Open Journal of Obstetrics and Gynecology, 2011, 1, 153-157
doi:10.4236/ojog.2011.13029 Published Online September 2011 (http://www.SciRP.org/journal/ojog/
OJOG
).
Published Online September 2011 in SciRes. http://www.scirp.org/journal/OJOG
Chemo-resistant gestational trophoblastic neoplasia, 5-years
experience of Mansoura University Hospital, Egypt
Reda Abd Elhady Hemida 1*, Eman Toson2, Hend Shalaby1, Ehsan Refaie1, Doaa Sharaf Eldin2
1Department of Obstetrics and Gynaecology, Mansoura University Hospital, Mansoura, Egypt.
2Department of Clinical Oncology, Mansoura University Hospital, Mansoura, Egypt.
Received 25 April 2011; revised 23 May 2011; accepted 30 May 2011.
ABSTRACT
Introduction: Gestational trophoblastic neoplasia
(GTN), is recognized as the most curable gynaecolo-
gic malignancy. However, many cases are resistant to
first line chemotherapy. Objective: The aim of the
study is to report our 5 years experience in the ma-
nagement of GTN cases with special stress on the
chemo-resistant cases. Methods: The study was per-
formed through reviewing the records of 51 patients
who were diagnosed as GTN during the period from
1/1/2006 to 31/12/2010 in Mansoura University Hos-
pital, Egypt. Results: Resistance to methotrexate the-
rapy was reported in 15.15% of low risk cases and
received etoposide or cisplatinum/etoposide. Sixty
percent of high risk cases were resistant to MAC
combination and received salvage chemotherapy or
hysterectomy. There was significant correlation be-
tween patient response and initial B-hCG, as well as
WHO risk score (P value = 0.001 in both) but corre-
lations with age, parity, type of antecedent pregnancy,
and histopathology were non significant (p = 0.95,
0.53, 0.47& 0.83 respectively). Conclusion: Low risk
GTN cases who were resistant to methotrexate mono-
therapy received etoposide or cisplatinum/etoposide
as a second-line therapy. High risk GTN cases who
were resistant to MAC combination received second-
line combination chemotherapy and/or hysterectomy.
WHO risk score and initial B-hCG were correlated to
resistance to first line chemotherapy.
Keywords: Gestational Trophoblastic Neoplasia-
Chemotherapy-Resistance
1. INTRODUCTION
Gestational trophoblastic neoplasia (GTN), is the term
now commonly applied to persistent or invasive gesta-
tional trophoblastic disease [1]. GTN is typically diag-
nosed in asymptomatic women undergoing routine hCG
monitoring after evacuation of a complete molar pre-
gnancy. It is recognized today as the most curable gynae-
cologic malignancy [1]. The reported incidence of GTN
is 2/1000 pregnancies in Japan and 0.6 - 1.1/1000 pregn-
ancies in Europe [2]. In Africa, Moodley and colleagues
reported that the incidence of GTN was 0.5 /1000 deli-
veries in South Africa [3].
There are many classifications of GTN, in 1973, Ham-
mond et al. classified GTN into non metastatic and me-
tastatic diseases, the later is further subdivided into good
prognosis metastatic disease and poor prognosis meta-
static disease. In 1976, Bagshawe suggested the use of a
prognostic scoring system. The WHO has adopted a mo-
dification of Bagshawe's scoring system [1].
Patients scored as low risk (score 0 - 6) receive
methotrexate and folinic acid and have a survival rate of
about 100%, but a third require second-line chemo-
therapy, either with single-agent intravenous actinomycin
D or with etoposide, methotrexate, actinomycin D alter-
nating with cyclophosphomide and vincristine (EMA/CO)
[4-6].
Patients scored as high risk (score ≥ 7) receive EMA/
CO as first-line therapy and have a survival rate of 90%
but more than 10% of patients fail this therapy [6,7]. To
salvage women failing EMA/CO, Newlands et al. [8]
have previously shown that the addition of cisplatin to
etoposide (EP) alternating weekly with EMA (1 day only)
with or without surgery salvages a further 75% of cases.
El-lamie et al. [9], recommended incorporation of pacli-
taxel in the third-line treatment of resistant GTN. How-
ever, Deng et al. [10], concluded from a Cochrane syste-
matic review that a MAC regimen was better than other
regimens for high-risk GTN because of lower toxicity.
Furthermore, adjuvant surgical procedures could be
excellent adjuncts to salvage chemotherapy in removing
known foci of chemotherapy-resistant disease in selected
patients with persistent GTN [11].
Zhou et al. [12], classified refractory GTN as chemo-

R. A. E. Hemida et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 153-157 154
resistant GTN group who had never a normal serum beta
subunit of human chorionic gonadotropin (β-hCG) level
during their previous treatment, relapsed GTN group
who had elevated serum β-hCG levels in the absence of
the pregnancy after finished treatment 3 months or more,
and undetermined GTN group who had elevated serum
β-hCG levels in the absence of the pregnancy less than 3
months after completed treatment. They concluded that
comparing with the patients with chemo-resistant GTN,
the outcome of patients with relapsed GTN was better.
Optimization of treatment strategies for patients who
develop drug resistance remains a key challenge. We
tried to clarify factors that were linked to resistance to
first-line chemotherapy and management of the chemo-
resistant cases during the last 5 years in our university
hospital
2. PATIENTS AND METHODS
The study was performed through reviewing the records
of 51 patients who were diagnosed as gestational tropho-
blastic neoplasia during the period from 1/1/2006 to
31/12/2010 in the departments of Gynaecology and Cli-
nical Oncology, Mansoura University Hospital, Egypt.
The cases were diagnosed as GTN after persistent
positive hCG more than 6 months, plateuing, or rising
serum level of B-hCG after evacuation of molar preg-
nancy or after histological diagnosis of choriocarcinoma,
invasive mole, or placental site trophoblastic tumour
(PSTT).
The patients were evaluated with respect to age, parity,
type of antecedent pregnancy, clinical presentation, and
presence of metastasis. The level of serum B-subunit of
hCG at diagnosis, and its level on follow up visits were
studied. Uterine re-curettage and pathological findings
were evaluated. All women were classified as low-risk
or high-risk disease using FIGO and WHO scoring
systems [1].
The first line chemotherapy treatment for these cases
was studied regarding its type (single or multiple agent),
number of courses, and the response rate. Patients needed
second, third lines of combination chemotherapy as well
as performing hysterectomy or other surgical procedures
were also analyzed.
3. STATISTICAL ANALYSIS
The statistical analysis of data done by using excel pro-
gram for figures and SPSS program (SPSS, Inc, Chicago,
USA) statistical package for social science version 16.
To test the normality of data distribution K-S (Kolmo-
gorov-Smirnov) test was done only significant data
revealed to be nonparametric. The description of the data
done in form of mean (+/-) SD for quantitative data and
Frequency & proportion for qualitative data.
The analysis of the data was done to test statistical
significant difference between groups. For quantitative
date student t-test was used to compare between two
groups.
Paired sample t-test was used to compare one group
at different times. Chi square test was used for for quali-
tative data. P is considered significant if less than or
equal to 0.05 at confidence interval 95%.
4. RESULTS
This retrospective study included 51 cases who were
diagnosed as GTN. The mean follow up duration was
28.45 months (range: 3 - 54). Thirty-six cases (70.6%)
were low risk and 15 cases (29.4%) high risk according
to WHO scoring system. The mean age was 28.7 years
(range: 17 - 50 years). The mean parity was 1.29 (range:
0 - 5). Mean B-hCG level on admission was 52705.8
mu/ml (range: 60.0 - 500,000). The mean time since the
last pregnancy was 6.15 months (range: 1 - 72).
The history of the previous pregnancy was shown in
Table 1, as can be seen from the table, 30 cases (58.8%),
followed complete hydatidiform mole.
The initial clinical presentation of the studied cases
was post molar bleeding in 24 cases (47.05%), non-
normalization of hCG after molar evacuation in 10 cases
(19.60%), abnormal vaginal bleeding in 16 cases (31.38%),
and one case (1.97%), was presented to the emergency
unit by internal haemorrhage with elevated hCG (1000
mu/ml) and diagnosed after laparotomy as ruptured he-
patic metastasis of choriocarcinoma .
Dilatation and curettage was done in 36 cases (70.6%),
the histopathology of these cases was shown in Table 2.
There were 8 cases (15.68%) with distant metastases, the
sites of metastasis are shown in Table 3.
Forty-eight patients received first line chemotherapy
for 2 - 15 cycles, 3 low risk cases (5.9%) did not receive
chemotherapy due to spontaneous decline of B-hCG
after uterine re-curettage (a total of 51 cases). Complete
response was achieved in 34 patients (70.83%), while 14
cases were resistant to chemotherapy (29.17%).
Regarding first- line treatment, 33 low-risk cases re-
ceived methotrexate in a dose of 1 mg/kg in days 1, 3, 5,
and 7 alternating with oral folinic acid 0.1 mg/kg in days
2, 4, 6, and 8. Mean number of courses was 5.09 (range:
2 - 15). Twenty-eight cases (84.85%) achieved remission,
while 5 cases (15.15%) needed second line therapy in
the form of etoposide (3 cases) and cisplatinum/etopo-
side (2 cases) with a complete response.
High risk patients (15 cases) received methotrexate -
actinomycin D-cyclophosphamide (MAC) combination
as first-line chemotherapy, 6 cases (40%) responded to
this treatment while 9 cases (60%) were resistant. Ac-
cording to our tumour discussion panel, 6 of the resistant
cases received cisplatinum/etoposide as second-line
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Table 1. The type of antecedent pregnancy.
Count Percentage
Abortion 10 19.6%
Partial mole 9 17.6%
Complete mole 30 58.8%
Term pregnancy 2 3.9%
Total 51 100.0%
Table 2. Histopathology of the studied cases.
Count %
No endometrial biopsy* 15 29.4%
Choriocarcinoma 20 39.2%
Molar tissues 10 19.6%
Invasive mole 3 5.9%
PSTT** 3 5.9%
Total 51 100.0%
*: Diagnosis of GTN was done by non-normalization of B-hCG after
evacuation of hydatidiform mole; PSTT**: Placental site trophoblastic
tumor.
Table 3. Sites of distant metastases.
Percentage Number
62.5% 5 Lungs
12.5% 1 Lungs and brain
12.5% 1 Bone and brain
12.5% 1 Liver
100 % 8 Total
therapy, where 4 of them achieved remission by this
salvage chemotherapy and the other 2 cases did not re-
spond and had hysterectomy. The remaining 3 cases
were not given second line chemotherapy; 2 cases had
hysterectomy as they refused salvage chemotherapy and
they had no distant metastasis while the last case died
during the first line therapy after rapid progress with
lung and brain metastasis.
Radiotherapy was used in two cases (3.92%) with
brain and/or bone metastasis. Surgical treatment was
done in 5 high risk cases (9.8%). Hysterectomy was
done in 4 cases (7.84%); as a second line in 2 cases and
as a third line in 2 further cases. Hepatic resection was
done in one case who presented by internal haemorrhage
due to rupture of hepatic metastasis.
The overall survival of GTN cases in our study was
98.04% and was found to be 100% for low risk patients.
Ta b l e 4 shows the correlation of age, parity, and ini-
tial B-hCG to patient response to first-line chemotherapy.
As can be seen from this table, patient response was not
Table 4. Correlation of age, parity, and initial B-hCG to patient
response to first-line chemotherapy.
ResponseN*Mean S D** P value
Responders37 28.73 7.85
Age Non
responders 14 28.57 9.97
0.953
(NS)***
Responders37 1.38 1.497
Parity Non
r
esponders 14 1.07 1.73
0.534 (NS)
Responders37 27533.65 46849.297
Initial
hCG Non
responders 14 119232.14 1.40103.5
0.001
(Sig.)****
N*: Number of patients; SD**: Standard deviation; (NS)***: Non signifi-
cant; (Sig.)****: Significant.
significantly correlated to age and parity but there was
significant correlation to initial B- hCG.
Table 5 shows the correlation between type of ante-
cedent pregnancy and patient response to first-line che-
motherapy, P value was 0.74 (non significant).
Table 6 shows the correlation between histopathology
and patient response to first-line chemotherapy, again,
there was no significant correlation. Ta bl e 7 shows the
correlation between WHO risk score and patient re-
sponse to first-line chemotherapy, there was significant
correlation (P value = 0.001).
5. DISCUSSION
Gestational trophoblastic neoplasia is highly responsive
to chemotherapy and prognosis is excellent following
treatment, especially in low-risk patients [13]. However,
resistance to first line chemotherapy was reported to
occur in 33% of low risk cases and about 10% of high
risk cases (4,8). There is a need to find out the factors
that linked to chemo-resistance as well as to reach the
ideal treatment strategies for these patients.
This retrospective study was performed through re-
viewing the records of 51 patients who were diagnosed
as gestational trophoblastic neoplasia during the period
from 1/1/2006 to 31/12/2010 in the departments of Gy-
naecology and Clinical Oncology, Mansoura University
Hospital, Egypt.
The socio-demographic criteria of GTN patients may
differ according to the geographic distribution. The mean
age of our cases was 28.7 years which agreed with find-
ings of other authors [8,12] but did not agree with data
published by Kaye [14], from Uganda who reported that
most of his cases occurred below 20 years or above 35
years. The mean parity of patients in our study was 1.3
which did not agree with Kaye [14] as 68% of his pa-
tients had 5 or more deliveries. This may be explained
by different community criteria.
Most of our GTN cases occurred after complete molar
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Table 5. Correlation of type of antecedent pregnancy to patient
response to first-line chemotherapy.
Response
Responders Non responders Total
Abortion 6 (60%) 4 (40%) 10
Partial mole 8 (88.89%) 1 (11.11%) 9
Complete mole 22 (73.33%)8 (26.66%) 30
Term pregnancy 1 (50%) 1 (50%) 2
Total 37 14 51
P value : 0.47 (non significant).
Table 6. Correlation of histopathology to patient response to
first-line chemotherapy.
Response Total
Responders
Non
res
p
onders
Endometrial biopsy not done 13 (86.67%) 2 (13.33%)15
Choriocarcinoma 13 (65%) 7 (35%) 20
Molar tissues 9 (90%) 1 (10%) 10
Invasive mole 1 (33.33%) 2 (66.67%)3
PSTT 1 (33.33%) 2 (66.67%)3
Total 37 14 51
P value : 0.083 (non significant).
Table 7. Correlation of WHO risk score to patient response to
first-line chemotherapy.
Response Total
Responders
Non
r
es
p
onders
Low risk (score 0 - 6) 31 (86.11%) 5 (13.99%) 36
High risk (score ≥ 7) 6 (40%) 9 (60%) 15
Total 37 14 51
P value: 0.001 (Significant).
pregnancies (58.8%), as can be seen from Ta bl e 1 , this
was in agree with other authors [15,16]. Ta b l e 2 shows
the histopathology of the cases who had been performed
uterine curettage. Twenty of thirty-six cases (55.56%),
were found to be choriocarcinoma this finding was
agreed with other authors [17,18]. Distant metastases
were shown in Table 3, lung metastasis was the com-
monest, a similar finding was reported by Kumar et al.
[19].
Low risk GTN cases received Methotrexate/folinic
acid but there was 15.15% of patients fail to respond to
this monotherapy. Resistance to methotrexate therapy
was reported also by other authors [5,6].
High risk cases received MAC combination chemo-
therapy, however, 60% of them were resistant to this
protocol. This figure was higher than reports of other
authors [10,12], this can be explained by smaller number
of patients in the current study.
In this study, we tried to determine whether there were
any factors linked to resistance to first line chemothe-
rapy during initial treatment of GTN. Tables 4-7,
showed that there was significant correlation of chemo-
therapy response to initial B-hCG and WHO score (p =
0.001 in both). These findings were supported by other
author [20,21]. No significant correlation of age, parity,
type of antecedent pregnancy, and histopathologic type
(p = 0.95, 0.53, 0.47& 0.83 respectively). This was sup-
ported by the results of Wang et al [22] but did not agree
with Bagshawe [20]. This discrepancy may be as result
of small number of patients who performed endometrial
biopsy (36 cases).
Surgical procedures may be good adjuncts to chemo-
therapy in properly selected cases as the majority of
women with GTN are young and wish to preserve their
fertility. Hysterectomy was done in 4 high-risk cases
who failed to respond to first line chemotherapy as a
second or third line therapy. This findings was also sup-
ported by other authors [12,17,23].
We have to report that this retrospective study re-
presented a single center experience and had relatively
small number of cases. A large multicenter prospective
trial is recommended.
6. CONCLUSIONS
Low risk GTN cases were found to be resistant to meth-
otrexate monotherapy in 15.15%, these cases received
etoposide or cisplatinum/etoposide as a second-line the-
rapy. High risk GTN cases received MAC combination
but 60% were resistant and needed second line com-
bination chemotherapy or hysterectomy. WHO score and
initial B-hCG were significantly correlated to resistance
to first-line chemotherapy.
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