Chemotherapy and Targeting therapy in Colon Cancer

Aru W. Sudoyo

Div. Hematology – Medical Oncology

Dept. Internal Medicine

University of Indonesia

Chemotherapy and Targeting therapy

in Colon Cancer

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

colorectal tumor

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.

Normal colonic epithelium

Dysplastic aberrant crypt foci

Initial adenoma develops

Intermediate adenoma

Late adenoma

Carcinoma

Metastasis

Mutation in APC

Mutation in K-ras

Mutation in DCC

Mutation in p53

Other alteration?

clinicaloptions.com/onco

Colorectal Cancer – Oncology Conference Coverage

5-year colon cancer survival by stages

5th and 6th AJCC edition system

Stage I

N0 M0

T1 or T2

Stage II

N0 M0

T3 or T4

Stage IVStage III

N1 M0

Any T

Any N M1

Any T

83% 60%93% 8%

1. Surveillance, Epidemiology, and End Results registry; 2 O’ Connell et al, J Natl Cancer Inst 2004, 96: 1420-25

IIa IIb IIIa IIIb IIIc

N0 M0

T3

N0 M0

T4

N1 M0

T1-2

N1 M0

T3-4

N2 M0

Any T

85% 72% 83% 64% 44%

6th AJCC

(2002)

72% 83%

P<0.001

5-yr OS

5th AJCC

(1997)

5-yr OS

119 363 patients with colon cancer in the SEER1 US registry (1991-2000)

Median OSMonths

1980s 1990s 2000s 2008

Cetuximab

BSC

Irinotecan

Xeloda

Oxaliplatin

Avastin

5-FU

PanitumumabBSC: best supportive care

Evolution of Colorectal Cancer

treatment landscape

15

10

5

0

20

25

30

Survival by surgical stage in colon cancer

Surgical stage 5-year survival (%)

I 85–95%

II 60–80%

III 30–60%

IV <5%

Adapted from O’Connell In: ASCO Educational Book 1994

Place for

systemic

therapy

9/12/2010

Template

copyright 2005 www.b

10

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

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 /

CPT -11

FA2hrs.IV

200mg/m2

5-Fubolus & 5-

FU22hrs.IV

400mg/m2

600mg/m2

FA 2hrs.IV

200mg/m2

5-FU/FA: D1 & D2

5-Fubolus & 5-

FU22hrs.IV

400mg/m2

600mg/m2

Disease-free Survival: Stage II and Stage

III Patients

Data cut-off: June 2006

HR [95% CI] p-value

Stage II 0.84 [0.62–1.14] 0.258

Stage III 0.78 [0.65–0.93] 0.005

FOLFOX4 stage II

LV5FU2 stage II

FOLFOX4 stage III

LV5FU2 stage III

Months

Pro

ba

bil

ity

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 72

3.8%

7.5%

p=0.258

p=0.005

Oxaliplatin and capecitabine

Day 1 8 15 21Oxaliplatin

130mg/m2

as a

2-hour i.v. infusion

Oral capecitabine

1,000mg/m2

twice daily

Days 1–14 Rest

Repeat cycle at day 22

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

Irinotecan and capecitabine

Irinotecan

200–350mg/m2

30-minute

i.v. infusion

capecitabine

750–1,250mg/m2

twice daily

Rest

Day 1 8 15 21

Days 1–14

Repeat cycle at day 22

RSCM, 2007

de Gramont, 2005

de Gramont, 2005

METASTATIC COLON CANCER

De Gramont, 2006

toxicity

safety

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

clinicaloptions.com/oncology

Advances in Metastatic Colorectal Cancer

Role of Biologic,

Targeted Therapy



Proliferation MetastasisAngiogenesisApoptosis

Shc

PI3-K

RafMEKK-1

MEKMKK-7

JNK

ERK

Ras

mTOR

Grb2

AKT

Sos-1

Which Target?



Shc

PI3-K

RafMEKK-1

MEKMKK-7

JNK

ERK

Ras

mTOR

Grb2

AKT

Sos-1

Which Target?



Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center.

Sos-1

Ras

MEKK-1MEK

Shc

PI3-K

Raf

MKK-7

Grb2

AKT

JNK

ERK



Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center.

Sos-1

Ras

MEKK-1MEK

Shc

PI3-K

Raf

MKK-7

Grb2

AKT

JNK

ERK

Where’s the Target?



The VEGF Family and Its Receptors

Neufeld G, et al. FASEB J. 1999;13:9-22.

VEGFR-3

(Flt-4)

VEGFR-2

(Flk-1/KDR)

VEGFR-1

(Flt-1)

Angiogenesis Lymphangiogenesis

Angiogenesis

Lymphangiogenesis

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

VEGF regulates angiogenesis via interaction with receptor tyrosine kinases

– VEGFR-2/KDR and VEGFR-1/Flt-1



VEGF and other signals promote the

angiogenic switch in tumours

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

Small tumour (1–2mm)

• Avascular

• Dormant

Larger tumour

• Vascular

• Metastatic potential

Angiogenic switchResults in overexpression

of pro-angiogenic signals,

such as VEGF



Angiogenesis is involved throughout

tumour formation, growth and

metastasis

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

Stages at which angiogenesis plays a role in tumour progression

Premalignant

stage

Malignant

tumour

Tumour

growth

Vascular

invasion

Dormant

micrometastasis

Overt

metastasis

(Avascular

tumour)

(Angiogenic

switch)

(Vascularised

tumour)

(Tumour cell

intravasation)

(Seeding in

distant organs)

(Secondary

angiogenesis)

AVF2107: bevacizumab + IFL extends OS

and PFS in first-line mCRC

OS

esti

mate

15.6 20.3

0 6 12 18 24 30

Time (months)

Hurwitz, et al. NEJM 2004

1.0

0.8

0.6

0.4

0.2

0

Bevacizumab

+ IFL (n=402)

Placebo

+ IFL (n=411)

HR=0.66

p<0.001

0 10 20 30

Time (months)

10.66.2

4.7 month

increase

in median

OS

4.4 month

increase

in median

PFS

Bevacizumab + IFL

Placebo + IFL

HR=0.54

p<0.001

PF

S e

sti

mate

1.0

0.8

0.6

0.4

0.2

0

OS

esti

mate

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24

Bevacizumab era (2006)

30.6% received bevacizumab

Pre-bevacizumab (2003–2004)

5.9% received bevacizumab p<0.001

Time (months)

30

Bevacizumab era (2006), n=448

Pre-bevacizumab (2003–2004), n=969

Bevacizumab + standard chemotherapy

significantly improved OS (2006):

23.6 vs 18.6 months (p<0.001)

Experience in British Columbia:

impact of bevacizumab in mCRC

Renouf, et al. ASCO 2009

30

25

20

15

10

5

0

Med

ian

OS

(m

on

ths)

Bevacizumab + oxaliplatin-based

regimens: median OS

XELOX/

FOLFOX4

XELOX/

FOLFOX4

Bevacizumab +

FOLFOX FOLFOX XELOXXELOXOxaliplatin-

based

chemotherapy

1. Saltz, et al. JCO 2008; 2. Arnold, et al. ASCO GI 2010

3. Kozloff, et al. Oncologist 2009; 4. Van Cutsem, et al. Ann Oncol 2009Note: cross-study comparison

19.921.3

27.0

24.4 23.6

25.9

23.0

Non-randomised/observational studiesPhase III studies

NO16966

(n=701)1

NO16966

(n=699)1

German

registry

(n=312)2

BRiTE

(n=1,093)3BRiTE

(n=94)3

BEAT

(n=552)4

BEAT

(n=346)4

EGFR


Translating Science Into Clinical Practice: Targeted Therapies

Shc

PI3K

RafMEKK-1

MEKMKK-7

JNK

ERK

Ras

mTOR

Grb2

AKT

Sos-1

EGFR activation mediates multiple processes

EGF Pathway

Adapted from:Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174.



Shc

PI3K

RafMEKK-1

MEKMKK-7

JNK

ERK

Ras

mTOR

Grb2

AKT

Sos-1

EGFR activation mediates

multiple processesEGF Pathway

Adapted from:

Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174.



ProliferationApoptosis Resistance Transcription

TGFα Interleukin-8

bFGF VEGF

MetastasisAngiogenesis

Shc

PI3K

RafMEKK-1

MEKMKK-7

JNK ERK

Ras

mTOR

Grb2

AKT

Sos-1

EGF Pathway

RAS Mutations: 30% of Human

Cancers

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

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%



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



HR: 0.54

(95% CI: 0.42-0.71)

P < .0001

Time to Progression

HR: 0.91

(95% CI: 0.68-1.21)

P = .48

OS

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

0

20

40

60

80

100

0 2 4 6 8 10 12

Pro

gre

ssio

n F

ree (

%)

00 2 4 6 8 10 12 14 16

MonthsMonths

Ali

ve (

%)

Cunningham D, et al. N Engl J Med. 2004;351:337-345. Copyright ©

2004 Massachusetts Medical Society. All rights reserved.

The BOND Study: Survival Data

20

40

60

80

100

Cetuximab (CRYSTAL): OS and PFS in

KRAS wild-type

FOLFIRI

(n=350)

FOLFIRI + cetuximab

(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

Su

rviv

al (M

os

)

16

14

12

10

8

6

4

2

0

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.

No reaction Grade 2 rashGrade 1 rash Grade 3 rash

CRC[1] CRC[2] CRC[3] CRC[4] Pancreatic[5] HNSCC[6]

Study: 9923 0141 BOND

PTEN null

(all other WT)

~6%

BRAF MT

8–10%

Reason

unknown

6–8%

NRAS MT

3–5%

Not all KRAS wild-type mCRC patients

will respond to EGFR inhibitors1

1. Hawkes, Cunningham. JCO 2010; 2. Cejas, et al. ASCO 2010

In 59% of patients, BRAF, PI3KCA and PTEN mutational status of primary tumour

is not representative of the related metastases2

PTEN null

(all other WT)

~10%

PI3KCA MT

(all other WT)

~7%

Possible responders 22–30% (includes response to dose escalation)

PI3KCA MT

(all other WT)

~5%

Non-responders 70%

KRAS MT

40%

MT = mutant; WT = wild-type

Overall Survival

S Berry et al. ASCO 2008 Abstract 4025

50

Significant Progress has Already

been Achieved in Extending Life

50

12 mo

15-17 mo

23+ mo

2000s

1980s

Anthracyclines

BSC

Taxanes (Docetaxel, Paclitaxel)

1990s

Metastatic Breast Cancer(Median Overall Survival - months)

6 mo

10-12 mo

18-22+ mo

2000s

1980s

5-FU/LV

+Oxaliplatin/ Irinotecan/bevacizumab

1990s

BSC

Metastatic Colorectal Cancer(Median Overall Survival - months)

BSC – Best Supportive Care

First line strategy of metastatic

CRC

Does the patients need (or desire) aggressive

therapy ?

NO~15%YES~85

%

5FU/Cape±

bev

K-RAS

MUTWTUnavailable

Double +

bev

Doublet +

cetuximab

Doublet +

bevacizumab

Doublet +

bev

10.0

11.3

11.2

11.0

(n=1,092)

(n=346)

(n=552)

(n=94)

10 months

PFS benefit of bevacizumab with oxaliplatin-based therapy confirmed in daily practice

1. Saltz, et al. JCO 2008; 2. Hecht, et al. ASCO GI 2008 (poster)

3. Reinacher-Schick, et al. ASCO 2008 (poster); 4. Kozloff, et al. ASCO GI 2007 (poster)

5. Van Cutsem, et al. Ann Oncol 2009

*Secondary endpoint†Large prospective,

observational trials

XELOX/FOLFOX4 alone (NO16966)1

Bevacizumab + XELOX/FOLFOX4

(NO16966)1

Bevacizumab + XELOX/FOLFOX4

‘on treatment’* (NO16966)1

Bevacizumab + oxaliplatin (PACCE)2

Ph

ase II/III

clin

ical

tria

ls

Bevacizumab + FOLFOX (BRiTE)4

Bevacizumab + FOLFOX (BEAT)5

Bevacizumab + XELOX (BEAT)5

Bevacizumab + XELOX (BRiTE)4

Daily p

racti

ce

†

9.4

11.1

8.0

10.4

(n=699)

(n=699)

(n=699)

(n=410)

0 2 4 6 8 10 12

Median PFS (months)

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

Treatment strategy in mCRC is driven by

patient assessment

Figure modified from Nordlinger, et al. Ann Oncol 2009

First-line therapy for patients with metastases

Upfront

resectable

Curative surgery

Chemotherapy

resection

Borderline

resectable

Make eligible for

curative surgery

Chemotherapy

± biologics

Unresectable

Extend survival and

maintain quality of life

Chemotherapy

± biologics

Patient

assessment

Treatment

goal

Treatment

strategy

Future biomakers

– BRAF, PI3K, PTEN?

Treatment strategy in mCRC is becoming

more complex

Patient-related

– Age and comorbidities

Tumour- and treatment-related

– Adjuvant therapy with

oxaliplatin?

– Resectable metastases?

– Resectable sites?

– KRAS status?

– Prognostic?

– Oxaliplatin reintroduction: stop

and go?

After initial therapy

– Resectability after tumour

shrinkage

– Can we stop

chemotherapy?

– Bevacizumab beyond

progression

– Neurotoxicity

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

Figure modified from Nordlinger, et al. Ann Oncol 2009

First-line therapy for patients with metastases

Upfront

resectable

Curative surgery

Chemotherapy

resection

Borderline

resectable

Make eligible for

curative surgery

Chemotherapy

biologics

Unresectable

Extend survival and

maintain quality of life

Chemotherapy

± biologics

Patient

assessment

Treatment

goal

Treatment

strategy

NCCN V.2. 2010 recommendations for first-

line treatment of mCRC

NCCN clinical practice guidelines in oncology: colon cancer. V.2.2010

Previously

untreated

mCRC

Patients appropriate

for intensive therapy

FOLFOX ± bevacizumab

FOLFIRI + bevacizumab

FOLFOX ± cetuximab* or panitumumab*

FOLFIRI ± cetuximab* or panitumumab*

5-FU/LV + bevacizumab

FOLFOXIRI‡

XELOX ± bevacizumab

*KRAS wild-type only‡Category 2B recommendation

Patients not appropriate

for intensive therapy

Capecitabine ± bevacizumab

Infusional 5-FU/LV ± bevacizumab

Cetuximab*‡

Panitumumab*‡

Liver ± lung metastases

Potential resectability after ‘conversion’

Most active combination

Goal: resection cure?

Parameters: RR, pCR?, (OS)

Multiple metastases

Rapid progression

Tumour-related symptoms

At risk for deterioration or complications

Most feasible option

Goal: relief of symptoms, no additional

toxicity

Parameters: PFS, (RR), toxicity, (OS)

Multiple metastases

No option for resection

No symptoms

(Severe comorbidity)

Active upfront combination or sequential

strategy

Goal: PFS without unnecessary toxicity

Parameters: PFS, PFS 1+2, toxicity, OS

Schmoll, Sargent. Lancet 2007

Schmiegel, et al. J Gastroenterol 2008; Arnold, et al. Onkologie 2009

Therapeutic strategy according to

clinical situation and treatment goal according to German S3 guideline

First line strategy of metastatic CRCDoes the patients need (or desire) aggressive

therapy ?

NO~15%YES~85

%

5FU/Cape±

bev

K-RAS

MUTWTUnavailable

Double +

bev

Doublet +

cetuximab

Doublet +

bevacizumab

Doublet +

bev

Liver ± lung metastases

Potential resectability after ‘conversion’

Most active combination

Goal: resection cure?

Parameters: RR, pCR?, (OS)

Multiple metastases

Rapid progression

Tumour-related symptoms

At risk for deterioration or complications

Most feasible option

Goal: relief of symptoms, no additional

toxicity

Parameters: PFS, (RR), toxicity, (OS)

Multiple metastases

No option for resection

No symptoms

(Severe comorbidity)

Active upfront combination or sequential

strategy

Goal: PFS without unnecessary toxicity

Parameters: PFS, PFS 1+2, toxicity, OS

Schmoll, Sargent. Lancet 2007

Schmiegel, et al. J Gastroenterol 2008; Arnold, et al. Onkologie 2009

Therapeutic strategy according to

clinical situation and treatment goal according to German S3 guideline

Terima kasih atas perhatiannya ….TERIMA KASIH !!!

Documents

Chemotherapy and Targeting therapy in Colon Cancer