HepatoCellularCarcinoma management full.pptx

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1. Hepatocellular carcinoma: management

2. Introduction aggressive tumor curative options :surgery only 70%–80% patients inoperable due to advanced stage underlying liver disease

3. Management depends on following factors Tumor related Size Stage Location Single vs. multiple vascular involvement Lymphatic spread Extra hepatic spread Patient related Age Performance status Medical co morbidities Previous treatment liver function Child-Pugh score Portal hypertension Cirrhosis Treatment related factor Multimodality treatment High volume centres Transplant facility radiotherapy techniques cost

4. Treatment modalities Surgery liver resection transplantation Local ablative therapies Radiofrequency ablation Microwave ablation cryoablation Chemical ablation: ethanol, acetic acid Regional therapies Tran arterial therapy Radiotherapy Systemic therapies Chemotherapy Nonchemotherapy agents Targeted therapy Supportive care

5. Grading System For Cirrhosis: Child-Pugh Score Barcelona Clinic Liver Cancer staging System For Hepatocellular cancer

6. Llovet , J. M., Fuster , J., & Bruix , J. (2004). The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society , 10 (2 Suppl 1), S115–S120.

7. SURGERY Resection Inclusion criteria AJCC Stage 1-2 Preferable size ≤5 cm, solitary tumor No macro vascular, L.N, or distant metastases Non cirrhotic or compensated cirrhotic child Pugh A Adequate remnant liver medically fit Exclusion criteria Advanced stage Multiple tumors portal hypertension Child Pugh B & C Transplantation Milan Criteria for inclusion Single tumours ≤ 5 cm or ≤3 nodules, each≤ 3 cm No vascular invasion or distant metastases Medically fit In patients with multiple nodules & chronic liver disease or chirrhosis-transplantation preferred

8.   Types of Hepatic Resections Non anatomic resection: wedge resection Anatomic resection segmentectomy lobectomy (right and left) trisegmentectomy (right and left)

9. Removal of a single segment -  Segmentectomy Small triangular-shaped portion of the liver along with tumor removed–  Wedge Resection . Indicated for small superficial& peripheral lesions

10. Right lobe which consists of two segments –  Right Lobectomy Left lobe which consists of two segments –  Left Lobectomy Lobectomy: indications multiple lesions are located in different areas of one lobe .

11. Removal of the complete left lobe plus the medial segment of the right lobe –  Left Trisegmentectomy  (also known as extended left hepatic lobectomy) Removal of the complete right lobe plus the medial segment of the left lobe –  Right Trisegmentectomy  (also known as extended right hepatic lobectomy

12. aim of surgery complete resection with at least 1 cm margin maximum preservation of normal hepatic parenchyma Post resection liver volume: at least 30% in non cirrhotic At least 40-50% in cirrhotic if potential remnant liver volume is less then following should be considered portal vein embolization trans arterial chemoembolization Liver resection

13. ICG retention test ICG is delivered systemically and the hepatic retention is measured at 15 minutes. It determines the amount of liver resection for patients with impaired liver function When the retention rate is less than 10%, all resections are possible. If 10% to 20%, a bisegmentectomy is well tolerated; if 20% to 29%, a single segment can be excised safely; if 30% or more, the risk of liver failure with any form of resection is high. Dynamic liver function test: to guide resection

14. Outcomes of Resection With improving patient selection and perioperative care, the outcome of hepatic resection has improved In past 10 years perioperative mortality rate of less than 7%, 5yr overall survival rate of 30% to 50%

15. Predictive factors determining outcome after liver resection TNM stage . 1 Size liver resection for >5 cm tumor --more recurrences. Large HCC :propensity for vascular invasion, intraluminal & intrahepatic satellite mets surgical margins 2,3,4 1-cm margin associated with 77% 3-year survival vs.21% with <1-cm margin. Type of liver resect ion 2,3,4 improved outcome for anatomic vs. nonanatomic resections 5-year :66% vs. 35%. for small solitary tumors, anatomic resections less importance Hasegawa K, Kokudo N, Imamura H, et al. Prognostic impact of anatomic resection for hepatocellular carcinoma.  Ann Surg  2005;242:252–259 Shi M, Guo RP, Lin XJ, et al. Partial hepatectomy with wide versus narrow resection margin for solitary hepatocellular carcinoma: a prospective randomized trial.  Ann Surg 2007;245:36–43  Ikai I, Arii S, Kojiro M, et al. Reevaluation of prognostic factors for survival after liver resection in patients with hepatocellular carcinoma in a Japanese nationwide survey. Cancer  2004;101:796–802.  Kang CM, Choi GH, Kim DH, et al. Revisiting the role of nonanatomic resection of small (< or = 4 cm) and single hepatocellular carcinoma in patients with well-preserved liver function.  J Surg Res  2010;160:81–89

16. Liver transplantation

17. Liver Transplantation: results Milan Criteria Single tumours ≤ 5 cm or no more than 3 nodules, each≤ 3 cm No vascular invasion or distant metastases

18. excellent outcomes of Milan criteria led to explore more expansive criteria . Expanded Criteria for Liver Transplantation: UCSF Criteria Solitary lesion Within ≤ 6.5 cm Multiple:≤ 3 nodules,each ≤ 4.5 cm Total tumor diameter ≤ 8 cm

19. Milan criteria :5 yr survival of ≈ 70% The UCSF criteria :5 years survival of ≈46% Transplanted patients with tumours beyond the UCSF criteria had a survival 35%

20. Multimodality Management While Awaiting Transplant: bridge therapy major disadvantage with liver transplantation :long waiting time for donor organs. high risk of tumor progression To reduce tumor progression many local treatments are used such as TACE TART RFA PEI called as bridging therapies . limits wait list dropout. downstage HCC beyond transplant criteria. decreases post transplant recurrence

21. Resection vs. Transplantation for small HCC≤ 2cm comparable OS rates patients with normal LFT should be resected because No need of immunosuppression donor organ shortage In patients with end-stage liver disease transplant preferred resection :used as bridging therapy for transplant

22. Ablative therapies

23. Ablative Therapy Indications: non surgical HCC Contraindication: tumor near vital structure –major vessel, bile duct, diaphragm, viscera curative intent: early stage solitary tumor ≤3 cm, child Pugh-A, PS-0 Neoadjuvant therapy: downstage tumor for resection Bridge therapy : reduce tumor progression Adjuvant therapy: after limited resection or in combination with TACE/TART Palliative intent: Large lesions Old & frail patients: poor performance status Child Pugh B-C

24. ABLATIVE THERAPY Types: Radiofrequency ablation Microwave ablation Chemical ablation

25. Radiofrequency Ablation most widely used In this technique, the RF electrode placed into tumor (percutaneous or laparoscopic) with imaging guidance.(CT,USG) The percutaneous approach may be limited by structures at risk such as major vessels, bile duct, diaphragm and other intraabdominal organs These structures can be retracted free with a laparoscopic approach.

26. Radiofrequency Ablation thin probe (18 gauge) is inserted into middle of a tumor needle electrodes are deployed to adjustable distances. A.C current (400 to 500 kHz) is delivered through electrodes -agitation of particles of surrounding tissues, Generate frictional heat lead to sphere of necrosis. Size of the sphere depends on length of deployment of electrodes. Currently, the maximum size of probe arrays allows for 7-cm zone of necrosis, adequate for a 5-cm tumor. .

27. Advantages: Well tolerated OPD procedure best suited to small tumors (3-5 cm) deep within hepatic parenchyma, away from hilum. repeated easily especially percutaneous approach Spares uninvolved hepatic parenchyma Less invasive then resection Disadvantges difficulty of positioning probe Anatomic limitation: large blood vessels may act as heat sinks, preventing adequate cytodestruction tumors close to main portal pedicles -lead to bile duct injury local recurrence rate (at the site of ablation) : 5% and 20%. theoretical risk of needle tract tumor seeding:

28. BEFORE RF AFTER RF

29. RFA Vs. Liver Resection RFA was as effective as surgical resection in the treatment of early HCC four randomized trials comparing RFA and hepatic resection

30. no significant difference in 1-year overall survival between resection and radiofrequency ablation long-term efficacy of surgery is better than that of RFA .

31. Microwave Ablation Like RFA, microwave ablation (MWA) uses electromagnetic waves to produce heating. Unlike RFA, the MW energy is much higher frequency range 300 MHz to 300 GHz. Similar safety and efficacy results * perceived advantages of MW over RF energy include broader deposition of MW energy much larger zone of active heating. less severe heat sink effects. larger resultant ablative volume faster treatment time Still not tested in clinical trials *Wright AS, Lee FT Jr, Mahvi DM. Hepatic microwave ablation with multiple antennae results in synergistically larger zones of coagulation necrosis.  Ann Surg Oncol 2003;10:275–283. *Martin RC, Scoggins CR, McMasters KM. Safety and efficacy of microwave ablation of hepatic tumors: a prospective review of a 5-year experience.  Ann Surg Oncol 2010;17:171–178 .

32. Chemical Ablation chemicals such as ethanol or acetic acid injected into tumor destroy tumor tissue by dehydration, protein denaturation, coagulation necrosis & vascular thrombosis  advantages: Inexpensive Minimally invasive Favourable at some anatomic location where RFA not suitable due to heat sink Disadvantages: Non selective for tumor cell & normal parenchyma Multiple applications required 15% risk of recurrence at site of injection RFA is superior to chemical ablation* for early stage Tsai WL, Cheng JS, Lai KH, et al. Clinical trial: percutaneous acetic acid injection vs. percutaneous ethanol injection for small hepatocellular carcinoma—a long-term follow-up study.  Aliment Pharmacol Ther  2008;28:304–311

33. Lin, S.-M., Lin, C.-J., Lin, C.-C., Hsu, C.-W., & Chen, Y.-C. (2005). Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less. Gut , 54 (8), 187 patients with HCCs of 3 cm or less randomly assigned to RFTA (n = 62), PEI (n = 62), or PAI (n = 63). Tumour recurrence and survival rates were assessed P value RFA PEI PAI NS 96.1 % 88.1 % 92.4 Complete Necrosis RFTA v PEI, p = 0.012; RFTA v PAI, p = 0.017 14% 34% 31% 3yr local recurrence rate RFTA v PEI, p = 0.031; RFTA v PAI, p = 0.038 74% 51% 53% 3yr survival rate RFTA vs. PAI/PEI p = 0.035 4.8% none none Major complications

34. Radiofrequency ablation vs. chemical ablation RFA : more effective more complication, more expensive, PEI/PAI: less effective more Sessions, minimally invasive, inexpensive Lin SM, Lin CJ, Lin CC, et al. Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less.  Gut  2005;54:1151–1156

35. Embolic Therapies Indications: Non surgical HCC intermediate stage patients multifocal liver-disease not candidates for resection, transplantation, ablation no vascular invasion; no shunting; no extra hepatic disease Contraindications Absolute Child’s C cirrhosis Total bilirubin > 3mg/dl Main PV thrombosis Relative Bilirubin ≥2mg/dl Cardiac & renal insufficiency variceal bleed,thrombocytopenia

36. Arterial directed Embolic Therapies: Principal rely on the dual blood supply of the liver: arterial and portal venous. portal vein provides 75-80% of the blood to hepatic parenchyma, hepatic artery is primary supply of tumor. Selectively delivering agents trans arterially into hepatic artery targets the tumor while sparing the liver. portal blood flow protect the noncancerous liver from the treatment agents and ischemia.

37. Trans arterial embolic therapy: procedure  interventional radiology  performed by angiography  gaining percutaneous access to  hepatic artery  passing catheter into branch supplying tumor. selective angiogram performed distal most branches supplying the tumor(s) identified embolic particles gel foam/microspheres are injected At completion catheter and removed & bleeding from punctured artery controlled by applying pressure to the entry site

38. Trans-arterial Therapy Types: bland hepatic artery embolization (HAE) Chemoembolization (CE) Conventional TACE DEB DOX-TACE Trans-arterial radiotherapy(TART ) Yttrium-90 microspheres Iodine-131 lipiodol Rhenium-188, Holmium-166

39. Three types of trans arterial therapies 1. bland hepatic artery embolization (HAE) tumor killing due to ischemia not very effective 2. Chemoembolization (CE) kills tumor with ischemia & chemotherapy mitomycin C, doxorubicin, cisplatin loaded in gelatin ,pvc microspheres most commonly used DEB: allow more distal occlusion of small vessels and delivery of high-dose chemotherapy to tumor with low systemic circulation 3. radio embolization (RAE)/TART/internal radiotherapy involves the administration of radioactive source loaded in glass or resin microspheres intra-arterially.  .

40. Internal radiotherapy delivery of radioisotopes by direct intra-tumour implantation via percutaneous route injecting radioisotope through the hepatic artery directly into the tumour or trans-arterial radioisotope therapy (TART). parenteral injection of radiolabelled antibodies specific to HCC antigens (radio immunotherapy)

41. TART: trans arterial radiotherapy Indication inoperable HCC Small HCC close to vital structure: ablation contraindicated as a neoadjuvant therapy before surgery as an adjuvant therapy, after limited surgery or ablative therapy to reduce the risk of recurrence HCC with portal vein thrombosis Palliative

42. Radioisotope

43. Systemic therapy large number of clinical trials performed with chemotherapy, given as single agent or in combination no proven benefits on survival Most promising results with gemcitabine 1 as single agent & gemcitabine + oxaliplatin 2 or cisplatin, doxorubicin, 5-fluorouracil 3 in combination. Many other non- chemotherapeutic agents tried including LHRH agonists, tamoxifen, IFN, statin, megestrol, vitamin K, thalidomide, interleukin-2, without any definitive success, 1.Yang TS, Lin YC, Chen JS, et al. Phase II study of gemcitabine in patients with advanced hepatocellular carcinoma.  Cancer  2000;89:750–756. 2. Leung TW, Patt YZ, Lau WY, et al. Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma.  Clin Cancer Res  1999;5:1676–1681 3. Louafi S, Boige V, Ducreux M, et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC).  Cancer 2007;109:1384

44. MOLECULAR THERAPY vascular endothelial growth factor (VEGF) promotes HCC development and metastasis , Hence antiangiogenic agents studied extensively sorafenib is the only molecular agent approved. Sorafenib is a multikinase inhibitor that targets VEGF,PDGF receptor, RAF inhibitor

45. Phase III, multicentre RCT , 602 patients with advanced HCC   Child-Pugh Class A randomized to either sorafenib 400 mg b.d or placebo. primary outcomes: O.S & time to symptomatic progression. study was stopped, after 2 nd prespecified interim analysis( 321pts.were dead) Median OS 10.7 vs.7.9 months in sorafinib vs. placebo (HR=0.69; 95% C.I, 0.55 to 0.87; P<0.001) N.S difference in median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). 7pts. in sorafenib (2%) and 2 in placebo (1%) had PR ;no patients had CR Diarrhea, weight loss, hand–foot skin reaction, and hypophosphatemia were more frequent in sorafenib gp . Llovet et al. (2008) SHARP-Sorafenib HCC Assessment Randomized Protocol

46. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001 There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001

47. Radiotherapy

48. Why RT is not the initial choice in HCC Late presentation: large tumour-underlying chirrhosis: ONLY palliative care HCC considered ‘ radio-resistant ’. Liver is relative radiosensitive; low tolerance EBRT dose of 30 Gy@ 2Gy/# whole liver considered threshold for RILD: far less than standard tumoradical doses. Even 25 Gy in 10 # or 32 Gy in 1.5 Gy/# bid was associated with >5% risk of RILD, particularly with cirrhosis and chronic liver ds. Difficult to deliver high dose Difficult to spare liver: moves with respiration: large margin Technology not available to deliver precise RT

49. RILD: limit dose of RT RILD can be categorized as classic and non-classic. Classic RILD : anicteric ascites, hepatomegaly, and elevated liver enzymes (particularly alkaline phosphatase) typically occurs within 4 months of therapy veno-occlusive disease  Nonclassic RILD : in patients with hepatitis and cirrhosis, jaundice and markedly elevated serum transaminases (>5 times the upper limit of normal) within 3 months of completion of therapy. direct hepatocyte rather than endothelial injury

50. Radiotherapy For Unresectable HCC Dose Response Relationship higher the radiation doses given, the higher the tumor response seen

51. Sem Rad Onc-Dawson L 2013,21; 241-246 portal vein thrombosis obstructive jaundice recurrent HCC

52. Klein, J., & Dawson, L. a. (2013). HCC radiation therapy: Review of evidence and future opportunities. IJROBP 87 (1), 22–32.

53. Klein, J., & Dawson, L. a. (2013). Hepatocellular carcinoma radiation therapy: Review of evidence and future opportunities. International Journal of Radiation Oncology Biology Physics , 87 (1), 22–32. SBRT has comparable effectiveness in treating HCC compared with other local therapies

54. Klein, J., & Dawson, L. a. (2013).HCC therapy: Review of evidence and future opportunities. IJROBP 87 (1), 22–32.

55. Klein, J., & Dawson, L. a. (2013). Hepatocellular carcinoma radiation therapy: Review of evidence and future opportunities. International Journal of Radiation Oncology Biology Physics , 87 (1), 22–32. SBRT as bridge to transplant RT has been delivered safely as a bridge to liver transplant, especially if other bridging therapies are contraindicated.

56. Klein, J., & Dawson, L. a. (2013). Hepatocellular carcinoma radiation therapy: Review of evidence and future opportunities. International Journal of Radiation Oncology Biology Physics , 87 (1), 22–32.

57. Combination TACE & RT In Unresectable HCC

58. Klein, J., & Dawson, L. a. (2013). Hepatocellular carcinoma radiation therapy: Review of evidence and future opportunities. International Journal of Radiation Oncology Biology Physics , 87 (1), 22–32.

59. Klein, J., & Dawson, L. a. (2013). Hepatocellular carcinoma radiation therapy: Review of evidence and future opportunities. International Journal of Radiation Oncology Biology Physics , 87 (1), 22–32 .

60. Klein, J., & Dawson, L. a. (2013). Hepatocellular carcinoma radiation therapy: Review of evidence and future opportunities. International Journal of Radiation Oncology Biology Physics , 87 (1), 22–32

61. Soliman , H.,Dawson , L. a. (2012). Phase II Trial of Palliative Radiation Therapy for Symptomatic Hepatocellular Carcinoma and Liver Metastases. International Journal of Radiation Oncology*Biology*Physics , 84 (3), S10 . N=40 (21 HCC) tumors unsuitable for resection, transplantation, RFA, systemic therapy, conformal RT, or SBRT Eligible patients had ≥ 1 of following symptoms attributed to liver cancer: pain, abdominal discomfort, nausea, or fatigue. ECOG 0 to 2, expected survival > 3 months,Child Pugh A-B 8Gy SFRT The Brief Pain Inventory (BPI), EORTC QoL completed by patients at baseline & each follow-up At 1 month, 48% had an improvement in symptom (primary end point) 25% had improvement of QoL (sec. end point)

62. Radiotherapy techniques Internal radiotherapy 3D-conformal radiation therapy intensity-modulated radiation therapy [IMRT] stereotactic body radiation therapy [SBRT] Proton beam therapy (PBT )

63. EBRT TECHNIQUES Simulation And Field Design CT-based treatment planning recommended Position: Supine with arms above head Immobilization: wing board, alpha cradle Contrast: oral and I.V The CT scan taken 3- to 5-mm-thick slices from the level of the carina to L5-S1 . Treatment plans individualized multiple fields used to precisely irradiate the tumor and spare normal tissues

64. Treatment volumes Whole Liver (palliation only). AP/PA, chose borders based on CT scan 3DCRT reasonable because permits generation of DVHs Partial Liver (definitive option). For 3DCRT/IMRT treatment planning GTV: defined by a arterial phase CT scan & MRI scan , fusion preferred CTV = GTV+ 1 cm in all directions PTV = CTV + 0.5 cm for setup error + margin for organ motion error

65. SBRT Indications One to three lesions, Maximum tumor diameter ≤ 6 cm no extra hepatic disease. Child-Pugh A or selective B liver disease Comprehensive, N., & Network, C. (2015). Hepatobiliary Cancers. NCCN Clinical Practice Guidelines in Oncology , I , 1–94.

66. For SBRT treatment planning breathing motion should be less than 5 mm or controlled with external compression or an ABC device. The CTV for SBRT should include the GTV + 0.5–1 cm. The PTV should include the CTV + 0.5 cm for set-up uncertainty and an additional margin for breathing motion. fiducials such as gold seeds placed in the tumor by CT or US guidance can sometimes be used to track tumor motion during respiration Normal tissues to be delineated include bilateral kidneys, normal and diseased liver, spinal cord, stomach, and small bowel. Dose volume histograms should be used to outline dose to these structures.

67. No extra hepatic, L.N vascular invasion Non surgical HCC intermediate stage patients multifocal liver-disease no vascular invasion; no shunting; no extra hepatic disease Not suitable for lesion > 10cm Contraindicated in shunting Same as TACE Portal vein thrombosis RESECTION RF ABLATION TACE Y-90 TART SBRT TRANSPLANT

68. Thank you

69. Acute and Late Complications of RT The dose-limiting tissue injuries include the liver, stomach, duodenum, bowels, and kidneys. Acute complications include general fatigue, transient elevation of LFT, nausea, fever, and pancytopenia. Sub acute and late complications include hepatic failure, radiation pneumonitis, and G.I bleeding Hepatic failure can be avoided by an appropriate selection of patients and careful treatment planning.

70. .

71. Conclusion :   TACE/TAE versus Control: no proof of survival benefit no firm evidence to support or refute TACE or TAE for patients with unresectable HCC. More adequately powered and bias-protected trials are needed. Criticism of Cochrane metaanalysis: