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Eva Gallardo, MDMedical Manager, Biocompatibles UK

Drug Eluting Bead: Advanced Applications

Colorectal MetastasesNeuroendocrine Metastases

Combination with RFA

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Doxorubicin Bead Irinotecan Bead

Primary Liver Cancer Colorectal MetastasesVery Early/Early Stage Prior to resection Bridge to transplant RFA + PRECISION TACE

Intermediate Stage Precision I Precision II Precision V

Advanced Stage Sorafenib + PRECISION TACE

Secondary Liver Cancer Other Primary Cancers

Renal Breast Melanoma Gastric Neuroendocrine Cholangiocarcinoma Sarcoma

Early CT Lines

Late Stage

DEB: Clinical Programme

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Investigators: Camillo Aliberti, MD Giammaria Fiorentini, MD

Department of Diagnostic and Interventional Radiology,Delta Hospital AUSL Ferrara, Ferrara Italy

Department of Oncology, General Hospital San Giuseppe, Empoli, Florence, Italy

PRECISION TACE in treatment of Colorectal Metastases

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Advanced Colorectal Cancer • The liver is the most common site of metastatic disease.

• 15-30% of patients will have synchronous liver metastases at the time of diagnosis. Up to 60% will develop hepatic metastases during the course of their disease

• Metastatic disease in the liver is the primary determinant of survival in patients with colorectal cancer

• Low (around 20%) response rates to 5-FU containing chemotherapy regimens

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Median Survival in First Line Phase III StudiesMonths

Best supportive care 5

Biomodulation of 5-FU Piedbois JCO 1992 10

Saltz NEJM 2001 (IFL) 14 Irinotecan/5-FU/LV Goldberg JCO 2004 (IFL) 15

17 Douillard Lancet 2000 (Folfiri)

De Gramont JCO 2000 (Folfox) 16 Oxaliplatin/5-FU/FA

Goldberg JCO 2004 (Folfox) 20

23 FOLFOXIRI

24.4 Hoschster ASCO 2006 - TREE2 Oxali/Bev + salvage CP11 2 drugs+biologic+salvage

**subgroup

Hurwitz NEJM 2004 IFL/Bev + salvage Oxali 25.1

BMJ 1993

FOLFOX/FOLFIRI 22Tournigand JCO 2004 sequential 2 drugs

Falcone ASCO 2006 concurrent 3 drugs - no biologics

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Rationale for Chemoembolization treatment in metastatic CRC

• Blood supply from hepatic artery

• Maximize tumour cell kill while minimizing toxicity to normal tissues (heavily systemically treated patients)

• Increase tumour response throughout increased drug delivery into tumour

• Increase resectability rates

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Disease control after Chemoembolization

• n= 207 • Local tumour control:

– Partial response: 12%, stable: 51%, progression: 37%

• Survival rates: – 1y: 62%, 2y: 38%

• Median survival times:– From diagnosis: 3.4y, from TACE: 1.34y

Prof T Vogl, ASCO 2007

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• 62 patients (M/F = 42/20), median aged 64.6 (range 42-85) • Not operable and pretreated at least two lines of chemo

(range 2-6) • Measurable lesions with size > 1cm• Tumour burden <70% of liver volume• Presence of minimal extrahepatic sites • Performance Status: 0-2 (WHO criteria), life expectancy >3

months, age < 86 years • Normal or 2xN bilirubine

Irinotecan Bead in Advanced Colorectal Cancer: Patient

Selection

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• Diagnostic angiography (DSA) was performed

• Under fluoroscopic guidance, a solution of DC beads loaded with Irinotecan and mixed with non-ionic contrast was injected into: RHA 39%, LHA 36%, RHA & LHA 25%

• Maximum dose 4 ml (2ml of 100-300mm and 2ml of 300-500mm) with 200mg of Irinotecan

• 2-3 TACE 4 weeks

Irinotecan Bead in Advanced Colorectal Cancer: Methods

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• 138 TACE procedures

• 48 with 100mgr Irinotecan into 2ml DC Bead

• 98 with 200mgr Irinotecan into 4ml DC Bead (no significant toxicity observed)

• 100% technical success

• One case of acute pancreatitis, resolved spontaneously

Irinotecan Bead in Advanced Colorectal Cancer: Feasibility

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Postembolization-syndrome

RUQP (G2-G3) 100%

Fever (G2) 90%

Nausea and Vomiting (G2-G3)

100%

Increased Transaminases (G2-G3)

80% 0

5

10

15

20

25

30

35

40

Procedures

Pain Vomiting Fever Asthenia

Irinotecan Bead in Advanced Colorectal Cancer: Toxicity

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• Prophylactic treatment against nausea

• Tropisetron 5mg, 1 vial before TACE and at +6 hours,Prednisone 25mg tb 08.00 am and 08.00 pm day 0,+1,+2,+3,+4,+5

• Prophylactic treatment against pain

• Morphine 10mg, 1 vial, 30 minutes before TACE and at +6 hours.

• Intra-arterial Lidocaine 5ml just before TACE.

• Prophylactic treatment against infection

• Cefazolin 2000mg 08.00 am and 08.00 pm day 0,+1,+2

• On day +1, +2 at 08.00 am and 08.00 pm following observed symptoms.

Postembolization-syndrome: Selected Therapy

Irinotecan Bead in Advanced Colorectal Cancer: Toxicity

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• The median follow-up was 15.4 months

• 1 month CT scan showed reduction of metastatic CE 85%, range 75-100% in all patients

• RECIST at 3 months: 78%

• 55/62 pts (90%) declared a general improvement of QoL lasting 6.5 months, range 3-12 

Irinotecan Bead in Advanced Colorectal Cancer: Response to

Treatment

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• Median survival not reached at 22 months

• Median Free Time from symptoms 5.3 (5-20 months)

• Median Time to further chemoteraphy 6.3 (5-22 months )

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16 18 20 22time months

surv

ival

(%

)

Irinotecan Bead in Advanced Colorectal Cancer: Survival

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18 months after TACE

Irinotecan Bead in Advanced Colorectal Cancer: Cases

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02.2005 09.2005

6 months after TACE

Irinotecan Bead in Advanced Colorectal Cancer: Cases

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• TACE with Irinotecan DC Bead could be proposed as palliative therapy for unresectable pretreated Liver Metastases from CRC

• Promising preliminary results should be confirmed in further studies in larger population

Irinotecan Bead in Advanced Colorectal Cancer: Conclusion

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Principal Investigator: Thierry De Baere, MDChief of Interventional Radiology Department

Institut de Cancérologie Gustave Roussy - Villejuif - France

Neuroendocrine Metastasis

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Neuroendocrine Tumours

• Variety of primaries with shared characteristics including hormone secretion, high vascularization and somatostatin receptor expression

• Tumours arise most often from the gastro-intestinal tract and mainly the small bowel

• The malignancy grade and the stage at diagnosis are the two major prognostic factors

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Management Protocol

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Reported HAE and HACE Series

Carcinoid tumours Islet cell carcinomas

HACE HAE HACE HAE

Study% CR + PR (no.) Study

% CR + PR (no.) Study % CR + PR (no.) Study

% CR + PR (no.)

Hazarizadeh et al., 1992 50.0 (4/8) Hanssen et al., 1989

71.0 (5/7) Carrasco et al., 1983

100.0 (3/3) Carrasco et al., 1983

50.0 (3/6)

Rusznieweski et al., 1993] 33.3 (6/18) Moertel et al., 1994

69.6 (16/23) Mavligit et al., 1993

80.0 (4/5) Moertel et al., 1994

82.0 (14/17)

Therasse et al., 1993 35.0 (6/17) Wangberg et al., 1996

42.5 (17/40) Kim et al., 1999

50.0 (7/14) Eriksson et al., 1998

17.0 (2/12)

Kim et al., 1999 25.0 (4/16) Eriksson et al., 1998

38.0 (11/29) Dominguez et al., 2000

57.0 (4/7) Ajani et al., 1988 60.0 (12/20)

Dominguez et al., 2000 50,0 (4/8) Carrasco et al., 1983

83.0 (5/6) Rusznieweski et al., 1993

0.0 (0/5)

Roche et al., 2003 43.0 (6/14) Loewe et al., 2003 73.0 (16/22)

Drougas et al., 1998 6.7 (1/15)

Average 32.0 (31/96) Average 55.0 (70/127)

Average 53.0 (18/34) Average 56.0 (31/55)

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Doxorubicin Bead in NET:Materials and Methods

• 20 patients with liver metastases from low-grade GEP tumour

• Progressive liver disease on two subsequent imaging studies according to RECIST criteria

• Disease predominant to the liver

• Up to 4ml DC Bead 500-700mm loaded with up to 100mg doxorubicin

• Concomitant treatment with long-acting ST analog

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Doxorubicin Bead in NET:Results

• 34 sessions (6 unilobar, 14 bilobar)

• RECIST 3M: – 16/20 (80%) partial response– 3/20 (10%) stable disease– 1/20 (15%) progressive disease

• After a median follow-up of 15 months (6-24), disease remained controlled without tumour progression in 45%

• 1 patient become resectable

Progression

161520

0%10%

20%30%

40%50%60%

70%80%

90%100%

0 6 12 18 24Months since treatment

Pro

gre

ssio

n r

ate

Patients at risk

At 12 months : 47% (95%CI = 23% - 72%)

Median Time to Progression: 15 months

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• Post-embolisation syndrome:– < 7 days in 67% sessions– > 7 days in 22% sessions– No symptoms in 11% sessions

• Hypodense subsegmental peripheral areas (TACE-induced necrotic liver tissue?) in 5 patients at 1 month CTscan

• 1 death: resected patient due to postoperative septic complications

Doxorubicin Bead in NET:Toxicity

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Doxorubicin Bead in NET:Cases

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Doxorubicin Bead in NET:Cases

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Tumour resected 2 months after PRECISION TACE

Doxorubicin Bead in NET:Cases

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• TACE with doxorubicin bead yielded a 90% response rate in patients with progressive liver metastases from a GEP tumor without severe complications

• These promising preliminary results warrant a comparative study in a larger population

Doxorubicin Bead in NET: Conclusion

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Principal Investigator: Riccardo Lencioni, MDAssociate Professor of Diagnostic and Interventional

RadiologyDepartment of Oncology, Transplants, and Advanced

Technologies in Medicine – Pisa University, Italy

Combined PRECISION TACE/RFA: Results and Outcome

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HCC

PST 0-2, Child-Pugh A-BPST > 2

ChildPugh C

Very earlystage

Single< 2 cm

Earlystage

Single or 3 < 3 cmPS 0

Advancedstage

Portal invasionN1 – M1PS 1-2

Terminalstage

Intermediatestage

MultinodularPS 0

BSC

PST 0Child

Pugh A

New agentsResection Transplant Ablation TACE

SingleNo portal HT

Normal bilirubin

Associated diseases

No Yes

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Bio-Heat Equation

ct

2 Qcs

4r2

r

cb Io

216 2r4

Coagulation

Necrosis

Energy

Deposited

Tissue

Interactions

Heat

Loss= x -

RFA: Inherent Limitations

modified from Goldberg SN et al, AJR 2000

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Vessel

Sub-lethal heating(45-50 °C)

50 °C

RFA: Inherent Limitations

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modified from Ahmed et al, Radiology 2005

RFA plus Doxorubicin vs RFA Alonein Animal Tumour Models

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RF-induced coagulation

Increased peripheral necrosis

Normal tissue

modified from Ahmed et al, Radiology 2005

RFA plus Doxorubicin vs RFA Alonein Animal Tumour Models

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• Rossi S, Radiology 2000• Yamasaki T, Cancer 2001• Yamakado K et al,JVIR 2002• Gasparini D, Radiol Med 2002 • Akamatsu M, Liver Int 2004• Luo BM, World J Gastroenterol 2005• Maluccio M, JVIR 2005• Shen SQ, Hepatogastroenterology 2005• Yamasaki T, J Gastroenterol 2005• Liu YM, World J Gastroenterol 2006• Veltri A, Eur Radiol 2006• Kurokohchi K, Oncol Rep 2006• Lim HS, AJR 2006• Takaki H, JVIR 2007• Kobayahi M, Liver Int 2007• Helmberger T, Digestion 2007• Wang JB, Qual Life Res 2007• Liao GS, Eur J Surg Oncol 2008• Fuke H, Aliment Pharmacol Ther 2008• Yamakado K, Radiology 2008

Combined TACE / TAE and RFA in HCC

20 clinical studies

all “support” the combined

approach

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Lencioni R et al, J Hepatol 2008 (in press)

DC Bead (Biocompatibles, UK): embolic microsphere that has the ability to actively sequester doxorubicin hydrochloride from solution and release it in a controlled and sustained fashion

Hypothesis: intra-arterial administration of doxorubicin eluting bead to HCC tumours incompletely killed by RFA induces necrotic phenomena in peripheral areas exposed to sub-lethal heating, improving tumour response

DEB-Enhanced RFA of HCC: A Pilot StudyBackground / Hypothesis

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DEB-Enhanced RFA of HCC: A Pilot StudyDesign / Enrollment Criteria

Prospective, intention-to-treat, single-arm pilot study

Primary endpoints: safety and tumour response

Inclusion criteria

- Adult patient with single HCC 3.0 – 7.0 cm - Residual viable tumour at CT / MRI 1-2 hrs after RFA- Child-Pugh class A, ECOG 0, ASA ≤ 3- PT ratio > 50%, platelets > 50,000/mm3

Exclusion criteria

- Eligibility for liver resection or transplantation- Vascular invasion / extrahepatic disease- Any previous treatment for HCC

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DEB-Enhanced RFA of HCC: A Pilot StudyMaterials and Methods

20 pts (mean age, 70 ± 6 ) enrolled 09/05 – 11/06

- Tumour diameter 3.3-7.0 cm (mean, 5.0 cm ± 1.4)

Follow-up period 6-20 months (mean, 12 months ± 5)

DC Bead (Biocompatibles) injection < 24 hrs of RFA

- 50 mg doxorubicin in 2 ml of 100-300 μm beads - Additional loads (100-300 / 300-500 µm) if needed

Tumour response: RECIST criteria - EASL amendment

- CR: absence of enhancement at 1-month CT / MRI- Confirmed CR: CR lasting no less than 6 months- OR: confirmed CR target lesion, no new lesions

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61% +

Abl

atio

n V

olum

e (m

m3)

0,000

20,000

40,000

60,000

80,000

100,000

120,000

140,000

160,000

180,000

Standard RFA DEB-Enhanced RFA

DEB-Enhanced RFA of HCC: A Pilot StudyResults – Change in Ablation Volume

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DEB-Enhanced RFA of HCC: A Pilot StudyResults – Clinical Case # 2

Pre-treatment CT

6 cm

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DEB-Enhanced RFA of HCC: A Pilot StudyResults – Clinical Case # 2

MRI after standard RFA

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DEB-Enhanced RFA of HCC: A Pilot StudyResults – Clinical Case # 2

DEB administration

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DEB-Enhanced RFA of HCC: A Pilot StudyResults – Clinical Case # 2

MRI after DEB administration

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15

10

5

CR IR PD

14

6

DEB-Enhanced RFA of HCC: A Pilot StudyResults – Target Tumour Response

CR IR PD

12

6

2

15

10

5

Final Response

(mean follow-up, 1 year)

Initial Response(1-month CT / MRI))

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Target lesions

Table. Overall Response at the End of Follow-Up

New lesions

CR

PR

CR / PR

PD

Note: Numbers are numbers of patients. Overall number of patients: 20.

No

No

Yes

Yes / No

Overall response

CR

PR

PD

No. (%)

10 (50%)

5 (25%)

3 (15%)

2 (10%)

DEB-Enhanced RFA of HCC: A Pilot StudyResults – Overall Response

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0 6 12 18 240

20

40

60

80

100

DEB-enhanced RFA (n = 20)

months

30

100%

DEB-Enhanced RFA of HCC: A Pilot StudyResults – Overall Survival

92%

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DEB-Enhanced RFA of HCC: A Pilot Study

Results – Conclusion• This pilot clinical study provides the first evidence of

the synergy between RF ablation and local delivery of a chemotherapeutic agent in human cancer treatment

• Intraarterial DEB administration substantially increased the effect of RF ablation and did not cause any major complication. DEB-enhanced RF ablation induced a high rate of CR and has potential to become the standard of care for uninodular nonsurgical HCC resistant to standard RF treatment