Germ Cell Tumors. Karim Fizazi, MD, PhD Institut Gustave Roussy, France

Transcription

1 Germ Cell Tumors Karim Fizazi, MD, PhD Institut Gustave Roussy, France

2 Surveillance for stage I GCT

3 NSGCT A 26 year-old patient had a orchiectomy revealing embryonal carcinoma (40%), seminoma (40%) and YST (20%). No vascular invasion. AFP was 90 ng/ml pre, 4 ng/ml post (N<10), hcg and LDH normal. TAP CT normal. After discussing the various options with the patient, a surveillance policy is agreed. How will you proceed?

4 Minimum follow-up for stage I NSGCT (at least low-risk) Procedure Year Physical examination 4 times 4 times Once/year Once/year Tumour markers 4 times 4 times Once/year Once/year Chest X-ray Twice Twice Abdominopelvic CT Twice (at 3 and 12 months) Personal comments: Testosterone monitoring and treatment? Really no imaging after 2 years? Yearly really required post year 5? (I do every 2 years)

5 Stage I NSGCT, post-adjuvant BEP (or RPLND) Procedure Year Physical examination 4 times 4 times Once/year Once/year Tumour markers 4 times 4 times Once/year Once/year Plain radiography chest Twice Twice Abdominopelvic CT Once Once

6 Pure seminoma A 33 year-old patient had a orchiectomy revealing pure seminoma, 4 cm, rete testis invasion. AFP, hcg and LDH normal. TAP CT normal. After discussing the various options with the patient, a surveillance policy is agreed. How will you proceed?

7 Stage I seminoma follow-up for surveillance (only) or post-carboplatin/rxt Procedure Year Physical examination 3 times 3 times Once/year Once/year Tumour markers 3 times 3 times Once/year Once/year Plain radiography chest Twice Twice Abdominopelvic CT Twice Twice Personal comments: Median time to relapse=12-18 m Some late relapse: US examination starting year 3?

8 Poor prognosis NSGCT

9 Poor prognosis metastatic NSGCT Definition: any of: Primary tumor site: Mediastinal Extra-pulmonary visceral mets: Yes Tumor marker before chemo: hcg: > AFP > LDH > 10 x norm 15% of metastatic NSGCT Cure rate: 50% J Clin Oncol 1997, 15:

10 Poor-risk GCT: A standard established in BEP > 4 PVB: DFS (p<0.05) and OS (p<0.05) Better tolerance (neurotoxicity) 4 BEP= standard Presented by: Karim Fizazi

11 Clinical case A 23 year-old patient has consulted for dyspnea and haemoptysia. hcg is , AFP normal, LDH 10N TAP CT: multiple lung nodules Clinically pathologic right testis What would you do? Orchiectomy: yes/no? Additional imaging: yes/no? If GCT is confirmed: what chemotherapy regimen?

12 Brain MRI recommended in poor-risk NSGCT

13 Management of pts at high risk of ARDS: «Very high risk NSGCT» ARDS 13/15 (87%) Death from ARDS Longterm survivor Extensive lung mets Dyspnea or po2< /10 (30%) Total 16/25 10/15 2/10 12/25 4/15 (27%) 4/10 (40%) 8/25 Massard C, Ann Oncol 2010

14 Clinical case A patient with poor-prognosis NSGCT (LN and liver metastases, high tumor markers) has received 1 cycle of BEP with a good tolerance. When he s hospitalized again at day 21, his tumor markers show: hcg: 3100 before, 200 after AFP: 1300 before, 300 after LDH: x 2 before, x 1.5 after Will you continue BEP or swich to another regimen?

15 Survival according to tumor marker decline in Poor-prognosis GCT Tumor markers assessed at Day 21 Tumor markers assessed at Day 42 IGCCCG - POOR RISK Overall Survival Time to Normalization FAVORABLE UNFAVORABLE p= Years Fizazi, J Clin Oncol 2004, 22: Motzer, J Clin Oncol 2007; 25: Presented by: Karim Fizazi

16 Calculation of tumor marker decline Decline rates are calculated using a logarithmic formula : M0=initial marker value; M1=marker value at 3 w; MN=Normal value Tumor marker decline = 3 A / B A = log(m0)-log(mn) B = log(m0)-log(m1) Patients can then be classified into 4 categories as follows : AM Normal at cycle 1 and at cycle 2 BM Abnormal at cycle 1 and Normalization at cycle 2 CM Abnormal cycle 1 and TNM < TM DM Abnormal cycle 1 and TNM TM or abnormal and increasing marker at cycle 2 Cut-off points (TM) vary for each marker: TAFP = 9 w, ThCG = 6 w A favorable pattern of decline is defined by hcg and AFP being both A, B, or C. Fizazi, J Clin Oncol 2004, 22:

17 GETUG 13 Phase III design Median follow-up: 4.1 years (0.3 ; 8.8 years) Favorable decline 4 BEP (total) n=263 n=254 Poor-risk GCT (IGCCCG) Registration 1st BEP Day 21: Tumor marker n=51 Unfavorable decline n=203 R Dose-dense regimen n=105 4 BEP (total) n=98 Presented by: Karim Fizazi

18 GETUG 13: Dose-dense regimen BEP 1 Cisplatin 20 mg/m 2 /d d1-5 Etoposide 100 mg/m 2 /d d1-5 Bleomycin 30 u/w Paclitaxel-BEP + Oxaliplatin + G-CSF / 3 weeks 2 cycles Paclitaxel 175 mg/m 2 d1 BEP as above Oxaliplatin 130 mg/m 2 d10 G-CSF 263 μg/d (excepted chemo days) Cisplatin, Ifosfamide, Bleomycin + G-CSF / 3 weeks 2 cycles Cisplatin 100 mg/m 2 d1 Ifosfamide 2g/m 2 d10,12,14 Mesnum Bleomycin 25 U/d d10-14 (continuous IV) G-CSF as above Presented by: Karim Fizazi

19 Primary endpoint: PFS in randomized patients with an unfavorable decline At risk 100% 80% 60% 40% 20% 0% HR: 0.66 [ ] p= Years year PFS: 59% vs 48% Unfav-Dose-dense Unfav-BEP Unfav-DoseDense cned: 63 vs 46 pts Fizazi K, Lancet Oncol 2014 (in press)

20 OS in randomized patients with an unfavorable decline At risk 100% 80% 60% 40% 20% 0% Years HR: 0.78 (0.46 ; 1.31), p= year OS: 73% vs 65% Unfav-Dose-dense Unfav-BEP Unfav-BEP Unfav-DoseDense Alive: 78 vs 66 pts Presented by: Karim Fizazi Fizazi K, Lancet Oncol 2014 (in press)

21 Outcome according to tumor marker decline 100% PFS 100% OS 80% 80% At risk 60% 40% 20% 0% Years Fav-BEP Unfav-BEP Unfav-Dose-dense Unfav-DoseDense Unfav-BEP Fav-BEP At risk 60% 40% 20% 0% Years Fav-BEP Unfav-BEP Unfav-Dose-dense Unfav-DoseDense Unfav-BEP Fav-BEP Fav-BEP vs Unfav-BEP: 3-year PFS: 70% vs 48% HR=0.66 (0.49 ; 0.88), p=0.01 Fav-BEP vs Unfav-BEP: 3-year OS: 84% vs 65% HR=0.65 (0.45 ; 0.95), p=0.024 Fizazi K, Lancet Oncol 2014 (in press)

22 Clinical case A patient with poor-prognosis NSGCT (hcg=40 000, AFP=1200, LDH=5N), LN, lung and liver metastases, has received the planned chemotherapy regimen CT: major response AFP and LDH=normalized, hcg still 50 What would you do?

23 Clinical case A patient with poor-prognosis NSGCT (hcg=40 000, AFP=1200, LDH=5N), LN, lung and liver metastases, has received the planned chemotherapy regimen CT: major response hcg and LDH=normalized, AFP still 50 What would you do?

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