1. Early disease 2. Advanced disease (liver metastasis)

Stefano Iacobelli

Cancer Clinic & Laboratory of Molecular Oncology

Colorectal Cancer – Medical Treament

The Mediterranean School of Oncology

Stage I 15%

Stage II 20-30%

Stage III 30-40%

Stage IV 20-25%

Hamilton IM, Grem JL. Current Cancer Therapeutics, 3rd ed. 1998.

CRC - Incidence by Stage

Adjuvant treatment (?)

Adjuvant treatment

Surgery only

EARLY DISEASE

ADAVANCED DISEASE

“THE HISTORY”

Moertel CG, et al. N Engl J Med 1990;322:352-8.Moertel CG, et al. Ann Intern Med 1995;122:321-6.

Reduced recurrence rate by 40%

Reduced death rate by 33%

Main Steps in the 5-FU Era

1990 5-FU/LEV > surgery alone1

1994 5-FU/FA > surgery alone2

1996 5-FU/FA > 5-FU/LEV3

1998 LEV unnecessary4,5

1998 6 months 5-FU/FA = 12 months 5-FU/FA5

2000 HD FA = LD FA4,5

2001 Elderly benefit from therapy6

1Moertel CG, et al. N Engl J Med 1990;322:352-8; 2Wolmark N, et al. J Clin Oncol 1993;11:1879-87; 3Wolmark N, et al. J Clin Oncol 1999;17:3553-9; 4QUASAR Collaborative Group. Lancet 2000;355:1588-

96; 5Haller DG, et al. J Clin Oncol 2005;23:8671-8; 6Sargent DJ, et al. N Engl J Med 2001;345:1091-7.

NCCTG,1 NSABP C-03,2 NSABP C-04,3QUASAR,4 INT0089,5 Pooled Analysis6

Standard of Care Before 2003

Treatment: Bolus 5-FU/FA x 6 months*

Population: All “fit” stage III patients (including elderly)

Some stage II patients (???)

*Mayo Clinic: FU 425 mg/m2 IV bolus x 5 days

FA 20 mg/m2 IV bolus x 5 daysevery 4 weeks

*RPMI: FU 500 mg/m2 IV bolusFA 500 mg/m2 IV over 2 hoursweekly for 6 every 8 weeks

New Data After 2004

5-FU by C.I. = 5-FU bolus, but less toxic

Oral 5-FU = 5-FU bolus, but less toxic

Oxaliplatin + 5-FU > 5-FU alone

Irinotecan + 5-FU not superior to 5-FU alone!

Trial Pts Treatment Data

MOSAIC(NEJM 2004, ASCO 2005, ASCO 2007)

2246 FOLFOX-4 x 6 mos5-FULV2 x 6 mos

5-y DFS6-y OSSafety

NSABP C-07(JCO 2007)

2407 FLOX x 6 mos Bolus 5-FULV w x 6 mos

4-y DFSSafety

ROCHE NO16968(JCO 2007)

1886 XELOX x 6 mosBolus 5-FULV w/q4w x 6 mos

Safety

Trials Evaluating LOHP in the Adjuvant Setting

MOSAIC

2246 patientsFOLFOX-4

LV5FU2

RANDOM

André T, et al. N Engl J Med 2004;350:2343-51.André T, et al. J Clin Oncol 2009;27:3109-16.

Stage II/III ratio = 40/60%

Expected 3-year DFS: 79% for test arm and 73% for control arm or 25% reduction in risk of recurrence

N = 2200 for a statistical power of 90% (= 0.05)

OS Updated

André T, et al. J Clin Oncol 2009;27:3109-16.

OS Updated – By Stage

André T, et al. J Clin Oncol 2009;27:3109-16.

Long-Term Neurotoxicity

André T, et al. J Clin Oncol 2009;27:3109-16.

Issues with Central Venous Catheters

• Additional costs

• Inconvenient for patients

• Need for invasive surgical procedure

• possible complications include infections,bleeding, pneumothorax, deep vein thrombosis, and pulmonary embolism

1,2

• varying level of risk (7-20%), but basal rate of complications unavoidable, regardless of Center/experience

3

1Kuter DJ. Oncologist 2004;9:207-16;

2Verso M, et al. J Clin Oncol 2003;21:3665-75;

3Sobrero A, Sciallero S. Ann Oncol 2005;16:521-2.

Capecitabine Similar to Infusional 5-FU

Mackean M, et al. J Clin Oncol 1998;16:2977-85.

Twelves C, et al. N Engl J Med 2005;352:2696-704.

1st endpoint

DFS

2nd endpoints

RFS

OS

Tolerability

Pharmacoeconomics

Surgery

Capecitabine1250 mg/m

2 twice daily,

d1-14, q21 n = 1004

Bolus 5-FU 425 mg/m2 plus

LV 20 mg/m2, d1-5, q28

n = 983

24 weeks

RANDO

M

X-ACT Study

X-ACT: 5-Year DFS and OS Updated Data

Twelves C, et al. ASCO GI 2008. Abstract 274.

0 1 2 3 4 5 6 7 8Years

1.0

0.8

0.6

4 Absolute differenceat 5 years: 4.1%

HR = 0.88 (95% CI 0.77-1.01)p = 0.0682

DF

S e

stim

ate

Capecitabine (n = 1,004)

5-FU/LV (n = 983)

5-year DFS (%)

60.8

56.7

5-year OS (%)

71.4

68.4

Absolute difference at 5 years: 3.1%

HR = 0.86 (95% CI 0.74-1.01)p = 0.0600

Years0 1 2 3 4 5 6 7 8

1.0

0.8

0.6

4

OS

est

imat

e

Twelves C, et al. N Engl J Med 2005;352:2696-704.

Safety Profile

*p<0.001

Treatment-related AEs

*

*

*

*

100

80

60

40

20

0

Capecitabine (n=993)Bolus 5-FU/LV (n=974)

*

*

Patients (%)

Hand-foot Diarrhea Stomatitis Neutropenia† Nausea/

Alopecia

syndrome vomiting

*

*

*

Toxic deaths 0.3 vs 0.4%

“WHERE DO WE STAND?”

“OLD and NEW UNCERTAINTIES” • Stage B (II)

To B or Not To B?

Should Stage II Patients Receive Adjuvant Therapy?

A Statistical Perspective

Number of patients needed to detect a realistic treatment benefit assuming a true relative risk reduction of 18% with a power of 90% (two sided)Survival ARR No. of

patients

At 3 years 85% 2.5% 8000

At 4 years 80% 3.3% 5800

At 5 years 75% 4.0%

Buyse M, Piedbois P. Semin Oncol 2001;28(1 Suppl 1):20-4.

4700

HOW TO SELECT STAGE IIHIGH RISK PATIENTS

G3

T4

Gene Signature

Perforated/Occlusion

TS

LOH

Lympho-Vascular orPerineural Invasion

MSI

DPD

No. of Nodes <12 lfn

????

“BREAKING NEWS AND FORTHCOMING DATA”

RRmFF6 q2wk x 6 mos

Beva q2wk x 1 yr

mFF6 q2wk x 6 mos

+

NSABP C-08

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

0

20

40

60

80

100

Ev 3-y DFSmFF6 + B 291 77.4mFF6 312 75.5

HR 0.89P 0.15

NSABP C-08

DFS

%

Years

NSABP C-08

1.0 1.5 2.0 2.5 3.0 3.5

Ev mFF6 + B 216mFF6 190HR 1.07P 0.48

Event-Free at 1 Yr

0.0 0.5 1.0

60

70

80

90

100 DFS at 1 Yr

Ev 1-y DFS mFF6 + B 75 94.3mFF6 122 90.7

HR 0.60P 0.0004

∆ 3.6

Time-Treatment Interaction P = 0.001

Study Treatment Arms Duration

AVANT FOLFOXFOLFOX + bevacizumabXELOX + bevacizumab

6 months1 year1 year

PETACC-8 FOLFOXFOLFOX + cetuximab

6 months6 months

TOSCA FOLFOXFOLFOX

6 months3 months

Forthcoming Results

What we can tell a radically resected pt (stage II-III) in 2010?

10-year probability of survival: 75%

(10 to 20% due to CHT)

Colorectal Cancer Liver Metastases

(CRLM)

Liver Metastases

Resectable20% to 25%

5-yr Survival Benefit:

30% to 40% historically; approaching 60% in recent series

Resectable10% to 20%

Downsizing

Size

LocationNumber

Leonard GD, et al. J Clin Oncol. 2005Carpizo DR et al., Lancet Oncol, 2009

Nonresectable75% to 80%

Study Last Year Included Span, Years Patients, N 5-Year OS, %Adson 1982 34 141 25

Registry* 1985 37 859 33

Jamison 1987 27 280 27

Nordlinger* 1990 22 1568 28

Gayowski 1991 10 204 32

Scheele 1992 32 434 33

Jenkins 1993 18 131 25

Kato* 1996 4 585 33

Fong 1998 13 1001 37

Choti 1999 16 226 40

Bramhall 2001 12 212 28

Wei 2002 10 395 47

Abdalla 2002 10 358 58

Fernandez 2002 7 100 58

Pawlik* 2004 14 557 58

Adam* 2004 30 2122 42

Figueras 2004 14 501 45

*Patients included from multiple institutions (vs single-institution series)

Resection of CRLM: 5-Year Survival,Selected Reports (≥ 100 Pts) Over Time

Survival After Hepatic Resection Has Improved Over Time

Lower operative mortality ~ 1% with experienced hepatobiliary surgeons

Improved patient selection CT, MRI, PET, PET/CT

Improved surgical techniques Intraoperative US, portal vein embolism, radiofrequency

ablation

Increased rates of repeat hepatectomy after recurrence

More frequent and better perioperative chemotherapy Irinotecan, oxaliplatin, biologics

Role of Chemotherapy for Resectable CRC liver metastases

Adjuvant systemic chemotherapy

Peri-operative chemotherapy

Hepatic artery infusion therapy

Adjuvant Therapy: FFCD (AURC) 9002

R

Surgery 5-FU + LV days 1-5 q28 x 6 cycles

Surgery

• 171 patients

• Resected liver metastases

• 95% had 3 or fewer

• Primary Endpoint: Improved DFS

Portier G. et al. J Clin Oncol 2006

Disease-free survival after liver resection

Group Median DFS

Surgery 17.6 months

Chemotherapy 24.4 months

(p=0.028)

Portier G. et al. J Clin Oncol 2006

Adjuvant Chemotherapy After Resection of Metastases from CRC: A Pooled Analysis of Two Randomized Trials

Two phase III trials: FFCD Trial and EORTC/NCIC/GIVIO (ENG trial)

CT arm5-FU + LV d1-5 q28

X 6 cyclesn=138

S armn=140

vs.

Mitry E et al, J Clin Oncol 2008

Rationale for peri-operative cht in pts with resectable liver

metastases1.To test the chemoresponsiveness which can

guide treatment choice after resection

2. It can eradicate dormant cancer cells in the liver

3. If tumor shrinkage is achieved during cht, the rate of complete resection or complete resection with more conservative liver surgery may be increased

4. Response to cht is a prognostic factor for survival and can allow a better selection of candidates for surgeryLeonard GD et al, JCO 2005; Tanaka K et al, Br J Surg 2003; Allen PJ et al, J Gastrointest Surg 2003; Adam R et al, JCO 2008

EORTC 40983: FOLFOX4 in mCRC With Resectable Liver Metastases

Phase III Trial 364 patients randomized Potentially resectable (≤ 4 liver

metastases) Primary Endpoint: Improve PFS Interim objective: Evaluate tumor

response to perioperative CT Perioperative CT (n = 182)

• 159 (87.3%) underwent surgery

• 151 (83.0%) resected

Surgery (n=182)• 170 (93.4%) underwent surgery

• 152 (83.0%) resected

R

FOLFOX4For 6 cycles (12

wks)

(n= 182)

Surgery FOLFOX4 x for 6 cycles

Surgery(n= 182)

Nordlinger B et al, Lancet 2008

EORTC 40983: PFSby treatment group

Nordlinger B et al, Lancet 2008

+9.2%

at 3 yrs

Response to Preoperative Chemotherapy

156 patients randomized

Initial resection of liver metastases from CRC

R

Systemic 5-FU/LV4 wks post-surgery

+HAI FUDR + DEX

2 wks later for 2 wks;

1 wk rest (6 cycles)

Systemic 5-FU/LVq 4 wks (6 cycles)

Hepatic Arterial Infusion Memorial Sloan-Kettering Randomized Study

Kemeny N, et al. N Engl J Med. 1999;341:2039-2048

DEX, DexamethasoneHAI, Hepatic Arterial Infusion

Combination Therapy 5-FU/LV P Value

10-y OS (%) 41.1 27.2 Not reported

mOS (mo) 68.4 58.8 NS

PFS (mo) 31.3 17.2 0.02

*All patients followed for a minimum of 6 y, with a median follow-up of 10.3 y.

150Months after resection

Monotherapy

Combined therapy

Pro

port

ion

su

rviv

ing

100500

0.2

0.4

0.6

0.8

1.0

HAI Versus Systemic Therapy Alone: Long-term Follow-up*

0

Kemeny N, et al. N Engl J Med. 2005;352:734.

Summary of Therapy for Initially Resectable Disease

Use of chemotherapy appears to enhance outcomes achieved with surgery

Adjuvant chemotherapy

Peri-operative chemotherapy

Adjuvant hepatic arterial infusion chemotherapy combined with systemic chemotherapy

Role of Chemotherapy for Unresectable CRC liver metastases

Down-staging to resectable disease

Folprecht G et al, Ann Oncol 2005

There is a strong and highly significant correlation between

response rate and liver resectionSelected pts

Unselected pts

Resection Rate 30-40%

Resection Rate 10-15%

Survival Related to Response toPre-operative Cht (Retrospective Analysis of

131 pts)

Overall survival was much lower for pts with progressive disease to preoperative cht than for those with responsive

or stable disease

P=0.0001

Resection of multiple metastasesGroup 3Group 2Group 1

Adam R et al, Ann Surg 2004

Responders

Progressors

Which Chemotherpy Combinations?

FOLFOXIRI vs. FOLFIRI (N=244)

• Randomized phase III trial for metastatic CRC

• R0 resection rate secondary endpoint in patients with liver-only metastases

Falcone A, et al. J Clin Oncol 2007; 25:1670.

FOLFOXIRI FOLFIRI

n 39 42

Resection 36% 12%

Other Chemotherapy Regimens

Selected population (liver metastases)

CTCT + ERBITUX Unselected population

Res

pons

e (%

)

POCHER CRYSTAL

39.7

57.3

P<0.0001

OPUS

p=0.0027

57.3

34

CELIM

79*

* **

0

10

20

30

40

50

60

70

80

79

Doublets Triplet

LLD

*

77

Van Cutsem E, et al. ECCOESMO 2009 Abs 6077Van Cutsem E, et al. N Engl J Med 2009;360:1408–1417

Van Cutsem E, et al. Ann Oncol 2008;19(Suppl.8):viii4 [Update to 710]Bokemeyer C, et al. J Clin Oncol 2009;27:663–671

Bechstein WO, et al. J Clin Oncol 2009;27(Suppl. 15): Abstract No. 4091Garufi C, et alECCO/ESMO, Berlin, 2009

0

10

20

30

40

50

60

70

80

0

10

20

30

40

50

60

70

80

0

10

20

30

40

50

60

70

80

*KRAS wt, **ITTLLD=liver-limited disease

Role of Biologic, Targeted Therapy

ERBITUX improves resections

60

CTCT + ERBITUX

Treat to Best Response or to Resectability? Considerations

Increased duration of therapy increases risk of hepatic toxicity

Duration of therapy must be balanced with limiting liver toxicity

(Irinotecan: steatohepatitis; Oxaliplatin: vascular lesions and sinusoidal obstruction syndrome; 5-FU: steatosis)

CR may inhibit ability to resect or ablate

Resect as soon as possible

Treatment choices for patients with colorectal liver metastases

5-yr OS < 5%5-yr OS 25-40%

Nordlinger B et al, Ann Oncol 2009

Optimal control of liver metastases with i.v. cetuximab and HAI of irinotecan, 5-FU

and oxaliplatin in patients with liver-only metastases from colorectal cancer

An European multicenter phase II trial

OPTILIV 07Clinical Study Protocol

P.I. Dr Francis LEVI, Paul Brousse

Primary end-point

Incidence of complete macroscopic resections of liver metastases (R0+R1)

Planned number of patients

60 patients enrolled over a 18-months period by 12 European centers

·

Main Inclusion Criteria

Histologically or cytologically confirmed carcinoma of the colon and/or rectum with evidence of liver metastases

Pts with at least one of the following criteria:. less than 30% estimated residual liver after resection,. more than 3 liver metastases,. documented progressive disease on imaging

documents or doubling of serum levels of CEA or CA19.9 over the past 90 days or less.

. disease in contact with liver main vessels

Patients whose liver metastases are considered to be non resectable with curative intent in medico-surgical staff meeting

One, two or three prior chemotherapy lines for CRC

Cetuximab 500 mg/mq

Irinotecan 180 mg/mq

Oxaliplatin 85 mg/mq

5-FU 2800 mg/mq

Every 2 wks

Treatment Plan

Thank you for your attention!