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