Stephen W Fenwick MD FRCS Stephen W Fenwick MD FRCS

Aintree University Hospital

Liverpool, UK

Consultant Hepatobiliary Surgeon Consultant Hepatobiliary Surgeon

Belfast, September 2011

Irinotecan Loaded DC Beads as Neoadjuvant

Treatment of Resectable Colorectal Liver Metastases

DeclarationStephen Fenwick is a consultant to Biocompatibles UK LTD.

Plan

• Systemic chemotherapy in CRLM

• Targeted chemotherapy

• Phase II trial of targeted chemotherapy in resectable colorectal metastases (Paragon II study)

Five-year survival of English colorectal cancer patients

Morris EJA et al. Brit J Surg 2010; 97: 1110-8

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5

1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Su

rviv

al p

rob

abil

ity

Years

All Stage 4

All patients

All stage 3

All stage 4 resected n=3116

Patients with resected liver metastases All patients without resected metastases Dukes C Dukes D

Survival after liver resection for colorectal liver metastases

0.0

0.2

0.4

0.6

0.8

1.0

40003000200010000Survival Time

Cu

mu

lativ

e S

urvi

val

Survival stratified by year of surgery (1997–2005)

1997199819992000200120022003200420051997-censored1998-censored2000-censored2001-censored2002-censored2003-censored2004-censored2005-censored

Not due toselection bias

So why are wegetting better?

Lancet 2008; 371: 1007-1016

EPOC study

Study design

Randomize

SurgeryFOLFOX4 FOLFOX4

Surgery

6 cycles

(3 months)

N=364 patients

6 cycles

(3 months)

Nordlinger et al. Lancet 2008; 371: 1007-16

Progression-free survival in resected patients

HR= 0.73; CI: 0.55-0.97, p=0.025

Surgery only

Periop CT

33.2%

42.4%

+9.2%At 3 years

(years)

0 1 2 3 4 5 6

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk :104 152 85 59 39 24 10

93 151 118 76 45 23 6

Nordlinger et al. Lancet 2008; 371: 1007-16

Completeresponse

Majorresponse

Minorresponse

Correlation of outcome after hepatectomy to histologic response to neoadjuvant

chemotherapy

2008; 26: 5344-51

Blazer et al.

Secondary liver resection rates of metastases and tumour response

Studies including non-selected patients with mCRC (solid line) (r=0.74; p<0.001)

Studies including selected liver metastases only patients (no extrahepatic disease)(r=0.96; p=0.002)

Phase III studies including non-selected patients with mCRC (dashed line)(r=0.67; p=0.024)

Folprecht G, et al. Ann Oncol 2005;16:1311–1319

Res

ectio

n ra

te

Response rate

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0.3 0.4 0.5 0.6 0.7 0.8 0.9

Response rates >70%in unresectable liver only patients equates>40% liver resectionrate

How to bring more patients to resection?

Downstage the disease to make it resectable

“Upstage” the surgical techniques

And / Or

What are the problems with pre-operative chemotherapy ?

Chemotherapy liver damage

‘Blue’ liver ‘Yellow’ liver

Oxaliplatin Irinotecan

Sinusoidal Obstruction Syndrome

Increased peri-operativebleeding

Steatohepatitis

Increased post operative liver

failure & 90 daymortality

Complications of surgery

Peri-op CT Surgery

Post-operative complications*

40 /159 (25.2%)

27 / 170 (15.9%)

Cardio-pulmonary failure 3 2

Bleeding 3 3

Biliary Fistula 12 5

(Incl Output > 100ml/d, >10d)

(9) (2)

Hepatic Failure 11 8

(Incl. Bilirubin>10mg/dl, >3d)

(10) (5)

Wound infection 4 4

Intra-abdominal infection 8 2

Need for reoperation 5 3

Other 25

16

Incl. post-operative death 1 patient 2 patients

*P=0.04Nordlinger et al. Lancet 2008; 371: 1007-16

EPOC Study (EORTC 40983)

**

*

*

*

"Complete response" : does it mean cure ?

Before treatment After 6 cycles of chemotherapy

?

Wait for it tocome back?

Macroscopic CR after chemotherapy: ~20% of cells in periphery are viable

Courtesy of Professors G Mentha and L Rubbia Brandt, University of Geneva

DangerousHalo

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 radio-locate 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

• 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

• 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

• 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

Exclusion Criteria

• Extra-hepatic disease• Contraindications to Irinotecan• Active infection• Allergy to Contrast media• Contraindications to Hepatic Artery embolisation• Severe atherosclerosis

Baseline (PET)CT within 1 month of procedure

TACE

CT followed by liver resection

Follow up CT at 3, 6, 9 & 12 months.

4 weeks

Trial Schedule

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 so far

Centre Recruited Embolized Laparotomy

Basingstoke 1 1 1Girona 3 3 3Liverpool 26 26 25

Paris 1 1 1

Vienna 8 8 8

39 patients 26/08/2011 1st patient 11/02/2009 1.3 patients/month

Recruitment

Recruitment

Patients treated with TACE (n = 39)

Included Patients (n = 48, intention to treat population)

Patients treated with surgery (n = 36, one patient is waiting for surgery)

Ineligible for TACE after inclusion (n = 9)

Ineligible for resection after TACE (n = 2)

12 months follow-up (n = 18)

Withdrawn after surgery (n = 11)

Patients excluded before TACE

• 9 patients excluded

– 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) • 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

• 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%)

Paragon II R0 Resection

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

CompleteMajorMinorNone

Outcomes

Histological tumour response (n=26)

16%

61%

23%

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

• Treated with 70mg Irinotecan

• Discharged at 48 hrs post procedure

Patient 1 - TACE

• Right anterior sectionectomy

• R0 resection• Complete tumour

necrosis

• Background steatosis, portal chronic inflammatory change

Patient 1 - 4 weeks post TACE

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