Rak trzustki Wieslaw Wiktor Jędrzejczak

Rak trzustki Wieslaw Wiktor Jędrzejczak Katedra i Klinika Hematologii, Onkologii i Chorób Wewnętrznych Warszawskiego Uniwersytetu Medycznego

Trzustka Narząd znajdujący się w środkowym nadbrzuszu pełniący funkcje zewnątrzwydzielniczą i wewnątrzwydzielniczą. Około 97% trzustki tworzą zraziki złożone z komórek nabłonkowych wydzielających sok trzustkowy zawierający enzymy trawienne. Około 3% trzustki tworzą wyspy Langerhansa złożone (w 20%) z komórek alfa wytwarzających glukagon i w 80% z komórek beta wytwarzających insulinę.

Rak trzustki Nowotwór wywodzący się z nabłonkowych komórek części zewnątrzwydzielniczej trzustki, najczęściej tzw. gruczolakorak przewodowy, najczęściej zlokalizowany w przedniej części trzustki tzw. głowie, rzadziej w trzonie lub ogonie. Około nowych 3500 chorych rocznie, w większości powyżej 65 roku życia. Występują też nowotwory części wewnątrzwydzielniczej (należą one do tzw. nowotworów neuroendokrynnych) stanowią 1-2% nowotworów trzustki i mają lepsze rokowanie.

Rak trzustki epidemiologia Spośród wspomnianych około nowych 3500 chorych rocznie tylko około 20% ma nowotwór możliwy do operacyjnego usunięcia. A to jest jedyny sposób, aby takich chorych można było wyleczyć. Prawie wszyscy pozostali umrą na ten nowotwór, chyba, że uda im się wcześniej umrzeć z innego powodu.

Pancreatic Cancer by Stage (SEER Database) Stage Classification* Localized/ resectable Localized/ unresectable % at Diagnosis 5-Yr Survival, % 9 26 28 10 Metastatic 53 2 *Unknown: 10%; 5-yr survival 4.4% Siegel R, et al. CA Cancer J Clin. 2015;65:5-29.

Guidelines for Chemotherapy for Pts With Metastatic Pancreatic Adenocarcinoma First-line Treatment Good performance status Poor performance status Category 1 NCCN Regimens FOLFIRINOX (preferred) Gem + nab-paclitaxel (preferred) Gem + erlotinib Gem monotherapy Clinical trial is the recommended first option for all pts. Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Pancreatic Adenocarcinoma. V.1.2016. 2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK, NCCN, NCCN GUIDELINES, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. Other NCCN Regimens Category 2A Gem + cape Gem + cisplatin Category 2B GTX FP + Ox Category 2B FDR gem Cape or continuous infusion 5-FU

OS (%) PFS (%) FOLFIRINOX vs Gemcitabine: OS and PFS 100 75 50 25 0 OS 0 3 6 9 12 15 1821 24 2730 33 36 39 42 Mos FOLFIRINOX Gemcitabine 100 75 50 25 PFS 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Mos FOLFIRINOX Gemcitabine Median OS: 11.1 vs 6.8 mos HR: 0.57 (95% CI: 0.45-0.73; P <.001) Median PFS: 6.4 vs 3.3 mos HR: 0.47 (95% CI: 0.37-0.59; P <.001) Conroy T, et al. N Engl J Med. 2011;364:1817-1825.

FOLFIRINOX vs Gemcitabine: Efficacy Outcome FOLFIRINOX (n = 171) Gemcitabi ne (n = 171) ORR,* % 31.6 9.4 Median PFS, mos HR (95% CI) 6.4 3.3 0.47 (0.37-0.59) P <.001 Median OS, mos 11.1 6.8 0.57 (0.45-0.73) P <.001 *RR, FOLFIRINOX vs gemcitabine: CR, 0.6% vs 0%, PR, 31.0% vs 9.4%. 1-yr survival, % 48.4 20.6 Conroy T, et al. N Engl J Med. 2011;364:1817-1825.

FOLFIRINOX vs Gemcitabine: AEs Grade 3/4 AE, % Hematologic FOLFIRINOX (n = 171) Gemcitabine (n = 171) P Value Neutropenia 45.7 21.0 <.001 Febrile neutropenia 5.4 1.2.03 Thrombocytopenia 9.1 3.6.04 Nonhematologic Fatigue 23.6 17.8 NS Vomiting 14.5 8.3 NS Diarrhea 12.7 1.8 <.001 Sensory neuropathy 9.0 0.0 <.001 Elevated ALT 7.3 20.8 <.001 Conroy T, et al. N Engl J Med. 2011;364:1817-1825.

Deterioration (Probability) FOLFIRINOX vs Gemcitabine: Quality of Life Time until definitive deterioration > 20 points, EORTC-C30 global health status/qol questionnaire 1.0 0.8 0.6 0.4 0.2 Gemcitabine FOLFIRINOX 0 0 P <.001 3 6 9 12 Mos Prolongation of QoL in pts treated with FOLFIRINOX compared with gemcitabine, despite greater toxicity Specifically, longer time to deterioration in: Global health status Physical, cognitive, and social functioning Symptoms such as fatigue, N/V, pain, and anorexia Gourgou-Bourgade S, et al. J Clin Oncol. 2013;31:23-29

MPACT: Phase III Gemcitabine ± Nab-Paclitaxel in Metastatic Pancreatic Cancer Stratified by KPS, region, liver metastasis Pts with metastatic pancreatic cancer, no previous treatment for metastatic disease, KPS 70, bilirubin ULN (N = 861) Gemcitabine 1000 mg/m 2 /wk IV + Nab-Paclitaxel 125 mg/m 2 /wk IV for 7 wks, and then on Days 1, 8, 15 Q4W (n = 431) Gemcitabine 1000 mg/m 2 /wk IV for 7 wks, and then on Days 1, 8, 15 Q4W (n = 430) Treat until PD Primary endpoint: OS Secondary endpoints: PFS, ORR, safety Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703.

OS (%) MPACT: Gemcitabine ± Nab-Paclitaxel in Metastatic Pancreatic Cancer OS 100 80 60 40 Median OS, mos Gem + Nab-P (n = 431) Gem (n = 430) HR (95% CI) 8.5 6.7 0.72 (0.62-0.83) P <.001 Gemcitabine + nab-paclitaxel Gemcitabine 20 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Mos Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703.

PFS (%) MPACT: Gemcitabine ± Nab-Paclitaxel in Metastatic Pancreatic Cancer PFS* 1.0 0.8 0.6 Median PFS, Mos Gem + Nab-P (n = 431) Gem (n = 430) HR (95% CI) 5.5 3.7 0.69 (0.58-0.82) P <.001 0.4 0.2 Gemcitabine + nab-paclitaxel Gemcitabine 0 0 3 6 9 12 15 18 21 24 Mos *Based on independent review. Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703.

MPACT: Gemcitabine ± Nab-Paclitaxel in Pancreatic Cancer OS by Subgroup OS HR for Death (95% CI) All pts Age Younger than 65 yrs 65 yrs or older Sex Female Male Karnofsky performance status 70-80 90-100 Primary tumor location Head Other Liver metastases Yes No No. of metastatic sites 1 2 3 > 3 Level of CA19-9 Normal < 59 x ULN 59 x ULN Favors Gem + Nab-Pac Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703. 0.72 (0.62-0.83) 0.65 (0.53-0.79) 0.81 (0.63-1.03) 0.72 (0.57-0.93) 0.72 (0.59-0.88) 0.61 (0.48-0.78) 0.75 (0.65-0.92) 0.59 (0.46-0.75) 0.80 (0.65-0.98) 0.69 (0.59-0.81) 0.86 (0.56-1.33) 0.41 (0.19-0.88) 0.75 (0.60-0.95) 0.79 (0.61-1.04) 0.50 (0.33-0.76) 1.07 (0.69-1.66) 0.83 (0.61-1.12) 0.61 (0.48-0.77) Favors Gem Monotherapy

OS (%) First-line FOLFIRINOX vs Gemcitabine- Based Tx: OS (Retrospective Analysis) 1.0 0.8 0.6 FOLFIRINOX Gem-based therapy Gem + nab-paclitaxel P <.0001 First-line Treatment N Median OS, Mos FOLFIRINOX 666 11 Gem only or gem + other chemotherapy* 1567 7 Gem + nab-paclitaxel 189 10 *Gem only, n = 1141. 0.4 0.2 0 0 10 20 30 40 50 Mos EMR data from US Oncology Network June 2010 to November 2013 Dosing based on standard doses in US Oncology system Cartwright T, et al. ASCO 2014. Abstract 4132.

Gem/ Nab-Pac FOLFIRINOX Gem Dose- Modified Gem/ Nab-Pac Carboplatin/ Pac Monthly Cost (US$) Metastatic Pancreatic Cancer: Cost of First-line Chemotherapy Direct costs in 2014 US$ Drug costs: Centers for Medicare and Medicaid services average sales price 14,000 12,000 10,000 AEs Administrati on Drugs Administration costs: Medicare physician fee schedule Costs for grade 3/4 AEs: 5-day hospitalization for FN Outpatient for nausea, vomiting, diarrhea Growth factor support Blood product transfusion 8000 6000 4000 2000 0 Goldstein D, et al. ASCO GI Symposium 2015. Abstract 368.

Investigational Agents for Advanced Pancreatic Cancer Class Novel cytotoxics Stromal-depleting agents Signal transduction inhibitors Examples TH-302 (evofosfamide, hypoxia-activated mustard) did not improve OS in pancreatic trial (2015) Negative PEGPH20 (recombinant hyaluronidase) Vitamin D analogues Necuparanib JAK inhibitors (ruxolitinib) Negative MM-141 (bispecific anti-igfr/her3 antibody) BTK inhibitors (ibrutinib) Notch inhibitors (eg, demcizumab, tarextumab) Negative PARP inhibitors (eg, olaparib) ClinicalTrials.gov.

Investigational Immunotherapies for Advanced Pancreatic Cancer Category Vaccines Immune checkpoint inhibitors Anti-CD40 MAbs CCR2 inhibitors Agent(s) CRS-207 (mesothelin-expressing Listeria) Negative in ECLIPSE trial combined with GVAX GVAX Algenpantucel-L ( Hyperacute vaccine) Reolysin Negative Anti PD-1 and anti PD-L1 antibodies (eg, PD-1 nivolumab, pembrolizumab; PD-L1, atezolizumab) Anti CTLA-4 antibodies (eg, tremelimumab) IDO inhibitors (eg, indoximod) Multiple agents PF-04136309 ClinicalTrials.gov.

Immunotherapy Platforms in Pancreatic Cancer GVAX Pancreas Irradiated, whole-cell tumor vaccine GVAX GM-CSF Dendritic cell CRS-207 Live-attenuated Listeria monocytogenes Potent activation of innate and antigen-specific immune response ΔactA ΔinlB Tumor antigens Tumor cell destruction Antigen uptake and activation Deletion of virulence genes (acta, inlb) Insertion of mesothelin expression cassette validated immune target T-cell Le DT, et al. J Clin Oncol. 2015;33:1325-1333. Le DT, et al. ASCO GI 2014. Abstract 177.

Phase II Study: GVAX/CRS-207 vs GVAX Alone in Metastatic Pancreatic Cancer CY/GVAX Arm A (n = 60) CRS-207 Pts with metastatic pancreatic cancer; failed or refused chemotherapy R Randomized 2:1 20-wk treatment course*: 6 doses, Q3W Arm B (n = 30) 24 mos of follow-up *Additional courses if clinically stable 24 mos of follow-up Prior phase I trial of CRS-207 showed markedly improved survival (17 months) in 3 pancreatic cancer pts who had previously undergone boost with GVAX vaccine Primary objective: OS Le DT, et al. Clin Cancer Res. 2012;18:858-868. Le DT, et al. J Clin Oncol 2015;33:1325-1333.