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Esquemas optimos de quimioterapia para
la resecabilidad de la enfermedad
potencialmente resecable
Dra E. González- Flores
HMQ “Virgen de las Nieves”
Granada
Adam R et al. Gastrointest Cancer Res. 2009
Nueva definición de resecabilidad:
• Todas las metástasis de hígado que se pueden extirpar completamente, dejando al menos 30% de hígado remanente ...
• Incluso en casos con enfermedad extrahepática si es
resecable… Más “práctico” que “dogmático”
Resecable 20% a 25%
Beneficio en SG 30% a 50% a 5 años 15% a 10 años
Resecable 10% a 20%
conversión
Tamaño
Localización
Número
Metástasis hepáticas de CCR
No resecable 75% a 80%
Chu, et al. Clin Colorectal Can 2006; Kemeny, et al. NEJM 1999; Kemeny, et al. Oncologist 2007; Leichman. Surg Oncol Clin N Am 2007; Leonard GD, et al. J Clin Oncol. 2005;23:2038-2048.
Metástasis hepáticas 250.000 CRC casos/año (Europa) 30% metástasis sincrónicas ~50% desarrollaran metastasis 30–35% Sólo serán hepáticas
Selección de la estrategia óptima
IRRESECABLES POTENCIALMENTE
RESECABLES
RESECABLES
ALTO RIESGO BAJO RIESGO
QT paliativa QT de conversión QT neoadyuvante
seguida de cirugía Cirugía de entrada
+ Correlación tasa de resección de metástasis y tasa de respuesta
Response rate
,9,8,7,6,5,4,3
Res
ectio
n ra
te ,6
,5
,4
,3
,2
,1
0,0
Studies including all patients with mCRC (solid line) (r=0.74, p=0.001)
Studies including selected patients (liver metastases only, no extrahepatic disease) (r=0.96, p=0.002)
Phase III studies in mCRC (dashed line) (r=0.67, p=0.024)
Folprecht G, et al. Ann Oncol (2005).
Resection of liver metastases improves survival
Simmonds PC, et al. Br J Cancer. 2006;94:982–99. R0, resection with microscopically negative margins.
70
60
50
40
30
20
10
0
R0 resected (16 studies)
Med
ian
5-y
ear
surv
ival
(ra
nge
), %
Resected, R0/R1 unclear (19 studies)
Non-radical resection (11 studies)
Not resected (6 studies)
30% 32%
0%
Surgical series published after 1980
7%
An oncosurgical approach offers the chance of cure to a subgroup of initially non-resectable patients
Adam R, et al. J Clin Oncol 2009;27:1829‒35.
Cure = disease-free ≥ 5 years after last hepatectomy/last resection of extrahepatic metastases.
DFS, disease-free survival; OS, overall survival.
0 2 3 4 5 8 10 Time (years)
7 9 6
Surv
ival
p
rob
abili
ty
1.0
0.6
0.8
0.4
0.2
0
33%
19%
27%
15%
OS (n = 184) DFS (n = 184)
1
10-year survival 5-year survival
• Cure was achieved in 16% of CRC patients with liver metastases who
became eligible for surgery after response to conversion chemotherapy
Aumento en la tasa de respuestas
Aumento de las resecciones hepáticas
Aumento de la
supervivencia
Qumioterapia ±
Fármacos dirigidos
¿Elección de tratamiento?
• PEDRO, de 64 años
• HTA, DM
• DX ABRIL 2011: adenocarcinoma de sigma a 20 cm
• CEA 1.100, CA 19.9 733
• RAS NATIVO
¿EXISTE UNA QUIMIOTERAPIA DE
ELECCIÓN EN ESTE PACIENTE?
Author QT n RR Resec
Goldberg, 2004
IFL 264 31% 1%
FOLFOX 267 45% 4%
IROX 265 35% 4%
Colucci, 2004 FOLFIRI 178 31%
FOLFOX 182 34%
Tournigand, 2004 FOLFIRI 109 56% 9%
FOLFOX 111 54% 22%
FOLFOX VS FOLFIRI
CPT-11 STEATOHEPATITIS
• > Infection complications
• increased 90-day mortality after
hepatic surgery (14,7% vs 1,6%)
OXALIPLATINO
VASCULAR LESIONS
• Sinusoidal obstruction syndrome (SOS)
• Hemorrhagic centrilobular necrosis
• Nodular regenerative hiperplasia
• No increase perioperative mortality and
morbility
Vauthey. J Clin Oncol 2006, Karoui. Ann Surg 2006 Vauthey. J Clin Oncol 2006, Karoui. Ann Surg 2006
Vauthey. J Clin Oncol 2006, Karoui. Ann Surg 2006
Vauthey. JCO 2006. Karoui. Ann Surg 2006
N=244 FOLFOXIRI N=122 FOLFIRI N=122 P
TR 60% 34% <0,0001
R0 15% 6% 0,033
R0 en sólo hepát. 36% 12% 0.017
Toxicidad
Neurotoxicidad 2-3 19% 0% < 0,0001
Neutropenia 3-4 50% 28% < 0,0001
Diarrea 3-4 20% 12% n.s.
TRIPLET TREATMENT: FOLFOXIRI
CCR m con
enfermedad
metastásica
irresecable
N= 244
FOLFIRI N=122
FOLFOXIRI N= 122
Falcone et al. J Clin Oncol 2007
CCR RAS MUTADO
CCR RAS NATIVO
QT + BEVACIZUMAB
QT + ANTIEGFR
QT+ BEVACIZUMAB
SELECCIÓN DE ANTICUERPOS: ESCENARIOS
FOLFOX
FOLFIRI
XELOX
FOLFOXIRI
FOLFOX BEVACIZUMAB
FOLFOX PANITUMUMAB
FOLFOX CETUXIMAB
FOLFIRI BEVACIZUMAB
FOLFIRI PANITUMUMAB
FOLFIRI CETUXIMAB
FOLFOXIRI BEVACIZUMAB
FOLFOXIRI PANITUMUMAB
- LA MAYORÍA FASES II - FASES III NO DISEÑADOS PARA QX HEPÁTICA - POBLACIÓN HETEROGÉNEA - CRITERIOS DIFERENTES DE RESECABILIDAD
Hurwitz 2004, Saltz 2008, Masi 2010, Wong 2011, Gruenberger 2008
Study Treatment Selected patients n TR (%) R0 (%)
AVF 2107 B-IFL IFL
No 402 45 < 2
NO 16966 B-FOLFOX B-XELOX
No 700 701
38 38
6.3 4.9
First-BEAT B-CT (oxali/CPT) No 1914 - 9 (12/7)
GONO B-FOLFOXIRI No 57 77 26
BOXER
OLIViA
B- XELOX
B- FOLFOX vs B- FOLFOXIRI
non-resectable and borderline
No resecables
46
80
78
23 48
10-40
61 80
Gruenberger B-XELOX Resectable 56 73 92
BEVACIZUMAB EN METÁSTASIS HEPÁTICAS
FOLFOX
FOLFIRI
XELOX
FOLFOXIRI
FOLFOX BEVACIZUMAB
FOLFOX PANITUMUMAB
FOLFOX CETUXIMAB
FOLFIRI BEVACIZUMAB
FOLFIRI PANITUMUMAB
FOLFIRI CETUXIMAB
FOLFOXIRI BEVACIZUMAB
FOLFOXIRI PANITUMUMAB
BOXER
GONO
OLIVIA
MET RESECABLES DE ALTO RIESGO DE RECAIDA
- M. sincrónicas - > 4 metástasis - > 5 cm - Dificultad de R0 por localización o
distribución - Poco volumen hepático postQx
Pacientes irresecables
+
Bevacizumab
+ mFOLFOX6
(up to 12 cycles)
FASE II OLIVIA: first-line treatment of mCRC with bevacizumab plus doublet or triplet chemotherapy
Gruenberg et a. Annals of Oncology 2015:
Bevacizumab
+ FOLFOXIRI
(up to 12 cycles)
mCRC patients
with liver-only
metastases clearly
defined as unresectable
(n=80)
R
CRITERIOS DE IRRESECABILIDAD: - Imposibilidad de resecciones R0/R1 - <30% volumen hepático postQx - Contacto vasos
Variable (95% CI)
Bevacizumab + FOLFOXIRI
(n=41)
Bevacizumab + mFOLFOX-6
(n=39) Difference
p value
Resection rate
R0/R1/R2 61.0% (44.5–75.8%) 48.7% (32.4–65.2%) 12.3% (-11.0–35.5%) 0.271
R0/R1 51.2% (35.1–67.1%) 33.3% (19.1–50.2%) 17.9% (-5.0–40.7%) 0.106
R0 48.8% (32.9–64.9%) 23.1% (11.1–39.3%) 25.7% (3.9–47.5%) 0.017
ORR (tumour) 80.5% (65.1–91.2%) 61.5% (44.6–76.6%) 18.9% (-2.1–40.0%) 0.061
PFS 18.8 (12.4–21.0%) 12.0 (9.5–14.1) – 0.0002
Bevacizumab +
FOLFOXIRI
Bevacizumab + FOLFOXIRI
Bevacizumab + XELOX
Response (%)
GONO1
(n=57*) OLIVIA (N = 41
BOXER3
(n=45) Doi4
(n=57*)
ORR 44 (77) 33 (80,5) 35 (78) 41 (72)
CR 7 (12) ----- 4 (9) 2 (4)
PR 37 (65) ----- 31 (69) 39 (68)
Tasas de Respuesta
BEVACIZUMAB
1. Masi, et al. Lancet Oncol 2010; 2. Gruenberger, et al. JCO 2008 3. Wong, et al. Ann Oncol 2011; 4. Doi, et al. Jpn J Clin Oncol 2010 1. Masi, et al. Lancet Oncol 2010; 2. Gruenberger, et al. JCO 2008
3. Wong, et al. Ann Oncol 2011; 4. Doi, et al. Jpn J Clin Oncol 2010
1. Masi, et al. Lancet Oncol 2010; 2. Gruenberger, et al. JCO 2008 3. Wong, et al. Ann Oncol 2011; 4. Doi, et al. Jpn J Clin Oncol 2010
Estudio Rama experimental N R0 tasa de resección (%)
BOXER BVZ + XELOX 45 20
GONO BVZ + FOLFOXIRI 30 40
OLIVIA BVZ+FOLFOXIRI 41 48,8
Tasas de resección R0 de 20–49% en pacientes con solo metástasis hepáticas
Tasas de resección R0 de 20–49% en pacientes
con solo metástasis hepáticas
Tasas de Resección BEVACIZUMAB
ORR: 45,4%
Resección tras tratamiento con
FOLFIRI-aflibercept: experiencia española
o El 46.2 % de los pacientes ha recibido biológico previo.
o ORR (overall response rate): RC+RP= 45,4% Presented By Andres Muñoz at 2015 SEOM Congress
FOLFOX
FOLFIRI
XELOX
FOLFOXIRI
FOLFOX BEVACIZUMAB
FOLFOX PANITUMUMAB
FOLFOX CETUXIMAB
FOLFIRI BEVACIZUMAB
FOLFIRI PANITUMUMAB
FOLFIRI CETUXIMAB
FOLFOXIRI BEVACIZUMAB
FOLFOXIRI PANITUMUMAB
CRYSTAL
OPUS
CELIM
POCHER
NCT01564810
CETUXIMAB EN METÁSTASIS HEPÁTICAS
TRIAL CT N RR (%) R0 (%)
P-II trials LLD CRC patients
CELIM FOLFOX + C FOLFIRI + C
>5 lesions, tecnically non resectable
56 55
68 57
38 32
POCHER crono-IFLO >5cm, >4 lesions, hiliar 43 79 60
P-III trials CRC, non selected KRASwt patients
CRYSTAL FOLFIRI + C FOLFIRI
LLD-CRC 68 72
70 44
13.2 5.6
OPUS FOLFOX + C FOLFOX
LLD-CRC 25 23
76 39
16 4.3
META-ANALYSIS CT CT+anti-EGFR
LLD-CRC
242 240
43 72
11 18
Folpretch. Lancet 2010; Garufi. Br J Cancer 2010; VanCutsem. J Clin Oncol 2011, Bokemeyer, Ann Oncol 2011;
Petrelli. Int J Colorectal Dis 2012
ESTUDIO CELIM Pacientes con
CRC +
metástasis
hepáticas no
resecables
*Technically non-resectable/ > 5 liver metastases
Cetuximab
+ FOLFOX
Cetuximab
+ FOLFIRI
R Terapia: 8 ciclos
Evaluación de resecabilidad
TÉCNICAMENTE NO RESECABLES
TÉCNICAMENTE
RESECABLES
4 ciclos más de
quimioterapia Resección
Continuar QT por 6 ciclos Folprecht G, Gruenberger T. Lancet Oncol 2010; 11: 38-47.
70 pts K-RAS
NATIVO
TR 70% R0 34%
ESTUDIO POCHER
Garufi et al. Br J Cancer 2010; 103:1542-47
CCR con M1 hepáticas no resecables*
*Técnicamente no resecables >4 lesiones, >5 cm, hiliar, enfermedad extrahepática
OBJETIVO PRINCIPAL: tasa de resección
Crono-IFLO + cetuximab x 4 ciclos n:43
No Resecable Resecable
Continuar tratamiento hasta PE
Crono-IFLO + cetuximab x 4 ciclos
Resección
Completar 6 meses de tratamiento
RP o EE: evaluación de resecabilidad
80% K-RAS NATIVO
TR 79% R0 60%
N=138
QT + CETUXIMAB
TR 57%
RO 25.7%
QT
TR 29%
RO 7.4%
Ye et al. JCO 2013
FOLFOX
FOLFIRI
XELOX
FOLFOXIRI
FOLFOX CETUXIMAB
FOLFIRI CETUXIMAB
Fase II N= 30 R0 37%
FOLFOXIRI CETUXIMAB
Saridaki et al. British Journal of Cancer. 107(12):1932-7, 2012
FOLFOX
FOLFIRI
XELOX
FOLFOXIRI
FOLFOX BEVACIZUMAB
FOLFOX PANITUMUMAB
FOLFOX CETUXIMAB
FOLFIRI BEVACIZUMAB
FOLFIRI PANITUMUMAB
FOLFIRI CETUXIMAB
FOLFOXIRI BEVACIZUMAB
FOLFOXIRI PANITUMUMAB
PRIME
PLANET
TRIP
PRIME study post-hoc analysis (WT RAS and LLD)
Douillard JY, et al. Eur J Cancer 2015;51:1231−42.
†Descriptive P-value (Wald test).
Updated analysis
Panitumumab + FOLFOX4
(n = 48) FOLFOX4 (n = 41)
Median PFS, months 11.3 9.9
HR (95% CI) P-value†
0.75 (0.48–1.19) 0.2223
Median OS, months 40.7 33.4
HR (95% CI) P-value†
0.71 (0.43–1.16) 0.1737
Updated analysis Panitumumab
+ FOLFOX4 FOLFOX4
Objective response,* n (%) 38 (81) 27 (66)
% difference (95% CI) P-value†
15.0 (-3.4–33.4) 0.146
PRIME study post-hoc analysis Resection rates (WT RAS and LLD)
Douillard JY, et al. Eur J Cancer 2015;51:1231−42. *Descriptive P-value (Fisher exact test).
Patients
(%
) ∆ = 6.5%
P = 0.644*
Any resection 0
10
20
30
Panitumumab + FOLFOX4 (n = 48)
35
25
15
5
Complete resection
FOLFOX4 (n = 41) Updated analysis
33%
27%
31%
17%
∆ = 14.2%
P = 0.145*
PLANET FASE II
R
1:1
FOLFOX4 (Q2W) +
panitumumab 6 mg/kg (Q2W)
FOLFIRI (Q2W) +
panitumumab 6 mg/kg (Q2W))
Response Rate, Resectability Rate, Safety, PFS,OS
WT KRAS liver-only mCRC not suitable for initial surgery
N=80
WT = 53
• ≥4 liver metastases • at least 1 metastasis >10 cm in diameter • Liver metastases technically not resectable (vascular compromise and/or location in which complete resection is impossible and/or 25-30% of healthy liver would not remain functional after resection)
PLANET study Response rate and resectability (WT RAS population)
ORR: Objective response rate (not confirmed*); *patients resected before response confirmation
Abad et al. Presented at the 2014 European Society of Medical Oncology Meeting, September 26-30, 2014, Madrid, Spain; Abstract # 7823
PLANET study RAS analysis (interim results) OS and resectability (WT RAS)
• In the overall group, surgery was associated with longer OS
Abad A, et al. Eur J Cancer 2015;51(Suppl 3):S1‒S810:abstract 2128 (and poster). N/S, not significant.
Median, months
(95% CI)
Surgery done 51.5 (35.1–51.5)
Surgery not done 26.5 (10.8–39.0)
100
80
60
40
20
0
Months
Pro
port
ion e
vent-
free (
%)
0 1
2
2
4 3
6
4
8
HR = 0.20 (95% CI, 0.07–0.56)
Log-rank P = 0.002
OS by resection status
Fornaro L, et al. Ann Oncol 2013; 24:2062-7.
irinotecan 150 mg/m 2, oxaliplatin 85 mg/m 2 , and folinate 200 mg/m 2 on day 1, followed byfluorouracil
3000 mg/m2 as a 48-h continuous infusion starting on day 1) repeated every 2 weeks
.
FOLFOXIRI# (Q2W) +
panitumumab 6 mg/kg (Q2W)
RAS* WT / BRAF WT initially unresectable mCRC (n = 37)
Resectability of metastases: - assessed every 2 months - recommended when feasible
*RAS, KRAS, NRAS, and HRAS (codons 12, 13, and 61)
TRIP
ENFERMEDAD EXTRAHEPÁTICA 68%
Panitumumab + FOLFOXIRI
All patients
(n = 37)
Patients with LLD
(n = 12)
ORR, % 89 100
Median PFS, months 11.3 14.2
R0 resection, % 35 75
A meta analysis of resectability and outcomes with anti-EGFR mAb therapy (KRAS exon 2 WT, LLD)
Petrelli F, Barni S. Int J Colorectal Dis 2012;27:997-1004.
CT, chemotherapy; mCRC, metastatic colorectal cancer; LLD, liver
limited disease; mAb, monoclonal antibody; ORR, overall response
rate; OS, overall survival; PFS, progression-free survival.
• Comparison of first-line CT + / - cetuximab or panitumumb
– KRAS WT initially unresectable liver-limited mCRC
• Meta analysis of RCTs:
– Primary outcome: rate of R0 resection
– Secondary outcomes: PFS, OS and ORR
• Four RCTs involving 484 KRAS WT patients were included:
– PRIME, Douillard 2010
– COIN, Maughan 2011
– CRYSTAL, Van Cutsem 2011
– OPUS, Van Cutsem 2011
Impact of anti-EGFR mAb therapy on outcomes (KRAS exon 2 WT, LLD)
Petrelli F, Barni S. Int J Colorectal Dis 2012;27:997-1004.
CT, chemotherapy; mAb, monoclonal antibody;
R0, resection with microscopically negative margins.
• Meta-analysis indicates EGFR inhibitors increase R0 resection rate by 60% in mCRC patients with unresectable liver-limited disease
43
72
0
20
40
60
80
Pro
port
ion,
%
Response rate
CT alone
P = 0.001
CT+ EGFR mAb
11
18
0
5
10
15
20
Pro
port
ion,
%
R0 resection rate
CT alone
P = 0.04
CT + EGFR mAb
CCR RAS MUTADO
CCR RAS NATIVO
QT + BEVACIZUMAB
QT + ANTIEGFR
QT+ BEVACIZUMAB
SELECCIÓN DE ANTICUERPOS: ESCENARIOS
CALGB/SWOG 80405
1. Venook A, et al. ESMO 2014 (Abstract LBA10), updated information presented at meeting
Resected,
n R0-resected, n N (Events)
Median,
months (95%
CI)
Bevacizumab +
FOLFOX/FOLFIRI 75 50
132
(45)
64.7
(59.8–78.9)
Erbitux + FOLFOX/FOLFIRI 105 82
18%
13%
CALGB/SWOG 80405: Overall Survival
(KRAS wild type, NED Post-Surgery, N=132)
Arm N
(Events)
Median
(95% CI)
HR
(95% CI)
p
Chemo +
Bev
50(15) 67.4
(50.6-NA) 1.2
(0.6-2.2)
0.56
Chemo +
Cetux
82(30) 64.1
(51.1-78.9)
Presented By Alan Venook at 2014 ESMO Annual Meeting
La mediana de SG es superior a los 64 m independientemente del biológico
recibido en 1ª línea.
• Primary endpoint: PFS
Phase 3 CAIRO5 study (DCCG, ongoing) 1st-line treatment of initially unresectable,
liver-limited, WT or MT RAS mCRC
Huiskens J, et al. BMC Cancer 2015;15:365.
ClinicalTrials.gov identifier: NCT01328171 (Accessed 17-07-2015).
†Patients will not be selected for potential resectability. The (un)resectability status will
be prospectively assessed by a central panel according to predefined criteria; ‡Irinotecan 165 mg/m2, followed by oxaliplatin 85 mg/m2 and
leucovorin 400 mg/m2 over 2h, followed by 5-FU 3200 mg/m2 CIV.
CIV, continuous intravenous infusion. DCCG, Dutch Colorectal Cancer Group.
WT RAS = WT KRAS exons 2/3/4 and NRAS exons 2/3.
mCRC LLD
Unresectable†
(N ~ 640)
R RAS/BRAF
mutation
testing
WT RAS
MT RAS
Panitumumab 6 mg/kg
+ FOLFOX or FOLFIRI (Q2W)
Bevacizumab 5 mg/kg
+ FOLFOX or FOLFIRI (Q2W)
Bevacizumab 5 mg/kg
+ FOLFOX or FOLFIRI (Q2W)
Bevacizumab 5 mg/kg
+ FOLFOXIRI‡ (Q2W)
Stratification by resectability of liver metastases (potentially resectable vs permanently unresectable
Cytoreduction (shrinkage)
MOLECULAR PROFILE
ESMO Draft mCRC treatment algorithm Presented at WCGIC
CLINICAL CONDITION OF THE PATIENT
Unfit (but may be suitable) Fit Unfit
FP ± bevacizumab; reduced dose doublet;
anti-EGFR
BSC GOAL
MT BRAF MT RAS WT RAS
Triplet + bevacizumab
Combination + bevacizumab
Doublet + anti-EGFR
NED
Clearly resectable metastases
Surgery alone; surgery with
perioperative/ postoperative CT
Re-evaluation/assessment of response Q2M
GOAL
Cytoreduction (shrinkage)
Continue
Progressive disease
Disease control
Continue; maintenance;
or pause
Second-line
Surgery
Disease control (control progression)
MOLECULAR PROFILE
MT BRAF MT RAS WT RAS
Unusual, see text
CT + bevacizumab CT + biological agent
Re-evaluation/assessment of response Q2−3M
Continue; maintenance;
or pause
Progressive disease Second-line
Evolución PET_TAC
CIRUGIA R0 OS: 5 AÑOS sin recaida
• El objetivo fundamental en un paciente con M1 hepáticas potencialmente resecables es la resección R0/R1 de las mismas pues es lo que puede llevar a la curación del paciente.
• El esquema de tratamiento que más tasas de respuestas y de resecciones consigue es aquel que incluye las drogas más activas en el tratamiento del CCR metastásico asociado a terapias dirigidas
• No podemos decir que un agente biológico asociado a quimioterapia sea claramente superior a otro ni en ORR ni en tasa de resecciones R0.
• A la vista de los resultados de los estudios disponibles la combinación de quimioterapia + anti EGFR en RAS WT y FOLFOXIRI + BEVACIZUMAB representan una buena opción en esta población de pacientes consiguiendo alta tasa de respuestas, respuesta precoz y elevado porcentaje de resecciones