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Treatment for low-risk gestational trophoblastic disease: Comparison of

single-agent methotrexate, dactinomycin and combination regimens

Renato Antonio Abro, Jurandyr Moreira de Andrade, Daniel Guimares Tiezzi ,Heitor Ricardo Cosiski Marana, Francisco Jos Candido dos Reis, Willian Simes Clagnan

Department of Gynecology and Obstetrics, Hospital das Clnicas of Ribeiro Preto School of Medicine, University of So Paulo.

3900 Bandeirantes Ave 8 floor Ribeirao Preto, So Paulo, 14048-900, Brazil

Received 23 July 2007

Available online 10 October 2007

Abstract

Objectives.To compare the efficacy of three different standard chemotherapy regimens for low-risk gestational trophoblastic disease according

to the FIGO staging system in a single-institute setting.

Methods. From 1980 until 2002, we retrospectively reviewed 108 cases with low-risk persistent gestational trophoblastic disease who were

treated with first-line chemotherapy. Patients were divided in three groups according to chemotherapy regimen: patients treated with methotrexate

(MTX group; n = 42), patients treated with dactinomycin (ACT group; n = 42) and patients treated with methotrexate and dactinomycin in

combination (MACT group; n =24). We compared the number of chemotherapy courses for achieving remission, the duration of treatment, the

adverse side effects, the efficacy of the treatment and the need for performing a hysterectomy among the groups

Results. The complete remission rates were 69%, 61.4% and 79.1% for methotrexate (MTX), dactinomycin (ACT) and the combination

regimen (MACT) treated groups, respectively (p =0.7). The duration of the treatment and the number of chemotherapy courses were similar

among the groups (p =0.2 andp =0.4, respectively). Adverse side effects rate was reported to be 62.5% in the MACT group, 28.6% in the MTXgroup and 19.1% in the ACT group (p =0.0003). Second-line chemotherapy was indicated for 30 patients. Hysterectomy was performed in 21

patients overall, and there was no difference among the groups (p =0.6).

Conclusion. Our analysis indicates that single-agent chemotherapy regimens are as effective as combination chemotherapy for low-risk

gestational trophoblastic disease. Dactinomycin is a less toxic drug and might offer the best cost-effective treatment option. Methotrexate must be

considered as the regimen of choice for low resource areas because of the feasibility of its administration.

2007 Elsevier Inc. All rights reserved.

Keywords: Human chorionic gonadotrophin; Gestational trophoblastic disease; Chemotherapy

Introduction

During the last 50 years, several chemotherapy schemes and

schedules have been reported for the treatment of gestational

trophoblastic disease (GTD). From the first moment, two

particular characteristics of GTD have been observed. First, that

a serum tumor marker, the subunit of the human gonadotrophichormone (hCG), is able to monitor disease activity with high

sensitivity and specificity, and second, that the disease is highly

sensitive to cytotoxic drugs. The first report from the National

Institute of Health demonstrated that dactinomycin (ACT-D) and

methotrexate (MTX) were effective drugs for the treatment of

GTD, and that several clinical factors could predict disease

outcome [1]. However, fewreports exist that compare the efficacy

and toxicity of chemotherapy treatment for low-risk gestational

trophoblastic disease (LRGTD) in a single institution. Mean-

while, the majorityof studies do not reach level 1 or 2 evidence on

the best chemotherapeuticmanagement for low-riskGTD [2],and

Available online at www.sciencedirect.com

Gynecologic Oncology 108 (2008) 149153www.elsevier.com/locate/ygyno

Corresponding author. Hospital das Clinicas da Faculdade de Medicina de

Ribeiro Preto, Departamento de Ginecologia e Obstetrcia, Avenida Bandeir-

antes nmero 3900, Ribeiro Preto, So Paulo, CEP: 14049-900, Brazil. Fax:

+55 16 36330946.

E-mail address: dtiezzi@hcrp.fmrp.usp.br(D.G. Tiezzi).

0090-8258/$ - see front matter 2007 Elsevier Inc. All rights reserved.doi:10.1016/j.ygyno.2007.09.006

mailto:dtiezzi@hcrp.fmrp.usp.brhttp://dx.doi.org/10.1016/j.ygyno.2007.09.006http://dx.doi.org/10.1016/j.ygyno.2007.09.006mailto:dtiezzi@hcrp.fmrp.usp.br

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the information regarding criteria for selecting patients for che-

motherapy, remission of disease and indication of surgery are not

uniform[24].

Based on reported results, some risk grouping and prognostic

scoring systems were developed to aid in the therapeutic deci-

sion making for GTD [5,6]. At least three different staging

systems are now being used[7]. Although this diversity makesthe comparison among studies difficult, the retrieval of retro-

spective data is useful to classify patients according to a current

scoring system condoned by the International Federation of

Gynecology and Obstetrics (FIGO)[8,9]. The staging systems

considered by FIGO places patients into two groups of risk. The

stage standardization enables the comparison of different che-

motherapy treatment outcomes with similar categories of risk,

which facilitates retrospective analyses[9].

Several first-line chemotherapy regimens have been reported

with no high level of evidence to support the use of a particular

one [2]. Methotrexate and dactinomycin continue to be used

as either single agents or in a combination regimen. Differentregimens, such as 5-day intramuscular methotrexate, the 8-day

schedule with alternate folinic acid rescue or a single-dose

regimen, were considered [2,10]. Dactinomycin can either be

administered as a 5-day regimen or as a pulse regimen [1,11].

Single-agent chemotherapy is the standard care for low-risk

persistent trophoblastic disease (LRPTD). The remission rate

ranges from 60% to 90%[12]. In spite of the fact that a quarter

of patients will require second-line chemotherapy either due to

resistance to the first-line drug or toxic adverse effects [14],

most patients will be cured with single or multi agent chemo-

therapy strategy[12]. Combination therapy with dactinomycin

and methotrexate was shown to be an effective regimen in non-

metastatic gestational trophoblastic disease; however, a highrate of toxic effects was observed [13].

Currently, there is no consensus on the best regimen for first-

line therapy in the treatment of LRGTD yet. The current main

concern in the treatment of LRGTD is the identification of a

low-cost and highly acceptable chemotherapy schedule. The

present study was undertaken to compare the efficacy of three

different standard chemotherapy regimens for LRGTD accord-

ing to the FIGO staging system.

Materials and methods

From 1978 until 2002, 425 patients with the histological diagnosis of

hydatidiform mole after uterine evacuation were followed up in our medical

center. Persistent t rophoblastic disease was observed in 157 patients. Criteria for

persistent disease were based on serum hCG levels (a rise of over 10% of

hCG titers in three subsequent weeks or a plateau in four or more subsequent

weeks if the serum level was higher than 1000 mU/ml). Upon reviewing the

medical records of patients with persistent disease, all patients were staged

according to the FIGO 2000 scoring system [14]. Following this scoring

protocol, 123 patients were classified as low-risk gestational trophoblastic

disease (LRGTD), and 34 patients were classified as having high-risk persistent

disease.

The inclusion criterion were patients diagnosed as having gestational non-

metastatic trophoblastic neoplasia or a low-riskmetastatic neoplasia (lung metastases

only) who were also diagnosed to have gestational trophoblastic neoplasia for less

than 4 months, had serum hCG values less than 40,000 mIU/ml hCG, had a WHO

scoreof 6 orless and who were a FIGOStage I,II orIII.All patients weresubjectedtotreatment with a primary first-line chemotherapy. Exclusion criteria were prior

hysterectomy, withdrawal from follow-up during the first year after mole evacuation

and treatment with chemotherapy regimens that did not follow our protocol. We

retrospectively reviewed a total of 108 patients files. All patients with persistent

trophoblastic disease wererestaged and submitted to complete physical examination,

blood cell count, thoracic X-ray and pelvic and abdominal ultrasound. Thoracic,

abdominal and brain computer tomography examination were performed in the case

of pelvic or lung metastasis.

A totalof 42 patients weresubjectedto single-agentmethotrexate chemotherapythrough an intramuscular injection of 20 mg/m2 D1D5 (MTX group); 42 patients

were treated with single-agent dactinomycin chemotherapy by i.v. infusion of

12g/kg a day D1D5 (ACT group); and 24 patients received a combination of

both drugs with 20 mg methotrexate administered via an intramuscular injection

D1D5 and with 500 g dactinomycin administered by i.v. infusion D1D5

(MACT group). We included the combination therapy instead the sequential

schedule [1] in ourprotocol during the1990s as analternativetreatment forLRGTD

assuming that we were going to reduce the number of chemotherapy courses.

However,in a previous interim analysis,we observeda high rate oftoxiceffects, and

this regimen was abolished from our protocol in 1999.

All chemotherapy regimens were given every 14 days until normal hCG

levels wereobtained (b5 mIU/ml).Completeremission was confirmed after three

consecutive weeks ofhCG levels being within normal range if the patient was

asymptomatic. No further chemotherapywas given aftercomplete remission, and

gonadotrophin hormone levels were determined monthly for 1 year. Patientsreceived orientations about the use of effective contraceptive methods and about

the risk of becoming pregnant before finishing 1 year of follow-up.

Second-line chemotherapy was used in case of resistance or a toxicity grade of

3 or 4 using a primary cytotoxicscheme. Criteria forchemotherapy resistancewere

based on weekly hCG titers (plateau or increasing levels in two consecutive

weeks). Patients treated witha single-agent whopresented with toxicitygrades of 3

or 4 were subjected to another single-agent regimen. In the case of grade 3 or 4

toxicity in patients treated with MACT, the treatment was switched to a single-

agent regimen. Surgery was performedas adjuvant therapy for disease-resistanceto

cytotoxic therapy. Overall, 21 patients were subjected to surgery. Twenty patients

were subjected to hysterectomy and one patient was subjected to excision of

vaginal metastasis.

The first endpoint was comparing the remission rate between the groups of

patients with LRGTD treated with different chemotherapy regimens using a

product-limit survival fit. The efficacy of each chemotherapy regimen wasevaluatedaccording to the needof second-line chemotherapy, the needof surgery

to reach remission (chi-square test) the number of cycles to remission (Kruskal

Wallis test) and the overall duration of treatment (one-way ANOVA test). The

second endpoint was the analysis of the overall outcome and a comparison of the

toxic effects[15]among patients treated with methotrexate, dactinomycin or a

combination chemotherapy. The level of statistical significance was pb0.05.

Results

The patients' mean ages were 27.7, 26 and 23.7 years for

MTX, ACTD and MACT groups, respectively (p = 0.3; Kruskal

Wallis test). The antecedent pregnancy was a molar pregnancy in

39 patients (92.8%) from the MTX group, in 42 patients (100%)from the ACT group and in 22 patients (88%) from the MACT

group. Two patients in the MTX group and one in the MACT

group had a term pregnancy. Three patients (one in the MTX

group and two in the MACT group) had an ectopic pregnancy

(p =0.2; chi-square test). The time from mole evacuation or

pregnancy resolution to chemotherapy treatment was less than

4 months in 97.6% of patients in the MTX group, in all patients in

the ACT group and in 84% of the patients in the MACT group

(p = 0.01; chi-square test). The mean uterine volume according to

ultra-sound measurements before mole evacuation was 516 cm3

in the MTX group, 616 cm3 in the ACT group and 346 cm3 in the

MACT group (p = 0.2, KruskalWallis test with). According to

hCG levels, 16.7% of patients in the MTX group, 44.2% of

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patients in the ACT group and 12% of patients in the MACT

group had titers of over 105 mIU/ml (p =0.002; chi-square test).

Metastatic disease was present in 5 patients (11.9%) in the MTX

group (one pelvic and four lung metastases), in 6 patients (14.2%)

in the ACT group (all lung metastases) and in 6 patients (25%) in

the MACT group (three pelvic and three lung metastases); there

were no significant differences (p =0.1; chi-square test). FIGOstage I was the most common stage in all groups (p =0.1; chi-

square test). Classifying patients according to the WHO score of

risk,witha low score being3 and a high score beingN3and6,

19%, 38% and 8% of patients in the MTX, ACT and MACT

groups, respectively, were classified as having a high score

(p =0.01; chi-square test).Table 1summarizes the characteristics

of patients in the MTX, ACT and MACT groups.

The overall remission rate after the first-line treatment was

72.2%. We observed a complete remission in 70.2% of patients

treated with a single-agent chemotherapy (MTX group and ACT

group). The remission rate was 69% in the MTX group and

71.4% in the ACT group. The group subjected to a combinationregimen (MACT) had a remission rate of 79.1%. The difference

was not significant (p =0.6).

Overall, we observed 30 first-line treatment failures and all of

these patients were subjected to a second-line therapy. Among

ten patients with resistant disease to first-line dactinomycin, two

patients were treated with the single-agent methotrexate, seven

were treated with methotrexate and dactinomycin in combina-

tion and one patient was treated with a multi-agent chemother-

apy (EMA-CO). In the MTX group, we observed resistant

disease to first-line therapy in 11 patients; they were treated withmethotrexate and dactinomycin in combination. Two patients

presented toxic effects and the chemotherapy was switched to

single-agent dactinomycin. In the MACT group, five patients

were resistant to first-line therapy. Four patients were subjected

to multiple agent chemotherapy (MAC), and one was treated

with radiation therapy. Two patients presented with toxic effects

and the treatment was switched to a single-agent chemotherapy.

Surgery was performed on seven patients in the MTX group

(16.7%), on 10 patients in the ACT group (23.8%) and on four

patients in the MACT group (16.7%). There was no difference in

terms of the need for surgery to reach disease remission among

the groups (p =0.65). After classifying patients according to the

WHO score of risk, patients in the high score group were moreoften subjected to surgery than the subset of patients with a low

score (34.6% versus 14.6%, p = 0.02; chi-square test).

The overall duration of treatment until normal hCG levels

were reached among patients in theMTX, ACT andMACT groups

was 11.8, 10.5 and 8.9 weeks, respectively (p =0.2). The mean

number of chemotherapy cycles administered during this period

was 2.0 in the MTX group, 2.2 in the ACT group and 2.3 in the

MACT group (p =0.4).

Toxic effects were more often seen in the MACT group

(62.5%). Toxic effects were recorded in 28.6% of patients in the

MTX group and in 19.1% of patients in the ACT group. There is a

significant difference in the rates of toxic effects between subsetsof patients treated with either a single-agent or a combination

chemotherapy (p =0.0003). Grade 3 or 4 side effects were not

observed in the ACT group of patients. Grade 3 or 4 side effects

were observed in two patients in the MTX group (4.7%) and in

two patients in the MACT group (8.3%).Table 2summarizes the

results.

Discussion

The most commonly reported outcome measure in the

treatment of LRGTD is effectiveness. Under this context, the

efficacy of a cytotoxic treatment is evaluated through the rate of

cure (disease remission), the number of courses required to reach

Table 1

Characteristics of 108 patients with low-risk gestational trophoblastic disease treated

with single-agent methotrexate (MTX), dactinomycin (ACT) and methotrexate/

dactinomycin combination (MACT)

MTX

(n =42)

ACT

(n =42)

MACT

(n =24)

p

Mean age

(range)

27.7 (1750) 26 (1649) 23.7 (1335) NS

FIGO stage (n)

I 37 36 18

II 1 0 3

III 4 6 3 NS

WHO score (n)

b3 34 26 22

N3 and 6 8 16 2 0.01

Mean uterine

volume cm3

(range)

516

(831800)

616

(801955)

346

(651000)

NS

Antecedent pregnancy (n)Mole 39 42 22

Term 2 0 1

Ectopic 1 0 1 NS

Timea (n)

4 months 40 42 20

N4 months 2 0 4 0.001

hCG levelb (n)

b105 mIU/ml 35 24 21

105 mIU/ml 7 18 3 0.002

Metastasis (n)

Yes 5 6 5

No 37 36 19 NS

aTime between mole evacuation or pregnancy resolution and the diagnosis of

persistent gestational trophoblastic disease;

b

hCG level before mole evacua-tion;n =number of patients.

Table 2

Effectiveness of first-line chemotherapy in 108 patients with low-risk gestational

trophoblastic disease treated with single-agentmethotrexate (MTX), dactinomycin

(ACT) and methotrexate/dactinomycin combination (MACT)

MTX

(n =42)

ACT

(n =42)

MACT

(n =42)

p

Outcome [n (%)]Complete remission 29 (69) 30 (71.4) 19 (79.1)

Failure 13 (30) 12 (28.6) 5 (28.9) NS

Mean time to cure in

weeks (range)

11.8 (230) 10.5 (152) 8.9 (1 32) NS

Mean number of CT

courses (range)

2.0 (15) 2.2 (15) 2.3 (14) NS

Toxic effects [n(%)]

Yes 12 (28.6) 8 (19.1) 15 (62.5)

No 30 (71.4) 34 (80.9) 9 (37.5) 0.003

CT=chemotherapy; n =number of patients.

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complete remission, the rate of cure with second-line therapy in

case of first-line treatment failure and the rate of adverse effects

when the second-line treatment is needed [2]. However, two other

points should be taken as relevant: the cost and the compliance to

the treatment. Cost is a limiting factor for low-income countries,

and the duration of the treatment and number of courses necessary

to reach remission in association with side effects due to treatmenttoxicity has a direct impact on compliance to treatment[2].

There is no large randomized prospective clinical trails

comparing the efficacy of different chemotherapy regimens for

LRGTD, andthere is no consensus according to the best treatment

[2,12]. Overall, the efficacy of several chemotherapy regimens is

quite similar with remission rates being about 70% and with

adverse effects more common in patients receiving 5-day chemo-

therapy schemes [2,3]. As a single-agent, etoposide (VP16)

is reported to be the most efficient drug[4,16]. In a large retros-

pective study reviewing 247 patients comparing traditional

treatment schemes (MTX and ACT) with etoposide, the authors

reported a remission rate of 90.1% in the VP16 group (200 mg i.v.infusion D1D5) in contrast to 84% and 73.6% in the ACT and

MTX groups, respectively [4]. Although etoposide has been

reported to be more effective than other drugs as a single-agent

regimen, this drug is more toxic with high rates of total alopecia,

bone marrow depression, gastrointestinal disorders and a slight

increased risk of a second neoplasia[1618].

Methotrexate was the first agent used in the treatment of

persistent trophoblastic disease and still remains the most

prescribed drug. The earliest schedule consists of a daily intra-

muscular injection over the course of 5 days. The response rate

reported varies from 81% to 92.3%[17,1921]. The frequency of

adverse effects with this regimen was the motivation behind

alternative schedules with folinic acid rescue[22]. However, thelong duration of this regimen (8 days), the need for inpatient

treatment and the infusion pumps increased the costs and limited

this chemotherapy schedule, in particular being restrictive for low-

income countries[2].

An alternative schedule is the weekly methotrexate pulse

therapy with doses ranging from 30 to 50 mg/m2 [23]. This

regimen is associated with a higher number of chemotherapy

courses than a 5-day schedule [2]. Better results with single-agent

chemotherapy for LRGTD were reported with infusional metho-

trexate[10,24,25]. This regimen consists of 100 mg methotrexate

i.v.infused for 30 min followed by 200 mg in continuous injec-

tion over 12 h. Folinic acid rescue was described by New EnglandTrophoblastic Disease Center group [25]. According to these

authors, 44.8% to 81.5% of patients reached complete remission

after the first chemotherapy course. The infusional regimen seems

to be the most effective schedule when taking into account the

number of courses necessary to reach complete remission and the

duration of treatment. However, its use is limited by the need for

inpatient treatment and for infusion pumps.

The safety of dactinomycin in LRGTD is well established.

Several regimens have been used and the mean remission rate is

about 80%witha higher rate of toxic effects than the methotrexate

5-day schedule[11,26]. The pulse regimen of dactinomycin was

tested in a Gynecologic Oncology Group prospective trial [11].

The high response rate observed in this trial suggested that it

would be the best regimen for the treatment of LRGTD. However,

the study of Kohorn[7]observed a treatment failure of 20% for

patients treated with pulse therapy (1250 g/m2) in contrast to an

8% failure with the 12 g/kg i.v. 5-day dactinomycin regimen.

Additionally, the number of courses is higher in pulse therapy than

in the 5-day dactinomycin scheme [2]. We observed that the

number of chemotherapy courses was similar with the methotrex-ate and dactinomycin 5-day regimens (mean number of courses

was 2.0 and 2.2, respectively), and thecombination therapyneither

reduced the number of courses nor the duration of treatment.

Few reports describe the use of a sequential combination of

methotrexate and dactinomycin[1,5,13]. Although a high rate of

complete response was reported [13], we did not observe a

substantial gain in terms of effectiveness when comparing the

combination regimen with a single-agent treatment regimen. The

frequency of toxic effects in addition with the modest increase in

remission rate brought us to the conclusion that the use of

methotrexate in combination with dactinomycinis not suitablefor

LRGTD and its use must be suggested only for second-linetherapy.

With the good outcome observed with using chemotherapy for

treatment of LRGTD,hysterectomy became an adjuvant treatment

for emergency situations (uterine bleeding) and to remove

resistant residual disease[27]. Some studies report complete re-

mission for all patients treated with chemotherapy regardless of

the use of adjuvant hysterectomy [4]. On the other hand, per-

forming hysterectomy at the beginning of the cytotoxic treatment

decreases the duration of treatment and the number of chemo-

therapy courses[28]. In our study, no patient had a hysterectomy

prior to chemotherapy. Overall, 21 patients (19%) were subjected

to surgerydue to persistenthCG levels after at least one course of

chemotherapy. Upon classifying patients according to WHOscore, more patients in the group subjected to hysterectomy were

classified as having a high score in comparisonto the group treated

with no surgery. In addition, in the subset of patients subjected to

treatment, the number of chemotherapy courses was higher and

more time was needed to reach remission than observed for

patients not subjected to surgery. This observation supports the

hypothesis that some patients with non-metastatic LRGTD deve-

lop resistance to chemotherapy and surgical resection of the

residual disease must be considered.

Our analysis indicates that single-agent chemotherapy regi-

mens are as effective as combination chemotherapy for low-risk

gestational trophoblastic disease. Dactinomycin is the less toxicdrug and might offer the best cost-effective treatment option.

Methotrexate must be considered the regimen of choice for low

resource areas because of the feasibility of its administration.

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