Keywords
β-HCG - choriocarcinoma - gestational trophoblastic neoplasia - methotrexate - WHO
score
Introduction
Gestational trophoblastic neoplasia (GTN) incorporates the spectrum of invasive mole,
choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic
tumor, which can occur following any type of pregnancy. Of these, the first two are
associated with significantly elevated levels of serum β-human chorionic gonadotrophin
(β-HCG) and occur at a short interval following the pregnancy. On the other hand,
the latter two are associated with lower levels of β-HCG and occur at a much longer
interval following the pregnancy.[1]
[2]
These are a group of rare but highly curable malignancies if appropriate treatment
is instituted early and judiciously. Further, the fact that these occur in young women
of reproductive age group makes them a high priority for society.[2] Of note, the incidence of these diseases is higher in the Asians, particularly the
South-Asian population.[3]
Thus, it is important to be aware of the treatment policies followed and the results
obtained in different regional settings. However, due to their rare nature, there
is a paucity of prospective data on this topic from our country. Here, we have attempted
to analyze the records of patients with this group of diseases at a tertiary care
oncology center in north India.
Materials and Methods
This is a retrospective analytical study conducted at our center with the timeframe
being from May 2018 to December 2021. Registration numbers of patients were retrieved
from the electronic medical records by using the keywords “Gestational trophoblastic
neoplasia,” “Invasive mole,” “choriocarcinoma,” and “GTN.”
Case records were studied in detail and evaluated for a complete history and physical
examination as well as investigational reports. Data was acquired about patients'
age, antecedent pregnancy interval (in months), history of abortion or molar pregnancy,
pretreatment β-HCG levels, largest tumor dimension (in centimeters), site and number
of metastases, and the number of prior failed lines of chemotherapy (if any). Based
on the above details, patients were categorized into the low-risk group and the high-risk
group as per the World Health Organization (WHO) risk stratification.[4]
Those with a score of 6 or less were deemed to have a low risk of resistance to single-agent
chemotherapy and they were treated with single-agent methotrexate 1mg/kg intravenous
on days 1,3,5 and 7 along with leucovorin per orally 15 mg on days 2, 4, 6, and 8
given to these patients. This cycle was repeated every 2 weeks. β-HCG was monitored
before each consecutive cycle.
Those with a score of 7 and more (the high-risk patients) were considered a high probability
of resistance to single-agent chemotherapy and therefore were treated with combination
chemotherapy, that is, EMACO regimen (etoposide, methotrexate actinomycin D on day
1 and cyclophosphamide and vincristine given on D8, respectively). β-HCG was similarly
monitored before every consecutive cycle. Chemotherapy was continued for three more
cycles after the normalization of β-HCG levels. High-dose methotrexate was added to
EMACO regimen for the patients with brain metastases.
Patients not responding in terms of serial decrement in β-HCG values with first-line
EMACO or relapse were treated with second-line EMAEP (etoposide, methotrexate, actinomycin
D given on day 1 and etoposide and cisplatin given on day 8, respectively) regimen.
After completion of treatment, patients were kept under regular follow-up with monitoring
of β-HCG levels every 3 months. Patients were also counseled on standard contraceptive
methods and the need for the same.
The response to treatment was standardized in the following manner—complete response
when β-HCG values have normalized for a period of 3 consecutive weeks, partial response
when more than 50% decline in β-HCG levels is noted concerning the baseline, and no
response when there is less than 50% decrease from the baseline. Progressive disease
is deemed when there is an increase in the size of any measurable lesion by at least
25% or the appearance of any new lesion on imaging and/or progressively increasing
β-HCG levels. Recurrence was defined as an increase in β-HCG levels after more than
three values in the normal range while excluding a confirmed pregnancy.
Statistics
The data were analyzed by SPSS Version 26 using appropriate statistical tools for
the parameters mentioned in the results.
Results
A total of 42 patients were diagnosed with GTN and evaluated further. Of these, 39
patients started treatment at our center and 38 completed the treatment and were included
in the analysis as shown in [Fig. 1]. The salient characteristics of these patients are provided in [Table 1].
Table 1
Clinical characteristics and treatment outcomes in GTN
|
Characteristics
|
Results in number (percentage)
|
|
Age (in years)
|
Median: 28 (range: 20–51)
|
|
Median follow-up
|
26 months (range: 8–42 months)
|
|
Baseline symptoms at presentation
|
|
Bleeding per vagina
Abdominal pain
Hemoptysis
Dyspnea
Headache
Seizure
|
25 (64.1%)
20 (51.3%)
4 (10.3%)
4 (10.3%)
1 (2.6%)
1 (2.6%)
|
|
Histopathological confirmation
|
8 (20.5%)
|
|
Antecedent pregnancy
|
|
Abortion
Mole
Term
|
23 (59%)
11 (28.2%)
5 (12.8%)
|
|
The interval from the last pregnancy
|
3.5 months (range: 1–8 months)
|
|
Baseline β-HCG in mIU/mL
|
90,000 (1300–6,52,318)
|
|
Tumor size (in cm) median (range)
|
3.3 cm (0–13)
|
|
Number of patients with distant metastasis
|
28 (71.8%)
|
|
Sites of metastasis
|
|
Lung
Brain
Omentum
Liver
Mediastinal node
|
22 (56.4%)
5 (12.8%)
8 (20.5%)
5 (12.8%)
10 (25.6%)
|
|
Number of metastases
|
4.4 (0–16)
|
|
Failed chemotherapy previously
|
None
|
|
FIGO stage
|
|
1
2
3
4
|
7
4
11
17
|
|
WHO risk score
|
8.5 (range: 3–15)
|
|
WHO risk category
|
|
Low risk
High risk
|
14 (35.9%)
25 (65.1%)
|
|
Chemotherapy protocol received at our center
|
|
Methotrexate
Actinomycin D
EMACO
EMAEP
HD methotrexate
|
11
1
29
2
5
|
|
The median number of cycles
|
8 (range: 3–16)
|
|
Response
|
|
Low risk
High risk
|
85.7%
87.5%
|
|
Toxicity
|
|
Grade 3 neutropenia
Grade 3 thrombocytopenia
Grade 3 oral mucositis
|
10 (26.3%)
5 (15.2%
2 (5.3%)
|
Abbreviations: EMACO, etoposide, methotrexate actinomycin D; EMAEP, etoposide methotrexate
and actinomycin D/ etoposide and cisplatin; FIGO, The International Federation of
Gynecology and Obstetrics; GTN, gestational trophoblastic neoplasia; β-HCG, β-human
chorionic gonadotrophin; HD, high-dose; WHO, World Health Organization.
Fig. 1 Scheme of the inclusion of patients with gestational trophoblastic neoplasia (GTN)
in the study.
The median age of patients diagnosed with GTN at our center is 28 years with the range
being from 20 to 51 years. The diagnosis was made only based on elevated β-HCG levels
and clinical history in 31 (79.4%) patients, while 8 (20.5%) patients had a histologically
proven diagnosis.
The most common symptom was bleeding per vagina in 25 patients (64.1%), while pain
abdomen was present in 20 (51.3%) patients. A few patients (4; 10.3%) presented with
hemoptysis, while headache and seizures were also present in one patient.
The majority of antecedent pregnancies were abortions, as reported in 23 (59%) patients,
while molar pregnancy and term pregnancy were recorded in 11 (28.2%) and 5 (12.8%)
cases, respectively. The median interval between pregnancy and the development of
GTN was 3.5 months (range: 1–8 months). The median β-HCG levels were 90203 IU/L (range:
1300–6,52,318 IU/mL).
Twenty-eight (71.8%) patients also had distant metastasis on presentation. The lung
was the most common site of distant metastasis reported in 22 (56.4%) patients. Other
sites of metastasis were mediastinal nodes, liver, and omentum. Brain metastases were
recorded in 5(12.8%) patients.
As per the WHO risk category, 14 (35.9%) patients were categorized as low risk, while
the remaining 25 (65.1%) patients came under the high-risk category. Overall, 11 (78.6%)
patients in the low-risk category were treated with single-agent methotrexate. One
patient was treated with single-agent actinomycin D and two were treated with the
EMACO regimen.
Twelve (85.7%) of these low-risk category patients attained complete response, while
two of them had no response and were later switched to the EMACO regimen to attain
complete response. Among the 25 high-risk category patients, 20 patients were treated
with EMACO regimen, while five patients who had brain metastases were treated with
EMACO + high-dose methotrexate regimen.
Twenty-one (87.5%) out of 24 of these high-risk category patients completed treatment
at our center and went into complete response at a median of eight cycles of chemotherapy.
Two among these had progression despite being on treatment, while one patient died
during the course of treatment.
Among the seven (17.9%) patients with brain and/or liver metastasis, three achieved
complete response, while two of them progressed on the first-line EMACO regimen and
were later treated with EMAEP with high-dose methotrexate regimen. The other treatment
nonresponding patient expired while on treatment.
Salvage Therapy
Out of 14 patients at low risk, two patients could not attain complete response and
were later treated with the EMACO regimen. Two patients in the high-risk group with
brain and/or liver metastases did not achieve complete response and were later treated
with EMAEP + high-dose methotrexate regimen. Both of them responded but one of them
expired later after defaulting on regular hospital follow-ups.
Toxicities
Chemotherapy was tolerated fairly well in all the patients. The most common toxicity
noted was neutropenia. Other notable toxicities reported were thrombocytopenia and
mucositis as shown in [Table 1].
Follow-Up
The median follow-up was 26 months. Median overall survival was not reached due to
low number of events. Two-year overall survival was 94.7% as shown in [Fig. 2].
Fig. 2 Overall survival curve.
Discussion
In our study, the major chunk of cases of GTN has occurred after pregnancies resulting
in abortion. In most of the other studies, the highest incidence had occurred after
molar pregnancies.[5] But, in another study from the eastern part of our country, abortions were the commonest
type of pregnancy preceding GTN.[6] We hypothesize that this may be due to the very high numbers of abortions performed
outside of appropriate healthcare facilities in India where there is a very high chance
of the diagnosis of molar pregnancy being missed.[7]
The percentage of patients with lung and brain and/or liver metastasis is similar
to that reported by Gulia et al that is the largest published database from our country.
The median β-HCG value in our study is 90,000 mIU/mL that is significantly higher
than this study probably as our study has a higher proportion of high-risk GTN patients.[5] Again, this may be due to different referral patterns or maybe because more patients
from our region come at a later stage. Also, variation in β-HCG levels may occur if
samples are tested without dilution at levels more than 1000 mIU/mL.[8]
In the patients with low-risk GTN, the response rate with single-agent methotrexate
or actinomycin-D is 85.7% with a small percentage of nonresponding patients achieving
complete response with the EMACO regimen. This is comparable to the figures reported
widely in literature.[9]
A recent study has tried to identify the risk factors for resistance to single-agent
chemotherapy among patients of low-risk GTN but with a score of 5 or 6.[10] They identified metastatic disease, choriocarcinoma, and pretreatment β-HCG levels
of more than 4,11,000 mIU/mL in those without metastasis and choriocarcinoma and levels
of more than 1,49,000 mIU/mL in those with metastasis or choriocarcinoma, respectively,
as identifiers for the same. Our study had only five patients with a WHO score of
5 or 6. But, none of them had any of these features predicting resistance to single-agent
chemotherapy, and all of them responded. This is in resonance with the findings of
the mentioned study. Thus, this group of patients represents a separate subgroup among
low-risk GTN and should be considered for initial combination chemotherapy when mentioned
features of resistance to single-agent chemotherapy are present.
In our patients with high-risk GTN, there was an 87.5% response rate to combination
chemotherapy. This is higher than other similar studies. A definite reason for the
same could not be established as the number of patients is relatively small.
Some of the factors that predict early death and poor response in high-risk GTN patients
include a WHO score of more than 12, brain and/or liver metastasis, and extensive
lung metastasis.[11] This seems to be an ultra-high-risk category among these patients. In our study,
out of the six patients with a WHO score of more than 12, four (66%) responded, while
one expired during treatment. Among those with brain and/or liver metastasis, only
57.1% out of the seven patients responded initially, while one patient expired. Although
the numbers are small, early deaths in these ultra-high-risk patients remain one of
the few unmet needs for this malignancy. Hence, the use of low-dose etoposide and
cisplatin in the first cycle as a prephase to reduce the disease burden and to avoid
the risk of early mortality as advocated by this study should be adapted.
The median follow-up of our patients was 26 months. Median overall survival and progression-free
survival were not reached due to the low number of events. This is as expected for
a highly curable malignancy.[5]
The toxicity profile was favorable. As most of the patients with these malignancies
are young, this is as expected and in tune with other studies.[6]
The limitation of our study is the small sample size and retrospective nature of the
study. However, this is true for all rare malignancies.
Conclusion
Our results of treatment for low- and high-risk category GTN patients align with other
available national and international studies. Low-risk GTN with scores of 5 and 6
and ultra-high-risk GTN patients represent subcategories needing further research
to improve treatment outcomes. This may be feasible by conducting multicenter studies
in our country to achieve results of significance.
