|Year : 2013 | Volume
| Issue : 1 | Page : 38-43
The WHO score predicts treatment outcome in low risk gestational trophoblastic neoplasia patients treated with weekly intramuscular methotrexate
Mitra M Gilani1, Behnamfar Fariba2, Nadereh Behtash1, Fatemeh Ghaemmaghami1, Azam S Moosavi1, Elahe Rezayof1
1 Department of Gynecology and Oncology, Tehran University of Medical Sciences, Valie Asr Hospital, Tehran, Iran
2 Department of Gynecology and Oncology, Tehran University of Medical Sciences, Valie Asr Hospital, Tehran; Department of Gynecology, Beheshti Hospital, Motahari street, Isfahan, Iran
|Date of Web Publication||10-Apr-2013|
Tehran University of Medical sciences, Vaie Asr Hospital, Tehran
Background: Gestational trophoblastic neoplasia (GTN) includes a spectrum of disease ranging from hydatidifrom mole to choriocarcinoma. Low risk GTN is defined as persistent molar pregnancy with a WHO score lower than seven. The optimal chemotherapeutic regimen still remains controversial.
Aim: The objectives of this study was to determine efficacy and safety of weekly intramuscular methotrexte in the treatment of low risk gestational trophoblastic neoplasia.(LRGTN) and also identify prognostic factors associated with treatment failure, necessitating second line chemotherapy.
Materials and Methods: Sixty-six women with LRGTN from 2001 to 2009 were treated with weekly intramuscular methotrexate at 40mg/m 2 as first line therapy.Monitoring of treatment was done with weekly checking of βhCG level. Three consecutive negative βhCG measurements showed complete response. After first negative βhCG measurement, one additional dose was administered for consolidation.
Results: Of 66 patients, who started the treatment five continued their treatment in other medical centres and were excluded from final analysis for treatment evaluation, and seven discontinued first line therapy because of hepatotoxicity. Of the remaining 54, complete remission occurred in 43 (79.6%) and eleven were resistant to first line therapy. Mean WHO score prior to starting chemotherapy was significantly different between two groups of response and resistance according to our data. Change of treatment to second line Actinomycin-D was necessary in eigtheen cases because of resistance to first line in eleven and liver enzyme elevation in seven patients. Sixteen of these 18 responded to Actinomycin-D as second line and one needed hysterectomy for complete response. One patient received multiagent chemotherapy for complete remission.
Conclusion: We recommend this effective and safe method of chemotherapy for women with LRGTN. According to our data, lower mean WHO score predicts a better outcome for this regimen.
Keywords: Gestational trophoblastic neoplasia, Methotrexate, Mole hydatiform
|How to cite this article:|
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 Can Res Ther 2013;9:38-43
|How to cite this URL:|
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 Can Res Ther [serial online] 2013 [cited 2015 Feb 1];9:38-43. Available from: http://www.cancerjournal.net/text.asp?2013/9/1/38/110357
| > Introduction|| |
Gestational trophoblastic neoplasia (GTN) includes a spectrum of disease ranging from hydatidifrom mole to choriocarcinoma. Hydatidifrom mole including complete and partial mole are benign expressions of GTN with similar management, surgical evacuation and βhCG follow up for six months. An increase or plateau in βhCG level defines persistent GTN which requires treatment with chemotherapy. 
Various prognostic and staging systems have been developed to predict outcome and treatment failure. Based on the modified World Health Organization (WHO) prognostic system as adapted by the International Federation of Gynecology and Obstetrics (FIGO), low risk GTN (LRGTN) is defined as persistent molar pregnancy with a WHO score lower than seven. 
Following the success of Methotrexate (MTX) in the treatment of metastatic choriocarcinoma reported by Li et al. in 1956, many investigators began to administer MTX as first line therapy for nonmetastatic GTN (NMGTN) and low risk metastatic GTN (LRMGTN).  Several different chemotherapy regimens have been reported including 5 day regimen of MTX (conventional MTX), and 5 day regimen of Actinomycin-D (conventional Act-D), 8-day alternating intramuscular MTX-folinic acid (MTX-CF) every 2 weeks, high dose interavenous MTX and weekly intramuscular MTX.
Complete response rate for these various treatment regimens have ranged from 49 to 92.3% (with most patients being salvaged with second-line chemotherapy). ,,,
Over time, 5 day regimens of MTX and Act-D have evolved to pulse regimens for lesser toxicity and ease of administration. The optimal chemotherapeutic regimen still remains controversial because of the challenge in balancing effectiveness, toxicity, convenience and cost. 
The primary objective of this study was to determine the complete response rate and toxicity of weekly intramuscular MTX at 40mg/m 2 for patients with LRGTN. Complete response was defined as the attainment of a serum βhCG level<5IU/lit for three consecutive weeks.
The secondary objective was to determine possible predictors of treatment failure with pulse weekly MTX in patients with LRGTN.
| > Materials and Methods|| |
A retrospective review of all patients treated with single-agent weekly intramuscular MTX for LRGTN was conducted.This research was done after obtaining appropriate approval from local ethical committee.
Medical records identified all patients coded with a diagnosis of GTN from 2001-2009.
Only patients with LRGTN who received single - agent weekly intramuscular MTX as first-line therapy were included in this review.
A diagnosis of GTN was made based on a history of molar pregnancy confirmed by pathological study of curettage specimen and a plateau (less than 10% fall) of βhCG over 3 weeks or more or a rise of βhCG (more than 10%) over 2 weeks or more according to the FIGO criteria.  Method of βhCG measurement was Electrochemiluminescence(ECL).
Sixty six patients entered the study. After entering to the study, D and C was performed for patients with symptomatic uterine bleeding and whenever imaging suggested significant molar disease in the uterine cavity.
Initial clinical workup included a complete history and physical examination, baseline pretreatment serum βhCG level, complete blood count (CBC) including hemoglobin, leukocyte, neutrophil and platelet counts,liver function tests including AST, ALT, LDH, total bilirubin, alkaline phosphatase (LFTs) and renal function tests (RFTs) including electrolytes, blood urea nitrogen and creatinin. Radiological examination included chest X-ray, abdominal and pelvic ultrasound, followed by a computerized tomographic scan if chest X-ray or abdominal and pelvic ultrasound revealed evidence of disease.
Sixty six patients started to receive MTX 40mg/m 2 weekly intramuscularly (IM). Five patients discontinued chemotherapy in our centre before complete remission. These were all from very distant areas who continued treatment in their local medical centres. As far as we didn't have access to detail of their treatment courses they were excluded from final analysis for treatment evaluation.
Weekly βhCG titer, CBC, LFTs and RFTs were obtained before each treatment cycle. All patients received this agent until remission or nonresponse condition occurred, where remission was defined as βhCG<5IU/litr and non response condition was defined as less than 10% decrease of βhCG titer over two consecutive weeks or the appearance of a new metastatic disease or an abnormal βhCG level after dropping to normal. After initial normalization of βhCG titer, an additional cycle was administered as consolidation therapy.
Antiemetics were not routinely prescribed. All women were treated on an outpatient basis. Hematologic, hepatic, renal and gastrointestinal toxicities were evaluated at each weekly visit during treatment by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 3.0 .
After treatment follow up of the Patients was continued with monthly βhCG titers for 12 months. Then they returned to the care of their referring physician.
Second line chemotherapy for MTX resistant cases (non responders) and sever toxicity cases (chiefly liver function deterioration) was required. This consisted of Act-D at 1.25mg/m 2 intravenously every 2 weeks until complete response or drug resistance occurred. If complete response was not achieved with Act-D patients were administered Etoposide, Methotrexate, Actinomycin-D, Cyclophosphamide and vincristine (EMA-CO) as third line chemotherapy.
A one -way analysis of variance and students t- test were used for comparison of continuous variables and the Yates corrected Chi-Squared test were used for comparison of categorical variables. Software program was SPSS version 14.
Statistical significance was defined as P<0.05.
| > Results|| |
Our study population consisted of sixty six patients who received MTX 40mg/m 2 weekly intramuscularly (IM) as first line therapy for LRGTN. Five patients discontinued chemotherapy in our centre before complete remission. These were all from very distant areas who decided to continue treatment in their local medical centres. As we didn't have access to detail of their treatment courses they were excluded from final analysis for treatment evaluation.
[Table 1] summarizes patient characteristics.
Fifty eight patients had nonmetastatic disease (87.5%) and 8 had metastases in lung (7 patients, 11%) or vagina (1 patient, 1.5%).
Nine patients underwent hysterectomy before start of chemotherapy. These were all multiparas over 40 with stage I disease to whom hysterectomy was offered.
The mean WHO score before treatment was 1.5. (±1.14SD, range 0-6) Patients received between 2-15 courses of MTX. Dosage was 40mg/m 2 .
The median βhCG level before treatment was 4930 (IQR: 11282.5) which was 3975(IQR: 5460) for responders and 10,000(IQR: 31335) for resistant cases. Although median βhCG level was higher in resistant group than response group this difference was not significant. (P value 0.09)
Characteristics of the patients are compared between two groups of MTX response and resistance by using univariate analysis, shown in [Table 2].
In 7 patients treatment with MTX was discontinued after a few courses and changed to Act-D because of liver enzyme elevation. Of the remaining 54 patients, 43 responded to weekly MTX.(79.6%)
There were 11 patients who were resistant to weekly intramuscular MTX.
With respect to age, gravidity, history of hysterectomy before starting chemotherapy, stage of disease and histopathologic type, there were no differences between those who were successfully treated and those who failed first - line treatment with MTX [Table 2].
Response rate for patients with WHO score of zero and one was 87% and for patients with WHO score of ≥2 was 68.2%. Mean WHO score before treatment was 1.25 (±0.76SD) for responders and 1.91 (±1.51SD) for resistant cases which was significantly different between two groups. (P value 0.4).
Mean number of MTX chemotherapy cycles required to achieve complete response was 6.9 which included administration of one additional cycle past initial normalization of βhCG titers. (Range 2-15 cycles, median 7)
Response rate of the patients who underwent hysterectomy before start of chemotherapy (nine cases) was 66.7% which was not significantly different from other patients. (P value 0.785)
Of the remaining 18 who didn't achieve complete responses with MTX (11 resistant cases and 7 cases with hepatic toxicity) 17 received weekly Act-D and 1 received EMA-CO as second line chemotherapy. The patient who received EMA-CO was a 27 year old primigravida with a history of molar pregnancy and curettage four months prior to presentation. At the time of admission βhCG level was 884 IU/L and metastatic work up was negative. She received two courses of MTX as first line chemotherapy, but βhCG level raised to 2380 and at this time multiple lung micrometastases were found in chest CT scan. She received EMA-CO regimen. Complete remission occurred after five courses of EMA-CO and she received two additional courses as consolidation. Complete remission was achieved in 16 out of 17 patients who received Act-D (94.12%). The mean number of cycles required to achieve complete response with Act-D was 4.33. (Range 2-9)
The only patient who did not respond to Act-D as second line therapy required a hysterectomy for complete response. She was a 35year old multipara with a history of complete mole and curettage 6 weeks before first admission. WHO score was 1 at the time of first admission.She received 6 courses of MTX and because of βhCG raising received 7 courses of Act-D as second line therapy. She had a plateau level βhCG after these therapies and finally βhCG dropped to negative after hysterectomy.
Systemic toxicity from weekly MTX was minimal. There were no cases of grade 3 or 4 toxicity.
Treatment toxicity totally happened in 24 patients.
There were 7 patients with hepatic toxicity (11.4%), 11 with gastrointestinal toxicity (18%),four with alopecia (6.56%), one with stomatitis (1.6%) and one with hematotoxicity (neutropenia) (1.6%) which where all grade 1-2 based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 3.0. 
There were two events of transient generalized skin rush and one event of injection site skin necrosis in the patients receiving Act-D.
Median follow up of the patients was 27 months. (Range 12-52)
There were no recurrence events. Six were pregnant after one year of follow up ending in 4 live births with healthy babies and 2 molar pregnancies.
The only significant prognostic factor for failure was pretreatment WHO score.
All patients were free of disease after 12 months of follow up. No deaths have occurred and no recurrence has been documented.
| > Discussion|| |
In this study single agent weekly MTX without dose escalation was effective in 79.6% of patients with LRGTN. Mean WHO score prior to starting chemotherapy was significantly different between two groups of response and resistance according to our data.
Several chemotherapy regimens have been reported in the management of LRGTN.
MTX was the first agent used and still remains the most prescribed drug in the treatment of LRGTN. Daily intramuscular injection over the course of 5 days (conventional MTX) has been the earliest regimen. ,,
High rate of toxic effects in this method of treatment was the reason of introducing alternative schedules with folinic acid (CF) rescue.
Eight-day alternating intramuscular MTX -CF regimen is the most widely used regimen in the world and has been treatment of choice for LRGTN in the UK for the last 30 years, because of its long term safety profile. Response rates of 66.8-72% have been reported. ,,
Although side effects have been reduced by folinic rescue, long duration of this regimen causes inconvenience and on the other hand, need for hospitalization increases the costs which are a limiting factor for low income countries. ,,,,,,,
Weekly MTX pulse therapy is another treatment method in which MTX is injected intramuscularly with doses ranging 30-50mg/m 2 every week.
This regimen has been reported with and without dose escalation. 
Weekly MTX was first reported by the Gynecologic Oncology Group (GOG) for the treatment of NMLRGTN. Homesly et al. treated their 63 patients with weekly MTX 30 mg/m 2 and escalated 5 mg/m 2 at three week intervals up to maximum dose of 50 mg/m 2 . They reported 81% primary remission rate for their patients. They concluded that the weekly MTX regimen was the preferred choice of several MTX or Act-D schedules when efficacy, toxicity and costs were taken into consideration. ,
Hoffman et al. in a study on 20 cases with NMLRGTN with dose escalation method started with 40 mg/m 2 and rapidly escalated up to 60mg did not have better remission rate. 
Although several schedules have been reported for weekly MTX, there are few reports in the literature to evaluate weekly MTX without dose escalation in the treatment of LRGTN. 
Gilani et al. and Yarandi et al. in two different studies used weekly MTX 30 mg/m 2 not escalated, for 28 and 81 cases of LRGTN respectively. They reported 50% and 48% initial complete responses. ,
Also Mohit et al. reported their study results using weekly intramuscular MTX 30mg/m 2 , not escalated, for 33 LRGTN cases. Twenty one of 33 patients (63.6%) were cured with first line therapy. 
In another study Kang et al. used weekly MTX 50 mg/m 2 without dose escalation for 48 patients with LRGTN. Their primary remission rate was 70.8%. 
Recently Osborne et al. in a phase III trial comparing weekly MTX 30mg/m 2 with pulsed Act-D 1.25 mg/m 2 for LRGTN, used MTX for 107 patients and had a 53% response with this regimen. In Act-D group which were 109 patients response rate was 70%. In the MTX group eight patients had a WHO score of 5 or 6. Only one of these eight patients had complete remission with weekly MTX which showed significant effect of WHO score on prognosis of treatment. 
Response rate in our study and study by Kang et al. have been higher than studies by Mohit, Gilani, Yarandi and Osborne et al. As far as all of these studies have been done with lower doses (30mg/m 2 ) of MTX, These data suggest that in the fixed dose regimens higher response rate may be achieved with higher doses (40-50mg/m 2 ) of MTX.This should be confirmed with prospective randomized trials.
In our study 11 patients with low risk GTN did not respond to weekly MTX. Initial mean WHO risk score was the only significant factor, predictive of failure. (P value=0.04) This is consistent with the study by Osborne et al. which showed a significant lower response in LRGTN patients with higher WHO scores. 
In our study hepatotoxicity occurred in 7 patients which was grade one or two. We had 10.1% rate of changing drug for toxicity. Our protocol to replace Act-D instead of MTX even with low grade hepatotoxicity and not only in severe toxic cases can explain this result. In the study by Kang et al. high grade hepatotoxicity occurred in 8 of 59 (13%) patients in MTX-CF 8-day regimen group but this happened only for 2 cases of their 48 patients in weekly MTX group.  These results are similar to our results.
Mean number of cycles to achieve response was 6.9. This was similar to study by Hoffman and Homesly regardless of their escalation method. ,
Although mean pretreatment βhCG level was higher in the failure group, this difference was not significant. Also in our study similar to study by Matsui et al., maternal age and presence of metastases did not influence the development of resistance.  Lack of significance may be related to small numbers.
In our study nine patients underwent hysterectomy before start of chemotherapy.One of them discontinued first line treatment because of liver enzyme elevation and two showed resistance. Response rate for hysterectomy patients was 66.7% which was not significantly different from other patients. (P value 0.72).
May et al reported 32 patients with NMLRGTN whom were treated with a hysterectomy and perioperative chemotherapy. All of their patients achieved complete remission without additional adjuvant therapy. They concluded that administration of chemotherapy at the time of hysterectomy is a safe and effective treatment strategy for selected women with stage I GTN.  In our centre the strategy for these cases was starting chemotherapy in the post operative follow up period only in the case of rising of βhCG. This may explain why they had no resistant cases but this occurred in two from eight cases who underwent hysterectomy in our study.
In present study, there has been a high remission rate (79.6%) and a low rate of toxicity for weekly MTX in treating low risk GTN. These results should be considered in mind with this point that this schedule is done in an outpatient manner, which will cause more convenience for the patient.
We recommend this outpatient regimen as an effective and safe method for treating LRGTN especially for patients with lower WHO scores. This study is especially important because there are only few studies with a fixed dose of weekly MTX for LRGTN in the literature.
Of course, the design of this study has been retrospective and a single treatment method has been used for all of the patients. We suggest prospective randomized studies comparing different dosages of MTX to confirm our results.
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[Table 1], [Table 2]