Transcript Management of Liver Metastases of CRC origin Mohamed Abdulla (M.D.) Professor of Clinical Oncology Kasr El-Aini School of Medicine Cairo University 12/2008

Management of Liver
Metastases of CRC origin
Mohamed Abdulla (M.D.)
Professor of Clinical Oncology
Kasr El-Aini School of Medicine
Cairo University
12/2008
Challenges
Magnitude
Resection
or not?
Neoadjuvant
Chemotherapy
Targeted
Therapies
Toxicity
Of Therapy
Duration of
Therapey
Hepatic Metastases From
Colorectal Carcinoma
CRC annual US incidence[1]
~ 150,000 patients
Hepatic metastases (~ 50%)[2]
75,000 patients
Mets confined to liver (~ 30%)
22,500 patients
Hepatic resection, with
expanded indications[3]
10,000-15,000 patients
Historical hepatic resection,
rate (10% to 25%)[2]
2250-5625 patients
1. Jemal A, et al. CA Cancer J Clin. 2007;57:43-66. 2. Leonard GD, et al. J Clin Oncol.
2005;23:2038-2048. 3. Pawlik TM, et al. J Gastrointest Surg. 2007;11:1057-1077.
Hepatic Metastases From
Colorectal Carcinoma
Liver Metastases
Location
Resectable
20% to 25%
Nonresectable
75% to 80%
Number
Size
Downsizing
Survival Benefit
30% to 50% at 5 years
15% at 10 years
Resectable
10% to 20%
Leonard GD, et al. J Clin Oncol. 2005;23:2038-2048.
Hepatic Resection:
A Cure for mCRC?
Disease
Status
Treatment
Intent
Unresectable
Resectable
Unresectable
to resectable
Palliation
Cure
Cure
5-Year Survival
Uncommon
30% to 40% historically;
approaching 60% in
recent series
Pawlik TM, et al. J Gastrointest Surg. 2007;11:1057-1077.
Resection of CRLM: 5-Year Survival,
Selected Reports (≥ 100 Pts) Over
Time
Last Year
Span, Years
Patients, N
Included
Adson
1982
34
141
Registry*
1985
37
859
Jamison
1987
27
280
Nordlinger*
1990
22
1568
Gayowski
1991
10
204
Scheele
1992
32
434
Jenkins
1993
18
131
Kato*
1996
4
585
Fong
1998
13
1001
Choti
1999
16
226
Bramhall
2001
12
212
Wei
2002
10
395
Abdalla
2002
10
358
Fernandez
2002
7
100
Pawlik*
2004
14
557
Adam*
2004
30
2122
Figueras
2004
14 series).
501
*Patients
included from multiple
institutions (vs single-institution
Study
5-Year OS, %
25
33
27
28
32
33
25
33
37
40
28
47
58
58
58
42
45
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
Historical Contraindications For
Resection of Liver Limited mCRC:
Factors
 Advanced age
 > 3 or 4 liver metastases
Tumor size > 5 cm
 Inability to resect to 1-cm margins
 Bilobar disease

Hilar lymphadenopathy
 Extrahepatic disease

Abdalla EK, et al. Ann Surg Oncol. 2006;13:1271-1280.
Pawlik TM, et al. J Gastrointest Surg. 2007;11:1057-1077.
Expanded Indications: New Criteria
Defining Resectability
Macroscopic and microscopic (R0) treatment is feasible with
1 either resection alone or resection combined with radiofrequency
ablation*
2 2 adjacent liver segments can be spared
3 Vascular inflow, outflow, and biliary drainage can be preserved
4
Sufficient future liver remnant (> 20% of the total estimated liver
volume)†
5
Ability to tolerate the surgery (eg, no excessive risk due to
comorbidities)
*1-cm margins not required.
†Portal vein embolization may be used to preoperatively increase the size of the future liver
remnant by inducing hypertrophy.
Abdalla EK, et al. Ann Surg Oncol. 2006;13:1271-1280.
Pawlik TM, et al. J Gastrointest Surg. 2007;11:1057-1077.
Neoadjuvant Cytotoxic
Chemotherapy
 Is there an “optimal” cytotoxic regimen?
– FOLFOX
– FOLFIRI
– FOLFOXIRI
EORTC 40983: FOLFOX4 in mCRC
With Resectable Liver Metastases
Phase III study:
patients with CRC
and resectable liver
metastases;
WHO/ECOG
performance
score 0-2
FOLFOX4
for 6 cycles (12 wks)
(n = 182)
Surgery
(n = 182)
(N = 364)
Nordlinger B, et al. ASCO 2007. Abstract LBA5.
Surgery
FOLFOX4
for 6 cycles (12 wks)
EORTC 40983: PFS in
Resected Patients
100
Patients (%)
80
PFS at 3 Years
HR: 0.73; 95% CI: 0.55-0.97; P = .025
60
42.4
40
33.2
20
0
Peri-Op CT
Nordlinger B, et al. ASCO 2007. Abstract LBA5.
Surgery Only
Summary: Initially Resectable
Little clinical trial data to guide
treatment decisions
– EORTC 40983: benefit less than expected
– Current EORTC 40051 trial assessing
addition of targeted agents
– Cetuximab plus bevacizumab vs cetuximab
alone when administered preoperatively and
perioperatively
Resection of Initially Unresectable Liver
Metastases After Systemic Chemo
Authors
Year
Patients, Chemotherap
n
y Type
No
Resection,
n(%)
5-Year
Survival,
%
Levi
1992
98
Fu-Fol-Ox
18 (19)
--
Fowler
1992
--
Fu-Fol
11
--
Bismuth
1996
330
Fu-Fol-Ox
53 (16)
40
Giacchetti
1999
389
Fu-Fol-Ox*
77 (20)
50
Adam
2001
701
Fu-Fol-Ox
95 (14)
39
Wein
2001
53
Fu-Fol
6 (11)
--
Rivoire
2002
98
Fu-Fol-Ox
18 (19)
--
Lévi F, et al. Cancer. 1992;69:893-900. Fowler WC, et al. J Surg Oncol.1992;51:122-125. Bismuth H, et al. Annals of
Surgery. 1996;224:509-522. Giacchetti S, et al. Ann Oncol. 1999;10:663-669. Adam R, et al. Ann Surg Oncol. 2001;8:347353. Wein A, et al. Ann Oncol. 2001;12:1721-1727. Rivoire M, et al. Cancer. 2002;95:2283-2292.
Outcome Based on Initial Response
to Chemotherapy
131 patients with colorectal metastases received preoperative Cth.
100
95
Partial response (n = 58)
Stabilization (n = 39)
Progression (n = 34)
92
80
OS (%)
63
60
55
P < .0001
44
37
40
20
0
30
12
8
88
1 Year
3 Years
Adam R, et al. Ann Surg. 2004;240:1052-1064.
5 Years
Neoadjuvant Oxaliplatin Before Surgery
Paul Brousse hospital study: 2047 patients with colorectal liver
metastases treated from April 1988 to December 2003
14% of 1512 patients treated with chemotherapy achieved a response,
permitting resection
Chemotherapy (N = 1512)
205 (14%)
Resection (N = 740)
205 (28%) Initially unresectable
1307 (86%)
535 (72%) Initially resectable
Adam R et al. Ann Surg Oncol. 2001;4:347-353.
(Updated at ASCO GI Cancer Symposium 2007)
Survival After Primary or Secondary
Resection of Liver Metastases
100
Proportion Surviving
Resectable (n = 425)
80
Initially nonresectable (n = 95)
54%
60
40
50%
34%
27%
34%
20
29%
19%
0
0
1
2
3
4
5
6
Survival Time (Years)
7
8
9
10
Adam R, et al. Chemotherapy and surgery: new perspectives on the treatment of unresectable liver metastases, Annals of
Oncology, 2003, Vol. 14, supplement 2, pp.ii13-ii16, by permission of Oxford University Press.
Adam R. Ann Oncol. 2003;14(suppl 2):ii13-iii16.
NCCTG Study 97-46-51: FOLFOX4 in
Unresectable Colon Cancer
Prospective, multi-institutional study
Patients with unresectable
liver-only metastases received
FOLFOX4*
(N = 42)
Clinical response
to chemotherapy
(n = 25)
No response to
chemotherapy†
(n = 17)
Surgery not
possible
(n = 8)
Surgery
(n = 17)
*FOLFOX4: biweekly oxaliplatin 85 mg/m2 followed sequentially by leucovorin 200 mg/m2,
bolus FU 400 mg/m2 and continuous FU infusion 600 mg/m2 over 22 hours on Day 1.
Alberts SR, et al. J Clin Oncol. 2005;23:9243-9249.
NCCTG Study 97-46-51:
Response and OS
Parameter
Clinical response (N = 42), %
 Complete
 Partial
 Regression
 SD
 Progression
Surgical response (n = 17), n
 Complete resection
 Partial resection
 Unresectable
OS (N = 42), mos
 Resected patients
Time to recurrence/progression
 Median time to recurrence in resection patients (n = 15)
 Overall time to disease progression (N = 42)
Alberts SR, et al. J Clin Oncol. 2005;23:9243-9249.
Outcome
2
50
10
26
12
14
1
2
26
35
19
12
FOLFIRI for Unresectable Liver
Metastases
Neoadjuvant FOLFIRI
Therapy Followed by
Surgical Resection of
Liver Metastases[1]
Gruppo Oncologico
Nord Ovest Study of
FOLFIRI in First-Line
Treatment of
mCRC[2]
Patients
40
122
Median follow-up,
mos
56
18.4
Response rate, %
48
41
Resection rate, %
33
12
Parameter
1. Barone C, et al. Br J Cancer. 2007;97:1035-1039.
2. Falcone A, et al. J Clin Oncol. 2007;25:1670-1676.
Summary of Cytotoxic Regimens
Regimen, %
FOLFOX
FOLFIRI
FOLFOXIRI
Response Rate
45-52
48
Resection Rate
33
33
55-64
10-50
Alberts SR, et al. J Clin Oncol. 2005;23:9243-9249.
Barone C, et al. Br J Cancer. 2007;97:1035-1039.
De La Cámara R, et al. ASCO 2004. Abstract 3593.
Falcone A, et al. J Clin Oncol. 2007;25:1670-1676.
Abad A, et al. ASCO 2005. Abstract 3618.
Ho WM, et al. Med Oncol. 2005;22:303-312.
Role of Biologic,
Targeted Therapy
Role of Targeted Therapy:
EGFR Inhibitors

First-line therapy with FOLFOX + cetuximab for
metastatic colorectal cancer
– Response rate: 72%
– 10 of 43 (23%) patients underwent potentially curative
resection
Regimen
n
RR
(%)
AIO/IRI + cetuximab
21
67
24
Folprecht
FOLFOX + cetuximab
42
79
23
Cervantes
FOLFIRI + cetuximab
42
45
24
Peeters
Resectability (%)
Author
Tabernero J, et al. J Clin Oncol. 2007;25:5225-5232. Folprecht, et al. Ann Oncol. 2006;17:450-456. Cervantes,
et al. ECCO 2005. Abstract 642. Peeters, et al. ECCO 2005. Abstract 664.
N014A: Resection of Unresectable
CRC Limited to Liver
FOLFOX6 + Cetuximab
CR/PR resectable  OR  CT x 2
Evaluation
PR, unresectable  Rx to prog/tolerability
Prog  off study, Rx per MD


Endpoints: resectability, response rate, survival
Initial assessment: surgical response rate 25%
Clinical Trials.gov. Available at: http://clinicaltrials.gov/ct2/show/NCT00056030.
Accessed January 10, 2008.
CRYSTAL Trial:
Surgery With Curative Intent

In cetuximab arm, significantly more patients
undergoing surgery with curative intent had
successful resection
Outcome, %
FOLFIRI + Cetuximab
(n = 599)
FOLFIRI
(n = 599)
Surgery with curative intent
6.0
2.5
No residual tumor after resection
4.3*
1.5
No residual tumor in patients
with liver metastases only
9.8
4.5
*P = .0034
Van Cutsem, et al. ASCO 2007. Abstract 4000.
Summary: Current Experience With
Cetuximab
Compared with chemotherapy alone
– Consistently increased RR in all trials
– Evidence of improved resectability
Initially unresectable metastatic colorectal cancer
First-line and refractory
Nonselected and selected (liver-limited) patients
Role of Bevacizumab

Phase II trial: XELOX + bevacizumab
– 54 patients with potentially resectable liver
metastases
– 6 cycles of neoadjuvant therapy (1 week on, 1
week off)
– Clinical response: 74%
– pCR: 11%
– No long-term follow-up reported
Gruenberger B, et al. ASCO 2007. Abstract 4060.
Downstaging of Unresectable mCRC:
Randomized Studies
Study
N
Regimen
Van Cutsem
2007
(CRYSTAL)
Bokemeyer
2007
(OPUS)
599
IR/FU/Cet
599
IR/FU
169
OX/FU/Cet
168
OX/FU
700
700
OX/FU/Bev
OX/FU
Cassidy 2007
(NO16966)
Metastasis, %
Liver
Liver
>1
Limited
Site
21
NR
85
38
88
40
25
NR
NR
*P =.0034 for cetuximab + FOLFIRI vs FOLFIRI alone, all patients.
Van Cutsem E, et al. ASCO 2007. Abstract 4000.
Bokemeyer C, et al. ASCO 2007. Abstract 4035.
Cassidy J, et al. ASCO 2007. Abstract 4030.
Hecht JR, et al. World GI Congress 2007.
47
Resectability
(Liver Limited), %
R0
All
4.3 (9.8)*
6.0
39
1.5 (4.5)
2.5
46
4.7
6.5
36
2.4
3.6
38
38
NR
8.4 (19.2)
6.1 (12.9)
ORR
Liver Toxicity of
Neoadjuvant Therapy
A Combined Study of Liver Toxicity
of Neoadjuvant Therapy


Patients from M. D. Anderson Cancer Center and Istituto per la Ricera e la Cura del
Cancro Candiolo (Torino, Italy) who underwent hepatic surgery for colorectal
metastases with curative intent between (June 1992 - June 1999)
Primary endpoint: toxicity
n = 158
No chemotherapy
5-FU/LV
n = 63
5-FU/LV + Irinotecan
n = 94
5-FU/LV + Oxaliplatin
n = 79
Other Therapy
n = 12
Patients aged 18-86 years
divided on basis
of preoperative
chemotherapy regimen*
(N = 406)
*Primary colon carcinoma: 76.3%; node-positive disease: 60.3%
Vauthey JN, et al. J Clin Oncol 2006;24:2065-2072.
Liver Toxicity of Neoadjuvant Therapy
Patients, n (%)
Sinusoidal dilation
 Yes
 No
Steatosis > 30%
 Yes
 No
Steatohepatitis
 Yes
 No
No CTx
5-FU/LV
5-FU/LV +
Irinotecan
5-FU/LV +
Oxaliplatin
Other
3 (1.9)
155 (98.1)
0
63 (100)
4 (4.3)
90 (95.7)
15 (18.9)
64 (81.1)*
0
12 (100)
14 (8.9)
144 (91.1)
9 (16.6)
54 (83.3)
9 (10.6)
85 (89.4)
3 (3.8)
76 (96.2)
1 (8.3)
11 (91.7)
7 (4.4)
151 (95.6)
3 (4.8)
60 (95.2)
19 (20.2)
75 (79.8)*
5 (6.3)
74 (93.6)
0
12 (100)
*P = .0001 compared with no treatment arm.
Patients with steatohepatitis had an increased 90-day mortality compared
with patients who did not develop steatohepatitis (P = .001)
Vauthey JN, et al. J Clin Oncol. 2006;24:2065-2072.
Complications Following Neoadjuvant
Bevacizumab
Retrospective study of preoperative bevacizumab
therapy and postoperative complications in
patients with colorectal cancer who underwent
hepatic surgery for liver metastases (N = 1186)
– No increase in hepatobiliary, wound, or other
postoperative complications
– Optimal timing of surgery in patients receiving
bevacizumab not known
Patient Selection??
Kesmodel S, et al. ASCO 2007. Abstract 234.
Treatment-Associated Liver Toxicity
 Irinotecan: steatohepatitis (80%)
 Oxaliplatin: sinusoidal/vascular injury
 Bevacizumab
– Impaired liver regeneration
– Wound healing complications
– Need to wait 6-8 weeks before surgical resection
 Cetuximab: no acute or chronic effects to date
 Morbidity increased with prolonged use
Does a Clinical CR or Pathologic CR Lead
to Survival Benefit?

Clinical series from MSKCC[1]
– 435 patients treated with neoadjuvant therapy




39 (9%) of patients had 117 lesions disappear on CT scan
43 pathological CR in lesions
Durable CR in 26 patients (> 40 months)
791 consecutive patients receiving neoadjuvant
therapy[2]
– Pathological CR: 4% (31 patients)
– “Strongly impacted” OS
1. Taylor RA, et al. ASCO 2007. Abstract 4058.
2. Wicherts, DA et al. ASCO 2007. Abstract 4063.
Issues to Consider
 Increased duration of therapy raises risk of
hepatic toxicity
– Duration of therapy must be balanced with limiting
liver toxicity
 CR may inhibit ability to resect and/or ablate
Summary
 Neoadjuvant chemotherapy appears to enhance
long-term outcomes
 Multiagent chemotherapy regimens provide similar
clinical benefit with resection rates in the 20% to
30+% range
 pCR appears to be 5% to 10% with current
regimens
 Role of targeted therapy appears promising
– Cetuximab may offer advantages in clinical efficacy and
safety over bevacizumab
 Active area of clinical investigation
 Multidisciplinary team approach required