|Year : 2014 | Volume
| Issue : 3 | Page : 646-650
Evaluation of weekly intramuscular methotrexate in the treatment of low risk gestational trophoblastic neoplasia
Malihe Hasanzadeh1, Azadeh Tabari2, Fatemeh Homae3, Mohammadtaghi Shakeri4, Tahereh Bakhshandeh5, Faezeh MadaniSani6
1 Department of Gynecologic Oncology, Women Health Research Center, Harvard Medical School, USA
2 Renal Basic Science Laboratory, Brigham and Women's Hospital, Harvard Medical School, USA
3 Department of Oncology Radiotherapy, Mashhad University of Medical Sciences, Ghaem Hospital, Mashhad, Iran
4 Department of Community Medicine, School of Medicine, Ghaem Hospital, General Physician, Mashhad, Iran
5 Department of Gynecologic Oncology, Ghaem Hospital, General Physician, Mashhad, Iran
6 Student of Medical Sciences, Mashhad University of Medical Sciences, Ghaem Hospital, Mashhad, Iran
|Date of Web Publication||14-Oct-2014|
Room 520, HIM, 4 Blackfan, Cir, Boston
Source of Support: None, Conflict of Interest: None
Background: The gestational trophoblastic neoplasms (GTNs) are rare and potentially life-threatening malignancies.
Aims: The aim of this study was to determine the rate of response to weekly intramuscular (IM) methotrexate (MTX) in patients with low-risk GTN (LR-GTN).
Settings and Design: The study was designed cross-sectional and prospectively. Patients followed for 1 year.
Materials and Methods: From 2006 to 2011, a total of 117 women with LR-GTN were studied. A weekly MTX regimen (50 mg/m 2 with dose escalation to 75 mg/m 2 ) was administered to 87 of patients. A biweekly pulsed intravenous bolus of 1.25 mg/m 2 of actinomycin D was administered in patients resistant to MTX (n = 30) and combination therapy was performed in those who did not respond to aforesaid treatments (n = 8).
Statistical Analysis: The data were analyzed using Statistical Package for Social Sciences (SPSS) 11.5 and Chi-square model was applied. Descriptive statistics and compare means (t-test) was used as well. P < 0.05 was statistically significant.
Results: All 117 patients with LR-GTN were cured. The primary remission rate was 74.3%, with primary dose of 50 mg/m 2 of MTX and escalation to 75 mg/m 2 . Another patient achieved complete remission with actinomycin and combination chemotherapy. There were significant statistical correlation between remission and World Health Organization (WHO) scoring, International Federation of Gynecology and Obstetrics (FIGO) staging, pretreatment beta-human chorionic gonadotropin (β-hCG) level, and antecedent pregnancy (P < 0.05).
Conclusion: We suggest that cases with score ≥6 should be considered high risk. First-line combination chemotherapy is advised in GTN with score ≥6.
Keywords: Gestational trophoblastic neoplasia, low-risk, methotrexate
|How to cite this article:|
Hasanzadeh M, Tabari A, Homae F, Shakeri M, Bakhshandeh T, MadaniSani F. Evaluation of weekly intramuscular methotrexate in the treatment of low risk gestational trophoblastic neoplasia. J Can Res Ther 2014;10:646-50
|How to cite this URL:|
Hasanzadeh M, Tabari A, Homae F, Shakeri M, Bakhshandeh T, MadaniSani F. Evaluation of weekly intramuscular methotrexate in the treatment of low risk gestational trophoblastic neoplasia. J Can Res Ther [serial online] 2014 [cited 2019 Sep 21];10:646-50. Available from: http://www.cancerjournal.net/text.asp?2014/10/3/646/138199
| > Introduction|| |
Gestational trophoblastic disease includes complete and partial hydatidiform moles, invasive mole, choriocarcinoma, and placental site trophoblastic tumor (PSTT).
The improvement in overall survival is >98% with fertility preserving, while most of the patients died 60 years ago. 
Choosing the best method of treatment due to complete evaluation and staging of the disease enhances the cure rate and decreases toxicity to the least. Nonmetastatic (stage 1) and low-risk metastatic gestational trophoblastic neoplasm (GTN; stage 2 and 3, World Health Organization (WHO) score <7) can be treated with single-agent chemotherapy (methotrexate (MTX) or actinomycin D) and the survival rate will be then about 100%. ,
There are multiple single-agent chemotherapy regimens:
- Weekly intramuscular (IM) MTX with 30-50 mg/m 2
- MTX with 0.4 mg/m 2 for 5 days every 2 weeks, or biweekly alternate MTX-leucoverine for 8 days
- Actinomycin at 1.25 mg/m 2 (maximum 2 mg) every 2 weeks; the response rate to these regimens is 60-98%. 
Approximately 30% of patients with low-risk GTN (LR-GTN; with the score of 5 and 6) have responded to these regimens, while reconsidering in scoring and staging system would be effective in recognizing 70% of resistant patients of this group. 
Various studies have been performed to evaluate the efficacy of weekly administration of IM MTX starting with 30-50 mg/m 2 . Dose escalation has been done in some studies. In 1988, a study was performed by Gynecology Oncology Group (GOG) in which the treatment was initiated with 30 mg/m 2 and the dose was escalated by 5 mg/m 2 every 3 weeks up to a maximum dose of 50 mg/m 2 . The response rate was 81%. 
In another GOG study in 1990, the treatment was initiated with 40 mg/m 2 and with rapid escalation by 5 mg/m 2 weekly with 2 weeks interval attained a maximum dose of 50 mg/m2. The response rate was 74%. 
Hoffman et al., reported 60% response rate in women receiving weekly IM MTX. In this study, treatment was initiated with 40 mg/m 2 weekly and rapidly increased to 60 mg/m 2 . 
In 2011, another study was done by GOG with the aim of comparing MTX versus actinomycin in treating patients. Treatment at the initial dose of 30 mg/m 2 MTX without escalation had the response rate of 53%. They concluded that MTX and pulse actinomycin regimen is less effective in LR-GTN with the score of 5 or 6. 
Two studies by Yarandi et al., and Mohit et al., cited a response rate of 48 and 63.6%, respectively. ,
The aim of our study is to evaluate the response rate and efficacy of weekly IM MTX in LR-GTN.
| > Materials and methods|| |
The study was designed cross-sectional and prospectively. From 2006 to 2011, 117 patients with LR-GTN who were referred to the oncology clinic of Obstetrics and Gynecology department were entered into the study. The project was approved by Ethics Committee of Mashhad University of Medical Sciences and it conforms to provisions of the Declaration of Helsinki. Informed consent of all the patients was taken and the patients' anonymity was preserved. The inclusion criteria were WHO score 0-6, stage of 1-3 (metastatic and nonmetastatic patients), persistent disease (according to the plateau level of beta-human chorionic gonadotropin (β-hCG) or decreasing to less than 10% for 3 weeks or increasing during two consecutive weeks follow-up, or abnormality in β-hCG level 4 months after evacuation of the primary mole), being a suitable candidate for starting single-agent chemotherapy.
The exclusion criteria were as followed; stage 4 of GTN (brain or liver metastases), patients with score ≥7, having contraindication for using MTX.
All patients have been examined completely. Pre-chemotherapy assessments were physical examination, laboratory and imaging evaluation including complete blood cell count, basic β-hCG level, liver and renal function tests, and plain chest X-Ray. A computed tomography (CT) of chest was performed only if the patient showed evidence of pulmonary metastasis on the plain chest X-Ray. In case of evidence for pulmonary metastasis on chest imaging, a brain CT scan or magnetic resonance imaging (MRI) was performed. Considering WHO and International Federation of Gynecology and Obstetrics (FIGO) scoring and staging systems, patients with persistent disease and pathology confirmation for disease were treated outpatient with weekly IM MTX at 50 mg/m 2 after primary evacuation of the mole.
Serial weekly β-hCG levels were measured unless three negative reports (serum β-hCG < 5 IU/l) were documented. On the other hand, in case of failure which defined as one of the following, plateau or decline <10% in β-hCG levels for 3 weeks, or an elevation greater than 10% above the prior obtained β-hCG value in two consecutive weeks, MTX dosage was increased to 75 mg/m 2 . During administration of MTX, other than β-hCG level, weekly CBC, liver and renal function tests were measured to supervising MTX toxicity and deciding whether to change regimen or not. If failure to dose escalation occurred, regimen was converted to pulse actinomycin at 1.25 mg/m 2 . Eventually, patients with failure to previous treatment were candidates for combined chemotherapy regimen of EMA/CO (etoposide, MTX, actinomycin D, cyclophosphamide, vincristine/oncovine) or BEP (bleomycin, etoposide, and cisplatin). All patients were followed 1 year after treatment. They were divided into two groups of responder (success) and resistant to MTX therapy (failure). The data were analyzed using Statistical Package for Social Sciences (SPSS) 11.5 and Chi-square model was applied. Descriptive statistics and compare means (t-test) was used as well. P < 0.05 was statistically significant.
| > Results|| |
The study recruited 117 women with the mean age of 27.9 years (range, 15-52 years). The hormone range was 25-462500 IU/l and the mean level of β-hCG was 29945.2 ± 76444.7IU/l. According to WHO scoring; 96 patients had score ≤ 4 (82%) and 21 patients had score 5 and 6 (18%), out of which 13 of them had score 5 GTN (11.1%) and other eight patients had score 6 GTN (6.8%) [Table 1]. There were 96 (82%) metastatic and 21 (18%) nonmetastatic patients (stage 2 or 3).
|Table 1: Evaluation of patients with score 6 GTN according to their characteristics|
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All 117 patients were treated with initial dose of 50 mg/m 2 MTX, 74 of them (63.2%) responded completely, while in other 43 (36.8%) patients, dose was increased to 75 mg/m 2 . 11.1% of patients (13 out of 43) responded to treatment. Therefore, 87 (74.3%) patients achieved complete response with MTX. 25.7% of patients (30 out of 43) received pulse actinomycin with dosage of 1.25 mg/m 2 . Finally, 22 patients (18.8% of sum) had complete response to pulse actinomycin. (93.1% complete response by single-agent chemotherapy) While, eight patients (6.8%) did not respond to actinomycin, but achieved remission with combination chemotherapy. In this study, patients were followed for 1 year. One hundred percent were alive and there was no recurrence during the follow-up period. Total cycles of chemotherapy were 2-24 with a mean cycle of 8.02. Complete response was obtained by a median of 6.8 MTX cycles (2-20), 3.8 actinomycin cycles (2-8), and 5 cycles of combination chemotherapy (3-7 cycles). Complete response with 75 mg/m 2 MTX regimen (after dose escalation) was achieved by mean cycles of 6.3 ± standard deviation (SD) (2-14 cycles). Response rate, according to WHO scoring system, was 81.3% in patients with score ≤ 4 and 42.6% in patients with score >4 (5 or 6; P = 0.001).
The comparison between response rate of score 5 and 6 manifested that eight out of 13 patients with score 5 (61.5%) and one out of eight patients with score 6 (12.5%) responded to treatment. In our study, 17 (81%) of nonmetastatic and 41 (43%) of metastatic GTN achieved remission, and there was a significant difference between them (P = 0.001).
Response rate in pulmonary (seven out of 17 patients) and vaginal (two out of four patients) metastasis were 41.2% and 50%, respectively [Table 2],[Table 3]. Patients were divided into two groups: 1 - Those who responded to MTX therapy (success group) and 2 - who were resistant to treatment (failure group). Patients' characteristics were compared between these two groups with respect to age, type of pregnancy, the interval with antecedent pregnancy, β-hCG level, scoring, and staging of the disease and number of chemotherapy cycles, as shown in [Table 1].
|Table 2: Evaluation of metastatic patients according to response to treatment and score of the disease|
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|Table 3: Patient characteristics based on response to first-line chemotherapy|
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| > Discussion|| |
In our study, the efficacy of weekly IM MTX regimen with dose escalation (in LR-GTN: Score 0-6 and stage 1-3) was 74.3%, which is in fact the highest rate among present studies. Additionally, this study showed that the mentioned MTX regimen was less effective in patients with score 5 and 6, especially score 6. Therefore, more schedules should be performed to make changes in management, therapeutic protocols, and also classification of this group. The initial complete response to MTX chemotherapy at 50 mg/m 2 was 63.2% in our series and increased to 74.3% after dose escalation to a maximum dose of 75 mg/m 2 . Our response is lower than the result of GOG study (81% at 30 mg/m 2 ), but is higher than the results reported by Kang et al., (70.8% at 50 mg/m 2 ), Mohit et al., (63.6% at 30 mg/m 2 ), Hoffman et al., (60% at the initial dose of 40 mg/m 2 and rapid escalation until a maximum dose of 60 mg/m 2 ), Lipmann et al., (54.2% with the initial dose at 30 mg/m 2 and increased to 50 mg/m 2 ), Osborne et al., (53%, 30 mg/m 2 ),  Modaresgilani et al., (50%, 30 mg/m 2 ), and Yarandi et al.,(48.14%). ,,,,,, Owing to nonmetastatic patients in GOG study,  their results had higher response comparing to ours. The complete response rate varies between 48 and 81% in different articles, which is due to various treatment management and doses. Increasing the MTX dose also occurred in three studies. ,,
It should be considered that recent researches showed that rapid escalation of the dose did not necessarily cause higher response rate. However, in our study, the initiate dose was higher than other studies and we had maximum dose of 75 mg/m 2 and response rate increased significantly up to 11% (from 63.4 to 74.3%).
According to WHO scoring system, we concluded that this therapeutic regimen is not appropriate for LR-GTN score 6. Moreover, in 2011 Osborne et al., cited that both weekly IM MTX and actinomycin are not suitable for treating patients with score >4 and choriocarcinoma. They reported that complete response rate in patients with score ≤ 4 and >4 was 58.3 and 9.1% respectively. 
Multiple studies pointed out that the mean levels of β-hCG in responder and resistant groups were significantly different. ,
In this study, there was a statistically significant relationship between response rate in nonmetastatic and metastatic patients.
The complete response rate in pulmonary and vaginal metastasis groups were 41.2 and 50%, respectively (owing to small numbers of vaginal metastasis, two out of four patients, this conclusion is not precise enough).
In addition to our study, Chapman-Davis et al., and Gorwdon et al., cited significant difference between metastatic and nonmetastatic patients according to the response rate. ,
There was not a statistically significant difference in other studies. Regarding this, Mohit et al., pointed out that the small sample of patients might be one of the main reasons. 
The type of pregnancy was also one of the significant prognostic factors in our study. However, there was not a significant relationship between the type of pregnancy and complete response in the studies by Yarandi et al., Kang et al., and Chapman-Davis et al. ,,
This is due to small population of patients who were diagnosed following term pregnancy.
Our results show that despite weekly IM MTX has an acceptable response rate in treatment of LR-GTN, it is less effective in patients with score 5 and 6 GTN (especially score 6) and metastatic patients (even pulmonary metastasis). As a result, combination therapy should be considered the optimal first-line chemotherapy for these patients. We suggest that the time for changing the WHO scoring system has come and patients with score ≥ 6 should be considered high risk, and combination therapy should be administered for them.
| > References|| |
Seckl MJ, Sebire NJ, Berkowitz RS. Gestational trophoblastic disease. Lancet 2010;376:717-29.
Lurain JR. Gestational trophoblastic disease II: Classification and management of gestational trophoblastic neoplasia. Am J Obstet Gynecol 2011;204:11-8.
Gilani MM, Fariba B, Behtash N, Ghaemmaghami F, Moosavi AS, Rezayof E. The WHO score predicts treatment outcome in low risk gestational trophoblastic neoplasia patients treated with weekly intramuscular methotrexate. J Cancer Res Ther 2013;9:38-43.
Mohit M, Sarraf Z, Sheikhi G, Robati M, Vasheghani-Farahani A. Weekly intramuscular methotrexate in the treatment of low-risk gestational trophoblastic neoplasia. Arch Gynecol Obstet 2009;280:775-80.
Homesley HD, Blessing JA, Rettenmaier MA, Capizzi RL, Major FJ, Twiggs LF. Weekly intramuscular methotrexate for nonmetastatic gestational trophoblastic disease. Obstet Gynecol 1988;72:413-8.
Homesley HD, Blessing JA, Schlaerth J, Rettenmaier M, Major FJ. Rapid escalation of weekly intramuscular methotrexate for nonmetastatic gestational trophoblastic disease: A Gynecologic Oncology Group study. Gynecol Oncol 1990;39:305-8.
Hoffman MS, Fiorica JV, Gleeson NC, Roberts WS, Cavanagh D. A single institution experience with weekly intramuscular methotrexate for nonmetastatic gestational trophoblastic disease. Gynecol Oncol 1996;60:292-4.
Osborne RJ, Filiaci V, Schink JC, Mannel RS, Secord AA, Kelly JL, et al
. Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational trophoblastic neoplasia: A gynecologic oncology group study. J Clin Oncol 2011;29:825-31.
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 neoplasia. Int J Gynaecol Obstet 2008;103:33-7.
Kang WD, Choi HS, Kim SM. Weekly methotrexate (50 mg/m2) without dose escalation as a primary regimen for low-risk gestational trophoblastic neoplasia. Gynecol Oncol 2010;117:477-80.
Lipmann QK, Hanna RK, Soper JT. Single-agent methotrexate for low risk gestational trophoblastic disease. J Clin Oncol 2011;29:155-58.
Modaresgilani M, Yarandi F, Eftekhar Z, Hanjani P. Comparison of pulse methotrexate and pulse dactinomycin in the treatment of low-risk gestational trophoblastic neoplasia. Aust N Z J Obstet Gynaecol 2005;45:161-4.
Chapman-Davis E, Hoekstra AV, Rademaker AW, Schink JC, Lurain JR. Treatment of nonmetastatic and metastatic low-risk gestational trophoblastic neoplasia: Factors associated with resistance to single-agent methotrexate chemotherapy. Gynecol Oncol 2012;125:572-5.
Growdon WB, Wolfberg AJ, Goldstein DP, Feltmate CM, Chinchilla ME, Lieberman ES, et al
. Evaluating methotrexate treatment in patients with low-risk postmolar gestational trophoblastic neoplasia. Gynecol Oncol 2009;112:353-7.
[Table 1], [Table 2], [Table 3]