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From June 1980 through December 1985, 36 high-risk GTT patients received Bagshawe's
EMA/CO regimen, 22 as first-line, and 14 as second-line treatment, after primary chem-
otherapy with CHAMOCA, or cyclic regimen, or MTX-CF. All treated patients were
metastatic at the start of treatment with EMA/CO; three showed liver metastases and one
brain metastasis. Seventeen patients had a high score, > 15. Nineteen patients had histologically
confirmed diagnosis of choriocarcinoma. The overall response rate was 86% with 81%
survival during a median observation time of 32 months. The median number of courses
needed to achieve complete remission was 3 (range 3-7). Toxicity was acceptable, and
was less than with CHAMOCA and MAC regimens. Only 1 out of 17 high-risk patients
developed drug resistance, and 3 needed urgent surgery. The relapse rate of responders
was 19% after a median of 5.5 months. The survival rate of high-risk patients was 88%,
of which 76% are alive with no evidence of disease, while 12% have still detectable /3-
chorionic gonadotrophin. The remission rate in the second-line treatment group was 64%,
higher than using other regimens such as MAC or CHAMOCA. In conclusion, we consider
EMA/CO to be the best choice for patients with high-risk GTT, because it is effective
and well tolerated. In our opinion, the cure rate of high-risk GTT could perhaps be improved
by starting trials to establish what salvage treatment to employ after EMA/CO failure and
using more aggressive first-line chemotherapy in selected high-risk patients, on the basis
of the scoring system. 1988AcademicPress. Inc.
Gestational choriocarcinoma today is one of the solid tumors with the best
cure rate [1]. Nevertheless, the failure rate among patients classified as "high-
risk," is still too high despite aggressive multidrug therapy regimens [2,3]. The
drugs considered most active in trophoblastic tumor are still MTX and ACT D,
and they are in fact widely employed in the treatment of high-risk patients, in
a variety of multidrug schedules, mainly associated with alkylating agents [2,4].
Recently there have been reports of the efficacy in GTT of etoposide (VP-16-
213), administered either orally or intravenously. This drug shows promising
To whom reprint requests should be addressed at III Department of Obstetrics and Gynecology,
University of Milan, Via Macedonio Melloni 52, 20129 Milan, Italy.
439
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Copyright 1988by AcademicPress, Inc.
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440 BOLIS ET AL.
activity not only as first-line therapy, but also in patients who have become
resistant to conventional therapies [4,7]. Thus its inclusion in a multichemo-
therapeutic schedule, together with drugs whose activity is already acknowledged,
might help improve the survival of high-risk patients.
Preliminary investigations with the EMA/CO schedule have given excellent
results, with the additional advantage of considerably less toxicity than with
other multidrug chemotherapy regimens [8].
TABLE 1
SCORING SYSTEM IN GESTATIONALTROPHOBLASTIC TUMOR
Risk factor": 0 1 2 6
Antecedent preg-
nancy (AP) Mole Abortion or Term
unknown
Interval (AP-chem-
otherapy months) <4 4-7 7-12 >12
Serum/3-hCG level
in m I U / m l < 103 103-10 4 104-10 5 > 105
Uterus involvement Normal Endometrial Myometrial
involvement involvement
(hysteroscopy) (ultrasonography)
No. of metastases Not detected 1-4 4-8 >8
Site of metastases Vagina, lungs g.i. tract-spleen- brain-liver
kidney-unusual
Largest metastatic
tumor mass <2 cm 2-5 cm 5-10 cm >10 cm
Drug resistance Single drug 2 or more drugs
Previous related tu-
mor surgery Genital Distant
TABLE 2
RESULTS OF TREATMENT WITH EMA/CO REGIMEN
Complete Treatment
Indication Pts. response failure Relapse Alive
Primary therapy 22 21 1 4 20
Medium risk 5 5 -- l 5
High risk 17 16 1 3 15
Second-line therapy 14 10 4 2 9
Total 36 31 (86%) 5 (14%) 6 (19%) 29 (81%)
442 BOLIS ET AL.
7). The overall treatment failure rate for drug-resistance was 14%. The overall
relapse rate after complete response was 19%.
Of the 17 patients at high risk, only one, with a high score, developed drug
resistance. Three of these 17 required emergency surgery before treatment: 1
underwent excision of an intracardiac tumor, a second hemicolectomy for neoplastic
perforation, and the third hysterectomy to deal with intractable hemorrhage.
Of the responders, 19% relapsed, in a median time of 5.5 months (range 4-
7); one was in the medium-risk group, three in the high-risk group, and two were
second-line cases. In the four cases of relapse after first-line therapy with EMA/CO,
t h e s a m e regimen was repeated but complete remission was attained in only one
case. The others proceeded to a regimen containing cis-platinum. One patient
died and two are still alive with low, persistent fl-hCG levels, but no clinical
evidence of disease.
The two second-line therapy cases that relapsed were given EMA/CO again,
followed by a regimen containing c/s-platinum. Chemotherapy was associated in
one of these patients with pulmonary lobectomy, and in the other with craniotomy.
The latter is still alive, in complete remission, but the former died.
Toxicity consisted mainly of myelodepression, observed in 14 patients (39%),
and classified according to WHO criteria [12] (Table 3). Eight cases presented
multiple hematological toxicity. Six cases suffered mild mucositis. Variable degrees
of nausea and vomiting occurred in all patients. One patient presented transient
peripheral neuropathy, and two had hepatotoxicity documented by increases in
SGOT, which regressed on discontinuation of treatment. Treatment never had
to be suspended because of toxicity. Two patients had live births 24 and 30
months after completing therapy.
DISCUSSION
The present findings show that the EMA/CO regimen is active in the treatment
of GTT, as either first- or second-line therapy. The 88% survival rate in high-
risk cases, 76% of which are still alive and disease-free and 12% alive with only
biochemical disease, is in good agreement with 84% recently reported by Newlands
et al. referring to the same combination [8]. The 64% cure rate in pretreated
cases is highly encouraging and suggests the use of this combination in failures
with first-line regimens containing MTX and ACT D. The higher response rate
than with the MAC combination [13] or CHAMOCA [14] is probably achieved
through the introduction of etoposide which, when used alone, has proved as
active as MTX and ACT D [5,6].
TABLE 3
MYELOSUPPRESSION IN E M A / C O REGIMEN
2 4 3 3
3 3 2 2
4 2 -- --
Total 9 (40,9%) 5 (22.7%) 5 (22.7%)
EMA/CO IN HIGH-RISK GTT 443
Our relapse rate was higher than previously reported by Newlands et al., with
this regimen (11%) [8] and by Lurain et al. with MAC-CHAMOCA-DDP (4.5%)
[13]. However, it is always hard to compare this because it depends on the
scoring system applied to patients entering the study. The high score is predictive
of treatment failure. In this study, in fact, 47% of the cases presented a high
score.
Toxicity in this study was acceptable and was less than with CHAMOCA [14]
and MAC III [4]. This is an important finding as regards not only acceptance
by patients but also the efficacy of treatment. With CHAMOCA and MAC III,
myelodepression often makes it necessary to suspend treatment, whereas with
EMA/CO this is much rarer, meaning that the timing of treatment cycles can
be respected, with less risk of drug resistance arising.
Another important consideration is that EMA/CO only needs a few days in
hospital (on average, 2 days for each cycle), with obvious psychological advantages
for the patient. Naturally, the fact that part of the regimen can be given on an
out-patient basis makes it preferable to others which may be equally effective.
Additionally, the number of cycles needed to obtain complete remission was no
larger than with other more intensive regimens, requiring longer hospital stays
[41.
To conclude, we believe that EMA/CO can currently be considered the regimen
of choice in most high-risk patients with GTT in view of its good activity and
excellent tolerance. The challenge today lies in patients with a high initial score,
who present a high probability of treatment failure. We believe there are two
paths that may, in the short term, lead to further improvements in curing high-
risk GTT: one is to arrange trials to establish effective salvage treatments to
follow up EMA/CO failures, and the other is to propose more aggressive first-
line chemotherapy for that small part of the high-risk population selected on the
basis of the scoring system.
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444 BOLIS ET AL.
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