International Journal of Gynecology and Obstetrics 116 (2012) 39–42

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International Journal of Gynecology and Obstetrics

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CLINICAL ARTICLE

Comparison of pulsed actinomycin D versus 5-day methotrexate for the treatment of

low-risk gestational trophoblastic disease
Azamsadat Mousavi a, Fatemeh Cheraghi a,⁎, Fariba Yarandi b, Mitra Modaress Gilani a, Hadi Shojaei b
a
Department of Gynecological Oncology, Vali-e-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
b
Department of Gynecological Oncology, Mirza-Koochak-Khan Hospital, Tehran University of Medical Sciences, Tehran, Iran

a r t i c l e i n f o a b s t r a c t

Article history: Objective: To determine the effectiveness of 2 standard chemotherapy regimens for low-risk gestational tro-
Received 11 April 2011 phoblastic disease according to the International Federation of Gynecology and Obstetrics (FIGO) staging sys-
Received in revised form 29 July 2011 tem. Methods: From 2008 until 2010, 75 women with low-risk gestational trophoblastic disease received
Accepted 14 September 2011 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
Keywords:
complete remission rates were 90% for the actinomycin D group and 68% for the methotrexate group
Actinomycin D
Low-risk gestational trophoblastic disease
(P = 0.018). The mean number of chemotherapy courses administered to achieve complete remission (in-
Methotrexate cluding courses of second-line therapy) was 3.1 in the methotrexate group and 5.3 in the actinomycin D
group (P = 0.01). No major adverse effects were experienced in either treatment group and there were no
significant 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 treatment
for patients with low-risk gestational trophoblastic disease.
© 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction that approximately 25% of patients require second-line chemothera-

Gestational trophoblastic disease (GTD) is a proliferative neoplasia
of trophoblastic cells. It includes a spectrum of interrelated conditions
ranging from hydatidiform mole to choriocarcinoma. Gestational tro-
phoblastic disease is highly sensitive to chemotherapy and is recog-
nized as the most curable gynecologic malignancy [1].
The choice of an appropriate therapeutic regimen has an important
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 drugs
for the treatment of patients with low-risk GTD [2]. Many different
protocols and regimens have been proposed by the reference centers.
Methotrexate regimens include a 5-day regimen of intramuscular
methotrexate, an 8-day schedule of methotrexate and folinic acid res-
cue given on alternate days, and pulsed therapy [3,4]. Actinomycin D
can be used as a 5-day regimen or as a pulsed regimen [5,6]. Over
the years, the 5-day regimens of methotrexate and actinomycin D
have been replaced by pulsed regimens for reduced toxicity and
ease of administration [1,7,8].
Single-drug regimens as a standard regimen for low-risk GTD are
successful in approximately 60%–90% of patients [9], despite the fact
⁎ Corresponding author at: Department of Gynecological Oncology, Vali-e-Asr
Hospital, Bager-Khan St, Keshavarz Boulevard, PO Box 1417613151, Tehran, Iran.
Tel./fax: + 98 21 66909309.
E-mail address: dr_cheraghi@ajums.ac.ir (F. Cheraghi).
py because of resistance to the first-line drug or adverse effects
[1,3,5,10]. Most patients can be cured with multiple-agent chemo-
therapy; however; this regimen has significant toxicity [11].
Currently, there is no universal agreement regarding the selection
of the best regimen for patients with low-risk GTD. The present
study was undertaken to compare the efficacy of 2 standard chemo-
therapy regimens for this condition, namely 5-day methotrexate
and pulsed actinomycin D.
2. Materials and methods
The present study was conducted at Vali-e-Asr Hospital in Tehran,
Iran, from January 1, 2008, until December 31, 2010. It included patients
with a diagnosis of low-risk GTD according to the modified WHO prog-
nostic scoring system for gestational trophoblastic neoplasia as adapted
by the International Federation of Gynecology and Obstetrics (FIGO)
[12]. 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-
onic gonadotropin (β-hCG) level of more than 10% in the 3 weeks fol-
lowing termination of the last pregnancy or a β-hCG level plateau for
at least 4 consecutive weeks. Exclusion criteria were prior chemothera-
py and prior hysterectomy. Institutional Review Board approval for
the present study was obtained from the Tehran University of Medical
Sciences Committee on Human Research. Informed consent was
obtained from all patients.

0020-7292/$ – see front matter © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijgo.2011.08.003
40 A. Mousavi et al. / International Journal of Gynecology and Obstetrics 116 (2012) 39–42

Before the start of chemotherapy, all patients with persistent Table 2

trophoblastic disease were submitted to a complete physical exam- Number of treatment courses and treatment duration needed to achieve remission in
patients with low-risk gestational trophoblastic tumors a.
ination, determination of the blood cell count and serum β-hCG,
renal function tests, liver function tests, thoracic X-ray, and pelvic Efficacy measure Methotrexate Actinomycin D P value
and abdominal ultrasound. Computed tomography examination of (n = 25) (n = 50)

the thorax, abdomen, and brain were performed in the case of pelvic Mean duration of therapy in responding 43.5 ± 11.6 74.65 ± 28.3 0.004
or lung metastasis. patients, days
Mean number of courses in responding 3.1 ± 1.2 5.3 ± 1.7 0.01
The patients were randomized to receive an intramuscular injec-
patients
tion of 0.4 mg/kg methotrexate per day for 5 days or an intravenous
a
bolus of 1.25 mg/m 2 actinomycin D. Both chemotherapy regimens Values are given as mean ± SD.

were repeated every 2 weeks until normal β-hCG levels (less

than 5 IU/L) were obtained. Complete remission was confirmed if
the β-hCG levels were within the normal range for 3 consecutive
weeks 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; χ 2 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.
pleting 1 year of follow-up. 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
Group toxicity criteria [6]. 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. (P = 0.01; Table 2).
In a subgroup analysis, no significant differences between re-
3. Results sponders and nonresponders were found in terms of age, number of
days 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 (Table 3). 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 (Table 1). The preceding pregnancy was a molar preg-
nancy in 45 (90.0%) patients in the actinomycin group and 22 4. Discussion
(88.0%) patients in the methotrexate group. Two (4.0%) patients in
the 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 [13,14]. Matsui et al. reported a re-
Table 1 mission rate of 90% with etoposide, in contrast to rates of 73.6% and
Patient characteristics a. 84% with methotrexate and actinomycin D, respectively [13]. Howev-
Methotrexate Actinomycin D P value er, the high frequency of adverse effects—myelosuppression, gastro-
(n = 25) (n = 50) intestinal disturbances, alopecia, and an increased risk of a second
Age, y 25.2 ± 7.2 26.8 ± 4.6 0.48 neoplasia—associated with etoposide resulted in replacement of this
Preceding pregnancy agent with drugs such as methotrexate and actinomycin D as first-
Mole 22 (88.0) 45 (90.0) 0.17 line therapies in the treatment of low-risk GTD [14,15].
Abortion 2 (8.0) 1 (2.0) Various methotrexate and actinomycin D protocols for the
Ectopic pregnancy 0 (0.0) 2 (4.0)
treatment of low-risk GTD have been studied. In 3 randomized
Term pregnancy 1 (4.0) 2 (4.0)
Pretreatment β-hCG level clinical trials [16–18], the primary complete remission rates for
≤103 IU/L 16 (64.0) 29 (58.0) 0.33 pulsed methotrexate (49–53%) were significantly lower than
N103 IU/L 9 (36.0) 21 (42.0) those for pulsed actinomycin D (69–90%). Two retrospective stud-
Duration since index pregnancy
ies [19,20] compared 5-day intramuscular methotrexate with the
≤4 months 23 (92.0) 47 (94.0) 0.61
N4 months 2 (8.0) 3 (6.0) 8-day methotrexate–folinic acid regimen. In the study by Smith
Uterine mass 10 (40.0) 18 (36.0) 0.23 et al. [19], the response rate was 92% in methotrexate alone group
Lung metastasis 4 (16.0) 6 (12.0) 0.08 versus 72% in the methotrexate–folinic acid group. The remission
Abbreviations: β-hCG, beta-human chorionic gonadotropin. rate was 76% in the study by Wong et al. [20] and there was no sig-
a
Values are given as mean ± SD or number (percentage). nificant difference between 2 groups. In a randomized study [21]
 A. Mousavi et al. / International Journal of Gynecology and Obstetrics 116 (2012) 39–42
Table 3
Toxicity of pulsed actinomycin D and 5-day methotrexate a.
Adverse effect Methotrexate (n = 25)
Grade1 Grade2
Hematologic
Neutropenia 2 1
Thrombocytopenia 3 2
Hemoptysis 1 1
Gastrointestinal
Nausea 8 5
Vomiting 2 3
Diarrhea 4 2
Constipation 3 2
Anorexia 2 2
Dermatologic
Alopecia 3 1
Constitutional
Fatigue 12 5 0
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 complete
response rate was 100% in the actinomycin D group and 74% in the
methotrexate–folinic acid group.
Patients with low-risk GTD who were treated with 5-day regi-
mens of actinomycin D or methotrexate or with a combination of ac-
tinomycin D and methotrexate were analyzed in a retrospective study
by Abrão et al. [22]. There was no significant difference in the remis-
sion rates between these 3 groups (61.4%, 69%, and 79.1%, respective-
ly). The rates of adverse effects were 62.5% with the combination
therapy, 28.6% with 5-day methotrexate, and 19% with 5-day actino-
mycin D (P = 0.0003).
To our knowledge, no retrospective, prospective, or randomized
study has previously compared the efficacy of 5-day methotrexate
with that of pulsed actinomycin D. In the present study, the remission
rate with 5-day intramuscular methotrexate was only 68%, which is
lower than the rate reported in other studies [19,20,23]. However,
the response rate for first-line chemotherapy with pulsed actinomy-
cin D was 90%. The Gynecologic Oncology Group tested pulsed bi-
weekly actinomycin D in a prospective phase III trial [17] and
reported a complete remission rate of 73%, compared with a rate of
58% with pulsed weekly methotrexate. Biweekly intravenous actino-
mycin D was statistically superior to weekly intramuscular metho-
trexate. Kohorn et al. [24] reported a treatment failure rate of 20%
for patients treated with pulsed actinomycin D, in contrast to a failure
rate of 8% with 5-day actinomycin D.
The number of chemotherapy courses in the present study was
higher with pulsed actinomycin D than with the 5-day methotrexate
regimen (mean number of courses 6.3 versus 3.1). However, treat-
ment once every 14 days has obvious advantages such as cost savings
and convenience. According to other studies, the median number of
treatment courses required to achieve a complete response is 2–
8 with methotrexate [1] and 4 with actinomycin D [5,6,25].
In the present study, the most significant prognostic factor for
response to first-line chemotherapy was the pretreatment serum
β-hCG level. This result is similar to that reported by Yarandi et al.
[18] and Kwon et al. [26].
Although the present findings indicate that the efficacy of pulsed
actinomycin D for the treatment of low-risk GTD is higher than that
of 5-day methotrexate, a comparison with other regimens with larger
sample sizes is required to determine the optimal single-agent thera-
py. However, actinomycin D is the least toxic agent [17,22] and might
offer the best treatment option for patients with low-risk GTD.
Conflict of interest
The authors have no conflicts of interest.
41
Actinomycin D (n = 50)
Grade3 Grade4 Grade1 Grade2 Grade3 Grade4
0 0 2 1 0 0
0 0 2 2 0 0
0 0 2 0 0 0
0 0 14 8 0 0
0 0 4 3 0 0
0 0 3 5 0 0
0 0 5 2 0 0
0 0 3 2 0 0
0 0 4 2 0 0
0 23 8 0 0
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