Cáncer de Páncreas: Optimización del tratamiento sistémico

Transcription

1 Cáncer de Páncreas: Optimización del tratamiento sistémico Alfredo Carrato Hospital Universitario Ramón y Cajal, Madrid 16 de Mayo de 2015

2 Pancreatic cancer screening There is a latency period of about 10 years between the start of pancreatic carcinogenesis and symptomatic disease Non-invasive precursors and early disease stages can be identified by screening high-risk individuals: Several family members affected by pancreatic cancer An inherited predisposition harboring early curable diseases, such as pancreatic intraepithelial neoplasms, noninvasive intraductal papillary mucinous neoplasms and mucinous cystic neoplasms Endoscopic ultrasound is widely used as a screening test due to its ability to detect small pre-invasive lesions (~1 cm) An ideal screening test would be a highly accurate blood marker that could be measured non-invasively: ctdna, CTC, etc.

3 Exocrine Pancreatic Adenocarcinoma This is a very tough disease! Progress in pancreatic ductal adenocarcinoma has been very slow 80% of patients are diagnosed with advanced unresectable disease 80% of patients who have resection and adjuvant therapy, relapse Cure rate is only 7% Median survival of patients with metastases without treatment is only about 3 months

4 Treatment Algorithm Overview Diagnosis and stage of pancreatic cancer confirmed Resectable Borderline resectable Advanced Distal pancreatectomy (tail) Total pancreatectomy (multifocal) ± Neoadjuvant chemotherapy ± radiotherapy Locally advanced Metastatic Whipple procedure (head) Adjuvant chemotherapy (usually gemcitabine or 5-FU) Surgery ± venous resection (hepatic portal or superior mesenteric) Palliative chemotherapy (gemcitabine, gemcitabine/nab-paclitaxel, or FOLFIRINOX) 5-FU, 5-fluorouracil; FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin. Adapted from: Kanji ZS, et al. CMAJ. 2013;185(14):

5 Pancreatic Cancer Adjuvant Treatment 25% 30% of patients die early Adjuvant therapy works Gemcitabine and optimally administered 5 FU/leucovorin have similar effects The role of radiation is unclear Remember, these trials focus on highly selected patients! 25% of patients do not receive adjuvant therapy

6 Trial Key Ongoing Phase III Adjuvant Trials Estimated Enrollment Experimental Arm Comparator Arm Primary Endpoint CONKO Gemcitabine + erlotinib Gemcitabine RFS CONKO NR Gemcitabine + sorafenib Gemcitabine DFS NEOPAC Neoadjuvant treatment with gemcitabine + oxaliplatin adjuvant treatment with gemcitabine Adjuvant treatment with gemcitabine PACT Adjuvant PEXG ± neoadjuvant PEXG Gemcitabine OS NCT Gemcitabine ± CRT + algenpantucel-l immunotherapy Gemcitabine ± CRT PRODIGE 24/ ACCORD mfolfirinox Gemcitabine DFS RTOG 0848, first rand RTOG 0848, second rand Gemcitabine + erlotinib Gemcitabine OS Gemcitabine ± erlotinib Gemcitabine ± erlotinib + CRT APACT Gemcitabine + nab-paclitaxel Gemcitabine DFS mfolfirinox, modified regimen of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin; NEOPAC, Neoadjuvant Pancreatic Cancer; NR, not reported; PEXG, cisplatin, epirubicin, capecitabine, and gemcitabine; rand, randomization; RFS, relapse-free survival; Tx, treatment. PFS OS OS World Health Organization: CONKO World Health Organization: CONKO ClinicalTrials.gov: NCT ClinicalTrials.gov: NCT ClinicalTrials.gov: NCT ClinicalTrials.gov: NCT ClinicalTrials.gov: NCT ClinicalTrials.gov: NCT

7 A Pilot Study of Neoadjuvant Chemo and ChemoRT followed by Surgical Resection and Adjuvant Chemo for Borderline Resectable Pancreatic Cancer A02101 Single-arm Phase II study schema FOLFIRINOX x 2 months CAPECITABINE XRT 50.4 GY SURGERY GEMCITABINE x 2 months RESTAGING Hypothesis: The time required for pre-op therapy allows aggressive disease to declare itself and patients who will not benefit from surgery can receive alternate treatment Patients who are not resected seem to fare better if systemic therapy was given

8 Definition of Borderline Resectable Disease Defined by the 2008 AHPBA/SSO/SSAT consensus guidelines Adopted by the National Comprehensive Cancer Network guidelines (Image modified from SMV/portal vein SMA Hepatic artery Involved lymph nodes outside areas of resection or presence of distant metastasis Tumour abutment, encasement, or short segment of venous occlusion Tumour abutment <180 degrees Gastroduodenal artery encasement up to the hepatic artery with either short segment encasement, or direct abutment of the hepatic artery, without extension to the celiac axis No AHPBA, American Hepato-Pancreato-Biliary Association; SSAT, Society for Surgery of the Alimentary Tract; SSO, Society of Surgical Oncology. Vauthey JN, et al. Ann Surg Oncol Jul;16(7): Callery MP, et al. Ann Surg Oncol. 2009;16: NCCN Clinical Practice Guidelines in Oncology, Pancreatic Adenocarcinoma, v 1, 2013.

9 Treatment Overview: Borderline Resectable Disease Borderline resectable ± Neoadjuvant chemotherapy ± radiotherapy Surgery ± venous resection (hepatic portal or superior mesenteric) Adapted from: Kanji ZS, et al. CMAJ. 2013;185(14):

10 Treatment Overview: Advanced Disease Advanced Locally advanced Metastatic Palliative chemotherapy (gemcitabine, gemcitabine/nab-paclitaxel, or FOLFIRINOX) Kanji ZS, et al. CMAJ. 2013;185(14):

11 Treating advanced pancreatic cancer: the story so far Pre-1997: 5-fluorouracil monotherapy 1997: GEM monotherapy shown to improve survival, 1 becomes standard of care for advanced PC 2000s: Various GEM-based combinations fail to demonstrate clinically significant survival benefit 2007: Erlotinib/GEM shows significant survival benefit vs GEM, 2 approved in Europe 2011: FOLFIRINOX shows significantly improved survival and response rates vs GEM, 3 but is associated with greater toxicity 2013: MPACT Trial of ABX-GEM as a backbone therapy of metastatic Pancreatic Cancer 1. Burris HA, et al. J Clin Oncol. 1997;15: ; 2. Moore MJ, et al. J Clin Oncol. 2007;25: ; 3. Conroy T, et al. N Engl J Med. 2011;364: GEM, gemcitabine; FOLFIRINOX, oxaliplatin, irinotecan, fluorouracil, leucovorin; PC, pancreatic cancer The FOLFIRINOX regimen has not been approved by the EMA for treatment of pancreatic cancer.

12

13 Prodige 4 - ACCORD 11 trial design and overall survival Making FOLFIRINOX Tolerable (Tempero MA): 1) omit bolus 5FU; 2)reduce doses; 3) chemotherapy holidays Conroy T, et al. N Eng J Med. 2011;364:

14 FOLFIRINOX vs gemcitabine: Safety Most common grade 3 or 4 adverse events occurring in more than 5% of patients in the safety population No. of patients/total no. (%) Event FOLFIRINOX (n=171) Gemcitabine (n=171) p-value Hematologic Neutropenia 75/164 (45.7) 35/167 (21.0) <0.001 Febrile neutropenia 9/166 (5.4) 2/169 (1.2) 0.03 Thrombocytopenia 15/165 (9.1) 6/168 (3.6) 0.04 Anemia 13/166 (7.8) 10/168 (6.0) NS Non-hematologic Fatigue 39/165 (23.6) 30/169(17.8) NS Vomiting 24/166 (14.5) 14/169(8.3) NS Diarrhea 21/165 (12.7) 3/169(1.8) <0.001 Sensory neuropathy 15/166 (9.0) 0/169 <0.001 Elevated level of alanine aminotransferase 12/165 (7.3) 35/168 (20.8) <0.001 Thromboembolism 11/166 (6.6) 7/169(4.1) NS Conroy T, et al. N Engl J Med 2011; 364:

15 MPACT Study Design and overall survival Von Hoff DD, et al. N Engl J Med. 2013:369(18):

16 Date of preparation September 2014 INT-ABR MPACT long-term survivors (post hoc analysis) Survival parameter nab-paclitaxel + gemcitabine (n=431) Original data cut-off (Sep 12) Updated cutoff (May 13) Gemcitabine (n=430) Original data cut-off (Sep 12) Updated cut-off (May 13) Median OS, months Survival rates 6 months 67% 66% 55% 55% 12 months 35% 35% 22% 22% 24 months 9% 10% 4% 5% 36 months 4% 0 40 months 3% 0 42 months 3% 0 Goldstein D, et al. Oral presentation at: ASCO GI 2014 (abs 178)

17 MPACT benefit in patient subgroups (post hoc analysis) Group All patients Age < 65 years Age 65 years Female Male KPS KPS Primary tumor location: head Primary tumor location: other Liver metastases No liver metastases 1 metastatic site 2 metastatic sites 3 metastatic sites >3 metastatic sites Normal CA 19-9 CA 19-9 ULN to < 59 ULN CA ULN Australia Eastern Europe Western Europe North America HR nab-p + Gem Events/n Median OS, mo Events/n Gem Median OS, mo HR P Value 380/ / < / / < / / / / / / / / < / / / / < / / / / < / / / / / / / / / / / / / / / / < / / / / / / / / < Favours nab-p + Gem Favours Gem Goldstein D, et al. Oral presentation at: ASCO GI 2014 (abstract 178)

18 Abraxane-gem vs Folfirinox Diseño Abraxane - Gemcitabina Regulatorio Fase III FOLFIRINOX No regulatorio Fase II/III Promotor Celgene PRODIGE Geografía Internacional 3 continentes Francia Tamaño muestral 861 pacientes 342 pacientes Periodo de inclusión Mayo 2009 a abril años Número de centros Elegibilidad Sin límite de edad (10% de pacientes >75 años) KPS 100 (16%) KPS (77%) - KPS 70 (7%) Dic 2005 a oct años < 75 años ECOG 0 (37.4%) ECOG 1 (62%) ECOG 2 (0.6%)

19 Bayesian network meta-analyses A network meta-analysis is not justified in advanced pancreatic cancer since only 2 regimens FOLFIRINOX and nab-paclitaxel + gemcitabine have demonstrated a significant improvement in OS compared with the former standard of care, gemcitabine Differences between the MPACT and ACCORD trials limit the validity of any cross-trial comparisons for these 2 regimens Both network analyses indicate that there is no significant difference in efficacy between FOLFIRINOX and nab-paclitaxel + gemcitabine The large CIs/credible regions observed for many indirect comparisons limit any robust interpretation of these efficacy results Despite the limitations of Bayesian network meta-analyses, both groups indicate that nab-paclitaxel + gemcitabine and FOLFIRINOX are the most likely to provide the best OS benefit among available regimens, given the magnitude of benefit seen with both regimens in the Phase III trials Gresham et al, BMC Cancer 2014;14:471 Chan et al, PLoS ONE 2014;9:e108749

20 Cartwright TH et al. J Clin Oncol 2014:32(15s):287s (Abs 4132)

21 Eligibility of metastatic pancreatic adenocarcinoma (MPA) patients for first-line palliative intent nab- Paclitaxel plus gemcitabine (NG) versus FOLFIRINOX Peixoto RD, Renouf DJ, Lim HJ, Cheung WY - Department of Medical Oncology, British Columbia Cancer Agency & University of British Columbia, Vancouver, BC, Canada Conclusion In our population-based analysis, almost twice as many pts would be eligible for NG (45.2%) when compared to FOLFIRINOX (24.7%), mostly due to ECOG PS. The longer mos observed in the FOLFIRINOX-eligible population likely reflects the exclusion of ECOG PS 2 patients (8.6 months vs 6.7 months). ASCO 2014

22 Suggested treatment algorithm for mpc by PS Poor PS Reduced PS Good PS KPS 50-60% Disease control KPS >60% Bilirubin <5ULN High pressure for rapid remission KPS % Bilirubin <2 ULN Gemcitabine OR BSC nab-paclitaxel + gemcitabine OR Gemcitabine ± erlotinib nab-paclitaxel + gemcitabine OR FOLFIRINOX Adapted from Oettle. Cancer Treatment Reviews, 2014

23 Metastatic disease treatment options Several treatment options based on phase III trials are available for patients with metastatic pancreatic cancer FOLFIRINOX is an effective treatment option in fit patients Nab-paclitaxel is the only cytotoxic agent that, when combined with gemcitabine, significantly improved OS, PFS, and ORR vs. gemcitabine Gemcitabine plus platinum derivatives or fluoropyrimidines represent options in fit patients, who are not considered candidates for FOLFIRINOX or nab-paclitaxel-gemcitabine Gemcitabine monotherapy may be reserved for patients with poor performance status and the elderly Targeted therapeutic agents have been disappointing for a variety of clinical and biologic reasons, but promising new drugs are on the horizon (next talk)

24 Muchas gracias!