Carcinoma hepatocelular

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  • HCC, hepatocellular carcinoma.   Jorge A. Marrero, MD, MS: Worldwide, HCC is a common cancer, with 694,000 deaths from liver cancer yearly worldwide. The American Cancer Society estimated that there were approximately 24,000 cases in the United States in 2010. Hepatocellular carcinoma is the fifth leading cause of cancer death in males in the United States .
  • Figure 13-24. The relative frequency of various tumors of the liver. Note that metastases are by far the most frequent, particularly in the developed western world. Among the primary malignant tumors, hepatocellular carcinoma is the most frequent.
  • Hepatocellular Carcinoma: Epidemiology and Molecular Carcinogenesis Gastroienterology Volume 132 , Issue 7 , Pages 2557-2576 (June 2007) http://www.gastrojournal.org/article/PIIS0016508507007998/fulltext
  • Molecular mechanisms inducing hepatocarcinogenesis at the cirrhosis stage. Molecular mechanisms that could explain the increased cancer risk at the cirrhosis stage are summarized. These mechanisms include cell-intrinsic and cell-extrinsic alterations. On the cell intrinsic level, cirrhosis is associated with telomere shortening. Telomere shortening leads to an activation of the cell cycle and apoptosis checkpoints that restrain the proliferative capacity of liver cells and in turn select for hepatocytes carrying deletions of checkpoint genes. In addition, telomere shortening induces chromosomal instability, which can be accelerated further by loss of checkpoint function. On the cell extrinsic level, cirrhosis induces alterations of the microenvironment including altered cytokine secretion from activated stellate cells as well as inflammatory signaling from infiltrating immune cells. Moreover, the decrease in liver function at the cirrhosis stage could increase toxic metabolites in blood serum, inducing alteration of the macroenvironment. Both alterations of the macroenvironment and the microenvironment could stimulate proliferation of hepatocytes, thus leading to a further selection of genetically altered (pre-) malignant clones.
  • HCC, hepatocellular carcinoma; NASH, nonalcoholic steatohepatitis.   Jorge A. Marrero, MD, MS: This slide illustrates the multistep transformation that results in the development of HCC. The process starts with a normal liver that undergoes chronic liver injury, for example, infection with hepatitis C or hepatitis B, leading to fibrosis development and, eventually, cirrhosis. The next phase is dysplasia, which in turn evolves through genetic or epigenetic alterations into HCC. This sequence has been studied in detail and more is being discovered about the exact pathways that underlie malignant transformation as time goes by.  
  • Figure 13-32. Ultrasound examination of the liver showing a 5 × 10 cm hypoechoic mass (between markers). Ultrasound is one of the most sensitive methods for detecting tumors within the liver and is also relatively inexpensive and noninvasive [19]. Hepatocellular carcinoma often has echogenicity different from that in the remainder of the liver. Thus, small tumors are often hyperechoic with a thin hypoechoic rim. With time, and as the tumor grows, the whole tumor often becomes hypoechoic, and finally, when the tumor is large, it often has mixed echogenicity. References: [19]. Kobayashi K, Sugimoto T, Makino H, et al. Screening methods for early detection of hepatocellular carcinoma. Hepatology 1985 5 1100-1105
  • Figure 13-33. Computed tomographic scan of the liver showing enhancement of a 3-cm lesion in the right lobe of the liver. Biopsy confirmed this to be hepatocellular carcinoma (HCC). The three-phase CT is generally considered the optimal radiologic examination to detect HCC. The three phases in which the liver is imaged are precontrast, arterial phase, and venous phase. Because HCC is hypervascular, it typically enhances rapidly in the arterial phase of the scan.
  • Figure 13-44. Contrast-enhanced computed tomography (CT) shows a hepatocellular carcinoma (M) with an enhancing capsule (white arrow) in a patient with cirrhosis. The CT scan also demonstrates a thrombus in the left portal vein (arrow), collateral veins (white arrowheads), splenomegaly, and perisplenic varices (black arrowhead).
  • Figure 13-36. A smaller hepatocellular carcinoma (arrow) that is marked by a small area of neovascularization on hepatic arteriography. Here the arteriogram may be useful in planning surgical resection.
  • Figure 13-31. Relative sensitivity of various imaging modalities in diagnosis of hepatocellular carcinoma (HCC). Some of the typical clinical features of HCC include abdominal swelling, right upper quadrant pain, weight loss, and apparent worsening of liver disease in patients known to have cirrhosis. This tumor only becomes clinically apparent, however, when it is far advanced. When patients present with these symptoms they usually have extensive tumor involvement within the liver as well as distant metastases. The use of radiologic imaging studies has allowed detection of HCC at an earlier stage, often before the development of symptoms. CT—computed tomography; MRI—magnetic resonance imaging. (Adapted from Di Bisceglie [2].) References: [2]. Stromeyer FW, Ishak KG, Nodular transformation (nodular "regenerative" hyperplasia) of the liver. Hum Pathol 1981 12 60-71
  • HBV, hepatitis B virus; HCC, hepatocellular carcinoma.   Jorge A. Marrero, MD, MS: This slide shows patients for whom HCC surveillance is recommended. According to guidelines from the American Association for the Study of Liver Disease (AASLD), surveillance is recommended in Asian males or females with hepatitis B who are older than 40 or 50 years of age, respectively; carriers of hepatitis B with a family history of HCC; Africans or North African black persons with hepatitis B; cirrhotic patients with hepatitis B; and patients with hepatitis C cirrhosis or cirrhosis from other causes.   Josep M. Llovet, MD: The great majority (approximately 80%) of patients with HCC has underlying cirrhosis whereas only a small proportion of patients with noncirrhotic livers develop HCC. Mostly, these are patients with chronic hepatitis B, but most patients who should be included in surveillance programs are cirrhotic patients.
  • AASLD, American Association for the Study of Liver Diseases; HCC, hepatocellular carcinoma.   Jorge A. Marrero, MD, MS: The AASLD guidelines recommend that HCC surveillance be performed with ultrasound and that patients should be screened at 6-month intervals.
  • BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of Liver Italian Program; CTP, Child-Turcotte-Pugh; CUPI, Chinese University Prognostic Index; GETCH, Groupe d'Etude de Traitement du Carcinome Hepatocellular; HCC, hepatocellular carcinoma; JIS, Japanese Integrated Staging System; TNM, tumor node metastasis.   Josep M. Llovet, MD: Several staging systems have been proposed for HCC. All systems include an assessment of tumor stage and most also include liver function. An exception is the tumor necrosis metastasis (TNM) system, which measures fibrosis rather than liver function. Only a few staging systems capture variables related to health status such as Eastern Cooperative Oncology Group (ECOG) performance or Karnofsky score. In fact, only the Barcelona Clinic Liver Cancer (BCLC) system includes ECOG performance score; the French Groupe d'Etude de Traitement du Carcinome Hepatocellular system includes Karnofsky score, and the Chinese University Prognostic Index (CUPI) system includes the presence of symptoms.   In the West, the staging systems that are most widely applied are the BCLC system and, less so, the TNM system. The Japanese Integrated Staging System score and the CUPI system are widely used in Asia.   For more information, go online to: http://clinicaloptions.com/Hepatitis/Journal%20Options/Collections/2005%20JO%20Hepatitis%20Volume%202/Articles/Marrero-Hep-2005-04/Capsule.aspx  
  • BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; PST, performance status. Josep M. Llovet, MD:   The Barcelona system differentiates 5 stages of HCC disease. Stage 0 cases are chronic patients with small lesions, < 2 cm in size, with single tumors, and no evidence of vascular invasion or extrahepatic spread. These should be asymptomatic, Child-Pugh A class patients. Early-stage patients have a single tumor or 3 nodules < 3 cm according to the Milan criteria, and an ECOG performance score of 0, whereas intermediate-, advanced-, and terminal-stage patients have multinodular or disseminated disease.  
  • HCC, hepatocellular carcinoma.   Josep M. Llovet, MD: For patients with liver dysfunction, such as portal hypertension or abnormal bilirubin or those with Child-Pugh class B disease, the first-line treatment option is liver transplantation. When used appropriately, transplantation has been associated with 5-year survival rates of 70% and a 5-year recurrence rates of < 15%. However, there is a shortage of donors in almost every country worldwide. Were this not the case, liver transplantation could be considered in patients with single tumors not > 5 cm or with up to 3 tumors < 3 cm that are not resectable.
  • PEI, percutaneous ethanol injection; RFA, radiofrequency ablation.   Josep M. Llovet, MD: A third option is percutaneous local ablation. This procedure is suitable for patients who are not candidates for surgery or liver transplantation. Radiofrequency ablation is considered the first-line treatment option for these patients based on data from 4 randomized, controlled trials that found this approach to be significantly more effective than percutaneous ethanol injection regarding local control of disease. In addition, meta-analyses suggest there may be an overall survival benefit in favor of radiofrequency ablation.
  • GETCH, Groupe d'Etude de Traitement du Carcinome Hepatocellular; HCC, hepatocellular carcinoma; OR, odds ratio; RCT, randomized controlled trial.   Josep M. Llovet, MD: Several randomized, controlled trials have been conducted in this patient population. The results of a meta-analysis published in 2003 found that chemoembolization was significantly more effective than best supportive care or suboptimal therapies, with a median survival of 20 months. Based on these data, both the European Association for the Study of the Liver and AASLD guidelines recommend chemoembolization as the first-line treatment option for this patient group.
  • BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; PS, performance score; RCT, randomized controlled trial.   Josep M. Llovet, MD: Median survival in patients with intermediate-stage disease is approximately 17 months if left untreated but may be extended with chemoembolization.  
  • TACE, transarterial chemoembolization.   Josep M. Llovet, MD: Chemoembolization is not appropriate for all patients with intermediate-stage disease. For instance, extrahepatic spread, lack of portal blood flow, advanced disease, or clinical symptoms of end-stage cancer are contraindications for chemoembolization.
  • ASCO, American Society for Clinical Oncology; HCC, hepatocellular carcinoma; TACE, transarterial chemoembolization.   Josep M. Llovet, MD: Trials emerging in this area are exciting. In 2011, at least 12 phase III trials of molecular therapies are ongoing. In first-line therapy, several studies are evaluating the combination of sorafenib with another agent, for example, erlotinib. This tyrosine kinase inhibitor blocks epidermal growth factor receptor 1. In HCC, epidermal growth factor signaling is activated and is a factor in the pathogenesis of the disease. Sorafenib does not target epidermal growth factor signaling, and so the combination of these 2 agents may provide dual activity.   Another phase III trial is comparing sorafenib vs brivanib in the first-line setting. Brivanib is another novel tyrosine kinase inhibitor, which blocks several pathways, including vascular endothelial growth factor (VEGF) and FGF receptor. A trial comparing sorafenib with sunitinib was halted in 2010 for futility and toxicity, and sunitinib is no longer under investigation in the setting of advanced HCC. Sunitinib is a potent multikinase inhibitor that blocks several signaling cascades, some of which are also blocked by sorafenib.   Gefitinib, another multikinase inhibitor is also under evaluation as first-line therapy, and there are additional trials involving other types of therapies. One is evaluating sorafenib with or without internal radiation with yttrium 90. Another study is investigating first-line use of sorafenib plus or minus doxorubicin. This combination showed some efficacy in a phase II study, although there is concern about potential cardiac toxicity.   For patients with progression on sorafenib, there are 3 trials of second-line therapy under way. One compares brivanib with placebo, and another involves everolimus, an mammalian target of rapamycin inhibitor that has shown some efficacy in HCC. Finally, there is the phase III, placebo-controlled study of ramucirumab, a monoclonal antibody against VEGF receptor 2.   These phase III trials provide a range of options to the patient. In addition, there are a number of phase II studies ongoing, involving c-Met inhibitors, for instance, monoclonal antibodies against glypican 3 or hedgehog protein 90.
  • BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; PST, performance status. Josep M. Llovet, MD:   The Barcelona system differentiates 5 stages of HCC disease. Stage 0 cases are chronic patients with small lesions, < 2 cm in size, with single tumors, and no evidence of vascular invasion or extrahepatic spread. These should be asymptomatic, Child-Pugh A class patients. Early-stage patients have a single tumor or 3 nodules < 3 cm according to the Milan criteria, and an ECOG performance score of 0, whereas intermediate-, advanced-, and terminal-stage patients have multinodular or disseminated disease.  
  • HCC, hepatocellular carcinoma; OS, overall survival; PS, performance score; TACE, transarterial chemoembolization.   Jorge A. Marrero, MD, MS: The current paradigm in HCC is that approximately 30% to 40% of patients are either stage 0 or A, whereas the majority has more advanced disease. If we do a good job of identifying patients at risk by promoting appropriate surveillance, then perhaps this paradigm will change in the future so that most patients will present with early-stage disease, perhaps leading to better outcomes.   Josep M. Llovet, MD: I agree. This is what is happening now in Japan, where surveillance programs target the at-risk population effectively. Now, some 60% of Japanese patients are diagnosed at early stages of disease and 30% at a very early stage. Wider implementation of surveillance programs in the West could also achieve this goal.  
  • HCC, hepatocellular carcinoma.   Jorge A. Marrero, MD, MS: Management of HCC requires a multidisciplinary approach. Treatment options involve surgery, medical oncology, diagnostic and interventional radiology, as well as hepatology.   Josep M. Llovet, MD: Hepatocellular carcinoma is a complex and unique disease, involving cirrhosis and liver disease as well as cancer. Hepatic resection and liver transplantation requires specialist surgeons, and skilled pathologists are needed to confirm diagnosis. Use of local ablation therapies and chemoembolization depends on access to interventional radiologists, and finally, hepatologists and oncologists must be well versed in treatment strategy. The multidisciplinary team is central to the management of this disease.
  • For more oncology activities, please go to clinicaloptions.com/oncology.
  • Carcinoma hepatocelular

    1. 1. Carcinoma Hepatocelular Elaborado por: Médico Freddy García Ortega Hospital Sergio E. Bernales Freddy_g_o@yahoo.es
    2. 2. Epidemiologia del HCC A nivel mundial causa 694,000 muertes[1] Incidencia ajustada por edad en EEUU se ha incrementado en 2 veces entre 1985-1998[2] El incremento continuara hasta el 2015-2020[3] Para cancer hepatico el 2010, la American Cancer Society statistics: Estima 24,120 casos nuevos Estima 18,910 muertes La 5º causa de muertes por cancer en hombres1. GLOBOCAN 2008. 2. SEER stat fact sheets: liver and intrahepatic bile duct. 3. Llovet JM. JGastroenterol. 2005;40:225-235. 4. American Cancer Society. Cancer facts & figures 2010.
    3. 3. HEPATOCARCINOMA INCIDENCIA 5ª Neoplasia más frecuente en varones 6ª en mujeres. (1 millón de defunciones/año) 5% de todos los Cánceres en el mundo. HVC 60-80% de pacientes Occidentales y Japón: Promedio de edad 61-64 años HVB 60-70% en Asia y África: Promedio de edad 50 años. ( 10 años antes que HVC) 1901 Eggel describe 200 casos en autopsias. Bosch FX, et al. Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004; 127: S5-S16
    4. 4. Manejo de carcinoma hepatocelular (HCC) un reto dificil Debido a: Epidemiologia cambiante Fondo cirrotico Multiplicidad de algoritmos terapeuticos En EEUU 7 casos de HCC por 100,000 habitantes
    5. 5. FACTORES DE RIESGO EDAD Hepatitis B y C. Cirrosis Hepática.Alcohol. (Hepatitis B y C + 80g Alcohol/día = 7.5 riesgo) Aflatoxina Exposición a Vinilos. Parásitos Porfiria Cutánea, Hemacromatosis. Diabetes NASH Hemocromatosis Okuda K. Hepatocellular carcinoma: recent progress. Hepatology 1992; 15: 948-63.
    6. 6. MORTALIDAD POR CARCINOMA HEPATOCELULARMortalidad por HCC ajustado por edad, por 100,000 habitantes Fuente
    7. 7. Tumores que afectan al hígado
    8. 8. Tendencia de mortalidad por cáncer en EU El mortalidad por cáncer hepático es el que mas rápidamenteesta variando en los EU, en general la mortalidad por cáncer ha Fuentedisminuido, pero hay canceres que están creciendo más rápido
    9. 9. Incidencia de HCC en Pacientes con cirrosis compensada Fattovich et al, Hu and Tong, Serfaty et al., Italia EEUU Francia Numero de pacientes 384 112 103Periodo de seguimiento, años 5.0 4.5 3.3Descompensacion, % por año 3.9 4.4 5.0 HCC, % por año 1.4 2.3 3.3 Fuente
    10. 10. Mortalidad por cancer en varones obesos en EEUU Fuente
    11. 11. Diabetes y riesgo de HCCEn 73,463 pacientes diabeticos y 650,620 no diabeticos Fuente
    12. 12. CH: Presentación Clínica en 547 paciente U. de Pittsburghs Síntomas Pacientes % Asintomáticos 129 24 Dolor abdominal 219 40 Otro (Anemia etc.) 64 12 PFH alteradas 129 24 Pérdida de peso 112 20 Pérdida del apetito 59 11 Debilidad/ cansancio 83 15 Ictericia 30 5 TC alterada de rutina en 92 17 cirróticos Síntomas de cirrosis 98 18 Diarrea 7 1 Ruptura del tumor 1Dr. Gabriel Kraus Fischer, http://www.intramed.net/contenidover.asp?contenidoID=70193&uid=402969
    13. 13. CH: Presentación Clínica en 547 paciente U. de Pittsburghs Variable Edad media 56 +/- 13 Hombre: Mujer 3:1 Raza: Caucásicos 72% Medio oriente 10% Asiáticos 13% Negros 5% Cirrosis 81% No cirrosis 19%Dr. Gabriel Kraus Fischer, http://www.intramed.net/contenidover.asp?contenidoID=70193&uid=402969
    14. 14. CH: Presentación Clínica en 547 paciente U. de Pittsburghs Características del tumor # de tumores 1 20% 2 25% 3 o más 65% Invasión a vena porta 75% 25% Unilobar Bilobar 75%Dr. Gabriel Kraus Fischer, http://www.intramed.net/contenidover.asp?contenidoID=70193&uid=402969
    15. 15. Presentacion clinica del HCC Lo ideal: Detectarlo en estadio temprano en despistaje de hepatitis viral Lo real: La gran mayoria llega en estados avanzadosOcasionalmente puede manifestarse con dolor agudo y pensar en posible ruptura del tumor y hemoperitoneo La metastasis osea es mas frecuente que antes y se explica por un mejor manejo de la cirrosis, habiendose triplicado
    16. 16. Mecanismos moleculares inductores de hepatocarcinogenesis en cirróticos Disfuncion del telomero Microambiente: Hepatitis Activacion de celulas cronica esteladas, señales Ambiente inflamatorias inhibitorio de crecimiento: inhibicion de ciclo celular, apoptosis Macroambiente: Perdida de metabolitos de masa hepatica Cirrosis Delecion en Estimulo Inestabilidad puntos de proliferativo cromosomal control Fuente Seleccion de clones malignos
    17. 17. Secuencia de Transformacion maligna HCC[2] Alteraciones epigeneticas Alteraciones geneticas Nodulos displasicos[1] Cirrosis hepatica Hepatitis C Hepatitis B Puntos blancos potenciales Etanol Estress oxidativo Oncogenes Carcinogenos NASH e inflamacion Virales Higado Factores de Acortameniento Celulas madrre crecimiento de Telomeros de cancer Normal Perdidad de Antiapoptosis Angiogenesis checkpoints del ciclo celular1. Tornillo L, et al. Lab Invest. 2002;82:547-553.2. Verslype C, et al. AASLD 2007. Abstract 24.
    18. 18. HEPATITIS C Y CARCINOMA HEPATOCELULAREstudio en norteamericanos en el MD Andersen Medical Center in Houston,Texas, se busco evidencias serologicas de HCVy HBV, solo el CHC con HCV se Fuenteincremento.
    19. 19. Ayuda diagnostica en HCC Alfa-fetoprotein: su validez como marcador pronostico no ha sido confirmada En un estudio de 263 HCC 70 (29.3%) tuvieron AFP >400 ng/mL, pero 107 (41.1%) tuvieron AFP <20 ng/mL * Tomografia computarizada con componente trifasico ayuda a mejor identificacion de las lesiones hepaticas Resonancia magnetica tambien es util Ecografia: util, uso en programas de deteccionConfirmacion histologica, aunque no requerida, es benefica para confirmar diagnostico y analizar el tejido a fin de entender nuevas terapias * World J Gastroenterol 2006 August 7; 12(29): 4656-4659 http://www.wjgnet.com/1007-9327/12/4656.pdf
    20. 20. Ecografia mostrando masa hipoecoica de 5x10 cm
    21. 21. Tomografia computarizada mostrando una lesion de 3cm enlobulo derecho
    22. 22. Tomografia mostrando HCC encapsulado con patron de mosaico y trombo en porta
    23. 23. Angiografia mostarndo pequeño carcinoma hepatocelular
    24. 24. Sensibilidad relativa de varios modalidades de imagenes en el diagnostico de carcinoma hepatocelular
    25. 25. Carcinoma hepatocelularTumor hepático con coloración verdosa, cursan con elevación de AFP y de fosfatasa alcalina por que obstruyen vías biliares en forma localizada Fuente
    26. 26. Carcinoma hepatocelular Comúnmente se dan en hígados cirróticos, frecuentemente por virus perotambién en otras causas de cirrosis. Se ve gran tumor algo verdoso por su contenido de bilis, y a la derecha se observas nódulos satélites Fuente
    27. 27. Histología normal del hígadohttp://www.udel.edu/biology/Wags/histopage/colorpage/clg/clg.htm
    28. 28. Histología normal del hígadohttp://escuela.med.puc.cl/paginas/Cursos/tercero/AnatomiaPatologica/Imagen
    29. 29. Carcinoma hepatocelular Las células malignas están sobre todo al lado derecho, son biendiferenciadas e interdigitan con hepatocitos grandes que se ven mas al lado izquierdo
    30. 30. Carcinoma hepatocelularCordones hepáticos mucho mas anchos que lo normal , se ha perdido laarquitectura lobular normal, pero aun se ven las estructuras vasculares
    31. 31. ¿En quienes hacer despistaje de HCC?  Varones asiaticos portadores de HBV mayores de 40 años  Mujeres asiaticas portadoras de HBV mayores de 50 años  Portadores de HBV con historia familiar de HCC  Africanos/norte americanos negros con HBV  Cirroticos por HBV  Hepatitis C con cirrosis  Cirrosis biliar primaria en estadio 4  Hemocromatosis genetica y cirrosis  Deficit de alfa-1 antitripsina y cirrosis  Otras cirrosis  80% de pacientes con HCC tienen cirrosis defondoBruix J, et al. AASLD HCC guidelines. July 2010.Simonetti RS, et al. Dig Dis Sci. 1991;36:962-972.
    32. 32. Guias de despistaje del AASLD  Se recomienda despistaje en grupos en riesgo – Pacientes con virus de hepatitis B – Cirrosis hepatitis B negativos  El despistaje de HCC debe hacerse con ECO  El despistaje deben hacerse con intervalos de 6 meses – No es necesario hacer despistajes mas frecuentesBruix J, et al. AASLD HCC guidelines. July 2010.
    33. 33. Sistemas de estadiaje en HCC y variables que usanSistema Estadio del tumor Funcion hepatica Estado de saludEuropa-EEUUGETCH/ French Trombosis de vena porta ; AFP < 35 or > Bilirubina, Fosfatasa Karnofsky 35 ug/L alcalinaCLIP Numero de nodulos, tumor > o < 50% de CTP No area hepatica, y trombosis de vena porta ; AFP< 400 o ≥ 400 ng/mLBCLC Tamaño del tumor, numero de nodulos y CTP PST trombosis de vena portaTNM Numero de nodulos, tamaño del tumor, No No presencia de trombosis de vena porta, y presencia de metastasisAsiaJIS TNM CTP NoOkuda/ Tokyo Tumor > o < 50% de area de seccion Ascitis, albumina, y No transversal del higado bilirubinaCUPI TNM; AFP< 500 or ≥ 500 ng/mL Bilirubina, ascitis, Sintomas fosfatasa alcalina Marrero JA, et al. Hepatology. 2005;41:707-716.
    34. 34. Sistemas de estadiaje por HCCClasificacion Tipo Estadios Okuda 3 Estadios Estadios I, II, III A: 0 puntos French 3 grupos B: 1–5 puntos C: ≥6 puntos CLIP 7 puntos 0, 1, 2, 3,4, 5, 6 0: Muy temprano A: Temprano BCLC 5 estadios B: Intermedio C: Avanzado D: Terminal Bajo riesgo: score ≤1 CUPI 3 grupos Riesgo intermedio: score 2–7 Riesgo alto: score ≥8 TNM 3 estadios Estadios I, II, III JIS 4 estadios Estadios I, II, III, IV ER tipo salvaje ER 2 grupos ER variante
    35. 35. Comparacion de sistemas de estadiajeAutores Revista Año Pais Comparacion El mejor ConclusionCillo et al. J Hepatol 2004 Italy 5 sistemas BCLC ValidarVilla et al. J Clin Oncol 2003 Italy 5 sistemas ER Propone ER Eur J GastroenterolRabe et al. 2003 Germany 5 sistemas None – Hepatol ProponeLeung et al. Cancer 2002 China 4 sistemas CUPI CUPIGiannini et al. J Intern Med 2004 Italy 4 sistemas None –Ueno et al. Hepatology 2002 Japan 3 sistemas CLIP ValidarFarinati et al. Cancer 2000 Italy 3 sistemas CLIP ValidarLevy and Gut 2002 Canada 3 sistemas CLIP ValidarShermanKudo et al. J Gastroenterol 2003 Japan 2 sistemas JIS Propone JIS
    36. 36. Clasificacion Japan Integrated Staging (JIS) Parametro/ score 0 1 2 3 Child Child-Pugh A B C Estadio por el LCSGJ I II III IVA o IVBLCSGJ: Liver Cancer Study Group of Japan Fuente: J Gastroenterol Hepatol 2004 Blackwell Publishing
    37. 37. Criterios de las categorias T de la LCSGJ 1- Tumor solitario 2- Diametro <= 2 cm 3- No invasion vascular o de conducto biliarLCSGJ: Liver Cancer Study Group of Japan
    38. 38. categorias T de la LCSGJLCSGJ: Liver Cancer Study Group of Japan
    39. 39. Clasificacion SLiDe Parametro/ score 0 1 2 3 Child Child-Pugh A B C Estadio por el LCSGJ I II III IVA o IVB Des-♉-carboxy prothrombin (mAU/ <400 ≥400 ml)LCSGJ: Liver Cancer Study Group of JapanSlide: S (stage), Li (liver damage), De (des-♉-carboxy prothrombin) Fuente: J Gastroenterol Hepatol 2004 Blackwell Publishing
    40. 40. Grado de daño hepático por la LCSGJ Grado de daño hepatico Item A B C Ascitis No Controlable Incontrolable Bilirrubina ( mg/dL) < 2.0 2.0 – 3.0 > 3.0 Albumina (g/dL) > 3.5 3.0 – 3.5 < 3.0 ICG R15 (%) < 15 15 - 40 > 40Actividad de protrombina (%) > 80 50 - 80 < 50ICG R15: retención de verde de indocianina a los 15 minutosLCSGJ: Liver Cancer Study Group of Japan
    41. 41. CLIP Staging Classification Variables 0 Puntos 1 Punto 2 Puntos Child-Pugh A B C Nodulo unico y Nodulos Masiva oMorfologia del tumor < 50% area Multiples > 50% areaAlfa-fetoproteina, ng/ < 400 ≥ 400 mL Trombosis de vena No Si porta CLIP: Cancer of the Liver Italian Program
    42. 42. Sistema Child-Pugh Variable 1 Punto 2 Puntos 3 puntos Bilirubina (total), < 34 (< 2) 34-50 (2-3) > 50 (> 3) μmol/L (mg/dL) Serum albumin, g/L > 35 28-35 < 28 INR < 1.7 1.71-2.20 > 2.20 Cede con Ascitis No Refractaria medicacion Grado 1-2Encefalopatia hepatica Grade 3-4 No (o mejora con encephalopathy (o refractaria) medicacion) INR, international normalized ratio.
    43. 43. Sistema de estadiaje de Okuda Puntos Variables 0 1Tamaño del tumor* <= 50% del higado > 50% Ascitis No Si Albumina (g/dl) >=3 <3 Bilirrubina (mg/dl) <= 3 >3* La mayor area de seccion cruzada del tumor al area de seccion cruzada del higado Estadio I 0 puntos, Estadio II 1 a 2 puntos, Estadio III 3 o 4 puntos
    44. 44. Eastern Cooperative Oncology Group Performance Status Eta escala se usa para ver progresion de enfermedad, ver como la enfermedad afecta el quehacer cotidiano del paciente, y para el tratamiento y pronostico Grado Performance Status (PS) Totalmente activo, capaz de llevar a cabo todas las actividades previas a la 0 enfermedad sin restriccion alguna Restriccion de actividades forzadas, ambulatorio y puede realizar actividades 1 ligeras o de naturaleza sedentaria, e.g., trabajo de casa simple, trabajo de oficina Ambulatorio y capaz de prodigarse autocuidados pero incapaz de trabajar. En 2 pie y asi mas del 50% de las horas que esta despierto. Capacidad de autocuidado solo limitadamente, confinado en cama o en una 3 silla mas del 50% de las horas que esta depierto Completamente incapaz. No puede prodigarse autocuidado, totalmente 4 confinado a la cama o en una silla 5 Muerto*. Oken, M.M., Creech, R.H., Tormey, Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.
    45. 45. Sistema de estadiaje de BCLC (Barcelona-Clínic Liver Cancer) HCC Estadio 0 Estadio A-C Estadio D PS 0, Child-Pugh A Okuda 1-2, PS 0-2, Child-Pugh A-B Okuda 3, PS > 2, Child-Pugh C Muy temprano (0) Temprano (A) Intermedio (B) Avanzado (C) Terminal (D) 1 nodulo < 2 cm 0 a 3 nodulos Multinodular, PST Invasion portal, Carcinoma in situ < 3 cm, PST 0 0 N1, M1, PST 1-2 HCC No resecable PS: performance status , PST: performance status testLlovet JM, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. Journal of the NationalCancer Institute. 2008;100(10):698-711, by permission of Oxford University Press.
    46. 46. Sistema de estadiaje de BCLC (Barcelona-Clínic Liver Cancer)
    47. 47. Trasplante hepatico para HCC:Criterios de Milan (Estadios 1 y 2) Tumor unico , no > 5 cm Hasta 3 tumores, ninguno > 3 cm + Ausenciaa de invasion vascular macroscopica, Ausencia de diseminacion extrahepatica  Supervivencia a 5-años con transplante: ~ 70%  Tasa de recurrencia a los 5-años: < 15%Mazzaferro V, et al. N Engl J Med. 1996;334:693-699.Llovet JM. J Gastroenterol Hepatol. 2002;17(suppl 3):S428-S433.
    48. 48. Candidatos para radiofrecuencia (RFA)/inyeccion percutanea de etanol (PEI) Incluye pacientes no tributarios de cirugia Se prefiere ablacion con radiofrecuencia sobre la inyeccion percutanea de etanol El efecto de necrosis es mas predecible Los metanalisis favorecen la supervivencia de balacion por radiofrecuencia sobre la inyeccion percutanea de etanolBruix J, et al. AASLD HCC guidelines. July 2010.
    49. 49. Embolizacion arterial en HCC Meta-analisis de 6 RCTs (Supervivencia a 2-años) Modelo de efectos aleatorios, OR (95% CI) Autor, Revista año Pacientes, 0.01 0.1 0.5 1 2 10 100 n Lin, Gastroenterology 1988 63 GETCH, NEJM 1995 96 Bruix, Hepatology 1998 80 Pelletier, J Hepatol 1998 73 Lo, Hepatology 2002 79 Z = -2.3 P = .017 Llovet, Lancet 2002 112 Global 503 Supervivencia mediana: ~ 20 meses FavoreceTratamiento Favorece ControlLlovet JM, et al. Hepatology. 2003;37:429-442.
    50. 50. Historia natural de HCC no resecable  102 cirroticos con HCC no resecable – Solo con tratamiento sintomatico  Mediana de supervivencia 17 meses (rango: 1-60 meses) – Supervivencia a 1-año 54% – Supervivencia a 2-años 40% – Supervivencia a 3-años 28%Llovet JM, et al. Hepatology. 1999;29:62-67.
    51. 51. Contraindicaciones de embolizacion arterial (TACE)  Diseminacion extrahepatica del tumor  Ausencia de flujo de sangre portal – Trombosis de vena porta, anastomosis portosistemica, o flujo hepatofugal  Enfermedad hepatica avanzada (Child-Pugh Clase B o C)  Sintomas clinicos de cancer terminalBruix J, et al. AASLD HCC guidelines. July 2010.
    52. 52. Terapias moleculares para HCC en evaluacion en fase III (2011)Indicacion Comparacion fase III 1. Sorafenib vs placeboAdyuvante Previene recurrencias NEGATIVO: 2. Retinoides vs placebo ASCO 2010 Mejora la quimio 1. TACE ± sorafenibHCC intermedio embolizacion 2. TACE ± brivanib transarterial (TACE) 1. Sorafenib ± erlotinib Primera linea: 2. Sorafenib vs brivanib Suspendido: 3. Sorafenib vs sunitinib 2010 4. Sorafenib vs lifitinib 5. Sorafenib ± Y90HCC avanzado 6. Sorafenib ± doxorubicin 8. Brivanib vs placebo Segunda linea: 9. Everolimus vs placebo 10. Ramucirumab vs placebo
    53. 53. Estadiaje BCLC y tratamiento HCC Estadio A-C Estadio D Estadio 0 Okuda 1-2, PS 0-2, Child-Pugh A-B Okuda 3, PS > 2,PS 0, Child-Pugh A Child-Pugh C Temprano (A) Intermedio (B) Avanzado (C) Terminal (D)Muy temprano (0) 0 a 3 nodulos Multinodular, PS 0 Invasion portal, 1 nodulo < 2 cm < 3 cm, PS 0 N1, M1, PS 1-2Carcinoma in situ Presion Enfermedad portal Aumentada asociada bilirubina Normal No SI Reseccion Trasplante RFA/PEI TACE Sorafenib hepaticoTratamiento curativo (30%); sobrevida a 5-años : 40%-70% RCTs (50%); sobrevida a 3 años 10%-40% Sintomaticos (20%); sobrevida < 3 meses PS: performance status , PST: performance status test, RFA: radiofrecuencia, PEI: percutaneos ethanol injection TACE: Transarterial embolization
    54. 54. Sobrevida en pacientes con HCC HCC Stadio 0 Stadio A-C Stadio DPS 0, Child-Pugh A Okuda 1-2, PS 0-2, Child-Pugh A-B Okuda 3, PS > 2, Child-Pugh CMuy temprano (0) Temprano (A) Intermedio (B) Avanzado (C) Terminal (D)1 nodulo < 2 cm 1 a 3 nodulos Multinodular, PS 0 Invasion portal ,Carcinoma in situ < 3 cm, PS 0 N1, M1, PS 1-2 Supervivencia global 2010 Historia Mediana 6 meses (4-8 Natural Mediana > 36 meses Mediana 16 meses meses) Con Tto Con terapias curativas Quimioembolizacion Con Sorafenib 10.7 > 60 meses transarterial 20 meses meses 2011 40% 20% 40% Estadio al 2020 60% 20% 20% diagnosticoCourtesy of Josep M. Llovet, MD.
    55. 55. Manejo multidisciplinario de HCC El HCC es la interseccion de 2 enfermedades – Enfermedad hepatica y cancer Se requieren patologos entrenados para el diagnostico Se requieren los siguientes especialistas para brindar las opciones terapeuticas – Cirujanos para reseccion o transplante – Radiologos para ablacion y quimioembolizacion Hepatologos y oncologos siguen las estrategiass de tratamiento y control de laboratorio Proveedores de mando medio ofrecen soporte, particularmente para el tratamiento oral
    56. 56. Fuentes:clinicaloptions.com/oncologyAlbum de Feldman (estuvo disponible en Gastrosource hasta hace 2 años)Otros que figuran en los slides Hospital sergio Bernales - Lima Perú

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