DIAGNOSIS, TREATMENT AND FOLLOW-UP IN AREAS OF LIMITED RESOURCES Virach Wootipoom, MD Prince of Songkla University Songkhla, Thailand Gestational Trophoblastic.

DIAGNOSIS, TREATMENT DIAGNOSIS, TREATMENT AND FOLLOW-UP IN AND FOLLOW-UP IN AREAS OF LIMITED AREAS OF LIMITED

RESOURCES RESOURCES

Virach Wootipoom, MDVirach Wootipoom, MDPrince of Songkla Prince of Songkla UniversityUniversitySongkhla, ThailandSongkhla, Thailand

Gestational Trophoblastic Gestational Trophoblastic LesionsLesions

Limited resourcesLimited resources

Gynecologic Gynecologic OncologistsOncologists

Laboratory (hCG)Laboratory (hCG) ImagingImaging ChemotherapyChemotherapy RadiotherapyRadiotherapy SurgerySurgery

Lancet Oncol 2003; 4: 670–78

Incidence of hydatidiform mole from selected studies

Lancet Oncol 2003; 4: 670–78

Ratios of choriocarcinoma from selected studies*

Age-standardised incidence rates of choriocarcinoma per 100 000 women from cancerregistry- based statistics in different areas of the world.Lancet Oncol 2003; 4: 670–78

GTD variationGTD variation

The reason for this variation The reason for this variation is not understoodis not understood

women over 40 years having at least a women over 40 years having at least a fivefold increase in risk.fivefold increase in risk.

previous molar is a predisposing previous molar is a predisposing factorfactor

GTD in South-East Asia GTD in South-East Asia

GTD used to be a common GTD used to be a common gynecological problem in South-gynecological problem in South-East Asian countries.East Asian countries.

The true incidence is unknown The true incidence is unknown because of the lack of a tumor because of the lack of a tumor registry in many countries.registry in many countries.

Gynecologic Gynecologic OncologistsOncologists

Laboratory (hCG)Laboratory (hCG) ImagingImaging ChemotherapyChemotherapy RadiotherapyRadiotherapy SurgerySurgery

DIAGNOSIS, TREATMENT AND DIAGNOSIS, TREATMENT AND FOLLOW-UP IN AREAS OF LIMITED FOLLOW-UP IN AREAS OF LIMITED RESOURCES RESOURCES

Population (millions) : ………….… 63Population (millions) : ………….… 63 Provinces : ……………………….…… 76 Provinces : ……………………….…… 76 Gynecologic Oncologists : ……….. 110Gynecologic Oncologists : ……….. 110 Fellowship training centers : .…… 9Fellowship training centers : .…… 9 Fellowship Training (years) :. …. 2Fellowship Training (years) :. …. 2 Society : …………….…… TGCSSociety : …………….…… TGCS

ThailandThailand

Hydatidiform Hydatidiform molemole

Ultrasound has replaced all other Ultrasound has replaced all other noninvasive means for diagnosis.noninvasive means for diagnosis.

Ultrasound + hCG is suggestive.Ultrasound + hCG is suggestive. Today, US and hCG are available Today, US and hCG are available

in nearly every areas of limited in nearly every areas of limited resources.resources.

Diagnosis of Diagnosis of HMHM

Management of Management of HMHM patients should be monitored patients should be monitored

with with – serum quantitative hCG valuesserum quantitative hCG values– CBCCBC– chest X-raychest X-ray– coagulation testscoagulation tests– renal and liver function testsrenal and liver function tests

Mole should be evacuated as Mole should be evacuated as soon as possible.soon as possible.

Suction curettageSuction curettage– preferred method of evacuation.preferred method of evacuation.

Hysterectomy Hysterectomy – an alternative treatment in selected an alternative treatment in selected

cases.cases.– reduces malignant postmolar sequelae.reduces malignant postmolar sequelae.– risk of postmolar GTN remains 3–5%risk of postmolar GTN remains 3–5%– these patients should be monitored these patients should be monitored

postoperatively with serial hCG levels.postoperatively with serial hCG levels.

Management of HMManagement of HM

Prophylactic Prophylactic chemotherapychemotherapy

May be appropriate for some May be appropriate for some specific circumstances in specific circumstances in areas of limited resourcesareas of limited resources

– High-risk casesHigh-risk cases

Limpongsanurak S. Prophylactic Limpongsanurak S. Prophylactic actinomycin D for high-risk complete actinomycin D for high-risk complete hydatidiform mole. J Reprod Med hydatidiform mole. J Reprod Med 2001;46:110–6 2001;46:110–6

High-risk criteriaHigh-risk criteria– Initial hCG > 100,000 mIU/mLInitial hCG > 100,000 mIU/mL– Size > dateSize > date– Theca lutein cysts > 6 cmTheca lutein cysts > 6 cm– Maternal age > 40 Maternal age > 40 – Associated medical problems Associated medical problems

(toxemia, hyperthyroid, embolization, DIC)(toxemia, hyperthyroid, embolization, DIC)

Limpongsanurak S. Prophylactic actinomycin D Limpongsanurak S. Prophylactic actinomycin D for high-risk complete hydatidiform mole. J for high-risk complete hydatidiform mole. J Reprod Med 2001;46:110–6 Reprod Med 2001;46:110–6

one course of Actinomycin-D given.one course of Actinomycin-D given. ResultResult : : 72% decrease in malignant 72% decrease in malignant

sequelae (14% VS 50%)sequelae (14% VS 50%) Prophylaxis may be beneficial in high-risk Prophylaxis may be beneficial in high-risk

cases who cannot be followed closely.cases who cannot be followed closely. considered in selected patients or special considered in selected patients or special

situations (poor compliance).situations (poor compliance).

Surveillance After Surveillance After EvacuationEvacuation

Serial quantitative serum hCGSerial quantitative serum hCG– 48 hours of evacuation 48 hours of evacuation – baseline values (5 mIU/mL)baseline values (5 mIU/mL)– every 1–2 weeks, then at 1-2 month every 1–2 weeks, then at 1-2 month

intervals for 6–12 months.intervals for 6–12 months. Reliable contraception Reliable contraception

recommended during hCG recommended during hCG surveillance.surveillance.

Rationale for Rationale for monitoringmonitoring

Identifify patients at risk of Identifify patients at risk of postmolar malignant GTN.postmolar malignant GTN.

almost all malignant almost all malignant sequelae occur within 6 sequelae occur within 6 months of evacuation.months of evacuation.

They should be able to manage HMThey should be able to manage HM– diagnosis of postmolar GTN.diagnosis of postmolar GTN.– evaluating patient’s risk for referral.evaluating patient’s risk for referral.

Currently, suction curettage and Currently, suction curettage and hCG monitoring for postmolar GTN hCG monitoring for postmolar GTN are available in nearly every areas are available in nearly every areas of limited resources.of limited resources.

Role of general OB-GYN

PSU Management of PSU Management of HMHM(January 2002 - April 2006)(January 2002 - April 2006)

33 complete HM33 complete HM– remission = 16 (64%)remission = 16 (64%)– low-risk GTN = 9 (36%)low-risk GTN = 9 (36%)

Gestation Gestation Trophoblastic Trophoblastic Neoplasia (GTN)Neoplasia (GTN)

GTN GTN Staging/classificationStaging/classification

FIGO staging system of GTN FIGO staging system of GTN 1982 : anatomically based1982 : anatomically based 1992 : include two prognostic factors 1992 : include two prognostic factors

(Bagshawe 1976, modified by WHO in 1983)(Bagshawe 1976, modified by WHO in 1983)

2000 : FIGO revised GTN staging/ 2000 : FIGO revised GTN staging/ classification, adopted in 2000 classification, adopted in 2000 and published in 2002 and published in 2002 (ISSGTD, IGCS, FIGO)(ISSGTD, IGCS, FIGO)

Anatomical staging into I-IVAnatomical staging into I-IV scoring system modified from WHOscoring system modified from WHO

1967

UICC

Clinical+Morphological classn

1973

Clinical classn

Hammond

1976

Bagshawe

Prognostic scoring system

1982

FIGO

Anatomical staging

1983

WHO

Modified Bagshawe

1992

FIGO

New anatomical substage

2000

Revised FIGOanatomical staging

Modified-WHO-scoring

1.1. The term The term “GTN”“GTN” is recommended for abnormal is recommended for abnormal gestational trophoblastic proliferation that gestational trophoblastic proliferation that required Rx for potential of malignancy.required Rx for potential of malignancy.

2.2. The The diagnostic criteriadiagnostic criteria of GTN following HM. of GTN following HM.

3.3. The recommendation of The recommendation of investigative toolsinvestigative tools..

4.4. The use of The use of 2 risk groups2 risk groups instead of 3 as instead of 3 as recommended by WHOrecommended by WHO

• low-risk group (score ≤ 6)low-risk group (score ≤ 6)• High-risk group (score ≥7)High-risk group (score ≥7)

4 major consensus 4 major consensus statementsstatements

Criteria for the diagnosis of postmolar GTNCriteria for the diagnosis of postmolar GTN

11 Plateau of hCG over a period of ≥ 3 weeks (day 1, 7, Plateau of hCG over a period of ≥ 3 weeks (day 1, 7, 14, 21)14, 21)

22 Rising of hCG over a period of ≥ 2 weeks (days 1, 7, Rising of hCG over a period of ≥ 2 weeks (days 1, 7, 14)14)

33 hCG remains elevated for ≥ 6 monthshCG remains elevated for ≥ 6 months

44 Histologic diagnosis of choriocarcinomaHistologic diagnosis of choriocarcinoma

Diagnostic Diagnostic criteriacriteria

Mostly based onMostly based on History takingHistory taking Serum Serum ββ-hCG-hCG Chest X-rayChest X-ray UltrasoundUltrasound

All are available in All are available in area of limited area of limited resourcesresources

Current FIGO guidelines for the Current FIGO guidelines for the diagnosis and staging of GTN diagnosis and staging of GTN allow allow uniformityuniformity for reporting for reporting results of treatment.results of treatment.

It is important to individualize It is important to individualize treatment of patients with treatment of patients with malignant GTN based on risk malignant GTN based on risk factorsfactors– Single agent therapy for low-risk.Single agent therapy for low-risk.– Multiagent therapy for high-risk.Multiagent therapy for high-risk.

FIGO 2000 staging and classification of GTNFIGO 2000 staging and classification of GTN

FIGO Anatomical StagingFIGO Anatomical Staging

Stage IStage I Disease confined to the uterusDisease confined to the uterus

Stage IIStage II GTN extends outside of uterus, but is limited to the genital structures (adnexa, vagina, GTN extends outside of uterus, but is limited to the genital structures (adnexa, vagina, broad ligament)broad ligament)

Stage IIIStage III GTN extends to the lungs, with or without known genital tract involvementGTN extends to the lungs, with or without known genital tract involvement

Stage IVStage IV All other metastatic sitesAll other metastatic sites

Modified WHO Prognostic Scoring System as Adapted by FIGOModified WHO Prognostic Scoring System as Adapted by FIGO

scoresscores 00 11 22 44

Age Age <40<40 ≥≥4040 -- --

Antecedent pregnancyAntecedent pregnancy H-Mole H-Mole AbortionAbortion termterm --

Interval Interval (mo)(mo) from index from index pregnancypregnancy

<4<4 4 - 64 - 6 7 - 127 - 12 >12>12

Pretreatment hCG Pretreatment hCG (mIU/mL)(mIU/mL) <10<1033 10103 3 - 10- 1044 >10>104 4 - 10- 1055 >10>1055

Largest tumor size Largest tumor size (including (including uterus)uterus)

-- 3 - 4 cm3 - 4 cm ≥≥5 cm5 cm --

Site of metastases Site of metastases -- kidney, spleenkidney, spleen GI tractGI tract brain, liverbrain, liver

Number of metastasesNumber of metastases -- 1 - 41 - 4 5 – 8 5 – 8 >8>8

Previous failed chemotherapyPrevious failed chemotherapy -- -- Single drugSingle drug two or more two or more drugsdrugs

Tochareonvanich, Chichareon S, Wootipoom V, et al. Tochareonvanich, Chichareon S, Wootipoom V, et al. Correlation of risk categorization in gestational trophoblastic Correlation of risk categorization in gestational trophoblastic tumor between old and new combined staging and scoring tumor between old and new combined staging and scoring system. J Obstet Gynaecol Res 2003;29:20-27system. J Obstet Gynaecol Res 2003;29:20-27

Comparing the treatment Comparing the treatment pattern and the outcome pattern and the outcome among the different among the different classifications, we found that all classifications, we found that all classifications were equivalent classifications were equivalent without compromising the without compromising the outcome.outcome.

FIGO 2000FIGO 2000

User friendly User friendly Feasible and practical in Feasible and practical in

areas of limited resources, areas of limited resources, using only using only – complete history takingcomplete history taking– serum serum ββ--hCGhCG– chest X-raychest X-ray– ultrasoundultrasound

Investigative Tools to Diagnose Investigative Tools to Diagnose MetastasesMetastases

1.1. Chest X-rays are appropriate for Chest X-rays are appropriate for lung metastases and for counting lung metastases and for counting the number of metastases.the number of metastases.

2.2. Liver metastases may be Liver metastases may be diagnosed by US or CT scan.diagnosed by US or CT scan.

3.3. Brain metastases may be Brain metastases may be diagnosed by MRI or CT scan.diagnosed by MRI or CT scan.

The diagnostic problem in The diagnostic problem in the areas of limited the areas of limited resources may be only resources may be only lacking of CT or MRI for lacking of CT or MRI for detection of brain detection of brain matastasis matastasis

High-risk sites of metastases rarely occur High-risk sites of metastases rarely occur without pulmonary metastases. without pulmonary metastases.

(Hunter V, et al. Cancer 1990;65:1647–50)(Hunter V, et al. Cancer 1990;65:1647–50)

Cerebral metastases are rare unless there Cerebral metastases are rare unless there are concurrent lung or vaginal metastases.are concurrent lung or vaginal metastases.

Therefore CT or MRI brain scans may be Therefore CT or MRI brain scans may be omitted in those patients without vaginal omitted in those patients without vaginal or lung metastases on chest X-ray. or lung metastases on chest X-ray.

(TY Ng, LC Wong. Best Practice & Research Clinical Obstetrics and Gynaecology 2003;17:93–903)(TY Ng, LC Wong. Best Practice & Research Clinical Obstetrics and Gynaecology 2003;17:93–903)

NOTE :NOTE : 40% postmolar GTN with negative chest X-rays have pulmonary lesions 40% postmolar GTN with negative chest X-rays have pulmonary lesions detected by CT scan, but small pulmonary metastases do not affect survival.detected by CT scan, but small pulmonary metastases do not affect survival.

Treatment of GTN in the Treatment of GTN in the areas of limited resourcesareas of limited resources

Treatment should be limited to Treatment should be limited to low-risk GTN (score ≤6).low-risk GTN (score ≤6).

Patients with score ≥7 should be Patients with score ≥7 should be referred to specialized center.referred to specialized center.

Chemotherapy for low-risk nonmetastatic Chemotherapy for low-risk nonmetastatic and low-risk metastatic GTN and low-risk metastatic GTN

11 Methotrexate 1 mg/kg intramuscular (IM) on days 1, 3, 5, and 7, Methotrexate 1 mg/kg intramuscular (IM) on days 1, 3, 5, and 7, with folinic acid 0.1 mg/kg IM on days 2, 4, 6, and 8; repeat every with folinic acid 0.1 mg/kg IM on days 2, 4, 6, and 8; repeat every 7 days if possible (10% primary failure rate).7 days if possible (10% primary failure rate).

22 Methotrexate 0.4 mg/kg (20–25 mg) intravenous (IV) or IM daily for Methotrexate 0.4 mg/kg (20–25 mg) intravenous (IV) or IM daily for 5 days; repeat every 7 days if possible. If no response, increase 5 days; repeat every 7 days if possible. If no response, increase dose to 0.6 mg/kg or switch to actinomycin D dose to 0.6 mg/kg or switch to actinomycin D

(20%-25% primary failure rate).(20%-25% primary failure rate).

33 Methotrexate 40 mg/M2 IM weekly Methotrexate 40 mg/M2 IM weekly

(30% primary failure rate).(30% primary failure rate).

44 Actinomycin D 12 µg/kg IV daily for 5 days; repeat every 7 days Actinomycin D 12 µg/kg IV daily for 5 days; repeat every 7 days (8% primary failure rate).(8% primary failure rate).

55 Pulse actinomycin D: 1.25 mg/M2; repeat every 2 weeks Pulse actinomycin D: 1.25 mg/M2; repeat every 2 weeks (20% primary failure rate).(20% primary failure rate).

At PSU, we treat low-risk GTN patients with At PSU, we treat low-risk GTN patients with weekly methotrexate regimen.weekly methotrexate regimen.

40 mg/m2 given intramuscularly every week.40 mg/m2 given intramuscularly every week. This is the most cost-effective regimens This is the most cost-effective regimens

when feasibility, efficacy, toxicity, and when feasibility, efficacy, toxicity, and cost are taken into consideration.cost are taken into consideration.

Chemotherapy is continued until normal hCG Chemotherapy is continued until normal hCG is achieved, and one additional course is is achieved, and one additional course is given.given.

If hCG values have not decreased by If hCG values have not decreased by 10%, treatment should be changed 10%, treatment should be changed to alternative single-agent regimen.to alternative single-agent regimen.

In case of failure, the patient should In case of failure, the patient should be referred to specialized center.be referred to specialized center.

Cure rate for low-risk disease Cure rate for low-risk disease ~~ 100%, with recurrence rates less 100%, with recurrence rates less than 5%.than 5%.

Management of Management of Hydatidiform moleHydatidiform mole– Appropriate treatment is avialable.Appropriate treatment is avialable.– Prophylactic chemotherapy may be Prophylactic chemotherapy may be

considered in high-risk cases.considered in high-risk cases.

Conclusion Conclusion In areas of limited resourcesIn areas of limited resources

Management of GTNManagement of GTN Based on FIGO 2000Based on FIGO 2000

– Low-risk GTN (score ≤6) can be Low-risk GTN (score ≤6) can be managed.managed.

– Weekly methotrexate is a cost effective Weekly methotrexate is a cost effective chemotherapy.chemotherapy.

Conclusion Conclusion In areas of limited resourcesIn areas of limited resources

Management of GTNManagement of GTN Based on FIGO 2000Based on FIGO 2000

– High-risk GTN (score ≥7) should High-risk GTN (score ≥7) should be referred to specialized center.be referred to specialized center.

Conclusion Conclusion In areas of limited resourcesIn areas of limited resources

GTD at PSUGTD at PSU

Hydatidiform Mole (HM)Hydatidiform Mole (HM) 2.8/1,000 deliveries2.8/1,000 deliveries

Gestation trophoblastic Gestation trophoblastic neoplasia (GTN)neoplasia (GTN)

4.6/1,000 deliveries4.6/1,000 deliveries

PSU : CPG for the PSU : CPG for the Management of Management of GTN GTN

GTNGTN

Investigate, stage, risk-score (FIGO 2000)Investigate, stage, risk-score (FIGO 2000)

Stage I-III low-risk (≤6)

hCG, CBC, BUN, Cr, LFT, TFT, Coagulogram, CXR, US, CT/MRI in +ve CXR

Stage IV any score or Stage I-III, high-risk (≥7)

Single-agent chemoRx (weekly MTX)

Stage I Stage II-III

Weekly hCG until –ve X 3

one addition course

-hCG q 1mo. x 12 mo., OCP, pregy if need

-CXR q 3 mo. (in lung metas)

Multi-agent chemoRx (EMA-CO)

-ve hCG-ve hCG

EMA-CE

Salvage therapy

2 additional courses

-hCG q 1mo. X 24 mo., OCP, pregy if need

-CXR q 3 mo. (lung metas)

Plateau or rising hCG

Investigate +ve

-ve Act-D

-ve Plateau or hCGPlateau or

hCG

Plateau or hCG

Investigate

Management of GTN at Management of GTN at PSU PSU (January 2002 - April 2006)(January 2002 - April 2006)

57 GTN57 GTN– Low-risk GTN (39 cases)Low-risk GTN (39 cases)

Remission = 100%Remission = 100%

– High-risk GTN (18 cases)High-risk GTN (18 cases) Remission = 77%Remission = 77%

The most important The most important factors to assure factors to assure successful therapysuccessful therapy

Experience with gestational Experience with gestational trophoblastic lesions trophoblastic lesions

Reliable hCG assayReliable hCG assay Experience with Experience with

chemotherapychemotherapy Patient’s compliancePatient’s compliance