Neoadjuvant and Adjuvant Neoadjuvant and Adjuvant Chemotherapy for Liver Chemotherapy for Liver Limited Metastases from Limited Metastases from

Colorectal CancerColorectal Cancer

Heinz-Josef Heinz-Josef LenzLenz, MD FACP, MD FACP

Professor of MediciProfessor of Medicine ne

USC Norris Comprehensive Cancer USC Norris Comprehensive Cancer CenterCenter

Questions Questions

When to treat with chemotherapyWhen to treat with chemotherapy

What is the right chemotherapy prior What is the right chemotherapy prior surgery surgery

When to do the surgery for primary and When to do the surgery for primary and liver metastasesliver metastases

What is the right chemotherapy after What is the right chemotherapy after surgery surgery

Outline of PresentationOutline of Presentation

OverviewOverview

Therapy for Initially Resectable Liver Therapy for Initially Resectable Liver MetastasesMetastases

Therapy for Initially Unresectable Liver Therapy for Initially Unresectable Liver MetastasesMetastases

SummarySummary

Hepatic Metastases from Hepatic Metastases from Colorectal CancerColorectal Cancer

Approximately 30 to 40% of patients will Approximately 30 to 40% of patients will have liver-only metastases at time of have liver-only metastases at time of recurrencerecurrence

Approximately 20 to 30% will have liver-Approximately 20 to 30% will have liver-only metastases at the time initial only metastases at the time initial evaluationevaluation

25-30,000 patients with 25-30,000 patients with Liver-only metastasesLiver-only metastases

LIVER METASTASESLIVER METASTASES

RESECTABLERESECTABLE

20-25%20-25%NON RESECTABLENON RESECTABLE

75-80%75-80%

SURVIVAL BENEFITSURVIVAL BENEFIT

30-40% AT 5 YEARS30-40% AT 5 YEARS

15% AT 10 YEARS15% AT 10 YEARS

RESECTABLERESECTABLE

10-20%10-20%

Downsizing

size

location

number

Therapy for Initially Therapy for Initially Resectable Liver MetastasesResectable Liver Metastases

Results of liver surgeryResults of liver surgeryfor metastatic CRC (N for metastatic CRC (N >> 100) 100)

N. of patients Operative mort 5-yr survival

Adson, 1984 (1) 141 2.8% 23%

Hughes, 1988 (2) 859 - 33%

Doci, 1991 (3) 100 5% 30%

Scheele, 1991 (4) 219 6% 39%

Rosen, 1992 (5) 280 4% 25%

Nordlinger, 1992 (6) 1818 2.4% 26%

Gayowski, 1994 (7) 204 0% 32%

Rees, 1997 (8) 114 1% 37%

1 - MA. Adson et al., Arch. Surg., 1984; 119: 647-51 5 - CB. Rosen et al., Ann. Surg., 1992; 216: 493-5052 - KS. Hugues, Surgery, 1988; 103: 278-88 6 - B. Nordlinger et coll., Ed. Paris Springer-Verlag, 1992; 141-59 3 - R. Doci et al., Br. J. Surg., 1991; 78: 797-801 7 - TJ. Gayowski et al., Surgery, 1994; 116: 703-11 4 - J. Scheele et al., Surgery, 1991; 110: 13-29 8 - M. Rees et al., Br. J. Surg., 1997; 84: 1136-40

NCCN GUIDELINES 2007NCCN GUIDELINES 2007

““Patients who have completely resected Patients who have completely resected liver metastases should be offered 4 to liver metastases should be offered 4 to 6 months of 6 months of adjuvantadjuvant chemotherapy… chemotherapy… observation or a shortened course of observation or a shortened course of chemotherapy is considered for chemotherapy is considered for patients who have completed patients who have completed neoadjuvantneoadjuvant chemotherapy.” chemotherapy.”

Adjuvant ChemotherapyAdjuvant Chemotherapy

May reduce the risk of recurrenceMay reduce the risk of recurrence

Focus of completed and current trialsFocus of completed and current trials– Systemic chemotherapySystemic chemotherapy– Hepatic artery infusion (HAI) Hepatic artery infusion (HAI)

Adjuvant ChemotherapyAdjuvant ChemotherapyMemorial Sloan-Kettering Randomized Memorial Sloan-Kettering Randomized

StudyStudy

HAI + systemic CTHAI + systemic CT Systemic CT Systemic CT#Pts 2-yr survival#Pts 2-yr survival #Pts 2-yr survival#Pts 2-yr survival p-p-

valuevalue

SurvivalSurvival 74 74 86%86% 82 82 72%72% 0.03 0.03

Hepatic DFSHepatic DFS 74 74 90%90% 82 82 60%60% <0.001 <0.001

Any DFSAny DFS 74 74 57%57% 82 82 42%42% 0.07 0.07

1 Liver Met1 Liver Met 27 27 72%72% 33 33 79%79% 0.55 0.55

2-4 Liver Mets2-4 Liver Mets 33 33 97%97% 34 34 60%60% 0.0003 0.0003

>4 Liver Mets>4 Liver Mets 14 14 84%84% 15 15 64%64% 0.24 0.24

Positive Margins 10Positive Margins 10 90%90% 11 11 44%44% 0.02 0.02

NEJM 341:2039, 1999NEJM 341:2039, 1999

Kemeny, N. E. et al. N Engl J Med 2005;352:734-735

Overall Survival among Patients Treated with Hepatic Arterial Infusion plus Systemic Chemotherapy (Combined Therapy) or with Systemic

Chemotherapy Alone (Monotherapy)

Median: 68.4 monthsMedian: 68.4 months

Median: 55.2 monthsMedian: 55.2 months

Adjuvant ChemotherapyAdjuvant ChemotherapyMemorial Sloan-Kettering Randomized Memorial Sloan-Kettering Randomized

StudyStudy

Adjuvant ChemotherapyAdjuvant ChemotherapyMemorial Sloan-Kettering Randomized Memorial Sloan-Kettering Randomized

StudyStudySite of recurrence HAI group Systemic group Site of recurrence HAI group Systemic group

Lung 15 (50%) 17 (38.6%)

LiverLiver 77 (23.3%)(23.3%) 3030 (68.2%)(68.2%)

Ovaries 4 (13.3%) 1 (2.3%)

Bone 3 (10%) 3 (6.8%)

Pelvis 4 (13.3%) 7 (15.9%)

Lymph nodes 3 (10%) 10 (22.7%)

Other 6 (20%) 6 (13.6%)

Lung 15 (50%) 17 (38.6%)

LiverLiver 77 (23.3%)(23.3%) 3030 (68.2%)(68.2%)

Ovaries 4 (13.3%) 1 (2.3%)

Bone 3 (10%) 3 (6.8%)

Pelvis 4 (13.3%) 7 (15.9%)

Lymph nodes 3 (10%) 10 (22.7%)

Other 6 (20%) 6 (13.6%)

N9945 - Preliminary ResultsN9945 - Preliminary Results

54 of 70 patients initiate HAI FUDR + SYS54 of 70 patients initiate HAI FUDR + SYS52% had a solitary metastases and 24% presented 52% had a solitary metastases and 24% presented with bilobar metastaseswith bilobar metastasesNo post-operative or treatment related deaths were No post-operative or treatment related deaths were reportedreportedPrimary endpoint:Primary endpoint: 2-yr survival (2YS), with 80% of 2-yr survival (2YS), with 80% of patients surviving 2 yrs as evidence of promising patients surviving 2 yrs as evidence of promising efficacyefficacy – 78% (42/54) of evaluable patients are alive with a minimum 28 78% (42/54) of evaluable patients are alive with a minimum 28

months of follow-upmonths of follow-up6 deaths occurred in less than 2 yrs6 deaths occurred in less than 2 yrs

– 48% (26/54) have recurred, with 42% having liver involvement48% (26/54) have recurred, with 42% having liver involvement– Median time-to-progression is 30 months with an Median time-to-progression is 30 months with an estimated 2YS rate estimated 2YS rate

of 88%of 88% (95% CI 76-97%) (95% CI 76-97%)

Adjuvant Chemotherapy - Current and Adjuvant Chemotherapy - Current and Future StudiesFuture Studies

C-09: C-09: Metastasectomy followed by with Metastasectomy followed by with Oxaliplatin and Capecitabine +/- FUDROxaliplatin and Capecitabine +/- FUDR

Resection of Resection of liver metastases liver metastases

(1-6)(1-6)

Capecitabine + OxaliplatinCapecitabine + Oxaliplatin

Capecitabine + Oxaliplatin Capecitabine + Oxaliplatin alternating with HAI FUDRalternating with HAI FUDR

RandomizeRandomize

Open – Planned Accrual 400

Peri-operative FOLFOX4 chemotherapy Peri-operative FOLFOX4 chemotherapy and surgery for resectable liver and surgery for resectable liver

metastases from colorectal cancermetastases from colorectal cancer Final efficacy results of the EORTC Final efficacy results of the EORTC Intergroup phase III study 40983.Intergroup phase III study 40983.

B. Nordlinger, H. Sorbye, B. Glimelius, G.J. Poston, P.M. Schlag, P. B. Nordlinger, H. Sorbye, B. Glimelius, G.J. Poston, P.M. Schlag, P. Rougier, W.O. Bechstein, J. Primrose, E.T. Walpole, T. GruenbergerRougier, W.O. Bechstein, J. Primrose, E.T. Walpole, T. Gruenberger

Statistical analysis L. ColletteStatistical analysis L. Collette

For the EORTC GI Group, CR UK, ALMCAO, AGITG and FFCDFor the EORTC GI Group, CR UK, ALMCAO, AGITG and FFCD

ALMCAO AGITG

g

Trial Design and ObjectivesTrial Design and Objectives

R

FOLFOX4 x 6 cycles Surgery

FOLFOX4 x 6 cycles

Surgery

• 364 patients

• Potentially resectable (1-4) liver metastases

• Goal: Improve progression-free survival to demonstrate a 40% increase in median PFS (HR=0.71) with 80% power and 2-sided significance level 5%

Pre-Operative AssessmentPre-Operative Assessment

Outcome in chemotherapy armOutcome in chemotherapy arm– CR: 3.3%CR: 3.3%– PR: 35.2%PR: 35.2%– Stable: 33.5%Stable: 33.5%– Progression 7.7%Progression 7.7%– Not evaluable: 20.3%Not evaluable: 20.3%

SurgerySurgery

Peri-op CTPeri-op CT(N=182)(N=182)

SurgerySurgery(N=182)(N=182)

Operated Operated 158 (86.8) 158 (86.8)

167 (91.8) 167 (91.8)

Resected Resected 151 (83.0) 151 (83.0)

149 (81.9) 149 (81.9)

Not operatedNot operated due to PDdue to PD due to refusal or due to refusal or toxicitytoxicity due to other reasondue to other reason

21 (11.5)21 (11.5)777777

9 (4.9)9 (4.9)550044

Unknown if operatedUnknown if operated 3 (1.6)3 (1.6) 6 (3.3)6 (3.3)

ResultsResultsN ptsN pts

CTCTN pts N pts

SurgerySurgery% absolute % absolute differencedifference

in 3-year PFSin 3-year PFS

HazardHazardRatio Ratio

(Confidence (Confidence Interval)Interval)

P-valueP-value

All patientsAll patients 182182 182182 +7.2%+7.2% (28.1% to (28.1% to

35.4%)35.4%)

0.790.79(0.62-1.02)(0.62-1.02)

P=0.058P=0.058

All eligibleAll eligiblePatientsPatients

171171 171171 +8.1%+8.1% (28.1% to (28.1% to

36.2%)36.2%)

0.77 0.77 (0.60-1.00)(0.60-1.00)

P=0.041P=0.041

All resectedAll resectedPatientsPatients

151151 152152 +9.2%+9.2% (33.2% to (33.2% to

42.4%)42.4%)

0.730.73(0.55-0.97)(0.55-0.97)

P=0.025P=0.025

Progression-free survival in Progression-free survival in eligible patientseligible patients

HR= 0.77; CI: 0.60-1.00, p=0.041

Periop CT

28.1%

36.2%

+8.1%At 3 years

(years)

0 1 2 3 4 5 6

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk :125 171 83 57 37 22 8

115 171 115 74 43 21 5

Surgery only

FOLFOX6 modified

+ cetuximab

6 cycles

RA

ND

OM

IZA

TIO

N

ResectableLiver

Metastases from

Colorectal Cancer

no extrahepatic

disease

WHO PS 0,1

No previous chemo for

mets

FOLFOX6 modified

+ cetuximab+ bevacizumab

6 cycles(no

bevacizumab in cycle #6)

FOLFOX6 modified

+ cetuximab

6 cycles

FOLFOX6 modified

+ cetuximab

+ bevacizumab

6 cycles

follow up

follow up

SU

RG

ER

YS

UR

GE

RY

Trial 40051 (BOS)Trial 40051 (BOS)

Resectable Liver MetastasesResectable Liver Metastases Summary Summary

Studies support role for adjuvant therapyStudies support role for adjuvant therapy

Value of HAI-based therapy to be Value of HAI-based therapy to be assessedassessed

Therapy for Initially Therapy for Initially Unresectable Liver DiseaseUnresectable Liver Disease

LIVER METASTASESLIVER METASTASES

RESECTABLERESECTABLE

20-25%20-25%NON RESECTABLENON RESECTABLE

75-80%75-80%

SURVIVAL BENEFITSURVIVAL BENEFIT

30-40% AT 5 YEARS30-40% AT 5 YEARSRESECTABLERESECTABLE

10-20%10-20%

Downsizing

size

location

number

DEFINITIONS: ASCO 2006 LIVER DEFINITIONS: ASCO 2006 LIVER THINK TANKTHINK TANK

Neoadjuvant Therapy - Neoadjuvant Therapy - PreoperativePreoperative systemic systemic therapy for therapy for resectableresectable hepatic metastases followed hepatic metastases followed by by post resectionpost resection therapy. therapy.

Adjuvant Therapy - Systemic/regional therapy Adjuvant Therapy - Systemic/regional therapy post post hepatic resection.hepatic resection.

Conversion Therapy – Systemic/regional therapy Conversion Therapy – Systemic/regional therapy utilized for patients with utilized for patients with unresectableunresectable hepatic hepatic metastases in an attempt to make the metastases metastases in an attempt to make the metastases resectableresectable . .

Hepatic Artery Infusion Hepatic Artery Infusion (HAI)(HAI)

for Unresectable Liver for Unresectable Liver MetastasesMetastases

CALGB 9481: HAI FUDR versus CALGB 9481: HAI FUDR versus Systemic 5FU and LeucovorinSystemic 5FU and Leucovorin

EligibilityEligibility– Liver-only, unresectable metastases from CRCLiver-only, unresectable metastases from CRC– No prior therapy for metastatic CRCNo prior therapy for metastatic CRC

HAI FUDR 0.18 mg/kg + DEX 25 mg over 14 days

Every 28 days (N = 68)

5-FU 425 mg/m2 + LV 20 mg/m2

Daily x 5 every 4 weeks (N = 67)

R

Kemeny NE et al. J Clin Oncol 24:1395-1403, 2006

CALGB 9481: Overall SurvivalCALGB 9481: Overall Survival

HAI 5FU/LV

Med OS (months) 24.4 20.0 (p=0.034)

THP (months) 9.8 7.3 (p=0.034)

TEP (months) 7.7 14.8 (p=0.029)

RR 47% 24%

HAI5FU/LV

CALGB 9481: Hepatic vs CALGB 9481: Hepatic vs Nonhepatic Disease ProgressionNonhepatic Disease Progression

Kemeny et al. J Clin Oncol. 2006;24:1395.

Hepatic Nonhepatic

HAISystemic, P=0.034

Years from trial entry

Pro

po

rtio

n h

epat

ic

pro

gre

ssi

on

–fre

e

0 1 2 30

0.2

0.4

0.6

0.8

1.0

0 1 2 30

0.2

0.4

0.6

0.8

1.0

HAISystemic, P=0.029

Pro

po

rtio

n n

on

hep

atic

p

rog

res

sio

n–fr

ee

Years from trial entry

HAI as Neoadjuvant Therapy for HAI as Neoadjuvant Therapy for Initially Unresectable DiseaseInitially Unresectable Disease

Potential LimitationsPotential Limitations– InvasiveInvasive

Percutaneously placed catheters have a high rate of Percutaneously placed catheters have a high rate of complicationscomplications

Surgical placement may delay systemic therapySurgical placement may delay systemic therapy

– Lack of treatment for potential extrahepatic Lack of treatment for potential extrahepatic diseasedisease

– Limited studiesLimited studies

Role of Neoadjuvant Systemic Role of Neoadjuvant Systemic Chemotherapy for Liver-only Chemotherapy for Liver-only

MetastasesMetastases

Resection of non-resectable liver metastases after systemic chemotherapy

Published series

Authors

Levi FowlerBismuthGiachettiAdamWeinRivoire

Year

1992199219961999200120012002

No Pts

98-

33038970153

131

Type Chemo

Fu-Fol-OxaliFu-FolFu-Fol-Oxali Fu-Fol-Oxali*Fu-Fol-OxaliFu-FolFu-Fol-Oxali

No Resect

18 (19%)11

53 (16%)77 (20%)95 (14%)6 (11%)57 (43%)

5-yr Surv

--

40%50%39%

--

Fu-Fol-Oxali : Chronomodulated* Liver only metastases

Survival after Liver Resection of Colorectal MetastasesPaul Brousse Hospital - 473 patients (Apr. 88 - Jul. 99)

Years

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10

Su

rviv

al (

%)

91%

48%

30%

66%

33%23%

52%

P= 0.01

Adam R et al. Ann Surg 2004

No Surgery

Resectable : 335

Initially non resectable : 138

Collaboration : Oncologists - Surgeons

For Non Resectable Metastases

1- Current chemotherapy allows at least 20% of patients

to be rescued by liver surgery

2- The survival benefit of these patients is substantial

(30% and 20% rate at 5 and 10 years)

3- Resectability: a new end point for treatment strategy

Neoadjuvant Oxaliplatin Neoadjuvant Oxaliplatin Paul Brousse Hospital StudyPaul Brousse Hospital Study

Neoadjuvant Oxaliplatin Neoadjuvant Oxaliplatin Paul Brousse Hospital StudyPaul Brousse Hospital Study

Adam R. et al., Ann. Surg. Oncol., 2001; 8: 347-353

Chemo: 701 (80%)Chemo: 701 (80%)

14%14%

900900

800800

700700

600600

500500

400400

300300

200200

100100

00

Resection: 266 (31%)Resection: 266 (31%)86%86%

36%36%

64%64%

95

171171

872 patients

1988 - 1996

872 patients

1988 - 1996

Initially non-resectable

Non-resectable

Resectable

Initially non-resectable

Non-resectable

Resectable

14% of 701 CT-treated patients achieved a response permitting resection

14% of 701 CT-treated patients achieved a response permitting resection 171171

Chemotherapy

Role of Neoadjuvant TreatmentRole of Neoadjuvant TreatmentRole of Neoadjuvant TreatmentRole of Neoadjuvant Treatment

Patient status at a mean follow-up of 4.2 yearsPatient status at a mean follow-up of 4.2 years

56 dead (59%)56 dead (59%) 39 alive (41%)39 alive (41%)

95 patients95 patients95 patients95 patients

25 alive disease free (26%)25 alive disease free (26%) 14 alive with disease (15%)14 alive with disease (15%)

Survival after primary or secondaryresection of liver metastases

N014A: Resection of Unresectable N014A: Resection of Unresectable CRC Limited to the Liver Using CRC Limited to the Liver Using

FOLFOX6 + CetuximabFOLFOX6 + Cetuximab

CR/PR resectable CR/PR resectable O.R. O.R. CT x 2 CT x 2

PR, unresectable PR, unresectable Rx to Rx to Prog/TolerabilityProg/Tolerability

Prog Prog Off Study, Rx per M.D. Off Study, Rx per M.D.

Endpoints: Resectability, Response Rate, SurvivalEndpoints: Resectability, Response Rate, Survival

EvaluationEvaluation

Oxaliplatin+5-FU/LV (FOLFOX6) + C225Oxaliplatin+5-FU/LV (FOLFOX6) + C225

Specific Chemotherapy Specific Chemotherapy Associated Hepatic ToxicityAssociated Hepatic Toxicity

Irinotecan – SteatohepatitisIrinotecan – Steatohepatitis

Oxaliplatin – Sinusoidal/vascular injuryOxaliplatin – Sinusoidal/vascular injury Acute & chronic clinical sequelaeAcute & chronic clinical sequelae

Biologics - ????Biologics - ???? Bevacizumab – 6 to 8 wks before resectionBevacizumab – 6 to 8 wks before resection

– Liver regeneration & hemorrhageLiver regeneration & hemorrhage

Morbidity is increased with prolonged course Morbidity is increased with prolonged course of chemotherapy of chemotherapy (Aloia et al, J Clin Oncol, 2006(Aloia et al, J Clin Oncol, 2006))

Liver Toxicity of Neoadjuvant Liver Toxicity of Neoadjuvant TherapyTherapy

% of Patients% of Patients

Sinusoidal DilationSinusoidal Dilation Steatosis >30%Steatosis >30% SteatohepatitisSteatohepatitis

YesYes NoNo PP ** YesYes NoNo PP

** YesYes NoNo PP **

No chemotherapyNo chemotherapy 1.91.9 98.198.1 –– 8.98.9 91.191.1 –– 4.44.4 95.695.6 ––

5-FU/LV5-FU/LV 00 100100 NSNS 16.616.6 83.483.4 NSNS 4.84.8 95.295.2 NSNS

5-FU/LV + irinotecan5-FU/LV + irinotecan 4.34.3 95.795.7 NSNS 10.610.6 89.489.4 NSNS 20.220.2 79.879.8 0.00010.0001

5-FU/LV + oxaliplatin5-FU/LV + oxaliplatin 18.918.9 81.181.1 0.000010.00001 3.83.8 96.296.2 NSNS 6.36.3 93.693.6 NSNS

OtherOther 00 100100 NSNS 8.38.3 91.791.7 NSNS 00 100100 NSNS

• Patients with steatohepatitis had an increased 90-day mortality compared with patients who did not have steatohepatitis (P=0.001)

*Comparison of each group vs no chemotherapy.Vauthey et al. J Clin Oncol. 2006;24:2065.

Vasodilation & CongestionPeliosis:

Hemorrhagic Centrilobular Necrosis Nodular Regenerative Hyperplasia

Vascular Changes in Liver Post Systemic Chemotherapy Aloia et al, J Clin Oncol 24: 4983,2006

Hepatic atrophy & sinusoidal congestion

▼▼

Collaboration Oncologists - Surgeons for

Timing of Surgery after Chemotherapy…

As soon as the metastases become resectable…

• Not to miss the « good » therapeutic window: Tumoral progression: Surgery even potentially curative, has poor results

• Not to « overtreat » the patient Complete response: a major problem for the surgeon with however a minority of pathology-proven necrosis

Hepatotoxicity: a clinical impact related to duration

Studies including nonselected patients with mCRC (solid line) (r=0.74; p<0.001)

Studies including selected patients(liver metastases only, no extrahepatic disease)(r=0.96; p=0.002)

Phase III studies including nonselected patients with mCRC (dashed line)(r=0.67; p=0.024)

Folprecht G, et al. Ann Oncol 2005;16:1311–1319

Response rate

0.90.80.70.60.50.40.3

Res

ectio

n ra

te

0.6

0.5

0.4

0.3

0.2

0.1

0

Impact of Increasing Response Impact of Increasing Response Rates Rates

CRYSTAL Trial: CRYSTAL Trial: Surgery with Curative IntentSurgery with Curative Intent

2.5

1.5

6.0

4.3

0

1

2

3

4

5

6

7

Surgery with curativeintent

No residual tumor afterresection

Percentage (%)

*CMH test

4.5

9.8

0

1

2

3

4

5

6

7

8

9

10

Percentage (%)

n=599 / group n=599 / group n=134 / n=122

p=0.0034*

odds ratio 3.0

[95% CI: 1.4 - 6.5]

FOLFIRI alone ERBITUX + FOLFIRI

No residual tumor in patients with liver metastases

ITT population Liver-limited disease population

Van Cutsem et al, ASCO 2007

OncoSurgical strategies in liver metastasesOncoSurgical strategies in liver metastases

from palliative to curativefrom palliative to curative……

PalliativeCurative

Su

rviv

al

Time

Summary - Unresectable Liver Summary - Unresectable Liver MetastasesMetastases

Patients with liver metastases benefit from Patients with liver metastases benefit from chemotherapy followed by surgerychemotherapy followed by surgery

Oxaliplatin-containing regimens render an Oxaliplatin-containing regimens render an additional 10% or more patients resectableadditional 10% or more patients resectable

Use of CPT-11 less well studiedUse of CPT-11 less well studied

Role of HAI remains uncertainRole of HAI remains uncertain

Response-enhancing agents neededResponse-enhancing agents needed

Potential for chemotherPotential for chemotherapy-induced liver diseaseapy-induced liver disease

Overall SummaryOverall Summary

Options available for patients in the Options available for patients in the adjuvant, perioperative, and neoadjuvant adjuvant, perioperative, and neoadjuvant settingssettings

Patients amenable to surgery have a Patients amenable to surgery have a better outcome, even if recurrencebetter outcome, even if recurrence

Variety of new studies open or in Variety of new studies open or in developmentdevelopment

Overall SummaryOverall Summary

Management requires multidisciplinary Management requires multidisciplinary approachapproach– Medical OncologyMedical Oncology– SurgerySurgery– RadiologyRadiology

Development of practice guidelinesDevelopment of practice guidelines