Liver directed therapy

– when and how?

V. HeinemannDepartment of Oncology and Comprehensive Cancer Center

University of Munich, Germany

…resection or ablation (either alone or in combination

with resection) should be reserved for patients with

disease that is completely amenable to local therapy.

Group 3Group 3Group 1Group 1

Scenarios for Locoregional TherapyScenarios for Locoregional Therapy

Group 2Group 2

probably never resectable

asymptomaticslowly

progressing

primarilyresectablemetastases

2apotentiallyresectablemetastasen

2b: symtomatic,

rapidly progressive

+ limited extrahepatic metastais

Multidisciplinary Decision MakingMultidisciplinary Decision Making

Staging

CT

MRT

US

PET

Surgery

Locoregional

treatment

Multidisciplinary

tumor board (TB)Conversion

chemotherapy

Secon-dary

Surgery

Palliative

chemotherapy

TB

Indications for a Non-Surgical Approach

Comorbidity

Size or location of metastatic lesion

Inadequate volume of liver after surgery

Combination with surgery in bilobar or extrahepatic disease

Early recurrence with small lesions after resection

Patient wish

RFA versus ResectionRFA versus Resection

Aloia TA, et al. Arch Surg 2006Gravante G, et al. J Gastrointest Surg 2011Wu Y-Z, et al. World J Gastroenterol 2011

Patients with solitary colorectal liver metastasesAnalysis of a prospective database

RFA RFA

RFA

Resection

Resection

Resection

OS DFS Local recurrence-free

Message: RFA clearly inferior to resection

Hammill CW, et al. Surgical Oncology 2011

Retrospective review of patients after laparoscopic RFAtechnically resectable vs non-resectable

5-year survival of resectable patients 48.7%

n=226Liver mets < 3cm

n=226Liver mets < 3cm

OSOS PFSPFS

OSOS PFSPFS

n=70Liver mets > 3cm

n=70Liver mets > 3cm

EORTC Phase IIEORTC Phase II Systemic Chemo +/- RFA in non-resectable ptsSystemic Chemo +/- RFA in non-resectable pts

• 1st randomized study on the efficacy of RFA

• 119 patients randomized

• Chemo: FOLFOX4 over 6 months

• primary endpoint: 30-mo OS >38% for the combined group

Ruers T, et al. Ann Oncol 2012

PFS

OS

+ RFA

+ RFA

Chemo Chemo + RFA

PFS (mo) 9.9 16.8

OS (mo) 40.5 45.3

30-mo-OS (%) 58 62

High risk of biliary injury in the demarcated area

Limitation of RFALimitation of RFA

Hammill CW, et al. Surgical Oncology 2011

RadiotherapyRadiotherapy Very limited database (mostly cohort studies)

Recommendation only in selected cases where surgery is not an option:

– 3D conformal radiation

– stereotactic body radiosurgery (SBRT)

– intensity modulated radiotherapy (IMRT)

– robotic radiosurgery (RRS)

Possible– 1-3 metastases

– maximum lesion size (3-6cm) depends on method used

– dose: 1 x 20-26 Gy; 3 x 12.5 Gy etc.

Van der Pool AEM, Br J Surg 2010

Advantages over RFA

– Proximity to large vessels not limiting(no heat-sink effect)

– Heat injury of major bile ducts not limiting

– Treatment of central lesions possible

Disadvantages

– Less feasible for treatment of multiple lesions

– Cost

Stereotactic Body Radiation (SBRT)Stereotactic Body Radiation (SBRT)

Van der Pool AEM, Br J Surg 2010

Robotic Radiosurgery vs RFA: Local DFSRobotic Radiosurgery vs RFA: Local DFSmatched pairs analysis of 60 mCRC patients with unresectable liver metastasismatched pairs analysis of 60 mCRC patients with unresectable liver metastasis

Stinzing S, et al. WCGIC, PD0021

Median follow-up 20.1 (RRS) and 24.6 months (RFA)

RFA RRS

12-mo local DFS 64% 85%

24-mo local DFS 60% 80%

How to Treat Recurrent Hepatic Metastasesafter Partial Hepatectomy ?

Risk of hepatic recurrence >60%

Surgery remains the first choice of treatment

RFA or Radiation: small liver remnant, small central lesion

Van der Pool AEM, et al. J Gastrointest Surg 13: 890, 2009

51 pts with hepatic recurrence 70% surgery; 20% RFA; 10% radiation 5-year OS 35% Morbidity 16%, mortality 0%

Clinical study

Treatment Algorithm for Recurrent Hepatic Metastases

After Hepatic Resection

Recurrent liver metastases

Recurrent liver metastases

Disease-free interval < 6 months

Disease-free interval < 6 months

Disease-free interval > 6 months

Disease-free interval > 6 months

CTxCTxCTxCTx Small liver remnant

Small liver remnant

YesYesYesYes NoNoNoNo

resection

resection

Metastases nearbybiliary ducts/vesselsMetastases nearby

biliary ducts/vessels

YesYesYesYes

SRxSRxSRxSRx

NoNoNoNo

RFARFARFARFAVan der Pool AEM J Gastrointest Surg 2009

Intraarterial Hepatic Therapy

Options hepatic arterial infusion (HAI)

drug-eluting beads (DEB-TACE)

radioembolization (SIRT)

Contraindications

poor liver function

hyperbilirubinemia

portal occlusion

extensive extrahepatic disease

Mocellin S, et al. JCO 25: 5649, 2007

Overall survival: HAI versus systemic Chemotherapy Overall survival: HAI versus systemic Chemotherapy

Meta-Analysis of HAI in non resectable Liver metastasis

ConclusionCurrently available evidence Currently available evidence does not supportdoes not support the clinical or investigational the clinical or investigational

use of fluoropyrimidine-based HAI alone for the treatment of patients with use of fluoropyrimidine-based HAI alone for the treatment of patients with

unresectable CRC liver metastases, unresectable CRC liver metastases, at least as a first-line therapyat least as a first-line therapy..

TACE with Irinotecan Loaded Beads TACE with Irinotecan Loaded Beads (DEBIRI)(DEBIRI)

Open label study of mCRC pts with LLD after failure of standard therapy

N = 55

DEBIRI (drug-eluting beads: irinotecan)

Median irinotecan dose 100 mg (range 100-200 mg)

Median number of total treatments: 2 (range 1-5)

Lack of biliary toxicity

ORR: 65% at 3 mo DFS: 11 months OS: 19 months

Martin RCG, et al. Ann Surg Oncol 2011

DEBIRI-TACE vs FOLFIRIDEBIRI-TACE vs FOLFIRIafter failure of at least 2 lines of chemotherapy

DEBIRI-TACE FOLFIRI syst

n 36 38

ORR 70% 20%

PFS 7.5 mo 3.1 mo

OS 23 mo 16 mo

2-year OS 38% 18%

DEBIRI: 2 courses of TACE at 1 month intervals

FOLFIRI: 8 courses iv at 2-wk intervals

Fiorentini G, et al. ESMO 2010; #588see also Anticancer Res 2012

Radioembolization (SIRT)

Yttrium-90 labelled microspheres

– mean diameter 32 µm

– beta 0.93 MeV

– half life of activity: 2.7 days

– mean tissue penetration 2.5 mm

– radiation dose in tumor 100-1,000+ Gy

– dose: 1.2-2.4 GBq (according to shunt)

SIRT + 5-FUSIRT + 5-FU vs 5-FU in mCRC Salvage Therapy vs 5-FU in mCRC Salvage Therapy TTP in the liver: primary endpoint

Hendlisz A, et al. J Clin Oncol 2010

SIRT + ChemotherapySIRT + Chemotherapy

Lim L, et al. BMC Cancer 2005

Van Hazel et al. J Clin Oncol 2009

van Hazel 2004 21SIRT + 5FU/FA

5FUFA

90%

0%

18.6 mo

3.6 mo

29.4 mo

12.8 mo

Sharma 2007 20 SIRT + FOLFOX4 90% 9.3 nr

1st line1st line

Investigator n Treatment ORR TTP/PFS Survival

Lim 2005 30 SIRT (+ 5FU)70% 33% 5.3 mo nr

van Hazel 2009 25 SIRT + irinotecan 48% 6.0 mo 12.2 mo

2nd-line or 3rd line2nd-line or 3rd line

Liver-dominant metastasis

Tumor resectable?Resection

10–20%

chemo-refractory?

1st-line chemotherapy

2nd-line chemotherapy

nth-line chemotherapy

<20%

Integration of SIRT into the Algorithm of mCRC-Therapy

Kennedy AS et al. ICACT 2008.

+ SIRT

+ SIRT

+ SIRT

SIRT

SIRT

SIRTsupportive therapy?

1st-Line SIRT + FOLFOX: Randomised Study

SIRFLOX Study – International, multicentre RCT (n=518)

FOXFIRE Study – UK, multicentre RCT

Planned combined analysis

Recruit:

non-resectable liver-dominant mCRC

Stratification:

•extrahepatic metastasis

•extent of liver involvement

•bevacizumab use

• Institution

R

A

N

D

O

M

I

Z

E

FOLFOXm (+Bev)

FOLFOXm (+Bev) + SIRT

SIRFLOX and FOXFIRE study design

PFS = primary endpoint

Bevacizumab not started unti cycle 4

SIRFLOX Trial

Limited extrahepatic metastasis of the lung and/or lymph nodes

– up to five small pulmonary metastases (<1cm)

– one single pulmonary lesion (≤1.7cm)

– involvement of lymph nodes in one single anatomic area (<2cm)

Conclusions

Primary Surgery remains the standard in resectable disease

Conversion chemotherapy is the treatment of choice in potentially resectable disease (group II)

RFA may be an alternative to resection in pts with solitary small lesions

Radiation is a promising approach, but requires more data

Hepatic arterial treatment with DEB-TACE or SIRT represent options for salvage therapy in experienced centres

Diagnosis of mCRC

Diagnosis of mCRC

Multidisciplinary tumor board (TB)Multidisciplinary tumor board (TB)

R0-resection possible

R0-resection possible

no contra-indication

s

no contra-indication

s

resectionresection

contra-indication

s

contra-indication

s

RFA / RSRFA / RS

R0-resection not likely

R0-resection not likely

conversion

therapy

conversion

therapy

TBTB

resectionresection

not resectable, disseminated disease

not resectable, disseminated disease

systemicchemotherapy

systemicchemotherapy

multi-organ metastasismulti-organ metastasis

liver-dominant metastasis

liver-dominant metastasis

systemic chemotherapy

systemic chemotherapy

resectionresection

RFA / RSRFA / RS

•SIRT•DEB-TACE•HAI

Treatment algorithm for liver directed therapy

intra-arterialsalvage therapy