Gestational Trophoblastic Neoplasia

Gestational Trophoblastic
Neoplasia
Chris DeSimone, MD
Assistant Professor
Division of Gynecologic Oncology
Department of Obstetrics & Gynecology
Gestational Trophoblastic Neoplasia
(GTN)
• Ancient disease
• Hippocrates documented a
•
hydatidiform mole in the 4th
century BC
William Smellie (Scottish midwife, circa 1700) was the first
to coin the terms Hydatid and
Mole
What is a mole?
What is a mole?
• A mole is the amount of pure substance containing the
same number of chemical units as there are atoms in
exactly 12 grams of carbon-12 (i.e., 6.023 X 1023). This
involves the acceptance of two dictates -- the scale of
atomic masses and the magnitude of the gram. Both
have been established by international agreement.
Formerly, the connotation of "mole" was "gram
molecular weight." Current usage tends to apply the
term "mole" to an amount containing Avogadro's
number of whatever units are being considered. Thus, it
is possible to have a mole of atoms, ions, radicals,
electrons, or quanta. This usage makes unnecessary
such terms as "gram-atom," "gram-formula weight," etc.
What is a mole?
What is a mole?
Epidemiology
• Incidence
– Less than 1/1000 pregnancies (World)
– Japan- 2/1000 pregnancies
• Age
–
–
–
Bandy et al. Obstet Gynecol. 1984.
Women < 15 years or > 40 years at increased risk
Greatest risk > 50 years (RR-519)
• Diet
– Decreased animal fat and Vitamin A
• Risk of another molar pregnancy
– Bagshawe et al. Cancer. 1976.
– 1 in 76 pregnancies have a second mole
– 1 in 6.5 pregnancies have a third mole with 2 prior molar
pregnancies
The Changing Symptoms of a
Complete Mole
Soto-Wright et al.
Obstet Gynecol. 1995.
19651975
19881993
Significance
Vaginal Bleeding
97%
84%
P=0.001
Excessive Uterine Size
51%
28%
P=0.001
Hyperemesis
26%
8%
P=0.001
Preeclampsia
27%
1.3%
P=0.001
Hyperthyroidism
7%
-
P=0.02
Median Age of
Evacuation
16 weeks
12 weeks
P=0.005
Symptoms of a Complete Mole
• Clinical hyperthyroidism occurs in less
than 1% of patients
• 10% of patients have an elevation of T3
and T4
• Theca-lutein cysts are found in 15% of
complete moles
• 57% of patients with a complete mole and
theca-lutein cysts will have GTN
Curry et al. Obstet Gynecol. 1975.
Diagnosis
• Intact HCG
• Ultrasound
• Evacuation
– Suction curettage
surgery of choice
– Pre-Op checklist
• CBC
• Thyroid panel
• Maternal Rh factor
• Type & Cross
Complete and Partial Moles
Partial Mole
Complete Mole
Fetal Tissue
Present
Absent
Villous Edema
Focal
Diffuse
Trophoblastic
Hyperplasia
Focal
Diffuse
Karyotype
Triploidy
XXX, XXY, XYY
46 XX (90%)
46 XY (10%)
GTN
3.5%
19%
Follow-up of Molar Pregnancy
• Intact HCG test of choice
• Β-HCG no longer used at
•
UK and in Lexington
Average time to reach
undetectable HCG, 73
days (Ho Yuen et al. Am J Obstet
• 1 week follow-up for 4
•
•
Gynecol, 1981.)
• CONTRACEPTION!
weeks then…
Once every 2 weeks for 4
weeks then…
Once a month for 4
months (Wolfberg et al. Obstet
Gynecol, 2006.)
• Total of 6 months
• 0/238 women with partial
•
molar pregnancies had
GTN with declining HCG’s
Complete moles should
be followed longer
Follow-up of Molar Pregnancy
• Should the HCG rise or
• Plateau (fails to drop by 10% of the
previous HCG level in one week) then the
diagnosis is…
• Gestational Trophoblastic Neoplasia (GTN)
Gestational Trophoblastic Neoplasia
• Hydatidiform mole precedes GTN in 50% of
•
•
•
•
•
patients
Antecedent pregnancy 25%
Ectopic pregnancy 25%
15% local metastases
4% distal metastases
Common sites: lung (60%), vagina (30%), liver
(10%) and brain (10%)
Berkowitz. Gynecologic Oncology,
1993.
Work-up of GTN
•
•
•
•
•
History and Physical
Pretreatment HCG titer
CXR
CBC, CMP
CT of head, chest, abdomen and pelvis
• Duke retrospectively evaluated 324 patients to
•
determine whether full radiologic imaging necessary
Patients with vaginal or lung metastases had full
evaluation: 100% sensitivity, 63% specificity for brain or
liver involvement
Soper et al. Obstet Gyncol. 1994.
Terminology of GTN
• Terminology
– Nonmetastatic GTN
– Metastatic GTN
• Good prognosis
• Poor Prognosis
• Histology
– Choriocarcinoma
• anaplastic syncytiotrophoblasts and cytotrophoblasts
– Placental Site Trophoblastic Tumor
• intermediate trophoblasts
Good vs. Poor Prognosis
• Good prognosis
– Last pregnancy < 4
months
– High HCG titer <
40,000 mIU/ml
– No brain or liver
metastasis
– No prior chemotherapy
• Poor prognosis
– Last pregnancy > 4
months
– High HCG titer >
40,000 mIU/ml
– Brain or liver
metastasis
– Prior chemotherapy
– Term pregnancy
FIGO Staging
•
•
•
•
Stage I: disease confined to the uterus
Stage II: pelvic extension
Stage III: lung
Stage IV: all other sites
•
•
•
A: no risk factors
B: 1 risk factor
C: 2 risk factors
• Risk factors
– HCG > 100,000 mIU/ml
– Last pregnancy > 6 months
WHO Staging System
Prognostic Factors
0
1
Age
≤ 39
> 39
Antecedent pregnancy
HM
Abortion
Term
Months from last
pregnancy
4
4-6
7-12
12
HCG (IU/L)
103
103-104
104-105
105
ABO (female × male)
O×A
A×O
B
AB
Largest tumor (cm)
3-5
5
Site of metastases
Spleen
Kidney
GI
Liver
Brain
Number of metastases
1-4
4-8
8
Single Drug
2 drugs or
more
Prior chemotherapy
• Low risk ≤ 4; middle risk 55-7; high risk ≥ 8
2
4
GTN Staging
• A 41 year old Texas socialite developed vaginal bleeding. She sought care
with her OB/GYN and discovered that she was pregnant. An ultrasound
diagnosed a molar pregnancy and bilateral cystic ovaries. A D&C was
performed; pathology returned as a complete mole. The patient was
followed once a week for HCG titers. Her pretreatment HCG was 212,000.
After six weeks, she reached a nadir of 52,000 and then her HCG titer rose
to 96,000. Her local OB/GYN ordered a chest X-ray and discovered a
suspicious nodule. A CT scan of the head, chest, abdomen and pelvis
identified 5 pulmonary nodules. The largest measured 3 cm. There were 2
liver nodules measuring 2 cm. The rest of the scan was normal.
•
•
•
•
What terminology?
Good or poor prognosis?
What Stage?
What WHO score?
Nonmetastatic GTN
• Single agent chemotherapy treatment of
choice
• Methotrexate or Actinomycin-D
• Both are well tolerated and have minimal
side effects
• Both have complete response rates of
around 90%
Methotrexate (MTX)
• 2 regimens
– 1st Methotrexate 1mg/kg IM D 1,3,5,7
• alternate with folic acid 0.1 mg/kg IM D 2, 4,6,8
– 2nd Methotrexate 30 mg/m2 IM Q week
• No folic acid rescue
Efficacy of MTX
• Berkowitz RS. 10 year experience with methotrexate and
folinic acid as primary therapy for gestational
trophoblastic disease. Gynecol Oncol 1986; 23: 111.
• Every other day regimen
• Complete remission with 162/185 patients (88%)
• 23 patients resistant to MTX
– 14 patients cured with Act-D
– 9 with combination chemotherapy
• Side effects
– Thrombocytopenia, 11 (6%)
– Neutropenia, 3 (1.6%)
– Hepatotoxicity, 26 (14%)
Efficacy of MTX
• Homesley HD. Weekly intramuscular methotrexate for
nonmetastatic gestational trophoblastic disease. Obstet
Gynecol 1988; 72: 413-418.
• Weekly regimen
• Complete remission with 51/63 patients (81%)
• 12 patients resistant to MTX
– 11 patients cured with Act-D
– 1 refused further treatment
• Side effects
– Thrombocytopenia, 3 (5%)
– Neutropenia, 13 (20%)
Efficacy of Actinomycin-D
• Petrilli ES. Single-dose actinomycin-D treatment for
nonmetastatic gestational trophoblastic disease. A
prospective phase II trial of the Gynecologic Oncology
Group. Cancer 1987; 60: 2173-6.
•
•
•
Act-D 1.25 mg/m2 IM Q 2 weeks
Complete remission with 29/31 patients (94%)
2 patients resistant to Act-D
– Both cured with MTX
• Side effects
– Mild to moderate neutropenia
– Alopecia
Prognosis for Stage I or
Nonmetastatic GTN
Remission Therapy
Patients N
(%)
Initial
Sequential MTX/ActMTX/Act-D
Hysterectomy
MAC
EMA
485 (91.9)
Resistant
MAC
EMA
EITP
Hysterectomy
Local uterine resection
Pelvic infusion
43 (8.1)
Total
528
Remissions N
(%)
446
31
3
5
(92)
(6.4)
(0.6)
(1)
16
20
1
3
2
1
(37.2)
(46.5)
(2.3)
(7)
(4.7)
(2.3)
528
(100)
• New England
•
Trophoblastic
Disease Center,
July 1965 to
May 2002
Hoskins 4th ED.
Prognosis for Stage I or
Nonmetastatic GTN
Therapy
Remission N
(%)
Chemotherapy
106/122 (86)
Chemotherapy + hysterectomy (2°)
9/122
Chemotherapy + pelvic infusion
3/122
Chemotherapy + pelvic infusion +
hysterectomy (3°)
4/122
Chemotherapy + hysterectomy (1°)
17/17
Total
139/139 (100)
• Hammond CB. The role of operation in the current therapy of gestational
gestational
•
•
trophoblastic disease. Am J Obstet Gynecol 1980; 136: 844.
Southeastern Trophoblastic Center (Duke)
DiSaia 6th ED.
Metastatic, Good Prognosis GTN
• Pelvic or lung involvement
• WHO score of ≤ 7
• 1st therapy is single agent MTX or Act-D
• If elevated HCG’s occur…
– Switch to other single agent chemotherapy
– Consider TAH for local disease (provided the patient
does not want further children)
– Combination chemotherapy (MAC or EMA-CO)
Prognosis for Stage II GTN
• New England
Remission Therapy
Patients N (%) Remissions N
(%)
Low risk
Initial
Sequential MTX/ActMTX/Act-D
Resistant
MAC
EMAEMA-CO
20 (71.4)
High Risk
Initial
Sequential MTX/ActMTX/Act-D
MAC
Resistant
MAC
CHAMOCA
8 (28.6)
Total
28
18
(80)
•
1
1
(10)
(10)
2
4
(25)
(50)
1
1
(12.5)
(12.5)
28
(100)
Trophoblastic
Disease
Center, July
1965 to May
2002
Hoskins 4th
ED.
Prognosis for Stage III GTN
Remission Therapy
Patients N
(%)
Low risk
Initial
Sequential MTX/ActMTX/Act-D
Resistant
MAC
EMA
EMAEMA-CO
104 (68)
High Risk
Initial
Sequential MTX/ActMTX/Act-D
MAC
EMAEMA-CO
Resistant
MAC
CHAMOCA
5-FUFU-Adria
VPB
EMA
EMAEMA-EP
49 (32)
Total
153
Remissions N
(%)
85
• New England
(81.7)
•
12
5
2
(11.5)
(4.8)
(1.9)
13
14
13
(26.5)
(28.6)
(26.5)
2
1
1
2
1
1
(4.1)
(2)
(2)
(4.1)
(2)
(2)
153
(99.3)
Trophoblastic
Disease Center,
July 1965 to
May 2002
Hoskins 4th ED.
Prognosis for Metastatic, Good
Prognosis GTN
Therapy
Remission N
(%)
Chemotherapy
35/40 (88)
Chemotherapy + hysterectomy (2°)
5/40
Chemotherapy + hysterectomy (1°)
15/15
Total
55/55 (100)
• Hammond CB. The role of operation in the current therapy of
•
•
gestational trophoblastic disease. Am J Obstet Gynecol 1980;
136: 844.
Southeastern Trophoblastic Center (Duke)
DiSaia 6th ED.
Poor Prognosis GTN
• Brain or liver involvement
• WHO score ≥ 8
• Resistance to first line chemotherapy
• Initiate treatment with MAC or EMA-CO
• Brain or liver metastases require XRT
MAC
• Berkowitz RS. Modified triple therapy in the management of high risk metastatic gestational trophoblastic tumors. Gynecol Oncol
1984; 19: 173-81.
•
•
•
•
Cyclophosphamide IV 3 mg/kg/day D1 -5
Act-D IM 12 µg/kg/day D1-5
Methotrexate IV 1 mg/kg/day D1,3,5,7
Brain metastases received 3000 cGy of whole brain irradiation (2
patients)
• 10/14 patients (71%) achieved CR with MAC
–
–
–
–
–
2 patients received VBP
1 patient received CHAMOCA
1 patient DOD
2 patients had a hysterectomy
2 patients had a pulmonary resection
• 13/14 patients (93%) achieved a CR with multi -agent chemotherapy
• Main side effect neutropenia
EMA-CO
• The standard of care for poor prognosis GTN
• Week #1
–
–
–
–
–
Etoposide 100 mg/m2 IV (30 minute) D1&2
Methotrexate 100 mg/m 2 IV push D1
Methotrexate 200 mg/m 2 IV (12 hour) D1
Act-D 350 µg/m2 IV push D1&2
Folinic acid 15 mg Q 6hrs for 4 doses
• Week #2
– Cyclophosphamide 600mg/m2 IV (1 hour) D8
– Vincristine 1 mg/m2 IV push D8
EMA-CO
Author
N
1st
line
(N)
2nd line
(N)
3rd
line
(N)
Surgery
(N)
Liver
(N)
Brain
(N)
CR (N)
Survival
(N)
Bolis G. Gynecol
Oncol. 1988
36
22
14
-
5
3
1
31
86%
29
Schink J. Obstet
Gynecol. 1992
12
12
-
-
3
1
1
10
83%
12 100%
Soper J. Obstet
Gynecol. 1994
22
6
16
-
12
6
5
11
69%
15
Bower M. J Clin
Oncol. 1997
272
151
121
-
n/a
17
34
213 78%
234 86%
Kim S. Gynecol
Oncol. 1998
165
96
61
8
42
6
19
138 84%
138 84%
Total
507
287
57%
212
41%
8
2%
62
12%
33
6.5%
60
12%
403 79%
428 84%
• Surgery: hysterectomy, pulmonary resection, nephrectomy,
splenectomy, colon resection, cardiac surgery
81%
68%
Brain Metastases
•
•
Recommend 3000 cGy whole brain irradiation (10 treatments)
Evans AJ. Gestational trophoblastic disease metastatic to the ce ntral
nervous system. Gynecol Oncol 1995; 59: 226.
– Reported that 12/16 patients (75%) had a CR with XRT and
combination chemotherapy
• Schechter NR. Prognosis of patient treated with whole -brain
radiation therapy for metastatic gestational trophoblastic disea se.
Gynecol Oncol 1998; 68:183.
– Dose > 2200 cGy versus 91% 5 year survival versus 24% 5 year
survival with a dose < 2200 cGy
– Survival based upon responsive multi-agent chemotherapy
• Newlands ES. Management of brain metastases in patients with
high-risk gestational trophoblastic tumor. J Reprod Med 2002; 47:
465.
– 31/35 patients (86%) cured with EMA-CO and intrathecal MTX
• Intrathecal MTX not standard of care for prophylaxis of CNS
metastases in patients with pulmonary metastases
Liver Metastases
• Extremely poor prognosis
• Crawford RA. Gestational trophoblastic disease with liver
metastases: the Charing Cross experience. Br J Obstet Gynecol
1997: 104:105.
–
–
–
–
46 of 1676 women with GTN (2.7%)
Concurrent metastatic disease to the lung (93%) and brain (33%)
5-year survival 27%
5-year survival 10% if the patient had brain metastases
• Hemorrhage worrisome; some recommend 2000cGy to prevent
hemorrhage
Resistance to EMA-CO
• Bower M. EMA/CO for high-risk gestational
trophoblastic tumors: results from a cohort of
272 patients. J Clin Oncol 1997: 15: 2636.
– EMA-EP (etoposide, cisplatin) ± surgery induced
remission in 16/21 patients (76%)
• Cisplatin, vinblastine, bleomycin (PVB) has some
efficacy
–
–
3 studies with few patients
CR of 20-50%
Placental Site Trophoblastic Tumor
(PSTT)
•
•
•
•
•
•
•
100 reported cases
Bleeding most common symptom
Intermediate trophoblasts
HCG weakly positive
Human placental lactogen (HPL) serum marker
Hysterectomy treatment of choice
Mainly benign tumor, although 15-20% mortality
rate for advanced stage tumors
Subsequent Pregnancy after Partial
Mole
Outcome
N
%
Term Delivery
189
75.3
Stillbirth
1
0.4
Preterm delivery
4
1.6
SAB
1st trimester
2nd trimester
Therapeutic AB
Ectopic
Repeat Mole
38
1
11
1
6
15.1
0.4
4.4
0.4
2.4
Total
251
N/Deliveries
(%)
• New England Trophoblastic
•
Congenital
malformation
3/194 (1.5)
Primary
Cesarean section
29/194 (14.9)
Disease Center, January
1979 to November 2001
Hoskins 4th ED.
Subsequent Pregnancy after
Complete Mole
Outcome
N
%
Term Delivery
877
68.6
Stillbirth
7
0.5
Preterm delivery
65
7.4
N/Deliveries
(%)
• New England
•
SAB
1st trimester
2nd trimester
Therapeutic AB
Ectopic
Repeat Mole
221
8
41
11
18
Total
1278
17.3
0.6
3.2
0.9
1.4
Congenital
malformation
40/979 (4.1)
Primary
Cesarean section
70/373 (18.8)
Trophoblastic Disease
Center, January 1979 to
November 2001
Hoskins 4th ED.
Subsequent Pregnancy after GTN
Outcome
N
%
Term Delivery
393
67.6
Stillbirth
9
1.5
Preterm delivery
35
6
N/Deliveries
(%)
• New England
•
SAB
1st trimester
2nd trimester
Therapeutic AB
Ectopic
Repeat Mole
92
7
28
7
8
Total
581
15.8
1.2
4.8
1.2
1.4
Congenital
malformation
10/437 (2.3)
Primary Cesarean
section
68/335 (20.3)
Trophoblastic Disease
Center, January 1979 to
November 2001
Hoskins 4th ED.
Secondary Malignancies
• Rustin GJ. Combination but not single-agent
methotrexate chemotherapy for gestational trophoblastic
tumors increases the incidence of second tumors. J Clin
Oncol 1996; 14: 2769.
–
–
–
–
RR leukemia
RR melanoma
RR colon
RR breast
16.6
3.4
4.6
5.8
• 1.5% of all patients treated with etoposide developed
•
leukemia
Increased risk for breast cancer is not apparent until
after 25 years