors. The tumors occur either infratentorial or
supratentorial. The fourth ventricle is the most common location.
Ependymomas can also occur in the spinal cord and account for 25% of
spinal cord tumors. Obstructive hydrocephalus is the most common
presenting condition.
Surgery
Total removal of these tumors is difficult to accomplish, especially in
tumors originating from the fourth ventricle. However, since gross total
tumor resection predicts a greatly improved outcome, this should be
attempted. In the posterior fossa, the use of evoked potentials helps to
make this process safer, but patients may still have multiple cranial
nerve palsies and may require tracheotomy and gastrostomy for
months until normal swallowing recovers. Patients with a subtotal
resection should receive two courses ofchemotherapy before potential
second-look surgery.
Radiotherapy
The recurrence rate with surgery alone is extremely high and
postoperative radiotherapy results in a significant increase in survival.
Local disease without evidence of subarachnoid spread should receive
local irradiation with a margin (that should include extension to lateral
ventricles or superior cervical spine when appropriate). Use of 3D-
conformal radiation or IMRT is appropriate and is currently under
investigation. The dose is 5400 - 6000 cGy for intracranial lesions.
Chemotherapy
No advantage has been demonstrated from the use of adjuvant
chemotherapy and although platinum agents are the most active they
are not currently part of standard therapy. In infants, chemotherapy is
used to postpone radiotherapy. There is some evidence that low dose
metronomic chemotherapy (i.e. oral etoposide at 50 mg/m /day for 21
or 28 days) can be effective in treating relapsed disease. Optimal length
of therapy is not yet determined.
Prognosis
The overall prognosis for ependymomas is dependent on the initial
extent of resection presence or absence of anaplasia and gender.
Patients with total resection who receive radiation have a 5-year
survival of 67-86% compared to 22-47% 5-year event-free survival for
patients who receive radiation after subtotal resection. Patients with
anaplasia or male gender have significantly worse event-free survival.
OPTIC GLIOMA
Optic gliomas constitute 5% of the primary CNS tumors in childhood
and the majority is diagnosed by 5 years of age with almost all
diagnosed by age 20. Involvement of the optic chiasm is usually seen in
older children. Neurofibromatosis is present in up to 70% of patients
with tumors of the optic nerve or chiasma tumors: isolated optic nerve
tumors are more commonly in patients with NF1. Patients may present
with decreased vision, proptosis, optic atrophy and papilledema. In
young children asymmetric nystagmus may be the presenting sign of a
chiasmatic tumor. Tumors that extend beyond the optic pathway may
be associated w hypothalamic dysfunction. Histologically approximately
90% are low-grade astrocytomas.
Surgery
Biopsy may compromise vision, MRI and CT should be used to make a
clinical diagnosis and biopsy should be used for unusual circumstances.
Surgery should be reserved for tumor extension into the optic canal or
increasing visual compromise.
Radiotherapy
The role of radiotherapy in optic gliomas has not been completely
established but it may have a beneficial role in preserving vision:
Radiation may be indicated in patient with progressive disease instead
of surgery, especially for chiasmatic-hypothalamic lesions. Patients with
NF-I may have exacerbation of moyamoya, which one must consider
before recommending radiation. A local field to the tumor of 45005000
cGy over 5-6 weeks isUsually recommended.
Chemotherapy
Chemotherapy has been used to treat progressive disease. Regimens
used include:
Actinomycin D and vincristine. Actinomycin D 0.015 mg/kg/d for 5 days
(0,5 mg maximum per dose) IV every 12 weeks for six cycles. Vincristine
1.5 mg/m2 ( 2 mg maximum dose) IV weekly for 8 weeks with a 4-week
rest between cycles. Four years progression-free survival (PFS) is 62.5%
but 7-year PFS is only about 33%, or
Carboplatin 560 mg/m IV every 4 weeks for up to 18 months with an
approximate 30% response rate, or
Carboplatin175 mg/m2 IV weekly for 4 weeks followed by a 2-week rest
and then four more weekly doses of carboplatin. Vincristine 1.5 mg/m
(maximum dose 2 mg/weekly for 10 weeks is given concurrently with
the carboplatin course. If a response or stabilization is obtained,
maintenance therapy is given consisting of courses of carboplatin 175
mg/m weekly for 4 weeks with vincristine 1.5 mg/m2 (maximum dose 2
mg) weekly for the first 3 weeks of each 4-week cycle. There is a 3-
week rest between each maintenance cycle. In children with stable or
improved disease the regimen is continued for 8-12 cycles (Table 21-9).
Recommendations
Since optic glioma can run an indolent course, the decision for
therapeutic intervention should be based on radiographic findings and
visual assessment of visual acuity, visual fields and visual-evoked
response. The following treatment plan is recommended:
Evidence of optic nerve tumor and normal visual assessment: No
therapeutic intervention is recommended. CT/MRI scan and visual
assessments are performed every 6 months to monitor progression of
disease.
Recommendations
Table 21-9 Chemotherapy for Optic Glioma
Evidence of progression on visual assessment, with or without tumor
extending posteriorly into the optic canal: A trial of chemotherapy is
recommended in an attempt to to preserve useful vision.
Prognosis
Progression-free survival rates with carboplatin and vincristine are 68%
at 3 years. Current studies seek to determine the benefit of adding
temozolomide to vincristine and carboplatin.
CRANIOPHARYNGIOMAS
Craniopharyngiomas may involve the pituitary gland. They account for
6-9% of all CNS tumors in children. The peak incidence is 5-10 years of
age. Patients present with symptoms of increased ICP, visual loss and
endocrine deficiencies. They typically require replacement therapy with
cortisone, thyroxine, growth hormone and/or sex hormones. These
tumors are slow-growing benign lesions amidst vital anatomic
structures.
Surgery
Craniopharyngiomas should be completely removed if possible without
producing untoward neurologic sequelae. Complete excision is possible
in 60-90% of cases. If radical excision can be accomplished without
significant postoperative morbidity, a primary surgical approach is
warranted. However, controversy exists over whether subtotal
resection followed by radiation will produce less morbidity and be an
equally effective strategy.Complete tumor removal is most easily
accomplished in cystic tumors and is most difficult in solid or mixed
tumors larger than 3 cm in size.
Radiotherapy
In tumors in which conservative surgery consisting only of drainage or
subtotal removal is performed, the addition of radiotherapy reduces
the local recurrence rate and improves long-term survival. For children
older than 5 years, 50005500 cGy are given. In children less than 5
years of age the dose may be reduced to 40004500 cGy.For patients
with complete resections, radiation may be reserved for those who
relapse.
Chemotherapy
At present there is no established role for systemic chemotherapy in
craniopharyngioma. Interferon-alpha 2a systemically shrank the lesion
in 25% of patients treated, primarily those with cystic lesions.
Prognosis
The long-term survival of patients treated with radical and total
removal is 80-90% at 5 years and 81% at 10 years. The 5-year
recurrence-free survival after subtotal removal is approximately 50%.
Survival after partial removal and radiation therapy is 62-84%.
INTRACRANIAL GERM CELL TUMORS
Primary intracranial germ cell tumors (GCT) comprise 1-3% of primary
pediatric brain tumors. The peak age is between 10 and 21 of age 21
years of age. Multiple tumor types can be seen:the majority are
germinomas (~55%), teratomas and mixed germ cell tumors (33%) and
the remaining 10% are malignant endodermal sinus tumors, embryonal
cell carcinomas. Choripcharcinomas and teratocarcinomas. In all but
the germinomas, serum and cerebrospinal fluid alpha-fetoprotein and
HCG may be elevated. MRI of the spine with Gd-DTPA should be
performed, as leptomeningeal spread is relatively common.The
outcome of patients with pure germinoma is considerably better than
with mixed germcell tumors.
Surgery
• Surgical biopsy is indicated in all germ cell tumors to make an appropriate diagnosis
unless elevated serum or CSF tumor markers establish the diagnosis. For patients with
benign tumors such as teratomas or dermoid, surgery can be curative
Radiotherapyy
• Conventional radiotherapy for a CNS germinoma includes doses to the primary tumol
o 5,000 cGy with 3,000 cGy craniospinal therapy. However, there are several studies
which demonstrate the ability to use chemotherapy to reduce the dose of radiation to
between 3,060 cGy and 5,040 cGy to gross tumor only (in non disseminated disease)
depending on response while maintaining outcomes of >90% event-free survival. Non
Germinoma germ cell tumors (NGGCT) respond poorly to radiation therapy but the
use of chemotherapy with radiation appears to improve survival substantially in
preliminary studies. These data needto be replicated in larger studies.
Chemotherapy
In both germinomas and nongerminoma germ cell tumors, cycles of
cisplatin 20 mg/m*/day IV days 1-5 with etoposide 100 mg/m2/day IV
days 1-5 alone or alternating with cyclophosphamide I g/m /day for 2
days with vincristine 1.5 mg/m/Iday weekly for 3 days has been used.
For high-risk disease (nongerminomatous disease, HCG >50 mlu/ml or
elevated AFP) doses of cisplatin and cyclophosphamide have been
doubled or ifosfamide
Prognosis
• The germinomas have the best overall survival rate followed by
teratomas and pineal parenchymal tumors. Non Germinoma germ cell
tumors such as embryonal carcinoma, endodermal and
choriocarcinoma have a worse survival. However, preliminary data
from nhined chemotherapy/radiation approaches demonstrate
encouraging data indicating that survival may now approach 60-80%.
MALIGNANT BRAIN TUMORS IN
INFANTS AND CHILDREN LESS THAN 3
YEARS OF AGE
• Infants and very young children with brain tumors have a worse prognosis than older
children. They are also at higher risk for neurotoxicity including mental retardation,
growth failure and leukoencephalopathy. Due to these factors there is a reluctance to
treat infants and young children with radiation therapy. Recent studies have been
designed to use chemotherapy and to either withhold radiation therapy or postpone its
use to a time when the patient is older. Postoperative chemotherapy with
cyclophosphamide, vincristine.cisplatin and etoposide in children under 36 months of
age at diagnosis are utilized (Table 21-4) followed by delayed radiation. Chemotherapy is
administered for 48-96 weeks, depending on age at diagnosis, to delay radiation until as
close to age 3 as possible or beyond. Ongoing studies are evaluating adding high-dose
methotrexate to higher-risk cases. Newer approaches using high-dose chemotherapy
with autologous stem cell rescue (Table 21-6) to intensify the chemotherapeutic
regimen have been employed in an attemptto avoid radiation altogether.
• Average-risk medulloblastoma and other PLANETS, which are generally
chemosensitive tumors do well using this approach with 2-vear PES of about
70%, in those who received chemotherapy and delayed, reduced craniospinal
irradiation. The results are worse when radiation is not employed, with 5-
year EFS and OS of 32 and 43% for medulloblastoma.Gliomas do not do as
well with this therapy. One-year EFS is generally respectable, between 34 and
77%, however, there is a drop-off to 20% for the entire group. However, with
localized disease that is completely resected, ependymoma 4-year PFS
isapproximately 58%.Atypical teratoid/rhabdoid tumors are very aggressive
tumors of infancy that present similarly to medulloblastoma and are at times
indistinguishable pathologically except for monosomy 22 (lack of expression
of INI-1). While uniformly fatal if treated with
conventional medulloblastoma therapy, these patients have a survival
approaching 50% if treated with high-dose chemotherapy followed by
autologous stem cell rescue. Trials of intensive chemotherapy followed
by stem cell rescue have also been attempted in young children with
malignant brain tumors with promising results with avoidance of
radiation therapy. The current COG study uses three tandem auto stem
cell rescues after 3D-conformal radiation and IMRT, the timing and use
of radiation therapy in subsets of disease that do worse (i.e. subtotal
resections) is being studied in children as young as 8 months with focal
radiotherapy alone. The use of second look Surgery is also being
evaluated in current trials.