Furthermore, this episode occurred in the setting of both abrupt Copyright © 2002 by AAN Enterprises, Inc.

stoppage of prophylactic medication and a urinary tract infection

with fever and leukocytosis. Such factors can exacerbate migraine
and account for the potentially unusual and more severe features
associated with this migraine attack, namely hemiparesis and
transient hyponatremia from an intracranial process.
In this patient, migraine with prolonged aura7 is associated
with a prolonged period of hyperperfusion with vasogenic leakage.
These processes may account for impairment of cortical function
and may contribute to the clinically observed neurologic deficits in
migraine with prolonged aura.
From the Department of Neurology (Dr. Sheen), Beth Israel Deaconess Med-
ical Center; Department of Neurology (Dr. Smith), Brigham and Women’s
Hospital; and Department of Neurology (Drs. Smith and Cros), Massachu-
setts General Hospital, Boston, MA.
V.L.S. is supported by a grant from the NIMH (IK08MH/NS63886-01).
V.L.S. is a Charles A. Dana fellow.
Received September 19, 2001. Accepted in final form January 7, 2002.
Address correspondence and reprint requests to Volney L. Sheen, Depart-
ment of Neurology, Beth Israel Hospital, Harvard Institutes of Medicine, 8th
floor, 77 Avenue Louis Pasteur, Boston, MA 02114; e-mail:
VSHEEN@CAREGROUP.HARVARD.EDU
References
1. Goadsby PH, Hargreaves RJ. Mechanisms of action of serotonin
5-HT1B/D agonists: insights into migraine pathophysiology using
rizatriptan. Neurology 2000;55(suppl 2):S8-S14.
2. Cutrer FM, O’Donnell A, Sanchez del Rio M. Functional neuroimaging:
enhanced understanding of migraine pathophysiology. Neurology 2000;
55(suppl 2):S36-S45.
3. Hadjikhani N, Sanchez del Rio M, Wu O, et al. Mechanisms of migraine
aura revealed by fMRI in human visual cortex. Proc Natl Acad Sci USA
2001;98:4687– 4692.
4. Cutrer FM, Sorensen AG, Weisskoff RM, et al. Perfusion-weighted imag-
ing defects during spontaneous migrainous aura. Ann Neurol 1998;43:
25–31.
5. Goadsby PJ. Current concepts of pathophysiology of migraine. In: Neurol
Clin 1997;15:27– 42.
6. Ghabriel MN, Lu MX, Leigh C, Cheung WC, Allt G. Substance P-induced
enhanced permeability of dura mater microvessels is accompanied by
pronounced ultrastructural changes, but is not dependent on the density
of endothelial cell anionic sites. Acta Neuropathol (Berl) 1999;97:297–
305.
7. Headache Classification Committee of The International Headache Soci-
ety. Classification and diagnostic criteria for headache disorders, cranial
neuralgias and facial pain. Cephalgia 1988;8(suppl 7):1–96.

Etoposide for recurrent spinal
cord ependymoma
Marc C. Chamberlain, MD
Primary spinal cord tumors are uncommon malignancies of the
CNS and constitute 5–10% of all primary CNS malignancies.1 We
report a prospective Phase 2 trial in 10 consecutive adult patients
with recurrent low-grade cellular spinal cord ependymoma treated
with the oral chemotherapy agent etoposide.
All patients underwent an initial subtotal tumor resection and
six underwent a second subtotal resection at the time of first
tumor recurrence (table). Median time to second resection was
3.75 years (range 3–7.5); overall median time to recurrence was
4.25 years (range 3– 8 years). One patient declined further sur-
gery. Three patients in whom tumor manifested as CSF dissemi-
nation did not undergo surgery again.
Six patients were treated with etoposide after their first tumor
relapse, and four patients were treated after a second tumor re-
lapse. Four patients received carboplatin or PCV-3 (treatment
duration 5– 8 months, median 5.5) at time of first tumor
recurrence.
Patients began treatment with etoposide at a median of 4.25
years (range 3–7.5 years) after initial surgery. Karnofsky Perfor-
mance Status (KPS) at time of entry onto study ranged from 50 to
70 (median 60). All patients were paraparetic (four walked with
an assistive device, three could bear weight and assist in trans-
fers, and three were paraplegic).
Etoposide was administered orally as 50 mg/m2/day for 21
consecutive days followed by a 14-day break and then an addi-
tional 21 days of oral etoposide at 50 mg/m2/day as previously
described.2 One cycle of etoposide was defined as 2.5 months of
therapy. Toxicity was assessed using the National Cancer Insti-
tute common toxicity scale.3 Dexamethasone was administered
concurrently in five patients (stable dose in four, tapering dose in
one).
Toxicity included alopecia in 9 patients, diarrhea in 6, weight
loss in 5, ⱖ grade 3 neutropenia in 3, ⱖ grade 3 thrombocytopenia

Table Patient characteristics and treatment

Prior therapy VP-16 therapy

Response
Patient age, Tumor Radiotherapy Chemotherapy Interval first No. of Best duration, Survival,
y/Sex location Surgery (gray) (cycles) surgery to VP-16, y cycles response mo mo

19/F Cervical STR3STR 50 PCV (4) 4.0 6 SD 15 17

21/M Cervical STR3STR 50 3.5 1 PD 2.5 4

23/F Thoracic STR3STR 54 PCV (3) 3.0 1 PD 2.5 5

27/M Thoracic STR3STR 54 3.5 6 SD 15 18

29/F Cervical STR 54 CBDCA (5) 6.0* 12 SD 30⫹ 30⫹

31/M C-T STR 50 5.5 1 PD 2.5 3

33/M Thoracic STR3STR 50 7.5 8 PR 20⫹ 20⫹

40/M Thoracic STR 54 CBDCA (5) 6.5* 3 SD 7.5 9

48/M Cervical STR3STR 50 4.5 12 SD 30⫹ 30⫹

52/F Cervical STR 54 4.0* 18 PR 45⫹ 45⫹

* Leptomeningeal dissemination.

STR ⫽ subtotal resection; SD ⫽ stable disease; PD ⫽ progressive disease; PR ⫽ partial response; PCV ⫽ procarbazine, CCNU, vincristine; CBCDA ⫽ car-
boplatin; C-T ⫽ cervicothoracic; 3 ⫽ second surgery; ⫹ ⫽ alive with evidence of neuroradiographic disease.

1310 NEUROLOGY 58 April (2 of 2) 2002

in 3, and ⱖ grade 3 anemia in 2. A total of 80 cycles of etoposide
was administered in which 4 cycles (5% of all cycles) in 3 patients
were complicated by a transfusion requirement (red blood cell
transfusion in 1 and platelet transfusion in 2). Two cycles of ther-
apy (2.5% of all cycles) in 2 patients were complicated by neutro-
penic fever without bacteriologic documentation and necessitated
antibiotic therapy. Because of myelosuppression, 8 cycles of ther-
apy (10% of all cycles) in 3 separate patients required delayed
initiation of etoposide. Eight cycles of therapy (10% of all cycles)
required etoposide dose reduction and delayed initiation because
of myelosuppression. There were no treatment-related deaths nor
were any patients removed from study because of drug-related
toxicity.
After one cycle of etoposide, three patients demonstrated pro-
gressive disease, two a partial response, and five stable disease.4
In responding patients, no improvement was seen in either pre-
treatment neurologic examination or KPS. A median of 12 cycles
of therapy (range 3–18) was administered in patients with either
objective neuroradiographic response or stable disease pattern.
Median response or stable disease duration was 15 months (range
2.5– 45⫹). Response duration was similar in patients who re-
curred either locally or with evidence of CSF disseminated dis-
ease. Overall median survival after initiation of etoposide was
17.5 months (range 3– 45⫹). In patients responding or with stable
disease, median survival was 20⫹ months (range 9 – 45⫹). Four
patients are alive and with residual disease. In nonresponding
patients, median survival was 4 months (range 3–5). Progression
free survival at 6, 12, and 24 months was 70%, 60%, and 30%. Six
patients have died, all as a consequence of spinal cord tumor
progression.
Extent of surgical resection is the strongest covariant predict-
ing survival in patients with spinal cord ependymoma.5 Radiation
therapy does not appear necessary after gross total resection as
5- and 10-year survival in excess of 80% is expected. Subtotally
resected spinal cord ependymoma are best palliated by the co-
administration of limited-field radiotherapy with median 5- and
10-year survival rates of 60% reported.6
Less clear is the management of recurrent spinal cord ependy-
moma having previously not responded successfully to surgery
and radiotherapy. Because salvage therapy chemotherapy is not
curative, no standard therapy exists and therefore investigative
trials are warranted. Chronic oral etoposide is attractive for a
number of reasons, particularly for its ease of administration,
modest toxicity, and novel mechanism of action.2,7
A variety of chemotherapy regimens have been used for recur-
rent intracranial ependymoma. These various studies conclude that
chemotherapy has modest activity and no chemotherapy regimen
has clear superiority over another. Extrapolating this data to recur-
rent intradural intramedullary ependymoma is problematic.
From the Department of Neurology, USC/Norris Cancer Center,
Los Angeles, CA.
Received October 15, 2001. Accepted in final form January 11, 2002.
Address correspondence and reprint requests to Marc C. Chamberlain, MD,
Department of Neurology, USC/Norris Cancer Center, 1441 Eastlake Ave.,
Suite 3459, Los Angeles, CA 90033-0804; e-mail: chamberl@usc.edu
Copyright © 2002 by AAN Enterprises, Inc.
References
1. Helseth A, Mork SJ. Primary intraspinal neoplasms in Norway, 1995 to
1986. J Neurosurg 1989;71:842– 845.
2. Chamberlain MC. Recurrent intracranial ependymoma in children: sal-
vage therapy with oral etoposide. Pediatr Neurol 2001;24:117–121.
3. National Cancer Institute. Guidelines for reporting adverse events.
Bethesda, MD: Division of Cancer Treatment, National Cancer Institute,
1998.
4. MacDonald DR, Cascino TL, Schold SC, Cairncross JG. Response criteri-
afor phase 2 studies of supratentorial malignant glioma. J Clin Oncol
1990;8:1277–1280.
5. Espstein FJ, Farmer JP, Freed D. Adult intramedullary spinal cord ependy-
momas: the result of surgery in 38 patients. J Neurosurg 1993;79:204 –209.
6. Wen CB, Hussey DH, Hitchon PW, et al. The role of radiation therapy in
the management of ependymomas of the spinal cord. J Radiation Oncol-
ogy Biol Phys 1991;20:781–786.
7. Needle MN, Molloy PT, Geyer JR, et al. Phase 2 study of daily oral
etoposide in children with recurrent brain tumors and other solid tu-
mors. Med Pediatr Oncol 1997;29:28 –32.
April (2 of 2) 2002 NEUROLOGY 58 1311
 Etoposide for recurrent spinal cord ependymoma
Marc C. Chamberlain
Neurology 2002;58;1310-1311
DOI 10.1212/WNL.58.8.1310

This information is current as of April 23, 2002

Updated Information & including high resolution figures, can be found at:
Services http://www.neurology.org/content/58/8/1310.full.html

References This article cites 5 articles, 1 of which you can access for free at:
http://www.neurology.org/content/58/8/1310.full.html##ref-list-1
Citations This article has been cited by 1 HighWire-hosted articles:
http://www.neurology.org/content/58/8/1310.full.html##otherarticles
Subspecialty Collections This article, along with others on similar topics, appears in the
following collection(s):
Chemotherapy-tumor
http://www.neurology.org//cgi/collection/chemotherapytumor
Clinical trials Observational study (Cohort, Case control)
http://www.neurology.org//cgi/collection/clinical_trials_observational_s
tudy_cohort_case_control
Spinal cord tumor
http://www.neurology.org//cgi/collection/spinal_cord_tumor
Permissions & Licensing Information about reproducing this article in parts (figures,tables) or in
its entirety can be found online at:
http://www.neurology.org/misc/about.xhtml#permissions
Reprints Information about ordering reprints can be found online:
http://www.neurology.org/misc/addir.xhtml#reprintsus

Neurology ® is the official journal of the American Academy of Neurology. Published continuously since
1951, it is now a weekly with 48 issues per year. Copyright . All rights reserved. Print ISSN: 0028-3878.
Online ISSN: 1526-632X.