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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

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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


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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 l.jpg

Five-year survival of English colorectal cancer patients

1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

All stage 4 resected n=3116

All patients

Survival probability

All stage 3

All Stage 4

1

2.5

4

0.5

2

3.5

5

0

1.5

3

4.5

Years

Patients with resected liver metastases

All patients without resected metastases

Dukes C

Dukes D

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


Survival after liver resection for colorectal liver metastases l.jpg

Survival after liver resection for colorectal liver metastases

Not due to

selection bias

Survival stratified by year

of surgery (1997–2005)

1.0

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

Cumulative Survival

0.4

So why are we

getting better?

0.2

0.0

0

1000

2000

3000

4000

Survival Time


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EPOC study

Lancet 2008; 371: 1007-1016


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Study design

Randomize

FOLFOX4

Surgery

FOLFOX4

6 cycles

(3 months)

6 cycles

(3 months)

Surgery

N=364 patients

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


Progression free survival in resected patients l.jpg

Progression-free survival in resected patients

100

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

90

80

Periop CT

+9.2%At 3 years

70

60

50

42.4%

40

Surgery only

30

33.2%

20

10

0

(years)

0

1

2

3

4

5

6

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


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Correlation of outcome after hepatectomy to histologic response to neoadjuvant chemotherapy

Blazer et al.

2008; 26:5344-51

Complete

response

Major

response

Minor

response


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Secondary liver resection rates of metastases and tumour response

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Resectionrate

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Responserate

Studies including selected liver metastases only patients (no extrahepatic disease)

(r=0.96; p=0.002)

Response rates >70%

in unresectable liver

only patients equates

>40% liver resection

rate

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)

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


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How to bring more patients to resection?

Downstage the disease to make it resectable

And / Or

“Upstage” the surgical techniques


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What are the problems with pre-operative chemotherapy ?


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Chemotherapy liver damage

Oxaliplatin Irinotecan

Steatohepatitis

Increased post

operative liver

failure & 90 day

mortality

Sinusoidal Obstruction

Syndrome

Increased peri-operative

bleeding

‘Blue’ liver

‘Yellow’ liver


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Complications of surgery

EPOC Study (EORTC 40983)

*

*

*

*

*

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

*P=0.04


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"Complete response" : does it mean cure ?

Wait for it to

come back?

?

Before treatment

After 6 cycles of chemotherapy


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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


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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


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Targeted chemotherapy?


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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?


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Trial proposal

Study to evaluate safety/toxicity of targeted neoadjuvant irinotecan DC beads in patients with resectable colorectal liver metastases

PARAGON II STUDY


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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


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Participating Centres

  • Liverpool

  • Basingstoke

  • Paris (Villejuif)

  • Girona

  • Vienna

Pathology review at a single centre


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Paragon II Trial Design

  • 40 patients with easily resectable colorectal liver metastases

  • One TACE using Irinotecan loaded beads

  • Liver resection 4 weeks later


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Paragon II Trial Design

  • 100-300 micron Paragon beads, loaded with irinotecan during manufacture

  • Aim to give 200mg

  • Selective embolisation to stasis


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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


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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


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Exclusion Criteria

  • Extra-hepatic disease

  • Contraindications to Irinotecan

  • Active infection

  • Allergy to Contrast media

  • Contraindications to Hepatic Artery embolisation

  • Severe atherosclerosis


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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.


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Technical considerations

  • PARAGON beads are easy to use

  • 4 hour “life”

  • Small tumours more difficulty to localise

    • Contrast enhanced US

    • C arm CT


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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


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Recruitment

39 patients 26/08/2011

1st patient 11/02/2009

1.3 patients/month

  • Recruitment so far


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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)


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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


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Patients excluded before resection

  • 2 patients excluded

    • Peritoneal disease at laparotomy


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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)


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Withdrawn During 12M Follow-up

01-001 B-L Progressive disease (new lesions, p.hepatis, lung nodules)

02-001 W-WProgressive 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


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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


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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

Serious Adverse Events


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Outcomes

Histological tumour response (n=26)

16%

23%

61%


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Surgical findings

  • Often marked capsular ischaemia

  • Increased inflammatory reaction around tumour

  • Areas of ischaemia difficult to differentiate from tumour

  • Ischaemic cholecystitis


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Patient 1

  • 62 year old male

  • Previous Segment VIII resection in 2005, with recurrence at site


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Patient 1 - TACE

  • Treated with 70mg Irinotecan

  • Discharged at 48 hrs post procedure


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Patient 1 - 4 weeks post TACE

  • Right anterior sectionectomy

  • R0 resection

  • Complete tumour necrosis

  • Background steatosis, portal chronic inflammatory change


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Patient 6

Known lesion segment 8

Pre-treatment 1 month post

PET-CT pre-treatment

Positive segment 8 Negative segment 4A


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Patient 6 histopathology

Untreated metastasis

Treated metastasis


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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


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Conclusion

  • Future work – explore differential tumour response

  • Future trials combining DC bead therapy with systemic chemotherapy are now awaited


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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)


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Thank you


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