Current Opinion in the Colorectal Cancer Treatment Dott. Carlo Garufi Oncologia Medica C Istituto...

Current Opinion in the Colorectal Cancer Treatment

Dott. Carlo Garufi

Oncologia Medica C

Istituto Regina Elena – Roma

[email protected]

5FU/FA Capecitabine or FOLFOX

Treatment Strategies in ACC in2007

I II IIIIFL+BEVA

FOLFIRI+BEVA

FU/FA+BEVACAPE+BEVA

FU/FA CAPE

FOLFOX

FOLFOX+BEVA

FOLFIRI

FOLFOX

CETU+IRI FOLFOX

CETU+IRI

FOLFOX

FOLFIRI

FOLFIRI

FOLFOX

CETU+IRI

CETU+IRI

CETU+IRI

FOLFOX

IRI O FOLFIRI

CETU + IRI

FOLFOX

CETU + IRI

CETU+IRI

FOLFOX

Adjuvant CHT

Cancro colon-retto avanzato:tutti i trattamenti sono uguali?

FOLFOX = FOLFIRI

CAPOX = CAPIRITournigand 2004, Colucci 2005, Grothey 2004

FOLFOX > IFLGoldberg 2004

The use of all available drugs is strongly suggested

Grothey 2004

Statistical ConsiderationsGoldberg Tournigand Colucci

Pts required per arm

375 109 (49 events)

176

Power 90% 80% 80%

α-error 5% 5% 5%

Primary Objective

To detect a HR of 0.75 in TTP between each experimental regimen and control

To detect a 20% difference in the proportion of patients without second progression at 15 m (60% in arm A, 40% in arm B)

To detect a 15%

difference in Objective

response

Cancro colon-retto avanzato: ruolo del bevacizumab

BEVA+ IFL >IFL in Prima LineaHurwitz H 2004

BEVA + FOLFOX4 >FOLFOX4 in II lineaGiantonio BJ 2005

ma ……

The addition of Bevacizumab to IFL increases PFS and OS

Saltz L ASCO 2007

Aggiunta di BEVA alle doppiettein prima linea

• Bevacizumab aumenta OS se usato con IFL

• Non aumenta OS se usato con XELOX o FOLFOX4

Canro colorettale e Cetuximab

Cetuximab is the most active drug in pretreated patients

Lentz 2005

Cetuximab + FOLFOX4 is a very active regimen (Resp Rate >60%)

Colucci 2006, Tabernero 2004

CRYSTAL Trial: Study Design

Stratification factors: – Regions– ECOG PS

Populations– Randomized patients n=1217– Safety population n=1202– ITT population: n=1198

FOLFIRI

irinotecan (180 mg/m2) + 5-FU 400 mg/m2 bolus + 2400 mg/m2 as 46-hr continuous infusion) + FA every 2 weeks

Cetuximab + FOLFIRI

Cetuximab 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

REGFR-expressing

metastatic CRC

Van Custen et al, ASCO 2007

CRYSTAL Trial: Study Endpoint

• Primary endpoint:

– Progression-free survival time (as assessed by blinded independent review)

• Secondary endpoints:

– Overall response rate (independently reviewed)

– Disease control rate (CR+PR+SD)

– Overall survival time

– Quality of life (EORTC QLQ C30)

– Safety

CRYSTAL trial: Primary endpoint PFS met ITT population independent review

Progression-free survival time (months)

PF

S e

sti

mat

e

1.0

0.8

0.9

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 2 4 6 8 10 12 14 16 18 200 2 4 6 8 10 12 14 16 18 20

HR = 0.851; 95% CI = [0.726-0.998]

Stratified log-rank p-value = 0.0479

8.9 mo

8.0 mo

FOLFIRI, n=599

Cetuximab + FOLFIRI, n=599

FOLFIRI, n=599


1-year PFS rate23% vs 34%

Subjects at risk

FOLFIRI alone 599 492 402 293 178 83 35 16 7 4 1Cetuximab + FOLFIRI

599 499 392 298 196 103 58 29 12 5 1

Subjects at risk


599 499 392 298 196 103 58 29 12 5 1

CRYSTAL Trial: Primary End-Point PFS

CRYSTAL trial:Independent Assessment of Response

38,7

46,9

0

10

20

30

40

50

60

Response rate

Per

centa

ge

(%)

FOLFIRI alone, n=599Cetuximab + FOLFIRI, n=599

p-value* = 0.0038

FOLFIRI

%

Cetuximab

+ FOLFIRI

%

CR

PR

SD

PD

0.3

38.4

46.7

9.0

0.5

46.4

37.4

8.8

ORR95%CI

38.7[34.8 - 42.8]

46.9[42.9 - 51.0]

DCR** 85.5 84.3

*Cochran-Mantel-Haenszel (CMH) test ** DCR: disease control rate

CRYSTAL trial: Primary endpoint PFS subgroup:liver metastases only


0 2 4 6 8 10 12 14 16 18 200 2 4 6 8 10 12 14 16 18 20

PF

S e

sti

mat

e

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


FOLFIRI, n=134

HR = 0.637; 95% CI = [0.432-0.941]

Stratified log-rank p-value = 0.023

9.2 mo

11.4 mo

Subjects at risk


122 100 84 74 51 26 15 6 2 1 1

CRYSTAL trial:Subgroup analysis of PFS time by

on-study skin reactions: cetuximab + FOLFIRI

Skin reaction grade 0 or 1, n=244

*There were no grade 4 skin reactions

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0


1.00

0.75

0.50

0.25

0.00

PF

S e

sti

mat

e

Skin reaction grade 2, n=243

Skin reaction grade 3*, n=112

11.3 mo5.4 mo 9.4 mo

Skin reaction grade 0 or 1, n=244

*There were no grade 4 skin reactions

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0


0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0


1.00

0.75

0.50

0.25

0.00

PF

S e

sti

mat

e

1.00

0.75

0.50

0.25

0.00

PF

S e

sti

mat

e

Skin reaction grade 2, n=243

Skin reaction grade 3*, n=112

11.3 mo5.4 mo 9.4 mo

CRYSTAL Trial: Conclusions

• The CRYSTAL trial met its primary objective of demonstrating that the addition of

cetuximab to FOLFIRI in the first-line treatment of EGFR-detectable mCRC

significantly increased PFS

– There was a 15% risk reduction for progression in patients treated with cetuximab

plus FOLFIRI compared to FOLFIRI

• The addition of cetuximab to FOLFIRI was associated with:

– Higher response rates (p=0.0038)

– Threefold higher R0 resection rates for initially unresectable disease (p=0.0034)

• Skin reactions showed a strong correlation with efficacy

Differences in Treatment Strategies Between US and Europe

United States Europe

First-line chemo FOLFOX » FOLFIRI

FOLFOX = FOLFIRI

XELOX Frequent Uncommon

BEV in first-line Majority of patients Minority of patients

BEV continuation beyond progression

Frequently Uncommon

EGFR Antibodies Common in second- and third-line, single agent or combination

Common in combination

A. Grothey WCGC 2007

Unsolved Questions

• Is there a clear advantage in survival with the use of polichemotherapy rather then monochemotherapy as first line treatment? (Seymour 2007, Punt 2007)

• What is the role of the stop and go strategy? (GISCAD 2006, )

• What is the role of triplet in patients with liver metastases? (Falcone A. 2006, Garufi C 2007)

• Is colorectal cancer a unique clinical disease?

Lancet 2007

FOCUS TRIAL

CAIRO TRIAL

Which strategy as first line treatment?

• Perhaps the answer is to define a “Minimal Therapy” or an “Intense Therapy”

• Introduction of the concept of “Continuum Treatment”(Hoff ASCO 2007)

(Hoff ASCO 2007)

Unsolved Questions

• Is there a clear advantage in survival with the use of polichemotherapy rather then monochemotherapy as first line treatment? (Maughan T. 2003)

• What is the role of the stop and go strategy? (GISCAD ASCO2006, OPTIMOX2 ASCO 2007)

• What is the role of triplet in patients with liver metastases? (Falcone A. 2006, Garufi C)

• Is colorectal cancer a unique clinical disease?

Rationale

• Chemotherapy-free intervals have been previously studied in patients receiving 5-FU based therapy

Hejna et al. (Br J Cancer 1998) Maughan et al. (Lancet 2003)

• New combination therapies have improved survival but there is still the risk of cumulative toxicities like Oxaliplatin sensory neuropathy

• Clinical rationale: quality of life preservation, costs reduction and social impact improvement

Continuos vs Intermittent Therapy ?MRC Trial

Maugan et al., Lancet 2003

“Our findings provided no clear evidence of benefit in continuing therapy indefinitly until disease progression”

GISCAD Trial: Design (ASCO 2006)

R

N=336

Evaluation

Primary end point: OSNon inferiority : 15< Median OS (months)< 11

4 mos

FOLFIRI

Greem ASCO 2007 Discussant

STOP and GO STRATEGY

• At this time there are no clear advantage from a stop and go strategy. It seems that continuing treatment until progression, if not hampered by severe toxicity, is still a valid option

We should consider Stage IV different groups of colorectal

cancer patients

• Clinical History (PS, comorbidity, age)

• Interdisciplinary Teams (surgery and/or RT)

• Different median survival (<12 e >24 mesi)

• Necessity to identify new prognostic factors

We need new trials for old and new Prognostic Factors

• Gender (Giacchetti S. et al JCO 2006)

• Hb (Tampellini M. et al Br J Cancer 2006)

• LDH (Koehne et al ASCO 2006)

• Resectability (Poston G et al JCO 2006)

• Genic Polimorphysm (Toffoli G et al JCO 2006)

Clinical determinants of survival in patients with 5-fluorouracil- based treatment for metastatic colorectal

cancer: results of a multivariate analysis of 3825 patients

C.-H. Kohne, D. Cunningham, F. Di Costanzo, B. Glimelius, et al

Ann. Onc., 2002; 13(2): 308 - 317.

Diferent Stage IV Disease in Different Patients

• Disseminated Disease • Local Recurrences • Peritoneal Carcinosis• Non-measurable Disease • Lung Metastases • Liver Metastases - Resected - Resectable - Non-resectable

EPOC: STUDY DESIGN

Elegibility Criteria

Rationale for timing of chemotherapy

Objectives of the trial

Surgery

PFS in resected patients

Diferent Stage IV Disease in Different Patients

• Disseminated Disease • Local Recurrences • Peritoneal Carcinosis• Non-measurable Disease • Lung Metastases • Liver Metastases - Resected - Resectable - Non-resectable

Treatment of liver metastases from colorectal cancer

Liver Metastases

85% non-resectable 15% resectable

Neoadiuvant Cht

Potentially resectable

(4-30%)

• R0•R0 uncertain

?

FA/FU FA/OXA o CPT11

5-FU/FA/OXA/CPT11 Biologic agents

5-year survival rate

Liver Resection = the only chance of survival

Adam R. PBH

What is non-resectable disease?

Classical Contraindications to liver resection: ≥ 4 metastases ; Size; Extraepatic Disease; Hilar location Resection margin < 1 cm; Incomplete Resection

Adam R., et al. Ann Surg Onc 2000

9

48

1226

0

10

20

30

40

50

large Multi-nodular ill-located extra-hepatic

1. Size 2. Multinodular3. Ilar location4. Extraepatic disease

5. Patients with >3 metastases who receive chemo-therapy in order to stabilize liver disease before surgery

6. Patients who present with huge resectable liver metastases at the time of resection of the primary tumor and need extended liver surgery. Primary tumor has to be resected.

Non-Resectability Criteria (IRE):

Response rate and surgery of metastases(First line 5-FU, LV and l-OHP)

Chrono 4-10

Chrono 5-16

Flat 5-16

0 30 40 50 60

40

30

10

0

Objective responses (%)

Co

mp

lete

res

ect

ion

of m

eta

sta

ses

(%)

r = 0.96 ; p = 0.0007

94-96

93-94

90-93

90-93

Secondary surgery of metastases : major prognostic factor of survival

20

70

Lévi F 2000

There is a strong and highly significant correlation between response rate and liver resections

Folprecht 2005

NON RESECTABLE « HEPATIC » PATIENTS

Multi Unilobar Multi Bilobar Multi Bilobar

Remnant Liver<30% ≤3 nod. ≤30 mm >3 nod >30 mm

Hepatectomy +RxF or Cryo

2-Stage Hepatectomy

Portal Embolization

Adam R

The Triplets

• “Triplets” are combinations of a fluoropyrimidin (5-FU o Capecitabine) modulated by LV + L-OHP and CPT-11

• Triplets come from original doublets combinations as FOLFOX, CPT-11+FF, or chronomodulated FFL.

Triplets were developped to answer to the following reasons:

1) To increase activity of the combination

2) To increase the number of resectable patients

3) To allow a reduction of cumulative toxicity

4) To have a tolerable acute toxicity

The Triplets

0 10 20 300

25

50

75

100

Months

Per

cen

t su

rviv

al

FOLFIRI

122 pts

FOLFOXIRI

122 pts

Progressed 108 96

Median PFS 6,8 m 9,8 m

HR: 0.60 (95%CI: 0.44-0.78)

log-rank P value < 0.001

PROGRESSION FREE SURVIVALPROGRESSION FREE SURVIVAL

Median follow up 14.0 months

FOLFIRI

122 pts

FOLFOXIRI

122 pts

R0 6%* 14%*

R1 1% 2%

Explorative 8% 1%

* P=0.05

Trattamento neoadiuvante: tripletta vs doppietta

Masi et al.

Studio POCHER

• PreOperative

• Chemotherapy

• Hepatic

• Resection

CPT-11 130 mg/m2day 1 peak 13:00

Chronomodulated delivery scheme(5d on/16d off or 4d on/10d off)

Time (clock hour)10:00 16:00 22:00 04:00 10:00

Flo

wra

te (

arb.

Uni

ts)

5-FU(600-1100 mg/m²/d)

LV(300 mg/m²/d)

L-OHP(25 mg/m²/d)

Cetuximab 400-250 mg/m2 day1

FFL4-10 day2-5 q 2 settimane

Istituto Regina Elena Roma

Ospedale S Maria degli Angeli Pordenone

CPT-11+L-OHP CPT-11+L-OHP in micein mice

D’Attino et alD’Attino et al

BJC ‘02BJC ‘02

CPT-11 bolus vs chrono + CPT-11 bolus vs chrono + FF FF 4-104-10

Garufi et alGarufi et al EJC ‘06EJC ‘06

CPT-11 + FF CPT-11 + FF 5-165-16

Garufi et alGarufi et al Cancer ‘01Cancer ‘01

EORTC 05011 EORTC 05011

CPT-11CPT-11 + FFL + FFL

Garufi et alGarufi et al ASCO 2007ASCO 2007

POCHER DevelopmentPOCHER Development

CPT-11bolus + FFLCPT-11bolus + FFL

Garufi et alGarufi et al BJC ‘03BJC ‘03

Cetuximab + Cetuximab + CPT-11CPT-11 + FFL + FFL

EORTC study 05011 Colorectal

DayDay 22--55•• OxaliplatinOxaliplatin 20 mg/m²/d20 mg/m²/d•• 55--FU FU 700 mg/m²/d700 mg/m²/d•• LeucovorinLeucovorin 300 mg/m²/d300 mg/m²/d

1616 0404

55--FUFU--LVLV

DayDay 11 IrinotecanIrinotecan180 mg/m²180 mg/m²

LL--OHPOHP

05

06

09

14

02 08

00 02 0422

0110

13

16

14

17

20

18

21

00

Randomized deliveryRandomized deliverypeakpeak time (h)time (h)

Fixed delivery peak timesFixed delivery peak times(h)(h)

Coordinator: C. Garufi – IRE - Rome

Garufi C. et al ASCO 2007

Peak Time for Diarrhea

Tolerability over the first 3

cycles: best timing h13:00

Tolerability is defined as no reduction or cycle delay. Dose reduction or cycle delay for not related reasons were not considered an event

Garufi C. et al

ASCO 2007

Resezioni Epatiche Post-Chemioterapia

1ª Line Chemotherapy

EORTC 05011-IRE

40 Patients

Candidate to Surgery

9 Pts (33%)

Radical Resections

8 Pts (30%)

Liver Mets only

27 Paz. (67%)

Patient with non-resectable colorectal liver metastases

Evaluation of Inclusion/Exclusion criteriaInformed consent

Treatment with CPT11/5FU-FA/L-OHP + CetuximabFirst evaluation of response after 4 cycles

Resectable

SurgeryNot before than 4 cycles and within 45 days from

the last cycle

Chemo + Cetuximab for 4-6 cycles

Evaluation for resectability

Non-resectable

Chemo + Cetuximab will be continued until PD,

unacceptable toxicity or patient refusal

Partial response, disease stabilization: other 2 cycles

POCHER Trial design

Study Design

• Primary End-Point: Resection rate

• Secondary End-Points: Rate of Pathological Complete ResponseResponse RateTolerabilityTime to disease ProgressionOverall Survival

Number of patients required with p0 =10% e p1= 25%: 40

Patients with unresectable colorectal liver metastases • study of EGFR pathway (FAS/FAS –lL sistem and AKT signalling)

• role of amplification and polisomy of EGFR gene

•evaluation of rest/activity rhythm (RAR) measured by Actigraph

• measurement ol serum levels of Cytokines TGF-α, TNF and IL-6

• Relationship between RAR and Quality of Life

Role of Erbitux plus a combination of CPT-11/5-fluorouracil/leucovorin/oxaliplatin combination as neoadjuvant

chemotherapy in patients with colorectal liver metastases

Chemotherapy Schedules for Colorectal Cancer Liver Metastases and Resectability

Schedule Author Selected Patients

N°. of Patients

RR (%) Resezioni R0(%)

FOLFOX4 Alberts Yes 42 52 30

FFL4-10 crono Giacchetti Yes 151 59 32

FOLFOX4 + Cetuximab

GOIM2402 No 53 60 21

FOLFOX4 + Cetuximab

André No 43 72 23

FOLFIRI Pozzo Yes 40 51 33

AIO+CPT-11 + Cetuximab

Folprecht No 19 68 21

CRYSTAL VanCutsem No 132 46.9 9.8

CPT-11+5-FU+FA+L-OHP

Tripletta crono Garufi Yes 27 45 30

FOLFOXIRI Falcone No 74 71 26

FOLFOXIRI De la Camara Yes 212 64 43

FOLFOXIRI Quenet Yes 26 73 35

POCHER Garufi Yes 15 86 69

Conclusions

• Cetuximab containing regimens as 1° line are associated with high response rate in patients with colorectal liver metastases

• POCHER combination is able to induce resectability in 69% of patients initially considered as non-resctable with our criteria

• These results must be confirmed in randomized studies which compare doublets or triplets ± cetuximab in selected patients and in selected centers

Current Opinion in the Colorectal Cancer Treatment Dott. Carlo Garufi Oncologia Medica C Istituto...

Documents

Transcript of Current Opinion in the Colorectal Cancer Treatment Dott. Carlo Garufi Oncologia Medica C Istituto...