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Hepatocellular carcinoma 2020
- 1. Management of Hepatocellular Carcinoma Abraham G. PGY3 Moderated by Dr Zeki August 12, 2020 Addis Ababa, Ethiopia 1
- 2. Overview Epidemiology Presentation Diagnosis Staging Management Risk factors Prevention Summary 2
- 3. Overview of Liver Cancers Primary • Hepatocytes • HCC • Fibrolamellar carcinoma • Hepatoblastoma • Blood vessels and Mesenchyme • Angiosarcoma • Cholangiocarcinoma • Fibrosarcoma • Leimyosarcoma • Germ cells/others • Teratoma • Yolksac tumors • Lymphoma Secondary • Colorectal • Neuroendocrine • Non-neuroendocrine non-colorectal 3
- 4. Epidemiology • Fifth most common cancer, third most common cause of cancer death. • HCC accounts for 90% of primary liver cancers. • M:F ~ 3:1 • Sixth decade, but earlier in Africa and Asia • Cirrhosis in 80 – 90%. • About 3 – 8% annually develop HCC. • HBC, HVC and Alcohol take lions share 4
- 5. Epidemiology • High incidence [>15 cases/100,000] • East Asia • Africa • Intermediate incidence [3-15 cases/100,000 • Europe • Southeast Asia • Low incidence [<3 cases/100,000 • Americas • Australia 5
- 6. Etiopathology Cirrhotic Pathway • HCV • HBV • Alcoholic liver disease • Autoimmune hepatitis Noncirrhotic Pathway • Fibrolamellar carcinoma • HBV • NASH • Aflatoxin induced • Metabolic 6
- 8. Hepatitis B Disease Progression Acute Infection[1] Chronic Infection Cirrhosis Death 5% to 10% of chronic HBV- infected individuals[2,3] Decompensation 20% to 30%[4] > 90% of infected children progress to chronic disease (< 5% of adults)[5] 23% of patients decompensate within 5 yrs of developing cirrhosis[3] Liver Cancer (HCC) Liver Transplantation 1. The elimination of hepatitis B. In: Buckley. Eliminating the public health problem of hepatitis B and C in the United States: Phase One Report. 2016. 2. Iloeje. Liver Int. 2012;32:1333. 3. Fattovich. Hepatology. 1995;21:77. 4. Niederau. World J Gastroenterol. 2014;20:11595. 5. Weinbaum. MMWR Recomm Rep. 2008;57:1. Slide credit: clinicaloptions.com
- 9. Ethiopian Context • HBV • Overall pooled prevalence of 6%. • HCC in TASH • 51 patients, 2 years retrospective • RFs: HBV and HCV: 48%; Alcohol : 45% • HCC in referral clinic in Addis: Amir et al • 46 patients with HCC, retrospective; • RFs: 41% HBV, 45% HCV; 78% with Cirrhosis • Management: TACE[16%], Sorafenib [18%], palliative care [31%]. 9Sultan, Amir et al. “Liver Cancer in Ethiopia: Presentation, Prognosis, and Therapy: 1077.” The American Journal of Gastroenterology 114 (2019): n. pag. Belyhun, Yeshambel et al. “Hepatitis viruses in Ethiopia: a systematic review and meta-analysis.” BMC infectious diseases vol. 16,1 761. 19 Dec. 2016, doi:10.1186/s12879-016-2090-1
- 10. Prevention • Primary • HBV newborn and highrisk group vaccination • Alcohol health education, policy measures to decrease consumption • Aflatoxin health education • Secondary treat HBV, HCV, NASH, NAFLD, … • Tertiary surveillance with US +/-AFP • Surveillance if • Effective prolongs survival • Cost-effective • Surveillance early detection, more than 20% 3 year survival 10
- 12. SURVIELLANCE RECOMMENDATION • Patients with cirrhosis, • Child-Pugh class A and B • Child-Pugh class C, only if awaiting liver transplantation • Noncirrhotic HBV with any of the following • Active hepatitis (elevated serum alanine aminotransferase [ALT] and/or high viral load) • Family history of HCC • Africans and African Americans • Asian males over 40 years of age • Asian females over 50 years of age
- 14. Evaluation of A Patient with Suspected HCC • Clinical • History • Symptoms • Risk factors • Physical • General condition • Performance status • Abdominal exam: Liver, ascites • Encephalopathy? 14 • Lab work • Baseline • AFP • Viral markers • Full liver panel and other OFTs •Imaging • Diagnostic • Multiphasic CT • Multiphasic MRI • Metastatic work up
- 15. Diagnosis • Imaging with CT or MRI • Classic arterial enhancement with venous wash out has Sn/Sp of 90/95%. • AFP • Is not specific. • More helpful to detect recurrence • Biopsy • If nodule is atypical • LR 4 and LR-M • In noncirrhotic HCC [EASL Recommendation] 15
- 16. 1. Noncontrast phase = no lesion seen 2. Arterial phase = enhancing lesion in the Rt lobe 3. Venous phase = faint lesion 4. Delayed phase = isodense lesion
- 17. Major Sources of Guidance/Guideline for Management of HCC WEST • Barcelona-Clínic Liver Cancer Staging system (BCLC) • American Association for Study of Liver Diseases [AASLD] • European Association for Study of Liver [EASL] • TNM [American Joint Committee on Cancer] • The Cancer of the Liver Italian Program (CLIP) EAST • The Hong-Kong Liver Cancer (HKLC) • The Japan Integrated Staging (JIS) • The Chinese University Prognostic Index (CUPI) • … 17
- 18. Several staging systems 18
- 19. BCLC Staging 19
- 20. HKLC Staging
- 21. BCLC vs HKLC 21
- 22. Management • Curative intent Rx • LT • Resection • Ablation • Regional Rx • Systemic • BSC 22
- 23. LT • Published in 1996 • 48 HCC patients • Milan criteria = single tumor ≤5 cm, or ≤3 tumor ≤3 cm each, no EVM or gross vascular invasion. • 4 year survival was ~75%, RFS 83%.
- 24. 24
- 25. Competing criteria for LT • UCSF criteria also reported 75% survival. • Mazzaferro then did large retrospective and found 71% survival • Tokyo [5 to 5 rule]: 5year OS 75% • Many more…
- 26. Preoperative Surgical Evaluation • Liver function reserve • Performance status • Liver stiffness/cause of HCC or CLD including fibroscan • Technical resectability • FLR volume • Portal hypertension 26
- 27. Preoperative Evaluation • General status • Assessment of important organs • Comorbidities • Tumor related factors • Generally, single, small tumor is preferred. • For advanced HCC with portal invasion, LR has acceptable results compared with Sorafenib. • Preop simulation and Volume estimation • FLR should be at least 50% in Cirrhotic liver, if less consider preop PVE. • Many softwares on the rise. 27
- 28. Preoperative Evaluation • Assessment of Liver Function Reserve : CP, PH, ICG • Child Pugh • Recommendation based on CP Classification • A WITHOUT CIRRHOSIS Can undergo major resection • B or WITH CIRRHOSIS Limited resection for small tumors located near the surface • C Resection NOT INDICATED even if small • Portal hypertension : remains controversial but generally disfavors resection. • HVPG >10, practically diagnosed with varices or low platelet with splenomegaly. • If resection planned, control varices and platelet. 28
- 29. Preoperative Evaluation • Assessment of Liver Function Reserve : CP, PH, ICG • ICG, Bilirubin and ascites 29
- 30. Exposure 30 • Generally right subcostal +/- left subcostal incision is used. • Apply fixed retractors
- 31. Exposure and Common Initial Steps • General inspection of abdomen. • Liver exam, +/- Intraop US • Take down round and falciform • Division of liver ligaments • Open Gastrohepatic ligament, assess for arterial anomalies • Cholecystectomy • Next steps are based on decided resection 31
- 32. Surgical Technique Inflow and Outflow Control: Decrease bleeding 32
- 33. • Intraop ultrasound : improved safety of LR remarkably. • Anatomic resection: introduced by Makuuchi in 1980s • Recurrence and met are related to Portal vein tumor thrombus and satellite lesion from the tumor-bearing hepatic segment • In AR, the entire segment fed by the tumor-bearing portal branches is completely and systematically removed. • Explained by unique character of HCC to spread thru PV. • NAR: tumor resection with some rim • ?AR is superior than NAR.? Surgical Technique 33
- 34. Resection types
- 36. Surgical Technique • Parenchymal Transection • Two steps: crushing of the liver parenchyma to detect vessels and their subsequent occlusion. • Tools • Clamp crushing and ligation: standard. • Others: CUSA, Vessel sealing system, ultrasonic scalpel… • Resection Margin • Opposing results have been reported. No agreed RM. • Usually capsulated, so nucleation is possible and effective. 36
- 37. Surgical Technique • Conventional Vs Anterior Approach for large right sided tumors • Conventional: • Right liver mobilization with outflow and inflow control before parenchymal transection • Risk of tumor embolization • Anterior: • Inflow control, then parenchymal division, outflow control, and lastly mobilization • Risk of bleeding 37
- 38. Post op Management after LR • Fluid and Transfusion • Fluid volume at 5ml/Kg/day • Sodium at 100 – 150mEq/day • No routine FFP • Avoid RBCs as much as possible. • Diuretics • Routine. Spironolactone is preferred. • Drainage: avoid if possible. Or remove early. • Nutrition: IV Nutrition is important. PO feeding on POD 1 according to ERAS. • Post discharge follow up with imaging and AFP. 38
- 39. Complications and Prognosis of LR COMPLICATIONS • Liver failure • Bile leak • Post op bleeding • Refractory ascites • Infection • Peptic Ulcer PROGNOSIS • Currently 2 – 5% mortality. • Overall 50 - 60% survival at 5 years. • Currently results are paralleling with LT. 39
- 41. Regional Therapies • Transarterial Chemoembolization [TACE] • First-line for unresectable, large/multifocal HCCs who do not have vascular invasion or extrahepatic spread. • Patients at early stage in whom RFA is difficult to perform because of tumor location or medical comorbidities • For downstaging tumors that exceed LT Criteria. • The objective response rate using enhancement criteria ranges between 58 and 86%. • Transarterial radioembolization [TARE] • ~40% objective tumor response rate with median survival of 15 months. • The main indication is inoperable HCC. 41
- 42. Systemic Therapy • Adjuvant and Neoadjuvant: No survival benefit. • Upfront Chemotherapy • No proven significant benefits on survival in HCC. • APSLD Recommendation • Sorafenib is recommended for the first-line treatment of advanced-stage patients (macrovascular invasion or extrahepatic metastasis) who are not suitable for locoregional therapy and who have Child–Pugh class A liver function. • Sorafenib may be used with caution in patients with Child–Pugh class B liver function. • Lenvatinib approved recently 42
- 43. Summary 43
- 44. Summary • HCC is predominantly sequalae of cirrhosis. • HBV, HCV and Alcohol are major causes of Cirrhosis. • Most HCC patients come late. Prevention is the best option. • Liver resection and LT remain best options of treatment. • Treatment options in our country are still limited. 45
- 45. References Papers • Ethiopia • Mekonnen HD, Sharma S, Shewaye A, Feld J, Lulu E. Major Risk Factors, Clinical And Laboratory Characteristics Of Patients With Hepatocellular Carcinoma; A Retrospective Study At Tikur Anbassa Hospital, Addis Ababa University, Addis Ababa, Ethiopia. Ethiop Med J. 2015;53(3):127-132. • Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Akinyemiju TF, et al. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol. 2018;4(11):1553-1568. doi:10.1001/jamaoncol.2018.2706. • Memirie ST, Habtemariam MK, Asefa M, et al. Estimates of Cancer Incidence in Ethiopia in 2015 Using Population-Based Registry Data. J Glob Oncol. 2018;4:1-11. doi:10.1200/JGO.17.00175. • Sultan, Amir et al. “Liver Cancer in Ethiopia: Presentation, Prognosis, and Therapy: 1077.” The American Journal of Gastroenterology 114 (2019): n. pag. 46
- 46. References Papers • International • Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693-699. doi:10.1056/NEJM199603143341104. • Yau T, Tang VY, Yao TJ, Fan ST, Lo CM, Poon RT. Development of Hong Kong Liver Cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology. 2014;146(7):1691-700.e3. doi:10.1053/j.gastro.2014.02.032. • Song P, Cai Y, Tang H, Li C, Huang J. The clinical management of hepatocellular carcinoma worldwide: A concise review and comparison of current guidelines from 2001 to 2017. Biosci Trends. 2017;11(4):389-398. doi:10.5582/bst.2017.01202. • Levi Sandri, Giovanni Battista et al. “Liver transplant for patients outside Milan criteria.” Translational gastroenterology and hepatology vol. 3 81. 26 Oct. 2018, doi:10.21037/tgh.2018.10.03 • Otsubo T. Control of the inflow and outflow system during liver resection. J Hepatobiliary Pancreat Sci. 2012;19(1):15- 18. doi:10.1007/s00534-011-0451-0 • Krenzien F, Schmelzle M, Struecker B, et al. Liver Transplantation and Liver Resection for Cirrhotic Patients with Hepatocellular Carcinoma: Comparison of Long-Term Survivals. J Gastrointest Surg. 2018;22(5):840-848. doi:10.1007/s11605-018-3690-4 47
- 47. References Papers • International • Gruttadauria S, Pagano D, Corsini LR, et al. Impact of margin status on long-term results of liver resection for hepatocellular carcinoma: single-center time-to-recurrence analysis. Updates Surg. 2020;72(1):109-117. doi:10.1007/s13304-019-00686-5. 48
- 48. References Guidelines and Guidance • Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. • Screening for Hepatocellular Cancer in Chronic Liver Disease: A Systematic Review. . http://www.cancer.gov/cancertopics/pdq/levels-evidenceadult-treatment/healthprofessional/. • Overview of the Updated AASLD Guidelines for the Management of HCC. Gastroenterology & Hepatology Volume 13, Issue 12 December 2017. • Asia–Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. 49
- 50. Thank you! 51
Hinweis der Redaktion
- Earlier in Africa and Asia because of HBV with Aflatoxin Non cirrhotic HCC is on the rise due to metabolic diseases and NASH.
- Cirrhosis is the consequence of sustained wound healing in response to chronic liver injury. Approximately 40% of cirrhotic patients are asymptomatic, but progressive deterioration leading to the need for liver transplantation or death is typical after the development of end-stage liver disease (ESLD). NAFLD is now the most common chronic liver disease worldwide. NASH affects 3% to 5% of the population, and approximately 1 in 10 NASH patients will progress to cirrhosis, thereby placing them at risk for the well described consequences of cirrhosis, including hepatocellular carcinoma.
- 8
- There are no experimental data to indicate the threshold incidence of HCC to trigger surveillance. Instead, decision analysis has been used to provide some guidelines as to the incidence of HCC at which surveillance may become effective. In general, an intervention is considered effective if it provides an increase in longevity of around 100 days (i.e., around 3 months). Interventions that can be achieved at a cost of less than approximately USD (U.S. dollars) 50,000/ year of life gained are considered cost-effective. Although there is some disagreement between published models, surveillance should be offered for patients with cirrhosis of varying etiologies when the risk of HCC is 1.5%/year or greater. The above cost-effectiveness analyses, which were restricted to populations with cirrhosis, cannot be applied to hepatitis B carriers without cirrhosis. A cost-effectiveness analysis of surveillance for hepatitis B carriers using US and AFP levels suggested that surveillance became cost-effective once the incidence of HCC exceeds 0.2%/year.
- Limitation of CP Doesn’t provide quantitative information for liver function reserve, so can not predict risk associated with liver surgery in cirrhosis. Ascites and encephalopathy are subjective.
- AFP 60 – 80% HCC have it. Almost diagnostic of HCC in the proper clinical scenario if level is >400 Marks poor prognosis if elevated much Other markers: Novel markers are being developed. None in practice yet.
- In 1990s: Okuda was widely used. It was good for advanced disease. But after surveillance started, early tumors weren’t properly addressed by Okuda, so BCLC developed.
- The HKLC system had significantly better ability than the BCLC system to distinguish between patients with specific overall survival times (area under the receiver operating characteristic curve values, approximately 0.84 vs 0.80; concordance index, 0.74 vs 0.70). More importantly, HKLC identified subsets of BCLC intermediate- and advanced-stage patients for more aggressive treatments than what were recommended by the BCLC system, which improved survival outcomes. Of BCLC-B patients classified as HKLC-II in our system, the survival benefit of radical therapies, compared with transarterial chemoembolization, was substantial (5-year survival probability, 52.1% vs 18.7%; P < .0001). In BCLC-C patients classified as HKLC-II, the survival benefit of radical therapies compared with systemic therapy was even more pronounced (5-year survival probability, 48.6% vs 0.0%; P < .0001).
- For primary liver cancers or hepatic metastases, hepatic resection is the gold standard and treatment of choice.
- Why we do LT is to cure both the HCC and cirrhosis. Also recurrence after resection is high. Although liver replacement could be curative for patients with tumors confined to the liver, the long-term results of liver transplantation in patients with hepatocellular carcinoma have been disappointing, with an overall five-year survival rate ranging from 30 to 40 percent. Criteria (1) single tumor diameter less than 5 cm; (2) not more than three foci of tumor, each one not exceeding 3 cm; (3) no angioinvasion; (4) no extrahepatic involvement. 295 patients judged to have unresectable tumor for reasons like location of the tumor in the liver, because the tumor was multifocal, or because the patient had advanced hepatic insufficiency related to cirrhosis. Among those 295 patients, 60 who had histologically proved cirrhosis (20 percent) were eligible for the present study because their tumors were at an early stage. Diagnosis confirmed by histology or AFP. TUMOR CHARACTERSTICS: Single less than 5cm, or multiple, less than 3 in number and less than 3cm. Invasion of vessels or LNs on imaging was exclusion criteria.
- In France, the Liver Transplantation French Study Group publish the “Duvoux Score” predicting the high risk of recurrence post LT according to AFP (12). The score includes a sum of variables: number of nodules (1–3=0 point; ≥4=2 points), largest diameter in cm (≤3=0 point; 3–6=1 point; >6=4 points) and AFP (ng/mL) (≤100=0 point; 100–1,000=2 points, >1,000=3 points). Patients with a score ≤2 points following down-staging treatment will be eligible for registration for liver transplantation.
- The University of Tokyo guidelines was up to five nodules with a maximum diameter of 5 cm, overall and recurrence-free survival rates at five years after transplantation were 75 and 90%, respectively
- Technically unresectable: centrally located, multiple,
- General status Function of important organs should be checked. Severe organ dysfunction is a contraindication. Comorbidities add another risk, especially DM. CKD, Portal hypertension and large intraop blood loss are associated with refractory ascites postop. Tumor related factors In general, a single and small HCC is a good indication for resection; however, multifocal and large lesions can also be treated by resection, providing satisfactory long-term outcomes. For advanced HCC with vascular invasion, liver resection can also offer acceptable results compared with the use of a molecular targeted agent (Sorafenib), which is recommended in the treatment algorithm of BCLC. Several additional algorithms are challenging BCLC.
- Limitation of CP Doesn’t provide quantitative information for liver function reserve, so can not predict risk associated with liver surgery in cirrhosis. Ascites and encephalopathy are subjective. Hassab’s operation, UGIE, Splenectomy for platelet <50,000
- Bookwalter and Thompson Retractors
- The goal is to minimize blood loss and hypotension, which add significant morbidity to the operation. Furthermore, intraoperative blood transfusion has been shown to be an independent risk factor for increased postoperative infection as well as worse patient survival in some studies. Therefore, all efforts should be made to minimize blood loss during hepatic resection. Although the liver has been shown to tolerate up to 1 hour of warm ischemia, some technical variations of the Pringle maneuver include intermittent vascular occlusion with cycles of approximately 15 minutes on and 5 minutes off. 7 Ischemic preconditioning refers to the brief interruption of blood flow to an organ, followed by a short reperfusion period, and then a more prolonged period of ischemia. Clavien and colleagues reported significantly less liver injury in the group who received ischemic preconditioning with a 10-minute clamp, a 10-minute reperfusion, and then a 30-minute clamp than in those who received a 30-minute clamp alone.1 Because ischemia-reperfusion injury was once viewed as a critical form of damage to the liver, neither inflow nor outflow occlusion was applied during liver parenchymal division. Thus liver resection was inevitably associated with a large loss of blood, which sometimes led to liver failure and death. In the early 1980s, the hemihepatic vascular occlusion method (Makuuchi et al, 1987a) was devised, and the total inflow occlusion (Pringle maneuver; Pringle, 1908) became widely utilized. The usefulness of Pringle maneuver was confirmed by a randomized controlled trial (RCT) performed in Hong Kong. 10 minutes of ischemic preconditioning by inflow occlusion significantly improved postoperative liver function. The superiority of intermittent inflow occlusion versus continuous or total occlusion is now widely accepted (Belghiti et al, 1999; Ishizaki et al, 2006) and is an indispensable technique for improving the safety of liver surgery.
- Intraoperative ultrasound is considered the gold standard for detecting liver lesions, and studies have shown that it can identify 20% to 30% more lesions than other preoperative imaging modalities. Importantly, it has been shown to influence surgical management in almost 50% of planned liver resections for malignancies. Hepatocellular carcinoma has a unique biologic characteristic in that it tends to scatter intrahepatically and to metastasize through the portal venous system. Because even a small HCC may be associated with portal venous invasion, which is correlated with worse prognosis, surgeons should consider removing potential intrahepatic metastases whenever possible. On the other hand, major hepatic resection should be avoided, especially in cirrhotic liver, because of the high risk of postoperative critical liver failure. To overcome this pitfall, anatomic resection, in which the entire segment fed by the tumor-bearing portal branches is completely and systematically removed, is a reasonable surgical procedure for preventing recurrence via this pathway. Depending on the size and location of the tumor, the resection of a complete Couinaud segment, part of a segment, or more than one segment extending to the adjacent region can be performed. To date, several retrospective studies have shown that anatomic resection is superior to nonanatomic resection. As long as the liver function is adequate, anatomic resection is strongly recommended as the surgical procedure of choice for HCC.
- The right dorsal sector (segment 9) is a prolongation of the left dorsal sector (Segment 1), posterior to the right portal pedicle and segment 8, anterior to the vena cava, inferior to the terminal portion of the middle and right superior hepatic vein. and extending at times posterior to segment 7.
- Resection margin Opposing results have been reported. Some saying wide margin [>1cm] has low recurrence rate, others say it has no relation with recurrence. Because HCC is typically covered by a capsule and exhibits expansive growth, nucleation of the tumor is often possible and effective. The relationship between the resection margin and the recurrence pattern remains unknown. However, exposure of the tumor capsule or a zero surgical margin may be acceptable from a practical perspective. Particularly when the tumor is adjacent to major vascular structures in cirrhotic liver, hepatic resection exposing the tumor is inevitable to preserve the vascular structures.
- This conventional approach hepatectomy (CAH) is considered to be effective in reducing intraoperative blood loss. However, this approach is diffcult and dangerous when performing liver resection for large hepatocellular carcinoma (HCC) or for tumors with extrahepatic organ invasion in the right retrohepatic region. AAH: This approach avoids the squeezing of tumor cells into the circulation during mobilization of the tumor[4-6]. However, torrential bleeding can occur at the deeper plane of parenchymal transection from the right or middle hepatic vein.