The Journal of Reproductive Medicine

Actinomycin D for Methotrexate-Failed

Low-Risk Gestational Trophoblastic Neoplasia
John R. Lurain, M.D., Eloise Chapman-Davis, M.D., Anna V. Hoekstra, M.D., M.P.H.,
and Julian C. Schink, M.D.

OBJECTIVE: To determine outcomes and factors associly associated with resistance to secondary actinomycin D
ated with failure of 5-day actinomycin D for treatment of
chemotherapy was clinicopathologic diagnosis of choriomethotrexate-failed low-risk gestational trophoblastic
carcinoma versus postmolar GTN (56% versus 20%, p =
neoplasia (GTN).
0.025).
STUDY DESIGN: We reCONCLUSION: ActinomyThe complete response rate to
viewed the records of 358 pacin D 0.5 mg IV q.d. 5 d
tients treated with methoevery 14 d used as secondsecondary actinomycin D
trexate 0.4 mg/kg (max 25
ary therapy in methotrexatechemotherapy for failed
mg) IV push q.d. 5 d every
failed low-risk GTN resulted
14 d for FIGO-defined, lowin a 75% complete response
methotrexate treatment of
risk GTN between 1979 and
rate and eventual 100% cure
low-risk GTN was 75%...
2009. Actinomycin D 0.5 mg
with subsequent multiagent
IV push q.d. 5 d every 14 d
chemotherapy with or withwas given to 64 of 68 patients (18%) who failed methoout surgery. Resistance to sequential methotrexate and
trexate: 48 (75%) for resistance and 16 (25%) for toxiciactinomycin D chemotherapy was significantly associatty. Adjuvant surgery was used in selected patients. Clined with original FIGO score 3 and clinicopathologic diical response and survival as well as factors affecting
agnosis of choriocarcinoma. (J Reprod Med 2012;57:
outcomes were analyzed retrospectively.
283287)
RESULTS: The complete response rate to secondary
chemotherapy with actinomycin D for failed methotrexKeywords: actinomycin D, chemotherapy, gestaate treatment of low-risk GTN was 75% (48/64), includtional trophoblastic neoplasia, methotrexate.
ing 71% (34/48) for methotrexate resistance and 88%
(14/16) for methotrexate toxicity. All 20 patients (6%)
Patients categorized as having low-risk gestational
who failed sequential single-agent chemotherapy with
trophoblastic neoplasia (GTN) usually can be treatmethotrexate and actinomycin D were placed into pered successfully with single-agent methotrexate or
manent remission with the use of multiagent chemotheractinomycin D chemotherapy.1 Several different
apy with or without surgery. The only factor significantoutpatient chemotherapy protocols have been used
From the John I. Brewer Trophoblastic Disease Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Presented at the XVIth World Congress on Gestational Trophoblastic Diseases, Budapest, Hungary, October 1619, 2011.
Address correspondence to: John R. Lurain, M.D., 250 East Superior Street, Suite 05-2168, Chicago, IL 60611 (jlurain@nmff.org).
Financial Disclosure: The authors have no connection to any companies or products mentioned in this article.

0024-7758/12/5707-80283/$18.00/0 Journal of Reproductive Medicine, Inc.

The Journal of Reproductive Medicine

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which, in mostly nonrandomized, retrospective

studies, have yielded overall primary remission
rates ranging from 4994%.2,3 In general, the weekly intramuscular or intermittent intravenous infusion methotrexate and the biweekly single-dose actinomycin D protocols are less effective than one of
the 5-day methotrexate or actinomycin D protocols
and the 8-day methotrexate-folinic acid regimen.
Also, older patient age, higher human chorionic gonadotropin (hCG) level, nonmolar antecedent pregnancy, histopathologic diagnosis of choriocarcinoma, presence of metastatic disease, and higher
FIGO score have each been associated with an increased risk of initial chemotherapy resistance.1,4
Therefore, appropriate selection of secondary
chemotherapy with the alternate single-agent versus multiagent chemotherapy is important to provide for optimal results with the least toxicity.
Chemotherapy is usually changed to an alternative
single agent if the hCG level plateaus above normal
after an initial good response or if toxicity precludes
an adequate dose or frequency of the initial chemotherapeutic agent. If, on the other hand, there is a
significant elevation in hCG level, development of
metastases or resistance to sequential single-agent
chemotherapy, multiagent chemotherapy should
be initiated.
Several studies have reported on the effectiveness of actinomycin D as a second-line single agent
after failure of methotrexate as the initial chemotherapy for low-risk GTN.5-11 We undertook to
evaluate the results of 5-day actinomycin D (0.5 mg
IV q.d. 5 d every 14 d) as secondary therapy for
patients with low-risk GTN who failed initial 5-day
methotrexate (0.4 mg/kg max 25 mg IV q.d. 5 d
every 14 d) because of resistance or toxicity and to
determine factors responsible for actinomycin D
failure and eventual need for multiagent chemotherapy.
Materials and Methods
Three hundred fifty-eight patients with FIGOdefined low-risk GTN (stages IIII, score < 7) were
treated with methotrexate 0.4 mg/kg (max 25 mg)
IV push q.d. 5 d every 14 d at the John I. Brewer
Trophoblastic Disease Center of Northwestern University between 1979 and 2009. Sixty-four patients
(18%) who failed methotrexate were subsequently
treated with actinomycin D: 48 (75%) for methotrexate resistance and 16 (25%) for methotrexate toxicity. Actinomycin D was administered at a dose of 0.5
mg IV push q.d. 5 d every 14 d.

The Journal of Reproductive Medicine

Twenty patients, including 4 who failed methotrexate alone and 16 who failed sequential
single-agent methotrexate and actinomycin D,
were managed with combination drug regimens,
including methotrexate, actinomycin D, and cyclophosphamide (MAC) from 19791982 (2 patients), cyclophosphamide, hydroxyurea, actinomycin D, methotrexate, vincristine and doxorubicin
(CHAMOCA) from 19831985 (2 patients), etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA-CO) from 19862009 (16
patients), as well as EMA-EP (substituting etoposide and cisplatin for cyclophosphamide and vincristine in the EMA-CO protocol) or ICE (ifosfamide, carboplatin and etoposide) in 2 patients
resistant to EMA-CO. Adjuvant surgical procedures were performed in 6 patients: hysterectomy
at the time of initiation of actinomycin D (4), as well
as uterine wedge resection (1) and pulmonary resection (1) along with multiagent chemotherapy
after failed sequential single-agent chemotherapy.
Routine surveillance during treatment included
blood counts, serum chemistries, and hCG levels
the first day of each course of treatment. No treatment was started if the WBC count was < 3,000/
mm3 and the platelet count was < 100,000/mm3.
Response to treatment was determined by a decrease in hCG levels. Complete response or remission was diagnosed after three consecutive weekly
hCG levels were within normal range (< 2 mIU/
mL). Two additional courses of chemotherapy were
usually given after the first normal hCG level.
Follow-up after achieving remission and completing treatment consisted of one year of monthly hCG
levels and the use of contraception, preferably oral
contraceptive pills, for pregnancy prevention.
Patient and disease characteristics, including age,
antecedent pregnancy, clinicopathologic diagnosis,
hCG at the start of secondary actinomycin D treatment, and FIGO stage and score were collected
retrospectively. Univariate statistical analysis was
done with 2 to determine factors associated with
actinomycin D resistance. Toxicity was graded according to the Common Toxicity Criteria, v. 2.0. The
study was approved by the Northwestern University Institutional Review Board.
Results
Sixty-four (18%) of 358 patients with FIGO-defined
low-risk GTN who failed primary treatment with
methotrexate between 1979 and 2009 were treated
with actinomycin D 0.5 mg IV push q.d. 5 d every

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Volume 57, Number 7-8/July-August 2012

14 d. Patient and disease characteristics are presented in Table I. The average age of patients was 28
years (range, 1451 years). Most patients had a history of hydatidiform mole (88%) as their antecedent
pregnancy, an hCG level < 100 mIU/mL at the start
of actinomycin D (80%), and a clinicopathologic
diagnosis of postmolar GTN/invasive mole (86%).
Metastatic pulmonary disease was present in 17%
of patients, and 23% of patients had an original
FIGO score of 3. The mean number of courses of
methotrexate prior to actinomycin D was 5.1 (range,
112), for an average treatment duration of 10
weeks (224 weeks). The average number of
courses of actinomycin D administered was 3.2
(range, 18), encompassing 216 weeks.
The complete response rate to secondary actinomycin D chemotherapy for failed methotrexate
treatment of low-risk GTN was 75% (48/64), including 71% (34/48) for methotrexate resistance
and 88% (14/16) for methotrexate toxicity.
Four patients (6.3%) had grade 3 toxicity to actinomycin D, including stomatitis (2), nausea and
vomiting (2) and alopecia (1), necessitating discontinuation of actinomycin D. No patient experienced
grade 3 or 4 hematologic toxicity or drug extravasation.
All 20 patients who failed sequential single-agent

Table I Actinomycin D for Methotrexate-Failed Low-Risk GTN

Patient Characteristics (N = 64)
Characteristic
Age (yrs)
Antecedent pregnancy
Hydatidiform mole
Abortion
Term
Clinicopathology
Postmolar GTN
Choriocarcinoma
FIGO stage
I
III
FIGO score
<3
3
hCG at start of Act D
< 100 mIU/mL
> 100 mIU/mL
Reason for treatment change
Resistance
Toxicity

chemotherapy with methotrexate and actinomycin

D were placed into permanent remission with the
use of multiagent chemotherapy with or without
surgery, including 2/2 with MAC, 2/2 with
CHAMOCA and 14/16 with EMA-CO. The two patients who were resistant to EMA-CO were subsequently cured with EMA-EP or ICE. Additionally,
4 patients underwent hysterectomy at initiation of
actinomycin D chemotherapy, and 2 patients had
surgery for resistant choriocarcinoma in the uterus
(wedge resection) and lungs (video-assisted thoracoscopic surgery).
The only factor significantly associated with secondary actinomycin D resistance was clinicopathologic diagnosis of choriocarcinoma (5/9, 56%) versus postmolar GTN/invasive mole (11/55, 20%)
(p = 0.025). Although patients with a FIGO score 3
and an hCG level > 100 mIU/mL had approximately twice the rate of actinomycin D failure compared
to patients with a FIGO score < 3 and an hCG level
< 100 mIU/mL, the differences were not statistically significant. Metastatic disease and reason for
methotrexate treatment change were not associated
with actinomycin D resistance (Table II). On the
other hand, both clinicopathologic diagnosis of
choriocarcinoma and FIGO score 3 were significantly associated with resistance to sequential
single-agent chemotherapy with methotrexate and
actinomycin D chemotherapy for low-risk GTN
(Table III).

No. (%)
Mean = 28
(range, 1451)
56 (88)
4 (6)
4 (6)
55 (86)
9 (14)
53 (83)
11 (17)
Mean = 2, median = 2
(range, 07)
49 (77)
15 (23)
Mean = 415, median = 7
(range, 215,000)
51 (80)
13 (20)
48 (75)
16 (25)

Table II Factors Associated with Resistance to Secondary

Actinomycin D Chemotherapy for Methotrexate-Failed
Treatment of Low-Risk GTN

Factor
FIGO stage
I
III
FIGO score
<3
3
Clinicopathology
Postmolar GTN
Choriocarcinoma
hCG level
< 100 mIU/mL
> 100 mIU/mL
Reason for treatment
change
Resistance
Toxicity

Complete
response
No. (%)

Resistance
No. (%)

39 (74)
9 (82)

14 (26)
2 (18)

NS

39 (80)
9 (60)

10 (20)
6 (40)

NS

44 (80)
4 (44)

11 (20)
5 (56)

0.025

40 (80)
8 (57)

10 (20)
6 (43)

NS

34 (71)
14 (88)

14 (29)
2 (12)

NS

p Value

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Table III

The Journal of Reproductive Medicine

Factors Associated with Resistance to Sequential

Single-Agent Chemotherapy with Methotrexate and
Actinomycin D for Low-Risk GTN (N = 20)

Factor
FIGO score*
<3
3
Clinicopathology
Postmolar GTN
Choriocarcinoma

Complete
response
No. (%)

Resistance
No. (%)

258 (96)
77 (89)

10 (4)
10 (12)

0.005

299 (96)
39 (81)

11 (4)
9 (19)

< 0.0001

p Value

*Data missing on some patients.

Discussion
Of 358 patients with FIGO-defined low-risk GTN
treated with methotrexate at the Brewer Center
from 19792009, 64 (18%) were treated secondarily
with actinomycin D. Seventy-five percent of patients who failed methotrexate were placed into remission with actinomycin D, including 34 (71%) of
48 patients who were changed to actinomycin D
due to methotrexate resistance and 14 (88%) of 16
patients who were changed to actinomycin D due to
methotrexate toxicity. All 20 patients (6%) who
failed sequential single-agent chemotherapy were
subsequently cured with the use of multiagent
chemotherapy with or without surgery. Factors significantly associated with resistance to sequential
single-agent chemotherapy with methotrexate and
actinomycin D as given at our center for low-risk
GTN were clinicopathologic diagnosis of choriocarcinoma and FIGO score 3.
We previously reported our experience treating
both nonmetastatic and low-risk metastatic GTN
with methotrexate followed by actinomycin D as
secondary therapy. From 19621990 we treated 253
patients with nonmetastatic GTN with the 5-day
methotrexate regimen. Of 27 patients (11%) who
required a change in treatment, 22 (81%) had a
complete response to 5-day actinomycin D and 5
patients (19%) required multiagent chemotherapy
with or without surgery for cure.5 Between 1962
and 1992 we treated 61 patients with low-risk metastatic GTN with 5-day methotrexate. Of 21 patients
(34%) requiring a change in treatment, 20 (95%) had
a complete response to 5-day actinomycin D and 1
(5%) required multiagent chemotherapy for cure.6
Combining these two series, 48 (15%) of 314 patients required a change from methotrexate to

actinomycin D, and the complete response rate to

actinomycin D as secondary therapy was 88%.
Several other studies have reported on the effectiveness of actinomycin D as a second-line single
agent after failure of methotrexate as initial chemotherapy for low-risk GTN. McNeish et al7 at Charing Cross Hospital (London, UK) reported on the
treatment of 485 low-risk patients with 8-day
methotrexatefolinic acid, 161 (33%) of whom required a change in treatment because of either
methotrexate resistance (150, 31%) or toxicity (11,
2%). Only the 67 patients with hCG levels < 100
mIU/mL were subsequently treated with 5-day actinomycin D; 87% (58) had a complete response and
13% (9) required multiagent chemotherapy. The 94
patients with hCG levels > 100 mIU/mL were treated with multiagent EMA-CO chemotherapy, 99% of
whom had a complete response. Therefore, 103
(21%) of 485 low-risk patients ended up receiving
multiagent chemotherapy, although overall survival rate was 99.8%. Growden et al8 at the New
England Trophoblastic Disease Center (Boston,
Massachusetts) evaluated response to treatment
with 5-day actinomycin D after resistance to either
8-day methotrexatefolinic acid or infusion methotrexate protocols in 150 patients with low-risk GTN.
Forty-five patients (30%) developed methotrexate
resistance. Of the 37 methotrexate-resistant patients
who received actinomycin D, 73% had a complete
response. Twelve percent of all low-risk patients
eventually required multiagent chemotherapy for
cure. An hCG level > 600 mIU/mL one week after
the first dose of methotrexate was the only factor
associated with the eventual need for multiagent
chemotherapy.
There are three reports on the use of pulse actinomycin D (1.25 mg/m2 IV every 14 d) as salvage
therapy for methotrexate-failed low-risk GTN.
Chen et al9 reported a 60% complete response rate
in 10 patients, one of whom died of chemoresistant
metastatic choriocarcinoma. In a phase II Gynecologic Oncology Group study, Covens et al10 reported a 74% complete response rate to pulse actinomycin D in 38 patients with nonmetastatic postmolar
GTN excluding choriocarcinoma who had failed
weekly IM methotrexate chemotherapy. All 10
treatment failures achieved a complete response
after receiving additional chemotherapy as well as
hysterectomy in 3 patients. Kang et al11 from Korea
reported a 76% complete response rate to pulse actinomycin D in 37 patients with methotrexate-failed
low-risk GTN. They noted that the risk of requiring

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third-line chemotherapy was significantly associated with hCG level > 1,000 mIU/mL at initiation of
pulse actinomycin D and rising FIGO score of 2
after first-line methotrexate chemotherapy but was
not associated with reason for change from methotrexate (toxicity versus resistance), metastatic disease, or original FIGO score. The 9 patients who received multiagent chemotherapy were cured.
In summary, patients with FIGO-defined lowrisk GTN (stages IIII, score < 7) can be treated with
initial single-agent methotrexate chemotherapy
using one of the 5-day or alternating 8-day/folinic
acid protocols with a 6790% expectation of primary remission. Secondary treatment with actinomycin D will result in an additional 6080% of
methotrexate-failed patients entering remission.
Eventually, approximately 515% of patients will
require multiagent chemotherapy with or without
surgery to achieve remission, with cure rates approaching 100%. Factors associated with resistance
to sequential single-agent chemotherapy with
methotrexate and actinomycin D are clinicopathologic diagnosis of choriocarcinoma and higher
FIGO score, as demonstrated in our study, as well
as possibly higher hCG levels and presence of
metastases as noted in other reports.
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