„Advanced Disease“: Aktuelle Therapiestrategien · track / p rog ram s³ ... oh d y h s ulp d...

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Oligometastatic CRC: What do we know about it, and how to treat it?

Instituto CUF de Oncologia

Lisboa, Portugal

Asklepios Tumorzentrum Hamburg

AK Altona , Abt. Onkologie, Hämatologie und Palliativmedizin

ATZ: Organisationsfelder

„Disease

Track /

Programs“

per Tumorentität

Klinische

„Core

Facilities“

unabhängig von

Tumorentität

QM /

Zertifizierung /

Register

Fortbildung /

Veranstaltung

Studien /

Wissenschaft

Marketing / PR

Klinischer Bereichadministrativer

Bereich

Ergänzende

klinische

Angebote

unabhängig von

Tumorentität

Disclosures Dirk Arnold, 2014-2019

• Participate on Advisory Board with:

Roche, Merck Serono, Amgen, Bayer, Servier, Sanofi, BTG, Lilly

• Speaker and Chairman for educational events with:

Boston Scientific, BTG, Roche, Merck Serono, Bayer, Lilly, Servier, Sanofi

• Investigator and researcher in data generating activities supported and sponsored by

Roche, Mologen, AstraZeneca, Bayer

Metastases in colon cancer

primarily local disease

Prognosis determined by primary

Local treatment

Metastastatic diseasePrognosis determined by metastases

Systemic treatmentdiffuse metastatic diseaseUnfavourable biology, only systemictreatment

Oligometastatic diseasePrognosis „intermediate“ –

because of biology (?) and the optionfor additional (local) treatment

Prognosis

70 yrs „tumour biology“> 120.000 Publicationens

ca. 20 yrs< 50 publications on „biology“

Cure

Palliation

Chronic disease(potentially cure)

→ local (palliative) treatment

Why are pts with few mets. living longer?

• Lower tumour burden?

• better (= „less complicated“) sites?

• Additional use of ablative techniques?

Mathematical-mechanistical hypotheses

Mannsmann UR ASCO GI 2013, abstract no. 427

∆ OS

No tumor shrinkage

PFS

PFS

∆ PFS

Tumor shrinkage

Lethal tumor load

Baseline tumor load

Time under treatment

Time

Cel

lco

un

t

Goldie-Coldman Hypothesis:

less therapy-resistant clones with a smaller number of cells

- Goldie JH et al., Cancer Res. 1984

- Withers HR et al., Sem Radiat Oncol 2006

Cytoreduction: biological hypotheses

Norton-Simon Hypothesis: kinetic resistance - poorer response to chemotherapy in small residualsNorton L et al., Cancer Treat Rep 1986, Oncologist 2005

Chemotherapy

Metastasis 1

Metastasis 2Primary

Subclone

Gerlinger et al., New Engl J Med 2012

Are there really biological characteristicsexisting,

which may help us to distinguish betweenan oligometastatic and a whitespread

pattern of metastasation?

Similar – but (likely) not the same

Local tumour→ oligometastasation→ diffuse mets. → terminal disease

continuum over time?

Paget et al., Lancet 1898; Halstead et al., Ann Surg 1907

Metastasation as an evolutional process: The „SPECTRUM“ hypothesis

Adapted from: Hellman S., Karnofsky Memorial Lecture, J Clin Oncol 1994

Continuum over time?

„new biology“



Paget et al., Lancet 1898; Halstead et al., Ann Surg 1907Hellman et al., 1994

Continuum over time?

„new biology“ Cont. over time?

„new biology“?

Paget et al., Lancet 1898; Halstead et al., Ann Surg 1907Hellman et al., 1994



Oligometastatic vs. Disseminated Disease

Adapted from: Reyes et al., Oncotarget 2015

Oligometasta+c-vs.-Systemic-Disease-

Oncotarget3www.impactjournals.com/oncotarget

Actively migrating

cancer cells

Oligometastatic

Disease Systemic Disease

Hospitable target

organs

Poor primary

tumor conditions

Inhospitable target

organs

Sloughed

cancer cells

Good primary

tumor conditions

s

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Table 1: A comparison of migrants, diaspora, and the spectrum of cancer metastases

Social Demography Cancer Demography

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Adapted'from:'Reyes'et'al.,'Oncotarget'2015'Adapted from: Reyes et al., Oncotarget 2015

Oligometastatic vs. Disseminated Disease

A comparison of migrants, diaspora, and the spectrum of cancer metastases

adapted from: Pieta et al., Clin Cancer Res 2013

tumor mets capabilities: migration

environmental adverse„pressure“

environmental „hospitality“: tissue

environmental „hospitality“:immunogenicity

Consensus molecular subtypes of CRC

Molecular classification of CRC

31%

26% 19%

24% 56%

10%

27% 7%

51%

15%

31% 3%

Summary of associations

Dienstmann R, et al. WCGIC 2014 (Abstract No. O-0025)

Dienstmann et al., WCGC / ESMO GI 2016

Pitroda et al., Nature Communications 2018

Pitroda et al., Nature Communications 2018

Biology and oligometastasation: What is do we need to know clinically?

• Prognostic information

• How „ambitious“ should our treatment be?

• Predictive information

• E.g. selection of a (primary) local-ablative treatment (e.g. SBRT) vs. systemic tretament

→Biology: not ready for prime time!

Van Cutsem,....et al., Arnold. Ann Oncol 2016

ESMO Consensus: What is seen as „oligometastatic disease“?

Van Cutsem E, Cervantes A, …...Arnold D ESMO Consensus; Ann Oncol 2016





Therapeutic concepts -

What do we know ?

CLM: Surgery and retrospective seriesInitially non-resectable liver metastases

Adam et al., J Clin Oncol 2009

Vatandoust et al., World J Gastroenterol 2017

CRC: Single organ metastases

Perioperative treatment strategywith liver metastases

Van Cutsem E, Cervantes A, …...Arnold D. ESMO Consensus; Ann Oncol 2016



Retrospective blinded evaluation of (potential) resectabilityof 448 pat. @ baseline and best response

Independent assesent by 8 surgeons and 3 oncologists

Fig. 1

22%

Modest et al., Eur J Cancer 2018

Fig. 1

53%

Modest et al., Eur J Cancer 2018

Fig. 3

European Journal of Cancer 2018 88, 77-86DOI: (10.1016/j.ejca.2017.10.028) Modest et al., Eur J Cancer 2018

Fig. 3

European Journal of Cancer 2018 88, 77-86DOI: (10.1016/j.ejca.2017.10.028) Modest et al., Eur J Cancer 2018



ABSTRACT #3509

PHASE II TRIAL DESIGN

mCRCUnresectable

1st-line

WT RAS**

Age ≥ 18yrs

ECOG PS 0-1

N = 96

Randomization:

6/2011 - 1/2017

R

Treatment until PD, resectability,

or to maximum 12 cycles

mFOLFOXIRI +

panitumumab 6 mg/kg

Q2W

N = 63Irinotecan 150 mg/m2, oxaliplatin 85 mg/m2,

LV 200 mg/m2, 5-FU 3000 mg/m2 CIV;

Planned safety analysis after 10 patients

treated in panitumumab arm

FOLFOXIRI Q2W

N = 33

2:1

If resectable:

Surgery, then

protocol treatment to

maximum 12 cycles

If CR/PR/SD after 12 cycles:

re-induction

(same combination)

recommended on PD

Strata:

Cohort 1: histologically confirmed and definitively inoperable or unresectable

Cohort 2: chance of secondary resection with curative intent (* pretreatment liver/tumor biopsy)

**amendment in 11/2013 to include all RAS wild-type only

*

*

• 21 active centers in Germany

1 cycle FOLFOXIRI

prior R was allowed

.Geissler et al., ASCO 2018 #3509

VOLFI trial: FOLFOXIRI +/- panitumumabin RAS WT mCRC

PRIMARY ENDPOINT: OBJECTIVE RESPONSE RATEFINAL DATA AFTER EXTERNAL MONITORING

mFOLFOXIRI +

panitumumab

N = 63

FOLFOXIRI

N = 33

% 95%-CI % 95%-CI Odds ratio p

87.3 76.5 – 94.4 60.6 42.1 – 77.14.469

(1.614-12.376)0.004

p: Exact test of Fisher (2-sided, alpha = 0.05)

Geissler et al., ESMO 2018

VOLFI trial: FOLFOXIRI +/- panitumumabin RAS WT mCRC

Patient #1

• 64 y/o lawyer, active, no relevant comorbidity

• C. transversum adenocarcinoma, 4y ago stage II, R0, no adjuvant

• Now, at follow-up: 3 peripheral hepatic lesions: „segmental resection possible“

• CEA 23

Patient #2

• 59 y/o, female, shop assistant, no relevant comorbidity

• Sigmoid colon adenocarcinoma, stage III (N1), R0, just finished adjuvant FOLFOX

• Now, at follow-up: 3 peripheral hepatic lesions: „segmental resection possible“

• CEA 78







„best systemic therapy“ (if appropriate)



Patient #3

• 74 y/o, former mayor, hypertension

• Left colon adenocarcinoma , 11 months ago, stage II, RAS wt, BRAF w, R0

• Started adjuvant capecitabine for 6 months

• Now, after 3 months: 3 peripheral hepatic lesions: „segmental resection possible“

• CEA 239

What to do, if resectability isunclear?

Yoshino et al., Ann Oncol 2018 (online since Nov 2017)

ESMO Asia Consensus Guidelines 2018

Yoshino et al., Ann Oncol 2018 (online since Nov 2017)

Management of OMD


Ruers et al., JNCI 2017

EORTCCAO (ALM)NCRI CCCG

Median follow-up 9.7 yrs

OSHR 0.58p = 0.01

PFSHR 0.57p < 0.01

Ruers et al., JNCI 2017

Management of OMD

Van Cutsem,.....Arnold. ESMO Consensus Guidelines mCRC., Ann Oncol 2016

Management of OMD

Van Cutsem,.....Arnold. ESMO Consensus Guidelines mCRC., Ann Oncol 2016

Induction

Best systemictreatment

Best maintenance

De-escalation ?

pause ?

other compound?

Best ablation

resection

„ablation toolbox“

severalmanifeststions,

„palliative“

Oligometastastaticdisease

„ablative“

post induction

where ?response?

Metastatic CRC: Main principles

Example for (too?) early integration: The SIRFLOX trial

Treatment arm: FOLFOX + SIRT ( delayed start of bevacizumab/cetuximab)

Work up for

SIRT

Preparation

On day -14 to -3

Control arm: FOLFOX ( bevacizumab/cetuximab from Cycle 1)

Cycle 1

Bev/Cet

OX = 85

mg/m2

Cycle 2 Cycle 3 Cycle ≥4

FOLFOXOX = 85

mg/m2

OX = 85

mg/m2

OX = 85

mg/m2

OX = 60

mg/m2

OX = 60

mg/m2

Bev/Cet

OX = 85

mg/m2

SIRT(Cycle 1 or 2)

On day 3 or 4

FOLFOX

Bev/Cet

FOLFOX

Bev/Cet

FOLFOX

Bev/Cet

Cycle 1

FOLFOX

Cycle 2

FOLFOX

Cycle 3

FOLFOXOX = 60

mg/m2

Cycle ≥4

FOLFOX

Bev, bevacizumab; Cet, cetuximab

Sharma et al., ASCO 2017

Liver-failure free survival Progression free survival

Sharma et al., J Clin Oncol 2018

Example for (too?) early integration: The SIRFLOX trial

Where are our limitations...?

Tanis et al., Eur J Cancer 2014

6%



6%

25-30%

CELIM trial: Initially irresectable liver mets

··· Disease free survival after

resection

All patients

< 5 metastases

5-10 metastases

> 10 metastases

DFS 9.9 [95% CI: 5.8-14.0] months

Comparison between groups:

p < 0.001

Pro

ba

bilit

y o

f s

urv

iva

l

Folprecht et al, Ann Oncol 2014

··· Progression free survival

▬ Overall survival

R0 resected patients

R1 resection / ablation

Not resected patients

OS R0 resected 53.9 mo. [95% CI: 35.9-71.9]

not resected 21.9 mo. [95% CI: 17.1-26.7]

HR 0.29 [0.17-0.50], p <‍‍‍0.001

PFS R0 resected 15.4 mo. [95% CI: 11.4-19.5]

not resected 6.9 mo. [95% CI: 5.9-8.0]

HR 0.31 [0.19-0.50]p <‍‍‍0.001

46.2% [29.5-62.9%]

R0 resection vs. no resection:

HR 0.42 [95% CI: 0.21-0.86], p=0.021

Patients with PR/CR,

only

Folprecht et al, ASCO 2013

CELIM trial: Initially irresectable liver mets

Do we need a „proof of concept“ –

in randomised trials?

Resumefor

total of 6

months

Optimal LAAT

(to be determined)non progressive,

non resectable,

oligometastatic

(up to 3 sites/5

lesions) after

any chemo

for 3-6 monthsvtr

ialin

clu

sio

n

Do we need a randomised „strategy“ trialto proof the principle?

Continuation of CT until PD

Rand

Pro

gre

ssio

n

How can we improve this principle?


0

100

200

300

400

500

600

700

800

900C

EA (

ng/

ml)

CEA

Response by RECIST (CT scan)

Tumor burden (CT-scan)

1 32 4 5 6 7

Montagut, Siravegna & Bardelli . Ann Oncol 2015

cycles of chemotherapy


0

10

20

30

40

50

60

0

100

200

300

400

500

600

700

800

900

Mu

tate

d a

llele

s (%

)

CEA

(n

g/m

l)

CEA

ctDNA mutation in plasma

Molecular response by liquid

biopsy

Blood draws (ctDNA)

Tumor burden

1 32 4 5 6 7

Response by RECIST (CT scan)

cycles of chemotherapy


Montagut, Siravegna & Bardelli . Ann Oncol 2015

Methods / Concepts Issues Goals

2008 Liver surgery Technical limitations 5% selected→ „cure“ for about 20%

The spectrum of metastases in CRC: Consequences



2012 Liver surgeryTumour BoardSystemic treatment

Technical improvementPrognosticalconsiderations

20% selected→ „cure“ for about 30%







2016 Concept of oligometastaticdiseaseIntegration of ablativetreatments

New methods / multidisciplinarityNew strategic goals

25% liver mets onlyAbout 60% with „anyoligometastatic disease“










>2018 Broad acceptance of the currentconcept – to save lives!










>2018 Molecular determination ofpattern of mets.?Tumor → stroma, Immunotherapy?

Broad acceptance of the currentconcept – to save lives!


Dirk Arnold

Asklepios Tumorzentrum Hamburg

Instituto CUF de Oncologia, Lissabon

Statine

vor und während der Systemtherapie wirken protektiv!

Seicean et al., JACC 2012.

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