Systematic review of novel ablative methods in locally advanced pancreatic cancer

Table 1 Use of ablative therapies to treat cystic and solid premalignant lesions of the pancreas

Author	Premalignant lesion	n	Treatment	Median area of ablation, mm (range)	Outcome	Complications
Gan et al[46]	Cystic tumours of the pancreas	25	EUS guided ethanol lavage	19.4 (6-30)	Complete resolution 35%	None
Oh et al[73]	Cystic tumours of the pancreas	14	EUS guided ethanol lavage + paclitaxel	25.5 (17-52)	Complete resolution in 79%	Acute pancreatitis (n = 1) Hyperamylasaemia (n = 6) Abdominal pain (n = 1)
Oh et al[74]	Cystic tumours of the pancreas	10	EUS guided ethanol lavage + paclitaxel	29.5 (20-68)	Complete resolution in 60%	Mild pancreatitis (n = 1)
DeWitt et al[75]	Cystic tumours of the pancreas	42	Randomised double blind study: Saline vs ethanol	22.4 (10-58)	Complete resolution in 33%	Abdominal pain at 7 d (n = 5) Pancreatitis (n = 1) Acystic bleeding (n = 1)
Oh et al[47]	Cystic tumours of the pancreas	52	EUS guided ethanol lavage + paclitaxel	31.8 (17-68)	Complete resolution in 62%	Fever (1/52) Mild abdominal discomfort (1/52) Mild pancreatitis (1/52) Splenic vein obliteration (1/52)
Levy et al[76]	PNET	8	EUS guided ethanol lavage (5 patients) and intra-operative ultrasound guided (IOUS) ethanol lavage (3 patients)	16.6 (8-21)	Hypoglycemia symptoms disappeared 5/8 and significantly improved 3/8	EUS guided: No complications. IOUS-guided ethanol injection: Minor peritumoral bleeding (1/3), pseudocyst (1/3), pancreatitis (1/3)
Pai et al[21]	Cystic tumours of the pancreas + neuroendocrine tumours	8	EUS guided RFA	Mean size pre RFA, 38.8 mm vs mean size post RFA, 20 mm	Complete ablation in 25% (2/8)	2/8 patients had mild abdominal pain that resolved in 3 d

RFA: Radiofrequency ablation; EUS: Endoscopic ultrasound; PNET: Pancreatic neuroendocrine tumour.

Table 2 Endoscopic ultrasound administered non-ablative anti-tumour therapies for pancreatic ductal adenocarcinoma

Author	Therapy	Patients	n	Outcome and survival	Complications
Chang et al[77]	Cytoimplant (mixed lymphocyte culture)	Unresectable PDAC	8	Median survival: 13.2 mo. 2 partial responders and 1 minor response	7/8 developed low-grade fever 3/8 required biliary stent placement
Hecht et al[78]	ONYX-015 (55-kDa gene-deleted adenovirus) + IV gemcitabine	Unresectable PDAC	21	No patient showed tumour regression at day 35. After commencement of gemcitabine, 2/15 had a partial response	Sepsis: 2/15 Duodenal perforation: 2/15
Hecht et al[79] Chang et al[80,81]	TNFerade (replication-deficient adenovector containing human tumour necrosis factor (TNF)-α gene)	Locally advanced PDAC	50	Response: One complete response, 3 partial responses. Seven patients eventually went to surgery, 6 had clear margins and 3 survived > 24 mo	Dose-limiting toxicities of pancreatitis and cholangitis were observed in 3/50
Herman et al[82]	Phase III study of standard care plus TNFerade (SOC + TNFerade) vs standard care alone (SOC)	Locally advanced PDAC	304 (187 SOC + TNFerade)	Median survival: 10.0 mo for patients in both the SOC + TNFerade and SOC arms [hazard ratio (HR), 0.90, 95%CI: 0.66-1.22, P = 0.26]	No major complications. Patients in the SOC + TNFerade arm experienced more grade 1 to 2 fever than those in the SOC alone arm (P < 0.001)
Sun et al[83]	EUS-guided implantation of radioactive seeds (iodine-125)	Unresectable PDAC	15	Tumour response: "partial" in 27% and "minimal" in 20%. Pain relief: 30%	Local complications (pancreatitis and pseudocyst formation) 3/15. Grade III hematologic toxicity in 3/15
Jin et al[84]	EUS-guided implantation of radioactive seeds (iodine-125)	Unresectable PDAC	22	Tumour response: “partial” in 3/22 (13.6%)	No complications

PDAC: Pancreatic ductal adenocarcinoma; EUS: Endoscopic ultrasound.

Table 3 Studies of radiofrequency ablation in pancreatic ductal adenocarcinoma

Study	Patients	n	Route of administration	Device	RFA temp (°C)	RFA duration (min)	Outcome	Complications
Matsui et al[12]	Unresectable PDAC	20 LA:9 M:11	At laparotomy 4 RFA probes were inserted into the tumour 2 cm apart	A 13.56-MHz RFA pulse was produced by the heating apparatus	50	15	Survival: 3 mo	Mortality: 10% (septic shock and gastrointestinal bleeding)
Hadjicostas et al[14]	Locally advanced and unresectable PDAC	4	Intraoperative (followed by palliative bypass surgery)	Cool-tip™ RFAblation system	NR	2-8	All patients were alive one year post-RFA	No complications encountered
Wu et al[10]	Unresectable PDAC	16 LA:11 M:5	Intraoperative	Cool-tip™ RFAblation system	30-90	12 at 30 °C then 1 at 90 °C	Pain relief: back pain improved (6/12)	Mortality: 25% (4/16) Pancreatic fistula: 18.8% (3/16)
Spiliotis et al[11]	Stage III and IV PDAC receiving palliative therapy	12 LA:8 M:4	Intraoperative (followed by palliative bypass surgery)	Cool-tip™ RFAblation system	90	5-7	Mean survival: 33 mo	Morbidity: 16% (biliary leak) Mortality: 0%
Girelli et al[7]	Unresectable locally advanced PDAC	50	Intraoperative (followed by palliative bypass surgery)	Cool-tip™ RFAblation system	105 (25 pts) 90 (25 pts)	Not reported	Not reported	Morbidity 40% in the first 25 patients. Probe temperature decreased from 105°C to 90 °C Morbidity 8% in second cohort of 25 patients. 30-d mortality: 2%
Girelli et al[50]	Unresectable locally advanced PDAC	100	Intraoperative (followed by palliative bypass surgery)	Cool-tip™ RFAblation system	90	5-10	Median overall survival: 20 mo	Morbidity: 15%. Mortality: 3%
Giardino et al[51]	Unresectable PDAC. 47 RFA alone. 60 had RFA + radiochemotherapy (RCT) and/or intra-arterial systemic chemotherapy (IASC)	107	Intraoperative (followed by palliative bypass surgery)	Cool-tip™ RFAblation system	90	5-10	Median overall survival: 14.7 mo in RFA alone but 25.6 mo in those receiving RFA + RCT and/or IADC (P = 0.004)	Mortality: 1.8% (liver failure and duodenal perforation) Morbidity: 28%
Arcidiacono et al[19]	Locally advanced PDAC	22	EUS-guided	Cryotherm probe; bipolar RFA + cryogenic cooling	NR	2-15	Feasible in 16/22 (72.8%)	Pain (3/22)
Steel et al[41]	Unresectable malignant bile duct obstruction (16/22 due to PDAC)	22	RFA + SEMS placement at ERCP	Habib EndoHPB wire guided catheter	NR	Sequential 2 min treatments - median 2 (range 1-4)	Median survival: 6 mo Successful biliary decompression (21/22)	Minor bleeding (1/22) Asymptomatic biochemical pancreatitis (1/22), percutaneous gallbladder drainage (2/22). At 90-d, 2/22 had died, one with a patent SEMS
Figueroa-Barojas et al[42]	Unresectable malignant bile duct obstruction (7/20 due to PDAC)	20	RFA + SEMS placement at ERCP	Habib EndoHPB wire guided catheter	NR	Sequential 2 min treatments	SEMS occlusion at 90 d (3/22) Bile duct diameter increased by 3.5mm post RFA (P = 0.0001)	Abdominal pain (5/20), mild post-ERCP pancreatitis and cholecystitis (1/20)
Pai et al[20]	Locally advanced PDAC	7	EUS-guided	Habib EUS-RFA catheter	NR	Sequential 90s treatments - median 3 (range 2-4)	2/7 tumours decreased in size	Mild pancreatitis: (1/7)

PDAC: Pancreatic ductal adenocarcinoma; LA: Locally advanced PDAC; M: Metastatic PDAC; SEMS: Self-expanding metal stent; RFA: Radiofrequency ablation; EUS: Endoscopic ultrasound; ERCP: Endoscopic retrograde cholangiopancreatography.

Table 4 Studies of cryoablation in pancreatic ductal adenocarcinoma

Study	n	Patients	Study	Outcome	Complications
Patiutko et al[25] (non-English article)	30	Locally advanced PDAC	Combination of cryosurgery and radiation	Pain relief and improvement in performance status: 30/30	Not reported
Kovach et al[52]	9	Unresectable PDAC	Phase I study of intraoperative cryoablation under US guidance. Four had concurrent gastrojejunostomy	7/9 discharged with non-intravenous analgesia and 1/9 discharged with no analgesia	No complications reported
Li et al[53] (non-English article)	44	Unresectable PDAC	Intraoperative cryoablation under US guidance	Median overall survival: 14 mo	40.9% (18/44) had delayed gastric empting. 6.8% (3/44) had a bile and pancreatic leak
Wu et al[54] (non-English article)	15	Unresectable PDAC	Intraoperative cryoablation under US guidance	Median overall survival: 13.4 mo	1/15 patients developed a bile leak
Yi et al[55] (non-English article)	8	Unresectable PDAC	Intraoperative cryoablation under US guidance	Not reported	25% (2/8) developed delayed gastric emptying
Xu et al[26]	38	Locally advanced PDAC, 8 had liver metastases	Intraoperative or percutaneous cryoablation under US or CT guidance + (125) iodine seed implantation	Median overall survival: 12 mo. 19/38 (50.0%) survived more than 12 mo	Acute pancreatitis: 5/38 (one has severe pancreatitis)
Xu et al[56]	49	Locally advanced PDAC, 12 had liver metastases	Intraoperative or percutaneous cryoablation under US or CT guidance and (125) iodine seed implantation. Some patients also received regional celiac artery chemotherapy	Median survival: 16.2 mo. 26 patients (53.1%) survived more than 12 mo	Acute pancreatitis: 6/49 (one had severe pancreatitis)
Li et al[57]	68	Unresectable PDAC requiring palliative bypass	Retrospective case-series of intraoperative cryoablation under US guidance, followed by palliative bypass	Median overall survival: 30.4 mo (range 6-49 mo)	Postoperative morbidity: 42.9%. Delayed gastric emptying occurred in 35.7%
Xu et al[58]	59	Unresectable PDAC	Intraoperative or percutaneous cryotherapy	Median survival: 8.4 mo. Overall survival at 12 mo: 34.5%	Mild abdominal pain: 45/59 (76.3%) Major complications (bleeding, pancreatic leak): 3/59 (5%) 1/59 developed a tract metastasis
Niu et al[29]	36 (CT) 31 (CIT)	Metastatic PDAC	Intraoperative cryotherapy (CT) or cryoimmunotherapy (CIT) under US guidance	Median overall survival in CIT: 13 mo CT: 7 mo	Not reported

PDAC: Pancreatic ductal adenocarcinoma.

Table 5 Studies of photodynamic therapy in pancreatic ductal adenocarcinoma

Study	n	Study	Photosensitiser	Number of fibres	Number of ablations	Outcome and survival	Complications
Bown et al[30]	16	CT guided percutaneous PDT to locally advanced but inoperable PDAC without metastatic disease	mTH-PC	Single	1	Tumour necrosis: 16/16. Median survival: 9.5 mo. 44% (7/16) survived > 1 year	Significant gastrointestinal bleeding: 2/16 (controlled without surgery)
Huggett et al[31,32]	13 + 2	CT guided percutaneous PDT to locally advanced but inoperable PDAC without metastatic disease	Verteporfrin	Single (13) Multiple (2)	1	Technically feasible: 15/15. Dose dependent necrosis occurred	Single fibre: No complications. Multiple fibres: CT evidence of inflammatory change anterior to the pancreas, no clinical sequelae

PDAC: Pancreatic ductal adenocarcinoma; CT: Computed tomography.

Table 6 Studies of high intensity focused ultrasound in pancreatic ductal adenocarcinoma

Study	n	Study	Outcome and survival	Complications
Wang et al[59] (non-English article)	15	HIFU monotherapy in late stage PDAC	Pain relief: 13/13 (100%)	Mild abdominal pain (2/15)
Xie et al[60] (non-English article)	41	HIFU alone vs HIFU + gemcitabine in locally advanced PDAC	Pain relief: HIFU (66.7%),	None
			HIFU + gemcitabine (76.6%)
Xu et al[61] (non-English article)	37	HIFU monotherapy in advanced PDAC	Pain relief: 24/30 (80%)	None
Yuan et al[62] (non-English article)	40	HIFU monotherapy	Pain relief: 32/40 (80%)	None
Wu et al[63]	8	HIFU in advanced PDAC	Median survival: 11.25 mo	None
			Pain relief: 8/8
Xiong et al[64]	89	HIFU in unresectable PDAC	Median survival: 26.0 mo (stage II), 11.2 mo (stage III) and 5.4 mo (stage IV)	Superficial skin burns (3.4%), subcutaneous fat sclerosis (6.7%), asymptomatic pseudocyst (1.1%)
Zhao et al[65]	37	Phase II study of gemcitabine + HIFU in locally advanced PDAC	Overall survival: 12.6 mo (95%CI: 10.2-15.0 mo) Pain relief: 78.6%	16.2% experienced grade 3 or 4 neutropenia, 5.4% developed grade 3 thrombocytopenia, 8% had nausea vomiting
Orsi et al[66]	6	HIFU in unresectable PDAC	Pain relief: 6/6 (100%)	Portal vein thrombosis (1/6)
Sung et al[67]	46	Stage III or IV PDAC	Median survival: 12.4 mo. Overall survival at 12 mo was 30.4%	Minor complications (abdominal pain, fever and nausea): 57.1% (28/29) Major complications (pancreaticoduodenal fistula, gastric ulcer or skin burns): 10.2% (5/49)
Wang et al[68]	40	Advanced PDAC	Median overall survival: 10 mo (stage III) and 6 mo (stage IV). Pain relief: 35/40 (87.5%)	None
Lee et al[69]	12	HIFU monotherapy in unresectable PDAC (3/12 received chemotherapy)	Median overall survival for those receiving HIFU alone (9/12 patients): 10.3 mo	Pancreatitis: 1/12
Li et al[70]	25	Unresectable PDAC	Median overall survival: 10 mo. 42% survived more than 1 year. Performance status and pain levels improved: 23/25	1st degree skin burn: 12% Mortality: 0%
Wang et al[71]	224	Advanced PDAC	Not reported	Abdominal distension, anorexia and nausea: 10/ 224 (4.5%). Asymptomatic vertebral injury: 2/224
Gao et al[72]	39	Locally advanced PDAC	Pain relief: 79.5% Median overall survival: 11 mo. 30.8% survived more than one year	None

HIFU: High intensity focused ultrasound; PDAC: Pancreatic ductal adenocarcinoma.