Liver Metastases in Colorectal Cancer: Current and Emerging Approaches to Treatment

1
Liver Metastases in Colorectal Cancer Current
and Emerging Approaches to Treatment

• Ali Shamseddine ,MD
• Professor of Medicine
• AUBMC

2
Summary of Therapy for Initially Resectable
Disease

• Use of chemotherapy appears to enhance outcomes
  achieved with surgery
• Adjuvant chemotherapy
• Perioperative chemotherapy
• Adjuvant hepatic artery infusion chemotherapy
  combined with systemic chemotherapy

3
Managing Liver Metastases in Colorectal Cancer
Key Issues

• Defining resectability
• Role of chemotherapy
• Resectable patients
• Initially nonresectable patients
• Optimal chemotherapy regimen
• Role of targeted therapy
• Treat to best response or resectability?
• Multidisciplinary approach

4
Liver Metastases in Colorectal Cancer Outcomes
Liver Metastases
Location
Nonresectable75 to 80
Resectable20 to 25
Number
Size
Downsizing
Survival Benefit 30 to 40 at 5 years 15 at 10
years
Resectable10 to 20
5
Changing Definition of Resectability
Old What must come out?
New What will stay in?

• How many metastases?
• 4 lt lesions, with unilobar location,
  resectable
• How large?
• lt 5 cm resectable
• Extrahepatic disease?
• If none, resectable

Can R0 resection (negative margins) be achieved?
Can two contiguous liver segments be
preserved? Can adequate future liver remnant
(gt20) be preserved?
Charnsangavej C, et al. Ann Surg Oncol. 2006
131261-1268.
6
Role of Chemotherapy for Resectable Disease

• One adjuvant systemic chemotherapy versus surgery
  alone
• One peri-operative trial
• Hepatic artery infusion therapy

7
Adjuvant Therapy AURC 9002
5-FU LV days 1-5 every 4 weeks x 6
Surgery
R

• 171 patients
• Resected liver metastases
• 95 had 3 or fewer
• Goal Improved DFS

Surgery
Portier, G. et al. J Clin Oncol 2006
244976-4982.
8
Disease-free Survival After Liver Resection
Chemotherapy
100
No chemotherapy
90
80
Group Median DFS Surgery 17.6
months Chemotherapy 24.4 months (p0.028)
70
60
50
Survival ()
40
30
20
10
0
0
6
24
36
42
60
66
12
18
30
48
54
72
78
84
Months
Portier, G. et al. J Clin Oncol
2006244976-4982.
9
EORTC 40983 (EPOC Trial)
FOLFOX4 x 6 cycles
FOLFOX4 x 6 cycles
Surgery

• 364 patients randomized
• Potentially resectable ( 4 liver metastases)
• Goal Improve PFS
• Interim objective Evaluate tumor response to
  perioperative CT
• Perioperative CT (n 182)
• 159 (87.3) underwent surgery
• 151 (83.0) resected
• Surgery (n182)
• 170 (93.4) underwent surgery
• 152 (83.0) resected

R
Surgery
Nordlinger B, et al. ASCO 2007 Abstract LBA5
10
EORTC 40983 Progression-Free Survival in
Resected Patients
HR 0.73 CI 0.55-0.97, p0.025
100
90
9.2At 3 years
80
Periop CT
70
60
50
42.4
40
Surgery only
30
33.2
20
10
0
0
1
2
3
4
5
6
(years)
Nordlinger B, et al. ASCO 2007 Abstract LBA5
11
Hepatic Artery InfusionMemorial Sloan-Kettering
Randomized Study
Systemic 5-FU/CF4 wks post-surgeryHAI FUDR
DEX2 wks later for 2 wks 1 wk rest (6 cycles)

• 156 patients randomized
• Initial resection of liver metastases

R
Systemic 5-FU/CFq 4 wks (6 cycles)
Kemeny N, et al. N Engl J Med. 19993412039-2048
12
HAI Versus Systemic Therapy Alone Long-term
Follow-up
1.0
0.8
Combined therapy
0.6
Proportion surviving
0.4
Monotherapy
0.2
0
150
100
50
0
Months after resection
Kemeny N, et al. N Engl J Med. 2005352734.
13

• Meta-analysis of two phase III trials
• FFCD 9002 and EORTC/NCIC CTG/GIVIO

Mitry et al, ASCO 2006
14
Summary of Therapy for Initially Resectable
Disease

• Use of chemotherapy appears to enhance outcomes
  achieved with surgery
• Adjuvant chemotherapy
• Perioperative chemotherapy
• Adjuvant hepatic artery infusion chemotherapy
  combined with systemic chemotherapy

15
Randomized phase III trial comparing infused
5-fluorouracil/folinic acid (LV5FUs) versus
LV5FUsirinotecan (FOLFIRI) as adjuvant treatment
after complete resection of liver metastases from
colorectal cancer (LMCRC)CPT-GMA-301

• M. Ychou, W. Hohenberger, S. Thezenas,
• M. Navarro, P. Gascon, C. Bokemeyer,
• E. Shacham-Shmueli, F. Rivera,
• C. Kwok-Keung Choi, A. Santoro

Sponsored by Pfizer
16
Disclosure Slide

• Yes, I have Honoraria to disclose. Amgen, Merck,
  Roche, Pfizer
• Yes, I have Research Funding to disclose.
• Merck, Roche, Sanofi-Aventis, Pfizer

17

• Meta-analysis of two phase III trials
• FFCD 9002 and EORTC/NCIC CTG/GIVIO

Mitry et al, ASCO 2006
18
Study design
5-FU bolus 400 mg/m2 5-FU CI 46 hrs. 2400 mg/m2
FA 2 hrs. IV 400 mg/m2 (200 if Lform)
LV5FUs
and
5-FU bolus 400 mg/m2 5-FU CI 46 hrs. 2400 mg/m2
FA 2 hrs. IV 400 mg/m2 (200 if Lform)
and
FOLFIRI
Irinotecan30-90 min. IV180 mg/m2

• Every two weeks

• Chemotherapy will be administered for a total of
  12 cycles (6 months) except in case of
  unacceptable toxicity, progression or consent
  withdrawal.

19
Stratification factors

• A. Number of liver metastases
• 1 vs. 2-4 vs. 5
• B. Prior adjuvant chemotherapy
• Yes / No
• C. Delay between resection of primary tumour and
  diagnosis of liver metastasis
• ? 1 year / gt1 year

20
Main eligibility criteria - 1

• Histologically proven adenocarcinoma of the colon
  or rectum with complete resection of primary
  tumour.
• Complete surgical resection (R0) of the liver
  metastasis(es) within a minimum of three weeks,
  and a maximum of 8 weeks prior to the first study
  treatment infusion.  
• Prior adjuvant chemotherapy for the primary
  tumour allowed except Irinotecan based
  combination, with the last dose given at least
  six months before the first infusion of study
  treatment.

21
Main eligibility criteria - 2

• 18 lt Age lt 75.
• WHO PS lt 2.
• Exclusively hepatic metastasis (es)
• No prior hepatic resection and no prior
  radiofrequency ablation or cryoablation
• No prior chemotherapy for metastatic disease.

22
Endpoints

• Primary
• Disease-Free Survival (DFS) time from
  randomization to local or regional recurrence,
  metastasis, or death due to cancer
• Secondary
• Safety
• Overall Survival

23
Sample size

• Initial hypothesis (data from Kemeny et al. 1999)
• Expected median DFS
• LV5FUs 32.4 months
• FOLFIRI 55.4 months ? HR0.58
• 128 DFS events and 420 patients (? 0.05, ?
  15 )

• Protocol amendment (may 2006)
• Expected median DFS
• LV5FUs 19.0 months
• FOLFIRI 29.7 months ? HR0.64
• 147 DFS events and 320 patients

24
Results

• 321 patients from 16 countries (66 centers)
• 54 month accrual from 12/2001 to 07/2006
• 15 patients non treated
• 8 consent withdrawal
• 4 progressive disease before treatment
• 2 too long delay after surgery
• 1 neutropenia before treatment
• 1 patient randomised to LV5FUs received FOLFIRI
• 42 months median follow-up

25
Patient characteristics
26
Surgical Procedures
27
Treatment administration
28
Safety results
29
Survival Status
30
Disease-Free Survival
1-year DFS 63 vs. 77 2-year DFS 46 vs. 51
31
Multivariate analysis (Cox)
32
Delay to start CT from surgery
33
Conclusion 1

• No difference was observed in DFS between the 2
  arms, adjusted or not for important prognostic
  factors
• The safety profile of both treatment regimens was
  as expected
• Lower relative dose intensity of 5FU and FA was
  observed in the combination arm

34
Conclusion 2

• We cannot exclude a positive effect of FOLFIRI if
  chemotherapy starts before 6 weeks after surgery
• No bitherapy has yet been proven superior to 5FU
  alone even in peri-operative way (FOLFOX was
  compared to surgery alone in EORTC trial 40983)
• We urgently need large trials in this setting
  integrating tailored chemotherapy and targeted
  therapies

35
ACKNOWLEDGEMENTS

• All the patients participating in this trial and
  their families
• All the investigators from the following
  countries (nb pts)
• France (79), Germany (61), Spain (43), Korea
  (31), Italy (26), Israël (18), Hong-Kong (9),
  Sweden (9), Belgium (8), Denmark (7),
  United-Kingdom (7), Ukraine (7), Switzerland (6),
  Portugal (4), South-Africa (4), Taiwan (2).