INITIAL EVALUATION TREATMENT SURVEILLANCE History and physical; CBC/differential; Liver function tests; Viral labs if not known (HBV core and surface Abs; HCV Ab, and RNA if Ab positive; HIV serology if HCV Ab positive or HBV core Ab positive); alphafetoprotein (AFP), Creatinine and Electrolytes, PT/INR; Triple Phase CT or MRI of abdomen and pelvis, CT of chest PET Scan; lipid profile, Hemoglobin AC and PET scan. Consider consult if indicated. Hepatology for chronic liver disease or HBV treatment 2.Infectious Diseases for HCV or HIV treatment. Liver-only Disease Metastatic Disease Resectable,2 or transplantable 3? Consider biomarkers (See appendix A for MDA Approved Hepatocellular Biomarkers) 2 Minor or Major Resection based on: Minor Resection: Child-Pugh A, normal liver function tests (bilirubin less than or equal.0 mg%), absence of ascites, and platelet count greater than 00,000/mm 3 Major Resection: Same as minor resection plus absence of portal hypertension, portal vein embolization (PVE) for a small future liver remnant. 3 Milan criteria; criteria for eligibility for liver transplantation for patients with hepatocellular carcinoma and cirrhosis: the presence of a tumor 5 cm or less in diameter in patients with single hepatocellular carcinomas, or no more than three tumor nodules, each 3 cm or less in diameter, in patients with multiple tumors, and without macrovascular invasion per imaging studies. 4 See Appendix B for ECOG Performance Status 5 CLIP refer to Appendix C for determination of CLIP score 6 Child-Pugh refer to Appendix D for Child-Pugh scores 7 Treatment may be considered in select cases with Bilirubin 2-3 mg/dl Isolated metastasis? Yes No Yes No Surgery See Page 2 for unresectable tumors Treat isolated metastasis first Performance status 0-2 4, CLIP 5 0-3, and Child A B 6 and Bilirubin less than or equal to 2 mg/dl Performance status 4 greater than 2, CLIP 5 4-6, or Child C 6 or Bilirubin greater than 2 mg/dl 7 History and physical, CBC, Liver function tests, alpha-fetoprotein (AFP), electrolytes, INR Triple Phase CT of abdomen, CT of chest every 4 months for 2 years, then every 6 months for 3 years, then annually Further treatment based on primary liver lesions Systemic treatment (sorafenib) Best Supportive Care
CLINICAL PRESENTATION Performance status 0-2, CLIP 2 0-3, Child 3 A B and Bilirubin less than or equal to 2 mg/dl Unresectable Tumors This practice algorithm has been specifically developed for MD Anderson using a multidisciplinary approach and taking into consideration circumstances particular to MD Anderson, Performance status greater than 2, CLIP 2 4-6, Child 3 C or Bilirubin greater than 3 mg/dl 4 Well defined lesions? Yes, Early/ Intermediate disease No, Disease Morphology on imaging indicated infiltrative/ ill-defined disease or there is major vein involvement or disease burden greater than 50% See Appendix A for ECOG Performance Status 2 CLIP refer to Appendix B for determination of CLIP score 3 Child-Pugh refer to Appendix C for Child-Pugh scores STAGING Up to 3 lesions that are less than or equal to 3 cm in size. Single lesion greater than 3 cm 2. Multiple lesions (up to 3-4) 3. Overall tumor burden less than or equal to 25% Single lesion 25-50% tumor burden Multiple Lesions greater than 4 Any Tumor Burden above with Branch PV or HV Tumor Thrombus 4 Treatment may be considered in select cases with Bilirubin 2-3 mg/dl 5 TACE (transcatheter arterial chemoembolization) 6 PIAF cisplatin, interferon-alfa, 5-fluorouracil and doxorubicin Treatment options based on feasibility and safety (If Disease Morphology on imaging indicated infiltrative/ill-defined disease or there is major vein involvement consider adding therapy (Sorafenib).. Ablation 4. Radioembolization 2. TACE 5 5. Radiotherapy 3. Combination of ablation 6. Neoadjuvant PIAF 6 and TACE 5 when when clinically clinically appropriate appropriate. TACE 5 4. Radiotherapy 2. Combination of TACE 5 and 5. Neoadjuvant PIAF 6 ablation when appropriate when clinically 3. Radioembolization appropriate. Radioembolization 4. Neoadjuvant PIAF 6 2. TACE 5 when clinically 3. Radiotherapy appropriate. Radioembolization 3. Neoadjuvant PIAF 6 2. TACE 5 in select cases where when clinically lesions grouping allows for appropriate selective TACE 5. Radioembolization 3. Radiotherapy 2. TACE 5 in select cases where 4. Neoadjuvant PIAF 6 when lesions grouping allows for clinically appropriate selective TACE 5 Apply treatment options pathways 20-28 but consider adding systemic therapy (Sorafenib) as a stand alone option or in combination with local therapy feasible Best Supportive Care RE-STAGING WORKUP History and physical, CBC, differential, Liver function tests, alpha-fetoprotein (AFP), electrolytes, Triple Phase CT of abdomen and pelvis, and CT of chest every 2 months until stable disease, then every 3 months for 2 years, then every 6 months for 3 years, then annually
APPENDIX A: Hepatocellular Carcinoma Molecular Markers MD ANDERSON APPROVED DISEASE SITE BIOMARKER CELL TYPE FISH IMMUNOHISTOCHEMISTRY MOLECULAR GI Hepatocellular MET MET Literature support for MD Anderson approved Biomarkers is available and can be found under Clinical Management Algorithms Biomarkers MD Anderson Approved Literature support for MD Anderson approved Biomarkers is available and can be found under Clinical Management Algorithms Biomarkers MD Anderson Approved
APPENDIX B EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE STATUS CRITERIA APPENDIX C CLIP SCORING SYSTEM Grade 0 2 3 4 5 Scale Fully active, able to carry on all pre-disease performance without restriction (Karnofsky 90-00) Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, i.e., light housework, office work (Karnofsky 70-80) Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours (Karnofsky 50-60) Capable of only limited self-care, confined to bed or chair more than 50% of waking hours (Karnofsky 30-40) Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair (Karnofsky 0-20) Dead Variables Child-Pugh Stage Tumor morphology AFP Portal vein thrombosis APPENDIX D CHILD-PUGH SCALE Class A = 5 to 6 points Class B = 7 to 9 points Class C = 0 to 5 points 0 A Uninodular and extension less than or equal to 50% Less than 400 ng/dl No B Multinodular and extension less than or equal to 50% Greater than or equal to 400 ng/dl Yes 2 C Massive or Greater than 50% Chemical and Biochemical Parameters Scores (Points) for Increasing Abnomality 2 3 Encephalopathy None - 2 3-4 Ascites None Slight Moderate Albumin Greater than 3.5 g/dl 2.8 3.5 g/dl Less than 2.8 g/dl Prothrombin time prolonged 4 seconds 4 6 seconds Greater than 6 seconds Bilirubin For primary biliary cirrhosis 2 mg/dl 4 mg/dl 2 3 mg/dl 4 0 mg/dl Greater than 3 md/dl Greater than 0 mg/dl
SUGGESTED READINGS Child-Pugh scale: Pugh, R.N., et al., Transection of the oesophagus for bleeding oesophageal varices. Br J Surg, 973. 60(8): p. 646-9. CLIP score: A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology, 998. 28(3): p. 75-5. SURGERY: Huang Y, Chen C, Chant T et al. Evaluation of predictive value of CLIP, Okuda, TNM and JIS staging systems for hepatocellular carcinoma patients undergoing surgery. Journal of Gastroenterology and Hepatology (2005) 20, 765 77 Jarnagin W, Chapman WC, Curley S et al. Surgical treatment of hepatocelluar carcinoma: expert consensus statement. HPB (Oxford). 200;2(5): 302-30. Lei, HJ, Chau, GY, Lui, WY, et al. Prognostic value and clinical relevance of the 6th Edition 2002 American Joint Committee on Cancer staging system in patients with resectable hepatocellular carcinoma. J Am Coll Surg 2006; 203:426. Liu, CL, Fan, ST, Cheung, ST, et al. Anterior approach versus conventional approach right hepatic resection for large hepatocellular carcinoma: a prospective randomized controlled study. Ann Surg 2006; 244:94. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 996 Mar 4;334():693-9. Minagawa Staging of Hepatocellular Carcinoma Assessment of the Japanese TNM and AJCC/UICC TNM Systems in a Cohort of 3,772 Patients in Japan. (Ann Surg 2007;245: 909 922) Nagasue, N, Kohno, H, Chang, YC, et al. Liver resection for hepatocellular carcinoma. Results of 229 consecutive patients during years. Ann Surg 993; 27:375. Palavecino M, Chun YS, Madoff DC et al. Major hepatic resection for hepatocellular carcinoma with or without portal vein embolization: Perioperative outcome and survival. (Surgery 2009;45:399-405.) Pawlik, TM, Poon, RT, Abdalla, EK, et al. Critical appraisal of the clinical and pathologic predictors of survival after resection of large hepatocellular carcinoma. Arch Surg 2005; 40:450. Poon, RT, Fan, ST. Evaluation of the new AJCC/UICC staging system for hepatocellular carcinoma after hepatic resection in Chinese patients. Surg Oncol Clin N Am 2003; 2:35. Ramacciato G, Mercantini P, Cautero N, et al. Prognostic Evaluation of the New American Joint Committee on Cancer/International Union Against Cancer Staging System for Hepatocellular Carcinoma: Analysis of 2 Cirrhotic Patients Resected for Hepatocellular Carcinoma Ann. Surg. Oncol. Vol. 2, No. 4, 2005 Suggested Readings Continued on Next Page
SUGGESTED READINGS - continued SURGERY ( Continued) Varotti G, Ramacciato G, Ercolani G, et al. Comparison between the fifth and sixth editions of the AJCC/UICC TNM staging systems for hepatocellular carcinoma: multicentric study on 393 cirrhotic resected patients. Eur J Surg Oncol. 2005 Sep;3(7):760-7. Vauthey JN, Dixon E, Abdalla EK, Helton WS et al. Pretreatment assessment of hepatocellular carcinoma: expert consensus statement. HPB (Oxford). 200;2(5): 289-99. Vauthey, JN, Lauwers, GY, Esnaola, NF, et al. Simplified staging for hepatocellular carcinoma. J Clin Oncol 2002; 20:527. Wilson SR, Greig P, Kaseb AO, Pretreatment assessment of hepatocelluar cancer: Expert consensus conference. HPB (Oxford). 200;2(5): 300-30. Wu CC, Cheng SB, Ho WM et al. Liver resection for hepatocellular carcinoma in patients with cirrhosis. British Journal of Surgery 2005; 92: 348 355 RFA Hong SN, Lee SY, Choi MS et al. Comparing the Outcomes of Radiofrequency Ablation and Surgery in Patients With a Single Small Hepatocellular Carcinoma and Well- Preserved Hepatic Function (J Clin Gastroenterol 2005;39:247 252) Mazzaferro V, Battiston C, Perrone S et al. Radiofrequency Ablation of Small Hepatocellular Carcinoma in Cirrhotic Patients Awaiting Liver Transplantation A Prospective Study (Ann Surg 2004;240: 900 909) Pompili M, Mirante VG, Rondinara G et al. Percutaneous Ablation Procedures in Cirrhotic Patients With Hepatocellular Carcinoma Submitted to Liver Transplantation: Assessment of Efficacy at Explant Analysis and of Safety for Tumor Recurrence. Liver Transpl 2005;: 7-26. Vivarelli M., Guglielmi A, Ruzzenente, et al. Surgical Resection Versus Percutaneous Radiofrequency Ablation in the Treatment of Hepatocellular Carcinoma on Cirrhotic Liver Ann Surg 2004;240: 02 07 RADIOTHERAPY Krishnan S, Dawson, LA, Seong, J, Akine, Yasuyuki, A, et al. Radiotherapy for Hepatocellular Carcinoma: An Overview (Ann Surg Oncol Vol 5, No. 4, 2008; 05-024 SYSTEMIC THERAPY (SORAFENIB) Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, 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;0():25-34. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359(4):378-90. Schwarz RE, Abou-Alfa GK, Geschwind JF, Krishnan S et al. Non-operative therapies for combined modality treatment of hepatocellular cancer: expert consensus statement. HPB (Oxford). 200;2(5): 33-320. NEOADJUVANT CHEMOTHERAPY Kaseb, A.O., Shindoh, J., Patt, Y.Z., Roses, R., Zimmitti, G., Lozano, R., Hassan, M., and Vauthe, J.N. Modified Cisplatin/Interferon a-2b/doxorubicin/5-fluorouracil (PIAF) Chemotherapy in Patients With No Hepatitis or Cirrhosis Is Associated With Improved Response Rate, Resectability, and Survival of Initially Unresectable Hepatocellular Carcinoma. Cancer. 203 September 5; 9(8): 3334 3342.
SUGGESTED READINGS - continued SURGERY ( Continued) Oda, K., Uto H, Mawatari, S., Id, A.(205). Clinical features of hepatocellular carcinoma associated with nonalcoholic fatty liver disease: a review of human studies. Clin J Gastroenterol. Shah, M., Shankar, A., Gee, I., Nash, K., Hoare, M., Gibbs, P., Davies, S., et al. (205). A retrospective 5-year review: survival advantage after switching to sirolimus in hepatitis C virus infected liver graft recipients. Aliment Pharmacol Ther. 4 (4): 379-92. Siegel, A.B., Zhu, A.X., Metabolic syndrome and hepatocellular carcinoma: two growing epidemics with a potential link. Cancer. 2009.5(24): 565-6. Chou, R., Cuevas, C., Fu, R., Devine, B., Wasson, N., Ginsburg, A., Zakher, B., et al. Imaging Techniques for the Diagnosis and Staging of Hepatocellular Carcinoma. Agency for Healthcare Research and Quality. 204, 4(5) AHRQ Comparative Effectiveness Reviews. Lin, C.Y., Chen, J.H., Liang, J.A., Lin, C.C., Jeng, LB., Kao, C.H.. 8F-FDG PET or PET/CT for detecting extrahepatic metastases or recurrent hepatocellular carcinoma: a systematic review and meta-analysis. Eur J Radiol. 202 Sep;8(9):247-22.
DEVELOPMENT CREDITS This practice guideline is based on majority expert opinion of the Gastrointestinal Center Faculty at the University of Texas, MD Anderson Cancer Center. It was developed using a multidisciplinary approach that included input from the following medical oncologists, radiation oncologists, surgical oncologists, and interventional radiologists: Medical Oncology: Christopher Garrett, M.D. Milind Javle, M.D. Ahmed O. Kaseb, M.D. Ŧ Surgical Oncology: Thomas Aloia, M.D. Jean-Nicolas Vauthey, M.D. Ŧ Hepatology: Boris Blechacz, M.D. Frank Herlong, M.D. Ethan Miller, M.D. Radiation Oncology: Christopher Crane, M.D. Sunil Krishnan, M.D. Ŧ Interventional Radiology: Kamran Ahrar, M.D. Armeen Mahvash, M.D. Ravi Murthy, M.D. Alda Tam, M.D. Michael Wallace, M.D. Ŧ Core Development Team Lead