Presentation on theme: "Interventional Oncology vs. Liver Tumors: What’s in the quiver?"— Presentation transcript:
1Interventional Oncology vs. Liver Tumors: What’s in the quiver? Howard M. Richard, III, MD1. Explain the various modalities utilized in the treatment of liver tumors2. Discuss the nature of clinical evidence for the various interventional oncology options for treating liver tumors3. Discuss the rationale for choosing between the various options based on the varied clinical presentations of liver tumors
3OverviewExplain the various modalities utilized in the treatment of liver tumorsDiscuss the nature of clinical evidence for the various interventional oncology options for treating liver tumorsDiscuss the rationale for choosing between the various options based on the varied clinical presentations of liver tumors
4History Liver resection for cure Only 20% of patients are candidates for curative resectionLiver transplantScarcity of livers > up to 30% of candidates will have disease progression and fall off transplant listLiver resectionLobectomy, segmentectomy...
5Resection for cure Milan criteria for liver transplantation One lesion smaller than 5cmThree lesions smaller than 3cmNo extra-hepatic diseaseNo vascular invasionPartial liver resectionFunctional liver remnant
6Resection for cure26% functional liver reserve for patients with normal liver function40% high grade steatosis and after oxaliplatin- or irinotecan-based neoadjuvant chemotherapy>50% of the total liver volume for cirrhotic26.6% of the total functional liver volume in patients with normal liver parenchyma . The safe margin increases to 40% in patients with high-grade steatosis and after oxaliplatin- or irinotecan-based neoadjuvant chemotherapy, and the safe margins are >50% of the total liver volume for cirrhotic livers [2, 3].
8Modalities Resection Resection after down-staging Palliative Bridging treatmentPrior to OLT or hepatectomyResection after down-stagingPortal vein embolizationPalliativeAblationEmbolizationAdjuvant medications
9Resection for cure Extended resection Staged resection Preoperative portal vein embolization to increase future remnant liver volumeResection combined with tumor ablation
10Portal vein embolization Patients with marginal or insufficient functional liver reserveIpsilateral hepatic atrophyContralateral hepatic hypertrophyIn non cirrhotic patients % hypertrophy of contralateral lobePortal-vein embolizationIn some cases, the resection of one or more hepatic metastases is technically feasible, yet cannot be performed because the amount of liver tissue remaining after resection would be too small. To minimize the risk of postoperative hepatic insufficiency, ipsilateral hepatic atrophy and contralateral hepatic hypertrophy can be induced preoperatively by selective embolization of the hepatic portal vein, or else by ligation of the branch of the portal vein that leads to the hepatic lobe containing the metastasis. Portal-vein embolization should always be considered when the residual hepatic volume without it would be less than 30% of the normal size of the liver, and when at least two contiguous hepatic segments are free of metastases. For technical surgical reasons, the left lateral segments 2 and 3 are particularly suitable for this approach. As long as the liver is not cirrhotic, portal-vein embolization results in a 40% to 60% hypertrophy of the contralateral hepatic lobe. It remains unclear at present whether the stimulus to hypertrophy that portal-vein embolization provides might also accelerate the growth of tumor nodules (16, e35). In any case, the data regarding morbidity, mortality, and long-term survival are comparable to those of standard hepatic resections (16, e36– e39).
11Portal vein embolization Ipsilateral access into portal veinsLimits any iatrogenic damage to the eventually resected portion of the liver
12Portal vein embolization PVAN-butyl cyanoacrylateFibrin glue/LipiodolGelfoam and thrombinCoilsGentamycinEthanolNearly every commercially available embolic agent has been used for PVE, including N-butyl cyanoacrylate; fi- brin glue with Lipiodol; absolute ethanol; coils; and a mixture of Gelfoam, thrombin, contrast material, Lipiodol, and gentamicin with varying results.
13Portal vein embolization Can increase the size of the liver remnant %More effective in enlarging the left lobeUsing Ethanol requires balloon occlusion
15Ablation Thermal vs Non thermal Thermal Non thermal RFA is predominant Laser, Microwave, HiFUS, and Cryo are much less popularNon thermalEthanol is inexpensiveProven inferior to RFAIRE is emerging as an option
16Embolization Bland Chemoinfusion Chemoembolization Radio embolization Adjuvant medications
17Bland embolization Concept of hepatic arterial embolization 1950s Tumors derive 90% of blood from hepatic artery while portal vein provides majority of flow to liverGoal is terminal arterial blockade40 um particles optimally block tumor neo- vascular network
18Bland embolization Fistulas allow systemic non-target embolization Tumor ischemia > HypoxiaStimulation of angiogenesisUp-regulate pro-angiogenic factorsProvide mechanism for resisting apoptosisAssociated with metastasisPoor outcomes
19Bland embolization Benefits Disadvantages Inexpensive Repeatable Non target embolization of gallbladder, pancreatitis, liver failureLiver abscess
20Chemo infusion Infuse drug alone no embolization Infuse chemotherapeutics with first pass hepatic metabolismMaximize tumor exposure to drugMinimize systemic toxicity
21Chemo infusionFirst premise > liver can clear the drug at first pass even at high doseSecond premise > increased drug concentration in liver leads to increased responseThird premise > regional drug delivery leads to decreased systemic exposure to drug
22Chemo infusion Colorectal cancer Floxuridine FUDRIncrease response rate when compared to systemic chemoUsual referral is for patients who progress on traditional chemoHCC no improvement in survival when compared to systemic chemo
23Chemo embolizationDrugs and Gelfoam embolization introduced in the 1970s by YamadaCurrently defined asInfusion of a mixture of chemotherapeutics with or without iodized oil followed by particle embolizationPurposePrevent washout of drugInduce tumor ischemia
24Chemo embolization Higher local drug concentrations Lower systemic drug exposureCompared to systemic treatmentLipiodol is believed to increase intra-tumoral retention of the chemotherapeuticsWorldwide > single agent DoxyrubicinUS > Doxyrubicin, Cisplatin and Mitomycin C
25Chemo embolization 2002 Lo and Llovet reported RCT vs HCC Survival benefit for TX of HCCWhen compared to standard supportive treatment2006 Geschwind reported RCT vs CRCSurvival benefit for TX of CRCEffective in generating tumor responseNeuroendocrine, breast, cholangiocarcinoma...
26Chemo embolization 2009 Vogl retrospective TACE with Mitomycin C vs Mitomycin C and Gemcitabine for neuroendocrine liver metsCombination therapyImproved local controlImproved five year survival
27Chemo embolization Breast cancer mets to liver Sarcoma mets to liver Local control can be establishedSarcoma mets to liverSignificant tumor necrosisImproved survival
28Drug eluting Beads Chemoembolization with special beads Load PVA based beads with various types of chemo and deliver to hepatic arteryOnce on location, beads release drugSustained and controlled releaseImprove local delivery and minimize systemic exposure
29Drug eluting beads DC beads Biocompatibles 100-300 Yellow 300-500 Blue Red
30Drug eluting beads Quadraspheres Biosphere/Meritt Beads swell upon exposure to ionic fluidsConforms to vesselsStudies as a bland agentCan absorb Doxyrubicin
31Drug eluting beads Doxyrubicin-capable or DC beads Load with doxyrubicin 25mg/ml by immersion in drug solution for minutes.Requires drug compounding in the pharmacyDC beads have been loaded with Irinotecan for use against colorectal liver metsQuadraspheres can be loaded with Doxyrubicin
32Drug eluting beads Tumor response rates for DC beads vs HCC 10-20% total response40-60% partial response ratesIrinotecan vs CRC mets19 month overall survival in patients who had progressed on systemic chemoSafe and effectiveExpensive
38SIR-Spheres Initially developed in 1990 35 micron spheres Impregnated with yttrium-90 Particles emit beta radiationThe original concepts underpinning the core technology which has been commercialised by SIRTeX Medical was initially developed by Dr Bruce Gray and the Cancer Research Institute Inc (CRI) and have been published in the scientific literature. The CRI is an independently incorporated research institute, founded in and has undertaken many research programs investigating cancer over the past decade.Resin
39SIR Sphere Characteristics 35 μm100% ß emitterMeVHalf-life of 64.2 h2.5 mm av (max 11)Glass/Ceramic matrixSIR-Spheres® is a therapeutic radioactive implant, comprised of beta-emitting yttrium-90 microspheres. The microspheres are approximately 35 microns. The average penetration of the beta particles in tissue is 2.4 mm. The microspheres are suspended in sterile, pyrogen-free water for injection. The vials are shipped in lead shields for radiation protection.
40SIR-Spheres Selective Internal Radiation Particles lodge in capillaries of tumorSize and number of tumors does not matter
41SIR-Spheres 90Y-microspheres do not undergo any biologic degradation Activity decays to infinity at a mean life of dBeta particle decayaverage range in tissue is 2.5 mmwith a maximum range of < 11mmRADIATION DOSIMETRY90Y, a pure beta emitter, decays to stable zirconium 90 with a physical half-life of 64.2 hours (2.68 days). The average energy of the beta emissions from 90Y is MeV. The average range of the radiation in tissue is 2.5 mm, with a maximum range of less than 1 cm. A 1-GBq (27-mCi) dose of 90Y per kilogram of tissue gives an initial radiation dose of 13 Gy (1,297 rad) per day. The mean life of 90Y is 3.85 days. Thus, the radiation dose delivered by 90Y over complete radioactive decay starting at an activity level of 1 GBq (27 mCi) per kilogram of tissue is 50 Gy (5,000 rad).
43Radioembolization Response rate 90% * Falling tumor markers and serial 3-monthly CT scansHCC can be down-staged to OLT, resection or ablationIncreased survival, tumor response time and time to progression when compared to 5-FU vs CRCHepatogastroenterology Mar-Apr;48(38): Related Articles, LinksSelective internal radiation therapy (SIRT) with 90Yttrium microspheres for extensive colorectal liver metastases. Stubbs RS, Cannan RJ, Mitchell AW. Wakefield Clinic for Gastrointestinal Diseases, Private Bag 7909, Wellington, New Zealand. BACKGROUND/AIMS: SIRT (selective internal radiation therapy) is a new modality for the treatment of nonresectable liver tumors which has been reported to achieve high response rates. We report our initial experience in patients with extensive colorectal liver metastases. METHODOLOGY: Thirty-eight (38) patients were treated with SIRT between February 1997 and November Liver involvement was < 25% in 19 patients, 25-50% in 9 and > 50% in 10. Patients received 90Yttrium microspheres into the hepatic artery via an arterial port and subsequent 4-weekly cycles of hepatic artery chemotherapy with 5-fluorouracil. RESULTS: SIRT was well tolerated and no treatment-related mortality was observed. Responses to SIRT as indicated by falling tumor markers and serial 3-monthly computed tomography scans were seen in over 90% of patients. Estimated survival at 6, 12 and 18 months was 70%, 46% and 46%, respectively, and was principally determined by the development of extrahepatic metastases. CONCLUSIONS: SIRT is well tolerated in patients with extensive colorectal liver metastases and achieves encouraging liver tumor responses, which are well maintained by hepatic artery chemotherapy. The modality warrants wider use and investigation.* Hepatogastroenterology Mar-Apr;48(38):333-7.
44Dose Distribution and Effect MAAPET After TheraSphere®PET Before TheraSphere®
45Adjuvant chemotherapy Sorafenib (Nexavar, Bayer)MultiKinase inhibitor (anti VEGF)Can be used to decrease intratumoral arteriovenous fistulas and enable SIRBevacizumab (Avastin, Genentech)Monoclonal antibody to vascular endothelial growth factorAugments efficacy of TACE vs HCC
46Discussion Radioembolization vs HCC Radioembolization vs CRC Treatment can down stage patients to become eligible for transplant, resection or ablationRadioembolization vs CRCCompared to hepatic artery chemotherapyDecreased time to progressionIncreased survivalRadioembolization vs neuroendocrineIncreased survival compared to systemic treatment
47Discussion Lo and llovet RCT for HCC DEB vs embolization Chemoembolization is superior to best supportive careDEB vs embolizationDEB is superior to bland embolizationLonger time to progression
48Discussion DEB vs chemoembolization DEB higher rate of responseDEB fewer adverse eventsDEB has yet to show a survival benefitRadioembolization vs ChemoembolizationSIR better at downstaging HCCSIR less toxicitySIR has yet to show survival benefit
49DiscussionSurgery compared to embolization and ablation for HCC up to 7cmFive year survival 56 to 54%Chemoembolization vs CE and ablation for HCC 3-5cmCE & RFA is more effectiveRadio embolization & 5-FU vs 5-FU for CRCSIR & 5-FU is well tolerated, improved time to progression
50ConclusionsAblation with RFA is choice for small tumors when surgery or transplantation is not feasibleIRE is a choice when ablation target is adjacent to large vessels (Heat Sink) or central bile ductsEthanol or cryoablation can be used if target is in sensitive location ie. Near the dome of the diaphragm or heart
51ConclusionsChemoembolization is standard for intermediate/ advanced unresectable HCCCE can help select patients for OLT (bridge)Combination of CE and Ablation is effective with limited toxicityDrug eluting bead will replace oil based chemoembolization
52Conclusions Y-90 is safe and effective as outpatient TX Y-90 for HCC Downstaging / bridging to transplantation or resectionPortal vein thrombosisAdvanced disease
53Decisions decisions Milan criteria for resection Few lesions If close consider portal vein embolization, CE, SIRFew lesionsAblationModerate diseaseCEExtensive diseaseSIR