A common site for advanced colorectal cancer to spread is the liver. In this webinar we will discuss why that happens and some treatment options available for patients facing liver metastases. Presenting is Dr. Fakih’s whos research focuses on drug development, surveillance and prevention of colorectal cancer. In January 2015, he was appointed as the Interim Chair of Medical Oncology at City of Hope.

1. Liver Metastases - when
CRC Spreads to the Liver
Our webinar will begin shortly.
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2. • Speaker(s): Dr. Marwan Fakih
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6. Speaker:
MARWAN G. FAKIH, MD received his Medical Doctorate from
the American University of Beirut in 1992. He subsequently
completed his residency in Internal Medicine at the Detroit
Medical Center (Wayne State University) and a fellowship in
Hematology and Oncology at the University of Pittsburgh. He
was recruited to City of Hope in November of 2012 to lead the
GI Oncology Section. In January 2015, he was appointed as the
Interim Chair of Medical Oncology at City of Hope.
Dr. Fakih’s research focuses on drug development, surveillance
and prevention of colorectal cancer. His current clinical research
is focusing on developing strategies to optimize biomarker
driven-targeted therapy in colorectal cancer and to overcome
anti-EGFR resistance. Dr. Fakih has published more than 100
peer-reviewed articles and serves on the editorial boards of
several scientific journals.

7. Current and Emerging
Approaches to Unresectable
Colorectal Liver Metastases
Marwan Fakih, MD
Professor
Section Head, Gastrointestinal oncology
City of Hope comprehensive cancer center

8. Disclosures
•Research support: Novartis, Amgen
•Consulting: Amgen, Sanofi, Taiho, SIRTEX
•Speaker: Genentech, Bayer, Sanofi, Amgen,
SIRTEX

9. SEER Data: CRC in a Snapshot
seer.cancer.gov

10. Stage at Presentation and 5-Year Overall
Survival

11. Colorectal Cancer and Liver
Metastases
Colorectal Cancer
(~136,000)
20-25% Present with
Metastatic Disease
>60% have liver
involvement
>50% die of liver
failure
70-75% Localized or
Regional Disease
Another 20-25% Develop
Metastatic Disease
1. Siegel R, et al. CA Cancer J Clin. 2014;64(2):104-117. 2. National Cancer Institute. SEER Stat Fact Sheets: Colon and Rectum Cancer. Surveillance, Epidemiology,
and End Results Program. Turning Cancer Data Into Discovery (Cancer of the Colon and Rectum). http://seer.cancer.gov/statfacts/html/colorect.html. 3. Raval M, et al.
Front Oncol. 2014;4:120. 4. Ye LC, et al. J Clin Oncol. 2013;31:1931-1938. 5. Foster JH, et al. Semin Liver Dis. 1984; 4:170-179.

12. Management of Isolated or Liver-
Predominant Colorectal Liver Metastasis
Liver
Metastases
Resectabe
Potentially
Resection or
Ablation Candidate
Non-Resectable

13. Society of Surgical Oncology
Consensus for Resectability
• A positive surgical margin should be avoided
• A margin < 1cm is not an exclusion criteria for
resection
• Assessment of resctability should be based
on the ability to obtain a complete resection
(negative margin)
• Feasibility of resection should be based on
• Ability to preserve 2 contiguous segments
• Preservation of vascular inflow and outflow and
biliary drainage
• Ability to preserve adequate liver remnant (>20%
healthy liver)
• Extrahepatic disease is no longer a contraindication
for resection as long as complete resection of
hepatic and extrahepatic disease is feasible
Charnsaagavej el al. Annals of Surgical Oncol 2006

14. Selected Series of Hepatectomy for MCRC to
the Liver (N > 100)
N. of patients Operative Mortality 5-ys
Adson, 1984 141 2.8% 23%
Hughes, 1988 859 - 33%
Doci, 1991 100 5% 30%
Scheele, 1991 219 6% 39%
Rosen, 1992 280 4% 25%
Nordlinger, 1992 1818 2.4% 26%
Gayowski, 1994 204 0% 32%
Rees, 1997 114 1% 37%
Jamison, 1997 280 4% 27%
Fong, 1999 1001 2% 37%
Iwatsuki, 1999 305 1% 32%
Choti, 2002 226 - 40%
Abdalla, 2004 190 - 58%
Fernandez, 2004 100 1% 58%
Pawlic, 2005 557 - 58%

15. Long Term Disease Specific Survival of MCRC
Hepatic Resection
• 612 patients with hepatic resection for MCRC at MSKCC with FU > 10 years
• DSS 10 year survival of 17% - (if Loss to FU included - 25%)
• Only 1 patient of 102 patients with 10 year survival died of CRC
• 34% of 5-year survivors died of MCRC
Tomlinson JCO 2007
10 year survival = Cure

16. Management of Resectable Metastatic
Colorectal Cancer
Resectable
Metastatic Disease
to the Liver
Surgery (Resection
and/or ablation)
Chemotherapy x 6
months (FOLFOX in
oxaliplatin naïve
patients)
Resectable
Metastatic Disease
to the Liver
Chemotherapy x 3
months (FOLFOX)
Surgery
Addition
Chemotherapy x 3
months (FOLFOX)
Nordlinger B. Lancet, 2008: 1007-1016

17. Resectable Metastatic Colorectal
Cancer
74 year old female with sigmoid cancer and synchronous liver metastasis
3 m FOLFOX
Robotic segment 7
excision
1 year
post-op
NED

18. Colorectal Cancer Liver Metastases
Ablation (RFA)
Typically reserved for tumors < 5 cm. Risk of local relapse is minimal for tumors < 3 cm
http://www.colorectal-cancer.ca/en/treating-cancer/treatment-cancer/

19. Recurrence Free Survival and OS by Resection,
Resection + RFA, or RFA
• 358 patients treated with a curative resection, or resection + RFA, or RFA
• 190 resection only
• 101 RFA + resection
• 57 RFA only
• Liver only recurrence was 44% in RFA group vs. 11% surgery
• True local recurrence was 9% with RFA vs. 2% with resection
Abdallah, et al. Annals of Surgery; 2004

20. Management of Isolated or Liver-
Predominant Colorectal Liver Metastasis
Liver
Metastases
Resectabe
Potentially
Resection or
Ablation Candidate
Non-Resectable

21. Resectability of Liver Metastases
Nordlinger B. EJC 2007
Liver Metastases
85% Unresectable
10-30% potentially
resectable
70- 90% never resectable
15% Resectable
Resection
~30%
Chemotherapy

22. Paul Brousse Experience: 1988-99
Median chemotherapy = 10 cycles
70% oxaliplatin-based Adam R. Annals of Surgery 2004
138 pts
335 pts

23. Paul Brousse Experience: 1988-99
Adam R. Annals of Surgery 2004

24. Biological + Cytotoxic Results in Initially
Non-Resectable CRC Liver Metastases
Study Design Treatment Arm Comparator Arm RR and
Resection Rate
PFS/ OS
Gruenberger
OLIVIA TRIAL
2015
Randomized Phase II
Clinical Trial
N = 80
Primary Endpoint:
overall resection rate
FOLFOX + BV FOLFOXIRI + BV Favors FOLFOXIRI
Arm
RR: 81% vs. 62%
Resection Rate:
61% vs. 49%
R0: 49% vs. 23%
Favors FOLFOXIRI
Arm
PFS 18.6 m vs.
11.5 m
Ye
2013
Randomized Phase III
Trial
N = 138 (KRAS-WT)
Primary Endpoint:
conversion rate to
radical resection
FOLFOX FOLFOX + Cmab Favors Cmab
Arm
Resection Rate:
29% vs. 13%
R0: 26% vs. 7%
Favors Cmab
Arm
PFS (HR = 0.6, p =
0.04)
OS (HR = 0.54, p
=0.013)
Venook
CALGB 80405
2014
Randomized phase III
clinical trial
Primary Endpoint:
OS
N = 1137 KRAS-WT
(exon 2)
Chemotherapy + BV Chemotherapy +
Cmab
130 patients
achieved surgical
remission (favors
Cmab Arm)
Cmab arm: 62%
vs. 38%
No difference in
OS between
arms.
OS for overall
patient
population with
surgical
remission

25. Metastatic CRC RAS/BRAF-WT
February 2014 November 2014
FOLFIRI + Panitumumab for MCRC
SURGERY
Jan 2015
+
Adjuvant
FOLFOX

26. Metastatic CRC RAS/BRAF-WT: FOLFOXIRI/Bev
– followed by FOLFIRI + Pmab
February 2014 November 2014
SURGERY
DEC 2014
Kemeny N. JCO 2003
Kemeny N. JCO 2011

27. Metastectomy in CRC (2000-2011)
Bartlett E. Cancer. 2014, Nov. Ahead of Print

28. Management of Isolated or Liver-
Predominant Colorectal Liver Metastasis
Liver
Metastases
Resectabe
Potentially
Resection or
Ablation Candidate
Non-Resectable

29. Regional Therapy for Unresectable
Metastatic Colorectal Cancer
•DEBIRI (Drug eluting beads irinotecan)
•Hepatic arterial infusion with chemotherapy
•Radioembolization with Y90 microspheres

30. DEBIRI (Intra-arterial administration of
drug eluting beads irinotecan)
http://www.hopkinscoloncancercenter.org/CMS/CMS_Page.aspx?CurrentUDV=59&CMS_Page_ID=F8D44AA8-C114-4C69-9A45-256284D9D0A9

31. Randomized Phase III Clinical Trial of
DEBIRI vs. FOLFIRI
Previously Treated
MCRC to Liver
DEBIRI
FOLFIRI
22 vs. 15m
P < 0.05
7 vs. 4 m
P < 0.05
Most patients had 2-3 lines of treatment
About 1/3 of patients had prior irinotecan
Fiorentini, G. Anticancer Res. 2012

32. Chemotherapy Intensification:
Randomized Phase II Trial of FOLFOX +/-
DEBIRI
MCRC with Liver Metastases
FOLFOX +/- Bevacizumab
(n = 30)
FOLFOX +/- Bevacizumab +
DEBIRI
(n = 40)
DEBIRI + Chemo vs. Chemo p
DEBIRI + Chemo vs. Chemo p
Martin, R. GI ASCO 2014
Increase in RR in liver
Increased resection rate in liver
Systemic effect of irinotecan
suspected (increased BM
suppression)

33. DEBIRI in MCRC to the Liver
•Clinical activity noted but in small studies
•Requires repeated treatments
•Associated with a high rate of abdominal pain,
nausea and vomiting
•Often requires 24-48 hour admission
•Systemic impact of chemotherapy (irinotecan) is
likely a contributing factor to activity

34. Regional Therapy for Unresectable
Metastatic Colorectal Cancer
•DEBIRI (Drug eluting beads irinotecan)
•Hepatic arterial infusion with chemotherapy
•Radioembolization with Y90 microspheres

35. Hepatic Arterial Infusion Pumps
• FUDR (5-FU pro-drug) is metabolized in the liver with 95-99% first-pass
hepatic clearance
• Allows the administration of higher regional concentrations of
chemotherapy without systemic toxicity
• Placement requires surgery and cholecystectomy
• Risk of biliary sclerosis

36. CALGB 9481: Systemic vs. HAI Fluoropyrimidines
Metastatic CRC to
Liver
Mayo Clinic FU/LV
(67 pts)
HAI FUDR
(68 pts)
Kemeny N. et al. J Clin Oncol 2006: 1395
Time to Liver progression Overall survival
Median: 9.8 vs. 7.3 m Median: 24.4 vs. 20 m
HAI (FUDR) FU/LV
THF 9.8 m 7.3 m
TEHF 7.7 m 14.8 m
OS 24.4 m 20 m
THF = time to hepatic failure; TEHF: time to extra-hepatic failure

37. HAI in Chemotherapy Refractory
MCRC Limited to the Liver

38. Hepatic Arterial Infusion and MCRC to
Liver
• Limited applicability in the first-line (untreated) metastatic
colorectal cancer
• Potential benefits in subsequent lines of treatment are
based on single institute studies and do not include a control
arm
• May be associated with morbidity and toxicity
• Have to be performed in a high volume center
• May be most promising in the adjuvant setting in patients
with high risk for recurrence post hepatectomy

39. Regional Therapy for Unresectable
Metastatic Colorectal Cancer
•DEBIRI (Drug eluting beads irinotecan)
•Hepatic arterial infusion with chemotherapy
•Radioembolization with Y90 microspheres

40. FDA Indication: SIR-Spheres microspheres
40
SIR-Spheres microspheres are
indicated for the treatment of
unresectable metastatic liver
tumors from primary colorectal
cancer with adjuvant intra-
hepatic artery chemotherapy
(IHAC) of FUDR (Floxuridine)
SIR-Spheres® microspheres (Yttrium-90 Microspheres) [prescribing information]. Woburn, MA: Sirtex Medical, Inc.; October 2011.

41. SIR-Spheres microspheres
• Biocompatible resin microspheres
• Adsorbed Yttrium-90
• Mean diameter of 32.5μm (95%: 24μm to 36μm )
• lnjected into the right or left hepatic artery
Cell death through apoptotic mechanisms including double-strand
DNA breaks
SIR-Spheres® microspheres (Yttrium-90 Microspheres) [Prescribing Information]. Woburn, MA: Sirtex Medical, Inc.; October 2011

42. Common Adverse Events Associated with SIR-
Spheres Microspheres
42
Side Effect
Incidence, %
Grade 2 Grade 3
Weight loss 3 0
Fatigue 37 1
Fever 2 0
Nausea 9 1
Emesis 6 1
Pain 11 2
Gastric ulceration
5 (median)
(0-20)
Radiation-induced liver disease (RILD)
<1 (median)
(0-4)
Most Common Acute (0-30 Days) and Delayed (31+ Days) Grade 2/3 Toxicities*
*CTCAE 3.0.
Sirtex Clinical Safety and Tolerability. http://www.sirtex.com/ap/clinicians/safety/. Accessed October 16, 2014.

43. SIR-Spheres Microspheres:
Clinical Data
43

44. Gray, et al (2001)1 van Hazel, et al (2004)2 Sharma, et al (2007)3
SIR-Spheres
microspheres +
FUDR HAC
(n=36)
FUDR HAC
(n=34)
SIR-Spheres
microspheres +
5-FU/LV
(n=11)
5-FU/LV
(n=10)
SIR-Spheres microspheres +
FOLFOX4
(n=20)
Cohort Liver-only Liver-only
Liver-
dominant
Liver-
dominant
Liver-
dominant
Liver-only
ORR, %
44 18 72.7 0
90
P=0.01 P<0.001
CEA response, %
72 47
– –
0.004
Median TTP,
months
NR
18.6 3.6
9.3
P<0.0005
Median TTLP, months
15.9 9.7
NR 12.3
P=0.001
Median survival,
months
23.5 18.4 29.4 12.8
NRHR=1.14
P=0.18
HR=0.33
P=0.025
First Line: SIR-Spheres Microspheres with
Chemotherapy Are Associated with Improved
Outcome
5-FU/LV=5-fluorouracil/leucovorin; FOLFOX=5-FU/LV + oxaliplatin; HAC=hepatic arterial chemotherapy; NR=not reported; TTP= Time to progression, TTLP=time to liver progression.
1. Gray B, et al. Ann Oncol. 2001;12:1711-1720. 2. van Hazel G, et al. J Surg Oncol. 2004;88:78-85. 3. Sharma RA, et al. J Clin Oncol. 2007;25:1099-1106.
44

45. Second Line
SIR-Spheres microspheres + Irinotecan
(n=25)
Cohort Liver-dominant
ORR, % 48
Median TTP†, months 6.0
Median TTLP‡, months NR
Median survival, months 12.2
Second Line: Efficacy of SIR-Spheres
Microspheres with Chemotherapy
van Hazel G, et al. J Clin Oncol. 2009;27:4089-4095.
45
† Time to Progression
‡Time to Liver Progression

46. Refractory Setting: SIR-Spheres microspheres With
Chemotherapy Are Associated With Improved
Outcome (Level 1 Evidence)
SIR-Spheres
microspheres + 5-FU
(n=21)
5-FU
(n=23)
Cohort Liver-only Liver-only
ORR, %
10 0
P=0.22
Median TTP, months
4.5 2.1
HR=0.51; P=0.03
Median TTLP, months
5.5 2.1
HR=0.38; P=0.003
Median OS,* months
10.0 7.3
HR=0.92; P=0.8
*Crossover was allowed, which may have impacted P value.
Hendlisz A, et al. J Clin Oncol. 2010;28:3687-3694.
46

47. Integrating SIR-Spheresmicrospheres
in the Management of mCRC:
A Case Study–Based Approach
47

48. RefractorySecond LineFirst Line
Potential Applications of SIRT in mCRC
48

49. First-line Setting
Chemotherapy Tolerant
Chemotherapy Intolerant
49

50. Male, 74 years
Clinical history
• Diagnosed with predominant liver metastatic colon cancer (unresected primary, low-
volume lung disease)
• KRAS mutation
Treatment
• FOLFOX + Bev induction chemotherapy × 4 months with
stable disease
• Followed by maintenance 5-FU/LV + Bev with PD in
liver only
Case Study 1
Presentation
50

51. • SIR-Spheres microspheres
administered concurrently with
one cycle of FOLFOX
• Patient was remaintained on 5-
FU/LV + bevacizumab
• 14 months from initiation of
chemotherapy until progression
on maintenance treatment and
switch to a second-line
treatment
Case Study 1: Treatment and Outcome
Fakih. Colorectal Cancer. 2014;3:331-343.
51
SIR-Spheres
microspheres
7/2013 9/2013

52. Male, 72 years
Clinical history
• NHL with mediastinal involvement and malignant pleural effusion (lymphoma)
• 5/2013 PET/CT: right colon mass and multiple hepatic metastases
– Colon adenocarcinoma
• RAS mutation
Treatment
• FOLFOX + Bev for 3-4 months between 6/2013 and 9/2013
– Minor response with normalization in CEA; grade 3 neuropathy and severe
fatigue
– 10/2013-12/2013: FU/LV + Bev
• Rising CEA
• Minor progression in 12/2014
• Primary tumor stable to mildly improved
• Options: FOLFIRI + Bev or SIR-Spheres microspheres?
Presentation
Case Study 2: Rising CEA With Minimal
Progression in First-line Treatment
52
FOLFIRI=5-FU/LV + irinotecan.

53. Case Study 2: Rising CEA With Minimal
Progression in First-line Treatment (Cont.)
2/201412/2013
53
SIR-Spheres
microspheres

54. • SIR-Spheres microspheres
concurrent with 1 cycle of
FOLFOX
• Resumed 5-FU/Bev
• Patient without PD and normal
CEA
54
Case Study 2: Rising CEA With Minimal
Progression in First-line Treatment (Cont.)
2/2014 7/2014
PFS >15 months before second-line chemotherapy
SIR-Spheres
microspheres

55. Case Study 3: Patient Intolerant to
Chemotherapy in the First Line Setting
55
Female, 81 years
Clinical history
• Transanal excision of rectal cancer at 77 years of age
• 2/2013: recurrent perirectal pelvic mass with unresectable hepatic metastases
Treatment
• 3/2013-1/2014: treated with 5-FU/LV + Bev
– Worsening hand-foot syndrome despite reduction in 5-FU infusion to 1800 mg/m2
– Increasing fatigue despite dose reduction
– Improvement in metastatic disease but still PET/CT positive
• 1/2014-2/2014: radiation + low-dose capecitabine to the pelvis to control pelvic
recurrence
Presentation

56. • Right hepatic lobe SIR-Spheres microspheres + infusional 5-FU on 4/2014
• Right hepatic liver metastases with a CR by PET/CT. Left lobe of the liver has progressive disease
56
Case Study 3: Treatment and Outcome From SIR-Spheres
microspheres in a Patient With Chemotherapy Intolerance
5/20143/2014

57. 7/2014
Patient is 18 months from initiation of chemotherapy without a need to switch to
second-line therapy
• SIRT with SIR-Spheres
microspheres
• PET/CT repeated
7/2014 with a
complete PET/CT
response in the liver
57
Case Study 3: Treatment and Outcome
(Cont.)
5/2014

58. Case 4: 64 year-old intolerant to
chemotherapy with CRC liver metastases
June 2014 March 2015
June 2014 March 2015
Patient is 9 months from SIRT with SIR-Spheres x 1 (July 2014) with ongoing
regression of hepatic metastases

59. Second-line Setting
59

60. Male, 53 years
Clinical history
• Diagnosed with sigmoid colon cancer with metastatic disease to the liver
• Status post sigmoid resection for colon cancer with synchronous hepatic lesions: No
extrahepatic disease
• >10 lesions scattered in both lobes
• KRAS mutation
Treatment
• FOLFIRI + Bev in the first-line setting
– Myocardial infarction with first dose of FOLFIRI + Bev
• Subsequently treated with 5 cycles of IROX with stable disease, associated with severe
neuropathy
Case Study 5: Application in a Patient with
Inadequate Response in the 2nd Line-Setting
60
IROX=irinotecan + oxaliplatin.
Presentation

61. • SIR-Spheres
microspheres in
7/2013 in
combination with
irinotecan
• PD 6 months later
Case 5: Integration in the Second-line
Setting
7/2013 11/2013
Irinotecan + SIR-Spheres microspheres
61

62. Refractory Setting
62

63. Case Study 6: Refractory Case
63
Male, 52 years
Clinical history
• Progressive liver-dominant disease with
low-volume lung metastases
• Failed all systemic treatments
• RAS WT
Presentation

64. 7/2013 9/2013 11/2013
Rechallenge
FOLFIRI +
cetuximab
• Infusional 5-FU +
SIR-Spheres
microspheres
8/2013
• Systemic
chemotherapy
rechallenge with
FOLFIRI +
cetuximab
started on
10/2013
Case 6: Integrating SIR-Spheres
Microspheres in Refractory Settings
64
SIR-Spheres
microspheres

65. Case 6: Repeat SIRT Performed 8 Months
Later
65
Increasing
liver
metastases
Post
SIR-Spheres
microspheres
SIR-Spheres
microspheres
4/2014
SIR-Spheres
microspheres
3/2014 7/2014

66. Case Study 6: Advanced Refractory
Disease
66
FOLFOXIRI=5-FU/LV + oxaliplatin + irinotecan.
Male, 45 years
Clinical history
• Presented with rectal bleeding, change in bowel habits, increasing abdominal pain
• Colonoscopy showed an anorectal junction tumor and biopsy confirmed an adenocarcinoma
• KRAS mutation
• Staging showed widespread metastatic disease
– Extensive liver disease
– Low volume lung disease
– Pelvic adenopathy
– Large rectal primary
Treatment
• Patient was treated with 9 cycles of FOLFOXIRI followed by FOLFIRI + Bev as maintenance
therapy
Presentation

67. Case Study 7: Baseline PET Scan Imaging,
12/2012
67

68. Case Study 7: Best Response Achieved at
10 Months of Treatment
12/2012 9/2013
12/2012 2/2013 3/2013 4/2013 5/2013 5/2013 6/2013 7/2013 8/2013 9/2013
CEA 7160.9 851.7 85.7 40.8 18.5 15.9 10.8 8.4 5.8 5.4
68

69. Case Study 6: Post 1/2014 – SIR-Spheres
microspheres
12/2013 1/2014
69
SIR-Spheres
microspheres

70. 70
Case Study 7: PET/CT (4/2014) Post
SIR-Spheres microspheres

71. Chemotherapy Regimens in Combination
With SIRT
Chemotherapy Regimen SIRT Administration
FOLFOX1
mFOLFOX6 regimen with oxaliplatin reduced to 60
mg/m2, maintained for 2 cycles following SIRT
mFOLFOX6 ± bevacizumab (SIRFLOX)
Day 3 or 4 of first cycle
5-FU/LV bolus2 5-FU at 425 mg/m2 and LV at 20 mg/m2 daily × 5
(4-week cycle)
Day 3 or 4 of second cycle
5-FU protracted
infusion3
5-FU at 225 mg/m2/day for 14 days then
300 mg/m2/day for 14 days thereafter
(3-week cycle)
Day 1 of cycle
Capecitabine4 Capecitabine 1000 mg/m2 po bid for 14 days
(3-week cycle)
Day 2 of cycle
Irinotecan5 Irinotecan at 100 mg/m2 on days 1 and 8
(3-week cycle)
Day 2 or 3 of cycle
1. Sharma RA, et al. J Clin Oncol. 2007;25:1099-1106. 2. van Hazel G, et al. J Surg Oncol. 2004;88:78-85. 3. Hendlisz A, et al. J Clin Oncol. 2010;28:3687-3694.
4. Cohen SJ, et al. Br J Cancer. 2014;111:265-271. 5. van Hazel G, et al. J Clin Oncol. 2009;27:4089-4095.
71

72. • SIR-Spheres microspheres can be integrated safely with multiple chemotherapy
backbones
• First-line, second-line, and refractory settings
• Associated with down-staging
• Prospective studies support efficacy across different lines of treatment and a
favorable safety profile
• The procedure is an outpatient procedure (no hospitalization) with a favorable
toxicity profile
• SIR-Spheres microspheres constitute an effective tool in the control of mCRC to
the liver
Case Studies: Summary
72

73. SIRFLOX Study Design
• Multicenter, international study:
• US, Israel, Australia,
New Zealand, Europe
• Eligible patients:
• Unresectable liver-only or
liver-prominent colorectal cancer
metastases
• No prior chemotherapy for advanced
disease
• Fit for combination therapy and
SIRT
• Primary endpoint:
• Progression-free survival
SIR-Spheres
microspheres*
+
mFOLFOX6† ±
bevacizumabC4
mFOLFOX6†
±
bevacizumabC1
Stratify
• Presence of
extrahepatic
metastases
• Degree of liver
involvement
• Institution
• Use of
bevacizumab
R
1:
1
(n=532)‡
*SIR-Spheres microspheres administered day 3/4 of cycle 1. †Oxaliplatin administered at 60 mg/m2 (for cycles 1-3 in the SIR-Spheres
microspheres + FOLFOX arm). ‡Enrollment completed 4/2013. C4/C1At the investigator’s discretion, bevacizumab may commence at cycle 4 in the
test arm and at cycle 1 (or per institutional protocol) in the control arm.
http://clinicaltrials.gov/ct2/show/NCT00724503?term=nct00724503&rank=1. Accessed October 16, 2014.
73

74. SIRFLOX Preliminary Results
•Primary Endpoint
• No difference in PFS
• Chemo PFS = 10.2 m vs. Chemo + SIR-Spheres PFS = 10.7 m (HR =
0.93)
•Secondary Endpoints
• Significant delay in liver progression in favor of the
SIR-Spheres arm
• Liver PFS 20.5 vs. 12.6 m (HR = 0.69)
• Hepatic response rate was better on the SIR-Spheres
arm
• Liver RR = 78.7% vs. 68.6%
• OS data is not mature

75. Liver Directed Therapies
•Liver directed therapies should be focused on
curative intent strategies when feasible
• Surgery or RFA or combination
•Non-resectable liver metastases can benefit
from regional strategies
• Radioembolization (SIR-Spheres)
• DEBIRI
• Hepatic arterial infusion
•Radioembolization is the favored strategy in
non-resectable, chemo-resistant, liver limited
disease

76. Question & Answer:
SNAP A
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77. Contact Us!