Claus-Henning Köhne

Klinik für Onkologie und Hämatologie

North West German Cancer Center (NWTZ)

Unresectable or boarderline resectable disease

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 chemotherapyare options

� In boarderline and unresectable disease the most effective andstill tolerable chemotherapy according to the molecular profileshould be used within a multidisciplinary context

� Even if surgery might not be curative it extends overall survivaland can be considered as a further line of „chemotherapy“ or a form of „maintenance“ chemotherapy

Guidelines CRC

mut mut

ESMO Guidelines for resectable (liver) metastases

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 51yRectal Adeno-Ca: cT3, N+Synchroneous LLD, ø 12 cmCEA 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

Resectablemetastases

Disease specific survival (DSS)

Adjuvant systemic chemotherapy of CLM: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

ba

bili

ty

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

Resectable Colorectal Liver Metastases

Presented By Jeanne Tie at 2016 ASCO Annual Meeting

Neoadjuvant (perioperative) Chemotherapy in resectable CRC Liver metastases

EORTC 40983 (EPOC)

Nordlinger et al. Lancet Oncol 2013

RFSOS

FOLFOX -> OP -> FOLFOX

ROP

Progression-free survival in eligible patients

(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 :

125 171 83 57 37 22 8

115 171 115 74 43 21 5 Nordlinger et al. Lancet 2008

MOST LIKELY BENEFITBorderline resectable pts?High proliferative tumors?

MOST LIKELY NO BENEFITEasily resectable? Fong score 0-2?

New EPOC studyNeoadjuvant FOLFOX +/- Cetuximab in LLD

Primrose et al. Lancet Oncol 2014

FOLFOX -> OP -> FOLFOX

RFOLFOX + Cetuximab -> OP -> FOLFOX + Cetuximab

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

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 neoadjuvantchemotherapy inresectable liver metastases

Köhne JCO 2015

Resectable : Perioperative Chemotherapy questionable

Boarderline : no restrictions in Chemo regimens including useof EGFR

Conclusions resectable & boarderline resectable disease

Guidelines CRC unresectable (LLD)

mut mut

Case: Male 44 y, sigmoid adenocarcinomaCase: 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

Case: Male 44 y, Case: Male 44 y,

05/06 Base line

05/06-11/06FOLFIRI + 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 withneoadjuvantfocus

Trials withpalliativefocus 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

CELIM: Blinded surgical review

100%

50%

0%

50%

100%

| | | | | | | - | - | | | | | - - | - - | | | - | | | | | | - - -

Patient

resecta

ble

n

on

- r

esecta

ble

100%

50%

0%

50%

100%| | | - | | | | - | | - | | | - | | - | | - - | | - | | | - - | | -

Patient

rese

cta

ble

n

on

- r

es

ecta

ble

60%, p<0.0132%

Baseline Follow-up

Folprecht G….Köhne CH et al. Lancet Oncol 2010

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

Morb

idity

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

Steatohepatitis Sinusoidal distention

Karoui Nordlinger et al, Ann.Surg. 2006

Vauthey et al. JCO 2006

FOLFIRI vs. FOFOXIRI

Regimen N RR Author

FOLFIRI 122 41% Falcone

FOLFOXIRI 122 66% JCO 2007

FOLFIRI+Bev 256 53% Falcone

FOLFOXIRI+Bev 252 65% NEJM 2015

• FOLFOXIRI more effective than FOLFIRI• Unproven role of bevacizumab

Randomised trials of EGFR antibodies – 1st line k-ras exon 2 wt onlyEuropean & Asian experience

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%

Bolus 5FU

Cape

COIN

(n=729) XELOX/FOLFOX +/- Cetux 57% vs. 64%

NORDIC

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

sig. diff; (clinically relevant not statist. Sig); no sig. diff * LLD only

Chinese randomized trial in patients with non resectable

k-ras exon 2 wt CRC LLDChemotherapy +/- 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

Randomized trials in patients withnon resectable k-ras exon 2 wt CRC LLD

Chemotherapy +/- Cetuximab

METHEP Chinese study CELIM OLIVIA

FOLFIRI/F

OLFOX

~30

FOLFOXIRI

N=30

FOLFIRI/FOL

FOX

N=68

CT + Cet

N=70

FOLFIRI/F

OLFOX +

Cet

N=67

FOLFOX

+ Bev

N=39

FOLFOXIRI

+ Bev

N=41

RR ~60 73% 40% 57% 70% 62% 81%

R0 resection ~23 30% 7% 26% 33% 31% 54%

OS all pts

(mo)~29 48.8 21.0 30.9 35.7 32.2 NR

OS resected

pts (mo)- - 36.0 46.4 53.9 - -

Ychou Ann Surg Oncol 2013; Ye et al. JCO 2013; Folprecht...Köhne Lancet Oncol 2010; Gruenberger Ann Oncol 2015

Jones, Folprecht Eur J Cancer 2014

Response and resection rates within trials

Trials withpalliativefocus CRC

2016 - FIRE3: Blinded review for resectability

Neumann et al, ESMO 2016

2016 - FIRE3: Blinded review for resectability

Neumann et al, ESMO 2016

2016 - FIRE3: Blinded review for resectability

Neumann et al, ESMO 2016

Jones et al, BJS 2012

Patients treated with palliative chemoat a regional oncology centre

Overall response rate left & right

JY Douillard & JP Pignon ESMO 2016

Duration of response � 1st line: in most arms duration of response appears to be longer in left-sided disease

� 2nd line: not enough responses in right-sided disease to calculate duration of response

Left, n Right, n Median DoR (95% CI), months

Actual treatment

Responder

s Progressed

Responder

s Progressed Left Right

PRIME

(1st line)

Pmab + FOLFOX 114 72 16 6 11.8 (9.6–14.8) 9.7 (3.9–13.3)

FOLFOX alone 82 56 16 14 9.3 (7.7–11.0) 7.6 (4.2–9.4)

PEAK

(1st line)

Pmab + FOLFOX 34 28 14 13 16.1 (11.1–20.9) 8.7 (3.7–14.2)

Beva + FOLFOX 31 29 7 7 9.5 (7.9–13.8) 9.2 (5.9–16.6)

Left, n Right , n Median DoR (95% CI), months

Actual treatment Responders Progressed Responders Progressed Left Right

181

(2nd

line)

Pmab + FOLFIRI 73 56 4 1 7.7 (6.1–9.5) NE (9.5–NE)

FOLFIRI alone 19 12 1 0 9.3 (5.7–12.3) NE (NE–NE)

Beva, bevacizumab; CI, confidence interval; DoR, duration of response; NE, not evaluable; Pmab,

panitumumab

Liver limited / dominant diesase

Clearly resectable

Borderline resectable

Definitely NOT resectable

Surgery! � Adjuvant to chemotherapy� Maintenance or an additional

line of chemotherapy tochemotherapy

Chemotherapy ?• adjuvant to surgery

SURGERY

CHEMO

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 chemotherapyare options

� In boarderline and unresectable disease the most effective andstill tolerable chemotherapy according to the molecular profileshould be used within a multidisciplinary context

� Even if surgery is not curative it extends overall survival and canbe considered as a line of „chemotherapy“ or a form of„maintenance“ chemotherapy

Thank you for your attention!