Management of Stage Ic-IV Malignant Ovarian Germ Cell Tumours

Transcription

1 Management of Stage Ic-IV Malignant Ovarian Germ Cell Tumours Michael J Seckl Charing Cross Hospital Campus of Imperial College NHS Healthcare Trust Imperial College London, UK 9-12th June 2010 Caravaggio Meeting on Rare Gynae Cancers

2

3 Surgery in advanced MOGCT Is debulking/diagnostic surgery required? - if marker positive defer - if marker negative then biopsy Urgent neoadjuvant chemotherapy - may preserve fertility - saves lives

4 Management of Stage Ic/M-IV Charing Cross MOGCTs Stage Ic/M 23 Stage II 25 Stage III 27 Stage IV 22 Staging? 16 Total Ic/M-IV previously untreated: 113 Murugaesu et al J Clin Oncol 2006

5 Charing Cross MOGCTs Ic/M-IV Median age 24 yrs (range 4-60 yrs) Histol Dysgerminoma 12.5% NDGCT 45% (yolk sac 26.5%) Mixed 32% Unclassified 11.5% Surgery pre chemo None 6% Oophrect 56% Debulking 38% Murugaesu et al J Clin Oncol 2006

6 POMB/ACE regimen POMB Day 1 Vincristine 1mg/m2, Methotrexate 300mg/m2 12 h infusion Day 2 Bleomycin 15 mg 24 h infusion, FA rescue 15 mgs 12 hrly 24h post MTX x 4 doses Day 3 Bleomycin 15 mg 24 h infusion Day 4 Cisplatin 120 mg/m2 12 h infusion ACE Days 1-3 Etoposide 100mg/m2 Days 1-3 Actinomycin D 0.5 mgs Day 3 Cyclophosphamide 500mg/m2 POMB/POMB/ACE/POMB/ACE 10 wks

7

8 Treatment variations Low dose EP regimen Days 1-2 Etoposide 100mg/m2 Cisplatin 20mg/m2 BEP for stage Ic +/- IIa

9

10

11 Pre Chemo Post Chemo

12

13 Pre Chemo Post Chemo

14 Pre Chemo Post Chemo

15 Pre Chemo Post Chemo Post Surgery

16 Overall Survival after chemotherapy N = late relapse at 7.6 yrs 5 and 25 yr survival rates = 83 and 81% Murugaesu et al J Clin Oncol 2006

17 Stage does not predict outcome to chemotherapy 65 patients

18 Stage predicts outcome to chemotherapy Kaplan-Meier overall survival curves for 97 patients according to stage 1.0 Cumulative Survival stage 1c/M n= stage 2 n=25 p= stage 3 n= stage 4 n= Years Murugaesu et al J Clin Oncol 2006

19 Combined elevated AFP & hcg predicts poor outcome Cumulative Survival 1.0 N = Normal tumour markers or only one tumour marker elevated N = 17 Elevated HCG & AFP 0.2 P = years Murugaesu et al J Clin Oncol 2006

20 Age predicts outcome?

21 Age does not predict outcome 80 Age of Patient There is no difference in the age of patients that relapsed and those that did not No Yes Relapse Murugaesu et al J Clin Oncol 2006

22

23 Relapses 20 patients (RR 18%) Median time to relapse 7 months All received salvage chemo +/- surgery 4 high dose (1 cured) 2 cured overall 10% salvage rate Murugaesu et al J Clin Oncol 2006

24 Other active agents? Taxanes Gemcitabine Others? Pemetrexed Role for high dose therapy?

25 Hypothesis Can a novel taxol-containing regime (Carbop-EC-T) increase the salvage rate and overall survival? How might this compare with Carbop-EC alone?

26 The Carbop-EC-T Regime Day - 7 Paclitaxel Etoposide Carboplatin 75 mg/m2 over 3 hours (24 h) 450 mg/m2 over 2 hours AUC 10 [= 10 x (GFR + 25) mg] over 1 hour Day - 5 Paclitaxel Etoposide Carboplatin Cyclophosphamide 75 mg/m2 over 3 hours (24h) 450 mg/m2 over 2 hours AUC 10 over 1 hour 60 mg/kg over 1 hour + MESNA 120 mg/kg Day - 3 Paclitaxel Etoposide Carboplatin Cyclophosphamide 75 mg/m2 over 3 hours (24h) 450 mg/m2 over 2 hours AUC 10 over 1 hour 60 mg/kg over 1 hour + MESNA 120 mg/kg Day 0 Reinfuse Peripheral Blood Stem Cells McNeish et al Brit J Cancer 2004

27 Response of a Tumour to Carbop-EC-T previously failing Carbop-EC

28 Response of a Refractory Tumour to Carbop-EC-T Carbop-EC-T 1000 Beyer Score POMB POMB ACE POMB ACE RPLND Pac E Pac P Pac E EP EP EP E-PBSCH Serum hcg Apr-99 Jul-99 Oct-99 Date Carbop-EC-T Jan-00 Apr-00 Jul-00

29

30 Probability of survival Event-free Survival According to Cisplatin Sensitivity * * Sensitive Refractory Time (months) McNeish et al Brit J Cancer 2004

31 Probability of survival Overall Survival According to Cisplatin Sensitivity Sensitive Refractory Time (months) McNeish et al Brit J Cancer 2004

32 Median age Carbop-EC-T Carbop-EC N = 36 N = years 37 years p=ns (range 19 69) Median follow-up 27.1 months 35 months (range 4 83) Disease Teratoma Seminoma p=ns p=ns 3 (2 6) 3 (2 5) p=ns Sensitivity to cisplatin (Beyer criteria) Sensitive Refractory Absolutely refractory p=ns p=ns p=ns IGCCCG classification Good Intermediate Poor p=ns 12 p=ns Median estimated GFR 69.0 ml/min 75 ml/min p=ns Median previous chemotherapy regimes (range ) Left ventricular ejection fraction Lung function tests: FEV1 58% (range 30 78%) KCO 96% predicted (range %) N.D. N.D. 87% predicted (range %)

33 Probability of survival Carbop-EC-T vs Carbop-EC: Event-free Survival Carbop-EC-T Carbop-EC * * p = Time (months) McNeish et al Brit J Cancer 2004

34 Probability of survival Carbop-EC-T vs Carbop-EC: Overall Survival Carbop-EC-T Carbop-EC p = Time (months) McNeish et al Brit J Cancer 2004

35 Carbop-EC-T High dose Conclusions Carbop-EC-T is active: > 60% 2 year overall survival Cisplatin-sensitive does better than refractory disease Toxic deaths (pneumonitis) significant in cisplatin refractory patients Pneumonitis reported in other high dose regimes with paclitaxel 24 h paclitaxel with steroids overcomes toxic death problem

36 So does hi dose really work? CT chest/abdo/pelvis MRI brain if there are lung mets Consider PET +/- others

37 ..little or no debate on the use of high-dose chemotherapy for GCTs refractory to platinum-based chemotherapy. 18/40 with refractory disease median 49 months DFS 22/49 receiving hi dose as 3rd line or later median 46 months DFS.

38 What about Ovarian GCTs? 6 patients enrolled All failed 1 previous platinum regimen 3 died within wks of high dose 1 relapsed 1 yr post transplant died 8 mnths later 1 relapsed at 2 yrs and died 4 yrs out 1 in remission 3 yrs out

39 Autol SCT Etoposide/PBSCH TIP TIP TIP BEP BEP BEP BEP New AFP assay

40 Post-Chemotherapy Follow-up 1st yr: Monthly clin exam, CXR alt visits 3 months CT/MRI if end treatment CT/MRI is suspicous of residual disease 2nd yr: 2 monthly clin exam, CXR alt visits 3rd yr: 3 monthly clin exam 4th and 5th yr: 6 monthly clin exam 6th yr onwards: Annual visits

41 Post-Chemotherapy Follow-up Tumour Markers (hcg, AFP, LDH, CA125) 0-6 mnths: 2 wkly 7-24 mnths: 4 wkly mnths: 8 wkly mnths: 12 wkly > 5 yrs: 6 mnthly > 10 yrs: Annually

42 Summary May not need debulking surgery BEP x 3-4 for Ic/M-II POMB/ACE for stage IIc-IV Consider early high dose for poor risk patients Relapses do badly (unlike male GCTs) New regimens / high dose? required Fertility post-chemo next talk m.seckl@imperial.ac.uk

43 Acknowledgements Prof Edward S Newlands Dr Edward Kanfer Prof Fernando J Paradinas Mr Richard Smith Prof Gordon JS Rustin Mr Angus McIndoe Dr Philip Savage Mrs Delia Short Dr Iain Lindsay Mrs Sandra Fuller Dr Iain McNeish Dr Lydia Holden Dr Nirupa Murugaesu Mr Hugh Mitchell Dr Roshan Agarwal Dr Richard Harvey Dr Adrian Lim Dr Adam Mitchell Ms Linda Dyall Dr Joe Boultbee Ms Sarah Strickland m.seckl@imperial.ac.uk Wellcome Trust CTRT

44 Predicting outcome for relapsing pts? Beyer criteria Cisplatin sensitive relapse Cisplatin refractory Absolutely refractory

45 Predicting outcome for relapsing pts? Beyer prognostic score for hi dose Mediastinal primary = 1 Refractory disease = 1 Absolutely refractory = 2 hcg > 1000 before hi dose = 2 Score 0: good prognosis Score 1-2: intermediate Score 3: poor prognosis

46 Overall Survival According to Beyer score McNeish et al Brit J Cancer 2004