Cáncer páncreas 2017

Cáncer Páncreas

Epidemiología

Biología Molecular

Dr. Daniel Agüero V

Residente Oncología Médica

Septiembre 2017

Mundial

Incidencia: 8 x 100.000

Mortalidad: 7-8 x 100.000

Ocupa 8º Lugar en Frecuencia

Globocan 2012, OMS

Mundial

Hombres:

- I: 4.9 x 100.000

- M: 4.5 x 100.000

Mujeres:

- I: 3.6 x 100.000

- M: 3.5 x 100.000

Globocan 2012, OMS

© International Agency for Research on Cancer 2016

INCIDENCIA

Chile 4.8

http://globocan.iarc.fr/Pages/Map.aspx

© International Agency for Research on Cancer 2016

MORTALIDAD

Chile 5.2

Hombres

Chile 4.9 Chile 5.3

Incidencia Mortalidad

Mujeres

Incidencia Mortalidad

Chile 4.6 Chile 5.0

Hombres:

- Incidencia: 5.7 x 100.000

VALDIVIA

Primer informe de registros poblacionales de cáncer de Chile,

Quinquenio 2003-2007. Minsal Publicado 2012

Mujeres:

- Incidencia: 5.4 x 100.000

VALDIVIA



Mortalidad Valdiva



USA

Cancerstatisticscenter.cancer.org

ACS 2017

Cancerstatisticscenter.cancer.org

ACS 2017

Otros Datos:

71 a Promedio Dg

74% entre 55 y 84 años

12% < 55 años

14% > 84 años

H:M 1.3:1

Mayor en Afroamericanos.

Riesgo de Desarrollar Ca.Páncreas 1.5% (1/65)

Cáncer de páncreas

60% -

Metastásico

30% - Localmente

avanzado

10% - Temprano

Distribución por estadío

Temprano

Localmenteavanzado

Metastásico

• 15-19 meses

• 9-12 meses

• 3-6 meses

Mediana Sobrevida

Estroma:

- Fibroblastos asociados a Cáncer (predominantemente)

- Células Inmunes.

- Matriz Extracelular

Von Ahrens et al. Journal of Hematology & Oncology (2017)

Nielsen MFB et al . Tumour-stroma interaction in pancreatic cancer

Gnatenko et al, Biochemistry (Moskow) 2017

Ansari et al, SJOG, 2017

Cross Talk

Zeitouni et al, Cancers 2016

Aprox 95%

Tratamiento Cáncer de Páncreas

Dr. Daniel Agüero V

Residente Oncología Médica

Septiembre 2017

Quimiorradioter

apia adyuvante

con FU (GITSG,

1985)

Gemcitabina

mejor que FU en

enfermedad

metastásica

(Burris, et al.)

FOLFOXIRI

mejor que

Gemcitabina en

enfermedad

metastásica

(PRODIGE)

Radioterapia

adyuvante

supérflua –

(ESPAC)

Cáncer de páncreas: Evolución del tratamiento

Adyuvancia / Metastásico

1985 1997 2004 2010

Quimioterapia

adyuvante mejor

que

Observación –

(CONKO-01)

Gemcitabina

adyuvante menos

tóxica que FU –

(ESPAC 3)

Gemcitabina +

Capecitabina

adyuvante mejor

que Gemcitabina

sola– (ESPAC 4)

2017

Adyuvancia:

Trial Therapy N Med Surv 2 Yr

Surv

5 Yr

Surv

GITSG FU+RT+FU 21 20m 43% 18%

Observation 22 11m 18% 5%

EORTC 40891 FU+RT 60 17.1m 37% 20%

Observation 54 12.6m 26% 10%

CONKO 001

Estratificado por: Endpoint Primario:

– R0 vs R1 - Sobrevida Libre de Enfermedad

– T1/2 vsT3/4 Endpoint Secundario:

– N+ vs N - - Toxicidad, Calidad de vida, SG

Adenocarcinoma

Pancreas Qx

R0 o R1

(N = 368)

Gemcitabina

1000mg/m2 d1,8,15 c/28d x 6

(n = 179)

Observación

(n = 175)

Oettle et al JAMA 297:267-277, 2007

®


CONKO-001 Trial

Med DFS 13.4 m Gem

6.9 m ObsOS 3/5 yr 34/22.5% Gem

20.5/11.5% Obs

Med Sob. 13.1 m Gem

7.3 m Obs

Med Sob. 15.8 m Gem

5.5 m Obs


CONKO-001 Trial

R0 vs R1

CONKO-001

DFS

CONKO-001

OS

Gemcitabine Observation P-value

Median DFS 13.4m 6.9m HR: 0.55 CI 0.44-0.69 P= <0.001

Median OS 22.8m 20.2m HR: 0.76 CI 0.61-0.95 P= 0.01

5 year OS 20.7% 10.4%

10 year OS 12.2% 7.7%

CONKO-001 Efficacy Results

Median Follow up: 11 years

Oettle et al JAMA 2007 Oettle et al JAMA 2013

Neoptolemos et al, Lancet 2001

CRT No CRT P-value

All 175 178

Median OS 15.5m 16.1m 0.24

2 x 2 design 145 144

Median OS 15.8m 17.8m 0.09

CT No CT P-value

All 238 235

Median OS 19.7m 14m 0.005

2 x 2 design 147 142

Median OS 17.4m 15.9m 0.19


ESPAC 1 Results:

- Este estudio no mostró beneficio CRT

adyuvante, pero sí reveló beneficio potencial

quimioterapia adyuvante.

- Peor Pronóstico:

- Márgenes ( + )

- Compromiso LN


ESPAC 1 Conclusiones:

After

potentially

curative

resection

(N = 289)

Observation

(n = 69)

Chemoradiotherapy

same as GISTG 20 Gy to tumor over 2 weeks plus

5-FU 500 mg/m2 on Days 1-3 of radiotherapy x 2 cycles

(n = 73)

Chemotherapy

Leucovorin 20 mg/m2 plus 5-FU 425 mg/m2,

Days 1-5 of 28 x 6 cycles

(MAYO) (n = 75)

Combination Chemoradiotherapy

Chemoradiotherapy followed by chemotherapy,

administered as above

(n = 72)

Neoptolemos JP, et al. NEJM. 2004;350:1200-1210.

4-arm study

ESPAC 1 Trial:

Median Survival

CTR vs No CTR:

– 2-year survival: 28.5% vs 41.4%

– 5-year survival: 10% vs 20%

QMT vs No QMT :



ESPAC 1 : CRT Resultados fueron

peores!


Median Survival

No chemoradiotherapy: 17.9 months

Chemoradiotherapy: 15.9 months

HR: 1.28 (95% CI: 0.99-.66); P = .05

0

100

75

50

25

012 24 36 48 60 72

Months

Su

rviv

al, %

Chemoradiotherapy

No chemoradiotherapy

ESPAC 1 Trial:


0

100%

75%

50%

25%

0%

12 24 36 48 60 72

Chemotherapy

No chemotherapy

Months

Su

rviv

al (%

)

ESPAC 1 Trial:

Median Survival

Chemotherapy: 20.1 months

No Chemotherapy: 15.5 months

HR: 0.71 (95% CI: 0.55-0.92); P = .009


Críticas ESPAC 1 :

Sólo 128 ptes tenían detalles de los campos irradiados y de éstos 90 recibieron dosis completa.

No se irradió a 19 pctes por Progresión.

La Radiación fue subóptima.

Los médicos y los pacientes evitaban la randomización original y seleccionaban directamente los brazos.

Pacientes en los brazos de observación podrian haber recibido quimioterapia y/o radioterapia, violando el protocolo.

Conclusiones

La quimioterapia de mantenimiento incrementa la supervivencia en pacientes con cáncer de páncreas resecado

Sin embargo, la combinación de quimioterapia con radioterapia puede disminuir la supervivencia

El estándar de tratamiento en pacientes con cáncer de páncreas resecable debe incluir quimioterapia adyuvante

Neoptolemos, et al. N Engl J Med. 2004;350:1200-1210.

ESPAC 3: Gemcitabina vs FU

adyuvante

Neoptolemos JP, et al. JAMA 310(10); 1073, 2010

Pacientes con cáncer

de páncreas

resecado

(n = 1088)

Gemcitabina x6 meses*

FULV x6 meses*

*Gemcitabina: 1000 mg/m2 IV cada semana x3, se repite ciclo cada 4 semanas, por 6 ciclos.

FULV: Leucovorina 20 mg/m2/día seguido por FU (Fluoruracilo) 425 mg/m2/día en bolo x5 días, cada 4 semanas, por 6 ciclos

No diferencia en Sobrevida al analizar todos los grupos– mSobrevida: 23 meses en ambos grupos

Gemcitabina con menores eventos adversos serios (7.5% vs 14%), p=0.01

ESPAC 3:

Sin Diferencia

Toxicidad: 5FU/LV Gemcitabina P

G 3 – 4 14% 7.5% <0.001

Tromobocitopenia 0% 1.5% 0.0034

Mucositis 10% 0% <0.001

Diarrea 13% 2% <0.001

Neoptolemos JP, et al. JAMA 310(10); 1073, 2010

Gemcitabine: 23.6m

FULV: 23m

HR: 0.94 (CI:0.81-1.08)

p= 0.39

RTOG 9704: Quimiorradioterapia con

FU + (Gemcitabina vs FU adyuvante)

Pacientes con cáncer

de páncreas

T1-T4 N0-N1 MO)

(N = 442)

FU x1 mes, seguido por XRT+FU,

seguido por FU x 3meses*

Gemcitabina x1 mes,

seguido por XRT+FU, seguido por

Gemcitabina x 3 meses

*Gemcitabina: 1000 mg/m2 IV cada semana x3 (antes de RT), y por 12 semanas (después de RT)

FU (Fluoruracilo) 250 mg/m2/día en infusión continua por 3 semanas (antes de RT) y por 3 meses (después de RT)

XRT: 50.4 Gy + FU 250 mg/m2/día en infusión continua durante la radioterapia

No diferencia en Sobrevida al analizar todos los grupos– Sin embargo, los pacientes con tumores de la cabeza de páncreas mostraron

incremento de la supervivencia a favor de gemcitabina– SG: 16.9m vs 20.6 m

– Sobrevida a 3 años: 31% vs 21%

Regine et al, JAMA 2008

Tumores de Cabeza de Páncreas

N: 381 Gemcitabina 5 FU

Mediana SG 20.6 m 16.9 m

3 a SG 32% 21%

p=0.03

- Tendencia Sobrevida para Gemcitabina

- Desequilibrio en T3 – T4, Brazo Gem 81% vs FU 70%

- Cuando en Analisis se incluye Tu. Cuerpo/Cola (n: 442) no hubo

diferencia significativa (p=0.15)


RTOG 9704 Trial

%

A L

I V

E

0

25

50

75

100

YEARS FROM RANDOMIZATION

0 1 2 3 4

/ // //

////

//

/ / // / // ///// // // / / / ///// ///// / / ////// / / //

RTOG 9704 / US INTERGROUPPhase III Adjuvant Study Overall Survival – ‘Pancreatic Head’ Patients Only

134

132

77

63

46

31

24

19

187

194

Patients at Risk

RT + GEM

RT + 5FU

Total Dead MST

CRT + Gemcitabine 187 134 1.72

CRT+ 5-FU 194 156 1.41

p = 0.033

Median: 20.6 vs 16.9mos

3-Year: 32% vs 21%


Site All pacients

n=197

Pancreatic Head

N=173

All pacients

n= 184

Pancreatic Head

N=155

Local 55 (28) 49 (28) 43 (23) 35 (23)

Regional 15 (8) 14 (8) 13 (7) 13 (8)

Distancia 140 (71) 123 (71) 138 (75) 119 (77)

Chemoradiation + 5 FU Chemoradiation + Gemcitabine

Nº ( % ) of Patients With Relapses

RTOG 9704 Trial


%

AL

IVE

0

25

50

75

100

YEARS FROM RANDOMIZATION

0 1 2 3 4 5

CA19-9 < 180

Lewis Antigen Negative

CA19-9 ≥ 180

164

94

10

93

46

3

56

29

0

39

21

0

Lewis Antigen Negative p = 0.25

CA19-9 ≥ 180 p = < 0.0001

Patients at Risk

CA19-9 < 180

Lewis Antigen Neg.

CA19-9 ≥ 180

220

132

33

22

10

0

Survival Curve for all patients by CA 19-9 grouping

SUMMARY

A post-resection CA 19-9 level ≤ 180 U/ml corresponds to a 72% reduction in death in all patients treated with adjuvant chemoradiation for pancreatic cancer compared to patients with CA 19-9 > 180 U/ml.

This is independent of treatment, margin status, size of primary tumor, and nodal involvement.

Post-resection CA 19-9 was a prognostic factor in all patient groups (all, head only, non-head lesions) with HR of 3.58, 3.52, and 4.61, respectively.

The incidence of Lewis Antigen negative patients (34%) may be higher than previously thought; these patients have survival which is comparable to patients with CA 19-9 levels ≤180 U/ml.

CONCLUSIONS

Post-resection CA 19-9 is an important prognostic factor in patients undergoing adjuvant chemoradiation for pancreatic adenocarcinoma.

Patients with post-resection CA 19-9 levels >180 U/ml have a very poor survival (median=9 months).

These patients should be considered for additional/prolonged chemotherapy.

JASPAC 01:

Randomized phase III trial

Fukutomi et al. J Clin Oncol 2013

R1:1

Stratification

• Institution, residual tumour status

(R0 / R1), nodal status (N0 / N1)

Patients with resected

pancreatic cancer

• ECOG PS 0–1

• Adequate organ

function

(n=385)Gemcitabine 1000 mg/m2 iv d1, 8, 15

q4w for 6 courses

S-1 80 / 100 / 120 mg/d based on BSA,

po, d1–28, q6w for 4 courses

Primary endpoint

• OS

Secondary endpoints

• RFS, adverse events, QoL (EQ-5D)

JASPAC 01 Overall Survival

Primary Endpoint

0

50

100

0 1 2 3 4 5 years

(%) P<0.0001 for non-inferiority

P<0.0001 for superiority

70%

53%

S-1

GEM

JASPAC 01 Trial

– Una gran Proporción de pctes en el brazo Gemcitabina descontinuaron el Tratamiento (42%) más que el Grupo S-1 (28%)

– Alta incidencia de Leucopenia Grado 3 – 4 con Gemcitabina (39%) vsS-1 (9%)

– QoL (EQ-5D) scores fueron mayores en S1

Outcome

S-1

% (95% CI)

Gemcitabine

% (95% CI) HR (95% CI) p-value

OS 70 (63, 76) 53 (46, 60) 0.54 (0.35, 0.83)* <0.0001 for non-inferiority

<0.0001 for superiority

RFS 49 (42, 56) 29 (23, 35) 0.57 (0.45, 0.72) <0.0001 for superiority

Puntos Claves:

– 378 pctes (G/S: 191/187) includos en el Analisis Final


Conclusiones:

– En pacientes con Ca. Páncreas Resecado, Adyuvancia S-1 fue bientolerada y superior a Gemcitabina en SG y SLR.

– S-1 es considerada el nuevo estandard de tratamiento en Ca. Páncreas resecado en Asia.


Gemcitabine vs. Fluoropyrimidine

(FP): Phase III Adjuvant Studies

CONKO-

001

RTOG 97-04 ESPAC-3 JASPAC 01 ESPAC-4

GEM v Obs GEM v inf-FU

+ C-RT

GEM v b-FU GEM v S-1 GEM+Cap

e v GEM

mD

FS

mon

G

E

M

13.4 11.4 14.3 11.2

F

P

6.9 10.1 14.1 23.2

mO

S

mon

G

E

M

22.8 20.5 23.6 25.5 25.5

F

P

20.2 16.9 23 46.3 28

CONKO-001 RTOG 97-04 ESPAC-3 JASPAC 01

GEM v Obs GEM v inf-FU

+ C-RT

GEM v b-FU GEM v S-1

Node positive, % 72 67 72 63

R0, % 81 66 65 87

ESPAC-4:Multicenter, International, Open-Label Randomized Controlled Phase III Trial

*1000 mg/m2 d1,8,16 (6 cycles); †1660 mg/m2 21/28d.Neoptolemos et al. J Clin Oncol 2016; 34 (suppl): abstr

LBA4006

R

1:1

PD

Gemcitabine* +

Capecitabine†

(n=364)

Key patient inclusion criteria

• Pancreatic ductal ADC

• R0 or R1 resection

• No ascites, liver or

peritoneal metastases

• WHO PS ≤2

• No malignancy diagnoses

(n=730)

PRIMARY ENDPOINT(S)

• OS

SECONDARY ENDPOINTS

• Safety

PDGemcitabine* alone

(n=366)

*Stratified by resection margin status and country.CAP, capecitabine; GEM, gemcitabine. Neoptolemos et al. J Clin Oncol 2016

Gemcitabine + Capecitabine (n=366) Gemcitabine (n=364)

5-year OS, % (95% CI) 28.8 (22.9, 35.2) 16.3 (10.2, 23.7)

χ2; p-value* 4.61; 0.032

0

0

OS by treatment armO

S (

%)

GEM+CAP mOS: 28.0 months (95% CI 23.5, 31.5)

GEM mOS: 25.5 months (95% CI 22.7, 27.9)

HR 0.82 (95% CI 0.68, 0.98)

x2=4.61; p=0.032

Months

100

90

80

70

60

50

40

30

20

10

10 20 30 40 50 60

ESPAC-4:

LN, lymph nodes; N/A, not available; RM, resection margin. Neoptolemos et al. J Clin Oncol 2016; 34 (suppl): abstr LBA4006

OS by disease grade OS by disease stage

OS by lymph nodes OS by resection margin

OS

(%

)

I

II

III

IV

x2=12.71; p=0.005

Months

mOS: N/A

mOS: 39.3 (95% CI 18.1, 49.2)

mOS: 26.0 (95% CI 23.5, 28.0)

mOS: 15.7 (95% CI 4.8, N/A)

0 20 30 40 50 6010

0

10

20

30

40

50

60

70

80

90

100

OS

(%

)

Negative LN

Positive LN

Months

x2=38.66; p<0.001

mOS: 58.6 (95% CI 43.5, 64.3)

mOS: 23.3 (95% CI 22.0, 26.0)

0 20 30 40 50 6010

0

10

20

30

40

50

60

70

80

90

100

OS

(%

)

Negative RM

Positive RM

x2=17.65; p<0.001

mOS: 34.6 (95% CI 28.0, 41.0)

mOS: 23.3 (95% CI 21.9, 26.2)

Months0 20 30 40 50 6010

0

10

20

30

40

50

60

70

80

90

100

OS

(%

)

Well

Moderate

Poor

x2=38.21; p<0.001

mOS: 41.1 (95% CI 30.9, 59.8)

mOS: 30.7 (95% CI 26.2, 36.9)

mOS: 19.0 (95% CI 16.6, 22.0)

0 20 30 40 50 6010

0

10

20

30

40

50

60

70

80

90

100

Months

ESPAC-4:

CAP, capecitabine; GEM, gemcitabine; RM, resection margin.

Neoptolemos et al. J Clin Oncol 2016; 34 (suppl): abstrLBA4006

OS by treatment arm and resection margin

OS

(%

)

x2=23.44; p<0.001

Months

mOS: 23.0 (95% CI 21.6, 26.2)

mOS: 27.9 (95% CI 23.8, 34.6)

mOS: 23.7 (95% CI 20.7, 27.1)

mOS: 39.5 (95% CI 32.0, 58.0)

0 20 30 40 50 6010

0

10

20

30

40

50

60

70

80

90

100GEM, Positive RM

GEM, Negative RM

GEM-CAP, Positive RM

GEM-CAP, Negative RM

ESPAC-4:

*Exploratory analysis: Fisher's exact test.

Treatment related SAEs: 24% gemcitabine + capecitabine vs 26% gemcitabine alone

Neoptolemos et al. J Clin Oncol 2016

AEs Grade 3–4 in ≥5% of patients, n (%)

Gemcitabine + Capecitabine (n=359)

Gemcitabine

(n=366)p-value*

Diarrhoea 19 (5) 6 (2) 0.008

Fatigue 20 (6) 19 (5) 0.870

Infection/infestation 9 (3) 24 (7) 0.012

Neutrophils 137 (38) 89 (24) <0.001

Hand-foot syndrome 26 (7) 0 <0.001

WBC 37 (10) 28 (8) 0.242

ESPAC-4:

Conclusiones:

Gemcitabina + Capecitabina Adyuvante demostró un aumentosignificativo en SG vs Gemcitabina sola en paciente con Cáncer de Páncreas Resecado.

Las toxicidades fueron ligeramente más frecuentes con la combinación vs monoterapia, pero en general estas fueronmanejables

La Tasa de SG 5 años fue superior a los ESPAC previos

Quimioterapia Adyuvante con Gemcitabina + Capecitabina es el nuevo SoC en este setting.

Neoptolemos et al. J Clin Oncol 2016

Metastásico:

Burris: Gemcitabina vs FU en Cáncer

de Páncreas Metastásico

Referencia: Burris HA, et al. JCO 15; 2403, 1997

Cáncer de páncreas

avanzado,

sintomático

(n = 126)

Gemcitabina*

n=63

FULV*

n= 63

*Gemcitabina: 1000 mg/m2 IV cada semana x7, seguido por 1 semana de descanso. Seguido por Gemcitabina semanal x3, de cada 4 semanas

FULV: Folinato de calcio 20 mg/m2/día seguido por FU (Fluoruracilo) 425 mg/m2/día en bolo x5 días, cada 4 semanas, hasta progresión

Endpoint 1º: Beneficio Clínico (índice compuesto por control del dolor, Karnofsky PS y

peso). Se requiere de la mejoría de 1 parámetro por más de 1 mes, sin el deterioro de

otros.

– Tasa de Respuesta

– Sobrevida Global y al Año

Cáncer Páncreas Metastásico:

Gemcitabina como Tto de Elección:

Mediana SG:

5.65 vs 4.41 m (P = .0025)

1º año SG:

18% vs 2%

Beneficio Clínico:

23.8% vs 4.8% (P = .0022)

Tasa Respuesta :

5.4% vs 0% (P = NS)

Burris HA, et al. J Clin Oncol. 1997;15:2403-2413.

Gemcitabine

5-FU

100

80

60

40

20

00 2 4 6 8 10 12 14 16 18 20

Mos

Pts

Su

rviv

ing

(%

)

ECOG E2297: Randomized phase III trial

Berlin et al. J Clin Oncol 2002

REstratification

• PS y Enfermedad Primaria

Paciente cancer

pancreas confirmado

por histologia e

irresecable.

ECOG PS 0–2

Buen estado funcional

(n=322)

Gemcitabina 1000mg /m2 semanal +

5 FU 600mg /m2 + LV 25mg /m2

cada 3 o 4s

n= 160

Gemcitabina 1000mg /m2 semanal

cada 3 o 4s

n= 162

Primary endpoint

• SG

Endpoints Secundarios

• Tasa Respuesta, Tiempo a la Progresion

Resultados:

Gem + FU Gem + FU

Gem sola

Gem sola

3.4m vs 2.2 m

p= 0.022

6.7m vs 5.4m

p= 0.09

SG SLP

No estadisticamente significativo

Randomizados Gem + 5FU:

Autor Tratamiento TTP (m) SG (m)

Di Costanzo

(2005) (FII)

Gemzar 1000mg/m2/sem

G + 5-FU 200mg/m2/d IC

3.2

4.2

7.2

6.9

Berlin

(2002)

Gemzar 1000 mg/m2/sem

G+ 5-FU 600 mg/m2 b

2.2

3.4*

5.6

6.9

Riess

(2005)


G+ 5-FU 750mg/m2ic/sem

+ LV 200mg/m2

3.5

3.5

5.8

6.2

Randomizados Gem + Capecitabina

Autor Tratamiento TTP (m) SG (m)

Scheithauer

(2003) (FII)

Gemzar 2200mg/m2/ 2 sem

G + XEL 2500mg/m2 D1-7

4.0

5.1

8.2

9.5

Cunningham

(2005)


G+ XEL 1660 mg/m2 D1-21

-

-

6.2

7.1

Herrmann

(2005)

Gemzar 1000 mg/m2 D1-8

G+ XEL 1300mg/m2 D1-14

4.0

4.8

7.3

8.4

Sobrevida Global GEM CAP

Median survival 12-month

(months, 95%CI) survival

GEM 6.2 22%

GEM-CAP 7.1 24%

Hazard Ratio:

0.86 (95% CI: 0.72, 1.02)

Log rank p=0.08

Cunningham et al, JCO 2009

Estudios Fase III: Gem/Platinos

Estudio Tratamiento Mediana SLP, m Mediana SG, m

Gruppo Oncologia dell‘Italia Meridionale Study (N = 107)

Gemcitabine 2.0 5.0

Gem/cisplatin 5.0 (P = .048) 7.5 (P = .48)

German Multicentre Study (N = 190)

Gemcitabine 3.1 6.0

Gem/cisplatin 5.3 (P = .053) 7.5 (P = .15)

GERCOR/GISCAD Study (N = 313)

Gemcitabine 3.7 7.1

Gem/oxaliplatin 5.8 (P = .04) 9.0 (P =.13)

ECOG 6201 (N = 833)*Third arm = FDR gem

Gemcitabine N/A 4.9

Gem/oxaliplatin N/A 5.9

Viret, et al (N = 83)Gemcitabine 2.5 6.7

Gem/cisplatin 2.2 (P = NS) 8.0 (P =.73)

Analisis Combinado: gemcitabina/platinos resulta en

Aumento significativo SG (HR: 0.85; P = .01).

Ciliberto et al, European Journal of Cancer 2013

PA.3: Erlotinib Becomes First

Targeted Agent Approved for

Pancreatic Cancer Use

Center

ECOG PS (0 or 1 vs 2)

Stage of disease

(locally advanced vs

distant metastases)

(N = 569)

R

A

N

D

O

M

I

Z

E

D

Gemcitabine 1000 mg/m2 IV+

Erlotinib 100 mg/day PO(n = 285)

orErlotinib 150 mg/day PO

(n = 48)

Gemcitabine 1000 mg/m2 IV+ Placebo(n = 284)

Stratified by

EGFR status was not an eligibility requirement

PA.3 Trial: Study Schema

Moore MJ, et al. J Clin Oncol. 2007;25:1960-1966.

PA.3: Survival Results


100

80

60

40

20

00 6 12 18 24

Months

Su

rviv

al

Pro

bab

ilit

y (

%)

Placebo (n = 284)

Median: 5.91 mos

1-yr survival: 17%

Erlotinib (n = 285)

Median: 6.24 mos

1-yr survival: 23%

HR: 0.82 (95% CI: 0.69-0.99;

P = .038)

PA.3: OS relative to grade of rash

p<0.0001 HR (rash)=0.71

Grade 0

Grade 1

Grade 2

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al

pro

bab

ilit

y

0 5 10 15 20Time (months)

Grade 0

(n=79)

Grade 1

(n=108)

Grade 2

(n=103)

Median OS (months) 5.29 5.75 10.51

1-year survival (%) 16 11 43

Moore M, et al. J Clin Oncol 2007;25:1960–6; Roche, data on file

PA.3: Toxicities Associated With

Erlotinib

Toxicities, All Grades/

Grade 3 or 4, %

Gemcitabine + Erlotinib

(n = 282)

Gemcitabine + Placebo

(n = 280)

Diarrhea 56/6 41/2

Fatigue 89/15 86/15

ILD-like syndrome* 2.1 0.4

Rash 72/6 29/1

Stomatitis 23/<1 14/0


*Pneumonitis, pulmonary infiltrate

Locally advanced/metastatic

pancreatic cancer: CALGB 80303

Locally advanced

or metastatic

Pancreatic Ca

N=602

R

Gemcitabine 1000mg/m2 d1 8 15

q28d Placebo

Gemcitabine 1000mg/m2 d1 8 15

q28d Bevacizumab 10mg/kg d1

d15 q28d

Primary endpoint:

•Overall survival

Secondary endpoints:

• objective response rate, duration of

response, progression-free survival, toxicity

Kindler et al JCO 2010

Trial closed by DSMB as crossed futility boundary

Locally advanced/metastatic pancreatic

cancer CALGB 80303

Gemcitabine

Placebo

Gemcitabine

Bevacizumab

CR (%) 2 1

PR (%) 8 10

SD (%) 31 36

Disease control

rate (%)40 47

Median OS

(months)6.1 5.8 P=0.78

PFS (months) 4.7 4.9 P=0.99

1yr OS (%) 20 18

Kindler et al JCO 2010

AViTA: study design

Stratified according to country, KPS (<80% vs ≥80%), albumin level (<2.9g/dL vs ≥2.9g/dL)

PDPreviously

untreated

metastatic

pancreatic cancer

GE-B

(n=306)

GE-P

(n=301)

B = bevacizumabKPS = Karnofsky performance statusPD = progressive disease

Gemcitabine: 1,000mg/m2 on days 1, 8, 15, 22, 29, 36, 43 for first 8 weeks, days 1, 8, 15 in

subsequent 4-week cycles; Erlotinib 100mg/day; Bevacizumab 5mg/kg q2w

PD

1:1

RANDOMIZATION

Vervenne W, Van Cutsem E, et al. J Clin Oncol2008;26(Suppl.):214s (Abs. 4507)

Van Cutsem E et al, accepted J Clin Oncol 2009

AViTA objectives and inclusion/

exclusion criteria Primary endpoint:

– OS

Secondary endpoints:

– Progression-free survival (PFS), response rate, and safety (adverse events [AEs] graded by NCI-CTC v3.0)

Exploratory analysis

– OS, PFS, and disease control rate according to occurrence and grade of rash

Inclusion criteria

– histologically confirmed, metastatic pancreatic adenocarcinoma; no prior therapy for metastatic disease; >6 months since adjuvant therapy; no prior gemcitabine or anti-vascular endothelial growth factor (VEGF) therapy; KPS ≥60; adequate hematologic, hepatic, and renal function

Exclusion criteria

– invasion of major blood vessels; surgery in last 28 days; bleeding disorders; significant cardiovascular disease

OS and PFS in AViTA

1.0

0.8

0.6

0.4

0.2

0

0 3 6 9 12 15 18 21 24

OS

pro

ba

bil

ity

GE-B

(n=221 with events)

GE-P

(n=233 with events)

Time (months)

7.16.0

p=0.2087 HR=0.89

(95% CI: 0.74–1.07)

OS

p=0.0002 HR=0.73

(95% CI: 0.61–0.86)

PFS

Vervenne W, Van Cutsem E, et al. J Clin Oncol 2008;26(Suppl.):214s (Abs. 4507)

GE-B

(n=257 with events)

GE-P

(n=278 with events)

0 3 6 9 12 15 18 21 24

Time (months)

1.0

0.8

0.6

0.4

0.2

0

PF

S p

rob

ab

ilit

y

4.63.6

Incidence of AEs in both treatment

armsGE-P

(n=287)

GE-B

(n=296)

AE, %a Any grade Grade 3/4 Any grade Grade 3/4

Hematologic

Anemia

Thrombocytopenia

Neutropenia

33

26

26

9

7

17

27

30

29

7

8

21

Non-hematologic

Diarrheaa

Nausea

Rash

Vomiting

Pyrexia

Fatigue

Constipation

Anorexia

Epistaxis

Peripheral edema

Abdominal pain

Asthenia

Hypertension

51

51

44

42

37

34

23

24

11

17

15

15

9

6

3

3

4

2

7

<1

2

0

1

1

6

1

49

46

49

37

34

33

27

21

29

17

16

14

19

4

4

8

5

3

5

1

2

<1

<1

3

5

3

aOne patient in the placebo arm had a grade 5 event

Baseline characteristics by grade of

rashSkin rash

NCI-CTC grade 0 NCI-CTC grade 1 NCI-CTC grade ≥ 2

GE-P

(n=123)

GE-B

(n=91)

GE-P

(n=101)

GE-B

(n=215)

GE-P

(n=77)

GE-B

(n=105)

Gender, male/female, % 64/36 46/54 55/45 57/43 69/31 66/34

<65 years / ≥65 years, % 59/41 56/44 68/32 61/39 68/32 61/39

Smoking status

Current/Former/Never, % 30/27/42 30/25/44 18/37/45 14/37/49 10/39/51 8/38/54

Pack years, median (range) 30.0

(3–162)

30.0

(3–120)

20.0

(0–105)

25.0

(0–100)

20.0

(0–80)

20.0

(1–135)

Laboratory parameters, %

Albumin, < or ≥ 2.9g/dL 7/93 8/92 2/98 5/95 4/96 3/97

LDH, ≤ or > ULN 67/33 68/32 72/28 68/32 67/33 63/37

Alkaline phosphatase, ≤ or

>484U/L

85/15 88/12 91/9 89/11 86/14 89/11

CRP, ≤ or >1.4mg/dL 36/64 34/66 55/45 62/38 61/39 49/51

CA19, ≤ or >1350kU/L 41/59 47/53 60/40 49/51 70/30 51/49

Neutrophils, ≤ or >ULN 75/25 78/22 87/13 80/20 86/14 78/22

OS

1.0

0.8

0.6

0.4

0.2

0

No. left

All gr 0 214 78 12 1 0

All gr 1 211 121 20 0 0

All gr 2 182 119 26 2 0

All grade 0

All grade 1

All grade 2


OS

1.0

0.8

0.6

0.4

0.2

0

No. left

All gr 0 214 78 12 1 0

All gr 1 393 240 46 2 0

All grade 0

All grade 1


p<0.0001 HR=0.54

(95% CI: 0.44–0.65)

OS relative to rash

0 6 12 18 24

OS

1.0

0.8

0.6

0.4

0.2

0

No. left

GE-B gr 0

GE-B gr 1

GE-P gr 0

GE-P gr 1

Time (months)

91 37 3 0 0

215 137 25 1 0

123 41 9 1 0

178 103 21 1 0

GE-B grade 0

GE-B grade 1

GE-P grade 0

GE-P grade 1

OS according to severity of rash

OS (months [95% CI])

No rash Grade 1 rash Grade ≥2 rash Any rash

GE-P arm 4.3 (3.4–5.4) 7.1(6.1–9.6) 8.3 (6.0–10.7) 8.1 (6.6–9.6)

HR=0.56

(95% CI: 0.41–0.76)

p=0.0001

HR=0.50

(95% CI: 0.36–0.70)

p<0.0001

HR=0.53

(95% CI: 0.41–0.68)

p<0.0001

GE-B arm 5.0 (3.9–6.4) 7.4 (5.8–9.1) 8.4 (7.2–10.2) 7.9 (7.1–9.1)

HR=0.60

(95% CI: 0.44–0.83)

p=0.0017

HR=0.49

(95% CI: 0.35–0.69)

p<0.0001

HR=0.54

(95% CI: 0.41–0.72)

p<0.0001

All patients 4.8 (3.7–5.4) 7.4 (6.4–9.1) 8.4 (7.2–9.9) 8.0 (7.1–9.1)

HR=0.59

(95% CI: 0.47–0.73)

p<0.0001

HR=0.50

(95% CI: 0.39–0.63)

p<0.0001

HR=0.54

(95% CI: 0.44–0.65)

p<0.0001

N.B. All hazard ratios (HRs) are for rash versus no rash

PF

S

1.0

0.8

0.6

0.4

0.2

0

No. left

All gr 0 214 36 0 0 0

All gr 1 393 122 15 1 0

All grade 0

All grade 1


p<0.0001 HR=0.53

(95% CI: 0.44–0.63)

PFS relative to rash

0 6 12 18 24

No. left

All gr 0 214 36 0 0 0

All gr 1 211 54 6 0 0

All gr 2 393 122 15 1 0

PF

S

1.0

0.8

0.6

0.4

0.2

0

All grade 0

All grade 1

All grade 2

Time (months)

PF

S

1.0

0.8

0.6

0.4

0.2

0

No. left

GE-B gr 0 91 21 0 0 0

GE-B gr 1 215 77 10 1 0

GE-P gr 0 123 15 0 0 0

GE-P gr 1 178 45 5 0 0


GE-B grade 0

GE-B grade 1

GE-P grade 0

GE-P grade 1

PFS according to severity of rash

PFS (months (95% CI])

No rash Grade 1 rash Grade ≥2 rash Any rash

GE-P arm 2.1 (1.9–2.8) 3.7 (3.6–4.2) 4.1 (3.6–5.5) 3.8 (3.7–4.7)

HR=0.67

(95% CI: 0.51–0.88)

p=0.0033

HR=0.47

(95% CI: 0.34–0.64)

p<0.0001

HR=0.56

(95% CI: 0.44–0.71)

p<0.0001

GE-B arm 3.0 (2.1–3.9) 4.0 (3.4–5.4) 5.8 (5.4–7.3) 5.4 (4.5–5.8)

HR=0.61

(95% CI: 0.45–0.83)

p=0.0011

HR=0.45

(95% CI: 0.33–0.62)

p<0.0001

HR=0.52

(95% CI: 0.40–0.68)

p<0.0001

All patients 2.5 (2.0–3.0) 3.8 (3.6–4.4) 5.5 (4.7–6.0) 4.6 (3.9–5.3)

HR=0.62

(95% CI: 0.51–0.76)

p<0.0001

HR=0.44

(95% CI: 0.35–0.55)

p<0.0001

HR=0.53

(95% CI: 0.44–0.63)

p<0.0001

N.B. All HRs are for rash versus no rash

Study Schema for Phase III Trial of

Gemcitabine vs FOLFIRINOX Prodige 4 - ACCORD 11

Metastatic PDAC

n = 342

Gemcitabine 1000 mg/m2

weekly x 7 of 8,

then weekly x 3 of 4

(n = 171)

FOLFIRINOX

Oxaliplatin 85 mg/m2

LV 400 mg/m2

Irinotecan 180 mg/m2

5-FU bolus 400 mg/m2, then

2400 mg/m2 infusional over

46 hrs (n = 171)

Stratified by ECOG PS (0 vs 1), center,

tumor location (head vs other)

Conroy T, et al. N Eng J Med. 2011;364:1817-1825.

Flow Chart

Folfirinox Gemcitabine Total

Total randomized 171 171 342

Did not fulfill all

eligibility criteria8* 7* 15 (4%)

Untreated patients 4 2 6 (2%)

ITT population 171 171 342 (100%)

Safety population 167 169 336 (98%)

*Folfirinox arm : 2 patients > 76 years; one patient PS=2;

5 patients with high bilirubin, high creatinine or low platelets

*Gemcitabine arm: 7 patients with high bilirubin, high creatinine or low platelets

Conroy et al, NEJM 2011

Patients characteristics

CharacteristicFolfirinox

N=171

Gemcitabine

N=171p

Median age (yrs)

[range]

61

[25-76]

61

[34-75]NS

Sex Male

Female

106 (62%)

65 (38%)

105 (61.4%)

66 (38.6%) NS

Baseline PS 0

1

2

64 (37.4%)

106 (62.0%)

1 (0.6%)

66 (38.6%)

105 (61.4%)

0 (0.0%)NS

Location of primary Head

Other

62 (36.3%)

109 (63.7%)

60 (35.1%)

111 (64.9%) NS


Disease characteristics

CharacteristicFolfirinox

N=171

Gemcitabine

N=171p

Synchronous metastases

Metachronous metastases

156 (91.2%)

15 (8.8%)

161 (94.2%)

10 (5.8%)

NS

NS

Median nr. of involved sites

CA19-9 59 ULN

2 (1-6)

68 (41.5%)

2 (1-6)

77 (46.7%)

NS

NS

Measurable site

Liver

Pancreas

Nodes

Lungs

Peritoneal

149 (88.2%)

89 (52.7%)

48 (28.4%)

33 (19.5%)

33 (19.5%)

150 (87.7%)

91 (53.2%)

39 (22.8%)

49 (28.7%)

32 (18.7%)

NS

NS

NS

0.049

NS


Objective Response Rate

Folfirinox

N=171

Gemcitabine

N=171p

Complete response 0.6% 0%

Partial response 31% 9.4% 0.0001

CR/PR 95% CI [24.7-39.1] [5.9-15.4]

Stable disease 38.6% 41.5%

Disease control

CR+PR+SD70.2% 50.9% 0.0003

Progression 15.2% 34.5%

Not assessed 14.6% 14.6%

Median duration

of response5.9 mo. 4 mo. ns


FOLFIRINOX vs Gemcitabine: OS

and PFS

OS PFS

100

75

50

00 3 6 9 12 15 18 21 24 27 42

Months

Pa

tie

nts

Ali

ve

(%

)

25

39363330

Gemcitabine

FOLFIRINOX

HR: 0.57 (95% CI: 0.45-0.73;

P < .001 by stratified log-rank test)

Gemcitabine

FOLFIRINOX

Pts at Risk, n

171 134 89 48 28 14 7 6 3 3 12222

171 146 116 81 62 34 20 13 9 5 22223

100

75

50

00 3 6 9 12 15 18 21 36

MonthsP

ati

en

ts W

ith

ou

t P

rog

resio

n (

%)

25

33302724

Gemcitabine

FOLFIRINOX

HR: 0.47 (95% CI: 0.37-0.59;

P < .001)

Gemcitabine

FOLFIRINOX

Pts at Risk, n

171 88 26 8 5 2 0 0 00000

171 121 85 42 17 7 4 1 00001

Conroy T, et al. N Eng J Med. 2011;364:1817-1825.

Overall Survival

Folfirinox

N=171

Gemcitabine

N=171 p HR

Median survival[CI 95%]

11.1 mo.[ 9 - 13.1]

6.8 mo.[ 5.5 - 7.6]

<0.0001 0.57

1-yr. survival 48.4% 20.6%

18-mo. survival 18.6% 6%

Median follow up: 26.6 months [95% CI: 20.5 – 44.9]


Safety: hematological AEs

AE, % per patient

Folfirinox

N=167

Gemcitabine

N=169

p

All Grade 3/4 All Grade 3/4 Grade 3/4

Neutropenia 79.9 45.7 54.8 18.7 0.0001

Febrile Neutropenia 7.2 2.4 0.6 0.009

Anemia 90.4 7.8 94.6 5.4 NS

Thrombocytopenia 75.2 9.1 54.8 2.4 0.008

5.4

42.5 % of the pts received G-CSF in the F arm vs 5.3% in the G arm

One toxic death occurred in each arm

AE, adverse eventConroy et al, NEJM 2011

Safety: main non-hematological AEs

AE, % per patientFolfirinox N=167 Gemcitabine N=169

pAll Grade 3/4 All Grade 3/4

Infection without

neutropenia6 1.2 7.1 1.8 NS

Peripheral neuropathy 70.5 9 0.6 0 0.0001

Vomiting 61.4 14.5 43.2 4.7 0.002

Fatigue 87.3 23.2 78.7 14.2 0.036

Diarrhea 73.3 12.7 30.8 1.2 0.0001

Alopecia (grade 2) 32.5 (11.4) 3.0 (0.6) 0.0001

ALT 64.8 7.3 83.8 0.002218.6


Phase III MPACT Trial: Gemcitabine ± nab-

Paclitaxel in Metastatic Pancreatic Cancer

Primary objective: OS

Secondary endpoints: PFS, ORR, safety

Von Hoff DD, et al. NEJM 2013

Patients with

metastatic pancreatic

cancer, no previous

treatment for

metastatic disease,

KPS ≥ 70, bilirubin

≤ ULN

(N = 861)

nab-Paclitaxel 125 mg/m2 IV q3w +

Gemcitabine 1000 mg/m2

on Days 1, 8, 15 q4w

(n = 431)

Gemcitabine 1000 mg/m2/wk for

7 wks, and then on Days 1, 8, 15 q4w

(n = 430)

Treat until

PD

Stratified by KPS, region, liver metastasis

MPACT Trial of Gemcitabine ± nab-

Paclitaxel in Metastatic Pancreatic Cancer:

OS

Von Hoff DD, et al. ASCO 2013. Abstract 4005. Used with permission.

1.0

0.9

0.8

0.7

1.6

0.5

0.4

0.3

0.2

0.1

00 3 6 9 12 15 18 21 24 27 30 33 36 39

Mos

Pro

po

rtio

n o

f S

urv

ivin

g P

ati

en

ts

nab-P + gemOS, Mos

Events,

n/N (%)

Median

(95% CI)

75th

Percentile

333/431 (77) 8.5 (7.89-9.53) 14.8

359/430 (83) 6.7 (6.01-7.23) 11.4

Gem

HR: 0.72(95% CI: 0.617-0.835;P = .000015)

431430

357340

269220

169124

10869

6740

4026

2715

167

93

41

10

10

00

Pts at Risk, nnab-P + gemGem

Gemcitabine ± nab-Paclitaxel in Metastatic

Pancreatic Cancer: PET & CA19-9 Correlates


Metabolic Response by PET (Independent Review)

Outcomenab-P + Gem

(n = 130)Gem

(n = 127)HR P Value

Metabolic response by PET, % 63 38 -- .000051

ORR by CT, % 31 11 -- .0001

Median OS in PET cohort, mos 10.5 8.3 0.71 .0096

Predictive Value of CA19-9 Response at Wk 8 on OS: Landmark Analyses

Decrease in CA19-9 Level at Wk 8

nab-P + Gem (n = 130)

Gem(n = 127)

HR P Value

nMedian

OS, Mosn

Median OS, Mos

≥ 20% 197 13.2 141 9.4 0.59 < .0001

≥ 90% 59 13.4 34 9.8 0.47 .0053

Significantly more patients experienced ≥ 20% and ≥ 90% reductions in CA19-9 with the addition of nab-paclitaxel (P < .0001)

MPACT Trial of Gemcitabine ± nab-

Paclitaxel in Metastatic Pancreatic Cancer:

AEsAE nab-P + Gem (n = 421) Gem (n = 402)

≥ 1 AE leading to death, % 4 4

Grade ≥ 3 hematologic AE,* %

Neutropenia 38 27

Leukopenia 31 16

Thrombocytopenia 13 9

Anemia 13 12

Receipt of growth factors % 26 15

Febrile neutropenia†, % 3 1

Grade ≥ 3 nonhematologic AE† in > 5% patients, %

Fatigue 17 7

Peripheral neuropathy 17 < 1

Diarrhea 6 1

Grade ≥ 3 neuropathy

Time to onset, median days 140 113

Time to improvement by grade, median days 21 29

Time to improvement to grade ≤ 1, median days 29 --

Resumed nab-paclitaxel, % 44 --


*Based on lab values. †Based on investigator assessment of treatment-related events.

MPACT Trial of Gem ± nab-Paclitaxel in

Metastatic Pancreatic Cancer: Conclusions

Addition of nab-paclitaxel to gemcitabine significantly improved survival

– Across entire curve at all time points

– Median OS: 8.5 vs 6.7 mos with gemcitabine alone

Metabolic response rates (by PET and CA19-9) significantly increased with addition of nab-paclitaxel to gemcitabine

– Predictive of OS

Serious AEs not increased, remain acceptable and manageable

Nab-paclitaxel + gemcitabine potentially a new standard for the treatment of metastatic pancreatic cancer

– Could become backbone of new regimens


Cáncer páncreas 2017

Health & Medicine

Transcript of Cáncer páncreas 2017