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Sorafenib in Advanced Hepatocellular Carcinoma

Sorafenib in Advanced Hepatocellular Carcinoma. 報告地點：萬芳醫院 報告時間： 2009/11/6 報 告 者：和信醫院 李建勳 藥師 指導藥師：. Five A ’ s. Assess ：了解臨床的需求（ Clinical Problem ） Ask ：發現問題的所在（ Question ） Acquire ：找尋最好的資料（ Best Evidence ） Appraise ：分析資料（ Validity, Importance ） Apply ：應用在病人身上（ Patient ）.

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Sorafenib in Advanced Hepatocellular Carcinoma

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  1. Sorafenib in Advanced Hepatocellular Carcinoma 報告地點：萬芳醫院 報告時間：2009/11/6 報 告 者：和信醫院 李建勳 藥師 指導藥師：

  2. Five A’s • Assess：了解臨床的需求（Clinical Problem） • Ask ：發現問題的所在（Question） • Acquire ：找尋最好的資料（Best Evidence） • Appraise ：分析資料（Validity, Importance） • Apply ：應用在病人身上（Patient）

  3. Clinical Situation • Mr. Cheng is a 60 year old male patient. He was diagnosed as hepatitis B and C virus infection related hepatocellular carcinoma (HCC) on 2003. • He has received radiotherapy during 2003/1/24~3/6, transarterial chemoembolization (TACE) during 2006/3/4~2007/12/4, computer tomography-guided radiofrequency ablation (RFA) on 2008/8/5. • In 2009 April, abdominal sonography showed that HCC progress to retroperitoneal lymph nodes, which is suspected extrahepatic seeding tumor between abdominal wall and right lobe liver. At that time, the lab data showed elevated alpha-fetoprotein (AFP) 93.46 ng/mL. • At that time, the doctor considered sorafenib 400mg PO BID for this patient. Is sorafenib effective for this patient?

  4. Five A’s • Assess：了解臨床的需求（Clinical Problem） • Ask ：發現問題的所在（Question） • Acquire ：找尋最好的資料（Best Evidence） • Appraise ：分析資料（Validity, Importance） • Apply ：應用在病人身上（Patient）

  5. 臨床問題的種類 • 背景問題（Background Questions）：對疾病的基本認識 • 5W1H：Who, Where, What, When, How, Why • 疾病的某一面向 • 前景問題（Foreground Questions）：對病人的特定問題 • 處理某疾病病人的特定問題 • 每個病人有不同的特性：年齡、性別、伴隨疾病與疾病嚴重程度等

  6. Epidemiology • 肝癌是全球排名第五位的癌症，每年約有五十萬至一百萬的新病例。 • 肝癌更是死亡率第三位的癌症，全球每年約有六十萬人死於肝癌。 • 全球肝癌的盛行率有地理分佈的差異，低盛行區如北美和中美洲等，其盛行率約每10萬人口3-4 人；而亞太地區屬於肝癌高盛行區，盛行率高達每10萬人口30-40 人。 • 西元 2000 年全球肝癌患者，亞洲地區高達44 萬人，而北美地區只有1萬 2仟人，全球肝癌患者約 75%集中於亞洲地區。 • 肝癌為台灣 10 大癌症發生率的第二位，每10萬人口發生率男性約 26人、女性約8人，男女比例約 3:1。 林志陵, 高嘉宏. 肝癌的流行病學. 中華癌醫會誌. 2008; 24(5): 277-281

  7. Liver cirrhosis Hepatitis B Virus Hepatitis C Virus Alcohol Cigarette smoking Betel nut Afaltoxin Obesity Fatty liver Non-alcohol steatohepatitis (NASH) Diabetes Hereditary tyrosinemia Hepatic porphyria Genetic hemochromatosis α1 antitrypsin deficiency Risk Factors 林志陵, 高嘉宏. 肝癌的流行病學. 中華癌醫會誌. 2008; 24(5): 277-281

  8. Common Symptoms Abdominal pain Weight loss Weakness Fullness and anorexia Abdominal Swelling Jaundice Vomiting Common Physical Sign Hepatomegaly Hepatic bruit Ascites Splenomegaly Jaundice Wasting Fever Clinical Features DeVita VT, et al. Devita, Hellman & Rosenberg’s Cancer: Principles & Practice of Oncology, 8th Edition

  9. Diagnosis • Radiology • X-ray • Sonography • Computed tomography (CT) • Magnetic resonance imaging (MRI) • Biopsy • Alpha-fetoprotein (AFP) Serology DeVita VT, et al. Devita, Hellman & Rosenberg’s Cancer: Principles & Practice of Oncology, 8th Edition

  10. Surgery Partial hepatectomy Liver transplantation Local Ablative Therapy Cryosurgery Microwave ablation Ethanol injection Acetic acid injection Radiofrequecy ablation (RFA) Regional Therapy (hepatic artery transcatheter treatments) Transarterial chemotherapy Transarterial embolization (TAE) Transarterial chemoembolization (TACE) Transarterial radiotherapy 90Y microspheres 131I lipiodol Conformal external-beam radiation therapy Systemic Therapy Treatment Option DeVita VT, et al. Devita, Hellman & Rosenberg’s Cancer: Principles & Practice of Oncology, 8th Edition

  11. Staging System in HCC • 除了腫瘤侵犯程度外，需考慮肝臟存留機能 • 病理報告取得不易，臨床分期應用廣泛 • 依應用目的區分預後的預測與治療方法的選擇

  12. Staging System • Prognosis • TNM • Okuda • CLIP (Cancer of the Liver Italian Program) • JIS (Japanese Integrated Score) • Treatment • BCLC (Barcelona Clinic Liver Cancer)

  13. Staging System – TNM 盧勝男, 顏毅豪, 林芷芸等. 肝細胞癌之臨床分期.中華癌醫會誌. 2008; 24(5): 295-303

  14. Staging System – Okuda

  15. Staging System – CLIP CLIP: Cancer of the Liver Italian Program

  16. Staging System – JIS JIS: Japanese Integrated Score

  17. Staging System – BCLC BCLC: Barcelona Clinic Liver Cancer Bruix J and Sherman M. Hepatology 2005; 42(5): 1208-1236

  18. Treatment Guideline – JSH JSH: Japan Society of Hepatology; TAI: transcatheter arterial infusion chemotherapy，也稱作hepatic arterial infusion (HAI) Kudo M. Oncology 2007; 72(supp1): 2-15

  19. 臨床問題的種類 • 背景問題（Background Questions）：對疾病的基本認識 • 5W1H：Who, Where, What, When, How, Why • 疾病的某一面向 • 前景問題（Foreground Questions）：對病人的特定問題 • 處理某疾病病人的特定問題 • 每個病人有不同的特性：年齡、性別、伴隨疾病與疾病嚴重程度等

  20. P. I. C. O.

  21. Five A’s • Assess：了解臨床的需求（Clinical Problem） • Ask ：發現問題的所在（Question） • Acquire ：找尋最好的資料（Best Evidence） • Appraise ：分析資料（Validity, Importance） • Apply ：應用在病人身上（Patient）

  22. Five A’s • Assess：了解臨床的需求（Clinical Problem） • Ask ：發現問題的所在（Question） • Acquire ：找尋最好的資料（Best Evidence） • Appraise ：分析資料（Validity, Importance） • Apply ：應用在病人身上（Patient）

  23. Sorafenib in Advanced Hepatocellular Carcinoma N Engl J Med 2008; 359: 378-90 Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, et al.

  24. Study Design • Study Design: Randomized, double-blinded, placebo-controlled trial • Study Place: 121 centers in 21 countries in Europe, North America, South America, and Australia • Intervention: sorafenib 400mg BID or placebo • Inclusion Criteria: • Advanced HCC, confirmed by pathological analysis • ECOG performance status of 2 or less • Child-Pugh liver function class A • Adequate hematological (PLT, Hb), hepatic (Alb, Bil-T, GOT, GPT), and renal function (sCr) • Exclusion Criteria: • Previously received molecularly targeted therapy or systemic treatment

  25. Outcome Assessment • The Primary Outcome • Overall Survival • Time to Symptomatic Progression: FHSI8↓4, ECOG progress to 4, or death • The Secondary Outcome • Time to Radiological Progression: by RECIST • The Disease-control Rate: CR+PR+SD • Safety FHSI8 Questionnaire：用以評估HCC病人症狀的嚴重程度 CR: complete response; PR: partial response; SD: stable disease

  26. Enrollment & Outcome 902 Patients were screened 300 were excluded 244 had protocol exclusion criteria 24 withdrew consent 15 had an adverse event 11 died 6 were lost to folloe-up 602 underwent randomization 299 were assigned to receive sorafenib (intention-to-treat population) 303 were assigned to receive placebo (intention-to-treat population) 1 had an adverse event 1 had a protocol violation 1 had a protocol violation 302 received placebo (safety population) 297 received sorafenib (safety population) 226 Discontinued sorfenib 86 had an adverse event 61 had radiologic and symptomatic progression 28 withdrew consent 3 died 1 had ECOG score of 4 47 had other reason 242 Discontinued placebo 90 had an adverse event 62 had radiologic and symptomatic progression 25 withdrew consent 7 died 6 had ECOG score of 4 52 had other reason 71 included in the ongoing study 60 included in the ongoing study Llovet JM, et al. New Engl J Med 2008; 359: 378-90

  27. Demographic & Baseline Profile

  28. Validity 可信度 • 本篇研究病人分配是否隨機？是 隨機分配是否對研究人員保密？是 • 本篇研究隨機分配後的病人是否都被納入分析？是 • 在接受治療當中，病人與醫療人員是否雙盲？是 • 除了要比較的治療外，兩組病人是否都被同等對待？是 • 一開始分配的兩組條件是否相同？是

  29. Summary of Efficacy Measurement Llovet JM, et al. New Engl J Med 2008; 359: 378-90

  30. Llovet JM, et al. New Engl J Med 2008; 359: 378-90

  31. 副作用 NNT (Number Need to Treat) or NNH (Number Need to Harm): 在一段實驗期間內，使一位病人達到實驗組治療之有益結果（或不良反應）所需治療的病人數目。

  32. 副作用 NNT (Number Need to Treat) or NNH (Number Need to Harm): 在一段實驗期間內，使一位病人達到實驗組治療之有益結果（或不良反應）所需治療的病人數目。

  33. Efficacy and Safety of Sorafenib in Patients in The Asia-Pacific Region With Advanced Hepatocellular Carcinoma: A Phase III Randomized, Double-blind, Placebo-Controlled Trial Lancet Oncol 2009; 10: 25-34 Cheng AL, Kang YK, Chen ZD, Tsao CJ, Qin SK, et al.

  34. Enrollment & Outcome 271 Patients were screened 45 Not randomized 3 had an adverse event 4 withdrew 1 lost to follow-up 37 protocol exclusion criteria 226 underwent randomization 150 were assigned to receive sorafenib (intention-to-treat population) 76 were assigned to receive placebo (intention-to-treat population) 1 had a protocol violation 1 excluded due to adverse event 75 received placebo (safety population) 149 received sorafenib (safety population) 129 Discontinued sorfenib 69 had disease progresson 22 had adverse events 23 withdrew consent 12 died 2 lost to follow-up 1 non-compliant to treatment 72 Discontinued placebo 48 had disease progression 7 had adverse events 11 withdrew consent 2 died 3 lost to follow-up 1 protocol violation 20 included in the ongoing study 3 included in the ongoing study Cheng AL, et al. Lancet Oncol 2009; 10: 25-34

  35. Demographic & Baseline Pofile

  36. Validity 可信度 • 本篇研究病人分配是否隨機？是 隨機分配是否對研究人員保密？是 • 本篇研究隨機分配後的病人是否都被納入分析？是 • 在接受治療當中，病人與醫療人員是否雙盲？是 • 除了要比較的治療外，兩組病人是否都被同等對待？是 • 一開始分配的兩組條件是否相同？是

  37. Summary of Efficacy Measurement

  38. Summary of Efficacy Measurement

  39. 副作用 NNT (Number Need to Treat) or NNH (Number Need to Harm): 在一段實驗期間內，使一位病人達到實驗組治療之有益結果（或不良反應）所需治療的病人數目。

  40. 副作用 NNT (Number Need to Treat) or NNH (Number Need to Harm): 在一段實驗期間內，使一位病人達到實驗組治療之有益結果（或不良反應）所需治療的病人數目。

  41. Comparison Between 2 RCTS Comment by Cheng AL. et al: More advanced disease (extrahepatic spread, number of tumor, ECOG PS, alpha-feroprotein (AFP) level)

  42. Sorafenib in HCC Treatment

  43. Five A’s • Assess：了解臨床的需求（Clinical Problem） • Ask ：發現問題的所在（Question） • Acquire ：找尋最好的資料（Best Evidence） • Appraise ：分析資料（Validity, Importance） • Apply ：應用在病人身上（Patient）

  44. Practicability • 目前Sorafenib (Nexavar®)在本院為臨採品項，健保給付規範如下：1. 晚期腎細胞癌且已接受interferon-alpha或 interleukin-2治療失敗，或不適合以上兩種藥物治療之病患。2.無效後則不給付temsirolimus及其他酪胺酸激酶阻斷劑（tyrosine kinase inhibitor, TKI）3.需經事前審查核准後使用，每次申請之療程以 3個月為限，送審時需檢送影像資料，每3個月評估一次 (98/10/1) 。病人需自費購買，自費價為一錠1387元，一天5547元。 • 研究結論應用在此病人時無已知可能的限制：根據病歷所記載資料，Child-Pugh A-B(未知腹水與腦病變程度)，BCLC Stage C (advanced stage)，亞洲人種，HBV/HCV-related HCC，大致符合臨床試驗收案條件。 • 依據鄭安理教授等人之亞太地區大型第三期臨床試驗的結果，我們預期此病人透過治療存活時間可延長2.3個月，但發生Grade 3/4的手足症候群、腹瀉的NNH分別為9和24。

  45. Clinical Effectiveness & Safety • 5/1：watery diarrhea 6~7 times on day 1, muscle soreness, arthritis, chest wall pain after cough, loss of appetite, hand-foot skin reaction • 5/8：hand-foot skin reaction & Gr 2-3 bullae at bilateral feet • 5/15：hand-foot skin reaction & Gr 2-3 bullae at bilateral feet, skin rash at face and leg • 5/22：Gr 2 hand-foot skin reaction, skin rash at face and leg↓ • 5/29：Gr 2 hand-foot skin reaction, skin rash at face and leg↓, hot flash, hypertension • 6/5：Gr 2 hand-foot skin reaction, skin rash at face and leg↓, hot flash, hypertension, general malaise,

  46. Thank You For Your Listening

  47. Reference • 教科書 • DeVita VT, et al. Devita, Hellman & Rosenberg's Cancer: Principles & Practice of Oncology, 8th Edition • 臨床準則 • AASLD Practice Guideline: Bruix J and Sherman M. Management of hepatocellular carcinoma. Hepatology 2005; 42(5): 1208-1236 • JSH Guideline: Kudo M, Okunoue T, and Clinical Practice Manual of HCC Expert Panel. Management of hepatocellular carcinoma in Japan: consensus-based clinical practice manual proposed by the Japan Society of Hepatology. Oncology 2007; 72(supp1): 2-15 • 英文期刊 • Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, et al. Sorafenib in Advanced Hepatocellular Carcinoma. N Engl J Med 2008; 359: 378-90 • Cheng AL, Kang YK, Chen ZD, Tsao CJ, Qin SK, et al. Efficacy and Safety of Sorafenib in Patients in The Asia-Pacific Region With Advanced Hepatocellular Carcinoma: A Phase III Randomized, Double-blind, Placebo-Controlled Trial. Lancet Oncol 2009; 10: 25-34 • 中文期刊 • 林志陵, 高嘉宏. 肝癌的流行病學. 中華癌醫會誌. 2008; 24(5): 277-281 • 盧勝男, 顏毅豪, 林芷芸等. 肝細胞癌之臨床分期.中華癌醫會誌. 2008; 24(5): 295-303

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