Gestational Trophoblastic Neoplasia: Experience from a Tertiary Care Center of India

Abstract

Aims
Gestational trophoblastic neoplasia (GTN) comprise a spectrum of interrelated
conditions originating from the placenta. With sensitive assays for human chorionic gonadotropin (β-hCG) and current approaches to chemotherapy, most women with GTN can be cured with preservation of reproductive potential. The purpose of this analysis was to address the outcome of GTN in patients from a tertiary care center of India.
Materials and Methods
We undertook a retrospective and prospective review of GTN cases treated at our center over a period of 7 years from 2008 to 2014. Patients of GTN were assigned to low-risk or high-risk categories as per the FIGO scoring system. The low-risk group was treated with combination of actinomycin-D and methotrexate and the high-risk group received the Etoposide, Methotrexate, Actinomycin-D/ Cyclophosphamide, Vincristine (EMA/CO) regimen. Salvage therapy was Etoposide, Paclitaxel /Paclitaxel, Cisplatin (EP/TP). Treatment was continued for three cycles after normalization of β-hCG level, after which the patients were followed up regularly.
Results
In total, 41 GTN patients were treated at our institution during the above period; 17 were in the low-risk and 24 were in the high-risk category. The lung was the most common site of metastasis. All low-risk patients achieved complete remission. Among high-risk patients, one patient died while receiving first cycle chemotherapy, one patient relapsed, and 22 patients achieved complete remission. The single relapsed patient also achieved remission with second-line chemotherapy.
Conclusion
Risk-stratified treatment of GTN was associated with acceptable toxicity and resulted in outcome that was comparable with international standards. The use of two-drug combination in low-risk patients is a better option especially in developing countries.

Full text

ORIGINAL ARTICLE
Gestational Trophoblastic Neoplasia: Experience
from a Tertiary Care Center of India
Ansar Hussain
1,2,3
•Sheikh Aejaz Aziz
4
•
Gul Mohd. Bhatt
5
•A. R. Lone
5
•Hk. Imran Hussain
5
•
Burhan Wani
5
•Nadeem Qazi
5
Received: 1 April 2015 / Accepted: 29 April 2015 / Published online: 11 June 2015
ÓFederation of Obstetric & Gynecological Societies of India 2015
About the Author
Abstract
Aims Gestational trophoblastic neoplasia (GTN) com-
prise a spectrum of interrelated conditions originating from
the placenta. With sensitive assays for human chorionic
gonadotropin (b-hCG) and current approaches to che-
motherapy, most women with GTN can be cured with
preservation of reproductive potential. The purpose of this
analysis was to address the outcome of GTN in patients
from a tertiary care center of India.
Materials and Methods We undertook a retrospective and
prospective review of GTN cases treated at our center over
a period of 7 years from 2008 to 2014. Patients of GTN
were assigned to low-risk or high-risk categories as per the
FIGO scoring system. The low-risk group was treated with
combination of actinomycin-D and methotrexate and the
high-risk group received the Etoposide, Methotrexate,
Actinomycin-D/ Cyclophosphamide, Vincristine (EMA/
CO) regimen. Salvage therapy was Etoposide, Paclitaxel /
Paclitaxel, Cisplatin (EP/TP). Treatment was continued for
three cycles after normalization of b-hCG level, after
which the patients were followed up regularly.
Results In total, 41 GTN patients were treated at our in-
stitution during the above period; 17 were in the low-risk
and 24 were in the high-risk category. The lung was the
most common site of metastasis. All low-risk patients
achieved complete remission. Among high-risk patients,
one patient died while receiving first cycle chemotherapy,
one patient relapsed, and 22 patients achieved complete
&Dr. Ansar Hussain
ansarhakim22@gmail.com
1
GMC, Srinagar, India
2
Internal Medicine, SKIMS, Srinagar, India
3
Medical Oncology, SKIMS, Srinagar, India
4
Medical Oncology, SKIMS, SGR, Srinagar 190011, India
5
SKIMS, SGR, Srinagar, India
Dr. Ansar Hussain completed his MBBS from the Govt. Medical College Srinagar, and MD in Internal Medicine from
SKIMS, Srinagar. Presently he is a DM (post-doctoral) scholar in the Department of Medical Oncology, SKIMS, Srinagar.
The Journal of Obstetrics and Gynecology of India (November–December 2016) 66(6):404–408
DOI 10.1007/s13224-015-0710-0
123

remission. The single relapsed patient also achieved re-
mission with second-line chemotherapy.
Conclusion Risk-stratified treatment of GTN was asso-
ciated with acceptable toxicity and resulted in outcome that
was comparable with international standards. The use of
two-drug combination in low-risk patients is a better option
especially in developing countries.
Keywords Gestational Trophoblast Neoplasia
Introduction
It is just 100 years since Marchand identified choriocarci-
noma as a tumor arising from placental villous trophoblast.
Earlier description of similar tumors failed to identify their
tissue of origin. Gestational trophoblastic disease (GTD) is
the terminological umbrella now used to describe the
spectrum of cellular proliferations ranging from villous
forms of hydatiform mole through invasive mole and
choriocarcinoma to placental site tumors. Each form of
GTD presents its own particular set of problems ranging
from social to therapeutic.
GTD is still an important reproductive health problem
worldwide. The problem is that much information of GTD
has come from less-developed countries, where proper di-
agnostic tools and up-dated treatment cannot be employed.
GTD can be benign or malignant. Histologically, it is
classified into hydatidiform mole, invasive mole
(chorioadenoma destruens), choriocarcinoma, and placen-
tal site trophoblastic tumor (PSTT). Those that invade lo-
cally or metastasize are collectively known as gestational
trophoblastic neoplasia (GTN). Hydatidiform mole is the
most common form of GTN. While invasive mole and
choriocarcinoma are malignant, a hydatidiform mole can
behave either in a malignant or benign fashion. We report
the clinical profile, management, and outcome of GTN
patients treated at our center over a 7-year period.
Materials and Methods
The data were extracted by retrieving all case records of
GTN patients registered during the study period. The ab-
stracted information included history and examination
findings: chest X-ray; pelvic ultrasound; computed to-
mography (if carried out); MRI Brain; CSF (as and when
required); serum human chorionic gonadotropin (b-hCG);
and histopathological evaluation of biopsy or curettage
specimen, if available. Using this information, patients
were categorized as low risk or high risk according to the
FIGO scoring system. Patients with a score of B6 were
treated with methotrexate (MTX) and Actinomycin D
combination. The MTX was given at a dose of 300 mg/m
2
over 4 h with calcium leucovorin rescue and Actinomycin
D at a dose of 0.5 mg on day 1. The cycles were repeated
once in 2 weeks. Serum b-hCG levels were measured once
every week, including before the start of every che-
motherapy cycle; any patient who had two static or one
increasing value on treatment was defined as having drug-
resistant disease. Patients with a score C7 were classified
as high risk and started on the EMA/CO (etoposide,
methotrexate, actinomycin D, cyclophosphamide, vin-
cristine) regimen. Patients who relapsed were subsequently
treated with EP/TP regimen. The patients with CNS disease
received EMA–CO with higher dose of MTX (1 g/m
2
)
(Table 1). Treatment was continued for three cycles after
normalization of Serum b-hCG in high-risk group and for
two cycles in low-risk group. After the last chemotherapy
cycle, patients were kept on regular follow-up using regular
b-hCG monitoring as per standard guidelines [1,2].
Specifically, b-hCG level was measured at 6–8 weeks after
the end of any pregnancy to exclude disease recurrence [3,
4]. Patients were also advised standard contraceptive
measures [5]. The response to therapy was defined as fol-
lows: complete response as b-hCG values in the normal
range for three consecutive weeks; a partial response as
more than 50 % decline in b-hCG levels compared with
baseline; no response as less than 50 % decline over
baseline values. Progressive disease was defined as an in-
crease of at least 25 % in the size of any measurable lesion
or appearance of any new lesion with the increasing b-hCG
levels. Recurrence was defined as elevation of b-hCG level
after more than three normal values in the absence of a
confirmed pregnancy [6]. All patients irrespective of age
with a diagnosis of GTN were included in the study.
Results
Of the 41 patients diagnosed with GTN, diagnosis was
based on histopathological evidence in six, and elevated
serum b-hCG and history were consistent with GTN in 36
patients. The most common presenting feature was bleed-
ing per vagina in 38 patients. The passage of grape like
vesicles was present in six patients. Other features at pre-
sentation included hemoptysis (five patients) and pain ab-
domen (five patients), and excessive vomiting in two
patients.
On examination, the most common finding was pallor
which was noted in 22 patients. In one patient, there was
mild abdominal tenderness, while the examination showed
normal features in rest of patients. Of the 41 patients, 24
belonged to high-risk category and 17 belonged to low-risk
category. The median age of our patients was 29.5 years
(range 20–46 years). Only three patients were more than
123
The Journal of Obstetrics and Gynecology of India (November–December 2016) 66(6):404–408 Gestational Trophoblastic Neoplasia...
405

40 years of age, and all of them belonged to high-risk
group. The FIGO stage 1 comprised the largest staging
group among our patients (20 patients), and FIGO 4, the
smallest group, only four patients. All stage 4 patients
belonged to high-risk group only. The antecedent preg-
nancy was term in three, abortion in 14, and molar in 24.
Interval from antecedent pregnancy to initiation of che-
motherapy was less than 4 months in 13 patients, between
4 and 7 months in 18 patients, between 7 and 12 months in
six patients, and more than 12 months in four patients. The
overall average pre-evacuation serum b-hCG was
174,461.5 IU/l: in high-risk patients, the average pre-e-
vacuation serum b-hCG was 274,523 IU/l (19,000–
1,410,000 IU/l). The cycle was repeated 10,000 IU/l),
while in low-risk patients, it was 78 347 IU/l (4500–462
417 IU/l).The overall average post-evacuation serum b-
hCG level was 88,085 IU/l (2800–726,151 IU/l): in high-
risk patients, the average post-evacuation serum b-hCG
was 128,809 IU/l (3620–726,151 IU/l), while in low-risk
patients, it was 47,933 IU/l (2800–509,991 IU/l). The lung
metastases were found in ten patients; CNS was involved
in four patients; one patient had MRI-documented brain
metastasis; and the other three had high CSF/serum b-hCG.
Among high-risk patients, lung metastasis were found in
nine patients, and CNS involvement was found in four
patients. Among low-risk patients, only one patient had
lung metastasis. The size of largest tumor was \3cmin13
patients, 3–5 cm in 21 patients, and [5 cm in seven pa-
tients. Among high-risk patients, the largest tumor was less
than 3 cm in five patients, 3–5 cm in 12 patients, and
[5 cm in seven patients. Among low-risk patients, the
largest tumor size was\3 cm in eight patients, and 3–5 cm
in nine patients. The number of metastases was 1–4 in four
patients of high-risk group, and more than four in one
patient of high-risk group. In low-risk group, the number of
metastases was zero in all patients [as per ESMO guideli-
nes, the lung metastases were counted on chest X-ray only
and not on chest Contrast enhanced computed tomography
(CECT)].
Only two patients had history of prior failed che-
motherapy, and both of them belonged to high-risk group.
The average number of chemotherapy cycles received for
normalization of serum b-hCG levels was 4.82 (2–12).In
high-risk group, patients received on average 5.1 cycles (3–
8), while in low-risk group, patients received on average
4.46 cycles (2–12) for normalization of serum b-hCG
levels.
The total number of chemotherapy cycles received on
average was 7.08 (4–14). In high-risk patients, average
number of cycles received was 7.6 (4–11), while in low-
risk patients, it was 6.13 (4–14).
The lung metastases on CECT were present in ten pa-
tients, among whom nine were in high-risk group and one
patient was in low-risk group, whereas on chest X-ray, it
was found that only five patients had lung metastases, and
all of them were from the high-risk group.
Table 1 Summaries the demographic baseline characteristics
Patient characteristics Low risk High risk
Age (in years)
\40 17 21
C40 0 3
FIGO stage
I128
II 4 3
III 1 9
IV 0 4
Antecedent pregnancy
Mole 13 11
Abortion 4 10
Term 0 3
Interval from antecedent pregnancy
\4 months 7 6
4–7 months 6 12
7–12 months 4 2
[12 months 0 4
Mean pre-evacuation b-hCG (IU/l) 78,347 274,523.5
Mean post-evacuation b-hCG (IU/l) 47,933 128,809
Site of metastasis
Lung 1 9
CNS 0 4
Tumor size (in cm)
\385
3–5 9 12
[507
Number of metastasis
01719
1–4 0 4
[401
Imaging evidence of metastasis
Chest X-ray 0 5
CECT 1 9
Previous failed chemo
Single drug 0 2
C2 drugs 0 0
Average number of chemo cycles
received for b-hCG normalization
4.82 5.1
Total chemotherapy cycles received 6.13 7.6
Survival
Complete remission 17 22
Relapse 0 1
Death 0 1
Fertility
Number of patients delivered healthy babies 3 4
123
Hussain et al. The Journal of Obstetrics and Gynecology of India (November–December 2016) 66(6):404–408
406

Discussion
There is no consensus on the best chemotherapy regimen
for initial management of low-risk GTN, and first-line
regimens vary by geography and institutional preference.
Most regimens have not been compared head-to-head, and
the level of evidence for efficacy is often limited.
As GTN is a highly curable disease, the aim of treatment
should be to minimize the drug toxicity, but not at the cost
of treatment efficacy. In our study patients, these goals
were demonstrably achieved as shown in the Table 2. All
the low-risk patients who were treated with MTX and
dactinomycin combination (17 patients) achieved remis-
sion, and there was no relapse in this subset of patients. In
another study from India, 92.9 % of post-molar GTN at-
tained complete remission with MTX [7]. Other studies
from developed countries have reported lower rates of re-
mission (72 %) with MTX and higher requirement of
second-line salvage regimens [8]. Although it is difficult to
draw definitive conclusions, it is possible that there may
not be proper risk stratification in developing countries, and
patients with risk scores of five and six may be relapsing on
single-agent chemotherapy. The two-drug regimen re-
ceived by our patients has prevented relapses, but at the
same time, it has caused minimal toxicity (Table 2). Only
six patients developed neutropenia, and two patients de-
veloped low-grade mucositis. It is pertinent to mention here
that no patient needed growth factor support, and there was
no delay in chemotherapy because of neutropenia. The
patients in our chemotherapy protocol received 300 mg/m
2
of MTX over 4 h with four doses of calcium leucovorin
and single dose Actinomycin-D 0.5 mg, and they were
discharged on same day. The cycle was repeated once in
2 weeks. This protocol could be a good option in low-risk
patients especially in developing countries. Our treatment
outcomes are comparable with national and international
data in low-risk disease [9–12].
Among the high-risk patients in our study, a large ma-
jority (91.6 %) achieved complete remission with the first-
line use of the EMA/CO regimen. The long-term survival
was 96 %, which is in the same range as most other centers
that treat high-risk disease [13].
The one high-risk patient who relapsed on EMA–CO
attained remission with a second-line salvage
chemotherapy.
Although the number of patients treated at our institute
was small, the survival was at par with national and in-
ternational data [12,14–17]. The single patient that died
had a high disease burden and died while receiving first
cycle of chemotherapy likely due to pulmonary hemor-
rhage. These deaths in future could be avoided by starting
with low-dose chemotherapy for 2–3 cycles and then
changing to usual EMA/CO chemotherapy in patients with
high disease load.
Thus, EMA/CO is appropriate for use in experienced
centers in developing countries in appropriately risk-s-
tratified patients.
The relatively low rate of documented fertility in our
data is probably a reflection of the completion of a family
at a young age in our community and effective adherence
to contraceptive advice. It is also possible that there has
been less than perfect long-term follow-up of these patients
with respect to their reproductive outcomes. It may be
concluded that 1 g/m
2
MTX is a good choice for patients
with CNS disease.
In summary, our data show that very high rates of re-
mission and survival are possible in both low- and high-
risk GTN patients in developing countries. Such patients
should preferably be referred to experienced centers that
have capabilities for appropriate risk stratification and
subsequent treatment, including good supportive care.
Compliance with Ethical Requirements and Conflict of Inter-
ests All procedures followed were in accordance with the ethical
standards of the responsible committee on human experimentation
(institutional and national) and with the Helsinki Declaration of 1975,
as revised in 2008, Informed consent was obtained from all patients
for being included in the study. The authors Ansar Hussain, Shiekh
Aejaz Aziz, Gul Mohd. Bhat, A. R. Lone, Imran Hussain, Burhan
Wani, and Nadeem Qazi have no conflicts of interest.
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