Transcript Diapositiva 1

Aintree University Hospital
Liverpool, UK
Irinotecan Loaded DC Beads as Neoadjuvant
Treatment of Resectable Colorectal Liver Metastases
Stephen W Fenwick MD FRCS
Consultant Hepatobiliary Surgeon
Belfast, September 2011
Plan
•
Systemic chemotherapy in CRLM
•
Targeted chemotherapy
•
Phase II trial of targeted chemotherapy in resectable
colorectal metastases (Paragon II study)
Declaration
Stephen Fenwick is a consultant to Biocompatibles UK LTD.
Five-year survival of English colorectal
cancer patients
1
Survival probability
0.9
All stage 4 resected n=3116
0.8
0.7
0.6
All patients
0.5
0.4
All stage 3
0.3
0.2
All Stage 4
0.1
0
0
0.5
1
1.5
Patients with resected liver metastases
2
2.5
Years
3
3.5
All patients without resected metastases
4
4.5
Dukes C
5
Dukes D
Morris EJA et al. Brit J Surg 2010; 97: 1110-8
Survival after liver resection for
colorectal liver metastases
Not due to
selection bias
Cumulative Survival
1.0
Survival stratified by year
of surgery (1997–2005)
0.8
1997
1998
1999
2000
2001
2002
2003
2004
2005
1997-censored
1998-censored
2000-censored
2001-censored
2002-censored
2003-censored
2004-censored
2005-censored
0.6
0.4
So why are we
getting better?
0.2
0.0
0
1000
2000
Survival Time
3000
4000
EPOC study
Lancet 2008; 371: 1007-1016
Study design
R
a
n
d
o
m
iz
e
FOLFOX4
Surgery
FOLFOX4
6 cycles
6 cycles
(3 months)
(3 months)
Surgery
N=364 patients
Nordlinger et al. Lancet 2008; 371: 1007-16
Progression-free survival in resected
patients
100
HR= 0.73; CI: 0.55-0.97, p=0.025
90
80
70
Periop CT
+9.2%
At 3 years
60
50
42.4%
40
Surgery only
30
33.2%
20
10
0
(years)
0
1
2
3
4
5
O N
104 152
Number of patients at risk :
85
59
39
24
10
93 151
118
23
6
76
45
6
Nordlinger et al. Lancet 2008; 371: 1007-16
Correlation of outcome after hepatectomy to
histologic response to neoadjuvant
chemotherapy
Blazer et al.
2008; 26: 5344-51
Complete
response
Major
response
Minor
response
Secondary liver resection rates of
metastases and tumour response
0.6
Studies including selected liver
metastases only patients
(no extrahepatic disease)
(r=0.96; p=0.002)
Resection rate
0.5
0.4
0.3
0.2
0.1
Response rates >70%
in unresectable liver
only patients equates
>40% liver resection
rate
0.0
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Studies including non-selected
patients with mCRC
(solid line)
(r=0.74; p<0.001)
Phase III studies including
non-selected patients with mCRC
(dashed line)
(r=0.67; p=0.024)
Response rate
Folprecht G, et al. Ann Oncol 2005;16:1311–1319
How to bring more patients to resection?
Downstage the disease to make it resectable
And / Or
“Upstage” the surgical techniques
What are the problems with preoperative chemotherapy ?
Chemotherapy liver damage
Oxaliplatin
Sinusoidal Obstruction
Syndrome
Increased peri-operative
bleeding
‘Blue’ liver
Irinotecan
Steatohepatitis
Increased post
operative liver
failure & 90 day
mortality
‘Yellow’ liver
Complications of surgery
EPOC Study (EORTC 40983)
Post-operative complications*
Peri-op CT
Surgery
40 /159 (25.2%)
27 / 170 (15.9%)
Cardio-pulmonary failure
3
2
Bleeding
3
3
Biliary Fistula
(Incl Output > 100ml/d, >10d)
Hepatic Failure
11
(Incl. Bilirubin>10mg/dl, >3d)
Wound infection
12 *
(9) *
8
(5)
*
2
8
Need for reoperation
5
Incl. post-operative death
(2)
(10) *
4
Intra-abdominal infection
Other
5
25
4
3
*
1 patient
16
2 patients
Nordlinger et al. Lancet 2008; 371: 1007-16
*P=0.04
"Complete response" :
does it mean cure ?
Wait for it to
come back?
?
Before treatment
After 6 cycles of
chemotherapy
Macroscopic CR after chemotherapy:
~20% of cells in periphery are viable
Dangerous
Halo
Courtesy of Professors G Mentha and L Rubbia Brandt, University of Geneva
Too much pre-surgery chemotherapy
• Problems for the liver surgeon
• Excessive Oxaliplatin
– Excessive bleeding at surgery
• Excessive Irinotecan
– Increased risk of post operative liver failure and 90 day mortality
• Complete response
– “Disappearing” tumours
Targeted chemotherapy?
What would be the advantages of DC bead
TACE over conventional therapy?
• Single administration, so reduced hepatic and
systemic toxicity?
• Targeted, so protecting ‘normal’ liver?
• Could be combined with metal filings to radiolocate disappearing lesions?
• Cheaper?
• Faster action, so possibly shorter delay from
treatment to surgery?
Trial proposal
• Study to evaluate safety/toxicity of targeted
neoadjuvant irinotecan DC beads in patients
with resectable colorectal liver metastases
PARAGON II STUDY
Study Design
• Multicentre, open label, single arm phase II study
• Primary endpoint – tumour resectability at surgery
(% with R0 resection)
• Secondary endpoints
–
–
–
–
Adverse events
Radiological response
Pathological response
Survival
Competitive studies:
UK: New EPOC
EORTC 40051: BOS
Participating Centres
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Liverpool
Basingstoke
Paris (Villejuif)
Girona
Vienna
Pathology review at a single centre
Paragon II Trial Design
• 40 patients with easily
resectable colorectal
liver metastases
• One TACE using
Irinotecan loaded
beads
• Liver resection 4
weeks later
Paragon II Trial Design
• 100-300 micron
Paragon beads,
loaded with irinotecan
during manufacture
• Aim to give 200mg
• Selective
embolisation to stasis
Inclusion Criteria
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18-80 yrs, not pregnant or lactating
Potentially resectable disease, confined to liver
Unilobar disease, <4 lesions
No chemotherapy up to 1 month previously
No other primary cancer within past 10 yrs
Not enrolled in another trial within 30 days
Adequate liver, and bone marrow function
–
–
WCC>3, Platelets >100, Bilirubin<1.5x normal
Prothrombin time not more than>50% of normal
Inclusion Criteria
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•
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18-80 yrs, not pregnant or lactating
Potentially resectable disease, confined to liver
Unilobar disease, <4 lesions
No chemotherapy up to 1 month previously
No other primary cancer within past 10 yrs
Not enrolled in another trial within 30 days
Adequate liver, and bone marrow function
–
–
WCC>3, Platelets >100, Bilirubin<1.5x normal
Prothrombin time not more than>50% of normal
Exclusion Criteria
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Extra-hepatic disease
Contraindications to Irinotecan
Active infection
Allergy to Contrast media
Contraindications to Hepatic Artery embolisation
Severe atherosclerosis
Trial Schedule
Baseline (PET)CT within
1 month of procedure
TACE
4 weeks
CT followed by liver
resection
Follow up CT at 3, 6, 9
& 12 months.
Technical considerations
• PARAGON beads are
easy to use
• 4 hour “life”
• Small tumours more
difficulty to localise
– Contrast enhanced US
– C arm CT
Post embolization
• Pain and nausea expected
• Pre procedure NSAIDs
• Manage with IV anti-emetics at time of
embolisation
• Post procedure IV Narcotics, Morphine via PCA, IV
paracetemol, NSAIDs, and occasionally Entonox
• Intra arterial lidocaine
Recruitment
39 patients 26/08/2011
1st patient 11/02/2009
1.3 patients/month
• Recruitment so far
Centre
Recruited Embolized Laparotomy
Basingstoke
1
3
26
1
8
Girona
Liverpool
Paris
Vienna
1
3
26
1
8
1
3
25
1
8
Recruitment
Included Patients (n = 48, intention to treat population)
Ineligible for TACE after inclusion (n = 9)
Patients treated with TACE (n = 39)
Ineligible for resection after TACE (n = 2)
Patients treated with surgery (n = 36, one patient is waiting for surgery)
Withdrawn after surgery (n = 11)
12 months follow-up (n = 18)
Patients excluded before TACE
• 9 patients excluded
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–
–
–
–
–
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Bilobar metastases (2)
Withdrew consent (2)
Pulmonary metastases
Suspected HCC
Allergy to contrast
Unable to canulate segmental artery
Tumour vessels not seen at angiography
Patients excluded before resection
• 2 patients excluded
– Peritoneal disease at laparotomy
Paragon II Patient characteristics
• n = 48, 10 female (21%), 38 male (79%)
• Age ±SD at TACE visit: 62 ±11 years (range 36-78)
• 1-3 tumours at screening, average 1.33
• 1-4 tumours prior to TACE, average 1.4
• Longest diameter pre TACE 44 mm (range 9-100)
Withdrawn During 12M Follow-up
• 01-001 B-L Progressive disease (new lesions, p.hepatis, lung nodules)
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02-001 W-W Progressive disease (new lesion)
01-007 JOD Progressive disease (new lesions)
01-010 JHO Progressive at 12 months (target+non-trgt)
01-014 V-L Progressive disease (new lesion)
04-001 AMR Diagnosed as HCC by histology
04-004 RAA Unrelated death (pneumomediastinum)
01-016 C-G Progressive disease (new lesions)
01-017 G-W Unrelated death (aspiration, organ failure)
04-003 JAB Outcome after 12 months to be confirmed
Paragon II R0 Resection
• Primary Endpoint: tumour resectability of targeted tumours
(% of patients with R0 resection, i.e. >2mm clearance margin)
• Patients:
R0 16/25 (64%),
R1 (<2mm) 9/25 (36%)
Serious Adverse Events
Two patient deaths
– Acute pneumomediastinum, during surgery
– Aspiration pneumonitis, post surgery in-patient stay
Eleven Serious Adverse Events
– Post embolisation syndrome in 4 patients (15%, expected)
– Pancreatitis (expected, TACE related, non-target embol.)
– Biloma (expected, surgical complication, MHRA: TACE)
– Urinoma (expected, surgical complication, not TACE related)
– Paroxysmal atrial fibrillation (not TACE related)
– Jaundice (due to recurrence, not TACE related)
– Neck haematoma (anaesthetic line complication)
– Aspiration pneumonitis (not TACE related)
– No serious and unexpected events
Outcomes
Histological tumour
response (n=26)
16%
23%
Complete
Major
Minor
None
61%
Surgical findings
• Often marked capsular ischaemia
• Increased inflammatory reaction around tumour
• Areas of ischaemia difficult to differentiate from
tumour
• Ischaemic cholecystitis
Patient 1
• 62 year old male
• Previous Segment
VIII resection in 2005,
with recurrence at site
Patient 1 - TACE
• Treated with 70mg
Irinotecan
• Discharged at 48 hrs
post procedure
Patient 1 - 4 weeks post TACE
• Right anterior
sectionectomy
• R0 resection
• Complete tumour
necrosis
• Background steatosis,
portal chronic
inflammatory change
Patient 6
Known lesion segment 8
Pre-treatment
1 month post
PET-CT pre-treatment
Positive segment 8
Negative segment 4A
Patient 6 histopathology
Treated metastasis
Untreated metastasis
Conclusion
• Neoadjuvant TACE with Paragon beads is
feasible and safe, with acceptable adverse
events
• R0 resection and tumour necrosis rates
are encouraging
• No negative effects seen at surgery
Conclusion
• Future work – explore differential tumour
response
• Future trials combining DC bead therapy
with systemic chemotherapy are now
awaited
Future trials?
Resctable disease
• Randomized phase III study with neoadjuvant irinotecan
DC bead TACE and perioperative systemic
chemotherapy (primary endpoint being PFS)
Unresectable patients
• Randomized phase II study looking at benefit of addition
of irinotecan DC bead TACE to systemic FOLFOX
(primary endpoint being liver resection rate)
Thank you