Presentation on theme: "Disclosures Participated in the following Advisory Boards: Gilead"— Presentation transcript:
1Disclosures Participated in the following Advisory Boards: Gilead Hoffman La RocheJanssenMerckVertexKathy PoldreCAHN 2013
2Liver Cancer is the Sixth Most Common Cancer Worldwide1 Lung1.5 millionBreast1.3 millionColon/Rectal1.1 millionStomach1 millionProstate782,000Liver711,000Cervix Uteri559,000Esophagus529,000Leukemia330,000Bladder314,000Ovary230,000Liver cancer is the sixth most common cancer worldwide, accounting for 711,128 (5.8%) of new cases per year inHCC is the most common primary tumor of the liver in adults.2Corpus Uteri226,000Oral Cavity200,000Non-Hodgkin's Lymphoma196,000200,000400,000600,000800,0001,000,0001,200,0001,400,0001,600,0001,800,000HCC is the most common primary liver malignancy in adults21. Garcia M, et al. American Cancer Society, Accessed March 20, 2008.2. Perz JF, et al. J Hepatol. 2006;45:Garcia M, Jemal A, Ward EM, et al. Global Cancer Facts & Figures Atlanta, GA: American Cancer Society; Accessed March 20, 2008.Perz JF, Armstrong GL, Farrington LA, Hutin YJF, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006;45:
3Number of estimated deaths Liver Cancer is the Third Most Common Cause of Cancer-Related Mortality Globally1,600,0001.3 million1,400,0001,200,0001,000,000800,000Number of estimated deaths800,000679,000602,000600,000Liver cancer is the third most common cause of cancer-related mortality globally, with the total number of deaths estimated at 679,871 per year.ADDITIONAL INFORMATIONLiver cancer is the third most common cause of cancer-related mortality in men and the sixth in women, around the world.The estimated 5-year survival rates are less than 11% in underdeveloped and developed countries.400,000200,000Lung and bronchusStomachLiverColon and rectumLiver cancer is the third most common cause of cancer-related deathGarcia M, et al. American Cancer Society, Accessed August, 2008.Garcia M, Jemal A, Ward EM, et al. Global Cancer Facts & Figures Atlanta, GA: American Cancer Society; Accessed August 2008.
4HCC Risk Factors Are Well Defined and Show Geographical Variation Europe and North AmericaAsia and Africa (excluding Japan)JapanHepatitis C virus(50-70%)Hepatitis B virus (70%)Hepatitis C virus(70%)HBV(10-20%)HBV(10-20%)HCV(20%)Alcohol(20%)Other(10%)Alcohol(10%)Alcohol(10%)Other(<10%)Other(<10%)Adapted from Llovet JM, et al. Lancet. 2003;362:
5AASLD Diagnostic Criteria for HCC Mass on surveillance ultrasound (US) in a cirrhotic liver<1 cm1-2 cm>2 cmRepeat US every 3-4 moTwo dynamic imaging studiesOne dynamic imaging techniqueCoincidental typical vascular patternTypical vascular pattern with 1 techniqueAtypical vascular pattern with both techniquesAtypical vascular patternTypical vascular pattern on dynamic imaging or AFP >200 ng/mLStable >18-24 moEnlargingBiopsyThis is the AASLD-suggested algorithm for evaluation of a nodule found by ultrasound during screening or surveillance.Nodules that are smaller than 1 cm should be followed with ultrasound at 3- to 4-month intervals. If there is no growth over a period of up to 2 years, then the patient can return to the standard surveillance every 6-12 months.Nodules between 1 and 2 cm found by ultrasound in a cirrhotic liver should be examined by 2 dynamic imaging studies, CT scan, contrast ultrasound, or magnetic resonance imaging (MRI) with contrast. If the appearance is typical of HCC, (ie, hypervascular in the arterial phase with washout in the portal/venous phase) in 2 of the imaging techniques, then the nodule should be treated as HCC. If the findings are not characteristic of HCC or if the vascular profile is not coincidental by both techniques, then the nodule should be biopsied.If the nodule is larger then 2 cm and it has the features typical of HCC by 1 dynamic imaging technique and/or AFP levels are higher than 200 ng/mL, biopsy is not necessary for the diagnosis of HCC. However, if the vascular profile is atypical or if the nodule is detected in a noncirrhotic liver, the lesion should be biopsied.Diagnostic of HCCNondiagnostic of HCCOther diagnosisReturn to surveillance every 6-12 moRepeat biopsy or imaging follow-upChange insize/profileProceed according to lesion size+Repeat imaging and/or biopsy-Adapted from Bruix J and Sherman M. Hepatology. 2005;42(5):Treat as HCCBruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology ;42(5):
6HCC treatment algorithm (BCLC) PST 0, Child-Pugh APST 0-2, Child-Pugh A-BPST > 2, Child-Pugh CVery early stageEarly stageIntermediate stageAdvanced stageTerminal stageSingle < 2 cmSingle or 3 nodules ≤ 3 cm, PST 0Multinodular, PST 0Portal invasion, N1, M1, PST 1-2Single3 nodules ≤ 3 cmHCC, hepatocellular carcinoma; LT, liver transplantation; PEI/RF, percutaneous ethanol injection/radiofrequency ablation; PST, performance status test; RCT, randomized clinical trial; TACE, transcatheter arterial chemoembolization.Staging and the recommended treatment of patients with HCC according to BCLC classification are as follows:Very early and early stage cases receive potentially curative treatments: resection, liver transplantation, and percutaneous therapyIntermediate stage HCC is mainly treated by transcatheter arterial chemoembolization (TACE) based on results from randomized clinical trialsAdvanced stage HCC’s standard of care is now sorafenib, based on data from a recent randomized clinical trial Terminal stage HCC, at present, is treated with best supportive careReferenceLlovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:Portal pressure/bilirubinPortal invasion, N1, M1IncreasedAssociated diseasesNormalNoYesNoYesResectionLiver transplantPEI/RFTACESorafenibCurative treatmentsSymptomatic (unless LT)Llovet JM, et al. J Natl Cancer Inst. 2008;100: Bruix J, et al. Hepatology. 2005;42:6
7BCLC Staging System and Treatment Algorithm HCCVery Early Stage Early StageIntermediate StageAdvanced StageEnd StageSurgical TreatmentLocal AblationTACESorafenibSymptomatic treatmentPatients diagnosed with very early and early stage HCC could be treated with potentially curative treatments, such as resection, liver transplantation, or ablation.If patients were diagnosed with intermediate stage HCC, transarterial chemoembolization (TACE) is the suggested treatment.Palliative care is applied to patients with end-stage HCC.Prior to sorafenib, patients diagnosed with advanced stage HCC had few treatment options.~30% patients~20% patients~30% patients~20% patients5-year survival: 40%-70% (treated)~20% (untreated)Median survival: ~19-20 months (treated)~16 months (untreated)Median survival: ~10-11 months (treated)~6-7 months (untreated)Median survival: <3 monthsADDITIONAL INFORMATIONPrevious studies have shown that patients treated with resection or liver transplantation had a 5-year survival rate of 40% to 70%.Patients treated with ablation had a 5-year survival rate of 40% to 50%.If a patient with intermediate or advanced HCC remains untreated, the median survival is 11 to 20 months.When diagnosed at an advanced stage, survival is <3 months.Most patients with HCC are not diagnosed until they have intermediate or advanced HCC, resulting in poor patient prognosis, since few treatment options are possible at these stages of HCC.TACE = transarterial chemoembolizationAdapted from Llovet JM, et al. J Natl Cancer Inst. 2008;100:Llovet JM, DiBisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008;100(10):
8Treatment OptionsLimited by liver function and characteristics of the malignant lesion i.e. Vascular invasionSolitary vs Multifocal diseaseLocation of lesion(s) – close to vital structuresSize of lesion(s)Childs Pugh ScoreVery early, early, intermediate transplant
10IndicationsNexavar® is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC).Nexavar is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).
11Sorafenib Targets Tumor Cell Proliferation and Angiogenesis Endothelial Cell or PericyteHGFParacrine stimulationPDGF-bVEGFAutocrine loopPDGFR-bVEGFR-2ApoptosisRASRASRAFMcl-1RAFMitochondriaSorafenibMEKSorafenibMitochondriaMEKAngiogenesis:Sorafenib can target both tumor cell proliferation and angiogenesis.1,2Inhibition of the Raf/MEK/ERK pathway can increase tumor cell apoptosis, and reduce tumor cell proliferation, survival, autocrine hepatocyte growth factor (HGF) signaling, as well as decrease the secretion of proangiogenic factors in response to intratumoral hypoxia.3,4In addition to reducing paracrine signaling from tumor cells to the vascular endothelium via growth factor secretion, sorafenib can directly target angiogenesis by inhibiting VEGF receptors -1, -2, and -3, as well as the PDGF receptor, increasing endothelial cell/pericyte apoptosis, and downregulating the expression of genes associated with blood vessel formation.3,4DifferentiationHIFERKHGFApoptosisERKProliferationPDGFMigrationVEGFNucleusTubule formationProliferationNucleusSurvivalHGF = hepatocyte growth factor.Avila MA, et al. Oncogene. 2006;25: ; Liu L, et al. Cancer Res. 2006;66: ;Semela D, et al. J Hepatol. 2004;41: ; Wilhelm SM, et al. Cancer Res. 2004;64:Wilhelm SM, Carter C, Tang L, et al. BAY exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006;66:Avila MA, Berasain C, Sangro B, Prieto J. New therapies for hepatocellular carcinoma. Oncogene. 2006;25:Semela D, Dufour JF. Angiogenesis and hepatocellular carcinoma. J Hepatol. 2004;41:
12Dosing Continuous daily dosing 400 mg (2 x 200 mg tablets) twice daily No dose adjustments for age, gender, or body weightCan be administered without food or low-moderate fat diet
13Sorafenib in Advanced HCC: The SHARP Trial Entry criteriaAdvanced HCCNot eligible for or failed surgical or locoregional therapiesChild-Pugh class A diseaseAt least 1 untreated target lesionExclusionsPrevious chemotherapyPrevious molecularly targeted therapyHCC, hepatocellular carcinoma; SHARP, Sorafenib HCC Assessment Randomized Protocol.The phase III SHARP trial was a landmark study that resulted in the approval of sorafenib and established it as the standard of care in the setting of advanced HCC because of significant improvements in median survival and time to progression compared with placebo.The SHARP study enrolled patients with advanced stage HCC who were not eligible for or had failed surgical or locoregional therapies. Child‑Pugh class A disease was required as was the presence of at least 1 untreated target lesion that could be measured in terms of response. Exclusion criteria included previous chemotherapy or previous molecularly targeted therapy.Llovet JM, et al. N Engl J Med. 2008;359:13
14SHARP Trial: Baseline Characteristics Sorafenib (n = 299)Placebo (n = 303)Median age, yrs64.966.3Male, %87BCLC stage, %B (intermediate)1817C (advanced)8283Vascular invasion, %70BCLC, Barcelona Clinic Liver Cancer; SHARP, Sorafenib HCC Assessment Randomized Protocol.The baseline characteristics of patients enrolled in the SHARP study included a mean age of approximately 65 years; the majority were male (this is a male‑predominant disease); an intermediate or advanced BCLC stage (more than 80% were BCLC stage C); and macroscopic vascular invasion visible on imaging in approximately 70% of patients.Llovet JM, et al. N Engl J Med. 2008;359:14
17Hand-Foot SyndromeA fairly severe example of hand‑foot syndrome is shown on this slide. More often, hand-foot syndrome manifests as very dry skin with flaking that may progress and make walking uncomfortable.Scheithauer W, et al. Oncology (Williston Park) 2004; 18:1161.17
18Grading of Hand-Foot Syndrome GradeSymptom1Minimal skin changes or dermatitis (eg, erythema) without pain2Skin changes (eg, peeling, blisters, bleeding, edema) or pain, not interfering with function3Skin changes with pain, interfering with functionThe common toxicity criteria for adverse events system is used to grade hand‑foot syndrome.Common Terminology Criteria for Adverse Events, Version 3.0. Available at: Accessed October 13, 2008.18
19Dose modification recommendations Temporary interruption and /or dose reduction of management of AEsReduced to 400 mg once dailyIf necessary, single 400 mg dose every other day
20Strategies for Managing AEs Hand-foot syndrome- Lanolin containing creams and lotionsAvoid tight footwear, protect feetMay require dose reductionDiarrheaAntidiarrheal agents –ImmodiumCarbohydrates : rice, potatoes- bulk forming agent- Separate solids from fluidsHypertensionStart or adjust antihypertensivesAEs, adverse events.This slide lists strategies for managing sorafenib-associated adverse events.20
22Case Study Mr. H: 79 yr old, 6 children HBV 2009- Hong Kong fatigue, hematuria, wt lossInvestigations: benign prostatic hypertrophy- mass in the liverCT Oct 2009 : 9 cm x 12 cm mass Seg 6 & 7- another lesion 8.8 cm Seg 7- suspicious lymph node
23Mr. H (cont’d) Would think about treatment – TACE March 17, 2010 – started on Sorafenib,200 mg bid to assess tolerabilityMarch 25, 2010 – mod-severe hand/foot syn.drug stopped x 1wk, restarted200 mg ODApril 29, 2010 – dose 400mg OD
24Mr. H (cont’d)May 26, ’10 – loss of appetite -hand/foot continues (blisters) June 21’ 10 – hand/foot continues -desquamating rash on heals - CT scan – stable ; will put up with the discomfort for the benefit Aug 19’ 10 – off for a few weeks waiting EAP reapproval. Restarts on full dose
25Mr. H. (cont’d) Sept 2010 – present - 83 years old - tolerating drug well- good response to Sorafenib “stable diseasewith no evidence of progression”- good liver function, Childs Pugh A, PS 1
26Mr. H (cont’d) CT Oct 13, 2009 Seg 6/7 lesion – 12.8 cm x 8.9 cm Seg 7 – 8.8 cmCT Jan 2, 2013Seg 6/7 – 9.1 cm x 6.7 cmSeg 7 – 4.9 cm
28Sorafenib is the Systemic Treatment Standard in HCC Sorafenib is the first and only drug ever proven to extend overall survival in patients with HCCTwo randomized phase III studies demonstrate that sorafenib prolongs overall survival and time to progression in both Western and Asian patient populationsSorafenib prolongs overall survival irrespective of patient characteristics or extent of diseaseSorafenib is safe and manageable in patients with HCCDrug-related adverse events are generally mild-to-moderate, predictable and manageableIn summary, the OS, TTP, and PFS hazard ratios were similar in the SHARP and the Asia-Pacific studies, despite more advanced disease in the Asia-Pacific liver cancer study patients.Therefore, it can be concluded that sorafenib is safe and efficacious in patients with HCC across geographic regions.