Radiologie Interventionnelle &

CHC

Thierry de BaèreImagerie thérapeutique - Gustave Roussy - Villejuif

Journée d’Hépatologie du Centre Hépato-Biliaire12 juin 2015 - Paris

J Hepatol 2012. 56; 908–943. JM. Llovet; R Lencioni; AM. Di Bisceglie; PR. Galle; JF Dufour; TF. Greten; E Raymond; T Roskams; T de Baere; Michel Ducreux; and Vincenzo Mazzaferro.

J Hepatol 2012. 56; 908–943. JM. Llovet; R Lencioni; AM. Di Bisceglie; PR. Galle; JF Dufour; TF. Greten; E Raymond; T Roskams; T De Baere; Michel Ducreux; and Vincenzo Mazzaferro.

% APn=928

EUn=1113

LAn=90

USAn=563

Japann=508

OverallN=3202

All LRTs 67.2 43.5 27.8 49.4 84.4 57.5

TACE 60.3 33.1 13.3 37.1 71.3 47.2

Conventional Lipiodol TACE * 90.2 59.2 83.3 40.7 82.3 73.9

DEB-TACE * 2.9 36.1 16.7 39.7 1.7 15.9

Ablation 15.5 20.2 17.8 12.6 50.0 22.2

Surgery 24.2 15.5 5.6 9.4 43.3 21.1

* For patients who received TACE: n=1511; AP=560, EU=368, LA=12, USA=209, Japan=362; AP, Asia-Pacific; LA, Latin America; LRTs, Loco-Regional Therapies

Lencioni R et al. Int J Clin Pract 2014;68:609-617

GIDEON Pre-Sorafenib therapy in 3202 HCC (observation)

Breen DJ,. Nat Rev Clin Oncol 2015;12:175-186

Ablation for Early-Stage HCC:

Italy

Japan

Corea

France

Feng K et al. J Hepatol 2012;57:794-802Huang J et al. Ann Surg 2010;252:903-912

● 230 patients, 94% Child A● Single ≤ 5 cm, up to 3 ≤ 3 cm

● 168 patients, 49% Child A● Up to 2 HCC tumors ≤ 4 cm

Overall Survival Overall Survival

months months

p = 0.001 (log-rank test) p = 0.342 (log-rank test)

Ablation vs. Resection : Randomized Trials

Feng K et al. J Hepatol 2012;57:794-802Huang J et al. Ann Surg 2010;252:903-912

● 230 patients, 94% Child A● Single ≤ 5 cm, up to 3 ≤ 3 cm

● 168 patients, 49% Child A● Up to 2 HCC tumors ≤ 4 cm

Overall Survival Overall Survival

months months

p = 0.001 (log-rank test) p = 0.342 (log-rank test)

Ablation vs. Resection : Randomized Trials

"Very Early” (stage 0) vs "Early" (stage A) VS “Milan”

Sasaki A et al. Cancer 2005;103:299-306

46% of patients with single HCC < 5 cm show microsatellites on histology

Radiofrequency ablation is recommended in most instances as the main ablative therapy in tumours less than 5 cm due to a significantly better control of the disease(evidence 1iD; recommendation 1A)

J Hepatol 2012. 56; 908–943. JM. Llovet; R Lencioni; AM. Di Bisceglie; PR. Galle; JF Dufour; TF. Greten; E Raymond; T Roskams; T de Baere; Michel Ducreux; and Vincenzo Mazzaferro.

Milan criteria : X3 <3cm ; >5cm

Pompili M et al. J Hepatol 2013;59:89-97

Tumor Recurrence

Overall Survival

Ablation in HCC : APASL Consensus

Omata M et al. Hepatol Int 2010;4:439-474

LOCATION!

T

Omata M et al. Hepatol Int 2010;4:439-474

Ablation in HCC : APASL Consensus

Forner et al. Lancet 2012;379:1245-1255

Ablation Ablation

The Two Roles of Ablation in HCC Treatment:Updated BCLC Treatment Algorithm

Focused Ultrasound Cryoablation

Radiofrequency Ablation

Irreversible Electroporation

Laser AblationMicrowave Ablation

Mazzaferro V, Lencioni R, Majno P. Semin Liver Dis 2014;34:415-426

Image-Guided Ablation of HCC: Evolving Methods and Technologies

• Resection et ablation sont probablement équivalente pour les stade 0 et A (very early; early)

Complémentaire plus que compétitive : localisation

• Pour les HCC < 5cm si candidat chirurgicaux limites

Rôle des nouvelles techniques d’ablation à définir , outil par outil Traitement combiné (TACE+RF)

• La difficultés est plus celle de la récidive à distance que de la récidive locale

Traitement préventif ! (STORM study)

Ablation for Early-Stage HCC

BCLC Staging and Treatment Strategy:Critical Considerations

EASL-EORTC. J Hepatol 2012;56:908-943 - Eur J Cancer 2012;48:599-641

BCLC Staging and Treatment Strategy:Critical Considerations

EASL-EORTC. J Hepatol 2012;56:908-943 - Eur J Cancer 2012;48:599-641

ADVANCED STAGE:

- ECOG PS 1-2- Portal Vein Invasion- Extrahepatic Disease

(Yau T. Gastroenterology  2014;146:1691–1700 )EVM :  extrahe-patic  or vascular  invasion/metastasis  

0 / 1 / 2 negative factor Tumor size: ≥ 5 cm

Tumor number: ≥ 3

Intrahepatic vascular invasion

(Yau T. Gastroenterology  2014;146:1691–1700 )

• HKC identified subsets of BCLC B & 50% of BCLCC C more aggressive treatments than recommended by BCLC

Such aggressive treatments Improved survival outcomes hypothetical median OS: HKLC 16.6 months, BCLC 8.9 months)

“The benefits of the HKLC system are clearly apparent when dealing with patients who have intermediate to advanced stage disease according to the BCLC”.

“In a European cohort of HCC patients, the newly developed HKLC staging system does not seem to allow a better predictive value than the BCLC”.

(Adhoute X. J Hepatol 2014)

(Chapiro J. Nat Rev Gastroenterol Hepatol 2014;11:334-336)

177 patients randomized to DEB-TACE or c-TACE (med number of TACE = 2)• 89 DEB-TACE • 88 cTACE

(Golfieri R. 2014 BJC; 111 : 255–264)

CR

OR

DC

Targeted Overall

(Golfieri R. 2014 BJC; 111 : 255–264)

(Golfieri R. 2014 BJC; 111 : 255–264)

• Median TTP = 9 months in both arms • 1- and 2-year survival

86.2% and 56.8% after DEB-TACE 83.5% and 55.4% after cTACE (p=0.949).

No difference in AE incidence and severity except post-TACE pain, more frequent and severe after cTACE (p=0.001). Pain did not affected the length of hospital stay and patient acceptance of

additional TACEs (Golfieri R. 2014 BJC; 111 : 255–264)

  

 

67 DEB-TACE (53 patients) 100-300 μm (Group 1)lobar in 42 and selective in 7 cases

65 DEB-TACE (54 patients) 70-150 μm (Group 2)lobar in 60 and selective in 11

m-RECIST1-2 months

CR (%)

PR (%)

SD (%)

PD (%)

Group 1 19 2 67 12

Group 2 16 8 69 7

(Deipolyi AR, J Vasc Interv Radiol 2015; 26:516–522)

BCLC Staging and Treatment Strategy:Critical Considerations

EASL-EORTC. J Hepatol 2012;56:908-943 - Eur J Cancer 2012;48:599-641

Radioembolization- Sarra- Soramic- STOPP HCC

A single-centre prospective study of 291 patients with HCC looked at long-term clinical outcomes with TheraSphere®

Overall response rate according to WHO criteria was 42%

TheraSphere® & HCC

29

Treatment response predicts survival benefit for BCLC A, B &C patients

Salem R, Lewandowski RJ, Mulcahy MF, et al. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology 2010;138(1):52–64.

(Garlipp B, de Baere T, Seidensticker M. Hepatology 2014.59:1864-1873)

26 matched pairs

PVE : 61.5 ± 39 % after 33 [24-56] days RE : 29 ± 28 % after 46 [27-79] days (p<0.001)

Traitements combinés

(Peng ZW; JCO 2013. 31 426-432)

HCC less than 7 cm (single), or X3 & <3cmTACE-RFA Vs RFAOS : (HR=0.525; 95% CI = 0.335-0.822; P = .002 )

DFS : (HR=0.575; 95% CI = 0.374-0.897; P = .009)OS : treatment allocation (HR=1.87), tum. Size 3cm (HR=1.73), and tum. number (HR=2.49)DFS : Treatment allocation (HR=1.67) and tum. Number (HR=1.97)

HR: 0.79795% Cl: 0.588, 1.08P = 0.072

SorafenibMedian: 169 days95% Cl: 166, 219 days

PlaceboMedian: 166 days95% Cl: 113, 168 days

Prim

ary

Endp

oint

Sorafenib 400mg bid

Matching Placebo

RANDOMIZE

1 3 5 7 9 11 13 15 17 19

TACE(optional)

Cycle no(=4 weeks)

n=154

n=153

SPACE Trial

PRODIGE 16 - ESSAI FFCD 0905ESSAI RANDOMISE EN DOUBLE AVEUGLE DE PHASE II-III EVALUANT LA CHIMIOEMBOLISATION COMBINEE AU SUNITINIB OU A UN PLACEBO CHEZ DES PATIENTS ATTEINTS DE CARCINOME HEPATOCELLULAIRE (SATURNE)

 DEB - TACE with sunitinib 37.5 mg/d orally 4 weeks out of 6 started 7-15 days before TACE for one year vs placebo. Primary end-point : specific safety of the TACE-sunitinib combination (severe bleeding, liver failure , …)Secondary end-points : general safety, progression-free survival (PFS), Overall Survival (OS), quality of life. May 2011 to May 2014 : 78 patients were randomized (39 in each arm)median age 66 years [IQR (60-70)]. Bilobar HCC : 41 / 70 patients The median number of cycles was 3 [IQR : 2 :5 ] in arm A and 5 [IQR : 4 :7 ] in arm B.No bleeding complication; 1liver failure (PT = 40%) armA, & 2 liver failure in arm B (PT=42%, ,encephalopathy).

Sunitinib dose was reduced to 25 mg/d as a result of toxicity for 19 pts (48.7%) in arm A. 6 patients are still under treatment (3 in each arm). The main grades 3-4 toxicities were: thrombocytopenia (28.2% vs. 2.6% in placebo arm), neutropenia (28.2% vs. none), asthenia (20.5% vs. 5.3%), diarrhea (5.1% vs. none) respectively in arm A and B. The median PFS in arm A was 8.8 [95%CI 5.8 -12] months, and 6.3 [95%CI 4.2 - 9.0 ] months in arm B.  ConclusionThis study indicated a modest and manageable toxicity of sunitinib when combined with TACE. Regarding efficacy endpoints (PFS and OS) we are waiting for more mature data as 6 patients are still under treatment.

RFA plus Sorafenib vs RFA Alone in RCC

Hakimé et al, Radiology 2007

4-time increase in ablation volume

125 HCC received TACE group A (n = 61) : TACE + As2O3 at 10 mg/d for 4 courses (21 days per course)group B (n = 64) : TACE alone

125 HCC received TACE group A (n = 61) : TACE + As2O3 at 10 mg/d for 4 courses (21 days per course)group B (n = 64) : TACE alone

J Vasc Interv Radiol 2014; 25:379–387

% EUn=1113

OverallN=3202

All LRTs 43.5 57.5

TACE 33.1 47.2Conventional Lipiodol TACE * 59.2 73.9

DEB-TACE * 36.1 15.9

Ablation 20.2 22.2Surgery 15.5 21.1

Conclusion

DOSISPHERES-01Y-90 GLASS MICROSPHERES FOR HCC : OPTIMIZED DOSIMETRY vs STANDARD DOSIMETRY

STOPP HCCY-90 GLASS MICROSPHERES FOR HCC PRIOR TO SORAFENIB THERAPY vs STANDARD DOSIMETRY

Sunitinib loaded beadsLipiodol ready to inject emulsion