Trophoblastic tumours
Professor Michael J Seckl
Director of the Charing Cross GTD Centre, London, UK
2nd Clinical Update on Rare Adult Solid
Cancers1st-3rd Dec 2018, Milan
Conflicts of interest: none to declare
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GTD spectrum
Complete Hydatiform Mole Invasive Mole
Choriocarcinoma
Pre-Malignant Malignant
Partial Hydatiform Mole
Placental site
trophoblastic
tumours/ETT
Seckl et al Lancet 2000 and Palmieri et al Lancet 2005
Atypical placental site nodule
Kaur et al Int J Gyn Pathol 2015Do not duplicate or d
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Scoring to determine therapy
Low Risk 0-6, High Risk >6 Ultra Hi Risk > 12
Kohorn et al Int J Gynecol Cancer 2000, Seckl et al Annals Oncol 2013
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Low Risk Rx
Methotrexate 50mg IM noon d1,3,5,7
Folinic acid 15 mg PO 6pm d2,4,6,8
Actinomycin D 1.25mg/m2 IV
or
GOG 0275 study closed early
Seckl et al Annals Oncol 2013, Schink et al ISSTD 2017
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Low Risk Therapy
6 weeks consolidation
Lybol et al Gynecol Oncol 2012
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Low risk therapy outcomes
67% 33%
87%
Low Risk
Hi Risk
~100% cure rate
13%
• 300 IU/L = same
• 1000 IU/L = sameSeckl et al ISSTD 2017
Sita-Lumsden et al BJC 2012
McNeish et al JCO 2002
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High risk vs ultra-high risk
High Risk Ultra-high Risk
FIGO score 7-12 FIGO score ≥ 13
No early deaths Risk of early death
Interval < 2.8 yrs Interval > 2.8 yrs
Liver ± brain mets
Advanced disease
Low risk of late death Increased risk
Alifrangis et al J Clin Oncol 2013, Bolze et al Am J Obstet Gynecol 2016
Low dose Etop 100mg/m2 + cisplat 20mg/m2 d1-2 wkly x 1-3
Consider adapted on-going therapy
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May ‘09 Aug ‘09
A dental visit
Woman childbearing age + unexplained mets
= measure hCG
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High Risk Investigations
• CT chest/abdo
• MRI brain/pelvis and spine
• Doppler ultrasound pelvis
• LP to assess CSF hCG: serum hCG
• FDG-PET scan
• Histopathology (not mandatory)
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EMA/CO
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Log-rank p< 0.001
Median follow-up 4.2 years
FIGO <7 (n=250)
FIGO ≥7 (n=140)
nGTT (n=6)
Overall survival: EMA/CO 1995-2010Non-gestational tumors do badly
Alifrangis et al J Clin Oncol 2013
20% relapse: how do we salvage them?
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Salvage approaches
• EP/EMA vs TE/TP: both salvage 75-80% but TE/TP less toxic • Hi dose: salvages ~40%• Gemcitabine/pemetrexed/capecitabine• Surgery• Radiotherapy - stereotactic in brain
- whole brain is toxic
• New agents?- TKIs: Erlotinib/gefitinib
- Anti-vascular: Bevasuzimab
- Anti-hCG antibodies/vaccine
- Anti-endoglin
- Immune checkpoint inhibitors
Seckl et al Annals Oncol 2013, ISSTD Amsterdam 2017, Worley et al Gynae Oncol 2018
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2013 2014 2015 2016
RANSOM E M elody DoB - 17/02/1973Gestational Choriocarcinoma HospNo - CC500217
HC
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Date
Pembrolizumab is active
Ghorani et al Lancet 2017 and unpublished data
7/10 pembro responders incl: PSTT & ETT
All PD-L1 +ve and TIL +ve, non-responders few TILs
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Which GTN for immunotherapy?
TROPHIMMUN trial: cohorts A and B
Single agent regimen(MTX, ACT-D)
PolychemotherapyEMA-CO; EMA-EP
Low-risk High-risk
hCGnormalization
Resistance hCGnormalization
Resistance
Cohort A Cohort B
hCG
Benoit You et al in Lyon, France trial using anti-PD-L1 antibody atezolizumab
Cohort A: 11 patients Cohort B: 4 patients
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Ipilimumab
Pembrolizumab
What about combinations?
Balancing toxicity vs efficacy vs cost
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Long-term outlook
Chemotherapy
hCG follow-up for 10 yrs
Remission
83% successful pregnancies
4% relapse
EMA/CO - hastens menapause ~ 3 yr- No increased risk 2nd tumours
Early pregnancy - no increase in abnormal fetus
- no increase in relapse rateWoolas et al BJOG 1998
Blagden et al BJC 2002
Williams et al J Reprod Med 2014
Savage et al JCO 2015, Giuliani et al ESGO rare cancer meeting 2018
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When to stop hCG monitoring after Rx
4201
Low risk = 3507 High risk = 694
Relapses: 154 (4.4%) Relapses: 44 (6.3%)
Year 1
Year 2
Year 3
Year 4
Years 5 & 6
Year 7
> Year 7
Year 1
Year 2
Year 3
Year 4
Years 5 & 6
Year 7
> Year 7
112 (73%)
2 (1%)3 (2%)1 (1%)
34 (86%)4 (9%)0 (0%)1 (2%)0 (0%)1 (2%)0 (0%)
19 (12%)17 (11%)
0 (0%)
Balachandran et al. Paper in prep 2018
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Summary
• 16% CHM and 0.5-1% PHM need chemo
• Registration, pathol review and hCG essential
• Know your hCG assay’s limitations
• Low risk: ~100% survival
• High risk (HR): >94% survival
• Ultra HR: low dose induction EP avoids early deaths
consider EP/EMA vs EMA/CO
CNS disease: 1g/m2 MTX EMA(1day)/CO ± iT MTX
• Salvage: surgery vs immunotherapy vs hi dose
• Fertility outcomes are excellent
• Stop follow-up at 7-10 yrs
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Acknowledgements
Dr Naveed Sarwar
Dr Philip Savage
Dr Baljeet Kaur
Prof Neil Sebire
Dr Rosemary Fisher
Dee Short
Sabrina Positano
Emma Humble
Dr Anna Tommasi
Dr Olivier Pardo
Dr Fieke Froeling
Dr Marina Georgiou
Dr Rajat Roy
Dr Richard Harvey
Terry Tin
Sarah Strickland
Linda Dayal
Lauren Jordan
Xianne Aguiar
Sinead Cope
Eimear Tummon
Jeanette Aristobal
Mr Richard Smith
Prof Cristina Fotopoulou
Dr Edward Kanfer
Mr John Anderson
Mr Long Jiao
Dr Costi Alifrangis
Tina Barker
Dr Adrian Lim
Daksha Patel
Dr Ehsan Ghorani
Dr Preetha Aravind
Prof Edward Newlands
Prof Ken Bagshawe
www.hmole-chorio.org.uk
Ulrika Joneborg
Joseph Carlson
Ayse Akarca
Teresa Marafioti
Sergio Quezada
Ross Berkowitz
Francois Golfier
Leon Massuger
Christianne Lok
Benoit You
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