training module 8 – version 1.1 for internal use only ® literature

Training Module 8 – Version 1.1

For Internal Use Only

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Literature



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Clinical Studies

mCRC

HCC

Other Cancer

Mode of Action and Procedure

Radiation Protection

Issues of Concern

Reviews

Literature



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Published outcome data

Literature

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

Some words about patient collective beforehand:



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Literature

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

Some words about response rate beforehand:

CEA = carcinoembryonic antigen

AFP = α-fetoprotein



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Literature

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

Some words about survival beforehand:



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Definitions

Literature

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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Definitions

Literature

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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Definitions

Literature


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.

Treatment A

Treatment B



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Clinical Studies

mCRC

HCC

Other Cancer



Issues of Concern

Reviews

Literature



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mCRC

Clinical Studies

Literature



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Clinical Studies

Literature

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 12:1711-1720, 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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Clinical Studies

Literature

B.Gray et al, Annals of Oncology 12:1711-1720, 2001

SIRT within 4 weeks after port implantation Angiotensin injected prior to implant

Randomization

SIRT +

HAC with FUDR• 12 day cycle

• 4 weekly

• 18 cycles

HAC with FUDR• 12 day cycle

• 4 weekly

• 18 cycles

n=34 n=36

n=70

4 patients weren't eligible



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Clinical Studies

Literature


CR=complete response, PR=partial response, NC=no change, PD= progressive disease, NA=not assessable



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Clinical Studies

Literature




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Clinical Studies

Literature


Kaplan-Meier: Survival



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Clinical Studies

Literature




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Clinical Studies

Literature


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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Clinical Studies

Literature


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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Clinical Studies

Literature

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 2004;88:78-85

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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Clinical Studies

Literature

G. Van Hazel et al, Journal of Surgical Oncology 2004;88:78-85

SIRT 3rd or 4th day of 2nd cycle Angiotensin injected prior to implant

Randomization

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

n=10 n=11

n=21



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Clinical Studies

Literature


Time to progressive disease



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Clinical Studies

Literature


Survival by treatment



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Clinical Studies

Literature

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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Clinical Studies

Literature


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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Clinical Studies

Literature

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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Clinical Studies

Literature

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

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



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Clinical Studies

Literature

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 CarcinomaPeter 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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Clinical Studies

Literature

P. Gibbs and G. Van Hazel, Unpublished – Study open to accrual soon

SIRT 1st week of 1st cycle

Randomization

SIRT +

Systemic Chemo• Oxaliplatin

• Leucovorin

• 5-FU

• repeated 2 weekly

Systemic Chemo• Oxaliplatin

• Leucovorin

• 5-FU

• repeated 2 weekly

n>150 n>150

n>300



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Clinical Studies

Literature

Statistical powerful study

State of the art chemotherapy regimen

Multicentre study

P. Gibbs and G. Van Hazel, Unpublished – Study open to accrual



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HCC



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Clinical Studies

Literature

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 1994;70:994-999

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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Clinical Studies

Literature

W.-Y. Lau et al, British Journal of Cancer 1994;70:994-999

Angiotensin injected prior to implant

Randomization

SIRT

< 120Gy

n=8 n=8

n=18

SIRT

> 120GyAngiotensin injected prior to implant



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Clinical Studies

Literature




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Clinical Studies

Literature


Significant better median survival for patients receiving the higher dose (55.9 versus 26.2 weeks)

Dose of >120Gy is recommended

Three SIRT patients still alive after 10.4, 17.2 and 27.4 month respectively



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Clinical Studies

Literature


Small number of patients only

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



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Clinical Studies

mCRC

HCC

Combined Cancer



Issues of Concern

Reviews

Literature



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Literature

Clinical Experience in mCRC

Kennedy et al, USA, 208 patientsStubbs et al, NZ, 165 patientsGray et al, Aus, 71 patientsLim et al, Aus, 30 patientsPoepperl et al, Germany, 23 patientsWong et al, USA, 19 patientsMurthy, USA, 12 patients



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Literature

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



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Literature

Sean Garrean, N. Joseph Espat Surgical Oncology 2005;14:179-193

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 >50% reduction in CEA

Remarks Intraoperative dosimetry



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Literature


Author Gray et al.

Year 1992


Type of tumour mCRC

Therapy Y-90 ± HAC

Dose 755 – 4240 MBq

Result70% average decrease in pretreatment CEA45% response rate based on CT

Remarks No significant toxicity



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Literature


Author Gray et al.

Year 2000


Type of tumour mCRC

Therapy Y-90 + HAC

Dose Average activity 2130MBq

Result85% overall response rateMedian survival 13.5 months

Remarks Fatal radiation hepatitis in one patient



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Literature


Author Gray et al.

Year 2001


Type of tumour mCRC

Therapy HAC ± Y-90

Dose 2000 – 3000MBq

Result72% overall response rate versus 47% (HAC)40% higher death rate in HAC alone

Remarks Phase III randomized trial



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Literature


Author Stubbs et al.

Year 2001


Type of tumour mCRC

Therapy Y-90 + HAC

Dose 2000 – 3000MBq

ResultMedian survival 24.7 / 11.4 months (without extrahepatic / with extrahepatic disease)

Remarks Duodenal ulceration in six patients



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Literature


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

ResultMedian 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


Author Van Hazel et al.

Year 2004


Type of tumour mCRC

Therapy Y-90 + Systemic Chemotherapy

Dose 1500 – 2500MBq

ResultTime to progression 18.6 months versus 3.6 months

RemarksPhase III randomized trialRadiation hepatitis in one patient



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Literature


Author Murthy et al.

Year 2005


Type of tumour mCRC


Dose Median dose 39.6mCi

Result4/7 patients with response on CEA levels5/12 patients with stable radiologic response

RemarksTreatment after failure of multiple chemotherapy regimensGastric ulceration in one patient



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Literature


Author Wong et al.

Year 2005


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


Author Lim et al.

Year 2005

Number of Patients 32 / 5

Type of tumour mCRC / HCC


Dose Unavailable

Result 12 of 43 patients with partial response (CT)

Remarks Severe gastric ulceration in four patients



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Literature

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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Clinical Studies

mCRC

HCC

Other Cancer



Issues of Concern

Reviews

Literature



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Literature

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



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Literature


Author Lau et al.

Year 1994


Type of tumour HCC

Therapy Y-90 alone

Dose 26-409Gy to tumour

Result50% partial response by CT scan100% response by AFP or ferritin levelsMedian survival 55.9 weeks

Remarks Significant better survival in patients >120Gy



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Literature


Author Lau et al.

Year 2001


Type of tumour HCC

Therapy Y-90 alone

Dose Median cumulative dose 332Gy and 268Gy

ResultMedian survival 21.0 months (332Gy) Median survival 4.5 months (268Gy)

Remarks



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Literature


Author Murthy et al.

Year 2005


Type of tumour mCRC


Dose Median dose 39.6mCi

Result4/7 patients with response on CEA levels5/12 patients with stable radiologic response

RemarksTreatment after failure of multiple chemotherapy regimensGastric ulceration in one patient



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Clinical Studies

mCRC

HCC

Other Cancer



Issues of Concern

Reviews

Literature



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Literature

G. Poepperl et al. Cancer Biotherapy & Radiopharmaceuticals 2005;20:200-208

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

ResultPromising responses, long term survival data to be published

RemarksMild pancreatitis and gastric ulceration in one patient each



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Literature

D. Rubin et al. Integrative Cancer Therapies 2004;3:262-267

Author Rubin et al.

Year 2004


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

D. Coldwell et al. Society of Interventional Radiology (SIR) conference

Author Coldwell et al.

Year 2005


Type of tumour Metastatic Breast Cancer

Therapy Y-90

Dose Average dose 1.75GBq

Result100% response (PET-Scan)30/34 still alive after 10 months

RemarksAll patients report palliation of liver related symptoms



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Literature

D. Coldwell et al. World Congress on Gastrointestinal Cancer

Author Coldwell et al.

Year 2005


Type of tumour Metastatic Neuroendocrine Tumours

Therapy Y-90

Dose Average dose 1000Gy to tumour volume

Result67% response (PET-Scan)Symptom relief in symptomatic patients

Remarks 14 cases of grade 3 GI toxicity



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Literature

A. Kennedy et al. International Congress on Anti-Cancer Treatment

Author Kennedy et al.

Year 2005



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

J. King et al. World Congress on Gastrointestinal Cancer

Author King et al.

Year 2005



Therapy Y-90

Dose -

ResultRadiological 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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Clinical Studies

mCRC

HCC

Other Cancer



Issues of Concern

Reviews

Literature



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Literature

a MUST to READ



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Literature

Murthy et al, RadioGraphics 2005; 25:41-55



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Literature

Murthy et al, RadioGraphics 2005; 25:41-55

SIRT therapy principles

Thera-Spheres® versus SIR-Spheres®

Patient selection criteria

Therapy planning and workup

Clinical outcomes

Complications



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Literature

a MUST to READ



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Literature

Salem et al, J Vasc Interv Radiol 2006; 17:1251-1278

Technical and methodological considerations

Patient screening and selection

Vascular anatomy

Treatment process

Thera-Spheres® and SIR Spheres®



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Literature

a MUST to READ



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Literature

Salem et al, J Vasc Interv Radiol 2006; 17:1425-1439

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

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

a MUST to READ



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Literature

Liu et al, J Vasc Interv Radiol 2005, 16:911-935



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Literature

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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Literature

Szyszko et al, Nuclear Medicine Communications 2007, 28:15-20

PET

CT

before treatment after treatment



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Literature

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

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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Clinical Studies

mCRC

HCC

Other Cancer



Issues of Concern

Reviews

Literature



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Literature



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Literature

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

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



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Clinical Studies

mCRC

HCC

Other Cancer



Issues of Concern

Reviews

Literature



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Issues of Concern

Literature

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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Clinical Studies

mCRC

HCC

Other Cancer



Issues of Concern

Reviews

Literature



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Literature

a MUST to READ



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Review article

Literature

There are at least 15 further review article available

Highly recommended



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Clinical Studies

mCRC

HCC

Other Cancer



Issues of Concern

Reviews

Literature



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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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RECIST criteria

Literature

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



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Definitions

Literature

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.



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Definitions

Literature


The hazard is the slope of the survival curve – a measure of how rapidly subjects are dying.



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Definitions

Literature


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.

training module 8 – version 1.1 for internal use only ® literature

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