ORIGINAL STUDY

Five-Day Intravascular Methotrexate Versus Biweekly

Actinomycin-D in the Treatment of Low-Risk
Gestational Trophoblastic Neoplasia
A Clinical Randomized Trial
Fariba Yarandi, MD,* Azamsadat Mousavi, MD,Þ Fereshteh Abbaslu, MD,*
Soheila Aminimoghaddam, MD,* Sepideh Nekuie, MD,* Khadijeh Adabi, MD,*
and Parviz Hanjani, MDþ

Objectives: Methotrexate (MTX) and Actinomycin-D (Act-D) are effective drugs used in the
treatment of low-risk gestational trophoblastic neoplasia (LRGTNs). The aim of the present
study was to compare intravenous (IV) MTX and IV Act-D in the treatment of LRGTNs.
Materials and Methods: Sixty-two patients with LRGTN were enrolled in a prospective
randomized clinical trial between 2010 and 2013 in Moheb e Yas Hospital, Tehran Uni-
versity of Medical Sciences. Primary treatment regimens were IV MTX, 0.4 mg/kg daily for
5 days every 14 days (25 mg maximum daily dose), and IV Act-D, 1.25 mg/m2 (2 mg
maximum dose) every 14 days.
Results: Thirty-two and 30 patients were enrolled to MTX and Act-D groups, respectively.
Complete remission after receiving first-line chemotherapy was achieved in 79% of all
cases, 80% in the Act-D group and 78.1% in the MTX group.
Twenty percent of the Act-D patients and 21.9% of the MTX patients showed resistance to
the first-line chemotherapy, of which 16.7% and 15.6% responded completely to the second-
line monotherapy, respectively. Multiple drug therapy was needed in 3.3% of the Act-D
group and 6.3% of the MTX group.
We did not find any correlation between treatment response and betaYhuman chorionic
gonadotropin level, uterine mass size, lung metastasis, antecedent pregnancy, and duration from
diagnosis to treatment. Adverse effects were not statistically different between the 2 groups.
Conclusions: Single-agent chemotherapy in the treatment of LRGTNs resulted in an
overall complete remission rate of 79%, 80% in the Act-D group and 78.1% in MTX group,
with no statistically significant difference. Whereas this study represents an important step
in comparing single-agent treatments, comparison of other regimens will be required to
determine the optimal single-agent therapy.
Key Words: Single-agent chemotherapy, Methotrexate, Actinomycin-D, Low-risk
gestational trophoblastic neoplasia

Received November 2, 2015, and in revised form December 27, 2015.

Accepted for publication January 17, 2016.
(Int J Gynecol Cancer 2016;26: 971Y976)

*Department of Gynecological Oncology, Moheb Yas Women
General Hospital, Tehran University of Medical Sciences, †Department
of Gynecological Oncology, Vali-e-Asr Hospital, Tehran University of
Copyright * 2016 by IGCS and ESGO
ISSN: 1048-891X
DOI: 10.1097/IGC.0000000000000687
Medical Sciences, Tehran, Iran; ‡Rosenfeld Cancer Center, Abington
Memorial Hospital, Abington, Pennsylvania.
Address correspondence and reprint requests to Khadijeh Adabi,
Moheb Yas Women General Hospital, North Ostad Nejatolahi
Avenue, Karim Khan Street, Tehran, Iran, Postcode 1598718311.
E-mail: khadabi@yahoo.com.
The authors received no funding for this work.
The authors declare no conflicts of interest.

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Yarandi et al International Journal of Gynecological Cancer
G estational trophoblastic neoplasms (GTNs) are relatively
infrequent and highly curable lesions even in the presence
of widespread metastases.1 According to the International
Federation of Gynecology and Obstetrics (FIGO) criteria, low-
risk GTN (LRGTN) is defined as both nonmetastatic (stage I)
and metastatic (stages II and III, score G7) GTNs.2
The treatment of choice in patients with LRGTN is
currently a matter of debate. Moreover, the treatment of
choice depends on various factors, most importantly the pa-
tient’s desire to preserve fertility. Methotrexate (MTX) and
actinomycin-D (Act-D) are effective drugs used widely in the
treatment of LRGTNs when fertility preservation is desired.
However, other chemotherapy regimens are also being used
worldwide at the moment. Some of these regimens are as
follows: daily intramuscular (IM) MTX injection over a
course of 5 days every other week, daily IV MTX injection
over a course of 5 days every other week, IM or IV MTX
weekly, pulse regimen of Act-D, IV Act-D every other week,
daily (IV) Act-D over 5 days every other week, and even
combination therapy. Unfortunately, no single best regimen
has yet been identified.3,4
As mentioned earlier, the aim of the present study was
to compare the efficacy of IV MTX , 0.4 mg/kg daily for 5 days
every 14 days, and IV Act-D , 1.25 mg/m2 every 14 days, in the
treatment of LRGTNs.
MATERIALS AND METHODS
Sixty-two patients with LRGTN were enrolled in a
prospective randomized clinical trial between 2010 and 2013
in Moheb e Yas Hospital affiliated to the Tehran University
of Medical Sciences. All patients signed written informed
consent. The study was approved by the ethical committee of
the faculty of medicine.
Low-risk GTN, invasive mole, and choriocarcinoma
diagnosed according to histologic and clinical criteria were
enrolled in the study. However, placental site tumors and
epithelioid trophoblastic tumors were excluded.
Inclusion Criteria
The inclusion criteria were as follows:
1. Postmolar GTN after a plateau level of betaYhuman
chorionic gonadotropin (A-hCG) for 4 consecutive tests
over 3 weeks at least more than 50 mIU/mL or a sustained
rise in A-hCG for more than 20% for 3 consecutive tests
over 2 weeks, at least more than 50 mIU/mL, or persistent
elevated level of A-hCG 6 months after molar evacuation
at least more than 50 mIU/mL.
2. Histopathologic diagnosis of nonmetastatic choriocarci-
noma, or presence of metastatic disease restricted to va-
gina, parametrium, or lung.
3. All patients were staged according to the FIGO 2002
scoring system.2 International Federation of Gynecology
and Obstetrics stages I, II, and III with WHO score 0 to 6
were enrolled in the study.
4. Laboratory test results within normal range including:
White blood cell count greater than 3000 cells/KL,
absolute neutrophil count greater than 1500 cells/KL, platelet
972
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& Volume 26, Number 5, June 2016
count greater than 100,000 cells/KL, a serum creatinine level
of 2 mg/dL or less, serum bilirubin level of less than 1.5 times
more than institutional normal, aspartate aminotransferase
and alanine aminotransferase less than or equal to 3 times
more than institutional normal.
5. Patients aged 18 and older.
Data including age, clinicopathologic diagnosis, ante-
cedent pregnancy, time from diagnosis to treatment, pretreat-
ment A-hCG level, and adverse effects were collected.
A sample size of 22 patients was calculated according
to reference,5 considering the power of 80% and type I error
of 0.05.
Eligible patients were allocated between assigned treat-
ment regimens using stratified block randomization. The per-
son responsible for random allocation was unaware of the
treatment assignments, and neither the treating physician nor
the patients were blind to the assigned treatment. Treatment
regimens were IV MTX, 0.4 mg/kg daily for 5 days every 14 days
(25 mg maximum daily dose), and IVAct-D, 1.25 mg/m2 (2 mg
maximum dose) every 14 days.
In case of failed single-agent chemotherapy, combina-
tion regimen including etoposide, MTX, Act-D, cyclophos-
phamide, and vincristine (EMA-CO) was considered.
The patients were followed during the treatment course
by physical examination, complete blood counts, blood chem-
istry profile, and A-hCG levels on the first day of each course.
Treatment response was determined by decrease in
A-hCG level. Complete response was diagnosed when 3 con-
secutive weekly A-hCG levels were within the reference range,
less than 5 mIU/mL, for a minimum period of 4 weeks.
Persistent disease was defined as 4 consecutive A-hCG
levels over 6 weeks that fluctuate within the range of 5 to
50 mIU/mL after ruling out phantom A-hCG and quies-
cence A-hCG.
Treatment failure was defined as a decrease in A-hCG
titer less than 10% for 4 times or an increase of more than
20% for 3 times measured during at least 2 weeks.
Two A-hCG levels of more than 5 after reaching a normal
A-hCG level, A-hCG level of more than 5 after 13 chemotherapy
cycles, and recent metastasis or new clinical and radiological
findings were also considered as failure of treatment.
Three additional courses of chemotherapy were given
after the first normal A-hCG level.
Treatment was terminated in the presence of any evi-
dence of treatment failure, biologic progression, disease
progression, or unacceptable toxicity despite dose modifi-
cation. Patients were treated for a maximum of 13 cycles if the
A-hCG levels remained elevated (95 mIU/mL). Follow-up
after normalization of A-hCG levels (G5 mIU/mL) consisted
of monthly checking of A-hCG level for 1 year beginning on the
first day of last chemotherapy cycle.
Use of contraception, preferably oral contraceptive
pills, was advised to all patients to prevent pregnancy. High-
dose folic acid supplementation was discontinued during
study. Use of sunscreen was advised to all patients to prevent
skin reactions due to sun exposure.
Toxicity was graded according to the Common Toxicity
Criteria, version 2.0. If any toxicity including pleuritis, stomatitis,
hematologic (myelosuppression), gastrointestinal, renal, or
* 2016 IGCS and ESGO
International Journal of Gynecological Cancer & Volume 26, Number 5, June 2016 MTX, Act-D in GTN management

TABLE 1. Demographic data of the patients and results

MTX Group Act-D Group P
Age, mean T SD 27.46 T 6.82 26.83 T 5.55 90.05
Antecedent pregnancy
Mole 28 (87.5%) 29 (96.7%) 90.05
Abortion 3 (9.4%) 1 (3.3%) 90.05
Unknown 1 (3.1%) 0 90.05
Treatment started within 4 months 25 (90.6%) 27 (90%) 90.05
No. courses 6.40 T 2.3 7.16 T 2.1 90.05
Cost of treatment, $ 358.12 T 109.43 159.3 T 81.7 0.000
Lung metastasis present 3 1 90.05
Uterine mass present
No 15 (46.9%) 17 (56.7%) 90.05
G3 cm 11 (34.4%) 8 (26.7%) 90.05
3Y5 cm 6 (18.8%) 4 (13.3%) 90.05
95 cm 0 1 (3.3%) 90.05
Cure 25 (78.1%) 24 (80%) 90.05
Resistant single drug 5 (15.6%) 5 (16.7%) 90.05
Resistant multiple drug 2 (6.3%) 1 (3.3%) 90.05
Pretreatment beta 9 10,000 26 (85.7%) 20 (69%) 90.05

hepatic problems occurred, the dosage was modified in all cases, 80% of the Act-D group and 78.1% of the MTX
2 levels or discontinued according to the grade of toxicity. group (P = 0.86).
Dose modification was done for an initial dose of 1.25 mg/m2 Twenty percent of the Act-D patients and 21.9% of
of Act-D to the first level reduction dose of 1.0 mg/m2 and MTX patients showed resistance to the first chemotherapy;
second level reduction dose of 0.75 mg/m2. For IV MTX 16.7% and 15.6%, respectively, responded to the second-line
initial dose of 0.4 mg/kg for 5 days, first level reduction was monotherapy. Multiple-drug therapy was required in 3.3% of
treatment for 4 days and second level was for 3 days. the Act-D group and 6.3% of MTX group (P = 0.86).
In the presence of grade 3 or 4 toxicity, despite dose Regarding the number of chemotherapy courses, the
modification, treatment was switched to another single- 2 groups were statistically the same, with a mean of 7.16 for
agent regimen. Act-D and 6.4 for MTX.
The efficacy of each chemotherapy regimen was eval- Moreover, considering the 5-day course of MTX and
uated according to the need of second-line chemotherapy 1-day course of Act-D therapy, cost of chemotherapy was
(W2 test), the number of cycles leading to remission (Kruskal- higher in the MTX group (P = 0.001).
Wallis test), and the overall duration of the treatment (one-way Adverse effects are shown in Table 2.
analysis of variance test). The overall outcome and compar-
ison of the toxic effects were also analyzed. The level of
statistical significance was P G 0.05.
TABLE 2. Adverse effects in MTX and Act-D study group
RESULTS Adverse Effects MTX Act-D
A total of 62 patients were enrolled in this study, 32
in the MTX group and 30 in the Act-D group. Allocation Nausea 1 (3.12%) 11 (36.66%)
concealment algorithm is presented in algorithm 1. Demo- Vomiting 1 (3.12%) 4 (13.33%)
graphic data and other characteristics of the patients are Alopecia 2 (6.25%) 3 (10%)
shown in Table 1. A total of 52 patients (91.2%) have received
Stomatitis 12 (37.5%) 2 (6.66%)
chemotherapy within 4 months of their pregnancy.
A total of 32 patients (51.2%) had no uterine mass: Neutropenia 2 (6.25%) 0
17 patients (56.7%) in the Act-D group and 15 patients (46.9%) Hepatic toxicity 3 (9.37%) 1 (3.33%)
in the MTX group. A-hCG titer of more than 10,000 before Phlebitis 4 (12.5%) 0
therapy initiation was present in 69% of the Act-D group and Ophthalmic 2 (6.25%) 0
85.7% of the MTX group. Complete remission after re- Anorexia 0 4 (13.33%)
ceiving first-line chemotherapy was achieved in 79% of

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Yarandi et al International Journal of Gynecological Cancer & Volume 26, Number 5, June 2016

TABLE 3. Comparison of demographic data based on response to first-line chemotherapy

Response Failure P
hCG 9 10,000 36 (78.3%) 10 (21.7%) 90.05
Mass 90.05
No 25 (78.1%) 7 (21.9%)
G3 14 (73.37%) 5 (26.3%)
3Y5 9 (90%) 1 (10%)
95 1 (100%) 0
Lung metastasis present 4 (100%) 0 90.05
Treatment started after 4 months 3 (50%) 3 (50%) 90.05
Antecedent pregnancy 90.05
Mole 44 (77.2%) 13 (22.8%)
Abortion 4 (100%) 0
Unknown 1 (100%) 0

Two patients in the MTX group showed symptoms of
grade 3 stomatitis despite dose modification, and therefore,
their therapy was switched to alternative single-agent regimen.
Algorithm 1: allocation concealment
There was no difference in A-hCG level, uterine mass
size, lung metastasis, antecedent pregnancy, or the duration
from diagnosis to treatment in patients who responded to first-
line chemotherapy (Table 3).
DISCUSSION
Gestational trophoblastic neoplasms are rare tumors
that can be treated completely even in the presence of me-
tastases. These tumors mostly develop after molar pregnan-
cies, although they can follow any antecedent pregnancy.1,6
Diagnostic criteria and an anatomic staging for postmolar
GTN and modification of the risk-factor scoring system of the
World Health Organization (WHO) was publicized by the In-
ternational Federation of Gynecology and Obstetrics (FIGO) in
2002. According to these criteria, LRGTNs are defined as
patients with nonmetastatic (stage I) and metastatic (stages II
and III; score G7) GTN who could be treated with single-agent
chemotherapy with survival rates of approximately 100%.2
The primary treatment of LRGTNs greatly depends on
the patient’s desire to preserve fertility. When preserving
fertility is not desired, hysterectomy may be the first choice,
with one course of adjuvant single-agent chemotherapy for
treating possible metastases.
For those who like to preserve their fertility, single-
agent chemotherapy is the treatment of choice.1,7,8
Although several effective single-drug chemotherapy
protocols are available, the best regimen is not yet identified.
Some retrospective studies on protocols of MTX and Act-D in
LRGTNs have shown comparable results.2,8
Along with treatment effectiveness, other factors includ-
ing cost, ease of administration, toxicity, patient’s preference/
compliance and exposure to multidrug second-line regimens
should be taken into consideration when making the decision
for treatment.2,9
Patients who are resistant to single-agent chemotherapy
usually achieve remission by combination chemotherapy with
either MAC (MTX, Act-D, and cyclophosphamide) or EMACO
(etoposide, MTX, Act-D, cyclophosphamide, and oncovin).

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International Journal of Gynecological Cancer & Volume 26, Number 5, June 2016
If the disease is resistant to both single-agent and multiagent
therapies, hysterectomy may be considered.1,10
We have used the EMACO regimen as the second-
line therapy in our study and achieved complete remis-
sion in 97.2% of cases. Chapman-Davis et al used MAC and
cyclophosphamide, hydroxyurea, actinomycin-D, methotrex-
ate, vincristine, and doxorubicin) or EMA-CO (etoposide,
methotrexate, actinomycin-D, cyclophosphamide, and vin-
cristine) in patients resistant to single-agent and achieved
complete remission with or without surgery in all patients.2
In this series of 62 patients, we found a complete re-
sponse rate of 78.1% to chemotherapy with MTX and 80% to
chemotherapy with Act-D. A study by Lurain et al11 on patients
with nonmetastatic GTN who were undergoing chemotherapy
with 5-day single-agent IV MTX between 1962 and 1990
showed a cure rate of 89%, with 2% requiring multiagent
chemotherapy or surgery. In another study on 385 patients
between 1979 and 2009, a complete response rate of 81% to
initial single-agent 5-day IV MTX was reported.4
In a study on Act-D as first-line therapy, published in
2006, Covens et al12 observed a response rate of 74%; and in
another study published in 2011, Osborne et al3 reported a
cure rate of 70% compared to 80% in our study.
The remission rate for available single-drug chemo-
therapy protocols according to the literature can be summa-
rized as following: 60% to 89% for daily intramuscular (IM)
MTX injection over a course of 5 days every other week13,
81% to 89% for daily IV MTX injection over a course of
5 days every other week,2,11 74% to 81% for IM or IV MTX
weekly,14Y16 78% for pulse regimen of Act-D,17 70% to 94%
for IVAct-D every other week,3,18 60% to 100% for daily (IV)
Act-D over 5 days every other week.4,19
We could not find any study comparing 5-day IV MTX
with IM MTX. We had previously reported our experience
treating both nonmetastatic and low-risk metastatic GTNs
with initial single-agent chemotherapy using weekly IM MTX
or Act-D IV every other week.5 The results showed complete
remission rate of 90% for the pulse actinomycin-D group and
68% for the IM MTX group5 compared with 78.1% with IV
MTX and 80% with IV Act-D in current study.
In the study of Chapman-Davis et al, older patients’
age, higher pre treatment A-hCG levels, nonmolar antecedent
pregnancy, choriocarcinoma in preceding pregnancy, pres-
ence of metastases, and high FIGO score have been reported
to be significantly associated with an increased risk of initial
chemotherapy resistance.2 However, we did not find any
correlation between treatment response and A-hCG level,
uterine mass size, lung metastasis, antecedent pregnancy, and
duration from diagnosis to treatment.
In the study of Osborn et al, normalization of A-hCG
levels in both Act-D- and MTX-treated patients were achieved
within 8 weeks, although the Act-D group required half the
number of treatment cycles.3 This period in our study was almost
14 weeks. This may be because in their study, only 35% of
patients had a A-hCG level of more than 10,000 before treat-
ment initiation, whereas 74.1% of our patients had this level
before treatment.
In some studies, it is stated that Act-D has more adverse
effects like nausea, alopecia, and local tissue injury due to
* 2016 IGCS and ESGO
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MTX, Act-D in GTN management
extravasation from the vein, compared to MTX, of which sto-
matitis is the major adverse effect. Therefore, it is preferred to
start the treatment with MTX, reserving actinomycin D for cases
resistant to MTX or those in whom MTX is contraindicated.2
In 1975, Osathanondh et al20 stated that owing to alo-
pecia and nausea in 5-day parenteral Act- D, it is an unfa-
vorable regimen. In our study, we have shown that although
nausea and vomiting are considerably greater in the Act-D
group, alopecia is as frequent as it is in the MTX group.
Osborn et al3 also claimed that alopecia was not significant
among their patients receiving Act-D.
Intravenous administration of MTX likely results less
toxicity than administering it intramuscularly for 5 consecu-
tive days.2 In our study, we could not find any significant
difference in systemic toxicity among the 2 groups of IV
MTX and Act-D. In another study in our center, systemic
toxicities of IM MTX and Act-D were not significantly dif-
ferent between the 2 groups as well.5
In a study by Chapman-Davis et al,2 5% of patients
treated with MTX had to receive another chemotherapy regi-
men owing to toxicity. In our study, 6.25% of MTX-treated
patients had to have their treatment changed to an alternative
regimen owing to grade 3 stomatitis. According to the literature,
up to 10% of patients receiving 5-day and 8-day MTX regimens
may require a change in therapy owing to adverse effects.3
In a study, Covens et al12 treated nonmetastatic GTNs
with pulse Act-D (1.25 mg/m2 IV every 2 weeks). Although
10% showed grade 3 or 4 neutropenia, 5% experienced grade
3 nausea and vomiting, and 2.5% had grade 3 toxicity from
drug extravasation, they did not discontinue therapy in any
patients owing to toxicity.12
In another study by Osborne et al, grades 1 and 2 gas-
trointestinal toxicities due to Act-D, higher grades of neurologic
adverse effects (higher than 1), and grade 2 stomatitis due to
MTX were observed.3
Adverse effects were not statistically different between
MTX and actinomycin D in our study.
CONCLUSION
As a direct result, we found that complete remission rate
after receiving first-line chemotherapy was 79% in all cases,
80% in the Act-D group, and 78.1% in the MTX group, with
no statistically significant difference. Although this study
represents an important step in comparing single-agent treat-
ments, comparison of other regimens will be required to de-
termine the optimal single-agent chemotherapy.
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