Mts epatiche - Roma 20071 Optimal Management of Liver Metastases: Present Results and Future...

Mts epatiche - Roma 2007 1

Optimal Management of Liver Metastases: Present Results and Future Strategies

Highlights in the Management of CRC

Roma, 1-2 febbraio 2007

Carlo BaroneOncologia Medica

Università Cattolica del S. Cuore

Carlo BaroneOncologia Medica

Università Cattolica del S. Cuore

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CRC liver metastasesCRC liver metastases

1,025,152 new cases and 528,978 deaths per year in the world:

~ 50% CRC pts develop liver metastases~ 15% to 25% (118,000) operable~ 25% to 35% of operated pts alive at 5 years

~ 3% to 4% (40.000) of total can be really cured…

Decision Resources, Inc.Decision Resources, Inc.Globocan for Pharma induustries 2002Globocan for Pharma induustries 2002


Survival in advanced colorectal cancer in 2005

0 1 2 3 4 5

100

50

0

%

survivin

g

Years after diagnosis of colorectal metastases

2005 Median survival:Chemotherapy 24 mos.Overall >30 months

5 year survival:1984 2%1994 5%2005 20%

?

1984 overall1994 overall2005 chemotherapy2005 overall

1984 1994 2005 8 mos 12 mos 27 mos

Dr. G. Poston, Pfizer Satellite Symposium, ECCO 2005


Summary

The role of Surgery in CRC liver mtsPreoperative CT

Resectable mtsInitially not-resectable mts

Hepatotoxicity of CTThe need for a new staging systemThe role of targeted agents in the management of liver mtsAdjuvant chemotherapy, HAI o Sys


5-Yr Survivalafter resection of CRC Liver Mts

Authors Year Patients Op. Mort. Survival

Foster

Iwatsuki

Nordlinger

Adson

Hughes

Scheele

Rosen

AFC

Gayowski

Fong

Minigawa

Ercolani

Choti

Adam

Abdalla

1981

1986

1987

1987

1988

1991

1992

1992

1994

1999

2000

2002

2002

2003

2004

259

60

80

141

859

219

280

1818

204

1001

235

257

133

615

190

5%

0%

5%

3%

--

5%

4%

2%

0%

2.8%

0%

0.8%

-

1%

-

22%

35%

25%

25%

33%

39%

25%

26%

32%

37%

38%

34%

58%

41%

58%


5-year survival after resection of CRC liver metastasesAuthor Year Res. Y/N Survival %) P

Foster 1981 259 22 -Adson 1988 141/70 25 vs < 5 < .0001Hughes 1988 859 33 -Rosen 1992 280 25 -Stangl 1994 266/677 41 vs < 1 < .0001Gayowski 1994 204 32 -Scheele 1995 226/964 31 vs 0 < .0001Jaeck 1997 747 13 -Fong 1999 1001 37 -Adam 2000 615 41 -Scheele 2001 516 38 -Kato 2003 585/178 33 vs 3.4 < .001

30% to 40%


Surgery alone versus no surgery

25%

60 pts not operated*

60 pts operated

10

20

30

40

50

60

70

80

90

100

% p

atie

nts

10 20 30 40 50 60 70 80

Survival (months)5 years

*Same survival for non-curative resections

SM Wilson, MA Adson. Arch Surg. 1976;4:330–4.


Surgery ± chemotherapy vs no surgery

1.0 -

0.8 -

0.6 -

0.4 -

0.2 -

0.0 -0.0 1 2 3 4 5

Years from diagnosis

Pro

bab

ilit

y o

f su

rviv

al

Stangl R et al. Lancet 1994;343:1405–10.

Resection (n=340)

Regional chemotherapy (n=123)

Systemic chemotherapy (n=70)

No treatment (n=484)

Treatment


Resection of CRC liver and lung metastases

Authors Year N5-year

survival

Mc Afee 1992 139 31%

Okumura 1996 39 33%

Ambiru 1998 25 43%

Murata 1998 30 44%

Regnard 1998 43 11%

Robinson 1999 25 43%

Kobayashi 1999 47 31%

Adam

1999 59 35%

30%

to 4

0%


Patient survival based on level of surgery

1.0 -

0.8 -

0.6 -

0.4 -

0.2 -

0.0 -

Time from laparotomy /imaging (years)0 1 2 3 4 5 6 7 8 9 10

Figure 1. The number at the end of the curve indicates the number of patients surviving beyond 10 years.

J.Scheele and coll. Br.J.Surg. 1990, 77:1241.

7

Complete resection (n = 921)

Incomplete resection (n = 62)

Non-operated patients (n = 226)

Pro

bab

ilit

y o

f su

rviv

al

P < .0001


Overall Survival with Res. of Multiple (>3) CR Mts with Relation to Response to Neoadj CT

0 -

0.2 -

0.4 -

0.6 -

0.8 -

1.0 -

Cu

mu

lati

ve s

urv

ival

0 1 2 3 4 5Years

100%

63%

84%

58%

0%

45%

Log rank: P=.0001

Downstaging: 42

Progression: 28

Stabilisation: 57

Adam R. Ann Oncol. 2003;14 Suppl2:ii13-16.


Pre-operative chemotherapy in resectable CRC liver metastases

Treatment n RR RFS Survival Study

5-FU/LV (AIO) +

L-OHP 85 mg

pre-op

20 80%52% 2y

80% 2yWein, 2003

5-FU/LV (AIOm) + L-OHP 85 mg

pre-op42 34/40 - -

Lorenz, 2003

Oxaliplatin-based regimens


Non-resectable liver mts Phase II – non-selected patients (A)

Regimen N RR Resection Author

AIO 53 42% 17% Wein

AIO/IRI/C225 19 68% 21% Lutz/Folprecht

FOLFOX/C225 43 81% 16% Tabernero

FOLFIRI/C225 40 43% 13% Rougier

FOLFOX/Gef 27 78% 22% Fisher

FOLFIRI int. 55 53% 31% Ducreux



FOLFOXIRI 74 71% 26% Falcone

FOLFOXIRI 28 79% 21% Roth

FOLFOXIRI 34 50% 15% Cals

FOLFOXIRI 32 72% 25% Masi

OCFL 30 78% 23% Seium

Non-resectable liver mts Phase II – non-selected patients (B)

Triplets



IFL 264 31% 1% Goldberg

FOLFOX 267 45% 4%

IROX 265 35% 4%

AIO 216 34% 1% Köhne

AIO+IRI 214 64% 3%

FOLFIRI 109 56% 9% Tournigand

FOLFOX 111 54% 22% (p = n.s.)

FOLFIRI 178 34% 5.1% Colucci

FOLFOX 182 36% 4.4%

Non-resectable liver mts Phase III – non-selected patients



FOLFOX 43 50% 33% Alberts

FOLFIRI 40 48% 33% UCSC

FOLFIRI 28 54% 11% Ho

FU/IRI 32 - 34% Slater

FOLFOXIRI 39 64% 43%deLa

Camara

FOLFOXIRI 26 73% 34% Quenet

OXA/IRI/FU 47 69% 26% Abad

FOLFIRINOX 34 71% 41%* Ychou* + 38.2% resection + RF or CS

Non-resectable liver mts Phase II – selected patients


Neoadju treatment of CRC unresectable liver mts with IRI and 5-FU plus LV

Annals of Oncology 2004;15:933–9.

U.O.C. di Oncologia Medica

U.O.C. di Chirurgia Epatobiliare

Co-operation

Synchronous mts 67.5%

<3mts/>6 mts52.5%/27.5%

Largest mts >5 cm30%

Mts in hilum/bilobar/RL 17.5%55/27.5%

oxaliplatin85 mg/m2 2 h

FA200 mg/m² 2 h

5FU 1,200 mg/m² CI 46 h

FA200 mg/m² 2 hDAY 1 DAY 2

5FU bolus 400 mg/m² 5FU bolus 400 mg/m²


Criteria for unresectabilityUCSC experience

*Major hepatectomy (more than 4 segments resection, according to Coineau) needed

Criteria Definition

Unfavourable location of metastases

Contiguity with at least 2 hepatic veins, the inferior vena cava, or the liver hilum

Number of metastases Synchronous*: >6 metastases in the same lobe OR synchronous or metachronous: >3 metastases in each of 2 lobes

Size of metastases Synchronous*: largest diameter of >5 cm in at least 1 metastasis if there were 6 lesions in the same lobe or 3 lesions in each of 2 lobes

Insufficient liver reserve

>70% of liver involvement

Extra-hepatic disease Metastases in areas other than the liver

Pozzo C, et al. Ann Oncol. 2004;15:933-39.


Primary Endpoints


5

42.547.5

27.5 25

0

10

20

30

40

50

60

CR PR CR+PR SD PD

%

Response

40

40 %

Candidatesfor Surgery

16

Neoadjuvant chemotherapy

13

33%

24 3

16

R0• 10 multiple segmental res.• 3 right lobectomies

Resection Rate

•2 carci

nosis

•1 N+

RR

RC RP SD PD


Resection rate by response and main cause of unresectability

18%

PD=0%

Res

ecti

on

rat

e (%

)

0

10

20

30

40

50

60

70


CR

+ P

R

58%

SD

0

10

20

30

40

50

60

70

Siz

e o

f m

ts

Lo

cati

on

N°

Liv

er

Re

ser

ve =

0

14%

36%

60%

By Response By Main Cause ofUnresectability


Secondary Endpoints

Median Follow-up: 30 m (6-54) TTP (all) = 14.3 m Median OS = 30.6 m

Not resected = 24 m Resected = not reached

Months

Pat

ien

ts%

0,0 -

0,1 -

0,2 -

0,3 -

0,4 -

0,5 -

0,6 -

0,7 -

0,8 -

0,9 -

1,0 -

0 10 20 30 40 50 60 70

Non resected

Resected


Overall Survival


FOLFIRINOX as induction CT in pts with previously unresectable CRC liver mts


FA400 mg/m² 2 h

5FU 2,400 mg/m² CI 46 h

irinotecan180 mg/m2 1 h 30

5FU bolus 400 mg/m²

Ychou M, et al. ESMO 2004, Abs 273.

Reason for un-resectability

Invasion of hilum 6 ptsContact with inferior VC 16 ptsInvasion of >2 hepatic veins 4 ptsRemnant liver <25% 12 ptsUnlikely R0 4 pts


3

68 71

15.4 13.6

0

10

20

30

40

50

60

70

80

CR PR CR+PR SD PD

Primary Endpoints

%

Response

34

82 %


28


14

41%6

1428

Resection Rate

RR

RC RP SD PD• 9 R0• 5 R1

•13 Res+ RF/CS•1 R2

•13 Res+

R

F/CS

•1 R2



Secondary Endpoints

SURVIE GLOBALE, N=34

Délai J1C1/DDN (Mois)0 6 12 18 24 30 36

0.00

0.25

0.50

0.75

1.00

Median Follow-up = 30.9 m (26.4-35.6) TTP (resected and non-resected) = 11.9 m Median OS = 35.5 m MS RC post-surgery = not reached Survival (2 yrs) = 70%

Overall Survival(n = 34)

Median SurvivalRC post-surgery

(n = 27)

1.00


0.75

0.50

0.25

0.00


FOLFOX4 for Pts with Unresectable Liver-only Mts from CRC: a NCCTG Phase II Study

Alberts, JCO 2005; 23:9243–9.

Reasons for Unresectability

Number 19 pts (45%) Localization 3 pts (7%) Size 3 pts (7%) Combination 15 pts (36%)Not available 2 pts (5%)


FA200 mg/m² 2 h

5FU 1,200 mg/m² CI 46 h

5FU bolus 400 mg/m²5FU bolus 400 mg/m²

FA200 mg/m² 2 hDAY 1 DAY 2

Mts epatiche - Roma 2007 26Alberts SR, et al. JCO. 2005;23:9243-9

2.4

47.6

9.5

59.5

9.5

31

0

10

20

30

40

50

60

CR PR REGR RR SD PD

%

Response

42

40.5 %


16


14

33%

253

17

R0

Resection Rate

•2 unresect

.

•1 part. R

es.

RR

RC RP SD PDRE

FOLFOX4 for Patients with Unresectable Liver-Only Mts from CRC: Primary Endpoints


Time to Recurrence Time to Recurrence (from surgery)(from surgery)

OSOS Median follow-up: 36 m

Median OS: 26 m (95% C.I. 19-34 m)

Resected pts: not reached

3 yrs Surv. of res. pts: 67%

Resected ptsResected pts

Time to Progression Time to Progression (from registration)(from registration)

FOLFOX4 for Pts with Unresectable Liver-Only Mts from CRC: Secondary Endpoints


Neoadj CT for Pts with CRC Unresectable Liver-Only Mts: phase II studies

UCSC, 2004 Ychou, 2004 Alberts, 2005

Median Follow-up 30.4 m

(6-54)

30.9 m

26.4-35.6)

36 m

(29-36)

TTP All Pts

Not res. Pts

14.3 m

5.2 m

11.9 m

Not reported

Not reported

Not reported

Median OS (all pts) 30.1 m 35.5 m 26 m

MS Res. Pts

Not res. Pts

Not reached

24 m

Not reached

Not reported

Not reached

Not reported

Survival (resected Pts) 70% (2.5 yrs) 70% (2 yrs) 67% (3 yrs)


Liver metastasesLiver metastases

15% resectable15% resectable85% unresectable85% unresectable

• 10%-30% potentially resectable

• 70%-90% never resectable

• 10%-30% potentially resectable

• 70%-90% never resectable

ResectionResection

CT

30%?

Resectability in pts with CRC liver metastases – where are we now?


laparotomy, liver exam and ultrasound

Does complete response mean cure?

Benoist et al. JCO 2006;24:3939-45

38 pts with 183 LMs received CTx

CT scan

66 (36%) LMs disappeared

in 9 pts : 20 LM sites (24%)There was residual

macroscopic disease

in 29 pts : 46 LM sites (76%)There no evidence residual

macroscopic disease

15 initially resectable pts had surgery – viable tumor cells at

LM sites in 12 (80%) pts

14 initially unresectable pts had surgery – after 1 year 74% of

LMs had recurred in 11 (79%) pts

Persistent macro- or microscopic disease or early recurrence in situ in 55/66 LMs (83%) = 32/38 pts


66 LM disappeared on CT scan after chemotherapy

Surgery : Macroscopic cancer : 20 LM

No lesion : 46 LM

15 sites resected 31 sites left in place

Viable tumor cells : 12 In situ recurrence : 23

55/66 (83%) of metastases were not « cured »


Chemotherapy-induced liver changes

Vauthey et al. JCO 2006

Steatohepatitis (Irinotecan)

Sinusoidal distention and obstruction

(oxaliplatin)


Relation between type of liver damage and clinical outcome

Steatosis associated with higher infection rate (Kooby et al. 2003)

Steatohepatitis associated with higher mortality rate due to liver failure after surgery (Vauthey et al.,2006)

Vascular injury associated with higher rate of operative bleeding and transfusion requirement (Vauthey et al. 2006; Adam et al. 2005)


Type of ChemotherapyNo. Patients

Pathologic liver histology

n (%)

No chemotherapy 66 0 (0)

With chemotherapy 87 44 (51)

5-FU 27 6 (22)

5-FU / Irinotecan 17 4 (23)

5-FU / Oxaliplatin 27 20 (74)

5-FU / Oxali + Irinotecan 16 14 (88)

Rubbia-Brandt, Ann Oncol 2004

Type of CT prior to resection

44/87 pts (51%) who received CT exhibited centrolobular lesions


Incidence of steatohepatitis with modern CT regimens

Treatment N Evidence of fatty changes

5-FU/FA 25 6 (24%)

Iri/5-FU/FA 25 12 (48%)

Oxali/5-FU/FA 25 7 (28%)

Leonard et al ASCO 2005


Preoperative (neoadjuvant) CT

Adam et al ASCO 2005 92 patients resected for liver metastases

17 pts no CT 23 pts FUFOL 52 pts FOLFOX

FOLFOX-treated patients had < steatosis and fibrosis than FUFOL-treated patients

No clinically relevant impact on outcome following resection

Adam et al. ASCO 2005; #3529


EORTC 40983 study: Resectable liver mts

FOLFOX4 FOLFOX4 Surgery Surgery FOLFOX4FOLFOX4

RR

(N = 363)(N = 363)

Surgery aloneSurgery alone

Endpoints DFS and safety

6 cycles 6 cycles

More post-operative complications in FOLFOX arm(21.1% vs 9.7%): not definitive results


Resectable liver mts: CT vs Surgery aloneKaroui/Nordlinger (2006)

Chemo group

n=45

Surgery alone

n=22

p

Sinusoidal dilation 22 (49%) 3 (14%) 0.005

Steatosis

<20%

20-50%

>50%

25 (56%)

6 (13%)

9 (20%)

10 (22%)

14 (64%)

6 (27%)

5 (23%)

3 (14%)

NS

Fibrosis

F0-F1

F2

25 (56%)

19 (42%)

15 (68%)

7 (32%)

NS

Karoui et al. Annals Surgery 2006

Postoperative morbidity was correlated with no. cyclesbut not type of chemotherapy


Type of Chemotherapy

No.

pts

Sinusoidal

dilationn=22

Steatosis >30%n=36

Steatohepatitis

n=34

No CT 158 3 (2%) 9% 4%

5-FU 63 0 17% 5%

5-FU / IRI 94 4 (4%) 11% 20%

5-FU / Oxa 79 15 (19%) 4% 6%

90-day mortality 1% 1% 15%

Vauthey et al. JCO 2006

Hepatoxicity of preoperative CT


Hepatoxicity of preoperative CTSummary

Both Oxa and IRI may induce hepatotoxicity Oxa induces a prevalenty vascular damage

(sinusoidal obstruction or distention), whreas IRI induces a steatohepatitis

The clinical impact of this toxicity is not clear, but it could be a concern in pts with resectable liver mts

Post-operative morbidity seems correlate with the number of cycles, not with the type of CT


In 2006: A clear separation between resectable and unresectable?

Definition of resectability has evolved Many pts may be now considered resectable, as

a result of novel treatment strategies Resectability rates for liver only metastases

after chemotherapy 6%-60% Resection rates correlate with response to

chemotherapy 5-year survival rates after secondary liver

resection (possible after chemotherapy) are in line with those following primary liver resection

at 35%-50%

1. Folprecht et al. Ann Oncol, 2005; 2. Bismuth et al. Ann Surg, 1996; 3. Giacchetti et al. Ann Oncol, 1999

Mts epatiche - Roma 2007 42Poston GJ, JCO 2005

Which liver mts are resectable?

OncoSurge Strategy

Absolute Controindications

- Unresectable extrahepatic disease- More than 70% liver involvement- Liver failure- Surgically unfit

Not influencing factors

- Age/Primary tumor stage- Timing of mts detection- Past blood transfusion- Liver resection type- Preresection CEA- Previous hepatectomy

Immediate resection appropriate

- Adequate resection margins- No portal adenopathy-≤ 4 mts and unilobar involvement

Post-CT resection appropriate

- Independent of tumor response in the case of ≤ 4 mts and unilobar involvement- After tumour shrinkage for > 4 mts or bilobar liver involvement


French guidelines (2003)

Resectable patients

Class 1 Easily resectable:

involvement of ≤4 of 8 liver segments, vena cava clear,

≥ 1 hepatic vein, contra-lateral portal pedicle

Class 2 Potentially resectable:

involvement of 5-6 segments,

± contra-lateral major named vascular structures

within liver

Gastroenterologie Clinique et Biologique 2003;Special issue II


Resection rate of metastases and tumour response

Studies with all patients with metastatic CRC (solid line) R=0.74, P<0.001

Phase III studies in metastatic CRC(dashed line)R=0.67, P=0.024

Studies with selected patientsLiver metastases only, no extra-hepatic diseaseR=0.96, P=0.002

Folprecht et al, Ann Oncol 2005

Response rate,9,8,7,6,5,4,3

Re

sec

tio

n r

ate

,6 -

,5 -

,4 -

,3 -

,2 -

,1 -

0,0 -


Limitations of present Stage IV

Does not:

allow stratification of patients according to prognosis

guide therapeutic decision making

permit comparison of results from radical/non-radical treatments


Stage 4 – the catch-all

STAGE 4 CRC spread beyond N2

Potentially curable Resectable

Prognosis: long-term survival

IncurableUnresectable Prognosis: ≈6 months

A new system is needed to differentiate between these Stage 4 patients according to prognosis for

the appropriate decision-making process


Staging: why a new staging?

Our perceptions of ‘resectable’ and ‘unresectable’ disease has been altered

The developments in the field of liver resection are not reflected in our approach to staging

Patients with mCRC no longer form a homogeneous group We need a staging system which

Can differentiate between the patient sub-groups with different prognosis (resectable, initially unresectable, never resectable)

Provides guidance for therapeutic decision making Provides clear indication for surgery or chemotherapy


Guidance from Second Workshop, November 2005 Consensus for a proposed stratification of Stage 4 (IV)

patients:Stage 4a: easily resectable liver metastases

Stage 4b: resectable liver metastases

Stage 4c: liver metastases that are resectable after downsizing

Stage 4d: liver metastases that will never be resectable

Stage 5a: resectable extrahepatic disease

Stage 5b: unresectable extrahepatic disease

Consensus for a proposed stratification of Stage 4 (IV) patients:Stage 4a: easily resectable liver metastases

Stage 4b: resectable liver metastases

Stage 4c: liver metastases that are resectable after downsizing

Stage 4d: liver metastases that will never be resectable

Stage 5a: resectable extrahepatic disease

Stage 5b: unresectable extrahepatic disease


Guidance from Second Workshop, November 2005

Makes the distinction between: Resectable

Easy Difficult

Initially unresectable

Never resectable Defines disease outside of the liver


The compromise from the third workshop: may 2006 (1)

Consensus for a proposed stratification of Stage 4 (IV) patients:

Stage 4a: Resectable liver only metastases

Stage 4b: Initially unresectable liver only mts

Stage 4c: Liver only metastases that will never be resectable

Stage 5a: Resectable liver and extrahepatic disease

Stage 5b: Resectable extrahepatic disease only

Stage 5c: Unresectable extrahepatic disease


What benefits might a new staging system bring?

Alert physicians to the possibility of curative intent strategies Will allow more direct comparison between institutions Will permit further stratification for sub-set analyses in future

trials Provide clear indications of the type of therapy such as:

Surgery for Stage 4a and Stage 5a (5b) ‘Neoadjuvant’ chemotherapy for Stage 4b Palliative chemotherapy for Stages 4c and 5c disease


In Practice: Patients with resectable metastases

Neoadjuvant chemotherapy can be considered pending the results of EORTC study 40983

These patients also should not be overtreated

Increased risk of liver damage Risk of disappearance of metastases

which are not visible by the surgeon, but are not cured

Benoist Nordlinger JCO 2006


In Practice: Patients with initially unresectable metastases

Surgery should be performed as soon as metastases become resectable

And chemotherapy should not be continued until best radiographic response is observed

Because administration of excessive number of cycles may result in increased damage to the liver and potential loss of the opportunity to do surgical resection


Synchronous mts: When is it possible delay resection of liver mts?

1. Synchronous liver mets when a major hepatectomy is needed, especially for primary rectal cancer

2. Primary rectal T3-T4 with operable liver mets who can benefit from radiotherapy before systemic chemotherapy

3. Symptomatic colorectal cancer with operable liver mets who can have a benefit from an early tumor control

4. Patients with comorbidity who cannot afford an initial liver and primary tumor resection


Role of new targeted therapies

Are they relevant?

Can they prevent progression of micrometastases to metastases?

Can bevacizumab be combined with surgery?

Can healthcare systems afford them?


RR and resection rates of liver mts in unselected pts: CT + targeted agents

StudyCytotoxic + targeted agent combination

NResponse

rate

Resection

rate

Fisher FOLFOX4 + gefitinib 27 78% 22%

Peeters FOLFIRI + cetuximab 42 45% 21%

Cervantes FOLFOX4 + cetuximab

43 79% 19%

Folprecht 5-FU/FA (AIO) + irinotecan + cetuximab

21 67% 19%

Kopetz FOLFIRI + bevacizumab

23 74% 17%

Hurwitz IFL + bevacizumab 402 45%<2%

IFL 411 35%


ACROBAT phase II study: FOLFOX4 + CET first-line in mCRC

Cetuximab + FOLFOX-4(n=43)

Overall response rate 79%

Complete response rate 9%

Disease control rate 95%

Progression-free survival (months)

12.3

Cervantes A, et al. Eur J Cancer Suppl 2005;3:181 (Abstract No. 642)

Population: EGFR-expressing mCRC; ECOG PS 2


Resection of initially unresectable metastases

19

33

Remaining non-resectable R0 resections R1 resections

10 patients (23%) were rendered resectable by treatment

Metastases:

• Liver n=8

• Lung n=1

• Adrenal: n=1


XELOX + Bevacizumab

32 patients with CRC liver mets 6 cycles XELOX + 5 cycles bevacizumab

(5-week break prior to surgery) 19/32 evaluable

15 liver resection 4 also had primary resection 14 patients responded 5 SD

XELOX + bevacizumab resumed 5 weeks post surgery Bev can be administered up to 5 weeks prior to surgery without

increasing the rate of surgical or wound healing complications

Gruenberger ESMO 2006 Abstract 374 P


Preoperative chemotherapy may increase resection rate of liver CRC liver metastases

In unselected patients triplet combinations of cytotoxics induce higher response rate and resection rate

Hepatotoxicity could a major concern, expecially in patients with resectable liver metastases

Surgery should be performed as soon as metastases become resectable

Conclusion - 1


A new staging system is available which can differentiate between patients subgroups and provide guidance for therapeutic decision making

No sufficient data are available to define the potential role of targeted agents, but the increase in response rate is expected to translate in higher resection rate and survival

Possibility of using targeted agents post-surgery as maintenance therapy to suppress micrometastases could be considered

Comparison with cytotoxic triplets is needed

Conclusion - 2


Distinctive features of adjuvant CT after resection of liver mts - 1

High prevalence of local vs distant relapsesFacts

Blood network, lobule architecture and normal cells streaming are disrupted after S

Consequences

The biological situation after liver mts resection is different from that after resection of colon primary

Implications



Different blood supply for mts > 2-3 mm (hepatic artery) and normal liver (portal vein)

Facts

Micromts may be not supplied by hepatic artConsequences

Results obtained with CT of unresectable liver mts cannot be extrapolated to adjuvant CT after liver mts resection

Implications



Liver drug extractionFacts

Effects on hepatic and extrahep. mts related to extraction rate and administration route

Consequences

HAI has substantial pharmacodynamic and biological limits, but systemic CT not always ensure the target to be reached

Implications


HAI adjuvant therapy after liver mts resection Phase III studies – selected patients (A)

Treatment N RFS MS Author

S + FU/MMC HAIS

1416

15% 5y25% 5yP>.05

25% 5y31% 5yP>.05

Rudroff, 1990

S + LV/FU HAIS

113113

14.2 m13.7 mP>.05

34.5 m40.8 mP>.05

Lorenz, 1998

S+FUDR HAI+FU/LV SysS

53(30)56(45)

46% 4y25% 4yP=.04

63.7 m49.0 mP=.60

Kemeny, 2002


Surgery + HAI FU/LV vs SurgeryLorenz M, Ann Surg 1998

Pts “as treated”P>.05


Surgery vs HAI FUDR + Sys FA/FUKemeny M, JCO 2002

Time to recurrence (assessable patients; n =75)

Time to liver recurrence (assessable patients; n = 75)

Overall survival (assessable patients; n = 75)

Overall survival (all patients; n = 109)


HAI adjuvant therapy after liver mts resection Phase III studies – selected patients (B)


HAI CT/IT+S+HAI CT/ITS

2020

--

2011

P<.05

Lygidakis, 1995

S+FUDR HAI+FU/LV SysS + FU/LV Sys

7482

57% 2y42% 2yP=.07

72.2 m59.3 mP=.21

Kemeny, 1999

S+HAI FU+oral FUS + oral FU

910

66.7% 3 y20.0% 3 y

P=.045

77.8% 3y50% 3 yP=.27

Tono, 2000


Adjuvant HAI after resection of hepatic mts from CRCKemeny N et al, N Engl J Med 1999

HAI FUDR/DEX+ Sys FU

74 Patient

sRAND

SURGERY

82 Patient

s

• Completely resected CRC hepatic mts• No extrahepatic disease• Synchronous 32%• Metachronous 68%• Adj CT 39%• CT for mts 14%

Sys FU

End-points: Overall SurvivalSurvival without recurrence of hepatic mtsSurvival without any mts at two yrs



P = 0.21 by log-rank

Median Survival

PFS

P = 0.06 by log-rank



Up-dated resultsKemeny N, NEJM 2005

Combination therapy

Median OS: 68.4 m

Systemic therapy

Median OS: 58.8 m

N.S.

Only 26% of pts could have more than 50% of the HAI planned dose


Prospective studies on HAI adjuvant therapy after liver mts resection A Metanalysis (Clancy TE, J Gastroint Surg 2005)

Lorenz

Rudroff

Lygidakis

Lygidakis

Tono

Tono

Kusunoki

Kusunoki

Rudroff

Kemeny

Kemeny Kemeny

Kemeny

Lorenz

Combined Combined

1-year Survival 2-year Survival

P = 0.59 P = 0.11


HAI adj CT for pts having resection or ablation of liver CRC mtsCochrane Database Syst Rev 2006

Wagmann 1990: 12 pts, S+HAI FUDR vs S Rudroff 1990: 30 pts, S+HAI FU/MMC vs S Lorenz 1998: 226 pts, S+HAI FU/LV vs S Kemeny 2002: 109 pts, S+HAI FUDR+Sys vs S Lygidakis 1995: 40 pts, HAI CT/IT+S+HAI CT/IT

vs S Kemeny 1999: 156 pts, S+HAI FUDR+Sys vs

S+Sys Tono 2000: 19 pts, S+HAI FU+oral FU vs S+oral

FU

Nelson R and Freels S, 2006



Lygidakis excluded



Only studies with S as control


HAI adj after liver metastasectomyMain concerns HAI may reduce hepatic recurrences, but its

effect on overall survival is uncertain in comparison to surgery alone

HAI requires surgical implantation of a hepatic arterial catheter and requires the use of an impantable pump

HAI is impaired both by technical difficulties and high rate of complications

Floxuridine is not authorized in Europe


Neoadj CT in unresectable liver mts comparable with HAI or sys adj CT

UCSC, 2004 Ychou, 2004 Alberts, 2005

Median Follow-up 30.4 m

(6-54)

30.9 m

26.4-35.6)

36 m

(29-36)

TTP All Pts

Not res. Pts

14.3 m

5.2 m

11.9 m

Not reported

Not reported

Not reported

Median OS (all pts) 30.1 m 35.5 m 26 m

MS Res. Pts

Not res. Pts

Not reached

24 m

Not reached

Not reported

Not reached

Not reported

Survival (resected Pts) 70% (2.5 yrs) 70% (2 yrs) 67% (3 yrs)


Portal Vein Infusion

Rationale Micromts are primarily dependent on the PV

for their nutrition The biliary tree is essentially fed by the

hepatic artery Phase I study

PV can be delivered safely, but OS and DFS seem lower than that reported with HAI (Faynsod M, JCO 2005)

Adjuvant therapy after primary CRC resection No advantage


Prospective studies on systemic adj CT after liver mts resection

Treatment N RFS S Author

S+LV/FU

S

52

55

45% 4y

35% 4y

P=.35

57% 4y

47% 4y

P=.39

Langer, 2002

S+FU/LV

S

28

10

15 m

9 m

P=.35

SM 30m

SM 15m

P=.066

Loper-Ladron, 2003

S+FU/LV

S

86

87

33.5% 5y

26.7% 5y

P=.028

51.1% 5y

41.1% 5y

P=.13

Portier, 2006


Phase II studies on systemic adj CT after liver mts resection

Treatment N RFS S Author

S+LV/FU/IRI/UFT 58 13.9 m 18 m Kono, 2005

S+IRI 29 45.2 m 85% 2y Mackay, 2005


Adj sys FU/FA compared with S after resection of CRC liver mtsPortier G, JCO 2006

Sys FU/LV

86 Patient

sRAND

SURGERY

85 Patient

s

• Completely resected CRC hepatic mts• No extrahepatic disease• Stratification: - Size - Number - Time primary res- mts detection

No treatment

I End-point: Disease-free SurvivalII End-points: Overall Survival

Incidence of adverse effects


Adj sys FU/FA compared with S after resection of CRC liver mtsPortier G, JCO 2006

P = 0.028

P = 0.13

DFS

Overall Survival

Suspended after 173 ptsdue to slow accrual


Comparison HAI vs IV FU/LV for CRC liver mts – A randomized trial

HAI SysmPFS 7.7m 6.7m1y PF 28% 20%2y PF 4% 6%

p=.27

HAI Sys mOS 14.7m 14.8m1y S 57% 61%2y S 22% 27%

p=.79

Steady state venous concentrationof FU

Secondary Endpoints

HAI Sys RR 22% 19% mDR 7.6 m 7.5 m

Kerr DJ, The Lancet 2003


Post-operative chemoimmunotherapy Phase III studies


HAI CT/IT+S+HAI CT/ITS

2020

--

2011

P<.05

Lygidakis, 1995

S + HAI CT/ITS + HAI CT

3315

--

20.3 m9.9 m

Lygidakis, 1996

S + HAI CT/IT + sys CTS + sys CT/IT

6260

66% 2y48% 2y

92% 2y75% 2y

Lygidakis, 2001

S+TIL/IL2S+sys CT

2522

28% 3y37% 3yP=.27

55% 3y50% 3y

P=.7

Gardini, 2004


Adj immunotherapy vs sys FU/FA after resection of CRC liver mtsGardini A, J Surg Oncol 2004

TIL/IL2

25 (14)

Patients

RAND

SURGERY

22 (14)

Patients

• Completely resected CRC hepatic mts• No extrahepatic disease• TIL from surgical specimen• In-vitro activation with IL2• Reinfusion with IL2

FU/LV

End-point: Disease-free SurvivalOverall Survival


Adj immunotherapy vs sys FU/FA after resection of CRC liver mtsGardini A, J Surg Oncol 2004

Overall Survival

DFS


Conclusions - 3

No clear advantage with HAI after resection of liver metastases, but not irrelevant technical and toxicity concerns

Few and low-powered prospective studies both with HAI and sys post-operative CT

Prognostic factors were not homogeneous Only one well-designed randomized study

with post-resection systemic CT, whose accrual was early stopped because of a too slow accrual rhythm


Conclusions - 4

CT used in these trials is clearly inferior to currently available regimens

To date, immunotherapy has shown no value Neoadjuvant CT of unresectable liver mts

achieves results similar to (or better than) those obtained with adjuvant therapy

The assessment of resecability is a crucial step in decision making and prognosis

The control arm for future studies is a basic concern


Does CT benefit pts after resection of liver mts from CRC?

The Portier’s study provides a proof of concept of adj CT in this pts population

Additional trials, using more modern systemic approaches, are needed

The potential benefit of adding HAI therapy to systemic therapy is still hypothetical

Added costs , toxicities and technical issue associated with placement of an HAI pump are a reality


Metastatic CRC

85% unresectable 15% resectable

?% potentially resectable (after neoadjuvant)

• New staging system• Improved patient workup

• New endpoint• Timing?• Addition of targeted agents

CT

Cure?

Improved patient monitoring

• Syst. chemotherapy first?

• Patient selection

Resectability in pts with CRC liver metastases – where are we now?

> 30% resection


Prediction: Survival in advanced colorectal cancer in 2015?

0 1 2 3 4 5

100

50

0

%

survivin

g

Years after diagnosis of colorectal metastases

2005 Median survival:Chemotherapy 24 mos.Overall >30 months

5 year survival:1985 ~1%1995 ~4%2005 20%2015 ?50%

8 mos 13 mos 30 mos 60 mos?

Dr. G. Poston, Pfizer Satellite Symposium, ECCO 2005

Mts epatiche - Roma 20071 Optimal Management of Liver Metastases: Present Results and Future...

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