Colorectal Liver Metastases

What the IO Needs to Know

Michael C. Soulen, MD FSIR FCIRSEProfessor of Radiology & Surgery

University of Pennsylvania

Metastatic Colon CancerMetastatic Colon CancerThe OptionsThe Options

No therapyNo therapymedian survival 7-8 monthsmedian survival 7-8 months

ResectionResection25%-40% 5-year survival25%-40% 5-year survival

Systemic TherapySystemic Therapy• 18-20 month median survival with sequential 18-20 month median survival with sequential

FOLFOX-FOLFIRI and Avastin, +/- EGFR inhibitor.FOLFOX-FOLFIRI and Avastin, +/- EGFR inhibitor.• Longer for liver-only disease (including Longer for liver-only disease (including

downstaging).downstaging).

Metastatic Colon CancerMetastatic Colon CancerNCCN/ESMO GuidelinesNCCN/ESMO Guidelines

www.nccn.org/professionals/physician_gls/pdf/colon.pdfwww.esmo.org/Guidelines-Practice/Clinical-Practice-Guidelines/www.esmo.org/Guidelines-Practice/Clinical-Practice-Guidelines/

Gastrointestinal-Cancers/Advanced-Colorectal-CancerGastrointestinal-Cancers/Advanced-Colorectal-Cancer

• Need to know these!Need to know these!– ““talk the talk” at tumor boardstalk the talk” at tumor boards– Advise patients of all options for disease progressionAdvise patients of all options for disease progression– Recognize impact on IO and surgical proceduresRecognize impact on IO and surgical procedures

• 11stst-line:-line: FOLFOX or FOLFIRI, +/- Avastin FOLFOX or FOLFIRI, +/- Avastin (bevacizumab) (bevacizumab)

• Vectibix (panitumumab)/Erbitux (cetuximab) Vectibix (panitumumab)/Erbitux (cetuximab) for KRAS/BRAF wild-type genotypefor KRAS/BRAF wild-type genotype

– approx. 40% KRAS mutant, another 5%-10% BRAF approx. 40% KRAS mutant, another 5%-10% BRAF mutantmutant

• 22ndnd-line:-line: the other triplet, +/- EGFR inhibitor the other triplet, +/- EGFR inhibitor +/- Avastin+/- Avastin

Systemic ChemotherapySystemic ChemotherapyNeed to know the benefitNeed to know the benefit•Response rates 40%-60%Response rates 40%-60%

– Downstaging to resectability in 20%-25%!Downstaging to resectability in 20%-25%!– 5-year survival after downstaging to resection 5-year survival after downstaging to resection

33%!!33%!!•PFS 1st-line 7-9 monthsPFS 1st-line 7-9 months•PFS 2nd-line 3-5 monthsPFS 2nd-line 3-5 months•OS unresected 18-21 monthsOS unresected 18-21 months•Adam R, Delvart V, Pascal G, et al: Rescue surgery for unresectable colorectal liver Adam R, Delvart V, Pascal G, et al: Rescue surgery for unresectable colorectal liver metastases down-staged by chemotherapy: A model to predict long-term survival. metastases down-staged by chemotherapy: A model to predict long-term survival. Ann Surg 240:644-657, 2004Ann Surg 240:644-657, 2004•Delaunoit T, Alberts SR, Sargent DJ, et al: Chemotherapy permits resection of Delaunoit T, Alberts SR, Sargent DJ, et al: Chemotherapy permits resection of metastatic colorectal cancer: Experience from Intergroup N9741. Ann Oncol metastatic colorectal cancer: Experience from Intergroup N9741. Ann Oncol 16:425-429, 200516:425-429, 2005

Systemic ChemotherapySystemic Chemotherapy• Need to know the toxicitiesNeed to know the toxicities

– Oxaliplatin: neuropathy, “blue” liver, marrow Oxaliplatin: neuropathy, “blue” liver, marrow – Irinotecan : diarrhea, “yellow” liver, marrowIrinotecan : diarrhea, “yellow” liver, marrow– 5-FU: mucositis, diarrhea, marrow5-FU: mucositis, diarrhea, marrow– cetuximab - rashcetuximab - rash– bevacizumab - HTN, proteinuria, wound healing, bevacizumab - HTN, proteinuria, wound healing,

bowel perforation, bleeding, thrombosisbowel perforation, bleeding, thrombosis– >6 months chemo increases risk of liver failure >6 months chemo increases risk of liver failure

with resectionwith resectionrequired FLR increases from 25% to 40%required FLR increases from 25% to 40%

– Avastin : Hold two weeks for chest portsAvastin : Hold two weeks for chest portsProbably unimportant for embolizationProbably unimportant for embolization

Colorectal Liver MetastasesColorectal Liver Metastases

Colorectal MetastasesColorectal Metastases

Two 10cm metastases

Two 10cm metastasesWhat would you advise?•chemotherapy•resection•chemoembolization•radioembolization•portal vein embolization

The most important question!The most important question!Are they resectable?

Can you make them resectable?

Look at the cheese, not just the holes! A good relationship with a surgical oncologist is good for your patients and for your practice!

Chemo + PVE

16 mets in 7 segments

courtesy D. Madoff, MDACC

3 mo chemo, 1st-stage hepatectomy to clear segs

2/3

FFLLRR

PVE right lobe + seg 42nd-stage extended R

hepatectomy

Ablation: long-term outcomesAblation: long-term outcomes

Gillams, Eur Rad 2009;19:1206

Chemoembolization colon Chemoembolization colon cancercancer

Chemoembolization TrialsChemoembolization Trials

ref N drug embolic DCR TTP

Salman 2002 26 none PVA 50% 424 5FU+IFN PVA 63% 3

You 2006 40 5FU+LV Lipiodol 90% 9Nishiofuku 2013 24 cisplatin DSM 94% 6

Vogl 2014 564 mito, mito-gem, mito-iri, mito-iri-ox Lipiodol + DSM 65%

Albert 2010 121 CAM Lipiodol + PVA 43% 5

Chemoembolization TrialsChemoembolization Trialsref N median survival 1yr 2yr 3yr

from chemoembolization

Salman 2002 26 15 [8-17]

24 10 [8-11]

You 2006 40 16 90% 15%

Nishiofuku 2013 24 21 [8-24] 67% 42%

Vogl 2014 564 14.3 62% 28% 7%

Albert 2010 121 9 36% 13%

Hong 2009 21 7.7 43% 10%

Survival from Liver MetastasesSurvival from Liver Metastases

Median: 27mo1 yr: 85%2 yr: 55%3 yr: 22%4 yr: 14%5 yr: 6%

Prior Systemic LinesPrior Systemic Lines

0-1: 1 yr 41% 2 yr 16%2: 1 yr 42% 2 yr 13%3-5: 1 yr 12% 2 yr 0%

Extrahepatic DiseaseExtrahepatic DiseaseMedian Survival Without Extrahepatic Dz (n=65): 11moWith Extrahepatic Dz (n=55): 7mop=0.265HR= 0.81 (95% CI 0.53-1.19)

Survival by ECOG Performance StatusSurvival by ECOG Performance Status

Performance Status 0: 11 months>0: 3 monthsp>0.001HR= 0.46 (95% CI 0.15- 0.61)

Survival by Systemic EraSurvival by Systemic Era

Pre-irinotecanPre-bevacizumabPost-bevacizumab

Survival with liver metastases of colorectal cancer (n = 463) A) from diagnosis B) from chemoembolization

Vogl T J et al. Radiology 2009;250:281-289©2009 by Radiological Society of North America

1yr 2yr 3yr medDX 96% 80% 56% 38 moCE 62% 28% 14 mo

Survival by RECIST responseA) PARTIAL RESPONSE, B) STABLE , C) PROGRESSION

Vogl T J et al. Radiology 2009;250:281-289©2009 by Radiological Society of North America

Median (mo) PR 18.2 SD 13.5

PD 13p=0.015

Survival by drug regimenA) Mitomycin C, B) mito-C + irinotecan, C) mito-C + gemcitabine

Vogl T J et al. Radiology 2009;250:281-289

©2009 by Radiological Society of North America

DEBIRI International RegistryDEBIRI International Registry Martin RC, et al. Ann Surg Oncol. 2011 Jan;18(1):192-8

•55 patients with mCRC•Median irinotecan dose = 100 mg (range 100-200 mg) with total hepatic treatment of 200 mg (range 200-650 mg)•30% received concurrent systemic chemotherapy •Adverse events: 28% of patients with median grade of 2 (range 1-3) with no deaths at 30 days post procedure •Response rate: 75% at 12 months •OS =19 months median•Progression-free survival = 11 months median

Phase 3 Trial of DEBIRI vs. FOLFIRIPhase 3 Trial of DEBIRI vs. FOLFIRI

Anticancer Res 2012;32:1387-96

Intraarterial Therapy with Yttrium 90:Intraarterial Therapy with Yttrium 90:TheraSpheres and SIR-SpheresTheraSpheres and SIR-Spheres

Phase 3 Trial 5-FU +/- Y90

• 46 Patients randomized to infusional 5 FU +/- Y90

• Primary endpoint TTLP• 2.1 vs 5.5 mo with Y90

Med OS 11.9 vs. 6.3 mo

Bester et al. JVIR 2012

Radioembolization for salvage therapy

Y-90 radioembolizationY-90 radioembolization

• N= 606 patients/10 N= 606 patients/10 centerscenters

• PR @ 3 mo. 35%PR @ 3 mo. 35%• DC @3 mo. 90%DC @3 mo. 90%• Median survival 9.6 Median survival 9.6

mo mo – 10.5 mo. responders10.5 mo. responders– 4.5 mo. non-responders4.5 mo. non-responders

Kennedy et al., ASCO 2012

(Goldberg 2002) FOLFOX (Goldberg 2002) IFL

FOLFIRI FOLFOX

IFL/Saltz

5-FU/LV (de Gramont 2000)5-FU/LV (Douillard 2000)5-FU/LV (Saltz 2000)

Overall survival: Overall survival: fluoropyrimidine combination fluoropyrimidine combination

regimensregimens

Time (months)

Estim

ated

pro

babi

lity

1.0

0.8

0.6

0.4

0.2

0.00 6 12 18 24 30 36 42

(Sastre 2002) XELOX

TACETACE

ConclusionConclusion• The Interventional Oncologist is an The Interventional Oncologist is an

essential member of the colorectal essential member of the colorectal cancer teamcancer team

• IO procedures can increase the IO procedures can increase the potential for curative resectionpotential for curative resection

• Adding intra-arterial therapies Adding intra-arterial therapies provides survival better than expected provides survival better than expected from systemic therapy alonefrom systemic therapy alone

• Integration with other therapeutic Integration with other therapeutic modalities key to maximizing long-modalities key to maximizing long-term outcomes.term outcomes.