Conservative treatment of liver metastasis

Alvydas Cesas MD, head of chemotherapy department

Klaipeda Hospital

Frequency of Liver Metastasesof Colorectal Cancer

30 - 40% of colorectal primaries

Steele Jr G et al., Ann Surg, 1989

COLORECTAL CANCERLIVER METASTASES

Survivalbenefit

30%at 5 years

Resectable 10-20% Non resectable 80-90%

IV Chemo IA Chemo Others

Goal of chemotherapy for colorectal cancer liver metastases

• Management palliation and control symptoms

• Control tumor growth• Attempts to lengthen progression-free and

overall survival• Extreme care (chemotherapy) must be

taken to adequately assess each individual’s potential for both benefit and harm from chemotherapy

Goal of chemotherapy for colorectal cancer liver metastases

• Quality-of-life issues must be frankly and objectively discussed with patients about expectations can be within a realistic framework

• Keep in mind that virtually all of the clinical trials involving patients with metastatic disease were restricted by design to patients who were in good overall general condition.

Unresectable liver metastasis before treatment

Liver metastasis after 6 months treatment

The effects of chemotherapy for MCRC

• Objective response rates

• Time to disease progression

• Overall survival

• Quality of life

Chemotherapy Plus BSC Versus BSC Alone: Meta-analysis

Jonker W et al. Br Med J 2000;82:1789–94

Hine

Rougier

NGTATG

Scheithauer

Hafstrom

Allen-Mersh

Glimelius

Pooled

Relative risk (95% CI)

1.0 (0.41–2.45)

0.64 (0.46–0.92)

0.72 (0.54–0.95)

0.64 (0.44–0.93)

0.58 (0.34–0.99)

0.75 (0.53–1.06)

0.78 (0.40–1.53)

0.69 (0.60–0.81)

0.1 0.2 0.5 1 2 5 10

Risk ratio 1-year mortality

Favourschemotherapy

Favourscontrol

Chemotherapy in MCRC

Median survival Action taken(month)4-5 Supportive care5-7 Supportive care, trial patients10-12 5-Fu/LV, trial patients12-14 5-Fu/LV, good PS trial patients14-15 5-Fu/LV + new drug, good PS

trial patients15-17 5-Fu/LV+new drug, second line

treatment18-20 5-Fu/LV + new drug, sequential treatments,

local methodsUntil 25 5-Fu/LV + new drug + target therapy,

sequential treatments, local methods

Results of chemotherapy effects

• Until the very end of the 1980s there was no firm evidence that treatment had any meaningful influence on the well-being of many patients

• In 1989, two large randomised trials comparing 5-Fu alone and 5-Fu with biochemically modulated, reported slightly prolonged survival (median about 3 months) and QoL by the combined regimen.

NGTATG J Clin Oncol 1989,7:1437-1446; Poon MA et all J Clin Oncol 1989,7:1407-1418Borner MM et al Ann Oncol 1998,9:535-541Shmoll HJ et al Proc Am Soc Clin Oncol 2000,19:Abstr935

5-Fu regimes and leucovorin doses

• No firm evidence showing that any of the modulated 5-Fu regimens is superior to the others¹

• Low leucovorin dose is to be preferred for routine use since regimens using higher leucovorin doses are not superior²

¹Glimelius EJC Vol I;2003,6:173-180

²Sobrero AF et al J Clin Oncol 1997,15:808-815

Advanced CRC Meta-Analysis Project. J Clin Oncol 1992;12:960–9

TrialGITSGNCOGGOIRCGISCADGenovaTorontoCity of HopeRPCIBologna

Overall

Response rateodds ratio (95% CI)

Overall survivalodds ratio (95% CI)

0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.05-FU + LV better/5-FU + LV worse5-FU + LV better/5-FU + LV worse

0.45(0.34–0.60)

0.97(0.86–1.09)

Meta-analysis: What is impact of 5-FU modulation with LV?

Chemotherapy in MCRC

Median survival Action taken(month)4-5 Supportive care5-7 Supportive care, trial patients10-12 5-Fu/LV or Capecitabine trial patients12-14 5-Fu/LV, good PS trial patients14-15 5-Fu/LV + new drug, good PS

trial patients15-17 5-Fu/LV+new drug, second line

treatment18-20 5-Fu/LV + new drug, sequential treatments,

local methodsUntil 25 5-Fu/LV + new drug + target therapy,

sequential treatments, local methods

5-Fu bolus vs. infusional

• High-dose infused regimens with modulated 5-Fu are likely superior to conventional bolus regimens, since they result in more tumour regressions, longer times to disease progression, less toxicity and/or longer overall survival.

Schmoll et al Proc Am Soc Clin Oncol 2000, 19:abst 935 de Gramont A et al J Clin Oncol 1997, 15: 808-815 Aranda E Ann Oncol 1998, 9:727-731 Weh HJ Oncologie 1998,21 403-407

Safety of infused 5-FU/LV superior to bolus?

• de Gramont regimen superior in terms of – grade 3/4 diarrhoea: 3 vs 7%– severe stomatitis: 2 vs 13%– grade 3/4 neutropenia: 2 vs 7%

• But, similar incidence of all-grades principal 5-FU toxicities

• AIO regimen similar incidence of neutropenia and stomatitis, but more– severe diarrhoea (22 vs 9%)– dose reductions (34 vs 20%)– withdrawals for toxicity (11 vs 4%)

1de Gramont A et al. J Clin Oncol 1997;15:808–152Köhne CH et al. J Clin Oncol 2003;21:3721–28

How different are the 5-FU regimens?

1.0

0.8

0.6

0.4

0.2

0

de Gramont

Mayo Clinic

Time (months)

13.0 14.2

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25 30 35 40

EORTC AIO

EORTC AIO

Mayo Clinic

12.0 13.212.5

0 5 10 15 20 25 30 35 40

Time (months)

Est

imat

ed p

rob

abili

ty

RR TTP

Mayo Clinic 14% 5.0 mo

de Gramont 33% 6.3 mo

RR TTP Mayo Clinic 12% 4.1 moAIO 9% 4.4 moAIO/LV 21% 6.4 mo

Pooled data of two identical phase III trials in first-line MCRC

First-line MCRC

Prior adjuvant >6 months ago

Capecitabine(n=603)

Bolus 5-FU/LV(n=604)

Twelves C. Eur J Cancer 2002;38(Suppl. 2):S15–S20

• Endpoints – ORR – PFS – overall survival – tolerability – pharmacoeconomics

Capecitabine in first-line MCRC: Pooled data of two phase III trials

• Endpoints – ORR +– PFS =– overall survival =– tolerability +

• pharmacoeconomics +

First-line MCRC

Prior adjuvant >6 months ago

Capecitabine(n=603)

Bolus 5-FU/LV(n=604)

Twelves C. Eur J Cancer 2002;38(Suppl. 2):S15–S20

Chemotherapy in MCRCMedian survival Action taken(month)

4-5 Supportive care5-7 Supportive care, trial patients10-12 5-Fu/LV, trial patients12-14 5-Fu/LV, good PS trial patients14-15 5-Fu/LV + new drug, good PS

trial patients15-17 5-Fu/LV+new drug, second line

treatment18-20 5-Fu/LV + new drug, sequential

treatments, local methodsUntil 25 5-Fu/LV + new drug + target therapy,

sequential treatments, local methods

Combination Therapy

• Irinotecan improves RR, TTP and survival

– in first line (with 5-FU/LV)1,2

– in second line polychemotherapy1 and monotherapy3

• Oxaliplatin with 5-FU/LV

– improves RR and TTP in first line4,5

– is effective in 5-FU resistant disease in second line6

1Douillard JY et al. Lancet 2000;

2Saltz LB et al. N Engl J Med

20003Rougier P et al. Lancet 1998;

4de Gramont A et al. J Clin Oncol

20005Giacchetti S et al. J Clin Oncol 2000;

6André T et al. Ann Oncol

1999

Combination Therapy

Irinotecan/5-FU/FA is more active than 5-FU/FA in metastatic CRC, offering improved tumour control and prolonged survival with a manageable adverse event profile and can therefore be considered as a standard treatment

Bolus & Infusional regimens of 5-FU/FA/irinotecan are safe and have a manageable toxicity pattern. Infusional regimens may have a better risk/benefit ratio than bolus 5-FU/FA/irinotecan regimens

Combination Therapy

• Addition of oxaliplatin to 5-FU/LV – improves all efficacy outcomes in first line (1-3)– is effective in irinotecan-pretreated patients in

second line (4,6)• Addition of irinotecan to 5-FU/LV improves efficacy in

first line (6,7) • Combinations with infused 5-FU favoured in Europe

while bolus preferred in USA

1de Gramont A et al. J Clin Oncol 2000;18:2938–47; 2Giacchetti S et al. J Clin Oncol 2000;18:136–473Goldberg R et al. Proc Am Soc Clin Oncol 2003;22:252 (Abst 1009)4Rothenberg ML et al. J Clin Oncol 2003;21:2059–695Rothenberg ML et al. Proc Am Soc Clin Oncol 2003;22:252 (Abst 1011)6Douillard JY et al. Lancet 2000;355:1041–7; 7Saltz LB et al. N Engl J Med 2000;343:905–14

1st line 5-FU/LV +/– irinotecan

Regimen

Responserate (%)

PFS(months)

Median survival(months)

Bolus(USA)1

Irinotecan/5-FU/LV

5-FU/LV

Irinotecan

39*

21

18

7.0*

4.3

4.2

14.8*

12.6

12.0

Infused(Europe) 2

Irinotecan/5-FU/LV

5-FU/LV

35*

22

6.7*

4.4

17.4*

14.1

Combineddata 3

Irinotecan/5-FU/LV

5-FU/LV

37*

21

6.9*

4.3

15.9*

13.3

*p<0.05 (vs 5-FU/LV)

1Saltz LB et al. N Engl J Med 2000;343:905–142Douillard JY et al. Lancet 2000;355:1041–7

3Saltz LB et al. Proc Am Soc Clin Oncol 2000;19:242a (Abst 938)

0

20

40

60

80

100

0 1 2Years

Aliv

e (%

)

IFL

FOLFOX

IROX

IFL vs FOLFOX p=0.0001 IFL vs IROX p=0.04FOLFOX vs IROX p=0.09

Goldberg RM, et al. Proc Am Soc Clin Oncol 2003;22:252 (abst 1009)

Addition of oxaliplatin later shown also to prolong survival 1st line

XELOX compares favourablywith FOLFOX

1Van Cutsem E et al. Proc Am Soc Clin Oncol 2003;22 (Abst 1023)2Goldberg R et al. Proc Am Soc Clin Oncol 2003;22:252 (Abst 1009)

3de Gramont A et al. J Clin Oncol 2000;18:2938–47

XELOX (n=96) 1

FOLFOX4 (n=267) 2

FOLFOX4 (n=210) 3

PR + CR (%) 55 45 50

PFS (months) 7.6 8.7 8.2

OS (months) 19.5 19.5 16.2

Chemotherapy in MCRCMedian survival Action taken(month)

4-5 Supportive care5-7 Supportive care, trial patients10-12 5-Fu/LV, trial patients12-14 5-Fu/LV, good PS trial patients14-15 5-Fu/LV + new drug, good PS

trial patients15-17 5-Fu/LV+new drug, second line

treatment18-20 5-Fu/LV + new drug, sequential treatments,

local methodsUntil 25 5-Fu/LV + new drug + target therapy,

sequential treatments, local methods

1st line Irinotecan/5FU/LV ± bevacizumab

No Bevacizumab Past

Disease Progression

May Receive Bevacizumab

Past Disease Progression

May Receive Bevacizumab

Past Disease Progression

IFL: bolus 5-FU 500 mg/m2

leucovorin 20 mg/m2

irinotecan 125 mg/m2

5-FU/LV: bolus 5-FU 500 mg/m2

leucovorin 500 mg/m2

BV: 5 mg/kg

Previously Untreated

Metastatic CRC

IFL + BV(N = 403)

5-FU/LV + BV(N = 110)

IFL + Placebo

(N = 412)

Hurwitz H, et al. N Engl J Med 2004;350:2335–42

Effect on overall survival of adding bevacizumab to 1st line

IFL

Pro

bab

ilit

y o

f su

rviv

al

1.0

0.8

0.6

0.4

0.2

00 10 20 30 40

Survival (months)

IFL + placebo

IFL + bevacizumab

Median survival (months)IFL + placebo: 15.6 (95% CI: 14.3–17.0) vsIFL + Avastin: 20.3 (95% CI: 18.5–24.2)HR=0.66 (95% CI: 0.54–0.81)p<0.001

Kaplan-Meier curve Hurwitz H, et al. N Engl J Med 2004;350:2335–42

Phase III trial of IFL ± Avastin in metastatic CRC (AVF2107g): progression-free survival

Median progression-free survival (months)IFL + placebo: 6.2 (95% CI: 5.6–7.7)IFL + Avastin: 10.6 (95% CI: 9.0–11.0)HR=0.54 (95% CI: 0.45–0.66) p<0.001

Pro

babili

ty o

f bein

g p

rogre

ssio

n-f

ree

1.0

0.8

0.6

0.4

0.2

00 10 20 30

Progression-free survival (months)

6.2 10.6

IFL + Avastin

IFL + placebo

Hurwitz H, et al. N Engl J Med 2004;350:2335–42

Improvements in the RR of MCRC to 1st line infusional 5-FU based chemotherapy

0

10

20

30

40

50

60

70

5-FU 5-FU/FA FOLFIRI, FOLFOX (inf),

Bevacizumab + IFL Cituximab + IRI / 5-FU/FA

(inf)

RR (%)

Overall survival: first-line fluoropyrimidine combination

regimens5-FU/LV (Saltz)

5-FU/LV (Douillard)

5-FU/LV (de Gramont)

0 5 10 15 20 25Median OS (months)

IFL (Goldberg)

IFL (Saltz)

FOLFIRI (Douillard)

FOLFOX (de Gramont)

FOLFOX (Goldberg)

IFL+ Avastin

FOLFOX4 after failure of irinotecan/5-FU/LV (IFL) 2nd line

Rothenberg M, et al. Proc Am Soc Clin Oncol 2003;22:252 (abst 1011)

Pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20

Months

5.62.6

1.9 FOLFOX4Eloxatin®

LV5FU2

RR TTP OS

FOLFOX4 9.6% 5.6 mo 9.8 moLV5FU2 0.7% 2.6 mo 8.7 mo Eloxatin® 1.5% 1.9 mo 8.1 mo

Mono ComboNo. 111 218

Survival(months) 6.9 8.6 P = NS

11 23 P < 0.05

HR (95% CI): 0.54 (0.42; 0.71)log rank p-value < 0.0001

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12

Pro

po

rtio

n

Cetuximab +/- irinotecan 2nd lineafter irinotecan failure

Time to progression (months)

Response Rate (%)

Cunningham, Van Cutsem et al 2003 Proc Am Soc Clin Oncol 22: Abstract 1012

Cituximab as single agent in 2nd line treatment of irinotecan-refractory

mCRC

* ~ 40% of pts received cituximab as a 3rd or higher line treatment

Pts RR Dis Con mTTP mS

Saltz 2002 57 11% 34% 1.4 mths 6.4 mths

Cunningham 2003*

111 11% 34% 1.5 mths 6.9 mths

Cituximab plus irinotecan is active 2nd line in irinotecan-refractory mCRC

Saltz et al 2001 Proc Am Soc Clin Oncol 20: Abstract 7

Efficacy results

PR 27 / 120 (23%)

Disease control 36 / 120 (30%)

Median duration of response (MDR) 6.2 mths

HAI and systemic chemotherapy in randomized studies

Response rate 2-years survival

No. pts. HAI SYS p HAI SYS p

MSKCC 162 53 21 .001 17 12 -

NCI 64 62 17 .003 47 13 -

French 163 49 14 NS 22 10 .02

German 168 43 20 - 12,7 17,6 -

CALGB 135 48 25 .009 22,7 19,8 .027

Drugs for HAI Drug Half-life (min) Estimated Increased Exposure

bay HAI

5-Fluoruracil 10 5-10 foldFloxuridine <10 100-400 foldCarmustine < 5 6-7 foldMitomycin C <10 6-8 foldCisplatin 20-30 4-7 foldAdriamycin 60 2 fold

Vincent T. De Vita Cancer principles and practice of oncology 2005 7-th

Survival after Adjuvant Therapy Subsequent to liver resection with HAI and systemic therapy versus systemic therapy alone

Survival rate HAI+SYS

Comparison (n=74) SYS (n=82) P value

2-Y survival 85% 69% .02

2-Y hepatic DFS 89% 57% .00001

2-Y DFS 57% 41% .07

Kemeny MM et al N Engl J Med 1999:341-2039

Time from Second Progression to Death

• MST from 2nd line 9-10 months • TTP 2nd line 3- 4 months• Time from 2nd P to death 6 months

– From Cunningham and Rougier 1999

• MST folfiri folfox 21 months• TTP 1st + 2nd line 14 months• Time from 2nd P to death 7 months

– From Tournigand ASCO 2001

WHY NOT THIRD LINE CT ?

Where are we now?In the metastatic setting…….1. Addition of bevacuzimab to bolus 5-FU/irinotecan

prolongs survival as 1st line therapy2. After irinotecan failure, addition of cetuximab is an

alternative to FOLFOX as 2nd line treatmentBut • Unclear yet if both agents also effective with 5-FU

alone, Xeloda alone or oxaliplatin combinations• Optimal sequence not known• Don’t know how to tailor treatments to specific patients

Patient selection: Trials and the real world

Trials patients

1. Young and fit

2. Normal liver and renal function

3. Limited other medication

4. Treated at specialist units

5. Specific tumourand drug free!

Patient selection: Trials and the real world

Trials patients

1. Young and fit

2. Normal liver and renal function

3. Limited other medication

4. Treated at specialist units

5. Specific tumourand drug free!

Clinic patients

1. Older and less fit

2. Liver/renal function often abnormal

3. Many of them on other drugs

4. Treated by general oncologists

5. Variety of tumours?and drug costs money

Potential Prognostic Subgroups

• Older patients (>65 years old)• Poor performance status (>0)• >1 metastatic site• Prior adjuvant therapy with 5-FU/LV• Elevated LDH, alkaline phosphatase,

WBC

Prognostic Factors for Advanced CRC

AP = alkaline phosphatase

ECOG performance status

>1 0–1

WBC No. of sites

>10K <10K >1 1

No. of sites AP

>1 1 >300 <300

MST = 6 months MST = 10 months MST = 15 months

From Koehne, Ann. Oncol 2001

Conclusion Active drugs have had a dramatic impact on the treatment of colorectal cancer metastases:

• Capecitabin (tolerability), • Cetuximab (time to progression),• Irinotecan, oxaliplatin, bevacuzimab (survival)• HAI + Systemic chemotherapy improved

survival and hepatic DFS

Future improvements are probable using a multididciplinary approach, together with a hope that new treatments, based upon recent tumor-biological knovledge, will eventualy yield clinically meaningful effects.