Comparison of pulsed actinomycin d versus 5-day methotrexate for the treatment of low-risk gestational trophoblastic disease
International Journal of Gynecology and Obstetrics
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / i j g o
Comparison of pulsed actinomycin D versus 5-day methotrexate for the treatment of
low-risk gestational trophoblastic disease
Azamsadat Mousavi , Fatemeh Cheraghi ,Fariba Yarandi , Mitra Modaress Gilani Hadi Shojaei a Department of Gynecological Oncology, Vali-e-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iranb Department of Gynecological Oncology, Mirza-Koochak-Khan Hospital, Tehran University of Medical Sciences, Tehran, Iran
Objective: To determine the effectiveness of 2 standard chemotherapy regimens for low-risk gestational tro-
phoblastic disease according to the International Federation of Gynecology and Obstetrics (FIGO) staging sys-
tem. Methods: From 2008 until 2010, 75 women with low-risk gestational trophoblastic disease received
either pulsed actinomycin D (n = 50) or 5-day methotrexate (n = 25). The primary remission rate, the dura-tion of treatment, the number of treatment courses, and the adverse effects were compared. Results: The
complete remission rates were 90% for the actinomycin D group and 68% for the methotrexate group
(P = 0.018). The mean number of chemotherapy courses administered to achieve complete remission (in-
Low-risk gestational trophoblastic diseaseMethotrexate
cluding courses of second-line therapy) was 3.1 in the methotrexate group and 5.3 in the actinomycin Dgroup (P = 0.01). No major adverse effects were experienced in either treatment group and there were nosigniﬁcant differences in terms of adverse effects. Second-line chemotherapy was indicated for 11 patients. Conclusion: Based on the present study, pulsed actinomycin D seems to be an appropriate ﬁrst-line treatmentfor patients with low-risk gestational trophoblastic disease. 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
that approximately 25% of patients require second-line chemothera-py because of resistance to the ﬁrst-line drug or adverse effects
Gestational trophoblastic disease (GTD) is a proliferative neoplasia
Most patients can be cured with multiple-agent chemo-
of trophoblastic cells. It includes a spectrum of interrelated conditions
therapy; however; this regimen has signiﬁcant toxicity
ranging from hydatidiform mole to choriocarcinoma. Gestational tro-
Currently, there is no universal agreement regarding the selection
phoblastic disease is highly sensitive to chemotherapy and is recog-
of the best regimen for patients with low-risk GTD. The present
nized as the most curable gynecologic malignancy
study was undertaken to compare the efﬁcacy of 2 standard chemo-
The choice of an appropriate therapeutic regimen has an important
therapy regimens for this condition, namely 5-day methotrexate
role in the treatment of this disease. Single-agent chemotherapy is ac-
cepted as ﬁrst-line therapy for low-risk GTD. Since the early 1960s,methotrexate and actinomycin D have been used as the main drugsfor the treatment of patients with low-risk GTD Many different
protocols and regimens have been proposed by the reference centers. Methotrexate regimens include a 5-day regimen of intramuscular
The present study was conducted at Vali-e-Asr Hospital in Tehran,
methotrexate, an 8-day schedule of methotrexate and folinic acid res-
Iran, from January 1, 2008, until December 31, 2010. It included patients
cue given on alternate days, and pulsed therapy Actinomycin D
with a diagnosis of low-risk GTD according to the modiﬁed WHO prog-
can be used as a 5-day regimen or as a pulsed regimen Over
nostic scoring system for gestational trophoblastic neoplasia as adapted
the years, the 5-day regimens of methotrexate and actinomycin D
by the International Federation of Gynecology and Obstetrics (FIGO)
have been replaced by pulsed regimens for reduced toxicity and
. Other inclusion criteria were FIGO stage I, II, or III disease, a
WHO risk score of 6 or less, and a rise in the serum beta-human chori-
Single-drug regimens as a standard regimen for low-risk GTD are
onic gonadotropin (β-hCG) level of more than 10% in the 3 weeks fol-
successful in approximately 60%–90% of patients , despite the fact
lowing termination of the last pregnancy or a β-hCG level plateau forat least 4 consecutive weeks. Exclusion criteria were prior chemothera-py and prior hysterectomy. Institutional Review Board approval for
⁎ Corresponding author at: Department of Gynecological Oncology, Vali-e-Asr
the present study was obtained from the Tehran University of Medical
Hospital, Bager-Khan St, Keshavarz Boulevard, PO Box 1417613151, Tehran, Iran.
Sciences Committee on Human Research. Informed consent was
0020-7292/$ – see front matter 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:
A. Mousavi et al. / International Journal of Gynecology and Obstetrics 116 (2012) 39–42
Before the start of chemotherapy, all patients with persistent
trophoblastic disease were submitted to a complete physical exam-
Number of treatment courses and treatment duration needed to achieve remission inpatients with low-risk gestational trophoblastic tumors .
ination, determination of the blood cell count and serum β-hCG,renal function tests, liver function tests, thoracic X-ray, and pelvic
and abdominal ultrasound. Computed tomography examination of
the thorax, abdomen, and brain were performed in the case of pelvic
Mean duration of therapy in responding 43.5 ± 11.6
The patients were randomized to receive an intramuscular injec-
tion of 0.4 mg/kg methotrexate per day for 5 days or an intravenous
bolus of 1.25 mg/m2 actinomycin D. Both chemotherapy regimens
were repeated every 2 weeks until normal β-hCG levels (lessthan 5 IU/L) were obtained. Complete remission was conﬁrmed ifthe β-hCG levels were within the normal range for 3 consecutiveweeks and the patient was asymptomatic. After the initial normaliza-
patients in the methotrexate group; the difference was not signiﬁ-
tion of the serum β-hCG levels, 1 further course of chemotherapy was
cant (P = 0.08; χ2 test). None of the patients in either arm under-
given. Patients used an effective contraceptive method before com-
went hysterectomy as part of their ﬁrst-line treatment.
The overall remission rate after ﬁrst-line chemotherapy was 82.7%
Second-line chemotherapy was used in cases of nonresponse. The
(n = 62). The remission rate was 90.0% (n = 45) in the actinomycin D
criteria for nonresponse to ﬁrst-line chemotherapy were based on the
group and 68.0% (n = 17) in the methotrexate group (P = 0.018). All
weekly β-hCG titers (plateau or increasing levels for 2 consecutive
patients completed their ﬁrst-line chemotherapy.
weeks). Patients treated with a single agent who presented with re-
Overall, 11 (14.7%) ﬁrst-line treatment failures were observed; all
sistance were crossed over to the other single-agent regimen. Ad-
affected patients received a second-line therapy. Of the 8 (32.0%) pa-
verse effects were classiﬁed according to the Gynecologic Oncology
tients resistant to methotrexate, 6 (75.0%) patients responded to
treatment with actinomycin D and the 2 (25.0%) remaining patients
The outcome measures were the primary remission rate, other ef-
underwent multiple-agent chemotherapy. In the actinomycin D
ﬁcacy measures such as need for second-line chemotherapy and over-
group, resistance to the ﬁrst-line therapy was observed in 5 (10.0%)
all duration of treatment, and the toxicity in the 2 groups.
patients, all of whom switched to methotrexate.
The statistical analysis was performed using SPSS version 18.0
The mean number of chemotherapy courses administered to
(SPSS, Chicago, IL, USA). Comparisons were carried out by the
achieve a complete response (including courses of second-line therapy)
Mann–Whitney U test, the Fisher exact test, or the independent-
was 3.1 in the methotrexate group and 5.3 in the actinomycin D group
sample t test. P b 0.05 was considered statistically signiﬁcant.
In a subgroup analysis, no signiﬁcant differences between re-
sponders and nonresponders were found in terms of age, number ofdays from diagnosis to treatment, largest uterus size, and presence
Of 75 patients with low-risk GTD enrolled in the study, 50 were
of lung metastases. However, the pretreatment serum β-hCG concen-
randomized to receive pulsed actinomycin D and 25 to receive 5-
tration was lower among responders (P = 0.006).
day methotrexate. The 2 treatment groups were similar in terms of
There were no major adverse effects in the 2 treatment groups. The
patient age, number of days from diagnosis to treatment, pretreat-
most prevalent adverse effect was fatigue ). There were no sig-
ment concentration of serum β-hCG, and size and number of lung
niﬁcant differences between the 2 groups in terms of adverse effects.
metastases (. The preceding pregnancy was a molar preg-nancy in 45 (90.0%) patients in the actinomycin group and 22
(88.0%) patients in the methotrexate group. Two (4.0%) patients inthe actinomycin D group and 1 (2.0%) patient in the methotrexate
Several different regimens and protocols for the treatment of low-
group had a term pregnancy. Pulmonary metastasis was present in
risk GTD have been reported; however, the best protocol for this con-
6 (12.0%) patients in the actinomycin D group and in 4 (16.0%)
dition remains to be determined because of the challenge of balan-cing effectiveness, toxicity, and patient convenience and preference.
Etoposide (VP16) is the most effective single-agent cytotoxic drug
in the treatment of low-risk GTD . Matsui et al. reported a re-
mission rate of 90% with etoposide, in contrast to rates of 73.6% and
84% with methotrexate and actinomycin D, respectively . Howev-er, the high frequency of adverse effects
intestinal disturbances, alopecia, and an increased risk of a secondneoplasia—associated with etoposide resulted in replacement of this
agent with drugs such as methotrexate and actinomycin D as ﬁrst-
line therapies in the treatment of low-risk GTD
Various methotrexate and actinomycin D protocols for the
treatment of low-risk GTD have been studied. In 3 randomized
, the primary complete remission rates for
pulsed methotrexate (49–53%) were signiﬁcantly lower than
those for pulsed actinomycin D (69–90%). Two retrospective stud-
ies compared 5-day intramuscular methotrexate with the
8-day methotrexate–folinic acid regimen. In the study by Smith
et al. the response rate was 92% in methotrexate alone group
versus 72% in the methotrexate–folinic acid group. The remissionrate was 76% in the study by Wong et al. and there was no sig-
Abbreviations: β-hCG, beta-human chorionic gonadotropin.
a Values are given as mean± SD or number (percentage).
niﬁcant difference between 2 groups. In a randomized study
A. Mousavi et al. / International Journal of Gynecology and Obstetrics 116 (2012) 39–42
Table 3Toxicity of pulsed actinomycin D and 5-day methotrexate .
a Gynecologic Oncology Group grading system.
that compared 5-day actinomycin D with 8-day methotrexate–
folinic acid for the treatment of non-metastatic GTD, the completeresponse rate was 100% in the actinomycin D group and 74% in the
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The authors have no conﬂicts of interest.
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