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

Limited resources Gynecologic Oncologists Gynecologic Oncologists Laboratory (hCG) Laboratory (hCG) Imaging Imaging Chemotherapy Chemotherapy Radiotherapy Radiotherapy Surgery Surgery

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 women from cancerregistry- based statistics in different areas of the world. Lancet Oncol 2003; 4: 670–78

GTD variation The reason for this variation is not understood The reason for this variation is not understood women over 40 years having at least a fivefold increase in risk. women over 40 years having at least a fivefold increase in risk. previous molar is a predisposing factor previous molar is a predisposing factor

GTD in South-East Asia GTD used to be a common gynecological problem in South-East Asian countries. GTD used to be a common gynecological problem in South-East Asian countries. The true incidence is unknown because of the lack of a tumor registry in many countries. The true incidence is unknown because of the lack of a tumor registry in many countries.

Gynecologic Oncologists Gynecologic Oncologists Laboratory (hCG) Laboratory (hCG) Imaging Imaging Chemotherapy Chemotherapy Radiotherapy Radiotherapy Surgery Surgery DIAGNOSIS, TREATMENT AND FOLLOW- UP IN AREAS OF LIMITED RESOURCES

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

Hydatidiform mole

Ultrasound has replaced all other noninvasive means for diagnosis. Ultrasound has replaced all other noninvasive means for diagnosis. Ultrasound + hCG is suggestive. Ultrasound + hCG is suggestive. Today, US and hCG are available in nearly every areas of limited resources. Today, US and hCG are available in nearly every areas of limited resources. Diagnosis of HM

Management of HM patients should be monitored with patients should be monitored with – serum quantitative hCG values – CBC – chest X-ray – coagulation tests – renal and liver function tests Mole should be evacuated as soon as possible. Mole should be evacuated as soon as possible.

Suction curettage Suction curettage –preferred method of evacuation. Hysterectomy Hysterectomy –an alternative treatment in selected cases. –reduces malignant postmolar sequelae. –risk of postmolar GTN remains 3–5% –these patients should be monitored postoperatively with serial hCG levels. Management of HM

Prophylactic chemotherapy May be appropriate for some specific circumstances in areas of limited resources May be appropriate for some specific circumstances in areas of limited resources – High-risk cases

Limpongsanurak S. Prophylactic actinomycin D for high-risk complete hydatidiform mole. J Reprod Med 2001;46:110–6 High-risk criteria High-risk criteria –Initial hCG > 100,000 mIU/mL –Size > date –Theca lutein cysts > 6 cm –Maternal age > 40 –Associated medical problems (toxemia, hyperthyroid, embolization, DIC)

Limpongsanurak S. Prophylactic actinomycin D for high-risk complete hydatidiform mole. J Reprod Med 2001;46:110–6 one course of Actinomycin-D given. one course of Actinomycin-D given. Result : 72% decrease in malignant sequelae (14% VS 50%) Result : 72% decrease in malignant sequelae (14% VS 50%) Prophylaxis may be beneficial in high-risk cases who cannot be followed closely. Prophylaxis may be beneficial in high-risk cases who cannot be followed closely. considered in selected patients or special situations (poor compliance). considered in selected patients or special situations (poor compliance).

Surveillance After Evacuation Serial quantitative serum hCG Serial quantitative serum hCG –48 hours of evacuation –baseline values (5 mIU/mL) –every 1–2 weeks, then at 1-2 month intervals for 6–12 months. Reliable contraception recommended during hCG surveillance. Reliable contraception recommended during hCG surveillance.

Rationale for monitoring Identifify patients at risk of postmolar malignant GTN. Identifify patients at risk of postmolar malignant GTN. almost all malignant sequelae occur within 6 months of evacuation. almost all malignant sequelae occur within 6 months of evacuation.

They should be able to manage HM They should be able to manage HM –diagnosis of postmolar GTN. –evaluating patient’s risk for referral. Currently, suction curettage and hCG monitoring for postmolar GTN are available in nearly every areas of limited resources. Currently, suction curettage and hCG monitoring for postmolar GTN are available in nearly every areas of limited resources. Role of general OB-GYN

PSU Management of HM (January April 2006) 33 complete HM 33 complete HM – remission = 16 (64%) – low-risk GTN = 9 (36%)

Gestation Trophoblastic Neoplasia (GTN)

GTN Staging/classification FIGO staging system of GTN FIGO staging system of GTN 1982 : anatomically based 1982 : anatomically based 1992 : include two prognostic factors (Bagshawe 1976, modified by WHO in 1983) 1992 : include two prognostic factors (Bagshawe 1976, modified by WHO in 1983) 2000 : FIGO revised GTN staging/ classification, adopted in 2000 and published in 2002 (ISSGTD, IGCS, FIGO) 2000 : FIGO revised GTN staging/ classification, adopted in 2000 and published in 2002 (ISSGTD, IGCS, FIGO) Anatomical staging into I-IV Anatomical staging into I-IV scoring system modified from WHO scoring system modified from WHO

1967 UICC Clinical+Morphological class n 1973 Clinical class n Hammond 1976 Bagshawe Prognostic scoring system 1982 FIGO Anatomical staging 1983 WHO Modified Bagshawe 1992 FIGO New anatomical substage 2000 Revised FIGO anatomical staging Modified-WHO-scoring

1. The term “GTN” is recommended for abnormal gestational trophoblastic proliferation that required Rx for potential of malignancy. 2. The diagnostic criteria of GTN following HM. 3. The recommendation of investigative tools. 4. The use of 2 risk groups instead of 3 as recommended 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 statements

Criteria for the diagnosis of postmolar GTN 1 Plateau of hCG over a period of ≥ 3 weeks (day 1, 7, 14, 21) 2 Rising of hCG over a period of ≥ 2 weeks (days 1, 7, 14) 3 hCG remains elevated for ≥ 6 months 4 Histologic diagnosis of choriocarcinoma

Diagnostic criteria Mostly based on Mostly based on History taking History taking Serum β-hCG Serum β-hCG Chest X-ray Chest X-ray Ultrasound Ultrasound All are available in area of limited resources All are available in area of limited resources

Current FIGO guidelines for the diagnosis and staging of GTN allow uniformity for reporting results of treatment. Current FIGO guidelines for the diagnosis and staging of GTN allow uniformity for reporting results of treatment. It is important to individualize treatment of patients with malignant GTN based on risk factors It is important to individualize treatment of patients with malignant GTN based on risk factors –Single agent therapy for low-risk. –Multiagent therapy for high-risk.

FIGO 2000 staging and classification of GTN FIGO Anatomical Staging Stage I Disease confined to the uterus Stage II GTN extends outside of uterus, but is limited to the genital structures (adnexa, vagina, broad ligament) Stage III GTN extends to the lungs, with or without known genital tract involvement Stage IV All other metastatic sites Modified WHO Prognostic Scoring System as Adapted by FIGO scores0124 Age<40≥40-- Antecedent pregnancy H-MoleAbortionterm- Interval (mo) from index pregnancy < >12 Pretreatment hCG (mIU/mL) < > >10 5 Largest tumor size (including uterus) cm ≥5 cm - Site of metastases - kidney, spleen GI tract brain, liver Number of metastases – 8 >8 Previous failed chemotherapy -- Single drug two or more drugs

Tochareonvanich, Chichareon S, Wootipoom V, et al. Correlation of risk categorization in gestational trophoblastic tumor between old and new combined staging and scoring system. J Obstet Gynaecol Res 2003;29:20-27 Comparing the treatment pattern and the outcome among the different classifications, we found that all classifications were equivalent without compromising the outcome.

FIGO 2000 User friendly User friendly Feasible and practical in areas of limited resources, using only Feasible and practical in areas of limited resources, using only – complete history taking – serum β-hCG – chest X-ray – ultrasound

Investigative Tools to Diagnose Metastases 1. Chest X-rays are appropriate for lung metastases and for counting the number of metastases. 2. Liver metastases may be diagnosed by US or CT scan. 3. Brain metastases may be diagnosed by MRI or CT scan.

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

High-risk sites of metastases rarely occur without pulmonary metastases. High-risk sites of metastases rarely occur 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 are concurrent lung or vaginal metastases. Cerebral metastases are rare unless there are concurrent lung or vaginal metastases. Therefore CT or MRI brain scans may be omitted in those patients without vaginal or lung metastases on chest X-ray. Therefore CT or MRI brain scans may be omitted in those patients without vaginal 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 : 40% postmolar GTN with negative chest X-rays have pulmonary lesions detected by CT scan, but small pulmonary metastases do not affect survival.

Treatment of GTN in the areas of limited resources Treatment should be limited to low-risk GTN (score ≤6). Treatment should be limited to low-risk GTN (score ≤6). Patients with score ≥7 should be referred to specialized center. Patients with score ≥7 should be referred to specialized center.

Chemotherapy for low-risk nonmetastatic and low-risk metastatic GTN 1 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 7 days if possible (10% primary failure rate). 2 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 dose to 0.6 mg/kg or switch to actinomycin D (20%-25% primary failure rate). 3 Methotrexate 40 mg/M2 IM weekly (30% primary failure rate). 4 Actinomycin D 12 µg/kg IV daily for 5 days; repeat every 7 days (8% primary failure rate). 5 Pulse actinomycin D: 1.25 mg/M2; repeat every 2 weeks (20% primary failure rate).

At PSU, we treat low-risk GTN patients with weekly methotrexate regimen. At PSU, we treat low-risk GTN patients with weekly methotrexate regimen. 40 mg/m2 given intramuscularly every week. 40 mg/m2 given intramuscularly every week. This is the most cost-effective regimens when feasibility, efficacy, toxicity, and cost are taken into consideration. This is the most cost-effective regimens when feasibility, efficacy, toxicity, and cost are taken into consideration. Chemotherapy is continued until normal hCG is achieved, and one additional course is given. Chemotherapy is continued until normal hCG is achieved, and one additional course is given.

If hCG values have not decreased by 10%, treatment should be changed to alternative single-agent regimen. If hCG values have not decreased by 10%, treatment should be changed to alternative single-agent regimen. In case of failure, the patient should be referred to specialized center. In case of failure, the patient should be referred to specialized center. Cure rate for low-risk disease ~ 100%, with recurrence rates less than 5%. Cure rate for low-risk disease ~ 100%, with recurrence rates less than 5%.

Management of Hydatidiform mole Management of Hydatidiform mole –Appropriate treatment is avialable. –Prophylactic chemotherapy may be considered in high-risk cases. Conclusion In areas of limited resources

Management of GTN Management of GTN Based on FIGO 2000 Based on FIGO 2000 –Low-risk GTN (score ≤6) can be managed. –Weekly methotrexate is a cost effective chemotherapy. Conclusion In areas of limited resources

Management of GTN Management of GTN Based on FIGO 2000 Based on FIGO 2000 –High-risk GTN (score ≥7) should be referred to specialized center. Conclusion In areas of limited resources

GTD at PSU Hydatidiform Mole (HM) Hydatidiform Mole (HM) 2.8/1,000 deliveries 2.8/1,000 deliveries Gestation trophoblastic neoplasia (GTN) Gestation trophoblastic neoplasia (GTN) 4.6/1,000 deliveries 4.6/1,000 deliveries

PSU : CPG for the Management of GTN GTN 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 IStage II-III Weekly hCG until –ve X 3 one addition course -hCG q 1mo. x 12 mo., OCP, preg y if need -CXR q 3 mo. (in lung metas) Multi-agent chemoRx (EMA-CO) -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 -veAct-D -ve Plateau or  hCG Investigate

Management of GTN at PSU (January April 2006) 57 GTN 57 GTN – Low-risk GTN (39 cases) Remission = 100% Remission = 100% – High-risk GTN (18 cases) Remission = 77% Remission = 77%

The most important factors to assure successful therapy Experience with gestational trophoblastic lesions Experience with gestational trophoblastic lesions Reliable hCG assay Reliable hCG assay Experience with chemotherapy Experience with chemotherapy Patient’s compliance Patient’s compliance