Transcript Liver directed therapy – when and how? V. Heinemann

Liver directed therapy
– when and how?
V. Heinemann
Department 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.
Scenarios for Locoregional Therapy
Group 1
Group 2
Group 3
primarily
resectable
metastases
2a
potentially
resectable
metastasen
probably
never resectable
2b:
symtomatic,
rapidly progressive
+ limited extrahepatic metastais
asymptomatic
slowly
progressing
Multidisciplinary Decision Making
Surgery
Staging
CT
MRT
US
Multidisciplinary
tumor board (TB)
Conversion
chemotherapy
PET
Locoregional
treatment
Palliative
chemotherapy
TB
Secondary
Surgery
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 Resection
Patients with solitary colorectal liver metastases
Analysis of a prospective database
OS
DFS
Local recurrence-free
Resection
Resection
Resection
RFA
RFA
RFA
Message: RFA clearly inferior to resection
Aloia TA, et al. Arch Surg 2006
Gravante G, et al. J Gastrointest Surg 2011
Wu Y-Z, et al. World J Gastroenterol 2011
Retrospective review of patients after
laparoscopic RFA
technically resectable vs non-resectable
5-year survival of resectable
patients 48.7%
Hammill CW, et al. Surgical Oncology 2011
OS
PFS
n=226
Liver mets < 3cm
OS
PFS
n=70
Liver mets > 3cm
EORTC Phase II
Systemic Chemo +/- RFA in non-resectable pts
PFS
• 1st randomized study on the
efficacy of RFA
+ RFA
• 119 patients randomized
• Chemo: FOLFOX4 over 6 months
• primary endpoint: 30-mo OS >38%
for the combined group
OS
+ RFA
Chemo
Chemo + RFA
PFS (mo)
9.9
16.8
OS (mo)
40.5
45.3
30-mo-OS (%)
58
62
Ruers T, et al. Ann Oncol 2012
Limitation of RFA
High risk of biliary injury in the demarcated area
Hammill CW, et al. Surgical Oncology 2011
Radiotherapy
 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
Stereotactic Body Radiation (SBRT)
 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
Van der Pool AEM, Br J Surg 2010
Robotic Radiosurgery vs RFA: Local DFS
matched pairs analysis of 60 mCRC patients with unresectable liver metastasis
RFA
RRS
12-mo local DFS
64%
85%
24-mo local DFS
60%
80%
Median follow-up 20.1 (RRS) and 24.6 months (RFA)
Stinzing S, et al. WCGIC, PD0021
How to Treat Recurrent Hepatic Metastases
after Partial Hepatectomy ?
 Risk of hepatic recurrence >60%
 Surgery remains the first choice of treatment
 RFA or Radiation: small liver remnant, small central lesion
Clinical study
 51 pts with hepatic recurrence
 70% surgery; 20% RFA; 10% radiation
 5-year OS 35%
 Morbidity 16%, mortality 0%
Van der Pool AEM, et al. J Gastrointest Surg 13: 890, 2009
Treatment Algorithm for Recurrent Hepatic Metastases
After Hepatic Resection
Recurrent liver metastases
Disease-free interval < 6 months
Disease-free interval > 6 months
CTx
Small liver remnant
Van der Pool AEM J Gastrointest Surg 2009
Yes
No
Metastases nearby
biliary ducts/vessels
resection
Yes
No
SRx
RFA
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
Meta-Analysis of HAI
in non resectable Liver metastasis
Overall survival: HAI versus systemic Chemotherapy
Mocellin S, et al. JCO 25: 5649, 2007
Conclusion
Currently available evidence does not support the clinical or investigational
use of fluoropyrimidine-based HAI alone for the treatment of patients with
unresectable CRC liver metastases, at least as a first-line therapy.
TACE with Irinotecan Loaded Beads
(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 FOLFIRI
after 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; #588
see 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-FU vs 5-FU in mCRC Salvage Therapy
TTP in the liver: primary endpoint
Hendlisz A, et al. J Clin Oncol 2010
SIRT + Chemotherapy
1st line
van Hazel 2004
Sharma 2007
SIRT + 5FU/FA
90%
18.6 mo
29.4 mo
5FUFA
0%
3.6 mo
12.8 mo
SIRT + FOLFOX4
90%
9.3
nr
Treatment
ORR
TTP/PFS
Survival
21
20
2nd-line or 3rd line
Investigator
n
Lim 2005
30
SIRT (+ 5FU)70%
33%
5.3 mo
nr
van Hazel 2009
25
SIRT + irinotecan
48%
6.0 mo
12.2 mo
Lim L, et al. BMC Cancer 2005
Van Hazel et al. J Clin Oncol 2009
Integration of SIRT into the Algorithm of
mCRC-Therapy
Resection
Tumor
resectable?
Liver-dominant
metastasis
10–20%
<20%
1st-line chemotherapy
+ SIRT
2nd-line chemotherapy
+ SIRT
nth-line chemotherapy
+ SIRT
SIRT
SIRT
chemo-refractory?
supportive therapy?
SIRT
Kennedy AS et al. ICACT 2008.
1st-Line SIRT + FOLFOX: Randomised Study
 SIRFLOX Study – International, multicentre RCT (n=518)
 FOXFIRE Study – UK, multicentre RCT
 Planned combined analysis
SIRFLOX and FOXFIRE study design
Recruit:
Stratification:
nonresectable
liverdominant
mCRC
• extrahepatic
metastasis
• extent of liver
involvement
• bevacizumab use
• Institution
R
A
N
D
O
M
I
Z
E
FOLFOXm (+Bev)
PFS = primary endpoint
FOLFOXm (+Bev) + SIRT
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
Treatment algorithm for liver directed therapy
Diagnosis of mCRC
Multidisciplinary tumor board (TB)
R0-resection possible
R0-resection not likely
no contraindications
contraindications
conversion
therapy
resection
RFA / RS
TB
resection
RFA / RS
not resectable, disseminated disease
liver-dominant
metastasis
multi-organ
metastasis
systemic
chemotherapy
systemic
chemotherapy
resection
intra-arterial
salvage therapy
• SIRT
• DEB-TACE
• HAI