Il trattamento delle metastasi epatiche neoplasie del colon retto

Filippo de Braud MD

Clinical Pharmacology and New Drugs Development Unit

European Institute of OncologyMilano Italy

• Trattamento neoadiuvante delle metastasi epatiche resecabili

• Trattamento neoadiuvante delle metastasi epatiche non resecabili

• Trattamento adiuvante post-resettivo

• Trattamento delle metastasi epatiche sincrone da cancro del retto

• Trattamento delle metastasi epatiche con “minima” malattia extraepatica

ADVANCED COLORECTAL-CANCER:

DISEASE LIMITED TO THE LIVER

SURGICAL RESECTION

1984 - 199710 STUDIES> 2500 PTS

Mortality 1- 5 %1 yr surv 80 %5 yrs surv 25 - 37 %

Sem. Oncol. 26, 5: 514-523, 1999

ADVANCED COLORECTAL-CANCER:

DISEASE LIMITED TO THE LIVER

SURGICAL RESECTION WHEN IT IS POSSIBLE

BUT…..

WHEN IS IT POSSIBLE ?

ADVANCED COLORECTAL-CANCER:LIVER RESECTION

Disease Related Factors

AGE IS NOT (Fong et al, Ann Surg 222: 426, 1995)

MARGINS : It does not make sense

Size of Largest Met > 5 cmDisease Free Interval < 12 mos

Number of Mets > 3Primary Node Positive

CEA > 200 ng/mg(JCO, 15: 938 - 46, 1997)

ADVANCED COLORECTAL-CANCER:LIVER RESECTION

Disease Related Factors

Score Surv (%) Median

1yr 5yr months

0 - 1 84 - 92 57 73 2 92 47 503 89 16 304 62 8 15

JCO, 15: 938 - 46, 1997

Fong Y. et al, Ann Surg 1999, 230: 309-321

SURGICAL RESECTIONResults are very reproducible !

ADVANCED COLORECTAL-CANCERRESECTION OF LIVER METS’

Study # pts 5-yrs OS

Median Survival

months

Hughes

1986607 33% -

Scheele

1995434 33% 40

Nordinger

19961568 28% -

Jamison

1997280 27% 33

Fong

19991001 37% 42

Metastasi epatiche nel carcinoma del colon retto

2. Malattia solo epatica non operabile

• Chemioterapia intraarteriosa? • Chemioterapia sistemica?• Chemioterapia sistemica + intraarteriosa?

• Terapia neo-adiuvante?

Survival after primary and secondary resection of liver

metastasesAdam R, Ann Oncol 2003;14: ii13-ii16Adam R, Ann Oncol 2003;14: ii13-ii16

Resectable (n=425) Initially unresectable (n=95)

Surviving (%)Surviving (%)

54%

50% 34%

34%

27%

29% 19%

0

1

2

3

4

5

6

7

8

9

10

0

0.2

0.4

0.6

0.8

1.0

Survival time (years)Survival time (years)

Neoadjuvant chemotherapyPaul Brousse hospital study

Adam R et al., Ann Surg Oncol 8:347-53, 2001Adam R et al., Ann Surg Oncol 8:347-53, 2001N= 872 N= 872

N=171Primary resectablePrimary resectable

20% of all patients20% of all patients

Initially unresectable N=701

Never resectable N=95Secondary resectable 11% of all patients 14% of CT-treated

Resection: 266 patients (31%)Resection: 266 patients (31%)

Oxaliplatin/5FU/LVOxaliplatin/5FU/LV

OxaliplatinoMetastasi epatiche da Carcinoma

Colon• Bismuth 1996 330 pazienti con metastasi epatiche inoperabili

– N. pz. operati 53 (16%)– Resezione curativa 46 (75%)– OS a 3 anni 54% a 5 anni 40%

• Giacchetti, Ann Oncol. 1999 151 pz. con metastasi epatiche inoperabili

trattati con Oxa + 5FU (83% con cronoterapia):– 59% RP– OS casistica 24 mesi (28% vivi a 5 aa)– 51% operati (38% resezione radicale)– OS operati 48 mesi (50% vivi a 5 aa)

Oxaliplain- Oxaliplain- basedbasedAdam, 2001Adam, 2001Giacchetti, 1999Giacchetti, 1999Giacchetti, 2000Giacchetti, 2000Alberts, 2003Alberts, 2003Tournigand, 2004Tournigand, 2004

IrinotecanIrinotecan- - basedbasedPozo, 2004Pozo, 2004Ducreux, 2003Ducreux, 2003Tournigand, 2004Tournigand, 2004

OxOxIriIri- - basedbasedFalcone, 2004Falcone, 2004Quenet, 2004Quenet, 2004

7017011511511001004242

111111

40405555

109109

74743434

14%14%51%51%32%32%36%36%22%22%

33%33%31%31% 9%9%

40%40%58%58%

14%14% 38%38% 21%21% 33%33% 13%13%

28%28% -- 7%7%

26%26% 27%27%

39%39%50%50%

- - - - - -

------

----

Resection rates after Resection rates after chemotherapychemotherapy

in initially inoperable patientsin initially inoperable patients ChemotherapyChemotherapy Pts Pts SurgerySurgery R0 5-yr OS R0 5-yr OS

raterate

Resecabilità metastasi epatiche dopo 1^ linea

• Tournigand (JCO 2004: 22 229-237): FOLFIRIFOLFOX vs FOLFOXFOLFIRI

Arm A Arm B

FOLFIRI FOLFOX

N° PZ 109 111

N° responders 61 59

N° resecati 8 21

R0/R1 7/1 13/8

Metastasi epatiche nel carcinoma del colon retto

1. Malattia solo epatica operata

• Cosa fare dopo resezione? – Solo follow up?– Chemioterapia locoregionale?– Chemioterapia sistemica?– Chemioterapia locoregionale + sistemica?

Metastasi epatiche nel carcinoma del colon retto

EE-- mailmail Case Case DiscussionDiscussionMetastaticMetastatic colon colon cancercancer LiverLiver-- onlyonly DiseaseDisease: :

Post Post ResectionResection TreatmentTreatment

D. D. HallerHaller, D. , D. CunningamCunningam, D.J . , D.J . KerrKerr 25/9/0225/9/02

Trattamento adiuvante post-resettivo

• Necessario in ogni paziente resecato ?

• Dopo CT neoadiuvante sistemica ?

• Sola terapia sistemica ?

• Alternanza di CT sistemica di ultima generazione / CT i.a. meno tossica (5-FU) ?

Terapia sistemica

CT sistemica con schedule basate sul 5-FU sembra

poter dare beneficio ma le casistiche sono troppo

limitate per dare risultati significativi

ADJUVANT THERAPY AFTER RESECTION OF LIVER METS’ FROM

COLORECTAL-CANCERAuthor # pts Regimens Surv Hepatic

Rec Free

Lorenz 1998

226 HAI (LV/5-FU)Vs

Control

47%

30%At 5 yrs

-

-

Kemeny N

1999

156 HAI (FuDR) + iv LVFU

vsiv LVFU

61%

49%At 5 yrs

74%

44%

Kemeny M

2002 (4 yrs F.up)

75/109 HAI (FuDR) + iv LVFU

vsControl

63.7/47mos

49/34 mos

67%

43%

Chemotherapy for resectable liver metastases

HAI: 5FU/LV

Observation

1.Lorenz et al, Ann Surg 1998;228:756; 2. Kemeny et al, J Clin Oncol 2002;20:1499-505; 3. Kemeny et al, NEJM 1.Lorenz et al, Ann Surg 1998;228:756; 2. Kemeny et al, J Clin Oncol 2002;20:1499-505; 3. Kemeny et al, NEJM 1999;341:20391999;341:2039

HAI FUDR+ Systemic 5FU

Observation

HAI FUDR+Systemic 5FU/LV

Systemic 5FU/LV

German phase III1 (N=34 evaluable/226 enrolled)

ECOG/SWOG phase III2 (N=75 evaluable/109 enrolled)

MSKCC phase III3 (N=156)

No difference in TTP and OS, butresults difficult to interpretate asonly 30% of patients completed

4-yr liver PFS: 67% vs 43 (p=0.03) 4-yr OS: 62% VS 53% (NS)

2-yr liver PFS: 90% vs 60 (p=0.03)2-yr OS: 86% vs 72% (p=0.03)5-yr OS: 61% vs 45%

S

S

S

N. Kemeny NEJM 2005N. Kemeny NEJM 2005

Median FU = 10.3 yrsPFS = comb vs Syst = 31.3 vs 17.2 mos (p.02)OS = 68.4 vs 58.8 mos (p.10)10 yrs surv = 41.1 % vs 27.2 %Fong 0-2 = 83.3 mos vs 82.2 mosFong 3-5 = 60 mos vs 38.3 mos

10 yrs surv

Adjuvant HAI + SYS chemotherapy dopo metastasectomie multiple

epatiche . Studio Fase II NCCTG

49 pts resected49 pts resected44 % > 4 mets44 % > 4 mets

78 % bilobar disease78 % bilobar disease

12 % cryoablation12 % cryoablation36 treated36 treated

FUDR 0.2 mg / kg die 1 14 FUDR 0.2 mg / kg die 1 14 wks 0-2, 5-7, 10-12, 15-17wks 0-2, 5-7, 10-12, 15-17

AlternanteAlternante

MAYO “classica” MAYO “classica” wks 3 – 8 – 13 - 18wks 3 – 8 – 13 - 18

Median FU = 6.2 yrsMedian FU = 6.2 yrs

25 / 36 recurred25 / 36 recurred

5 yrs OS = 31 %5 yrs OS = 31 %

5 yrs liver free survival = 25 %5 yrs liver free survival = 25 %

Liver onlyLiver only 9 9

Extraliver onlyExtraliver only 1010

BothBoth 9 9

MJ O’Connel, Proc ASCO, Abs 3527, 2004MJ O’Connel, Proc ASCO, Abs 3527, 2004

Chemioterapia neoadiuvante nelle metastasi epatiche

resecabili

• Fattibile…ma a cosa serve ?

• “Finestra biologica” ?

• Ottimizzazione della durata del trattamento

Chemotherapy for resectable liver metastases: ongoing trials

Systemic XELOX + HAI FUDR

NSABP-C-09 phase III

EORTC/EPOC phase III

Systemic XELOX

Accrual completed (N=360)Preliminary results will be communicated at

ASCO 2005

SFOLFOX

Observation

FOLFOXR

S

Phase III - Intergroup: Pre - and postoperative CT with oxaliplatin/5-FU/LV versus surgery alone in resectable liver metastases from CRC - 40983

•LV5FU2+L-OHP (6 cycles) surgery LV5FU2+L-OHP (6 cycles)

R•Surgery

– Objectives: PFS, OS, Resection Rate, Toxicity– Sample Size: 330 pts in 3 y + 3.5 y follow-up– Start: June-July 2000

EORTC 40983EORTC 40983

Contraindications for resection• Unresectable extrahepatic disease

• Extensive liver involvement- > 6 segments involved- >70% liver parenchyma involved, or- all three hepatic veins involved

• Major liver insufficiency

• Patient unfit for or declining surgery

Analysis of appropriateness• Immediate resection • Resection after pre-operative

chemotherapy

LOCAL DESTRUCTION

CHEMOTHERAPY

LIVER M+ of CRC

UnresectableSinchronous or metachronous

I.A. I.V. CT

Responsive resectable

SURG

Responsive unresectable

further CTUnresponsive

2nd-line CT

LIVER M+ of CRC

Minimal residual unresectable liver disease after CT

RadiofrequencyTACE or TAE Surg + RF

Further CT

Follow-upPhase I trial

Conclusioni

Le metastasi epatiche non sono tutte uguali . . . . e neppure i

pazienti . . . . .e neppure i medici

Indispensabile la valutazione multidisciplinare di ogni caso

Studio organico delle caratteristiche biologiche e di quelle cliniche