Liver directed therapy

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Liver directed therapy when and how?
V. Heinemann Department of Oncology and
Comprehensive Cancer Center University of Munich,
Germany
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resection or ablation (either alone or in
combination with resection) should be reserved
for patients with disease that is completely
amenable to local therapy.
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Scenarios for Locoregional Therapy
Group 3
Group 1
Group 2
2a potentially resectable metastasen 2b
symtomatic, rapidly progressive
probably never resectable asymptomatic slowlyp
rogressing
primarily resectable metastases
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Multidisciplinary Decision Making
Surgery
Staging CT MRT US PET
Multidisciplinary tumor board (TB)
Secon- dary Surgery
Conversionchemotherapy
TB
Locoregional treatment
Palliative chemotherapy
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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

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RFA versus Resection
Patients with solitary colorectal liver
metastases Analysis of a prospective database
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
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Retrospective review of patients after
laparoscopic RFAtechnically resectable vs
non-resectable
5-year survival of resectable patients 48.7
Hammill CW, et al. Surgical Oncology 2011
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OS
PFS
n226 Liver mets lt 3cm
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n70 Liver mets gt 3cm
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EORTC Phase II Systemic Chemo /- RFA in
non-resectable pts
PFS

• 1st randomized study on the efficacy of RFA
• 119 patients randomized
• Chemo FOLFOX4 over 6 months
• primary endpoint 30-mo OS gt38 for the combined
  group

RFA
OS
Chemo Chemo RFA
PFS (mo) 9.9 16.8
OS (mo) 40.5 45.3
30-mo-OS () 58 62
RFA
Ruers T, et al. Ann Oncol 2012
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Limitation of RFA
High risk of biliary injury in the demarcated
area
Hammill CW, et al. Surgical Oncology 2011
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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
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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
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Robotic Radiosurgery vs RFA Local DFSmatched
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
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How to Treat Recurrent Hepatic Metastasesafter
Partial Hepatectomy ?

• Risk of hepatic recurrence gt60
• 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
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Treatment Algorithm for Recurrent Hepatic
MetastasesAfter Hepatic Resection
Recurrent liver metastases
Disease-free interval gt 6 months
Disease-free interval lt 6 months
CTx
Small liver remnant
Yes
No
resection
Metastases nearbybiliary ducts/vessels
Yes
No
SRx
RFA
Van der Pool AEM J Gastrointest Surg 2009
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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

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Meta-Analysis of HAI in non resectable Liver
metastasis
Overall survival HAI versus systemic
Chemotherapy
Mocellin S, et al. JCO 25 5649, 2007
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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.
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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
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DEBIRI-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 588 see also
Anticancer Res 2012
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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)

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SIRT 5-FU vs 5-FU in mCRC Salvage Therapy TTP
in the liver primary endpoint
Hendlisz A, et al. J Clin Oncol 2010
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SIRT Chemotherapy
1st line
van Hazel 2004 21 SIRT 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
2nd-line or 3rd 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
Lim L, et al. BMC Cancer 2005 Van Hazel et al. J
Clin Oncol 2009
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Integration of SIRT into the Algorithm of
mCRC-Therapy
Liver-dominant metastasis
Tumor resectable?
Resection
1020
Kennedy AS et al. ICACT 2008.
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1st-Line SIRT FOLFOX Randomised Study

• SIRFLOX Study International, multicentre RCT
  (n518)
• FOXFIRE Study UK, multicentre RCT
• Planned combined analysis

SIRFLOX and FOXFIRE study design
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)
PFS primary endpoint
FOLFOXm (Bev) SIRT
Bevacizumab not started unti cycle 4
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SIRFLOX Trial

• Limited extrahepatic metastasis of the lung
  and/or lymph nodes
• up to five small pulmonary metastases (lt1cm)
• one single pulmonary lesion (1.7cm)
• involvement of lymph nodes in one single anatomic
  area (lt2cm)

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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

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Treatment algorithm for liver directed therapy
Diagnosis of mCRC
Multidisciplinary tumor board (TB)
not resectable, disseminated disease
R0-resection possible
R0-resection not likely
no contra- indications
contra- indications
conversiontherapy
multi-organ metastasis
liver-dominant metastasis
resection
RFA / RS
RFA / RS
TB
systemicchemotherapy
systemic chemotherapy
resection
resection
intra-arterialsalvage therapy

• SIRT
• DEB-TACE
• HAI