Storia clinica Paziente maschio di 74 anni Storia di ipertensione arteriosa. Giunge alla nostra osservazione nel giugno 2002 per ictus ischemico. In tale occasione viene diagnostica epatopatia cronica HCV-relata in fase cirrotica ben compensata (ChildPugh A5). Inizia follow up ecografico e clinico semestrale. Ottobre 2002, sfumata area iperecogena di 10 mm nel VI segmento sottocapsulare. Lieve splenomegalia (area 54 cmq) Vene epatiche con flusso appiattito. Vena porta con velocità di 19 cm/sec, RI splenico 0.70) 1. Viene rivisto a 4 mesi circa (febbraio 2003). Si conferma il piccolo nodulo di 11 mm. Si consiglia TC. Viene eseguita e risulta negativa. Si programma uno stretto follow up. 2. Maggio 2003 Permane immodificata la lesione debolmente iperecogena di 11 mm nel VI segmento. Non ulteriori lesioni focali. 3. Ottobre 2003 In sede centroepatica, strettamente adiacente al ramo portale posteriore destro, è presente un'area ipoecogena di 17 mm con scarsi segnali vascolari al suo interno.Permane invariata la lesione focale debolmente iperecogena di 11 mm al 6° segmento. Si procede ad angioecografia perfusionale. Per vedere questa immagine occorre QuickTime™ e un decompressore Motion JPEG A. TC spirale trifasica (26.11.2003) Fase arteriosa Fase portale TC spirale trifasica (26.11.2003) ? Fase portale CLINICA, DIAGNOSTICA E TERAPIA DELL’EPATOCARCINOMA Luigi Bolondi Cattedra di Clinica Medica Dipartimento di Medicina Interna e Gastroenterologia Università di Bologna - Policlinico S. Orsola Malpighi “ INCIDENCE OF HCC IN LIVER CIRRHOSIS annual incidence Oka et al, 1990 6.5 % Colombo et al, 1991 3% Pateron et al, 1994 5.8 % Benvegnu et al, 1994 3% Cottone et al, 1994 1.5-10 % Solmi et al, 1996 1.4 % Bolondi et al, 2001 4.1 % CIRROSI VIRUS HCC Flogosi cronica Necrosi Rigenerazione epatocitaria Diminuita capacità riparatrice dei danni al DNA HCC Aumento errori di replicazione e trascrizione del DNA Eterogeneità geografica Diversi fattori di rischio Diversi bersagli a livello molecolare Factors affecting natural history Acute hepatitis Chronic hepatitis Cirrhosis 6% Decompensation Death HLA type 85% Male gender Age on onset Alcohol Interferon 20% Hepatitis B 4% Alcohol Interferon HCC 3,6% Transplantation Di Bisceglie, Hepatology, 2000 INCIDENCE OF HCC DURING THE SURVEILLANCE PROGRAMME OF LIVER CIRRHOSIS (1989-1997) 313 patients with a follow-up of 56 31 months 74 nodules (23,6 %) 13 cases non HCC 61 HCC (19,5 %) Bolondi et al. Gut 2001 SCREENING FOR HCC IN CIRRHOSIS ANALYSIS OF SURVIVAL BENEFIT Significant longer survivals for screened vs non screened p = 0.009 p < 0.0001 p < 0.02 p < 0.001 (Wong, Liver Transpl 2000) (Yuen, Hepatology 2000) (Bolondi, Gut 2001) (Trevisani, Am J Gastro 2002) No Significant difference * (Sarasin, Am J Med 1996) * transplantation not included in the model Tailoring screening on RISK FACTORS FOR HCC IN CIRRHOSIS • Age (Aizawa, Cancer 2000) • Male gender (Zoli, Cancer 1996 Bolondi, Gut 2001 El Serag, J Clin Gastro 2002) • Child-Pugh • HBsAg score + (Bolondi, GUT 2001) (Solmi, Am J Gastro 1996) Tsukuma, N Engl J Med 1993) • HCV+ (Velazquez, Hepatology 2003) • HBV + HCV (Parkin, IARC 1992) • HCV + alcol (Benvegnù, Gut 2001) • AFP (Bolondi, Gut 2001) DEVELOPEMENT OF NEOPLASTIC GROWTH IN MACROREGENERATIVE NODULES ARAKAWA 1986 RECOGNITION OF EARLY MALIGNANT FOCI IN 5 ADENOMATOUS HYPERPLASTIC NODULES N°nodules mean follow-up 9 neoplastic growth TAKAYAMA 1990 18 1-5 yrs 9 benign behaviour 10 neoplastic growth RAPACCINI 1990 12 10.2 mos 2 benign behaviour 0 neoplastic growth KONDO 1990 17 > 1 yr 17 benign behaviour 7 neoplastic growth BOLONDI 1993 12 22.6 mos 5 benign behaviour PREDICTION OF MALIGNANT EVOLUTION IN SMALL NODULES (< 1.5 cm) DETECTED AT IMAGING TECHNIQUES IMAGING •Assessment of vascularity NEW TISSUE MARKERS MOLECULAR ANALYSIS •Markers of proliferation (AgNORs, PCNA, Ki67...) •Enzymatic cytochemistry •DNA ploidy CLINICAL CRITERIA Volume increase at 4 month •Assessment of monoclonality •Genomic instability and LOH Probably no consequence on outcome Blood supply of liver nodules in cirrhosis Portal flow Arterial flow Large regenerative nodule Dysplastic nodule Borderline lesion HCC CHARACTERIZATION OF LIVER MASSES: ASSESSMENT OF VASCULARITY BY IMAGING TECHNIQUES DOPPLER QUANTITATIVE QUALITATIVE SPECTRAL ANALYSIS COLOR and POWER mapping + mdc SPIRAL CT Contrast-enhanced NMR CONTRAST-ENHANCED US Stimulated Acoustic Emission Pulse Inversion Harmonic Imaging C3-mode CnTi ARTERIAL HYPERVASCULARITY IN SMALL HEPATOCELLULAR CARCINOMA Perfusional Angiosonography with Sonovue Spiral CT enhanced artherial phase HCC Per vedere questa immagine occorre QuickTime™ e un decompressore Video. Per vedere questa immagine occorre QuickTime™ e un decompressore Motion JPEG A. - Hyperintensity in the arterial phase - Iso or Hypointensity in the portal and late phases DIAGNOSIS OF HCC Cirrhotic patients (US + AFP/6m) Liver nodule 1-2 cm > 2 cm FNAB No nodule < 1 cm US /3m Increased AFP* Normal AFP Spiral CT AFP > 400 ng/ml Doppler/CT/MRI/An HCC * AFP level >200ng/dl No HCC Surveillance US + AFP/6m Bruix, J Hepatol ,2001 STAGING: OPEN PROBLEMS AND AREAS FOR FUTURE RESEARCHES • Multinodularity • Vascular invasion Selection between radical treatment or palliation Imaging techniques insufficient • Recurrence potential Tissue and molecular markers (Currently not done) • Selection between OLT and ablation/destruction therapies • Need for adjuvant therapy THERAPEUTIC OPTIONS FOR HCC Local therapy Percutaneous echo-guided Intra-arterial Surgical resection Transplant Systemic chemotherapy or hormonal therapy EFFECT OF TREATMENT ON SURVIVAL OF 1108 PTS WITH HCC Multicentric Italian Study Group on HCC SURVIVAL OF SINGLE HCC <5 cm Child A 100 90 80 70 60 50 40 30 20 10 0 NT (n=73) SURG (n=82) PEI (n=105) TACE (n=30) 1 year 2 years 3 years J Hepatol, 1995 SCREENING FOR HCC IN CIRRHOSIS ELIGIBILITY FOR CURATIVE TREATMENTS HCC detected outside surveillance programme HCC detected within surveillance programme 47.5 % p < 0.01 31.7 % (Bolondi, Gut 2001) Rationale for the use of local treatments • High rate of exclusion criteria from surgical resection (5-9% of pts arising from screening are candidate to surgery) • High recurrence rate after surgical resection 3 year recurrence 72% Ikeda et al, 1993 5 year recurrence 83% Ng et al, 1995 100% Belghiti et al, 1991 91% Gouillat et al, 1999 INTERSTITIAL TUMOR ABLATION HEAT FROST DRUGS laser, radiofrequency, highly focused ultrasound cryosurgery alcohol injection RADIOACTIVITY implantation of radioactive seeds Survival Outcomes in PEI-Treated Pts (Retrospective Studies) Author and year Shiina S et al, AJR 1993 Livraghi T et al, Radiology 1995 Child A, single < 5 cm Child B, single < 5 cm Lencioni R et al, Cancer 1995 Child A, single / multiple < 3 cm Child B, single / multiple < 3 cm No. of Pts Survival (%) 1-yr 3-yr 5-yr 98 85 62 52 293 149 98 93 79 63 47 29 64 41 100 91 87 53 55 13 SURVIVAL AFTER SURGICAL AND NONSURGICAL TREATMENT FOR HCC HCC < 2 cm clinical stage I 5 cm > HCC > 2 cm Surgery (n=8.010) (retrospective study) all clinical stages > PEI (n=4.037) (Arii et al, Hepatology 2000 Liver Cancer Study Group of Japan) PEI versus Surgical Resection (Non-Randomized Studies) 90 100 80 90 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 PEI Resection p= N.S. 1-yr 2-yr 3-yr 83 81 66 73 55 44 PEI Resection 1-yr 3-yr 5-yr 100 96 82 84 59 61 - Same tumor stage - Poorer liver function in PEI groups Castells et al, Hepatology p= N.S. Yamamoto et al, Hepatology 2001 Okosa farmaka ouk ihtai, sidheros ihtai, osa sidheros ouk ihtai, pur ihtai, osa dh pur ouk ihtai tauta crh nomizein aniata Quae maedicamenta non sanant, ferrum sanat,quae ferrum non sanat, ignis sanat,quae vero ignis non sanat, insanabilia reputari oportet Ippocrate, Aforisma 7, 87 RF THERMAL ABLATION EXPANDABLE NEEDLE (1.9 mm) 90-115°C 4 to 10 nickel-titanium hooks with tip thermistors RF THERMAL ABLATION COOLED-TIP NEEDLE (1.2-1.3 mm) 20-25°C Peristaltic pump with 0°C saline solution RF Ablation of HCC: Local Effect (histologic assessment after OLT) 24 pts, 47 HCC lesions (0.4 – 5.5 cm; mean, 2.3 cm) - Complete necrosis on histology: 35 / 47 (74%) Lu DSK et al, Radiology 2005 Overall Survival 100 90 67 % 80 70 60 50 40 30 20 10 0 6 98 PEI RFTA 100 12 18 24 30 36 96 100 92 98 88 98 80 93 73 81 PEI series (n = 184) - Lencioni R et al, Eur Radiol 1997 74 % 50 % Lin SM et al Gastroenterology 2004 RANDOMIZED COMPARISON OF RF THERMAL ABLATION vs PEI 232 patients with up to 3 HCC < 3 cm each RF PEI ---------------------------------------------------------------- • Treatment sessions p<00001 2.1 6.4 • 4yr survival 74% 57% 70% 85% p=0.01 • 4yr Overall recurrence p=0.005 • 4yr Local progression 1.7% 11% p=0.003Shiina, Gastroenterology 2005 COMPARING THE OUTCOMES OF RF ABLATION AND SURGERY IN PTS WITH SINGLE SMALL HCC AND WELL-PRESERVED HEPATIC FUNCTION Hong SN et al, J Clin Gastroenterol 2005 Barcelona 2005 - PERCUTANEOUS ABLATION Summary and conclusions • RF thermal ablation has emerged as the most valid alternative to PEI. According to various studies, its failure in achieving local control is lower than PEI. Data on survival are still preliminary and are influenced by different patient selection • The complication rate of RF was initially considered higher but recent reports do not confirm this finding • In HCCs of 3 to 5 cm the efficacy of a percutaneous treatment in achieving local control is questionable • Individual factors play an important role in treatment selection • Other techniques such as microwave or Laser have a minor impact • PEI can probably maintain a place in the treatment of very small nodules (<2 cm) or in difficult locations (perivascular) multifocal HCC PROBLEMS IN EVALUATION RCTs ON TRANSARTERIAL CHEMOEMBOLIZATION • Small sample size • Differences in treatment procedures (chemoterapeutic agent - Cysplatin, Mytomicin, Doxorubicin - , embolization, number and interval of procedures) • Patients selection and stratification TERAPIA DELL’ HCC UNIFOCALE IN FEGATO CIRROTICO CONCETTI CHIAVE Pz in classe Child-Pugh A a basso rischio operatorio e nodulo unico candidati a resezione anatomica Pz con nodulo singolo < 5 cm (e buon compenso epatico) ottimi candidati alle terapie locoregionali percutanee: l’alcolizzazione è la tecnica di scelta Noduli < 3 cm: Noduli >3 cm: Risultati migliori Se non resecabili, si può associare PEI + TACE TERAPIA DELL’HCC UNIFOCALE IN FEGATO CIRROTICO CONCETTI CHIAVE Pz < 65 aa con nodulo singolo in classe Child-Pugh B e C Considerare indicazione a trapianto di fegato La TACE può essere utile nei pz in lista d’attesa per contrastare la crescita e la diffusione della neoplasia (?) BARCELONA RECOMMENDATIONS CURATIVE TREATMENTS PEI vs SURGICAL RESECTION Recurrence rate after percutaneous treatments is as frequent as after surgical resection (>50% at 3 years and > 70% at 5 years) The are no RCTs comparing surgical resection and PEI. While some series report that survival after PEI is lower than after surgical resection, some cohort studies have failed to detect significant differences PEI can be recommended for well compensated patients when surgery is precluded J Hepatol 2001 TERAPIA DELL’HCC MULTIFOCALE IN FEGATO CIRROTICO CONCETTI CHIAVE Pz fino a 3 noduli <3 cm, età <65 aa Pz con HCC bifocale nello stesso segmento Candidabili a trapianto di fegato Candidabili a resezione epatica con gli stessi criteri dell’HCC singolo CHEMIOEMBOLIZZAZIONE TRANSARTERIOSA: • è stato il trattamento più impiegato nel trattamento dei pz con HCC multifocale • mancano chiare dimostrazioni di efficacia sulla sopravvivenza TERAPIE INTERSTIZIALI: • l’ efficacia in pz con HCC multifocale non è sufficientemente nota BARCELONA RECOMMENDATIONS TREATMENT OF INTERMEDIATE – ADVANCED HCC Six RCTs, comparing arterial embolisation alone or associated with chemotherapy have failed to identify a survival benefit, even in those patients with local response to treatment Additional large RCTs are needed to clarify wheter differences in the selection of patients or in treatment schedules may result in a therapeutic benefit at least in a subgroup of HCC (Recent demonstration of advantages of TACE emerging from a metanalysis of puvblished RCTs and 2 new RCTs) None of the available options including tamoxifen, antiandrogens, Interferon and chemotherapeutic agents, offers an unequivocal survival benefit J Hepatol 2001 DIVISIONE DI MEDICINA INTERNA UNIVERSITA’ DI BOLOGNA POLICLINICO S.ORSOLA MALPIGHI Luigi Bolondi Centro per lo studio dei tumori del fegato Gianni Zironi Laura Gramantieri Patrizia Pini Fabio Piscaglia Valeria Camaggi Elena Silvagni Natascia Celli Simona Leoni NON-SURGICAL ABLATION OF SMALL HCC PEI RF +++ +++ • Complications -- -+ • Pts compliance + ++ • Efficacy • Physician involvement +++ ++ • Cost +++ + SURGICAL RESECTION LIVER TRANSPLANTATION High rate of complete response in selected candidates PERCUTANEOUS TECHNIQUES CURATIVE/EFFECTIVE TREATMENTS Assumed to improve the natural history, prolonging the survival of patients with single < 5 cm HCC or 3 nodules < 3 cm EASL Conference J Hepatol 2001 Multicentric Italian Study on PEI in HCC (746 cases) (Bologna, Brescia, Clusone, Napoli Cotugno, Napoli Policlinico, Padova, Roma, Torino, Vimercate) 100 Child A (293 cases) 5 years survival in unifocal (<5 cm) HCC Median: Child A23 months Child B (149 cases) 50 % Child B19 months 0 1 2 3 4 5 years Radiology 1996