Clinical determinants of our choices

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Clinical determinants of our choices
TUMOR
PATIENT
TREATMENT
BIOMARKER
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The MDT meeting
Surgery
Pathology
Interventional Radiology
Oncology
Radiology
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LIVERMETSURVEY SURVIVAL AFTER LIVER RESECTION
Dec 2008 9289 Pts - 147 Centers - 40 countries

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8771 Resected Pts
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518 non Resected
www.livermetsurvey.org
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• 5FU
• 5FU LCV
• CI 5-FU
• Xeloda,
• Irinotecan (cpt-11)
• Oxaliplatin
• Bevacizumab (Avastin)
• Afliberceft(Zaltrap)
• Panitumumab(Vectibics)
• Cetuximab (Erbitux)
• Regorafenib

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Treatment options

• Combination Chemotherapy
• FOLFOX
• FLOX
• FOLFIRI
• FOLFOXIRI
• XELOX
• XELIRI

• Targeted Therapy
• Bevacizumab
• Cetuximab
• Panitumumab
• Afliberceft
• Regorafenib

Single agent

• 5-FU/LV or capecitabine
• Irinotecan
• oxaliplatin

NCCN. Clinical practice guidelines in oncology
colon cancer. 2011.
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Pre-operative chemotherapy monoclonal antibodies
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Survival after chemotherapy plus surgery for
metastases
Resectable liver metastases Resectable after
chemotherapy FOLFIRI/FOLFOX6 FOLFOX6/FOLFIRI 5-FU
BSC
100
80
60
48
Survival ()
40
30
33
20
23
0
1
4
2
5
6
7
10
3
8
9
Time (years)
BSC best supportive care
Colon Cancer Collaborative Group. Br Med J
2000321521522 Tournigand C, et al. J Clin
Oncol 200422229237 Adam R, et al. Ann Surg
2004240644658
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  400-500 KHZ
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Concept of Selective Internal Radiation Therapy
(SIRT)(aka Radioembolization Hepatic Artery
Brachytherapy Microbrachytherapy )

• To selectively target a very high radiation dose
  to all tumours within the liverUses
  90Yttrium-labelled microspheres (SIR-Spheres
  TheraSphere)
• Diameter approx. 30 µm (microns)
• Half life 64 hours
• Beta 0.93 MeV
• Penetrates mean 2.5 mm tissue max 11 mm
• Achieves doses of 1001,000 Gy to tumour

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Liver Tolerance - Radiation
RILD Radiation induced Liver Disease Hepatitis
25 Gy
35 Gy
70-90 Gy
50 Gy
Curative Dose adenocarcinoma
Effectived Dose Hoden Ca, Lymphoma, Myeloma
Pre-operative radiation rectum Ca
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Progress in Metastatic Colon Ca

• 1995
• Monotherapy
• RR 20 (PR)
• TTP 5-6 mo
• OS 10-12 mo
• Single line

• 2014
• Polychemotherapy
• RR 60 (PR)
• TTP 11 mo
• OS over 30 mo
• Multiple line

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• 5FU
• 5FU LCV
• CI 5-FU
• Xeloda,
• Irinotecan (cpt-11)
• Oxaliplatin
• Bevacizumab (Avastin)
• Afliberceft(Zaltrap)
• Panitumumab(Vectibics)
• Cetuximab (Erbitux)
• Regorafenib

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Improved survival in metastatic colorectal cancer
is associated With adoption of hepatic resection
and improved chemotherapy

• Retrospective analysis of newly metastatic
  colorectal patients in two academic centers from
  1990 2006.
• 2470 patients were included in the analysis.
• Median overall survival for patients diagnosed
  from
• 1990 --1997 was 14.2 months
• 1998 2000 18 months
• 2001 2003 18.6 months
• 2004 2006 29.3 months

JCO 2009, Kopetz S et al.
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• Ligand level e.g. bevacizumab a humanized
  monoclonal antibody that binds to VEGF-A and
  prevents interaction between VEGF-A and VEGFR
• Receptor level extra-cellular e.g. ramucirumab,
  a fully humanized monoclonal antibody against
  VEGFR-2.
• Receptor level intra-cellular e.g. Sunitinib and
  regorafenib, binds to the intracellular kinase
  domain of the receptor and interfere with its
  tyrosine kinase activity

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EGFR inhibitor-induced rash
Pictures provided by S Segaert and E Van Cutsem
(Leuven, Belgium).
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• Biomarkers

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Key cancer biomarkers in patient care
Clinical biomarker use Clinical objective
Screening Detect and treat early stage cancers in the asymptomatic population1
Diagnostic Definitively establish the presence of cancer1
Prognostic Predict the probable outcome of cancer regardless of therapy1
Predictive Predict treatment safety and/or efficacy outcome2

• 1. Committee on Developing Biomarker-Based Tools
  for Cancer Screening Diagnosis
• and Treatment. Washington, D.C. The National
  Academic Press 2007
• 2. Heinemann V, et al. Cancer Treat Rev 2013
  39592-601.

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Biomarker-guided treatment has the potential to
improve clinical outcomes
Concentrate therapeutic interventions on patients
likely to benefit
Efficacy
Predictivebiomarkers
Spare potential sideeffects in patientsnot
likely to benefit
Safety
Efficiency
Spare expense in patientsnot likely to benefit

• Conley BA, Taube SE. Dis Markers 20042035?43
• Kelloff GJ, Sigman CC. Eur J Cancer
  200541491?501
• Presidents Council of Advisors on Science and
  Technology (PCAST) Priorities for Personalized
  Medicine September 2008
• Heinemann V, et al. Cancer Treat Rev 2013
  39592-601.

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Examples of predictive biomarkers in oncology
Tumour type Biomarker Drug
Breast cancer HER-2 overexpression Trastuzumab1, lapatinib2
Gastric cancer HER-2 overexpression Trastuzumab1
CML BCR/ABL fusion gene Imatinib3
GIST c-KIT mutation Imatinib3
NSCLC EGFR mutation Gefitinib4, erlotinib5
mCRC RAS mutation status Panitumumab6
KRAS mutation status Cetuximab7
Melanoma BRAF V600 Vemurafenib8
NSCLC ALK positive Crizotinib9
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Distribution of mutations in mCRC
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40
HR 1
60
HR 0.4-0.7
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CRYSTAL OS with cetuximab FOLFIRI vs FOLFIRI
1.0
Cetuximab FOLFIRI (n599)
Overall patient population
FOLFIRI (n599)
0.8
0.6
19.9
HR 0.88 p0.0419
OS estimate
18.6
0.4
0.2
0.0
54
42
48
18
0
6
12
24
30
36
Months
KRAS exon 2 wt population (63)
Cetuximab FOLFIRI (n316)
FOLFIRI (n350)
OS estimate

• 1. Van Cutsem E, et al. J Clin Oncol
  201129201120192. Erbitux SmPC June/2014

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Cetuximab FOLFIRI (n316)
1.0
FOLFIRI (n350)
KRAS exon 2 wt population1
0.8
HR 0.80 p0.0093
23.5
0.6
OS estimate
20.0
0.4
0.2
0.0
54
42
48
18
0
6
12
24
30
36
Months
Cetuximab FOLFIRI (n178)
RAS wt population (85)2,3
FOLFIRI (n189)
HR 0.69 p0.0024
28.4
OS estimate
20.2
54
42
48
18
0
6
12
24
30
36
Months
1. Van Cutsem E, et al. J Clin Oncol
20112920112019 2. Ciardiello F et al. J Clin
Oncol 325s, 2014 (suppl abstr 3506) 3. Van
Cutsem E, et al. Ann Oncol 201425(suppl
2)ii113 4. Erbitux SmPC June/2014
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CALGB/SWOG 80405 OS (RAS wt)FOLFOX/FOLFIRI
subgroup analysis
FOLFOX treated
FOLFIRI treated
Cetuximab FOLFIRI (n72) Bevacizumab
FOLFIRI (n64)
Cetuximab mFOLFOX6 (n198) Bevacizumab
mFOLFOX6 (n192)
HR 0.86 (95 CI 0.61.1)p0.20
Lenz HJ, et al. Ann Oncol 201425 (suppl 4)
(Abstract 5010), updated information presented
at meeting
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