First Percutaneous Laser Ablation Network (PLAN) educational initiative on laser ablation for liver tumors

7-8 July, 2017 - Naples, Italy First Percutaneous Laser Ablation Network (PLAN) educational initiative on laser ablation for liver tumors IMPROVING THE PATIENT S LIFE THROUGH MEDICAL EDUCATION www.excemed.org

Disclosure Giovan Giuseppe Di Costanzo Department of Transplantation Liver Unit Cardarelli Hospital Naples, Italy Advisory board Bayer, Abbvie.

Objectives Acquire knowledge of the laser physics and interaction laser-tissue Learning the basic concepts of the laser ablation with multifiber technique Laser ablation in literature Complications post-laser ablation Ablation of hard-to-treat hepatic nodules Translating all the aforementioned into clinical practice: towards a tailored approach Clinical cases

INTRODUCTION HYPERTERMIC ABLATION

Percutaneous ablation a) chemical (PEI, PAI) b) thermal - hyperthermic (RFA, MW, LA) - hypothermic (CRYO) c) non thermal (IRE)

Image-guided Tumor Ablation: Standardization of Terminology and Reporting Criteria The term Laser Ablation (LA) should replace terminology such as laser interstitial tumor therapy (or LITT), laser coagulation therapy, and laser interstitial photocoagulation. This term should be used for all types of ablation using light energy. Radiology 2014

Hyperthermic injury Mechanisms - Direct - Indirect or delayed Chu et al, Nature Reviews 2014

Chu et al, Nature Reviews 2014 Hyperthermic injury Direct effects - Changes to cell membrane integrity - Mitochondrial disfunction - Inhibition of DNA replication *- tumor tissue is more thermosensitive than normal tissue

Laser Ablation of Biological Tissue Biological effect of heat on tissue Thermoablation: induced necrosis of tissue due to local temperature increasing Temperature effects on tissue >300 C >100 C Fusion, sublimation Charring, carbonizzation 100 C Vapour bubble creation, mechanical rupture 60 C >50 C 42 C - 50 C Denaturation of protein and collagene, coagulation Decreased enzymatic activity, lost of cellular recovery mechanism Hyperthermia, bond destruction, modification of cell membrane Cancer cells have a heath resistance threshold lower than non cancer cells

Brace et al.radiology 2007

Temperatue [ C] Laser Ablation of Biological Tissue Biological effect of heat on tissue Irreversible necrosis of cells occurs for a joint action of local temperature and exposure time 75 70 65 Cellular death occurs within few seconds for a temperature > 60 C 60 55 irreversible cellular damage At 50 C irreversible damage occurs for an exposure time of few minutes 50 45 reversible cellular damage 1 10 1 10 2 10 3 10 4 Exposure time [s] For temperatures lower than 50 C necrosis occurs for exposure time in the order of decades of minutes Critical temperature for cellular death. Henriques (1947), Eichler, Seiler (1991)

Chu et al, Nature Reviews 2014 Hyperthermic injury Indirect or delayed effects - Induction of apoptosis - Vascular damage > ischemia - Release of lysosomal contents - Granulocytes chemotaxis - Cytokine release - Stimulation of immune response

Chu et al, Nature Reviews 2014

Microscopic changes after laser ablation At 6 At 12 h At 24 h At 48 h At 7 days Fujitomi, Lasers Surg & Med, 1999

Nikfarjam, Laser Surg Med 2005

Progressive Microvascular Injury in Liver and Colorectal Liver Metastases Following Laser Ablation Nikfarjam, Laser Surg Med 2005

Induction of Th1 immune responses following laser ablation in a murine model of colorectal liver metastases Lin et al. J Transl Med 2011

Lin et al. J Transl Med 2011

LASER PHYSICS INTERACTION LASER-TISSUE

Laser Ablation of Biological Tissue L.A.S.E.R. Light Amplification by Stimulated Emission of Radiation In laser ablation tissue heating occurs by means of Laser radiation which is absorbed by tissue increasing the local temperature

Laser working principles Monochromatic: single wavelenght Collimation: low divergence, concentrating high energies in limited areas Coherence: temporal and spatial, all the photons are in phase

Aesthet Surg J. 2013:1059-1064. doi:10.1177/1090820x13501174 Date of download: 2/9/2017 2013 The American Society for Aesthetic Plastic Surgery, Inc.

Absorption coefficient [cm-1] Laser Ablation of Biological Tissue Laser to tissue interaction A wavelength range (λ) exists, where light has good penetration into tissues: all thermal ablation applications are applied in this wavelength range known as therapeutic window 10 2 10 1 10 0 Therapeutic window Nd:YAG Water H2O In therapeutic window, tissues show a low radiation absorption and consequently excellent light penetration Therapeutic window is limited at lower wavelength due to hemoglobin absorption (oxygenated HbO2 and not oxygenated Hb ) and at upper wavelength due to water absorption 10-1 Hemoglobin Hb 10-2 400 600 800 1000 1200 1400 Wavelenght [nm]

Laser Ablation of Biological Tissue Why it s better to talk about energy (instead of time) If a man digs a hole in the ground, his body will consume a quantity of energy (that it previously takes by food). Energy is the work we must do to achieve a particular result If the man takes one day or 1 hour to terminate the work depends on the power he s able to put on Power is the ratio between Work and Time If we want to ablate a nodule of a specified volume we have a specific work to do and hence we have to spend a fixed energy i.e the energy dose. The Power we use for accomplished this duty define the time duration of treatment. The higher the power we use, the less is the treatment time

Laser Ablation of Biological Tissue Laser Ablation of tissue is a threshold phenomenon Ablation threshold 1,4-1,5W Over ablation threshold Under ablation threshold

Laser Ablation of Biological Tissue Ex-vixo bovine experimentation 3 Volume vs Power (Fixed dose 1200J) 2.5 2 1.5 1 0.5 0 0 2 4 6 8 10 12 14 16 18 20 Power [W] Minor axis [cm] Mayor axis [cm] Volume [cm^3]

Volume [ml] Laser Ablation of Biological Tissue Coagulation Volume vs Energy Dose with a single fiber Energy 600J Energy 1200J Energy 1800J Energy 2400J Coagulation Volume Calculation evaluation of the ellipsoidal area over the treated zone computation of the volume by rotation of the ellipse 3,0 2,5 2,0 1,5 1,0 0,5 0,0 600 1200 1800 2400 3600 Energy [J]

Laser Ablation of Biological Tissue Thermal damage dynamics during Laser irradiation* Start lasing Initial spherical coagulation occurs around the fiber tip (changing in optical properties from native to coagulated tissue) If threshold for ablation is achieved a cavity starts to grow with vapor formation Ablation front is moving forward. Tissue is coagulated, dehydrated and vaporized in a cyclic leading to a well defined cavity in the center Moving front velocity decreases with cavity enlargement leading to an asymptotic limit of treated volume *R M Verdaasdonk, Explosive onset of continuous wave laser tissue ablation Physics in Medicine & Biology, Volume 35, Number 8

Laser Ablation of Biological Tissue Thermal damage dimension produced by a single source Laser ablation produces a volume of necrosis of 16-18 mm x 8-10 mm for standard parameters (5W and 1800J, fiber flat tip) in the liver tissue Longitudinal section Cross section thickness 8-10 mm Lenght 16-18 mm

Laser Ablation of Biological Tissue In-Vivo Laser Ablation: biological effects at histology Porcine hepatic tissue in vivo (1h after treatment) Hyperaemic margin 4x Fiber position Necrosis margin 10x 4x <Dehydrated Tissue <Coagulated Tissue with vacuoles < Carbonized Tissue Not treated healthy tissue 4x

Laser Ablation of Biological Tissue Flat-tip ablation: tissue charring Charring occurs due to high temperature achieve during LA even if carbon layer is very thin (range 10-30 micron) 10x

From: Elesta brochure

CT at 24 hours

CT at 4 weeks

Hot cylindrical tip and flat tip

Precision: sharp transition zone between dead and viable tissue Transition zone in RF and Cryo can be 5-10 mm Visualase transition zone is less than 1 mm

Laser technology Diffuser tips are used to improve applicator heating profiles, and higher powers can offset the reduced penetration depth by increasing local temperatures, but when higher powers are used, fibers must been cooled to avoid skin burns or probe failure. hot cylindrical tip Cooling increases the diameter of each applicator. Larger ablation volumes are typically realized by using multiple applicators, which can be operated independently and simultaneously.

Laser technology the main disavantages is a caliber of 9 F (3mm); it is really hard to place without risks this type of device in cirrhotic patients!!!

2 fiber approach Laser Ablation of Biological Tissue Multi-fiber approach: Volume Amplification If required by the size or shape of the lesion to be treated, it is possible to use a multi-fiber approach. 3 cm Simultaneous delivery Ex vivo pig liver treated by 2 fibers spaced at 15mm Power 5W, Energy delivered 3600J, Time duration 6 minutes

Micro-invasiveness : Strong points of Laser Ablation Very thin needles and fiber optic (300 microns) are totally atraumatic for the patient: fewer complications and side effects, less risk of infection and bleeding, no general anaesthesia, short recovery times. These needles do not cause scarring and ensure excellent aesthetic results Control of the shape of coagulative necrosis : laser ablation produces highly repeatable thermal lesions with clearly defined edges; the multifiber approach in a geometrically known area gives rise to lesions with a predictable and controllable shape confinement in respect of the viable parts and critical areas of the organs; Safety: the quartz optic fibers (dielectric material) do not interact with external electromagnetic field, are biocompatible and ensure electric isolation between instrumentation and patient. Can also be used in magnetic resonance. Speed: Laser Ablation of Biological Tissue A single illumination lasts 4-6 minutes

Laser Ablation of Biological Tissue Energy dose per treatment: Laser Ablation vs MWA vs RFA Laser Ablation exploits a very effective mechanism of conversion from EM field to heat Laser MW RF Is like cooking an egg at fixed time Key point Fast treatment time Laser Ablation employ lowest energy dose to achieve tumor ablation as compared to MW and RF

BASIC CONCEPTS OF THE LASER ABLATION WITH MULTIFIBER TECHNIQUE

Laser ablation <15mm 15 mm 15 mm >25mm <25mm

Laser Ablation of Biological Tissue Multi-fiber approach In Multi-fiber approach laser energy is delivered simultaneously. The result is a synergic coalescence action allows for obtaining large volumes of ablation with perfect control of the edges even with large-sized lesions. possibility of treating extensive lesions; possibility of adapting the treatment to the shape and position of the lesion; possibility of treating critical lesions (high risk due to being close to vital structures); positioning of the fine needles with minimum trauma for the organ with the possibility of multiple re-positioning; the multi-fiber technique with fine needles is extremely well tolerated by the patient (reduced risk of side effects)

J. Heisterkamp, Lasers Med Sci 1999 Laser Ablation of Biological Tissue Multi-fiber approach: ablation volume vs mutual fiber distance

1 cm 2 cm 4 cm J. Heisterkamp, Lasers Med Sci 1999

Laser Ablation of Biological Tissue Multi-fiber approach: importance of fiber mutual distance Anatomic slices 4mm-spaced in ex-vivo ablation of porcine liver Power = 5W Energy = 1800J MD= 3.2cm; md = 2.3 cm; Depth = 3.2 cm; Volume = 12.3cm^3 Fiber distance of 1.5cm assures single fiber volume coalescence maximum volume of coagulation

Laser system based on EchoLaser device Laser Type: Solid state (diode) Number of Sources: 4 independent in activation and emission Wavelength: 1064nm Emission Mode: CW Maximum Power (CW): 7 W per fibre Output Mode: Multimode Aiming Beam: Diode laser 3 mw @ 635 nm Nominal Ocular Hazard Distance (NOHD): 4 m Control Panel: LCD Colour Touch Screen SMA 905 optical connector 1.5m length 300 μm core diameter

Laser kit According to nodule volume, one to eight 300 µm optic fibers advanced in 21-G (0.7mm) needle are positioned into the target lesion under US guide. A single optimal illumination is considered when 1200-1800 Joules/fiber are delivered in 4-6 min at 5 W.

Laser technology CM Pacella, G.Bizzarri, Z. Rossi La fotocoagulazione interstiziale laser nel trattamento del piccolo epatocarcinoma. Esperienza preliminare in dieci casi. IX Corso Nazionale di Aggiornamento in Ecografia Operativa. Salsomaggiore Terme, 26-27 Marzo 1991.

Pacella s technique: flat tip technique introducer sheath : needle 21G (0.8mm) laser source : flat-tip fiber (0.33mm) needle 21 G = 0.8mm optical fiber = 0.33mm laser beam =18mm needle 21G=0.8mm optical fiber=0.3mm 10mm

Laser Ablation (LA) liver ablation technique: different US guidance systems Claudio Maurizio Pacella, Regina Apostolorum Hospital, Rome, Italy Giovan Giuseppe Di Costanzo, Cardarelli Hospital, Naples, Italy

Laser Ablation of Biological Tissue Multi-fiber approach 4 fiber approach Porcine liver ex vivo 4 fibers at 1.5cm, 5W, 7200J, 6 minutes 3cm HCC treated with multi-fiber technique with 5W, 7200J, 6 minutes

LASER ABLATION IS A VERY FLEXIBLE TECHNIQUE: IT MAY ADAPT TO DIFFERENT SHAPE OF CANCER NODULES

LASER ABLATION IN LITERATURE

Author Yr Pts/Ts Ts size CA (%) LR (%) OS/ 3yr (%) OS/5yr (%) Major Compl (%) Mortality (%) Giorgio 2000 Pacella 2001 77/85 4.0 82.0 1.0 4.0 Child C 30/30 30/15 > 5.0 3.0 90.0 + TACE 100.0 7.0 0.0 68 40 1.3 Child C Pacella 2001 Eichler 2001 Pacella 2005 Pacella 2006 Pacella 2009 Francica 2012 Francica 2012 Eichler 2012 Di Costanzo 2013 Di Costanzo 2013 (RCT) 74/92 Child A 4.0 97.0 6.0 73 31 39/61 5.0 98.0 0.0 4.4 ys (m) 82/99 4.0 91.0 9.0 1.5 148/169 Child A 432/548* Child A 106/116 58/66 116/132 a.m. 7.5mm 4.0 3.0 2.0 4.0 3.0 2.0 4.0 4.0 82.0 89.0 95.0 80.0 82.0 85.0 92.0 96.0 13.0 6.0 0.0 w.d. 20.0 local & distant 4.0 100.0 18.0 52 27 58 (m) 53 (m) 65 (m) w.d. 68 (m) w.d. 0.6 0.6 1.6 0.2 11.0 1.0 0.5 2.0 57 30 113/175 5.0 98.0 1.0 54 30 116/104 6.0 5.0 70/80 (LA) 70/77 (RF) 5.0 5.0 88.0 92.0 96.0 97.0 16.0 22.9 25.7 66 59

Effectiveness and outcome data tumor size, tumor location, and complete ablation were the main factors affecting the outcomes. using multiple bare fibres introduced through 21-gauge needles positioned under US-guidance, the reported complete response rate ranges from 82% to 97%. in lesions in high-risk sites, complete response is 95.5%. in patients with monofocal HCC 4 cm or three nodules 3 cm each, reported cumulative survival rates at 3 and at 5 years range from 52% to 68% and from 15% to 34%, respectively.

Effectiveness and outcome data in a multicenter study, Child s class A patients had a 5-year cumulative survival of 41%; the median survival time was 65 mo with tumor size 3 cm and 68 mo in patients with well-differentiated tumor size 2 cm. the ideal candidates for LA are younger patients with serum albumin within the normal range and a tumor size 2 cm in whom it is very likely that complete ablation will be achieved. the median time to recurrence was 24 mo and the median disease-free survival time was 26 mo. like RFA and microwaves ablation (MWA), LA resulted safe and effective also in the treatment of cirrhotic patients awaiting liver transplantation

Size Complete ablation 2 cm (n=215) 85.1% 2-3 cm (n=242) 81.8% 3-4 cm (n=91) 60.4% Overall (n= 548) 79.6% Pacella, et al JCO 2009

Pacella, et al JCO 2009

Radiofrequency ablation versus laser ablation for the treatment of small hepatocellular carcinoma in cirrhosis: a randomized controlled trial GG Di Costanzo, R Tortora, G D'Adamo, A Galeota Lanza, F Lampasi, L Addario, M De Luca, F Zanfardino, MT Tartaglione, S Mattera, CM Pacella Liver Unit, Cardarelli Hospital, Napoli, Italy ClinicalTrials.gov identifier: NCT01096914 J Gastroenterol Hepatol, 2015

LA pros LA vs RFA - Thin needles (21 vs 17G) - Less time for ablation of the tissue (for a nodule of 3cm: 4-6 vs 12 min) - More precise - Less expensive (cost of the devices: RFA 1,600 - LA 300 per fiber) LA cons - Multiple needle insertion

Primary Outcome Measure Complete tumor ablation (CTA) Absence of any intratumoral contrast enhancement on CT or MRI imaging four weeks after treatment Secondary Outcome Measures Time to local recurrence (TTLR) Time from complete tumor ablation to reappearance of arterial enhancement on CT or MRI in a treated tumor Overall survival (OS) Time from randomization to death J Gastroenterol Hepatol, 2015

Sample size calculation Noninferiority RCT: complete necrosis of HCC nodules: (LA 86% 1-2 RFA 96% 3-5 ) noninferiority margin = 10% power of 80% for a 1-sided test significant level.025 70 patients would be required in each group 1. Pacella, 2006; 2. Pacella, 2009; 3.Lencioni, 2003; 4.Lin, 2004; 5. Shiina, 2005.

Inclusion Criteria Patients (18-85ys) with unresectable HCC or who refused surgery A solitary HCC 5.0cm in diameter, or multiple HCC 3 lesions, each 3.0cm in diameter Child-Pugh class A or B Platelet count of > 40,000/mm 3, INR < 2.0 No previous treatment of HCC

Exclusion Criteria History of encephalopathy or refractory ascites Vascular invasion or extrahepatic metastasis Nodules unsuitable for RFA/LA: a. tumors located within 5 mm of liver hilum or the main bile duct branches ; b. not visible on US; Other severe concomitant diseases that may reduce life expectancy

432 naive patients (1/09-09/12) n % Resection 23 9.3 n % BCLC 0-A 248 57.4 BCLC B 106 24.5 BCLC C 78 18.1 OLT 28 11.3 RFA/LA unfeasible 11 4.4 Decompensated 35 14.1 Comorbidity/ref usal Enrolled 14 0 11 4.4 56.5 J Gastroenterol Hepatol, 2015

Patients and methods 140 patients with 157 HCC nodules randomly received either RFA (n=70) or LA (n=70) treatment. If indicated, over a period of 6 months, treatment was repeated up to three times. 4 weeks after ablation, CT or MRI imaging was used to evaluate the necrosis of the HCC nodules according to mrecist.

Treatment failure: if, after 3 ablations, CT or MRI showed a residual nodule activity In case of treatment failure, transarterial chemoembolization was used To evaluate TTLR and OS in the two treatment groups, Kaplan-Meier figures and log-rank test were used

Results RFA n=70 LA n=70 Males, n (%) 53 (75.7) 47 (67.1) Median age (range) 70 (50-83) 70 (36-84) HCV, n (%) 53 (75.7) 60 (85.7) Child A, n (%) 63 (90.0) 67 (95.7) Median MELD score (range) 9.0 (6-17) 8.5 (6-21) F1 varices, n (%) 16/64 (25.0) 16/62 (25.8) F2-F3 varices, n (%) 20/64 (31.3) 15/62 (24.2) Platelet count <100,000 41 (58.6) 37 (52.9) J Gastroenterol Hepatol, 2015

RFA n=70 LA n=70 Single nodule, n (%) 63 (90.0) 61 (87.1) Number of nodules 77 80 Diameter mm, median (range) 25 (14-44) 25 (7-50) Diameter 30mm, n (%) 20 (26.0) 30 (37.5) Subcapsular/exophytic 9 13 Adjacent large vessels 2 8 Edmondson grade I-II, n (%) 27/48 (56.3) 36/54 (66.7) AFP ng/ml,median (range) 9 (1-1025) 20.5 (1-1526) AFP >200ng/mL, n (%) 4 (5) 9 (13) Median follow-up, months (range) 23 (6-52) 24 (5-55) J Gastroenterol Hepatol, 2015

Complete tumor ablation RFA LA Δ (95% CI) per patient, n (%; 95%CI) 68/70 (97.1; 90.2-99.2) 67/70 (95.7; 88.1-98.5) +1.4%* (-6.0% +9%) per nodule, n (%; 95%CI) 75/77 (97.4; 91.0-99.3) 77/80 (96.3; 89.6-98.7) +1.1%* (-5.7% +8.1%) J Gastroenterol Hepatol, 2015

Mean survival: - RFA = 71.2 months (95%CI, 63.0-79.4) - LA = 74.0 months (95%CI, 65.4-82.6) P = 0.579

Conclusions This is the first study that validates the use of LA for the treatment of HCC. LA resulted not inferior to RFA in achieving the CTA and therefore it should be considered as an evaluable alternative for thermal ablation of small HCC in cirrhotic patients. J Gastroenterol Hepatol, 2015

COMPLICATIONS POST-LASER ABLATION

Complications Radiology 2008 In a multicenter study involving nine centers in Italy with 520 patients who underwent 1064 laser sessions for 647 HCCs. Milano Udine Bologna Deaths (4/520) = 0.76% Albano Laziale Pozzuoli Ancona Benevento Major complications (15/1004 )= 1.5% Casoria Minor complications (62/1004) = 7.2% Side effects 416/1011 = 41.1%

Complications Deaths (4/520) = 0.76%* Major complications (15/1004 )= 1.5%** Minor complications (62/1004) = 7.2%*** Side effects 416/1011 = 41.1% * all with HCCs > 3 cm, two Child-Pugh C **associated with excess of energy and high risk location ** *associated with excess of energy, high bilirubin level and low protrombin time low rate of intrahepatic and peritoneal bleeding (1.1%) and hepatic abscess 0.4%. No seeding

ABLATION OF HARD-TO- TREAT HEPATIC NODULES

Hard-to-treat nodules 1. Position a) high-risk location Adjacent large vessels: vena cava, first or second branch of the portal vein, the base of hepatic vein Adjacent to extrahepatic organs: gallbladder, gastrointestinal tract b) difficult-to-reach location I segment or liver dome Behind large vessels Behind TIPS 2. Size (> 3cm) 3. Multifocality

1. Thin needles LA pros 1. Very precise deliver of energy 1. Greatest flexibility 1. No heat sink effect

Lesions close to gallbladder ronconi0003.jpg

Exophitic lesion close to gallbladder and g.i. bowel

Exophitic lesion close to the stomach

Extrahepatic growth

Extrahepatic growth Before LA After LA

Heat-sink effect The term heat-sink effect refers to the buffering effect of patent blood vessels or ventilated bronchi adjacent to the ablation zone. The shape of the thermal zone of ablation is altered away from the vessel, and the overall ablation size is diminished. Although this phenomenon serves to protect blood vessels and prevent bleeding from large vessels, it is also a major source of incomplete tumor ablation in many studies involving thermal ablation. Image-guided Tumor Ablation: Standardization of Terminology and Reporting Criteria Radiology 2014

Heat sink effect Statli, et al; Diagn Interv Radiol 2012

LARGE HCC

Two-square configuration of the laser sources into large lesion of 6-cm-diameter mass

Total amount of energy that can be used : up to 50,000 joules Duration of treatment: up to 42 minutes

MULTIFOCAL HCC

Treatment algorithm EASL, EORTC guidelines HCC Stage 0 PS 0, Child Pugh A Stage A C PS 0 2, Child Pugh A B Stage D PS > 2, Child Pugh C Very early stage (0) 1 HCC < 2 cm Carcinoma in situ Early stage (A) 1 HCC or 3 nodules < 3 cm, PS 0 Intermediate stage (B) Multinodular, PS 0 Advanced stage (C) Portal invasion, N1, M1, PS 1 2 End stage (D) 1 HCC Portal pressure/ bilirubin Increased 3 nodules 3 cm Associated diseases Normal No Yes Resection Liver transplantation PEI/RFA TACE sorafenib BSC Curative treatments (30%) Target: 20% Target: 40% Target: 10% 5-year survival (40 70%) OS: 20 mo (45-14) OS: 11 mo (6-14) OS: <3 mo PS, performance status; TACE, transarterial chemoembolization; BSC, Best Supportive Care EASL EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma Journal of Hepatology 2012 vol. 56 j 908 943 Available on: http://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdf.

Laser ablation is superior to TACE in large sized hepatocellular carcinoma: a case control study 80 70 60 50 40 LA TACE 30 20 10 0 40-50mm 51-60mm >61mm overall

TRANSLATING ALL THE AFOREMENTIONED INTO CLINICAL PRACTICE: TOWARDS A TAILORED APPROACH

TRANSLATING ALL THE AFOREMENTIONED INTO CLINICAL PRACTICE: TOWARDS A PATIENT-TAILORED APPROACH The reported local effectiveness and long-term outcomes obtained with LA are comparable with those of RFA. Specifically, in the subgroup of Child s class A cirrhotic patients with lesions 2 cm (BCLC 0-A) treated by LA, 5-year survival was equivalent to that of RFA. Thanks to thin needles and to the more effective tumoricidal action of heat compared to ethanol, we believe that LA could replace PEI in the treatment both of residual minimal viable tissue and of nodules at high-risk sites when RFA is not technically feasible.

TRANSLATING ALL THE AFOREMENTIONED INTO CLINICAL PRACTICE: TOWARDS A PATIENT-TAILORED APPROACH To completely ablate larger tumors (usually defined greater than 3 cm), a single ablation with RFA may be not be sufficient to entirely encompass the target volume. In these cases, multiple ovelapping ablations or simultaneous use of multiple applicators may be required to successfully treat the entire tumor and ablative margin, though accurate targeting and applicator placement can often be tecnically challenging.

TRANSLATING ALL THE AFOREMENTIONED INTO CLINICAL PRACTICE: TOWARDS A PATIENT-TAILORED APPROACH To obtain larger volumes of necrosis, a variety of devices of different shapes and designs used either with different algorithms or activated in different modes (consecutive, simultaneous, or switching) has been developed. In the treatment of large HCC ( 5 cm), conventional RFA is limited mainly by incomplete ablation, with reported complete ablation rate of 74% after single session in lesions between 3 and 5 cm and of 62% in tumours > 5 cm after multiple sessions. Using three internally cooled bipolar electrodes complete, ablation rates of 81% has been reported. Guglielmi A et al. Hepatogastroenterology ; 50: 480-484 [PMID: 12749252] Seror O et al, Radiology 2008; 248: 288-296 [PMID: 18483229 DOI: 10.1148/radiol.2481071101]

TRANSLATING ALL THE AFOREMENTIONED INTO CLINICAL PRACTICE: TOWARDS A PATIENT-TAILORED APPROACH Therefore, multiple heat sources are needed to obtain large volumes of necrosis; the laser technique with multiple thin needle fibres and simultaneous approach satisfies this need. Indeed, LA obtains interesting results with thin, very simple devices that are much less sophisticated and less expensive than those used by RFA. According to the size and shape of the lesions, one to eight fibers are used. For a single illumination, laser light is employed for 4-6 min. For nodules > 3.0 cm, multiple illuminations and the pullback technique are employed. The introduction of the novel needle guide has made it possible to obtain a complete ablation of lesions up to 5 cm.

With single source With four sources

TRANSLATING ALL THE AFOREMENTIONED INTO CLINICAL PRACTICE: TOWARDS A PATIENT-TAILORED APPROACH It is possible to customize the ablative treatment according to the size and location of the lesion to be treated. Laser techniques can be used effectively in patients with very early and early HCC (BCLC 0 and A) because of their high percentage of complete response. No specific methods are used for treating lesions in high-risk (i.e., near gallbladder, main biliary duct, hepatic hilum, adjacent hollow viscera, or exophytic location) and/or hard-toreach locations (e.g., in the dome of the liver, in the caudate lobe. Additionally, this technique makes it is relatively easy to obtain a safety margin 5 mm in a higher percentage of cases (62%) than that reported by other authors with RFA.

Laser ablation curative ablation

Clinical effectiveness Influence of necrosis excess (>5 mm)* 1,0 0,9 0,8 Cumulative Proportion Surviving (Kaplan-Meier) Complete Censored Cox s test p=.035 Group 1 necrosis excess>5 mm. Group 0 necrosis excess<5 mm. Cumulative Proportion Surviving 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0-0,1 0 20 40 60 80 100 120 Time Group 1, Group 0, An ablation zone with an ablative margin of 5 mm or greater was the most important factor for local control of hepatocellular carcinoma T Nakazawa AJR 2007

TRANSLATING ALL THE AFOREMENTIONED INTO CLINICAL PRACTICE: TOWARDS A PATIENT-TAILORED APPROACH As for the water-cooled laser applicators, it must be emphasized that their main advantage is their MRI compatibility, which allows pre-procedure planning and intraprocedure treatment monitoring using a variety of temperature-sensitive techniques. The Frankfurt group has provided compelling long-term survival data in patients treated with this method for the ablation of hepatic metastases and has recently published two papers on primary liver lesions in cirrhotic patients with a high percentage of complete response and low local recurrence. However, to achieve these excellent results, the authors used a large cross-sectional probe diameter (3 mm) that requires large bore cannula (9 gauge) for percutaneous treatment.

TRANSLATING ALL THE AFOREMENTIONED INTO CLINICAL PRACTICE: TOWARDS A PATIENT-TAILORED APPROACH In addition, the diffusion of MRI-guided LA is restricted by machine availability and by complexity of the procedure, requiring between 60 and 120 min to be completed. However, we think that although interventional MRI guidance is undoubtedly more accurate than US for monitoring ablation, its use would greatly limit the number of centers capable of performing tumor ablation, with ablation procedures being relegated to only those facilities with such specialized equipment.

Hot cylindrical tip

TRANSLATING ALL THE AFOREMENTIONED INTO CLINICAL PRACTICE: TOWARDS A PATIENT-TAILORED APPROACH Thus, given that US is readily available, its use has proven to be successful on a practical level in these last 20 years, compared to the potential benefits of less available technologies. These data show that touted advantages of a particular system do not have equal weight in the clinical scenario. Last but not least, we must add the costs of this option to its overall complexity.

TRANSLATING ALL THE AFOREMENTIONED INTO CLINICAL PRACTICE: TOWARDS A PATIENT-TAILORED APPROACH A new ablation laser system consisting of 980-nm diode laser with a power of 15-W and diffuser-tipped optical fiber inserted through a 17-gauge internally cooled catheter was recently introduced in field practice. This system achieves a large, well-circumscribed ellipsoid ablation zone up to 2.0 x 2.3 cm in a single application lasting about three minutes, and up to 3.7 x 3.2 cm with two parallel applicators placed 1.5 cm apart.

Ex vivo ablation demo Bovine Liver Tissue Temperate: 37 C 17 Ga Cooling Catheter 400mm Diffusing Tip Fiber Cooling (room temp. saline) at 15ml/min 15W 120 seconds Time Compressed 2 min = 20 sec

Results Ultrasound Visualization during LITT Ablation In Vivo Time Compressed 2 min = 10 sec

TRANSLATING ALL THE AFOREMENTIONED INTO CLINICAL PRACTICE: TOWARDS A PATIENT-TAILORED APPROACH Due to its characteristics, this system has been applied thus far to focal malignant lesions of the prostate and the brain; research and clinical applications on hepatic focal lesions are underway (oral communication). Therefore, the limitations of the previous system, which used high-calibre devices, can be overcome by this technical solution. Further, the execution time of the entire manoeuvre can be shortened significantly by using real-time RM guidance.

TRANSLATING ALL THE AFOREMENTIONED INTO CLINICAL PRACTICE: TOWARDS A PATIENT-TAILORED APPROACH Therefore, with laser technical improvements such as the new small cylindrical diffuser or the novel needle guide system, it possible to employ an array of applicators to increase the ablation zone without increasing invasiveness, procedural complexity, times of ablation, or costs. In clinical practice, a trade-off must be made between these multiple factors and the operator s skill, the available technology, and the biology of the tumor.

Costs Using multiple small-bore needles, the price of each laser disposable kit including a needle and a fiber is about 300 (US$ 400). Therefore, the cost of a single LA session varies in relation to the number of devices used: one kit is required for nodules 1.0 cm; 2 kits for nodules ranging from 1.0 to 2.0 cm, and 4 kits for larger nodules. Treatment can be performed in outpatient surgery by an operator, a nurse, and an anaesthesiologist and requires about 30-45 minutes (from targeting to final US assessment).

TRANSLATING ALL THE AFOREMENTIONED INTO CLINICAL PRACTICE: TOWARDS A PATIENT-TAILORED APPROACH Survival outcomes of patients with HCC <3 cm treated by percutaneous approach are competitive with those of surgery. However, a careful multidisciplinary evaluation of the age and comorbidities of the patients and of the location of these tumours is needed. In HCC >3 cm resection or combined treatment (TACE + RFA or PEI) has been suggested to improve survival, but available studies do not yet provide useful conclusions as the enrollment criteria of patients was too stringent. Studies are needed to define which population can benefit from the combined treatments.

TRANSLATING ALL THE AFOREMENTIONED INTO CLINICAL PRACTICE: TOWARDS A PATIENT-TAILORED APPROACH While outcomes after combined treatment (LA plus TACE) are interesting, they were obtained with a technique that is the opposite of what is commonly used in referral centers. When surgery is unfeasible, a combined/sequential approach (PEI plus RFA, TACE plus PEI, RFA, or MW) should be considered on an individual basis for multinodular nodules and for nodules > 3 cm, after multidisciplinary evaluation. A meta-analysis of RFA following TACE reported no significant difference in survival rates between RFA plus TACE and RFA for small HCC. On the contrary, this sequential treatment improved overall survival rate in patients with intermediate and large HCC. Therefore, the main indication of combined therapies is for lesions >3 cm and <8 cm.

TRANSLATING ALL THE AFOREMENTIONED INTO CLINICAL PRACTICE: TOWARDS A PATIENT-TAILORED APPROACH LA before TACE, instead, reduces the tumor burden and brings the lesion back within the range of TACE effectiveness. In other words, LA results in a minimal amount of tumor tissue, which can be destroyed with selective TACE using a lesser amount of embolizing material. Because it is possible to destroy lesions up to 5-6 cm with laser technique we think that this combined method might be effective in treating lesions larger than 6 cm both in cirrhotic patients and in non-cirrhotic patients, thereby avoiding surgery, as currently suggested by some authors.

Combined treatment: LA followed by TACE

TRANSLATING ALL THE AFOREMENTIONED INTO CLINICAL PRACTICE: TOWARDS A PATIENT-TAILORED APPROACH The safety of the procedure was investigated in a multicenter study sufficiently representative both of the type and of the number of possible complications when using either multiple thin needles or large water-cooled devices. The data reported above compare favourably with the more widely used RFA and MWA technique. The mortality rates of RFA range from 0 to 1.5% of cases and major complications from 1.5% to 5.8% of cases. The mortality and major complications rates of MWA have been reported as 0% to 5.1% and 2.6% to 5.1%, respectively.

CLINICAL CASES

Nodule adjacent to gallbladder

Nodule near heart

Nodule I segment

Nodule between porta and cava vein

Nodule near diaphragm

Nodule 5 cm

Nodule 7.5 cm

Nodule behind TIPS

tips Cava vein

Nodule adjacent cava vein

Portal thrombosis

Retreatment of a large HCC

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Conclusions (1) - LA is not inferior to RFA in the treatment of small HCC. - LA is safe and cheaper than RFA/MWA. - The use of thin needles allows the treatment of HCC in high-risk sites and in hard-to-reach locations.

Conclusions (2) - Thanks to the novel guide system which facilitates the parallel insertion of multiple needles, LA is more effective in achieving with safety large volumes of necrosis. - Using LA, it is possible to treat effectively and safely multiple lesions of different sizes in different sites in the same session.

Conclusions (3) - More in general, we think that the reference centres that treat more than 50 patients/year should be equipped with all the available techniques so as to be able to use the best and the most suitable for each type of lesion in each patient.

Optimizing tumor ablation OPTIMAL ABLATION BIOLOGY

Take-home message - Laser is an ideal energy source to perform ablation of liver tumors: very precise, highly efficient at low powers, minimally invasive - Laser ablation is not inferior to the most widely used radiofrequency ablation - It is a very flexible techniques that can be used for the treatment of nodules with different shape - Laser ablation has the advantage of being less traumatic than other techniques - Complication rate is not higher of that observed after other ablation technique - It can be used to treat cancers in every location, in particular hard-to-treat tumors - It is cheaper and more simple than other ablative methods

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