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.
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
 Foulmann K, Guastalla JP, Caminet N, Trillet-Lenoir V, Raudrant D, Golﬁer F, et al.
What is the best protocol of single-agent methotrexate chemotherapy in nonme-
tastatic or low-risk metastatic gestational trophoblastic tumors? A review of the
Patients with low-risk GTD who were treated with 5-day regi-
evidence. Gynecol Oncol 2006;102(1):103–10.
mens of actinomycin D or methotrexate or with a combination of ac-
 Ross GT, Stolbach LL, Hertz R. Actinomycin D in the treatment of methotrexate-
tinomycin D and methotrexate were analyzed in a retrospective study
resistant trophoblastic disease in women. Cancer Res 1962;22:1015–7.
 Osborne R, Gerulath A. What is the best regimen for low-risk gestational tropho-
by Abrão et al. . There was no signiﬁcant difference in the remis-
blastic neoplasia? A review. J Reprod Med 2004;49(8):602–16.
sion rates between these 3 groups (61.4%, 69%, and 79.1%, respective-
 Garrett AP, Garner EO, Goldstein DP, Berkowitz RS. Methotrexate infusion and foli-
ly). The rates of adverse effects were 62.5% with the combination
nic acid as primary therapy for nonmetastatic and low-risk metastatic gestationaltrophoblastic tumors. 15 years of experience. J Reprod Med 2002;47(5):355–62.
therapy, 28.6% with 5-day methotrexate, and 19% with 5-day actino-
 Ross GT, Goldstein DP, Hertz R, Lipsett MB, Odell WD. Sequential use of metho-
trexate and actinomycin D in the treatment of metastatic choriocarcinoma and re-
To our knowledge, no retrospective, prospective, or randomized
lated trophoblastic diseases in women. Am J Obstet Gynecol 1965;93:223–9.
 Petrilli ES, Twiggs LB, Blessing JA, Teng NH, Curry S. Single-dose actinomycin-D
study has previously compared the efﬁcacy of 5-day methotrexate
treatment for nonmetastatic gestational trophoblastic disease. A prospective
with that of pulsed actinomycin D. In the present study, the remission
phase II trial of the Gynecologic Oncology Group. Cancer 1987;60(9):2173–6.
rate with 5-day intramuscular methotrexate was only 68%, which is
 Chen LM, Lengyel ER, Bethan Powell C. Single-agent pulse dactinomycin has only
modest activity for methotrexate-resistant gestational trophoblastic neoplasia.
lower than the rate reported in other studies . However,
the response rate for ﬁrst-line chemotherapy with pulsed actinomy-
 Matsui H, Suzuka K, Yamazawa K, Tanaka N, Mitsuhashi A, Seki K, et al. Relapse
cin D was 90%. The Gynecologic Oncology Group tested pulsed bi-
rate of patients with low-risk gestational trophoblastic tumor initially treatedwith single-agent chemotherapy. Gynecol Oncol 2005;96(3):616–20.
weekly actinomycin D in a prospective phase III trial and
 Carney ME. Treatment of low risk gestational trophoblastic disease. Clin Obstet
reported a complete remission rate of 73%, compared with a rate of
58% with pulsed weekly methotrexate. Biweekly intravenous actino-
 Matsui H, Suzuka K, Iitsuka Y, Seki K, Sekiya S. Combination chemotherapy with
mycin D was statistically superior to weekly intramuscular metho-
methotrexate, etoposide, and actinomycin D for high-risk gestational trophoblas-tic tumors. Gynecol Oncol 2000;78(1):28–31.
trexate. Kohorn et al. reported a treatment failure rate of 20%
 Rose PG, Piver MS. Alternating methotrexate and dactinomycin in nonmetastatic
for patients treated with pulsed actinomycin D, in contrast to a failure
gestational trophoblastic disease. J Surg Oncol 1989;41(3):148–52.
rate of 8% with 5-day actinomycin D.
 Oncology FIGO. Committee. FIGO staging for gestational trophoblastic neoplasia
2000. FIGO Oncology Committee. Int J Gynaecol Obstet 2002;77(3):285–7.
The number of chemotherapy courses in the present study was
 Matsui H, Iitsuka Y, Seki K, Sekiya S. Comparison of chemotherapies with metho-
higher with pulsed actinomycin D than with the 5-day methotrexate
trexate, VP-16 and actinomycin-D in low-risk gestational trophoblastic disease.
regimen (mean number of courses 6.3 versus 3.1). However, treat-
Remission rates and drug toxicities. Gynecol Obstet Invest 1998;46(1):5–8.
 Wong LC, Choo YC, Ma HK. Primary oral etoposide therapy in gestational tropho-
ment once every 14 days has obvious advantages such as cost savings
blastic disease. An update. Cancer 1986;58(1):14–7.
and convenience. According to other studies, the median number of
 Rustin GJ, Newlands ES, Lutz JM, Holden L, Bagshawe KD, Hiscox JG, et al. Combina-
treatment courses required to achieve a complete response is 2–
tion but not single-agent methotrexate chemotherapy for gestational trophoblastictumors increases the incidence of second tumors. J Clin Oncol 1996;14(10):2769–73.
8 with methotrexate and 4 with actinomycin D
 Gilani MM, Yarandi F, Eftekhar Z, Hanjani P. Comparison of pulse methotrexate
In the present study, the most signiﬁcant prognostic factor for
and pulse dactinomycin in the treatment of low-risk gestational trophoblastic
response to ﬁrst-line chemotherapy was the pretreatment serum
neoplasia. Aust N Z J Obstet Gynaecol 2005;45(2):161–4.
 Osborne RJ, Filiaci V, Schink JC, Mannel RS, Alvarez Secord RS, Kelley JL, et al.
-hCG level. This result is similar to that reported by Yarandi et al.
Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gesta-
tional trophoblastic neoplasia: a gynecologic oncology group study. J Clin Oncol
Although the present ﬁndings indicate that the efﬁcacy of pulsed
actinomycin D for the treatment of low-risk GTD is higher than that
 Yarandi F, Eftekhar Z, Shojaei H, Kanani S, Shariﬁ A, Hanjani P. Pulse methotrexate
versus pulse actinomycin D in the treatment of low-risk gestational trophoblastic
of 5-day methotrexate, a comparison with other regimens with larger
neoplasia. Int J Gynaecol Obstet 2008;103(1):33–7.
sample sizes is required to determine the optimal single-agent thera-
 Smith EB, Weed Jr JC, Tyrey L, Hammond CB. Treatment of nonmetastatic gesta-
py. However, actinomycin D is the least toxic agent and might
tional trophoblastic disease: results of methotrexate alone versus methotrexate—folinic acid. Am J Obstet Gynecol 1982;144(1):88–92.
offer the best treatment option for patients with low-risk GTD.
 Wong LC, Choo YC, Ma HK. Methotrexate with citrovorum factor rescue in gesta-
tional trophoblastic disease. Am J Obstet Gynecol 1985;152(1):59–62.
 Lertkhachonsuk AA, Israngura N, Wilailak S, Tangtrakul S. Actinomycin d versus
methotrexate-folinic acid as the treatment of stage I, low-risk gestational tropho-blastic neoplasia: a randomized controlled trial. Int J Gynecol Cancer 2009;19(5):
The authors have no conﬂicts of interest.
A. Mousavi et al. / International Journal of Gynecology and Obstetrics 116 (2012) 39–42
 Abrão RA, de Andrade JM, Tiezzi DG, Marana HR. Candido dos Reis FJ, Clagnan WS.
 Petrilli ES, Morrow CP. Actinomycin D toxicity in the treatment of trophoblastic dis-
Treatment for low-risk gestational trophoblastic disease: comparison of single-
ease: a comparison of the ﬁve-day course to single-dose administration. Gynecol
agent methotrexate, dactinomycin and combination regimens. Gynecol Oncol
 Kwon JS, Elit L, Mazurka J, Moens F, Schmuck ML. Weekly intravenous methotrexate
 Hammond CB, Hertz R, Ross GT, Lipsett MB, Odell WD. Primary chemotherapy
with folinic acid for nonmetastatic gestational trophoblastic neoplasia. Gynecol
for nonmetastatic gestational trophoblastic neoplasms. Am J Obstet Gynecol
 Kohorn EI. Single-agent chemotherapy for nonmetastatic gestational trophoblas-
tic neoplasia. Perspectives for the 21st century after three decades of use. J ReprodMed 1991;36(1):49–55.
Erythema Multiforme and Stevens-Johnson Syndrome What are erythema multiforme and Stevens-Johnson syndrome? Erythema multiforme (E. multiforme) is a rash that can range from spots to sores. When severe, the condition is called Stevens-Johnson syndrome. In this severe form you have sores over much of your body and you feel sick. How does erythema multiforme occur? E. multiforme
In vitro models for the determination of drug mode of action IBAM GbR Dr. Rainer Knörle & Dr. Peter SchnierleFerdinand-Porsche-Str. 5, 79211 Denzlingen Our service offering includes several models for the identification of the molecular targets of a drug and of its off-target effects It has been shown that melanin a pigment found in the skin and other parts of the body has an ability