Management of Gestational Management of Gestational ChoriocarcinomaChoriocarcinoma

Presented by Dr Omoregie O.B.Presented by Dr Omoregie O.B.

managementmanagement

IntroductionIntroductionHistory History Clinical examinationClinical examinationLaboratory investigationsLaboratory investigationsTherapyTherapy

- Medical treatmentMedical treatment- Surgical treatmentSurgical treatment- RadiotherapyRadiotherapy- Follow-upFollow-up

IntroductionIntroduction

Gestational choriocarcinoma is an extreme of a Gestational choriocarcinoma is an extreme of a spectrum of diseases known as trophoblastic spectrum of diseases known as trophoblastic neoplasmsneoplasms

It is a life-threatening conditionIt is a life-threatening condition

GTD elaborate a unique tumour marker HCG – GTD elaborate a unique tumour marker HCG – used for diagnosis and monitoring of Rx used for diagnosis and monitoring of Rx

Virtually all patients are now potentially curable Virtually all patients are now potentially curable with chemotherapy, especially if correctly with chemotherapy, especially if correctly diagnosed and appropriate chemotherapy diagnosed and appropriate chemotherapy commenced early in the course of the disease.commenced early in the course of the disease.

History History

Exaggerated pregnancy symptoms -Exaggerated pregnancy symptoms -hyperemesishyperemesis

Hydatidiform mole usually presents with Hydatidiform mole usually presents with vaginal bleeding at about 12 weeks GAvaginal bleeding at about 12 weeks GA

Passage of vesiclesPassage of vesicles

Recent miscarriage, ectopic gestation or a Recent miscarriage, ectopic gestation or a term deliveryterm delivery

USS diagnosis – snow storm appearance USS diagnosis – snow storm appearance

Clinical examinationClinical examination

Height and weight required for surface area Height and weight required for surface area normogramnormogram

Early onset pre-eclampsia.Early onset pre-eclampsia.

Disproportionate uterine size – greater or less Disproportionate uterine size – greater or less than date.than date.

Multiple theca lutein cyst – causing ovarian Multiple theca lutein cyst – causing ovarian enlargement may be present.enlargement may be present.

Hyperthyroidism may be present due to excess Hyperthyroidism may be present due to excess production of thyrotropin by molar tissuesproduction of thyrotropin by molar tissues

Investigations Investigations

FBC (Hb, WBC, Platelet, prothrombin time, PTT, FBC (Hb, WBC, Platelet, prothrombin time, PTT, fibrinogen).fibrinogen).Serum electrolyte, urea and creatinine.Serum electrolyte, urea and creatinine.Liver function test.Liver function test.Urinalysis Urinalysis Blood group and crossing matching.Blood group and crossing matching.HIV screeningHIV screeningTSH/TTSH/T44

Pregnancy test (hCG assay)Pregnancy test (hCG assay)USS/vaginal colour doppler flow USSUSS/vaginal colour doppler flow USS

Principal Investigations Principal Investigations

Before commencement of treatmentBefore commencement of treatmentAssessment of the primary tumour size in Assessment of the primary tumour size in the uterus by clinical examination and the uterus by clinical examination and USSUSSChest X-rayChest X-rayLiver spanLiver spanLumbar puncture for C.S.F. measurement Lumbar puncture for C.S.F. measurement of hCG.of hCG.CT/MRI – scan brain/liver CT/MRI – scan brain/liver

Diagnosis of choriocarcinomaDiagnosis of choriocarcinoma

Biochemical (mainly) an elevated Biochemical (mainly) an elevated ββ-hCG plateau -hCG plateau or rising hCG titre over a period of several or rising hCG titre over a period of several weeksweeks

Histology – absent villi structure, sheets or foci Histology – absent villi structure, sheets or foci of trophoblasts on an haemorrhagic or necrotic of trophoblasts on an haemorrhagic or necrotic tissue background, marked nuclear atypia (the tissue background, marked nuclear atypia (the entire specimen must be processed for entire specimen must be processed for histologic study, when curettage is done, since histologic study, when curettage is done, since only a small foci of isolated area of only a small foci of isolated area of choriocarcinoma may be present).choriocarcinoma may be present).

Pregnancy testPregnancy test

HCG, LH, FSH, TSH have a common HCG, LH, FSH, TSH have a common αα-subunit, -subunit, but the biological specificity is conferred by but the biological specificity is conferred by ββ--subunit, by raising an antisera to the subunit, by raising an antisera to the ββ-subunit of -subunit of HCG, the cross reactivity with other glycoprotein HCG, the cross reactivity with other glycoprotein hormones is reduced.hormones is reduced.A good A good ββ-HCG assay can detect values greater -HCG assay can detect values greater than 2miu/ml in normal serum.than 2miu/ml in normal serum.HCG can also be monitored using urine, but has HCG can also be monitored using urine, but has lots of interference, hence monitoring using lots of interference, hence monitoring using serum is preferable especially in patients on serum is preferable especially in patients on therapy.therapy.

Hydatidiform mole follow-upHydatidiform mole follow-up

The commonest antecedent pregnancy to The commonest antecedent pregnancy to choriocarcinoma is HMchoriocarcinoma is HMUsing HCG measurement to determine if the Using HCG measurement to determine if the mole is regressing spontaneously or actively mole is regressing spontaneously or actively growing.growing.The amount of HCG found in the serum or The amount of HCG found in the serum or excreted urine correlates closely with the excreted urine correlates closely with the number of viable tumour cells present. number of viable tumour cells present. Approximately 90% of patient with HM have Approximately 90% of patient with HM have spontaneous regression, but 10% would require spontaneous regression, but 10% would require chemotherapychemotherapy

Rx of Hydatidiform moleRx of Hydatidiform mole

Suction curettage is Suction curettage is advocated (largest advocated (largest curette possible), curette possible), followed by a gentle followed by a gentle sharp curettage.sharp curettage.i.v oxytocin should be i.v oxytocin should be started after removing started after removing a moderate amount of a moderate amount of tissue, and may tissue, and may continue for 24hrs if continue for 24hrs if necessarynecessary

Prostaglandin Prostaglandin induction, oxytocin induction, oxytocin induction or intra-induction or intra-amniotic instillation of amniotic instillation of prostaglandin or prostaglandin or hypertonic solutions hypertonic solutions (saline, glucose, urea (saline, glucose, urea etc) are not etc) are not acceptable methods acceptable methods for evacuation – for evacuation – increase need for increase need for chemotherapy chemotherapy

Surveillance post-evacuation of HMSurveillance post-evacuation of HM

Weekly Weekly ββ-hCG assay post--hCG assay post-evacuation, until it evacuation, until it becomes undetectedable becomes undetectedable on 3 consecutive assayson 3 consecutive assays

If hCG titre remission If hCG titre remission occurs spontaneously occurs spontaneously within 14wks without a titre within 14wks without a titre plateau, the hCG assay plateau, the hCG assay thereafter is done 4 weekly thereafter is done 4 weekly for at least 1 year before for at least 1 year before patient is discharge from patient is discharge from surveillance.surveillance.

Partial mole – 6-12 months Partial mole – 6-12 months

Contraception – oral contraceptive.Contraception – oral contraceptive.Gynaecologic examination started Gynaecologic examination started 1 week post evacuation – assess 1 week post evacuation – assess Ut size, adnexal masses, check for Ut size, adnexal masses, check for metastases on the vulva, vagina, metastases on the vulva, vagina, urethra, and cervix. If no urethra, and cervix. If no complication repeat exam 4 wkly complication repeat exam 4 wkly throughout period of surveillance.throughout period of surveillance.CXR repeated every 4wks for those CXR repeated every 4wks for those that had pulmonary metastasis prior that had pulmonary metastasis prior to evacuation, until remission, to evacuation, until remission, thereafter every 3 months for period thereafter every 3 months for period of surveillance. of surveillance. Pregnancy – allowed after 1yr of Pregnancy – allowed after 1yr of been negative during surveillance. been negative during surveillance.

Indications for chemotherapyIndications for chemotherapy

A high level of hCG more than 4 weeks after A high level of hCG more than 4 weeks after evacuation (serum level >20,000iu/l or urine evacuation (serum level >20,000iu/l or urine level >30,000iu/l)level >30,000iu/l)Progressively rising hCG levels at any time after Progressively rising hCG levels at any time after evacuation.evacuation.Histological diagnosis of choriocarcinoma at any Histological diagnosis of choriocarcinoma at any site, or evidence of CNS, renal, hepatic, site, or evidence of CNS, renal, hepatic, gastrointestinal metastases or pulmonary gastrointestinal metastases or pulmonary metastases >2cm in diameter or > 3 in number.metastases >2cm in diameter or > 3 in number.Persistent uterine bleeding and positive hCG Persistent uterine bleeding and positive hCG levels levels

Prognostic assessmentPrognostic assessment

The principal investigations are for The principal investigations are for prognostic categorisation.prognostic categorisation.

(FIGO 2002 cancer committee)(FIGO 2002 cancer committee)

Low risk (0-6)Low risk (0-6)

High risk (High risk (>>7)7)

Treatment Treatment

Patients should be managed in a specialist Patients should be managed in a specialist unit.unit.

ChemotherapyChemotherapy

SurgerySurgery

RadiotherapyRadiotherapy

Pelvic artery (hypogastric A) embolizationPelvic artery (hypogastric A) embolization

Chemotherapy RegimenChemotherapy Regimen

Non-metastatic ChoriocarcinomaNon-metastatic ChoriocarcinomaSingle agent chemotherapy:Single agent chemotherapy:

(a)(a) Methotrexate 0.4mg/kg IM for 5 days repeated Methotrexate 0.4mg/kg IM for 5 days repeated every 2 wks (ass 10% primary failure rate).every 2 wks (ass 10% primary failure rate).

(b)(b) Methotrexate 1.0mg/kg IM every other day for 4 Methotrexate 1.0mg/kg IM every other day for 4 doses (day 1,3,5 and 7) with folinic acid doses (day 1,3,5 and 7) with folinic acid (leucovorin) 0.1mg/kg IM every 24hrs after each (leucovorin) 0.1mg/kg IM every 24hrs after each dose of methotrexate (ass 20-25% primary failure dose of methotrexate (ass 20-25% primary failure rate).rate).

(c)(c) Methotrexate 50mg/mMethotrexate 50mg/m22 IM given wkly. this regimen IM given wkly. this regimen has 30% primary failure rate.has 30% primary failure rate.

Chemotherapy contd.Chemotherapy contd.(d) Actinomycin-D, 1.25mg/m(d) Actinomycin-D, 1.25mg/m22 IV given every 2 wks. (Ass 20% IV given every 2 wks. (Ass 20%

primary failure rate).primary failure rate).(e) Actinomycin-D, 12mcg/kg IV daily for 5 days, repeated (e) Actinomycin-D, 12mcg/kg IV daily for 5 days, repeated

every 2wks (it may be used for patient with hepatic every 2wks (it may be used for patient with hepatic dysfunction) it has 8% primary failure rate.dysfunction) it has 8% primary failure rate.

(f) Methotrexate 250mg infusion over 12hrs. This is the MTX (f) Methotrexate 250mg infusion over 12hrs. This is the MTX portion of the EMA-CO protocol. It is associated with a portion of the EMA-CO protocol. It is associated with a 30% primary failure rate.30% primary failure rate.

Note: Actinomycin-D causes severe slough if infiltrated into the Note: Actinomycin-D causes severe slough if infiltrated into the skin, therefore ensure inject via a new free running skin, therefore ensure inject via a new free running intravenous infusion. If extravasation occurs infiltrate the intravenous infusion. If extravasation occurs infiltrate the area with 100mg hydrocortisone and 2 cc of 1% xylocaine. area with 100mg hydrocortisone and 2 cc of 1% xylocaine.

Repeat FBC, platelet, E/U/Cr, LFT should be done before Repeat FBC, platelet, E/U/Cr, LFT should be done before

commencement of next course of Rx.commencement of next course of Rx.

Chemotherapy contd.Chemotherapy contd.

Metastatic choriocarcinoma.Metastatic choriocarcinoma.

Combination chemotherapyCombination chemotherapy

First line drugs:First line drugs:

EMA-CO regimen – Etoposide, EMA-CO regimen – Etoposide, methotrexate with leucovorin rescue and methotrexate with leucovorin rescue and actinomycin-D given on days 1 and 2, then actinomycin-D given on days 1 and 2, then cyclophosphamide and vincristine cyclophosphamide and vincristine (oncovin) are given on day 8. (oncovin) are given on day 8.

Chemotherapy contd.Chemotherapy contd.

EMA-CO is more acceptable and far less EMA-CO is more acceptable and far less toxic than MAC chemotherapy.toxic than MAC chemotherapy.

MAC (methotrexate, Actinomycin, and MAC (methotrexate, Actinomycin, and Cytoxan; originally C was chlorambucil).Cytoxan; originally C was chlorambucil).

However, several centres are returning to However, several centres are returning to use of MAC due to risk of leukaemia with use of MAC due to risk of leukaemia with EMA-CO (used for more than 6 courses).EMA-CO (used for more than 6 courses).

Course of EMA-CO are repeated sequentially until remission is Course of EMA-CO are repeated sequentially until remission is obtained. Neupogen is usually given to sustain white cells.obtained. Neupogen is usually given to sustain white cells.

Chemotherapy “for the road”Chemotherapy “for the road”

Following the 1Following the 1stst non-detectable non-detectable ββ-hCG, at least -hCG, at least 3 further courses of chemotherapy should be 3 further courses of chemotherapy should be administered, with the 1administered, with the 1stst course being course being combination chemotherapy.combination chemotherapy.

A negative hCG value implies that the number of A negative hCG value implies that the number of malignant trophoblastic cells present in the body malignant trophoblastic cells present in the body is less than 10is less than 1077. it does not mean that the . it does not mean that the disease at that time is completely eradicated.disease at that time is completely eradicated.

Brain metastasisBrain metastasis

Increase the methotrexate dose in EMA-CO Increase the methotrexate dose in EMA-CO protocol to 1g/mprotocol to 1g/m22, the urine should be alkalinized , the urine should be alkalinized with iv bicarbonatewith iv bicarbonateDepending on tumour size there might be need Depending on tumour size there might be need for irradiation of whole brain or excisional for irradiation of whole brain or excisional surgery.surgery.The irradiation is to prevent catastrophic The irradiation is to prevent catastrophic haemorrhage rather than controlling the haemorrhage rather than controlling the trophoblastic disease.trophoblastic disease.Irradiation may also be needed for liver Irradiation may also be needed for liver metastasis.metastasis.

Resistance to EMA-COResistance to EMA-CO

Or recurring after previous multiagent Or recurring after previous multiagent chemotherapy.chemotherapy.Rx with EMA-EP protocol, i.e EMA alternating Rx with EMA-EP protocol, i.e EMA alternating with etoposide and platinum.with etoposide and platinum.OROREMA alternating with cis-platinum and EMA alternating with cis-platinum and adriamycin – EMA-PA.adriamycin – EMA-PA.For EMA-EP resistant cases Taxol with cisplatin For EMA-EP resistant cases Taxol with cisplatin alternating with Taxol-etoposide or Taxol-5FU or alternating with Taxol-etoposide or Taxol-5FU or iphosphamide, cisplatinium, etoposide (ICE) or iphosphamide, cisplatinium, etoposide (ICE) or vinblastine, etoposide, cisplatin (BEP) vinblastine, etoposide, cisplatin (BEP)

Radiotherapy: used concomitantly with Radiotherapy: used concomitantly with combined chemotherapy in patients with combined chemotherapy in patients with liver or brain metastasis.liver or brain metastasis.Cerebral metastasis Rx over 2 wks with Cerebral metastasis Rx over 2 wks with 300 rads daily, 5 days a week, to a total 300 rads daily, 5 days a week, to a total organ dose of 3000 rads.organ dose of 3000 rads.Whole liver irradiation Rx over 10 days Whole liver irradiation Rx over 10 days with 200 rads daily, 5 days a week, to a with 200 rads daily, 5 days a week, to a total organ dose of 2000 rads total organ dose of 2000 rads

Pelvic artery embolization is used in cases Pelvic artery embolization is used in cases of intractable haemorrhage.of intractable haemorrhage.

Surgery for chemotherapy resistant Surgery for chemotherapy resistant and persistent metastases.and persistent metastases.

Lung, liver, brain, or other sites Lung, liver, brain, or other sites metastases that do not regress with metastases that do not regress with chemotherapy may be amenable to chemotherapy may be amenable to surgical extirpation. surgical extirpation.

Prophylactic chemotherapyProphylactic chemotherapy

The concensus is that, it is only now The concensus is that, it is only now recommended for those likely to default recommended for those likely to default follow-up follow-up

Pregnancy after chemotherapyPregnancy after chemotherapy

Patients need to wait for 12 months after Patients need to wait for 12 months after chemotherapy before undertaking further chemotherapy before undertaking further pregnancy.pregnancy.

CONCLUSIONCONCLUSION

It should be noted that choriocarcinoma It should be noted that choriocarcinoma remains an enigma in gynaecological remains an enigma in gynaecological practice.practice.

It stretches both the patient and the It stretches both the patient and the managing physician to the limit.managing physician to the limit.

There is the need to continuously audit its There is the need to continuously audit its management in our environment, so as to management in our environment, so as to improve management outcome.improve management outcome.