Management of Early stage Management of Early stage Malignant Ovarian Germ Cell TumoursMalignant Ovarian Germ Cell Tumours

Michael J Seckl

Charing Cross Hospital Campus of Imperial College NHS Healthcare TrustImperial College London, UK

9-129-12thth June 2010 Caravaggio Meeting on Rare Gynae June 2010 Caravaggio Meeting on Rare Gynae CancersCancers

What are OGCTs? - PathologyWhat are OGCTs? - Pathology

• DysgerminomasDysgerminomas

• Anaplastic GCTs/ Malig teratomas Anaplastic GCTs/ Malig teratomas embryonal Ca (undifferentiated)embryonal Ca (undifferentiated)polyembryoma (embryoid bodies)polyembryoma (embryoid bodies)endodermal sinus/yolk sacendodermal sinus/yolk sachepatoidhepatoidchoriocarcinomachoriocarcinoma

• Immature grade II/IIIImmature grade II/III

• MixedMixed

Pre-malignantPre-malignant MalignantMalignant• TeratomasTeratomas

immature (grade I)immature (grade I)mature (cystic)mature (cystic)monodermal teratomasmonodermal teratomas

Clinical presentationClinical presentation

• Abdominal distension, obstructionAbdominal distension, obstruction

• Rapid growth: haemoperitoneum/acute abdomenRapid growth: haemoperitoneum/acute abdomen

• hCG suppressed menstruation/ breast tendernesshCG suppressed menstruation/ breast tenderness

• Dysgerminomas: rare hypercalcaemiaDysgerminomas: rare hypercalcaemia

• Elevated hCG or AFP (CA125 and LDH)Elevated hCG or AFP (CA125 and LDH)

InvestigationsInvestigations

• U/S Doppler pelvisU/S Doppler pelvis

• CT chest/abdo/pelvisCT chest/abdo/pelvis

• MRI pelvisMRI pelvis

• Tumour markers (hCG, AFP, CA125, LDH)Tumour markers (hCG, AFP, CA125, LDH)

• If lung mets then MRI brainIf lung mets then MRI brain

• 1818FDG-PET?FDG-PET?

• Genetics?Genetics?

SurgerySurgery

• Unilateral salpingoophrectomy Unilateral salpingoophrectomy

• Biopsy omentum Biopsy omentum

• Biopsy contralateral ovary?Biopsy contralateral ovary?

• Locoregional LN samplingLocoregional LN sampling

• Peritoneal washingsPeritoneal washings

Surgical issues: a cancer perspectiveSurgical issues: a cancer perspective

• Laparoscopy vs laparotomy?Laparoscopy vs laparotomy?

• less invasive butless invasive but

• large tumours require morcellationlarge tumours require morcellation

• Morcellation in-situ may convert to IcMorcellation in-situ may convert to Ic

• Port-site metastasis??Port-site metastasis??

• Ease of staging??Ease of staging??

Surgical issues: LN staging importance?Surgical issues: LN staging importance?

Kumar et al et al Gynecol Oncol 2008Kumar et al et al Gynecol Oncol 2008

Stage IA management choicesStage IA management choices

• Surveillance?Surveillance?

• Adjuvant chemotherapy?Adjuvant chemotherapy?

• Adjuvant radiotherapy for dysgerminomas?Adjuvant radiotherapy for dysgerminomas?

• Surgery?Surgery?

CXH Stage Ia SurveillanceCXH Stage Ia Surveillance3-6 wks post-op: 3-6 wks post-op: CT chest/abdo/pelvis, MRI + Doppler U/S pelvisCT chest/abdo/pelvis, MRI + Doppler U/S pelvis

3 months (m):3 months (m): CT chest/abdo, MRI + Doppler U/S pelvisCT chest/abdo, MRI + Doppler U/S pelvisNormal then laparoscopyNormal then laparoscopy

6 - 48 m (6 mthly):6 - 48 m (6 mthly): MRI + U/S pelvis and abdomenMRI + U/S pelvis and abdomen

12 m:12 m: CT chest/abdoCT chest/abdo

24 m:24 m: CT chest/abdo (dysgerminomas only)CT chest/abdo (dysgerminomas only)

11stst yr: yr: Mnthly clinical examination, CXR alternate visitsMnthly clinical examination, CXR alternate visits22ndnd yr: yr: 2 mnthly clin exam, CXR alt visits2 mnthly clin exam, CXR alt visits33rdrd yr: yr: 3 mnthly clin exam, CXR alt visits3 mnthly clin exam, CXR alt visits44thth yr: yr: 4 mnthly clin exam4 mnthly clin exam55thth & 6 & 6thth yr: yr: 6 mnthly6 mnthly77thth yr onwards: yr onwards: Annual visitsAnnual visits

Tumour Markers (hCG, AFP, LDH, CA125)Tumour Markers (hCG, AFP, LDH, CA125)

0-6 months:0-6 months: 2 wkly2 wkly

7-24 months:7-24 months: 4 wkly4 wkly

25-36 months:25-36 months: 8 wkly8 wkly

37-60 months:37-60 months: 12 wkly12 wkly

> 5 yrs:> 5 yrs: 6 monthly6 monthly

> 10 yrs:> 10 yrs: AnnuallyAnnually

Stage Ia SurveillanceStage Ia Surveillance

Stage Ia Surveillance: Results 1981-2003Stage Ia Surveillance: Results 1981-2003

• 31 patients included (9 dysgerminomas, 22 NDGCTs)31 patients included (9 dysgerminomas, 22 NDGCTs)

4 mature teratomas + 2 Stage Ic excluded4 mature teratomas + 2 Stage Ic excluded

• median 26 yrs (range 14-48 yrs)median 26 yrs (range 14-48 yrs)

• 64% elevated pre-op hCG and/or AFP64% elevated pre-op hCG and/or AFP

• 1 dysgerminoma with bilat disease1 dysgerminoma with bilat disease

Patterson et al Int J Gynaecol Cancer 2008Patterson et al Int J Gynaecol Cancer 2008

Stage Ia Surveillance: Results 1981-2003Stage Ia Surveillance: Results 1981-2003

• median follow-up 6 yrs (range 5 m-21 yrs)median follow-up 6 yrs (range 5 m-21 yrs)• 10 relapses (32%)10 relapses (32%)

2 dysgerminomas (22%) 2 dysgerminomas (22%) 8 NDGCTs (36%)8 NDGCTs (36%)

Patterson et al Int J Gynaecol Cancer 2008Patterson et al Int J Gynaecol Cancer 2008

Location and Time of relapsesLocation and Time of relapses

• Pelvis:Pelvis: 6 (3 other ovary-1 dysgerminoma)6 (3 other ovary-1 dysgerminoma)

• Abdo:Abdo: 22

• Marker + ve:Marker + ve: 4 (2 marker only)4 (2 marker only)

• Latest relapse 13 mnths from surgeryLatest relapse 13 mnths from surgery

Patterson et al Int J Gynaecol Cancer 2008Patterson et al Int J Gynaecol Cancer 2008

Salvage treatmentsSalvage treatments

• 9/10 salvaged with chemo (90%)9/10 salvaged with chemo (90%)7 POMB/ACE (1 died despite surgery)7 POMB/ACE (1 died despite surgery)3 BEP x 3-43 BEP x 3-4

• 1 patient died 8 yrs later - melanoma1 patient died 8 yrs later - melanoma

Patterson et al Int J Gynaecol Cancer 2008Patterson et al Int J Gynaecol Cancer 2008

• 29/31 alive and in remission after median 6 yrs29/31 alive and in remission after median 6 yrs

• 5 yr disease free survival 68% (95% CI: 46-84%) 5 yr disease free survival 68% (95% CI: 46-84%)

• 5 yr overall survival 5 yr overall survival 93% (95% CI: 78-99%) 93% (95% CI: 78-99%)

• 5 yr DSS5 yr DSS 97% 97%

Stage Ia Surveillance: Results 1981-2003Stage Ia Surveillance: Results 1981-2003

Patterson et al Int J Gynaecol Cancer 2008Patterson et al Int J Gynaecol Cancer 2008

• CarboplatinCarboplatin

• EPEP

• DXTDXT

• BEPBEP

• Surgery??Surgery??

Stage Ia Adjuvant treatment?Stage Ia Adjuvant treatment?

Dysgerminoma vs NDGCT?Dysgerminoma vs NDGCT?

Carboplatin / EP/ BEP / DXT??Carboplatin / EP/ BEP / DXT?? AdvantagesAdvantages Disadvantages Disadvantages

Less relapsesLess relapses Still relapseStill relapse

Less surveillanceLess surveillance Surveillance still requiredSurveillance still required

Improved OS?Improved OS? Second cancers?Second cancers?

Cardiovascular?Cardiovascular?

Drug resistance?Drug resistance?

Reduced fertility?Reduced fertility?

Stage Ia Adjuvant Rx for OGCTs?Stage Ia Adjuvant Rx for OGCTs?

Stage Ia Adjuvant for Dysgerminomas?Stage Ia Adjuvant for Dysgerminomas?

Vicus et al Gynecol Oncol 2010Vicus et al Gynecol Oncol 2010

38 stage IA

15 Adjuvant 23 surveillance

11 DXT 4 BEP/EP

0 Relapses: 52 other ovary

3 abdo OS: 100% 100%

2nd cancer: 1 0

Williams et al JCO 1994Williams et al JCO 1994

93 patients93 patients60 stage 1, 10 stage 2, 23 stage 2360 stage 1, 10 stage 2, 23 stage 23

BEP > PVBBEP > PVB2 relapses after BEP NDGCT (1 dead 1??)2 relapses after BEP NDGCT (1 dead 1??)

1 stage Ic1 stage Ic2 patients 22 patients 2ndnd Cancers (1 death: AML) Cancers (1 death: AML)

Stage Ia Chemo for NDGCTs?Stage Ia Chemo for NDGCTs?

• No right answerNo right answer

• Costs are similarCosts are similar

• Surveillance is least toxicSurveillance is least toxic

• If patient can’t comply we give:If patient can’t comply we give:

- Carbo AUC 7 x 2 for DGCT- Carbo AUC 7 x 2 for DGCT

- BEP x 3 for NDGCT- BEP x 3 for NDGCT

• Long term monitoring required with bothLong term monitoring required with both

Stage Ia Adjuvant vs SurveillanceStage Ia Adjuvant vs Surveillance

• Lymphovascular invasionLymphovascular invasion

• Marker positiveMarker positive

• Very large tumoursVery large tumours

• Endodermal sinus and/or yolk sacEndodermal sinus and/or yolk sac

• Pure ChoriocarcinomaPure Choriocarcinoma

- Surveillance is still OK- Surveillance is still OK

What about poor prognostic features?What about poor prognostic features?

Case 1 example of Stage I surveillanceCase 1 example of Stage I surveillance

Pure seminoma

NSGCT

Chorio

Stage Ia Surveillance: ResultsStage Ia Surveillance: ResultshC

G

So when is it safe to attempt pregnancy?So when is it safe to attempt pregnancy?

CX Stage Ia Surveillance: Results 2003CX Stage Ia Surveillance: Results 2003

Fertility?Fertility?

• 30/31 had unilat oophrectomy30/31 had unilat oophrectomy• Non-relapsed group: Non-relapsed group: 50% (10/20) babies50% (10/20) babies• Relapsed group:Relapsed group: 50% (5/10) babies50% (5/10) babies

• Desire for pregnancy 75% (15/20)Desire for pregnancy 75% (15/20)

Patterson et al Int J Gynaecol Cancer 2008Patterson et al Int J Gynaecol Cancer 2008

Fertility with adjuvant therapy?Fertility with adjuvant therapy?

• DXT impairs fertilityDXT impairs fertility11/11 treated with DXT no pregnancies11/11 treated with DXT no pregnancies

• Carbo or BEP probably little effectCarbo or BEP probably little effect

Surveillance for stage Ic MOGCT?Surveillance for stage Ic MOGCT?

• Likely increased recurrence riskLikely increased recurrence risk

• Don’t currently do this at CXDon’t currently do this at CX

• Fertility conserving surgeryFertility conserving surgery

• Surveillance is reasonableSurveillance is reasonable- 22-36% relapse but nearly all cured- 22-36% relapse but nearly all cured

• Adjuvant therapy an alternativeAdjuvant therapy an alternative- for non-compliant pts- for non-compliant pts

- over-treats 75%- over-treats 75%

-22ndnd cancer risk cancer risk

• Relapses within 1-2 yrs in Relapses within 1-2 yrs in

pelvis/abdopelvis/abdo

• Fertility is high but not with DXTFertility is high but not with DXT

Summary for Stage IaSummary for Stage Ia

AcknowledgementsAcknowledgementsProf Edward S NewlandsProf Edward S NewlandsProf Fernando J ParadinasProf Fernando J ParadinasProf Gordon JS RustinProf Gordon JS RustinDr Philip SavageDr Philip SavageDr Iain LindsayDr Iain LindsayDr Iain McNeishDr Iain McNeishDr Nirupa MurugaesuDr Nirupa MurugaesuDr Daniel PattersonDr Daniel PattersonDr Roshan AgarwalDr Roshan AgarwalDr Adrian LimDr Adrian LimMs Linda DyallMs Linda DyallMs Sarah StricklandMs Sarah Strickland

Dr Edward KanferDr Edward KanferMr Richard SmithMr Richard SmithMr Angus McIndoeMr Angus McIndoeMrs Delia ShortMrs Delia ShortMrs Sandra FullerMrs Sandra FullerDr Lydia HoldenDr Lydia HoldenMr Hugh MitchellMr Hugh MitchellDr Richard HarveyDr Richard HarveyDr Adam MitchellDr Adam MitchellDr Joe BoultbeeDr Joe Boultbee

Wellcome TrustWellcome TrustCTRTCTRT

m.seckl@imperial.ac.ukm.seckl@imperial.ac.uk