1. early disease 2. advanced disease (liver metastasis) stefano iacobelli cancer clinic &...
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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!