Therapie des Pankreaskarzinoms

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

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

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: 267 3 PD Dr. S. Böck

CONKO-001: Gemcitabin vs. Observation 5-Jahres OS: 21% vs. 10% 10-Jahres OS: 12% vs. 8% Oettle H et al, JAMA 2013; 310: 1473 4 PD Dr. med. S. Böck

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: 1073 5 PD Dr. med. S. Böck

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

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: 326 7 PD Dr. med. S. Böck

CONKO-007 Studie PI: Prof. Fietkau (Erlangen), PD Dr. Oettle (Berlin) 8 PD Dr. med. S. Böck 24.11.2012

Metastasiertes Pankreaskarzinom (~60%) Standard: palliative Chemotherapie Optionen: - Gemcitabin - Gemcitabin + Erlotinib - FOLFIRINOX - Gemcitabin + nab-paclitaxel (FDA Zulassung: 06.09.13) 9 PD Dr. med. S. Böck

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 = 0.0022 p = 0.0025 n = 126 5-FU CBR = 4,8% Überleben = 4,41 Mo. Burris HA et al, J Clin Oncol 1997; 15: 2403 10 PD Dr. med. S. Böck * CBR = Veränderung von Allgemeinzustand, Körpergewicht, Schmerzen / Analgetikabedarf

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: 843 11 PD Dr. med. S. Böck

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

Gemcitabin + Erlotinib (PA.3) Moore MJ et al, J Clin Oncol 2007; 25: 1906 13 PD Dr. med. S. Böck

Gemcitabin + Erlotinib (PA.3) Moore MJ et al, J Clin Oncol 2007; 25: 1906 14 PD Dr. med. S. Böck

FOLFIRINOX 1.00 0.75 0.50 HR=0.57 : 95%CI [0.45-0.73] Folfirinox: 11.1 mo Gemcitabin: 6.8 mo Stratified Log-rank test, p<0.0001 ECOG 0/1 Bili < 1.5 ULN Keine sig. kardiovaskuläre Ko-Morbidität 15 PD Dr. med. S. Böck 0.25 0.00 Number at risk Gemcitabine Folfirinox Conroy T et al, NEJM 2011; 364: 1817 0 3 6 9 12 15 18 21 24 27 30 33 36 Months 171 134 89 48 28 14 7 6 3 3 2 2 2 171146116 81 62 34 20 13 9 5 3 2 2 Gemcitabine Folfirinox

FOLFIRINOX 1.00 Kaplan-Meier estimation for TUDD of Global health status/qol (MCID 10 points) 0.75 0.50 0.25 0.00 Number at risk Gemcitabine Folfirinox p=.001 0 3 6 9 12 15 18 Months 157 53 9 1 0 0 0 163 89 35 13 4 1 1 Gemcitabine Folfirinox Gourgou-Bourgade S et al, J Clin Oncol 2013; 31: 23 16 PD Dr. med. S. Böck

FOLFIRINOX Folfirinox Gemcitabine p AE, % per patient N=167 N=169 All Grade 3/4 All Grade 3/4 Grade 3/4 Neutropenia 79.9 45.7 54.8 18.7 0.0001 Febrile Neutropenia 7.2 2.4 0.6 0.009 Anemia 90.4 7.8 94.6 5.4 NS Thrombocytopenia 75.2 9.1 54.8 2.4 0.008... 42.5 % 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: 1817 17 PD Dr. med. S. Böck

FOLFIRINOX AE, % per patient Folfirinox N=167 Gemcitabine N=169 All Grade 3/4 All Grade 3/4 p Infection without neutropenia 6 1.2 7.1 1.8 NS Peripheral neuropathy 70.5 9 0.6 0 0.0001 Vomiting 61.4 14.5 43.2 4.7 0.002 Fatigue 87.3 23.2 78.7 14.2 0.036 Diarrhea 73.3 12.7 30.8 1.2 0.0001 Alopecia (grade 2) 32.5 (11.4) 3.0 (0.6) 0.0001 ALT 64.8 7.3 83.8 0.0022 18.6 Conroy T et al, NEJM 2011; 364: 1817 18 PD Dr. med. S. Böck

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: 4548 19 PD Dr. med. S. Böck

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

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 = 0.769 (2 sided α = 0.049) Treat until progression CT scans every 8 weeks Von Hoff DD et al, NEJM 2013; Epub Oct 16 21 PD Dr. med. S. Böck

Proportion of Survival 52. Bayer. Internistenkongress 2013 Gemcitabin + nab-paclitaxel 1.0 0.9 0.8 0.7 0.6 0.5 nab-p + Gem Gem Events/N (%) OS, months Median (95% CI) 75 th Percentile 333/431 (77) 8.5 (7.89 9.53) 14.8 359/430 (83) 6.7 (6.01 7.23) 11.4 0.4 0.3 0.2 HR = 0.72 95% CI (0.617 0.835) P = 0.000015 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Pts at Risk Months nab-p + Gem: 431 357 269 169 108 67 40 27 16 9 4 1 1 0 Gem: 430 340 220 124 69 40 26 15 7 3 1 0 0 0 22 PD Dr. med. S. Böck

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

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

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

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 16 26 PD Dr. med. S. Böck

FOLFIRINOX 1.00 HR=0.47 : 95%CI [0.37-0.59] 0.75 0.50 Folfirinox: 6.4 mo. (ORR: 32%) Gemcitabine: 3.3 mo (ORR: 9%) p<0.0001 0.25 27 PD Dr. med. S. Böck 0.00 Number at risk Gemcitabine Folfirinox Conroy T et al, NEJM 2011; 364: 1817 0 3 6 9 12 15 18 21 24 27 30 33 36 Months 171 88 26 8 5 2 0 0 0 0 0 0 0 171 121 85 42 17 7 4 1 1 0 0 0 0 Gemcitabine Folfirinox

FOLFIRINOX Bolus 5-FU 400 mg/m 2 2 h Oxaliplatin Leucovorin Continuous 5-FU 85 mg/m 2 400 mg/m 2 2.400 mg/m 2 Irinotecan 2 h 180 mg/m 2 46 h 1 h 30 Modifikationen: kein 5-FU Bolus (mfolfirinox adjuvant, Phase III, NCT01526135) Dosisreduktion von Oxaliplatin und/oder Irinotecan 28 PD Dr. med. S. Böck

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 38 31 13 13 27 16 9 12 Pts Who Received Growth Factors, % 26 15 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, % 17 17 6 140 21 29 44 7 <1 1 113 29 -- -- Von Hoff DD et al, NEJM 2013; Epub Oct 16 29 PD Dr. med. S. Böck

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

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 19-9 2.5 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 01077427 (PI: Prof. R. D. Issels) 31 PD Dr. med. S. Böck 10/2013: n=24 (Screening GH: n=86) Kontakt: www.pancreas-heat.de (heat@med.uni-muenchen.de)

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 5 1248 0.85 0.010 0.76-0.96 6 1813 0.90 0.03 0.81-0.99 4 1404 0.99 0.80 0.88-1.10 Total 15 4465 0.91 0.004 0.85-0.97 Heinemann V et al, BMC Cancer 2008; 8: 82 32 PD Dr. med. S. Böck

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 127 131-0.2460 (0.1380) 15.13 0.78 [0.60, 1.02] 02 Heinemann 40 44-0.4850 (0.2401) 5.00 0.62 [0.38, 0.99] 06 Riess 86 80-0.2150 (0.1577) 11.58 0.81 [0.59, 1.10] 09 Cunnigham 217 215-0.2130 (0.1143) 22.05 0.81 [0.65, 1.01] 10 Herrmann 84 84-0.3710 (0.1663) 10.42 0.69 [0.50, 0.96] Subtotal (95% CI) 554 554 64.18 0.76 [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 < 0.0001) 02 Poor performance status 01 Louvet 29 26 0.1120 (0.2855) 3.53 1.12 [0.64, 1.96] 02 Heinemann 42 34 0.1310 (0.2536) 4.48 1.14 [0.69, 1.87] 06 Riess 95 99 0.0730 (0.1459) 13.53 1.08 [0.81, 1.43] 09 Cunnigham 49 52-0.2740 (0.2462) 4.75 0.76 [0.47, 1.23] 10 Herrmann 73 75 0.2150 (0.1740) 9.52 1.24 [0.88, 1.74] Subtotal (95% CI) 288 286 35.82 1.08 [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) 842 840 100.00 0.87 [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: 82 33 PD Dr. med. S. Böck 0.5 0.7 1 1.5 2 Favours GEM+X Favours GEM