„advanced disease“: aktuelle therapiestrategien · track / p rog ram s³ ... oh d y h s ulp d...
TRANSCRIPT
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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
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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
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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
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Why are pts with few mets. living longer?
• Lower tumour burden?
• better (= „less complicated“) sites?
• Additional use of ablative techniques?
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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
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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
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Are there really biological characteristicsexisting,
which may help us to distinguish betweenan oligometastatic and a whitespread
pattern of metastasation?
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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
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Metastasation as an evolutional process: The „SPECTRUM“ hypothesis
Adapted from: Hellman S., Karnofsky Memorial Lecture, J Clin Oncol 1994
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Continuum over time?
„new biology“
Local tumour→ oligometastasation→ diffuse mets. → terminal disease
Similar – but (likely) not the same
Paget et al., Lancet 1898; Halstead et al., Ann Surg 1907Hellman et al., 1994
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Continuum over time?
„new biology“ Cont. over time?
„new biology“?
Paget et al., Lancet 1898; Halstead et al., Ann Surg 1907Hellman et al., 1994
Local tumour→ oligometastasation→ diffuse mets. → terminal disease
Similar – but (likely) not the same
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Oligometastatic vs. Disseminated Disease
Adapted from: Reyes et al., Oncotarget 2015
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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
Figure 1: Oligometastatic disease versus systemic disease. OHIW2 OLJRP HWDVWDWLF GLVHDVH 0 HWDVWDWLF JURZWKSRWHQWLDOLVOLP LWHG
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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
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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
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Consensus molecular subtypes of CRC
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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
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Pitroda et al., Nature Communications 2018
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Pitroda et al., Nature Communications 2018
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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!
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Van Cutsem,....et al., Arnold. Ann Oncol 2016
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ESMO Consensus: What is seen as „oligometastatic disease“?
Van Cutsem E, Cervantes A, …...Arnold D ESMO Consensus; Ann Oncol 2016
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ESMO Consensus: What is seen as „oligometastatic disease“?
Van Cutsem E, Cervantes A, …...Arnold D ESMO Consensus; Ann Oncol 2016
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ESMO Consensus: What is seen as „oligometastatic disease“?
Van Cutsem E, Cervantes A, …...Arnold D ESMO Consensus; Ann Oncol 2016
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Therapeutic concepts -
What do we know ?
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CLM: Surgery and retrospective seriesInitially non-resectable liver metastases
Adam et al., J Clin Oncol 2009
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Vatandoust et al., World J Gastroenterol 2017
CRC: Single organ metastases
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Perioperative treatment strategywith liver metastases
Van Cutsem E, Cervantes A, …...Arnold D. ESMO Consensus; Ann Oncol 2016
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Perioperative treatment strategywith liver metastases
Van Cutsem E, Cervantes A, …...Arnold D. ESMO Consensus; Ann Oncol 2016
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Retrospective blinded evaluation of (potential) resectabilityof 448 pat. @ baseline and best response
Independent assesent by 8 surgeons and 3 oncologists
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Fig. 1
22%
Modest et al., Eur J Cancer 2018
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Fig. 1
53%
Modest et al., Eur J Cancer 2018
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Fig. 3
European Journal of Cancer 2018 88, 77-86DOI: (10.1016/j.ejca.2017.10.028) Modest et al., Eur J Cancer 2018
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Fig. 3
European Journal of Cancer 2018 88, 77-86DOI: (10.1016/j.ejca.2017.10.028) Modest et al., Eur J Cancer 2018
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Perioperative treatment strategywith liver metastases
Van Cutsem E, Cervantes A, …...Arnold D. ESMO Consensus; Ann Oncol 2016
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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
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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
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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
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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
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Perioperative treatment strategywith liver metastases
Van Cutsem E, Cervantes A, …...Arnold D. ESMO Consensus; Ann Oncol 2016
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Perioperative treatment strategywith liver metastases
Van Cutsem E, Cervantes A, …...Arnold D. ESMO Consensus; Ann Oncol 2016
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Perioperative treatment strategywith liver metastases
„best systemic therapy“ (if appropriate)
Van Cutsem E, Cervantes A, …...Arnold D. ESMO Consensus; Ann Oncol 2016
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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
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What to do, if resectability isunclear?
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Yoshino et al., Ann Oncol 2018 (online since Nov 2017)
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ESMO Asia Consensus Guidelines 2018
Yoshino et al., Ann Oncol 2018 (online since Nov 2017)
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Management of OMD
Van Cutsem E, Cervantes A, …...Arnold D. ESMO Consensus; Ann Oncol 2016
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Ruers et al., JNCI 2017
EORTCCAO (ALM)NCRI CCCG
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Median follow-up 9.7 yrs
OSHR 0.58p = 0.01
PFSHR 0.57p < 0.01
Ruers et al., JNCI 2017
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Management of OMD
Van Cutsem,.....Arnold. ESMO Consensus Guidelines mCRC., Ann Oncol 2016
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Management of OMD
Van Cutsem,.....Arnold. ESMO Consensus Guidelines mCRC., Ann Oncol 2016
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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
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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
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Liver-failure free survival Progression free survival
Sharma et al., J Clin Oncol 2018
Example for (too?) early integration: The SIRFLOX trial
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Where are our limitations...?
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Tanis et al., Eur J Cancer 2014
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6%
Tanis et al., Eur J Cancer 2014
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Tanis et al., Eur J Cancer 2014
6%
25-30%
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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
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··· 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
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Do we need a „proof of concept“ –
in randomised trials?
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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
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How can we improve this principle?
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Consensus molecular subtypes of CRC
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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
Consensus molecular subtypes of CRC
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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
Consensus molecular subtypes of CRC
Montagut, Siravegna & Bardelli . Ann Oncol 2015
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Methods / Concepts Issues Goals
2008 Liver surgery Technical limitations 5% selected→ „cure“ for about 20%
The spectrum of metastases in CRC: Consequences
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Methods / Concepts Issues Goals
2008 Liver surgery Technical limitations 5% selected→ „cure“ for about 20%
2012 Liver surgeryTumour BoardSystemic treatment
Technical improvementPrognosticalconsiderations
20% selected→ „cure“ for about 30%
The spectrum of metastases in CRC: Consequences
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Methods / Concepts Issues Goals
2008 Liver surgery Technical limitations 5% selected→ „cure“ for about 20%
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“
The spectrum of metastases in CRC: Consequences
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Methods / Concepts Issues Goals
2008 Liver surgery Technical limitations 5% selected→ „cure“ for about 20%
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!
The spectrum of metastases in CRC: Consequences
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Methods / Concepts Issues Goals
2008 Liver surgery Technical limitations 5% selected→ „cure“ for about 20%
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 Molecular determination ofpattern of mets.?Tumor → stroma, Immunotherapy?
Broad acceptance of the currentconcept – to save lives!
The spectrum of metastases in CRC: Consequences
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Dirk Arnold
Asklepios Tumorzentrum Hamburg
Instituto CUF de Oncologia, Lissabon
Statine
vor und während der Systemtherapie wirken protektiv!
Seicean et al., JACC 2012.