State of the Art: Gestational Trophoblastic Lesions

Treatment beyond single agents

Barry Hancock(Sheffield, UK)

International Gynecologic Society Meeting 2006

Which group of patients?

Risk (WHO score, Dutch classification)

Prognosis (Hammond)

Stage (Song, FIGO)

Choriocarcinoma risk (Japan)

Criteria for treatment

Two scenarios

Single agent resistance

‘High’ risk disease

Single agent resistance

Alternative single agent

Combination chemotherapy (EMA-CO, MAC, EA etc)

Single agent resistance

For ‘low’ risk non-metastatic disease single agent chemotherapy is 60-90% successful

Second line multi-agent therapy is virtually always (>95%) successful in dealing with single agent resistance

Benefits

Is intensive chemotherapy necessary for all high risk patients?

Higher CR

Less salvage treatment

Shorter treatment period

Risks

Over treatment

Higher financial costs

More toxicity

What is the evidence base?

One randomized controlled trial

Lots of small-moderate sized series

One retrospective comparative study

Primary treatment for high risk GTNMAC (MTX, dactinomycin, chlorambucil or cyclophosphamide)

EMA-CO (etoposide, MTX, dactinomycin, cyclophosphamide, vincristine)

EMA/MEA

CHAMOCA (cyclophosphamide, hydroxyurea, dactinomycin, MTX, vincristine, doxorubicin)

CHAMOMA (+ melphalan)

FME (FU, MTX, etoposide)

Previously single agent MTX!

Primary remission rates in high risk GTN

MAC 63-80%

CHAMOCA 82%

MAC vs CHAMOMA 73% vs 65%

EMA-CO >80%

EMA/MEA/FME 75-80%

Salvage treatment in high risk GTN

EMA-EP (EMA - etoposide, cisplatin)

BEP (bleomycin, etoposide, cisplatin)

CEC (cyclophosphamide, etoposide, cisplatin)

MISC (high dose chemotherapy, carboplatin/paclitaxel, paclitaxel/etoposide and paclitaxel/cisplatin doublet)

Salvage treatment

20-60% success

Surgery

Toxicity

EP-EMA

CHAMOCA

EMA-CO

MAC

EMA/MEA/FME

Toxicity

Multi-treated patients

Potential mortality whatever is chosen

Acute toxicityAlopecia +++++

Neutropenia ++++

Anemia +++

Nausea/vomiting ++

Stomatitis ++

Neutropenic sepsis ++

Thrombocytopenia +

Long-term toxicity

Increased second malignancy

Premature menopause

Unknown!

Staff Nurse Ellen Zitek in BBCs ‘Casualty’ Treated for ‘cancer’ after a molar pregnancy

FIGO SCORING 0 1 2 4

Age < 40 40 - -

Antecedent pregnancy

Mole Abortion Term -

Interval months from index pregnancy

< 4 4 - < 7 7 - < 13 13

Pre-treatment serum hCG (IU/L)

< 103 103 - < 104 104 - < 105 105

Largest tumour size (including uterus) cm

< 3 3 - < 5 5 -

Site of metastases Lung Spleen, kidney

Gastro-intestinal

Liver, brain

Number of metastases - 1-4 5-8 > 8

Previous failed chemotherapy

- - Single drug 2 or more drugs

Chemotherapy for High Risk GTN(Sheffield UK)

Day 1 MTX 100mg/m2 iv Folinic acid rescue

Day 8, 9, 10 Dactinomycin 500µg iv Etoposide 100mg/m2 iv

et seq 7 days

M/AE

Sheffield Trophoblast Centre, UK

1986-2005Registration 8211

459 (6%)Persistent GTN

Low risk High risk

54 (12%) MAE

79 8

405 (88%)MTX

Resistant

AEA

Methotrexate resistant GTN

CR 78 (99%)

EA 79 Refractory 1

1 †

Median follow-up 8 years

Late deaths 0

2nd malignancy 0Further pregnancy >60%

High risk GTNMEA 54

CR 42 (78%)

Refractory12 2 other

TAH 5 5 CEC

24 1+7

49 (91%) alive and well

Median follow-up 8.5 yearsLate deaths 0

Further pregnancy >60%2nd malignancy 0

1 4 †

Cure rates in GTN1st line Salvage

Low risk

(70-90%)75% 99%

High risk

(10-30%)75% 95%

Overall 98% cure

Conclusion The majority of patients are curable whatever the ‘risk’ or ‘stage’

It doesn’t seem to matter which regimen you choose as long as it works and you are familiar with it!

‘Specialist’ center skills may be more important than the actual therapy

But - occasional patients still die despite multiple chemotherapy and surgical interventions

Methotrexate in high riskGTN (Sheffield, UK 1973-86)

AVC - dactinomycin, vincristine, cyclophosphmide

Median follow-up 24y

22MTX

12 4Other

Resistance

AVC

6 (27%)CR

20 Alive and well3 + 11

2†Late deaths 0

2nd malignancies 0