Therapie des Pankreaskarzinoms

Transkript

1 CAMPUS GROSSHADERN POLIKLINIK III UND COMPREHENSIVE CANCER CENTER (CCC LMU ) Therapie des Pankreaskarzinoms PD Dr. S. Böck 52. Bayerischer Internistenkongress,

2 Resektables Pankreaskarzinom (~10-15%) Standard: radikale chirurgische Resektion gefolgt von adjuvanter (Gemcitabin-) Chemotherapie unklar: - Stellenwert Strahlentherapie - in Studien: Therapieintensivierung (u. a. Therapie-Dauer > 6 Monate) neue Substanzen 2 PD Dr. med. S. Böck

3 CONKO-001: Gemcitabin vs. Observation Chemotherapie mit Gemcitabin Median: 13.4 Monate (95% CI, 11.4; 15.3) Observation Median: 6.9 Monate (95% CI, 6.1; 7.8) log rank: p<0.001 Benefit in allen Subgruppen! (T-/N-Status, R0 vs. R1) Oettle H et al, JAMA 2007; 297: PD Dr. S. Böck

4 CONKO-001: Gemcitabin vs. Observation 5-Jahres OS: 21% vs. 10% 10-Jahres OS: 12% vs. 8% Oettle H et al, JAMA 2013; 310: PD Dr. med. S. Böck

5 ESPAC-3v2: Gemcitabin vs. 5-FU/FA Gemcitabin: Median OS 23.6 Monate 5-FU/FA: Median OS 23.0 Monate höhere nicht-hämatologische Tox. (v. a. Diarrhoe und Stomatitis) mit 5-FU/FA Neoptolemos JP et al, JAMA 2010; 304: PD Dr. med. S. Böck

6 Lokal-fortgeschrittenes Pankreaskarzinom (~25%) Standard: primäre (Induktions-)Chemotherapie Optionen / Perspektiven: - primär palliative Chemotherapie - sequentielle Radiochemotherapie nach Erkrankungskontrolle - sekundäre Resektabilität? 6 PD Dr. med. S. Böck

7 Lokal-fortgeschrittenes Pankreaskarzinom GERCOR (n=181, gepoolte Analyse) Initiale Chemotherapie für 3 Monate: falls keine PD => RCT Median PFS: 7.4 vs 10.8 mo (p=0.005) Median OS: 11.7 vs 15.0 mo (p=0.0009) Huguet F et al, J Clin Oncol 2007; 25: PD Dr. med. S. Böck

8 CONKO-007 Studie PI: Prof. Fietkau (Erlangen), PD Dr. Oettle (Berlin) 8 PD Dr. med. S. Böck

9 Metastasiertes Pankreaskarzinom (~60%) Standard: palliative Chemotherapie Optionen: - Gemcitabin - Gemcitabin + Erlotinib - FOLFIRINOX - Gemcitabin + nab-paclitaxel (FDA Zulassung: ) 9 PD Dr. med. S. Böck

10 GEMCITABIN VS. 5-FU Gemcitabin 1000 mg/m 2 d1,8,15 5-FU Bolus 600 mg/m 2 wöchentl. prim. Endpunkt: Clinical benefit response (CBR) Gemcitabin CBR = 23,8% Überleben = 5,65 Mo. p = p = n = FU CBR = 4,8% Überleben = 4,41 Mo. Burris HA et al, J Clin Oncol 1997; 15: PD Dr. med. S. Böck * CBR = Veränderung von Allgemeinzustand, Körpergewicht, Schmerzen / Analgetikabedarf

11 Gemcitabin + X Gemcitabin + Paltinanaloga Cisplatin, Oxaliplatin Gemcitabin + Antimetabolite 5-FU (Bolus oder Dauerinfusion), Capecitabin, Pemetrexed, S-1 Gemcitabin + Topoisomerase-Inhibtitoren Irinotecan, Exatecan Gemcitabin + Biologicals Marimastat, Tipifarnib, Cetuximab, Bevacizumab, Axitinib, Sorafenib, Aflibercept Heinemann V, Haas M & Boeck S, Cancer Treat Rev 2012; 38: PD Dr. med. S. Böck

12 Gemcitabin + Erlotinib (PA.3) erbb-1 EGFR Erlotinib PTEN PI3-K AKT RAS SOS py K K py GRB2 py STAT RAF MEK MAPK mtor Gen - Transcription Zellcycle - Progression G2 M S G1 Proliferation Zelltod Angiogenese Metastasierung 12 PD Dr. med. S. Böck

13 Gemcitabin + Erlotinib (PA.3) Moore MJ et al, J Clin Oncol 2007; 25: PD Dr. med. S. Böck

14 Gemcitabin + Erlotinib (PA.3) Moore MJ et al, J Clin Oncol 2007; 25: PD Dr. med. S. Böck

15 FOLFIRINOX HR=0.57 : 95%CI [ ] Folfirinox: 11.1 mo Gemcitabin: 6.8 mo Stratified Log-rank test, p< ECOG 0/1 Bili < 1.5 ULN Keine sig. kardiovaskuläre Ko-Morbidität 15 PD Dr. med. S. Böck Number at risk Gemcitabine Folfirinox Conroy T et al, NEJM 2011; 364: Months Gemcitabine Folfirinox

16 FOLFIRINOX 1.00 Kaplan-Meier estimation for TUDD of Global health status/qol (MCID 10 points) Number at risk Gemcitabine Folfirinox p= Months Gemcitabine Folfirinox Gourgou-Bourgade S et al, J Clin Oncol 2013; 31: PD Dr. med. S. Böck

17 FOLFIRINOX Folfirinox Gemcitabine p AE, % per patient N=167 N=169 All Grade 3/4 All Grade 3/4 Grade 3/4 Neutropenia Febrile Neutropenia Anemia NS Thrombocytopenia % of the pts received G-CSF in the F arm vs 5.3% in the G arm. One toxic death occurred in each arm. Conroy T et al, NEJM 2011; 364: PD Dr. med. S. Böck

18 FOLFIRINOX AE, % per patient Folfirinox N=167 Gemcitabine N=169 All Grade 3/4 All Grade 3/4 p Infection without neutropenia NS Peripheral neuropathy Vomiting Fatigue Diarrhea Alopecia (grade 2) 32.5 (11.4) 3.0 (0.6) ALT Conroy T et al, NEJM 2011; 364: PD Dr. med. S. Böck

19 Gemcitabin + nab-paclitaxel Phase I/II, Gem + nab-paclitaxel, n=67: RR 48%, median OS: 12.2 Monate Von Hoff DD et al, J Clin Oncol 2011; 29: PD Dr. med. S. Böck

20 Gemcitabin + nab-paclitaxel nab-paclitaxel (Abraxane ): Cremophor-freie, Albumin-gebundene 130 nm-partikelform von Paclitaxel 20 PD Dr. med. S. Böck

21 Gemcitabin + nab-paclitaxel (MPACT) Planned N = 842 Stage IV No prior treatment for metastatic disease KPS 70 Measurable disease Total bilirubin ULN Primary Endpoint: OS Secondary Endpoints: PFS and ORR by Independent Review nab-paclitaxel 125 mg/m 2 IV qw 3/4 weeks + Gemcitabine 1000 mg/m 2 IV qw 3/4 weeks 1:1, stratified by KPS, region, liver metastasis Gemcitabine 1000 mg/m 2 IV qw for 7/8 weeks then qw 3/4 weeks With 608 events, 90% power to detect OS HR = (2 sided α = 0.049) Treat until progression CT scans every 8 weeks Von Hoff DD et al, NEJM 2013; Epub Oct PD Dr. med. S. Böck

22 Proportion of Survival 52. Bayer. Internistenkongress 2013 Gemcitabin + nab-paclitaxel nab-p + Gem Gem Events/N (%) OS, months Median (95% CI) 75 th Percentile 333/431 (77) 8.5 ( ) /430 (83) 6.7 ( ) HR = % CI ( ) P = Pts at Risk Months nab-p + Gem: Gem: PD Dr. med. S. Böck

23 Metastasiertes Pankreaskarzinom ECOG 2 wesentliche Komorbidität ECOG 0-1 keine/geringe Komorbidität ECOG 0-1 good-risk Patienten Behandlungsoption Gemcitabin/ supp. Therapie Gemcitabin + Erlotinib FOLFIRINOX Gem/nab-Pac Studie ACCEPT RASH 23 PD Dr. med. S. Böck

24 Studien vs. europäischer Alltag? Bjerregaard JK et al. Eur J Cancer 2013; 49: 98 Histologie: 77% Pat. in Studien: 3%! 24 PD Dr. med. S. Böck

25 Take Home Gemcitabin Standard in der Adjuvanz nach RO/R1 Resektion Primäre Induktionschemotherapie bei lokal-fortgeschrittenen Tumoren, Stellenwert Strahlentherapie weiter nicht ganz klar FOLFIRINOX und Gemcitabin + nab-paclitaxel als neue Optionen zur Therapie des metastasierten Pankreaskarzinoms Gemcitabin bei Pat. in reduziertem AZ/mit signifikanten Co- Morbiditäten immer noch valide Option - von Erlotinib profitieren nur Pat. die einen Rash entwickeln bisher keine (prädiktiven) Biomarker verfügbar 25 PD Dr. med. S. Böck

26 Prodige 4 - ACCORD 11/0402: FOLFIRINOX MPACT Studie (CA046): Gem + nab-paclitaxel Medianes Alter: 61 (25-75) Medianes Alter: 63 (27-88) Metastasiertes Adenokarzinom Metastasiertes Adenokarzinom ECOG 0 1 KPS 70% Bilirubin 1.5 x ULN [Stent: 16%] Bilirubin ULN [Stent: 17%] RR 9% vs 32% 8% vs 29% PFS 3.3 vs 6.4 mo (HR 0.47) 3.7 vs 5.5 mo (HR 0.69) OS 6.8 vs 11.1 mo (HR 0.57) 6.7 vs 8.5 mo (HR 0.72) Conroy T et al, NEJM 2011; 364: 1817 Von Hoff DD et al, NEJM 2013; Epub Oct PD Dr. med. S. Böck

27 FOLFIRINOX 1.00 HR=0.47 : 95%CI [ ] Folfirinox: 6.4 mo. (ORR: 32%) Gemcitabine: 3.3 mo (ORR: 9%) p< PD Dr. med. S. Böck 0.00 Number at risk Gemcitabine Folfirinox Conroy T et al, NEJM 2011; 364: Months Gemcitabine Folfirinox

28 FOLFIRINOX Bolus 5-FU 400 mg/m 2 2 h Oxaliplatin Leucovorin Continuous 5-FU 85 mg/m mg/m mg/m 2 Irinotecan 2 h 180 mg/m 2 46 h 1 h 30 Modifikationen: kein 5-FU Bolus (mfolfirinox adjuvant, Phase III, NCT ) Dosisreduktion von Oxaliplatin und/oder Irinotecan 28 PD Dr. med. S. Böck

29 nab-p + Gem (n = 421) Gem (n = 402) Pt with at least 1 AE Leading to Death, % 4 4 Grade 3 Hematologic AE, % Neutropenia Leukopenia Thrombocytopenia Anemia Pts Who Received Growth Factors, % Febrile Neutropenia, % 3 1 Grade 3 Nonhematologic AE in >5% Pts, % Fatigue Peripheral Neuropathy Diarrhea Grade 3 Neuropathy Time to Onset, median days Time to Improvement by 1 Grade, median days Time to Improvement to Grade 1, median days Pts Who Resumed nab-p, % < Von Hoff DD et al, NEJM 2013; Epub Oct PD Dr. med. S. Böck

30 AIO Studien RASH N=56/150 (FPI: 07/12) 2:1 Randomisation R 2 Gemcitabin + Afatinib Gem: 1000 mg/m 2 d1, 8, 15 q 4 wks Afatinib: 40 mg/d ACCEPT N=16/117 (FPI: 04/13) 1 Gemcitabin mono Gem: 1000 mg/m 2 d1, 8, 15 q 4 wks PI: Prof. Heinemann (LMU München) 30 PD Dr. med. S. Böck

31 Randomization 1:1 52. Bayer. Internistenkongress 2013 Aktuelle Studien: HEAT (ESHO, AIO) For patients with: Complete (R0) or marginal (R1) resected pancreatic cancer Ductal adenocarcinoma Age 18 years ECOG 0 2 CA x ULN N = 336 Gemcitabine Standard Gemcitabine 1000 mg/m 2 : days 1, 8 and 15, q4w Primary Endpoint: Disease-free Survival (14 => 19 Mo.) Gemcitabine + Cisplatin + RHT Gemcitabine 1000 mg/m 2 : days 1 and 15, q4w Cisplatin 25 mg/m 2 : days 2, 3* and 16, 17*, q4w Regional Hyperthermia (RHT) 60 min, 42 C: days 2, 3* and 16, 17*, q4w * as an exception: RHT and cisplatin can be applied day 4 instead of 3 and day 18 instead of 17 Secondary Endpoints: Overall Survival, Toxicity, Quality of Life clinicaltrials.gov: NCT (PI: Prof. R. D. Issels) 31 PD Dr. med. S. Böck 10/2013: n=24 (Screening GH: n=86) Kontakt: (heat@med.uni-muenchen.de)

32 Meta-Analyse: Kombinationschemotherapie Chermotherapieregime n (Stuien) n (Pat.) HR P 95% CI Gem versus Gem + Platinanalog Gem versus Gem + Fluoropyrimidin Gem versus Gem + andere Substanz Total Heinemann V et al, BMC Cancer 2008; 8: PD Dr. med. S. Böck

33 Meta-Analyse: Kombinationschemotherapie Review: Comparison: Outcome: GEM vs. GEM+X in advanced pancreas cancer (X = cytotoxic) 01 GEM vs. GEM+X 02 Survival by Performance Status Study GEM GEM+X Hazard ratio (fixed) Weight Hazard ratio (fixed) or sub-category N N log[hazard ratio] (SE) 95% CI % 95% CI 01 Good performance status 01 Louvet (0.1380) [0.60, 1.02] 02 Heinemann (0.2401) [0.38, 0.99] 06 Riess (0.1577) [0.59, 1.10] 09 Cunnigham (0.1143) [0.65, 1.01] 10 Herrmann (0.1663) [0.50, 0.96] Subtotal (95% CI) [0.67, 0.87] Test for heterogeneity: Chi² = 1.57, df = 4 (P = 0.81), I² = 0% Test for overall effect: Z = 4.00 (P < ) 02 Poor performance status 01 Louvet (0.2855) [0.64, 1.96] 02 Heinemann (0.2536) [0.69, 1.87] 06 Riess (0.1459) [0.81, 1.43] 09 Cunnigham (0.2462) [0.47, 1.23] 10 Herrmann (0.1740) [0.88, 1.74] Subtotal (95% CI) [0.90, 1.29] Test for heterogeneity: Chi² = 2.72, df = 4 (P = 0.61), I² = 0% Test for overall effect: Z = 0.84 (P = 0.40) Total (95% CI) [0.78, 0.96] Test for heterogeneity: Chi² = 13.72, df = 9 (P = 0.13), I² = 34.4% Test for overall effect: Z = 2.70 (P = 0.007) Heinemann V et al, BMC Cancer 2008; 8: PD Dr. med. S. Böck Favours GEM+X Favours GEM