This slide deck has been created for clinician use in creating presentations detailing Colorectal Cancer Liver Metastases, the Selective Internal Radiation Therapy (SIRT) procedure available to treat this condition, supported by the clinical data that supports this treatment and and ongoing RCT trials to further document the success of this treatment. This information maybe used in its entirety or in sections, according to the material being presented and the audience to which it will be used. The sections included in this slide deck are as follows: Colorectal Cancer Liver Metastases (mCRC) Overview Selective Internal Radiation Therapy (SIRT) Overview SIR-Spheres(r) microspheres Clinical Data in mCRC Ongoing Level 1 RCT for mCRC in the liver

1. 1
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2. Disclaimer
• The content and opinions presented in this activity are not meant to
serve as a guideline for patient management and do not necessarily
reflect the views of Sirtex Medical Limited.
• Healthcare professionals are encouraged to critically appraise the
information presented and are advised to consult appropriate
resources for clinical information surrounding disease management
and FDA-approved labeling for information about any product or
device discussed in this activity.
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3. Agenda
1. Colorectal Cancer Liver Metastases (mCRC): Overview
2. Selective Internal Radiation Therapy (SIRT): Overview
3. SIR-Spheres® microspheres: Clinical Data in mCRC
4. Ongoing Level 1 RCT for mCRC in the liver
SIR-Spheres® is a registered trademark of Sirtex SIR-Spheres Pty Ltd. 3
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4. Section I
Colorectal Cancer Liver Metastases
(mCRC): Overview
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5. Colorectal Cancer (CRC):
US Epidemiology
• Third most common cancer diagnosed in the US 1
– Estimated new cases in 2012 :1
– Colon: 103,170
– Rectal: 40,290
– Age-adjusted incidence: 46.3 per 100,000 persons/yr2
• Median age at diagnosis (2005-2009): 69 yrs2
• Prevalence (2009):
– ~ 1.1 million people were alive in the US with a history of CRC2
• 20% of subjects present with metastatic disease2
1. American Cancer Society. 2012. Cancer Facts & Figures (page 4). 5
2. NCI Cancer Topics Colon and Rectal Cancer. http://seer.cancer.gov/statfacts/html/colorect.html
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6. Colorectal Cancer:
US Mortality
• CRC is the second leading cause of all cancer deaths1
– 51,690 Estimated deaths in 2012:2
• CRC-related deaths have steadily declined over past 20
yrs1
– Due to improvements in screening, early detection, and
treatment
– 65% overall 5-yr relative survival3
1. American Cancer Society. 2011. Cancer Facts & Figures.
2. NCI Cancer Topics Colon and Rectal Cancer.
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3. SEER Stat Fact Sheets: Colon and Rectum. 582-U-0712

7. Colorectal Cancer: Stage Distribution
and 5-year Relative Survival at Diagnosis
(2001-2007)
Stage 5-year
Stage at
Definition Distribution Relative
diagnosis
(%) Survival (%)
Localized (confined to primary
Stage I/IIA/B/C 39 90.1
site)
Regional (spread to regional
Stage IIIA/B/C 37 69.2
lymph nodes)
Stage IV Distant (cancer has metastasized) 20 11.7
Unknown (unstaged) 5 33.3
1. SEER Stat Fact Sheets: Colon and Rectum, NCI PDQ Colon. 7
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8. mCRC liver metastases:
Treatment Options
• Surgery
– Cytoreduction or Resection
• 5 year survival goes from <15% to >50% following successful
resection but only 15% of patients present with resectable disease
• Ablation
• Systemic Chemotherapy
– Adjuvant, neoadjuvant, and palliative
• Targeted agents
– EGFR inhibitors
– VEGFR inhibitors
• Intra-arterial Therapies
– Selective Internal Radiation Therapy (SIRT) with Y-90
– Chemoembolization
• Clinical trials
1. NCCN. 2012. Clinical practice guidelines in oncology: colon cancer. 8
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9. Bulk Reduce Tumors:
Improvement in Survival
• Survival improvement has been shown in
ovarian cancer, hepatocellular cancer (HCC),
head-and-neck cancer (HNC) due to:1-4
– Removal of poorly vascularized areas, thereby
increasing chemotherapy exposure
– Removal of chemoresistant cells
– Reducing adverse metabolic consequences
– Enhancement of immune function after tumor debulking
1. Covens AL. Gynecol Oncol. 2000;78:269-274. 2. Thigpen T. N Engl J Med. 2004;351:2544-2546. 9
3. Wyse G, et al. Neuroimaging Clin N Am. 2009;19:161-168. 4. Atwell TD, et al. Cardiovasc Intervent Radiol. 2005;28:409-421.
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10. FDA-Approved Agents for mCRC
Adjuvant First-Line Refractory
Levamisole Leucovorin Irinotecan
(+ 5FU) (with 5FU) 1996
1990 1991 Oxaliplatin
Irinotecan (+ 5FU/LV)
(+ 5FU/LV; FOLFIRI) 2002
2000 Cetuximab*
Capecitabine 2004
2001 Panitumumab*
Oxaliplatin 2006
(+ 5FU/LV; FOLFOX) Aflibercept
2004 2012
Oxaliplatin
(+ capecitabine; XELOX)
2004
Regorafenib currently
Bevacizumab
2004 under Priority Review
Bevacizumab for refractory
(+ 5FU/LV, + FOLFIRI, + FOLFOX) disease
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* Benefit only demonstrated in KRAS wild type patients
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11. mCRC Systemic chemotherapy
Treatment Pathways1,2
First-line FOLFIRI + FOLFOX +
or
therapy bevacizumab bevacizumab
Second-line Irinotecan + Single-agent
FOLFOX or or FOLFIRI
therapy cetuximab irinotecan
Third-line Cetuximab +/- Cetuximab +/-
FOLFOX
therapy irinotecan irinotecan
1. Köhne C-H, Lenz H-J. Oncologist. 2009;14:5478-5488. 11
2. NCCN. 2011. Clinical practice guidelines in oncology: colon cancer. 582-U-0712

12. Survival Benefit of Systemic Chemotherapy
and Biological Combinations
1. Source: Venook et al The Oncologist 2005;10:250–261 12
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13. Section II
Selective Internal Radiation Therapy
(SIRT): Overview
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14. SIRT: Design Concept
• Selectively targets liver tumor cells with lethal
radiation dose
while at the same time
• Minimizing radiation exposure to the normal
liver parenchyma
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15. SIRT: Microsphere Delivery Concept
• SIRT takes advantage of the hepatic dual blood supply
• Normal liver parenchyma:
– Majority of blood supply from portal vein (A)
• Metastatic liver tumors:
– Majority of blood supply from hepatic artery (B)
B
A
1. Archer S, Gray BN. Br J Surg. 1989;76:545-548, LIV_MOA. 15
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16. SIRT: Delivery Procedure
Minimally invasive microcatheter therapy:
Transfemoral access (A) to the hepatic artery (B)
B
A
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17. SIRT: Brachytherapy Implantation
• Liver tumor vessel diameter: 25μm -75μm with end arteriole
diameter: 8μm
• Resin microspheres mean diameter: 32.5μm
• Microspheres are too large to pass through the capillary bed within
the tumor, where they become permanently implanted
1. Source: Andrew S. Kennedy, MD, Wake Radiology Oncology, Cary, NC. 17
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18. SIR-Spheres microspheres
 Biocompatible resin
 32.5μm average diameter
 Yttrium90 permanently bound
 Mean pure beta emission @
0.93MeV
 Half life 64.1 hours
 Penetration
– 2.5mm mean
– 11mm max
Scanning electron
micrograph
1. Data on file, Sirtex Medical Limited 18
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19. Section III
SIR-Spheres microspheres:
Clinical Data in mCRC
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20. The SIR-Spheres microspheres
Patient
• Non-resectable, liver only or liver dominant metastatic
colorectal cancer
• Progressed on first line chemotherapy
• Remaining chemotherapy / biological agent options
• Good performance status (PS <2)
• Adequate liver function (bilirubin <2 or stable)
• Expected survival >3 months
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21. SIR-Spheres microspheres in mCRC:
First-Line Treatment
Investigator n Treatment ORR TTP*/‡PFS Survival
Gray1 74 SIR-Spheres† + HAC 44% 15.9 mo* 39% at 2 yr
HAC (FUDR) 18% 9.7 mo* 29% at 2 yr
P=0.01 P=0.001 P=0.06
van Hazel2 21 SIR-Spheres† + 5FU/LV 91% 18.6 mo* 29.4 mo
5FU/LV 0% 3.6 mo* 12.8 mo
P<0.001 P<0.0005 HR 0.33; P=0.025
Sharma3 20 SIR-Spheres† + FOLFOX4 90% 9.2 mo‡ nr
14.2 mo‡L
*TTP; ‡ PFS; ‡ LPFS in the liver; nr: not reported ,† SIR-Spheres microspheres
1. Gray, et al. Ann Oncol. 2001;12:1711–1720.
2. van Hazel, et al. J Surg Oncol. 2004;88:78–85.
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3. Sharma, et al. J Clin Oncol. 2007;25:1099–1106. 582-U-0712

22. SIRT in First-Line Treatment of mCRC:
Objective Response Rate and Time to Progression
Objective Response Rate Time to Progression
100% 20.0 18.6
91% 90%
90% 18.0
15.9
80% 16.0
13.8
70% 14.0
60% 12.0
9.7 9.3
50% 44% 10.0
%
)
(
40% 8.0
30% 6.0
18% 3.6
20% 4.0
m
o
h
n
P
e
T
g
s
r
t
)
(
i
w
10% 2.0
R
o
b
p
h
n
P
C
e
T
a
E
y
S
s
t
I
i
0% -
FUDR ± 5FU/LV ± FOLFOX4 + FUDR ± 5FU/LV ± FOLFOX4 +
SIR-Spheres† SIR-Spheres† SIR-Spheres† SIR-Spheres† SIR-Spheres† SIR-Spheres†
(Gray et al., 2001) (van Hazel et al., 2004) (Sharma et al., 2007) (Gray et al., 2001) (van Hazel et al., 2004) (Sharma et al., 2007)
(n=74) (n=21) (n=20) (n=74) (n=21) (n=20)
†
SIR-Spheres microspheres
1. Gray, et al. Ann Oncol. 2001;12:1711–1720.
2. van Hazel, et al. J Surg Oncol. 2004;88:78–85.
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3. Sharma, et al. J Clin Oncol. 2007;25:1099–1106. 582-U-0712

23. SIR-Spheres microspheres in First-Line
Treatment : Cycles of Chemotherapy
received
Chemotherapy Cycles Administered
P = 0.03
9.0
8.1
8.0
7.0
6.0
5.0
4.0 3.8
3.0
M
m
N
o
b
u
n
e
a
r
f
2.0
m
A
o
h
n
d
p
C
e
a
y
c
s
r
t
i
l
1.0
0.0
5FU/LV 5FU/LV +
SIR-Spheres
Microspheres
1. van Hazel, et al. J Surg Oncol. 2004;88:78–85. 23
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24. SIR-Spheres microspheres in mCRC:
Second-Line Treatment
ORR: 33% ORR: 48%
14.0 SD: 27% SD: 39%
12.2
12.0
10.0 9.2
8.0
6.0
6.0 5.3
M
o
h
n
s
t
4.0
2.0
-
TTP PFS Liver PFS Survival
SIR-Spheres † SIR-Spheres †
+ 5FU/LV + irinotecan
Lim, et al. (n=30) van Hazel, et al. (n=25)
†
SIR-Spheres microspheres
1. Lim, et al. BMC Cancer. 2005;5:132. 24
2. van Hazel, et al. J Clin Oncol. 2009;27:4089–4095. 582-U-0712

25. SIR-Spheres microspheres in mCRC:
Salvage Therapy
Investigator n Treatment ORR SD TTP/PFS Survival
◊
Hendlisz1 4444 SIR-Spheres† + 5FU 10% 76% 5.5 /4.5 mo 10.0 mo
5FU > salvage with 0% 35% 2.1 mo 7.3 mo
SIR-Spheres at PD P=0.001 HR 0.38◊/0.51;
P=0.003◊/P=0.03
Seidensticker2 2929SIR-Spheres† 41% 17% 5.5 mo 8.3 mo
29 best supportive care nr nr 2.1 mo 3.5 mo
(matched-pairs) HR 0.38; HR 0.26;
P<0.001 P<0.001
Cosimelli3 50 SIR-Spheres† 24% 24% 4 mo 12.6 mo
◊
time to liver progression (TTP); nr: not reported; † SIR-Spheres microspheres
1. Hendlisz, et al. J Clin Oncol. 2010;28:3687–694.
2. Seidensticker et al Cardiovasc Intervent RadiolDOI 10.1007/s00270-011-0234-7 – E-Pub. 25
3. Cosimelli, et al. Br J Cancer. 2010;103:324–331. 582-U-0712

26. SIR-Spheres microspheres + 5FU
Salvage Therapy: Study Design
Eligible Patients Stratify
Liver-only mCRC, •Institution
PS 0–2, refractory to •Interval to progression on chemotherapy
chemotherapy
Random Assignment
Arm A: Arm B:
90
Y resin microspheres
on Day 1 (D1) Cycle 1 (C1)
+
5FU protracted IV infusion (300 5FU protracted IV infusion (225
mg/m2 D1–14 q3w) mg/m2 D1–14 C1
and 300 mg/m2 D1–14
q3w thereafter)
until progression until progression
Eligible Patients
Liver-dominant mCRC, 90
Y resin microspheres
PS 0–2
1. Hendlisz, et al. J Clin Oncol. 2010;28:3687–3694. 26
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27. SIR-Spheres microspheres + 5FU Salvage
Therapy:
Time to Liver Progression
1. Adapted from: Hendlisz, et al. J Clin Oncol. 2010;28:3687–3694. 27
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28. SIR-Spheres microspheres
+ 5FU Salvage Therapy:
TTP and OS
5FU Alone 5FU + Hazard Ratio
SIR-Spheres† (95% CI)
n = 23 n = 21 P value
Median Time to 0.38 (0.20–0.72)
Liver Progression: 2.1 months 5.5 months P=0.003
TTLP censored to 0.35 (0.18–0.69)
change of Tx plan: 2.1 months 5.6 months P=0.002
Median Time to 0.51 (0.28–0.94)
Progression: 2.1 months 4.5 months P=0.03
Median Overall 0.92 (0.47–1.78)
Survival: 7.3 months *
10.0 months P=0.80
8.8 months
*
Note: 10 patients in the 5FU arm received SIR-Spheres microspheres as salvage therapy after disease progression which potentially
compromised the overall survival data
†
SIR-Spheres microspheres
28
1. Hendlisz, et al. J Clin Oncol. 2010;28:3687–3694.
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29. SIR-Spheres microspheres + 5FU Salvage
Therapy:
Adverse Events
Parameter 5FU Alone 5FU + SIR-Spheres microspheres
n = 23 n = 21
Grades 1–2 Grades 3–4 Grades 1–2 Grade 3–4
Gastrointestinal
Stomatitis 1 1 2 -
Nausea - - 5 -
Constipation 3 - - -
Anorexia 6 1 5 -
Pain
Abdominal pain 3 - 4 -
Myalgia 1 - 2 -
Constitutional
Fatigue 6 5 8 -
Dermatological/Skin 2 - - -
Hand-foot syndrome 2 - - 1
Pulmonary 1 2 - -
Other Toxicity 1† - 2‡ -
†
ascites; ‡ 1 with thrombocytopenia, 1 with stomach ulcer, ascites
1. Hendlisz A, et al. J Clin Oncol. 2010;28:3687–3694. 29
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30. Matched Pair SIRT in Chemotherapy
Refractory Liver-Dominant mCRC: Study
Design
Matched mCRC
pairs by prior SIR-Spheres† + BSC
treatment history
and
tumor burden +
liver involvement;
metastases;
ALP; CEA level BSC
(N=29 per arm)
• 1° end point: OS
• 2° end points: PFS, ORR, safety and tolerability
ALP=alkaline phosphatase; BSC=best supportive care; CEA= carcinoembryonic antigen.
*
Per investigator’s discretion starting at cycle 4 (treatment arm) or cycle 1 (control arm)
†
SIR-Spheres microspheres
1. Seidensticker R, Denecke T, Kraus P, et al. Cardiovasc Intervent Radiol. 2011; [Epub ahead of print]. 30
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31. Matched Pair SIRT in Chemotherapy
Refractory Liver-Dominant mCRC:
Overall Survival
1. Seidensticker R, Denecke T, Kraus P, et al. Cardiovasc Intervent Radiol. 2011; [Epub ahead of print]. 31
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32. Matched Pair SIRT in Chemotherapy
Refractory Liver-Dominant mCRC:
Study Conclusions
• Addition of radioembolization improved OS in
chemotherapy refractory liver-dominant mCRC patients
– Median 8.3 months vs. 3.5 months, (P <.001)
• Improved PFS in patients receiving radioembolization
– Median 5.5 months vs. 2.1 months
– Progression was defined as a clinically significant change in:
• Symptoms
OR • CEA levels
• Confirmed by radiological imaging
1. Seidensticker R, Denecke T, Kraus P, et al. Cardiovasc Intervent Radiol. 2011; [Epub ahead of print]. 32
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33. Matched Pair SIRT in Chemotherapy
Refractory Liver-Dominant mCRC:
Safety
• Adverse events following SIRT were predominately transient
and self-limiting, including:
– grade 1–2 fatigue (69%)
– grade 1 abdominal pain/nausea (48%)
– 3 patients developed grade 2 gastrointestinal ulcer, which were
managed medically
– 3 cases of grade 3 radiation-induced liver disease (RILD) were
medically managed and not life-threatening
1. Seidensticker R, Denecke T, Kraus P, et al. Cardiovasc Intervent Radiol. 2011; (Epub ahead of print) 33
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34. SIR-Spheres microspheres in mCRC:
Retrospective Data
Investigator n Treatment ORR SD TTP*/‡ PFS Survival
Kennedy1 176 SIR-Spheres microspheres 35.5%** 55% 7.2 mo* 10.5 mo
responders
31 non-responders/controls na na na 4.5 mo
HR 0.38; HR 0.26;
P<0.001 P<0.001
Bester2 224¥ SIR-Spheres microspheres nr nr nr 11.9 mo
29 best supportive care nr nr nr 6.6 mo
HR 0.50;
P=0.001
‡
PFS; *TTP; ‡L PFS in the liver; **L OS in the liver; nr: not reported, ¥: CRC cohort
1. Kennedy, et al. Int J Radiat Oncol Biol Phys. 2006;65:412–425. 2. Bester et al. J Vasc Inter Rad, 2011;23: 96-10. 34
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35. Multi-center Retrospective Responder
Analysis (Kennedy): Overall Survival
N Median Survival (95% CI)
Responders (PET) : 176 10.5 months
P=0.0001
Non-responders: 31 4.5 months
1. Kennedy, et al. Int J Radiat Oncol Biol Phys. 2006;65:412–425 35
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36. Comparative Retrospective Study (Bester):
Overall Survival
N Median Survival (95% CI)
SIR-Spheres microspheres : 224 11.9 months (10.1 –
P=0.001
14.9)
Standard Care: 29 6.6 months
Hazard Ratio: 0.50 (0.30 – 0.77)
75
50
25
0
0.3 0.4 0.5 0.6 0.7 0.8
Overall Survival ( Hazard Ratio
0 6 12 18 24 30 36
Time from receiving or potentially eligible for SIR-Spheres microspheres (months)
1. Bester et al. J Vasc Inter Rad, 2011;23: 96-105 36
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37. Adjuvant Care Parallel
for Non-resectable mCRC Liver Tumors
Similar
Level
of
Evidence
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38. Section IV
Ongoing Level 1 RCT for mCRC
in the liver
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39. SIRFLOX: Study Design
mCRC patients SIR-Spheres† (day 3-4/cycle 1) +
WHO PS 0-1 FOLFOX6m ± Bevacizumab*
All patients have
no prior
chemotherapy
unresectable liver
metastases
FOLFOX6m ± Bevacizumab*
(N=450)
• 1° end point: PFS
• 2° end points: OS, TRR, recurrence rate, HR-QoL, liver resection
rate
*
Per investigator’s discretion starting at cycle 4 (treatment arm) or cycle 1 (control arm)
†
SIR-Spheres microspheres
1. Source: www.clinicaltrials.gov. NCT00724503. 39
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40. SIRFLOX 120 Patient Safety Data:
Constitutional adverse events
Oxaliplatin package insert SIRFLOX Study Patient Group
safety data
(n =122)
Constitutional
(n = 259)
Treatment related
Adverse Events Grade Grade Grade Grade
1-4 3-4 1-4 3-4
% % % %
Nausea 71 6 59 2
Vomiting 41 4 31 3
Diarrhea 69 12 47 7
Constipation 32 4 22 0
Abdominal pain 29 8 18 3
* Nausea and vomiting reported as a single event in this study
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41. SIRFLOX 120 Patient Safety Data:
Other Treatment related Adverse Events
Oxaliplatin package insert SIRFLOX Study Patient Group
safety data
Other Treatment
(n = 259) (n = 122)
Related Adverse
Events Grade Grade Grade Grade
1-4 3-4 1-4 3-4
% % % %
Fatigue 70 7 63 7
Neuropathy 77 19 87 6
Anorexia 35 2 26 2
Stomatitis / 38 0 38 5
Mucositis
Alopecia 38 0 11 0
* Nausea and vomiting reported as a single event in this study
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42. Questions?
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43. Appendix
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44. SIRT Treatment Algorithm
Patient Selection
Patient Selection
1-2 weeks
Tumor Mapping
Tumor Mapping Labs
Labs
Lung Shunt
Lung Shunt
Vessel
Vessel Vessel
Vessel CT/Hepatic
CT/Hepatic Breakthrough
Breakthrough
Mapping
Mapping Embolization
Embolization Angiogram **
Angiogram Scan
Scan
1-2 weeks
Review
Review Treatment Plan
Treatment Plan Dosimetry
Dosimetry Ordering
Ordering
SIR-Spheres
SIR-Spheres Post Treatment
Bremsstrahlung
Bremsstrahlung Post Treatment
Labs
Labs microspheres
microspheres Care
Scan **
Scan Care
Delivery
Delivery
*optional
Follow Up
Follow Up
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45. Pre-treatment Planning and Microsphere Implant:
2012 Medicare APC Reimbursement
Procedure CPT Quantity APC Natl Pymt
1 - pretreatment $7,358.35 (2) =
Transcatheter embolization w S&I 37204/ 75894
1 - day of treatment $14,716.70
36247 Operator determined (pre-
Selective catheter 2-3rd order Packaged
36248 x ___ treatment & day of treatment)
Diagnostic angiogram (Visceral) 75726 1 – pretreatment $2,086.63
Diagnostic selective – addl vessel Operator determined (pre-
75774 Packaged
beyond basic treatment & day of treatment)
1 - pretreatment $75.48 (2) =
F/U angiogram post Embo 75898
1 - day of treatment $150.96
Basic dosimetry 77300 1 $107.56
Triple phase CT 74170 1 $334.09
Lung shunt imaging 78205 1 $293.36
Post treatment imaging 78201 or 78205 1 $293.36
Radiopharma by intra-arterial
79445 1 – day of treatment $230.32
administration
$15,716.28
Microspheres C2616 1 – day of treatment (- $15,000 dose acquisition cost)
$716.28
45
Total $18,929.26

46. Level of Evidence Example
SIRT # of Patients Level of
Study & Year Evidence
ABLATION # of Level of Gray et al, 2001 10 74 I
Study & Year Patients Evidence
Hendlisz et al, 2010 11 46 I
Hur et al, 2009 1 25 II-2
Solbiati et al, 2001 2 117 II-2 Seidensticker et al, 201112 58 II-1
Giliams & Lees, 309 II-2 Bester et al, 2012 13 339 II-1
2008 3
Elias et all, 2002 4 29 II-2 Cosimelli et al, 2010 14 50 II-2
Oshowo et al, 2003 25 II-2 Kennedy et al , 2006 15 208 II-2
5
Machi et al, 2006 6 100 II-2 van Hazel et al, 2004 16 21 II-1
Vogel et al, 2004 7 603 II-2 Sharma et al, 2007 17 20 II-1
Sorenson et al, 100 II-2 Evans et al, 2010 18 140 II-2
2007 8
Sofocleous et al, 56 II-2
2011 9
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