Chemotherapy and Targeting therapy

in Colon Cancer

Aru W. Sudoyo
Div. Hematology – Medical Oncology
Dept. Internal Medicine
University of Indonesia
 Colorectal Cancer: Epidemiology
 Data from the United States (2006)[1]
 148,610 new cases: third highest cancer incidence
 55,170 deaths: second leading cause of cancer-related death in
men, third leading cause in women
 Worldwide (2002)[2]
 1,023,256 new cases: third highest incidence after lung, breast
cancer
 529,020 deaths: fourth overall cause of cancer-related death
after lung, gastric, liver cancer
 INDONESIA ? One of 10 most common cancers

1. Jemal A, et al. CA: Cancer J Clin. 2006;56:106-130.

2. Kamangar F, et al. J Clin Oncol. 2006; 24:2137-2150.
 The Adenoma-Carcinoma Process
 Mutations leading
to formation of
Normal colonic epithelium
colorectal tumor Mutation in APC
Dysplastic aberrant crypt foci

Initial adenoma develops

Mutation in K-ras
Intermediate adenoma
Mutation in DCC
Late adenoma
Mutation in p53
Carcinoma
Other alteration?
Metastasis
Kinzler KW, et al. New York, The genetic basis of human cancer. NY: McGraw-Hill,
1998:565-87. Vogelstein B, et al. N Engl J Med. 1988;319:525-532. Fearon ER, et al.
Cell. 1990;61:759-767.
 Colorectal Cancer – Oncology Conference Coverage

5-year colon cancer survival by stages

5th and 6th AJCC edition system
119 363 patients with colon cancer in the SEER1 US registry (1991-2000)

Stage I Stage II Stage III Stage IV

T1 or T2 T3 or T4 Any T Any T
5th AJCC
(1997) N0 M0 N0 M0 N1 M0 Any N M1

5-yr OS 93% 83% 60% 8%

IIa IIb IIIa IIIb IIIc

6th AJCC T3 T4 T1-2 T3-4 Any T
(2002)
N0 M0 N0 M0 N1 M0 N1 M0 N2 M0

5-yr OS 85% 72% 83% 64% 44%

P<0.001
clinicaloptions.com/onco
1. Surveillance, Epidemiology, and End Results registry; 2 O’ Connell et al, J Natl Cancer Inst 2004, 96: 1420-25
 Evolution of Colorectal Cancer
treatment landscape
Months
30 Median OS
25
20
15
10
5
0

1980s 1990s 2000s 2008

BSC
5-FU
Irinotecan
Xeloda
Oxaliplatin
Avastin
Cetuximab
BSC: best supportive care Panitumumab
 Survival by surgical stage
in colon cancer

Surgical stage 5-year survival (%)

I 85–95%

II 60–80%
Place for
III 30–60% systemic
therapy
IV <5%

Adapted from O’Connell In: ASCO Educational Book 1994

 Key therapeutic agents in CRC:
Historical perspectives

• 1960 5-FU is the cornerstone of first-l ine therapy in MCRC

• 1985 Addition of LV to 5-FU bolus regimens
• 1998 Irinotecan as single agent approved as second-line in
CRC
• 2000 Irinotecan approved as adjuvant first-line in CRC
• 2001 Capecitabine approved as first-line in MCRC
• 2002 Oxaliplatin approved as second-line agent in CRC
• 2004 Oxaliplatin approved as adjuvant first-line agent in
CRC
• 2004 Introduction of biologicals
• Bevacizumab
• Cetuximab

Templa
te
9/12/2010 10
copyrig
ht 2005
Adjuvant Therapy
 Goals of adjuvant chemotherapy
 Target viable and occult tumor cells kan sel tumor
 Eradicate tumor cells before refractory to treatment
 Risk: benefit
 Balance between possibility of cure and tolerance to
side effects

Rectal cancer : +
radiotherapy
 Protokol De Gramont @ 2 wks

Oxaliplat / FA2hrs.IV 5-Fubolus & 5-

CPT -11 200mg/m2 FU22hrs.IV
400mg/m2
600mg/m2

FA 2hrs.IV 5-Fubolus & 5-

200mg/m2 FU22hrs.IV
400mg/m2
5-FU/FA: D1 & D2
600mg/m2
 Disease-free Survival: Stage II and Stage
III Patients
1.0

0.9 p=0.258
0.8 3.8%
p=0.005
0.7
Probability

0.6 7.5%
0.5

0.4

0.3 FOLFOX4 stage II

HR [95% CI] p-value
LV5FU2 stage II
0.2 Stage II 0.84 [0.62–1.14] 0.258
FOLFOX4 stage III
0.1 Stage III 0.78 [0.65–0.93] 0.005 LV5FU2 stage III
0
0 6 12 18 24 30 36 42 48 54 60 66 72
Data cut-off: June 2006 Months
 Oxaliplatin and capecitabine

Oxaliplatin
130mg/m2 as a Day 1 8 15 21
2-hour i.v. infusion

Oral capecitabine
1,000mg/m2 Days 1–14 Rest
twice daily

Repeat cycle at day 22

Díaz-Rubio E et al. Ann Oncol (in press)

 Irinotecan and capecitabine

Irinotecan
Day 1 8 15 21
200–350mg/m2
30-minute
i.v. infusion

capecitabine
750–1,250mg/m2 Days 1–14 Rest
twice daily

Repeat cycle at day 22

RSCM, 2007
de Gramont, 2005
de Gramont, 2005
METASTATIC COLON CANCER
 toxicity

safety
De Gramont, 2006
Advanced or Metastatic Colorectal Cancer
1st Line
 FOLFOX 4 Oxaliplatin 85 mg/m2 IV over 2 hours, day
1; Leucovorin 200 mg/m2 IV over 2 hours, days 1 and
2; 5-FU 400 mg/m2 IV bolus, then 600 mg/m2 IV over
22 hours continuous infusion, day 1 and 2 Repeat
every 2 weeks
 FOLFIRI Irinotecan 180 mg/m2 IV over 2 hours, day
1; Leucovorin 400mg/m2 IV over 2 hours prior to 5-FU,
days 1 and 2; 5-FU 400 mg/m2 IV bolus, then 600
mg/m2 IV over 22 hours continuous infusion, days 1
and 2 Repeat every 2 weeks
 Bevacizumab 5 mg/kg IV every 2 weeks + 5-FU and
Leucovorin or IFL or FOLFOX or FOLFIRI
 Cetuximab irinotecan Cetuximab 400 mg/m2 1st
infusion, then 250 mg/m2 Weekly
Advances in Metastatic Colorectal Cancer

Role of Biologic,
Targeted Therapy

clinicaloptions.com/oncology
Advances in Metastatic Colorectal Cancer

Which Target?

Shc
Grb2
PI3-K Sos-1

Ras
AKT
Raf
MEKK-1

MEK
mTOR MKK-7

ERK
JNK

Apoptosis Proliferation Angiogenesis Metastasis clinicaloptions.com/oncology

Advances in Metastatic Colorectal Cancer

Which Target?

Shc
Grb2
PI3-K Sos-1

Ras
AKT
Raf
MEKK-1

MEK
mTOR MKK-7

ERK
JNK

clinicaloptions.com/oncology
 Advances in Metastatic Colorectal Cancer

Sos-1
PI3-K

Ras
Grb2
Shc

Raf
MEK
MEKK-1

JNK
MKK-7
ERK
AKT

Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center. clinicaloptions.com/oncology

 Advances in Metastatic Colorectal Cancer

Where’s the Target?

Sos-1
PI3-K

Ras
Grb2
Shc

Raf
MEK
MEKK-1

JNK
MKK-7
ERK
AKT

Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center. clinicaloptions.com/oncology

 Advances in Metastatic Colorectal Cancer

The VEGF Family and Its Receptors

PIGF VEGF-A VEGF-B VEGF-C VEGF-D

VEGFR-1 VEGFR-2 VEGFR-3

(Flt-1) (Flk-1/KDR) (Flt-4)

Angiogenesis
Angiogenesis Lymphangiogenesis Lymphangiogenesis

 VEGF regulates angiogenesis via interaction with receptor tyrosine kinases

– VEGFR-2/KDR and VEGFR-1/Flt-1
Neufeld G, et al. FASEB J. 1999;13:9-22. clinicaloptions.com/oncology
Advances in Metastatic Colorectal Cancer

VEGF and other signals promote the

angiogenic switch in tumours
Small tumour (1–2mm) Larger tumour
• Avascular • Vascular
• Dormant • Metastatic potential

Angiogenic switch
Results in overexpression
of pro-angiogenic signals,
such as VEGF

Adapted from Bergers G, et al. Nature 2002;3:401–10

clinicaloptions.com/oncology
 Advances in Metastatic Colorectal Cancer

Angiogenesis is involved throughout

tumour formation, growth and
metastasis
Premalignant Malignant Tumour Vascular Dormant Overt
stage tumour growth invasion micrometastasis metastasis

(Avascular (Angiogenic (Vascularised (Tumour cell (Seeding in (Secondary

tumour) switch) tumour) intravasation) distant organs) angiogenesis)

Stages at which angiogenesis plays a role in tumour progression

Adapted from Poon RT, et al. J Clin Oncol 2001;19:1207–25

clinicaloptions.com/oncology
AVF2107: bevacizumab + IFL extends OS
and PFS in first-line mCRC
1.0 4.7 month 1.0 4.4 month
increase increase
in median in median
OS PFS
0.8 0.8 Bevacizumab + IFL
Placebo + IFL
HR=0.54

PFS estimate
OS estimate

0.6 0.6 p<0.001

Bevacizumab
0.4 0.4
+ IFL (n=402)
Placebo
+ IFL (n=411)
0.2 HR=0.66 0.2
p<0.001

15.6 20.3 6.2 10.6

0 0
0 6 12 18 24 30 0 10 20 30
Time (months) Time (months)

Hurwitz, et al. NEJM 2004

Experience in British Columbia:
impact of bevacizumab in mCRC
1.0

0.8
Bevacizumab era (2006)
30.6% received bevacizumab
OS estimate

0.6

0.4 Pre-bevacizumab (2003–2004)

5.9% received bevacizumab p<0.001

0.2 Bevacizumab + standard chemotherapy

significantly improved OS (2006):
23.6 vs 18.6 months (p<0.001)
0
0 6 12 18 24 30
Time (months)
Bevacizumab era (2006), n=448
Pre-bevacizumab (2003–2004), n=969 Renouf, et al. ASCO 2009
Bevacizumab + oxaliplatin-based
regimens: median OS
Phase III studies Non-randomised/observational studies
German
30 registry
(n=312)2 BEAT
BRiTE BRiTE (n=552)4
27.0 (n=1,093)3 BEAT
25 (n=94)3 25.9
NO16966 (n=346)4
NO16966 (n=699)1 24.4 23.6
Median OS (months)

(n=701)1 23.0
20 21.3
19.9

15

10

0
Bevacizumab +
XELOX/ XELOX/ Oxaliplatin- FOLFOX XELOX FOLFOX XELOX
FOLFOX4 FOLFOX4 based
chemotherapy
1. Saltz, et al. JCO 2008; 2. Arnold, et al. ASCO GI 2010
Note: cross-study comparison 3. Kozloff, et al. Oncologist 2009; 4. Van Cutsem, et al. Ann Oncol 2009
EGFR
 Translating Science Into Clinical Practice: Targeted Therapies

 EGFR activation
EGF Pathway mediates multiple
processes

Shc
Grb2
PI3K Sos-1

Ras
AKT
Raf
MEKK-1

MEK
mTOR MKK-7

ERK
Adapted from:
Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174. JNK clinicaloptions.com/oncology
 Translating Science Into Clinical Practice: Targeted Therapies

EGFR activation mediates

EGF Pathway multiple processes

Shc
Grb2
PI3K Sos-1

Ras
AKT
Raf
MEKK-1

MEK
mTOR MKK-7

ERK
Adapted from: JNK
Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174. clinicaloptions.com/oncology
Translating Science Into Clinical Practice: Targeted Therapies

EGF Pathway
Angiogenesis Metastasis

TGFα Interleukin-8
bFGF VEGF
Shc
Grb2
Sos-1
PI3K
Ras

AKT MEKK-1 Raf

MKK-7 MEK
mTOR
JNK ERK

Apoptosis Resistance Proliferation Transcription clinicaloptions.com/oncology

 RAS Mutations: 30% of Human
Cancers
Pancreatic carcinoma 72% to 90%
Cholangiocarcinoma 55%
Colon adenocarcinoma 32% to 57%
Thyroid carcinoma 30%
Seminoma 40%
Embryonal rhabdomyosarcoma 35%
Acute myelogenous leukemia 35%
Myeloblastic syndromes 30%
Lung carcinoma 15% to 50%

Bos JL. Cancer Res. 1989;49:4682-4689.

Translating Science Into Clinical Practice: Targeted Therapies

EGFR-Directed Therapeutics:
Clinical Indications
Agent Indication
Gefitinib Locally advanced or metastatic NSCLC
Erlotinib Advanced NSCLC
Advanced pancreatic cancer
Cetuximab Head and neck cancer
mCRC
Panitumumab mCRC

clinicaloptions.com/oncology
 Translating Science Into Clinical Practice: Targeted Therapies

The BOND Study: Survival Data

 Addition of cetuximab to irinotecan improved the response rate and time to
progression but not overall survival

Time to Progression OS
100 100
Progression Free (%)

HR: 0.54 HR: 0.91

80 80
(95% CI: 0.42-0.71) (95% CI: 0.68-1.21)
P < .0001 P = .48

Alive (%)
60 60

40 40

20 20

0 0
0 2 4 6 8 10 12 0 2 4 6 8 10 12 14 16
Months Months
Cunningham D, et al. N Engl J Med. 2004;351:337-345. Copyright ©
2004 Massachusetts Medical Society. All rights reserved. clinicaloptions.com/oncology
Cetuximab (CRYSTAL): OS and PFS in
KRAS wild-type

FOLFIRI FOLFIRI + cetuximab

(n=350) (n=316) HR; p value

Median OS, months 20.0 23.5 0.796

0.0093

Median PFS, months 8.4 9.9 0.696

0.0012

ORR, % 40 57 –
<0.0001

Van Cutsem, et al. ASCO GI 2010

Correlation of Rash and Survival in
Cetuximab-Treated Patients
16 No reaction Grade 1 rash Grade 2 rash Grade 3 rash
14
12
Survival (Mos)

10
8
6
4
2
0
CRC[1] CRC[2] CRC[3] CRC[4] Pancreatic[5] HNSCC[6]
Study: 9923 0141 BOND
1. Saltz LB, et al. ASCO 2001. Abstract 7. 2. Saltz LB, et al. J Clin Oncol.
2004;22:1201-1208. 3. Cunningham D, et al. N Engl J Med. 2004;351:337-345.
4. Van Cutsem, et al. EORTC/NCI 2004. Abstract 279. 5. Xiong HQ, et al.
J Clin Oncol. 2004;22:2610-2616. 6. Kies MS, et al. ASCO 2002. Abstract 925.
Not all KRAS wild-type mCRC patients
1
will respond to EGFR inhibitors
Possible responders 22–30% (includes response to dose escalation)
PI3KCA MT PTEN null
(all other WT) (all other WT)
~5% ~6%

PI3KCA MT
(all other WT)
~7% PTEN null
(all other WT)
Reason ~10%
unknown
6–8%

KRAS MT
40%
NRAS MT BRAF MT
3–5% 8–10%

Non-responders 70%
In 59% of patients, BRAF, PI3KCA and PTEN mutational status of primary tumour
is not representative of the related metastases2

MT = mutant; WT = wild-type 1. Hawkes, Cunningham. JCO 2010; 2. Cejas, et al. ASCO 2010
Overall Survival

S Berry et al. ASCO 2008 Abstract 4025

 Significant Progress has Already
been Achieved in Extending Life
Metastatic Colorectal Cancer Metastatic Breast Cancer
(Median Overall Survival - months) (Median Overall Survival - months)

BSC BSC
1980s 6 mo 1980s 12 mo

5-FU/LV Anthracyclines
1990s 10-12 mo
1990s 15-17 mo

2000s +Oxaliplatin/ Irinotecan/bevacizumab 2000s Taxanes (Docetaxel, Paclitaxel)

18-22+ mo 23+ mo

BSC – Best Supportive Care

50 50
 First line strategy of metastatic
CRC
Does the patients need (or desire) aggressive
therapy ?

YES~85 NO~15%
%
K-RAS 5FU/Cape±
bev

Unavailable WT MUT

Double + Doublet +
cetuximab Doublet +
bev bev
Doublet +
bevacizumab
 PFS benefit of bevacizumab with oxaliplatin-based
therapy confirmed in daily practice

XELOX/FOLFOX4 alone (NO16966)1 (n=699) 8.0 10 months

Phase II/III clinical

Bevacizumab + XELOX/FOLFOX4
(n=699) 9.4
(NO16966)1
trials

Bevacizumab + XELOX/FOLFOX4
(n=699) 10.4
‘on treatment’* (NO16966)1

Bevacizumab + oxaliplatin (PACCE)2 (n=410) 11.1

Bevacizumab + XELOX (AIO 0604)3 (n=127) 10.4

Bevacizumab + FOLFOX (BRiTE)4 (n=1,092) 10.0

Daily practice†

Bevacizumab + FOLFOX (BEAT)5 (n=552) 11.3

Bevacizumab + XELOX (BRiTE)4 (n=94) 11.2

Bevacizumab + XELOX (BEAT)5 (n=346) 11.0

0 2 4 6 8 10 12
Median PFS (months)

*Secondary endpoint 1. Saltz, et al. JCO 2008; 2. Hecht, et al. ASCO GI 2008 (poster)
†Large prospective, 3. Reinacher-Schick, et al. ASCO 2008 (poster); 4. Kozloff, et al. ASCO GI 2007 (poster)
observational trials 5. Van Cutsem, et al. Ann Oncol 2009
 Treatment strategy in mCRC is driven by
patient assessment
First-line therapy for patients with metastases

Patient Upfront Borderline

Unresectable
assessment resectable resectable

Treatment Make eligible for Extend survival and

Curative surgery
goal curative surgery maintain quality of life

Treatment Chemotherapy Chemotherapy Chemotherapy

strategy  resection ± biologics ± biologics

Figure modified from Nordlinger, et al. Ann Oncol 2009

Treatment strategy in mCRC is becoming
more complex

 Patient-related  After initial therapy

– Age and comorbidities – Resectability after tumour
 Tumour- and treatment-related shrinkage
– Adjuvant therapy with – Can we stop
oxaliplatin? chemotherapy?
– Resectable metastases? – Bevacizumab beyond
– Resectable sites? progression
– KRAS status? – Neurotoxicity
– Prognostic?
– Oxaliplatin reintroduction: stop
and go?
 Future biomakers
– BRAF, PI3K, PTEN?
Strategy for the treatment of metastatic CRC (modified from
Expert discussion ESMO/WCGIC Barcelona June 2009)
 Treatment strategy in mCRC is driven by patient
assessment

First-line therapy for patients with metastases

Patient Upfront Borderline

Unresectable
assessment resectable resectable

Treatment Make eligible for Extend survival and

Curative surgery
goal curative surgery maintain quality of life

Treatment Chemotherapy Chemotherapy Chemotherapy

strategy  resection biologics ± biologics

Figure modified from Nordlinger, et al. Ann Oncol 2009

 NCCN V.2. 2010 recommendations for first-
line treatment of mCRC
FOLFOX ± bevacizumab

XELOX ± bevacizumab

FOLFOX ± cetuximab* or panitumumab*

Patients appropriate
FOLFIRI + bevacizumab
for intensive therapy
FOLFIRI ± cetuximab* or panitumumab*

5-FU/LV + bevacizumab
Previously
untreated FOLFOXIRI‡
mCRC
Capecitabine ± bevacizumab

Patients not appropriate Infusional 5-FU/LV ± bevacizumab

for intensive therapy Cetuximab*‡

Panitumumab*‡

*KRAS wild-type only

‡Category 2B recommendation NCCN clinical practice guidelines in oncology: colon cancer. V.2.2010
 Therapeutic strategy according to
clinical situation and treatment goal
according to German S3 guideline
Liver ± lung metastases Most active combination
Potential resectability after ‘conversion’ Goal: resection  cure?
Parameters: RR, pCR?, (OS)

Multiple metastases Most feasible option

Rapid progression Goal: relief of symptoms, no additional
Tumour-related symptoms toxicity
At risk for deterioration or complications Parameters: PFS, (RR), toxicity, (OS)

Multiple metastases Active upfront combination or sequential

No option for resection strategy
No symptoms Goal: PFS without unnecessary toxicity
(Severe comorbidity) Parameters: PFS, PFS 1+2, toxicity, OS

Schmoll, Sargent. Lancet 2007

Schmiegel, et al. J Gastroenterol 2008; Arnold, et al. Onkologie 2009
 First line strategy of metastatic CRC
Does the patients need (or desire) aggressive
therapy ?

YES~85 NO~15%
%
K-RAS 5FU/Cape±
bev

Unavailable WT MUT

Double + Doublet +
cetuximab Doublet +
bev bev
Doublet +
bevacizumab
 Therapeutic strategy according to
clinical situation and treatment goal
according to German S3 guideline
Liver ± lung metastases Most active combination
Potential resectability after ‘conversion’ Goal: resection  cure?
Parameters: RR, pCR?, (OS)

Multiple metastases Most feasible option

Rapid progression Goal: relief of symptoms, no additional
Tumour-related symptoms toxicity
At risk for deterioration or complications Parameters: PFS, (RR), toxicity, (OS)

Multiple metastases Active upfront combination or sequential

No option for resection strategy
No symptoms Goal: PFS without unnecessary toxicity
(Severe comorbidity) Parameters: PFS, PFS 1+2, toxicity, OS

Schmoll, Sargent. Lancet 2007

Schmiegel, et al. J Gastroenterol 2008; Arnold, et al. Onkologie 2009
 TERIMA
Terima kasih atasKASIH !!!
perhatiannya ….