Conservative treatment of liver metastasis

1
Conservative treatment of liver metastasis

• Alvydas Cesas MD,
• head of chemotherapy department
• Klaipeda Hospital

2
Frequency of Liver Metastasesof Colorectal Cancer
? 30 - 40 of colorectal primaries
Steele Jr G et al., Ann Surg, 1989
3
(No Transcript)
4
COLORECTAL CANCER
LIVER METASTASES
Resectable 10-20
Non resectable 80-90
IV Chemo
IA Chemo
Others
Survivalbenefit30at 5 years
5
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 individuals potential for
  both benefit and harm from chemotherapy

6
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.

7
Unresectable liver metastasis before treatment
Liver metastasis after 6 months treatment
8
The effects of chemotherapy for MCRC

• Objective response rates
• Time to disease progression
• Overall survival
• Quality of life

9
Chemotherapy Plus BSC Versus BSC Alone
Meta-analysis
Risk ratio 1-year mortality
0.1 0.2 0.5 1 2 5 10
Relative risk (95 CI) 1.0 (0.412.45) 0.64
(0.460.92) 0.72 (0.540.95) 0.64
(0.440.93) 0.58 (0.340.99) 0.75
(0.531.06) 0.78 (0.401.53) 0.69 (0.600.81)
Hine Rougier NGTATG Scheithauer Hafstrom Allen-Mer
sh Glimelius Pooled
Favours chemotherapy
Favours control
Jonker W et al. Br Med J 200082178994
10
Chemotherapy in MCRC

• Median survival Action taken
• (month)
• 4-5
  Supportive care
• 5-7
  Supportive care, trial patients
• 10-12 5-Fu/LV,
  trial patients
• 12-14 5-Fu/LV,
  good PS trial patients
• 14-15 5-Fu/LV
  new drug, good PS trial patients
• 15-17 5-Fu/LVnew
  drug, second line treatment
• 18-20 5-Fu/LV
  new drug, sequential treatments,
  local methods
• Until 25 5-Fu/LV
  new drug target therapy, sequential
  treatments, local methods

11
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 1989,71437-1446
• Poon MA et all J Clin Oncol 1989,71407-1418
• Borner MM et al Ann Oncol 1998,9535-541
• Shmoll HJ et al Proc Am Soc Clin Oncol
  2000,19Abstr935

12
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 I2003,6173-180
• ²Sobrero AF et al J Clin Oncol 1997,15808-815

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Meta-analysis What is impact of 5-FU modulation
with LV?
Response rate odds ratio (95 CI)
Overall survival odds ratio (95 CI)
Trial GITSG NCOG GOIRC GISCAD Genova Toronto City
of Hope RPCI Bologna Overall
0.45 (0.340.60)
0.97 (0.861.09)
0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0

5-FU LV better/5-FU LV worse
5-FU LV better/5-FU LV worse
Advanced CRC Meta-Analysis Project. J Clin Oncol
1992129609
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Chemotherapy in MCRC

• Median survival Action taken
• (month)
• 4-5
  Supportive care
• 5-7
  Supportive care, trial patients
• 10-12 5-Fu/LV or
  Capecitabine trial patients
• 12-14 5-Fu/LV,
  good PS trial patients
• 14-15 5-Fu/LV
  new drug, good PS trial patients
• 15-17 5-Fu/LVnew
  drug, second line treatment
• 18-20 5-Fu/LV
  new drug, sequential treatments,
  local methods
• Until 25 5-Fu/LV
  new drug target therapy, sequential
  treatments, local methods

15
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,
  19abst 935
• de Gramont A et al J Clin Oncol 1997, 15
  808-815
• Aranda E Ann Oncol 1998, 9727-731
• Weh HJ Oncologie 1998,21 403-407

16
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
19971580815 2Köhne CH et al. J Clin Oncol
200321372128
17
How different are the 5-FU regimens?
RR TTP Mayo Clinic 14 5.0 mo de
Gramont 33 6.3 mo
RR TTP Mayo Clinic 12 4.1 mo AIO 9 4.4
mo AIO/LV 21 6.4 mo
1.0 0.8 0.6 0.4 0.2 0
1.0 0.8 0.6 0.4 0.2 0
EORTC AIO EORTC AIO Mayo Clinic
de Gramont Mayo Clinic
Estimated probability
12.5
12.0
13.2
13.0
14.2
0 5 10 15 20 25 30 35 40
0 5 10 15 20 25 30 35 40
Time (months)
Time (months)
18
Pooled data of two identical phase III trials in
first-line MCRC
Capecitabine (n603)

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

First-line MCRC Prior adjuvant gt6 months ago
Bolus 5-FU/LV (n604)
Twelves C. Eur J Cancer 200238(Suppl. 2)S15S20
19
Capecitabine in first-line MCRC Pooled data of
two phase III trials
Capecitabine (n603)

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

First-line MCRC Prior adjuvant gt6 months ago
Bolus 5-FU/LV (n604)
Twelves C. Eur J Cancer 200238(Suppl. 2)S15S20
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Chemotherapy in MCRC

• Median survival Action taken
• (month)
• 4-5
  Supportive care
• 5-7
  Supportive care, trial patients
• 10-12 5-Fu/LV,
  trial patients
• 12-14 5-Fu/LV,
  good PS trial patients
• 14-15 5-Fu/LV
  new drug, good PS trial patients
• 15-17 5-Fu/LVnew
  drug, second line treatment
• 18-20 5-Fu/LV
  new drug, sequential treatments, local
  methods
• Until 25 5-Fu/LV
  new drug target therapy, sequential
  treatments, local methods

21
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 2000 3Rougier 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
22
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

23
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
200018293847 2Giacchetti S et al. J Clin
Oncol 20001813647 3Goldberg R et al. Proc Am
Soc Clin Oncol 200322252 (Abst
1009)4Rothenberg ML et al. J Clin Oncol
2003212059695Rothenberg ML et al. Proc Am Soc
Clin Oncol 200322252 (Abst 1011) 6Douillard JY
et al. Lancet 200035510417 7Saltz LB et al. N
Engl J Med 200034390514
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1st line 5-FU/LV / irinotecan
Response
PFS
Median survival
rate ()
(months)
(months)
Regimen
Bolus
Irinotecan/5-FU/LV
39
7.0
14.8
1
(USA)
5-FU/LV
21
4.3
12.6
Irinotecan
18
4.2
12.0
Infused
Irinotecan/5-FU/LV
35
6.7
17.4
2
(Europe)
5-FU/LV
22
4.4
14.1
Combined
Irinotecan/5-FU/LV
37
6.9
15.9
3
data
5-FU/LV
21
4.3
13.3
plt0.05 (vs 5-FU/LV)
1Saltz LB et al. N Engl J Med 200034390514 2Dou
illard JY et al. Lancet 200035510417 3Saltz LB
et al. Proc Am Soc Clin Oncol 200019242a (Abst
938)
25
Addition of oxaliplatin later shown also to
prolong survival 1st line
Goldberg RM, et al. Proc Am Soc Clin Oncol
200322252 (abst 1009)
26
XELOX compares favourablywith FOLFOX

XELOX

FOLFOX4
FOLFOX4
(n96)
(n267)

(n210)

1

2
3
PR CR ()

55

45

50

PFS (months)

7.6

8.7

8.2

OS (months)

19.5

19.5

16.2


1Van Cutsem E et al. Proc Am Soc Clin Oncol
200322 (Abst 1023) 2Goldberg R et al. Proc Am
Soc Clin Oncol 200322252 (Abst 1009)3de
Gramont A et al. J Clin Oncol 200018293847
27
Chemotherapy in MCRC

• Median survival Action taken
• (month)
• 4-5
  Supportive care
• 5-7
  Supportive care, trial patients
• 10-12 5-Fu/LV,
  trial patients
• 12-14 5-Fu/LV,
  good PS trial patients
• 14-15 5-Fu/LV
  new drug, good PS trial patients
• 15-17 5-Fu/LVnew
  drug, second line treatment
• 18-20 5-Fu/LV
  new drug, sequential treatments,
  local methods
• Until 25 5-Fu/LV
  new drug target therapy, sequential
  treatments, local methods

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1st line Irinotecan/5FU/LV bevacizumab
IFL Placebo (N 412)
No Bevacizumab Past Disease Progression
Previously Untreated Metastatic CRC
IFL BV (N 403)
May Receive Bevacizumab Past Disease Progression
5-FU/LV BV (N 110)
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
Hurwitz H, et al. N Engl J Med 2004350233542
29
Effect on overall survival of adding bevacizumab
to 1st line IFL
1.0 0.8 0.6 0.4 0.2 0
Median survival (months)IFL placebo 15.6 (95
CI 14.317.0) vs IFL Avastin 20.3 (95 CI
18.524.2) HR0.66 (95 CI 0.540.81)plt0.001
Probability of survival
IFL placebo IFL bevacizumab
0 10 20 30 40
Survival (months)
Kaplan-Meier curve
Hurwitz H, et al. N Engl J Med 2004350233542
30
Phase III trial of IFL Avastin in metastatic
CRC (AVF2107g) progression-free survival
Median progression-free survival (months)IFL
placebo 6.2 (95 CI 5.67.7)IFL Avastin
10.6 (95 CI 9.011.0)HR0.54 (95 CI
0.450.66) plt0.001
1.0 0.8 0.6 0.4 0.2 0
Probability of being progression-free
IFL Avastin IFL placebo
6.2
10.6
0 10 20 30
Progression-free survival (months)
Hurwitz H, et al. N Engl J Med 2004350233542
31
Improvements in the RR of MCRC to 1st line
infusional 5-FU based chemotherapy
RR ()

• 5-FU
• 5-FU/FA
• FOLFIRI, FOLFOX (inf), Bevacizumab IFL
• Cituximab IRI / 5-FU/FA (inf)

32
Overall survival first-line fluoropyrimidine
combination regimens
5-FU/LV (Saltz) 5-FU/LV (Douillard) 5-FU/LV (de
Gramont)
0 5 10 15 20 25
Median OS (months)
33
FOLFOX4 after failure of irinotecan/5-FU/LV (IFL)
2nd line
1.0 0.8 0.6 0.4 0.2 0
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
5.6
2.6
Probability
1.9
FOLFOX4EloxatinLV5FU2
0 5 10 15 20
Months
Rothenberg M, et al. Proc Am Soc Clin Oncol
200322252 (abst 1011)
34
Cetuximab /- irinotecan 2nd lineafter
irinotecan failure
Mono
Combo
1
No.
111
218
11
23 P lt 0.05
Response Rate ()
0.8
Survival (months) 6.9 8.6 P
NS
0.6
Proportion
HR (95 CI) 0.54 (0.42 0.71)log rank p-value lt
0.0001
0.4
0.2
0
0
2
4
6
8
10
12
Time to progression (months)
Cunningham, Van Cutsem et al 2003 Proc Am Soc
Clin Oncol 22 Abstract 1012
35
Cituximab as single agent in 2nd line treatment
of irinotecan-refractory mCRC
40 of pts received cituximab as a 3rd or
higher line treatment
36
Cituximab plus irinotecan is active 2nd line in
irinotecan-refractory mCRC
Saltz et al 2001 Proc Am Soc Clin Oncol 20
Abstract 7
37
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

38
Drugs for HAI

• Drug Half-life (min)
  Estimated Increased Exposure bay
  HAI
  
  
• 5-Fluoruracil 10
  5-10 fold
• Floxuridine lt10
  100-400 fold
• Carmustine lt 5
  6-7 fold
• Mitomycin C lt10
  6-8 fold
• Cisplatin 20-30
  4-7 fold
• Adriamycin 60
  2 fold
• Vincent T. De Vita Cancer principles and practice
  of oncology 2005 7-th

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

• Survival rate HAISYS
• Comparison (n74) SYS (n82)
  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 1999341-2039
40
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 ?
41
Where are we now?

• In the metastatic setting.
• Addition of bevacuzimab to bolus 5-FU/irinotecan
  prolongs survival as 1st line therapy
• After irinotecan failure, addition of cetuximab
  is an alternative to FOLFOX as 2nd line treatment
• But
• Unclear yet if both agents also effective with
  5-FU alone, Xeloda alone or oxaliplatin
  combinations
• Optimal sequence not known
• Dont know how to tailor treatments to specific
  patients

42
Patient selection Trials and the real world

• Trials patients
• Young and fit
• Normal liver and renal function
• Limited other medication
• Treated at specialist units
• Specific tumourand drug free!

43
Patient selection Trials and the real world

• Clinic patients
• Older and less fit
• Liver/renal function often abnormal
• Many of them on other drugs
• Treated by general oncologists
• Variety of tumours?and drug costs money

• Trials patients
• Young and fit
• Normal liver and renal function
• Limited other medication
• Treated at specialist units
• Specific tumourand drug free!

44
Potential Prognostic Subgroups

• Older patients (gt65 years old)
• Poor performance status (gt0)
• gt1 metastatic site
• Prior adjuvant therapy with 5-FU/LV
• Elevated LDH, alkaline phosphatase, WBC

45
Prognostic Factors for Advanced CRC

ECOG performance status
gt1
01
WBC
No. of sites
gt10K lt10K
gt1 1
No. of sites
AP gt1
1 gt300
lt300 MST 6 months MST 10
months MST 15 months
AP alkaline phosphatase
From Koehne, Ann. Oncol 2001
46
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.