- Email: [email protected]
THU-05 Does size matter in embolotherapy?
S234
Abstracts of the 3rd ITLT Essen 2013 / Digestive and Liver Disease 45S (2013) S233–S260
same tumor. Corresponding data in colorectal cancer are as yet not available, but it is fair to assume that also colorectal cancers at least to some degree also exhibit intratumoral heterogeneity. This adds another level of complexity when we interpret gene expression profiles that have been obtained from single tumor biopsies, in particular when we want to use these signatures to personalize a patients cancer treatment. Finally, we have to consider that the selection pressure exerted on a primary tumor or its metastases by chemotherapy combinations or targeted therapies may be even more relevant than molecular differences between the primary tumor and the metastases. Recent data show that during treatment of patients with K-ras wild type CRC using anti-EGFR antibodies the amount of K-ras mutant DNA detectable in the patients blood substantially increases most likely due to increased proliferation of K-ras mutated, anti-EGFR resistant tumor cell clones that were present already at the beginning of the treatment albeit at low frequency (Diaz et al., 2012). Conclusions: – Core mutations as well as chromosomal aberrations and gene expression profiles are surprisingly similar in CRC primary tumors and matched metastases. – Effective dissemination of tumor cells appears to occur rather late in the molecular development of colorectal cancer. – Metastases may gain a stem cell signature and change their behaviour. – Novel data also suggest substantial intratumoral heterogeneity that will affect the behaviour of tumors and their metastases. – We have so far few molecular data on tumor evolution during drug therapy, but it certainly exists and is relevant. References: [1] Diaz LA Jr, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, Allen B, Bozic I, Reiter JG, Nowak MA, Kinzler KW, Oliner KS, Vogelstein B. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 201228;486(7404):537–40. doi: 10.1038/nature11219. [2] Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366(10):883–92. doi: 10.1056/NEJMoa1113205. Erratum in: N Engl J Med 2012 Sep. [3] Shibayama M, Maak M, Nitsche U, Gotoh K, Rosenberg R, Janssen KP. Prediction of Metastasis and Recurrence in Colorectal Cancer Based on Gene Expression Analysis: Ready for the Clinic? Cancers 2011;3(3):2858–69; doi: 10.3390/cancers3032858. [4] Stange DE, Engel F, Longerich T, Koo BK, Koch M, Delhomme N, Aigner M, Toedt G, Schirmacher P, Lichter P, Weitz J, Radlwimmer B. Expression of an ASCL2 related stem cell signature and IGF2 in colorectal cancer liver metastases with 11p15.5 gain. Gut 2010;59(9):1236–44. doi: 10.1136/gut.2009.195701. Epub 2010 May 17. [5] Vakiani E, Janakiraman M, Shen R, Sinha R, Zeng Z, Shia J, Cercek A, Kemeny N, D’Angelica M, Viale A, Heguy A, Paty P, Chan TA, Saltz LB, Weiser M, Solit DB. Comparative genomic analysis of primary versus metastatic colorectal carcinomas. J Clin Oncol 2012;30(24):2956–62. doi: 10.1200/JCO.2011.38.2994. Epub 2012 Jun 4.
THU-03
Angiogenesis inhibition in cancer P. Carmeliet ∗ Vesalius Research Center (VRC), Katholieke Universiteit Leuven, Belgium Angiogenesis, the growth of new blood vessels, plays a crucial role in numerous diseases, including cancer. Anti-angiogenesis therapies have been developed to deprive the tumor of nutrients. Clinically approved anti-angiogenic drugs offered prolonged survival to numerous cancer patients. However, the success of anti-angiogenic VEGF-targeted therapy is limited in certain cases by intrinsic refractoriness and acquired resistance. New strategies are needed to block tumor angiogenesis via alternative mechanisms. We are therefore exploring whether targeting endothelial metabolism can be a possible alternative therapeutic strategy for anti-angiogenic therapy.
THU-04
Rationale for intraarterial therapies of liver malignancies J.F. Geschwind ∗ Interventional Radiology Center, Johns Hopkins University School of Medicine, Baltimore, USA The rationale for regional chemotherapy is to maximize drug concentrations and tumor drug uptake in the target organ and minimize systemic toxicity. For regional drug delivery to successfully impact relevant outcomes, several important principles regarding tumor biology, drug pharmacology and delivery systems must be fulfilled. Liver cancer, either primary or secondary from colorectal cancer, complies with these principles, as liver cancer has a regional pattern of dissemination (with the liver being the only site of metastatic disease for long periods of time in some cases) that supports a loco-regional approach. Other salient features include the selective blood supply of liver cancer by the hepatic artery and availability of active drugs with suitable pharmacokinetic properties. The ultimate goal of regional therapy is to improve the therapeutic index by increasing efficacy and decreasing systemic toxicity. Hepatic arterial therapy relies on two important assumptions: Regional delivery of the drug leads to increased local concentration and therefore increased therapeutic response and regional delivery of the drug leads to decreased systemic exposure and reduced systemic toxicity. The suitability of any specific drug for regional therapy can be evaluated by the extent to which it fulfills these assumptions. However, drugs that must be activated at a site other than the arterial infusion site have no regional delivery advantage. It should be noted that although pharmacokinetic parameters may allow a selective increase in hepatic tumor exposure, the crucial target effect of a particular drug (e.g. DNA incorporation of a thymidine analog) might also exhibit non-linear kinetics. In this case, the impact on what actually is most important, the drug effect, rather than the increased drug concentration, might be less selective at high rather than at low dose rates. This is the concept of tissue-related pharmacokinetics and takes into account not only saturating pharmacokinetics in the tumor but also in systemic tissues. If at high dose rates, the plateau for the effect is higher in systemic tissues rather than for the tumor itself, loss of regional selectivity is observed. The paradigm that increased dose will result in increased biologic effect has been challenged by the recent development of targeted agents active against cancer. Most cytotoxic drugs act on DNA or tubulin, exhibit a sigmoidal steep dose-response curve and dose selection is based on maximal tolerated dose. However, for targeted therapies, more is not necessarily better. Pharmacodynamic effect is thought to be the result of receptor occupancy and saturation. Optimal target inhibition occurs at a specific drug concentration, and increasing the dose will not increase the effect. Furthermore, at useful drug concentrations, the maximum tolerated dose may have not been reached. As this has been recognized, the need for new strategies to define the clinically active dose level for this kind of drugs is evident. The traditional phase I trial, useful for cytotoxic drugs dose selection, does not accomplish the goal for targeted agents. Other parameters including pharmacokinetic endpoints such as achieving a predefined target plasma level or direct measurement of target inhibition may be more relevant. As the field of interventional radiology continues to evolve, the notion of how intraarterial-based procedures impact the tumor microenvironment will become increasingly important and relevant. As a result, the knowledge of how drugs can be better delivered to tumor tissue will be even more critical in order to improve tumor response and more importantly patient survival.
THU-05
Does size matter in embolotherapy? F. Orsi ∗ Unit of Interventional Radiology, IEO IstitutoEuropeo di Oncologia Milan, Italy Although liver resection remains the gold-standard curative local treatment, during the past three decades, several local treatments have been developed, such as intra-arterial treatments, percutaneous thermal ablation, stereotac-
Abstracts of the 3rd ITLT Essen 2013 / Digestive and Liver Disease 45S (2013) S233–S260 tic radiotherapy and, more recently, high intensity focused ultrasound. The intra-arterial route for tumor liver therapy is based on the premise that hepatic tumors are fed mainly, if not exclusively, by arteries. Based upon this theory, investigators proposed different local treatments for liver tumors, such as chemoembolization (TACE), bland embolization (TAE), intra-arterial chemotherapy (HIAC) and more recently the so called “radio-embolization” (SIRT). TACE and TAE, however, represent the most common endovascular approaches for local treatment of liver tumors, for which were developed many different embolic agents. Gelfoam sponge powder was used as one of the first embolic agents, but the efficacy was reported to be low because it stayed only temporarily within the tumor vascular mesh. Polyvinyl-alcoholic foam (PVA) is another embolic agent often used for liver tumor; it has been reported too heterogeneous in shape and size. The embolizing performance of this material can be very unpredictable, mainly because the particles clump and aggregate within the vessel lumen (and very often, to the catheter) and cause occlusion of larger and too peripheral vessels. It may allow for the development of new distal feeding arteries to the target lesion, with poor clinical outcomeIn the past two decades several different spherical embolic agents have been then intensively investigated, such as trisacryl gelatin microspheres, collagen-coated microspheres, dextran microspheres and PVA spheres. The development or refinement of spherical embolic particles has remarkably increased the spectrum of interventional radiology, especially in the treatments of HCC or the so called “hypervascular” liver lesions, reducing or avoiding particle clusters within peripheral vessels and allowing for a deeper penetration in the neoplasm vasculature, with permanent and effective staining. Up to now, several new different embolic agents were developed, some of them with promising new features, such as drug elution.According to the literature, microsphere calibration should allow for adapting the microspheres to the size of the vessels to be occluded, so that accurate targeting can be obtained. Moreover, the use of calibrated microspheres should permit a better control of the extent of occlusion, which depends on the number of injected particles and the penetration of the embolic agent within the tissue.Until now, there has been no evidence to determine the most important feature an embolic agent should have for effective local treatment. The dimension and shape of embolic particles, however, seem to be the most important characteristics for this aim. In the majority of published studies on HCC treatment with TAE, the reported embolic agent is gelatine sponge, which may induce only temporarily ischemia and without distal tumor vessel embolization. Only recently, few new studies on new embolic agents, such as resin or gelatine microspheres, are available. Even if there is no evidence for a better survival benefit from DEB TACE than TACE and also TAE, if performed with small particles (40/100 micron), there is an increasing general consensus about the need to use the smallest available particles in treating HCC, in order to achieve a better, durable and deeper embolic effect, independently by the use of drug or not. Few papers on HCC treatment with TAE, using very small particles, reported an interesting safety profile with local results comparable with DEBTACE/TACE series (33). However, based on data coming from old papers on TAE with gelatin sponge, BCLC doesn’t recommend the use of TAE for HCC.
THU-06
Does size matter in local ablation? L. Crocetti ∗ Division of Diagnostic Imaging and Intervention Department of Hepatology and LiverTransplantation, University Hospital of Pisa, Italy Loco-regional treatments play a key role in the management of primary and liver tumors. Due to the inner features of all ablative modalities, related to the type of energy and the design of the devices, the size of tumor represents one of the most important factors to be taken into consideration in order to guarantee the highest probability of treatment success. Hepatocellular carcinoma (HCC) represents a unique example on how different interventional techniques – ablative and intra-arterial – can be used and combined according to tumor size, number and location. In very early stage HCC the presence of a solitary small nodule, less than <2 cm in diameter, in Child-Pugh A patients, the absence of microvascular invasion and dissemination offers the highest likelihood of cure. Nodules
S235
<2 cm that are not not subcapsular nor perivascular are the ideal target for percutaneous RFA, which is considered the standard technique for liver tumor ablation at most institutions. In patients with very early HCC the complete response rate approaches 97%, with 5 year survival rates of 68%. It has also been pointed out that individual components belonging to each patient (e.g. whether the tumor is central or peripheral, close or distant form bile ducts, in patient who is lean or overweight, presenting with or without portal hypertension, etc.) influence the results of each treatment making it better or worse than average. Since clinical experience suggests that treatment by RFA of HCC tumors in subcapsular location or adjacent to the gallbladder is associated with an increased risk of major complications and incomplete ablation, such tumor locations are considered favourable for hepatic resection. Therefore, in patients with very early HCC, RFA can be offered as a first-line treatment, considering surgical approach when individual variables, including tumor location, would make RFA not feasible or not safe. Patients with early stage disease have preserved liver function (Child–Pugh A and B) with solitary HCC or up to 3 nodules <3 cm in size. These patients can be effectively treated by resection, liver transplantation or percutaneous ablation with possibility of long term cure, and 5-year survival figures ranging from 50% to 75%. Among different ablative techniques, RFA is currently considered as the best treatment option in patients with early stage HCC. Five randomized controlled trials (RCTs) have compared RFA versus PEI for the treatment of early-stage HCC. These investigations consistently showed that RFA is more effective than PEI, leading to a better local control of the disease. The assessment of the impact of RFA on survival has been more controversial. While a survival benefit was identified in the three RCTs performed in Asia, the two European RCTs failed to show statistically significant differences in overall survival between patients who received RFA and those treated with PEI, despite the trend favoring RFA. Nevertheless, three independent meta-analyses including all RCTs, have confirmed that treatment with RFA offers a survival benefit as compared with PEI, particularly for tumors larger than 2 cm, thus establishing RFA as the standard percutaneous technique in these patients. Recent reports on long-term outcomes of RFA-treated patients have shown that in patients with Child-Pugh class A and early-stage HCC, 5-year survival rates are as high as 51–64%, and may reach 76% in patients who meet the BCLC criteria for surgical resection. An important factor that affects the success of RFA is the ability to ablate all viable tumor tissue and create an adequate tumor-free margin. The target tumor should not exceed 3 cm at its longest axis to achieve best rates of complete ablation using most of the currently available devices. Moreover, even in small tumors, the ability of RFA to achieve complete tumor eradication appears to be dependent on tumor location. Histological studies performed in liver specimens of patients who underwent RFA as bridge treatment to transplantation showed that the presence of large (3 mm or more) abutting vessels results in about 50% drop in the rate of complete tumor necrosis because of the heat loss due to perfusion-mediated tissue cooling within the area to be ablated. Therefore in patients with solitary HCC >3 cm and <5 cm in size the success rate of RFA alone is decreased; combination with intra-arterial treatment could be considered in these patients. A combination of TACE followed by RFA has been used to minimize heat loss due to perfusion-mediated tissue cooling and increase the therapeutic effect of RFA. Recently the results of a RCT aimed to evaluating the therapeutic efficacy of combining RFA with TACE for treating intermediate-sized (3.1–5 cm) HCCs have been published. Local tumor progression rate were significantly lower in the TACE–RFA treated group with respect to the RFA–only group (6% versus 39%, p=0.012). Under a different perspective, TACE with drug-eluting beads has been performed after an RFA procedure to increase tumor necrosis by exposing to high drug concentration the peripheral part of the tumor, where only sub-lethal temperatures may be achieved in a standard RFA treatment. Further research to determine optimal methods of combining chemotherapeutic regimens (both agent and route of administration) with RFA is needed. Patients with solitary large tumors (exceeding 5 cm in size) deserve a special mention. Even if these patients cannot be considered in an early stage because they do not qualify for transplantation, no upper limit of size for surgical resection appears in the BCLC flowchart, and these patients should not escape surgical referral because their tumors are too large. Different ablative modalities are not currently providing sufficient volume of ablation to treat successfully these tumors and the results of trans-arterial therapies as stand-alone treatment are highly variable in this clinical scenario. Moreover,
Abstracts of the 3rd ITLT Essen 2013 / Digestive and Liver Disease 45S (2013) S233–S260
same tumor. Corresponding data in colorectal cancer are as yet not available, but it is fair to assume that also colorectal cancers at least to some degree also exhibit intratumoral heterogeneity. This adds another level of complexity when we interpret gene expression profiles that have been obtained from single tumor biopsies, in particular when we want to use these signatures to personalize a patients cancer treatment. Finally, we have to consider that the selection pressure exerted on a primary tumor or its metastases by chemotherapy combinations or targeted therapies may be even more relevant than molecular differences between the primary tumor and the metastases. Recent data show that during treatment of patients with K-ras wild type CRC using anti-EGFR antibodies the amount of K-ras mutant DNA detectable in the patients blood substantially increases most likely due to increased proliferation of K-ras mutated, anti-EGFR resistant tumor cell clones that were present already at the beginning of the treatment albeit at low frequency (Diaz et al., 2012). Conclusions: – Core mutations as well as chromosomal aberrations and gene expression profiles are surprisingly similar in CRC primary tumors and matched metastases. – Effective dissemination of tumor cells appears to occur rather late in the molecular development of colorectal cancer. – Metastases may gain a stem cell signature and change their behaviour. – Novel data also suggest substantial intratumoral heterogeneity that will affect the behaviour of tumors and their metastases. – We have so far few molecular data on tumor evolution during drug therapy, but it certainly exists and is relevant. References: [1] Diaz LA Jr, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, Allen B, Bozic I, Reiter JG, Nowak MA, Kinzler KW, Oliner KS, Vogelstein B. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 201228;486(7404):537–40. doi: 10.1038/nature11219. [2] Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366(10):883–92. doi: 10.1056/NEJMoa1113205. Erratum in: N Engl J Med 2012 Sep. [3] Shibayama M, Maak M, Nitsche U, Gotoh K, Rosenberg R, Janssen KP. Prediction of Metastasis and Recurrence in Colorectal Cancer Based on Gene Expression Analysis: Ready for the Clinic? Cancers 2011;3(3):2858–69; doi: 10.3390/cancers3032858. [4] Stange DE, Engel F, Longerich T, Koo BK, Koch M, Delhomme N, Aigner M, Toedt G, Schirmacher P, Lichter P, Weitz J, Radlwimmer B. Expression of an ASCL2 related stem cell signature and IGF2 in colorectal cancer liver metastases with 11p15.5 gain. Gut 2010;59(9):1236–44. doi: 10.1136/gut.2009.195701. Epub 2010 May 17. [5] Vakiani E, Janakiraman M, Shen R, Sinha R, Zeng Z, Shia J, Cercek A, Kemeny N, D’Angelica M, Viale A, Heguy A, Paty P, Chan TA, Saltz LB, Weiser M, Solit DB. Comparative genomic analysis of primary versus metastatic colorectal carcinomas. J Clin Oncol 2012;30(24):2956–62. doi: 10.1200/JCO.2011.38.2994. Epub 2012 Jun 4.
THU-03
Angiogenesis inhibition in cancer P. Carmeliet ∗ Vesalius Research Center (VRC), Katholieke Universiteit Leuven, Belgium Angiogenesis, the growth of new blood vessels, plays a crucial role in numerous diseases, including cancer. Anti-angiogenesis therapies have been developed to deprive the tumor of nutrients. Clinically approved anti-angiogenic drugs offered prolonged survival to numerous cancer patients. However, the success of anti-angiogenic VEGF-targeted therapy is limited in certain cases by intrinsic refractoriness and acquired resistance. New strategies are needed to block tumor angiogenesis via alternative mechanisms. We are therefore exploring whether targeting endothelial metabolism can be a possible alternative therapeutic strategy for anti-angiogenic therapy.
THU-04
Rationale for intraarterial therapies of liver malignancies J.F. Geschwind ∗ Interventional Radiology Center, Johns Hopkins University School of Medicine, Baltimore, USA The rationale for regional chemotherapy is to maximize drug concentrations and tumor drug uptake in the target organ and minimize systemic toxicity. For regional drug delivery to successfully impact relevant outcomes, several important principles regarding tumor biology, drug pharmacology and delivery systems must be fulfilled. Liver cancer, either primary or secondary from colorectal cancer, complies with these principles, as liver cancer has a regional pattern of dissemination (with the liver being the only site of metastatic disease for long periods of time in some cases) that supports a loco-regional approach. Other salient features include the selective blood supply of liver cancer by the hepatic artery and availability of active drugs with suitable pharmacokinetic properties. The ultimate goal of regional therapy is to improve the therapeutic index by increasing efficacy and decreasing systemic toxicity. Hepatic arterial therapy relies on two important assumptions: Regional delivery of the drug leads to increased local concentration and therefore increased therapeutic response and regional delivery of the drug leads to decreased systemic exposure and reduced systemic toxicity. The suitability of any specific drug for regional therapy can be evaluated by the extent to which it fulfills these assumptions. However, drugs that must be activated at a site other than the arterial infusion site have no regional delivery advantage. It should be noted that although pharmacokinetic parameters may allow a selective increase in hepatic tumor exposure, the crucial target effect of a particular drug (e.g. DNA incorporation of a thymidine analog) might also exhibit non-linear kinetics. In this case, the impact on what actually is most important, the drug effect, rather than the increased drug concentration, might be less selective at high rather than at low dose rates. This is the concept of tissue-related pharmacokinetics and takes into account not only saturating pharmacokinetics in the tumor but also in systemic tissues. If at high dose rates, the plateau for the effect is higher in systemic tissues rather than for the tumor itself, loss of regional selectivity is observed. The paradigm that increased dose will result in increased biologic effect has been challenged by the recent development of targeted agents active against cancer. Most cytotoxic drugs act on DNA or tubulin, exhibit a sigmoidal steep dose-response curve and dose selection is based on maximal tolerated dose. However, for targeted therapies, more is not necessarily better. Pharmacodynamic effect is thought to be the result of receptor occupancy and saturation. Optimal target inhibition occurs at a specific drug concentration, and increasing the dose will not increase the effect. Furthermore, at useful drug concentrations, the maximum tolerated dose may have not been reached. As this has been recognized, the need for new strategies to define the clinically active dose level for this kind of drugs is evident. The traditional phase I trial, useful for cytotoxic drugs dose selection, does not accomplish the goal for targeted agents. Other parameters including pharmacokinetic endpoints such as achieving a predefined target plasma level or direct measurement of target inhibition may be more relevant. As the field of interventional radiology continues to evolve, the notion of how intraarterial-based procedures impact the tumor microenvironment will become increasingly important and relevant. As a result, the knowledge of how drugs can be better delivered to tumor tissue will be even more critical in order to improve tumor response and more importantly patient survival.
THU-05
Does size matter in embolotherapy? F. Orsi ∗ Unit of Interventional Radiology, IEO IstitutoEuropeo di Oncologia Milan, Italy Although liver resection remains the gold-standard curative local treatment, during the past three decades, several local treatments have been developed, such as intra-arterial treatments, percutaneous thermal ablation, stereotac-
Abstracts of the 3rd ITLT Essen 2013 / Digestive and Liver Disease 45S (2013) S233–S260 tic radiotherapy and, more recently, high intensity focused ultrasound. The intra-arterial route for tumor liver therapy is based on the premise that hepatic tumors are fed mainly, if not exclusively, by arteries. Based upon this theory, investigators proposed different local treatments for liver tumors, such as chemoembolization (TACE), bland embolization (TAE), intra-arterial chemotherapy (HIAC) and more recently the so called “radio-embolization” (SIRT). TACE and TAE, however, represent the most common endovascular approaches for local treatment of liver tumors, for which were developed many different embolic agents. Gelfoam sponge powder was used as one of the first embolic agents, but the efficacy was reported to be low because it stayed only temporarily within the tumor vascular mesh. Polyvinyl-alcoholic foam (PVA) is another embolic agent often used for liver tumor; it has been reported too heterogeneous in shape and size. The embolizing performance of this material can be very unpredictable, mainly because the particles clump and aggregate within the vessel lumen (and very often, to the catheter) and cause occlusion of larger and too peripheral vessels. It may allow for the development of new distal feeding arteries to the target lesion, with poor clinical outcomeIn the past two decades several different spherical embolic agents have been then intensively investigated, such as trisacryl gelatin microspheres, collagen-coated microspheres, dextran microspheres and PVA spheres. The development or refinement of spherical embolic particles has remarkably increased the spectrum of interventional radiology, especially in the treatments of HCC or the so called “hypervascular” liver lesions, reducing or avoiding particle clusters within peripheral vessels and allowing for a deeper penetration in the neoplasm vasculature, with permanent and effective staining. Up to now, several new different embolic agents were developed, some of them with promising new features, such as drug elution.According to the literature, microsphere calibration should allow for adapting the microspheres to the size of the vessels to be occluded, so that accurate targeting can be obtained. Moreover, the use of calibrated microspheres should permit a better control of the extent of occlusion, which depends on the number of injected particles and the penetration of the embolic agent within the tissue.Until now, there has been no evidence to determine the most important feature an embolic agent should have for effective local treatment. The dimension and shape of embolic particles, however, seem to be the most important characteristics for this aim. In the majority of published studies on HCC treatment with TAE, the reported embolic agent is gelatine sponge, which may induce only temporarily ischemia and without distal tumor vessel embolization. Only recently, few new studies on new embolic agents, such as resin or gelatine microspheres, are available. Even if there is no evidence for a better survival benefit from DEB TACE than TACE and also TAE, if performed with small particles (40/100 micron), there is an increasing general consensus about the need to use the smallest available particles in treating HCC, in order to achieve a better, durable and deeper embolic effect, independently by the use of drug or not. Few papers on HCC treatment with TAE, using very small particles, reported an interesting safety profile with local results comparable with DEBTACE/TACE series (33). However, based on data coming from old papers on TAE with gelatin sponge, BCLC doesn’t recommend the use of TAE for HCC.
THU-06
Does size matter in local ablation? L. Crocetti ∗ Division of Diagnostic Imaging and Intervention Department of Hepatology and LiverTransplantation, University Hospital of Pisa, Italy Loco-regional treatments play a key role in the management of primary and liver tumors. Due to the inner features of all ablative modalities, related to the type of energy and the design of the devices, the size of tumor represents one of the most important factors to be taken into consideration in order to guarantee the highest probability of treatment success. Hepatocellular carcinoma (HCC) represents a unique example on how different interventional techniques – ablative and intra-arterial – can be used and combined according to tumor size, number and location. In very early stage HCC the presence of a solitary small nodule, less than <2 cm in diameter, in Child-Pugh A patients, the absence of microvascular invasion and dissemination offers the highest likelihood of cure. Nodules
S235
<2 cm that are not not subcapsular nor perivascular are the ideal target for percutaneous RFA, which is considered the standard technique for liver tumor ablation at most institutions. In patients with very early HCC the complete response rate approaches 97%, with 5 year survival rates of 68%. It has also been pointed out that individual components belonging to each patient (e.g. whether the tumor is central or peripheral, close or distant form bile ducts, in patient who is lean or overweight, presenting with or without portal hypertension, etc.) influence the results of each treatment making it better or worse than average. Since clinical experience suggests that treatment by RFA of HCC tumors in subcapsular location or adjacent to the gallbladder is associated with an increased risk of major complications and incomplete ablation, such tumor locations are considered favourable for hepatic resection. Therefore, in patients with very early HCC, RFA can be offered as a first-line treatment, considering surgical approach when individual variables, including tumor location, would make RFA not feasible or not safe. Patients with early stage disease have preserved liver function (Child–Pugh A and B) with solitary HCC or up to 3 nodules <3 cm in size. These patients can be effectively treated by resection, liver transplantation or percutaneous ablation with possibility of long term cure, and 5-year survival figures ranging from 50% to 75%. Among different ablative techniques, RFA is currently considered as the best treatment option in patients with early stage HCC. Five randomized controlled trials (RCTs) have compared RFA versus PEI for the treatment of early-stage HCC. These investigations consistently showed that RFA is more effective than PEI, leading to a better local control of the disease. The assessment of the impact of RFA on survival has been more controversial. While a survival benefit was identified in the three RCTs performed in Asia, the two European RCTs failed to show statistically significant differences in overall survival between patients who received RFA and those treated with PEI, despite the trend favoring RFA. Nevertheless, three independent meta-analyses including all RCTs, have confirmed that treatment with RFA offers a survival benefit as compared with PEI, particularly for tumors larger than 2 cm, thus establishing RFA as the standard percutaneous technique in these patients. Recent reports on long-term outcomes of RFA-treated patients have shown that in patients with Child-Pugh class A and early-stage HCC, 5-year survival rates are as high as 51–64%, and may reach 76% in patients who meet the BCLC criteria for surgical resection. An important factor that affects the success of RFA is the ability to ablate all viable tumor tissue and create an adequate tumor-free margin. The target tumor should not exceed 3 cm at its longest axis to achieve best rates of complete ablation using most of the currently available devices. Moreover, even in small tumors, the ability of RFA to achieve complete tumor eradication appears to be dependent on tumor location. Histological studies performed in liver specimens of patients who underwent RFA as bridge treatment to transplantation showed that the presence of large (3 mm or more) abutting vessels results in about 50% drop in the rate of complete tumor necrosis because of the heat loss due to perfusion-mediated tissue cooling within the area to be ablated. Therefore in patients with solitary HCC >3 cm and <5 cm in size the success rate of RFA alone is decreased; combination with intra-arterial treatment could be considered in these patients. A combination of TACE followed by RFA has been used to minimize heat loss due to perfusion-mediated tissue cooling and increase the therapeutic effect of RFA. Recently the results of a RCT aimed to evaluating the therapeutic efficacy of combining RFA with TACE for treating intermediate-sized (3.1–5 cm) HCCs have been published. Local tumor progression rate were significantly lower in the TACE–RFA treated group with respect to the RFA–only group (6% versus 39%, p=0.012). Under a different perspective, TACE with drug-eluting beads has been performed after an RFA procedure to increase tumor necrosis by exposing to high drug concentration the peripheral part of the tumor, where only sub-lethal temperatures may be achieved in a standard RFA treatment. Further research to determine optimal methods of combining chemotherapeutic regimens (both agent and route of administration) with RFA is needed. Patients with solitary large tumors (exceeding 5 cm in size) deserve a special mention. Even if these patients cannot be considered in an early stage because they do not qualify for transplantation, no upper limit of size for surgical resection appears in the BCLC flowchart, and these patients should not escape surgical referral because their tumors are too large. Different ablative modalities are not currently providing sufficient volume of ablation to treat successfully these tumors and the results of trans-arterial therapies as stand-alone treatment are highly variable in this clinical scenario. Moreover,