Optimal approach to medical management of synchronous

colorectal liver metastases

MSO, School of Oncology

Dott.ssa Angela TorselloAngela TORSELLOOncologia Medica A Istituto Regina Elena, Roma

Roma, 4 marzo 2011

Colorectal cancer liver metastases

Liver metastases

25% synchronous with the primary tumor

20% metachronous

Colorectal cancer liver metastases

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

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-y SurvivalResected patients: 25-40%

Liver resection= Possibility to cure

Adam R.

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…

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

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

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

Postoperative outcome of 142 pts with different surgical strategy for synchronous liver mets

Outcome Combined (n=43)

Classic (n=72)

Reverse (n=27)

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) <0.01

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

The impact of multidisciplinary management

0 1 2 3 4 5

100

50

0

%

surviving

Years after diagnosis of colorectal metastases

2009 chemotherapyMedian survival >24 months5 year survival 9 %

3%

1999

2009 overall (Surgery + Chemo)Median survival ~36 months5 year survival 20 %

20%

Poston GJ. EJSO 2005; 31: 325-30

9%

2019?

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

Postoperative complications Peri-op SurgNumber in group 159 170Reversible 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 >100 mL/day for >10 days 9 (6%) 2 (1%)Hepatic failure 11 (7%) 8 (5%)Bilirubin >100 mg/day for >3 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%) 0Pleural effusion 3 (2%) 1 (1%)Pulmonary embolism/deep-venous thrombosis 2 (1%) 1 (1%)Pneumopathy 2 (1%) 0Neutropenia 2 (1%) 0Ascites 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%)

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

Liver metastases treatment

Liver metastases

85% non resectable 15% resectable

Neoadjuvant chemotherapy

Potentially resectable

(4-30%)

• R0•R0 uncertain

more?

FA/FU FU/OXA o CPT11

FA/OXA/CPT11

(Triplet)Target therapies

Topics of liver metastases neoadiuvant chemotherapy

Patients selectionType of treatment (systemic; hepatic

intra-arterial) and schedule (new biological drugs)

Liver damageRespose to treatment (complete vs

partial response)

PATIENTS SELECTION

What does it mean “resectable disease”?

Traditional controindications:

•≥ 4 metastases

•Size

•Extrahepatic disease

•Ilar disease

•Resection margin< 1 cm

•Incomplete resection

Now is admitted:Resection margin≤ 1 cmNumberSizeExtrahepatic disease

Need standard resection criteria

Adam R., et al. Ann Surg Onc 2000

9

48

12 26

01020304050

large Multi-nodular

ill-located

extra-hepatic

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

• Size • Multinodular• Ilar location• Extraepatic disease

• Patients with >3 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

Criteri di non resecabilità (IRE):

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

It is important:

• Staging of metastastic patients (TC, US, RMN, PET)

• Resection criteria

• Prognostic factors (outcome predictors)

NEOADJUVANT CHEMOTHERAPY

Response rate and surgery of metastases(First line 5-FU, LV and l-OHP)

Chrono 4-10

Chrono 5-16

Flat 5-16

0 30 40 50 60

40

30

10

0

Objective responses (%)

Co

mp

lete

res

ect

ion

of m

eta

sta

ses

(%)

r = 0.96 ; p = 0.0007

94-96

93-94

90-93

90-93

Secondary surgery of metastases : major prognostic factor of survival

20

70

Resection rate of metastases and tumor response

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)Response rate

0.90.80.70.60.50.40.3

Res

ecti

on r

ate

0.6

0.5

0.4

0.3

0.2

0.1

0

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

Which Regimen: doublets or triplets?

Pozzo C. et al Cancer Treat Rev, 2008

1) Activity and efficacy increase

2) Resection rate increase

3) Balance between activity and toxicity

4) Acute toxicity acceptable

Triplets

New drugs and new combinations

• Oral 5-FUs (capecitabine, UFT) • Irinotecan• Oxaliplatin • Cetuximab• Bevacizumab•

Treatment of metastatic CRC

Tumor response rates typically >50−60%…and even 72%

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

CRYSTAL: resection rate ITT

Cetuximab raddoppia i pazienti portati alla chirurgia e triplica le % di R0

Curative liver resections

Res

ecti

on r

ate

(%)

CRYSTAL

FOLFIRI

ERBITUX + FOLFIRI

Res

pon

se r

ate

(%)

Response rates

FOLFIRI

ERBITUX + FOLFIRI

CRYSTAL

R R0

3.7

7

1.8

4.8

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

OPUS: resection rate ITT

Cetuximab raddoppia i pazienti portati a resezione e le % di resezioni R0

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

Response rate

KRAS/WT KRAS/MT

Resection rate

56% 38%

15% 7%

ASCO 2010, abs 3545

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 > 2nd-line 3rd-line Heavily pretreated

No. of patients* 151 56 32

Overall response rate, % NR 32 34

Resection rate, % 18 (27/151) 18 (n=8 R0, n=2 R1) 13 (n=3 R0, n=1 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

IFO=irinotecan/5-FU/FA/oxaliplatin; NR=not reported

Studio EMR 604-CELIM

Adjuvant therapy for

6 cycles (same schedule as pre-

operatively)R

Patients with technically unresectable/

≥5 liver metastases without extrahepatic disease

ERBITUX +

FOLFOX

(n=54)

8 cycles (~4 months)

Technically resectable

Primary endpoint: Response rate

4 further treatment

cycles

RESECTION

ERBITUX +

FOLFIRI

(n=54)

Technically unresectable

Started December 2004

Patient characteristics

    FOLFOX6 + FOLFIRI + All

    ERBITUX ERBITUX patients

  n=56 n=55  n=111

KRAS (n=99)      

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%

Resections by patient subgroup

  Technically ≥ 5 liver KRAS

  non-resectable metastases wild-type

n=57 n=48 n=67

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: p=0.4

POCHER STUDY

Adjuvant therapy for

4-6 courses (same schedule as pre-

operatively)

Patients with unresectable

liver metastases +/- extrahepatic disease

ERBITUX +

CPT-FFL ~ (n=43)

for 4-6 courses

8 cycles (~4 months)

Technically resectable

Primary endpoint: Response rate

4 further treatment

cycles

RESECTION

Technically unresectable

Started December 2004

Table 1. Patient characteristics at baseline

Number of patients

%

Entire population 43 100

Median (range) age, years 61 (33-75)

Male/female 27/16 63/37

Colon/rectum 34/9 79/21

Primary tumor resected 39 90

Synchronous Metastases 35 81

Liver involvement > 25% 34 79

Unresectability

Size > 5 cm 9 21

Multinodular > 4 29 68

Hilar location 1 2

Extrahepatic disease 4 9

Median (range) CEA, ng/ml 55 (1-6600)

Median (range) CA19-9, U/l 92 (2-66440)

EGFR (extent of staining)

0

1

2

3

8

4

18

5

23

11

52

14

KRAS wild-type/mutanta 30/7 81/19

an=37

CA 19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; EGFR, epidermal growth factor receptor.

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)

Table 2. Major grade 2-4 toxicities before and after dose reductions

Patients experiencing toxicity (%)

Type of toxicity Grade Before dose

reduction

After dose

reduction

P

value

Diarrhea 2

3

4

6

81

13

26

35

1

ns

0.005

0.006

Abdominal pain

2

3

4

31

2

0

25

7

0

ns

0.05

ns

Fatigue 2

3

4

43

8

2

37

12

0

ns

ns

ns

Nausea/vomiting 2

3

4

50

12

1

44

10

0

ns

ns

ns

Afebrile neutropenia 2

3

12

7

7

6

ns

ns

Cutaneous rash 2

3

50

20

66

15

ns

ns

Ns, not significant.

Table 3. Chemotherapy trials of neoajuvant chemotherapy for colorectal cancer liver metastases

Schedule Selected patients

N° of patients

RR (%)

R0 resection (%)

Cetuximab plus doublets

Cetuximab+FOLFIRI Van Cutsem E, JCO 2009

No 132 46.9 4.8

Cetuximab+FOLFOX4 Bokemeyer C, JCO 2009

No 169 46.0 4.7

Cetuximab+FOLFOX or FOLFIRI Folprecht G, Lancet Oncol 2010

Yes 111 85.0 (Oxa)-66.0 (CPT)

34

Triplets

FOLFOXIRI Falcone A, JCO 2007

No 39 66 36

FOLFOXIRI De la Cámara J, JCO 2004

Yes 39 64 43

FOLFOXIRI Ychou M, Canc Chem Pharm 2008

Yes 34 70 26

Monoclonal antibody plus triplets

Cetximab+chronoIFLO Garufi C et al (present study)

Yes 43 79.1 60

Bevacizumab+FOLFOXIRI Masi G, Lancet Oncol 2010

No 30 80 40

RR: response rate R0 resection: radical resection

Patient with colorectal liver metastases±

primary tumor

BEV ACIZUMAB+Capecitabine

+ L-OHP:

ORR = 78%

Surgery:-Resection rate 40%in pts with

metachronous mets

- Reasection rate 67% in pts with

synchronous mets

Bevacizumab + CAPOX

ESMO 2006Wong R et al, Ann oncol 2011

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)

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

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 l’approccio ottimale per la difficoltà a comparare studi di chemioterapia neoadiuvante sistemica e intra-arteriosa epatica (eterogeneità): necessità di studi randomizzati

Pazienti: 44pre-CPT-11 ev: 70% HAI+ SYS OXAL –5-FAFURR: 82%Resect: 20-36%

Terapia sistemica + Terapia Locoregionale

Leonard GD, et al. ASCO ’04 abs 3542

LIVER DAMAGE

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 <30% epatociti, moderata 30-60% epatociti e severa >60% epatociti)

Oxaliplatino= danno vascolare CPT-11= steatoepatite

Vascular hepatic damage

Aloia T et al., JCO 2006

Complete response to chemotherapy

Benoist S, JCO 2006

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

KL, nata in Ucraina il 17.04.1972,Anam Fam: negativaAnam. Fisiol: 3 gravidanzeAnam 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

KL TC pre terapia: 1.9.2009

KL TC pre terapia: 2.9.2009

KL PET/TC pre terapia: 11.9.2009

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 >80% su T ed M

Chronomodulated delivery scheme(5d on/16d off or 4d on/10d off)

Time (clock hour)10:00 16:00 22:00 04:00 10:00

Flo

wra

te (

arb.

Uni

ts)

5-FU(600-1100 mg/m²/d)

LV(300 mg/m²/d)

L-OHP(25 mg/m²/d)

CPT-11 110 mg/m2day 1

peak 13:00

Cetuximab 400-250 mg/m2 day1

C. Garufi et al Br J Cancer 2010

Ecoendo: 11.11.2010 risposta dopo 4 cicli di chrono-IFLO

TC: 23.11.2010 risposta dopo 4 cicli di chrono-IFLO

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

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”

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

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

• 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 el’organizzazione 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”

Neoplasia del retto con metastasi epatiche : KL n 17.4.1972

KL, nata in Ucraina il 17.04.1972

TC 6.8.2010

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

Neoplasia del retto con metastasi epatiche : KL n 17.4.1972