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Gestational Trophoblastic
Gestational Trophoblastic
Neoplasia
Neoplasia
Chris DeSimone, MD
Chris DeSimone, MD
Assistant Professor
Assistant Professor
Division of Gynecologic Oncology
Division of Gynecologic Oncology
Department of Obstetrics & Gynecology
Department of Obstetrics & Gynecology
Gestational Trophoblastic Neoplasia
Gestational Trophoblastic Neoplasia
(GTN)
(GTN)
•
•
Ancient disease
Ancient disease
•
•
Hippocrates documented a
Hippocrates documented a
hydatidiform
hydatidiform
mole in the 4
mole in the 4
th
th
century BC
century BC
•
•
William
William
Smellie
Smellie
(Scottish mid
(Scottish mid
-
-
wife, circa 1700) was the first
wife, circa 1700) was the first
to coin the terms
to coin the terms
Hydatid
Hydatid
and
and
Mole
Mole
What is a mole?
What is a mole?
What is a mole?
What is a mole?
•
•
A mole is the amount of pure substance containing the
A mole is the amount of pure substance containing the
same number of chemical units as there are atoms in
same number of chemical units as there are atoms in
exactly 12 grams of carbon
exactly 12 grams of carbon
-
-
12 (i.e., 6.023 X 10
12 (i.e., 6.023 X 10
23
23
). This
). This
involves the acceptance of two dictates
involves the acceptance of two dictates
--
--
the scale of
the scale of
atomic masses and the magnitude of the gram. Both
atomic masses and the magnitude of the gram. Both
have been established by international agreement.
have been established by international agreement.
Formerly, the connotation of "mole" was "gram
Formerly, the connotation of "mole" was "gram
molecular weight." Current usage tends to apply the
molecular weight." Current usage tends to apply the
term "mole" to an amount containing
term "mole" to an amount containing
Avogadro's
Avogadro's
number of whatever units are being considered. Thus, it
number of whatever units are being considered. Thus, it
is possible to have a mole of atoms, ions, radicals,
is possible to have a mole of atoms, ions, radicals,
electrons, or quanta. This usage makes unnecessary
electrons, or quanta. This usage makes unnecessary
such terms as "gram
such terms as "gram
-
-
atom," "gram
atom," "gram
-
-
formula weight," etc.
formula weight," etc.
What is a mole?
What is a mole?
What is a mole?
What is a mole?
Epidemiology
Epidemiology
•
•
Incidence
Incidence
–
–
Less than 1/1000 pregnancies (World)
Less than 1/1000 pregnancies (World)
–
–
Japan
Japan
-
-
2/1000 pregnancies
2/1000 pregnancies
•
•
Age
Age
–
–
Bandy et al. Obstet Gynecol. 1984.
Bandy et al. Obstet Gynecol. 1984.
–
–
Women < 15 years or > 40 years at increased risk
Women < 15 years or > 40 years at increased risk
–
–
Greatest risk > 50 years (RR
Greatest risk > 50 years (RR
-
-
519)
519)
•
•
Diet
Diet
–
–
Decreased animal fat and Vitamin A
Decreased animal fat and Vitamin A
•
•
Risk of another molar pregnancy
Risk of another molar pregnancy
–
–
Bagshawe
Bagshawe
et al. Cancer. 1976.
et al. Cancer. 1976.
–
–
1 in 76 pregnancies have a second mole
1 in 76 pregnancies have a second mole
–
–
1 in 6.5 pregnancies have a third mole with 2 prior molar
1 in 6.5 pregnancies have a third mole with 2 prior molar
pregnancies
pregnancies
The Changing Symptoms of a
The Changing Symptoms of a
Complete Mole
Complete Mole
12 weeks
12 weeks
-
-
1.3%
1.3%
8%
8%
28%
28%
84%
84%
1988
1988
-
-
1993
1993
P=0.005
P=0.005
P=0.02
P=0.02
P=0.001
P=0.001
P=0.001
P=0.001
P=0.001
P=0.001
P=0.001
P=0.001
Significance
Significance
16 weeks
16 weeks
Median Age of
Median Age of
Evacuation
Evacuation
7%
7%
Hyperthyroidism
Hyperthyroidism
27%
27%
Preeclampsia
Preeclampsia
26%
26%
Hyperemesis
Hyperemesis
51%
51%
Excessive Uterine Size
Excessive Uterine Size
97%
97%
Vaginal Bleeding
Vaginal Bleeding
1965
1965
-
-
1975
1975
Soto
Soto
-
-
Wright et al.
Wright et al.
Obstet Gynecol. 1995.
Obstet Gynecol. 1995.
Curry et al. Obstet Gynecol. 1975.
Curry et al. Obstet Gynecol. 1975.
Symptoms of a Complete Mole
Symptoms of a Complete Mole
•
•
Clinical hyperthyroidism occurs in less
Clinical hyperthyroidism occurs in less
than 1% of patients
than 1% of patients
•
•
10% of patients have an elevation of T3
10% of patients have an elevation of T3
and T4
and T4
•
•
Theca
Theca
-
-
lutein
lutein
cysts are found in 15% of
cysts are found in 15% of
complete moles
complete moles
•
•
57% of patients with a complete mole and
57% of patients with a complete mole and
theca
theca
-
-
lutein
lutein
cysts will have GTN
cysts will have GTN
Diagnosis
Diagnosis
•
•
Intact HCG
Intact HCG
•
•
Ultrasound
Ultrasound
•
•
Evacuation
Evacuation
–
–
Suction curettage
Suction curettage
surgery of choice
surgery of choice
–
–
Pre
Pre
-
-
Op checklist
Op checklist
•
•
CBC
CBC
•
•
Thyroid panel
Thyroid panel
•
•
Maternal
Maternal
Rh
Rh
factor
factor
•
•
Type & Cross
Type & Cross
Complete and Partial Moles
Complete and Partial Moles
46 XX (90%)
46 XX (90%)
46 XY (10%)
46 XY (10%)
Triploidy
Triploidy
XXX, XXY, XYY
XXX, XXY, XYY
Karyotype
Karyotype
19%
19%
3.5%
3.5%
GTN
GTN
Diffuse
Diffuse
Focal
Focal
Trophoblastic
Trophoblastic
Hyperplasia
Hyperplasia
Diffuse
Diffuse
Focal
Focal
Villous Edema
Villous Edema
Absent
Absent
Present
Present
Fetal Tissue
Fetal Tissue
Complete Mole
Complete Mole
Partial Mole
Partial Mole
Follow
Follow
-
-
up of Molar Pregnancy
up of Molar Pregnancy
•
•
Intact HCG test of choice
Intact HCG test of choice
•
•
Β
Β
-
-
HCG no longer used at
HCG no longer used at
UK and in Lexington
UK and in Lexington
•
•
Average time to reach
Average time to reach
undetectable HCG, 73
undetectable HCG, 73
days
days
(Ho Yuen et al. Am J Obstet
(Ho Yuen et al. Am J Obstet
Gynecol, 1981.)
Gynecol, 1981.)
•
•
CONTRACEPTION!
CONTRACEPTION!
•
•
1 week follow
1 week follow
-
-
up for 4
up for 4
weeks then…
weeks then…
•
•
Once every 2 weeks for 4
Once every 2 weeks for 4
weeks then…
weeks then…
•
•
Once a month for 4
Once a month for 4
months
months
(
(
Wolfberg
Wolfberg
et al. Obstet
et al. Obstet
Gynecol, 2006.)
Gynecol, 2006.)
•
•
Total of 6 months
Total of 6 months
•
•
0/238 women with partial
0/238 women with partial
molar pregnancies had
molar pregnancies had
GTN with declining
GTN with declining
HCG’s
HCG’s
•
•
Complete moles should
Complete moles should
be followed longer
be followed longer
Follow
Follow
-
-
up of Molar Pregnancy
up of Molar Pregnancy
•
•
Should the HCG rise or
Should the HCG rise or
•
•
Plateau (fails to drop by 10% of the
Plateau (fails to drop by 10% of the
previous HCG level in one week) then the
previous HCG level in one week) then the
diagnosis is…
diagnosis is…
•
•
Gestational Trophoblastic Neoplasia (GTN)
Gestational Trophoblastic Neoplasia (GTN)
Berkowitz. Gynecologic Oncology,
Berkowitz. Gynecologic Oncology,
1993.
1993.
Gestational Trophoblastic Neoplasia
Gestational Trophoblastic Neoplasia
•
•
Hydatidiform mole precedes GTN in 50% of
Hydatidiform mole precedes GTN in 50% of
patients
patients
•
•
Antecedent pregnancy 25%
Antecedent pregnancy 25%
•
•
Ectopic
Ectopic
pregnancy 25%
pregnancy 25%
•
•
15% local metastases
15% local metastases
•
•
4% distal metastases
4% distal metastases
•
•
Common sites: lung (60%), vagina (30%), liver
Common sites: lung (60%), vagina (30%), liver
(10%) and brain (10%)
(10%) and brain (10%)
Soper et al. Obstet Gyncol. 1994.
Soper et al. Obstet Gyncol. 1994.
Work
Work
-
-
up of GTN
up of GTN
•
•
History and Physical
History and Physical
•
•
Pretreatment HCG titer
Pretreatment HCG titer
•
•
CXR
CXR
•
•
CBC, CMP
CBC, CMP
•
•
CT of head, chest, abdomen and pelvis
CT of head, chest, abdomen and pelvis
•
•
Duke retrospectively evaluated 324 patients to
Duke retrospectively evaluated 324 patients to
determine whether full
determine whether full
radiologic
radiologic
imaging necessary
imaging necessary
•
•
Patients with vaginal or lung metastases had full
Patients with vaginal or lung metastases had full
evaluation: 100% sensitivity, 63% specificity for brain or
evaluation: 100% sensitivity, 63% specificity for brain or
liver involvement
liver involvement
Terminology of GTN
Terminology of GTN
•
•
Terminology
Terminology
–
–
Nonmetastatic GTN
Nonmetastatic GTN
–
–
Metastatic GTN
Metastatic GTN
•
•
Good prognosis
Good prognosis
•
•
Poor Prognosis
Poor Prognosis
•
•
Histology
Histology
–
–
Choriocarcinoma
Choriocarcinoma
•
•
anaplastic syncytiotrophoblasts and cytotrophoblasts
anaplastic syncytiotrophoblasts and cytotrophoblasts
–
–
Placental Site Trophoblastic Tumor
Placental Site Trophoblastic Tumor
•
•
intermediate trophoblasts
intermediate trophoblasts
Good vs. Poor Prognosis
Good vs. Poor Prognosis
•
•
Good prognosis
Good prognosis
–
–
Last pregnancy < 4
Last pregnancy < 4
months
months
–
–
High HCG titer <
High HCG titer <
40,000
40,000
mIU
mIU
/ml
/ml
–
–
No brain or liver
No brain or liver
metastasis
metastasis
–
–
No prior chemotherapy
No prior chemotherapy
•
•
Poor prognosis
Poor prognosis
–
–
Last pregnancy > 4
Last pregnancy > 4
months
months
–
–
High HCG titer >
High HCG titer >
40,000
40,000
mIU
mIU
/ml
/ml
–
–
Brain or liver
Brain or liver
metastasis
metastasis
–
–
Prior chemotherapy
Prior chemotherapy
–
–
Term pregnancy
Term pregnancy
FIGO Staging
FIGO Staging
•
•
Stage I: disease confined to the uterus
Stage I: disease confined to the uterus
•
•
Stage II: pelvic extension
Stage II: pelvic extension
•
•
Stage III: lung
Stage III: lung
•
•
Stage IV: all other sites
Stage IV: all other sites
•
•
A: no risk factors
A: no risk factors
•
•
B: 1 risk factor
B: 1 risk factor
•
•
C: 2 risk factors
C: 2 risk factors
•
•
Risk factors
Risk factors
–
–
HCG > 100,000
HCG > 100,000
mIU
mIU
/ml
/ml
–
–
Last pregnancy > 6 months
Last pregnancy > 6 months
WHO Staging System
WHO Staging System
8
8
4
4
-
-
8
8
1
1
-
-
4
4
Number of metastases
Number of metastases
2 drugs or
2 drugs or
more
more
Single Drug
Single Drug
Prior chemotherapy
Prior chemotherapy
Brain
Brain
GI
GI
Liver
Liver
Spleen
Spleen
Kidney
Kidney
Site of metastases
Site of metastases
5
5
3
3
-
-
5
5
Largest tumor (cm)
Largest tumor (cm)
B
B
AB
AB
O
O
×
×
A
A
A
A
×
×
O
O
ABO (female
ABO (female
×
×
male)
male)
10
10
5
5
10
10
4
4
-
-
10
10
5
5
10
10
3
3
-
-
10
10
4
4
10
10
3
3
HCG (IU/L)
HCG (IU/L)
12
12
7
7
-
-
12
12
4
4
-
-
6
6
4
4
Months from last
Months from last
pregnancy
pregnancy
Term
Term
Abortion
Abortion
HM
HM
Antecedent pregnancy
Antecedent pregnancy
> 39
> 39
≤
≤
39
39
Age
Age
4
4
2
2
1
1
0
0
Prognostic Factors
Prognostic Factors
•
•
Low risk
Low risk
≤
≤
4; middle risk 5
4; middle risk 5
-
-
7; high risk
7; high risk
≥
≥
8
8
GTN Staging
GTN Staging
•
•
A 41 year old Texas socialite developed vaginal bleeding. She so
A 41 year old Texas socialite developed vaginal bleeding. She so
ught care
ught care
with her OB/GYN and discovered that she was pregnant. An ultraso
with her OB/GYN and discovered that she was pregnant. An ultraso
und
und
diagnosed a molar pregnancy and bilateral cystic ovaries. A D&C
diagnosed a molar pregnancy and bilateral cystic ovaries. A D&C
was
was
performed; pathology returned as a complete mole. The patient wa
performed; pathology returned as a complete mole. The patient wa
s
s
followed once a week for HCG titers. Her pretreatment HCG was 21
followed once a week for HCG titers. Her pretreatment HCG was 21
2,000.
2,000.
After six weeks, she reached a nadir of 52,000 and then her HCG
After six weeks, she reached a nadir of 52,000 and then her HCG
titer rose
titer rose
to 96,000. Her local OB/GYN ordered a chest X
to 96,000. Her local OB/GYN ordered a chest X
-
-
ray and discovered a
ray and discovered a
suspicious nodule. A CT scan of the head, chest, abdomen and pel
suspicious nodule. A CT scan of the head, chest, abdomen and pel
vis
vis
identified 5 pulmonary nodules. The largest measured 3 cm. There
identified 5 pulmonary nodules. The largest measured 3 cm. There
were 2
were 2
liver nodules measuring 2 cm. The rest of the scan was normal.
liver nodules measuring 2 cm. The rest of the scan was normal.
•
•
What terminology?
What terminology?
•
•
Good or poor prognosis?
Good or poor prognosis?
•
•
What Stage?
What Stage?
•
•
What WHO score?
What WHO score?
Nonmetastatic GTN
Nonmetastatic GTN
•
•
Single agent chemotherapy treatment of
Single agent chemotherapy treatment of
choice
choice
•
•
Methotrexate or Actinomycin
Methotrexate or Actinomycin
-
-
D
D
•
•
Both are well tolerated and have minimal
Both are well tolerated and have minimal
side effects
side effects
•
•
Both have complete response rates of
Both have complete response rates of
around 90%
around 90%
Methotrexate (MTX)
Methotrexate (MTX)
•
•
2 regimens
2 regimens
–
–
1
1
st
st
Methotrexate 1mg/kg IM D 1,3,5,7
Methotrexate 1mg/kg IM D 1,3,5,7
•
•
alternate with folic acid 0.1 mg/kg IM D 2, 4,6,8
alternate with folic acid 0.1 mg/kg IM D 2, 4,6,8
–
–
2
2
nd
nd
Methotrexate 30 mg/m
Methotrexate 30 mg/m
2
2
IM Q week
IM Q week
•
•
No folic acid rescue
No folic acid rescue
Efficacy of MTX
Efficacy of MTX
•
•
Berkowitz RS. 10 year experience with methotrexate and
Berkowitz RS. 10 year experience with methotrexate and
folinic acid as primary therapy for gestational
folinic acid as primary therapy for gestational
trophoblastic disease. Gynecol Oncol 1986; 23: 111.
trophoblastic disease. Gynecol Oncol 1986; 23: 111.
•
•
Every other day regimen
Every other day regimen
•
•
Complete remission with 162/185 patients (88%)
Complete remission with 162/185 patients (88%)
•
•
23 patients resistant to MTX
23 patients resistant to MTX
–
–
14 patients cured with Act
14 patients cured with Act
-
-
D
D
–
–
9 with combination chemotherapy
9 with combination chemotherapy
•
•
Side effects
Side effects
–
–
Thrombocytopenia, 11 (6%)
Thrombocytopenia, 11 (6%)
–
–
Neutropenia, 3 (1.6%)
Neutropenia, 3 (1.6%)
–
–
Hepatotoxicity, 26 (14%)
Hepatotoxicity, 26 (14%)
Efficacy of MTX
Efficacy of MTX
•
•
Homesley
Homesley
HD. Weekly intramuscular methotrexate for
HD. Weekly intramuscular methotrexate for
nonmetastatic gestational trophoblastic disease. Obstet
nonmetastatic gestational trophoblastic disease. Obstet
Gynecol 1988; 72: 413
Gynecol 1988; 72: 413
-
-
418.
418.
•
•
Weekly regimen
Weekly regimen
•
•
Complete remission with 51/63 patients (81%)
Complete remission with 51/63 patients (81%)
•
•
12 patients resistant to MTX
12 patients resistant to MTX
–
–
11 patients cured with Act
11 patients cured with Act
-
-
D
D
–
–
1 refused further treatment
1 refused further treatment
•
•
Side effects
Side effects
–
–
Thrombocytopenia, 3 (5%)
Thrombocytopenia, 3 (5%)
–
–
Neutropenia, 13 (20%)
Neutropenia, 13 (20%)
Efficacy of Actinomycin
Efficacy of Actinomycin
-
-
D
D
•
•
Petrilli
Petrilli
ES. Single
ES. Single
-
-
dose actinomycin
dose actinomycin
-
-
D treatment for
D treatment for
nonmetastatic gestational trophoblastic disease. A
nonmetastatic gestational trophoblastic disease. A
prospective phase II trial of the Gynecologic Oncology
prospective phase II trial of the Gynecologic Oncology
Group. Cancer 1987; 60: 2173
Group. Cancer 1987; 60: 2173
-
-
6.
6.
•
•
Act
Act
-
-
D 1.25 mg/m
D 1.25 mg/m
2
2
IM Q 2 weeks
IM Q 2 weeks
•
•
Complete remission with 29/31 patients (94%)
Complete remission with 29/31 patients (94%)
•
•
2 patients resistant to Act
2 patients resistant to Act
-
-
D
D
–
–
Both cured with MTX
Both cured with MTX
•
•
Side effects
Side effects
–
–
Mild to moderate neutropenia
Mild to moderate neutropenia
–
–
Alopecia
Alopecia
Prognosis for Stage I or
Prognosis for Stage I or
Nonmetastatic GTN
Nonmetastatic GTN
16 (37.2)
16 (37.2)
20 (46.5)
20 (46.5)
1 (2.3)
1 (2.3)
3 (7)
3 (7)
2 (4.7)
2 (4.7)
1 (2.3)
1 (2.3)
43 (8.1)
43 (8.1)
Resistant
Resistant
MAC
MAC
EMA
EMA
EITP
EITP
Hysterectomy
Hysterectomy
Local uterine resection
Local uterine resection
Pelvic infusion
Pelvic infusion
528 (100)
528 (100)
528
528
Total
Total
446 (92)
446 (92)
31 (6.4)
31 (6.4)
3 (0.6)
3 (0.6)
5 (1)
5 (1)
485 (91.9)
485 (91.9)
Initial
Initial
Sequential MTX/Act
Sequential MTX/Act
-
-
D
D
Hysterectomy
Hysterectomy
MAC
MAC
EMA
EMA
Remissions N
Remissions N
(%)
(%)
Patients N
Patients N
(%)
(%)
Remission Therapy
Remission Therapy
•
•
New England
New England
Trophoblastic
Trophoblastic
Disease Center,
Disease Center,
July 1965 to
July 1965 to
May 2002
May 2002
•
•
Hoskins 4
Hoskins 4
th
th
ED.
ED.
Prognosis for Stage I or
Prognosis for Stage I or
Nonmetastatic GTN
Nonmetastatic GTN
•
•
Hammond CB. The role of operation in the current therapy of gest
Hammond CB. The role of operation in the current therapy of gest
ational
ational
trophoblastic disease. Am J Obstet Gynecol 1980; 136: 844.
trophoblastic disease. Am J Obstet Gynecol 1980; 136: 844.
•
•
Southeastern Trophoblastic Center (Duke)
Southeastern Trophoblastic Center (Duke)
•
•
DiSaia
DiSaia
6
6
th
th
ED.
ED.
139/139 (100)
139/139 (100)
Total
Total
17/17
17/17
Chemotherapy + hysterectomy (1
Chemotherapy + hysterectomy (1
°
°
)
)
4/122
4/122
Chemotherapy + pelvic infusion +
Chemotherapy + pelvic infusion +
hysterectomy (3
hysterectomy (3
°
°
)
)
3/122
3/122
Chemotherapy + pelvic infusion
Chemotherapy + pelvic infusion
9/122
9/122
Chemotherapy + hysterectomy (2
Chemotherapy + hysterectomy (2
°
°
)
)
106/122 (
106/122 (
86
86
)
)
Chemotherapy
Chemotherapy
Remission N
Remission N
(%)
(%)
Therapy
Therapy
Metastatic, Good Prognosis GTN
Metastatic, Good Prognosis GTN
•
•
Pelvic or lung involvement
Pelvic or lung involvement
•
•
WHO score of
WHO score of
≤
≤
7
7
•
•
1
1
st
st
therapy is single agent MTX or Act
therapy is single agent MTX or Act
-
-
D
D
•
•
If elevated
If elevated
HCG
HCG
’
’
s
s
occur
occur
…
…
–
–
Switch to other single agent chemotherapy
Switch to other single agent chemotherapy
–
–
Consider TAH for local disease (provided the patient
Consider TAH for local disease (provided the patient
does not want further children)
does not want further children)
–
–
Combination chemotherapy (MAC or EMA
Combination chemotherapy (MAC or EMA
-
-
CO)
CO)
Prognosis for Stage II GTN
Prognosis for Stage II GTN
•
•
New England
New England
Trophoblastic
Trophoblastic
Disease
Disease
Center, July
Center, July
1965 to May
1965 to May
2002
2002
•
•
Hoskins 4
Hoskins 4
th
th
ED.
ED.
28 (100)
28 (100)
28
28
Total
Total
2 (25)
2 (25)
4 (50)
4 (50)
1 (12.5)
1 (12.5)
1 (12.5)
1 (12.5)
8 (28.6)
8 (28.6)
High Risk
High Risk
Initial
Initial
Sequential MTX/Act
Sequential MTX/Act
-
-
D
D
MAC
MAC
Resistant
Resistant
MAC
MAC
CHAMOCA
CHAMOCA
18 (80)
18 (80)
1 (10)
1 (10)
1 (10)
1 (10)
20 (71.4)
20 (71.4)
Low risk
Low risk
Initial
Initial
Sequential MTX/Act
Sequential MTX/Act
-
-
D
D
Resistant
Resistant
MAC
MAC
EMA
EMA
-
-
CO
CO
Remissions N
Remissions N
(%)
(%)
Patients N (%)
Patients N (%)
Remission Therapy
Remission Therapy
Prognosis for Stage III GTN
Prognosis for Stage III GTN
•
•
New England
New England
Trophoblastic
Trophoblastic
Disease Center,
Disease Center,
July 1965 to
July 1965 to
May 2002
May 2002
•
•
Hoskins 4
Hoskins 4
th
th
ED.
ED.
153 (99.3)
153 (99.3)
153
153
Total
Total
13 (26.5)
13 (26.5)
14 (28.6)
14 (28.6)
13 (26.5)
13 (26.5)
2 (4.1)
2 (4.1)
1 (2)
1 (2)
1 (2)
1 (2)
2 (4.1)
2 (4.1)
1 (2)
1 (2)
1 (2)
1 (2)
49 (32)
49 (32)
High Risk
High Risk
Initial
Initial
Sequential MTX/Act
Sequential MTX/Act
-
-
D
D
MAC
MAC
EMA
EMA
-
-
CO
CO
Resistant
Resistant
MAC
MAC
CHAMOCA
CHAMOCA
5
5
-
-
FU
FU
-
-
Adria
Adria
VPB
VPB
EMA
EMA
EMA
EMA
-
-
EP
EP
85 (81.7)
85 (81.7)
12 (11.5)
12 (11.5)
5 (4.8)
5 (4.8)
2 (1.9)
2 (1.9)
104 (68)
104 (68)
Low risk
Low risk
Initial
Initial
Sequential MTX/Act
Sequential MTX/Act
-
-
D
D
Resistant
Resistant
MAC
MAC
EMA
EMA
EMA
EMA
-
-
CO
CO
Remissions N
Remissions N
(%)
(%)
Patients N
Patients N
(%)
(%)
Remission Therapy
Remission Therapy
Prognosis for Metastatic, Good
Prognosis for Metastatic, Good
Prognosis GTN
Prognosis GTN
•
•
Hammond CB. The role of operation in the current therapy of
Hammond CB. The role of operation in the current therapy of
gestational trophoblastic disease. Am J Obstet Gynecol 1980;
gestational trophoblastic disease. Am J Obstet Gynecol 1980;
136: 844.
136: 844.
•
•
Southeastern Trophoblastic Center (Duke)
Southeastern Trophoblastic Center (Duke)
•
•
DiSaia
DiSaia
6
6
th
th
ED.
ED.
55/55 (100)
55/55 (100)
Total
Total
15/15
15/15
Chemotherapy + hysterectomy (1
Chemotherapy + hysterectomy (1
°
°
)
)
5/40
5/40
Chemotherapy + hysterectomy (2
Chemotherapy + hysterectomy (2
°
°
)
)
35/40 (
35/40 (
88
88
)
)
Chemotherapy
Chemotherapy
Remission N
Remission N
(%)
(%)
Therapy
Therapy
Poor Prognosis GTN
Poor Prognosis GTN
•
•
Brain or liver involvement
Brain or liver involvement
•
•
WHO score
WHO score
≥
≥
8
8
•
•
Resistance to first line chemotherapy
Resistance to first line chemotherapy
•
•
Initiate treatment with MAC or EMA
Initiate treatment with MAC or EMA
-
-
CO
CO
•
•
Brain or liver metastases require XRT
Brain or liver metastases require XRT
MAC
MAC
•
•
Berkowitz RS. Modified triple therapy in the management of high
Berkowitz RS. Modified triple therapy in the management of high
-
-
risk metastatic gestational trophoblastic tumors. Gynecol Oncol
risk metastatic gestational trophoblastic tumors. Gynecol Oncol
1984; 19: 173
1984; 19: 173
-
-
81.
81.
•
•
Cyclophosphamide IV 3 mg/kg/day D1
Cyclophosphamide IV 3 mg/kg/day D1
-
-
5
5
•
•
Act
Act
-
-
D IM 12
D IM 12
µ
µ
g/kg/day D1
g/kg/day D1
-
-
5
5
•
•
Methotrexate IV 1 mg/kg/day D1,3,5,7
Methotrexate IV 1 mg/kg/day D1,3,5,7
•
•
Brain metastases received 3000 cGy of whole brain irradiation (2
Brain metastases received 3000 cGy of whole brain irradiation (2
patients)
patients)
•
•
10/14 patients (71%) achieved CR with MAC
10/14 patients (71%) achieved CR with MAC
–
–
2 patients received VBP
2 patients received VBP
–
–
1 patient received CHAMOCA
1 patient received CHAMOCA
–
–
1 patient DOD
1 patient DOD
–
–
2 patients had a hysterectomy
2 patients had a hysterectomy
–
–
2 patients had a pulmonary resection
2 patients had a pulmonary resection
•
•
13/14 patients (93%) achieved a CR with multi
13/14 patients (93%) achieved a CR with multi
-
-
agent chemotherapy
agent chemotherapy
•
•
Main side effect neutropenia
Main side effect neutropenia
EMA
EMA
-
-
CO
CO
•
•
The standard of care for poor prognosis GTN
The standard of care for poor prognosis GTN
•
•
Week #1
Week #1
–
–
Etoposide 100 mg/m
Etoposide 100 mg/m
2
2
IV (30 minute) D1&2
IV (30 minute) D1&2
–
–
Methotrexate 100 mg/m
Methotrexate 100 mg/m
2
2
IV push D1
IV push D1
–
–
Methotrexate 200 mg/m
Methotrexate 200 mg/m
2
2
IV (12 hour) D1
IV (12 hour) D1
–
–
Act
Act
-
-
D 350
D 350
µ
µ
g/m
g/m
2
2
IV push D1&2
IV push D1&2
–
–
Folinic acid 15 mg Q 6hrs for 4 doses
Folinic acid 15 mg Q 6hrs for 4 doses
•
•
Week #2
Week #2
–
–
Cyclophosphamide 600mg/m
Cyclophosphamide 600mg/m
2
2
IV (1 hour) D8
IV (1 hour) D8
–
–
Vincristine 1 mg/m2 IV push D8
Vincristine 1 mg/m2 IV push D8
EMA
EMA
-
-
CO
CO
8
8
2%
2%
8
8
-
-
-
-
-
-
-
-
3
3
rd
rd
line
line
(N)
(N)
138 84%
138 84%
138 84%
138 84%
19
19
6
6
42
42
61
61
96
96
165
165
Kim S. Gynecol
Kim S. Gynecol
Oncol. 1998
Oncol. 1998
403
403
79%
79%
213 78%
213 78%
11 69%
11 69%
10 83%
10 83%
31 86%
31 86%
CR (N)
CR (N)
60
60
12%
12%
34
34
5
5
1
1
1
1
Brain
Brain
(N)
(N)
33
33
6.5%
6.5%
17
17
6
6
1
1
3
3
Liver
Liver
(N)
(N)
428
428
84%
84%
62
62
12%
12%
212
212
41%
41%
287
287
57%
57%
507
507
Total
Total
234 86%
234 86%
n/a
n/a
121
121
151
151
272
272
Bower M. J
Bower M. J
Clin
Clin
Oncol. 1997
Oncol. 1997
15 68%
15 68%
12
12
16
16
6
6
22
22
Soper
Soper
J. Obstet
J. Obstet
Gynecol. 1994
Gynecol. 1994
12 100%
12 100%
3
3
-
-
12
12
12
12
Schink
Schink
J. Obstet
J. Obstet
Gynecol. 1992
Gynecol. 1992
29 81%
29 81%
5
5
14
14
22
22
36
36
Bolis
Bolis
G. Gynecol
G. Gynecol
Oncol. 1988
Oncol. 1988
Survival
Survival
(N)
(N)
Surgery
Surgery
(N)
(N)
2
2
nd
nd
line
line
(N)
(N)
1
1
st
st
line
line
(N)
(N)
N
N
Author
Author
•
•
Surgery: hysterectomy, pulmonary resection, nephrectomy,
Surgery: hysterectomy, pulmonary resection, nephrectomy,
splenectomy, colon resection, cardiac surgery
splenectomy, colon resection, cardiac surgery
Brain Metastases
Brain Metastases
•
•
Recommend 3000 cGy whole brain irradiation (10 treatments)
Recommend 3000 cGy whole brain irradiation (10 treatments)
•
•
Evans AJ. Gestational trophoblastic disease metastatic to the ce
Evans AJ. Gestational trophoblastic disease metastatic to the ce
ntral
ntral
nervous system. Gynecol Oncol 1995; 59: 226.
nervous system. Gynecol Oncol 1995; 59: 226.
–
–
Reported that 12/16 patients (75%) had a CR with XRT and
Reported that 12/16 patients (75%) had a CR with XRT and
combination chemotherapy
combination chemotherapy
•
•
Schechter
Schechter
NR. Prognosis of patient treated with whole
NR. Prognosis of patient treated with whole
-
-
brain
brain
radiation therapy for metastatic gestational trophoblastic disea
radiation therapy for metastatic gestational trophoblastic disea
se.
se.
Gynecol Oncol 1998; 68:183.
Gynecol Oncol 1998; 68:183.
–
–
Dose > 2200 cGy versus 91% 5 year survival versus 24% 5 year
Dose > 2200 cGy versus 91% 5 year survival versus 24% 5 year
survival with a dose < 2200 cGy
survival with a dose < 2200 cGy
–
–
Survival based upon responsive multi
Survival based upon responsive multi
-
-
agent chemotherapy
agent chemotherapy
•
•
Newlands
Newlands
ES. Management of brain metastases in patients with
ES. Management of brain metastases in patients with
high
high
-
-
risk gestational trophoblastic tumor. J
risk gestational trophoblastic tumor. J
Reprod
Reprod
Med 2002; 47:
Med 2002; 47:
465.
465.
–
–
31/35 patients (86%) cured with EMA
31/35 patients (86%) cured with EMA
-
-
CO and intrathecal MTX
CO and intrathecal MTX
•
•
Intrathecal MTX not standard of care for prophylaxis of CNS
Intrathecal MTX not standard of care for prophylaxis of CNS
metastases in patients with pulmonary metastases
metastases in patients with pulmonary metastases
Liver Metastases
Liver Metastases
•
•
Extremely poor prognosis
Extremely poor prognosis
•
•
Crawford RA. Gestational trophoblastic disease with liver
Crawford RA. Gestational trophoblastic disease with liver
metastases: the
metastases: the
Charing
Charing
Cross experience. Br J Obstet Gynecol
Cross experience. Br J Obstet Gynecol
1997: 104:105.
1997: 104:105.
–
–
46 of 1676 women with GTN (2.7%)
46 of 1676 women with GTN (2.7%)
–
–
Concurrent metastatic disease to the lung (93%) and brain (33%)
Concurrent metastatic disease to the lung (93%) and brain (33%)
–
–
5
5
-
-
year survival 27%
year survival 27%
–
–
5
5
-
-
year survival 10% if the patient had brain metastases
year survival 10% if the patient had brain metastases
•
•
Hemorrhage worrisome; some recommend 2000cGy to prevent
Hemorrhage worrisome; some recommend 2000cGy to prevent
hemorrhage
hemorrhage
Resistance to EMA
Resistance to EMA
-
-
CO
CO
•
•
Bower M. EMA/CO for high
Bower M. EMA/CO for high
-
-
risk gestational
risk gestational
trophoblastic tumors: results from a cohort of
trophoblastic tumors: results from a cohort of
272 patients. J
272 patients. J
Clin
Clin
Oncol 1997: 15: 2636.
Oncol 1997: 15: 2636.
–
–
EMA
EMA
-
-
EP (etoposide, cisplatin)
EP (etoposide, cisplatin)
±
±
surgery induced
surgery induced
remission in 16/21 patients (76%)
remission in 16/21 patients (76%)
•
•
Cisplatin, vinblastine, bleomycin (PVB) has some
Cisplatin, vinblastine, bleomycin (PVB) has some
efficacy
efficacy
–
–
3 studies with few patients
3 studies with few patients
–
–
CR of 20
CR of 20
-
-
50%
50%
Placental Site Trophoblastic Tumor
Placental Site Trophoblastic Tumor
(PSTT)
(PSTT)
•
•
100 reported cases
100 reported cases
•
•
Bleeding most common symptom
Bleeding most common symptom
•
•
Intermediate trophoblasts
Intermediate trophoblasts
•
•
HCG weakly positive
HCG weakly positive
•
•
Human placental
Human placental
lactogen
lactogen
(HPL) serum marker
(HPL) serum marker
•
•
Hysterectomy treatment of choice
Hysterectomy treatment of choice
•
•
Mainly benign tumor, although 15
Mainly benign tumor, although 15
-
-
20% mortality
20% mortality
rate for advanced stage tumors
rate for advanced stage tumors
Subsequent Pregnancy after Partial
Subsequent Pregnancy after Partial
Mole
Mole
•
•
New England Trophoblastic
New England Trophoblastic
Disease Center, January
Disease Center, January
1979 to November 2001
1979 to November 2001
•
•
Hoskins 4
Hoskins 4
th
th
ED.
ED.
3/194 (1.5)
3/194 (1.5)
Congenital
Congenital
malformation
malformation
15.1
15.1
0.4
0.4
4.4
4.4
0.4
0.4
2.4
2.4
1.6
1.6
0.4
0.4
75.3
75.3
%
%
29/194 (14.9)
29/194 (14.9)
Primary
Primary
Cesarean section
Cesarean section
251
251
Total
Total
38
38
1
1
11
11
1
1
6
6
SAB
SAB
1
1
st
st
trimester
trimester
2
2
nd
nd
trimester
trimester
Therapeutic AB
Therapeutic AB
Ectopic
Ectopic
Repeat Mole
Repeat Mole
4
4
Preterm delivery
Preterm delivery
1
1
Stillbirth
Stillbirth
189
189
Term Delivery
Term Delivery
N/Deliveries
N/Deliveries
(%)
(%)
N
N
Outcome
Outcome
Subsequent Pregnancy after
Subsequent Pregnancy after
Complete Mole
Complete Mole
40/979 (4.1)
40/979 (4.1)
Congenital
Congenital
malformation
malformation
17.3
17.3
0.6
0.6
3.2
3.2
0.9
0.9
1.4
1.4
7.4
7.4
0.5
0.5
68.6
68.6
%
%
70/373 (18.8)
70/373 (18.8)
Primary
Primary
Cesarean section
Cesarean section
1278
1278
Total
Total
221
221
8
8
41
41
11
11
18
18
SAB
SAB
1
1
st
st
trimester
trimester
2
2
nd
nd
trimester
trimester
Therapeutic AB
Therapeutic AB
Ectopic
Ectopic
Repeat Mole
Repeat Mole
65
65
Preterm delivery
Preterm delivery
7
7
Stillbirth
Stillbirth
877
877
Term Delivery
Term Delivery
N/Deliveries
N/Deliveries
(%)
(%)
N
N
Outcome
Outcome
•
•
New England
New England
Trophoblastic Disease
Trophoblastic Disease
Center, January 1979 to
Center, January 1979 to
November 2001
November 2001
•
•
Hoskins 4
Hoskins 4
th
th
ED.
ED.
Subsequent Pregnancy after GTN
Subsequent Pregnancy after GTN
•
•
New England
New England
Trophoblastic Disease
Trophoblastic Disease
Center, January 1979 to
Center, January 1979 to
November 2001
November 2001
•
•
Hoskins 4
Hoskins 4
th
th
ED.
ED.
10/437 (2.3)
10/437 (2.3)
Congenital
Congenital
malformation
malformation
15.8
15.8
1.2
1.2
4.8
4.8
1.2
1.2
1.4
1.4
6
6
1.5
1.5
67.6
67.6
%
%
68/335 (20.3)
68/335 (20.3)
Primary Cesarean
Primary Cesarean
section
section
581
581
Total
Total
92
92
7
7
28
28
7
7
8
8
SAB
SAB
1
1
st
st
trimester
trimester
2
2
nd
nd
trimester
trimester
Therapeutic AB
Therapeutic AB
Ectopic
Ectopic
Repeat Mole
Repeat Mole
35
35
Preterm delivery
Preterm delivery
9
9
Stillbirth
Stillbirth
393
393
Term Delivery
Term Delivery
N/Deliveries
N/Deliveries
(%)
(%)
N
N
Outcome
Outcome
Secondary Malignancies
Secondary Malignancies
•
•
Rustin
Rustin
GJ. Combination but not single
GJ. Combination but not single
-
-
agent
agent
methotrexate chemotherapy for gestational trophoblastic
methotrexate chemotherapy for gestational trophoblastic
tumors increases the incidence of second tumors. J
tumors increases the incidence of second tumors. J
Clin
Clin
Oncol 1996; 14: 2769.
Oncol 1996; 14: 2769.
–
–
RR leukemia
RR leukemia
16.6
16.6
–
–
RR melanoma
RR melanoma
3.4
3.4
–
–
RR colon
RR colon
4.6
4.6
–
–
RR breast
RR breast
5.8
5.8
•
•
1.5% of all patients treated with etoposide developed
1.5% of all patients treated with etoposide developed
leukemia
leukemia
•
•
Increased risk for breast cancer is not apparent until
Increased risk for breast cancer is not apparent until
after 25 years
after 25 years
