Transcript corso perfezionamento 25/settembre/97

Il trattamento delle metastasi
epatiche neoplasie del colon retto
Filippo de Braud MD
Clinical Pharmacology and New Drugs Development Unit
European Institute of Oncology
Milano 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 - 1997
10 STUDIES
> 2500 PTS
Mortality
1 yr surv
5 yrs surv
Sem. Oncol. 26, 5: 514-523, 1999
1- 5 %
80 %
25 - 37 %
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 cm
Disease Free Interval < 12 mos
Number of Mets > 3
Primary Node Positive
CEA > 200 ng/mg
(JCO, 15: 938 - 46, 1997)
ADVANCED COLORECTAL-CANCER:
LIVER RESECTION
Disease Related Factors
Score
0 - 1
2
3
4
JCO, 15: 938 - 46, 1997
Surv (%)
1yr
5yr
84 - 92
92
89
62
57
47
16
8
Median
months
73
50
30
15
Fong Y. et al, Ann Surg 1999, 230: 309-321
SURGICAL RESECTION
Results are very reproducible !
ADVANCED COLORECTAL-CANCER
RESECTION OF LIVER METS’
Study
# pts
5-yrs
OS
Median
Survival
months
Hughes
1986
Scheele
1995
Nordinger
1996
Jamison
1997
Fong
1999
607
33%
-
434
33%
40
1568
28%
-
280
27%
33
1001
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 metastases
Adam R, Ann Oncol 2003;14: ii13-ii16
Surviving (%)
1.0
Resectable (n=425)
Initially unresectable (n=95)
0.8
54%
0.6
34%
50%
0.4
27%
34%
0.2
29%
19%
0
0
1
2
3
4
5
6
Survival time (years)
7
8
9
10
Neoadjuvant chemotherapy
Paul Brousse hospital study
Adam R et al., Ann Surg Oncol 8:347-53, 2001
N= 872
Initially unresectable
N=701
Primary resectable
N=171
20% of all patients
Oxaliplatin/5FU/LV
Never resectable
N=95
Secondary resectable
11% of all patients
14% of CT-treated
Resection: 266 patients (31%)
Oxaliplatino
Metastasi 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)
Resection rates after chemotherapy
in initially inoperable patients
Chemotherapy
Pts
Surgery
rate
R0
5-yr OS
Oxaliplain- based
Adam, 2001
Giacchetti, 1999
Giacchetti, 2000
Alberts, 2003
Tournigand, 2004
701
151
100
42
111
14%
51%
32%
36%
22%
14%
38%
21%
33%
13%
39%
50%
-
Irinotecan- based
Pozo, 2004
Ducreux, 2003
Tournigand, 2004
40
55
109
33%
31%
9%
28%
7%
-
74
34
40%
58%
26%
27%
-
OxIri- based
Falcone, 2004
Quenet, 2004
Resecabilità metastasi epatiche dopo
1^ linea
•
Tournigand (JCO 2004: 22 229-237):
FOLFIRIFOLFOX vs
FOLFOXFOLFIRI
Arm A
FOLFIRI
Arm B
FOLFOX
N° PZ
109
N° responders
61
59
8
21
7/1
13/8
N° resecati
R0/R1
111
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
E-mail Case Discussion
Metastatic colon cancer Liver-only Disease:
Post Resection Treatment
D. Haller, D. Cunningam, D.J. Kerr 25/9/02
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-CANCER
Author
# 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
vs
61%
74%
iv LVFU
49%
44%
At 5 yrs
Kemeny M
2002
(4 yrs F.up)
75/109
HAI (FuDR) + iv LVFU 63.7/47mos
vs
Control
49/34 mos
67%
43%
Chemotherapy for resectable liver
metastases
German phase III1 (N=34 evaluable/226 enrolled)
S
HAI: 5FU/LV
Observation
No difference in TTP and OS, but
results difficult to interpretate as
only 30% of patients completed
ECOG/SWOG phase III2 (N=75 evaluable/109 enrolled)
HAI FUDR+ Systemic 5FU
S
Observation
4-yr liver PFS: 67% vs 43 (p=0.03)
4-yr OS: 62% VS 53% (NS)
MSKCC phase III3 (N=156)
S
HAI FUDR+Systemic 5FU/LV
Systemic 5FU/LV
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%
1.Lorenz et al, Ann Surg 1998;228:756; 2. Kemeny et al, J Clin Oncol 2002;20:1499-505;
1999;341:2039
3. Kemeny et al, NEJM
N. Kemeny NEJM 2005
Median FU = 10.3 yrs
PFS = 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 mos
10 yrs surv
Fong 3-5 = 60 mos vs 38.3 mos
Adjuvant HAI + SYS chemotherapy dopo metastasectomie multiple
epatiche . Studio Fase II NCCTG
49 pts resected
36 treated
44 % > 4 mets
78 % bilobar disease
12 % cryoablation
FUDR 0.2 mg / kg die 1
14
wks 0-2, 5-7, 10-12, 15-17
Alternante
MAYO “classica”
wks 3 – 8 – 13 - 18
Median FU = 6.2 yrs
Liver only
25 / 36 recurred
5 yrs OS = 31 %
Extraliver only
Both
9
10
9
5 yrs liver free survival = 25 %
MJ 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
NSABP-C-09 phase III
S
Systemic XELOX
Systemic XELOX
+ HAI FUDR
EORTC/EPOC phase III
R
FOLFOX
S
Observation
FOLFOX
Accrual completed (N=360)
Preliminary results will be communicated at ASCO 2005
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 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
Unresectable
Sinchronous or metachronous
Responsive
unresectable
further CT
I.A.
I.V. CT
Unresponsive
2nd-line CT
Responsive
resectable
SURG
LIVER M+ of CRC
Phase I trial
Further CT
Follow-up
Minimal residual unresectable
liver disease after CT
TACE or TAE
Surg + RF
Radiofrequency
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