By: Annisa

INTRODUCTION
Complete mole GTT

Locally invasive GTT 15% of patients after evacuation Metastases GTT 4%

Approximately 8590% of patients in low risk GTT are cured by the initial chemotherapy regimen

Berkowitz RS, Goldstein DP. Gestational trophoblastic disease. Dalam: penyunting JS Berek. Berek and Novaks Gynecology. Edisi 14. California: Lippincott Williams & Wilkins. 2007; 1581-602. Ehlen TG, Bessette P, Gerulath AH, Jolicoeur L, Savoie R. Gestational trophoblastic disease. SOGC clinical practice guidelines. J Obstet Gynaecol Can. 2002; 24(5): 434-9.

IDENTITY

Name Age Address Education

: Mrs. T : 33 years old : Jatinangor : Elementary school

Occupation : Housewife Medrec

Admission Referred by Note

: 0905 xxxx

: May 13, 2009 : Sumedang Hospital : GTT stage I

Chief complaint : Vaginal bleeding

ANAMNESIS

P2A1 (LC 2; YC 3 y.o)

Vaginal bleeding since 3 months b.a

History of curettage (hydatidiform mole) on July 2008 at Sumedang Hospital hystological finding (-) Abdominal mass since 3 months b.a

GTT stage I

-hCG (08/05/2009) 641.06 mIU/mL

50 mg

-hCG (07/09/2009) 3.11 mIU/mL

II

GTT stage II

-hCG (03/06/2009) 8200 mIU/mL

-hCG (07/10/2009) 2.6 mIU/mL III

Time line....

Resistance to first-line chemotherapy

No firm criteria for the diagnosis of resistance to first-line single-agent therapy exist Generally accepted definition for resistance to first-line chemotherapy is lacking, although some clinics define: by a plateau or increase in serum hCG or

by detection of (new) metastases

Van Trommel NE, Massuger LF, Schijf CP, Ten Kate-Booij MJ, Sweep FC, Thomas CM. Early identification of resistance to first-line single-agent methotrexate in patients with persistent trophoblastic disease. J Clin Oncol. 2006; 24: 52-8.

Resistance to first-line chemotherapy

Serum hCG measurement preceding the fourth and sixth single-agent chemotherapy have excellent diagnostic accuracy for identifying resistance to single-agent Chemotherapy (with an area under the curve (AUC) for receiver operating characteristic curve analysis of 0.949 and 0.975, respectively) At 97.5% specificity, serum hCG measurements after 7 weeks showed 50% sensitivity.

Van Trommel NE, Massuger LF, Schijf CP, Ten Kate-Booij MJ, Sweep FC, Thomas CM. Early identification of resistance to first-line single-agent methotrexate in patients with persistent trophoblastic disease. J Clin Oncol. 2006; 24: 52-8.

In this case...
Progressive GTT new metastasis, hCG

Resistance
Plateau or increase in serum hCG or by detection of (new) metastases Serum hCG measurement preceding the fourth and sixth

The management of this patient at Hasan Sadikin Hospital

GTT Therapy

Chemotherapy the 1st choice (GTT was response to chemotherapy) Operative: complication resection chemotherapy resistance disease

Berkowitz RS, Goldstein DP. Current management of gestational trophoblastic disease. Gynecology Oncology. 2009; 654-62.

GTT Therapy

Approximately 9% to 33% of patients treated with single-agent chemotherapy for low-risk PTD will require multiagent chemotherapy because resistance to the first-line drug or toxic adverse effects occurred.

Most of the others will respond to alternate drugs;

combination chemotherapy is rarely needed.

Ehlen TG, Bessette P, Gerulath AH, Jolicoeur L, Savoie R. Gestational trophoblastic disease. SOGC clinical practice guidelines. J Obstet Gynaecol Can. 2002; 24(5): 434-9.

GTT Therapy
Methotrexate 0.4 mg/kg (maximum 25 mg) five days Methotrexate 1 mg/kg intramuscularly given days 1, 3, 5, and 7 with calcium leucovorin rescue 0.1 mg/kg days 2, 4, 6, and 8 is an alternative Dactinomycin 913 g/kg intravenously daily for five days every two weeks (maximum 500 g/d) primary therapy for patients with hepatic and renal disease Etoposide 200 mg/m2 per os daily for five days every 12 to 14 days has been found to be highly effective and less toxic.

Ehlen TG, Bessette P, Gerulath AH, Jolicoeur L, Savoie R. Gestational trophoblastic disease. SOGC clinical practice guidelines. J Obstet Gynaecol Can. 2002; 24(5): 434-9.

Gynecologic oncology group (GOG)

Complete response Weekly methotrexate low dose 81% Methotrexate with leucovorin rescue 90.2% Dactinomycin 94%

Homesley HD. Treatment of non-metastatic gestational trophoblastic disease. Hancock BW, Seckl MD, Berkowitz RS editors. Gestational trophoblastic disease. ISSTD. 3rd edition. 2009; 298-9.

Chemotherapy regiment protocol at Hasan Sadikin Hospital

Low risk GTT 20 mg MTX for 5 days 50 mg MTX 1-3-5-7

Etoposide for 5 days have used satisfied response

Aziz F, Andrijono, Saifuddin AB. Buku acuan nasional: Onkologi Ginekologi. 2006. Edisi pertama. Jakarta: Yayasan Bina Pustaka. Hal: 564-5

In this case...

GTT stage I low risk 50 mg MTX leucovorin rescue After the 3rd and 4th 50 mg MTX massive bleeding Oncology consultant decission ME chemotherapy given directly etoposide 5 days Response therapy

If resistance to single-agent chemotherapy develops, combination chemotherapy is employed

Ehlen TG, Bessette P, Gerulath AH, Jolicoeur L, Savoie R. Gestational trophoblastic disease. SOGC clinical practice guidelines. J Obstet Gynaecol Can. 2002; 24(5): 434-9.

THANK YOU

FIGO Risk Factor Scoring

0 Age Antecedent pregnancy Interval months from index pregnancy Pretreatment hCG Largest tumor size including uterus Site of metastasis including uterus Number of metastasis identifies <40 Hydatidiform mole <4 <103

1 40 Abortion

Term

4-6 103-104

7-12 104-105

>12 >105

3-4 cm
Spleen Kidney 1-4

5 cm
Brain Liver >8

GI tract

5-8

Previous failed
chemotherapy

Single drug

Two or more
drug

SCORE 4

USG (18/05/2009)

Uterine Homogen density S: 7.53x7.14x7.76 cm Seen heterogen density mass with necrotic foci Neovascularization (+), RI: 0.43 Adnexa Normal Others Normal liver, kidney Impression Suspect GTT

USG (03/06/2009)
Uterine Heterogen density S: 7.53x7.14x7.76 cm Seen heterogen density mass with necrotic foci Neovascularization (+), RI: 0.43 Adnexa Right adnexa seen complex mass s: 5.5x5.03 cm Left adnexa seen complex mass s: 2.5x2.65 cm surrounded by hypervascularization Others Normal liver, kidney Impression Suspect GTT; adnexal tumor with unknown substrat

USG (10/06/2009)
Uterine Heterogen density S: 8.35x4.76 cm Seen heterogen density mass s: 2.88x3.78 cm Surrounded by hypervascularization Neovascularization (-) Adnexa Right adnexa seen hypoechoic mass s: 4.11x5.22 cm Left adnexa seen hypoechoic mass s: 4.60x3.28 cm Others Normal liver, kidney Impression GTT (improvement)

ANAMNESIS

Appetite Bowel habit Micturition

: normal : normal : normal

Menarche
Contraception Body weight Body height

: 15 y.o
: (-) : 50 kg : 152 cm

ADITIONAL ANAMNESIS

Living with her husband and 2 children at 5x4 m2 house reachable with motorbike or car Her husband farmer (Rp 300,000/month) Vaginal bleeding (-), abdominal mass (-)

External exam: mass 1 finger above symphisis

Contraception (-) Blood sample -hCG 3.11 mIU/mL

PHYSICAL EXAMINATION

General condition : good

BP Pulse Respiration Temperature : 130/90 mmHg : 88 bpm : 20 tpm : afebrile

GYNECOLOGY EXAMINATION

ABDOMEN Flat, soft DM (-), shiffting dullness (-), pain (-) Mass (-)

SPECULUM EXAMINATION Vagina: metastasis (-) Portio: smooth, fluxus (+)

GYNECOLOGY EXAMINATION

INTERNAL EXAMINATION V/V : normal Portio : S/C normal Uterine corpus : ~12-13 weeks L-R uterine : soft, mass (-), tenderness (-) Douglas pouch : not bulging

-hCG (08/05/2009) 641.06 mIU/mL

LABORATORY (13/05/09)
PT-INR PT INR APTT Haemoglobine White blood cell Platelet Packed cell volume 12.7 1.05 20.5 4.0 g/dL 3,500/mm3 385,000/mm3 13% AST ALT Ureum Creatinine Sodium Potassium 20 U/L 37C 13 U/L 37C 15 mg/dL 0.55 mg/dL 135 mEq/L 3.5 mEq/L

Chest X-ray (13/05/2009) No metastases

DIAGNOSIS

Gestational trophoblastic tumor stage I; severe anemia

PLAN OF MANAGEMENT IV line, cross match, blood reserve Transfusion Hb 8 g/dL Plan: chemotherapy Plan USG Bleeding, vital signs observation

Trophoblast conference result (20/05/09)

DIAGNOSIS

Gestational trophoblastic tumor stage I PLAN OF MANAGEMENT MTX 50 mg chemotherapy

After giving the 3rd MTX 50 mg

Massive bleeding was occured vaginal tamponade Hb 8.3 g/dL transfusion

After giving the 4th MTX 50 mg

Massive bleeding was occured vaginal tamponade

RE-EXAMINATION (03/06/09)

ABDOMEN Flat, soft DM (-), shiffting dullness (-) Palpated mass s: 8x6x6 cm, solid-rubbery, smooth surface, limited movement

SPECULUM EXAMINATION Vagina: metastasis (-) Portio: smooth, fluxus (+)

GYNECOLOGY EXAMINATION

INTERNAL EXAMINATION V/V : normal Portio : soft Uterine corpus : ~12-14 weeks L-R uterine : palpated mass s: 8x6x6 cm, solid-rubbery, smooth surface, limited movement Douglas pouch : not bulging
-hCG (03/06/2009) 8200 mIU/mL

DIAGNOSIS

Gestational trophoblastic tumor stage II

PLAN OF MANAGEMENT USG Consult to oncology consultant

EXAMINATION by TROPHOBLAST CONSULTANT (03/06/09)

ABDOMEN Flat, soft DM (-), shiffting dullness (-), RLQ tenderness (+) Above symphisis palpated irregular mass Left sided 2 fingers above symphisis, right sided 4 fingers above symphisis

GYNECOLOGY EXAMINATION

INTERNAL EXAMINATION V/V : normal Portio : S/C normal Uterine corpus : ~12-14 weeks, solid, immobile, push to the left Left uterine : tense Right uterine : palpated mass as big as adult human fist, poorly border, limited movement, tenderness (+)

DIAGNOSIS

Gestational trophoblastic tumor with recurrent bleeding with more bigger tumor mass threatened perforation

PLAN OF MANAGEMENT USG Haemoglobine check

CONSULT TO ONCOLOGYST CONSULTANT (04/06/09)

DIAGNOSIS Gestational trophoblastic tumor stage II with adnexal involvement PLAN OF MANAGEMENT ME chemotherapy etopusid given directly If bleeding occured change with another chemotherapy probably for hysterectomy Adnexal mass evaluation with clinical and USG

After giving 5 days etoposide

Relieve symptoms External examination Mass above symphisis still exist, but smaller Advice USG

PROBLEMS
1. How is the natural history of

this patient?
2. Was the management of this patient at Hasan Sadikin

Hospital correct?
3. How about the prognosis of this patient?

1. How is the natural history of this patient?

In this case...

Progressive GTT with single agent chemotherapy

With MTX 50 mg: Massive bleeding Adnexal mass hCG

Neoplastic transformation of trophoblast

Multi-step process, multiple genetic alterations (activation of oncogenes and inactivation of tumor suppressor genes) Potential biological markers: c-erbB-2, cyclin E, DOC-2/hDab2, Ras GTPase activating protein,

telomerase activity, apoptotic index, and

matrix metalloproteinases

Xue WC, Chan K, Feng HC, Chiu PM, Ngan HYS, Tsao SW, dkk. Promoter hypermethylation of multiple genes in hydatidiform mole and choriocarcinoma. JMD. 2004; 6(4).

Neoplastic transformation of trophoblast

Promoter hypermethylation an important epigenetic mechanism causing gene inactivation Tumor suppressor genes, involving cell cycle regulation (p16),

DNA repair and protection (BRCA1 and GSTP1),

apoptosis (DAPK), cell adherence and metastasis process (E-cadherin, TIMP3), may be silenced by

promoter CpG island methylation in many human tumors

Xue WC, Chan K, Feng HC, Chiu PM, Ngan HYS, Tsao SW, dkk. Promoter hypermethylation of multiple genes in hydatidiform mole and choriocarcinoma. JMD. 2004; 6(4).

TIMP3

Decreased the activation of metalloproteinases inhibiting degradation of the extracellular matrix and reducing the invasive potential of tumor cells Some unique properties in human cancer development: growth suppression, inhibition of angiogenesis, and induction of apoptosis Transcriptional inactivation of TIMP3 by hypermethylation more malignant and invasive phenotype

Xue WC, Chan K, Feng HC, Chiu PM, Ngan HYS, Tsao SW, dkk. Promoter hypermethylation of multiple genes in hydatidiform mole and choriocarcinoma. JMD. 2004; 6(4).

Patient monitoring

Approximately 3050% of patients will develop resistance to the first drug and require alternative treatments. Weekly hCG tests until normal for 3 consecutive weeks and then monthly for 12 months. In this case... Counselling has been given economic and environment factors (lack of family support) inadequate follow up

Ehlen TG, Bessette P, Gerulath AH, Jolicoeur L, Savoie R. Gestational trophoblastic disease. SOGC clinical practice guidelines. J Obstet Gynaecol Can. 2002; 24(5): 434-9. Berkowitz RS, Goldstein DP. Current management of gestational trophoblastic disease. Gynecology Oncology. 2009; 654-62.

Contraception in GTT

Avoid pregnancy until hCG levels have been normal one year following chemotherapy for gestational trophoblastic tumor. The combined oral contraceptive pill is safe for use by women with GTT.

Ehlen TG, Bessette P, Gerulath AH, Jolicoeur L, Savoie R. Gestational trophoblastic disease. SOGC clinical practice guidelines. J Obstet Gynaecol Can. 2002; 24(5): 434-9.

Subsequent pregnancies

Following chemotherapy for GTN, patients occasionally become pregnant before completing hCG follow up. Matsui et al. reported that pregnancies which occur within 6 months following GTN remission increased risk of abnormalities, including spontaneous miscarriage, stillbirths, and repeat moles.

Berkowitz RS, Goldstein DP. Current management of gestational trophoblastic disease. Gynecology Oncology. 2009; 654-62.

In this patient...

Counselling for contraception and important of follow up to patient and her husband, and her family patient advice to come to Hasan Sadikin Hospital as soon as possible

3. How about the prognosis of this patient?

PROGNOSIS

The prognosis of gestational choriocarcinoma is getting better by advances of combination chemotherapy. The survival rate is increasing and 96.4% in 15 years since 1985.

Yamamoto E. Ovary: Choriocarcinoma. Atlas Genet Cytogenet Oncol Haematol. September 2008. URL: http://AtlasGeneticsOncology.org/Genes/OvaryChoriocarcID5219.html

Risk of relapse
Chemotherapy should be given as often as toxicity permits until the patient achieves three consecutive normal hCG levels.
After normal hCG levels are attained, at least two additional courses of chemotherapy are administered to reduce the risk of relapse

Berkowitz RS, Goldstein DP. Gestational trophoblastic disease. Dalam: penyunting JS Berek. Berek and Novaks Gynecology. Edisi 14. California: Lippincott Williams & Wilkins. 2007; 1581-602.

In this patient...
After mole evacuation at Sumedang Hospital never been follow up until 10 months later.
After the 1st chemotherapy not perform follow up until giving counselling for many times. Economic and family support very important. Counselling not only for the patient, but also for her husband, family, and people arround her. Complete remission cant achieve if the patient not doing an adequate follow up

In this case
At home visit - Symtomps (-) - Theres still abdominal mass with smaller size - Blood sample was taken serum hCG 3.11 mIU/mL

Next management Etoposide chemotherapy as an alternative single agent Prevent toxicity

CONCLUSION 1. Natural history of this patient progressive dissease with single agent chemotherapy.

Resistance of MTX chemotherapy still

debatable. 2. Management of this patient wasnt adequate no routine follow up. 3. Poor prognosis will happen if the patient still obey the doctors advice.

SUGGESSTION

1. All person who closed to the patient should

give motivation including familiy and the doctors from Hasan Sadikin Hospital.

2. Etoposide
another

as

alternative
should be achieve

single

agent
for

chemotherapy

thinking

way to

remission, as

important as toxicity.

Case Presentation Monday, Sepetember 14 2009

Failed of chemotherapy stage I persistent trophoblastic disease on woman who given methrotrexate as single agent chemotherapy
By: Annisa

Moderator: dr. Ady BG

Resource persons: dr. Ali Budi, SpOG(K)