Presentation on theme: "Intermediate stage HCC management. Index Definition of intermediate stage HCC patients Treatment algorithms Treatment option: TACE –Results supporting."— Presentation transcript:
Intermediate stage HCC management
Index Definition of intermediate stage HCC patients Treatment algorithms Treatment option: TACE –Results supporting BCLC recommendations on TACE –TACE contraindications –Efficacy of TACE –Indications for stopping or continuing TACE –ART score –HAP score –Complications associated with TACE Treatment option: Sorafenib –Treatment guidelines –SHARP –GIDEON –SOFIA –INSIGHT
HCC, hepatocellular carcinoma; TACE, transarterial chemoembolization. Forner A, et al. Seminars Liver Dis 2010; 30:61 74. Intermediate stage HCC: Patient definition – BCLC 2010 Definition of intermediate stage patients: Single/large multifocal disease Asymptomatic No vascular invasion or extrahepatic spread Preserved liver function (Child-Pugh A or B) If liver function is compensated Optimal candidates for TACE If liver function is decompensated or fitting into Child-Pugh B classification Increased risk of severe adverse events and liver failure; patients may not benefit at all from TACE If vascular invasion is detected by imaging Increased risk of severe adverse events and liver failure; patients may not benefit at all from TACE
Intermediate stage HCC: Definition and Prognosis - EASL, EORTC Definition of intermediate stage patients –Multinodular –Tumors without an invasive pattern –Asymptomatic Prognosis of intermediate stage patients –these patients have poor prognoses –median survival of 16 months or 49% at 2 year –outcome prediction is heterogeneous for BCLC B subclass patients, and has been reported to range from around 36–45 months for the best responders to chemoembolization in recent series, to 11 months for the worst scenario of untreated candidates (placebo arm SHARP study) EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma Journal of Hepatology 2012 vol. 56 j 908–943 Available on:
Intermediate-stage HCC: Heterogeneous patient population Patients with intermediate-stage HCC differ in: 1-3 Tumour burden Liver function (Child-Pugh A or B) Disease aetiology General health status 1. Forner A et al. Semin Liver Dis 2010;30:61-74; 2. Piscaglia F & Bolondi L. Digestive Liver Dis 2010;42S:S258-63; 3. Raoul J-L et al. Cancer Treat Rev May;37(3):
Highly heterogeneous population Patients may differ according to tumour load, age, liver function and comorbidities Decision is only whether to TACE or not to TACE There is no BCLC-B subclassification in the current BCLC system Up-to-7 criterion for tumour burden Liver function Presence of peripheral/(sub)segmental portal vein thrombosis Evaluation of patient characteristics by a multidisciplinary team Proposed subclassification based on clinical evidence and expert opinion Bolondi L, et al. Semin Liver Dis 2012;32:348–359 Intermediate-stage HCC: BCLC B sub-classification based on tumor burden and liver function
*with severe/refractory ascites and/or jaundice.; **only if up-to-7 IN and PS0. BSC, best supportive care; PS, performance status; PVT, portal vein thrombosis; TARE, transarterial radioembolization. Adapted from Bolondi L, et al. Semin Liver Dis 2012;32:348–359. Intermediate-stage HCC: BCLC B sub-classification
Intermediate-stage HCC: Implications of a heterogeneous patient population Implications of this heterogeneity: Not all patients will benefit from TACE to the same degree 1-3 Some patients may benefit more from other treatment options 3 Prognostic factors for a response to TACE could improve treatment decisions and thus patient outcomes 1. Forner A et al. Semin Liver Dis 2010;30:61-74; 2. Piscaglia F & Bolondi L. Digestive Liver Dis 2010;42S:S258-63; 3. Raoul J-L et al. Cancer Treat Rev May;37(3):
EASL 2013 – From the presentation of F. Piscaglia – Abstract BCLC-B patients, included in the ITA.LI.CA. (Italian Liver Cancer) database, were divided into subgroups (B1–B4) according to the sub-classification. Survival of each group was assessed and compared using Kaplan-Meyer method and log-rank test, after a follow-up of 60 months. The new substaging proposal is able to refine prognostic prediction in the intermediate HCC stage Cumulative survival Prognostic significance of the new BLBC B substaging system
Portal pressure/ bilirubin HCC PEI/RFAsorafenib Stage 0 PS 0, Child–Pugh A Very early stage (0) 1 HCC < 2 cm Carcinoma in situ Early stage (A) 1 HCC or 3 nodules < 3 cm, PS 0 End stage (D) Liver transplantationTACEResection Curative treatments (30%) 5-year survival (40–70%) Associated diseases YesNo 3 nodules ≤ 3 cm Increased Normal 1 HCC Stage D PS > 2, Child–Pugh C Intermediate stage (B) Multinodular, PS 0 Advanced stage (C) Portal invasion, N1, M1, PS 1–2 Stage A–C PS 0–2, Child–Pugh A–B PS, performance status; TACE, transarterial chemoembolization; BSC, Best Supportive Care EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma Journal of Hepatology 2012 vol. 56 j 908–943 Available on: Target: 40% OS: 11 mo (6-14) Target: 20% OS: 20 mo (45-14) BSC Target: 10% OS: <3 mo Intermediate stage HCC: Treatment algorithm – EASL, EORTC guidelines
Adjuvant therapy after resection OLT-extended Neoadjuvant therapy in waiting list LDLT Downstaging Internal radiation Y90 Resection Levels of evidence (NCI) Grade of recommendation (GRADE) (weak) 1 (strong) RF (<5 cm), RF/PEI (<2 cm) Chemoembolization External/palliative radiotherapy Sorafenib ACB ACB OLT-Milan EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma Journal of Hepatology 2012 vol. 56 j 908–943 Available on: Intermediate stage HCC: Levels of evidence and grade of recommendation
* : each TACE; ** : with cTACE, MRI is preferred to CT *** : Response must be assessed by modified RECIST criteria Position paper AISF DLD (2013) SORAFENIB HCC not amenable to curative treatments Child Pugh class A or B7 Performance Status ≤1 No portal/hepatic vein invasion (except segmental or subsegmental portal branches)) 1 st treatment (cTACE or DEB-TACE) 2 nd treatment (cTACE or DEB-TACE) MRI or CT** at 1 month No complete response Partial responseNewly developed HCC Complete response Disease recurrence MRI or CT every 3 months Consider another course of cTACE or DEB-TACE (and/or ablation techniques) Liver failure or severe adverse events* Yes No Resolution Palliation Disease progression or stable desease sorafenib Intermediate stage HCC: Treatment algorithm – AISF guidelines
Kudo M, et al. Dig Dis 2011; 29: HCC Extrahepatic spread Liver function Vascular invasion Number Size Treatment NoYes Child-Pugh A/B No 1-3Single NoYes Child-Pugh CChild-Pugh B/CChild-Pugh A Hypovascular early HCC Within Milan criteria and age ≤65 Exceeding Milan criteria or age >65 SorafenibPalliative care Transplantation TACE/ablation for Child-Pugh C patients HAIC (Vp3, 4) Sorafenib (Vp3, 4) TACE (Vp1, 2) Resection (Vp1, 2) Intensive follow-up Ablation Resection Ablation Resection TACE TACE + ablation Sorafenib (TACE refractory, Child-Pugh A) TACE HAIC Resection Ablation ≤3 cm>3 cm ≥4 HAIC: hepatic arterial infusion chemoterapy; Intermediate stage HCC: JSH consensus-based treatment algorithm
B1B2B3B4Quasi C Child–Pugh score 5–6–75–678–9*A Beyond Milan and within up-to-7 INOUT ANY Tumour-related ECOG PS 0000–10 PVTNO YES*** 1st option TACE TACE or TARE BSCsorafenib Alternative Liver transplantation TACE + ablation sorafenib Trials TACE sorafenib Liver transplantation** TACE TARE *with severe/refractory ascites and/or jaundice.; **only if up-to-7 IN and PS0, *** segmentary or subsegmentary BSC, best supportive care; PS, performance status; PVT, portal vein thrombosis; TARE, transarterial radioembolization. Adapted from Bolondi L, et al. Semin Liver Dis 2012;32:348–359. Intermediate HCC: Proposed treatment algorithm for BCLC B sub- classification
Intermediate stage HCC: Treatment algorithm adherence The proliferation of so many guidelines reflects broad geographic differences in HCC epidemiology, etiology, high-risk patients, health systems and resources, medical technology and clinical impact of HCC in different countries In Italian clinical practice adherence to guidelines is alarmingly low Borzio M, Sacco R. Future Oncol. (2013) 9(4), 465–467
Intermediate stage HCC treatment options: TACE
Example of transarterial embolization. On the left we can see the typical arterial hypervascularization of HCC on arteriography. The right picture shows the result after selective embolization of the feeding arteries Forner A et al. Critical Reviews in Oncology/Hematology 2006;60:89–98 Non Surgical Treatments: TransArterial ChemoEmbolization (TACE)
Intermediate stage HCC: candidates to TACE If liver function is compensated optimal candidates for TACE If liver function is decompensated or fitting into Child-Pugh B classification increased risk of severe adverse events and liver failure; patients may not benefit at all from TACE If vascular invasion is detected by imaging increased risk of severe adverse events and liver failure; patients may not benefit at all from TACE HCC, hepatocellular carcinoma; TACE, transarterial chemoembolization. Forner A, et al. Seminars Liver Dis 2010; 30:61 74.
Odds ratio (95% CI) Study Overall Favours treatmentFavours control Patients 503 Lin, Gastroenterology GETCH, NEJM Bruix, Hepatology Pelletier, J Hepatol Lo, Hepatology Llovet, Lancet p=0.017 p=0.086 OR=0.53 [95% CI, 0.32–0.89]; p= Child-Pugh B <10 % of all patients - Around 10% had tumor portal vein thrombosis - In most trials no selective TAE - Trials in EU e Asia BCLC = Barcelona Clinic Liver Cancer; GRETCH = Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire; HCC = hepatocellular carcinoma; TACE = transarterial chemoembolization Outcome assessed = 2 yr survival Llovet JM, et al. Lancet 2003; 362: 1907–17 BCLC recommendations on TACE are based on the results of a single meta-analysis
1. Llovet JM, et al. Lancet. 2002;359: Lo C-M, et al. Hepatology. 2002;35: TACE: long-term survival outcomes 3-year overall survival (OS): 26% 2 –29% 1 Sustained objective response rate (ORR) (3–6 months): 35% 1 –39% 2 No difference in survival of intention-to-treat (ITT) population between non-responders and control group Chemoembolization Control Chemoembolization Control p < p = Time since randomization (months) Probability of survival (%) Time since randomization (months) Llovet JM, et al.Lo C-M, et al.
Concluding observations on the meta-analysis by Llovet et al Individual studies included in the meta-analysis reflect: Heterogeneity of the intermediate patient population Diversity in TACE methodologies BCLC, Barcelona Clinic Liver Cancer; TACE, transarterial chemoembolization. Outcome is a function of patient characteristics, tumour characteristics, and TACE technique To allow a more differentiated prognosis of outcome following TACE, additional data on these factors are required Llovet JM, et al. Lancet 2003; 362: 1907–17
Raoul et al, Cancer Treatment Reviews 37 (2011) 212–220 Reported relative contraindications Tumour size ≥10 cm Comorbidities involving compromised organ function: - Active cardiovascular disease - Active lung disease Untreated varices at high risk of bleeding Bile-duct occlusion or incompetent papilla due to stent or surgery Reported absolute contraindications Decompensated cirrhosis (Child-Pugh B ≥8) including: - Jaundice - Clinical encephalopathy - Refractory ascites - Hepato-renal syndrome Extensive tumour with massive replacement of both entire lobes Severely reduced portal vein flow (e.g. non-tumoural portal vein occlusion or hepatofugal blood flow) Technical contraindications to hepatic intra-arterial treatment (e.g. untreatable arteriovenous fistula) Renal insufficiency (creatinine ≥2 mg/dL or creatinine clearance <30 mL/min) Indications and contraindications to TACE
■Objective response (OR) using WHO criteria: 40 ± 20% ■Complete tumor necrosis: 44 ± 30% ■Survival rate at 1, 2, 3 and 5 years: 62 ± 20%, 42 ± 17%, 30 ± 15%, 19 ± 16% respectively ■Mean survival time: 18 ± 9 months Marelli L et al. Cardiovasc Intervent Radiol (2007) 30:6-25 Efficacy of TACE
Kaplan–Meier curves were generated to compare survival between responders and non-responders according to mRECIST radiological assessment methods. Assessments were also defined according to overall responses (A) and target lesion responses (B) A B Adapted from Gillmore R et al. Journal of Hepatology 2011 vol. 55 j 1309–1316 Overall responses Target lesion responses Non–responders vs responders to TACE treatment
Evaluation of per-nodule efficacy of TACE 271 cirrhotic patients with 635 nodules underwent a first cTACE Repeated TACE "on demand" after local recurrences (LR) or partial responses (PR) Aim of the study: evaluation of complete response (CR), time to nodule progression (TTnP), and local recurrence rate (LRR), according to three size classes (≤ 2 cm, cm, and>5 cm) Evaluation of tumor response according to mRECIST (after 1 month and every 3-4 months afterwards) Median follow-up: 12 months (1-51) Golfieri R, et al. J Vasc Interv Radiol 2013; 24(4): Tumor size≤ 2 cm (N=386) cm (N=211) > 5 cm (N=36) Nodules, n% % % Risposta tumorale CR PR LR
Precision V study: only half of eligible patients respond to TACE Phase II Precision V study (n=2121) Patient population: –ECOG PS 0/1 75/25% –Child–Pugh A/B 82/18% CR, complete response; cTACE, conventional transarterial chemoembolization; DEB, drug-eluting beads; ECOG PS, Eastern Cooperative Oncology Group performance status; OR, objective response; TACE transarterial chemoembolization Lammer J et al. Cardiovasc Intervent Radiol 2010;33:41– ORCR % of patients DEB-TACE TACE In Precision V, only 52% of patients were reported to have an OR (with DEB-TACE) Time to progression: not reached – >8.9 months (DEB-TACE) vs 7.5 months (cTACE) Many patients are refractory to TACE
Terzi E. J Hepatol Dec;57(6): Recurrence Rate The estimated recurrence rate in patients with complete response was 37% and 61% at 6 and 12 months after first cTACE and 40% and 59% after second cTACE. Percentage Cohort study conducted on 151 patients consecutively treated with cTACE as a retrospective analysis of a prospective database. Recurrence rate after TACE cycles
>3 liver lesions 1 3 Tumour diameter ≥5cm 4 7 Multi-nodular/diffuse tumour 1,5,8 Bilobar tumour 1,3 Portal vein thrombosis 1,9 Tumour characteristics: Child-Pugh B 1–9 Alpha-fetoprotein (≥400 ng/mL) 2,6,8,9 Presence of grade 3 ascites 5,10,11 Bilirubin >3 mg/dL 2,7,8,12 Performance status ≥1 3,12,13 Patient characteristics: Less selective TACE procedures (lobar or bilobar) 1 3 Conventional TACE 4 6 Technique-related: 1. Cammà C, et al. Radiology 2002;224:47–54; 2. Yip WM, et al. Hong Kong Med J 2009;15:339-45; 3. Kothary N, et al. J Vasc Interv Radiol 2007;18:1517–26; 4. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 Malagari K et al. Cardiovasc Intervent Radiol 2010; 33: Varela M et al. J Hepatol 2007;46:474– Lladó L, et al. Cancer 2000;88:50–7; 2. Mabed et al. Eur J Cancer Care 2009;18:492-9; 3. Vogl TJ, et al. Radiol 2000;214:349-57; 4. Sotiropoulos GC, et al. Dig Dis Sci 2009;54: ; 5. Dumortier J, et al. Dig Liver Dis 2006;38:125–33; 6. Savastano S, et al. J Clin Gastroenterol 1999; 28:334–40; 7. Doffoël M, et al. Eur J Cancer 2008; 44:528–38; 8. Lopez RR, et al. Arch Surg 2002; 137:653–658; 9. Stuart K, et al. Cancer 1993;72:3202–9. 1. Dumortier J, et al. Dig Liver Dis 2006;38:125–33.; 2. Savastano S, et al. J Clin Gastroenterol 1999; 28:334–40; 3. Doffoël M, et al. Eur J Cancer 2008; 44:528–38; 4. Florio F, et al. Cardiovasc Intervent Radiol 1997;20:23–8; 5. Pietrosi G, et al. J Vasc Intervent Radiol 2009;20: ; 6. Yip WM, et al. Hong Kong Med J 2009;15:339-45; 7. Gomes AS, et al. AJR Am J Roentgenol 2009;193: ; 8. Mabed et al. Eur J Cancer Care 2009;18:492-9; 9. Forner et al. Seminars Liver Dis 2010;30:61-74; 10. Cho YK, Cancer 2008;112:352-61; 11. Lladó L, et al. Cancer 2000;88:50–7; 12. Cabibbo G, et al. Aliment Pharmacol Ther 2011;34:196–204; 13. Bruix J, et al. Hepatology 1994;20:643 50. Factors that may negatively affect prognosis after TACE
1. Bruix J, Sherman M. Hepatology 2010 e-pub ahead of print available at: 2. EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma Journal of Hepatology 2012 vol. 56 j 908–943 Available on: ; 3. NCCN Clinical Practice Guidelines V Available at: ; 4.Hepatology Research 2010; 40 (Suppl. 1): 8–9; 5. Raccomandazioni AISF per la gestione integrata del paziente con Epatocarcinoma; published on Available on: *Considered a relative contraindication RecommendationContraindications AASLD 1 First-line non-curative for non-surgical pts with large/multifocal tumours EHS, vascular invasion EASL EORTC 2 Intermediate (stage B) pts (PS 0 and Child- Pugh A–B) with multinodular, asymptomatic tumours EHS, vascular invasion NCCN 3 Pts not eligible for curative therapies (resection, transplantation) Bilirubin >3 mg/dL,*PVT or Child-Pugh C JSH 4 Child-Pugh A–B with large (>3 cm), multinodular tumours Child-Pugh C, single tumour AISF 5 Pts with PS 0-1 and Child-Pugh A–B7 with multinodular, asymptomatic tumours Bilirubin >3 mg/dL,*EHS, PVT or Child-Pugh C *Considered a relative contraindication Current recommendations and contraindications for using TACE in HCC patients
AISF guidelines: patient suitability for TACE TACE is not indicated in patients with jaundice, untreatable ascites, main or branch portal vein thrombosis, hepatofugal portal blood flow, HCC nodules larger than 10 cm TACE is indicated in BCLC stage patients, not eligible for surgery or ablation. The best candidates for TACE are asymptomatic Child-Pugh class A patients, although those with a Child- Pugh score of B7 or ECOG PS 1 can also be considered Patients suitable for TACE Patients unsuitable for TACE Position paper AISF DLD (2013)
Grado di raccomandazione SIGNRaccomandazione clinica Forza della raccomandazione clinica A Nei pazienti con cirrosi epatica Child-Pugh A la TACE deve essere preferita come trattamento per le forme multinodulari e per i tumori singoli di grandi dimensioni (> 5 cm) in caso di controindicazione alla chirurgia Positiva forte AIOM Guidelines. Available at: AIOM Guidelines
Repeating TACE or switching To ensure that patients have the best possible outcomes it is important to understand when to repeat and when to switch TACE 1,2 This may be achieved in part by defining those patients who will respond well to TACE vs. those who are less likely to respond well 1,2 Generally TACE is carried out through: Regular repetition (usually every 2 months, range 1-6 months) 3-6 ‘On-demand’ (driven by response to previous cycle of TACE) 7,8 TACE, transarterial chemoembolization. 1. Cammà C, et al. Radiology 2002; 224:47 54; 2. Peck-Radosavljevic M. Liver Int. 2010;30:3-4; 3. Vogl TJ, et al. Radiology 2000;214:349–35; 4. Saccheri S, et al. J Vasc Interv Radiol 2002;13:995–9; 5. Grieco A, et al. Hepatogastroenterology 2003;50:207–12; 6. Farinati F, et al. Dig Dis Sci 1996; 41:2332–9; 7. Lu W, et al. Hepatogastroenterology 2003; 50:2079–83; 8. Ernst O et al. AJR 1999;172:59–64.
Potential indications for stopping or continuing TACE Stopping TACE TACE can be stopped –As soon as a complete response is obtained* † –In the absence of response after 2 3 TACE sessions 1 –If there is progression of the treated lesion* TACE should be stopped in cases of: –SAE –Arterial thrombosis 2 –Liver failure 3,4 –Portal vein thrombosis 4 –Patient’s decision Continuing TACE TACE can be continued in cases of: – Local tumour recurrence* – New tumour growth* SAE, serious adverse event; TACE, transarterial chemoembolization. 1. Bruix J, et al. Hepatology 1998;27:1578–83; 2. Ahrar K, Gupta S. Surg Oncol Clin N Am 2003;12:105 26; 3. Pleguezuelo M, et al. Expert Rev Gastroenterol Hepatol 2008;2:761 Cammà C, et al. Radiology 2002;224:47–54; 5. Bruix J, et al. J Hepatol 2001;35:421 30. *Expert opinion expressed at a specialist workshop on TACE † CR as defined per the EASL guidelines 5
Developed by multivariate regression analysis of –baseline characteristics –radiological response after 1st TACE (EASL-response criteria) –changes of liver function after the 1st TACE Determined prior to 2nd TACE in BCLC-A*/B patients, who received ≥ 2x TACE Training cohort: n=107 (Vienna), validation cohort: n=115 (Innsbruck) ART score categoryPoints Absence of radiological tumour response1 (0 if present) AST increase >25%4 (0 if absent) Increase in CP score by 1 point1.5 (0 if absent) Increase in CP score by ≥2 points3 (0 if absent) *BCLC-A not suitable for liver transplantation/local ablative treatment AST, aspartate transaminase; BCLC, Barcelona Clinic Liver Cancer; CP, Child–Pugh; EASL, European Association for the Study of the Liver; TACE, transarterial chemoembolization Sieghart W et al. Hepatology 2013 Jan 12. doi: /hep Assessment for Retreatment with TACE: the ART score
Training cohortValidation cohort 0–1.5 points ART score ≥2.5 points ART score Time (months) Cumulative survival Sieghart W et al. Hepatology 2013 Jan 12. doi: /hep Time (months) The ART score was developed in the training cohort by using a stepwise Cox regression model. Patients were then investigated for the effect of the first TACE on cumulative survival (OS, long rank test). 0 ‒ 1.5 points (n=60): 23.7 months (CI: 16–32) ≥2.5 points (n=37): 6.6 months (CI: 5–9) P=0.001 The ART score was externally validated in an independent validation cohort. 0 ‒ 1.5 points (n=74): 28.0 months (CI: 23–33) ≥2.5 points (n=37): 8.1 months (CI: 6–11) P< –1.5 points ART score ≥2.5 points ART score An ART score of ≥ 2.5 prior the second TACE identifies patients with a dismal prognosis who may not profit from further TACE sessions ART score: prognostic significance
Developed by multivariate analysis of prognostic factors –albumin (<36 g/dl) –bilirubin (>17 μmol/l) –AFP (>400 ng/ml) –size of dominant tumour (7 cm) Training dataset: n=114 patients treated with TACE/TAE; validation dataset: n=167 treated with TACE Prognostic factorPoints Albumin (<36 g/dl)1 AFP > 400 ng/ml1 Bilirubin > 17 μmol/l1 Maximum tumour diameter >7 cm1 HAP classificationPoints HAP A0 HAP B1 HAP C2 HAP D>2 L. Kadalayil, et al. Annals of Oncology 24: 2565–2570, 2013 The Hepatoma Arterial-embolisation Prognostic (HAP) score
Training datasetValidation dataset Kaplan–Meier survival curves according to the Hepatoma arterial-embolisation prognostic (HAP) score in the training dataset (A) and the validation dataset (B). For the training dataset, the median overall survival (OS) times were 27.6 months (95% CI16 to not estimable), 18.5 months (95% CI15.5–30.4), 9.0 months (95% CI 6.9–15.4) and 3.6 months (95% CI 1.7–8.5) for HAP A, B, C and D, respectively. For the validation set, OS median values were 25.5 (95%CI 13.7–32.8), 18.1 (95% CI 9.9 to not estimable), 8.9 (95% CI 6.8–16.1) and 5.9 (95% CI 2.8–12.7) months, respectively. A HAP score of C or D defined poor prognosis groups which are unlikely to benefit from TACE and might be better served with systemic therapy L. Kadalayil, et al. Annals of Oncology 24: 2565–2570, 2013 The Hepatoma Arterial-embolisation Prognostic (HAP) score
Considerations for multiple TACE cycles There is a lack of RCTs that compare regular with on-demand TACE Multiple TACE cycles may: Increase liver damage 1,2 Increase survival 2,6 Regular TACE cycles may increase complications 3–6 Repetition on demand may be more acceptable Patients often refuse multiple TACE cycles because of side effects 7 Patient’s treatment goals should be considered Quality of life can be increased by use of repetition on demand 8 Could regular increases in VEGF levels lead to increased vascularization of remaining and/or metastatic tumours? 9–11 RCT, randomized controlled trial; TACE, transarterial chemoembolization; VEGF, vascular endothelial growth factor. 1. Kwok PC, et al. J Hepatol 2000;32:955 64; 2. Grieco A, et al. Hepatogastroenterol 2003; 50:207 12; 3. Cammà C, et al. Radiology 2002; 224:47 54; 4. Herber SCA, et al. AJR 2008;190:1035 42; 5. Huo T, et al. Aliment Pharmacol Ther 2004; 19:1301 8; 6. Ernst O, et al. AJR 1999;172:59 64; 7. Savastano S, et al. J Clin Gastroenterol 1999;28:334 40; 8.Venook AP, et al. J Clin Oncol 1990;8:1108 14; 9. Li X, et al. W J Gastroenterol 2004;10:2878 82; 10. Sergio A, et al. Am J Gastroenterol 2008;103:914 21; 11. Wang B, et al. Acta Radiologica 2008;49:523 9.
GI, gastrointestinal; TACE, transarterial chemoembolization. 1. Cammà C, et al. Radiology 2002; 224:47 54; 2. Pelletier G, et al. J Hepatol 1998;29:129–34; 3. Saccheri S, et alJ Vasc Interv Radiol 2002;13:995–9; 4. Poon RT-P, et al. J Surg Oncol 2000;73:109 14; 5. Hsieh MY, et al. World J Gastroenterol 2004;10:505–8; 6. Bruix J, et al. Hepatol 1998;27:1578–83; 7. Chan AO, et al. Cancer 2002;94:1747 52; 8. Farinati F, et al. Dig Dis Sci 1996; 41:2332 9; 9. Kirchhoff TD, et al. Hepatobiliary Pancreat Dis Int 2007; 6:259 66; 10. Lopez RR, et al. Arch Surg. 2002; 137:653 8; 11. Savastano S, et al. J Clin Gastroenterol 1999; 28:334 40; 12. Llovet JM, et al. Lancet 2002;359:1734–39; 13. Shi M, et al. World J Gastroenterol 2010; 16: 264–69. *Defined as one or more of: encephalopathy, increasing ascites, increase in prothrombin time, increase in serum bilirubin, deterioration of CP status. Most frequent complications of TACE Liver failure (15–51% of pts) 1 5 GI bleeding [variceal hemorrhage or GI ulcers] ( 10%) 1 3 Ascites (10–17%) 2,5 Post-embolization syndrome (>80%) 5 7 Reported at <10% frequency 1,3,5,7 13 Tumour abscess formation Tumour rupture Haemoperitoneum Hepatic artery occlusion Portal vein thrombosis Ischemic cholecystitis or pancreatitis Renal failure Bacterial peritonitis Pleural effusion Pulmonary thromboembol. Sepsis/septic shock Complications commonly associated with TACE
The number of patients with major or severe complications associated with TACE varies greatly TACE methodology Rate of major/severe complications,% (n/N) Epirubicin/ lipiodol + gelatin sponge 1 ~9.7 (8/82) † Doxorubicin/DEB (19/93) ‡ Doxorubicin/polyvinyl alcohol (9/20) § Doxorubicin + cisplatin/ lipiodol + starch microsphere (6/47)** Doxorubicin + gelfoam (2/42) †† Doxorubicin/ lipiodol + polyvinyl alcohol (14/80) ‡‡ Various (meta-analysis of 18 RCTs) 7 Range 0–57% §§ AEs, adverse events; RCTs, randomized controlled trials; DEB, drug-eluting beads ; TACE, transarterial chemoembolization. 1. Savastano S, et al. J Clin Gastroenterol 1999;28:334– Lammer J, et al. Cardiovasc Intervent Radiol ;33:41– Hsieh MY, et al. World J Gastroenterol 2004;10:505–8. 4. Kirchhoff TD, et al. Hepatobiliary Pancreat Dis Int 2007;6:259– Pelletier G, et al. J Hepatol 1990;11:181–4. 6. Molinari M, et al.Clin Oncol (R Coll Radiol) 2006;18:684– Cammà C, et al. Radiology 2002;224:47–54. ‡ Complications in 80/182 patients (44%), 38% of complications were major. § Major complications were regarded as any prolongation of stay in hospital caused by hepatic failure, pulmonary embolism, stroke, pneumonia, upper GI bleeding, or refractory ascites. ** Focal liver necrosis, partial dissection of the hepatic artery, gastric ulcer, and cholecystitis. † † Death from renal failure and GI bleeding; ‡‡ Complications by number of TACE sessions (major complications included: partial portal vein thrombosis, upper GI bleeding, dehydration and cachexia requiring re-admission, flare of hepatitis B virus hepatitis, neutropenic fever requiring parenteral antibiotics, femoral artery pseudo aneurysm, paraduodenal chemotherapy extravasation and psoas muscle abscess).. § § Serious AEs (those AEs resulting in death or were immediately life-threatening or resulted in permanent or significant disability/incapacity or required extending inpatient hospitalization or congenital anomaly/birth defects) occurring within 30 days of treatment.
Variables Use of embolizing agents Severe post-embolization syndrome* (PES) 1,2 Associated with duration of PES-related fever 1 Low number of treatment cycles Associated with duration of PES-related fever 1 TACE method Lower rate of serious liver toxicity with DEB-TACE (2.9%) vs. conventional TACE (9.0%) 3 Dose Larger doses of cisplatin/lipiodol associated with increased risk of hepatic decompensation 1,4,5 Multiple treatment cyclesPotential to increase the risk of complications 6–9 * requiring anaesthetics for > 7 days 1. Pelletier G, et al. J Hepatol 1990;11:181 4; 2. Chan AO, et al. Cancer 2002; 94:1747 52; 3. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:41 52; 4. Hwang JI, et al. Anticancer Res 2005;25:2551 4; 5. Poon RT, et al. J Surg Oncol 2000;73:109 14; 6. Huo T, et al. Aliment Pharmacol Ther 2004;19:1301–8; 7. Herber SC, et al. AJR 2008;190:1035 42; 8. Cammà C, et al. Radiology 2002;224:47 54; 9. Ernst O, et al. AJR 1999;172:59 64. Factors reported to be associated with TACE- related complications
Factors associated with TACE-related complications Patient characteristics Liver function Liver damage after TACE is more common in patients with poor liver function 1–5 Child–Pugh B status is associated with risk of acute renal failure 6 Disease characteristics Tumor size Larger tumor size associated with post-TACE liver failure (p < 0.001) 4 TACE characteristics Number of sessions Multiple TACE sessions can increase the risk of complications 6–8 TACE method Lower rate of serious liver toxicity with DEB-TACE (2.9%) versus “conventional” TACE (9.0%) 9 Dose Larger doses of cisplatin/lipiodol are associated with an increased risk of hepatic decompensation 1,2,4 1. Chan AO, et al. Cancer. 2002; 94: Hwang JI, et al. Anticancer Res. 2005;25: Chen MS, et al. World J Gastroenterol. 2002; 8: Poon RT, et al. J Surg Oncol. 2000;73: Shah SR, et al. QJM. 1998; 91: Huo T, et al. Liver Int. 2004;24: Herber SC, et al. AJR 2008;190: Cammà C, et al. Radiology. 2002;224: Lencioni R, et al. ASCO-GI. 2009;[abstract 116]. DEB = drug-eluting beads.
Majority of studies report some TACE-related death within 30 days Causes of TACE-related death Decompensated cirrhosis 3,4 Liver failure Gastrointestinal bleeding Renal failure Hepatic encephalopathy Septic shock Embolic nature of TACE 4,5 Tumor rupture Hepatic abscesses Perforated duodenal ulcer Perforation of an ischemic colon Portal vein thrombosis Respiratory failure Most studies describing the use of TACE report some treatment- related death (0.5% 1 to 17% 2 ) 1. Takayasu K, et al. Gastroenterol. 2006;131: Stuart K, et al. Cancer. 1993;72: Bruix J, et al. Hepatol. 1998;27: Pelletier G, et al. J Hepatol. 1998;29: Chan AO, et al. Cancer. 2002; 94:
Variables Number of TACE sessions Multiple TACE sessions are associated with a higher risk of post- treatment mortality (OR 1.50, p<0.0001) 1 Portal vein thrombosis Treatment of patients with portal vein thrombosis was associated with a higher risk of post-TACE mortality (OR 3.24, p=0.013) 1 Lobar vs. superselective Mortality at 30 days correlated with extent of embolization (lobar vs. superselective, p=0.03) 2 Nature of embolic agents Can be associated with mortality due to tumour rupture, hepatic abscesses, perforated duodenal ulcer, perforation of an ischaemic colon, portal vein thrombosis, respiratory failure 3,4 OR, odds ratio; TACE, transarterial chemoembolization. 1. Cammà C, et al. Radiology 2002;224:47–54; 2. Kothary N, et al. J Vasc Interv Radiol 2007;18:1517 26; 3. Pelletier G, et al. J Hepatol 1998;29:129–134; 4. Chan AO, et al. Cancer 2002; 94:1747–52. Factors reported to be associated with TACE- related mortality
Sub-analyses from the SHARP and Asia-Pacific studies suggest that sorafenib may benefit some patients with intermediate stage HCC 4,5 TACE may not be suitable for all patients with intermediate stage HCC Not all patients are suitable for TACE 1 Evidence of efficacy is limited 2,3 Most studies carried out in ‘pre-staging’ era TACE protocols are highly heterogeneous Intermediate-stage patient segment is not well defined A number of guidelines/recommendations recognize that management strategies are needed for patients who have failed or are unsuitable for TACE HCC, hepatocellular carcinoma; SHARP, Sorafenib Hepatocellular carcinoma Assessment Randomized Protocol; TACE, transarterial chemoembolization. 1. Bruix J, Sherman M. Hepatology 2011;53:1020–2; full guidelines available at: 2. Llovet JM, Bruix J. Hepatology 2003;37:429–42; 3. Oliveri et al. Cochrane Database Syst Rev 2011;3:CD Bruix J et al. J Hepatol 2009;50(Suppl 1):S28-9 [abstr 67]; 5. Cheng A, et al. Lancet Oncol 2009;10:25 34; 6. Forner A et al. Semin Liver Dis 2010;30:61–74; 7. Raoul J-L et al. Cancer Treat Rev May;37(3): ; 8. Thomas MB et al. J Clin Oncol 2010;28:3994–4005; 9. Piscaglia F, Bolondi L. Digestive Liver Dis 2010;42S:S258–63http://www.aasld.org/practiceguidelines/Pages/SortablePracticeGuidelinesAlpha.aspx
In caso di mancata risposta o di progressione dopo TACE o di controindicazione alla TACE, se la funzione epatica è buona, è raccomandata la terapia con sorafenib (Livello di evidenza 1+). I pazienti con questo tipo di HCC trattati con sorafenib nell’ambito dello studio prospettico randomizzato controllato con placebo (studio SHARP) dimostrano un significativo miglioramento della sopravvivenza (14,5 vs 10,2 mesi; HR=0,52; IC 95%: 0,32-0,85) Grado di raccomandazione SIGNRaccomandazione clinica Forza della raccomandazione clinica B Nei casi di controindicazione o di mancata risposta alla TACE deve essere considerato il trattamento con sorafenib Positiva forte AIOM Guidelines AIOM Guidelines. Available at:
Increased OS and TTP with sorafenib (n=54) vs placebo (n=51) Median OS: 14.5 vs 11.4 months (HR: 0.72; 95% CI: ) Median TTP: 6.9 vs 4.4 months (HR: 0.47; 95% CI: ) SHARP 1 BCLC-B subgroup Increased OS and TTP with sorafenib (n=86) vs placebo (n=90) Median OS: 11.9 vs 9.9 months (HR: 0.75; 95% CI: ) Median TTP: 5.8 vs 4.0 months (HR: 0.57; 95% CI: ) SHARP 1 Previous TACE subgroup Good efficacy demonstrated in BCLC-B HCC Longer survival in BCLC-B vs BCLC-C patients: 20.6 vs 8.4 months SOFIA 4 Good efficacy demonstrated in BCLC-B HCC Longer survival in BCLC-B vs BCLC-C patients: 25.4 vs 14.4 months INSIGHT 3 Similar safety profile for sorafenib across BCLC stages Longer survival in BCLC-B vs BCLC-C patients15.6 vs 9.1 months GIDEON final analysis 2 1. Bruix et al. J Hepatol. 2012:57:821-9; 2. Bronovicki J-P, et al. Presented at ECC P 2594; 3. Koschny R, et al. Presented at ESMO P437; 4. Iavarone M et al. Hepatology 2011;54: BCLC= Barcelona Clinic Liver Cancer; HCC= hepatocellular carcinoma; HR= hazard ratio; OS= overall survival; TTP= time to progression Intermediate HCC: data from SHARP and real- world practice
BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; HR, hazard ratio; CI, confidence interval. Bruix J et al. J Hepatol 2009;50(Suppl 1):S28-9 [abstr 67]. Advanced HCC (BCLC C) Favours placebo HR (95% CI) for survival Overall HR in SHARP Favours sorafenib Intermediate HCC (BCLC B) Sorafenib: n=245 Placebo: n=252 Sorafenib: n=54 Placebo: n=51 Preliminary evidence from SHARP subgroup analysis suggests sorafenib has survival benefits in intermediate HCC
Adapted from Bruix J et al. J Hepatol Oct;57(4): Epub 2012 Jun 19 Overall Survival Sorafenib consistently improved median OS compared with placebo in patients with intermediate HCC Median (months) SHARP subgroup analysis: sorafenib prolongs OS in BCLC B patients
Overall SurvivalTime to progression BCLC B patients treated with sorafenib (n = 54) had a longer median OS (14.5 vs months) and TTP (6.9 vs.4.4 months) and a higher DCR (50.0% vs. 43.1%) than those who received placebo (n = 51). Bruix J et al. J Hepatol Oct;57(4): Epub 2012 Jun 19 These exploratory subgroup analysis shows that sorafenib consistently improves median OS and TTP compared with placebo in patients with BCLC B HCC SHARP subgroup analysis: sorafenib prolongs OS and TTP in BCLC B patients
Overall SurvivalTime to progression Patients treated with sorafenib (n = 86) post TACE failure had a longer median OS (11.9 vs. 9.9 months) and TTP (5.8 vs.4.0 months) and a higher DCR (44.2% vs. 34.4%) than those who received placebo (n = 90). Bruix J et al. J Hepatol Oct;57(4): Epub 2012 Jun 19 Sorafenib improved TTP and demonstrated a trend toward improved OS, irrespective of prior therapy SHARP subgroup analysis: sorafenib prolongs OS and TTP post TACE failure
Overall survival GIDEON final analysis: sorafenib shows longer OS in BCLC-B vs BCLC-C patients Bronovicki J-P, et al. Presented at ECC P 2594
GIDEON final analysis: sorafenib prolongs TTP in BCLC-B vs BCL-C patients Bronovicki J-P, et al. Presented at ECC P 2594 Time to progression
BCLC-C BCLC-B unfit for any or failed to respond to locoablative treatments Objectives Primary: safety Secondary: treatment effectiveness [OS, early radiologic response, and time to radiologic progression] Treatment duration and cumulative dose 296 pts 25% BCLC-B 75% BCLC-C Results: Median OS = 10,5 months Median OS BCLC-B = 20.6 months Median OS BCLC-C = 8.4 months Iavarone M et al. Hepatology 2011;54: Multicenter (6 centers), investigator sponsored, observational, non- interventional study to assess the safety and effectiveness of sorafenib SOFIA analysis: sorafenib prolongs OS in BCLC B vs BCLC C patients
Koschny R, et al. Presented at ESMO P437 Overall survival according to BCLC stage 0,00 0,50 1,00 0,25 0,75 0 1: Stage A 2: Stage B : Stage C 4: Stage D p<0,0001 Median OS (months):BCLC A: 29.1 monthsBCLC C: 14.4 months BCLC B: 25.1 monthsBCLC D: 3.1 months Censored Preliminary median overall survival for BCLC stage C for BCLC stage B is promising in this ongoing study INSIGHT subgroup analysis: OS according to BCLC stage
Piscaglia and Bolondi Dig Liver Dis 2010;42:S Position paper AISF DLD (2013) Treatment of Intermediate stage HCC: key messages Intermediate patients with contraindications to TACE (and not suitable for alternative locoregional therapies) or suffering from severe side effects of TACE or refractory to 2(-3) cycles of TACE should be considered for treatment, from a practical point of view, as if they were advanced. The decision when to stop or repeat TACE is not univocal and should be tailored for each individual patient by a multidisciplinary team, considering: liver function, tumor burden technicalities alternative therapies Full dose sorafenib is the recommended treatment for HCC patients with preserved liver function who are not amenable to surgery and loco-regional treatments or in whom TACE failed, according to the Italian National Health Service rules (1b-A).