Principles of Management of Hepatocellular Carcinoma

management of HCC

1. Presenter: Dr Chandrima Mukherjee Moderator: Dr Rahul Sisodiya Faculty Moderator: Dr Prashanth G MANAGEMENT OF 8/27/2024 1

2. Discuss the CTP & BCLC Criteria and its implications in Mgt of HCC Broad Principles of Surgery for HCC Broad Principles of Locoregional Therapy Basic of Liver transplant Broad Principles of Radiation Therapy including role of SBRT Broad Principles of Sytemic Therapy LEARNING OBJECTIVES 8/27/2024 2

3. ISSUES IN MANAGEMENT OF HEPATOCELLULAR CARCINOMA Stage of underlying liver disease – Assessed using Child-Turcotte-Pugh Score Etiology – Viral vs Non Viral Tumor related factors Size Number Vessel Involvement Biological Behavior Response to treatment 8/27/2024 3

4. CHILD-TURCOTTE-PUGH SCORE 8/27/2024 4

5. Types of Management strategies: Curative Surgical Resection Liver Transplatation Non-curative Liver Directed Therapies Systemic Therapy Supportive Rx “For individual patients, appropriate treatment options are determined both by the extent of the HCC and the severity of underlying liver disease, which can limit tolerance to all therapies (medical, interventional, or surgical).” 8/27/2024 5

6. 6 UPDATED BARCELONA CLINIC LIVER CANCER (BCLC) CRITERIA - 2022 8/27/2024

7. 8/27/2024 7

8. 8/27/2024 8

9. SURGICAL RESECTION Preferred t/t for Non cirrhotic HCC with Normal Liver function, No Portal Hypertension Potential Remnant Functional Liver Volume ( RFLV) > 30% - Resection <30 % – Portal vein embolization( PVE) ± Total liver venous deprivation - Radiation Lobectomy For cirrhotic patients, the primary determinant of outcome and therapy selection is the degree of hepatic dysfunction and portal hypertension. Most perioperative deaths are due to postoperative liver failure 8/27/2024 9 Only compensated cirrhotics like CTP A

10. METHODS TO IMPROVE FLR: 1 ) Portal Vein Embolization (PVE ): Portal vein embolization of the affected segment allows for hypertrophy of the anticipated FLR allowing for more extensive resection. In general, there is a 30% increase in the FLR and 10% increase in SLV at the end of 2 weeks following PVE . 2 ) Trans Arterial Chemo Embolisation (TACE) : TACE has been proposed as a complimentary adjunct to PVE in the preoperative setting. In addition to embolizing the arterial supply to the tumour , it also blocks the small arterio-portal shunts that attenuate the effect of PVE in cirrhotic patients. 3) The Associating Liver Partition with Portal vein ligation for Staged hepatectomy (ALPPS) procedure has also been successfully used to increase FLR in cirrhotic patients with HCC. 4) Radiation Lobectomy - A potential advantage of radiation lobectomy is that it results in tumor control in addition to inducing contralateral hepatic hypertroph y 8/27/2024 10

11. CRITERIA FOR RESECTABILITY Solitary lesion upto 5 cm Child Pugh A Confined to liver No radiographic evidence of invasion of the hepatic vasculature, No evidence of portal hypertension ( splenomegaly, esophagogastric varices, and thrombocytopenia or directly determined by hepatic venous wedge pressures ( ≥ 10 mmHg). 8/27/2024 11

12. 8/27/2024 12

13. LIVER TRANSPLANTATION Liver transplantation (LT) is the ideal therapy for HCC in cirrhotic patients because it treats cancer and the underlying parenchymal disease. 8/27/2024 13 For patients with end-stage liver disease (ESLD) and limited HCC, OLT is currently the best treatment modality

14. MILAN CRITERIA 8/27/2024 14 MC USED CRITERIA FOR SELECTING HCC PTS FOR TRANSPLANT

15. USCF CRITERIA 8/27/2024 15 The UCSF criteria were associated with 90% and 75% survival at 1 and 5 years, respectively

16. 16 8/27/2024

17. To qualify for the waitlist, a biopsy or one of the following criteria must be fulfilled: AFP > 500 ng/mL, arterial enhancement followed by a portal venous washout on computed tomography (CT) scans or magnetic resonance imaging (MRI), or a history of loco regional treatment . The tumor should be assessed every 3 months by CT scans or MRI to rule out disease progression beyond the established criteria. 17 8/27/2024

18. BRIDGE TO TRANSPLANT •Patients fit for transplant often have a long list of waiting for orthotopic liver transplant– Bridge therapy is recommended Bridge therapy prevents disease progression while awaiting turn for orthotopic liver transplant 8/27/2024 18

19. 19 8/27/2024 Limmatal et al, Feb 2021 Multimodal treatment strategies for colorectal liver metastases Tumors adjacent (within 1 cm) to larger (>3 mm) blood vessels may be undertreated due to the thermal sink effect. The effect occurs when blood flowing near the lesion causes a cooling effect, which reduces the volume of the ablation. L esser susceptibility to heat sink effects and faster treatment time, particularly with multiple simultaneous applicators, are attractive features of MWA compared to RFA.

20. Irreversible Electroporation Irreversible electroporation (IRE) is a relatively new, largely nonthermal electrical ablation technology. It is less susceptible to the thermal heat sink  limit the efficacy of thermal ablation devices in treating tumors adjacent to blood vessels  less likely to damage critical structures, such as major bile ducts. IRE uses high-power large electrical currents delivered between electrode pairs placed into tumors. 8/27/2024 20

21. Arterially Directed Therapies for Regional Disease Recommended for patients with BCLC B (intermediate stage) disease. Intermediate stage disease includes multifocal liver–confined tumor in patients with preserved liver function and good performance status (ECOG 0). In practice, the indications for ADT often extend to include patients with BCLC C (advanced stage) that have limited extrahepatic disease and/or portal vein tumor involvement or mildly compromised performance status. 8/27/2024 21 Approximately 75% of the nutrient blood flow to the liver comes from the portal vein, and most of the tumor supply is from the hepatic artery. Therefore, we can administer intraarterial treatment safely to the tumor with little effect on the non–tumor-bearing liver parenchyma. Rationale for ADTs – Dual blood supply of liver

22. BLAND EMBOLISATION Bland embolization refers to the use of small particles (≤100 μ) to induce complete stasis of the arterial supply to the tumor to cause ischemic necrosis P ostembolization syndrome of pain, fever, and nausea that may last several days to a few weeks 8/27/2024 Video – TACE Procedure - https://youtu.be/36hxiPXPTWQ?si=9eDigBYaX30MZTsV 22 TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION HCC is a highly vascular tumor, has strong neoangiogenic activity during its progression. TACE combines selective injection of chemotherapeutic agents through arteries feeding the tumor followed by intra-arterial embolization of tumorfeeding arteries with lipiodol , an iodized oily contrast agent, Gelfoam , or plastic particles such as Ivalon . Preferred modality for Bridge therapy – due to easy availability (L evel I evidence of a survival benefit to conventional TACE compared to conservative management) Llovet et al ( 2002) Lancet

23. 8/27/2024 23 RAE Radioembolization (RAE) or selective internal radiation therapy involves the administration of glass or resin beads loaded with Y90 into the arterial supply of the tumor. Y90 -beta emitter - range of only a few millimeters in tissue and a half-life of 2.67 days. Standard dosimetry is calculated based on the volume of the liver to be treated and the intended dose to the tumor based on pre t/t angio . Y90 is the preferred ADT in patients with portal vein tumor thrombus (PVTT). Side effects of RAE consist of mild nausea, pain (although typically less than TACE), and fatigue. Rare complications include radiation-induced liver disease, radiation pneumonitis, and GI ulceration from nontarget embolization.

24. RADIATION THERAPY AS LOCAL ABLATION Liver – One of the most Radiosensitive organs – Aim of Planning – Max dose to tumor, min dose to normal tissue Radiation therapy (RT) for liver tumors was historically limited by hepatic toxicity Who are the candidates for RT Ablation?? Unresectable Tumors Medically Inoperable pts Size > 3cm Proximity to Diaphragm , Large Vessel, Gall Bladder 8/27/2024 24 Pts who could not be effectively t/t by RFA

25. Radiation segmentectomy and radiation lobectomy - use ablative doses of radiation to improve tumoricidal effect and cause contralateral hepatic hypertrophy, respectively. In radiation segmentectomy, a tumor localized to a single segment can be selectively treated with a dose calculated for the entire liver lobe, achieving doses of over 400 Gy to cause segmental liver ablation. Radiation lobectomy is performed to treat tumors and induce ipsilateral lobar atrophy and contralateral hypertrophy in patients who are potential candidates for resection . 8/27/2024 25

26. SBRT SBRT can be considered as an alternative to ablation/embolization techniques or when these therapies have failed or are contraindicated. ( NCCN 2022) With high doses per fraction, the biologic effect is greater than with the same dose delivered in a standard fractionated course, up to the equivalent of 80 to 150 Gy in 2-Gy fractions Postulated mechs of RT injury: (a) Ablative direct cell kill (b) Endothelial targets – RT increases tumor Ag specific immune response SBRT is used in patients with 1-3 tumors. Parameters in Deciding T/t: 8/27/2024 26 For tumors < 2cm , SBRT = RT ablation For Tumors > 2cm, SBRT gives a better PFS

27. SIDE EFFECTS OF RT Primary toxicity of concern is a radiation-induced liver disease (RILD), categorized as classic and non-classic. Classic RILD is a constellation of anicteric ascites, hepatomegaly, and elevated liver enzymes (particularly alkaline phosphatase), which typically occurs within 4 months of therapy and is a type of veno -occlusive. Nonclassic RILD , a more recent classification, is characterized by jaundice and markedly elevated serum transaminases (>5 times the upper limit of normal ) within 3 months of therapy completion. This is thought to represent direct hepatocyte rather than endothelial injury RILD is typically self-limited but can be severe, even leading to mortality. It is managed symptomatically using diuretics and paracentesis. 8/27/2024 27 Even low doses to the whole liver of 25 Gy in 10 fractions or 32 Gy in 1.5 Gy per fraction twice daily are associated with a >5% risk of RILD, particularly for patients with cirrhosis and already compromised liver function RILD: i ) Transaminase / ALP > 2.5-5X ULN ii) Sr Bil > 1.5-3X ULN iii) Non malignant ascites in the absence of disease progression Hallmark – small venous obstruction – central venous congestion & collagen deposition without inflammation Rx: Diuretics, paracentesis, Vit K

28. SORAFENIB VS TACE-RT 8/27/2024 28 Randomized, open-label clinical trial Between July 1, 2013, and October 31, 2016 90 treatment-naive patients with liver-confined hepatocellular carcinoma showing macroscopic vascular invasion Primary Endpoint – 12 week PFS by ITT analysis Results: Median age- 55y At week 12, the progression-free survival rate was significantly higher in the TACE-RT group than the sorafenib group (86.7% vs 34.3%; P < .001). TACE-RT had a significantly longer median time to progression (31.0 vs 11.7 weeks; P < .001) ARMS 45 pts, Sorafenib 400 mg BD TACE (every 6 weeks) plus RT (within 3 weeks after the first TACE, maximum 45 Gy with the fraction size of 2.5 to 3 Gy

29. ROLE OF NEOADJUVANT THERAPY Recurrences, post resection, in HCC tend to be intrahepatic. Use of trans arterial chemo-embolization (TACE) was done prior to surgery in resectable cases with the aim of decreasing in-liver recurrences and a hope to prolong survival. A systematic review of 18 studies, including 3 randomized trials demonstrated that the use of TACE in the neoadjuvant setting in resectable HCC was safe and efficacious with a high rate of pathological response. However, it did not improve survival 8/27/2024 29

30. Role of Adjuvant Therapy STORM, a phase III, randomized controlled trial evaluated the benefit of Sorafenib in the adjuvant setting after resection/ ablation of HCC  showed no added survival advantage. The 2018 EASL guidelines do not recommend any neo-adjuvant or adjuvant therapy after curative resection or ablation 8/27/2024 30

31. SYSTEMIC THERAPY FOR HCC Systemic chemotherapies have had no proven benefits on survival in HCC. * 8/27/2024 31

32. SYSTEMIC THERAPY IN ADVANCED HCC 8/27/2024 32

33. 8/27/2024 33

34. 8/27/2024 34

35. BIBLIOGRAPHY Devita’s Principles & Practices of Oncology – 12 th Edition UptoDate Pubmed 8/27/2024 35

36. THANK YOU! 8/27/2024 36