“Manejo Actual del Cáncer de Colon y Recto”

P. García Alfonso Sr. Oncología Médica HGU Gregorio Marañón de Madrid

Tasas de mortalidad USA 1975-2008 57.100 en 2003 vs 51690 en 2012

Fundamento actual del tratamiento del CCR Nuevos Fármacos

Cirugía de metástasis

Cirugía de metástasis 16 - 21

Xeloda = 5 FU IC 5-FU IC 10-12 6

5 FU bolo

Com bi OXA nación LIPL ATIN O

14-15

Co m bi IRIN nacion OTE CAN

S U P E R V I V E N C I A

21 –25 ++

Bevacizumab Y Cetuximab

Panitu mumab

Soporte 1960

1980

1990

1999

2005

Tratamiento Individualizado

K-ras

La era de la Quimioterapia

5-FU es la base de la quimioterapia en el tratamiento del CCR • 5-FLUOROURACILO – – – –

1957 (1): primera experiencia en el tto de CCR. Limitada eficacia 1989 (2): biomodulación con leucovorín (Clínica Mayo) 1990-95 (3): infusión continua prolongada de 5FU (Lokich) 1997 (4): infusión continua intermitente (de Gramont)

(1) (2) (3) (4)

Heidelberger. Nature 1957 Poon. J Clin Oncol 1989 Díaz-Rubio Eur J Cancer 1990 De Gramont. J Clin Oncol 1997

FOLFIRI and FOLFOX6 sequencing trial in advanced CRC: Survival 1.00

FOLFIRI/FOLFOX6 FOLFOX6/FOLFIRI

Probability

0.75 0.50

0.25 0

P = .99 0

10

20 30 Median OS (Mos)

40

50

Conclusion: no survival advantage to starting either FOLFIRI or FOLFOX6 Tournigand C, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22(2):229-37. Reprinted with permission from the American Society of Clinical Oncology.

Tournigand C, et al. J Clin Oncol. 2004;22:229-237.

Access to Chemotherapy Improves Survival

22

First-line therapy Infusional 5-FU/LV + irinotecan Infusional 5-FU/LV + oxaliplatin Bolus 5-FU/LV + irinotecan Irinotecan + oxaliplatin Bolus 5-FU/LV LV5FU2

Median OS (Mos)

20 18 16 14 12 0

20 40 60 Patients With 3 Drugs (%)

Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.

80

 La era de los Biológicos

Various therapeutic strategies targeting VEGF have been explored 



Angio

Approaches to VEGF inhibition include:1 –

Anti-VEGF antibodies

–

Anti-VEGFR antibodies

–

Soluble VEGFR

–

Small-molecule TKIs

Precise inhibition of VEGF-mediated pathways avoids „off target‟ pathways affected by receptortargeting agents2–7

Antibodies inhibiting VEGF

VEGFR

Small molecules inhibiting VEGFRs (TKIs)

Soluble VEGFRs (VEGFTRAP)

Angiogenesis

1. Hicklin & Ellis. JCO 2005; 2. Baka et al. Expert Opin Ther Targets 2006 3. Presta et al. Cancer Res 1997; 4. Jain et al. Nat Clin Pract Oncol 2006 5. Morabito et al. Oncologist 2006; 6. Kerbel. Science 2006; 7. Verheul & Pinedo. Nat Rev Cancer 2007

Persistent activation of the EGFR pathway is a frequent event in mCRC

From Ciardiello F & Tortora G. N Engl J Med 2008;358:1160–1174. Copyright © (2008) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

Mutación de ras

inactive GDP

 En el cáncer colorrectal ocurre en el 35-45%

de los pacientes

 >95% de las mutaciones ocurren en el exon 2 de K-ras

– codón 12 (>90%) – codón 13 – codón 62  Impiden la hidrólisis del GTP (RAS permanentemente

“on”), y causan transformación celular

*

active

GTP

Clasificación del CCRm KRAS wild-type

versus

KRAS mutant

Therapeutic implications

Anti-VEGF or anti-EGFR antibodies

versus

No anti-EGFR antibodies. Si anti-VEGF

Bevacizumab targets VEGF  Avastin binds all known

isoforms of VEGF, preventing

– interaction with its receptors – activation of downstream signalling pathways

 This ultimately leads to

vascular regression, leaving the tumour dormant

VEGF

Avastin

X –P –P

P– P–

X Growth Proliferation Migration Survival

First-Line Irinotecan/5-FU/LV + Bevacizumab IFL/bevacizumab (n = 402) 15.6 20.3

100

60 40

40

20

0

0

10

20 Months

30

40

0

Copyright © 2004 Massachusetts Medical Society. All rights reserved. Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342.

HR: 0.54; P < .001

60

20

0

6.2 10.6

80 PFS (%)

OS (%)

100

HR: 0.66; P < .001

80

IFL/placebo (n = 411)

10

Months

20

30

Adding bevacizumab to FOLFOX4 significantly improved OS and PFS in the 2nd-line setting...

Median survival (months)

All patients had received prior chemotherapy for advanced CRC with irinotecan + a fluoropyrimidine

14

12.9*

12

10,8

10

FOLFOX4 (n=291) FOLFOX4 + bevacizumab (n=286) 7.3†

8

6

4,7

4

Adding bevacizumab also improved the overall response rate: 22.7% vs 8.6% (p