Cáncer de Páncreas estadio IV

Cáncer de Páncreas
estadio IV
Barcelona 19 de noviembre 2013
Dra. Antonieta Salud Salvia
Servicio de Oncología Médica
Hospital Universitari Arnau de Vilanova de LLeida
EPIDEMIOLOGIA
•
•
•
•
4ª causa de muerte por cáncer en países desarrollados
En Europa en 2000 Æ 60.139 nuevos casos, con 64.801 muertos
En USA en 2010 Æ 36.800 muertos
Incidencia en aumento
•
Etiología desconocida: obesidad, pancreatitis crónica, cirrosis hepática, alcohol,
factores genéticos , tabaco, café
•
•
•
Baja tasa de curaciones
Tasa global de supervivencia a los 5 años <5%
Enfermedad metastática tiene un pronóstico muy pobre
– Mediana Supervivencia Global sin tratamiento es 3 - 6 meses
•
No posibilidad de screening eficaz
1.
2.
3.
1.Hariharan D. HPB (Oxford). 2008;10(1):58-62.
2.Cancer Facts & Figures 2010. Atlanta, Ga: American Cancer Society; 2010.
3.Willett CG, et al. J Clin Oncol. 2005;23(20):4538-4544.
CLINICA
• Síntomas iniciales escasos Æ diagnóstico
en estadios avanzados
• Tumor de cabeza Æ el más frecuente
- Ictericia Æ afecta al coledoco intrapancreático
• Tumor de cuerpo y cola Æ diagnóstico más tardío
- Dolor epigástrico profundo
- Síndrome constitucional, pérdida de
peso y anorexia
• Diabetes de nueva apariciónÆ 10 % de pacientes
ESTADIFICACIÓN
• Estadio IA (T1N0)
• Estadio IB (T2N0)
• Estadio IIA (T3N0)
• Estadio IIB (T1,2,3N1)
• Estadio III (T4N0,1)
• Estadio IV (TNM1)
ENFERMEDAD
RESECABLE
L. AVANZADO
IRRESECABLE
quimioterapia
Meta-analyses of chemotherapy for locally advanced and metastatic
pancreatic cancer (113 randomized controlled trials, 9970 patients)
Chemotherapy versus best supportive care (BSC)
Fluorouracil (FU) vs FU combination chemotherapy
Gemcitabine vs FU
Gemcitabine vs gemcitabine combination chemotherapy
- The primary end point was overall survival (OS)
- Chemotherapy improved survival compared with BSC (HR=0.64;95% CI, 0.42-0.98)
- FU-based combination no improved OS than FU alone (HR=0.94;95% CI, 0.82-1.08)
- Insufficient survival difference in Gem vs FU (HR=0.75;95% CI, 0.42-1.31)
- Improved survival after Gem combination vs Gem alone (HR=0.91;95% CI, 0.85-0.97)
-There was a significant survival benefit for chemotherapy over BSC and
gemcitabine combinations over gemcitabine alone. This supports the use of
gemcitabine-based combination chemotherapy in the treatment of advanced
pancreatic cancer
Sultana A, et al. J Clin Oncol 2007
GEMCITABINA
Meta-analysis of randomized trials: Benefit from gemcitabine-based combination
chemotherapy (15 randomized controlled trials, 4465 patients)
- Gem is a standard treatment . Gem-based combination chemotherapy can improve efficacy?
- The primary end point Æ overall survival (OS)
- Gem + Chemotherapy (HR of 0.91 (95% CI: 0.85 - 0.97, p = 0.004) Æ significant > OS
- Platinum-based combinations (HR of 0.85 (95% CI: 0.76 - 0.96, p = 0.010)
- Fluoropyrimidine-based combinations (HR of 0.90 (95% CI: 0.81 - 0.99, p = 0.030)
- Information of performance status (PS) was performed, 5 trials, 1682 patients.
- Patients with good PS Æ OS > with combination chemotherapy (HR=0.76; 95% CI: 0.67-0.87; p< 0.0001)
- Patients with poor PS Æ combination chemotherapy is ineffective (HR=1.08; 95% CI: 0.90-1.29, p=0.40)
Significant survival benefit with Gem+platinum analogs or Gem+fluoropyrimidines
Based on a preliminary subgroup analysis (38% of all patients included in this metaanalysis), patients with a good PS appear to benefit from Gem-based cytotoxic
combinations, whereas patients with a poor PS seem to have no survival benefit from
combination chemotherapy.
Heinemann V et al. BMC Cancer 2008
OXALIPLATINO
• After relapse in the adjuvant setting
• GEMOX vs Gem: GERCOR and GISCAD trial:
- RR 26.8% vs 17.3%, PFS 5.8 vs 3.7m (p=0.04)
- OS: 9 vs 7 meses (p=0.14)
• XELOX: mOS 23w, PFS 9.9w (2ª línea)
• FOLFOX:
- mTTP 12w, OS 22w,
Disease control rate 49%
- CONKO 003 Æ 2nd line FOLFOX vs BSC:
OS 4,82m vs 2,3m
Louvet et al. J Clin Oncol 2005
Xiong HQ, et al. Cancer 2008
Pelzer U, et al.Onkologie 2009
Pelzer U, et al. Eur J Cancer 2011.
FOLFIRINOX
Oxaliplatin 85mg/m2 Irinotecan 180mg/m2
5FU bolus 400mg/m2
Ci 2400mg/m2 46h
–
–
–
–
–
Phase II/III
342 patients
ECOG 0-1
FOLFIRINOX (N=171) vs GEM 1000mg/m2 (N=171)
Median number cycles
• FOLFIRINOX 10 (1-47) vs GEM 6 (1-26)
– Disease progression before 12 cycles
• FOLFIRINOX 54.6% vs GEM 79.9%
Conroy T, et al. N Engl J Med 2011
FOLFIRINOX
Conroy T, et al. N Engl J Med 2011
FOLFIRINOX
mOS: 11.1m vs 6.8m
mPFS: 6.4m vs 3.3m
Conroy T, et al. N Engl J Med 2011
FOLFIRINOX
Conroy T, et al. N Engl J Med 2011
nab- PACLITAXEL
nab-Paclitaxel + Gemcitabine In Patients With Metastatic
Pancreatic Cancer
Study Design
Open label phase I/II study in chemotherapy-naive patients with
metastatic adenocarcinoma of the pancreas
Phase I
gemcitabine 1000 mg/m2 followed by
nab-paclitaxel 100, 125, or 150 mg/m2 IV
on days 1, 8, and 15 every 28 days
using standard 3+3 phase I dose-escalation design
Phase II
accrual continued at the MTD to ≥ 42 patients to
evaluate efficacy and safety of the combination
IV, intravenous; MTD, maximum tolerated dose.
Von Hoff D, et al. J Clin Oncol. 2011;29(34):4548-4554.
nab-Paclitaxel + Gemcitabine
in Pancreatic Cancer
• - Preclinical models
– . nab-Paclitaxel (nab-P) active as single agent
– . Synergistic activity in combination with gemcitabine
– nab-Paclitaxel improved intratumoral concentration of
gemcitabine
• - In a 67-patient phase I/II trial of nab-P + Gem
– . MTD: nab-P 125 mg/m2 + Gem 1000 mg/m2 days 1, 8,
and 15 every 28 days
– . Promising activity at MTD
• ORR: 48%
• Median PFS: 7.9 months
• Median OS: 12.2 months
Gem, gemcitabine; MTD, maximum tolerated dose; OS, overall survival.
1. Von Hoff DD, et al. J Clin Oncol. 2011;29:4548-4554. 2. Frese KK, et al. Cancer Discov. 2012;2:260-269.
Phase I/II nab- PACLITAXEL + GEM
PET-TC
SPARC expression was evaluated by IHC
by IHC
Von Hoff, et al. J Clin Oncol 2011
Personalized Treatment: SPARC as a
Biomarker
Marker
Effect
• . High SPARC mRNA expression in the stroma was
associated with a poorer prognosis than low SPARC,
historically
SPARC
• . Inverse correlation between SPARC expression in
distal stromal cells and survival
• . Stromal SPARC expression may be an important
marker of early activity of gemcitabine plus nabpaclitaxel combination regimens
PaC, advanecd pancreatic cancer;
SPARC, secreted protein acidic and rich in cysteine.
1.Infante JR, et al. J Clin Oncol. 2007;25:319-325.
2.Miyoshi K, et al. Anticancer Res. 2010;30:867-871.
3.Mantoni TS, et al. Cancer Biol Ther. 2008;7:1806-1815.
4.Von Hoff D, et al. J Clin Oncol. 2011;29:4548-4554.
nab-Paclitaxel + Gemcitabine In Patients With Metastatic
Pancreatic Cancer
Changes in Tumor Stroma in Xenograft Model
• . The stromal content of 2 gemcitabine resistant tumors in each of the treatment groups was
analyzed by IHC for collagen type1 fibers
• . nab-Paclitaxel treatment was associated with depletion of the desmoplastic stroma
accompanied by dilated blood vessels in the tumor milieu
• . These results suggest that reduction in tumor stroma and the accompanied
increase in vascularization facilitated the delivery of gemcitabine to these
tumors
IHC, immunohistochemistry.
1. Von Hoff D, et al. J Clin Oncol. 2011;29(34):4548-4554.
nab-Paclitaxel Leads to a Higher Bioavailability of Unbound Paclitaxel
vs Conventional Paclitaxel
Nanoparticle
Mean size 130 nm
Albumin-bound paclitaxel + free paclitaxel
Hydrodynamic diameter ~ 7 nm
nab-Paclitaxel’s ~ 10-fold
higher maximal plasma
concentration and ~3-fold
higher AUC of
free paclitaxel may
contribute to higher
tumor accumulation
Upon infusion,
paclitaxel exits
Cremophor®
micelles slowly
compared with
the
dissolution of
nab
paclitaxel
Gardner et al. Clin Cancer Res. 2008;14(13):4200-4205.
Desai et al. Clin Cancer Res. 2006;12:1317-1324
Sparreboom A et al. Cancer Res. 1999;59[7]:1454-1457.
nab-Paclitaxel Concentrates in Tumors in Mice
Fluorescently-labeled nab-paclitaxel
is injected
1 min after iv injection
Imaged tumor
Mouse tumour model
15 min after iv injection
Nab-paclitaxel® containing 0.3% fluorescent marker
Imaging under Hg-lamp with 500–550 nm bandpass excitation
Relative concentration
(nab-Paclitaxel/Conventional paclitaxel)
nab-Paclitaxel Demonstrates Greater Tumor Selectivity
1.5
1.0
nab®-Paclitaxel
>
Conv paclitaxel
nab®-Paclitaxel
=
Conv paclitaxel
nab®-Paclitaxel
<
Conv paclitaxel
0.5
0
nab® is a registered trademark of Celgene Corporation.
conv, conventional.
• Comparative tissue distribution (ratio) of radiolabeled drug in mice
bearing human breast tumor xenografts 1 hour after dose
1. Hawkins et al. AACR. 2003. Poster 1189.
2. Scheff . Community Oncol. 2008;5(7 suppl 8):7-13.
nab-Paclitaxel + Gemcitabine In Patients With Metastatic
Pancreatic Cancer
Changes in CA19-9
• In the 125 mg/m2 nab-paclitaxel
cohort, 92% of evaluable patients
had ≥ 20% decrease in CA19-9
levels
• In patients with ≥ 50% decrease
in CA19-9 levels
–
ORR: 62%
–
Median PFS: 8.0 months
–
Median OS: 13.6 months
• In patients with < 50% decrease
in CA19-9 levels
a
–
ORR: 33%
–
Median PFS: 3.6 months
–
Median OS: 6.5 months
In patients receiving 125 mg/m2 nab-paclitaxel + gemcitabine.
CA19-9, carbohydrate antigen 19-9; ORR, overall response rate; OS, overall
survival; PFS, progression-free survival; PR, partial response; SD, stable
disease.
1. Von Hoff D, et al. J Clin Oncol. 2011;29(34):4548-4554.
nab®-Paclitaxel + Gemcitabine In Patients With
Metastatic Pancreatic Cancer
(Phase I/II)
Conclusions
• - nab-Paclitaxel + gemcitabine was generally well tolerated in patients
with advanced pancreatic cancer
– MTD established as nab-paclitaxel 125 mg/m2 + gemcitabine 1000
mg/m2
• - nab-Paclitaxel + gemcitabine demonstrated substantial activity in
pancreatic cancer
• - Preliminary analysis suggested that SPARC positivity correlated with
increased median OS
• - Decrease in serum CA19-9 levels ≥ 50% was observed in a majority of
patients and correlated with median PFS and OS
CA19-9, carbohydrate antigen 19-9; MTD, maximum tolerated dose; OS,
overall survival; PFS, progression-free survival; SPARC, secreted protein
acidic and rich in cysteine.
Von Hoff D, et al. J Clin Oncol. 2011;29(34):4548-4554
Randomized Phase III Study of Weekly
nab-Paclitaxel Plus Gemcitabine vs
Gemcitabine Alone in Patients With
Metastatic Adenocarcinoma of the
Pancreas (MPACT)
DD Von Hoff, T Ervin, FP Arena, EG Chiorean, J Infante, M Moore,
T Seay, SA Tjulandin, W Ma, MN Saleh, M Harris, M Reni,
RK Ramanathan, J Tabernero, M Hidalgo, E Van Cutsem,
D Goldstein, X Wei, J Iglesias, MF Renschler
Von Hoff DD, et al. N Engl J Med. 2013
Phase III MPACT: Study Design
Planned N = 842
• Stage IV
• No prior treatment for
metastatic disease
• KPS ≥ 70
• Measurable disease
• Total bilirubin ≤ ULN
ƒ
ƒ
ƒ
431: nab-Paclitaxel
125 mg/m2 IV qw 3/4 weeks
+
Gemcitabine
1000 mg/m2 IV qw 3/4 weeks
1:1, stratified by KPS, region, liver metastasis
430: Gemcitabine
1000 mg/m2 IV qw for 7/8 weeks
then qw 3/4 weeks
Primary endpoint: – OS
Secondary endpoints:
– PFS and ORR by independent review (RECIST)
Safety and tolerability
– by NCI CTCAE v3.0
• With 608 events, 90% power to detect OS
HR = 0.769 (2-sided α = 0.049)
• One interim analysis for futility
• Treat until progression
• CT scans every 8 weeks
Von Hoff DD, et al. N Engl J Med. 2013
2
4
Phase III MPACT: Overall Survival
Von Hoff DD, et al. N Engl J Med. 2013
PFS by Independent Review
Von Hoff DD, et al. N Engl J Med. 2013
Phase III MPACT: Response Rate
Variable
nab-P +
Gem
n = 431
Gem
n = 430
Overall response rate
23
7
(19.1 - 27.2)
(5.0 - 10.1)
<0.001
29
8
3.3 × 10−16
(25.0 - 33.8)
(5.3 - 10.6)
48
33
(43.0 - 52.6)
(28.4 - 37.5)
Independent review %
P Value
(95% CI)
Investigator assessment
%
(95% CI)
Disease control rate
independent review %
(95% CI)
7.2 × 10−6
Von Hoff DD, et al. N Engl J Med. 2013
Phase III MPACT: safety results
nab-P + Gem
n = 421
Gem
n = 402
Patients with at least 1 AE leading to death, %
4
4
Grade ≥ 3 hematologic AEs,%
Neutropenia
Leukopenia
Thrombocytopenia
Anemia
38
31
13
13
27
16
9
12
Patients who received growth factors, %
26
15
Febrile neutropenia, %
3
1
Grade ≥ 3 nonhematologic Aes (> 5% of patients,%)
Fatigue
Peripheral neuropathy
Diarrhea
17
17
6
7
<1
1
Preferred Term
Von Hoff DD, et al. N Engl J Med. 2013
Phase III MPACT: Conclusions
ƒ Survival with nab-paclitaxel + gemcitabine is superior to
gemcitabine:
ƒ Median OS: 8.5 vs 6.7 months; HR 0.72; P = 0.000015
ƒ Long-term survival:
ƒ 1 year: 59% increase (35% vs 22%)
ƒ 2 years: doubled (9% vs 4%)
ƒ Significant improvement in PFS, ORR, and all other efficacy
endpoints
ƒ Serious life-threatening toxicity not increased; AEs
acceptable and manageable
ƒ nab-Paclitaxel + gemcitabine, a new standard for
metastatic pancreatic cancer, is superior to gemcitabine
alone and could become the backbone for new regimens
Von Hoff DD, et al. N Engl J Med. 2013
Guidelines - NCCN
Treatment Options: Overview of NCCN Guidelines
• - Metastatic: Acceptable chemotherapy combinations for
patients with good performance status
– FOLFIRINOX (Category 1)
– Gemcitabine + nab-paclitaxel (Category 1)
– Gemcitabine + erlotinib (Category 1)
– Gemcitabine + capecitabine (Category 2A)
– Gemcitabine + cisplatin (Category 2A)
– Fixed-dose rate gemcitabine + docetaxel + capecitabine (GTX regimen) (Category 2B)
– Fluropyrimidine + oxaliplatin (Category 2B)
• - Metastatic: Acceptable monotherapy options for patients
with poor performance status
– Gemcitabine at 1000 mg/m2 over 30 minutes, weekly for 3 weeks every 28 days
(Category 1)
– Capecitabine or continuous infusion 5-FU (Category 2B)
• - The NCCN strongly encourages patients with pancreatic
cancer to enroll in clinical trials
5-FU, 5-fluorouracil; FOLFIRINOX, 5-FU/LV + irinotecan + oxaliplatin; LV,
leucovorin; NCCN, National Comprehensive Cancer Network.
1.NCCN Clinical Practice Guidelines in Oncology, Pancreatic
Adenocarcinoma, v1.2013.
ESMO/WCGC recommendations for the
first-line treatment of metastatic pancreatic cancer
Recommendations:
1. FOLFIRINOX or the nab-paclitaxel + gemcitabine are reference
treatments in patients ECOG PS 0-1, <75 years old, no/limited comorbidities,
serum bilirubin <1.5 ULN) Æ 10–35% of the population
– The anticipated benefits may be greater with FOLFIRINOX although
toxicity is considered higher for FOLFIRINOX
2. Combination of gemcitabine with erlotinib, platinum derivatives or
fluoropyrimidines represent options in ECOG PS 0-1 patients, who are not
considered candidates for FOLFIRINOX or nab-paclitaxel Æ 20–30% of
the population
3. Gemcitabine monotherapy may be reserved for patients with poor
performance status, the elderly and/or significant comorbidities Æ 20–30%
of the population
Verslype et al. Ann Oncol 2013;24(Suppl 4):iv5-10
Nab-paclitaxel + Gem or FOLFIRINOX?
Summary results of MPACT study and FOLFIRINOX
Efficacy parameters
Nab-paclitaxel +
FOLFIRINOX
gemcitabine
Median overall survival
8.7 months
11.1 months
Median progression free survival
5.5 months
6.4 months
Response rate
23%
32.9%
Toxicities of MPACT study and FOLFIRINOX
Adverse events (grade ≥3)
Fatigue
Diarrhea
Neutropenia
Febrile neutropenia
Peripheral neuropathy
Thrombocytopenia
Nab-paclitaxel +
gemcitabine
FOLFIRINOX
17%
6%
38%
3%
17%
13%
24%
13%
46%
5%
9%
9%
Farmacoeconomía
FOLFIRINOX
Gemcitabina Gemcitabina Abraxane ® Oxaliplatino
PVL
50.20 €
50.20 €
PVL ‐7,5% RD 8/2010 (marcas)
240
5‐FU Leucovorin Irinotecan
5‐FU (bolo)
(infusión contínua)
165.2
6.8
245
3.67
3.67
222
mg/vial o mg/comp
1000
1000
100
100
100
500
100
100
Pauta de tratamiento (mg/m²)
1000
1000
125
85
400
180
400
2400
Superficie corporal (m²)
1.7
1.7
1.7
1.7
1.7
1.7
1.7
1.7
Dosis/dia (mg)
1700
1700
212.5
170
680
306
680
4080
Viales/dia
1.7
1.7
2
1.7
6.8
0.6
6.8
40.8
Dias tratamiento/ciclo
3
3
3
2
2
2
2
2
Numero de ciclos (PFS)
3.7
5.5
5.5
6.4
6.4
6.4
6.4
6.4
Coste tratamiento (reutilización vial)
947.27
1,408.11 €
7783.88
3594.75
592
1919.23
319
1916.62
Coste tratamiento (reutilización vial)
947 €
9191,99 €
8341,91 €
Tarceva
(erlotinib)
2045.4
Gemcitabina36
Abraxane®
Gemcitabina
PVL
PVL ‐ 7,5% RD 8/2010 (marcas)
240
50.2
Mg per vial o mg/comp
100
1000
150
1000
Pauta de tratamiento (mg/m2)
125
1000
100
1000
1.7
1.7
1.7
1.7
212.5
2.1
1700
1.7
100
1700
1.7
3
3
28
3
5.5
5.5
3.75
3.75
€
7,783.88 €
1,408.11 €
6,622.35 €
960.08 Superficie corporal (m2)
Dosis/día (mg)
Viales/día Días tratamiento/ciclo Número de ciclos Coste por tratamiento (reutilización vial)
Coste por tratamiento
(reutilización vial)
222
50.2
1892
9191,99 €
7582,43 €
COSTE DE ADMINISTRACIÓN
NAB-PACLITAXEL+GEMCITABINA vs FOLFIRINOX
Coste de administración de nab-paclitaxel/gemcitabina vs
FOLFIRINOX es un 44% inferior
FUENTE DE DATOS TABLA:
Tiempos de administración validados por un experto clínico
Costes de administración publicados en la base de datos de costes sanitarios e-salud
COSTE DE LOS FACTORES
NAB-PACLITAXEL+GEMCITABINA vs FOLFIRINOX
El coste de los factores de crecimiento es un 75% inferior con
nab-paclitaxel/gemcitabina vs folfirinox
FUENTE DE DATOS TABLA:
% de pacientes estimado a partir del ensayo Fase III (MPACT Von Hoff DD, et al. N Engl J Med. 2013) y estimación de
experto clínico para Folfirinox
Precios de los fármacos (PVL) publicados por el Ministerio de Sanidad
CON QUE GUIA NOS QUEDAMOS?
1ª Línea
•
•
•
•
Valorar ensayo clínico
FOLFIRINOX en ECOG 0 o IK 90-100
Gemcitabina+Abraxane en ECOG 1 o IK > 70
Gemcitabina en ECOG 2
2ª Línea
•
•
•
Valorar ensayo clínico
FOLFIRINOX Æ Gemcitabina+Abraxane si IK > 70
Gemcitabina+Abraxane Æ FOLFIRINOX, FOLFOX ó Xelox o capecitabina ó 5FU
IC en función del ECOG.
3ª Línea
•
•
•
Valorar ensayo clínico, Ensayo Fase I
Gemcitabina+Abraxane Æ FOLFOX, Xelox,Capecitabina, 5FU ICÆ FOLFIRI en
función del ECOG.
FOLFOXIRI Æ Gemcitabina+Abraxane Æ No línea
MOLTES GRÀCIES