1/26 novak 34. gestational trophoblastic disease 부산백병원 산부인과 r1 손영실

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NOVAK 34.

Gestational Trophoblastic Disease

부산백병원 산부인과부산백병원 산부인과

R1 R1 손영실손영실

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INDEX

# Persistent Gestational Trophoblastic Tumor# Persistent Gestational Trophoblastic Tumor 1. Nonmetastatic Disease1. Nonmetastatic Disease 2. Metastatic Disease2. Metastatic Disease 3. Staging3. Staging 4. Prognostic Scoring System4. Prognostic Scoring System 5. Diagnostic Evaluation5. Diagnostic Evaluation 6. Management of Persistent GTT6. Management of Persistent GTT

# Chemotherapy# Chemotherapy 1. Single-agent Treatment1. Single-agent Treatment 2. Combination Chemotherapy2. Combination Chemotherapy

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# Persistent Gestational Trophoblastic Tumor

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◎ ◎ Locally invasive GTTLocally invasive GTT : about 15% of patients after molar evacuation and after: about 15% of patients after molar evacuation and after other gestationsother gestations

◎ ◎ SymptomsSymptoms ① ① irregular vaginal bleedingirregular vaginal bleeding ② ② theca lutein cyststheca lutein cysts ③ ③ uterine subinvolution or asymmetric enlargementuterine subinvolution or asymmetric enlargement ④ ④ persistently elevated serum hCG levelspersistently elevated serum hCG levels

◎ ◎ Histology of persistent GTTHistology of persistent GTT ① ① after molar evacuation ⇒ H-mole or choriocarcinomaafter molar evacuation ⇒ H-mole or choriocarcinoma ② ② after nonmolar pregnancy ⇒ always choriocarcinomaafter nonmolar pregnancy ⇒ always choriocarcinoma

NONMETASTATIC DISEASE

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• • 4% of patients after evacuation of a complete mole4% of patients after evacuation of a complete mole

• • usually associated with choriocarcinomausually associated with choriocarcinoma

• • early vascular invasion with widespread disseminationearly vascular invasion with widespread dissemination

• • spontaneous bleeding at meatstatic focispontaneous bleeding at meatstatic foci

• • metastatic sitemetastatic site

: lung(80%), vagina(30%), pelvis(20%), liver(10%),: lung(80%), vagina(30%), pelvis(20%), liver(10%),

and brain(10%)and brain(10%)

METASTATIC DISEASE

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1. Pulmonary1. Pulmonary • • lung involvement is visible on chest x-ray of 80% oflung involvement is visible on chest x-ray of 80% of patients with metastatic GTTpatients with metastatic GTT ① “ ① “snowstorm” patternsnowstorm” pattern ② ② discrete rounded densitydiscrete rounded density ③ ③ pleural effusionpleural effusion ④ ④ an embolic pattern by pulmonary arterial occlusionan embolic pattern by pulmonary arterial occlusion • • Sx : chest pain, cough, hemoptysis, dyspnea,Sx : chest pain, cough, hemoptysis, dyspnea, or asymptomatic lesionor asymptomatic lesion

2. Vaginal2. Vaginal • • occurs in 30% of patients with metastatic tumoroccurs in 30% of patients with metastatic tumor • • highly vascular, may bleed vigorously if sample is takenhighly vascular, may bleed vigorously if sample is taken for biopsyfor biopsy • • Sx : irregular bleeding, purulent dischargeSx : irregular bleeding, purulent discharge

METASTATIC DISEASE

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3. Hepatic3. Hepatic • • 10% of patients10% of patients

• • Sx : epigastric or RUQ painSx : epigastric or RUQ pain

(if metastases stretch the hepatic capsule)(if metastases stretch the hepatic capsule)

• • hemorrhagic → causing hepatic rupture & intraperitonealhemorrhagic → causing hepatic rupture & intraperitoneal

bleedingbleeding

4. CNS4. CNS • • 10% of patients10% of patients

• • generally seen in patients with advanced diseasegenerally seen in patients with advanced disease

• • spontaneous bleeding → acute focal neurologic deficitsspontaneous bleeding → acute focal neurologic deficits

METASTATIC DISEASE

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- by FIGO classification- by FIGO classification ◎ ◎ Stage ⅠStage Ⅰ : patients have persistently elevated hCG levels and tumor: patients have persistently elevated hCG levels and tumor confined to the uterine corpusconfined to the uterine corpus ◎ ◎ Stage ⅡStage Ⅱ : patients have metastases to the vagina and pelvis or both: patients have metastases to the vagina and pelvis or both ◎ ◎ Stage ⅢStage Ⅲ : patients have pulmonary metastases with or without: patients have pulmonary metastases with or without uterine, vaginal, or pelvic involvementuterine, vaginal, or pelvic involvement ◎ ◎ Stage ⅣStage Ⅳ : patients have advanced disease and involvement of the: patients have advanced disease and involvement of the brain, liver, kidneys, or gastrointestinal tractbrain, liver, kidneys, or gastrointestinal tract

STAGING

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STAGINGStage ⅠStage Ⅰ Disease confined to uterusDisease confined to uterusStage ⅠAStage ⅠA Disease confined to uterus with no risk factorsDisease confined to uterus with no risk factorsStage ⅠBStage ⅠB Disease confined to uterus with one risk factorDisease confined to uterus with one risk factorStage ⅠCStage ⅠC Disease confined to uterus with two risk factorsDisease confined to uterus with two risk factors

Stage ⅡStage Ⅱ Gestational trophoblastic tumor extending outside uterus but limited to genital Gestational trophoblastic tumor extending outside uterus but limited to genital structures (adnexa, vagina, broad ligament)structures (adnexa, vagina, broad ligament)

Stage ⅡAStage ⅡA Gestational trophoblastic tumor involving genital structures without risk factorsGestational trophoblastic tumor involving genital structures without risk factors

Stage ⅡBStage ⅡB Gestational trophoblastic tumor extending outside uterus but limited to genitalGestational trophoblastic tumor extending outside uterus but limited to genital structures with one risk factorstructures with one risk factor

Stage ⅡCStage ⅡC Gestational trophoblastic tumor extending outside uterus but limited to genitalGestational trophoblastic tumor extending outside uterus but limited to genital structures with two risk factorsstructures with two risk factors

Stage ⅢStage Ⅲ Gestational trophoblastic disease extending to lungs with or without known genitalGestational trophoblastic disease extending to lungs with or without known genital tract involvementtract involvement

Stage ⅢAStage ⅢA Gestational trophoblastic tumor extending to lungs with or without genital tractGestational trophoblastic tumor extending to lungs with or without genital tract involvement and with no risk factorsinvolvement and with no risk factors

Stage ⅢBStage ⅢB Gestational trophoblastic tumor extending to lungs with or without genital tractGestational trophoblastic tumor extending to lungs with or without genital tract involvement and with one risk factorinvolvement and with one risk factor

Stage ⅢCStage ⅢC Gestational trophoblastic tumor extending to lungs with or without genital tractGestational trophoblastic tumor extending to lungs with or without genital tract involvement and with two risk factorsinvolvement and with two risk factors

Stage ⅣStage Ⅳ All other metastatic sitesAll other metastatic sitesStage ⅣAStage ⅣA All other metastatic sites without risk factorsAll other metastatic sites without risk factorsStage ⅣBStage ⅣB All other metastatic sites with one risk factorAll other metastatic sites with one risk factorStage ⅣCStage ⅣC All other metastatic sites with two risk factorsAll other metastatic sites with two risk factors

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◎ ◎ to consider other variables to consider other variables

to predict the drug resistanceto predict the drug resistance

to assist in selecting appropriate to assist in selecting appropriate chemotherapychemotherapy

◎ ◎ higher than 7higher than 7

: categorized as high risk requires intensive : categorized as high risk requires intensive combination combination

chemotherapychemotherapy

PROGNOSTIC SCORING SYSTEM

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PROGNOSTIC SCORING SYSTEM

ScoreScore 00 11 22 44

Age (years)Age (years) ≤≤3939 ＞＞ 3939 -- --Antecedent pregnancyAntecedent pregnancy H-moleH-mole AbortionAbortion TermTerm --Interval between end of Interval between end of antecedent pregnancy andantecedent pregnancy and start of chemotherapystart of chemotherapy (months)(months)

＜＜ 44 4-64-6 7-127-12 ＞＞ 1212

Human chorionic gonadotroinHuman chorionic gonadotroin (IU/liter)(IU/liter)

＜＜ 101033 101033-10-1044 101044-10-1055 ＞＞ 101055

ABO groupsABO groups -- O or AO or A B or ABB or AB --

Largest tumor, includingLargest tumor, including uterine (cm)uterine (cm)

＜＜ 33 3-53-5 ＞＞ 55 --

Site of metastasesSite of metastases -- Spleen,Spleen, kidneykidney

GastrointestinalGastrointestinal tract, livertract, liver

BrainBrain

Number of metastasesNumber of metastases -- 1-31-3 4-84-8 ＞＞ 88

Prior chemotherapyPrior chemotherapy -- -- 1 drug1 drug ≥≥2 2 drugsdrugs

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◎ ◎ All patients with persistent GTT should undergo a carefulAll patients with persistent GTT should undergo a careful pretreatment evaluationpretreatment evaluation ① ① complete history and physical examcomplete history and physical exam ② ② measurement of serum hCG level measurement of serum hCG level ③ ③ hepatic, thyroid, and renal function testhepatic, thyroid, and renal function test ④ ④ determination of baseline peripheral WBC & platelet countdetermination of baseline peripheral WBC & platelet count

◎ ◎ The metastatic workupThe metastatic workup ① ① chest radiograph or CT scanchest radiograph or CT scan ② ② ultrasonography or CT scan of the abdomen & pelvisultrasonography or CT scan of the abdomen & pelvis ③ ③ CT or MRI scan of the headCT or MRI scan of the head

◎ ◎ When the pelvic exam & chest radiographic findings areWhen the pelvic exam & chest radiographic findings are negative, metastatic involvement of other sites is uncommonnegative, metastatic involvement of other sites is uncommon

DIAGNOSTIC EVALUATION

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MANAGEMENT OF PERSISTENT GTTStage ⅠStage Ⅰ

InitialInitial Single-agent chemotherapy or hysterectomy with Single-agent chemotherapy or hysterectomy with adjunctiveadjunctive chemotherapychemotherapy

ResistantResistant Combination chemotherapyCombination chemotherapyHysterectomy with adjunctive chemotherapyHysterectomy with adjunctive chemotherapyLocal resectionLocal resectionPelvic infusionPelvic infusion

Stage Ⅱ and ⅢStage Ⅱ and Ⅲ

Low riskLow riskaa

InitialInitial Single-agent chemotherapySingle-agent chemotherapy

ResistantResistant Combination chemotherapyCombination chemotherapy

High riskHigh riskaa

InitialInitial Combination chemotherapyCombination chemotherapy

ResistantResistant Second-line combination chemotherapySecond-line combination chemotherapy

Stage ⅣStage Ⅳ

InitialInitial Combination chemotherapyCombination chemotherapy

BrainBrain Whole-heat irradiation (3,000 cGy)Whole-heat irradiation (3,000 cGy)Craniotomy to manage complicationsCraniotomy to manage complications

LiverLiver Resection to manage complicationsResection to manage complications

ResistantResistantaa Second-line combination chemotherapySecond-line combination chemotherapyHepatic arterial infusionHepatic arterial infusion

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1. Stage Ⅰ1. Stage Ⅰ - the selection of Tx is based primarily on whether the- the selection of Tx is based primarily on whether the patients desire to retain fertilitypatients desire to retain fertility

A. Hysterectomy plus ChemotherapyA. Hysterectomy plus Chemotherapy • • If patient does not wish to preserve fertilityIf patient does not wish to preserve fertility ⇒ ⇒ hysterectomy + adjuvant single chemotherapyhysterectomy + adjuvant single chemotherapy • • Reasons of adjuvant chemotherapyReasons of adjuvant chemotherapy ① ① to reduce disseminating viable tumor cells at surgeryto reduce disseminating viable tumor cells at surgery ② ② to maintain a cytotoxic level of chemotherapy in caseto maintain a cytotoxic level of chemotherapy in case viable tumor cells are disseminated at surgeryviable tumor cells are disseminated at surgery ③ ③ to treat any occult metastases that may already beto treat any occult metastases that may already be present at surgerypresent at surgery

MANAGEMENT OF PERSISTENT GTT

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B. Chemotherapy AloneB. Chemotherapy Alone

• • In patients with stage Ⅰ who desire to retain In patients with stage Ⅰ who desire to retain fertilityfertility

⇒ ⇒ single-agent chemotherapysingle-agent chemotherapy

⇒ ⇒ 92.1% of patients attained complete 92.1% of patients attained complete remissionremission

• • Patients are resistant to single-agent Patients are resistant to single-agent chemotherapy chemotherapy

(desire to retain fertility)(desire to retain fertility)

⇒ ⇒ combination chemotherapycombination chemotherapy

• • If resistant to bothIf resistant to both

⇒ ⇒ local uterine resection may be consideredlocal uterine resection may be considered


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2. Stage Ⅱ and Ⅲ2. Stage Ⅱ and Ⅲ - low-risk : single agent chemoTx- low-risk : single agent chemoTx - high-risk : combination chemoTx- high-risk : combination chemoTx

A. Vaginal and Pelvic MetastasisA. Vaginal and Pelvic Metastasis • • vaginal metastases may bleed profuselyvaginal metastases may bleed profusely (∵ highly vascular and friable)(∵ highly vascular and friable) ⇒ ⇒ controlled by packing or by wide local excisioncontrolled by packing or by wide local excision

B. Pulmonary MetastasisB. Pulmonary Metastasis • • persistent viable pulmonary metastasis despite intensivepersistent viable pulmonary metastasis despite intensive chemotherapychemotherapy ⇒ ⇒ thoracotomy may be attempted to excise thethoracotomy may be attempted to excise the resistant focusresistant focus


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C. HysterectomyC. Hysterectomy • • may be required in patients with metastases to controlmay be required in patients with metastases to control uterine hemorrhage or sepsisuterine hemorrhage or sepsis

D. Follow-up (Stage Ⅰ ~ Ⅲ)D. Follow-up (Stage Ⅰ ~ Ⅲ) ① ① weekly measurement of hCG levels until normalweekly measurement of hCG levels until normal for 3 consecutive weeksfor 3 consecutive weeks ② ② monthly measurement of hCG values until normalmonthly measurement of hCG values until normal for 12 consecutive monthsfor 12 consecutive months ③ ③ effective contraception during the entire interval ofeffective contraception during the entire interval of hormonal follow-uphormonal follow-up


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3. Stage Ⅳ3. Stage Ⅳ - primary intensive combination chemotherapy and the - primary intensive combination chemotherapy and the

selective use of radiation therapy and surgeryselective use of radiation therapy and surgery

A. Hepatic MetastasisA. Hepatic Metastasis • • resistant to systemic chemotherapyresistant to systemic chemotherapy

→ → hepatic arterial infusion of chemotherapyhepatic arterial infusion of chemotherapy

• • acute bleeding of tumoracute bleeding of tumor

→ → hepatic resectionhepatic resection


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B. Cerebral MetastasisB. Cerebral Metastasis • • If diagnosed, whole-brain irradiation (3,000 cGy in 10If diagnosed, whole-brain irradiation (3,000 cGy in 10 fractions) can be instituted promptlyfractions) can be instituted promptly • • conurrent use of combination chemotherapy and brainconurrent use of combination chemotherapy and brain irradiationirradiation → → spontaneous cerebral hemorrhage ↓spontaneous cerebral hemorrhage ↓

C. Follow-up (Stage Ⅳ)C. Follow-up (Stage Ⅳ) ① ① weekly determination of hCG levels until they areweekly determination of hCG levels until they are normal 3 consecutive weeksnormal 3 consecutive weeks ② ② monthly determination of hCG levels until they aremonthly determination of hCG levels until they are normal for 24 consecutive monthsnormal for 24 consecutive months • • increased risk of late recurrenceincreased risk of late recurrence → → prolonged gonadotropin follow-up is requiredprolonged gonadotropin follow-up is required


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Evacuation andweekly hCG titers

GTN

Mole

Metastaticwork-up

↓ hCGtiters

↑ or plateaudhCG titers

Choriocarcinoma

Distant metastasis

Uterine disease

Careful follow-upand contraception

Lung metastasis

Single drugchemotherapy orhysterectomy

Pelvic metastasis

Calculaterisk

Combinationchemotherapy± surgery ± RT

Low High

Follow-up Resistant

Stage ⅣStage Ⅰ Stage ⅢStage Ⅱ

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# Chemotherapy

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◎ ◎ Nonmetastatic and low-risk GTTNonmetastatic and low-risk GTT ⇒ ⇒ actinomycin D (Act-D) or MTX has achieved comparable actinomycin D (Act-D) or MTX has achieved comparable and excellent remission ratesand excellent remission rates

◎ ◎ ProtocolsProtocols ① ① Act-D can be given every other week as a 5-day regimenAct-D can be given every other week as a 5-day regimen or in a pulsatile fashionor in a pulsatile fashion ② ② use of MTX was the sameuse of MTX was the same

◎ ◎ Methotrexate with folic acid (MTX-FA)Methotrexate with folic acid (MTX-FA) ① ① the preferred single agent in the Tx of GTTthe preferred single agent in the Tx of GTT ② ② remission ratesremission rates - 90.2% in stage Ⅰ- 90.2% in stage Ⅰ - 68.2% in low-risk stages Ⅱ & Ⅲ- 68.2% in low-risk stages Ⅱ & Ⅲ ③ ③ after Tx with MTX-FA, thrombocytopenia, granulocytopeniaafter Tx with MTX-FA, thrombocytopenia, granulocytopenia and hepatotoxicity developed in only 1.6%, 5.9% and 14.1%and hepatotoxicity developed in only 1.6%, 5.9% and 14.1% of patientsof patients

SINGLE-AGENT TREATMENT

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1. Technique of Single-agent Treatment1. Technique of Single-agent Treatment ◎ ◎ Serum hCG levels is measured weekly after each course ofSerum hCG levels is measured weekly after each course of chemotherapychemotherapy ◎ ◎ hCG regression curve serves as the primary basis forhCG regression curve serves as the primary basis for determining the need for additional Txdetermining the need for additional Tx ◎ ◎ After 1st TxAfter 1st Tx ① ① Further chemotherapy is withheld as long as the hCG levelFurther chemotherapy is withheld as long as the hCG level is falling progressivelyis falling progressively ② ② Additional single-agent chemotherapy is not administeredAdditional single-agent chemotherapy is not administered at any predetermined or fixed intervalat any predetermined or fixed interval ◎ ◎ 2nd course of chemotherapy is administered under the2nd course of chemotherapy is administered under the following conditionsfollowing conditions ① ① If the hCG level plateaus for more than 3 conseutive weeks If the hCG level plateaus for more than 3 conseutive weeks or begins to rise againor begins to rise again ② ② If the hCG level does not decline by 1 log within 18 daysIf the hCG level does not decline by 1 log within 18 days after completion of the first treatmentafter completion of the first treatment

SINGLE-AGENT TREATMENT

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1. Triple Therapy1. Triple Therapy ◎ ◎ etoposide, MTX, Act-D, cyclophosphamideetoposide, MTX, Act-D, cyclophosphamide and vincristine (EMA-CO)and vincristine (EMA-CO) - had complete remission in patients with metastasis and a- had complete remission in patients with metastasis and a high-risk score (76~94%)high-risk score (76~94%) - remission occurred in 13 of 15 patients (86%) with brain- remission occurred in 13 of 15 patients (86%) with brain metastasismetastasis

◎ ◎ EMA-CO regimenEMA-CO regimen ① ① the preferred primary Tx in patients with metastasis and athe preferred primary Tx in patients with metastasis and a high-risk prognostic scorehigh-risk prognostic score ② ② generally well toleratedgenerally well tolerated ③ ③ seldom has to be suspended because of toxicityseldom has to be suspended because of toxicity

COMBINATION CHEMOTHERAPY

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2. Duration of therapy2. Duration of therapy

◎ ◎ Combination chemotherapy should be given as often asCombination chemotherapy should be given as often as

toxicity permits until the patients achieves threetoxicity permits until the patients achieves three

consecutive normal hCG levelsconsecutive normal hCG levels

◎ ◎ After normal hCG levels are attained, at least twoAfter normal hCG levels are attained, at least two

additional course are administered to reduce the riskadditional course are administered to reduce the risk

of relapseof relapse

COMBINATION CHEMOTHERAPY

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1/26 novak 34. gestational trophoblastic disease 부산백병원 산부인과 r1 손영실

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