“estrategia terapeutica del cáncer colorrectal:...

“Estrategia terapeutica del cáncer colorrectal: Selección

individualizada del tratamiento”

P. García Alfonso

Jefe de Sección de Oncología Médica

HGU Gregorio Marañón de Madrid

Metastatic Colorectal Cancer

0 10 20 30 40 50

FOLFOXIRI-Bev 2wt

FOLFOX-Pani 2wt

FIRE Ras wt

FOLFOX-Pani

FOLFIRI-Cetu

FOLFOX-Cetu

FOLFOX-Bev

FOLFOX->FOLFIRI

IFL-Bev

FOLFOX

FOLFIRI

5FU i.c.

5FU bolus

41,7 41,3

33,1 29

25,8 23,5

22,8 21,3

20,6 20,3

19,5 17,4

14,8 14,1

12,6 5

Mediana Sup FOLFOXIRI-Bev 2wt

FOLFOX-Pani 2wt

FIRE Ras wt

FOLFOX-Pani

FOLFIRI-Cetu

FOLFOX-Cetu

FOLFOX-Bev

FOLFOX->FOLFIRI

IFL-Bev

FOLFOX

FOLFIRI

5FU i.c.

5FU bolus

ESMO GUIDELINES 2015

(1) Referencia: Van Cutsem, Arnold and Cervantes. Session XIX: Metastatic Colorectal Cancer. World Congress on Gastrointestinal Cancer

Características

del tumor (1) Presentación clínica:

Localización del tumor Carga tumoral

Edad Performance status Función del órgano Comorbilidades

Perfil de toxicidad Flexibilidad Factores socio- económicos Calidad de vida Preferecias y expectativas del paciente

Para la toma de decisión de la1L de tratamiento en CCRm

Medicina Personalizada significa:

Biología del tumor Estatus mutacional de RAS Estatus mutacional de BRAF

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

21.5 months

20.6 months

Significant improvement in

Trial Fluoropyrimidine Irinotecan or

oxaliplatin EGFR

inhibitor RR PFS OS

CRYSTAL Inf + bolus 5-FU Irinotecan Cetuximab + + +

COIN Inf + bolus 5-FU Oxaliplatin Cetuximab + + –

Capecitabine Oxaliplatin Cetuximab – – –

NORDIC Bolus 5-FU Oxaliplatin Cetuximab – – –

PRIME Inf + bolus 5-FU Oxaliplatin Panitumumab + + +

Resultados de los ensayos fase III con inhibidores de EGFR

Grothey & Lenz. J Clin Oncol 2012

Resultados de los ensayos fase III con Bevacizumab en

primera línea de CCRm

1. Hurwitz, et al. NEJM 2004; 2. Saltz, et al. JCO 2008; 3. Tebbutt, et al. JCO 2010 4. Cunningham, et al. ASCO GI 2013; Falcone NE Med 2014

Regimen

line N Post-study therapy

Median

(months)

Median

(months)

Dobletes

IFL + bevacizumab1 1L 813 2L: ~50%

2L: ~50%

XELOX/FOLFOX

XELOX/FOLFOX + bevacizumab2 1L 1,401 2L: 53%

2L: 46%

Monoterapia

Capecitabine

Capecitabine + bevacizumab3 1L 313 68%

Capecitabine

Capecitabine + bevacizumab4 1L 280 37%

*Statistically significant difference vs the control arm

NR = not reported

12,1 vs 9,7 p 0,003

31 vs 25,8 p 0,054

Estudio TRIBE

508 pacientes CCR EIV

FOLFOXIRI + beva

FOLFIRI + beva

OR: 62.7 % vs 51.9%; p=0.025

Marcadores moleculares

Mutaciones RAS

RAS wild-type

KRAS codon 12 mutant

KRAS Exon 3 mutant

KRAS Exon 4 mutant

NRAS Exon 2 mutant

NRAS Exon 3 mutant

NRAS Exon 4 mutant

KRAS Exon 2

KRAS wild-type

Extended RAS wild-type

(2014) KRAS exon 2 wild-type

(2008)

OS con inhibidores de EGFR en CCRm RAS/KRAS exon 2 MT

EGFR inhibitors are authorised only for RAS WT mCRC Sorich, et al. Ann Oncol 2015

Meta-analysis of >5,000 patients from randomised clinical trials

20020408

20050181

CRYSTAL

PICCOLO

Summary

1.06 (0.79–1.42)

0.91 (0.76–1.10)

1.05 (0.86–1.28)

1.29 (0.91–1.84)

1.22 (0.85–1.76)

1.21 (1.01–1.45)

1.08 (0.97–1.21)

p=0.14

N Study OS

Hazard ratio (95% CI)

Any RAS MT

0.5 1 2

Favours no cetux/panit

Favours cetux/panit

1.02 (0.75–1.39)

0.94 (0.76–1.15)

1.03 (0.83–1.28)

1.29 (0.87–1.91)

1.05 (0.69–1.61)

1.15 (0.94–1.41)

1.05 (0.95–1.71)

p=0.32

KRAS exon 2 MT

0.5 1 2

Favours no cetux/panit

Favours cetux/panit

OS Hazard ratio (95% CI)

AVF2107g: OS con bevacizumab acorde a estado mutacional de KRAS

Hurwitz, et al. Oncologist 2009

0 15 25 30 5 10 20

KRAS MT (n=78)

KRAS WT (n=152)

Time (months)

Bevacizumab + IFL (n=44)

Placebo + IFL (n=34)

HR=0.69; p=0.26

Bevacizumab + IFL (n=85)

Placebo + IFL (n=67)

HR=0.58; p=0.04

0 15 25 30 5 10 20

13.6 19.9 27.7 17.6

BRAF MT se asocia con peor pronóstico

Seligmann, et al. ASCO 2015

1L treatment OS for BRAF MT vs BRAF WT

BRAF MT patients have a significantly shorter median OS in 1L; only 39% of BRAF MT patients vs 60% BRAF WT received 2L treatment

Time (months)

0 6 12 18 24 30 36 42

Time (months)

0 3 6 9 12 15 18 24

BRAF WT BRAF MT

HR=1.48 p<0.001

BRAF WT BRAF MT

HR=1.17 p=0.33

6.9 10.2 10.8 16.4

2L treatment OS for BRAF MT vs BRAF WT

OS con inhibidores de EGFR en CCRm BRAF MT

EGFR inhibitors are authorised only for RAS WT mCRC Pietrantonio, et al. Eur J Cancer 2015

Meta-analysis of randomised clinical trials of cetuximab or panitumumab

Bokemeyer 2012

Douillard 2013

Karapetis 2013

Seymour 2013

Peeters 2014

Stintzing 2014

Total (95% CI)

–0.478

–0.105

–0.174

–0.446

–0.139

Log (hazard ratio) Study

0.62 (0.36–1.06)

0.90 (0.46–1.76)

0.84 (0.20–3.56)

1.84 (1.10–3.08)

0.64 (0.32–1.28)

0.87 (0.47–1.61)

0.91 (0.62–1.34)

Hazard ratio (95% CI) SE

0.2 1 5

Favours control

Favours EGFR inhibitors

Weight (%)

Heterogeneity: Tau2=0.11; Chi2=10.09 df=5 (p=0.07); I2=50% Test for overall effect: Z=0.48 (p=0.63)

TRIBE Predictive impact - OS

0 20 40 600

Months

FOLFIRI + bev

Median OS

FOLFOXIRI + bev

Median OS

HR [95% CI]

ITT population 508 25.8 31.0 0.79 [0.63-1.00]

R&B evaluable 375 25.8 31.0 0.86 [0.65-1.12]

RAS mutated 218 23.1 30.8 0.86 [0.60-1.22]

BRAF mutated 28 10.8 19.1 0.55 [0.24-1.23]

All wt patients 129 34.4 41.7 0.85 [0.52-1.39]

RAS mutated – FOLFOXIRI plus bev

RAS mutated – FOLFIRI plus bev

BRAF mutated – FOLFOXIRI plus bev

BRAF mutated – FOLFIRI plus bev

All wt – FOLFOXIRI plus bev

All wt – FOLFIRI plus bev

VISNÚ PROGRAM CTC Screening (n= 750 pts)

≥3 CTC

(n=350)

VISNÚ 1 (TTD-12-01)

FOLFOX

Avastin

(n = 193)

FOLFOXIRI

Bevacizumab

(n = 175)

FOLFOX

Bevacizumab

(n = 175)

Design Randomized Phase III

Primary endpoint: PFS (superiority 8 m vs 11,2 m, HR: 0.71)

Secondary endpoint: RR, OS. R0 surgery, toxicity, CTC level

basal, KRAS, BRAF, PI3K, Pten

VISNÚ 2 (TTD-12-02)

(n=191)

FOLFIRI

Cetuximab

< 3 CTC

(n=400)

BRAF WT, PI3K WT

(n=194)

FOLFIRI

Bevacizumab

KRAS WT N = 240

BRAF MUT o PI3K MUT

(n=46)

Design: Randomized Phase II

Primary endpoint:

-Group without mutation: minimum value 8.5 months optimum value 13 months

and 1 year PFS rate IC less than (+/-10%)

- Group with mutation: minimum value 2,5 months optimum value 6 months

Secondary endpoint: TR, OS, R0 surgery, toxicity, CTC level basal, Pten

FOLFIRI

Cetuximab

FOLFIRI

Bevacizumab

VISNÚ

ESMO 2015: Consensus on treatment of advanced mCRC

Progressive disease Disease control Cytoreduction

(shrinkage) Progressive disease

Unusual, see publication CT + Bevacizumab CT + biological agent Triplet + Bevacizumab Combination +

Bevacizumab Doublet + anti-EGFR

Continue; maintenance, or pause

Continue; maintenance, or pause Continue

FP +/- Bevacizumab Reduced dose doublet

Anti-EGFR

Surgery alone Surgery with perioperative/ postoperative CT

Unfit (but may be suitable) Unfit Fit

Cytoreduction Disease control

Re-evaluation/assessment of response every 2-3 months

RAS WT RAS MT BRAF MT RAS WT RAS MT BRAF MT

Van Cutsem, Arnold and Cervantes. Session XIX: Metastatic Colorectal Cancer. World Congress on Gastrointestinal Cancer, 2015

Anti-EGFR

Metástasis Hepáticas Irresecables o Potencialmente resecables

CELIM: Cetuximab + FOLFOX o FOLFIRI en metástasis hepáticas de CCR irresecables o mas de 5 metástasis

PLANET study

Response rate and resectability

†percentages calculated over the total number of patients with surgical resection in each group; ORR: Objective response rate

(not confirmed*); *patients resected before response confirmation

Criteria for unresectability

• Patients had to meet at least one of the following criteria:

– no upfront R0/R1 resection of all hepatic lesions possible

– less than 30% estimated residual liver after resection

– disease in contact with major vessels of the remnant liver

• FDG-PET was performed to exclude extrahepatic metastases

• Primary endpoint: overall resection rate (R0/R1/R2)

Previously untreated,

unresectable colorectal

cancer with metastases

confined to the liver

N=80 Bevacizumab + mFOLFOX6

Bevacizumab 5 mg/kg, oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, bolus 5-FU 400 mg/m2 then 5-FU 2400 mg/m2

46-hr infusion on day 1 q2w

Bevacizumab + FOLFOXIRI Bevacizumab 5 mg/kg, oxaliplatin

85 mg/m2, irinotecan 165 mg/m2, folinic acid 200 mg/m2 and 5-FU 3200 mg/m2

46-hr infusion on day 1 q2w

Stratification factors:

• Centre

• ECOG performance status

• No. of metastatic lesions

Randomization 1:1

Gruenberger, et al. Annals of Oncology 2014

Resection and response rates

% (95% CI)

Bev + FOLFOXIRI (n=41)

Bev + mFOLFOX6 (n=39)

Difference

p-value

Resection rate

R0/R1/R2a 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

Overall response rate 80.5 (65.1–91.2) 61.5 (44.6–76.6) 18.9 (–2.1–40.0) 0.061

Intent to treat population. aOnly two-stage hepatectomy

Bridgewater, et al. ECC 2013. Abstract 2159

Tratamiento de Metástasis Hepáticas: Revaluación de la respuesta cada 2 meses

Citoreducción

RAS y BRAF wt

RAS mutado BRAF

mutado

Doblete + Anti-EGFR* Doblete o Triplete + Bevacizumab

Triplete + Bevacizumab

Anti-EGFR

Phase 2 PEAK study mFOLFOX6 + panitumumab or bevacizumab in 1st-line treatment of

WT KRAS exon 2 mCRC

Schwartzberg LS, et al. J Clin Oncol 2014;32:2240−7;

Protocol ID: 20070509; ClinicalTrials.gov identifier: NCT00819780. mFOLFOX6, modified FOLFOX6.

• Study endpoints: PFS (1); OS, ORR, resection rate, safety, exploratory biomarker analysis

• No formal hypothesis testing was planned

Follow-up • Survival: Q3M (± 28

days) • Safety: 30 days after

last study drug administration

mCRC WT KRAS exon 2 (n = 285)

Tumour assessment Q8W (± 7 days); Treatment administered until disease progression, unacceptable toxicity, death, or withdrawal from study

mFOLFOX6 (Q2W) +

panitumumab 6 mg/kg (Q2W)

mFOLFOX6 (Q2W) + bevacizumab 5 mg/kg (Q2W)

PEAK: PFS & OS WT KRASKRAS WT RAS

Schwartzberg LS. J Clin Oncol. 2014 Jul 20;32(21):2240-7

RAS WT

FIRE-3 study design

Heinemann V et al. Lancet 2014;.

Fire-3: Tasa de Respuestas

Heinemann V et al. Lancet 2014

FIRE-3: PFS and OS

Heinemann V et al. Lancet 2014

FIRE-3: Depth of Response (DpR) Correlates With OS

CALGB/SWOG 80405: <br /> FINAL DESIGN

Presented By Alan Venook at 2014 ASCO Annual Meeting

CALGB 80405: RAS-WT - Supervivencia Global

Lenz, et al. ESMO 2014. abstract 501O

31.2 32.0

Grupo N Mediana RR p (Eventos) (IC 95%) (IC 95%)

No. en riesgo Meses desde el ingreso al estudio

CALGB 80405 RAS-WT: Resultados de SLP

Lenz, et al. ESMO 2014. abstract 501O

Grupo N Mediana RR p (Eventos) (IC 95%) (IC 95%)

No. en riesgo Meses desde el ingreso al estudio

ORR: Chemo+cetux: 68,6% vs Chemo + Beva: 53,6% (p<0,01)

FIRE-3: diferencias en eficacia en tumores del lado derecho vs lado

izquierdo

Heinemann, et al. ASCO 2014

Cetuximab + FOLFIRI Bevacizumab + FOLFIRI

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

OS 0.34 (0.20–0.57)

<0.0001 1.04 (0.60–1.81)

PFS 0.43 (0.27–0.68)

0.0003 1.13 (0.73–1.75)

Multivariate Cox regression analysis (OS and PFS): location (left- vs right-sided tumour)

Cetuximab + FOLFIRI (n=167)

Bevacizumab + FOLFIRI (n=166)

Right-sided (n=30)

Left-sided (n=137)

OR (p value)

Right-sided (n=39)

Left-sided (n=127)

OR (p value)

ORR, % 46.7 70.1 2.7 (0.019)

48.7 62.2 1.7 (0.14)

PFS, months 6.9 10.8 0.35 (>0.001) 8.8 10.5 0.69 (0.065)

OS, months 16.1 38.7 0.26 (<0.0001)

22.7 28.0 0.63 (0.034)

Effect of primary tumour location on outcomes

Tratamiento de mantenimiento

CAIRO-3: Cape-Bev Maintenance vs Observation

• Primary endpoint: PFS2

– Time from randomization to progression upon reintroduction of CAPOX-B

– PFS2 considered equal to PFS1 in patients who do not receive CAPOX-B again (for any reason)

• Median follow-up: 40 mos

Patients with

mCRC and SD or

better after 6

cycles CAPOX-B,

WHO PS 0-1

(N = 558)

Observation

(n = 279)

Capecitabine +

Bevacizumab

(n = 279)

Reintroduce

CAPOX-B PD

PFS1 PFS2

Any treatment,

including

CAPOX-B

Koopman M, et al. ASCO 2013. Abstract 3502.

CAIRO3: Maintenance Cape-Beva

Meta-analisis Beva maintenance

Clin Colorectal Cancer 2015

Opciones terapéuticas en segunda línea

Lancet Oncol 2013 Jan;14(1):29-37.

Median: BEV + CT 11.2 months, CT 9.8 months

Median: BEV + CT 5.7 months, CT 4.1 months

Aflibercept

1. Adapted from Holash. Proc Natl Acad Sci. 2002;99:11393–11398. 2. Adapted from Tew. Clin Cancer Res. 2010;16:358–366.

Aflibercept

Tabernero et al. Eur J Cancer. 2011;47(2): Abstract 6LBA

RAISE: Ramucirumab en CCR

OR: 13.4% vs 12.5% p : 0.6

Antiangiogénicos en 2º línea

asociados a FOLFIRI

2º line: Anti-EGFR combination

Ciardielo F et al. Annals of Oncology Advanced Acess 2016

Cetuximab + 1L

FOLFIRI (n=153)

kras wt

Cetu + FOLFOX

FOLFOX

• Primary endpoint: PFS from randomisation

• Secondary endpoints: OS from randomisation, best ORR, safety

CAPRI: PFS wt/mutated

Opciones terapéuticas en tercera y cuarta línea

ASPECCT study

Panitumumab vs. cetuximab in 3rd-

line treatment of WT KRAS exon 2

mCRC (open-label, phase 3)

Price T, et al. EJC 2013; 49 (suppl 3):LBA 18 (and oral presentation); Protocol ID: 20080763; ClinicalTrials.gov identifier: NCT01001377. WT KRAS, WT KRAS in codons 12/13

• Study endpoints: OS (1°); PFS, ORR, safety

• Crossover between arms during study treatment was not allowed

Panitumumab

6 mg/kg IV (Q2W)

Cetuximab

400 mg/m2 loading dose,

250 mg/m2 IV (QW)

Metastatic mCRC

WT KRAS exon 2

(n = 999)

ASPECCT study: OS (primary analysis)

Price T, et al. EJC 2013; 49 (suppl 3):LBA 18 (and oral presentation).

HR = 0.97 (95% CI, 0.84–1.11)

P = 0.0007

Z-score = -3.19

Retention score = 1.06 (95% CI, 0.82–1.29)

Events

Median (95% CI)

months

Panitumumab

(n = 499) 383 (76.8) 10.4 (9.4–11.6)

Cetuximab

(n = 500) 392 (78.4) 10.0 (9.3–11.0)

live (

Months

0 6 12 18 24 30 36

• Multicenter, randomized, double-blind, placebo-controlled, phase III

– Stratification: prior anti-VEGF therapy, time from diagnosis of metastatic disease, geographical region

• Global trial: 16 countries, 114 centers

• Recruitment: May 2010 to March 2011

Regorafenib: Estudio CORRECT

Regorafenib 160 mg daily

3 weeks on / 1 week off (4-week cycle)

n = 136

Placebo n = 68

Stratification

• Metastases: single vs multiple

• Time from mCRC diagnosis:

>18 vs <18 months

• All patients received best supportive care

• Treat until progression, unacceptable toxicity, or withdrawal

Asian patients with mCRC who progressed after standard

therapies 25 Centers: mainland China,

Hong Kong, South Korea, Taiwan, Vietnam

CONCUR trial design Clinicaltrials.gov NCT01584830

Primary endpoint: overall survival (OS) • One-sided alpha 0.2 and assumed 33.3% OS improvement

(HR=0.75 favoring regorafenib) with 154 events had 80% power

Secondary endpoints: progression-free survival,

response rate , disease control rate

J. Li, et al. WCGI 2014. Abstract O-0023. Presented at WCGI 2014, Barcelona, Spain. Kim TW et al Presented at ESMO 2014, 26 – 30 September, Madrid Li J et al. Lancet 2015

CORRECT CONCUR

Regorafenib 1.9 m

Placebo 1.7 m

Regorafenib 6.4 m

Placebo 5.0 m

Regorafenib 8.8 m

Placebo 6.3 m

Regorafenib 3.2 m

Placebo 1.7 m

Mayer RJ et al. NEJM 2015

TAS 102 EN CCR m REFRACTARIO, FASE III

• Mayer & Van Cutsem et al.

Exposure to as many agents as

possible prolongs OS

Adapted from Grothey & Sargent. JCO 2005

OS (months) = 13.2 + (3 drugs % x 0.1), R2=0.85

Infusional 5-FU/LV

+ irinotecan

Infusional 5-FU/LV

+ oxaliplatin

Bolus 5-FU/LV

+ irinotecan

Irinotecan

+ oxaliplatin

Bolus 5-FU/LV

LV5FU2

First-line therapy

Patients with 3 drugs (%)

0 10 20 30 40 50 60 70 80

p=0.0001

FOLFOXIRI

CR-SEQUENCE Planned study design

Unresectable

WT RAS

FOLFOX +

bevacizumab

FOLFOX +

panitumumab

N cycles until PD, toxicity or

conversion surgery FOLFIRI +

bevacizumab

FOLFIRI +

panitumumab

N cycles until PD or toxicity

Investigator choice:

1st-line reintroduction

Regorafenib

FOLFIRI +

bevacizumab

Futuro en CCR

CRC consensus molecular subtypes characteristics

Liquid Biopsy

Can Targeting EGFR Overcome Resistance to BRAF + MEK Inhibitors in BRAFm CRC?

Presented By Chloe Atreya at 2015 ASCO Annual Meeting

Best Response With Confirmation <br />Percent Change from Baseline at Maximum Reduction in Tumor Measurement

Presented By Chloe Atreya at 2015 ASCO Annual Meeting

Pembrolizumab: 10m g/k cada 2 semanas iv

Pembrolizumab en CCRm con MSI

2.2 m 5.0 m

HER2 como diana en CCRm: HERACLES trial: Lapatinib + Trastuzumab

• Primary endpoint was met with 8/23 objective responses (as per protocol, 6/27 needed to declare the study positive)

• Disease control rate (DCR): 78%

Siena, et al. ASCO 2015

Response n (%)

ORR 8 (34.7)

CR 1 (4.3)

PR 7 (30.4)

SD ≥4 months 7 (30.4)

SD <4 months 3 (13.0)

PD 5 (21.7)

Response rate TTP

Time (months)

HER2 3+ (95% CI: 1.8–NR)

HER2 2+ (95% CI: 1.9–NR)

6 9 12

4.2 7.3

N: 54 previamente tratados HER2 +

¡ Muchas Gracias! pgarcaalfonso@gmail.com

¡ Muchas Gracias!

0 10 20 30 40 50

FOLFOXIRI-Bev 2wt

FOLFOX-Pani 2wt

FIRE Ras wt

FOLFOX-Pani

FOLFIRI-Cetu

FOLFOX-Cetu

FOLFOX-Bev

FOLFOX->FOLFIRI

IFL-Bev

FOLFOX

FOLFIRI

5FU i.c.

5FU bolus

41,7 41,3

33,1 29

25,8 23,5

22,8 21,3

20,6 20,3

19,5 17,4

14,8 14,1

12,6 5

Mediana Sup FOLFOXIRI-Bev 2wt

FOLFOX-Pani 2wt

FIRE Ras wt

FOLFOX-Pani

FOLFIRI-Cetu

FOLFOX-Cetu

FOLFOX-Bev

FOLFOX->FOLFIRI

IFL-Bev

FOLFOX

FOLFIRI

5FU i.c.

5FU bolus

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