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341
Adjuvant Chemotherapy for the Treatment of
Intracranial Ependymoma of Childhood
Michael N. Needle, M.D.1
Joel W. Goldwein, M.D.2
Jeffrey Grass, M.D.3
Avital Cnaan, Ph.D.4
Ira Bergman, M.D.5
Patricia Molloy, M.D.6
Leslie Sutton, M.D.7
Huaqing Zhao, M.A.4
James H. Garvin, Jr., M.D.8
Peter C. Phillips, M.D.6
BACKGROUND. Current treatment for childhood intracranial ependymomas with
surgery and radiation therapy (RT) yields 5-year survival rates ranging from 50–
70% after complete resection to 0–30% after incomplete surgical resection. The
role of chemotherapy in the treatment of ependymoma has not been established.
In this pilot study, children with newly diagnosed intracranial ependymoma were
1
Division of Oncology, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania.
2
Department of Radiation Oncology, Hospital
of the University of Pennsylvania, Philadelphia,
Pennsylvania.
3
Division of Radiation Oncology, University of
Cincinnati Medical Center, Cincinnati, Ohio.
4
Division of Biostatistics, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania.
5
Department of Neurology, Children’s Hospital
of Pittsburgh, Pittsburgh, Pennsylvania.
6
Division of Neurology, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania.
treated with RT and chemotherapy using agents comparable to those found to be
active in the treatment of intracranial ependymoma in infants.
METHODS. Nineteen children age 3–14 years (median, 7.5 years) were treated with
postoperative RT and chemotherapy. Chemotherapy was comprised of carboplatin,
560 mg/m2, with vincristine, 1.5 mg/m2, weekly for 3 weeks, alternating at 4-week
intervals with ifosfamide, 1.8 g/m2, and etoposide, 100 mg/m2, for 5 consecutive
days for a total of 4 cycles.
RESULTS. The 5-year progression free survival (PFS) estimate was 74%. The extent
of surgical resection was not a significant prognostic factor in this study. By contrast, ependymomas located in the posterior fossa were associated with a higher
rate of progression (P Å 0.036). Toxicity, limited predominantly to myelosuppression, was manageable.
CONCLUSIONS. The PFS for children with postoperative residual ependymoma
treated with RT and chemotherapy in this study was higher than published survival
results for RT alone. These results suggest a role for multialkylator chemotherapy
in incompletely resected intracranial ependymoma and provide the rationale for
a randomized trial comparing this strategy with conventional postoperative RT.
Cancer 1997;80:341–7. q 1997 American Cancer Society.
KEYWORDS: ependymoma, childhood, chemotherapy, surgery, location, pediatric
oncology.
7
Division of Neurosurgery, Children’s Hospital
of Philadelphia, Philadelphia, Pennsylvania.
8
Division of Pediatric Oncology, Babies and
Children’s Hospital of New York, New York, New
York.
I
ntracranial ependymomas constitute 8 – 12% of all childhood brain
tumors.1 The majority of children with intracranial ependymomas
will die of progressive tumor growth.2 – 4 Although a variety of clinical
factors may have prognostic importance, including age at diagnosis,4–6
histology,2,3,7 and location,3 treatment variables are among the most
important determinants of clinical outcome. The extent of surgical
resection has clear prognostic significance in some recent reported
studies, with 5-year survival rates of 75 – 85% after complete surgical
Presented in part at the Sixth International Symposium on Pediatric Neuro-Oncology, Houston,
Texas, May 18–21, 1994; and in abstract form in
Needle M, Goldwein, J, Grass J, Bergman I, Garvin
J. Treatment of childhood ependymoma with hyperfractionated radiotherapy (HFRT) followed by
carboplatin (CBDCA), vincristine (VCR), ifosfamide
(IFOS) and etoposide (ETP) chemotherapy. Proc
Am Soc Clin Oncol 1994;13:184.
The authors acknowledge Drs. Jeffrey Allen,
Steven Goins, Marc Jennings, Kenneth Lazarus,
and Michael Willoughby for providing patient
data.
Support for Dr. Cnaan was provided by Grant
CA 16520-20 from the National Cancer Institute.
Address for reprints: Michael N. Needle, M.D.,
Division of Oncology, Children’s Hospital of
q 1997 American Cancer Society
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Philadelphia, 324 South 34th Street, Philadelphia, PA 19104.
Received September 20, 1996; revisions received January 6, 1997, and March 10, 1997;
accepted March 10, 1997.
342
CANCER July 15, 1997 / Volume 80 / Number 2
excision versus 0 – 30% 5-year survival rates for incompletely resected patients.4,6
The role of radiation therapy (RT) is also well established. Standard fraction, involved-field radiation
therapy clearly contributes to local tumor control.8 – 10
The benefit of craniospinal radiation for ependymoma
patients with leptomeningeal metastases is not disputed9,11 ; however, the role of prophylactic craniospinal radiation for children with localized posterior fossa
or anaplastic ependymomas is less certain.9,11 Hyperfractionated radiation therapy (HFRT) dose schedules
have been proposed as potentially increasing the effectiveness of RT by exploiting potential differences in
radiation repair capacity between tumor and surrounding normal brain and thereby improving treatment outcome.12 A recently completed study of intracranial ependymoma by the Pediatric Oncology Group
(POG) did not demonstrate any difference between
children treated with HFRT and historic controls
treated with standard RT.13
In contrast to surgery and RT, a role for adjuvant
chemotherapy in the treatment of childhood intracranial ependymoma has not been identified. Moderate objective response rates have been reported for
several cross-linking agents, including cisplatin,14,15
carboplatin,16 and ifosfamide.17 Recently, Duffner et
al. reported a 48% objective response rate for newly
diagnosed intracranial ependymomas in infants
treated with a multiagent regimen comprised of cisplatin, etoposide, cyclophosphamide, and vincristine.18
The objectives of this pilot study were to assess
progression free survival (PFS) and toxicity in children
with intracranial ependymoma after RT and four-drug
chemotherapy. In this article, the authors present the
treatment outcome and toxicity data for 19 children
with newly diagnosed intracranial ependymoma in
whom the PFS was 74% with a median follow-up of
5 years after diagnosis. These results are superior to
previously published reports, particularly for patients
with residual postoperative tumor, suggesting a survival benefit for patients treated with combination
chemotherapy.
to institutional review board approval) was signed by
the parent or legal guardian.
Prior to study entry, all patients underwent postoperative, contrast-enhanced magnetic resonance imaging (MRI) of the brain. Patients were considered to
have residual disease only if there was bulky enhancement in the tumor region. Linear enhancement at the
surgical margin was not considered postoperative residual tumor. Extent of disease evaluation included
contrast-enhanced MRI of the entire spine and evaluation of cerebrospinal fluid cytology, and normal hematologic, renal, and hepatic function. Patients with recurrent ependymoma were not eligible.
Treatment Protocol
Radiation therapy
This study was originally proposed as a randomized
study of a radiation fractionation schedule (single daily
fraction vs. twice daily fractionation) with all patients
receiving chemotherapy. In this pilot, there was no
randomization and the physicians were left to choose
the field and fractionation schedule. Physicians were
encouraged to pilot the ‘‘experimental’’ arm and use
HFRT to the involved field. Patients were treated with
RT within 4 weeks of maximal surgery and confirmation of histologic diagnosis.
Chemotherapy
Eligibility
Vincristine, 1.5 mg/m2 (2 mg maximum), was given
weekly during RT for a total of 7 doses. Combination
chemotherapy was initiated 4 – 6 weeks after the completion of RT. Patients received alternating courses of
chemotherapy (Fig. 1). C/V was comprised of carboplatin (C), 560 mg/m2 intravenously (i.v.), and vincristine (V), 1.5 mg/m2 i.v., weekly for 3 doses. Four
weeks after C/V administration and contingent on adequate hematologic recovery, patients received I/E,
which was comprised of ifosfamide (I), 1800 mg/m2
i.v., and etoposide (E), 100 mg/m2 i.v., daily for 5 doses.
If the absolute neutrophil count (ANC) was ú1000/
mm3 and the platelet count was ú100,000/mm3 4
weeks after I/E doses, the patient received a second
course of C/V. In the absence of tumor progression or
unacceptable toxicity during treatment, chemotherapy was continued for 4 cycles (i.e., C/V 1 4 and I/E
1 4; approximately 32 weeks).
Children with a histologic diagnosis of ependymoma
(benign, cellular) and anaplastic (malignant) ependymoma were eligible. Those with primitive neuroectodermal tumor with ependymal differentiation (ependymoblastoma), myxopapillary ependymoma, or subependymoma were not. Diagnosis was made by the
institutional pathologist without central review. An informed consent form for all eligible patients (subject
Evaluation of Disease
MRI with and without gadolinium was performed after
surgery and prior to study entry within 72 hours of
surgery. Thereafter, MRIs were performed prior to the
first (after RT) and each subsequent cycle of chemotherapy (every 8 weeks). Increases in existing enhancement or new areas of enhancement were treated as
MATERIAL AND METHODS
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343
FIGURE 1. Cycles of chemotherapy given to study population.
evidence of progression or recurrence unless biopsy
proved otherwise. Biopsy confirmation was not required. Perioperative corticosteroids were discontinued in all patients prior to completion of RT. Once
therapy was completed, patients were assessed by
physical examination and MRI every 3 months for 2
years and at physician discretion thereafter.
Statistical Analysis
Statistical analysis of this study was based on the time
from diagnosis to tumor progression documented on
MRI or last follow-up. PFS rates were estimated using
the method of Kaplan and Meier.19 Log rank tests were
used to evaluate prognostic variables.20 Confidence intervals were calculated using the method of Greenwood.21
RESULTS
Patient Population
Between March 1990 and December 1992, 19 children
between the ages of 3 and 14 years (median, 7.5 years)
with newly diagnosed and histologically proven ependymoma were entered in a pilot study of RT and
multiagent chemotherapy. Six institutions participated in this study. All 19 patients were evaluable for
toxicity and event free survival. Twelve of the patients
were male. Twelve of the patients were white, 4 were
African-American, and 3 were Hispanic. The histologic
diagnosis was ependymoma in ten patients and anaplastic ependymoma in nine patients. The tumor location was supratentorial in 8 patients and infratentorial
in 11 patients. Nine patients had complete resections
and ten had partial resections as determined by postoperative gadolinium-enhanced MRI. No patient had
metastatic tumor spread at diagnosis. Sixteen patients
were treated with HFRT (1 gray [gy] per fraction, 2
treatments per day, with at least 6 hours between
treatments) involved-field irradiation to a mean dose
of 70.7 Gy (range, 65 – 72 Gy) to the tumor bed. Two
of these patients received HFRT craniospinal axis irradiation to 36 Gy using the fractionation schedule de-
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FIGURE 2. Progression free survival (solid lines) and 95% confidence
intervals (dashed lines) for 19 patients with intracranial ependymoma
treated with radiation therapy and chemotherapy.
scribed earlier. Three patients received single daily 1.8Gy fraction RT at the discretion of the treating physician. One patient received 54 Gy to the tumor bed and
36 Gy to the whole brain. The second patient received
54 Gy to the tumor bed and 36 Gy to the craniospinal
axis. The third patient was treated with 45 Gy to the
tumor bed alone. Sixteen of 20 patients completed 4
cycles of therapy.
Progression Free Survival
The Kaplan-Meier PFS curve is shown in Figure 2. Of
the 19 patients treated on this study, 14 remained free
of tumor progression or recurrence for a median follow-up period of 5 years. All treatment failures occurred in the primary site without evidence of metastatic spread. The PFS estimate at 5 years was 74% with
a 95% confidence interval of 50 – 89%. At last follow-up,
15 of 19 patients remained alive.
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CANCER July 15, 1997 / Volume 80 / Number 2
TABLE 1
Prognostic Factors in Ependymoma
Gender
Female
Male
Race
White
African American
Mexican American
Location
Posterior fossa
Supratentorial
Histology
Anaplastic
Benign
Extent of surgery
Gross total resection
Subtotal resection
Total
Failed
7
12
2
3
NS
12
4
3
3
1
1
NS
11
8
5
0
P Å 0.036
9
10
3
2
NS
9
10
3
2
NS
NS: not significant.
FIGURE 3. Progression free survival (solid lines) and 95% confidence
intervals (dashed lines) for 19 patients with intracranial ependymoma
segregated based on the location of the tumor.
Tumor Progressions and False Recurrences
Three patients had increased gadolinium enhancement at the margin of the surgical bed suggesting tumor progression 5 months from diagnosis after completing HFRT and 1 cycle of chemotherapy. Two patients did not have a biopsy performed at this time.
Both children were considered to have progressed and
subsequently were treated with thiotepa without objective response. At last follow-up, 1 patient had remained stable for 5 years, and the other died of metastases to the spine 4 years after the first recurrence. A
third patient, who underwent partial resection at the
time of diagnosis, had an increase in gadolinium enhancement after one cycle of chemotherapy. She underwent surgery for excision of the recurrent lesion;
however, the histopathologic diagnosis was primarily
gliosis with minimal amounts of residual tumor. This
patient was not considered to have progressed, but
rather as having residual disease. The patient resumed
chemotherapy, completed all 4 planned cycles, and
was progression free at 50 months.
In addition to the two patients previously mentioned, there were three other recurrences. One patient recurred after chemotherapy was discontinued
after complications from a ‘‘second look’’ surgical procedure. This patient had an incomplete resection and
RT, and had completed two cycles of chemotherapy.
The patient had completely recovered from chemotherapy prior to the second resection. Immediately
after the second attempt at resection, the patient developed a persistent cerebrospinal fluid leak leading
to two episodes of bacterial meningitis. At this point
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chemotherapy was discontinued. Tumor progression
was identified 6 months later and the patient died 24
months after diagnosis. A second patient developed
progressive neurologic deterioration prompting discontinuation of treatment midway through the second
cycle of chemotherapy. The patient recurred and died
from progressive tumor 20 months later. The final patient to recur did so after completion of therapy, and
died shortly thereafter.
Prognostic Factors
The following clinical data were evaluated for prognostic significance: gender, race, histology, primary tumor
location, and extent of resection (Table 1). Only tumor
location proved to have prognostic value at the 95%
confidence level, with all the patients who progressed
having posterior fossa tumors (P Å 0.036) (Fig. 3). The
5-year PFS estimate for patients with and without
postoperative residual disease was 80% (95% confidence interval, 41% – 95%) and 67% (95% confidence
interval, 28% – 88%), respectively. It must be kept in
mind that in this small patient sample there was only
80% power to show a 3-fold difference in the failure
rate.
Toxicity
The acute toxicities from RT included local skin reactions (alopecia, epilation, and desquamation). One patient had a ú10% weight loss during RT. There were
no interruptions or delays in the RT.
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Chemotherapy for Childhood Ependymoma/Needle et al.
Myelosuppression was the major toxicity occurring during combination chemotherapy. Toxicity
was graded using the NCI common toxicity criteria.
After 80 courses of chemotherapy there were 33 episodes (41%) of Grade 3 leukopenia (leukocyte count
between 1000 and 2000/mm3), 31 episodes (39%) of
Grade 4 leukopenia (leukocyte count õ 1000/mm3), 8
episodes (10%) of Grade 3 thrombocytopenia (platelet
count between 25,000 and 50,000/mm3) and 8 episodes (10%) of Grade 4 thrombocytopenia (platelet
count õ 25,000/mm3). Data for neutrophil counts was
available for 55 courses of chemotherapy. These were
followed by 11 episodes (20%) of Grade 3 neutropenia
(ANC between 500 and 999/mm3) and 38 episodes
(69%) of Grade 4 neutropenia (ANC õ 500/mm3).
There were 12 patient admissions for fever and neutropenia, 9 of which occurred after I/E administration.
There were no episodes of documented sepsis. One
patient did have a positive culture from the tip of a
central venous catheter removed during an episode of
fever and neutropenia. One patient had a peripheral
neuropathy attributed to the weekly vincristine and
required dose reduction.
One patient with a completely excised posterior
fossa ependymoma had progressive neurologic deterioration while receiving chemotherapy. Seven months
after initiation of HFRT and after two cycles of chemotherapy, the patient developed a left hemiparesis,
ataxia, and lower cranial nerve dysfunction. Initially
there were no abnormalities on MRI; however, 2
months after the onset of neurologic symptoms, diffuse gadolinium enhancement in the posterior fossa
was apparent on MRI. The radiographically abnormal
regions were within the radiation field and neuroimaging studies were consistent with the diagnosis of radiation injury.
DISCUSSION
Survival rates for children with intracranial ependymoma are generally poor and current treatment strategies remain the subject of considerable controversy.
Many retrospective studies indicate that a dose-response relationship can be demonstrated for ependymoma (i.e., involved-field radiation doses ú 50 Gy are
associated with higher survival rates). 3,5,9,11,22 However, others have not identified a dose-response relationship.2,10 The therapeutic benefit of prophylactic
craniospinal irradiation for ependymoma patients is
also controversial, with some authors recommending
craniospinal RT, particularly for anaplastic tumors,23
and others failing to identify any benefit.3,6,7,24,25 In
spite of these controversies, the role of RT in the treatment of childhood intracranial ependymoma is firmly
established.11
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345
The potential role of chemotherapy in the treatment of childhood ependymoma has been addressed
in a limited number of clinical trials. Objective responses have been demonstrated to a number of single agents alone in patients with recurrent ependymoma including cisplatin,14,15 carboplatin,16 and ifosfamide.17 Particularly encouraging are the results of
the POG infant study in which Duffner et al. reported
12 of 25 evaluable infants with ependymoma had an
objective response to a combination of vincristine, cyclophosphamide, cisplatin, and etoposide.18 Of the five
most common tumor types in the infant POG study,
ependymoma had both the highest PFS and overall
survival rates.
Despite Phase II studies that demonstrate modest
objective response rates, there is no evidence that chemotherapy contributes to long term survival for children with ependymoma beyond that achieved with
RT. Between 1975 and 1981, The Children’s Cancer
Group (CCG) conducted a randomized trial that compared RT alone with RT plus lomustine and vincristine
in children with posterior fossa ependymoma.26 This
study included infants as well as older children. Children treated with RT and chemotherapy had no survival advantage compared with those treated with RT
alone, and PFS for the entire group was 36% at 10
years. Twenty-two of the 36 patients entered on study
had tumor progression and all but 2 patients had tumor growth within 3 years of initial diagnosis. The
median time to progression was 18 months. Notably,
the slope of the failure free survival curve was nearly
linear over the first 3 years, with a drop of 20% per
year. By comparison, only 26% of patients in the current study had tumor progression during the 5-year
median follow-up period. However, comparisons between the CCG study and the current study must be
made with caution, because none of the patients in
the CCG trial underwent postoperative neuroimaging
studies to confirm the extent of resection and evaluations to detect leptomeningeal metastasis were not required.
Previous studies report that PFS rates for intracranial ependymoma patients with postoperative residual tumor treated with RT alone range from 0 –
30%.4,6 In the current study, the 5-year actuarial PFS
estimate of 80% for patients with postoperative residual ependymoma was higher than all previous reports.2 – 7,10,27 Furthermore, the extent of surgical excision did not reach prognostic significance in this
study. These results suggest that the major benefit of
chemotherapy was observed in patients with postoperative residual tumor. By contrast, the PFS rate of
67% at 5 years for patients who underwent complete
surgical excision was not different from the 70% PFS
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346
CANCER July 15, 1997 / Volume 80 / Number 2
rate after complete resection and RT reported by
Healey et al.6
The only significant prognostic factor identified in
this study is the location of primary tumor. All treatment failures occurred in patients with posterior fossa
tumors, whereas all children with supratentorial tumors remained free of progression at last follow-up.
The literature is most interesting in this regard, with
reports supporting supratentorial location as a poor
prognostic factor3,25 whereas others claim location is
not of prognostic significance.2,5,9 It remains for larger
trials to evaluate this finding.
Hematologic toxicity was comparable to the toxicity of current regimens in use for medulloblastoma28
or malignant brain tumors in infants.18 Myelosuppression resulted in approximately one admission for fever
and neutropenia per four chemotherapy cycles.
The serious neurologic toxicity observed in one
patient is distressing. These symptoms (progressive
corticospinal tract, cerebellar, and lower cranial nerve
dysfunction) were noted 7 months after the initiation
of HFRT. The MRI appearance of diffuse gadolinium
enhancement was consistent with radiation-induced
brain injury. Three additional patients had MRI abnormalities characterized by increased gadolinium enhancement at the margin of the surgical bed 4 – 6
months after the initiation of HFRT. It is possible that
their apparent tumor progression was a hyperfractionated radiation effect, possibly enhanced by chemotherapy. This is not unlike the experience with HFRT
in patients with brain stem glioma reported by Packer
et al.29 The authors’ experience suggests that caution
should be exercised in the interpretation of enhancing
lesions identified by MRI within the first year after
HFRT. It can be difficult to distinguish tumor progression and radiation injury in this situation, and strong
consideration should be given to obtaining biopsy
confirmation of progressive disease within the first
year after HFRT, before chemotherapy is discontinued.
Despite these concerns, the toxicity results from
this pilot study support the feasibility of combining
RT (standard fraction or HFRT) and multiagent chemotherapy in the treatment of patients with newly
diagnosed childhood ependymoma with postoperative residual disease. The survival results of this study,
particularly the apparent improved survival for incompletely resected patients, are particularly encouraging.
Moreover, at last follow-up, all the patients in the current study were beyond the period of greatest risk for
recurrence observed in the CCG ependymoma trial.
The recently completed POG trial of postoperative
HFRT for ependymoma did not demonstrate any benefit compared with standard fraction RT.13 Future trials
will need to be designed to test the hypothesis that
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intensive adjuvant chemotherapy will improve survival in a randomized study design, requiring a substantially larger sample size. The chemotherapy regimen utilized in this study clearly warrants further
study of the treatment of childhood intracranial ependymoma.
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