Claus-Henning Köhne

Klinik für Onkologie und Hämatologie

North West German Cancer Center (NWTZ)

Treating Liver Limited or Oligometastatic CRC

ESMO Preceptorship Colorectal Cancer Nov 2016 Barcelona

Learning objectives

▪ All patients with liver limited or oligometastatic disease have a

potential chance for cure

▪ A multidisciplinary aproach is essential

▪ The clinical presentation may be considered as

▪ Resectable, boarderline resectable, potentially resectable after

chemotherapy

▪ In resectable disease surgery alone or following chemotherapy

are options

▪ In boarderline and unresectable disease the most effective and

still tolerable chemotherapy according to the molecular profile

should be used within a multidisciplinary context

▪ Even if surgery might not be curative it extends overall survival

and can be considered as a further line of „chemotherapy“ or a

form of „maintenance“ chemotherapy

Guidelines CRC

mut mut

2016 - FIRE3: Blinded review for Resektability of CRC Metastases

Neumann et al, ESMO 2016

Liver limited disease: Patient groups

Clearly

resectable

Borderline

resectable

Definitely NOT

resectable

Resectable LLD but high risk of recurrence

Fong Score

▪ Primary tumor N +

▪ DFI < 12 Monate

▪ > 1 Metastasis

▪ > 5 cm

▪ CEA > 200 ng/ml

Age 51y

Rectal Adeno-Ca: cT3, N+

Synchroneous LLD, ø 12 cm

CEA 568 ng/ml

High Fong Score

Estimated survival @ 5y < 10%

>12cm

▪ Primary tumor N +

▪ DFI < 12 Monate

▪ > 1 Metastasis

▪ > 5 cm

▪ CEA > 200 ng/ml

Fong score > 2

Group 0

Resectable

metastases

Disease specific survival (DSS)

Adjuvant systemic chemotherapy of CLM:

Overall survival

Combined analysis

FFCD / EORTC trial 5-FU/FA

Mitri et al. JCO 2008

0.00

0.25

0.50

0.75

1.00

Pro

bab

ility

153 114 70 41 22LV5FUs+IRI153 95 65 44 25LV5FUs

Number at risk

0 12 24 36 48Months

LV5FUs LV5FUs+IRI

adjusted Logrank p=0.43

HR=0.89: 95%CI [0.66-1.19]

Treatment

1-year DFS: 63% vs. 77%

2-year DFS: 46% vs. 51%

Ychou et al. ASCO 2008

Overall survival

FOLFIRI

Neoadjuvant (perioperative) Chemotherapy in resectable CRC Liver metastases

EORTC 40983 (EPOC)

Nordlinger et al. Lancet Oncol 2013

RFS

OS

FOLFOX -> OP -> FOLFOX

R

OP

Resectable : Perioperative Chemotherapy questionable

Boarderline : no restrictions in Chemo regimens including use

of EGFR

Conclusions resectable & boarderline resectable disease

Case: Male 44 y,

05/06

Base line05/06-11/06

FOLFIRI + Cetux

11/06-03/07

FOLFOX + Cetux

PS 2 PS 0 liver mets operable

primary tumor pCR

+ 5 kg

mets not operable Patient died 02/15

Response and resection rates within trials

Trials with

neoadjuvant

focus

Trials with

palliative

focus CRC

Give the most active (RR) regimen still tolerable by the patient

Folprecht G….Köhne CH et al. Ann Oncol 2005; Jones R et al. Eur J Cancer, 2014

ESMO acknowledges response parameters like early tumor shrinkage

(ETS) or depth of response (DpR) for conversion therapy

Time since start of treatment

OS

ETS

Tumor nadir

Fire-3 data

PFS

Tu

mo

rlo

ad

at

Baselin

e

Lethal tumor load

0

10

20

30

40

50

60

70

Mo

rbid

ity

No CT =<5 cycles 6-9 cycles =>10 cycles

Steatohepatitis Sinusoidal distention

Karoui Nordlinger et al, Ann.Surg. 2006

Vauthey et al. JCO 2006

Arguments disfavouring CapeOX over infusional Doublets

(FOLFOX or FOLFIRI)

Randomised trials Doublets vs. Triplets and Doublets +/- VEGF – 1st line

RASwt and RASmut disease

Trial Therapy ORR

NO16966

(n=700)

FOLFOX

+/- Beva

38% vs. 38%

n.s.

(n=700) CAPOX

+/- Beva

38% vs. 38%

n.s.

ITACA

(n=376)

FOLFOX or

FOLFIRI

+/- Beva

48% vs. 49%

n.s.

EORTC

requestFOLFIRI +/- Bev not done

Saltz et al. JCO 2008, Cassidy BJC 2007, Passardi Ann Oncol 2015

Van Cutsem NEJM,

CTx +/- VEGF

Trial Therapy ORR

GONO

(n=244)

FOLFIRI

+/- Oxaliplatin

41% vs.

66%

TRIBE

(n=700)

FOLFIRI / BEV

+/- Oxaliplatin

53% vs.

65%

Austria

(n=80)

FOLFOX / Bev

+/- Irinotecan

62% vs.

81%

AIO

(n=242)

FOLFOX / Bev

+/- Irinotecan

60% vs.

79%

DOUBLET vs. TRIPLET

Randomisierte Studien mit EGFR AK – 1. Linie k-ras exon 2 wt

Europäische & Asiatische Erfahrungen

Trial Therapy ORR

Infusional 5FU

CRYSTAL

(n=666) FOLFIRI +/- Cetux

40% vs. 57%

Chinese*

(n=138)FOLFIRI or FOLFOX+/- Cetux 40% vs. 57%

PRIME

(n=656) FOLFOX +/- Pani

48% vs. 57%

OPUS

(n=197) FOLFOX +/- Cetux

34% vs. 57%

Tailor

(n=380)FOLFOX +/- Cetux 34% vs. 56%

VOLFI all RASwt

(n=99) 2:1FOLFOXIRI +/- Pani 61% vs. 86%

Bolus 5FU

Cape

COIN

(n=729) XELOX/FOLFOX +/- Cetux

57% vs. 64%

NORDIC

(n=194)FLOX +/- Cetxu 47 vs. 46%

Chinese randomized trial in patients with non resectable

k-ras exon 2 wt CRC LLD

Chemotherapy +/- Cetuximab

Ye et al. JCO 2013

CELIM: R0 Resection as a surgical „maintenance therapy“

in the continuum of care

R0 resected: 15.495%CI: 11.3-19.5

Not R0 res.: 8.995%CI: 6.7-11.0

HR 2.10 [1.37-3.20]

p<0.001

R0 resected: 53.995%CI: 35.9-71.9

Not R0 res.: 27.395%CI: 21.1-33.4

HR 2.25 [1.34-3.78],

p=0.002

5y-OS: 45.8%

Overall survivalProgression free survival

Update CELIM 12/2012, ASCO 2013

few patients

without relaps

Theo Ruers et al, ASCO 2015

EORTC CLOCC trial

EORTC CLOCC trial

N=152

Theo Ruers et al, ASCO 2015

Arm Resection Resection

+RFA

RFA

only

CT 12%

CT+RFA 47% 6%

Liver limited / dominant diesase

Clearly

resectable

Borderline

resectable

Definitely NOT

resectable

Surgery! ➢ Adjuvant to chemotherapy

➢ Maintenance or an additional

line of chemotherapy to

chemotherapy

Chemotherapy ?• adjuvant to surgery

S

U

R

G

E

R

Y

C

H

E

M

O

OPEN QUESTIONS

• Right / Left

• RASmut

• BRAFmut

Overall response rate left & right

JY Douillard & JP Pignon ESMO 2016

24

EVALUATION OF RESPONSE SIDEDNES

mFOLFOXIRI +

panitumumab

mFOLFOXIRI +

panitumumab

FOLFOXIRIFOLFOXIRI

left right

ORR (%)

10

20

30

40

50

60

70

80

90

100

90,6

68,0

60,0

37,5

OR 4.518

(1.29-15.71)

P=0.0210

OR 2.500

(0.37-16.88)

P=0.6372

N=78 N=18

Geissler et al. ESMO 2017

Treatment for RASmut or BRAFmut Disease ?

Cremolini et al. Lancet Oncol 2015

Cremolini et al. Lancet Oncol 2015

Triplette nicht besser als Doublette Group Events/No. OS (95% CI), months

RAS/BRAF WT (Arm

A)51/79 25.2 (20.8-29.8)

RAS/BRAF WT (Arm

B)40/79 32.2 (26.1-46.1)

RAS MT (Arm A) 68/97 21.3 (19.6-23.0)

RAS MT (Arm B) 65/97 23.2 (18.1-28.4)

BRAF MT (Arm A) 11/12 12.4 (10.2-20.2)

BRAF MT (Arm B) 8/10 7.8 (4.7-13.5)

Doublette nicht besser als FP+Bev

Welches ist die beste therapie für RASmut Erkrankung?

FOLFIRI/Bev +/- Oxaliplation FP/Bev +/- Irinotecan

Modest et al. ESMO 2017

Jones et al. et al. JCO 2017

Prognosis of BRAFmut Disease

mFOLFOXIRI +

panitumumab

mFOLFOXIRI +

panitumumab

FOLFOXIRIFOLFOXIRI

super wild-type

ORR (%)

BRAF mutation

10

20

30

40

50

60

70

80

90

100

86,0

64,7

71,4

22,2

Geissler et al. ESMO 2017

Triplett +/- Panitumumab

CELIM 2

PI Gunnar Folprecht Dresden

Liver limited / dominant diesase

Clearly

resectable

Borderline

resectable

Definitely NOT

resectable

Surgery! ➢ Adjuvant to chemotherapy

➢ Maintenance or an additional

line of chemotherapy to

chemotherapy

Chemotherapy ?• adjuvant to surgery

S

U

R

G

E

R

Y

C

H

E

M

O

Learning objectives

▪ All patients with liver limited or oligometastatic disease have a

curative chance

▪ A multidisciplinary aproach is essential

▪ Clinical presentation may be considered as

▪ Resectable, boarderline resectable, potentially resectable after

chemotherapy

▪ In resectable disease surgery alone or following chemotherapy

are options

▪ In boarderline and unresectable disease the most effective and

still tolerable chemotherapy according to the molecular profile

should be used within a multidisciplinary context

▪ Even if surgery is not curative it extends overall survival and can

be considered as a line of „chemotherapy“ or a form of

„maintenance“ chemotherapy

Thank you for

your attention!

Metastatic disease including

locoregional treatment

FOXFIRE (n=1103, 3 Studies)

Slide 12

Presented By Ricky Sharma at 2017 ASCO Annual Meeting

FOXFIRE (n=1103, 3 Studies)

HR: 1.04

P=0.6

HR: 0.90

P=0.1

Best radiological response by study

Presented By Ricky Sharma at 2017 ASCO Annual Meeting

FOXFIRE (n=1103, 3 Studies)

CALGB/SWOG 80405: Baseline Characteristics

Resected Patients

Characteristic

Kras WT codons 12/13

n=1137

Resected Pts

n=180

Chemo + Bev

n=559

Chemo + Cetux

n=578

Chemo + Bev

n=75

Chemo + Cetux

n=105

Age, years

Median (range) 59 (21–85) 59 (20–89) 55 (24–82) 55 (21–79)

Male, % 62.3 60.4 64.0 60.0

Non-Caucasian, % 14.6 16.5 9.3 20.0

FOLFOX, %* 73 74 77 81

Prior Radiation, %* 14.5 13.7 8.0 6.7

Prior Adjuvant Chemotherapy, %* 8.9 9.0 6.7 9.5

Palliative intent, % 86.4 82.5 62.7 60.0

Primary in place, % 28 27 30 20

Liver metastases only, % 29.3 39.8 53.3 50.0*Stratification Factor

Achieve NED: 132

/180

CALGB/SWOG 80405: Baseline Characteristics

Resected Patients

Characteristic

Kras WT codons 12/13

n=1137

Resected Pts

n=180

Chemo + Bev

n=559

Chemo + Cetux

n=578

Chemo + Bev

n=75

Chemo + Cetux

n=105

Age, years

Median (range) 59 (21–85) 59 (20–89) 55 (24–82) 55 (21–79)

Male, % 62.3 60.4 64.0 60.0

Non-Caucasian, % 14.6 16.5 9.3 20.0

FOLFOX, %* 73 74 77 81

Prior Radiation, %* 14.5 13.7 8.0 6.7

Prior Adjuvant Chemotherapy, %* 8.9 9.0 6.7 9.5

Palliative intent, % 86.4 82.5 62.7 60.0

Primary in place, % 28 27 30 20

Liver metastases only, % 29.3 39.8 53.3 50.0*Stratification Factor

CALGB/SWOG 80405: Baseline Characteristics

Resected Patients

Characteristic

Kras WT codons 12/13

n=1137

Resected Pts

n=180

Chemo + Bev

n=559

Chemo + Cetux

n=578

Chemo + Bev

n=75

Chemo + Cetux

n=105

Palliative intent, % 86.4 82.5 62.7 60.0

curative intent % 13.6% 17.5%

curative intent N 76 101

Resected NED (R0) N Pat 45 66 45 66

Resected NED (R0) % 8.0% 11.4% 60.0% 62.8%

Primary in place, % 28 27 30 20

Liver metastases only, % 29.3 39.8 53.3 50.0

*Stratification Factor

Discrepance of numbers:

Resected NED =111; Resected achieved NED=132

CALGB/SWOG 80405: Overall Survival (KRAS wild type, NED Post-Surgery, N=132)

ArmN

(Events)

Median

(95% CI)

HR

(95% CI)p

Chemo +

Bev50(15)

67.4

(50.6-NA) 1.2

(0.6-2.2)

0.56

Chemo +

Cetux82(30)

64.1

(51.1-78.9)

Most pts were resectable

upfront, thus surgery is

the main driver or

survival rather than pre-

op chemotherapy

Resectable Colorectal Liver Metastases

Presented By Jeanne Tie at 2016 ASCO Annual Meeting

Neumann et al, ESMO 2016

2016 - FIRE3: Blinded review for Resektability of CRC Metastases

Jones et al, BJS 2012

Patients treated with palliative Chemotherapy in a regional Center in UK

Guidelines CRC

unresectable (LLD)

mut mut

Case: Male 44 y, sigmoid adenocarcinoma

well until 4 months ago, PS 2

weight loss ~ 5 Kg within last 3 months

grossly enlarged palpable liver

abdominal US:

difuse hypodensic liver leasons

CT scans:

Synchroneous diffuse liver metastases

LDH elevated, WBC 12.000 /dl

Bilirubin normal, LFT < 4x ULN

Neoadjuvant (perioperative) Chemotherapy in resectable CRC Liver metastases

EORTC 40983 (EPOC) and new EPOC

Nordlinger et al. Lancet Oncol 2013

Primrose et al. Lancet Oncol 2014

RFS

OS

OS

RFS

FOLFOX -> OP -> FOLFOX

R

OP

FOLFOX -> OP -> FOLFOX

R

+Cet -> OP -> +Cet

Liver limited diesase: Patient selection

EPOC New EPOC

Surgery Chemo Chemo

Inclusion Definitely resectable Definitely and

„suboptimal“

resectable

N Lesions Maximum 4 unlimited

unresectable 10% 4% 12-19%

Köhne JCO 2015

Visible on CT/MRI

Non - visible on CT/MRI, potentially visible during operation

CT/MRI prior chemoCT/MRI after chemo

prior surgery

Potential disadvantage of effective neoadjuvant

chemotherapy inresectable liver metastases

Köhne JCO 2015