Thermal ablation of pancreatic cancer: A systematic literature review of clinical practice and pre-clinical studies

Figures & data

Figure 1. Flowchart showing selection of the articles.

Figure 2. Laser Ablation: (A) schematisation of the EUS-guided LA; (B) right side, during EUS-guided LA, the hyperechoic spot visible close to the needle tip, inside the tumour (arrow); left side, at the end of the procedure, EUS showed a hyperechoic area along the path of the probe surrounded by nonhomogeneous tissue with hyperechoic spots. Reprinted from [31] Copyright 2018, with permission from Elsevier. (C) H&E Histology of the lesion induced by Nd:YAG laser on in vivo healthy pig. (D) Schematization of nanoparticles-mediated LA.

Table 1. Laser Ablation in preclinical and ex vivo settings.

Author	Year	Study type	Device	N animals	Tumor	Application technique	Thermometry	Survival	Control	Complications
Stroszczynski et al. [29]	2001	in vivo	Nd:YAG lasers (Medilas Fibertom 5060/5100 Dornier, Wessling, Germany)	15 pigs	–	Percutaneous approach	MRI thermometry	7 days	MRI and histology	Thrombosis of intrapancreatic vessels close to the treated area
Di Matteo et al. [20,21]	2010-2013	in vivo and ex vivo	Nd:YAG laser (1064nm, Smart1064, DEKA M.E.L.A s.r.l, Florence, Italy)	8 pigs		EUS guided LA	–	24h	Histology	Small peripancreatic collection of fluid in 6 out of 8 pigs
Saccomandi et al. [24–26]	2011-2012	in silico and ex vivo	Nd:YAG laser (1064nm, Smart1064, DEKA M.E.L.A s.r.l, Florence, Italy)	30 pancreas	–	–	Fiber Bragg Gratings	–	–	–
Mocan et al. [18,23]	2011-2014	in vitro and ex vivvo	808 nm continuous laser generator (Apel Laser, Bucharest), and MWCNTs-PEG (PEGylated Multi-Walled Carbon Nanotubes) nanoparticles	>6 pancreas	Human pancreatic adenocarcinoma cells PANC-1	contactless	Therma 20 thermistors (Electronic Temperature Instruments, Worthing, UK)		Mitochondrial dehydrogenase activity, viability, histopathology, fluorescence	–
Guo et al. [22]	2013	in vitro	808 nm NIR BWF5; B&W Tek, Inc, Newark, DE, USA +2 kinds of nanopart.: GoldMag nanopart (Fe3O4/Au core/shell nanopart) and bare Fe3O4 nanopart.		Human pancreatic cancer cell line		Fiber optic temperature probe (FTP-LN2; Photon Control Inc, Burnaby, BC, Canada)		Viability assay	–
Schena et al. [27,28]	2013-2014	ex vivo	Nd:YAG laser (1064nm, Smart1064, DEKA M.E.L.A s.r.l, Florence, Italy)	>10 pancreas	–	–	Thermocouples and CT-based thermometry	–	–	–
Allegretti et al. [19]	2015	ex vivo	Nd:YAG laser (1064nm, Smart1064, DEKA M.E.L.A s.r.l, Florence, Italy)	3 pancreas	–	–	MRI thermometry			–

Figure 3. Radiofrequency Ablation: A) Measurement of Hounsfield Unit value of the RFA induced lesion in pancreatic adenocarcinoma and B) of the necrotic area. Reprinted from [43] Copyright 2018, with the permission of Pioneer Bioscience Publishing Company. C) Gross pathology of the porcine RF-ablated pancreas. D) Hystological image of the thermal outcome: coagulated necrosis, fibrous tissue and normal pancreatic parenchyma. (H&E, orig. mag. x40). Reprinted from [39] Copyright 2018, with the permission of Elsevier.

Table 2. Radiofrequency Ablation in preclinical and ex vivo settings.

Author	Year	Study type	Device	N animals	Tumor	Application technique	Thermometry	Survival	Control	Complication
Goldberg et al. [36]	1999	in vivo	Monopolar RF generator (Series 3; Radionics, Inc., Burlington, Mass)	13 pigs	–	EUS guidance	Thermocouple	14 days	EUS and CT images, laboratory tests	Transmural burns extending from the gastric mucosa through the serosa on 3 pigs. Elevation in serum lipase and amylase in 1 pig
Date et al. [35]	2005	ex vivo	Starburst XL multi-array probe (RITA Systems Inc., Mountain View, CA, USA) bearing thermal sensors	30 pigs	–	–	5 Thermocouples	–	Histology	Complete ablation of pancreatic parenchyma and thermal damage to portal vain and biliary structure at a target temperature of 100 °C for 10 min
Date et al. [37]	2005	ex vivo	Starburst XL multi-array probe (RITA Systems Inc., Mountain View, CA, USA) bearing thermal sensors	20 pigs	–	–	7 Thermocouples	–	NADH evaluation	Bile duct damage in 1 pig treated at 90 °C and 100 °C; portal vein damage in 1 pig at 80 °C and 100 °C
Kim et al. [39]	2012	ex vivo and in vivo	VIVA RF generator (STARmed, Korea)	Ex vivo: 6 bovine livers; In vivo: 10 adult mini pigs	–	EUS guidance	–	7 days	EUS, histology and laboratory tests	Fibrosis and adhesions in 3 pigs
Gaidhane et al. [38]	2012	in vivo	Habib EUS RFA, Emcision Ltd., London, UK	5 yucatan pigs	–	EUS guidance	–	6 days	Histology and laboratory test	Minimal amount of pancreatitis
Raoof et al. [42]	2013	in vivo	Kanzius non-invasive external RF generator (ThermMed LLC, Erie, PA)	Mice	Orthotopic liver and pancreas tumour in mice	Contactless	Infrared thermal camera (FLIR SC 6000, FLIR Systems, Inc., Boston, MA) and Fiber optic thermography (Fluotemp, PhotonControl, Burnaby, BC, Canada)	up to 7 weeks	Histopathology
Fegrachi et al. [40]	2014	in vivo	CELON Power System generator (Olympus Surgical Technologies Europe, Teltow, Germany)	6 pigs	–	Laparotomy	–	14 days	Clinical parameters and blood analysis; NADH and H&E	High amylase level in 2 out of 6 pigs
Quesada et al. [41]	2014	in vivo	Coolinside device (Apeiron Medical, Valencia, Spain)	39 rats (7 were control)		Laparotomy		up to 21 days	Histopathology

Table 3. Radiofrequency Ablation in clinical settings. PA: pancreatic adenocarcinoma; NT: neuroendocrine tumour.

Author	Year	Patients (N)	Age (mean)	Pancreatic lesion			Localization			Mean size of the lesion		Indication to RFA ablation			RFA application technique (N)
				PA	NT	Cystic	Head	Body-tail	Uncinate	(mm)	(mm^2)	Unresectable	Unfit for surgery	Refuse surgery
Varshney et al. [54]	2006	3	58	3	–	–	2	–	1	65	nr	3	–	–	Laparotomy (3)
Hadjicostas et al. [46]	2006	4	70	4	–	–	4	–	–	62.5	nr	4	–	–	Laparotomy (4)
Spiliotis et al. [53]	2007	12	68.3	12	–	–	11	1	–	45	nr	12	–	–	Laparotomy (12)
Zou et al. [56]	2010	32	68	32	–	–	23	9	–	nr	nr	32	–	–	Laparotomy (32)
Ikuta et al. [47]	2012	1	60	1	–	–	1	–	–	35	nr	1	–	–	Laparotomy (1)
Giardino et al. [45]	2013	107	64.6	107	–	–	74	33	–	37.5	nr	107	–	–	Laparotomy (107)
Rossi et al. [51]	2014	10	63.1	–	10	–	7	3	–	16	nr	–	10		Percutaneous (7) Laparotomy (2) EUS-guided (1)
Song et al. [52]	2015	6	60	6	–	–	4	2	–	21	nr	6	–	–	EUS-guided (6)
Pai et al. [50]	2015	8	65	–	2	–	8	–	–	27.5	nr	–	8	–	EUS-guided (8)
				–	6	36.5
Kallis et al. [48]	2015	23	68.9	23	–	–	23	–	–	nr	nr	23	–	–	Endoscopic fluoroscopy-guided (23)
Waung et al. [55]	2016	1	70	–	1	–	–	–	1	18	nr	–	1	–	EUS-guided (1)
Lakthakia et al. [49]	2016	3	45	–	3	–	1	2	–	nr	nr	–	1	2	EUS-guided (3)
D’Onofrio et al. [43]	2016	51	64	51	–	–	nr	nr	nr	nr	1.036	51	–	–	Laparotomy (51)
D’Onofrio et al. [44]	2017	18	62.4	18	–	–	–	18	–	48.1	nr	18	–	–	Percutaneous (18)
Total		279	63.3	257	16	6	158	68	2	37.4		257	22

Figure 4. Microwave Ablation: A) Schematization of the MWA guided with the percutaneous. approach; B) US-image guided MWA (white arrow indicates the antenna); C) Sagittal CT view in a patient with internal/external biliary drainage (black arrow) showing the MWA antenna (white arrow) deployed a few millimetres away from the drain. Reprinted from [65] Copyright 2018, with the permission of Elsevier.

Figure 5. HIFU: (A) Schematization of HIFU procedure; (B) Volume ratio changes (tumour volume at day 28/tumour volume at day 0) with weekly treatment of PANC-1 xenografts in BALB/c nude mice with HIFU and/or gemcitabine (GEM). Reprinted from [71] Copyright 2018, with the permission of Elsevier. (C) MR-guided HIFU treatment planning of the pancreatic cancer with the patient placed in the supine position over the US transducer (t): image shows liver (l), spleen (s), right kidney (k), and abdominal aorta (a), as well as the predicted ultrasound beam path (triangles) with the focal spot placed over the target lesions (rectangular box). (D) PRF shift-weighted image for MR thermometry demonstrate increase of tissue temperature in the focal spot area (up to about 80 °C) as well as heat distribution beyond the target zone (up to 95 °C), along the abdominal aorta and within the coeliac plexus. (E) Temperature chart shows increase of tissue temperature during sonication in the target area. Reprinted from [75] Copyright 2018, with the permission of Springer.

Table 4. HIFU in preclinical and ex vivo settings.

Author, Year, Ref	year	Study type	Device	N animals	Tumor	Application technique	Thermometry	Survival	Control	Complications
Hwang et al. [69]	2009	in vivo	YDME FEP-BY02 (Yuande Bio-Medical Engineering, Beijing, China)	12 pigs	–	Extracorporal HIFU	–	7 days	Histopathology and laboratory test	Burns to skin and abdominal wall.
Xie et al. [74]	2010	in vivo	HIFU system (Model JC, Chongqing HaifuTech Co., Ltd, Chongqing City, China)	12 pigs	–		–	24h and 7days	Histopathology and US images	Infiltration and inflammatory cells and fubrosis after 7 days
Lee et al. [71]	2013	in vivo	FEP-BY02 HIFU unit (Yuande Biomedical Engineering, Beijing, China)	48 BALB/c nude mice	Pancreatic cancer xenograft model using human pancreatic cancer cells (PANC-1)	Extracorporal HIFU	–	28 days	TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) and histology	–
Li et al. [72]	2014	phantom, ex vivo and in vivo	Customized pre-clinical system (VIFU 2000, Alpinion US Inc, Bothell, WA)	5 mice	Pancreatic ductal adenocarcinoma		–		US imaging
Kim et al. [70]	2014	in vivo	Customized pre-clinical system, VIFU-2000 (Alpinion Medical Systems, Seoul, Korea)	48 nude mice	PANC-1	Extracorporal HIFU		8 days	Dynamic contrast–enhanced ultrasound, DC-EUS	8 mice died during the survival study
Li et al. [73]	2015	phantom, ex vivo and in vivo pancreas and liver	Custom spherically curved HIFU transducer integrated with a 10 MHz EUS imaging probe (BF-Y0044; Olympus Medical System Corp, Tokyo, Japan)	5 pigs		EUS guided HIFU	–	no	Videoscope imaging in living animals, and histological analysis	Thermal injury to the gastric mucosa

Table 5. HIFU in clinical settings.

Author	year	Patients (N)	Age (mean)	Pancreatic lesion			Localization			Mean size of the lesion		Indication to HIFU ablation
				PA	NT	Cystic	Head	Body-tail	Uncinate	(cm)	(mm^2)	Unresectable	Borderline	Refuse surgery
Wu et al. [90]	2005	8	62	8	–	–	8	–	–	5.9	–	8	–	–
Zhao et al. [91]	2010	39	55	–	–	–	27	12	–	3.4	–	31	8	–
Orsi et al. [83]	2010	7	64.3	6	1	–	7	–	–	4.6	–	7	–	–
Sung et al. [85]	2011	46	60.7	46	–	–	17	29	–	4.2	–	46	–	–
Jung et al. [77]	2011	35	62.6	35	–	–	–	–	–	3.7	–	35	–	–
Orgera et al. [82]	2011	6	61	3	3	–	–	–	–	–	–	5	0	–
Wang et al. [88]	2011	40	57	40	–	–	9	31	–	4.3	–	40	–	–
Lee et al. [78]	2011	12	–	12	–	–	7	4	1	3.5	–	12	–	–
Li PZ et al. [79]	2012	25											–	–
Wang et al. [89]	2013	224	60	224	–	–	47	177	–	5	–	224	–	–
Ge et al. [76]	2014	20	68.3	20	–	–	–	20	–	3.5x4.5	–	20	–	–
Anzidei et al. [75]	2014	2	–	2	–	–	–	–	–	–	–	–	–	–
Wang et al. [87]	2015	30	57	30	–	–	23	7	–	3.2	–	–	30	–
Vidal Jove et al. [86]	2015	43	63	–	–	–	–	–	–	–	–	43	–	–
Li YJ et al. [80]	2016	16	62.3 ± 10.5	16	–	–	9	7	–	3.7	nr	16	–	–
Marinova et al. [81]	2016	13	66.2	13	–	–	4	9	–	–	–	13	–	–
Strunk et al. [84]	2016	15	66.9	–	–	–	7	8	–	–	–	15	–	–
Total		581	59,7	455	4	–	165	304	1	4.1	–	515	38	–

Figure 6. Cryoablation. Hyperechoic line along the path of the probe surrounded by nonhomogeneous tissue with hyperechoic spots. T, tumour; SMA, superior mesenteric artery. Reprinted from [103] Copyright 2018, with the permission of Elsevier.

Table 6. Hybrid and new ablation techniques in preclinical and ex vivo settings.

Author, Year, Ref	Year	Study type	Device	N animals	Tumor	Application technique	Thermometry	Survival	Control	Complications
Carrara et al. [100]	2008–2010	in vivo	VIO 300D (ERBE) + RBOKRYO CA system (ERBE)	14 pigs	–	EUS-guidance	–	up to 14 days	EUS after procedure and before euthanasia; macroscopic measurement and histology after euthanasia	One major complication (7%), 6 minor complications (43%)
Petrone et al. [101]	2010	ex vivo	A VIO 300D RF generator (ERBE) and ERBOKRYO CA system (ERBE Elektromedizin GmbH	16 human pancreases	Adenocarcinoma	US guidance	MRI thermometry	–	Histology
Adams et al. [102]	2016	in vivo	MRI compatible Ultrasound custom system	3 pigs	–	Endoluminal guidance	MRI thermometry (PRF-based GRE sequence)		Histology and MRI

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