Controversias actuales en el manejo de cáncer colorrectal metastàsico

Controversias actuales en el manejo de cáncer colorrectal
metastásico – sesión interactiva con los fellows
Mauricio Lema Medina MD
Clínica de Oncología Astorga / Clínica SOMA, Medellín, Colombia
Instituto Nacional de Cancerología
Bogotá, 16.02.2017

Page  2
Disclaimer
 “Esta presentación ha sido creada por el autor de la charla y es de su
propiedad. La información, conceptos y opiniones aquí expresados son
responsabilidad del autor y no comprometen a Productos Roche S.A., sus
colaboradores o compañías vinculadas.”

Van Cutsem E, Cervantes A, Nordlinger B, Arnold D, ESMO Guidelines Working Group. Metastatic colorectal
cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(suppl
3):iii1-iii9. doi:10.1093/annonc/mdu260.

Metastatic patterns in mCRC
Van Cutsem E, Cervantes A, Nordlinger B, Arnold D, ESMO Guidelines Working Group. Metastatic colorectal
cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(suppl
3):iii1-iii9. doi:10.1093/annonc/mdu260.
Group 0: Technically R0-resectable
Group 1: Potentially resectable
Group 2: Disseminated disease /
intermediate intensive treatment
Group 3: Disseminated disease / non-
intensive, sequential treatment

Initially
resectable
Metastasic
“Convertible”

Systemic therapy in metastatic colorectal cancer
In the XXI century

Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for
metastatic colorectal cancer: a multicentre randomised trial. Lancet (London, England). 2000;355(9209):1041-1047.
http://www.ncbi.nlm.nih.gov/pubmed/10744089. Accessed February 7, 2017.
Irinotecan combined with fluorouracil compared with fluorouracil alone as first-
line treatment for metastatic colorectal cancer: a multicentre randomised trial.
OS (mo)
TTP (mo)
ORR (%)
Irinotecan + FL (n=199)
FL (n=188)
35*
17.4*
6.7*
4.4*
14.1*
22*
Grade ¾ toxicity
* Statistically significant

de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal
cancer. J Clin Oncol. 2000;18(16):2938-2947. doi:10.1200/jco.2000.18.16.2938.
Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in
advanced colorectal cancer.
OS (mo)
PFS (mo)
ORR (%)
FOLFOX
DeGramont
50*
16.2
9.0*
6.2*
14.7
22*
Grade ¾ neuropathy (%)
n=420
18* 0*

Tournigand C, André T, Achille E, et al. FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized
GERCOR Study. J Clin Oncol. 2003;22(2):229-237. doi:10.1200/JCO.2004.05.113.
FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal
cancer: a randomized GERCOR study.
OS (mo)
1st-PFS (mo)
ORR (%)
FOLFIRI then FOLFOX (n=109)
FOLFOX then FOLFIRI (n=111)
56
21
8.5
8.0
20.6
54
2nd-PFS (mo)
10.914.2

Falcone A Ricci S Brunetti I Pfanner E Allegrini G et. al. Journal of Clinical Oncology. 2007 vol: 25 (13) pp: 1670-1676
Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan
(FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan
(FOLFIRI) as first-line treatment for metastaticcolorectal cancer: the Gruppo
Oncologico Nord Ovest.
OS (mo)
PFS (mo)
ORR (%)
FOLFOXIRI
FOLFIRI
60*
22.0*
9.8*
6.9*
16.7*
34*
R0 resection (%)
n=244
6*15*

Souglakos J Androulakis N Syrigos K Polyzos A Ziras N et. al. British Journal of Cancer. 2006 vol: 94 (6) pp: 798-805
FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI
(folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in
metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from
the Hellenic Oncology Research Group (HORG).
OS (mo)
PFS (mo)
ORR (%)
FOLFOXIRI
FOLFIRI
43.0
21.5
8.4
6.9
19.5
33.6
n=283

Falcone A Ricci S Brunetti I Pfanner E Allegrini G et. al. Journal of Clinical Oncology. 2007 vol: 25 (13) pp: 1670-1676
Souglakos J Androulakis N Syrigos K Polyzos A Ziras N et. al. British Journal of Cancer. 2006 vol: 94 (6) pp: 798-805
FOLFOXIRI vs FOLFIRI.
OS (mo)
PFS (mo)
ORR (%)
FOLFOXIRI
FOLFIRI
43.0
21.5
8.4
6.9
19.5
33.6
n=283
OS (mo)
PFS (mo)
ORR (%)
FOLFOXIRI
FOLFIRI
60*
22.0*
9.8*
6.9*
16.7*
34*
R0 resection (%)
6*15*
n=244

Access to Chemotherapy Improves Survival
Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.
22
20
18
16
14
12
MedianOS(Mos)
0 20 40 60 80
Patients With 3 Drugs (%)
LV5FU2
Bolus 5-FU/LV
Infusional 5-FU/LV
+ irinotecan
Infusional 5-FU/LV
+ oxaliplatin
Bolus 5-FU/LV
+ irinotecan
Irinotecan
+ oxaliplatin
First-line therapy

Macedo LT, da Costa Lima AB, Sasse AD. Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review
and meta-analysis, with emphasis on chemotherapy subgroups. BMC Cancer. 2012;12(1):89. doi:10.1186/1471-2407-12-89.
Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer:
a systematic review and meta-analysis, with emphasis on chemotherapy
subgroups.
OS (HR)
CT + Bevacizumab vs CT
0.84*
PFS (HR)
ORR (HR)
1.0
1.0
1.0
0.84*
1.12
n=3060

Schmiegel, W., Reinacher-Schick, A., Arnold, D., Kubicka, S., Freier, W., Dietrich, G., … Graeven, U. (2013). Capecitabine/irinotecan or
capecitabine/oxaliplatin in combination with bevacizumab is effective and safe as first-line therapy for metastatic colorectal cancer: a
randomized phase II study of the AIO colorectal study group. Annals of Oncology, 24(6), 1580–1587. https://doi.org/10.1093/annonc/mdt028
Capecitabine/irinotecan or capecitabine/oxaliplatin in combination with
bevacizumab is effective and safe as first-line therapy for metastatic colorectal
cancer: a randomized phase II study of the AIO colorectal study group.
OS (mo)
PFS (mo)
ORR (%)
CapOx - Bevacizumab
CapIri - Bevacizumab
53
24
12.1
25
56
Grade ¾ diarrhea (%)
1622
n=255
10.4
Bevacizumab 7.5 mg/kg with
Oxaliplatin 130 mg/m(2)/day 1 plus
capecitabine 1000 mg/m(2) bid/days 1-
14
Irinotecan 200 mg/m(2)/day 1 plus
capecitabine 800 mg/m(2) bid/days 1-
14 both every 21 days

Title
OS (mo)
ORR (%)
Grade ¾ toxicity (%)
n=280
PFS (mo)
3020103366100
33
66
100
12
8
4
Reference

Yamazaki, K., Nagase, M., Tamagawa, H., Ueda, S., Tamura, T., Murata, K., … Hyodo, I. (2016). Randomized phase III study of bevacizumab plus
FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Annals of
Oncology, 27(8), 1539–1546. https://doi.org/10.1093/annonc/mdw206
Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus
mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer
(WJOG4407G).
OS (mo)
PFS (mo)
ORR (%)
FOLFIRI - Bevacizumab
FOLFOX - Bevacizumab
64
31
10.7
30.1
62
Grade ¾ neuropathy (%)
22*
n=402
12.1
0*

Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with
metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol.
2015;16(13):1306-1315. doi:10.1016/S1470-2045(15)00122-9.
FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line
treatment of patients with metastatic colorectal cancer: updated overall survival
and molecular subgroup analyses of the open-label, phase 3 TRIBE study
OS (mo)
PFS (mo)
ORR (%)
FOLFOXIRI + Bevacizumab
FOLFIRI + Bevacizumab
65
29.8*
12.2*
9.7*
25.8*
53
N=508

CRC: Biologic Subsets That Respond
Differently to EGFR-Targeted Agents
BRAF
KRAS
EREG or AREG
PI3K PTEN
EGFR
PIP1
PIP3
Signaling to the nucleus
Low expression of EGFR
ligands → decreased response
to EGFR-targeted agents
PTEN loss of expression →
decreased response to
EGFR-targeted agents
Siena S, et al. J Natl Cancer Inst. 2009;101:1308-1324. Rizzo S, et al. Cancer Treat Rev. 2010;36 Suppl 3:S56-61.

CRC: Biologic Subsets That Respond
Differently to EGFR-Targeted Agents
BRAF
KRAS
EREG or AREG
PI3K PTEN
EGFR
PIP1
PIP3
Signaling to the nucleus
Low expression of EGFR
ligands → decreased response
to EGFR-targeted agents
Mutant BRAF → decreased response to
PTEN loss of expression →
decreased response to
Mutant KRAS → decreased
response to EGFR-targeted
agents
Siena S, et al. J Natl Cancer Inst. 2009;101:1308-1324. Rizzo S, et al. Cancer Treat Rev. 2010;36 Suppl 3:S56-61.

Van Cutsem E, Kohne C-H, Lang I, et al. Cetuximab Plus Irinotecan, Fluorouracil, and Leucovorin As First-Line Treatment for Metastatic
Colorectal Cancer: Updated Analysis of Overall Survival According to Tumor KRAS and BRAF Mutation Status. J Clin Oncol. 2011;29(15):2011-
2019. doi:10.1200/JCO.2010.33.5091.
Cetuximab Plus Irinotecan, Fluorouracil, and Leucovorin As First-Line Treatment for
Metastatic Colorectal Cancer: Updated Analysis of Overall Survival According to
Tumor KRAS and BRAF Mutation Status
OS (mo)
PFS (mo)
ORR (%)
FOLFIRI - Cetuximab
FOLFIRI
57.3*
23.5*
8.4*
20*
39.7*
n=1198 – 89% RAS status ascertained
9.9*
wtKRAS

Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, Leucovorin, and Oxaliplatin With and Without Cetuximab in the First-Line
Treatment of Metastatic Colorectal Cancer. J Clin Oncol. 2009;27(5):663-671. doi:10.1200/JCO.2008.20.8397.
Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-
line treatment of metastatic colorectal cancer.
PFS (HR)
ORR (%)
FOLFOX - Cetuximab
FOLFOX
0.57*
37*
n=233 KRAS status ascertained
61*
wtKRAS

Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-
line treatment of metastatic colorectal cancer (WT KRAS analysis)
OS (mo)
ORR (%)
Complete resection rate
(%)
n=1183
PFS (mo) – Primary endpoint
3020103366100
33
66
100
12
8
4
FOLFOX – Panitumumab
FOLFOX
23.9
10*
10
57*
19.7
8.6*
8
48*
Douillard JY, Siena S, Cassidy J, et al. Final results from PRIME:
randomized phase III study of panitumumab with FOLFOX4 for first-line
treatment of metastatic colorectal cancer. Ann Oncol. 2014;25(7):1346-
1355. doi:10.1093/annonc/mdu141.

Douillard J-Y, Oliner KS, Siena S, et al. Panitumumab–FOLFOX4 Treatment and RAS Mutations in Colorectal Cancer. N Engl J Med.
2013;369(11):1023-1034. doi:10.1056/NEJMoa1305275.
Panitumumab–FOLFOX4 Treatment and RAS Mutations in Colorectal Cancer
OS (mo)
PFS (mo)
FOLFOX - Cetuximab
FOLFOX
26*
7.9*
20*
n=512 wtKRAS
10.1*
wtKRAS

Molecular Biomarkers for the Evaluation of Colorectal Cancer
Guideline From the American Society for Clinical Pathology, College of
American Pathologists, Association for Molecular Pathology, and
American Society of Clinical Oncology
Patients with CRC being considered for anti-
EGFR therapy must receive RAS mutational
testing. Mutational analysis should include KRAS
and NRAS codons 12 and 13 of exon 2, 59 and
61 of exon 3, and 117 and 146 of exon 4
(‘‘expanded’’ or ‘‘extended’’ RAS)
Sepulveda AR, Hamilton SR, Allegra CJ, et al. EARLY ONLINE RELEASE. Arch Pathol Lab Med.:2016-2554.

MAPK pathway mutations in mCRC
Aprox. 65% mCRC
Codon 61/146 mKRAS
5%
V600E BRAF
8%Codon 12/13
mKRAS
48%
mNRAS
6%
Schirripa M, et al. J Clin Oncol. 2013;31(Suppl): Abstract 3613.

Clinicians should order mismatch repair status
testing in patients with colorectal cancers for
the identification of patients at high risk for
Lynch syndrome and/or prognostic
stratification.

BRAF p.V600 mutational analysis should be
performed in dMMR tumors with loss of MLH1
to evaluate for Lynch syndrome risk. Presence of
a BRAF mutation strongly favors a sporadic
pathogenesis. The absence of BRAF mutation
does not exclude risk of Lynch syndrome.

Sporadic dMMR
CpG Methyl-MLH1
BRAF mutation (75%)
dMMR
Lynch syndrome
No BRAF mutation
15-20% mCRC
¾ dMMR ¼ dMMR
MLH1, MSH2, MSH6, PMS2

Bevacizumab vs Anti-EGFRs in WT
KRAS mCRC

Stintzing S, Modest DP, Rossius L, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a
post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol.
2016;17(10):1426-1434. doi:10.1016/S1470-2045(16)30269-8.
FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic
colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final
RAS wild-type subgroup of this randomised open-label phase 3 trial.
OS (mo)
Secondary Endpoint
Depth of response (-%)
ORR (%) – Primary Endpoint
FOLFIRI - Cetuximab
FOLFIRI - Bevacizumab
72
33*
-32*
56
n=400
-48*
wtKRAS
25*

PEAK: A Randomized, Multicenter Phase II Study of Panitumumab Plus Modified Fluorouracil,
Leucovorin, and Oxaliplatin (mFOLFOX6) or Bevacizumab Plus mFOLFOX6 in Patients With
Previously Untreated, Unresectable, Wild-Type KRAS Exon 2 Metastatic Colorectal Cancer
OS (mo)
ORR (%)
Serious Adverse Event
(%)
n=285
3020103366100
33
66
100
12
8
4
Schwartzberg LS, J Clin Oncol. 2014 Jul 20;32(21):2240-7
FOLFOX – Panitumumab
FOLFOX – Bevacizumab
34.2*
10.9
44
57.8
24.3*
10.1
38
53.5

Phase III 80405 Trial: First-line CT + Either
Cetux or Bev in KRAS-WT mCRC
 Primary endpoint: OS
 Secondary endpoints: ORR, PFS, TTF, duration of response
Patients with mCRC
and KRAS WT
(codons 12, 13),
ECOG PS 0/1
(N = 1137)
FOLFOX or FOLFIRI +
Bevacizumab q2w
(n = 559)
ClinicalTrials.gov. NCT00265850. Venook AP, et al. ASCO 2014. LBA3..
FOLFOX or FOLFIRI +
Cetuximab q1w
(N = 578)
A third arm with CT + bevacizumab + cetuximab
was closed to accrual in September 2009

CALGB/SWOG 80405: OS in the ITT
Population
mOS (95% CI), mos
CT + Cetux 29.9 (27.0-32.9)
CT + Bev 29.0 (25.7-31.2)
HR 0.925 (0.78-1.09)
P = 0.34
Venook AP, et al. ASCO 2014. Abstract LBA3.
0
12 24 36 48 60 72
Mos
80
100
60
40
0
OS(%)
20
84

Venook AP, et al. ASCO 2014, Abstract LBA3.
Phase III 80405 Trial: First-Line CT + Either Cetuximab or
Bevacizumab in KRAS-WT mCRC
OS (mo)
PFS (mo)
CT – Cetuximab (n=559)
CT – Bevacizumab (n=578)
29.9
10.8
29.0
wtKRAS
10.4

OS in mCRC
24 mo
CT-only
CT + Biologic

ESMO Consensus Guidelines for the Management of
Patients with Metastatic Colorectal Cancer
Group 0
Group 1
Group 2
Group 3
Resectable R0
Convertible
Unlikely
resectable/High
tumor burden
Never resectable
Surgery/ +/- Adj CT
Conversion CT/Surgery
Active CT + Biologic
Less-toxic CT+Biologic
Cure
Cure
Long OS
QoL
Criticism: solely based on DISEASE characteristics
Van Cutsem E, Cervantes A, Nordlinger B, Arnold D, ESMO Guidelines Working Group. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann
Oncol. 2014;25(suppl 3):iii1-iii9. doi:10.1093/annonc/mdu260.

A
• Nacida en 04/1944 con masa de 9 cm a 4 cm del reborde anal altamente
sugestiva de carcinoma y síntomas obstructivos.
• Fibrilación auricular.
• Se le practica biopsia que muestra un adenocarcinoma infiltrante
moderadamente diferenciado (07/2015).
• Se encuentran además 2 lesiones en hígado, segmento V y segmento VIII
de 46 mm y 22 mm.
• KRAS wt
• Se clasifica como un cT4a cN0 cM1a
• Se inició quimiorradiación con Fluoruracilo + Folinato 07/09/2015-
15/10/2015.
• Sin cambio en las lesiones hepáticas.
• Qué sigue?

Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with
metastatic colorectal cancer. Ann Oncol. 2016;27(8):1386-1422. doi:10.1093/annonc/mdw235.

Assessment of clinical condition of the patient
Fit Unfit (but may be suitable) Unfit
BSC
FP-bevacizumab; reduced doublet, anti-
EGFR
Goal

OS after resection in liver metastasis
Adam R, Oncologist, 2012

B
• Nacida en 30/03/1942 *Trastorno lifoproliferativo crónico /
malformación arteriovenosa cerebral* - AdenoCa Colon (ciego) -
mal diferenciado - pT3 pN1c (múltiples implantes tumorales
perilesionales, no compromiso ganglionar en 2 GL resecados) cM0
- IIIB - 14/11/2015: Hemicolectomía derecha (17/11/2015)--R0.
Inició FOLFOX en 17/12/2015. Se atenúa la dosis por toxicidad
importante en 31/03/2016 (luego de la infusión número 1 del
ciclo 4). Terminó quimioterapia en 31/05/2015.
• TAC muestra anormalidad.
• En 11/08/2016 PET-CT: Lesión de 2 cm en la pared abdominal
adherida a la fascia, por delante del colon transverso con SUV de
5. El mesenterio con SUV de 2.7 con adenopatía de 1.4 cm, con
CEA de 6.5. Resección R0 de metástasis de tejidos blandos en
pared abdominal por carcinoma pobremente diferenciado.

B
• Nacida en 30/03/1942 *Trastorno lifoproliferativo crónico / malformación
arteriovenosa cerebral* - AdenoCa Colon (ciego) - mal diferenciado - pT3 pN1c
(múltiples implantes tumorales perilesionales, no compromiso ganglionar en 2 GL
resecados) cM0 - IIIB - 14/11/2015: Hemicolectomía derecha (17/11/2015)--R0.
Inició FOLFOX en 17/12/2015. Se atenúa la dosis por toxicidad importante en
31/03/2016 (luego de la infusión número 1 del ciclo 4). Terminó quimioterapia en
31/05/2015.
• TAC muestra anormalidad.
• En 11/08/2016 PET-CT: Lesión de 2 cm en la pared abdominal adherida a la fascia,
por delante del colon transverso con SUV de 5. El mesenterio con SUV de 2.7 con
adenopatía de 1.4 cm, con CEA de 6.5. Resección R0 de metástasis de tejidos blandos
en pared abdominal por carcinoma pobremente diferenciado.
• Inició en quimioterapia con Quásar. Inicia en fecha: 29/08/2016. En 31/01/2017 TAC
de tórax y abdomen: quistes hepáticos. Dos lesiones subpleurales de 3 mm, de
significancia incierta. Adenopatías axilares de hasta 11 mm.

C
• Nacido en 12/1969.
• Adenocarcinoma moderadamente diferenciado de colon
derecho, con metástasis hepáticas no resecables, pero
convertibles, diagnosticado en 06/02/2015. cT4a cN2
cM1a.
• Mutación del KRAS en codón 2.
• Inició FOLFOX + Bevacizumab en 12/03/2015, seguido por
Bevacizumab.
• En 07/07/2015 TAC de abdomen contrastado: respuesta
parcial por RECIST de las lesiones en el segmento VI, VII y II
de 15, 14 y 11 mm respectivamente. No aparición de
nuevas lesiones. Respuesta parcial por RECIST (luego de
ciclo 4).

Conversion chemotherapy approach in
patients with liver-limited disease
Vie-LM-Bev
CELIM
GONO
POCHER
BOXER
OLIVIA
Ye et al.
ORR
73%
70%
80%
79%
78%
81%
62%
57%
29%
FOLFOXIRI
Bevacizumab
Cetuximab
No biologic agent

C
• Adenocarcinoma moderadamente diferenciado de colon derecho, con
metástasis hepáticas no resecables, pero convertibles, diagnosticado en
06/02/2015. cT4a cN2 cM1a.
• Inició FOLFOX + Bevacizumab en 12/03/2015, seguido por Bevacizumab.
• En 07/07/2015 TAC de abdomen contrastado: respuesta parcial por
RECIST de las lesiones en el segmento VI, VII y II de 15, 14 y 11 mm
respectivamente. No aparición de nuevas lesiones. Respuesta parcial por
RECIST (luego de ciclo 4).
• En 05/10/2015 Metastasectomía hepática R0 (se resecan 3 lesiones de
los segmentos VI x2, III de 25, 8 y 3 mm, respectivamente) CEA (Normal
<4): 1.4.

D
• Nacido en 08/1941. Carcinoma de colon -
sigmoides - pT4a pN0 cM0 - Estadío IIB, alto
riesgo (por invasión perineural y vascular, y por n
resecados). Resecado en 27/06/2013. Recibe
quimioterapia adyuvante con fluoruracilo +
folinato entre 07/08/2013 y 16/01/2014. En
20/02/2014 durante el cierre de colostomía se
establece recaída con carcinomatosis peritoneal
y compromiso retroperitoneal.

D
• Nacido en 08/1941. Carcinoma de colon - sigmoides -
pT4a pN0 cM0 - Estadío IIB, alto riesgo (por invasión
perineural y vascular, y por n resecados). Resecado en
27/06/2013. Recibe quimioterapia adyuvante con
fluoruracilo + folinato entre 07/08/2013 y
16/01/2014. En 20/02/2014 durante el cierre de
colostomía se establece recaída con carcinomatosis
peritoneal y compromiso retroperitoneal.
• Se inicia quimioterapia CAPOX-bevacizumab
(capecitabina + oxaliplatino) - bevacizumab en
21/03/2014. Sin evidencia de enfermedad en tac de
12/06/2014, 17/09/2015, 27/07/2016

Assessment of clinical condition of the patient
Fit Unfit (but may be suitable) Unfit
BSC
FP-bevacizumab; reduced doublet, anti-
EGFR
Goal

Phase 3 trial,
Patients aged 70 years and older with
previously untreated, unresectable,
metastatic colorectal cancer, who
were not deemed to be candidates
for oxaliplatin-based or irinotecan-
based chemotherapy regimens, were
randomly assigned in a 1:1 to
capecitabine alone or with
bevacizumab
Cunningham D, Lang I, Marcuello E, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously
untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14(11):1077-1085.
doi:10.1016/S1470-2045(13)70154-2.
Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with
previously untreated metastatic colorectal cancer (AVEX): an open-label,
randomised phase 3 trial.
OS (mo)
ORR (%)
Capecitabine - Bevacizumab
Capecitabine
19*
20.7
5.1*
16.8
10*
Grade ¾ toxicity (%)
22*40*
n=280
9.1*

E
• Síntomas obstructivos
• Cáncer de colon ascendente pT4a cN1c cM1b
estadío iv (metastásico a pulmón, hígado,
retropritoneo, óseo ?). Adenocarcinoma bien
diferenciado.
• KRAS no mutado
• Colectomía parcial en 08/05/2014 (con
colostomía temporal).
• Qué sigue?

Primary tumour location
• Incidence: ~40% (increasing)
• Older patients
• Microsatellite instability
• BRAF mutations
• Worse prognosis
Right-sided tumours
• Incidence: ~60%
• Younger patients
• Predominantly WT
• Better prognosis
Left-sided tumours
R L
Iacopetta, et al. Int J Cancer 2002; Brule, et al. ASCO 2013. Abstract 3528;
Missiaglia, et al. ASCO 2013. Abstract 3526

CALGB 80405: retrospective analysis of
effect of primary tumour location on OS and PFS
Venook, et al. ASCO 2016. Abstract 3504
• CALGB 80405 (NCT00265850) is a phase III, randomised, open-label study
• Primary endpoint: OS
• Secondary endpoints: PFS, time to treatment failure, DoR
Avastin + FOLFOX/FOLFIRI
Previously untreated
patients with mCRC
(N=1137 KRAS WT)
252 KRAS MT patients
enrolled prior to KRAS
WT protocol amendment
Cetuximab + FOLFOX/FOLFIRI
R
All KRAS Avastin Cetuximab All KRAS All KRAS Avastin Cetuximab
Right Left Right Left Right Left Right Left Right Left Right Left Right Left
OS 19.4 33.3 24.2 31.4 16.7 36.0 23.1 30.3 PFS 8.9 11.7 9.6 11.2 7.8 12.4
HR (95% 1.55
(1.32–1.82)
1.32
(1.05–1.65)
1.87
(1.48–2.32)
1.28
(0.95–1.73)
HR (95% 1.03
(1.11–1.50)
1.06
(0.86–1.31)
1.56
(1.26–1.94)
p value <0.0001 0.01 <0.0001 p value 0.0006 0.55 <0.0001

CALGB 80405: OS by primary tumour location
1.0
OSestimate
0.8
0.6
0.4
0.2
0
0 12 24 36 48 60 108
Time (months) Time (months)
1.0
OSestimate
0.8
0.6
0.4
0.2
0
Left
Right
HR=1.55 (1.32–
1.82)
p<0.0001
Left/Avastin
Right/Avastin
72 84 96
Total population By treatment
0 12 24 36 48 60 10872 84 96
19.4 33.3
16.7
24.2 36.0
31.4
This CALGB 80405 retrospective subset analysis was hypothesis generating
and should be interpreted with caution
Primary tumour location is a prognostic factor for poorer outcome in patients with right-sided tumours
irrespective of therapy
More biomarker data are needed to fully understand the predictive value of these data
In previous studies, Avastin has consistently shown efficacy in both right- and left-sided tumours
Cetuximab vs Avastin
HR (95% CI) p value
Left 0.817
(95% CI: 0.69–0.96)
0.018
Righ
t
1.269
(95% CI: 0.98–1.63)
0.065
Venook, et al. ASCO 2016. Abstract 3504
Left/Cetuximab
Right/Cetuximab

Relationship between primary tumour
sidedness and prognosis in CRC
• Observational analysis from the SEER database
• Primary endpoints: median OS and 3-year OS
Provides further evidence from a large population that right-sided stage III and IV tumours are associated with
poor survival
Stage III and IV
primary CRC
PD
SEER
analysis
Stage IV (N=64,770) Stage III (N=91,009)
Right Left Rectal Right Left Rectal
mOS (months) 9.5 15.5 15.5 62.5 93.5 85.5
Survival probability
Unadjusted HR (95% CI)
1.32 (1.30– 1.0 1.01 (0.99– 1.35 (1.32– 1.0 1.03 (1.01–
Survival probability
Adjusted HR (95% CI)
1.25 (1.22– 1.0 0.83 (0.81– 1.12 (1.09– 1.0 1.11 (1.08–
Schrag, et al. ASCO 2016. Abstract 3505

Association of tumour location and molecular
features with PFS and OS after anti-EGFR therapy
• Retrospective study
• Primary endpoint: PFS
• Secondary endpoint: OS
Right CIMP-High BRAF MT NRAS MT
PFS, HR (95% CI); p value 1.56 (1.01–2.41);
0.040
2.38 (1.47–
3.85); 0.0006
2.14 (1.26–3.65);
0.004
2.12 (1.23–3.65);
0.006
OS, HR (95% CI); p value 1.45 (1.04–2.01);
0.028
1.53 (1.08–
2.16); 0.001
2.46 (1.61–3.74);
<0.0001
NA
KRAS WT mCRC treated
with anti-EGFR therapy
(N=198)
CIMP testing
BRAF, NRAS
and PIK3CA
sequencing
MSI status
• On multivariate analysis, BRAF MT (p=0.001), and NRAS MT (p=0.060) remained significant for OS, but primary
tumour location did not (p=0.121)
• Right-sided CRC and CIMP-high were associated with hypermethylation of EREG and AREG, and distinct expression
patterns of consensus molecular subtypes (CMS) 1 and 3
Lee, et al. ASCO 2016. Abstract 3506
Right-sided tumours were associated with inferior OS and PFS after anti-EGFR therapy
Factors influencing outcome in right-sided tumours were BRAF MT, NRAS MT, molecular subtypes,
and tumour methylation

Primary tumour location: combined analysis of
JACCRO CC-05 and -06 studies
Sunakawa, et al. ASCO GI 2016. Abstract 613
Cetuximab + mFOLFOX6
(n=57)
Cetuximab + S-1 + oxaliplatin
(n=67)
Patients with KRAS exon 2 WT mCRC
with EGFR-expressing tumours
JACCRO CC-05
JACCRO CC-06
Objective: to assess the prognostic impact of primary tumour location on clinical outcomes of Japanese patients with
KRAS exon 2 WT mCRC enrolled in the JACCRO CC-05 or -06 trials
PFS in ITT population OS in ITT population
Time (months)
0 6 12 18 24 30 36 42
5.6 11.1
Left-sided tumours (n=90)
Right-sided tumours (n=20)
HR=0.47 (95% CI: 0.28–0.80); p=0.0041
1.0
PFSestimate
0.8
0.6
0.4
0.2
0
Time (months)
12.6 36.2
HR=0.28 (95% CI: 0.15–0.52);
p<0.0001
0 6 12 18 24 30 36 42 48
1.0
OSestimate
0.8
0.6
0.4
0.2
0

Primary tumour location: combined analysis of
JACCRO CC-05 and -06 studies
Sunakawa, et al. ASCO GI 2016. Abstract 613
PFS in FOLFOX group
HR=0.15 (95% CI: 0.06–0.37); p<0.0001
Time (months)
5.7 42.8
0 6 12 18 24 30 36 42 48
1.0
OSestimate
0.8
0.6
0.4
0.2
0
OS in FOLFOX group
Primary tumour location may be a negative predictive factor in patients with mCRC and KRAS WT tumours who
receive
cetuximab + oxaliplatin-based therapy
HR=0.26 (95% CI: 0.12–0.56); p=0.0002
Time (months)
3.0
11.3
0 6 12 18 24 30 36 42
1.0
PFSestimate
0.8
0.6
0.4
0.2
0

Proc ASCO, 2016, 3505
.
Association of primary (1°) site and molecular features
with progression-free survival (PFS) and overall survival
(OS) of metastatic colorectal cancer (mCRC) after anti-
epidermal growth factor receptor (αEGFR) therapy.
Michael Sangmin Lee

Association of primary (1°) site and molecular features
with progression-free survival (PFS) and overall survival
(OS) of metastatic colorectal cancer (mCRC) after anti-
epidermal growth factor receptor (αEGFR) therapy.
Michael Sangmin Lee
Proc ASCO, 2016, 3505
.

E
• Cáncer de colon ascendente pT4a cN1c cM1b estadío iv
(metastásico a pulmón, hígado, retropritoneo, óseo ?).
Adenocarcinoma bien diferenciado.
• KRAS no mutado
• Colectomía parcial en 08/05/2014 (con colostomía temporal).
• Se inició quimioterapia con FOLFOX- bevacizumab en 04/06/2014.
• Se suspende el oxaliplatino en 01/2015 por neuropatía periférica.
• Estable en TAC de 25/02/2015: con progresión documentada en
pulmón e hígado, y química en 29/07/2015.

F
• Cáncer de colon ascendente pT4a cN1c cM1b estadío iv (metastásico a pulmón,
hígado, retropritoneo, óseo ?). Adenocarcinoma bien diferenciado.
• KRAS no mutado
• Colectomía parcial en 08/05/2014 (con colostomía temporal). Se inició quimioterapia
con folfox - bevacizumab en 04/06/2014.
• Estable en TAC de 25/02/2015: con progresión documentada en pulmón e hígado, y
química en 29/07/2015.
• Inició FOLFIRI + panitumumab en 10/08/2015. Con respuesta parcial en 04/03/2016.
En 19/08/2016 TAC de tórax y abdomen contrastado que muestra incremento de las
lesiones hepáticas de hasta 18 en múltiples segmentos y lóbulos, estabilidad de la
lesiones metastásicas pulmonares y lesiónes costales en la parrilla 6, 7 y 9 derecha
(posiblemente, por trauma).

F
• Cáncer de colon ascendente pT4a cN1c cM1b estadío iv (metastásico a pulmón,
hígado, retropritoneo, óseo ?). Adenocarcinoma bien diferenciado.
• KRAS no mutado
• Colectomía parcial en 08/05/2014 (con colostomía temporal). Se inició quimioterapia
con folfox - bevacizumab en 04/06/2014.
• Estable en TAC de 25/02/2015: con progresión documentada en pulmón e hígado, y
química en 29/07/2015.
• Inició FOLFIRI + panitumumab en 10/08/2015. Con respuesta parcial en 04/03/2016.
En 19/08/2016 TAC de tórax y abdomen contrastado que muestra incremento de las
lesiones hepáticas de hasta 18 en múltiples segmentos y lóbulos, estabilidad de la
lesiones metastásicas pulmonares y lesiónes costales en la parrilla 6, 7 y 9 derecha
(posiblemente, por trauma).
• Inició FOLFOX - Bevacizumab en 06/09/2016:

BRAF p.V600 (BRAF c.1799 [p.V600]) position
mutational analysis should be performed in CRC
tissue in selected patients with colorectal
carcinoma for prognostic stratification.

There is insufficient evidence to recommend BRAF c.1799 (p.V600)
mutational status as a predictive molecular biomarker for response to anti-
EGFR inhibitors.
There is insufficient evidence to recommend PIK3CA mutational analysis of
colorectal carcinoma tissue for therapy selection outside of a clinical trial.
There is insufficient evidence to recommend PTEN analysis (expression by
immunohistochemistry [IHC] or deletion by fluorescence in situ
hybridization [FISH]) in colorectal carcinoma tissue for patients who are
being considered for therapy selection outside of a clinical trial.

2015;16(13):1306-1315. doi:10.1016/S1470-2045(15)00122-9.
OS (mo)
PFS (mo)
ORR (%)
FOLFOXIRI + Bevacizumab
FOLFIRI + Bevacizumab
65
29.8*
12.2*
9.7*
25.8*
53
BRAF+ OS (mo)
N=508
10.7*19*

2015;16(13):1306-1315. doi:10.1016/S1470-2045(15)00122-9.

90CONFIDENTIAL – for internal use only
 Retrospective analysis of two RAS/BRAF WT, mCRC cohorts:
 Cohort 1: HER2 tested by IHC / ISH, 14/97 HER2 amplified
 Cohort 2: all patients HER2 tested by next generation sequencing (n=37)
HER2 amplification as a negative predictor of efficacy
of anti-EGFR inhibitors
In this retrospective analysis, HER2 amplification was indicated to be a negative predictive
biomarker of efficacy of anti-EGFR inhibitors
Raghav, et al. ASCO 2016. Abstract 3517
Cohort 1: PFS on anti-EGFR tx
Median 2.9 vs 8.1 months
(p<0.001)
Cohort 2: PFS on anti-EGFR tx
Median 2.9 vs 9.3 months
(p<0.001)
Months Months
Percentsurvival
Percentsurvival
HER2 amplified
HER2 non-amplified
HER2 amplified
HER2 non-amplified

C
• Adenocarcinoma moderadamente diferenciado de colon derecho, con metástasis hepáticas no
resecables, pero convertibles, diagnosticado en 06/02/2015. cT4a cN2 cM1a.
• Inició FOLFOX + Bevacizumab en 12/03/2015, seguido por Bevacizumab.
• En 07/07/2015 TAC de abdomen contrastado: respuesta parcial por RECIST de las lesiones en el
segmento VI, VII y II de 15, 14 y 11 mm respectivamente. No aparición de nuevas lesiones.
Respuesta parcial por RECIST (luego de ciclo 4).
• En 05/10/2015 Metastasectomía hepática R0 (se resecan 3 lesiones de los segmentos VI x2, III
de 25, 8 y 3 mm, respectivamente) CEA (Normal <4): 1.4.
• Inició FULV. Inicia en fecha: 09/11/2015. Terminó curso programado en 11/04/2016.
• En 12/07/2016 TAC que muestra lesión de 21 x 22 mm en la unión de los segmentos IV y VII,
adenopatía aortocava.
• Inicia quimioterapia con FOLFIRI + Bevacizumab. Inicia en fecha: 10/08/2016.
• En 17/08/2016 se establece deficiencia de MLH1 y PMS2 en inmunohistoquímica.
• En 31/10/2016 PET-CT: Estabilidad de las lesiones hepáticas que ahora miden 3.3 y 1.8 cm, con
necrosis central, adenopatía retroperitoneal de 1.3 cm y mesentérica de 1.2 cm, así como la
lesión de tejidos blandos subctostal en niveles 11 y 12 de 4 cm.
• En 31/01/2017 PET-CT: Estabilidad de las lesiones hepáticas, mesentéricas y retroperitoneales.
• Qué sigue?

Le DT et al. N Engl J Med 2015;372:2509-2520.
Clinical Benefit of Pembrolizumab Treatment According to
Mismatch-Repair Status.

The consensus molecular subtypes of colorectal cancer
Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350-
1356. doi:10.1038/nm.3967.

Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350-
1356. doi:10.1038/nm.3967.
The consensus molecular subtypes of colorectal cancer

ESMO Consensus Guidelines for the
Management of Patients with Metastatic
Colorectal Cancer
• Biologicals (targeted agents) are indicated in the first-line
treatment of most patients unless contraindicated [I, A].
• The VEGF antibody bevacizumab should be used in combination
with:
° the cytotoxic doublets FOLFOX/CAPOX/FOLFIRI,
° the cytotoxic triplet FOLFOXIRI in selected fit and motivated
patients where cytoreduction (tumour shrinkage) is the goal—and
potentially also in fit patients with tumour BRAF mutations [II, B],
° fluoropyrimidine monotherapy in patients unable to tolerate
aggressive treatment [I, B].
• EGFR antibodies should be used in combination with:
° FOLFOX/FOLFIRI [I, A],
° capecitabine-based and bolus 5-FU based regimens should not
be combined with EGFR antibodies [I, E].

Colorectal Cancer
recommendation 13: conversion therapy.
• In potentially resectable patients (if conversion is the goal), a regimen
leading to high RRs and/or a large tumour size reduction (shrinkage) is
recommended [II, A].
• There is uncertainty surrounding the best combination to use as only few
trials have addressed this specifically:
° In patients with RAS wild-type disease, a cytotoxic doublet plus an
anti-EGFR antibody seems to have the best benefit risk/ratio, although the
combination of FOLFOXIRI plus bevacizumab may also be considered and, to
a lesser extent, a cytotoxic doublet plus bevacizumab [II, A].
° In patients with RAS-mutant disease: a cytotoxic doublet plus
bevacizumab or FOLFOXIRI plus bevacizumab [II, A].
• Patients must be re-evaluated regularly in order to prevent the
overtreatment of resectable patients as the maximal response is expected to
be achieved after 12–16 weeks of therapy in most patients

Colorectal Cancer
Recommendation 19: maintenance therapy.
• Patients receiving FOLFOX or CAPOX plus bevacizumabbased therapy as induction therapy should be considered for
maintenance therapy after 6 cycles of CAPOX and 8 cycles of FOLFOX. The optimal maintenance treatment is a combination of
a fluoropyrimidine plus bevacizumab. Bevacizumab as monotherapy is not recommended [I, B].
• Patients receiving FOLFIRI can continue on induction therapy—at a minimum—for as long as tumour shrinkage continues
and the treatment is tolerable [V, B].
• For patients receiving initial therapy with FOLFOXIRI plus or minus bevacizumab, a fluoropyrimidine plus bevacizumab may
be considered as maintenance therapy (as was done in the pivotal trials examining FOLFOXIRI).
• For patients receiving initial therapy with a single-agent fluoropyrimidine ( plus bevacizumab), induction therapy should be
maintained [V, A].
• Individualisation and discussion with the patient is essential [V, A].
• Initial induction therapy or a second-line therapy have to be reintroduced at radiological or first signs of symptomatic
progression. If a second-line therapy is chosen, re-introduction of the initial induction treatment should be a part of the
entire treatment strategy as long as no relevant residual toxicity is present [III, B].

Colorectal Cancer
Recommendation 20: second-line combinations with targeted agents.
• Patients who are bevacizumab naïve should be considered for treatment
with an antiangiogenic (bevacizumab or aflibercept) second line [I, A].
The use of aflibercept should be restricted to combination with FOLFIRI
for patients progressing on an oxaliplatin-containing regimen [I, A].
• Patients who received bevacizumab first line should be considered for
treatment with: ° Bevacizumab post-continuation strategy [I, A].
° Aflibercept or ramucirumab (in combination with FOLFIRI) when
treated in first line with oxaliplatin [I, A].
° EGFR antibodies in combination with FOLFIRI/irinotecan for patients
with RAS wild-type (BRAF wild-type) disease
• Relative benefit of EGFR antibodies is similar in later lines compared with
second line [II, A].

Colorectal Cancer
Consensus recommendation for patients where cytoreduction with
‘conversion’ and/or the integration of local ablative treatment is the goal
• A1a. For those patients who have RAS wild-type disease, a cytotoxic
doublet plus an EGFR antibody should be the treatment of choice
• A1b. For those patients with RAS mutant disease, a cytotoxic doublet
plus bevacizumab or cytotoxic triplet plus bevacizumab are the preferred
options
• A1c. Patients should be revaluated for their disease status every 2
months in order to ensure that resectable patients are not over- treated
• A1d. If, after the first re-evaluation at 2 months, there is evidence of
tumour shrinkage, patients should be recommended for either potentially
curative surgery or the most suitable LAT strategy—with a view to eliminating
all evidence of disease (i.e. R0 resection, NED)

Colorectal Cancer
Consensus recommendation for patients where cytoreduction with
‘conversion’ and/or the integration of local ablative treatment is the
goal
• A1e. If no response is evident at first evaluation, it is suggested
that the cytotoxic doublet is changed in order to maximise the
chance of resection [5]
• A1f. Where there is evidence for cytoreduction but the patients
are not suitable for surgery, they should continue on combination
chemotherapy plus the appropriate biological dependent on RAS
and BRAF mutation status as indicated in Figure 4.
• A1g. Where there is evidence of disease progression, patients
should continue to second-line therapy (Figure 5).
• A1h. Toxicity might also require a change to an alternative
regimen.

Colorectal Cancer
Consensus recommendation for patients where cytoreduction is needed because of
aggressive biology and/or risk of developing or existing severe symptoms
• A2a. For those patients who have RAS wild-type disease, a cytotoxic doublet plus
an EGFR antibody is a preferred option, although a cytotoxic doublet plus
bevacizumab is an equally valid alternative. A cytotoxic triplet plus or minus
bevacizumab may be an alternative for selected, very fit and motivated patients
• A2b. For those patients with RAS mutant disease, a cytotoxic doublet plus
bevacizumab is the preferred option. A cytotoxic triplet plus or minus bevacizumab
may be an alternative for selected, very fit and motivated patients
• A2c. Patients should be revaluated for their disease status every 2 months
• A2d. Treatment should not be changed in patients without tumour progression
and not suffering from major toxicity

Colorectal Cancer
Consensus recommendation for patients where disease control is the goal
• B1a. For these patients, a cytotoxic doublet in combination with bevacizumab or in
patients with RAS wild-type tumours, a cytotoxic doublet plus an EGFR antibody are
recommended
• B1b. Patients should be revaluated for their disease status every 2–3 months
• B1c. In patients with a good response or at least disease control, active
maintenance therapy should be considered. A fluoropyrimidine plus bevacizumab
is the preferred option if they started their treatment with a cytotoxic doublet plus
bevacizumab
• B1d. Where there is evidence of disease progression, patients should continue to
second-line therapy (Figure 5)
• B1e. Toxicity might also require a change to second-line therapy.

Controversias actuales en el manejo de cáncer colorrectal metastàsico

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