Title: Interim Analysis of DC/LC Bead Open Surgical Registry in Primary and Metastatic Liver Tumours
1Interim Analysis of DC/LC BeadOpen Surgical
Registry in Primary and Metastatic Liver Tumours
- Robert Martin, MD
- Associate Professor of Surgery
- Division of Surgical Oncology
- University of Louisville
2HCC
- Data suggests that HCC will be on the rise due to
hepatitis for 10-15 more years. - 70-95 of HCC patients also have HBV or HCV
infections. - HCC is more common in men than in women, with a
male-to-female ratio of 3-61. - In areas of low incidence such as the United
States and parts of Europe, the average patient
age at diagnosis is 60-80 years. - In areas of high incidence, patients present
earlier, typically at the age of 30-50 years.
3Metastatic Cancer
- In the United States and Europe, metastatic liver
disease is the most common cause of malignancy in
the liver. - World-wide, it is estimated that there are over
1.3 million cases. - Between 30-70 of patients who die from cancer
have liver metastasis at autopsy.
4Metastatic Colorectal US
- Colorectal Cancer
- In the US 145,000 - 160,000 new cases of
colorectal cancer occur annually and account for
an estimated 60,000 cancer deaths. - Colorectal cancer is the second leading cause of
cancer-related death in the US and approximately
50 of these deaths can be attributed to liver
metastases.
5Current Therapies for Primary and Secondary
Cancers to Liver
- Surgical
- Resection
- Transplantation
- Local
- Radiofrequency Ablation
- Transcatheter Arterial Chemoembolisation (TACE)
- Precision Transcatheter Arterial
Chemoembolisation (TACE) - Transarterial Embolisation
- Cryoablation
- Microwave Ablation
- Radio-Embolisation (Yttrium-90)
- Hepatic Arterial Infusion Pump
- Systemic
- Chemotherapy
- Best Supportive Care
6Rationale of Intra-arterial Hepatic Infusion
TEMPORARY VASCULAR BLOCKING
REGIONALLY ADMINISTERED CHEMOTHERAPY
7Cytotoxic Drug Characteristics
Drug Half life (mins) Liver extrac Clearance TB (l/min)
5-FU 10 22-45 2-5
FUDR lt10 69-92 5-15
IRINO-SN 38 60-90 38-72 9-25
MITO-C lt10 7-18 3-5
CDDP 20-30 8-50 0.3-0.5
DOXO 60 45-50 -
8Hepatic Arterial Infusaid Pump
9Hepatic Intra-arterial Pump Chemotherapy
Author Year No. Patients Type of Patients Response Rate Rate of Biliary Sclerosis ()
Balch 1983 81 Unresectable 88 NR
Niederhuber 1984 50 Unresectable 83 NR
Chang 1987 21 Unresectable 62 21
Kemeny 1987 48 Unresectable 50 8
Hohn 1989 50 Unresectable 42 24
Wagman 1990 31 Unresectable 55 NR
15 Resected NA NR
Martin 1990 33 Unresectable 48 26
Rougier 1992 70 Unresectable 43 25
Allen-Mersh 1994 51 Unresectable NR 0
Lorenz 1998 226 Resected NA 0.5
Kemeny, N. 1999 74 Resected NA 5.4
Kemeny, M. 2002 30 Resected NA 6.7
Martin, RCG 2002 21 Resected NA 35
NR, Not Reported
10Treatment of Liver Tumours
- Surgical Resection
- Lobectomy
- Segmentectomy
- Non Anatomic wedge resection
- Orthotopic Liver Transplantation
- only for selected cases of hepatoma,
hepatoblastoma, neuoroendocrine tumours - Cryoablation
- Radiofrequency ablation
- Ethanol injection
- Hepatic artery infusion pump
- Chemoembolisation
- Systemic chemotherapy trials
11Rationale
- Normal liver tissue receives its 75-83 of its
blood supply from the portal vein - Liver tumours receive 90-100 of their blood
supply from the hepatic artery - Logically you can destroy the tumour using this
pathway while preserving normal liver function
12TACE Side Effects
- Post CE Syndrome Admission for 2-4 days
- Pain, fever, fatigue, anorexia, increased LFTs
- Complications
- Bacteremia, effusions, encephalopathy, renal
dysfunction, hepatic failure, ischemic colon,
hypotension (carcinoid crisis) - Procedure Related Mortality 2-6 of patients
dependant on severity of underlying liver
function impairment - Mortality is dependant on bilirubin, albumin,
portal vein involvement, technique
13TACE Outcomes
- Over 1200 papers have been published regarding
Embo/TACE - Protocols outcomes vary by investigators
- Total tumour necrosis ranges from 50-100
- Patient Survival (Lo, 2002 Llovet, 2002)
- One Year 57-82
- Two Year 31-63
- Three Year 26
- But can we do better? Can we achieve same
results with better QOL, less SE, better
response?
14Precision TACE
15TACE vs DEB Drug Distribution
Doxorubicin and Lipiodol with embolisation
Doxorubicin Drug Eluting Beads
Doxorubicin Systemic Injection
16Precision TACE
- PRECISION Clinical Trials
17PRECISION I II Trials
- Structure
- Multi-center, prospective, phase I/II studies
- Principal Investigators
- Drs Jordi Bruix and Joseph Llovet, BCLC Group,
Barcelona. - Dr Ronnie T.P. Poon, Queen Mary Hospital, Hong
Kong. - Endpoints
- Safety
- Pharmacokinetics
- Efficacy (3 and 6M CT Scan)
- European Association for the Study of Liver
(EASL) - Response Evaluation Criteria in Solid Tumours
(RECIST) - Population
- 63 patients, Child Pugh A, non-surgical
candidates
18Key Findings ASIA Trial
- Preliminary data from PRECISION I Asia trial
showed the following key findings - Low levels of Plasma Doxorubicin
- Low complication rate for first 30 patients
- Positive trend in tumour response
- The Drug-Eluting Bead demonstrated a significant
reduction in systemic exposure compared with the
TACE procedure. Peak doxorubicin levels were
reduced by more than 99. - Conclusion reduction in systemic plasma levels
of doxorubicin observed with the Drug-Eluting
Bead lead to better patient tolerance of the
therapy.
19Tumour Response
More than a doubling of response rate from 35 to
87 in the same hospital
Tumour Response
The 6-month tumour response of 35 went on to
deliver a statistically-significant survival
benefit at 2 years of 63.
20DC/LC Bead vs TACE HCC
1 yr survival 2 yr survival
DC/LC Bead 92.5 88.9
TACE 82 63
Bland 75 50
Observe 63 27
Improved Overall Survival at same institution and
similar patients
Llovet Lancet 02, Llovet J Hepatol 07
21Trans Arterial Chemoembolisation (TACE) of liver
metastases (LM) from colorectal cancer (CRC)
using irinotecan-eluting beads
Giammaria Fiorentini, Camillo Aliberti,
Istituto Tumori Toscano Department of Oncology,
General Hospital San Giuseppe, Empoli, Florence,
Italy Department of Diagnostic and
Interventional Radiology, Delta Hospital AUSL
Ferrara, Ferrara Italy
22Phase II clinical study Objectives and design
Objectives Assess safety and effectiveness of
embolic microspheres loaded with irinotecan,
administered as TACE, (DEB-TACE), in pre-treated
patients with unresectable LM from
CRC Design Single-arm Phase II study (N20)
23RESULTS Longer Term Results
- Performed with 100 technical success
- Response Rate 16/20 pts (80), according RECIST
- CT showed a reduction of the lesional contrast
enhancement in 16/20 pts (80) - Reduction of more than 50 of CEA in 12 pts (60)
- Median duration survival 210 d. ( 90-380), 15
pts are alive - Median duration response 178 d. (65-320)
- Mortality 3 progressions, 1 pulmun embolism, 1
heart stroke
24Irinotecan Better Second Line Agent
- 2007 Meeting of the Cardiovascular and
Interventional Radiological Society of Europe
(CIRSE) on September 9th, Dr Camillo Aliberti. - 20 pts HCM who had progressed
- 38 cycles of DEBIRI 100mgs of irinotecan.
- Median survival of 210 days (range 90 to 380
days). - The procedure was well tolerated
- median LOS 3 days (range 1-10 days).
- Additional quality of life data demonstrated that
90 of the patients reported an improvement.
25Irinotecan DC/LC Bead vs FOLFIRI
- DEBIRI v FOLFIRI 32 pts disease progression
- Prior first line systemic chemotherapy.
- 14 patients were treated with 27 procedures of
DEBIRI and 18 patients with 144 doses of FOLFIRI. - DEBIRI Overall response 80 vs FOLFIRI 10
- 8 week quality of life improvement 70 vs 30
- Survival data is pending.
26DC Bead Europe LC Bead United States
27Open Surgical RegistryWhy a registry?
- Optimal Evaluation of new technology
- New Device
- New Delivery System
- New Chemotherapy
- Allows for Multi-institutional collaboration
- Overcomes the single institutional bias
- Steepens the learning curve
- Improves quality assurance
- Provides the basis for future Phase I, II, and
III trials
28DC/LC Bead Open Surgical Registry
- A multi-institutional registry initiated 06/2007
- Goals
- gain further insight and response to this
established liver directed therapy. - Aims of the Registry
- 1) Gain a better understanding of the uses of
DC/LC Bead therapy in metastatic and primary
hepatic malignancies - 2) Understand the limitations, concerns, and
complications that earlier users or non-DC/LC
Bead users have. - 3) Identify the next important question that
should be answered through a clinical trial. - 4) Create a multi-institutional group that will
both enroll in this study, but more importantly
enroll in future, prospective intra-arterial
hepatic therapy studies.
29Open Surgical Registry Patient Selection
- Inclusion Patients w/ unresectable primary or
metastatic tumours - Patients considered suitable for conventional
TACE. - Patients with Primary or Secondary liver tumours
not suitable for radical therapies such as
resection, liver transplantation, or percutaneous
therapies. - Patients with well preserved liver function
without any liver decompensation - Exclusion
- Advanced Tumoural Disease
- BCLC class C (vascular invasion including
segmental portal obstruction, extrahepatic spread
or cancer-related symptoms). - Diffuse HCC meaning massive ill-defined tumour
involvement. - Advanced liver disease
- Active gastrointestinal bleeding, encephalopathy
or clinically relevant ascites. - Any contraindication for hepatic embolisation
procedures.
30Open Surgical Registry Tumour Selection
- DC/LC Bead is indicated for the embolisation of
vessels feeding malignant hypervascularised
tumours. - When evaluating tumours suitable for PRECISION
TACE with the DC/LC Bead, it is relevant to
consider the tumour mass as a percent of the
total liver volume. - Suggested limits are to keep tumour mass at 33
of total liver mass, 50 of a single lobe and/or
maximum single tumour diameter 15cm. - Limited extra-hepatic disease (i.e. gt80 of
disease liver) - Usually Lobar treatment with repeat treatments
performed every 3-4 weeks.
31Open Surgical Registry Treatment Guidelines
- PRECISION TACE with the DC/LC Bead can be
performed every 1-2 months for the first 6 months
then as required. - Current TACE practice should be followed.
Initially 3-4 treatments would be the common
practice depending on tumour response. - Follow-up recommendations for PRECISION TACE with
the DC/LC Bead should follow current practice
recommended for conventional TACE.
32Open Surgical Registry Dosage Guidelines
- Doxorubicin for lobar dose 150mg per treatment.
- Dose reduction needed for smaller volume disease
or underlying hepatic dysfunction. - Irinotecan 100 mg per embolisation with
appropriate dose reduction.
33Open Surgical Registry Clinical Follow-up
- Day of Treatment - Day 0
- Two week clinic visit Performance Status
Clinical Follow-up (FU) - Day 15-30 re-treatment of other lobe
- Day 30-45 additional treatments (if required)
- First imaging 2 months from first treatment
- Metastatic Disease CT/PET
- HCC CT or MRI
- Long term imaging clinical FU every 2-3 mo
- For Two years or until death
34Open Surgical Registry United States Centers
- Currently have 9 Centers (86 patients)
- Huntville, Ala Dana Tomalty (IR), Mike Samatoka
(HPB Surg), Melissa Frazier (RN) - Little Rock, Ar Ken Robbins (IR), Kathy King
(RN) - Brown University Greg Dubel (IR)
- Colorado Springs, CO Ryan OHara (IR)
- Louisville, Ky Cliff Tatum (IR), Robert Martin
(Surg Onc) - Atlanta, GA Piedmont Steve Citron (IR)
- Mobile, Ala Lee Thompson (HPB Surg)
- Phoneix, Az David Wood (IR)
- Denver, CO Charlie Nuttering (IR)
35Open Surgical Registry USA Pending IRB
- Atlanta, GA Henry Krebs (IR)
- UC Davis Wayne Monsky (IR)
- Tupelo, Miss Jeff Howard (IR)
- Gainesville, Fl Will Williams (IR)
- U of Maine Lisa Rustein (HPB Surgeon)
- Brigham and Womens Rick Swanson (HPB Surgeon)
36Open Surgical Registry Europe Pending Sites
- 9 Current Europe Centers Pending
- Nis Serbia Prof Bonsjakovik (IR)
- Barcelona Spain Joan Falcó Fagés (IR)
- FH Plzen, CzechFrantisek Slauf M.D.
- FH Brno, Czech prof. Vlatimil Valek M.D.
- Prague Homolka Radko Kriz M.D.
- Prague UVN Jiri Lacman M.D.
- Prague Motol Radek Padr M.D.
- LiberecJan Beran M.D.
- Scotland- Aberdeen Royal Infirmary Hospital
Jana Maskova, MD
37Registry UpdateHepatocellular Cancer
- Total of 24 patients 90 Hepatitis.
- Child A 20 Child B 40 Child C 40
- Liver Involvement lt25 60
- 26-50 30 gt50 10
- 15 Prior Resection/ RFA with recurrence
- Median Number of Tumours 5 (1-14)
- Median Size 4.3 (2-11.5)
38Registry UpdateHepatocellular Cancer
- Treatment Doxorubicin bead (75-150mg)
- Median treatments 3 (1-4)
- 25 Treated with concurrent Nexavar
- Median LOS 23 hour (outpatient 2 days)
- Adverse Events 10 from Post Embo Syn
- Response Rates 3 months 80, 6 months 75
39Registry UpdateMetastatic Breast
- 5 patients metastatic Breast
- All patients with liver dominant disease
- Patients received repeat embolisations with
Doxorubicin loaded beads (max 150mg per
embolisation) - Chemotherapy was loaded in DC Bead of 100-300µm
or 300-500µm. - Two patients continued oral therapy at same time
40Registry UpdateMetastatic Breast
- Median number treatments 3 (2-4)
- 100 Had prior systemic Doxo for their adjuvant
therapy for primary breast. - Cardiac function MUGA no change
- Overall, objective response using modified RECIST
criteria was 95 at 3months, and 92 at 6 months
41Met Sarcoma
- Two patients treated
- Liver Only disease.
- Appropriate biology assessment prior to therapy.
42Other Disease Sites
- Lung n4 (Doxo)
- Esophageal n3 (Irinotecan)
- Kidney n2 (Doxo)
- Thyroid n2 (Doxo)
- Sarcoma n1 (Doxo)
- Cholangiocarcinoma n2 (Irino)
43Transarterial Chemoembolization of Metastatic
Colorectal Carcinoma with Drug Eluting Beads
Multi-Institutional Study.
- R.C.G. Martin1, D. Tomalty3, M. Samotowka3, C.
Tatum1, K. Robbins2 - Oral Presentation Society of Interventional
Radiology - Washington, DC March 14th
1University of Louisville Norton Cancer
Institute, Louisville, KY 2Baptist Health,
Little Rock, AR 3Huntsville Hospital,
Huntsville, AL
44Irinotecan Bead Infusion Technique
- At initial evaluation treatment angiography was
performed. - For treatment and to plan for contralateral
dosing - Under fluoroscopic guidance
- Pretreatment with 1 Xylocaine 3-5cc
- Then 2-4 ml of 100-300um and/or 300-500um of DC
Beads loaded with IRI 100mg and mixed with
non-ionic c.m. was injected into the artery
feeding the metastases. - Response measured by Modified RECIST
45Results Patient Demographics
- 30 Patients treated 55 Women 45Men
- 71 Caucasian Age median 52 (42-75 years)
- 85 Failed at least first line chemotherapy
- 66 at First and Second Line therapy
- FOLFOX, FOFIRI, Avastin, Erbitux, Xeloda, etc
- 60 on Therapy for gt 12 months
- 50 had some extra-hepatic disease.
46Results Patient Tumor Burden
- 64 26-50 Tumor Replacement
- 15 lt25 21 gt50
- Median tumors 5 (2-25)
- 50 had bilobar tumor distribution
47Results Treatment Irinotecan Beads
- Median treatments 2 (range 1-5)
- Treatment dose 100mg (Range 100-200)
- Total treatment pt 200mg (range 200-650)
- 86 Lobar treatment
- 2 patients whole liver 2pts segmental
- 60 treatment caused partial stasis
- 30 of patients were treated with concurrent
chemotherapy - FOLFOX or Xeloda
48Results Peri-procedural outcomes
- Outpatient 60 of patients
- Admission LOS (1-5 days)
- Multivariate analysis found increased risk admit
- 1) Increasing number of treatments gt3
- 2) Degree of stasis complete
- Adverse Events
- 20 experienced Post-embolic syndrome (the
admitted patients) - Bilirubin, ?-GT, aspartate aminotransferase
(AST), alanine aminotransferase (ALT), and
alkaline phosphatase (ALP) transient increase.
49Results Initial Response Rates
- Median Follow Up 9 months
- Response rates (PR CR) 75 3months
- 66 at 6 months.
50Summary
- Chemoembolization using Irinotecan LC Bead was
safe and effective in the treatment of MCC - Minimal complication rate and minimal quality of
life interruption. - Acceptable tumor response and sustained reduction
of CEA levels.
51Conclusion
- Further enrollment in the registry is needed
confirm this data - Stasis, LOS, QOL effects, etc
- The precise timing of Hepatic Arterial Drug
Eluting Beads is not known now. - Needs to be discussed on a case by case basis
True Multi-disciplinary team. - IR, Med Onc, Surg Onc, Surg, Rad Onc,
52Open Surgical Registry Summary
- Seen minimal toxicity
- PE syndrome 5
- Max response rates at 3 an 6 months
- 95 and 92
- Metastatic Colorectal Experience
- Safe and Effective, further Phase 3 studies
initiated - Need more sites to make this a true working group
(United States, Europe, Asia)
53The Key Personnel Hepatic Intra-arterial
Therapy Program
Surgeon Oncology
Patients
Patients
Must involve a true Multi-Disciplinary Team
approach and Communication on a weekly and daily
basis. No one therapy is effective in providing
success alone!!
Transplant
Interventional Radiology
Radiation Oncology
Medical Oncology
Gastroenterology
Patients
Patients
54Summary
- Paradigm Shifts in treatment
- Not going to Stasis.
- Goal are to deliver a cytotoxic chemotherapy not
to make it ischemic. - Not a One and Done! Requires multiple Rx
55Conclusion
- DC/LC Bead technology represents a novel drug
delivery device that is safe and effective. - Future Phase I, II, and III trials are needed to
further define the true indications.
56Thank You
- Robert Martin, MD
- Robert.Martin_at_louisville.edu
- 502-629-3355