ORIGINAL ARTICLE

Actinomycin D Versus Methotrexate-Folinic Acid as

the Treatment of Stage I, Low-Risk Gestational
Trophoblastic Neoplasia
A Randomized Controlled Trial
Arb-aroon Lertkhachonsuk, MD, Nathpong Israngura, MD, MSc,
Sarikapan Wilailak, MD, and Somsak Tangtrakul, MD

Abstract: This study is to compare the remission and complication rates of actinomycin D
(Act-D) and methotrexate-folinic acid (MTX-FA) as single-agent treatments of stage I, lowrisk gestational trophoblastic neoplasia (GTN). From 1994 to 2005, all women with
International Federation of Gynecology and Obstetrics stage I, low-risk GTN were
randomly assigned to received either intravenous Act-D 10 Kg/kg per day for 5 days every 2
weeks or intramuscular methotrexate 1 mg/kg per day on days 1, 3, 5, and 7 with
intramuscular folinic acid 0.1 mg/kg per day on days 2, 4, 6, and 8 every 2 weeks. Fortynine women met the eligibility criteria. Age, human chorionic gonadotropin level, and
International Federation of Gynecology and Obstetrics score were similar in both treatment
groups. Of the 22 women who received Act-D, 2 were lost to follow-up. Among the 27
women who received MTX-FA, 2 were lost to follow-up, and 6 had to switch to Act-D
because of the rising levels of liver enzymes. All 20 women (100%) in the Act-D arm
achieved remission compared with 14 (73.6%) in 19 women in the MTX-FA arm (P = 0.02).
Mucositis and alopecia were reported more frequently in the Act-D group, whereas
elevations of liver enzyme levels were more frequent in the MTX-FA group. Actinomycin D
seems to be more effective than MTX-FA in the treatment of stage I, low-risk GTN. Larger
multicenter randomized controlled trials should be conducted to establish the most
appropriate regimen for these patients.
Key Words: Gestational trophoblastic neoplasia, Actinomycin, Methotrexate
(Int J Gynecol Cancer 2009;19: 985Y988)

estational trophoblastic neoplasia (GTN) is an infrequent

malignant condition resulting from abnormal growth of the
trophoblasts. Although fatal outcomes are imminent among untreated patients, this condition is extremely responsive to chemotherapy and is recognized as the most curable gynecologic malignancy.
Almost all patients with low-risk GTN are cured with chemotherapy.
Various single-agent chemotherapy regimens had been used
in low-risk cases with different effectiveness outcomes and toxicity
Department of Obstetrics and Gynaecology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Address correspondence and reprint requests to Arb-aroon Lertkhachonsuk,
MD, Department of Obstetrics and Gynaecology, Faculty of Medicine,
Ramathibodi Hospital, Rama VI Rd, Bangkok 10400, Thailand.
E-mail: arbaroon@hotmail.com, raalk@mahidol.ac.th.
Copyright * 2009 by IGCS and ESGO
ISSN: 1048-891X
DOI: 10.1111/IGC.0b013e3181a8333d

International Journal of Gynecological Cancer

proles. Four general agents reported were methotrexate (MTX)

with/without folinic acid rescue, actinomycin D (Act-D), etoposide,
and 5-ourouracil.1 Act-D and MTX regimens are the most widely
used drugs2 and have been suggested as the treatment of choice for
nonmetastatic/low-risk GTN.3,4
The rst report of successful treatment of GTN with MTX
was described5 by Li in 1956. A variety of MTX regimens followed;
however, the best protocol cannot be identied by evidence-based
review.6 The most commonly used regimen in Europe and
worldwide apart from North America is the Charing Cross regimen
of MTX-folinic acid (MTX-FA).1,7 The protocol consists of intramuscular MTX 50 mg or 1 mg/kg on days 1, 3, 5, and 7 with folinic
acid 7.5 to 15 mg orally or 0.1 mg/kg intramuscularly on days 2, 4, 6,
and 8. Complete remission rates from large studies ranged from
66.8% to 90.2%, with severe toxicity of 0% to 6%.5,7Y9
Actinomycin D was rst reported as a treatment of GTN by
Goldstein et al10 in 1972. The classic regimen is intravenous Act-D
8 to 14 Kg/kg per day for 5 days every 14 days. This is an effective

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Lertkhachonsuk et al

International Journal of Gynecological Cancer

regimen with complete remission rates ranging from 77% to

94%.11Y14 Although earlier studies did not report serious adverse
effects,13 the regimen was claimed to have the drawback of signicant gastrointestinal toxicity and alopecia.1 In the United States,
the Gynecologic Oncology Group (GOG) prefers pulse Act-D with a
single dose given every 2 weeks because of less toxicity.
Although several treatment regimens have been published,
there is a scarcity of levels I and II evidence on the best chemotherapeutic treatment of this disease.1,2 At present, there had been
few prospective randomized controlled trials. One report from Iran
compared between weekly intramuscular methotrexate and biweekly
intravenous actinomycin; complete response was higher in the actinomycin group.15 Another trial of similar protocols has been conducted by the GOG with the results pending.
In Thailand, the most common regimens used for low-risk
trophoblastic neoplasia have long been the 8-day regimen of MTX-FA
and, less commonly, 5-day Act-D. Thus, the purpose of this study was
to compare the remission and complication rates of 5-day Act-D and
MTX-FA as single-agent treatments of stage I, low-risk GTN.

MATERIALS AND METHODS

Patient Selection and Eligibility
Between January 1994 and December 2005, all women who
had diagnoses of nonmetastatic GTN at the Faculty of Medicine,
Ramathibodi Hospital, Mahidol University, were recruited for the
study. The eligibility criteria were nonmetastatic GTN with normal
pretreatment laboratory evaluation results and a performance status
of 0 to 1 by Zubrod. The patients conditions were diagnosed as
GTN if there was a plateau or rising of serum human chorionic
gonadotropin (hCG) level after evacuation of hydatidiform mole or a
histologic diagnosis of choriocarcinoma. For staging and pretreatment evaluation, all patients underwent complete physical and pelvic
examination, complete blood cell count, urinalysis, liver and renal
function tests, and chest x-ray. Ultrasonography and/or computed
tomographic scanning were performed when clinically indicated.
Diagnosis, staging, and risk scoring were subsequently revised with
the International Federation of Gynecology and Obstetrics (FIGO)
2000 criteria for diagnosis and staging for GTN,16 and all of the
patients had stage I, low-risk GTN.
Pretreatment laboratory data included a serum creatinine level
of 1.5 mg/dL or less, serum bilirubin level, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) less than or equal to the upper limit of normal,
hemoglobin level higher than 10 g/dL, white blood cell count greater
than 3000/KL, absolute neutrophil count greater than 1500/KL, and
platelet count greater than 100,000/KL.
The study protocol was approved by the departmental ethical
committee, and written informed consents were obtained from all
patients. The patients were recruited by the authors (S.T. and A.L.)
according to the protocol. They were then randomly assigned into
2 treatment groups, Act-D and MTX-FA, using a table of random
numbers from the Epidemiology Unit. The recruitment and management protocols were strictly followed throughout the study.

Treatment

Patients in the Act-D arm received Act-D 10 Kg/kg per day

intravenously for 5 days. Patients in the MTX-FA arm received
intramuscular MTX 1 mg/kg per day on days 1, 3, 5, and 7,
alternating with intramuscular folinic acid 0.1 mg/kg per day on days
2, 4, 6, and 8. Both treatment regimens were administered every
2 weeks until remission with one additional cycle as consolidation
therapy. Remission was dened as 3 consecutive normal weekly
hCG titers.

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During treatment, physical and pelvic examination, complete

blood cell counts, and serum hCG level measurements were performed every 1 to 2 weeks in both groups. The DPC Immulite
immunoassay system was used for serum hCG assay. Serum
glutamic oxaloacetic transaminase and SGPT were measured on
days 1, 3, 5, and 7 in the MTX-FA arm. Toxicities were recorded as
grades according to the World Health Organization (WHO).17
In patients who had complications from chemotherapy or who
demonstrated rising or a plateau of hCG level, the other regimen was
administered. Patients who were lost to follow-up or unable to complete the protocol were excluded from the study.
The follow-up after remission consisted of biweekly serum
hCG level determination for 1 more month, then monthly for 5 months,
and then every 2 months up to 1 year.

Statistical Analysis
The primary end point was remission rate, and the secondary
end point was complication rate. Based on previous data from our
institution, the required sample size was estimated as 26 patients
for each group, on the basis of the ability to detect 26% difference
between the 2 regimens, with a statistical power of 80% and a 2sided signicance level of 0.05.
Statistical analyses were performed using SPSS version 11.5
(SPSS Inc, Chicago, Ill). W2 tests were used to compare patient
characteristics, remission rates, and complication rates between the
2 groups. All P values are based on 2-sided tests with P G 0.05 taken
as signicant.

RESULTS
Patient Characteristics
Between January 1994 and December 2005, there were a total
of 71 patients with low-risk GTN in our institution; 12 had metastases in the pelvis or the lungs, 6 had been partially treated from
other hospitals before referral, and 4 refused to be included in the
clinical trial. Thus, there were 49 eligible patients who were registered in the study. Twenty-two were randomized to the Act-D arm
and 27 to the MTX-FA arm.
As shown in Table 1, the 2 study groups were well balanced
for patient characteristics including age, FIGO score, antecedent
pregnancy, interval months from index pregnancy, pretreatment
serum hCG level, and largest tumor size. The mean ages T SD of
the patients were 28.7 T 8.2 and 30.5 T 7.1 years in the Act-D and the
MTX-FA groups, respectively. The mean FIGO scores T SD were
1.59 T 1.14 and 1.59 T 1.22 in the Act-D and the MTX-FA groups,
respectively. The median serum hCG levels were 3449 and 3389
mIU/mL in the Act-D and the MTX-FA groups, respectively, with
the range of 30 to 43,297 and 98 to 500,000 mIU/mL. None of these
characteristics were signicantly different between the 2 groups in
univariate analysis.

Treatment Compliance
Of the 22 women who were randomized to the Act-D arm, 2
were lost to follow-up after only one cycle of treatment. Among the
27 women who were randomized to the MTX-FA arm, 2 were lost to
follow-up after 1 and 3 cycles of treatment, and 6 had to switch to
Act-D because of rising liver enzyme levels up to twice the upper
limit of normal level after the mean of 1.45 T 1.1 cycles (range,
0.5Y3.5 cycles) of treatment.

Adverse Effects
As shown in Table 2, mucositis and alopecia were reported
more frequently in the Act-D group, whereas elevations of liver
enzyme levels were more frequent in the MTX-FA group. Most
cases of alopecia were grade 2 with moderate, patchy alopecia. All
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International Journal of Gynecological Cancer

& Volume 19, Number 5, July 2009

were reversible after completion of treatment. There were 6 patients

in the Act-D group with grade 3 mucositis, that is, oral ulcers, which
required only liquid diet. Chemotherapy had to be postponed until
recovery of the oral mucosa. Alopecia and mucositis usually
commenced on the second cycle. One patient in the MTX-FA group
experienced grade 3 neutropenia on the third cycle, and granulocyte
colony-stimulating factor had to be administered. One patient in the
Act-D group had grade 3 thrombocytopenia without neutropenia
after the fourth cycle. Fortunately, it occurred after remission had
been achieved, and the patient was well after platelets had been
transfused and further chemotherapy withheld. One patient in the
Act-D group experienced obviously darkened skin on the second
and the third cycles of treatment without other adverse effects.
Hepatotoxicity was observed in 6 of the patients in the MTXFA arm. In 3 cases, SGOT and SGPT increased to approximately
3 times the upper limit of normal. In the other 3 cases, physicians
were alarmed after SGOT and SGPT demonstrated a rising trend;
thus, methotrexate was withheld when both values were just higher
than 1.25 times the upper limit of normal. Elevations of liver enzyme
levels usually occurred just before the second cycle. Liver function
returned to normal within a few weeks after cessation of methotrexate in all patients except in one who was inaccessible because
she was lost to follow-up.

Outcomes
All 20 women (100%) in the Act-D arm achieved remission
compared with 14 (73.6%) of the 19 women in the MTX-FA arm

TABLE 1. Patient characteristics

Act-D
(n = 22)

MTX-FA
(n = 27)

Characteristics

G40
Q40
FIGO score
0
1
2
3
4
5
6
Antecedent pregnancy
Molar
Abortion
Term
Interval from index
G4
pregnancy, mo
4 j G7
7 j G13
Q13
Pretreatment serum hCG
G103
103 j G104
104 j G105
Q105
Largest tumor size, cm
G3
level, mIU/mL
3 j G5
95

20
2
3
9
6
2
2
0
0
20
2
0
17
4
1
0
7
10
5
0
19
2
1

90.9
9.1
13.6
40.9
27.3
9.1
9.1
0
0
90.9
9.1
0
77.3
18.2
4.5
0
31.8
45.5
22.7
0
86.4
9.1
4.5

25
2
5
8
10
2
1
1
0
26
1
0
26
0
1
0
7
10
9
1
26
0
1

92.6
7.4
18.6
29.6
37.0
7.4
3.7
3.7
0
96.3
3.7
0
96.3
0
3.7
0
25.9
37.0
33.4
3.7
96.3
0
3.7

Age, yr

Actinomycin D Versus MTX-FA for GTN

TABLE 2. Patients with adverse events

Act-D

MTX-FA

WHO Grade
(n = 22)

WHO Grade
(n = 27)

Adverse Events

Alopecia
Liver toxicity
Mucositis
Neutropenia
Thrombocytopenia

5
0
3
1
0

6
0
3
0
0

1
0
6
0
0

0
0
0
0
1

0
3
1
2
0

0
3
1
0
0

0
0
0
1
0

0
0
0
0
0

(P = 0.02). The patients in the Act-D group received a mean of

3.50 T 1.47 cycles of chemotherapy, whereas the patients in the
MTX-FA group received a mean of 4.13 T 1.61 cycles.
All patients who had MTX-FA resistance or elevated levels of
liver enzymes achieved remission after switching to Act-D, except
one patient who was lost to follow-up after one cycle of Act-D.
Averagely 3 additional cycles of Act-D were required to achieve
remission.

DISCUSSION
Gestational trophoblastic neoplasia is an uncommon neoplasm that usually responds well to chemotherapy. Various singleagent therapeutic regimens for low-risk, stage I GTN have been
reported with high efcacy. However, with the paucity of randomized controlled trial, it is difcult to determine the best regimen
for this condition.
In this study, we chose to compare between the 8-day MTXFA and the classic 5-day Act-D regimens. Both regimens have long
been recommended in major gynecologic oncology textbooks, and
the 8-day MTX-FA is the most common regimen for low-risk GTN
worldwide and the most widely used regimen in Thailand.
The original Bagshawe regimen from Charing Cross Hospital
consists of intramuscular MTX 50 mg on days 1, 3, 5, and 7 with
folinic acid 6 mg intramuscularly on days 2, 4, 6, and 8, repeated
every 2 weeks. Remission was obtained in 80% of 348 low-risk
patients according to the Charing Cross scoring system.7 The protocol was later changed to oral folinic acid 7.5 mg/d on days 2, 4, 6,
and 8. McNeish et al8 reported 66.8% remission rate in 485 patients
with low-risk GTN. The second largest series by Khan et al9 reported
72% overall complete response rate among 250 patients with lowrisk GTN with a hepatotoxicity rate of 2%. The New England
Trophoblastic Disease Center modied the regimen to intramuscular
MTX 1 mg/kg on days 1, 3, 5, and 7 with folinic acid 0.1 mg/kg
intramuscularly on days 2, 4, 6, and 8. A further course of 1- to 2mg/kg MTX per day would be given only if hCG level rose,
plateaued, or decreased less than 1 log for 18 days. Berkowitz et al5
reported complete remission rate of 90.2% in 163 patients with
nonmetastatic GTN, using this regimen. Hepatotoxicity was
discovered in 14.1% of 185 patients, including low-risk metastatic
diseases. Granulocytopenia was found in 5.9%.
In Thailand, Srisomboon et al18 retrospectively reported 89%
complete remission after primary treatment of 55 patients who had
nonmetastatic GTN with intramuscular MTX 1 mg/kg on days 1, 3,
5, and 7 and with folinic acid 0.1 mg/kg intramuscularly on days 2,
4, 6, and 8, repeated every 14 days. The mean number of chemotherapy course was 4.7. Five patients had mild stomatitis with no
abnormal liver function test results. Another case series from

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987

Lertkhachonsuk et al

International Journal of Gynecological Cancer

Thailand included GTN of all stages with low and intermediate risks
according to modied WHO scoring system. Using intramuscular
MTX 50 mg/d alternating with 15-mg/d oral folinic acid for a total
of 8 days, complete remission was achieved in 68% with 6.4% of
mucositis and hepatotoxicity.19
After exclusion of patients who were lost to follow-up and
who had a change of chemotherapy regimen because of rising liver
enzyme levels, the complete remission rate of stage I, low-risk GTN
in the MTX-FA arm of our study was 73.6%. All of the resistant
patients were cured after being switched to 5-day Act-D.
Hepatotoxicity is the major problem of MTX-FA in our study.
Six (22.2%) of the 27 patients had grades 1 and 2 elevations of liver
enzyme levels, which prompted the change of therapeutic regimen.
However, liver functions returned to normal after cessation of MTX
in all cases. This hepatotoxic rate was higher than that in previous
studies. Although none of our patients were seropositive for hepatitis
B surface antigen, further investigations are required to nd the
explanation for this phenomenon. This nding complied with the
long-held recommendation that this regimen should not be used in
the area where parenchymal liver diseases might be prevalent.13
Charing Cross Hospital had improved mucositis rate by escalating
oral folinic acid dosage from 7.5 to 15 mg/d.8 Whether increasing
intramuscular folinic acid dosage would improve liver functions
awaits further exploration.
From this study, the 5-day Act-D regimen was found to be
more effective than 8-day MTX-FA for the treatment of stage I, lowrisk GTN, with the complete remission rate of 100%. This high remission rate resembles that in the earlier preliminary report of 5-day
Act-D by Goldstein et al.10 However, the remission rate in nonmetastatic trophoblastic disease slightly decreased to 94% when the
same authors increased the number of subjects13 from 12 to 31.
Further data from various authors also reported this regimen as
highly effective with the mean of 3 to 4 cycles of treatment.11Y14 The
major toxicities are neutropenia and stomatitis in 42% of patients in
the study of Petrilli and Morrow14; however, most of them are mild,
and no serious adverse effects were reported in the study of
Osathanondh et al.13 To overcome these toxicities, pulse Act-D
regimen was proposed, with 1.25-mg/m2 Act-D administered in
bolus doses every 2 weeks. A phase 2 trial of the GOG reported a
remission rate of 94% with comparable toxicity.20 Because of the
ease of administration, greater patient convenience, and improved
cost-effectiveness, pulse Act-D had been recommended as the treatment of choice in nonmetastatic GTN in the United States.14,20
However, many patients who failed to respond to pulse regimen were
found to achieve remission after being switched to the classic 5-day
regimen, proving the superior efcacy of the latter.21
Major toxicities of Act-D in our study included mucositis and
alopecia. Six (22%) of 22 patients experienced grade 3 mucositis.
Alopecia was also an undesirable effect for most patients, but full
recoveries of hair growth were observed in virtually all patients after
cessation of chemotherapy. The shorter duration of treatment from
the more effective chemotherapeutic regimen makes the unpleasant
adverse effects shorter, thus being more tolerable and increasing
patients compliance.
From our study, 5-day Act-D seems to be more effective than
8-day MTX-FA in the treatment of stage I, low-risk GTN, with the
expense of more alopecia and mucositis. Because these adverse effects are reversible and manageable, the authors preferred Act-D as
the rst-line treatment in this group of patients. Some institutions
might prefer less toxic primary regimen and reserve 5-day Act-D
as a second-line therapy; however, if more effective primary therapy
is preferred, 5-day Act-D should be the regimen of choice. Patients
should be counseled regarding the pros and cons of each regimen.
With the scarcity of level III evidence in the treatment
of gestational trophoblastic neoplasia, we recommend that more

988

& Volume 19, Number 5, July 2009

randomized controlled trails be conducted, with similarly dened

FIGO staging and criteria to gain a clearer insight regarding the best
treatment of this disease.

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