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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 [1] Foulmann K, Guastalla JP, Caminet N, Trillet-Lenoir V, Raudrant D, Golfier F, et al.
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mens of actinomycin D or methotrexate or with a combination of ac- [2] 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.
[3] 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- [4] 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- [5] 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.
[6] 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 [7] 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- [8] 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.
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rate of 8% with 5-day actinomycin D.
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[14] 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 [15] 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 [16] 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.
[17] 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 [18] 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- [19] 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.
[20] 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.
[21] 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 [22] Abrão RA, de Andrade JM, Tiezzi DG, Marana HR. Candido dos Reis FJ, Clagnan WS.
[25] 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 [26] Kwon JS, Elit L, Mazurka J, Moens F, Schmuck ML. Weekly intravenous methotrexate [23] 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 [24] 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.


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