Cáncer de Páncreas: Optimización
del tratamiento sistémico
Alfredo Carrato
Hospital Universitario Ramón y Cajal, Madrid
16 de Mayo de 2015
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.
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
Treatment Algorithm Overview
Adapted from: Kanji ZS, et al. CMAJ. 2013;185(14):1219-1226.
Diagnosis and stage of pancreatic cancer confirmed
Borderline resectable Resectable Advanced
Locally advanced Metastatic Distal
pancreatectomy (tail)
Total pancreatectomy
(multifocal)
Whipple procedure (head)
Adjuvant chemotherapy (usually gemcitabine or 5-FU)
Palliative chemotherapy (gemcitabine, gemcitabine/nab-paclitaxel, or FOLFIRINOX)
± Neoadjuvant chemotherapy ± radiotherapy
Surgery ± venous resection (hepatic portal or
superior mesenteric)
5-FU, 5-fluorouracil; FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin.
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
Key Ongoing Phase III Adjuvant Trials
Trial Estimated Enrollment
Experimental Arm Comparator Arm Primary Endpoint
CONKO-0051 450 Gemcitabine + erlotinib Gemcitabine RFS
CONKO-0062 NR Gemcitabine + sorafenib Gemcitabine DFS
NEOPAC3 310 Neoadjuvant treatment with gemcitabine + oxaliplatin adjuvant treatment with gemcitabine
Adjuvant treatment with
gemcitabine PFS
PACT-154 370 Adjuvant PEXG ± neoadjuvant PEXG Gemcitabine OS
NCT010729815 722 Gemcitabine ± CRT + algenpantucel-L immunotherapy
Gemcitabine ± CRT
OS
PRODIGE 24/ ACCORD 246 490 mFOLFIRINOX Gemcitabine DFS
RTOG 0848, first rand RTOG 0848, second rand7
950
Gemcitabine + erlotinib Gemcitabine OS
Gemcitabine ± erlotinib Gemcitabine ± erlotinib + CRT
OS
APACT8 800 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.
1. 1. World Health Organization: CONKO-005. http://apps.who.int/trialsearch/trial.aspx?trialid=DRKS00000247. 2. World Health Organization: CONKO-006. http://apps.who.int/trialsearch/trial.aspx?trialid=EUCTR2007-000718-35-DE. 3. ClinicalTrials.gov: NCT01314027. 4. ClinicalTrials.gov: NCT01150630.
2. 5. ClinicalTrials.gov: NCT01072981. 6. ClinicalTrials.gov: NCT01526135. 7. ClinicalTrials.gov: NCT01013649. 8. ClinicalTrials.gov: NCT01964430.
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
Definition of Borderline Resectable Disease
SMV/portal vein Tumour abutment, encasement, or short segment of venous occlusion
SMA Tumour abutment <180 degrees
Hepatic artery 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
Involved lymph nodes outside areas of resection or presence of distant metastasis
No (Image modified from http://visualsonline.cancer.gov/)
Vauthey JN, et al. Ann Surg Oncol. 2009 Jul;16(7):1725-1726. Callery MP, et al. Ann Surg Oncol. 2009;16:1727-1733.
NCCN Clinical Practice Guidelines in Oncology, Pancreatic Adenocarcinoma, v 1, 2013.
Defined by the 2008 AHPBA/SSO/SSAT consensus guidelines Adopted by the National Comprehensive Cancer Network guidelines
AHPBA, American Hepato-Pancreato-Biliary Association; SSAT, Society for Surgery of the Alimentary Tract; SSO, Society of Surgical Oncology.
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):1219-1226.
Treatment Overview: Advanced Disease
Kanji ZS, et al. CMAJ. 2013;185(14):1219-1226.
Advanced
Locally advanced Metastatic
Palliative chemotherapy (gemcitabine, gemcitabine/nab-paclitaxel, or
FOLFIRINOX)
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;15:2403‒2413; 2. Moore MJ, et al. J Clin Oncol. 2007;25:1960‒1966; 3. Conroy T, et al. N Engl J Med. 2011;364:1817‒1825.
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.
Prodige 4 - ACCORD 11 trial design and overall survival
Conroy T, et al. N Eng J Med.
2011;364:1817-1825
Making FOLFIRINOX Tolerable
(Tempero MA):
1) omit bolus 5FU; 2)reduce doses; 3)
chemotherapy holidays
Most common grade 3 or 4 adverse events occurring in more than 5% of patients in the safety population
FOLFIRINOX vs gemcitabine: Safety
Conroy T, et al. N Engl J Med 2011; 364:1817-25.
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
MPACT Study Design and overall survival
Von Hoff DD, et al. N Engl J Med. 2013:369(18):1691-703.
Survival parameter
nab-paclitaxel + gemcitabine (n=431) Gemcitabine (n=430)
Original data cut-off
(Sep ‘12)
Updated cut-off
(May ‘13)
Original data cut-off
(Sep ‘12)
Updated cut-off
(May ‘13)
Median OS, months 8.5 8.7 6.7 6.6
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)
Date of preparation September 2014 INT-ABR140149
MPACT long-term survivors (post hoc analysis)
MPACT benefit in patient subgroups (post hoc analysis)
nab-P + Gem Gem
HR P Value Events/n
Median
OS, mo Events/n
Median
OS, mo
380/431 8.7 394/430 6.6 0.72 <0.0001
220/254 9.6 222/242 6.8 0.65 <0.0001
160/177 7.7 172/188 6.5 0.80 0.0484
157/186 9.7 156/173 7.1 0.71 0.0039
223/245 8.1 238/257 6.2 0.74 0.0016
156/179 7.6 153/161 4.3 0.59 <0.0001
220/248 9.7 240/268 7.9 0.77 0.0053
167/191 9.5 170/180 6.4 0.59 <0.0001
210/237 8.1 221/246 6.9 0.79 0.0171
331/365 8.3 331/360 5.9 0.71 <0.0001
49/66 11.1 63/70 10.2 0.73 0.1109
25/33 12.9 20/21 9.0 0.47 0.0384
184/202 8.6 185/206 6.9 0.77 0.0164
117/136 7.9 129/140 5.9 0.79 0.0688
54/60 8.7 60/63 5.0 0.51 0.0012
50/60 9.3 49/56 7.0 0.90 0.6401
108/122 8.8 109/120 7.3 0.80 0.1114
177/197 8.4 184/195 5.7 0.61 <0.0001
52/61 9.4 57/59 6.7 0.59 0.0104
63/64 7.7 60/62 5.9 0.84 0.3715
28/38 10.7 27/38 6.9 0.82 0.4705
237/268 8.8 250/271 6.6 0.69 <0.0001
Goldstein D, et al. Oral presentation at: ASCO GI 2014 (abstract 178)
Group
0.125 0.25 0.5 1.0 2.0
HR
All patients
Age < 65 years
Age ≥ 65 years Female
Male
KPS 70 - 80 KPS 90 - 100
Australia
Western Europe North America
Eastern Europe
Primary tumor location: head Primary tumor location: other
No liver metastases Liver metastases
Normal CA 19-9
CA 19-9 ULN to < 59 ULN CA 19-9 ≥59 ULN
>3 metastatic sites
1 metastatic site
3 metastatic sites
2 metastatic sites
Favours Gem Favours nab-P + Gem
Abraxane-gem vs Folfirinox
Abraxane - Gemcitabina FOLFIRINOX
Diseño Regulatorio Fase III
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 2012 3 años
Dic 2005 a oct 2009 4 años
Número de centros 151 48
Elegibilidad Sin límite de edad (10% de pacientes >75 años) KPS 100 (16%) – KPS 90-80 (77%) - KPS 70 (7%)
< 75 años ECOG 0 (37.4%) – ECOG 1 (62%) – ECOG 2 (0.6%)
• 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
Bayesian network meta-analyses
Gresham et al, BMC Cancer 2014;14:471
Chan et al, PLoS ONE 2014;9:e108749
Cartwright TH et al. J Clin Oncol 2014:32(15s):287s (Abs 4132)
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
Suggested treatment algorithm for mPC by PS
KPS 50-60% Disease control
KPS >60%
Bilirubin <5ULN
High pressure
for rapid remission
KPS 90-100%
Bilirubin <2 ULN
Poor PS
Reduced PS Good PS
Gemcitabine nab-paclitaxel + gemcitabine
nab-paclitaxel + gemcitabine
Gemcitabine ± erlotinib FOLFIRINOX
OR OR
BSC
OR
Adapted from Oettle. Cancer Treatment Reviews, 2014
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)
¡Muchas gracias!