The Role of Irreversible Electroporation and Other Ablative Techniques in Patients with Borderline Resectable Pancreatic Cancer


Author

Premalignant lesion

n

Treatment

Median area of ablation, mm (range)

Outcome

Complications

Gan, et al.

Cystic tumors of the pancreas

25

EUS-guided ethanol lavage

19.4 (6–30)

Complete resolution in 35 %

None

Oh, et al.

Cystic tumors of the pancreas

14

EUS-guided ethanol lavage + paclitaxel

25.5 (17–52)

Complete resolution in 79 %

Acute pancreatitis (n = 1)

Hyperamylasemia (n = 6)

Abdominal pain (n + 1)

Oh, et al.

Cystic tumors of the pancreas

10

EUS-guided ethanol lavage + paclitaxel

29.5 (17–52)

Complete resolution in 60 %

Mild pancreatitis (n = 1)

DeWitt, et al.

Cystic tumors of the pancreas

42

Randomized double blind study: Saline vs. ethanol

22.4 (20–68)

Complete resolution in 33 %

Abdominal pain at 7 d (n = 5)

Pancreatitis (n = 1)

Acystic bleeding (n = 1)

Oh, et al.

Cystic tumors of the pancreas

52

EUS-guided ethanol lavage + paclitaxel

31.8 (17–68)

Complete resolution in 62 %

Fever (1.52)

Mild pancreatitis (1/52)

Splenic vein obliteration (1/52)

Levy, et al.

PNET

8

EUS-guided ethanol lavage (5 patients) and intraoperative 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)

Pai, et al.

Cystic tumors of the pancreas + neuroendocrine tumors

8

EUS-guided RFA

Mean size pre-RFA, 38.8 mm vs. mean size post-RFA, 20 mm

Complete resolution in 25 % (2/8)

2/8 patients had mild abdominal pain that resolved in 3 days


RFA radiofrequency ablation, EUS endoscopic ultrasound, PNET pancreatic neuroendocrine tumor




Table 18.2
Endoscopic ultrasound administered non-ablative and antitumor therapies for pancreatic ductal adenocarcinoma
































































Author

Therapy

Patients

n

Outcome and survival

Complications

Chang, et al.

Cytoimplant (mixed lymphocyte culture)

Unresectable PDAC

8

Median survival: 13.2 months. 2 partial responders and 1 minor response

7/8 developed low-grade fever

3/8 required biliary stent placement

Hecht, et al.

ONYX-015 (55-kDa gene-deleted adenovirus) + IV gemcitabine

Unresectable PDAC

21

No patient showed tumor regression at day 35. After commencement of gemcitabine, 2/15 had a partial response

Sepsis: 2/15, duodenal perforation: 2/15

Hecht, et al.

TNFerade (replication-deficient adenovector containing human tumor necrosis factor (TNF)-a gene)

Locally advanced PDAC

50

Response: One complete response, 3 partial responses. 7 patients eventually went to surgery, 6 had clear margins and 3 survived >24 months

Dose-limiting toxicities of pancreatitis and cholangitis were observed in 3/50

Chang, et al.

Herman, et al.

Phase III study of standard care plus TNFerade (SOC + TNFerade) vs. standard of care alone (SOC)

Locally advanced PDAC

304 (187 SOC + TNFerade)

Median survival: 10.0 months for patients in both the SOC + TNFerade and SOC arms [hazard ratio (HR), 0.90, 95 % Cl; 0,66–1.22, P—0.26]

No major complications. Patients in the SOC+TNFerade arm experienced more grade 1–2 fever than those in the SOC alone arm (p < 0.001)

Sun, et al.

EUS-guided implantation of radioactive seeds (iodine-125)

Unresectable PDAC

15

Tumor response: “partial” in 27 % and “minimal” in 205. Pain relief: 30 %

Local complications (pancreatitis and pseudocyst formation) 3/15. Grade III hematologic toxicity in 3/15

Jin, et al.

EUS-guided implantation of radioactive seeds (iodine-125)

Unresectable PDAC

22

Tumor response: “partial” in 3/22 (13.6 %)

No complications


PDAC pancreatic ductal adenocarcinoma, EUS endoscopic ultrasound



Table 18.3
Studies of cryoablation in pancreatic ductal adenocarcinoma

































































































Study

n

Patients

Study

Outcome

Complications

Patiutko et al. (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.

9

Unresectable PDAC

Phase I study of intraoperative cryoablation under US guidance; 4 had concurrent gastrojejunostomy

7/9 discharge with non-intravenous analgesia and 2/9 discharged with no analgesia

No complications reported

Li et al. (non-English article)

44

Unresectable PDAC

Intraoperative cryoablation under US guidance

Median overall survival: 14 months

40.9 % (18/44) had delayed gastric emptying. 6.8 % (3/44) had a bile and pancreatic leak

Wu et al. (non-English article)

15

Unresectable PDAC

Intraoperative cryoablation under US guidance

Median overall survival: 13.4 months

1/15 patients developed a bile leak

Yi et al. (non-English article)

8

Unresectable PDAC

Intraoperative cryoablation under US guidance

Not reported

25 % (2/8) developed delayed gastric emptying

Xu et al.

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 months. 19/38 (50,9 %) survived more than 12 months

Acute pancreatitis: 5/38 (one has severe pancreatitis)

Xu et al.

49

Locally advanced PDAC, 12 had liver metastases

Intraoperative or percutaneous cryoablation under US or CT guidance + (125) iodine seed implantation. Some pts also received regional celiac artery chemotherapy

Median survival: 16.2 months. 26 patients (53.1 %) survived more than 12 months

Acute pancreatitis: 6/49 (one had severe pancreatitis)

Li et al.

68

Unresectable PDAC requiring palliative bypass

Retrospective case series of intraoperative cryoablation under US guidance, followed by palliative bypass

Median overall survival: 30.4 months (range 6–49 months)

Postoperative morbidity: 42.9 %

Delayed gastric emptying occurred in 35.7 %

Xu et al.

59

Unresectable PDAC

Intraoperative or percutaneous cryotherapy

Overall survival at 12 months: 34.5 %

Mild abdominal pain: 45/59 (76.3 %)

Major complications (bleeding, pancreatic leak): 3/59 (5 %)

Niu et al.

36 (CT)

Metastatic PDAC

Intraoperative cryotherapy (CT) or cryo-immunotherapy (CIT) under US guidance

Median overall survival in

Not reported

31 (CIT)

CIT: 13 months

CT: 7 months



Table 18.4
Studies of photodynamic therapy in pancreatic ductal adenocarcinoma












































Study

n

Study

Photosensitizer

Number of fibers

Number of ablations

Outcome and survival

Complications

Brown et al.

16

CT-guided percutaneous PDT to locally advanced but inoperable PDAC without metastatic disease

mTH-PC

1

Single

Tumor necrosis: 16/16

Significant gastrointestinal bleeding: 2/16 (controlled without surgery)

Median survival: 9.5 months. 44 % (7/16) survived > 1 year

Huggett et al.

13 + 2

CT-guided percutaneous PDT to locally advanced but inoperable PDAC without metastatic disease

Verteporfin

1

Single (13)

Technically feasible: 15/15. Dose-dependent necrosis occurred

Single fiber: No complications. Multiple fibers: CT evidence of inflammatory change anterior to the pancreas, no clinical sequellae

Multiple (2)


PDAC pancreatic ductal adenocarcinoma


Thermal ablation is based on the increase or the decrease of tumor temperature. When heat is applied, a target temperature of 50 °C (particularly temperatures ranging from 60 to 100 °C or more) results in tissue thermal injury and tumor ablation. The method of cell death results from apoptosis and eventually coagulative necrosis. Cold temperatures can also be utilized to ablate tumors (cryoablation), temperatures lower than the tissue freezing edge (i.e., temperature lower than −40 °C,) can cause necrosis of target cells [11, 12]. There are several thermal ablation studies on the treatment of pancreatic cancer, mainly with the use of applied heat. Very few studies have evaluated the use of cryotherapy for the management of locally advanced pancreas cancer.

Electrical current ablation is a technology that is based on the irreversible increase of permeability of the cellular membrane with the use of high voltage (3000 V), short pulse (70–90 μs) electric currents (IRE). IRE is one of the latest technological advances, and recent studies have been performed on its application in the local treatment of pancreatic cancer. Improvements in intraoperative imaging, electrodes, and ultrasound (US) technology have enabled the technology to accurately treat tumors [1315]. IRE has been applied to patients who are not considered suitable for surgical resection and have failed previous therapy with chemoradiotherapy. IRE may offer consolidative disease control, with symptom relief, control of pain, and definitive eradication of the lesion.

The inherent limitation for local ablative therapy of the pancreas is the heterogeneity of the tissue and the surrounding structures, as these can be damaged and lead to complications such as pancreatitis, vascular thrombosis, or enteric injury.


Radiofrequency Ablation


The first initial report of the use of RFA in an animal model was by Goldberg et al. [16] who reported that RFA could be used safely and effectively. This conclusion was extrapolated to the clinical scenario of small neuroendocrine tumors and possibly in the palliation of LAPC. An additional report from Date et al. [17] reported the safety of RFA in a normal pancreas of a porcine model. The first clinical report on 20 patients was published by Matsui et al. [18] in 2000 (Table 18.5). Since then, several case reports have been published from various groups of investigators [1922] (Table 18.3). The use of RFA in the pancreas has been recently summarized in a systematic review in the treatment of LAPC [19]. Five cohort studies (four prospective and one retrospective) were reported through 2012. This report did not include reports of < five cases and included only studies that reported RFA of pancreatic adenocarcinoma. A total 158 patients were treated with four different ablation devices: 100 patients using a 1500× generator (RITA Medical Systems, Mountain View, CA), 28 patients using a Radionics generator (Radionics Inc., Burlington, MA), 10 patients using a generator manufactured by Berchtold GmbH & Co., KG (Tuttlingen Germany), and 20 patients using a generator manufactured by Omron Co., Ltd (Kyoto, Japan). In the initial study by Matsui et al. [18], the technique they utilized was a controlled ablation of 50 °C for 15 min using 4 needles and reported a median overall survival of 3 months. Matsui’s poor survival outcomes may have been related to the fact that they included patients with metastatic disease. Overall survival was reported to be better in two additional studies at 20 months [20] and 33 months, respectively [21]. A systematic review by Singh et al. [23] reported an overall survival range of 9–36 months. The largest series published to date was from Girelli et al. [20]. In this series of 100 patients, a morbidity of 15 % and mortality of 3 % was reported. The authors utilized extreme heat (105 °C) in the first 25 patients leading to significant vascular and intestinal injury. They then modified their technique slightly with target temperatures of 90 °C. Others have also reported significant morbidity and mortality rates. Wu et al. reported a morbidity of 38 % and mortality of 25 % [22]. These results were related to three patients developing a pancreatic fistulas, three having massive gastrointestinal bleeding after portal vein thrombosis, with four procedure-related deaths. These results demonstrate that the use of a coagulative temperature will not only result in necrosis of the tumor, but also of the surrounding soft tissue(s). In an attempt to minimize these complications, several authors have described using cooling devices inserted endoscopically into the duodenum [24]. Similar intraoperative cooling devices have also been utilized as reported by Cavallini et al. [25] with encouraging results.


Table 18.5
Studies of radiofrequency ablation in pancreatic ductal adenocarcinoma




































































































































Study

Patients

n

Route of administration

Device

RFA temp

RFA duration (min)

Outcome

Complication

Matsui, et al.

Unresectable PDAC

20 LA:9 M:11

At laparotomy 4 RFA probes were inserted into the tumor 2 cm apart

A 13.56-MHz RFA pulse was produced by the heating apparatus

50

15

Survival: 3 months

Mortality: 10 % (septic shock and gastrointestinal bleeding)

Hadjicostas, et al.

Locally advanced and unresectable PDAC

4

Intraoperative—followed by palliative bypass surgery

Cool-tip™ RFAblation system

NR

2–8

All patients were alive 1-year post-RFA

No complications encountered

Wu, et al.

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.

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 months

Morbidity:16 % (biliary leak)

Mortality: 0 %

Girelli, et al.

Unresectable locally advanced PDAC

50

Intraoperative—followed by palliative bypass surgery

Cool-tip™ RFAblation system

105 (25 pts)

Not reported

Not reported

Morbidity 40 % in the first 25 patients. Probe temperature decreased from 105 to 90 °C. Morbidity 8 % in second cohort of 25 patients

90 (25 pts)

30-day mortality: 2 %

Girelli, et al.

Unresectable locally advanced PDAC

100

Intraoperative—followed by palliative bypass surgery

Cool-tip™ RFAblation system

90

56–10

Median overall survival: 20 months

Morbidity: 15 %.

Mortality: 3 %

Giardino, et al.

Unresectable PDAC, 47 RFA alone, 60 had RFA + RCT and/or IASC

107

Intraoperative—followed by palliative bypass surgery

Cool-tip™ RFAblation system

90

5–10

Median overall survival: 14.7 months in RFA alone but 25.6 months in those receiving RFA + RCT and/or IADC (p = 0.004)

Mortality 1,8 % (liver failure and duodenal perforation) Morbidity: 28 %

Arcidiacono et al.

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.

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)

Neduab syrvuvakL 5 ni Successful biliary decompression 21/22

Minor bleeding (1/22) Asymptomatic biochemical pancreatitis (1/22), percutaneous gallbladder drainage (2/22). At 90-day, 2/22 had died, one with a patent SEMS

Figueroa-Barojas et al.

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-day (3/22) bile duct diameter increased by 3.5 mm post-RFA (p = 0.0001)

Abdominal pain (5/20), mild post-ERCP pancreatitis and cholecystitis (1/20)

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Jan 29, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on The Role of Irreversible Electroporation and Other Ablative Techniques in Patients with Borderline Resectable Pancreatic Cancer

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