Hepatocellular carcinoma: management

Hepatocellular carcinoma: managementPresented By: Dr. Isha JaiswalModerator: Prof. Kamal Sahni,Dr. Madhup RastogiDate: 22nd September 2015

Introductionaggressive tumorcurative options :surgery only70%80% patients inoperable due toadvanced stage underlying liver disease

Management depends on following factorsTumor related

Size

Stage

Location

Single vs. multiple

vascular involvement

Lymphatic spread

Extra hepatic spread

Patient related

AgePerformance statusMedical co morbiditiesPrevious treatment

liver function

Child-Pugh score Portal hypertension Cirrhosis

Treatment related factor

Multimodality treatmentHigh volume centresTransplant facilityradiotherapy techniquescost

Treatment modalitiesSurgeryliver resectiontransplantation

Local ablative therapiesRadiofrequency ablationMicrowave ablationcryoablationChemical ablation: ethanol, acetic acid

Regional therapiesTran arterial therapyRadiotherapy

Systemic therapiesChemotherapyNonchemotherapy agentsTargeted therapy

Supportive care

Grading System For Cirrhosis: Child-Pugh Score

Barcelona Clinic Liver Cancer staging System For Hepatocellular cancer

Changes in behavior with minimal change in level of consciousness+1Gross disorientation, drowsiness, possibly asterixis, inappropriate behavior+2Marked confusion, incoherent speech, sleeping most of the time but arousable to vocal stimuli+3Comatose, unresponsive to pain; decorticate or decerebrate posturing+4

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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), S115S120.

Harris, W. (n.d.). Hepatocellular Carcinoma: Clinical Update and Evolving Treatment Options.

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SURGERY ResectionInclusion criteriaAJCC Stage 1-2 Preferable size 5 cm, solitary tumorNo macro vascular, L.N, or distant metastases Non cirrhotic or compensated cirrhotic child Pugh AAdequate remnant livermedically fit

Exclusion criteriaAdvanced stageMultiple tumorsportal hypertensionChild Pugh B & C

TransplantationMilan Criteria for inclusionSingle tumours 5 cm or 3 nodules, each 3 cm No vascular invasion or distant metastasesMedically fit

In patients with multiple nodules & chronic liver disease or chirrhosis-transplantation preferred

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Types of Hepatic ResectionsNon anatomic resection:wedge resection

Anatomic resection segmentectomylobectomy (right and left)trisegmentectomy (right and left)

The excision of surface tumors may be best accomplished as a nonanatomic wedge excision, in which the tumor is simply excised with a 1-cm margin.The hepatic parenchyma can be divided using a variety of techniques, with the goal to minimize blood loss and maintain adequate exposure to ensure accurate margins are obtained. This can be performed safely for tumors up to 5 cm in diameter with minimal blood loss.

Deep tumors within the hepatic parenchyma and tumors greater than 5 cm must be managed by an anatomic resection, where the most distal portal triad to the region involved by the tumor is controlled and the segment or segments are resected.

Centrally located tumors may require a lobectomy

large tumors may require an extended hepatectomy.

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Removal of a single segment -Segmentectomy

Small triangular-shaped portion of the liver along with tumor removedWedge Resection.Indicated for small superficial& peripheral lesions

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Right lobe which consists of two segments Right Lobectomy

Left lobe which consists of two segments Left LobectomyLobectomy: indications multiple lesions are located in different areas of one lobe.

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

Lesions confined to the right lobe are amenable to en bloc removal (removal in one piece) with a right hepatectomy (liver resection) surgery.

Smaller lesions of the central or left liver lobe may sometimes be resected in anatomic segments.

Large lesions of the left hepatic lobe are resected by a procedure called hepatic trisegmentectomy (see diagram and explanation below).

When lesions are located peripherally (on the edges of the liver), hepatic wedge resection or anatomic segmentectomy are performed.

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aim of surgerycomplete resection with at least 1 cm margin maximum preservation of normal hepatic parenchyma

Post resection liver volume:at least 30% in non cirrhoticAt 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

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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

technetium-99m DTPA human serum albumin [99mTc-GSA] scintigraphy)

ICG binds tightly toplasma proteinsand becomes confined to the vascular system.[2]ICG has ahalf-lifeof 150 to 180 seconds and is removed from circulation exclusively by the liver to bile juice.[2] fluorescent dyeIt is administered intravenously and, depending on liver performance, is eliminated from the body with a half life of approx. 34 minutes13

Outcomes of ResectionWith improving patient selection and perioperative care, the outcome of hepatic resection has improved In past 10 yearsperioperative mortality rate of less than 7%,

5yr overall survival rate of 30% to 50%

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Predictive factors determining outcome after liver resectionTNM stage. 1Sizeliver resection for >5 cm tumor --more recurrences.Large HCC :propensity for vascular invasion, intraluminal & intrahepatic satellite mets surgical margins2,3,41-cm margin associated with 77% 3-year survival vs.21% with 3mg/dlMain PV thrombosis

RelativeBilirubin 2mg/dlCardiac & renal insufficiencyvariceal bleed,thrombocytopenia

Arterial directed Embolic Therapies: Principalrely 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.

Trans arterial embolic therapy: procedureinterventional radiologyperformed byangiography gainingpercutaneousaccess to hepatic arterypassing catheterinto branch supplying tumor. selective angiogram performeddistal most branches supplying the tumor(s) identifiedembolic particles gel foam/microspheres are injectedAt completion catheter and removed & bleeding from punctured artery controlled by applying pressure to the entry site

Trans-arterial Therapy Types:bland hepatic artery embolization (HAE)Chemoembolization (CE)Conventional TACEDEB DOX-TACE Trans-arterial radiotherapy(TART)Yttrium-90 microspheresIodine-131 lipiodolRhenium-188, Holmium-166

drug-eluting microspheres allow more reliable distal occlusion of small vessels and delivery of high-dose chemother apy to the tumor with a very low systemic circulation of the chemotherapeutic agen39

Three types of trans arterial therapies1. bland hepatic artery embolization (HAE) tumor killing due to ischemianot very effective

2. Chemoembolization (CE) kills tumor with ischemia & chemotherapy mitomycin C, doxorubicin, cisplatin loaded in gelatin ,pvc microspheres most commonly usedDEB: 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 radiotherapyinvolves the administration of radioactive source loaded in glass or resin microspheres intra-arterially..

Drug is not washed out due to embolizationhigher concentration of drug in contact with the tumor for a longer period of time

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Internal radiotherapydelivery of radioisotopes bydirect intra-tumour implantation via percutaneous routeinjecting 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)

Radioimmunotherapy(RIT) uses anantibodylabeled with aradionuclideto deliver cytotoxic radiation to a target cell.[1]In cancer therapy, an antibody with specificity for a tumor-associated antigen is used to deliver a lethal dose of radiation to the tumor cells. The ability for the antibody to specificThe ability for the antibody to specifically bind to a tumor-associatedantigenincreases the dose delivered to the tumor cells while decreasing the dose to normal tissues41

TART: trans arterial radiotherapyIndicationinoperable HCCSmall HCC close to vital structure: ablation contraindicatedas a neoadjuvant therapy before surgeryas an adjuvant therapy, after limited surgery or ablative therapy to reduce the risk of recurrenceHCC with portal vein thrombosisPalliative

Sealed sources are dose-limited by their effects on surrounding tissues, whereas with unsealed sources the dose of radio-isotope administered is limited by bone marrow suppression. Iridium-192 wires are most frequently employed as a sealed intracavitary source. They may be inserted surgically, transhepatically or endoscopically. Doses of up to 60 Gy can be delivered to a malignant biliary stricture without damage to the surrounding parenchyma. The incidence of cholangitis is low if treatment is administered after insertion of an endoprosthesis.

Unsealed radio-isotope sources may be injected directly into the tumour, administered embolically via the hepatic artery in the form of microspheres or lipid droplets, or given via parenteral infusion attached to tumour-specific antibodies. Of these vehicles, the lipid agent Lipiodol appears to be the most effective and can deliver a potentially lethal dose of radiation to small tumours. Host reaction to the injected antibody remains a major drawback to the use of monoclonal antibodies as targeting agents. Iodine-131 is a beta- and gamma-emitter, producing a local tumoricidal effect and allowing accurate dosimetry by means of external scintigraphy. Yttrium-90 is a pure beta-emitter with a greater maximum beta energy and cytotoxic range; however, it is retained in bony tissues, resulting in a dose-related risk of marrow suppression. Bone absorption cannot be measured by external imaging owing to the absence of gamma emission. This lack of accurate dosimetry, coupled with the toxic side-effects of yttrium treatment, make iodine-131 the current isotope of choice42

Radioisotope

although due to their small size have much less embolic effect than a TACE procedure, with less effect on hepatic vascular dynamics[65]. Indeed, continued blood flow to treated tissue is necessary and desirable for radiation to have its intended effect through the production of free radicals. Yttrium-90 is a pure beta-emitting isotope that decays to zirconium-90 with a half-life of 64.1 h. Ninety-four percent of the total radiation dose is delivered within 11 d of the procedure. The emitted radiation penetrates surrounding liver tissue to an average depth of 2.5 mm and a maximum depth of 11 mm, such that there is essentially no expected radiation exposure to non-treated individuals in contact with the patient, and post-procedure isolation precautions are not necessary. Radiation doses delivered to the tumor, however, can be very high due to preferential flow of embolic particles toward hypervascular tumor tissue, in a ratio of between 3:1 and 20:1 compared43

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 gemcitabine1 as single agent & gemcitabine + oxaliplatin2 or cisplatin, doxorubicin, 5-fluorouracil3 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.Cancer2000;89:750756.2. Leung TW, Patt YZ, Lau WY, et al. Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma.Clin Cancer Res1999;5:167616813. Louafi S, Boige V, Ducreux M, et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC).Cancer2007;109:1384

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

RAF RAPIDLY GROWING FIBROSARCOMA46

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 2nd 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 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)

Radiotherapy techniquesInternal radiotherapy3D-conformal radiation therapyintensity-modulated radiation therapy [IMRT]stereotactic body radiation therapy [SBRT]Proton beam therapy (PBT)

EBRT TECHNIQUESSimulation And Field DesignCT-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

Treatment volumesWhole 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 planningGTV: defined by a arterial phase CT scan & MRI scan , fusion preferredCTV = GTV+ 1 cm in all directions PTV = CTV + 0.5 cm for setup error + margin for organ motion error

SBRTIndicationsOne to three lesions, Maximum tumor diameter 6 cmno 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, 194.

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For SBRT treatment planningbreathing motion should be less than 5 mm or controlled with external compression or an ABC device. The CTV for SBRT should include the GTV + 0.51 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 respirationNormal 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.

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No extra hepatic, L.N vascular invasionNon surgical HCC intermediate stage patients multifocal liver-diseaseno vascular invasion; no shunting; no extra hepatic disease

Not suitable for lesion > 10cmContraindicated in shuntingSame as TACEPortal vein thrombosis

RESECTIONRF ABLATIONTACEY-90 TARTSBRTTRANSPLANT

Thank you

Acute and Late Complications of RTThe 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.

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Conclusion:TACE/TAE versus Control: no proof of survival benefitno 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: