Paziente maschio di 74 anni Storia di ipertensione arteriosa.

Presentazione sul tema: "Paziente maschio di 74 anni Storia di ipertensione arteriosa."— Transcript della presentazione:

1 Paziente maschio di 74 anni Storia di ipertensione arteriosa.
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 (Child-Pugh 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)

2 Viene rivisto a 4 mesi circa (febbraio 2003)
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. Maggio 2003 Permane immodificata la lesione debolmente iperecogena di 11 mm nel VI segmento. Non ulteriori lesioni focali. 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.

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5 TC spirale trifasica (26.11.2003)
Fase arteriosa Fase portale

6 TC spirale trifasica (26.11.2003)
? Fase portale

7 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 “

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9 INCIDENCE OF HCC IN LIVER CIRRHOSIS
annual incidence Oka et al, % Colombo et al, % Pateron et al, % Benvegnu et al, % Cottone et al, % Solmi et al, % Bolondi et al, %

10 CIRROSI VIRUS HCC Diminuita capacità riparatrice dei danni al DNA Flogosi cronica Necrosi Rigenerazione epatocitaria HCC Aumento errori di replicazione e trascrizione del DNA Eterogeneità geografica Diversi fattori di rischio Diversi bersagli a livello molecolare

11 Acute hepatitis Chronic hepatitis 85% Cirrhosis 20% 6% Decompensation
Factors affecting natural history Acute hepatitis Chronic hepatitis HLA type 85% Male gender Age on onset Alcohol Interferon Cirrhosis 20% Hepatitis B Alcohol Interferon 6% Decompensation HCC 4% Transplantation Death 3,6% Di Bisceglie, Hepatology, 2000

12 DURING THE SURVEILLANCE PROGRAMME
INCIDENCE OF HCC DURING THE SURVEILLANCE PROGRAMME OF LIVER CIRRHOSIS ( ) 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

13 SCREENING FOR HCC IN CIRRHOSIS ANALYSIS OF SURVIVAL BENEFIT
Significant longer survivals for screened vs non screened p = (Wong, Liver Transpl 2000) p < (Yuen, Hepatology 2000) p < (Bolondi, Gut 2001) p < (Trevisani, Am J Gastro 2002) No Significant difference * (Sarasin, Am J Med 1996) * transplantation not included in the model

14 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 score (Bolondi, GUT 2001) HBsAg + (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)

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17 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 yrs 9 benign behaviour 10 neoplastic growth RAPACCINI mos 2 benign behaviour 0 neoplastic growth KONDO > 1 yr 17 benign behaviour 7 neoplastic growth BOLONDI mos 5 benign behaviour

18 PREDICTION OF MALIGNANT EVOLUTION IN SMALL NODULES (< 1
PREDICTION OF MALIGNANT EVOLUTION IN SMALL NODULES (< 1.5 cm) DETECTED AT IMAGING TECHNIQUES IMAGING NEW TISSUE MARKERS MOLECULAR ANALYSIS Markers of proliferation (AgNORs, PCNA, Ki67...) Enzymatic cytochemistry DNA ploidy Assessment of monoclonality Genomic instability and LOH Assessment of vascularity Probably no consequence on outcome CLINICAL CRITERIA Volume increase at 4 month

19 Blood supply of liver nodules in cirrhosis
Portal flow Arterial flow Large regenerative nodule HCC Dysplastic nodule Borderline lesion

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22 CHARACTERIZATION OF LIVER MASSES: ASSESSMENT OF VASCULARITY BY IMAGING TECHNIQUES
SPIRAL CT Contrast-enhanced NMR DOPPLER QUANTITATIVE QUALITATIVE SPECTRAL ANALYSIS COLOR and POWER mapping + mdc CONTRAST-ENHANCED US Stimulated Acoustic Emission Harmonic Imaging Pulse Inversion C3-mode CnTi

23 ARTERIAL HYPERVASCULARITY IN SMALL HEPATOCELLULAR CARCINOMA
Perfusional Angiosonography with Sonovue Spiral CT enhanced artherial phase

24 HCC - Hyperintensity in the arterial phase - Iso or Hypointensity in
the portal and late phases

25 Surveillance US + AFP/6m
DIAGNOSIS OF HCC Cirrhotic patients (US + AFP/6m) Liver nodule No nodule 1-2 cm > 2 cm < 1 cm Increased AFP* Normal AFP FNAB US /3m Spiral CT AFP > 400 ng/ml Doppler/CT/MRI/An HCC No HCC Surveillance US + AFP/6m * AFP level >200ng/dl Bruix, J Hepatol ,2001

26 STAGING: OPEN PROBLEMS AND AREAS FOR FUTURE RESEARCHES
Multinodularity Vascular invasion Selection between radical treatment or palliation Imaging techniques insufficient Selection between OLT and ablation/destruction therapies Need for adjuvant therapy Recurrence potential Tissue and molecular markers (Currently not done)

27 THERAPEUTIC OPTIONS FOR HCC 
Local therapy Surgical resection Transplant Percutaneous echo-guided Intra-arterial Systemic chemotherapy or hormonal therapy

28 EFFECT OF TREATMENT ON SURVIVAL OF 1108 PTS WITH HCC
Multicentric Italian Study Group on HCC SURVIVAL OF SINGLE HCC <5 cm Child A J Hepatol, 1995

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30 SCREENING FOR HCC IN CIRRHOSIS
ELIGIBILITY FOR CURATIVE TREATMENTS HCC detected outside surveillance programme HCC detected within surveillance programme 47.5 % % p < 0.01 (Bolondi, Gut 2001)

31 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

32 INTERSTITIAL TUMOR ABLATION
HEAT laser, radiofrequency, highly focused ultrasound FROST cryosurgery DRUGS alcohol injection RADIOACTIVITY implantation of radioactive seeds

33 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 85 98 93 100 91 62 79 63 87 53 No. of Pts 293 149 64 41 Survival (%) 3-yr 5-yr 1-yr 52 47 29 55 13

34 SURVIVAL AFTER SURGICAL AND NONSURGICAL TREATMENT FOR HCC
HCC < 2 cm clinical stage I 5 cm > HCC > 2 cm all clinical stages Surgery > PEI (n=8.010) (n=4.037) (retrospective study) (Arii et al, Hepatology 2000 Liver Cancer Study Group of Japan)

35 PEI versus Surgical Resection
(Non-Randomized Studies) p = N.S. p = N.S. - Same tumor stage - Poorer liver function in PEI groups Castells et al, Hepatology 1993 Yamamoto et al, Hepatology 2001

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37 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

38 RF THERMAL ABLATION EXPANDABLE NEEDLE (1.9 mm) 90-115°C
In order to increase the ablated volume, modified RF needles have been produced. The expandable needle is characterized by 4 to 10 nickel-titanium hooks, which are advanced into the nodule after the insertion of the needle and retracted before withdrawal. The thermistors at the tip of the hooks measure the operating temperature which should range from 90 to 100 and 15 degrees. One limitation of this needle is its rèlatively large size (1.9 mm) in comparison with the cool-tip needle…... 90-115°C 4 to 10 nickel-titanium hooks with tip thermistors

39 RF THERMAL ABLATION COOLED-TIP NEEDLE (1.2-1.3 mm) 20-25°C
…., whose caliber ranges from 1.2 to 1.3 mms. This needle is connected with a peristaltic pump which allows the flow of nout degrees saline solution inside the needle. This cooling system maintains a low temperature in the tissue just around the needle, thus avoiding impedance increase due to carbonaization. 20-25°C Peristaltic pump with 0°C saline solution

40 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

41 Overall Survival 67% PEI series (n = 184) - Lencioni R et al, Eur Radiol 1997

42 50% 74% Lin SM et al Gastroenterology 2004

43 RANDOMIZED COMPARISON OF RF THERMAL ABLATION vs PEI 232 patients with up to 3 HCC < 3 cm each
RF PEI Treatment sessions p<00001 4yr survival 74% 57% p=0.01 4yr Overall recurrence % % p=0.005 4yr Local progression % % p=0.003 Shiina, Gastroenterology 2005

44 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

45 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)

46 multifocal HCC

47 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

48 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: Risultati migliori Noduli >3 cm: Se non resecabili, si può associare PEI + TACE

49 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 (?)

50 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

51 TERAPIA DELL’HCC MULTIFOCALE IN FEGATO CIRROTICO
CONCETTI CHIAVE Pz fino a 3 noduli <3 cm, età <65 aa Candidabili a trapianto di fegato Pz con HCC bifocale nello stesso segmento 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

52 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

53 Centro per lo studio dei tumori del fegato
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

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55 NON-SURGICAL ABLATION OF SMALL HCC
PEI RF Efficacy Complications Pts compliance Physician involvement Cost If PEI is considered the reference procedure for local ablation of small HCC and RF the best alternative, a comparison between them should include several parameters which may be of some relevance in the clinical practice. Efficacy and complications have been compared in randomized trials: efficacy is about the same while complication are more frequent with RF. Pts compliance seems to be better for RF, as PEI is actually painful and usually patients does not enjoy to return many times to the hospital to repeat treatments. Physician involvement seems to be major for PEI, due to the higher number of treatment sessions, while the direct cost is higher for RF. The analysis of indirect costs is more complex but it could eventually balance the apparent higher cost of RF.

56 LIVER TRANSPLANTATION PERCUTANEOUS TECHNIQUES
SURGICAL RESECTION LIVER TRANSPLANTATION PERCUTANEOUS TECHNIQUES High rate of complete response in selected candidates 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

57 5 years survival in unifocal (<5 cm) HCC
Multicentric Italian Study on PEI in HCC (746 cases) (Bologna, Brescia, Clusone, Napoli Cotugno, Napoli Policlinico, Padova, Roma, Torino, Vimercate) 5 years survival in unifocal (<5 cm) HCC Median: Child A23 months Child B19 months % Radiology 1996