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Purpose: To evaluate the results of etoposide, metho- deaths, while 213 patients (78%) achieved a complete
trexate, and doctinomycin alternating with cyclophos- remission. Forty-seven (17%) developed drug resistance
phamide and vincristine (EMA/CO) chemotherapy in to EMA/CO, of whom 33 (70%) were salvaged by further
women with high-risk gestational trophoblastic tumors cisplatin-based chemotherapy and surgery. Two women
(GTT) and to document the middle- and long-term toxicity developed acute myeloid leukemia, two cervical malig-
of the regimen. nancy, and one gastric adenocarcinoma after EMA/CO.
Patients and Methods: A total of 272 consecutive More than half (56%) of the women who had fertility-
women with high-risk GTT, including 121 previously conserving surgery and who have been in remission at
treated patients, were treated with weekly EMA/CO. The least 2 years have become pregnant since the completion
median follow-up duration is 4.5 years (range, I to 16). of EMA/CO, with 112 live births, including three infants
Results: The cumulative 5-year survival rate is 86.2% with congenital abnormalities.
(95% confidence interval, 81.9% to 90.5%). No deaths Conclusion: EMA/CO is an effective and well-toler-
from GTT have occurred later than 2 years after the start ated regimen for high-risk GTT. More than half of the
of EMA/CO. In a multivariate model, adverse prognostic women will retain their fertility; however, there is a small
factors were the presence of liver metastases (P < but significant risk of second malignancy.
.0001), interval from antecedent pregnancy (P< .0001), J Clin Oncol 15:2636-2643. 1997 by American So-
brain metastases (P = .0008), and term delivery of ante- ciety of Clinical Oncology.
cedent pregnancy (P = .045). There were 11 (4%) early
EMA
Survey
Day 1
One hundred sixty patients had completed chemotherapy more Dactinomycin 0.5 mg IV bolus
2
than 5 years previously. Questionnaires were sent to 134 of these Etoposide 100 mg/m in 250 mL NS over 30 minutes
2
women (16 had died and 10 did not reside in the United Kingdom). Methotrexate 300 mg/m in 1 L NS over 12 hours
They were asked to complete a simple questionnaire that concerned Day 2
fertility, pregnancies, and major illnesses since treatment. Responses Dactinomycin 0.5 mg IV bolus
were obtained from 96 women (71%). Additional information con- Etoposide 100 mg/m2 in 250 mL NS over 30 minutes
cerning fertility and subsequent pregnancies was available for pa- Folinic acid 15 mg orally/IM twice a day for 2 days 24
tients on serologic follow-up evaluation at Charing Cross Hospital. hours after start of methotrexate
CO
Statistical Methods Vincristine 0.8 mg/m2 IV bolus (maximum, 2 mg)
Cyclophosphamide 600 mg/m2 in 250 mL NS over 30 minutes
Survival was calculated from the first day of treatment until death
Repeat EMA alternating weekly with CO to serologic remission plus a
or date of last follow-up visit. Overall survival duration curves were
further 6-8 weeks therapy
plotted according to the method of Kaplan and Meier.'o The log-
rank method was used to test for the significance of differences in Abbreviations: IV, intravenous; NS, normal saline; IM, intramuscularly.
1111111111111111I1 ,.,I.,,I,,,I,.I,.I,
.8
.2
0
' ' I I I I I I I I I I I, '
. . I I
0 2 4 6 8 10 12 14 16 18
Years
I I I I, i . =I I i. i , r . . . . . = i i , I
a. n=121 1 b. n=237
0 2 4 6 8 10 12 14 16 18 0 2 4 6 8 10 12 14 16 18
Years Years
b. n=254 1 b. n-263
Fig 2. Univariate analysis of
survival according to (1) prior
a. n-S9
chemotherapy, (2) presence of "L.6 -
brain metastases, (3) presence of
liver metastases, (4) PSTr histol- .4
E - a. n-17
.4
ogy, (5) interval since anteced-
ent pregnancy, and (6) anteced- .2 .2
ent term pregnancy.
0- O-
0 2 4 6 8 10 12 14 16 18 0 2 4 6 8 10 12 14 16 18
Years Years
0 2 4 6 8 10 12 14 16 18 0 2 4 6 8 10 12 14 16 18
Years Years
otomy). The median time to relapse following comple- of polyposis coli and this is thought to be the major
tion of chemotherapy was 4 months (range, 1 to 72). etiologic factor, rather than chemotherapy. A second
woman died of acute myeloid leukemia French-Ameri-
Deaths can-British (FAB) subtype M1 16 months after she com-
There have been 34 deaths in this cohort of 272 patients pleted EMA/CO, having received a total etoposide dosage
(12.5%). Thirty-one patients died of GTT (11 early of 3.0 g/m 2 . Karyotypic analysis of the blast population
deaths, one treatment-related, six relapsed, and 13 refrac- demonstrated a clonal t(9:11)(p:q23) translocation-an
tory disease) and three patients have died of other causes. abnormality found frequently in secondary leukemia fol-
One woman died of colonic cancer 1.7 years after she lowing topoisomerase II inhibitor therapy. A third woman
completed treatment with EMA/CO. There was a history died in a traffic accident 4 years after EMA/CO. All three
women were in serologic remission of GTT at the time the age of 52 years, 13 years after she completed initial
of death. EMA/CO therapy and 6 years after further EMA/CO for
relapsed disease. She remains in serologic remission of
Late Toxicity GTT. Two other women have reported that they have
Second malignancy. In addition to the two deaths received treatment for cervical malignancy (one invasive
from second malignancies (vide supra), another woman and one intraepithelial 2 and 1 years following completion
developed acute myeloid leukemia of FAB subtype M5 of chemotherapy). A further two women have reported
15 months after she completed EMA/CO (total etoposide benign breast lumps and one woman received treatment
dosage, 2.0 g/m 2) while in serologic remission of GTT. for a benign ovarian cyst.
No clonal karyotypic abnormality was identified. She was Other toxicities. Other potential late treatment-related
successfully treated with chemotherapy and a matched toxicities identified from the survey responses from 96 pa-
unrelated bone marrow allograft and remains in remission tients included thyroid dysfunction (n = 2), hypoparathy-
of both leukemia and GTT 4 years later. roidism (n = 1), epilepsy following craniotomy (n = 1),
One woman has developed gastric adenocarcinoma at and avascular necrosis of the femoral heads (n = 1).
Early death 11 4 11 7 0 0
Treatment-related death 1 0.4 1 0.7 0 0
Progressive disease 47 17 21 14 26 21
Complete remission 213 78 118 78 95 79
Table 5. Fertility in Patients More Than 2 Years After Completion of previously untreated group of women. In this group of
EMA/CO Chemotherapy patients, early deaths are the major cause of mortality.
Dead 25 The early deaths were all related to the extent of disease
Lost to long-term follow-up 17 at initiation of therapy. Earlier diagnosis may reduce these
Total dead & lost to follow-up 42
deaths; however, all 11 followed term deliveries or spon-
Hysterectomy 36
4
taneous abortions, rather than hydatidiform moles, and so
Laparoscopic sterilization
High-dose chemotherapy* 1 these patients were not on the surveillance program. To
latrogenic infertility 41 reduce the deaths in untreated patients, improved respira-
Not attempted 13 tory management is required, since over half of the deaths
No pregnancies 49
were due to respiratory complications.14 Mechanical ven-
Unsuccessful 4
Uncertain status 66
tilation in these patients presents problems, as barotrauma
At least 1 live birth 75 can cause intrapulmonary hemorrhage because the pul-
TOPs only 4 monary metastases are highly vascular. The use of an
Miscarriages only 3 intravascular oxygenator may be an alternative approach,
Currently pregnant 3
as anticoagulation is not necessary for this procedure.
Fertile 85
The other fatalities among previously untreated patients
Total 234 include five patients with drug-resistant primary disease
* For acute myelogenous leukemia. (including one patient with PSTT) and two patients with
Abbreviation: TOP, termination of pregnancy. drug-resistant disease at relapse (including one patient
with PSTT). All three deaths due to causes other than
GTT occurred in patients with untreated disease.
Fertility and Pregnancy In contrast, all deaths in previously treated patients
One hundred ninety-two patients are alive and free of were a consequence of drug resistance. Nine women had
disease at least 2 years after completing chemotherapy resistant disease and never achieved remission after start-
and continue on serologic follow-up at Charing Cross ing EMA/CO, while three achieved remission, but died
Hospital. Forty women (21%) have either had a hysterec- of drug-resistant disease at relapse. Drug resistance to
tomy (n = 36) or laparoscopic sterilization. Eighty-five EMA/CO occurs more frequently after failure of combi-
(56%) of the remaining 152 women are or have been nation chemotherapy (34%) than failure of single-agent
pregnant since the completion of treatment (70 have had chemotherapy (11%). Three quarters of untreated women
- one live birth, four have had terminations only, three and two thirds of previously treated women who devel-
have had miscarriages only, and three are currently preg- oped resistance to EMA/CO were successfully salvaged
nant). The other 67 women include 13 who reported that by a combination of cisplatin-based combination chemo-
they have not attempted to become pregnant and one who therapy and surgery, so that the initial treatment of low-
has received high-dose chemotherapy and a bone marrow risk disease with methotrexate does not make salvage
allograft (Table 5). There have been a total of 112 live difficult if drug resistance emerges. The ability to salvage
births in this cohort, including three infants with congeni- the majority of patients after initial treatment failure is one
tal abnormalities (one Down syndrome, one clubfoot, and of the unusual features of GTT and, given the relatively
one umbilical hernia). This is a similar incidence to that successful outcome in this disease, it is clinically justifi-
reported in other series.13 able to try to achieve a complete remission even after
several treatment failures. However, improvements in the
DISCUSSION therapy of drug-resistant GTT are needed to improve fur-
As previously reported, EMA/CO is effective therapy ther the survival in this group of women. High-dose che-
for high-risk GTT. The overall cumulative survival rate motherapy followed by autologous progenitor cell rescue
at 5 years is 86.2% (95% confidence interval, 81.9% to has been advocated."5 Two women with drug-resistant
90.5%) and the disease-specific survival rate at 5 years GTT in this series underwent this procedure, but neither
is 87.7%. This compares with previously published re- achieved a meaningful response and both died of rapidly
ports of EMA/CO from smaller cohorts that documented progressive disease 1 and 4 months after transplantation.'16
overall survival rates of 85%,6 88%,7 and 100%.8 A number of new cytotoxic agents are available (particu-
Prior treatment with chemotherapy does not signifi- larly taxanes and topoisomerase I inhibitors), but they
cantly alter survival. However, all of the early deaths have not yet been evaluated in drug-resistant GTT on
and the single treatment-related death occurred in the account of the small number of patients with this problem.
Many centers have used one of several prognostic scor- this cohort. Among 1,394 women treated with chemother-
ing systems to identify patients with high-risk disease. apy for GTT at Charing Cross Hospital, the incidence of
Both the Charing Cross Hospital system and that recom- second malignancies was significantly increased, with 37
mended by the WHO are similar.12 The results reported cases occurring, compared with an expected rate of 24
in this series confirm that the major risk factors in both (P = .011).20 The greatest increase in second tumors in
of these scoring systems (interval from antecedent preg- this large cohort was myeloid leukemia, with lesser but
nancy > 12 months, initial serum hCG level > 105 IU/ significant increases in melanoma, colon, and breast can-
L, CNS metastases, > eight metastases, and failure of cer. Other late events reported here include thyroid and
prior multiagent chemotherapy) are important. However, parathyroid dysfunction, although the relationship to the
both of these prognostic scoring schemes need to take chemotherapy is uncertain.
into account developments in the last decade. PSTT is Over half of the women monitored for at least 2 years
a rare and unpredictable variant of trophoblastic tumor, from the start of EMA/CO who had fertility-preserving
although it did not have a significantly worse prognosis surgery have become pregnant. Fertility is a major issue
in this series. The molecular genetics, clinical features, for many of the women with high-risk GTT and the con-
treatment response, and outcome of the PSTT patients servation of fertility with this regimen is valuable. By
included in this cohort are described fully elsewhere."7 comparison, in an analysis of 445 women treated with
The presence of liver metastases has been underestimated chemotherapy for GTT at Charing Cross Hospital, 97%
as an adverse prognostic variable and should be included of those who wished to become pregnant succeeded and
along with CNS metastases as a major risk factor. Since 86% of these had at least one live birth.21
the presence of both CNS and liver metastases carries an However, there have been three congenital abnormali-
even worse prognosis," each site of disease should be ties among the 112 babies born to these women and the
scored independently (ie, a WHO score of 4 x 2 if both role of the chemotherapy in the teratogenicity causes con-
CNS and liver metastases are present). Furthermore, a cern. This compares with reported rates of 0.8% to 3.4%
prolonged interval of 2 years or more between antecedent congenital abnormalities in infants born to mothers
pregnancy and diagnosis is a major adverse prognostic treated with all forms of chemotherapy for GTT.21-24 All
variable that is underscored in the current system. Our of our patients are advised that pregnancy is contraindi-
own data base is probably large enough to define the cated for the first year after the completion of chemother-
relative importance of the major adverse risk factors to apy to allow serologic monitoring of hCG levels to con-
refine the current prognostic scoring systems. However, firm remission and to minimize the potential teratogenic
the results will need to be confirmed independently on effects of chemotherapy.
data sets from other centers and should be evaluated pro- The EMA/CO regimen is a well-tolerated and effective
spectively at several centers. treatment for high-risk GTT that conserves fertility in a
The published early toxicities of EMA/CO include alo- high proportion of women. The medium- to long-term
pecia, nausea, reversible neurotoxicity, and myelosup- toxicity recorded so far with the EMA/CO schedule is
pression.' 6 The late toxicities reported here include sec- acceptable in view of the high-risk nature of the disease
ond malignancies, most prominently acute myeloid being treated. However, the small increase in second tu-
leukemia, which has been linked particularly to etoposide mors that is associated with combination chemotherapy
administration. The mechanism of topoisomerase II inhib- for this disease is worrying and emphasizes the need to
itor-induced leukemogenesis is obscure, but the myeloid develop effective chemotherapeutic agents with a better
blasts frequently have rearrangements of the MLL gene long-term toxicity profile than the agents in current clini-
on chromosome 11q23.' 9 The two cervical tumors and cal use. In our analysis of second tumors in women treated
the gastric adenocarcinoma are not well-recognized sec- for GTT, only methotrexate used as a single agent is free
ondary tumors and are possibly incidental associations in of the risk of inducing second malignancies. 20
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