S. Cascinu - Liver/Hepatobiliary - State of the art

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  • La diagnosi di HCC viene generalmente posta sulla base di tecniche di imaging , biopsia e test di laboratorio (livelli di AFP). La scelta e la sequenza degli esami dipende della grandezza della lesione. Per pazienti affetti da epatite B o cirrosi da altra eziologia una massa evidenziata incidentalmente o nel corso di uno screening ecografico ha un’elevata probabilità di rappresentare un HCC. Bruix J, Sherman M. Hepatology 2005 ; 42(5): 1208-1236
  • Depositato presso AIFA in data 28 ottobre 2009; AN n° IT/ONC/2009/10/0306
  • Lo schema di trattamento BCLC propone differenti opzioni terapeutiche in base allo stadio del tumore. I pazienti in stadio 0 (HCC molto precoce) sono candidati ideali alla resezione. I pazienti in stadio A presentano tumori in stadio precoce asintomatici e sono idonei a trattamenti radicali (resezione, trapianto, trattamenti percutanei, quali alcolizzazione o radiofrequenza). Lo stadio B (HCC intermedio) include pazienti con HCC multinodulare asintomatico che possono trarre beneficio dalla chemioembolizzazione. Nello stadio C (HCC avanzato) sono inclusi pazienti con tumori sintomatici e/o con invasione vascolare/disseminazione extraepatica. Questa categoria di pazienti è idonea al trattamento con sorafenib. I pazienti appartenenti allo stadio D presentano una prognosi molto sfavorevole, per loro si suggerisce un trattamento sintomatico. Llovet JM et al. J Gastroenterol 2005; 40: 225-235; Llovet JM et al. J Natl Cancer Inst 2008;100: 698 – 711 Depositato presso AIFA in data 28 ottobre 2009; AN n° IT/ONC/2009/10/0306
  • Fra i trattamenti curativi, la resezione chirurgica del tumore consente di ottenere buoni risultati, in termini di sopravvivenza, in pazienti accuratamente selezionati. In questi casi la sopravvivenza a 5 anni può raggiungere il 70%. Un aspetto negativo è rappresentato dall’elevato tasso di ricorrenza, pari al 70% a 5 anni. Bruix J et al . J Hepatol 2001; 35: 421-430 Llovet JM. J Gastroenterol 2005; 40: 225-235 Depositato presso AIFA in data 28 ottobre 2009; AN n° IT/ONC/2009/10/0306
  • Depositato presso AIFA in data 28 ottobre 2009; AN n° IT/ONC/2009/10/0306
  • Depositato presso AIFA in data 28 ottobre 2009; AN n° IT/ONC/2009/10/0306
  • Le liste di attesa per il trapianto sono lunghe e comportano una crescita del tumore e un relativo aumento delle controindicazioni al trapianto (invasione vascolare, diffusione extraepatica). Negli Stati Uniti viene promosso l’uso del MELD ( Model for End-Stage Liver Disease ) che dovrebbe consentire di priorizzare il trapianto in base al rischio di mortalità di ciascun paziente affetto da patologia epatica dovuta ad abuso di alcol o di origine virale. Tuttavia, inizialmente è stata data priorità troppo elevata a pazienti affetti da HCC, sfavorendo i pazienti non affetti da tumore. Inoltre 1/5 dei pazienti in lista come affetti da HCC, in realtà, non presentavano HCC nel fegato espiantato. Per tale motivo i criteri di eleggibilità sono stati modificati. Il più potente fattore predittivo di ricorrenza del tumore, in assenza di diffusione extraepatica, è l’invasione vascolare macro e microscopica. La possibilità che questo si verifichi è direttamente proporzionale alle dimensioni e al numero del tumore. Bruix J, Sherman M. Hepatology 2005; 42: 1208-1236 Depositato presso AIFA in data 28 ottobre 2009; AN n° IT/ONC/2009/10/0306
  • L’ablazione percutanea comporta il trattamento diretto delle lesioni dell’HCC attraverso la cute. È la tecnica più utilizzata nei pazienti con HCC in stadio precoce, non idonei alla resezione o al trapianto. La distruzione delle cellule tumorali può avvenire mediante iniezione di sostanze chimiche (etanolo, acido acetico, soluzione salina bollente) o per modificazione della temperatura (radiofrequenza, microonde, laser, crioterapia). L’efficacia della terapia viene valutata mediante TAC dinamica 1 mese dopo la terapia. L’iniezione percutanea di etanolo (PEI) viene eseguita mediante guida ecografica e comporta l’iniezione di etanolo direttamente nel tumore, determinando necrosi. I pazienti possono ricevere più trattamenti in giorni diversi, raramente accompagnata da necrosiin tumori maggiori di 3 cm. La PEI è principalmente impiegata nei pazienti con tumori di piccole dimensioni con presenza di cirrosi. In pazienti con lesioni uniche, di piccole dimensioni (<3 cm) e buona funzione epatica sono stati riportati tassi di sopravvivenza a 5 anni del 40-50%, con tassi di ricadute simili a quelli osservati nei pazienti sottoposti a resezione chirurgica di piccoli tumori. La PEI dovrebbe rappresentare lo standard verso il quale confrontare i nuovi approcci terapeutici. L’ablazione da radiofrequenza (RFA) comporta l’introduzione di una sonda all’interno del tumore (guidata mediante ecografia) per indurre necrosi. Per tumori di diametro < 2 cm ha un’efficacia pari alla PEI, ma richiede un numero inferiore di cicli di trattamento. L’efficacia in tumori di dimensioni > 2 cm è superiore a quella della PEI, tuttavia, presenta costi superiori e un tasso maggiore di eventi avversi (effusione pleurica, sanguinamento peritoneale). Llovet JM. J Gastroenterol 2005; 40 : 225-235; Bruix J, Sherman M. Hepatology 2005; 42: 1208-1236; Bruix J et al. J Hepatol 2001; 35: 421-430 Depositato presso AIFA in data 28 ottobre 2009; AN n° IT/ONC/2009/10/0306
  • Depositato presso AIFA in data 28 ottobre 2009; AN n° IT/ONC/2009/10/0306
  • Poor Prognosis for Patients with Advanced HCC Because of its asymptomatic nature, early HCC is difficult to detect and many patients (70% to 80%) present with intermediate or advanced disease at diagnosis 1 These patients have poor prognoses and treatment options are solely palliative Even in patients who undergo potentially ‘curative’ surgery, recurrence rates are high, and 30% to 50% of these patients go on to die from their disease within 5 years 2 Overall survival has been shown to decrease with advancing stage of disease 1,2 Fewer than 10% of patients with advanced HCC can expect to live longer than 5 years 2,3 References 1. Roberts LR, Gores GJ. Emerging drugs for hepatocellular carcinoma. Expert Opin Emerging Drugs 2006;11:469–87. 2. Llovet JM. Updated treatment approach to hepatocellular carcinoma. J Gastroenterol 2005;40:225–35. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003;37:429–42. Depositato presso AIFA in data 28 ottobre 2009; AN n° IT/ONC/2009/10/0306
  • Depositato presso AIFA in data 28 ottobre 2009; AN n° IT/ONC/2009/10/0306
  • Depositato presso AIFA in data 28 ottobre 2009; AN n° IT/ONC/2009/10/0306
  • Before the introduction of sorafenib, no survival benefits had been demonstrated for systemic treatments in patients with advanced HCC. No improvements in survival outcome have been demonstrated for hormonal agents such as tamoxifen 1,2 or octreotide. 3 Doxorubicin and cisplatin have some activity when used as single agents; 4 however, recent RCTs of combination chemotherapy have failed to demonstrate efficacy in this population. 5 – 7 This lack of effective systemic therapies for advanced HCC patients represented a considerable unmet medical need. Additional information Loco-regional therapies such as transarterial chemoembolization (TACE) have been shown to prolong survival in patients with unresectable HCC. 8 However, TACE is only suitable for patients with no vascular invasion or extrahepatic spread. References 1. Barbare JC, et al. J Clin Oncol; 2005;23:4338–4346. 2. Groupe d’Etude et de Traitement de Carcinome Hepatocellulaire. Hepatology 2004;40:1361–1369. 3. Yuen MF, Poon RT, Lai CL, et al. Hepatology 2002;36:687–91. 4. Lopez PM, et al. Ailiment Pharmacol Ther 2006;23:1535 –15 47. 5. Yeo W, et al. J Natl Cancer Inst 2005;97:1532–1538. 6. Beaugrand M, Sala M, Degos F, et al. J Hepatol 2005;42:17A. 7. Gish RG, Porta J, Lazar L, et al. J Clin Oncol 2007;25:3069–75 . 8. Llovet JM, Bruix J. Hepatology 2003;37:429 –4 42.
  • 7 5 5 902 pazienti (pazienti arruolati) sono stati sottoposti a screening; di questi, 602 pazienti rispondevano ai criteri di eligibilità e sono stati randomizzati a sorafenib (n=299) o placebo (n=303). I rimanenti pazienti sono stati esclusi dalla fase di screening a perchè non rispondevano ai criteri di inclusione, per ritiro del consenso informato, per eventi avversi, mancato follow-up , morte. Tra i 602 pazienti randomizzati, 297 e 302 hanno ricevuto almeno una dose di sorafenib o placebo, rispettivamente. Sono state previste due analisi ad interim (170 e 300 eventi) e una finale. La seconda analisi ad interim è stata condotta a ottobre 2006 (321 eventi; 143 per sorafenib e 178 per placebo); sulla base dei risultati ottenuti a febbraio 2007 il DMC ha raccomandato l’interruzione dello studio. Llovet JM et al. Presented at ASCO 2007, Chicago, IL, USA Depositato presso AIFA in data 28 ottobre 2009; AN n° IT/ONC/2009/10/0306
  • In contrast with most tumor types, risk factors for the development of HCC have been defined. While most predominant risk factor for the development of HCC is cirrhosis, infection with hepatitis viruses B or C is common among patients with HCC. The distribution of hepatitis virus types varies with geographic region, with HBV infection being more predominant among patients from Asia (except Japan) and Africa, and HCV more common among patients from Europe, North America, and Japan. 1 The SHARP trial enrolled patients with risk factors for the development of HCC, including infection with HCV (29%/27%) or HBV (19%/19%) and alcohol use (26%/26%). 2 Depositato presso AIFA in data 28 ottobre 2009; AN n° IT/ONC/2009/10/0306 1. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362:1907-1917 . 2. Llovet J, Ricci S, Mazzaferro V, et al. Sorafenib improves survival in advanced Hepatocellular Carcinoma (HCC): Results of a Phase III randomized placebo-controlled trial (SHARP trial). J Clin Oncol. 2007;25(suppl 18):LBA1.
  • La risposta è stata valutata da un comitato indipendente, utilizzando i criteri RECIST. Il FSHI-8, che misura nella loro globalità i sintomi legati al trattamento e quelli legati alla patologia stessa e la loro influenza sulla qualità di vita, non ha mostrato differenze significative nei due gruppi di trattamento. Llovet JM et al. ASCO Annual Meeting 2007; Abstr LBA1/oral presentation available at www.asco.org Depositato presso AIFA in data 28 ottobre 2009; AN n° IT/ONC/2009/10/0306
  • Depositato presso AIFA in data 28 ottobre 2009; AN n° IT/ONC/2009/10/0306
  • The SHARP study enrolled primarily patients with advanced HCC (Barcelona Clinic Liver Cancer stage C [BCLC C]; n=497); however, some BCLC B (intermediate) patients (n=105) were also included in the trial. This slide shows the results of a subgroup analysis of the SHARP study in which the overall survival (OS) and time to tumour progression (TTP) were determined according to stage of disease (BCLC B vs. BCLC C) The hazard ratios (HRs) for OS and TTP for sorafenib compared with placebo in each of the subgroups are presented. 1 The results demonstrate that the survival benefit with sorafenib is maintained regardless of stage of HCC, HRs were similar for patients with BCLC B (HR 0.72, 95% CI 0.38, 1.38) and BCLC C (HR 0.70; 95% CI 0.56, 0.89) HRs were consistent with that shown in the overall SHARP population (HR 0.69; 95% CI 0.55, 0.87). 2 As was the case for OS, the prolongation of TTP with sorafenib compared with placebo in the overall SHARP study population was maintained independent of BCLC stage. 1 Median TTP for sorafenib vs. placebo was: 1 BCLC B: 6.9 vs. 4.4 months (HR=0.47; 95% CI: 0.23, 0.96). BCLC C: 4.9 vs. 2.8 months (HR=0.59; 95% CI: 0.45, 0.77). The incidence of adverse events was comparable across BCLC stages and was consistent with that reported for the overall SHARP population. 1,2 Additional information Patients presenting with intermediate (BCLC B) HCC have significantly better OS than patients with advanced disease (BCLC C) The 3-year survival rate for intermediate HCC patients has been reported as 50% versus 8% for advanced HCC patients. 3 References 1. Bruix J. Presented at EASL April 22 -26, 2009; Copenhagen, Denmark: abstract 67. 2. Llo vet JM, Ricci S, Mazzaferro V, et al. N Engl J Med 2008;359:378–390. 3. Llovet JM, Bustamante J, Castells A, et al. Hepatology 1999;32: 2679–80.
  • Lo studio ASIA PACIFIC è un altro studio di fase III con sorafenib; i criteri esclusione-inclusione sono i medesimi dello studio SHARP. L’unica differenza è riscontrabile nella randomizzazione 2:1. Cheng A et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 4509) Depositato presso AIFA in data 28 ottobre 2009; AN n° IT/ONC/2009/10/0306
  • Depositato presso AIFA in data 28 ottobre 2009; AN n° IT/ONC/2009/10/0306
  • Depositato presso AIFA in data 28 ottobre 2009; AN n° IT/ONC/2009/10/0306
  • L’incidenza globale di eventi avversi correlati al trattamento è stata pari all’80% per i pazienti trattati con sorafenib e al 52% per i pazienti trattati con placebo. Gli eventi avversi più frequenti sono risultati sovrapponibili a quelli riscontrati nei precedenti studi di fase II nell’HCC. Gli eventi avversi riportati dai pazienti trattati con sorafenib erano prevalentemente di grado 1 o 2 e comprendevano eventi gastrointestinali, sintomi costituzionali e di natura dermatologica. Gli eventi avversi più rilevanti di grado 3 sono stati diarrea a sindrome mano-piede; non è stato riscontrato alcun evento di grado 4 correlato all’impiego di sorafenib. Llovet JM et al. Presented at ASCO 2007, Chicago, IL, USA Depositato presso AIFA in data 28 ottobre 2009; AN n° IT/ONC/2009/10/0306
  • Progression-free survival (PFS) for three groups in months. GE, modified gemcitabine and oxaliplatin; FUFA, fluorouracil and folinic acid; BSC, best supportive care.
  • S. Cascinu - Liver/Hepatobiliary - State of the art

    1. 1. Stefano Cascinu Department of Medical Oncology Ancona, Italy Liver/hepatobiliary cancers: state of the art
    2. 2. Liver/hepatobiliary cancers <ul><li>Hepatocellular carcinoma </li></ul><ul><li>Biliary tract cancers </li></ul>
    3. 3. Hepatocellular carcinoma <ul><ul><li>Epidemiology </li></ul></ul><ul><ul><li>Risk population (screening and surveillance programs) </li></ul></ul><ul><ul><li>Diagnosis </li></ul></ul><ul><ul><li>Staging </li></ul></ul><ul><ul><li>Therapy </li></ul></ul>
    4. 4. Worldwide incidence of HCC Fifth most common cancer globally. Over 600,000 new cases each year (IARC 2002) Third cause of death among all cancers (8.8%) Geographic distribution variable (HBV, HCV, aflatoxin) Age-adjusted mortality rates/100.000
    5. 5. Estimates of the attributable fractions for HCC HBV + HCV: ≥ 85% of cases (using HBsAg classical epidemiological markers) Bosch & Ribes, viruses and liver cancer 2002:1-15 22% 60% 45% 12% limited < 5% Hepatitis B virus Hepatitis C virus Alcohol Tobacco Aflatoxin exposure Other Europe and US 20% 63% 20% 40% limited  Japan 60% 20%  22% high < 5% Africa and Asia Risk factors
    6. 6. The changing global trends of HCC Singapore Sweden Spain India Shanghai Israel Norway Denmark Hong Kong New Zeland Costa Rica U.S. White U.S. Black Japan UK Canada Italy France Australia McGlynn KA et al., Int J Cancer 2001
    7. 7. Chang MH et al, NEJM 1997; 336:1855-1859 Impact of universal HBV vaccination on HCC incidence 0.70 0.57 0.36 1981-1988 1989-1990 1990-1994 Per 100,000/yr Incidence of HCC among children and adolescents The Taiwan Vaccination Program: 1984: newborns of HBsAg pos. mothers 1986: extended to all newborns 1987: pre-school & school children, teenagers, adults
    8. 8. Obesity, dyslipidemia and diabetes in HCC patients with cryptogenic cirrhosis P = 0.0086 P = 0.0003 P = 0.0034 Bugianesi et al, Gastroenterology 2003
    9. 9. Hepatocellular carcinoma <ul><ul><li>Epidemiology </li></ul></ul><ul><ul><li>Risk population (screening and surveillance programs) </li></ul></ul><ul><ul><li>Diagnosis </li></ul></ul><ul><ul><li>Staging </li></ul></ul><ul><ul><li>Therapy </li></ul></ul>
    10. 10. Individual susceptibility to HCC: Prevention, screening and surveillance programs <ul><li>HBV(genotype C) responsible for 50-80% HCC </li></ul><ul><li>HCV responsible for 10-25% HCC </li></ul><ul><li>HBV and HCV synergistic effect </li></ul><ul><li>Alcohol consumption; Aflatoxin intake; hereditary hemochromotosis </li></ul><ul><li>Diabetes; obesity; Non alcoholic fatty liver disease, nonalcoholic steatohepatitis </li></ul>prevention
    11. 11. Surveillance for early diagnosis in patients with chronic liver disease <ul><li>Ultrasonography (sensitivity and specificity 60%-80% for tumors <1 cm) </li></ul><ul><li>6-12 month intervals </li></ul><ul><li>(based on tumor-volume doubling 6 month potentially better) </li></ul><ul><li>AFP determination (never alone) </li></ul>
    12. 12. Hepatocellular carcinoma <ul><ul><li>Epidemiology </li></ul></ul><ul><ul><li>Risk population (screening and surveillance programs) </li></ul></ul><ul><ul><li>Diagnosis </li></ul></ul><ul><ul><li>Staging </li></ul></ul><ul><ul><li>Therapy </li></ul></ul>
    13. 13. Diagnosis of HCC <ul><li>Laboratory tests </li></ul><ul><ul><li>AFP serology </li></ul></ul><ul><li>Imaging studies </li></ul><ul><ul><li>Ultrasound </li></ul></ul><ul><ul><li>Spiral CT </li></ul></ul><ul><ul><li>MRI with gadolinium </li></ul></ul><ul><li>Biopsy </li></ul>Required to determine the extent of the disease The lesions could be find incidentally or on screeening ultrasound The sequence of tests used to diagnose HCC depends on the size of the lesion
    14. 14. Mass on surveillance ultrasound in a cirrhotic liver Repeat US at 3-4 month interval Two dynamic imaging studies One dynamic imaging technique Typical vascular pattern with one technique Coincidental typical vascular pattern on dynamic imaging Atypical vascular pattern with both techniques Typical vascular pattern on dynamic imaging or AFP > 200 ng/ml Atypical vascular pattern Biopsy Stable over 18-24 months Enlarging Return to standard surveillance protocol (6-12 monthly) Proceed according to lesion size Treat as hepatocellular carcinoma Diagnostic of HCC Non diagnostic Other diagnosis Repeat biopsy or imaging follow-up Change in size/profile Repeat imaging and/or biopsy Negative Positive < 1 cm 1 – 2 cm > 2 cm Suggested algorithm for investigation of a nodule found on ultrasound during screening or surveillance
    15. 15. Hepatocellular carcinoma <ul><ul><li>Epidemiology </li></ul></ul><ul><ul><li>Risk population (screening and surveillance programs) </li></ul></ul><ul><ul><li>Diagnosis </li></ul></ul><ul><ul><li>Staging </li></ul></ul><ul><ul><li>Therapy </li></ul></ul>
    16. 16. Staging Systems for HCC AFP: alpha fetoprotein; AP alcaline phosphatase; CTP: Child-Turcotte-Pugh; PS: performance status; PVT: portal vein thrombosis Staging System Hepatic function AFP PS Tumor staging BCLC CTP No Yes Tumor size, No. of nodules and PVT Okuda Ascites Albumin Bilirubin No No Tumor greater or less than 50% of cross-sectional area of liver TNM No No No No. of nodules, tumor size, presence of PVT and metastasis CLIP CTP < 400 or ≥ 400 ng/mL No No. of nodules, tumor greater or less than 50% area of liver, PVT CUPI Ascites Bilirubin AP < 500 or ≥ 500 ng/mL Symptoms TNM JIS CTP No No TNM GRETCH Bilirubin AP < 35 or ≥ 35 μg/mL Yes PVT
    17. 17. BCLC Staging and Treatment Schedule Llovet JM et al. J Natl Cancer Inst 2008;100: 698 – 711 HCC Stage 0 PST 0, Child-Pugh A Stage A-C PST 0-2, Child-Pugh A-B Stage D PST>2, Child-Pugh C Early stage (A) Single or 3 nodules < 3 cm, PS 0 Intermediate stage (B) Multinodular, Ps 0 Advanced stage (C) Portal invasion, N1, M1, PS 1-2 Terminal stage (D) Very early stage (O) Single < 2 cm Carcinoma in situ Single 3 modules  3 cm Portal pressure/bilirubin Normal No Yes Associated diseases Increased Resection Liver Transplantation (CLT/LDLT) PEI/RF Chemoembolization Sorafenib Curative Treatments (30%) 5-yr survival: 50-70% 3 yr survival: 20-40% Symptomatic ttc (20%) 1 yr survival: 10-20%
    18. 18. BCLC Staging and Treatment Schedule Llovet JM et al. J Natl Cancer Inst 2008;100: 698 – 711 HCC Stage 0 PST 0, Child-Pugh A Stage A-C PST 0-2, Child-Pugh A-B Stage D PST>2, Child-Pugh C Early stage (A) Single or 3 nodules < 3 cm, PS 0 Intermediate stage (B) Multinodular, Ps 0 Advanced stage (C) Portal invasion, N1, M1, PS 1-2 Terminal stage (D) Very early stage (O) Single < 2 cm Carcinoma in situ Single 3 modules  3 cm Portal pressure/bilirubin Normal No Yes Associated diseases Increased Resection Liver Transplantation (CLT/LDLT) PEI/RF Chemoembolization Sorafenib Curative Treatments (30%) 5-yr survival: 50-70% 3 yr survival: 20-40% Symptomatic ttc (20%) 1 yr survival: 10-20%
    19. 19. BCLC Staging and Treatment Schedule Llovet JM et al. J Natl Cancer Inst 2008;100: 698 – 711 HCC Stage 0 PST 0, Child-Pugh A Stage A-C PST 0-2, Child-Pugh A-B Stage D PST>2, Child-Pugh C Early stage (A) Single or 3 nodules < 3 cm, PS 0 Intermediate stage (B) Multinodular, Ps 0 Advanced stage (C) Portal invasion, N1, M1, PS 1-2 Terminal stage (D) Very early stage (O) Single < 2 cm Carcinoma in situ Single 3 modules  3 cm Portal pressure/bilirubin Normal No Yes Associated diseases Increased Resection Liver Transplantation (CLT/LDLT) PEI/RF Chemoembolization Sorafenib Curative Treatments (30%) 5-yr survival: 50-70% 3 yr survival: 20-40% Symptomatic ttc (20%) 1 yr survival: 10-20%
    20. 20. Surgical Resection <ul><li>Optimal candidates: </li></ul><ul><ul><li>BCLC stage 0 or A </li></ul></ul><ul><ul><ul><li>Child-Pugh A </li></ul></ul></ul><ul><ul><ul><li>Performance status 0 </li></ul></ul></ul><ul><ul><ul><li>Single tumors (< 3 cm) </li></ul></ul></ul><ul><ul><ul><li>Normal portal pressure </li></ul></ul></ul><ul><ul><ul><li>Normal bilirubin </li></ul></ul></ul><ul><ul><li>Excellent functional reserve </li></ul></ul>5-year survival 60-70% High recurrence rate 50% at 3 years 70% at 5 years
    21. 21. Factors contributing to early phase (<2 years) recurrence Risk Factors Contributing to HCC Intrahepatic Recurrence after Hepatectomy Imamura H et al J Hepatol 2003;38:200-207 Hazard ratio 95% CI Microscopic vascular invasion 2.36 1.62 – 3.45 Serum AFP value ≥ 32 ng/ml 1.83 1.25 – 2.68 Non anatomical resection 1.65 1.13 – 2.40
    22. 22. Is resection only a palliation? Yamamoto et al, Ann Surg 2004 The survival rate of patients with early HCC undergoing Liver Resection decreases 5 years after surgery. This phenomenon is explained by occurrence of second primary HCCs that should be prevented 186 patients with HCC  2 cm treated with curative hepatectomy Early HCC Small advanced HCC
    23. 23. Liver Transplantation Illustration Copyright © 2007 Nucleus Medical Art, All rights reserved. www.nucleusinc.com. 5-year survival 70% Recurrence rate < 15% <ul><li>Optimal candidates: </li></ul><ul><ul><li>BCLC Stage A disease </li></ul></ul><ul><ul><li>No vascular invasion </li></ul></ul><ul><ul><li>No metastases </li></ul></ul><ul><ul><li>Fulfill the Milan criteria </li></ul></ul><ul><ul><ul><li>Solitary tumor < 5 cm or </li></ul></ul></ul><ul><ul><ul><li>≤ 3 nodules < 3 cm </li></ul></ul></ul><ul><ul><ul><li>No vascular invasion </li></ul></ul></ul>Advantage Removal of the diseased liver together with the tumor Disadvantage Long waiting lists
    24. 24. Local ablation therapy <ul><ul><li>Radiofrequency ablation (RFA) </li></ul></ul><ul><ul><li>Percutaneous ethanol injection (PEI) </li></ul></ul><ul><ul><li>Small HCCs confined to the liver, unresectable because of the poor general conditions or compromised liver function </li></ul></ul>Illustration Copyright © 2007 Nucleus Medical Art, All rights reserved. www.nucleusinc.com. RFA
    25. 25. 232 pts Recurrence rates of HCC after local ablation therapy Pooled analysis: Bouza, BMC Gastroenterol 2009 RFA PEI OS 73% 58% Adverse events 19% 10%
    26. 26. BCLC Staging and Treatment Schedule Llovet JM et al. J Natl Cancer Inst 2008;100: 698 – 711 HCC Stage 0 PST 0, Child-Pugh A Stage A-C PST 0-2, Child-Pugh A-B Stage D PST>2, Child-Pugh C Early stage (A) Single or 3 nodules < 3 cm, PS 0 Intermediate stage (B) Multinodular, Ps 0 Advanced stage (C) Portal invasion, N1, M1, PS 1-2 Terminal stage (D) Very early stage (O) Single < 2 cm Carcinoma in situ Single 3 modules  3 cm Portal pressure/bilirubin Normal No Yes Associated diseases Increased Resection Liver Transplantation (CLT/LDLT) PEI/RF Chemoembolization Sorafenib Curative Treatments (30%) 5-yr survival: 50-70% 3 yr survival: 20-40% Symptomatic ttc (20%) 1 yr survival: 10-20%
    27. 27. Prognosis of patients with intermediate HCC (BCLB) Survival of untreated HCC patients in two randomised studies (n=102) 1 <ul><li>Overall, 70 – 80% of patients with HCC present with intermediate/advanced disease at diagnosis 2 </li></ul><ul><ul><li>these patients have poor prognoses </li></ul></ul><ul><li>Recurrence rates are high in patients undergoing curative treatment ( 30 – 50% of patients die within 5 years of resection) 1 </li></ul><ul><li>Llovet JM. J Gastroenterol 2005; </li></ul><ul><li>Roberts LR, Gores GJ. Expert Opin Emerging Drugs 2006; </li></ul>Overall survival (%) Disease stage 1 year 2 years 3 years Intermediate 80 65 50
    28. 28. Intermediate stage HCC <ul><li>TAE/TACE </li></ul><ul><ul><li>BCLC Stage B disease </li></ul></ul><ul><ul><li>Preserved liver function </li></ul></ul><ul><ul><li>Asymptomatic multinodular tumors </li></ul></ul><ul><ul><li>No vascular invasion or extrahepatic spread </li></ul></ul>
    29. 30. Random effects model (DerSimonian and Laird) Odds ratio (95% CI) Author, journal year Overall Heterogeneity p=0.14 Favours treatment Favours control Patients 503 Lin, Gastroenterology 1998 63 GETCH, NEJM 1995 96 Bruix, Hepatology 1998 80 Pelletier, J Hepatol 1998 73 Lo, Hepatology 2002 79 Llovet, Lancet 2002 112 z=–2.3 p=0.017 Llovet JM, et al. Lancet 2003;362:1907 –17 0.01 0.1 0.5 1 2 10 100
    30. 32. <ul><li>Level I recommendations: </li></ul><ul><ul><li>“ TACE is considered the standard treatment for patients with intermediate stage cancer , </li></ul></ul><ul><li>Level II recommendations: </li></ul><ul><ul><li>Other option, such as radio-labelled Yttrium glass beads, radio-labelled lipiodol or immunotherapy cannot be recommended as standard therapy for advanced HCC outside clinical trials </li></ul></ul><ul><ul><li>Systemic or selective intra-arterial chemotherapy is not recommended and should not be used as standard of care </li></ul></ul>TAE/TACE
    31. 33. Advanced stage HCC OS (%) Disease stage 1 year 2 years 3 years Advanced 29 16 8
    32. 34. No survival benefit demonstrated for systemic therapies for advanced HCC Survival Hormone analogues <ul><ul><li>Tamoxifen vs. Placebo 1 </li></ul></ul>1 year: 23% vs. 20% <ul><ul><li>Anti-androgens* + tamoxifen vs. Tamoxifen 2 </li></ul></ul>1 year: 23% vs 28% <ul><ul><li>Octreotide vs. Placebo 3 </li></ul></ul>Median OS: 1.9 m vs. 1.9 m <ul><ul><li>Chemotherapy </li></ul></ul><ul><ul><li>Doxorubicin vs. PIAF 4 </li></ul></ul>Median OS: 8.7 m vs. 6.8 m <ul><ul><li>Seocalcitol vs. Placebo 5 </li></ul></ul>Median OS: 9.6 m vs. 9.2 m <ul><ul><li>Nolatrexed vs. Doxorubicin 6 </li></ul></ul>Median OS: 5.5 m vs. 8.0 m
    33. 35. Sorafenib sorafenib (n=299) Intent-to-treat Placebo (n=303) Intent-to-treat 602 patients randomised 902 HCC patients screened 2 did not receive treatment 1 did not receive treatment Llovet JM, et al. N Engl J Med 2008;359:378-90 Not randomised n=300 Protocol exclusion criteria n=244 Consent withdrawn n=24 Adverse events n=15 Death n=4 Lost to follow-up/missing n=6
    34. 36. SHARP patients and aethiology Other Alcohol Hepatitis B Hepatitis C 50%-70% 70% 70% 20% 10%-20% 10%-20% 10%-20% ≤ 10% 0 20 40 60 80 Cases (%) *Excluding Japan Llovet JM et al. Lancet. 2003;362:1907-1917. Llovet JM, et al. N Engl J Med 2008;359:378-90 Asia/Africa* Europe/N. America Japan All
    35. 37. SHARP Phase III Trial in Advanced HCC: Sorafenib prolongs OS by 44% and TTP by 74% 1.00 Survival probability 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Sorafenib (n=299) = 10.7 months Placebo (n=303) = 7.9 months Time from randomisation (months) Probability of radiologic progression 0 1 2 3 4 5 6 7 8 9 10 11 12 Sorafenib (n=299) = 5.5 months Placebo (n=303) = 2.8 months Time from randomisation (months) 1.00 0.75 0.50 0.25 0 HR = 0.69 (95% CI: 0.55–0.87) p<0.001 0.75 0.50 0.25 0 HR = 0.58 (95% CI : 0.45–0.74) p<0.001 Overall Survival Time to Progression (independent central review) Llovet JM, et al. N Engl J Med 2008;359:378-90
    36. 38. R esponse Assessment and TTSP Llovet JM, et al. N Engl J Med 2008;359:378-90 Sorafenib (n=299) Placebo (n=303) Overall response Complete response (CR) Partial response (PR) 0 7 (2.3%) 0 2 (0.7%) Stable disease (SD) 211 (71%) 204 (67%) Progressive disease (PD) 54 (18%) 73 (24%) Progression-free rate at 4 mo 62 % 42 % Duration of treatment (Median; weeks) 23 19
    37. 39. Exploratory Sub-group Survival Analysis Hazard Ratio Llovet JM, et al. N Engl J Med 2008;359:378-90 Sorafenib benefit Placebo benefit ECOG PS 0 1-2 Extrahepatic spread No Yes Macroscopic vascular invasion (VI) No Yes Macroscopic VI/ extrahepatic spread No yes 0.0 0.5 1.0 1.5
    38. 40. SHARP: effectiveness of sorafenib in intermediate and advanced stage disease 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 Hazard ratio Favours placebo Favours sorafenib TTP OS BCLC B BCLC C BCLC B BCLC C OS = overall survival; BCLC = Barcelona Clinic Liver Cancer; TTP = time to tumour progression. Bruix J. Presented at EASL April 22 –26, 2009; Copenhagen, Denmark: abstract 67.
    39. 41. Asia-Pacific Study Phase III Sorafenib 400 mg b.i.d. Placebo <ul><li>Eligibility criteria </li></ul><ul><ul><li>Advanced HCC </li></ul></ul><ul><ul><li>Child–Pugh A status </li></ul></ul><ul><ul><li>ECOG PS 0–2 </li></ul></ul><ul><ul><li>No prior systemic therapy </li></ul></ul><ul><li>Stratification </li></ul><ul><ul><li>Region </li></ul></ul><ul><ul><li>ECOG PS (0 vs 1–2) </li></ul></ul><ul><ul><li>MVI/EHS (present/absent) </li></ul></ul>Randomization (2:1) (n=226) <ul><li>End points </li></ul><ul><ul><li>Overall survival </li></ul></ul><ul><ul><li>Time to symptom progression </li></ul></ul><ul><ul><li>Time to progression </li></ul></ul><ul><ul><li>Response (RECIST) </li></ul></ul><ul><ul><li>Safety </li></ul></ul>n=150 n=76 Asia-Pacific Study was requested by Asian health authorities Cheng AL et al. Lancet Oncol 2009; 10: 25–34
    40. 42. Overall Survival (OS) 22 Survival probability Months 16 12 10 8 6 4 2 0 14 Placebo sorafenib ® HR (S/P): 0.68 (95% CI: 0.50-0.93) p=0.014 20 18 Sorafenib: 6.5 months (95% Cl: 5.6-7.6) – Placebo: 4.2 months (95% Cl: 3.7-5.5) Cheng AL et al. Lancet Oncol 2009; 10: 25–34 Patients at risk Sorafenib 150 134 103 78 53 32 21 15 13 4 1 0 Placebo 76 62 41 26 23 15 9 5 4 1 0 0 1.00 0.50 0.25 0.75 0
    41. 43. Time to Progression (TTP) 22 Progression-free probability Months 16 12 10 8 6 4 2 0 14 Placebo sorafenib ® HR (S/P): 0.57 (95% CI: 0.42-0.79) p<0.001 20 18 Sorafenib: 2.8 months (95% Cl: 2.6-3.6) – Placebo: 1.4 months (95% Cl: 1.3-1.5) Cheng AL et al. Lancet Oncol 2009; 10: 25–34 Patients at risk Sorafenib 150 80 38 19 11 8 5 2 1 0 0 0 Placebo 76 19 10 8 3 0 0 0 0 0 0 0 1.00 0.50 0.25 0.75 0
    42. 44. Daniele B, Di Maio M . Hot Topics Oncol. 2009;5:19-29.
    43. 45. Adverse Events Llovet JM, et al. N Engl J Med 2008;359:378-90 Sorafenib (n=297) Placebo (n=302) p-value for between group comparison Incidence (%) at grade Adverse event Any 3 4 Any 3 4 Any 3-4 Overall incidence 80 52 Constitutional symptoms Fatigue 22 3 1 16 3 <1 0.07 1.00 Weight loss 9 2 0 1 0 0 <0.001 0.03 Dermatology/skin Alopecia 14 0 0 2 0 0 <0.001 N/A Dry skin 8 0 0 4 0 0 0.04 N/A Hand-foot skin reaction 21 8 0 3 <1 0 <0.001 <0.001 Pruritus 8 0 0 7 <1 0 0.65 1.00 Rash/desquamation 16 1 0 11 0 0 0.12 0.12 Gastrointestinal Anorexia 14 <1 0 3 1 0 <0.001 1.00 Diarrhea 39 8 0 11 2 0 <0.001 <0.001 Nausea 11 <1 0 8 1 0 0.16 0.62 Vomiting 5 1 0 3 1 0 0.14 0.68 Hepatobiliary Liver dysfunction <1 <1 0 0 0 0 0.496 0.496 Pain Pain, abdomen NOS 8 2 0 3 1 0 0.007 0.17 Bleeding 7 1 0 4 1 <1 0.07 1.00
    44. 46. Phase 3 trials: molecular targeted agents and their key targets Agent Antiangiogenic Antiproliferative VEGF VEGFR PDGFR EGFR Raf mTOR Bevacizumab ● Cediranib ● ● Thalidomide ● Erlotinib ● Gefitinib ● ABT-869 ● ● Sorafenib ● ● ● Lapatinib ● Sunitinib ● ● Cetuximab ● Brivanib ● SU6668 ● ● Everolimus ● Ramucirumab ●
    45. 47. Randomized phase III trial: Sunitinib vs sorafenib as first-line R A N D O M I S A T I O N 600 patients Sorafenib 600 patients Sunitinib malate ClinicalTrials.gov Identifier: NCT00699374 Sponsored by Pfizer Patients with advanced HCC; No previous systemic treatment; Child-Pugh class A ECOG PS 0-1 <ul><li>Primary endpoint </li></ul><ul><li>Overall survival </li></ul><ul><li>Secondary endpoint </li></ul><ul><li>PFS </li></ul><ul><li>TTP </li></ul><ul><li>Safety </li></ul><ul><li>Health status </li></ul>Study start date: July 2008 Study early stopped: April 2010 37.5 mg/die continuous 400 mg/die twice daily
    46. 48. Management of patients with advanced HCC: the need for a multidisciplinary approach <ul><li>Management of HCC requires consideration of both tumour- and liver-related factors </li></ul><ul><li>As over 85% of patients with HCC have liver cirrhosis, treatment requires input from: </li></ul><ul><ul><li>Hepatologist </li></ul></ul><ul><ul><li>Oncologist </li></ul></ul>Hepatology Oncology Nurse Palliative care PATIENT
    47. 49. Hepatobiliary cancers <ul><li>Hepatocellular carcinoma </li></ul><ul><li>Biliary tract cancers </li></ul>
    48. 50. Rare GI cancers Rare GI Cancers Incidence rate/100.00/year N° of patients/year Oesophagus 7.49 60.723 Small bowel 0.73 5.882 Anal 1.1 8.992 Pancreas 11.82 95.836 Biliary tract Intrahepatic 0.83 6.761 Gallbladder and extrahepatic 2.64 21.403
    49. 51. Biliary tract cancers: a spectrum disease <ul><li>2/3 of patients with irresectable disease at the time of diagnosis </li></ul><ul><li>Five-year survival in radically resected patients </li></ul><ul><ul><li>Intrahepatic 30-40% </li></ul></ul><ul><ul><li>Distal cholangiocarcinoma 20-30% </li></ul></ul><ul><ul><li>Perihilar cholangiocarcinoma 9-18% </li></ul></ul><ul><ul><li>Gallbladder 14-18% </li></ul></ul>
    50. 52. Distinct cholangiocyte subpopulations Large cholangiocytes <ul><li>Poorly specialized </li></ul><ul><li>No (minimal) functional activity </li></ul><ul><li>Resistant to injury </li></ul><ul><li>Prominently specialized </li></ul><ul><li>High functional activity </li></ul><ul><li>Susceptible to injury </li></ul>? Small cholangiocytes
    51. 53. 19/05/11
    52. 54. Biliary tract cancer: the role of chemotherapy? <ul><li>Adjuvant therapy </li></ul><ul><li>The treatment of the advanced disease </li></ul>
    53. 56. Adjuvant therapy <ul><li>There are no randomised trials able to show any advantage for this approach, but ……… </li></ul>
    54. 57. Intrahepatic bile duct cancer
    55. 58. Gallblader Two small (?!) trials seem to suggest a possible role for adjuvant 5FU or GEM-based chemotherapy and radiation except for patients T1N0 (Kresl Int J Radiat Oncol Biol Phys 2002: 21 patients 5-y survival 64 vs 33%; Takada, Cancer 2002; 5-y survival 26 vs 14% ). SEER 1992-2002: 3.187 cases Adjuvant radiation 17% of patients; median survival: radiation vs not 14 vs 8 m. Advantage presents only in patients with regional spread and tumors infiltrating the liver ( Mojica, J Surg Oncol 2007)
    56. 59. Extrahepatic bile duct cancer <ul><li>Chemotherapy </li></ul><ul><ul><li>No advantage (Takada, 2002) </li></ul></ul><ul><li>Chemoradiotherapy </li></ul><ul><ul><li>Effects on R1 or N+ tumors (Borghero, 2008) </li></ul></ul><ul><li>Radiotherapy </li></ul><ul><ul><li>9.3% falls in risk of death ( SEER) </li></ul></ul>
    57. 60. Biliary tract cancer <ul><li>Adjuvant therapy </li></ul><ul><li>Palliative treatment </li></ul>
    58. 61. Is it useful to perform a chemotherapy? Treatment patients mOS p . BSC 19 2.5 mo 5FU-LV o ELF 18 6.5 mo ns Improvement of quality of life including pancreatic cancer Glimelius Ann Oncol 1996
    59. 62. <ul><li>BSC: 27 pts </li></ul><ul><li>5FU: 28 pts </li></ul><ul><li>GEM: 26 pta </li></ul>
    60. 63. <ul><li>104 trials (4 randomised!) 85% 2000-2006 </li></ul><ul><li>2810 patients (about 25-27 patients/trial) </li></ul><ul><li>OR (634/2810) 23% </li></ul><ul><li> mPFS 4.1 mo mOS 8.2 mo </li></ul>
    61. 64. A pooled analysis of clinical trials in biliary tract cancers. <ul><li>RR gallbladder>cholangiocarcinoma </li></ul><ul><li> (34 vs 20%) </li></ul><ul><li>OS gallbladder<cholangiocarcinoma </li></ul><ul><li> (7.2 vs 9.3) </li></ul><ul><li>2 drugs>1 drug </li></ul><ul><li> (RR: 28 vs 15%; PFS: 4.4 vs 3.4 mo; OS: 9.3 vs 7.5 mo) </li></ul><ul><li>3 drugs = 2 drugs </li></ul><ul><li>CDDP+GEM > CDDP+FU (17 vs 9%); </li></ul><ul><li>Eckel F, Br J Cancer 2007 </li></ul>
    62. 66. “ ...Thus, therapeutic options are limited for many cholangiocarcinoma patients. Further, advances in the therapy of cholangiocarcinoma will most likely be predicated on a molecular understanding of this disease .” G.J. Gores, J Hepatol 2003
    63. 67. <ul><li>Treatment n° RR mPFS mOS </li></ul><ul><li>Sorafenib </li></ul><ul><li>El-Khoueiry, ASCO 07 36 6% 2.0 6.0 </li></ul><ul><li>Dealis, ASCO 08 (2l) 46 4% 2.5 6.0 </li></ul><ul><li>Erlotinib </li></ul><ul><li>Philip, J Clin Oncol 06 42 8% 2.6 nd </li></ul><ul><li>Lapatinib </li></ul><ul><li>Ramanathan, ASCO 06 19 0% 1.8 nd </li></ul><ul><li>Erlotinib+Bevacizumab </li></ul><ul><li>Holen, ASCO 08 34 20% nd nd </li></ul>Biological agents
    64. 68. Treatment n° RR mPFS mOS Cetuximab+GEMOX Gruenberger, ASCO 08 22 58% nd nd Bevacizumab+GEMOX Clark, ASCO 07 26 29% nd nd Biological agents and chemotherapy
    65. 69. Perspectives Biology Drug Bile acid metabolism Nuclear receptor agonists COX-2 COX-2 inhibitors IL-6 IL-6 neutralizing antibodies ErbB2 Cetuximab, Erlotinib, Gefitinib Akt/Mcl-1 Perifosine/Obatoclax Endogenous opioids OR inhibitors Serotonin 5HT metabolism Estrogens ER- β slective agonists VEGF Sorafenib/Bevacizumab

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