Hepatosellüler Kanserde klinik Yaklaşım 10. Girişimsel Radyoloji Yıllık Toplantısı Gloria Kongre Merkezi Belek 28 Mart 2015 Hepatosellüler Kanserde klinik Yaklaşım Dr. Şuayib Yalçın Hacettepe Üniversitesi Tıp Fakültesi Medikal Onkoloji Bilim Dalı syalcin@hacettepe.edu.tr

HEPATOSELLÜLER KANSER (HSK) NELER BİLİYORUZ Görülme hızı artmaktadır Prognozu iyi değildir Tarama, erken tanı, ant HBV ve anti HCV tedaviler prognozu iyileştirir Tanı biyopsisiz konabilir Kür mümkündür KC nakli, rezeksiyon, lokal ablasyon Bazı hastalarda uzun süreli yaşam mümkündür Sistemik tedavi yaşam süresini uzatır Tümör biyolojisi farklı olabilir Hastalığın doğal seyrini bilmek gerekir Multidisipliner yaklaşım gerekir

Neler Biliyoruz: HSK Ortanca görülme yaşı: 55 yıl Erkeklerde kadınlara göre 4-8 kat daha fazla Rezektabilite %20’den az Siroz hastaların yaklaşık %90 (+) AFPhastaların %80’inde yüksek

HBV versus HCV HBV’de HSK riskini artıran ko-faktörler HBV’de siroz görülmeden de HSK gelişebilir HBV’de siroz oranı % 70-80 HBV’de HSK riskini artıran ko-faktörler Yüksek virüs yükü HCV veya delta virus koenfeksiyonu Alkol Tütün Erken çocuklukta enfeksiyon HCV’de HSK riskini artıran ko-faktörler İleri yaş Erkek cinsiyet HIV/HBV co-infection, Muhtemelen diabetes ve obezite

HSK: Fibrolamellar varyant Keskin kenarlı- iyi sınırlı Erkek: Kadın oranı 1:1 Hastaların sadece %5’inde Siroz (+), HBV (+), AFP + Rezektabilite %50-70 Ortanca tanı yaşı: 25

Klinik presentasyon Sağ üst kadranda üfürüm %25 Ağrı Kitle Kilo kaybı Ateş Karaciğer yetmezliği bulguları Portal hipertansiyon bulguları Vasküler invazyon bulguları

Klinik özellikler GI kanama: Tümor perforasyonu tanı anında %2-5 Varis kanaması kötü prognoz HSK’de ölüm nedeni %25 varis kanamasından Tümor perforasyonu tanı anında %2-5 Cerrahi veya embolization Bilirubin yüksekliği kötü prognoz Klinik presentasyon Hipoglisemi, eritrositoz (PSV), hiperkalsemi, Porfiri Cutea Tarda, hipertrofik osteoarthropathy, virilizasyon

Metastatik yayılım Karaciğer Lenfatik Akciğer Periton Adrenal Kemik Tümöral trombüs

Epidemiyoloji Dünyada 5. en sık görülen kanser Yılda yaklaşık 500,000 yeni vaka Kanser ölümlerinde 3. sırada Asya ve Afrika’da HBV yaygınlığı nedeni ile sık HBV aşısının HSK riskini azalttığı gösterilmiştir Hepatit B tedavisi HSK riskini azaltır ABD’de steatohepatit ve HCV en sık nedendir. El-Serag HB. N Engl J Med 2011;365:1118-1127

Regional Variation in the Estimated Age-Standardized Incidence Rates of Liver Cancer. Figure 1 Regional Variation in the Estimated Age-Standardized Incidence Rates of Liver Cancer. The incidence rates shown (numbers of cases per 100,000 persons) pertain to both sexes and all ages. Adapted from the World Health Organization.3 El-Serag HB. N Engl J Med 2011;365:1118-1127

1975-2009 yılları arasında HSK görülme hızı 3 kat artmıştır Figure 2 Age-Adjusted Incidence and 5-Year Survival Rates for Patients with Hepatocellular Carcinoma in the United States, 1973–2007. El-Serag HB. N Engl J Med 2011;365:1118-1127

HSK’den ölüm hızı artmaktadır ABD’lerinde bir çok kanserden ölüm hızı azalırken HSK ölüm hızı artmaktadır HSK ölüm hızı en çok artan kanserdır US Cancer Mortality Trends in Men, 1990-2005 Better Worse Hodgkin’s lymphoma Stomach Prostate Colorectal Oropharynx Larynx Lung Gallbladder Non-Hodgkin’s lymphoma Small intestine Brain Leukemia Myeloma Sarcomas Bladder Kidney Pancreas Melanoma Esophagus Liver All malignant cancers -60 -40 -20 20 40 60 Percent Change Jemal A, et al. CA Cancer J Clin. 2009;59:225-249.

2013 Yılında kanserden ölümler Men 306,920 Lung& bronchus 28% Prostate 10% Colon & rectum 9% Pancreas 6% Liver & intraheptic bile duct 5% Leukemia 4% Esophagus 4% Urinary bladder 4% Non-Hodgkin’s lymphoma 3% Kidney & renal pelvis 3% All other sites 24% Women 273,430 26% Lung & bronchus 14% Breast 9% Colon & rectum 7% Pancreas 5% Ovary 4% Leukemia 3% Non-Hodgkin’s lymphoma 3% Uterine corpus 2% Liver & intrahepatic bile duct 2% Brain/other nervous system 25% All other sites ABD’de 2013 yılında karaciğer kanserleri: The #5 cancer killer in men (up from #7 in 2005) The #9 cancer killer in women (not among top 10 in 2005) Currently liver cancer is the fifth leading cause of cancer death in men in the U.S., behind lung, prostate, colon and pancreas, up from 7th just six years earlier. In women it is number 9 now, where previously it was not among the top 10. These are overall statistics. In the V.A. system, where we have a predominantly male patient population and a high prevalence of cirrhosis relative to the general population, it is likely that liver cancer already has passed pancreatic cancer and may soon pass colorectal cancer as a cause of cancer death in veterans. Siegel R, et al. CA Cancer J Clin. 2013;63:11-30.

HSK mortalitesi en yüksek tümörlerdendir 5-yıllık genel sağkalım %15 Pankreas kanserinden (%6) sonra 2. en kötü prognozlu This trend in incidence of liver cancers is particularly concerning because our success rate in curing this cancer is poor. Nationally, among all patients with liver cancer, the likelihood of surviving five years from diagnosis is only 14%, and is 10% in African Americans. This is an abysmal statistic. Survival after diagnosis liver cancer is worse than that of almost every other major form of cancer, including lung, esophagus and stomach. The only major cancer with a worse outcome is pancreatic. Siegel R, et al. CA Cancer J Clin. 2013;63:11-30.

HSK risk faktörleri Herhangi bir nedenle siroz varlığı Kronik Hepatitis B veya Hepatitis C Steatohepatit VKİ ve DM ile ilişkili Statins ve kahve riski azaltır? Riski artıran etmenler Erkek cinsiyet Yaş Diabetes Mellitus

HSK: Patogenez Normal KC Hepatit Siroz HSK Artan risk Persistan/Kronik hepatit Fibrozis Hücre ölümü Normal KC Hepatit Siroz HSK Rejenerasyon Artan risk HBV HCV Alkol Metabolik hastalıklar - NASH - Hemokromatozis As discussed in previous slides, the etiology of HCC is diverse and HCC generally develops in preneoplastic cirrhotic livers.1-5 Cirrhosis is a major risk factor for HCC, and often presents as a preneoplastic liver, frequently containing dysplastic lesions indicative of early HCC.4 The etiology of HCC is heterogeneous worldwide reflecting different underlying epidemiologic backgrounds and environmental risk factors.1 HBV and HCV infections are the main risk factors for patients with HCC.1 Excessive alcohol intake and metabolic disorders such as nonalcoholic steatohepatitis (NASH) and hemochromatosis also contribute to the development of HCC.4-6 The transformation of hepatocytes to the malignant phenotype can occur through a pathway of chronic liver injury and rapid proliferation and regeneration.4,5 ADDITIONAL INFORMATION Eighty percent of patients with HCC also have a cirrhotic liver.1 Chronic liver injury can lead to an increase in hepatocellular proliferation, with an accompanying increase in DNA synthesis and an increased mitosis rate that can lead to an elevated risk for malignancy or genetic alterations.3,5 1. Rivenbark AG, et al. Clin Cancer Res. 2007;13:2309-2312; 2. Marotta F, et al. Clin Ther. 2004;155:187-199; 3. Thorgeirsson S, et al. Nat Genet. 2002;31:339-346; 4. Wang XW, et al. Toxicology. 2002;181-182:43-47; 5. Koike K. Hepatol Res. 2005;33:145-150. Llovet JM. Updated treatment approach to hepatocellular carcinoma. J Gastroenterol. 2005;40:225-235. Marotta F, Vangieri B, Cecere A, Gattoni A. The pathogenesis of hepatocellular carcinoma is a multifactorial event: novel immunological treatment in prospect. Clin Ther. 2004;155(5):187-199. Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet. 2002;31:339-346. Rivenbark AG, Coleman WB. The use of epigenetic biomarkers for preclinical detection of hepatocellular carcinoma: potential for noninvasive screening of high-risk populations. Clin Cancer Res. 2007;13:2309-2312. Wang XW, Hussain SP, Huo TI, et al. Molecular pathogenesis of human hepatocellular carcinoma. Toxicology. 2002;181-182:43-47. Koike K. Hepatitis C as a metabolic disease: implication for the pathogenesis of NASH. Hepatol Res. 2005;33:145-150.

HSK etiyolojisinde değişim 1991-2008 yılları arasında HCV’ye bağlı HSK’da ~ %50 artış Others: 38% HBV:10% NAFLD:7% Alcohol alone: 45% 1976-1990 Others: 46% HBV: 4% Alcohol alone: 25% Alcohol and HCV: 7% HCV alone: 18% 1991-2000 Others: 21% NAFLD: 11% Alcohol alone: 19% Alcohol and HCV: 17% HCV alone: 28% 2001-2008 HBV, hepatitis B virus; HCB, hepatitis C virus; NAFLD, nonalcoholic fatty liver disease. Yang JD, et al. Mayo Clin Proc. 2012;87:9-16.

HSK’de kötü prognoz nedenleri Siroz ve siroz etkenin geç tespiti Sessiz seyir Multiple odaklı olması Vasküler invazyon özelliği Hem lenfatik hem de vasküler yayılım özelliği

Evreye göre sağkalım: VCU/McGuire VA Deneyimi, 1997-2005 Sağkalım tanı anındaki evre ile kuvvetli ilişkili Erken tanı prognozu geliştirebilir II III IV I 0.2 0.6 0.4 0.8 1.0 1 2 3 4 5 Yrs Sağkalım Stravitz RT, et al. Am J Med. 2008;121:119-126.

HSK’De Ultrason taraması: Sistematik Derleme Study Sensitivity (95% CI) % Weight Pateron 1994 0.58 (0.37-0.84) 6.45 Kobayashi 1985 0.40 (0.31-0.78) 5.10 Arrigoni 1988 0.69 (0.49-0.89) 9.60 Oka 1990 0.68 (0.54-0.81) 11.56 Cottone 1994 0.87 (0.77-0.96) 12.81 Zoli 1996 0.91 (0.84-0.98) 13.41 Tradati 1998 0.33 (-0.11 to 0.78) 4.30 Henrion 2000 0.67 (0.38-0.96) 7.16 Bolondi 2001 0.82 (0.73-0.91) 13.03 Tong 2001 0.58 (0.41-0.75) 10.47 Santa 2003 0.25 (0.62-0.82) 4.93 Subtotal 0.63 (0.52-0.82) 87.27 AFP, alpha-fetoprotein. 0 1.0 (I2 = 76.7%; P < .0001) AFP takibi tanıda %70 iyileşme sağlar Takip süresi: 6 ay 12 aydan daha üstündür Singal A, et al. Aliment Pharmacol Ther. 2009;30:37-47.

HSK Taraması/takibi: kılavuzlar Kimler: Siroz ve HBV enfeksiyonu olanlar Nasıl: VA ve NCCN: AFP ve USG 6-12 ay AASLD ve EASL: 6 ayda bir USG inceleme NCI ve USPHS Task Force HSK için takip ve tarama önermemektedir Çünkü: Sirozlu hastalarda yararı gösterilememiştir Maliyet, risk Bu konuda prospektif randomize çalışmalara ihtiyaç vardır

HSK tanısında biyopsi gerekli mi? Evet Positif biopsi ile Kesin tanı Prognostik bilgi Uygunsuz tedavi önlenir Deneysel veya yeni tedaviler için gereklidir Translational araştırma ve bireysel tedaviler ve tümör genetik profilleme için gereklidir Hayır Mümkün olmayabilir Radyolojik tanı yeterlidir Risk Hemoraji Ekilim (%2-3) Yetersiz biyopsi örneği veya false (-) sonuç tedaviyi geciktirebilir (%30) Heuman DM, et al. Eur J Intern Med. 2012;23:37-39.

Evrelendirme Hastalık prognozu ve tedavi seciminde önemlidir Anatomical extent of tumor (stage) Biological aggressiveness (grade) Cirrhosis severity and functional status Evrelendirme yöntemleri Görüntüleme Multifazik BT/MRI Toraks ve abdomen Kemik sintigrafisi PET

Anatomik Evrelendirme: TNM Tek tümor < 2 cm II 1 tümor 2-5 cm veya 2 vey 3 tümor, En büyük < 3 cm III 1 tümor > 5 cm veya 2 veya 3 tümor, En büyük > 3 cm IV 4 veya daha fazla intrahepatik tümör veya vasküler invazyon veya ekstrahepatik metastaz Goodman J, et al. Arch Surg. 2005;140:459-464.

AASLD Diagnostic Criteria for HCC Mass on surveillance US or high AFP in a cirrhotic liver > 2 cm 1 dynamic imaging technique < 1 cm Repeat US every 3-4 mos 1-2 cm 1 dynamic imaging study Typical vascular pattern Atypical vascular pattern with both techniques Atypical vascular pattern Typical vascular pattern on dynamic imaging Stable > 18-24 mos Enlarging Biopsy Diagnostic of HCC Nondiagnostic of HCC Other diagnosis Return to surveillance every 6-12 mos Repeat biopsy or imaging follow-up AFP, alpha-fetoprotein. http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf Proceed according to lesion size Change in size/profile + Repeat imaging and/or biopsy - Treat as HCC Adapted from Bruix J, et al. Hepatology. 2011;53:1020-1022.

Child-Pugh sınıflandırması Measure 1 Point 2 Points 3 Points Bilirubin, mg/dL < 2.0 2.0-3.0 > 3.0 Albumin, g/dL > 3.5 2.8-3.5 < 2.8 Prothrombin time, sec < 4.0 4.0-6.0 > 6.0 Ascites None Slight Moderate Encephalopathy, grade I-II III-IV Grade Total Points Surgical Risk 2-Yr Survival, % A (well-compensated disease) 1-6 Good 85 B (significant functional compromise) 7-9 Moderate 60 C (decompensated disease) 10-15 Poor 35 Hepatic function assessed often using the Child‑Pugh score. First developed to predict surgical mortality, the Child-Pugh scoring system was unique in stratifying the severity of end-stage liver disease based on 5 liver function parameters. However, the Child-Pugh scoring system does not include any parameters pertaining to the cancer itself. Pugh RN, et al. Br J Surg. 1973;60:646-649. Lucey MR, et al. Liver Transpl Surg. 1997;3:628-637.

BCLC Staging and Treatment Strategy HCC PS 0, Child-Pugh A Okuda 1-2, PS 0-2, Child-Pugh A-B Okuda 3, PS > 2, Child-Pugh C Very early stage (0) Single < 2 cm Carcinoma in situ 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) Single 3 nodules ≤ 3 cm Portal pressure/bilirubin Increased Associated diseases BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; PEI, percutaneous ethanol injection; PS, performance score; RCT, randomized controlled trial; RFA, radiofrequency ablation; TACE, transarterial chemoembolization.   Josep M. Llovet, MD: With appropriate use of resection, transplantation, and local ablation, 5-year survival rates > 50% can be expected, rising to 70% with resection and liver transplantation. However, these treatments are currently considered in approximately 30% of patients in the West and even fewer patients worldwide. For example, in Asia, only 5% to 10% of patients receive potentially curative therapies. Jorge A. Marrero, MD, MS: How does one choose between radiofrequency ablation and resection, given that there are data from a randomized trial showing no difference in overall survival between the 2 strategies? If the tumor is < 2 cm in diameter, radiofrequency ablation can achieve a complete response rate of up to 98%, which is comparable with resection. In tumors of this size, the decision of whether to apply radiofrequency ablation rather than resection may depend on local availability of a hepatobiliary team with experience in resecting tumors or, conversely, access to an interventional radiologist able to perform local ablation with high accuracy. For tumors > 2 cm in diameter, in my experience, local ablation does not achieve a complete response rate of 100%, and as the tumor size increases, the response rate decreases, such that for a tumor of 4-5 cm in diameter, radiofrequency ablation achieves complete response in approximately 50% to 60% of cases. This does not compete well with resection. Therefore, resection remains a first-line treatment option for tumors > 2 cm in diameter. For very small tumors of < 2 cm, there is a question about which approach is optimal, and local expertise should factor in the decision. Normal No Yes Resection Liver transplantation RFA/PEI TACE Sorafenib Symptomatic (20%); survival < 3 mos Curative treatments (30%); 5-yr survival: 40%-70% RCTs (50%); 3-yr survival: 10%-40% Llovet JM, et al. Journal of the National Cancer Institute. 2008;100:698-711. 27

Kötü prognostik faktörler: Agresif HSK Özellikler Mikrovaskuler invazyon Satellit nodüller Diffüz infiltratif büyüme Az/kötü differensiyasyon MixedKolanjiokanser Kötü moleküler imza FDG-PET pozitifliği Yüksek AFP ve AFP-L3% Hızlı Büyüme Klinik olarak Erken metastaz Multisentrisite? Yüksek rekürrens oranı Postop veya post transplant RFA/TACE ile lokal kontrol yetersizliği Kötü prognoz Tümör biyolojisi evrelendirme sistemine nasıl entegre edilebilir ?

Performans durumu ve Siroz şiddeti BCLC staging system combines anatomic extent of disease with severity of liver failure (CTP class) and functional status Patients with poor functional status or decompensated cirrhosis are stage D regardless of anatomical stage BCLC stage D has poorest survival and few treatment options B A D C 20 60 40 80 100 10 30 50 Mos Survival Probability 70 Log-Rank P Value A vs B: < .0001 B vs C: .04 C vs D: .01 Functional Status (performans durumu) Fully active, normal life; no symptoms 1 Minor symptoms; able to do light activity 2 Capable of self-care but unable to carry out work activities; up for more than 50% waking hrs 3 Limited self-care capacity; confined to bed or chair 50% waking hrs 4 Completely disabled; confined to bed or chair Pts at Risk, n Stage A 64 51 25 8 Stage B 60 22 11 4 Stage C 76 10 3 1 Stage D 39 7 1 0 Marrero JA, et al. Hepatology. 2005;41:707-716.

HSK’de tedavi seçenekleri Küratif (Evre I-II) Thermal ablation (radiofrequency, microwave) Resection (partial hepatectomy) Liver transplantation (total hepatectomy) Palyatif (Evre III-IV) Transarterial therapies Targeted therapy (sorafenib) Kemoterapi

Prognozu ve tedavi seçimini etkileyen faktörler Anatomik evre Biyolojik grad Siroz derecesi Performans durumu

HSK: Moleküler Patogenez Hepatokarsinogenezde çeşitli mekanizmalar rol oynamaktadır1,2 Hepatosit transformasyonu inflamasyon, rejenerasyon, hiperplazi, siroz ve genetik değişiklikler zemininde oluşur Sinyal ileti yollarının regülasyonu HSK’da sıklıkla bozulmaktadır1,2: Bozulmuş sinyal ileti yolları:1,2 Anjiogenik sinyaller Ras/Raf/MEK/ERK PI3K/Akt/mTOR Wnt/β-catenin Moleküler tedavide kilit hedefler It well-established that the alteration of numerous signaling pathways leading to autonomous and dysregulated cell proliferation and resistance to cell death in HCC include the angiogenic signaling pathways, the PI3K/Akt/mTOR, the Ras/Raf/MEK/ERK, and the wnt/β-catenin pathways.1,2 Further understanding of these pathogenetic mechanisms for HCC can lead to the identification of new targets for use in the molecular therapy of HCC.2 PI3K = phosphoinositid 3-kinaz; Akt = protein kinaz B; mTOR = mammalian target of rapamycin; Raf = serine-threonine protein kinaz (c-Raf); Ras = small GTPase; MEK = mitogen-activated protein kinaz; ERK = extracellular signal-regulated kinaz; Wnt = secreted signaling protein. 1. Thorgeirsson S, et al. Hepatology. 2006;43:S145-150. 2. Avila MA, et al. Oncogene. 2006;25:3866-3884. 1. Thorgeirsson S, Lee JS, Grisham JW. Functional genomics in hepatocellular carcinoma. Hepatology. 2006;43:S145-150. 2. Avila MA, Berasain C, Sangro B, Prieto J. New therapies for hepatocellular carcinoma. Oncogene. 2006;25:3866-3884.

Apoptosiz Inhibisyonu Apopitosiz Inhibisyonu Multi-kinaz inhibisyonu Tümör hücresi Endotel yada perisit PDGF-β VEGF Parakrin stimulason PDGFR-β VEGFR-2 KIT/Flt-3/ RET Ras Ras Raf Raf MEK Apoptosiz Inhibisyonu MEK Apopitosiz Inhibisyonu ERK ERK Proliferasyon PDGF VEGF EGF Hücre döngüsü Nukleus Nukleus Anjiiogenez PDGF VEGF Sorafenib etki yeri Sorafenib etkisinin sonucu

HSK’de Sorafenib Sorafenib Placebo P < .001 Time to Radiologic Progression Mos Since Randomization 1 2 3 4 5 6 7 8 9 10 11 12 1.00 0.75 0.50 0.25 Probability of Radiologic Progression 299 267 155 101 91 65 37 23 18 303 275 142 78 62 41 21 Pts at Risk, n Prior to 2007, no therapy was of benefit in advanced HCC SHARP trial: CTP A patients with advanced HCC randomized to sorafenib 400 BID vs placebo Sorafenib delayed progression and prolonged survival from 7.9 to 10.7 mos Led to approval by the FDA in 2008 for palliation of advanced-stage HCC It remains the only approved systemic therapy for HCC Sorafenib Placebo P < .001 OS Mos Since Randomization 1.00 0.75 0.50 0.25 Probability of Survival Pts at Risk. n 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 299 290 270 249 234 213 200 172 140 111 89 68 48 37 24 303 295 272 243 217 189 174 143 108 83 69 47 31 23 Llovet J, et al. N Engl J Med. 2008;359:378-390.

Sorafenib Ötesi: HSK’de yeni ajanlar Agent Molecular Targets Phase Response, % Median OS, Mos Median TTP, Median PFS, Safety: Grade 3-4 AEs, % Doxorubicin ± sorafenib[1] II PR: 4.0 13.7 6.4 6.0 Fatigue (6) Hand–foot skin reaction (6.4) Sunitinib[2] VEGFR, PDGFR, FLT3, KIT, RET III CR+PR: <7 7.9 4.1 3.6 Significant toxicities; discontinued Brivanib[3] VEGFR, FGFR ORR: 4.3 9.8 1.8 2.0 HTN (7.3) Diarrhea (6.5) Headache (4.3) Linifanib (ABT-869)[4] VEGFR, PDGFR ORR: 6.8 9.7 3.7 NR HTN (18) Fatigue (14) Cabozantinib (XL184)[5] c-MET, VEGFR2 PR: 9.0 4.2 Hand-foot syndrome (15) Diarrhea(9) TP (9) Tivantinib (ARQ197)[6] c-MET MET high: 7.2 MET high: 2.9 MET high: 2.4 Neutropenic sepsis (4.2) HTN, hypertension; NR; not reported; OS, overall survival; PFS, progression-free survival; TTP, time to progression; PPE, palmar-plantar erythrodysesthesia; TP, thrombocytopenia 1. Abou-Alfa GK, et al. JAMA. 2010;304:2154-2160. 2. Cheng A, et al. ASCO 2011. Abstract 4000. 3. Finn RS, et al. Clin Cancer Res. 2012;18:2090-2098. 4. Toh H, et al. ASCO 2010. Abstract 4038. 5. Cohn AL, et al. ASCO GI. 2012. Abstract 261. 6. Rimassa, L, et al. ASCO 2012. Abstract 4006.

Bevacizumab + Erlotinib: Faz II çalışma (N = 58) 1.0 Genel Sağkalım Progresyonsuz sağkalımF 0.9 Proportion of Patients 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Data from Oncology 2012 Kaseb et al 0.1 10 20 30 40 Mos Kaseb AO, et al. Oncology. 2012;82:67-74.

Bevacizumab-tabanlı tedavi rejimleri Regimen Study n Response Rate, % Median PFS/TTP, Mos 6-Mo PFS, % Median Survival, Mos Single agent Siegel[1] 46 ORR: 13 6.9 65 12.4 Malka[2] 24 PR: 12.5 SD: 54 NR + GEMOX Zhu[3] 30 PR: 20 SD: 27 5.3 48 9.6 + Capecitabine and oxaliplatin Sun[4] PR: 11 SD: 78 5.4 40 + Capecitabine Hsu[5] 25 ORR: 16 DCR: 60 4.1 34 10.7 + Erlotinib Kaseb[6] 59 ORR: 24 7.2 64 (at 4 mos) 13.7 DCR, disease control rate; NR, not reported; ORR, objective response rate; PFS, progression-free survival; PR, partial response; SD, stable disease. 1. Siegel AB, et al. J Clin Oncol. 2008;26:2992-2998. 2. Malka D, et al. ASCO 2007. Abstract 4570. 3. Zhu AX, et al. J Clin Oncol. 2006;24:1898-1903. 4. Sun W, et al. ASCO 2007. Abstract 4574. 5. Hsu C, et al. ASCO 2007. Abstract 15190. 6. Kaseb AO, et al. Oncology. 2012;82:67-74.

Cabozantinib (XL184) Target Profile Kinase IC50 (nM) MET 1.8 VEGFR2 0.035 RET 5.2 KIT 4.6 AXL 7.0 TIE2 14 FLT3 S/T Ks (47) > 200 RTK Cellular IC50 (nM) Autophosphorylation MET 8 VEGFR2 4 ATP competitive, reversible Yakes FM, et al. Mol Cancer Ther. 2011;10:2298-308.

HCC Cohort Effects on Measurable Lesions per Original RECIST (N = 27)* 20 40 60 - 60 - 40 - 20 - 80 Previous sorafenib No previous sorafenib ‡ ‡ ‡ ‡ † % Change From Baseline § AFP, alpha-fetoprotein; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors. Poster with original figures: http://www.exelixis.com/sites/default/files/GI_2012-Cohn_ASCO-poster.pdf 9 of 16 pts with AFP ≥ 20 ng/mL at baseline had reductions in AFP of >50% 47% of all HCC pts were on study treatment for > 6 mos (N = 30) *Best time point response by RECIST 1.0 in patients with ≥ 1 postbaseline tumor assessment. †0% change from baseline. ‡Confirmed PRs. §PR confirmed in randomized stage. Cohn AL, et al. ASCO GI 2012. Abstract 261.

Tivantinib (ARQ 197): Target MET in HCC Only known receptor for hepatocyte growth factor Correlated with poor prognosis Tivantinib Selective oral MET inhibitor

Tivantinib vs Placebo in Previously Treated Unresectable HCC Multicenter, randomized phase II trial Primary endpoint: TTP Stratification: MET status, HBV vs HCV, and duration of previous therapy Crossover on PD Tivantinib 360 mg PO BID (n = 38) Patients with unresectable HCC following failure of 1 systemic therapy, ECOG PS < 2 (N = 107) Tivantinib 240 mg PO BID (n = 33) Placebo PO BID (n = 36) BID, twice daily; DCR, disease control rate; ECOG PS, Eastern Cooperative Oncology Group performance score; HCC, hepatocellular carcinoma; PFS, progression-free survival; PO, orally; OS, overall survival; TTP, time to progression. Tivantinib has also been tested in other tumor types. For example, several presentations at the 2012 annual meeting of the American Society of Clinical Oncology focused on the use of tivantinib in hepatocellular carcinoma. Rimassa and colleagues[21] conducted a multicenter, randomized phase II trial of tivantinib compared with placebo in patients (N = 107) with unresectable hepatocellular carcinoma who had failed 1 systemic therapy and had a good Eastern Cooperative Oncology Group performance score. Patients were randomly assigned to receive a high dose of tivantinib at 360 mg orally twice daily or 240 mg orally twice daily or a placebo. The primary endpoint was time to progression, and the secondary endpoints included the disease-control rate, PFS, and OS. 21. Rimassa L, Porta C, Borbath I, et al. Tivantinib (ARQ 197) versus placebo in patients (Pts) with hepatocellular carcinoma (HCC) who failed one systemic therapy: results of a randomized controlled phase II trial (RCT). Program and abstracts of the 2012 Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, Illinois. Abstract 4006. Rimassa L, et al. ASCO 2012. Abstract 4006.

Tivantinib vs Placebo in Previously Treated Unresectable HCC: TTP MET level predictive of tivantinib benefit: TTP and OS similar with tivantinib vs placebo among patients with low MET expression ITT MET Diagnostic High Population 1.0 Median TTP 6.9 wks 6.0 wks Patients 71 36 Events 46 30 1.0 Median TTP 11.7 wks 6.1 wks Patients 22 15 Events 14 13 Tivantinib Placebo Tivantinib Placebo 0.8 0.8 HR: 0.43 (95% CI: 0.19-0.97; log-rank P = .03) 0.6 HR: 0.64 (90% CI: 0.43-0.94; log-rank P = .04) Proportion of Patients Progression Free Proportion of Patients Progression Free 0.6 0.4 0.4 0.2 0.2 10 20 30 40 50 60 10 20 30 40 Wks to Tumor Progression Wks to Tumor Progression 1.0 Median TTP 6.6 wks 6.2 wks Patients 71 38 Events 56 30 1.0 Median TTP 7.2 wks 3.8 wks Patients 22 15 Events 17 15 Tivantinib Placebo Tivantinib Placebo 0.8 HCC, hepatocellular carcinoma; OS, overall survival; TTP, time to progression. The MET level (by IHC) was predictive of benefit from tivantinib in both the intent-to-treat population and patients with high MET expression.[22] In studies of onartuzumab in NSCLC, MET-high patients responded better than MET-low patients, and these results with tivantinib in hepatocellular carcinoma appear to be quite similar. That is, the time to progression and median OS were similar with tivantinib vs placebo among patients with low MET expression but significantly different in those with high MET expression. Regarding adverse events, tivantinib is a well-tolerated agent overall, but there are effects, especially at the higher dose of 360 mg twice daily, where more grade 3-5 neutropenia has been reported (21% vs 6% with 240 mg twice daily). Other adverse events were less common. 22. Rimassa L, Porta C, Borbath I, et al. Tivantinib (ARQ 197) versus placebo in patients (Pts) with hepatocellular carcinoma (HCC) who failed one systemic therapy: results of a randomized controlled phase II trial (RCT). Program and abstracts of the 2012 Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, Illinois. Abstract 4006. 0.8 0.6 HR: 0.90 (90% CI: 0.57-1.40; log-rank P = .63) Proportion of Patients Surviving Proportion of Patients Surviving 0.6 HR: 0.38 (90% CI: 0.18-0.81; log-rank P = .01) 0.4 0.4 0.2 0.2 5 10 15 20 25 5 10 15 20 Wks From Date of Randomization Mos From Date of Randomization Rimassa L, et al. ASCO 2012. Abstract 4006.

Sorafenib as adjuvant to resection/ablation in early HCC 8 weeks Prior treatment Resection RFA PEI Randomization 1:1 (double-blind RCT) Stratification Prior curative treatment Geographical region Child–Pugh status Endpoints Recurrence-free survival Time to recurrence Overall survival Biomarkers Sorafenib 400 mg bid Placebo Prospective, randomized, double-blind, placebo-controlled, company-sponsored, Phase III study Primary endpoint: recurrence-free survival Patients: n = 1100 (randomized) Enrolment completed http://clinicaltrials.gov/ct2/show/NCT00692770.

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