PowerPoint-Pr

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Literature
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Literature

• Clinical Studies
• mCRC
• HCC
• Other Cancer
• Mode of Action and Procedure
• Radiation Protection
• Issues of Concern
• Reviews

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Literature
Published outcome data
Some words about patient collective beforehand

• SIRT is often regarded as second, third or even
  fourth line treatment
• The more treatments failed, the worse is the
  prognosis for the patient
• Comparing survival rates can therefore sometimes
  be misleading

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Literature
Published outcome data
Some words about response rate beforehand

• The response is usually measured either as an
  effect on a specific tumour marker (CEA or AFP)
  or as a decrease in the size of the lesion(s)
• It is known that the response (size of lesion)
  often seems to be delayed in CT, whereas a
  functional scan like PET shows quite quickly that
  there is a response
• Comparing response rates by tumour size can
  therefore sometimes be misleading

CEA carcinoembryonic antigen
AFP a-fetoprotein
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Literature
Published outcome data
Some words about survival beforehand

• Especially in older studies, HAC is used as the
  standard. But this local therapy does not treat
  any extrahepatic disease
• Often this extrahepatic disease mostly leads to
  the death of the patient rather than the
  secondary liver disease
• Comparing survival rates can therefore sometimes
  be misleading

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Literature
Definitions
Median Survival Kaplan Meier Plot
The median survival is the time at which half the
subjects have died. The example survival curve
shows 50 survival at 5 months, so median
survival is 5 months.
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Literature
Definitions
Hazard Kaplan Meier Plot
The hazard is the slope of the survival curve a
measure of how rapidly subjects are dying.
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Literature
Definitions
Hazard Kaplan Meier Plot
Treatment A
Treatment B
The hazard ratio compares two treatments. If the
hazard ratio is 2.0, then the rate of deaths in
one treatment group is twice the rate in the
other group. If it is 0.33, the rate of death is
one third of the rate in the other group.
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Literature

• Clinical Studies
• mCRC
• HCC
• Other Cancer
• Mode of Action and Procedure
• Radiation Protection
• Issues of Concern
• Reviews

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10
Literature
Clinical Studies
mCRC
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Literature
Clinical Studies
Randomized trial of SIR-Spheres plus chemotherapy
vs. chemotherapy alone for treating patients with
liver metastasis from primary large bowel cancer
B.Gray, G. Van Hazel, M.Hope, M.Burton, P.Moroz,
J.Anderson, V.Gebski
Annals of Oncology 121711-1720, 2001

• Phase III randomized trial (open for entry
  1991-1997)
• SIR-Spheres plus hepatic artery chemotherapy via
  port
• 74 patients with bipolar non-resectable CRC
  metastasis
• Primary objectives response, time to
  progression, survival, quality of life and
  toxicity

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Literature
Clinical Studies
B.Gray et al, Annals of Oncology 121711-1720,
2001
n70
Randomization
4 patients weren't eligible
n36
n34

• SIRT
• HAC with FUDR
• 12 day cycle
• 4 weekly
• 18 cycles

• HAC with FUDR
• 12 day cycle
• 4 weekly
• 18 cycles

SIRT within 4 weeks after port implantation
Angiotensin injected prior to implant
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Literature
Clinical Studies
B.Gray et al, Annals of Oncology 121711-1720,
2001
CRcomplete response, PRpartial response, NCno
change, PD progressive disease, NAnot assessable
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Literature
Clinical Studies
B.Gray et al, Annals of Oncology 121711-1720,
2001
CRcomplete response, PRpartial response, NCno
change, PD progressive disease, NAnot assessable
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Literature
Clinical Studies
B.Gray et al, Annals of Oncology 121711-1720,
2001
CRcomplete response, PRpartial response, NCno
change, PD progressive disease, NAnot assessable
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Literature
Clinical Studies
B.Gray et al, Annals of Oncology 121711-1720,
2001
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Literature
Clinical Studies
B.Gray et al, Annals of Oncology 121711-1720,
2001
Kaplan-Meier Survival
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Literature
Clinical Studies
B.Gray et al, Annals of Oncology 121711-1720,
2001
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Literature
Clinical Studies
B.Gray et al, Annals of Oncology 121711-1720,
2001

• Significant greater response rate
• Significant longer time to disease progression
• Increased survival
• No increased toxicity
• No loss of quality of life
• Risk of death from progression of liver
  metastasis was 3.1 times higher in the control
  group
• One patient treated with SIR-Spheres is
  considered permanently cured
• Study was basis for the pre-market approval of
  FDA (US)

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Literature
Clinical Studies
B.Gray et al, Annals of Oncology 121711-1720,
2001

• Study closed prior to completion (95 patients
  planned)
• Statistically the study with only 74 patients is
  not very powerful
• Most patients died from extra-hepatic disease
• Treatment regimen not suitable to treat any
  extra-hepatic disease

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Literature
Clinical Studies
Randomized Phase 2 Trial of SIR-Spheres Plus
Fluorouracil/ Leucovorin Chemotherapy Versus
Fluorouracil/Leucovorin Chemotherapy Alone in
Advanced Colorectal Cancer
Guy Van Hazel, Anthony Blackwell, James Anderson,
David Price, Paul Moroz, Geoff Bower, Guiseppe
Cardaci, Bruce Gray
Journal of Surgical Oncology 20048878-85

• Phase II trial with 21 patients
• Systemic chemotherapy with and without SIRT
  (femoral catheter)
• Patients with CRC liver metastasis with and
  without extra-hepatic disease
• Primary objectives response, time to progression
  and toxicity

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Literature
Clinical Studies
G. Van Hazel et al, Journal of Surgical Oncology
20048878-85
n21
Randomization
n11
n10

• SIRT
• Systemic Chemo
• 5-FU/Leucovorin
• 5 day cycle
• 4 weekly
• until progression

• Systemic Chemo
• 5-FU/Leucovorin
• 5 day cycle
• 4 weekly
• until progression

SIRT 3rd or 4th day of 2nd cycle Angiotensin
injected prior to implant
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Literature
Clinical Studies
G. Van Hazel et al, Journal of Surgical Oncology
20048878-85
Time to progressive disease
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24
Literature
Clinical Studies
G. Van Hazel et al, Journal of Surgical Oncology
20048878-85
Survival by treatment
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Literature
Clinical Studies
G. Van Hazel et al, Journal of Surgical Oncology
20048878-85

• Time to PD significantly longer for SIRT patients
  (18.6 month versus 3.6 month)
• Significant better median survival for SIRT
  patients (29.4 month versus 12.8 month)
• One SIRT patient still alive at date of
  publication

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Literature
Clinical Studies
G. Van Hazel et al, Journal of Surgical Oncology
20048878-85

• Small number of patients only

However, the high response rate, long time to
disease progression and survival suggest that
adding SIRT to systemic chemotherapy can improve
patient outcome.
SIRFLOX Study
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Literature
Clinical Studies
FOLFOX 4 Dose Escalation Trial
Guy Van Hazel et al
ASCO GI 2005, Florida, USA

• Phase II trial with 20 patients
• Systemic chemotherapy with Oxaliplatin in
  combination with SIRT (femoral catheter)
• Patients with CRC liver metastasis
• Primary objectives response and survival

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Literature
Clinical Studies
G. Van Hazel et al, ASCO GI 2005, Florida, USA

• 2 patients with complete response, 16 with
  partial response and 2 with static disease. None
  with PD
• Median time to progression is currently 11.9
  months
• For those with liver only disease the time to
  progression is currently 14.9 months
• Median survival cannot be determined at that stage

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Literature
Clinical Studies
Randomized Comparative Study Of FOLFOX6m Plus
SIR-Spheres versus FOLFOX6m Alone As First Line
Treatment In Patients With Non-Resectable Liver
Metastasis From Primary Colorectal Carcinoma
Peter Gibbs and Guy Van Hazel (Principal
Investigator)
Unpublished Study open to accrual

• Trial with more than 300 patients
• Systemic chemotherapy with and without SIRT
  (femoral catheter)
• Patients with CRC liver metastasis with and
  without extra-hepatic disease
• Primary objectives Progression free survival at
  any site and progression free survival in the
  liver

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Literature
Clinical Studies
P. Gibbs and G. Van Hazel, Unpublished Study
open to accrual soon
ngt300
Randomization
ngt150
ngt150

• SIRT
• Systemic Chemo
• Oxaliplatin
• Leucovorin
• 5-FU
• repeated 2 weekly

• Systemic Chemo
• Oxaliplatin
• Leucovorin
• 5-FU
• repeated 2 weekly

SIRT 1st week of 1st cycle
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Literature
Clinical Studies
P. Gibbs and G. Van Hazel, Unpublished Study
open to accrual

• Statistical powerful study
• State of the art chemotherapy regimen
• Multicentre study

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HCC
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Literature
Clinical Studies
Treatment of inoperable hepatocellular carcinoma
with intrahepatic arterial yttrium-90
microspheres a phase I and II study
W.-Y. Lau, W.-T. Leung, S. Ho, N.W.Y. Leung, M.
Chan, J. Lin, C. Metreweli, P. Johnson and A.K.C.
Li
British Journal of Cancer 199470994-999

• Phase I and II trial with 18 patients
• Patients with inoperable HCC, recruited 90-93
• SIRT via port
• Primary objectives response and survival

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Literature
Clinical Studies
W.-Y. Lau et al, British Journal of Cancer
199470994-999
n18
Randomization
n8
n8
SIRT lt 120Gy
SIRT gt 120Gy
Angiotensin injected prior to implant
Angiotensin injected prior to implant
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Literature
Clinical Studies
W.-Y. Lau et al, British Journal of Cancer
199470994-999
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36
Literature
Clinical Studies
W.-Y. Lau et al, British Journal of Cancer
199470994-999

• Significant better median survival for patients
  receiving the higher dose (55.9 versus 26.2
  weeks)
• Dose of gt120Gy is recommended
• Three SIRT patients still alive after 10.4, 17.2
  and 27.4 month respectively

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Literature
Clinical Studies
W.-Y. Lau et al, British Journal of Cancer
199470994-999

• Small number of patients only

However, the result clearly shows the advantage
of a well dosed SIRT treatment.
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Literature

• Clinical Studies
• mCRC
• HCC
• Combined Cancer
• Mode of Action and Procedure
• Radiation Protection
• Issues of Concern
• Reviews

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39
Literature
Clinical Experience in mCRC

• Kennedy et al, USA, 208 patients
• Stubbs et al, NZ, 165 patients
• Gray et al, Aus, 71 patients
• Lim et al, Aus, 30 patients
• Poepperl et al, Germany, 23 patients
• Wong et al, USA, 19 patients
• Murthy, USA, 12 patients

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Literature
Published outcome data

• Excellent overview on all published study data as
  well as clinical experience on both, glass
  spheres and SIR-Spheres

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Literature
Published outcome data
Sean Garrean, N. Joseph Espat Surgical Oncology
200514179-193
Author Gray et al.
Year 1989
Number of Patients 10
Type of tumour mCRC
Therapy Y-90 alone
Dose 16.8-138.9Gy to normal liver
Result 8 of 9 with gt50 reduction in CEA
Remarks Intraoperative dosimetry
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Literature
Published outcome data
Sean Garrean, N. Joseph Espat Surgical Oncology
200514179-193
Author Gray et al.
Year 1992
Number of Patients 29
Type of tumour mCRC
Therapy Y-90 HAC
Dose 755 4240 MBq
Result 70 average decrease in pretreatment CEA 45 response rate based on CT
Remarks No significant toxicity
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Literature
Published outcome data
Sean Garrean, N. Joseph Espat Surgical Oncology
200514179-193
Author Gray et al.
Year 2000
Number of Patients 71
Type of tumour mCRC
Therapy Y-90 HAC
Dose Average activity 2130MBq
Result 85 overall response rate Median survival 13.5 months
Remarks Fatal radiation hepatitis in one patient
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Literature
Published outcome data
Sean Garrean, N. Joseph Espat Surgical Oncology
200514179-193
Author Gray et al.
Year 2001
Number of Patients 74
Type of tumour mCRC
Therapy HAC Y-90
Dose 2000 3000MBq
Result 72 overall response rate versus 47 (HAC) 40 higher death rate in HAC alone
Remarks Phase III randomized trial
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Literature
Published outcome data
Sean Garrean, N. Joseph Espat Surgical Oncology
200514179-193
Author Stubbs et al.
Year 2001
Number of Patients 50
Type of tumour mCRC
Therapy Y-90 HAC
Dose 2000 3000MBq
Result Median survival 24.7 / 11.4 months (without extrahepatic / with extrahepatic disease)
Remarks Duodenal ulceration in six patients
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Literature
Published outcome data
Sean Garrean, N. Joseph Espat Surgical Oncology
200514179-193
Author Stubbs et al.
Year 2003
Number of Patients 100 (including 50 published earlier)
Type of tumour mCRC
Therapy Y-90 HAC
Dose 2000 3000MBq
Result Median survival 12.6 / 8.3 months (without extrahepatic progression / with extrahepatic progression at 6 month)
Remarks Fatal radiation hepatitis in one patient
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Literature
Published outcome data
Sean Garrean, N. Joseph Espat Surgical Oncology
200514179-193
Author Van Hazel et al.
Year 2004
Number of Patients 21
Type of tumour mCRC
Therapy Y-90 Systemic Chemotherapy
Dose 1500 2500MBq
Result Time to progression 18.6 months versus 3.6 months
Remarks Phase III randomized trial Radiation hepatitis in one patient
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Literature
Published outcome data
Sean Garrean, N. Joseph Espat Surgical Oncology
200514179-193
Author Murthy et al.
Year 2005
Number of Patients 12
Type of tumour mCRC
Therapy Y-90 Systemic Chemotherapy
Dose Median dose 39.6mCi
Result 4/7 patients with response on CEA levels 5/12 patients with stable radiologic response
Remarks Treatment after failure of multiple chemotherapy regimens Gastric ulceration in one patient
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Literature
Published outcome data
Sean Garrean, N. Joseph Espat Surgical Oncology
200514179-193
Author Wong et al.
Year 2005
Number of Patients 19
Type of tumour MET (metastatic)
Therapy Y-90 alone
Dose Median dose 76Gy
Result 15 of 19 patients with metabolic response (PET)
Remarks
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Literature
Published outcome data
Sean Garrean, N. Joseph Espat Surgical Oncology
200514179-193
Author Lim et al.
Year 2005
Number of Patients 32 / 5
Type of tumour mCRC / HCC
Therapy Y-90 Systemic Chemotherapy
Dose Unavailable
Result 12 of 43 patients with partial response (CT)
Remarks Severe gastric ulceration in four patients
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Literature
Published outcome data
Is there a common pattern of results?

• No All results seem to be different, because
• different patient collectives
• different outcome measurements

Yes Irregardless of patient collective and
outcome measurements, all SIRTEX patients are
doing extraordinary well!
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Literature

• Clinical Studies
• mCRC
• HCC
• Other Cancer
• Mode of Action and Procedure
• Radiation Protection
• Issues of Concern
• Reviews

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Literature
Published outcome data

• Excellent overview on all published study data as
  well as clinical experience on both, glass
  spheres and SIR-Spheres

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Literature
Published outcome data
Sean Garrean, N. Joseph Espat Surgical Oncology
200514179-193
Author Lau et al.
Year 1994
Number of Patients 18
Type of tumour HCC
Therapy Y-90 alone
Dose 26-409Gy to tumour
Result 50 partial response by CT scan 100 response by AFP or ferritin levels Median survival 55.9 weeks
Remarks Significant better survival in patients gt120Gy
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Literature
Published outcome data
Sean Garrean, N. Joseph Espat Surgical Oncology
200514179-193
Author Lau et al.
Year 2001
Number of Patients 82
Type of tumour HCC
Therapy Y-90 alone
Dose Median cumulative dose 332Gy and 268Gy
Result Median survival 21.0 months (332Gy) Median survival 4.5 months (268Gy)
Remarks
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Literature
Published outcome data
Sean Garrean, N. Joseph Espat Surgical Oncology
200514179-193
Author Murthy et al.
Year 2005
Number of Patients 12
Type of tumour mCRC
Therapy Y-90 Systemic Chemotherapy
Dose Median dose 39.6mCi
Result 4/7 patients with response on CEA levels 5/12 patients with stable radiologic response
Remarks Treatment after failure of multiple chemotherapy regimens Gastric ulceration in one patient
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Literature

• Clinical Studies
• mCRC
• HCC
• Other Cancer
• Mode of Action and Procedure
• Radiation Protection
• Issues of Concern
• Reviews

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Literature
Published outcome data
G. Poepperl et al. Cancer Biotherapy
Radiopharmaceuticals 200520200-208
Author Poepperl et al.
Year 2005
Number of Patients 12 / 4 / 2 / 1 / 1 / 2
Type of tumour CRC/Breast/Pancreas/Melanoma/NET/ HCC
Therapy Y-90 Systemic Chemotherapy prior to SIRT
Dose Mean activity 2270MBq
Result Promising responses, long term survival data to be published
Remarks Mild pancreatitis and gastric ulceration in one patient each
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Literature
Published outcome data
D. Rubin et al. Integrative Cancer Therapies
20043262-267
Author Rubin et al.
Year 2004
Number of Patients 1
Type of tumour Metastatic Breast Cancer
Therapy Y-90 Systemic Chemotherapy prior to SIRT
Dose -
Result Stable disease after 13 months
Remarks
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Literature
Published outcome data
D. Coldwell et al. Society of Interventional
Radiology (SIR) conference
Author Coldwell et al.
Year 2005
Number of Patients 34
Type of tumour Metastatic Breast Cancer
Therapy Y-90
Dose Average dose 1.75GBq
Result 100 response (PET-Scan) 30/34 still alive after 10 months
Remarks All patients report palliation of liver related symptoms
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Literature
Published outcome data
D. Coldwell et al. World Congress on
Gastrointestinal Cancer
Author Coldwell et al.
Year 2005
Number of Patients 84
Type of tumour Metastatic Neuroendocrine Tumours
Therapy Y-90
Dose Average dose 1000Gy to tumour volume
Result 67 response (PET-Scan) Symptom relief in symptomatic patients
Remarks 14 cases of grade 3 GI toxicity
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Literature
Published outcome data
A. Kennedy et al. International Congress on
Anti-Cancer Treatment
Author Kennedy et al.
Year 2005
Number of Patients 40
Type of tumour Metastatic Neuroendocrine Tumours
Therapy Y-90 (Thera-Spheres or SIR-Spheres)
Dose Average dose 36.59mCi (SIR-Spheres)
Result 3 CR, 3 SD, 34 PR
Remarks Follow-up 2-48 months with 7 patients dod
dod dead of disease
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Literature
Published outcome data
J. King et al. World Congress on Gastrointestinal
Cancer
Author King et al.
Year 2005
Number of Patients 22
Type of tumour Metastatic Neuroendocrine Tumours
Therapy Y-90
Dose -
Result Radiological response (RECIST) at one month 3 PR, 12 SD, 1 PD, 2 PR in one lobe
Remarks 2 patients dod at 4 and 7 months
dod dead of disease
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Literature

• Clinical Studies
• mCRC
• HCC
• Other Cancer
• Mode of Action and Procedure
• Radiation Protection
• Issues of Concern
• Reviews

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Literature
Mode of Action and Procedure
a MUST to READ
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66
Literature
Mode of Action and Procedure
Murthy et al, RadioGraphics 2005 2541-55
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Literature
Mode of Action and Procedure
Murthy et al, RadioGraphics 2005 2541-55

• SIRT therapy principles
• Thera-Spheres versus SIR-Spheres
• Patient selection criteria
• Therapy planning and workup
• Clinical outcomes
• Complications

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Literature
Mode of Action and Procedure
a MUST to READ
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69
Literature
Mode of Action and Procedure
Salem et al, J Vasc Interv Radiol 2006
171251-1278

• Technical and methodological considerations
• Patient screening and selection
• Vascular anatomy
• Treatment process
• Thera-Spheres and SIR Spheres

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Literature
Mode of Action and Procedure
a MUST to READ
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71
Literature
Mode of Action and Procedure
Salem et al, J Vasc Interv Radiol 2006
171425-1439

• Special Topics
• Patient selection
• Complications
• Lobar versus whole liver approach
• Treating patients after other other treatments
• Combination with other treatments
• Workup and treatment the same day?
• Patients with increased lung shunting
• Long-term follow up

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Literature
Mode of Action and Procedure
a MUST to READ

• Shows the high degree of variation in the anatomy
  of the hepatic arterial bed and the consequences
  with regard to SIRT

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73
Literature
Mode of Action and Procedure
Liu et al, J Vasc Interv Radiol 2005, 16911-935
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Literature
Mode of Action and Procedure

• Shows clearly that an early response on a
  treatment with SIR-Spheres can be detected by PET
  scanning but not by CT.

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75
Literature
Mode of Action and Procedure
Szyszko et al, Nuclear Medicine Communications
2007, 2815-20
PET
CT
before treatment
after treatment
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76
Literature
Mode of Action and Procedure

• Points out the importance of a proper work-up,
  gives a quite good perspective on likelihood of
  side effects and how to deal with those

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Literature
Mode of Action and Procedure
Further publications on

• Blood supply of hepatic metastasis
• Dose calculation via partition model
• Microsphere and dose distribution within the
  liver
• Intraoperative dosimetry
• Pathologic response
• Responses on PET and CT scan

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Literature

• Clinical Studies
• mCRC
• HCC
• Other Cancer
• Mode of Action and Procedure
• Radiation Protection
• Issues of Concern
• Reviews

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79
Literature
Radiation Protection
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80
Literature
Radiation Protection
Radiation Protection in Australia Series 4, 2002

• Dose limits and dose constrains
• The discharge of patients following treatment
• Maximum dose rate at time of discharge
• Maximum activity to be administered to an
  outpatient
• Use of public transport by the patient

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Literature
Radiation Protection

• Gives a good overview of all radiation safety
  aspects including exposure and doses

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82
Literature

• Clinical Studies
• mCRC
• HCC
• Other Cancer
• Mode of Action and Procedure
• Radiation Protection
• Issues of Concern
• Reviews

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Literature
Issues of Concern
Publications on

• Portal hypertension after SIRT
• Radiation induced ulceration of the stomach
• Radiation pneumonitis
• Extra-hepatic embolization
• Serum proinflammatory cytokine response

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84
Literature

• Clinical Studies
• mCRC
• HCC
• Other Cancer
• Mode of Action and Procedure
• Radiation Protection
• Issues of Concern
• Reviews

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85
Literature
a MUST to READ
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86
Literature
Review article

• There are at least 15 further review article
  available

Highly recommended
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87
Literature

• Clinical Studies
• mCRC
• HCC
• Other Cancer
• Mode of Action and Procedure
• Radiation Protection
• Issues of Concern
• Reviews

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Liver Cancer
What is most important to remember?

• All clinical studies with outcome
• Clinical experience published
• Overview to answer specific questions

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89
Literature
RECIST criteria
Complete Response (CR) Disappearance of all known
lesions on radiological grounds and normalization
of AFP for at least 4 weeks
Partial Response (PR) Decrease of 50 or more in
the tumour volume and/or a decrease of more than
50 in AFP or ferritin level for at least 4 weeks
Static Disease (SD) Decrease of tumour volume of
less than 50 or an increase in tumour volume of
not more than 25
Progressive Disease (PD) Increase of tumour
volume of more than 25 or the appearance of a
new lesion
90
Literature
Definitions
Median Survival Kaplan Meier Plot
The median survival is the time at which half the
subjects have died. The example survival curve
shows 50 survival at 5 months, so median
survival is 6 months.
91
Literature
Definitions
Hazard Kaplan Meier Plot
The hazard is the slope of the survival curve a
measure of how rapidly subjects are dying.
92
Literature
Definitions
Hazard Kaplan Meier Plot
The hazard ratio compares two treatments. If the
hazard ratio is 2.0, then the rate of deaths in
one treatment group is twice the rate in the
other group. If it is 0.33, the rate of death is
one third of the rate in the other group.