Weekly Alternating Etoposide, Methotrexate, and
Actinomycin/Vincristine and Cyclophosphamide Chemotherapy
for the Treatment of CNS Metastases of Choriocarcinoma
By Gordon J.S. Rustin, Edward S. Newlands, Richard H.J. Begent, Joan Dent, and Kenneth D. Bagshawe
Twenty-five patients with CNS metastases of choriocar-
cinoma were treated with a regimen incorporating
etoposide, methotrexate, and actinomycin (EMA) alter-
nating weekly with vincristine and cyclophosphamide
(CO). The dose of methotrexate was increased to 1
2 of the craniotomy in six of 18 patients treated initially
g/m . Eighteen patients presented with CNS me-
tastases, or developed them on inappropriate treat-
ment started elsewhere. Following EMA/CO chemo-
therapy, three patients died within the first 3 weeks,
one is alive with active disease, one died with drug
THE GREAT majority of patients with gesta-
tional choriocarcinoma are now cured if
treated appropriately with cytotoxic chemo-
therapy.1, 2 The National Hydatidiform Mole
Follow-up Service in the United Kingdom has
resulted in virtually no patients presenting with
advanced disease after a mole.3 However, in
countries without adequate follow-up and in
patients presenting with choriocarcinoma follow-
ing an abortion or term delivery, 3% to 15% of
patients present with CNS metastases. 4-6 In most
reports, the survival rate among these patients
has been poor.' We have previously reported our
experiences in the treatment of those patients
seen in our unit between 1957 and 1980.4 Since
that report, we have treated an additional 25
patients with the weekly alternating chemother-
apy regimen consisting of etoposide, methotrex-
ate, and actinomycin/vincristine and cyclophos-
phamide (EMA/CO).'
PATIENTS
All patients with CNS metastases from gestational tropho-
blastic tumors, who were treated at the Charing Cross
Hospital since 1980, have received the EMA/CO regimen
From the Cancer Research Campaign Laboratories,De-
partment of Medical Oncology, Charing Cross Hospital,
London.
Submitted November 28, 1988; accepted February 15,
1989.
Address reprint requests to G.J.S. Rustin, MD, Cancer
Research Campaign Laboratories, CharingCross Hospital,
London, W6 8RF, UK.
© 1989 by American Society of ClinicalOncology.
0732-183X/89/0707-001753.00/0
900
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Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
resistance, and 13(72%) patients are surviving disease-
free. Two of seven patients (29%) who developed CNS
metastases on treatment with EMA/CO or relapsed
after EMA/CO are disease-free after additional chemo-
therapy and surgery. The contribution toward survival
or early with EMA/CO remains unclear, but was
crucial to those patients with drug resistance.
J Clin Oncol 7:900-903. @ 1989 by American Society
of Clinical Oncology.
and are included in this analysis. Nine patients included in
the initial description of EMA/CO are included in this
analysis and the one patient with retinal metastases has been
reported in detail as a case report.' 8 The diagnosis was made
if a patient either had histologically confirmed choriocarci-
noma or evidence of a CNS mass with a grossly elevated
serum level of human chorionic gonadotrophin (HCG), and a
history suggestive of gestational choriocarcinoma. Cerebral
masses were noted on computed tomographic (CT) scans of
23 patients, on magnetic resonance imaging (MRI) scan of
the lumbar spine in one patient, and on fundal examination in
another. The presenting features of the patients are shown in
Table 1. All patients had elevated levels of serum HCG. A
CSF HCG level higher than /6oof the serum level has
previously been shown to indicate the presence of brain
metastases' and was the first indication of brain metastases in
two patients. A serum to CSF ratio of less than 60:1 was
found in an additional four patients already known to have
CNS metastases, but was more than 60:1 in ten patients.
Lumbar punctures were not performed within the first ten
days of diagnosis in nine patients.
All patients fitted into the high-risk group using a prognos-
tic scoring system2,"0 and had disease in other sites in addition
to the CNS. The two patients without lung metastases on
chest x-ray had disease in the uterus m one case and in the
kidney in the other
Treatment
Patients received the EMA/CO regimen with escalated
dosage of methotrexate and folinic acid (leucovvrin calcium),
plus intrathecal injections of methotrexate, 12.5 mg, as
follows. Course 1 (EMA) day 1-actinomycin, 0.5 mg
intravenous (IV) bolus; etoposide, 100 mg/m2 IV infusion
(30 minutes); and methotrexate, 1 g/m 2 IV infusion (24
hours); day 2-actinomycin, 0.5 mg IV bolus; etoposide, 100
mg/m 2 IV infusion (30 minutes); and leucovorin calcium, 15
mg intramuscularly (IM) or orally every eight hours for nine
doses starting 32 hours after start of methotrexate. Course 2
(CO): day 8-vincristine, 1.0 mg/m 2 IV bolus; cyclophospha-
mide, 600 mg/m 2 IV infusion; methotrexate, 12.5 mg intra-
Journalof ClinicalOncology, Vol 7, No 7 (July), 1989: pp 900-903
TREATMENT OF CNS METASTASES OF CHORIOCARCINOMA 901

Table 1. Patient Characteristics When Starting EMA/CO
Total no. of patients 25
Mean age (range) 32 (24-50)
Previous pregnancy
Mole 9
Term 8
Abortion 6 craniotomy 4 months earlier, and had cranial
Stillbirth 2 irradiation. She was moribund with widespread
Not UK residents
(8 of 9 post-mole) 13
No. of brain metastases
1 16
2 or 3 4 multiple brain metastases; one died from hernia-
> 10 2 tion of edematous brain through the foramen
Retinal metastases 1 magnum at 24 hours, and the other from com-
Cauda equina metastases 1
No. with lung metastases 23
Presenting with CNS metastases
No prior chemotherapy 13
Not EMA/CO initially 5 EMA/CO.
Median WHO prognostic score 16(9-23)
Developing CNS metostases later
Not EMA/CO initially 3
After EMA/CO 5
Abbreviation: WHO, World Health Organization.
thecally; and leucovorin calcium, 15 mg at 24 and 36 hours.
Course 3: day 15--same as course one.
Courses 1 and 2 were repeated in sequence with a six-day
internal, and chemotherapy was only delayed if the patient
had mucositis, or if the total leukocyte count was < 1.5 x
109/mL, or if the platelet count was < 75 x 109/mL. After
obtaining a biochemical remission (serum HCG < 2 IU/L),
chemotherapy was continued for a further 12 weeks. Intra-
thecal methotrexate was continued with courses of CO until
HCG levels had fallen to normal.
A high oral intake was encouraged, but no routine urine
alkalinization was performed. Methotrexate levels were only
measured in patients who were suspected of having impaired
renal function or who had had mucositis with a previous
course, and leucovorin calcium was continued as indicated. In
patients whose HCG level failed to progressively decrease,
cisplatin was added. After assessing toxicity in the first six
such patients, subsequent patients who required additional
therapy received full-dose EMA alternating every eight to ten
days with etoposide, 150 mg/m2, and cisplatin, 75 mg/m 2.
Patients presenting with cerebral metastases were consid-
ered for early craniotomy if they had solitary metastases on
CT scan and the lesions appeared resectable without causing
severe neurological deficit. All patients who had had prior
chemotherapy and those in whom drug resistance was evident
were considered for surgical resection of residual masses. The
choice of site for resection was aided by external scintigraphy
scans using 3 1I-labeled antibody to HCG."
RESULTS
PresentationWith Brain Metastases
Thirteen patients presented with CNS me-
tastases and started therapy with EMA/CO.
One of these patients had had a craniotomy 8
months earlier, when a subdural hematoma was
removed, but no choriocarcinoma was noted.
Another patient was incorrectly diagnosed as
having a poorly differentiated astrocytoma at
multisystem metastases on arrival at the Charing
Cross Hospital and died eight days later. There
were two other early deaths. Both patients had
bined respiratory failure and cerebral edema at
15 days. One additional patient received cranial
irradiation in the United States before starting
Three patients had a craniotomy, two on the
day they started EMA/CO, and one three days
later. This was because CT scans suggested the
presence of intracerebral hemorrhage and we
were concerned about the possibility of further
bleeding. Both choriocarcinoma and blood clots
were found in every case. In one patient, several
deposits of choriocarcinoma less then 5 mm in
diameter were noted, yet only one deposit was
seen on the CT scan.
Of the ten patients surviving for more than 3
weeks, nine obtained a complete sustained remis-
sion (Table 2). Cisplatin, either alone or with
etoposide, was substituted for the CO in five
patients because of persistently elevated HCG
levels after 2 to 4 months of EMA/CO therapy.
In two patients, it was difficult to ascertain the
HCG value (Fig 1), while in a third patient,
HCG levels increased, indicating drug resis-
tance. This patient presented with bilateral reti-
nal metastases and is currently alive on therapy
for persistent disease. Bilateral thoracotomies
Table 2. Results of Therapy
Patients presenting with CNS metastases 18
Early deaths 3
Dead of drug-resistant disease 1
Alive with drug-resistant disease 1
Sustained complete remission* 13(72%)
Patients developing CNS metastases on or after 7
EMA/CO
Dead of drug-resistant disease 4
Alive with drug-resistant disease 1
Sustained complete remission (31 and 46 months) 2
*Median, 33 months; range, 4 to 74 months.

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902 RUSTIN ET AL

_1

100000 -
CSF HCG "221 20 4 <2 <2 4 <4
10000
Serum
HCG 1000 - Fig. 1. Decrease in serum
IU/L and CSF HCG levels in a 33-
100- t year-old woman with postterm
CRANIOTOMY choriocarcinoma. Craniotomy
10-
was performed following the
1- normal range first course of EMA. EMA (E)and
t t f t ft I T METHOTREXATE
CO (C) therapy was given
weekly. Intrathecal methotrex-
C C C C C EP E E E E E E ate (12.5 mg)/CO was given
E E E E E E E EP C C C C C C until HCG was normal. Etopo-
RI nl ýInlýl I0 InI n InIn side and cisplatin (EP) was sub-
stituted for two courses of CO
Mar Apr May Jun Jul Aug Sept when HCG levels appeared to
1988 be increasing.

with resection of active choriocarcinoma contrib- Five patients relapsed after obtaining a com-
uted to the remission in another of these patients, plete biochemical remission to EMA/CO, and
while there was a clear-cut response to the four obtained further responses to EMA/CO.
addition of cisplatin in only one case. Three The four responding patients also had cranioto-
patients had hysterectomies because of abnormal- mies and active tumor was resected. Two of these
ities on pelvic ultrasound and slightly raised patients are alive in complete remission 31 and
HCG. No tumor was found histologically. 46 months off all therapy (Table 2).
Two other patients presented with brain me-
tastases and were treated in other hospitals with Toxicity
methotrexate plus actinomycin in one case and The toxicity of EMA/CO schedule using 1 g
mercaptopurine in the other. They both obtained methotrexate was similar to that reported using
a sustained complete remission on EMA/CO. 300 mg/m 2 methotrexate. 1 Because nausea and
Three patients in other hospitals received a vomiting was infrequent, it was well tolerated in
variety of drugs, but not etoposide, before the most patients. Among the 18 patients in the
diagnosis of brain metastases was considered. presentation group who had had little or no prior
These patients may well have had brain me- chemotherapy, five patients had no treatment
tastases when they started therapy, but did not delays beyond two days throughout their 16+
have initial CSF HCG measurements. Two of weeks of chemotherapy. Among the remaining
these patients had early elective craniotomies on ten patients who survived longer than 15 days,
arrival at the Charing Cross Hospital when five had only one course delayed, three had two,
active choriocarcinoma was removed; subse- one had three, and one had four courses delayed.
quently, they obtained a sustained complete Severe mucositis occurred in three patients, and
remission on EMA/CO. The third patient, from was prevented in later courses by increased fluid
Africa, developed drug-resistant disease, and at intake and leucovorin calcium.
craniotomy, an enhancing lesion was shown to be
toxoplasmosis. She has subsequently died from DISCUSSION
choriocarcinoma. This study confirms other reports that some
patients with persistently elevated levels of serum
CNS Disease Presentingon or After HCG that suggest drug-resistant choriocarci-
Chemotherapy noma can still be cured by surgical excision of
Two patients developed brain metastases at a residual tumor masses.12 The rationale for per-
time when they were clearly resistant to EMA/ forming an early craniotomy to remove single
CO chemotherapy. One of these patients had CNS metastases was to prevent intracerebral
cranial irradiation with resultant little effect and bleeding. In our previous study, eight of 33
died. The other remains alive on treatment after patients (24%) died within the first 15 days of
three thoracotomies, craniotomy, and laparot- presentation 4 and their deaths were attributed to
omy, but still has an elevated serum HCG 21/2 intracerebral bleeding in most cases. There were
years after starting EMA/CO. three early deaths (17%) in the present study.

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Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
TREATMENT OF CNS METASTASES OF CHORIOCARCINOMA
These patients either had multiple metastases or
were moribund when chemotherapy was started.
Although surgical tumor or clot removal was not
a possibility in these patients, one of them might
have been saved by an early reduction in intra-
cerebral pressure by the raising of a flap or by
barbiturate therapy.1 3 Trophoblastic tumors are
very hemorrhagic and have a propensity to bleed.
The exact role of elective early craniotomy in
these patients remains to be determined. Radio-
therapy has been extensively used in the treat-
ment of patients with CNS metastases of chorio-
carcinoma in other centers. 5' 7' 14,15 However, only
two surviving patients in the current study re-
ceived cranial irradiation, and its value is unclear
due to the subsequent chemotherapy. As in male
patients with CNS metastases from nonsemi-
nomatous germ cell tumors, we do not see a place
for cranial irradiation in patients with trophoblas-
tic tumors unless they have unresectable drug-
resistant metastases."6
REFERENCES
1. Newlands ES, Bagshawe KD, Begent RHJ, et al:
Developments in chemotherapy for medium and high-risk
patients with gestational trophoblastic tumours. Br J Obstet
Gynaecol 93:63-69, 1986
2. Rustm GJS, Bagshawe KD: Gestational trophoblastic
tumors. CRC Crit Rev Oncol/Hematol 3:103-142, 1984
3. Bagshawe KD, Dent J, Webb J: Hydatidiform mole in
England and Wales 1973-83. Lancet 2:673-677, 1986
4. Athanassiou A, Begent RHJ, Newlands ES, et al:
Central nervous system metastases of choriocarcinoma: 23
years experience at Charing Cross Hospital. Cancer 52:
1728-1735, 1983
5. Ishizuka T, Tomoda Y, Kaseki S, et al: Intracranial
metastases of choriocarcinoma. A clinicopathologic study.
Cancer 52:1896-1903, 1983
6. Weed JC, Woodward KT, Hammond CB: Choriocarci-
noma metastatic to the brain: Therapy and prognosis. Semin
Oncol 9.208-212, 1982
7. Kobayashi T, Kida Y, Yoshida J, et al: Brain metastasis
of choriocarcinoma. Surg Neurol 17:395-403, 1982
8. Barondes MJ, Hamilton AM, Hungerford J, et al:
Treatment of choroidal metastases from choriocarcmoma.
Arch Ophthalmol (in press)
9. Bagshawe KD, Harland S: Immunodiagnosis and moni-
toring of gonadotrophin producing metastases in the central
nervous system. Cancer 38:112-118, 1976
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Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
903
In the present study, only one of the ten
patients who had no prior chemotherapy devel-
oped drug-resistant disease. This compares with
one of 32 patients treated with EMA/CO for
high-risk disease outside the CNS.' 7 This sug-
gests that if aggressively treated from the outset,
patients with CNS metastases from trophoblas-
tic tumors have almost as good a chance of tumor
eradication as patients with high-risk disease
with no CNS metastases. The prognosis might be
further improved by earlier detection of brain
metastases so that patients do not present mori-
bund. Surgery at the time of presentation may
also prevent intracerebral hemorrhage, which
could hopefully lead to fewer early deaths.
ACKNOWLEDGMENT
We would like to thank all the clinicians who referred
patients to us and the staff of the Charing Cross Hospital for
excellent support. We thank the Cancer Research Campaign
and the Medical Research Council for long sustained support
of these studies.
10. Bagshawe KD: Risk and prognostic factors in tropho-
blastic neoplasia. Cancer 38:1373-1385, 1976
11. Begent RHJ, Bagshawe KD, Green AJ, et al: The
clinical value of imaging with antibody to human chorionic
gonadotrophin m the detection of residual choriocarcinoma.
Br J Cancer 55:657:660, 1987
12. Yordan EL, Schlaerth J, Gaddis O, et al: Radiation
therapy in the management of gestational choriocarcinoma
metastatic to the central nervous system. Obstet Gynecol
69:627-630, 1987
13. Hammond CB, Weed JC, Currie JL: The role of
operation in the current therapy of gestational trophoblastic
disease. Am J Obstet Gynecol 136:844-858, 1980
14. Wolf AL, Adcock LL, Hachiya JT, et al: Choriocarci-
noma with brain metastases. Successful management of
increased intracranial pressure with barbiturates. Cancer
57:1432-1436, 1986
15. Brace KC: The role of irradiation in the treatment of
metastatic trophoblastic disease. Radiology 91:540-544, 1968
16. Rustin GJS, Newlands ES, Bagshawe KD, et al:
Successful management of metastatic and primary germ cell
tumors in the brain. Cancer 57:2108-2113, 1986
17. Newlands ES, Rustin GJS, Bagshawe KD, et al:
Weekly EMA/CO chemotherapy for high risk gestational
trophoblastic tumors. Proc Am Soc Clin Oncol 5:112, 1986
(abstr)