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MSO, School of Oncology Optimal approach to medical management of synchronous colorectal liver metastases Roma, 4 marzo 2011 Dott.ssa Angela Torsello – PowerPoint PPT presentation

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1
MSO, School of Oncology
Optimal approach to medical management of
synchronous colorectal liver metastases
Roma, 4 marzo 2011
Dott.ssa Angela Torsello
Angela TORSELLO Oncologia Medica A Istituto
Regina Elena, Roma
2
Colorectal cancer liver metastases
3
Colorectal cancer liver metastases
Liver metastases
25 synchronous with the primary tumor
20 metachronous
  • Mets sinchronous
  • More often bilobar and greater in number/size
  • Poorer survival
  • Different management (i.e. the resection time of
    primary tumor and liver metastases represent an
    important issue)

Tan EK et al, Ann Acad Med 2010
4
Treatment of Colorectal Liver Metastases
  • In patients with liver metastases the main topic
    is to evaluate lesions resectability or the
    possibility of the lesions to became resectable
    after neoadjuvant chemotherapy

Strangl R et al. Lancet 1994
5
5-y Survival
  • Resected patients 25-40

Liver resection Possibility to cure
Adam R.
6
Synchronous Colorectal Liver Metastases I
  • Should primary tumor be resected before starting
    sistemic treatment?
  • This could represent a problem in the control of
    disease (delayed sistemic treatment)
  • BUT.. Importance of patient symptoms
    subocclusion/occlusion, bleeding

7
Synchronous Colorectal Liver Metastases II
  • Should liver metastases be resected at the same
    time as the primary tumor?
  • a) Importance of primary tumor site
  • - right sided tumors could be better resected at
    the same time of liver metastases in selected
    patients
  • left sided tumor (especially rectal cancer)
    present more thecnically difficulties and
    post-operative risks
  • b) A delayed (3-6 months) liver resection and
    chemotherapy administration permits a test of
    time selection of patients who really benefits
    of liver resection with curative intention

8
Surgery in synchronous colorectal liver metastases
  • The optimal timing of synchronous metastases
    resction is not well defined
  • Surgical strategy are defined as combined
    (combined resection of primary and liver),
    classic (primary before liver) and reverse (liver
    before primary)
  • These surgical strategies are associated with
    similar outcomes
  • The combined strategy is considered safe with no
    different in morbidity and mortality rates or in
    severity of complications, compared with staged
    resection

9
Reverse approach
  • Recently this kind of surgical approach is
    considered for rectal cancer with synchronous
    liver metastases
  • The treatment sequence proposed is the following
  • Systemic chemotherapy followed by liver resection
  • Chemoradiation followed by rectal resection

Van der Pool et al, ASCO 2010 abs e14027
10
Postoperative outcome of 142 pts with different
surgical strategy for synchronous liver mets
Outcome Combined (n43) Classic (n72) Reverse (n27) p
Margin status for resection of primary ()
R0 41 (95) 68 (94) 25 (93) NS
R1 2 (5) 4 (6) 2 (7)
Type of liver resection
3 liver segments, n () 15 (35) 48 (66) 24 (89) lt0.01
Margin status for resection of metastases
R0 40 (93) 62 (86) 23 (85) NS
R1 3 (7) 9 (13) 4 (15
Blood transfusion requirement, n () 7 (16) 9 (13) 2 (7) NS
30-d postoperative mortality 2 (5) 2 (3) 0 NS
90-d postoperative mortality 2 (5) 2 (3) 1 (4) NS
Overall postoperative morbidity 20 (47) 37 (51) 10 (37) NS
Cumulative major postoperative complication 8 (19) 12 (17) 2 (7) NS
Brouquet A et al, J Am Coll Surg 2010
11
The impact of multidisciplinary management
100
2009 chemotherapy Median survival gt24
months 5 year survival 9
2009 overall (Surgery Chemo) Median survival
36 months 5 year survival 20
surviving
50
2019?
1999
20
9
3
0
0 1 2
3 4 5
Years after diagnosis of colorectal metastases
Poston GJ. EJSO 2005 31 325-30
12
Perioperative chemotherapy with FOLFOX4 and
surgery versus surgery alone for resectable liver
metastases from colorectal cancer (EORTC
Intergroup trial 40983) a randomised controlled
trial
Nordlinger et al, Lancet 2008
13
Postoperative complications
Peri-op
Surg Number in group

159 170 Reversible
postoperative complications
40 (25) 27
(16) Cardio-pulmonary failure

3 (2) 2 (1) Bleeding

3 (2) 3
(2) Biliary fistula

13 (8) 7 (4) Output gt100 mL/day
for gt10 days
9 (6) 2 (1) Hepatic
failure
11
(7) 8 (5) Bilirubin gt100 mg/day for gt3
days
10 (6) 5 (3) Wound infection

5 (3) 4
(2) Intra-abdominal infection

11 (7) 4 (2) Need for reoperation

5 (3) 3 (2) Urinary
infection
4
(3) 0 Pleural effusion

3 (2) 1 (1) Pulmonary
embolism/deep-venous thrombosis
2 (1) 1
(1) Pneumopathy

2 (1) 0 Neutropenia

2 (1) 0 Ascites

1
(1) 1 (1) Ileus

2 (1) 1
(1) Cardiac arrhythmia

0 1 (1) Renal failure

0
1 (1) Other

4 (3) 4 (2) Postoperative
death
1 (1)
2 (1)
14
The timing of chemotherapy and surgery
  • Liver mets resectable at presentation the
    perioperative chemotherapy has become the
    standard treatment in many institutions (to be
    performed after maximum 6 cycles of chemotherapy)
  • Liver mets initially not resectable monitoring
    patients during chemotherapy to perform surgery
    as soon as the metastases become resectable
  • Nordlinger et al, Clin Colorectal Can 2010
    and Ann Oncol 2009

15
Liver metastases treatment
Liver metastases
85 non resectable
15 resectable
Neoadjuvant chemotherapy
  • R0
  • R0 uncertain

Potentially resectable (4-30)
more?
FU/OXA o CPT11
FA/OXA/CPT11 (Triplet)
FA/FU
Target therapies
16
Topics of liver metastases neoadiuvant
chemotherapy
  • Patients selection
  • Type of treatment (systemic hepatic
    intra-arterial) and schedule (new biological
    drugs)
  • Liver damage
  • Respose to treatment (complete vs partial
    response)

17
PATIENTS SELECTION
18
What does it mean resectable disease?
  • Traditional controindications
  • 4 metastases
  • Size
  • Extrahepatic disease
  • Ilar disease
  • Resection marginlt 1 cm
  • Incomplete resection
  • Now is admitted
  • Resection margin 1 cm
  • Number
  • Size
  • Extrahepatic disease
  • Need standard resection criteria

19
French Recommendations 2003
  • Potentially resectable class I (involvement max
    4 anatomic segments non-involvement of cava
    vein, almost one of hepatic veins and
    controlateral portal pedunculus)
  • Potentially resectable classe II (involvement of
    5-6 anatomic segments and/or major controlateral
    vascular structures)
  • Not resectble that became resectable classe III
  • Never resectable classe IV
  • Classe I easily resectable
  • Classe II resectable with difficult

20
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21
Criteri di non resecabilità (IRE)
  • Size
  • Multinodular
  • Ilar location
  • Extraepatic disease
  • Patients with gt3 metastases who receive
    chemotherapy in order to stabilize liver disease
    before surgery
  • Patients who present with huge resectable liver
    metastases at the time of resection of the
    primary tumor and need extended liver surgery

22
CRC Staging IV Stage (Consensus 2006)
  • Stage IVa easily resectable liver metastases
  • Stage IVb resectable liver metastases
  • Stage IVc liver metastases thet may become
    resectable after downsizing
  • Stage IVd liver metastases that are unlikely to
    become resectable
  • Stage Va resectable disease outside the liver
  • Stage Vb unresectable disease outside the
    liver
  • never resectable

EJC, 2006
23
  • It is important
  • Staging of metastastic patients (TC, US, RMN,
    PET)
  • Resection criteria
  • Prognostic factors (outcome predictors)

24
NEOADJUVANT CHEMOTHERAPY
25
Response rate and surgery of metastases (First
line 5-FU, LV and l-OHP)
40
93-94
Chrono 4-10
30
90-93
94-96
20
Complete resection of metastases ()
Chrono 5-16
90-93
10
Flat 5-16
r 0.96 p 0.0007
0
0
30
40
50
70
60
Objective responses ()
Secondary surgery of metastases major
prognostic factor of survival
26
Resection rate of metastases and tumor response
Folprecht G, et al. Ann Oncol 20051613111319
Studies including selected patients(liver
metastases only, no extrahepatic
disease) (r0.96 p0.002)
0.6
0.5
0.4
Studies including nonselected patients with mCRC
(solid line) (r0.74 plt0.001)
Resection rate
0.3
0.2
0.1
Phase III studies including nonselected patients
with mCRC (dashed line) (r0.67 p0.024)
0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
Response rate
27
Which Regimen doublets or triplets?
Pozzo C. et al Cancer Treat Rev, 2008
28
Triplets
1) Activity and efficacy increase 2) Resection
rate increase 3) Balance between activity and
toxicity 4) Acute toxicity acceptable
29
Treatment of metastatic CRC
New drugs and new combinations
  • Oral 5-FUs (capecitabine, UFT)
  • Irinotecan
  • Oxaliplatin
  • Cetuximab
  • Bevacizumab

Tumor response rates typically gt50-60 and even
72
30
Cetuximab and resection rate in first-line
FOLFIRI-based regimen
Folprecht et al 2006 Peeters et al 2005 Van Cutsem et al 2007
Trial Phase I/II Phase I/II Phase III
Treatment regimen Cetuximab irinotecan/AIO Cetuximab FOLFIRI Cetuximab FOLFIRI
No. of patientsa 21 42 599
Overall response rate () 67 45 47
Disease control rate () 96 83 84
Resection rate () 24b 24 6
R0 Resection rate () 19 19 4 (10c)
A Patients in ERBITUX arm b5 patients became
eligible for resection, 4 underwent surgery cR0
resection rate in patients with liver limited
disease
31
CRYSTAL resection rate ITT
  • Cetuximab raddoppia i pazienti portati alla
    chirurgia e triplica le di R0

R
R0
7
4.8
3.7
1.8
32
Cetuximab and resection rate in first-line
FOLFOX-based regimen
Bokemeyer et al 2007 Tabernero et al 2007 Colucci et al 2007
Trial Phase II Phase II Phase II
Treatment regimen Cetuximab FOLFOX-4 Cetuximab FOLFOX-4 Cetuximab FOLFOX4
No. of patientsa 169 43 67
Overall response rate () 46 72 64
Disease control rate () 85 95 NR
Resection rate () 7 23 -
R0 Resection rate () 5 21 21

aPatients in ERBITUX arm bR0 resection rate in
patients with liver limited disease NR, not
reported
33
OPUS resection rate ITT
  • Cetuximab raddoppia i pazienti portati a
    resezione e le di resezioni R0

34
Panitumumab (pmab) with FOLFIRI as first-line
treatment of patients (pts) with metastatic
colorectal cancer (mCRC) Resections and curative
surgery in a phase II single arm, multicenter
study (20060314).
R. Hofheinz, L. Mineur, R. Greil, C. Kohne, H.
Letocha, J. Thaler, E. Fernebro, E. Gamelin, L.
DeCosta, M. Karthaus
KRAS/MT
KRAS/WT
Response rate
56
38
Resection rate
15
7
ASCO 2010, abs 3545
35
CETUXIMAB and resection rate in pretreated
patients
Aloia et al 2007 Karaboue et al 2007 Levi et al 2007
Treatment regimen Ctuximab various CT Cetuximab chronomodulated CT Chronomodulated IFO (ia) /- Cetuximab
Treatment line gt 2nd-line 3rd-line Heavily pretreated
No. of patients 151 56 32
Overall response rate, NR 32 34
Resection rate, 18 (27/151) 18 (n8 R0, n2 R1) 13 (n3 R0, n1 R1)
Survival in resected patients 10 disease-free at 22 months follow-up Median PFS 11.7 months Survival estimate 80 at 21 months Median survival (all patients) 18.4 months
IFOirinotecan/5-FU/FA/oxaliplatin NRnot
reported
36
Studio EMR 604-CELIM
Patients with technically unresectable/5 liver
metastases without extrahepatic disease
RESECTION
Adjuvant therapy for 6 cycles (same schedule as
pre-operatively)
ERBITUX FOLFOX (n54)
Technically resectable
R
ERBITUX FOLFIRI (n54)
Technically unresectable
4 further treatment cycles
Primary endpoint Response rate
8 cycles (4 months)
Started December 2004
37
Patient characteristics
    FOLFOX6 FOLFIRI All
    ERBITUX ERBITUX patients
  n56 n55  n111
KRAS (n99)      
Wild-type   70 71 71
Primary tumour site      
Rectal cancer 36 52 44
Primary tumour stage      
T3/4 89 83 86
Adjuvant chemotherapy 9 23 16
Adjuvant radiotherapy 4 15 8
38
Resections by patient subgroup
  Technically 5 liver KRAS
  non-resectable metastases wild-type
n57 n48 n67
All resections 40 44 43
  (23 pts) (21 pts) (29 pts)
R0 resections 32 40 34
  (18 pts) (19 pts) (23 pts)
Comparison of R0 resections between strata
technically non-resectable and 5 liver mets
p0.4
39
POCHER STUDY
Patients with unresectableliver metastases /-
extrahepatic disease
RESECTION
Adjuvant therapy for 4-6 courses (same schedule
as pre-operatively)
Technically resectable
ERBITUX CPT-FFL (n43) for 4-6 courses
Technically unresectable
4 further treatment cycles
Primary endpoint Response rate
8 cycles (4 months)
Started December 2004
40
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41
POCHER RESULTS
N ()

Response rate Resection (R0) Follow-up (median) Median PFS (months) resected Median PFS (months) not resected Median OS (months) all population 34 26 22 (1-43) 15 (CI95 12-190) 9 (CI95 1-17) 37(CI95 21-53) 79 (CI95 66 - 91) 60 (CI95 45 - 75)
42
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43
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44
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45
Bevacizumab CAPOX
BEV ACIZUMAB Capecitabine L-OHP ORR 78
Patient with colorectal liver metastases
primary tumor
  • Surgery
  • Resection rate 40in pts with metachronous mets
  • - Reasection rate 67 in pts with synchronous
    mets

Wong R et al, Ann oncol 2011
ESMO 2006
46
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47
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48
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49
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50
Bevacizumab in synchronous metastases
  • In patients with asimptomatic primary tumour and
    synchronous metastases, Bevacizumab (plus
    FOLFOX6) can be used without increased risks of
    bleeding/perforation (McCahill et al, ASCO 2010
    abs 3527)
  • In neoadjuvant setting of liver metastases,
    Bevacizumab (plus Xelox) can be used safely
    without increased risks and with efficacy also in
    patients with primary insitu (Gruenberger T et
    al, ASCO 2010 abs e14032)

51
Anti EGFRab in synchronous metastases
  • Safe use of Cetuximab or Panitumumab in advanced
    CRC
  • No data are reported in the principal studies
    (Crystal, Opus) respect an increased
    toxicity/morbidity/mortality during treatment of
    patients with primary tumor insitu

52
Chemioterapia intra-arteriosa (IA) epatica I
  • Risposte 40-80 resecabilità variabile dal 10 al
    40, tuttavia le esperienze in neoadiuvante con
    la terapia IA epatica sono limitate
  • E possibile utilizzare alternativamente la
    chemioterapia sistemica e intra-arteriosa epatica
    o in combinazione (eventualmente con nuovi
    farmaci)
  • Non è comunque possibile definire lapproccio
    ottimale per la difficoltà a comparare studi di
    chemioterapia neoadiuvante sistemica e
    intra-arteriosa epatica (eterogeneità) necessità
    di studi randomizzati

53
Terapia sistemica Terapia Locoregionale
Pazienti 44 pre-CPT-11 ev 70 HAI SYS OXAL
5-FAFU RR 82 Resect 20-36
Leonard GD, et al. ASCO 04 abs 3542
54
LIVER DAMAGE
55
Quale è il danno sul fegato sano?
  • Fibrosi (portale, porto-portale, settale,
    cirrosi)
  • Lesioni vascolari (dilatazione e congestione
    sinusoidale, peliosi, necrosi emorragica
    centrolobulare, iperplasia nodulare rigenerativa
  • Steatosi macrovacuolare (lieve lt30 epatociti,
    moderata 30-60 epatociti e severa gt60
    epatociti)
  • Oxaliplatino danno vascolare
  • CPT-11 steatoepatite

56
Vascular hepatic damage
Aloia T et al., JCO 2006
57
Complete response to chemotherapy
Benoist S, JCO 2006
58
CONCLUSIONS
  • Actually there are not guideline on the use of
    chemotherapy and surgery in synchronous
    colorecltal liver metastases (clinical signs are
    important)
  • There is not a chemotherapy schedule indicated as
    standard treatment in neoadjuvant setting of
    colorectal liver metastases all schedules could
    be used
  • Triplet seems to be more effective
  • Adding molecular drugs, there is an activity
    increase in term of response rate and
    resectability
  • Prospective studies on predictive factors of
    response and resectability could be useful to
    select the better treatment for each patient

59
KL, nata in Ucraina il 17.04.1972, Anam Fam
negativa Anam. Fisiol 3 gravidanze Anam Patol
Remota negativa Osservata il 26.8.2009, da 4
mesi tenesmo ed astenia. Rettoscopia sulla
superficie laterale del retto neoplasia a 3 cm da
OA, occupando il 50 del lume e si estende per 7
cm in lunghezza TC (1.09.2009) Tumore del retto
con met epatiche bilaterali massive e polmonari
60
KL TC pre terapia 1.9.2009
61
KL TC pre terapia 2.9.2009
62
KL PET/TC pre terapia 11.9.2009
63
Neoplasia del retto con metastasi epatiche KL
n. 17.4.1972
  • 17.09.2009 Inizia chrono-IFLO Cetuximab per 4
    cicli (2 mesi)
  • 11.11.2009 RP gt80 su T ed M

Cetuximab 400-250 mg/m2 day1
CPT-11 110 mg/m2day 1 peak 1300
C. Garufi et al Br J Cancer 2010
64
Ecoendo 11.11.2010 risposta dopo 4 cicli di
chrono-IFLO
65
TC 23.11.2010 risposta dopo 4 cicli di
chrono-IFLO
66
Neoplasia del retto con metastasi epatiche KL n
17.4.1972
  • Dal 18.12.2009 al 24.12.2009 RT 25 Gy short
    course sul retto
  • 29.12.2009 Resezione del retto in VLS con
    anastomosi colo anale ed ileostomia di protezione
    ypT3N1a, TRG 1 sec Ryan

67
Neoplasia del retto con metastasi epatiche KL n
17.4.1972
  • Esame istologico tratto di grosso intestino
    sede di residui di adenocarcinoma rappresentati
    da occasionali aggregati cellulari neoplastici
    nel contesto di alcuni laghi di muco infiltranti
    il tessuto fibroso perirettale ed il margine
    radiale (circonferenziale) di resezione
    chirurgica. La neoplasia si associa a marcata
    fibrosi e focali calcificazioni, Si segnala
    angioinvasione dei vasi extramurali e
    modificazioni riferibili a terapia neoadiuvante.
  • Metastasi in 1/8 linfonodi perirettali
    repertati, mentre i restanti 7 mostrano
    modificazioni riferibili a terapia neoadiuvante.
    Residui neoplastici in2/7 noduli fibrosi
    repertati nel tessuto fibroadiposo perirettale,
    mentre i rimanenti 5 noduli mostrano fibrosi,
    occasionali calcificazioni e modificazioni
    riferibili a terapia neoadiuvante. Margine
    prossimale indenne da infiltrazione neoplastica

68
Neoplasia del retto con metastasi epatiche KL n
17.4.1972
  • Dal 26.1.2010 al 26.3.2010 continua ancora per 3
    cicli con chrono-IFLO (7 cicli totale)
  • 29.3.2010 chiusura colostomia
  • 26.4.2010 PET RC fegato

69
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70
Neoplasia del retto con metastasi epatiche KL n
17.4.1972
  • 28.5.2010 epatectomia dx allargata al IV segmento
    resezione met epatica a sinistra
  • 26.7.2010 FOLFIRI Cetuximab x 6 cicli
  • 3.11.2010 conclude chemioterapia

71
Neoplasia del retto con metastasi epatiche KL n
17.4.1972
  • Esame istologico
  • 1. Lobo destro al taglio nel parenchima
    epatico si apprezzano tre neoformazioni . Del
    diametro rispettivamente di cm 1,5 A,B di cm 1,8
    C,D di cm 2,7 E,F. Non alterazioni nel
    parenchima circostante G,H
  • Fegato sede di metastasi di adenocarcinoma
    moderat differenziato, coerente con primitività
    colica. I noduli metastatici sono costituiti solo
    in parte minore da tessuto neoplastico vitale
    (circa il 30 in A,B circa il 10 in C,D circa
    il 40 in E,F) prevalendo in tutti la necrosi
    elorganizzazione sclero-cicatriziale di questa.
    Margine chirugico libero da neoplasia. Non
    modificazioni di rilevo del parenchima non
    lesionale.
  • 2. Formazione lobo sinistro
  • frammento di parenchima epatico sede di
    metastasi di adenocarcinoma con aspetti
    morfologici sovrapponibili, in parziale (circa il
    50) sostitutuzione sclero-calcifica

72
KL, nata in Ucraina il 17.04.1972 TC 6.8.2010
73
Neoplasia del retto con metastasi epatiche KL n
17.4.1972
  • Conclusione
  • 14 mesi di trattamenti integrati
  • 13 cicli di chemioterapia, 7 chrono-IFLO 4
    FOLFIRI, sempre con Cetuximab
  • 5 sedute di RT
  • 3 interventi chirurgici resezione colo-anale,
    chiusura colostomia, epatectomia allargata al IV
  • Paziente senza segni di malattia ad oggi
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