Adenokarzinom des Ösophagus und Magens

Transkript

1 Adenokarzinom des Ösophagus und Magens Christian Meyer zum Büschenfelde Klinikum rechts der Isar der Technischen Universität München III. Medizinische Klinik und Poliklinik Schwerpunkt: Hämatologie / Internistische Onkologie

2 Therapiekonzepte Neoadjuvant Adjuvant Palliativ Second line

3 MAGIC-Studie St. II + III Gastric + Junction + Esophagus N = RANDOM Chemotherapy: ECF x 3 Resection ECF x 3 Primary endpoint: 5-y-survival Surgery alone *ECF: Epirubicin 50mg/m2 d1, Cisplatin 60mg/m2 d1, 5-FU 200mg/m2/d cont iv, qd 22 Cunningham D et al. N Engl J Med 2006;355:11-20

4 MAGIC Trial - Gesamtüberleben 5-y-OS 36% 23% Cunningham D et al. N Engl J Med 2006;355:11-20

5 FNCC FFCD 9703 St. II + III Gastric + Junction + N = RANDOM Chemotherapy: CF* x 2 Resection CF x 4 Primary endpoint: Survival 20% 35% after 5 years, =5%, =20% Surgery alone *CF: Cisplatin 100mg/m2 d1, 5-FU 800mg/m2/d d1-5, qd 28 Boige, V. et al. ASCO 2007 #4510

6 FNCC FFCD ,00 0,80 0,60 0,40 S CT + S Logrank p value = Hazard Ratio = 0.69 (95% CI ) 0,20 logrank : p = 0,021 A At risque risk 0, years 5-year-survival: 24% (16-33%) vs 38% (28-47%) Boige, V. et al. ASCO 2007 #4510

7 Neoadjuvant chemotherapy + surgery versus surgery alone for locally advanced adenocarcinoma of the stomach and cardia: EORTC phase III trial St. II + III Gastric + Junction + N = 144 T3/T4 NxM0 RANDOM Chemotherapy: PLF x 2 Resection Primary endpoint: Survival Surgery alone PLF: Cisplatin 50mg/qm d1, 15, 29, 5-FU 2000mg/qm + FA 500 mg/qm weekly Schuhmacher et al. ASCO 2009

8 Neoadjuvant chemotherapy + surgery versus surgery alone for locally advanced adenocarcinoma of the stomach and cardia: EORTC phase III trial # 4510 CS (N=70) S (N=68) D2 lymphadenectomy 67 (95.7%) 63 (92.6%) + transhiatal resection 31 (44.3%) 35 (51.5%) + hepatoduodenal lig. & rt. retroperitoneal excision 20 (28.6%) 22 (32.4%) Subtotal distal resection w/ systemic LN resection 1 (1.4%) 2 (2.9%) Multivisceral resection 6 (8.6%) 12 (17.6%) Type of reconstruction Roux-en-Y Pouch 48 (68.6%) 17 (24.3%) 50 (73.5%) 12 (17.6%) Schuhmacher, ASCO 2009; Abstract 4510 Schuhmacher et al. ASCO 2009

9 Neoadjuvant chemotherapy + surgery versus surgery alone for locally advanced adenocarcinoma of the stomach and cardia: EORTC phase III trial # 4510 CS (N=72) S (N=72) R0 59 (81.9%) 48 (66.7%) R1 9 (12.5%) 15 (20.8%) R2 2 (2.8%) 5 (6.9%) Not operated 2 (2.8%) 4 (5.6%) Schuhmacher et al. ASCO 2009

10 Neoadjuvant chemotherapy + surgery versus surgery alone for locally advanced adenocarcinoma of the stomach and cardia: EORTC phase III trial # HR 0.84 (0.52,1.35) Overall Logrank test: p= (years) O N Number of patients at risk : Treatment S CS Schuhmacher et al. ASCO 2009

11 D2 40% D2 90% Overall Logrank test: p= (years) O N Number of patients at risk : Treatment S CS 1,00 0,80 0,60 0,40 A risque 0,20 logrank : p = 0,021 0,

12 Therapiekonzepte Intensivierte Therapie Verbesserte Selektion

13 Phase III Comparison of Preoperative Chemotherapy Compared with Chemoradiotherapy in Patients with Locally Advanced Adenocarcinoma of the Esophagogastric Junction T3,T4 NXM0 Esophageal + Junction N = 126 RANDOM Primärer Endpunkt: OS Chemotherapy: PLF x 2 Resektion Primary endpoint: Survival Radiochemotherapie: PLF x 2 CE+30 Gy Resektion *PLF: Cisplatin 50 mg/m2 d1 biweekly, LV 500mg/m2/d, 5-FU 2g/m2/d, weekly; 6wk cycle *CE: Cisplatin 50 mg/m2 d1+8; Etoposide 80 mg/m2 d3+5 Stahl M. et al. J Clin Oncol 2009

14 Neoadjuvante RCTX: Overall Survival 3-year-survival: 27.7% ( %) vs 47.4% ( %; p=0.07) *Studie vorzeitig beendet; *Letalität RCTX>CTX; p NS Stahl M. et al. J Clin Oncol 2009

15 Therapiekonzepte Intensivierte Therapie Verbesserte Selektion

16 Response-Prediction Weber et al. J Clin Oncol, 2001; 19:

17 MUNICON I Non- Responder Resection AEG type I-II ut3/n+ CTx PET d14 n = 111 PET d0 Responder CTx: 3 months Resection Response definition: Decrease of the SUVmean PETd14 / PETbaseline > 35% Weber et al. J Clin Oncol 2001;19: Ott et al. J Clin Oncol 2006;24: Lordick et al. Lancet Oncol 2007 Sep; 8:

18 MUNICON I PET-Responder Median survival [95% CI] in months: Metabolic Responder: Not reached PET-Non-Responder Metabolic Non-Responder: 25.8 [19.4; 32.3] Hazard ratio 2.13 [ ] Log-rank p-value: p=0.015 Median follow-up: 28.0 months Lordick et al. Lancet Oncol 2007 Sep; 8:

19 MUNICON II Municon II Non-Responder RCTx CF + 32 Gy Resect PET d 14 Responder CTx: 3 Months Resect

20 Therapiekonzepte Neoadjuvant Adjuvant Palliativ Second line

21 SWOG 9008 / INT FU/LV 5-FU/LV 5-FU/LV Radiatio 45 Gy 5-FU/LV x 2 R0 res. Adeno-Ca des Magens n= 556 RANDOM Surgery alone Mac Donald JS et al. N Engl J Med 2001;345:725-30

22 Radiochemotherapie-Survival 100% 80% 5-FU+leucovorin+RT Observation N Events P =.0051 Median OS % 40% 20% 0% months Mac Donald JS et al. ASCO 2009

23 Radiochemotherapie-Survival 100% 80% Aber: D0- Resektion 54% D1- Resektion 36% D2- Resektion 10% 5-FU+leucovorin+RT Observation N Events P =.0051 Median OS % 40% 20% 0% months Mac Donald JS et al. ASCO 2009

24 Subgruppenanalyse Mac Donald JS et al. ASCO 2009

25 S1-Studie St. II + III D2 Resektion N = RANDOM Chemotherapy: S1 80 mg/qm d1-28 Wdh d 43 Primary endpoint: survival Surgery alone Sakuramoto et al. N Engl J Med 2007;357:

26 Orales Fluoropyrimidin S1- Rezidiv freies Überleben HR = 0.62 (95% CI; ) p<0.001 Sakuramoto et al. N Engl J Med 2007;357:

27 Orales Fluoropyrimidin S1-Survival 3-y-OS 80% 70% Sakuramoto et al. N Engl J Med 2007;357:

28 Adjuvante Therapie beim AEG/Magenkarzinom Metanalysen Studien (n) Hermans 1993 Patienten (n) odds ratio (CI) Ergebnis ( ) Kein Benefit Earle ( ) Benefit gering Mari ( ) Benefit gering Janunger ( ) Benefit unklar

29 Therapiekonzepte Neoadjuvant Adjuvant Palliativ Second line

30 Metastasiertes Magenkarzinom Gibt es eine Standardchemotherapie für metastasierte Stadien?

31 Metastasiertes Magen-Ca, welche Therapie? EOX or EOF ECX or EOX XP Gastro Tax FLO FUFIRI DCF ECF Pts %RR 44% 45% 41% 47% 34% 32% 37% 45% TTP, mos OS, mos

32 TAX325-Studie DCF vs CF Docetaxel 75 mg/qm d1 Cisplatin 75 mg/qm d1 5-FU 750 mg/qm d1-5 N = 445 RANDOM Primärer Endpunkt: Zeit bis zur Progression Cisplatin 100 mg/qm d1 5-FU 1000 mg/qm d1-5 Van Cutsem et al JCO2006; 24:4991-7

33 TAX325-Studie DCF vs CF Responserate 37 vs 25 % p=0,01 Zeit bis zur Progression 5,6 vs 3,7 Mo p<0,01 Gesamtüberleben Medianes Überleben 9,2 vs 8,6 Mo p=0,02 2 Jahres Überleben 18 vs 9% Van Cutsem et al JCO2006; 24:4991-7

34 Toga Studie: Studiendesign Phase III, randomized, open-label, international, multicenter study 3807 patients screened HER2-positive (22.1%) Stratification factors HER2-positive advanced GC (n=584) advanced vs metastatic GC vs GEJ measurable vs non-measurable ECOG PS 0-1 vs 2 capecitabine vs 5-FU R 5-FU or capecitabine a + cisplatin (n=290) 5-FU or capecitabine a + cisplatin + trastuzumab (n=294) a Chosen at investigator s discretion GEJ, gastroesophageal junction 1 Bang et al; Abstract 4556, ASCO 2009

35 Tumoransprechen, Nebenwirkungen Patients (%) 60 Intent to treat p= p= F+C + trastuzumab F+C % % 30 p= % 34.5% % 5.4% 0 CR PR ORR ORR= CR + PR CR, complete response; PR, partial response Keine signifikante Zunahme der hämatologischen, nichthämatologischen incl kardialen AEs Van Cutsem, ASCO 2009; Abstract 4509

36 Progressionsfreies Überleben Event FC + T FC Events Median PFS HR % CI 0.59, 0.85 Time (months) p value No. at risk Van Cutsem, ASCO 2009; Abstract 4509

37 Overall Survival Event FC + T FC Events Median OS HR % CI 0.60, 0.91 p value Time (months) No. at risk T, trastuzumab Van Cutsem, ASCO 2009; Abstract 4509

38 OS in Abhängigkeit des HER2 Status Subgroup N Median OS (months) Hazard ratio 95% CI All vs , 0.91 Pre-planned analysis IHC0/FISH+ IHC1+/FISH+ IHC2+/FISH+ IHC3+/FISH+ IHC3+/FISH vs vs vs vs vs , , , , , 3.38 Exploratory analysis IHC0 or 1+/FISH vs , 1.62 IHC2+/FISH+ or IHC vs , Favors T Risk ratio Favors no T Van Cutsem, ASCO 2009; Abstract 4509

39 OS bei ICH 2+/FISH+ oder IHC3+ (exploratory analysis) Event FC + T FC Events Median OS HR % CI 0.51, Time (months) No. at risk Van Cutsem, ASCO 2009; Abstract 4509

40 Therapiekonzepte Neoadjuvant Adjuvant Palliativ Second line

41 Magenkarzinom: 2nd Line Autor Phase Pat. Therapie RR TTP OS Rosati, Ann Oncol 2007 Kodera, Anticancer Res 2007 Barone, Gastric Cancer 2007 Ueda, Gastric Cancer 2007 Kim, Br J Cancer 2005 II 28 Doc 60mg, Cap 2000 II 44 Paclitaxel 80 mg II 38 Doc 75 mg, Ox 80 mg II 28 Iri 70 mg, Cisplatin 80 II 57 Iri 150 mg, 5FU/LV 29% 4 Mo 6 Mo 47% 2,6 Mo 7,8 Mo 47% 4 Mo 8,1 Mo 28% 3,5 Mo 9,4 Mo 21% 2,5 Mo 7,6 Mo

42 Multicenter Phase II Study of Everolimus in Patients with previously treated metastatic gastric cancer Studiendesign - zweistufiges Design (21: Disease Control in 8 -> Ergänzung mit 27 Patienten) - vorbehandelt mit 5FU/Cis/Iri/Taxan - Therapie: RAD mg/day po Primärer Endpunkt Disease Control Rate Sekundäre Endpunkte Chemorefraktäres, metastasiertes Magenkarzinom RAD 001 bis zur Progression oder Unverträglichkeit Progressionsfreies Überleben Gesamtüberlebensrate Sicherheit und Verträglichkeit von RAD 001 Yamada Y, ASCO GI 2009

43 Multicenter Phase II Study of Everolimus in Patients with previously treated metastatic gastric cancer PPS (n=50) FAS (n=53) CR 0 0 PR 0 0 SD 56% 55% PD 44% 42% DCR 56% 55% Median PFS: 83 d; 9 Month OS: 71.6% *PPS: per protocol set *FAS: full analysis set Yamada Y, ASCO GI 2009

44 Therapie des Magenkarzinoms FAZIT Perioperative Therapie ist Standard beim lokal fortgeschrittenem Magenkarzinom Lk Metastasierung und Chirurg wesentliche prognostische Faktoren Erfolg der adjuvanten Therapie abhängig vom Ausmaß der OP (?) 5FU=Cap, Cis=Ox, -> Standards in der palliativen Therapie Targeted Therapy HER2 Testung -> Kombination mit Herceptin Second line Therapie: Innovative Konzepte in Entwicklung

45 Danke für Ihre Aufmerksamkeit

46 S1 an oral fluoropyrimidine widely used for AGC in Japan. an oral formulation of Tegafur, CDHP (Gimeracil), and Oxo (Oteracil) at a molar ratio 1:0.4:1. observed high RR and MST of % and days in two independent phase II trials 1,2 Tegafur Anti-tumor activity F- -Ala Neuro Toxicity CDHP DPD inhibit 5-FU Oxo OPRT inhibit GI toxicity Myelo toxicity 1: Y Sakata et al. Eur J Cancer 1998; 34: : W Koizumi et al. Oncology 2000; 58: 191-7

47 Metastasiertes Magenkarzinom