clinical review of current treatment strategies for colorectal cancer john l. marshall, md chief,...

Clinical Review of Current Treatment Strategies for Colorectal Cancer

John L. Marshall, MDJohn L. Marshall, MDChief, Division Hematology and OncologyChief, Division Hematology and Oncology

Director, Developmental Therapeutics and GI OncologyDirector, Developmental Therapeutics and GI Oncology

Lombardi Cancer CenterLombardi Cancer Center

Georgetown UniversityGeorgetown University

Washington, DCWashington, DC

Oncology Journal Club

Management of mCRC: An Evolving Treatment Algorithm

Diagnosis of mCRC

Resectable Unresectable

Adjuvant therapy

Surgery

Neo-adjuvant/Pre-operative

therapy

First-line

Second-line

Third-line

Borderline/PotentiallyResectable

Fourth-line

Treatment continuum

Advances in the Treatment of Colorectal Cancer

1980 1985 1990 1995 2000 2005

Therapeutic concepts

Palliative chemotherapy

Adjuvant chemotherapy

Neoadjuvant chemotherapy

Capecitabine

Oxaliplatin

Cetuximab

Bevacizumab

Irinotecan

5-FU

PanitumumabTargeted Therapies {

News from ASCO 2008

• EGFR/KRAS: Colon Cancer is split in two

– Trials close to re-tool

• MSI-H: Colon Cancer is split again?

– 5-FU harmful in adjuvant setting

• VEGF/EGFR: Dual inhibition may be bad

– PACCE

– CAIRO-2

Management of mCRC: An Evolving Treatment Algorithm

Diagnosis of mCRC

Resectable Unresectable

Adjuvant therapy

Surgery

Neo-adjuvant/Pre-operative

therapy

First-line

Second-line

Third-line

Borderline/PotentiallyResectable

Fourth-line

Treatment continuum

NCCN Guidelines: Advanced mCRC

NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. v2.2007.

Good Tolerance to Intensive Therapy

Poor Tolerance to Intensive Therapy

First-line Second-line Third- or Fourth-line

FOLFOX + BEV or

CapeOx + BEV

FOLFIRI + BEV

5-FU/LV + BEV

Cape ± BEV or5-FU + LV ± BEV

FOLFIRI orIrinotecan

FOLFIRI + cetuximab orCetuximab + irinotecan

FOLFOX or CapeOx

Cetuximab or panitumumab or cetuximab + irinotecan

Improvement in functional status

No improvement in functional status

Cetuximab or panitumumab

or cetuximab + irinotecan





Clinical trial or best supportive care

FOLFOX or CapeOx

FOLFOX or CapeOx

Irinotecan or FOLFIRI

Irinotecan

Best supportive care

Therapy after first progression as above

Camptosar: 180 mg/mCamptosar: 180 mg/m22 D 1 q 2wk D 1 q 2wkLV: 400 mg/mLV: 400 mg/m22 over 2hr D 1 q 2 wk over 2hr D 1 q 2 wk5-FU: 400 mg/m5-FU: 400 mg/m22 (bolus) D1 q 2 wk (bolus) D1 q 2 wk5-FU: 2,400 mg/m5-FU: 2,400 mg/m22 (46 hr infusion) (46 hr infusion)D 1 q 2 wkD 1 q 2 wk

Arm A – Camptosar + infusional

Camptosar:Camptosar: 125 mg/m 125 mg/m22

5-FU:5-FU:500 mg/m500 mg/m22

LV:LV: 20 mg/m 20 mg/m22 D 1, 8, q 3 wksD 1, 8, q 3 wks

Arm B – D1, D8 bolus

Camptosar: Camptosar: 250250 mg/mmg/m22 d1 q 3 wks d1 q 3 wksCapecitabine: 1,000 mg/mCapecitabine: 1,000 mg/m22 bid d1-14 q 3 wks bid d1-14 q 3 wks

Arm C - Campcape

RANDOMIZATION

Met

asta

tic D

isea

se

+ Celecoxib or Placebo

400 mg bid

+ Celecoxib or Placebo

400 mg bid

N = 900N = 900

BICC-C Trial

+ Bevacizumab

+ Bevacizumab

Period 1: Progression Free Survival Data thru March 1, 2006 (ITT)

RegimenMedian PFS

(Months)HR

(95% CI) P Value

FOLFIRI 7.6 -- --

mIFL 5.8 1.55(1.2, 2.0)

0.0009

CapeIRI 5.5 1.47(1.1, 1.9)

0.0049

00.10.20.30.40.50.60.70.80.9

1

0 5 10 15 20 25 30Months

Pro

port

ion

of P

FS

FOLFIRI

mIFL

CapeIRI

Period 2: Overall Survival Data Thru March 1, 2006 (ITT)

Regimen Median OS (Months) 1 Year HR

(95% CI) P Value

FOLFIRI+ BEV Not Reached 87% -- --

mIFL + BEV 18.7 61% 2.5(1.3,5.0)

0.01

00.10.20.30.40.50.60.70.80.9

1

0 5 10 15 20 25 30

Pro

port

ion

of P

atie

nts

Who

Sur

vive

d

Survival Time (months)

mIFL + bevacizumab

FOLFIRI + bevacizumab

Phase III Trial of XELOX vs. FOLFOX4 + Bevacizumab or Placebo in First-line mCRC

Study Design and Drugs

Protocol amended to 2x2 placebo-controlled design after bevacizumab Phase III data1 became available (N=1,401)

1Hurwitz H., et al. Proc ASCO 2003;22 (Abstract 3646)

XELOX + placebo N=350

FOLFOX4 + placebo N=351

XELOX + bevacizumab N=350

FOLFOX4 + bevacizumab N=350

XELOX N=317

FOLFOX4 N=317

Recruitment June 2003–May 2004 Recruitment Feb 2004–Feb 2005

Initial 2-arm open-label study (N=634)

OX = oxaliplatin; LV = leucovorin; BV = bevacizumab; PL = placebo; 5-FU = 5-fluorouracil

XELOX + bevacizumab/placebo: 21-day cycle

D1 D2 D15

Rest

Oral capecitabine 1,000 mg/m2 BID

BV or PL 7.5mg/kg IV 30–90 min

OX 130mg/m2

IV 2 h

D21

D1

FOLFOX4 + bevacizumab/placebo: 14-day cycleOX 85mg/m2

IV 2 hBV or PL5mg/kg IV 30–90 min

5-FU 600mg/m2 IV 22 h

5-FU 600mg/m2 IV 22 h

D2 D3

LV 200mg/m2 IV 2 h

LV 200mg/m2 IV 2 h

5-FU

400m

g/m

2

IV b

olu

s

5-FU

400m

g/m

2

IV b

olu

s

Cassidy et al. ESMO 2006. Oral PresentationCassidy et al. ESMO 2006. Oral Presentation

Roche Medical Affairs. All rights reserved.Roche Medical Affairs. All rights reserved.


PFS XELOX Non-inferiority

FOLFOX/FOLFOX + placebo/FOLFOX + bevacizumab N = 1,017; 826 events XELOX/XELOX + placebo/XELOX + bevacizumab N = 1,017; 813 events

Primary Objective Achieved Based on ITTPrimary Objective Achieved Based on ITT


Roche Medical Affairs. All rights reservedRoche Medical Affairs. All rights reserved ..

FOLFOX + placebo/XELOX + placeboN = 701; 547 events FOLFOX + bevacizumab/XELOX+bevacizumabN = 699; 513 events

HR = 0.83 [97.5% CI 0.72–0.95] (ITT)P = 0.0023

Primary Objective Achieved XELOX Subgroup FOLFOX SubgroupHR = 0.77 [97.5% CI 0.63–0.94] (ITT)

P = 0.0026

XELOX + placeboN = 350; 270 events XELOX + bevacizumabN = 350; 258 events

HR = 0.89 [97.5% CI 0.73–1.08] (ITT)P = 0.1871

FOLFOX + placeboN = 351; 277 events FOLFOX + bevacizumabN = 349; 255 events


PFS Superiority of Bevacizumab + CT


ASCO 2007, Abstract 4013

Final Results of OPTIMOX-2 - A Large Randomized Phase II Study of Maintenance

Therapy or Chemotherapy-free Intervals (CFI) After FOLFOX in Patients with Metastatic Colorectal Cancer (Mrc):

A GERCOR Study

Maindrault-Goebel F, et al.

OPTIMOX Studies

OPTIMOX-1: Maintenance therapy

(N = 620)

FOLFOX 4 until progression

FOLFOX 7 FOLFOX 7

sLV5FU2

OPTIMOX-2: Chemotherapy-free interval

(N = 202)

mFOLFOX 7 mFOLFOX 7

sLV5FU2

mFOLFOX 7 mFOLFOX 7

Chemotherapy-free interval

Tournigand et al. J Clin Oncol. 2006;24:394.Maindrault-Goebel et al. ASCO 2007. Abstract 4013.

Progression-free Survival

0 10 20 30 40 50 60 70 80 90 1000.0

0.2

0.4

0.6

0.8

1.0

OPTIMOX1 median 36 weeks

OPTIMOX2 median 29 weeks

Weeks

Pro

babi

lity

P = 0.08

Overall Survival

0 10 20 30 40 500.0

0.2

0.4

0.6

0.8

1.0

OPTIMOX1 median 26 months

OPTIMOX2 median 19 months

P = 0.0549

Months

Pro

babi

lity

Intermittent Oxaliplatin (Oxali) Administrationand Time-to-Treatment-Failure (TTF) in

Metastatic Colorectal Cancer (mCRC): Final Results of the Phase III CONcePT Trial

Grothey A., et al.


CONcePT Trial Design

Grothey A, et al. ASCO 2008. Abstract 4010.

*Treat to failure. †8 cycles with oxaliplatin, 8 cycles without oxaliplatin, 8 cycles with oxaliplatin.

Patients with mCRC

(N = 140)

Continuous Oxaliplatin*mFOLFOX7 + bevacizumab +placebo

(N = 34)

Continuous Oxaliplatin*mFOLFOX7 + bevacizumab +Ca2+/Mg2+

(N = 35)

Intermittent Oxaliplatin†

mFOLFOX7 + bevacizumab + placebo

(N = 36)

Intermittent Oxaliplatin†

mFOLFOX7 + bevacizumab + Ca2+/Mg2+

(N = 35)

CONcePT: Kaplan-Meier Estimate of TTFP

ropo

rtio

n of

Pat

ient

s

0.00.10.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17Months

N at riskCO: 68 63 58 46 36 28 20 11 6 4 4 4 2 2 1 1 0

IO: 71 65 61 56 52 43 32 28 21 18 12 12 10 7 4 1 1

TTF(mos)

95% CI

COIO

4.25.6

3.7–5.54.7–7.0

Unstratified(IO relative to CO), P = .002*

Stratified by CaMg(IO relative to CO), P = .003*

* Log rank test

Continuous Oxaliplatin (CO)

Intermittent Oxaliplatin (IO)

Censored data


CONcePT: Kaplan-Meier Estimate of PFS


0.00.10.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Pro

port

ion

of P

atie

nts

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17Months

N at riskCO: 68 64 46 39 29 24 13 7 3 3 3 1 0 0 0 0 0

IO: 71 64 55 51 43 38 27 24 18 15 10 9 8 3 2 1 1

Unstratified (IO relative to CO), P = .044*

Stratified by CaMg (IO relative to CO), P = .030*

* Log rank test

CO

PFS(mos)

95% CI

IO7.312.0

6.9–NE8.2–NE

Continuous Oxaliplatin (CO)

Intermittent Oxaliplatin (IO)

Censored data


Randomized Phase III Study of Irinotecan and 5-FU/FA With or Without Cetuximab in the First-

line Treatment of Patients with Metastatic Colorectal Cancer (mCRC): The CRYSTAL Trial

Van Cutsem E, et al.

Irinotecan and 5-FU/FA ± CetuximabThe CRYSTAL Trial

Van Cutsem E, et al. ASCO 2007. Abstract 4000.

Stratification factors:

• Regions

• ECOG PS

Populations

• Randomized patients: N = 1,217

• Safety population: N = 1,202

• ITT population: N = 1,198

Study DesignStudy Design

Cetuximab + FOLFIRICetuximab IV 400 mg/m2 on day 1,

then 250 mg/m2 weekly+ irinotecan (180 mg/m2)

+ 5-FU (400 mg/m2 bolus + 2400 mg/m2 as 46-hr continuous infusion)

+ FA every 2 weeks

FOLFIRIIrinotecan (180 mg/m2)

+ 5-FU (400 mg/m2 bolus + 2400 mg/m2 as 46-hr

continuous infusion)+ FA every 2 weeks

RR

EGFR-expressingMetastatic CRC

CRYSTAL TrialProgression Free Survival

Van Cutsem E, et al. ASCO 2007. Abstract 4000.

What is the Role of the Epidermal Growth Factor Receptor (EGFR) in Cancer?

Proliferation MetastasisAngiogenesisApoptosis Resistance

Shc

PI3-K

RafMEKK-1

MEKMKK-7

JNKERK

Ras

mTOR

Grb2

AKT

Sos-1

Cell Membrane

EGFR

Signaling Proteins

Cell Response to

Signaling

A. Friedman and N. Perrimon, Cell 128, January 26, 2007

Pathway vs. Network SignalingPathway vs. Network Signaling

Network “Chaotic”Pathway “Newtonian”


KRAS Status and Efficacy in the First-line Treatment of Patients with Metastatic

Colorectal Cancer (mCRC) Treated with FOLFIRI With or Without Cetuximab: The

CRYSTAL Experience

Van Cutsem E, et al.

CRYSTAL PFS in Patients with KRAS Wild-type

Van Cutsem E, et al. ASCO 2008. Abstract 2. Reproduced with permission.

0.0

0.2

0.4

0.6

0.8

1.0

0 4 8 12

Months

PF

S E

stim

ate

18

Cetuximab + FOLFIRI

FOLFIRI

KRAS wild-type (N = 348) HR = 0.68: P = .017

2 6 10 14

Median PFS Cetuximab + FOLIFIRI: 9.9 months

Median PFS FOLIFIRI: 8.7 months

0.1

0.3

0.5

0.7

0.9

16

1-year PFS rate: 43%

1-year PFS rate: 25%

Relating KRAS Status to EfficacyProgression Free Survival

Cetuximab + FOLFIRI HR = 0.63; P = 0.007 mPFS wild-type (N = 172): 9.9 monthsmPFS mutant (N = 105): 7.6 months

FOLFIRI HR = 0.97; P = 0.87 mPFS wild-type (N = 176): 8.7 months

mPFS mutant (N = 87): 8.1 months

0.5

1.0

0.4

0.3

0.2

0.1

0.0

0.6

0.7

0.8

0.9

80 2 4 6 10 16

PF

S E

stim

ate

Months

Cetuximab +FOLFIRI wild-type

Cetuximab +FOLFIRI mutant

12 14

0.5

1.0

0.4

0.3

0.2

0.1

0.0

0.6

0.7

0.8

0.9

Months

FOLFIRI wild-type

FOLFIRI mutant

80 2 4 6 10 1612 14


KRAS Status and Efficacy of First-line Treatment of Patients with Metastatic Colorectal Cancer

(mCRC) with FOLFOX With or Without Cetuximab: The OPUS Experience

Bokemeyer C. et al.

1Bokemeyer C. et al, ASCO 2008. Abstract 4000.

Res

pons

e ra

te (

%)

59

37

0

10

20

30

40

50

60

70

CRYSTAL(N = 540)

OPUS1

(N = 233)

43

61

FOLFIRI FOLFOXCetuximab + FOLFIRI

Cetuximab + FOLF0X

CRYSTAL - KRAS wild-type: HR = 0.68

P = 0.017

32% risk reductionfor progression

OPUS - KRAS wild-type: HR = 0.57

P = 0.016

43% risk reductionfor progression

0.00.10.20.30.40.50.60.70.80.91.0

0 2 4 6 8 10 12 14 16 18

Months

PF

S e

stim

ate

0.00.10.20.30.40.50.60.70.80.91.0

0 2 4 6 8 10 12

Months

PF

S e

stim

ate

Cetuximab + CT in KRAS Wild-Type: Data Consistency

ECCO 2007, Abstract 0007

Amado RG, et al.

Analysis of KRAS Mutations in Patients with Metastatic Colorectal Cancer Receiving

Panitumumab Monotherapy

KRAS as a Biomarker for Panitumumab Response in mCRC

Amado RG, et al. ECCO 2007. Abstract 0007.

• Pts with mutant KRAS receiving panitumumab had 0% RR and SD similar to BSC alone (12% vs 8%)

• PFS log HR significantly different depending on K-ras status (P < .0001)• Percentage decrease in target lesion greater in patients with wild-type KRAS receiving

panitumumab

Patients With Mutant KRAS

Meanin Wks

Stratified log rank test: P < .0001

115/124 (93)

Patients With Wild-type KRAS

1.0

0.9

Pro

po

rtio

n W

ith P

FS 0.8

0.70.60.50.4

0.3

0.20.1

00 2 4 6 8 10

Events/N (%)Medianin Wks

Pmab + BSCBSC alone

114/119 (96)

12.37.3

19.09.3

HR: 0.45 (95% CI: 0.34-0.59)

12 14 16 18 20 22 24 26 28 30 32 3436 38 4042 44 46 48 50 52

Weeks

Pro

po

rtio

n W

ith P

FS

1.0

0.90.8

0.70.60.50.4

0.30.20.1

00 2 4 6 8 10 12 14 16 18 20 22 24 26 2830 32 3436 38 4042 44 46 48 50

Weeks

Pmab + BSCBSC alone Mean

in Wks

76/84 (90)

Events/N (%)Medianin Wks

95/100 (95)

7.47.3

9.910.2

HR: 0.99 (95% CI: 0.73-1.36)

52

Q: Is More Always Better?

Correlation Between Survival and Percentage of Patients Receiving Three Drugs in

Phase III Trials

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

12

13

14

15

16

17

18

19

20

21

22

0 10 20 30 40 50 60 70 80

Patients with three drugs (%)

Me

dia

n O

S (

mo

nth

s)

3 Drugs: 5-FU/LV, irinotecan, oxaliplatin

FOLFOXIRI vs. FOLFIRI

JCO 2007

Open-label, Phase II-III Trial of Irinotecan or Oxaliplatin-based CTX + Bevacizumab ±

Panitumumab in First-line mCRC: PACCE Trial

aThe choice of either Ox/CTX or Irino/CTX was at the oncologist’s discretion

• Discontinued 3/2007 due to significantly inferior PFS

in planned interim analysis

• OS significantly inferior in unplanned analysis

• ECOG score• Prior adjuvant TX• Disease site• Oxaliplatin doses/

Irinotecan regimen• Number of

metastatic organs

Oxaliplatin-based CTXa

Irinotecan-based CTXa

Oxaliplatin/CTX +Bevacizumab + Panitumumab

N = 407

Oxaliplatin/CTX +Bevacizumab

N = 405

Irinotecan/CTX +Bevacizumab +Panitumumab

N = 68

Irinotecan/CTX +Bevacizumab

N = 67

Phase III

Phase II

RANDOMIZATION

Hecht et al. World Congress on GI Cancer, 2007

ECCO 2007, Abstract 3000

Tol J, et al.

Randomised Phase III Study of Capecitabine, Oxaliplatin and Bevacizumab (CAPOXB) With or Without Cetuximab in Advanced Colorectal

Cancer (ACC), The CAIRO-2 Study of the Dutch Colorectal Cancer Group (DCCG)

an Interim Safety Analysis

Dutch Colorectal Cancer Group (DCCG)

Arm A Arm B

Randomization

CapecitabineOxaliplatin

Bevacizumab

CapecitabineOxaliplatin

BevacizumabCetuximab

CAIRO-2 Study Design

Adverse Event, %

Arm A:

Capecitabine, Oxaliplatin, Bevacizumab

(N = 197)

Arm B:

Capecitabine, Oxaliplatin, Bevacizumab, Cetuximab

(N= 192)

Gastrointestinal, grade 3/4

Diarrhea 20 23

Nausea 9 6

Vomiting 8 6

Cardiovascular, grade 3/4

Hypertension 7 4

Thromboembolic event 9 9

Grade 3/4 neurotoxicity 8 6

Grade 3/4 allergic reaction

3 7

Grade 3/4 bleeding 2 1

Tol J, et al. ECCO 2007. Abstract 3000.

CAIRO-2Interim Safety Analysis

Progression-free Survival


Arm A (without cetuximab) 10.7 months (9.7-12.5) Arm B (with cetuximab) 9.6 months (8.5-10.7)

HR: 1.21

P = 0.018

0 6 12 18 24 30

Months from randomization

0.0

0.2

0.4

0.6

0.8

1.0

Pro

gre

ssio

n f

ree

surv

ival

pro

bab

ility

Arm A (without cetuximab)

Arm B (with cetuximab)

Wildtype

N = 305 (61%)

Mutation

N = 196 (39%)P value

Arm A 152 (50%) 103 (53%)

Arm B 153 (50%) 93 (47%)

Median PFS (months)

Arm A 10.7 12.5 0.92

Arm B 10.5 8.6 0.47

P value 0.10 0.043

KRAS Genotyping (N = 501)


CALGB/Intergroup Front-line Trial

FOLFOX or

FOLFIRI

Bevacizumab

Cetuximab

Bevacizumab/Cetuximab

Adjuvant Oxaliplatin Mosaic Trial (3-year Data)

FOLFOX-4 (1,100 pts)

LV5FU2 (1,100 pts)

T3, T4 N0 = 40% (87% vs 84%)

Tx, N1, N2 = 60% (72% vs 65%)

77.8%

72.9%

P < 0.01

RANDOMIZATION

DFS Endpoint

Overall Survival: ITT

Data cut-off: January 2007

Overall survival (months)

FOLFOX4

LV5FU2

Pro

babi

lity

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 9672 78 84 90

Events

FOLFOX4 243/1123 (21.6%)

LV5FU2 279/1123 (24.8%)

HR [95% CI]: 0.85 [0.72–1.01]

2.6%

P = 0.057

Overall SurvivalStage II and III

Data cut-off: January 2007

FOLFOX4 stage II

LV5FU2 stage II

FOLFOX4 stage III

LV5FU2 stage III

Overall survival (months)

Pro

babi

lity

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 9672 78 84 90

HR [95% CI]

Stage II 1.00 [0.71–1.42]

Stage III 0.80 [0.66–0.98]

0.1%

4.4%

P = 0.996

P = 0.029

ASCO 2008 Abstract LBA4005

Wolmark N, et al.

A Phase III Trial Comparing FULV to FULV + Oxaliplatin in Stage II or III Carcinoma of

The Colon: Survival Results of NSABP Protocol C-07

Survival Results of NSABP C-07

Wolmark N, et al. ASCO 2008. Abstract LBA4005.

FULV5-FU 500 m2 IV bolus weekly x 6; LV 500 mg/m2 IV weekly x 6, each

8-week cycle x 3 (N = 1,209)

FLOX FULV + oxaliplatin 85 mg/m2 IV on Weeks 1, 3, and 5 of each 8-week

cycle x 3(N = 1,200)

Patients with stage II or III carcinoma of the colon

stratified by number of positive lymph nodes

N = 2,409

Primary endpoint: DFS

C-07: Disease-Free Survival


0

20

40

60

80

100

0 2 4 6

3-years 5-years

1 3 5 7

10

30

50

70

90

P = .002 HR: 0.81 [0.70-0.93]FLOX 76.1% 69.4%

FULV 71.5% 64.2%

∆ 4.6% 5.2%

FLOX (N = 1,200)

FULV (N = 1,209)

Years

Pro

port

ion

of P

atie

nts

(%)

C-07: Overall Survival


0

20

40

60

80

100

0 2 4 6

D(n) 3y 5y

1 3 5 7

10

30

50

70

90

FLOX 259 80.3% 77.7%

FULV 301 78.3% 73.5%

∆ 42 2.0% 4.2%

P = .06

HR: 0.85 [0.72-1.01]

FLOX (N = 1,200)

FULV (N = 1,209)

Years

Pro

port

ion

of P

atie

nts

(%)

C-07: Overall Survival Hazard Ratios


FLOX Better FULV Better

0.5 0.75 1 1.25 1.5 1.75

Overall

< 65 yr

≥ 65 yr

Stage II

Stage III

Confirmation of Deficient Mismatch Repair (Dmmr) as a Predictive Marker for Lack of Benefit from 5-FU Based Chemotherapy in

Stage II and III Colon Cancer (CC): A Pooled Molecular Reanalysis of Randomized

Chemotherapy Trials

ASCO 2008 Abstract 4008

Sargent D. J., et al.

MSI-H and Adjuvant 5-FUSargent, ASCO 2008

MSI-H and Adjuvant 5FUSargent, ASCO 2008

Accrual goal: 3,125

E5202: Stage II Colon Cancer

mFOLFOX6 vs.

mFOLFOX6 +bevacizumab qow

Tumor block risk assessed based on biology

(18q/MSI)

High risk (MSS and 18q LOH)

Low risk (MSI + or no

loss 18q) Observation

Surgery

Where We Are Today

AdjuvantAdjuvant

5-FU/LV

FOLFOX

Capecitabine

First-lineFirst-line

5-FU/LV

CPT-11

Oxaliplatin

Capecitabine

Bevacizumab

Second-lineSecond-line

5-FU/LV

Oxaliplatin

CPT-11

Capecitabine

Bevacizumab

Cetuximab

Third-lineThird-line

Cetuximab/CPT-11

Panitumumab

Colon Cancer is More than One Disease

KRAS Wild Type KRAS mutant

MSI-High MSS

+ EGFR Agents – EGFR Agents

? No 5-FU

50-60% 40-50%

15-20% 80-85%

Clinical Review of Current Treatment Strategies for Colorectal Cancer

Closing CommentsClosing Comments

Oncology Journal Club

clinical review of current treatment strategies for colorectal cancer john l. marshall, md chief,...

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