- Email: [email protected]
Phase 1 study of EUS-guided photodynamic therapy for locally advanced pancreatic cancer
NEW METHODS
Phase 1 study of EUS-guided photodynamic therapy for locally advanced pancreatic cancer John M. DeWitt, MD,1 Kumar Sandrasegaran, MD,2 Bert O’Neil, MD,4 Michael G. House, MD,3 Nicholas J. Zyromski, MD,3 Amikar Sehdev, MD,4 Susan M. Perkins, PhD,5 Janet Flynn, RN,4 Lynne McCranor, RN,4 Safi Shahda, MD4 Indianapolis, Indiana, USA
Background and Aims: Locally advanced pancreatic cancer (LAPC) has a poor prognosis. There are limited data describing the use of photodynamic therapy (PDT) for pancreatic cancer in humans. We hypothesized that EUSguided PDT for LAPC is safe, technically feasible, and produces a dose- and time-dependent increasing degree of image-defined tumor necrosis. Methods: In a single-center, prospective, dose-escalation phase 1 study, patients with treatment-naïve LAPC received intravenous porfimer sodium (Concordia Laboratories Inc, St Michael, Barbados) followed 2 days later by EUS-PDT. EUS-PDT was performed by puncture with a 19-gauge needle and insertion of a 1.0-cm light diffuser (Pioneer Optics, Bloomfield, Conn) and illumination with a 630-nm light (Diomed Inc, Andover, Mass). A CT scan 18 days after PDT was done to assess for change in pancreatic necrosis. Nab-paclitaxel (125 mg/ m2 intravenously) and gemcitabine (1000 mg /m2 intravenously) were initiated 7 days after CT and given weekly for 3 of 4 weeks (1 cycle) until disease progression or unacceptable toxicity. Results: Twelve patients (mean age, 67 6 years; 8 male) with tumors (mean diameter, 45.2 12.9 mm) in the head and/or neck (8) or body and/or tail (4) underwent EUS-PDT. Compared with baseline imaging, increased volume and percentage of tumor necrosis were observed in 6 of 12 patients (50%) after EUS-PDT. The mean overall increases in volume and percentage necrosis were 10 26 cm3 (P Z .20) and 18% 22% (P Z .016), respectively. After a median follow-up of 10.5 months (range, 1.0-37.4 months), median progression-free (PFS) and overall survival (OS) were 2.6 months (95% confidence interval, 0.7, not estimable) and 11.5 months (95% confidence interval, 1.1, 16.9), respectively. Surgical resection was attempted in 2 patients, and pathology showed a complete response (n Z 1) and residual 2-mm tumor (n Z 1). There were 8 serious adverse events and none related to EUS or EUS-PDT. Conclusion: EUS-PDT for LAPC appears to be safe and produces measurable imaged-defined tumor necrosis. Phase 2 studies are warranted. (Clinical trial registration number: NCT01770132.)
INTRODUCTION In the United States in 2018, an estimated 55,440 Americans will be diagnosed with pancreatic cancer with an estimated 44,330 deaths from the disease.1 Despite advances Abbreviations: LAPC, locally advanced pancreatic cancer; MRI, magnetic resonance imaging; OS, overall survival; PDT, photodynamic therapy; PFS, progression-free survival; SAE, serious adverse event. DISCLOSURE: Dr DeWitt has received a research grant from Concordia Laboratories Inc, St. Michael, Barbados, and has acted as a consultant for Olympus America and Boston Scientific. All other authors disclosed no financial relationships relevant to this publication. Copyright ª 2018 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 https://doi.org/10.1016/j.gie.2018.09.007
in chemotherapy for locally advanced and metastatic pancreatic cancer,2,3 5-year survival remains under 10%.1 Due to conflicting results from previous trials, it is not yet clear whether radiation is an essential component in the therapy of patients with locally advanced pancreatic Current affiliations: Department of Gastroenterology (1), Department of Radiology (2), Department of Surgery (3), Department of Oncology (4), Department of Statistics (5), Indiana University Health Medical Center, Indianapolis, Indiana, USA. Reprint requests: John DeWitt MD, FACG, FACP, FASGE, AGAF, Professor of Medicine, Division of Gastroenterology & Hepatology, Indiana University Health Medical Center, 550 N. University Blvd, UH 4100, Indianapolis, IN 46202. If you would like to chat with an author of this article, you may contact Dr DeWitt at [email protected].
Received August 2, 2018. Accepted September 7, 2018.
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cancer (LAPC).4 Clearly, novel agents, therapies, and approaches to treatment of this malignancy are needed. Photodynamic therapy (PDT) is an oxygen-dependent reaction between a photosensitizing dye and light that produces localized tissue necrosis. The light is usually given in the form of a laser and is applied after administration of a photosensitizing agent.5 The basis for PDT is the propensity of some chemicals for photoexcitation when exposed to intense white or specific wavelength laser light. Worldwide, endoscopists have used PDT in humans principally for ablative treatment of early malignant or nonmalignant/dysplastic Barrett’s esophagus,6,7 palliation of dysphagia in esophageal cancer, or palliation of biliary obstruction and recurrent cholangitis from inoperable cholangiocarcinoma.8,9 PDT in humans using various photosensitizers for the management of dysplasia and malignancy of the ampulla and pancreas has been reported to be safe, feasible, and possibly curative for small tumors.10-13 However, percutaneous delivery of the light fiber is required, which may be uncomfortable for the patient and requires passage of the fiber a long distance from the primary tumor. Due to the close proximity of the endoscope to the pancreas, EUS would appear to be an ideal modality to deliver PDT to the pancreas. To date, EUS-PDT in a healthy porcine model using the photosensitizers porfimer sodium14 and verteporfin15 have been published. Each study demonstrated the technique is feasible, well tolerated, and produces well-defined margins of fat necrosis, granulation tissue, inflammation, and fibrosis. EUS-guided PDT was well tolerated in 4 patients with locally advanced pancreaticobiliary malignancies; however, only 1 of these had pancreatic cancer.16 In this phase 1 study, we hypothesized that EUS-guided PDT using the photosensitizer porfimer sodium for pancreatic ductal adenocarcinoma in humans is safe, technically feasible and produces a dose-dependent, incrementally increasing degree of pancreatic tumor necrosis as detected by CT scan or magnetic resonance imaging (MRI) after treatment. The primary objective of this study was to determine the safety of this technique; secondary objectives were to determine the effect of EUS-PDT on the volume of tumor necrosis, tumor stabilization or decrease in size, surgical downstaging, and survival after treatment.
METHODS Patient selection and study design This is an investigator-initiated, open-label, singlecenter, prospective phase 1, dose-ranging study in patients with LAPC. Investigators and patients were aware of the treatment received. The protocol and supporting documents (ClinicalTrials.gov identifier, NCT01770132) were reviewed and approved by the Scientific Review Committee 2 GASTROINTESTINAL ENDOSCOPY Volume
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and Institutional Review Board at Indiana University Health Medical Center in Indianapolis, Indiana. Before enrollment, all patients underwent screening lab tests, imaging studies (ie, EUS, CT, and/or MRI) and consultations (surgery and oncology) to determine eligibility. Eligible patients signed informed consent before enrollment. Inclusion criteria included patients aged 18 to 75 years with treatment-naïve, biopsy-proven LAPC measuring 2.5 to 7.0 cm in diameter. Patients were also required to have a Karnofsky performance score 70% and a life expectancy of 3 months. LAPC was defined as a tumor imaged by dual-phase CT or MRI with direct extension to the superior mesenteric artery and/or celiac axis (with absence of a fat plane between the low-density tumor and these arterial structures) or loss of patent and/or thrombosed superior mesenteric-portal vein confluence. All patients with a dilated bile duct or increased total bilirubin level were required to have a biliary or transhepatic stent placed before consideration for the trial, with placement of a metal biliary stent required before study treatment. Exclusion criteria included the following: distant metastatic disease, previous surgical or medical treatment of the cancer, bowel fistula, portal hypertension, moderate to large volume ascites, gastroduodenal ulcers, bulky celiac adenopathy (>2.5 cm diameter), non-adenocarcinoma diagnosis (ie, endocrine tumor), uncorrected coagulopathy, renal insufficiency (serum creatinine >2.0 mg/dL), jaundice, anemia (hematocrit 28% or hemoglobin 9 g/ dL), thrombocytopenia (platelet count 100,000/mL), neutropenia (absolute neutrophil count 1500/mL), pancreatitis within 3 months, pregnancy, experimental medications within 4 weeks, inability to avoid exposure of skin or eyes to direct sunlight or bright indoor light for at least 30 days, porphyria, chronic corticosteroid use at superphysiologic doses (10 mg prednisone per day or equivalent), or any surgery within the previous 2 weeks.
Treatment administration The study schema is shown in Figure 1. Treatment consisted of 4 cohorts, which varied by the dose of photosensitizer given and time of light application (Table 1). Porfimer sodium. Intravenous administration of porfimer sodium (Photofrin, Concordia Laboratories Inc, St Michael, Barbados) as a photosensitizer was given at a dose of 1 mg/kg or 2 mg/kg and was considered as day 1 of the study. The first 6 patients received 1 mg/kg and the last 6 patients received 2 mg/kg. The lower dose was chosen first because that was used for the pilot study in a porcine model.14,15 EUS-PDT. Using a linear echoendoscope (Olympus GF-UC140P; Olympus America, Inc, Center Valley, Pa) under appropriate cardiorespiratory monitoring and sedation with propofol, we performed treatment between 40 and 50 hours after infusion of the photosensitizer. EUS-PDT was considered day 3 of the study. The stylet of a 19-gauge www.giejournal.org
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EUS-guided PDT for locally advanced pancreatic cancer
Nab-Paclitaxel IV Gemcitabine2 Cycle 1 Day 1
Consent & Baseline
CA 19-9 MDCT or MRI CMP/CBC
EUS
IV Photofrin1 Day 1
EUS-PDT Day 3 (Wed)
Labs at Discharge: amylase, lipase
Day 8 (Mon)
CA 19-9
Nab-Paclitaxel IV Gemcitabine Cycle 3 Day 1
Cycle 5+ Day 1
Surgical Resection3
Day 21
CA 19-9 MDCT or MRI
CA 19-9 MDCT or MRI
CA 19-9 MDCT or MRI
1. Photofrin administered by IV at a dose of 1 mg/kg for first 6 patients and 2 mg/kg for last 6 patients. 2. Gemcitabine was administered intravenously over 30 minutes at a dose of 1000 mg/m2. Nab-Paclitaxel was administered intravenously over 30 minutes at a dose of 125 mg/m2 prior to the administration of gemcitabine. Both medications were given on Day 1, Day 8, and Day 15 of a 28 day treatment cycle and were continued until disease progression or unacceptable toxicity. 3. Consideration for surgical resection if downstaging has occurred as seen on imaging. Figure 1. Study schema.
Flex needle (Boston Scientific, Natick, Mass) was removed and a plastic locking device was attached to the proximal side of the needle. A commercially available smalldiameter quartz optical fiber with a 1.0-cm cylindrical light diffuser (Pioneer Optics, Bloomfield, Conn)14,15 was passed through the locking device and needle until about 1.5 cm of the fiber exited the tip of the FNA needle (Figs. 2 and 3). The fiber was secured with the locking device and the locking device/fiber combination was withdrawn about 2 to 3 cm proximally so the fiber was completely inside the FNA needle. The needle was then passed into the endoscope and secured at the accessory channel. The tumor was punctured with the 19-gauge needle and the tip was intentionally passed toward the distal side of the tumor. The needle was then withdrawn 1 to 2 cm proximally inside the tumor. The PDT fiber was then advanced 1.5 cm into the tumor by advancing the locking device/fiber combination slowly inside the tumor and securing the locking device to the proximal end of the FNA needle. This pilot study was planned for 12 patients in 4 cohorts (Table 1). For each use of the light diffuser, the tumor was illuminated with a 630-nm light (Diomed Inc, Andover, Mass). A total light dose of 50 J/cm14,15 per use was used for the first 3 patients, which increased to 100 J/cm per use for the next 3 patients. A maximum of 3 punctures were made per patient and each treatment site (ie, puncwww.giejournal.org
ture site) was 7 to 10 mm apart from the previous site based on the expected region of necrosis produced by each treatment. A porfimer sodium dose of 1 mg/kg14,15 was used for the first 6 patients, which increased to 2 mg/kg for the last 6 patients.6,8 Treatment application time per site was either 125 or 250 seconds, and therefore total treatment energy for one or both procedures varied between 150 and 300 J (Table 1). After EUS, patients remained in recovery without oral intake for at least 2 hours. If required analgesics or antiemetics were given. If symptoms were well controlled, the patient was given water to drink. If symptoms were minimal or successfully treated, the patient was discharged. Samples for assessing serum amylase and lipase levels were taken before discharge. Gemcitabine and nab-paclitaxel therapy. Chemotherapy with gemcitabine and nab-paclitaxel was initiated after the conclusion of PDT therapy on treatment day 21 (which was also called cycle 1, day 1). Gemcitabine was administered intravenously over 30 minutes at a dose of 1000 mg /m2. Nab-paclitaxel was administered intravenously over 30 minutes at a dose of 125 mg/ m2 before the administration of gemcitabine. Both medications were given on day 1, day 8, and day 15 of a 28-day treatment cycle and were continued until disease progression or unacceptable toxicity. Volume
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TABLE 1. Treatment protocol for EUS-PDT for 12 patients (3 patients per cohort)
Cohort number (3 patients per cohort)
Photofrin dose (mg/kg)
Energy per site (J)
Maximal number of sites treated per EUS
Power output (mW)
Treatment application time per site (seconds)
Maximal total energy (J) of each EUS treatment
1
1
50
3
400
125
150
2
1
100
3
400
250
300
3
2
50
3
400
125
150
4
2
100
3
400
250
300
PDT, Photodynamic therapy; mW, milliwatts; J, joules.
Figure 2. Fiber with a 1.0cm cylindrical light diffuser passed through a locking device on the proximal side of a 19-gauge needle until about 1.5 cm of the fiber exited the tip of the FNA needle.
Criteria for treatment modifications and suggested guidelines for the management of toxicities related to nab-paclitaxel and/or gemcitabine were standardized for the study protocol, but these general guidelines were modified at the discretion of the investigator based on best clinical judgement at that time. Toxicities related to nab-paclitaxel and/or gemcitabine were managed according to standard medical practice. Once the toxicity resolved to the required level, nab-paclitaxel and/or gemcitabine were restarted. Dose escalation of nab-paclitaxel and/or gemcitabine was not allowed once a dose was reduced. If nab-paclitaxel and/or gemcitabine treatment was delayed for >28 days despite supportive treatment per standard clinical practice or more than 2 dose reductions (gemcitabine <600 mg/m2, nab-paclitaxel <75 mg/m2) were required, nab-paclitaxel and/or gemcitabine treatment was discontinued.
Radiology examinations All studies were reviewed by a single experienced gastrointestinal radiologist who reported tumor size, dimensions, vascular involvement, and degree of necrosis if present. CT was performed using Brilliance-64 (64channel) or Brilliance-40 (40-channel) CT scanners (Philips 4 GASTROINTESTINAL ENDOSCOPY Volume
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Figure 3. Fiber and FNA needle exiting the echoendoscope adjacent to the ultrasound transducer.
Medical Systems, Best, Netherlands) without oral contrast. Intravenous contrast was given only with an estimated glomerular filtration rate of more than 30 mL/min/1.73 m2). A dose of 120 mL of iopamidol (Isovue-370, Bracco Diagnostics, Princeton, NJ) was given at a rate of 4 mL/second using a power injector (CT Envision, Medrad Inc, Pittsburg, Pa) followed by flushing with 20 mL of saline solution. The abdomen (dome of the diaphragm to iliac crests) was imaged in the pancreatic parenchymal and venous phases, timed at 35 and 70 seconds, respectively, after the start of intravenous contrast injection.
Adverse events Adverse events occurring from porfimer sodium infusion, laser light application, CT, MRI, chemotherapy, and surgery (if performed) were evaluated. These were further classified as follows: (1) expected versus unexpected; (2) serious adverse event (SAE) versus important but not serious adverse event; (3) no reasonable possibility (where a medical condition or other cause for the event is identified); and (4) reasonable possibility. SAEs were considered to be any undesirable sign, symptom, or medical condition that was fatal, life-threatening, required inpatient hospitalization 24 hours, resulted in persistent or significant disability/incapacity, or was medically significant and www.giejournal.org
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TABLE 2. Baseline demographics, tumor characteristics, and EUS-PDT procedure
Cohort
Age (years)/ gender
Tumor location
Maximal tumor diameter (mm)
Vascular involvement by tumor*
Clinical TN stagey
Number of sites treated in tumor by PDTy
Site of puncturez
Serum amylase (U/L) before/after PDTx
1
1
69/M
Head
51
CAx1, PV1, SV1, SMA1
T4N0
3
Stomach
28/26
2
1
63/F
Body
50
CAx3, PV1, SA3, SMA3, SMV1
T4N1
3
Stomach
89/30
3
1
67/F
Neck
39
PV1, SMA3, SMV1
T4N0
3
Stomach
62/50
4 5
2
78/M
Body, tail
24
CAx1, HA1, SA1
T4N1
2
Stomach
24/24
2
71/M
Head
42
SMV1
T3N1
3
Duodenum
612/157
6
2
66/M
Head
39
PV1, SV1, SMA1
T4N1
3
Duodenum
43/26
7
3
67/M
Head, neck
56
PV3, SMA3, SMV3
T4N1
3
Duodenum
48/50
8
3
58/F
Head, neck
28
GDA1, PV1, SV1
T3N0
3
Stomach
17/18
9
3
60/M
Head, neck
65
HA2, PV2
T3N1
2
Stomach
59/35
10
4
71/M
Body, tail
65
CAx1, HA1, SA1
T4N1
3
Stomach
48/49
11
4
76/M
Body
45
CAx1, SA1, SV1
T4N0
3
Stomach
63/57
12
4
63/F
Head, neck
38
SMV1
T3N1
3
Duodenum
25/28
Patient
PDT, Photodynamic therapy; M, male; CAx, celiac axis; PV, portal vein; SV, splenic vein; SMA, superior mesenteric artery; F, female; SA, splenic artery; SMV, superior mesenteric vein; GDA, gastroduodenal artery; HA, hepatic artery. *Vessels names are abbreviated. Invasion, adherence, and abutment by CT scan are assigned a value of 1, 2, and 3, respectively, after the vessel name. yTumors assigned a tumor (T) and nodal (N) staging system according to the AJCC 8th Edition Cancer Staging System. zA maximum of 3 punctures were made per patient. xPost-PDT serum amylase (normal, 30-110 U/L) samples were drawn 2 hours after EUS-PDT.
which the investigator regarded as serious based on judgement. Adverse event intensity was assessed by investigators according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0, and ranged from grade 1 (mild), 2 (moderate), 3 (severe), or 4 (lifethreatening/disabling). Death (grade 5) was considered the outcome of an event and assigned a grade 4 severity. For EUS-PDT, adverse events were graded as possibly, probably, or definitively related to either endoscopy alone or EUS-PDT from the time period extending from the PDT until 1 week later. If any of the first 3 study patients undergoing EUS-PDT had any of the following adverse events requiring hospitalization for 5 days (acute pancreatitis, infected pancreatic necrosis, abdominal pain, retroperitoneal or gastrointestinal bleeding requiring transfusion or additional procedure, new gastrointestinal symptoms) or if any bowel perforation occurred, then an additional 3 patients were required to be accrued to that dose level. If 2 of the first 3 or 6 patients in any cohort experienced an adverse event related to EUS-PDT, then further enrollment was halted and the study terminated or amended to evaluate lower treatment doses. Dose escalation to a new 3person cohort proceeded only after the last patient (3 or 6 patients, depending on the incidence of adverse events) was followed for 2 weeks after the last EUS-PDT treatment.
Measurement of effect The primary objective of this phase 1 study was to determine the safety of increasing total energy and number of apwww.giejournal.org
plications sites treated for EUS-guided PDT for LAPC in humans and was evaluated as described above. The principal secondary endpoint of image-defined volume of tumor necrosis produced by EUS-PDT before chemotherapy was evaluated by CT or MRI 18 days after treatment. The volume of necrosis was measured by the formula d1 d2 d3/2, where d is the maximal diameter of tumor necrosis in 1 of the 3 dimensions. The percentage necrosis was the volume of tumor non-enhancement divided by the volume of whole tumor and was manually calculated by the radiologist by measuring necrotic and non-necrotic tumor area on each axial slice. Automatic segmentation software was not used for these calculations. Imaging was performed every 2 to 3 months thereafter to evaluate for further changes to the tumor dimensions while on systemic chemotherapy. Additional secondary study objectives of tumor stabilization or surgical downstaging were also assessed by cross-sectional imaging after EUS-PDT. If the necrosis produced by treatment was able to remove tumor adherence or involvement of a major abdominal blood vessel (ie, portal vein, superior mesenteric artery), then repeat surgical consultation was obtained to consider surgery if feasible. When surgery was performed, type of operation and presence of distant metastases, if any, were evaluated. Pathology was categorized as a complete or incomplete response, and margins were assessed as R0 (negative margins), R1 (microscopic residual cancer), R2 (macroscopically visible cancer). The final objective of survival was assessed by follow-up visits or phone calls. Volume
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TABLE 3. Change in tumor necrosis, chemotherapy, and follow-up after PDT
Cohort
Baseline volume tumor necrosis (cm3)
1
1
0
0
0
0
5
0
5
Death
321
2
1
0
0
0
0
0
1
1
Death
31
3
1
7.9
17.8
78
88
0
7
7
Death
323
4
2
0
1
0
28
2
5
7
Alive
1147
5
2
0
0
0
0
0
2
2
Death
352
6
2
0
0
0
0
0
6
6
Death
499
7
3
2.4
1.8
3
3
0
6
6
Death
232
8
3
0
9.4
0
58
0
1
1
Death
519
9
3
2.1
93.9
8
48
0
0
0
Death
39
10
4
0
9
0
48
0
2
2
Alive
342
11
4
0
0
0
0
0
2
2
Alive
287
12
4
0
1.7
0
33
0
2
2
Alive
30
Patient
Percentage Cycles of Time until Volume of Baseline tumor percentage tumor gemcitabineTotal death or last necrosis after tumor necrosis Cycles of nabcycles of follow-up PDT (cm3) necrosis after PDT gemcitabine paclitaxel chemotherapy Outcome (days)
PDT, Photodynamic therapy.
Statistics Descriptive statistics consisted of means standard deviations or medians with ranges for continuous variables, and simple proportions for dichotomous variables. Twosided paired t tests were used to test for change in tumor necrosis volume and percentage of tumor necrosis from baseline to post EUS-PDT and the change in CA 19-9 with treatment. Progression-free (PFS) and overall survival (OS) medians and 95% confidence intervals were estimated using the Kaplan-Meier method. All statistical analyses were performed using SAS v9.4 (Cary, NC).
RESULTS Study population Between August 2013 and June 2017, 16 patients were screened and 12 (mean age, 67 6 years; 8 male) were enrolled. Baseline patient demographics, tumor characteristics, and results of the EUS-PDT procedure are shown in Table 2. Mean axial, coronal, and sagittal tumor dimensions were 40.8 15.7 mm, 37.8 10.1 mm, and 34.4 10.5 mm, respectively. Maximal diameter was 45.2 12.9 mm. Tumors were located in the head and/or neck (n Z 8) or the body and/or tail (n Z 4).
EUS-PDT All patients successfully underwent all intended EUS-PDT treatments. Needle puncture was transgastric in 8 (67%) and transduodenal in 4 (33%). In 10 (83%), 3 intratumoral treatments were performed, whereas 2 treatments were used in 2 (17%). Compared with baseline tests, cross-sectional imaging performed 18 days after EUS-PDT showed increased volume and percentage of tumor necrosis 6 GASTROINTESTINAL ENDOSCOPY Volume
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(Table 3) in 6 of 12 (50%) patients including 4 of 6 (67%) in the last 2 cohorts (Figs. 4 and 5). Mean overall increase (n Z 12) in the volume and percentage of necrosis was 10 26 cm3 (P Z .20) and 18% 22% (P Z .016), respectively.
Follow-up after PDT A median of 2 (range, 0-7) chemotherapy cycles were successfully completed (Table 3). By the RECIST criteria, the best response to treatment was progressive disease in 6, stable disease in 3, partial response in 1, and not evaluable in 2. Surgical resection was performed in 2 patients. One in cohort 2 (number 4) had a 2.4-cm tumor at the body/tail junction with invasion of the celiac, hepatic, and splenic arteries. This patient underwent EUS-PDT, 7 rounds of chemotherapy, and distal pancreatectomy without vascular resection or reconstruction. Baseline CT showed no tumor necrosis but showed 28% necrosis on the first CT after PDT. Pathology showed a pathologic complete response. The second patient in cohort 4 (number 10) had a 6.5-cm tumor at the body/tail junction also with invasion of the celiac, hepatic, and splenic arteries. This patient underwent EUSPDT, 2 rounds of chemotherapy, and distal pancreatectomy without vascular resection or reconstruction. Baseline CT showed no tumor necrosis but showed 48% necrosis on the first CT after PDT. Pathology showed a residual 2-mm well-differentiated T1N0 adenocarcinoma with negative margins (R0 resection). Treatment with EUS-PDT did not change mean CA 19-9 values between baseline and before chemotherapy (P Z .30).
Adverse events There were 4 grade 1 or grade 2 adverse events related to porfimer sodium including sunburned hands from sun www.giejournal.org
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Dose of Photofrin = 1 mg/kg
Dose of Photofrin = 2 mg/kg
88
Percent Tumor Necrosis
80
78
58
60
48 48 40 33 28 20 8 0
000 0
000 0 0
3 0
0 3 0 0 0
Post PDT Baseline
Baseline
Post PDT
Time Period 100 Joules
150 Joules
200 Joules
300 Joules
Figure 4. Change in percentage tumor necrosis by porfimer sodium dose and total energy delivered.
exposure (n Z 1), nausea (n Z 1), photosensitivity (n Z 1), and skin hyperpigmentation (n Z 1). One patient had increased fatigue (grade 2) after endoscopy, but there were no SAEs related to porfimer sodium, endoscopy, or EUS-PDT. Specifically, no patient developed pancreatitis, infection, bleeding, bowel obstruction, or bowel perforation after endoscopy. Of the 14 grade III or IV toxicities from gemcitabine, the most frequent were neutropenia (37%), fatigue (18%), and anemia (18%). Of the 12 grade III and IV toxicities from nab-paclitaxel, the most frequent were neutropenia (30%) and anemia (20%). Eight SAEs occurred in 7 patients, all of which required hospitalization (Table 4). Seven patients with SAEs were discharged after hospitalization and 1 died during the hospitalization.
Survival Median follow-up from PDT to last contact with patient alive on protocol or to death was 10.5 months (range, 137.4 months). Four patients were still alive with a median follow-up of 315 days (range, 30-1147 days). Median PFS and OS were 2.6 months (95% CI, 0.7-not estimable) and 11.5 months (95% CI, 1.1-16.9), respectively. The KaplanMeier plot for time to death after photosensitizer administration is shown in Figure 6.
DISCUSSION The current phase 1 study represents the first case-series description of EUS-PDT for treatment-naïve pancreatic cancer www.giejournal.org
in humans. We found that EUS-PDT for locally advanced pancreatic ductal adenocarcinoma using the photosensitizer porfimer sodium is technically feasible and may be performed without SAEs related to porfimer sodium administration, endoscopy, or EUS-PDT. These findings further suggest that EUS-PDT is safe as previously shown in a healthy porcine model using the photosensitizers porfimer sodium14 and verteporfin.15 Furthermore, our study replicates the safety of PDT found in previous human trials that used fibers placed by duodenoscopy into ampullary tumors11 or percutaneously via needles placed into pancreatic cancer.12,13 Adverse events related to the photosensitizer or treatment noted in these human studies included skin photosensitivity11 and duodenal obstruction.13 Similar to animal and human studies,11-15 we noted in 6 of 12 patients that cross-sectional imaging after EUS-PDT produced increasing pancreatic tumor necrosis. As we hypothesized, necrosis was greatest in cohorts 3 and 4; 4 of 6 patients had tumor necrosis after therapy. These 2 cohorts received the higher dose of photosensitizer (2 mg/kg) and a maximum total of 150 J or 300 J per treatment. Two patients in the last cohort had no increased tumor necrosis after therapy. It has been postulated that differences in pharmacokinetics and tumor biology (ie, vascular perfusion) may account for the differences in observed responses to PDT treatment.13 Porfimer sodium, the photosensitizer used in the current study, has been used extensively and successfully in gastroenterology for treatment of early malignant or dysplastic Barrett’s esophagus,6,7 palliation of dysphagia Volume
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Figure 5. A 57-year-old woman with jaundice and 4.7-cm pancreatic head cancer (patient 8, cohort 3). Baseline tumor showed no pancreatic necrosis. Porfimer sodium 2 mg/kg was given intravenously followed 2 days later by 3 transgastric PDT treatments of 50 J each (150 J total).
TABLE 4. Serious adverse events observed during the trial
Subject 1
SAE
Hospitalization
Attribution to porfimer sodium or EUS-PDT
Attribution to chemotherapy
Toxicity grade Unexpected
Ascites, nausea
Yes
No
Possible, gemcitabine
2
No
Outcome Resolved and discharged
2
Nausea, vomiting
Yes
No
No
3
Yes
Death
5
Pulmonary emboli
Yes
No
No
3
Yes
Resolved and discharged
8
Pneumonia, sepsis
Yes
No
No
3
No
Resolved and discharged
8
Thrombocytopenia
Yes
No
No
4
No
Resolved and discharged
9
Jaundice, malaise, fatigue
Yes
No
No
4
No
Resolved with sequelae and discharged
10
Nausea
Yes
No
Probable, gemcitabine and nab-paclitaxel
3
No
Resolved and discharged
12
Dizziness, dysarthria, hallucinations
Yes
No
No
2
Yes
Resolved and discharged
SAE, Serious adverse event; PDT, photodynamic therapy.
in esophageal cancer or palliation of biliary obstruction, and recurrent cholangitis from inoperable cholangiocarcinoma.8,9 However, the pharmacology of the drug requires treatment 20 to 50 hours after injection and the long elimination half-life (about 3 weeks) causes photosensitivity to remain for up to 1 month. These properties are similar to the photosensitizer meso-tetrahydroxyphenylchlorin, which was used by Bown et al12 for treatment of pancreatic cancer. Patients in our study were counseled extensively about these risks, which likely accounts for the absence of SAEs from photosensitivity. Huggett et al13 used the second-generation photosensitizer verterporfin in a recent phase 1/2 study of PDT using percutaneously placed fibers. The short half-life of verteporfin permits treatment only 1 to 2 hours after administration, and patients are photosensitive for only 7 days. There are 8 GASTROINTESTINAL ENDOSCOPY Volume
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currently no comparative trials between photosensitizers in pancreatic cancer in humans; therefore, the clinical benefit of one agent over the other apart from differences in photosensitivity is unknown. Two patients in our study underwent surgery after an increase in tumor necrosis of 28% to 48% after PDT and further tumor downstaging during chemotherapy. The first patient had an R0 resection and was alive more than 3 years after PDT. Previous trials have also had patients undergo R0 resections after PDT.12,13 The second patient had a residual 3-mm T1N0 tumor. It is difficult to postulate the contribution of PDT alone to surgical downstaging, but both patients had significant necrosis from PDT treatment before starting chemotherapy. Choi et al16 described the first use of EUS-PDT in a single patient with pancreatic tail cancer that had progressed www.giejournal.org
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1.0 Survival Probability
and produces measurable image-defined tumor necrosis. Chemotherapy after EUS-PDT may occasionally lead to tumor downstaging to permit attempted surgical resection. Phase 2 studies with porfimer sodium and additional studies using EUS with other photosensitizers is warranted.
Product-Limit Survival Estimate With Number of Subjects at Risk Censored
0.8 0.6 0.4
REFERENCES 0.2
0.0 At Risk
12 0
7 1 1 20 10 30 Months to Death from Photofrin Administration
0 40
Figure 6. Kaplan-Meier plot for time to death after photosensitizer administration.
despite chemotherapy. These authors used a 19-gauge needle, 2-cm diffuser fiber, and a chlorin e6 photosensitizer. Treatment produced a 0.85-cm region of necrosis without adverse events. The current study used linear EUS and a flexible 19-gauge needle to deliver the diffuse fiber used for PDT. We found that transgastric puncture and fiber delivery to tumors in the body and tail were technically easier than transduodenal puncture of pancreatic head tumors. Furthermore, imaging of pancreatic head tumors smaller than 35 mm with metallic biliary stents was challenging. Nevertheless, treatment was technically successful in all patients. Development of a fiber that can be delivered with a 22gauge needle will likely make treatment easier. The use of EUS-FNA needles to deliver a diffuser fiber for PDT in pancreatic cancer stands in contrast to previous studies that used percutaneous needles for fiber delivery. Although endoscopy requires sedation, our procedures required less than 30 minutes to complete, and real-time imaging of the needle and fiber permits assurance that treatment is properly positioned. Although percutaneous delivery is likely more uncomfortable than endoscopy, it does permit use of simultaneous diffuser fibers to enhance the area of treatment.13 Because EUS appears to be the ideal modality to deliver therapy to pancreatic tumors, EUS-guided injection17-21 and ablation22 of pancreatic cancer are feasible. However, it is unclear whether delivery of ablation to pancreatic tumors to induce necrosis may improve survival.18 The principal study limitation is the use of EUS-PDT in highly selected, functional patients with treatment-naïve locally advanced pancreatic adenocarcinoma. The safety of EUS-PDT using porfimer sodium in patients with previously treated cancer, other histologic types of pancreatic cancer, or at energy doses not used in this study is not known. In conclusion, EUS-PDT using the photosensitizer porfimer sodium in patients with LAPC appears to be safe www.giejournal.org
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68:7-30. 2. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369: 1691-703. 3. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25. 4. Fogel EL, Shahda S, Sandrasegaran K, et al. A multidisciplinary approach to pancreas cancer in 2016: a review. Am J Gastroenterol 2017;112:537-54. 5. Sheng C, Pogue BW, Wang E, et al. Assessment of photosensitizer dosimetry and tissue damage assay for photodynamic therapy in advanced-stage tumors. Photochem Photobiol 2004;79:520-5. 6. Overholt B, Lightdale C, Wang K, et al. Photodynamic therapy (PDT) with porfimer sodium for the ablation of high-grade dysplasia in Barrett’s esophagus (BE): international, partially blinded randomized phase III trial. Gastrointest Endosc 2005;62:488-98. 7. Ackroyd R, Brown NJ, Davis MF, et al. Photodynamic therapy for dysplastic Barrett’s oesophagus: a prospective, double blind, randomised, placebo controlled trial. Gut 2000;47:612-7. 8. Ortner ME, Caca K, Berr F, et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology 2003;125:1355-63. 9. Kahaleh M, Mishra R, Shami VM, et al. Unresectable cholangiocarcinoma: comparison of survival in biliary stenting alone versus stenting with photodynamic therapy. Clin Gastroenterol Hepatol 2008;6:290-7. 10. Liu CD, Kwan D, Saxton RE. Hypericin and photodynamic therapy decreases human pancreatic cancer in vitro and in vivo. J Surg Res 2000;93:137-43. 11. Abulafi AM, Allardice JT, Williams NS, et al. Photodynamic therapy for malignant tumours of the ampulla of Vater. Gut 1995;36:853-6. 12. Bown SG, Rogowska AZ, Whitelaw DE, et al. Photodynamic therapy for cancer of the pancreas. Gut 2002;50:549-57. 13. Huggett MT, Jermyn M, Gillams A, et al. Phase I/II study of verteporfin photodynamic therapy in locally advanced pancreatic cancer. Br J Cancer 2014;110:1698-704. 14. Mino M, Lauwers GY, Puricelli WP, et al. EUS-guided photodynamic therapy of the pancreas: a pilot study. Gastrointest Endosc 2004;59: 95-9. 15. Yusuf TE, Matthes K, Brugge WR. EUS-guided photodynamic therapy with verteporfin for ablation of normal pancreatic tissue: a pilot study in a porcine model (with video). Gastrointest Endosc 2008;67:957-61. 16. Choi JH, Oh D, Lee JH, et al. Initial human experience of endoscopic ultrasound-guided photodynamic therapy with a novel photosensitizer and a flexible laser-light catheter. Endoscopy 2015;47:1035-8. 17. Levy MJ, Alberts SR, Bamlet WR, et al. EUS-guided fine-needle injection of gemcitabine for locally advanced and metastatic pancreatic cancer. Gastrointest Endosc 2017;86:161-9. 18. Hecht JR, Farrell JJ, Senzer N, et al. EUS or percutaneously guided intratumoral TNFerade biologic with 5-fluorouracil and radiotherapy for first-line treatment of locally advanced pancreatic cancer: a phase I/II study. Gastrointest Endosc 2012;75:332-8. 19. Nishimura M, Matsukawa M, Fujii Y, et al. Effects of EUS-guided intratumoral injection of oligonucleotide STNM01 on tumor growth,
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histology, and overall survival in patients with unresectable pancreatic cancer. Gastrointest Endosc 2018;87:1126-31. 20. Chang KJ, Nguyen PT, Thompson JA, et al. Phase I clinical trial of allogeneic mixed lymphocyte culture (cytoimplant) delivered by endoscopic ultrasound-guided fine-needle injection in patients with advanced pancreatic carcinoma. Cancer 2000;88:1325-35.
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21. Hirooka Y, Kasuya H, Ishikawa T, et al. A phase I clinical trial of EUSguided intratumoral injection of the oncolytic virus, HF10 for unresectable locally advanced pancreatic cancer. BMC Cancer 2018;18:596. 22. Arcidiacono PG, Carrara S, Reni M, et al. Feasibility and safety of EUSguided cryothermal ablation in patients with locally advanced pancreatic cancer. Gastrointest Endosc 2012;76:1142-51.
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Phase 1 study of EUS-guided photodynamic therapy for locally advanced pancreatic cancer John M. DeWitt, MD,1 Kumar Sandrasegaran, MD,2 Bert O’Neil, MD,4 Michael G. House, MD,3 Nicholas J. Zyromski, MD,3 Amikar Sehdev, MD,4 Susan M. Perkins, PhD,5 Janet Flynn, RN,4 Lynne McCranor, RN,4 Safi Shahda, MD4 Indianapolis, Indiana, USA
Background and Aims: Locally advanced pancreatic cancer (LAPC) has a poor prognosis. There are limited data describing the use of photodynamic therapy (PDT) for pancreatic cancer in humans. We hypothesized that EUSguided PDT for LAPC is safe, technically feasible, and produces a dose- and time-dependent increasing degree of image-defined tumor necrosis. Methods: In a single-center, prospective, dose-escalation phase 1 study, patients with treatment-naïve LAPC received intravenous porfimer sodium (Concordia Laboratories Inc, St Michael, Barbados) followed 2 days later by EUS-PDT. EUS-PDT was performed by puncture with a 19-gauge needle and insertion of a 1.0-cm light diffuser (Pioneer Optics, Bloomfield, Conn) and illumination with a 630-nm light (Diomed Inc, Andover, Mass). A CT scan 18 days after PDT was done to assess for change in pancreatic necrosis. Nab-paclitaxel (125 mg/ m2 intravenously) and gemcitabine (1000 mg /m2 intravenously) were initiated 7 days after CT and given weekly for 3 of 4 weeks (1 cycle) until disease progression or unacceptable toxicity. Results: Twelve patients (mean age, 67 6 years; 8 male) with tumors (mean diameter, 45.2 12.9 mm) in the head and/or neck (8) or body and/or tail (4) underwent EUS-PDT. Compared with baseline imaging, increased volume and percentage of tumor necrosis were observed in 6 of 12 patients (50%) after EUS-PDT. The mean overall increases in volume and percentage necrosis were 10 26 cm3 (P Z .20) and 18% 22% (P Z .016), respectively. After a median follow-up of 10.5 months (range, 1.0-37.4 months), median progression-free (PFS) and overall survival (OS) were 2.6 months (95% confidence interval, 0.7, not estimable) and 11.5 months (95% confidence interval, 1.1, 16.9), respectively. Surgical resection was attempted in 2 patients, and pathology showed a complete response (n Z 1) and residual 2-mm tumor (n Z 1). There were 8 serious adverse events and none related to EUS or EUS-PDT. Conclusion: EUS-PDT for LAPC appears to be safe and produces measurable imaged-defined tumor necrosis. Phase 2 studies are warranted. (Clinical trial registration number: NCT01770132.)
INTRODUCTION In the United States in 2018, an estimated 55,440 Americans will be diagnosed with pancreatic cancer with an estimated 44,330 deaths from the disease.1 Despite advances Abbreviations: LAPC, locally advanced pancreatic cancer; MRI, magnetic resonance imaging; OS, overall survival; PDT, photodynamic therapy; PFS, progression-free survival; SAE, serious adverse event. DISCLOSURE: Dr DeWitt has received a research grant from Concordia Laboratories Inc, St. Michael, Barbados, and has acted as a consultant for Olympus America and Boston Scientific. All other authors disclosed no financial relationships relevant to this publication. Copyright ª 2018 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 https://doi.org/10.1016/j.gie.2018.09.007
in chemotherapy for locally advanced and metastatic pancreatic cancer,2,3 5-year survival remains under 10%.1 Due to conflicting results from previous trials, it is not yet clear whether radiation is an essential component in the therapy of patients with locally advanced pancreatic Current affiliations: Department of Gastroenterology (1), Department of Radiology (2), Department of Surgery (3), Department of Oncology (4), Department of Statistics (5), Indiana University Health Medical Center, Indianapolis, Indiana, USA. Reprint requests: John DeWitt MD, FACG, FACP, FASGE, AGAF, Professor of Medicine, Division of Gastroenterology & Hepatology, Indiana University Health Medical Center, 550 N. University Blvd, UH 4100, Indianapolis, IN 46202. If you would like to chat with an author of this article, you may contact Dr DeWitt at [email protected].
Received August 2, 2018. Accepted September 7, 2018.
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cancer (LAPC).4 Clearly, novel agents, therapies, and approaches to treatment of this malignancy are needed. Photodynamic therapy (PDT) is an oxygen-dependent reaction between a photosensitizing dye and light that produces localized tissue necrosis. The light is usually given in the form of a laser and is applied after administration of a photosensitizing agent.5 The basis for PDT is the propensity of some chemicals for photoexcitation when exposed to intense white or specific wavelength laser light. Worldwide, endoscopists have used PDT in humans principally for ablative treatment of early malignant or nonmalignant/dysplastic Barrett’s esophagus,6,7 palliation of dysphagia in esophageal cancer, or palliation of biliary obstruction and recurrent cholangitis from inoperable cholangiocarcinoma.8,9 PDT in humans using various photosensitizers for the management of dysplasia and malignancy of the ampulla and pancreas has been reported to be safe, feasible, and possibly curative for small tumors.10-13 However, percutaneous delivery of the light fiber is required, which may be uncomfortable for the patient and requires passage of the fiber a long distance from the primary tumor. Due to the close proximity of the endoscope to the pancreas, EUS would appear to be an ideal modality to deliver PDT to the pancreas. To date, EUS-PDT in a healthy porcine model using the photosensitizers porfimer sodium14 and verteporfin15 have been published. Each study demonstrated the technique is feasible, well tolerated, and produces well-defined margins of fat necrosis, granulation tissue, inflammation, and fibrosis. EUS-guided PDT was well tolerated in 4 patients with locally advanced pancreaticobiliary malignancies; however, only 1 of these had pancreatic cancer.16 In this phase 1 study, we hypothesized that EUS-guided PDT using the photosensitizer porfimer sodium for pancreatic ductal adenocarcinoma in humans is safe, technically feasible and produces a dose-dependent, incrementally increasing degree of pancreatic tumor necrosis as detected by CT scan or magnetic resonance imaging (MRI) after treatment. The primary objective of this study was to determine the safety of this technique; secondary objectives were to determine the effect of EUS-PDT on the volume of tumor necrosis, tumor stabilization or decrease in size, surgical downstaging, and survival after treatment.
METHODS Patient selection and study design This is an investigator-initiated, open-label, singlecenter, prospective phase 1, dose-ranging study in patients with LAPC. Investigators and patients were aware of the treatment received. The protocol and supporting documents (ClinicalTrials.gov identifier, NCT01770132) were reviewed and approved by the Scientific Review Committee 2 GASTROINTESTINAL ENDOSCOPY Volume
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and Institutional Review Board at Indiana University Health Medical Center in Indianapolis, Indiana. Before enrollment, all patients underwent screening lab tests, imaging studies (ie, EUS, CT, and/or MRI) and consultations (surgery and oncology) to determine eligibility. Eligible patients signed informed consent before enrollment. Inclusion criteria included patients aged 18 to 75 years with treatment-naïve, biopsy-proven LAPC measuring 2.5 to 7.0 cm in diameter. Patients were also required to have a Karnofsky performance score 70% and a life expectancy of 3 months. LAPC was defined as a tumor imaged by dual-phase CT or MRI with direct extension to the superior mesenteric artery and/or celiac axis (with absence of a fat plane between the low-density tumor and these arterial structures) or loss of patent and/or thrombosed superior mesenteric-portal vein confluence. All patients with a dilated bile duct or increased total bilirubin level were required to have a biliary or transhepatic stent placed before consideration for the trial, with placement of a metal biliary stent required before study treatment. Exclusion criteria included the following: distant metastatic disease, previous surgical or medical treatment of the cancer, bowel fistula, portal hypertension, moderate to large volume ascites, gastroduodenal ulcers, bulky celiac adenopathy (>2.5 cm diameter), non-adenocarcinoma diagnosis (ie, endocrine tumor), uncorrected coagulopathy, renal insufficiency (serum creatinine >2.0 mg/dL), jaundice, anemia (hematocrit 28% or hemoglobin 9 g/ dL), thrombocytopenia (platelet count 100,000/mL), neutropenia (absolute neutrophil count 1500/mL), pancreatitis within 3 months, pregnancy, experimental medications within 4 weeks, inability to avoid exposure of skin or eyes to direct sunlight or bright indoor light for at least 30 days, porphyria, chronic corticosteroid use at superphysiologic doses (10 mg prednisone per day or equivalent), or any surgery within the previous 2 weeks.
Treatment administration The study schema is shown in Figure 1. Treatment consisted of 4 cohorts, which varied by the dose of photosensitizer given and time of light application (Table 1). Porfimer sodium. Intravenous administration of porfimer sodium (Photofrin, Concordia Laboratories Inc, St Michael, Barbados) as a photosensitizer was given at a dose of 1 mg/kg or 2 mg/kg and was considered as day 1 of the study. The first 6 patients received 1 mg/kg and the last 6 patients received 2 mg/kg. The lower dose was chosen first because that was used for the pilot study in a porcine model.14,15 EUS-PDT. Using a linear echoendoscope (Olympus GF-UC140P; Olympus America, Inc, Center Valley, Pa) under appropriate cardiorespiratory monitoring and sedation with propofol, we performed treatment between 40 and 50 hours after infusion of the photosensitizer. EUS-PDT was considered day 3 of the study. The stylet of a 19-gauge www.giejournal.org
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Nab-Paclitaxel IV Gemcitabine2 Cycle 1 Day 1
Consent & Baseline
CA 19-9 MDCT or MRI CMP/CBC
EUS
IV Photofrin1 Day 1
EUS-PDT Day 3 (Wed)
Labs at Discharge: amylase, lipase
Day 8 (Mon)
CA 19-9
Nab-Paclitaxel IV Gemcitabine Cycle 3 Day 1
Cycle 5+ Day 1
Surgical Resection3
Day 21
CA 19-9 MDCT or MRI
CA 19-9 MDCT or MRI
CA 19-9 MDCT or MRI
1. Photofrin administered by IV at a dose of 1 mg/kg for first 6 patients and 2 mg/kg for last 6 patients. 2. Gemcitabine was administered intravenously over 30 minutes at a dose of 1000 mg/m2. Nab-Paclitaxel was administered intravenously over 30 minutes at a dose of 125 mg/m2 prior to the administration of gemcitabine. Both medications were given on Day 1, Day 8, and Day 15 of a 28 day treatment cycle and were continued until disease progression or unacceptable toxicity. 3. Consideration for surgical resection if downstaging has occurred as seen on imaging. Figure 1. Study schema.
Flex needle (Boston Scientific, Natick, Mass) was removed and a plastic locking device was attached to the proximal side of the needle. A commercially available smalldiameter quartz optical fiber with a 1.0-cm cylindrical light diffuser (Pioneer Optics, Bloomfield, Conn)14,15 was passed through the locking device and needle until about 1.5 cm of the fiber exited the tip of the FNA needle (Figs. 2 and 3). The fiber was secured with the locking device and the locking device/fiber combination was withdrawn about 2 to 3 cm proximally so the fiber was completely inside the FNA needle. The needle was then passed into the endoscope and secured at the accessory channel. The tumor was punctured with the 19-gauge needle and the tip was intentionally passed toward the distal side of the tumor. The needle was then withdrawn 1 to 2 cm proximally inside the tumor. The PDT fiber was then advanced 1.5 cm into the tumor by advancing the locking device/fiber combination slowly inside the tumor and securing the locking device to the proximal end of the FNA needle. This pilot study was planned for 12 patients in 4 cohorts (Table 1). For each use of the light diffuser, the tumor was illuminated with a 630-nm light (Diomed Inc, Andover, Mass). A total light dose of 50 J/cm14,15 per use was used for the first 3 patients, which increased to 100 J/cm per use for the next 3 patients. A maximum of 3 punctures were made per patient and each treatment site (ie, puncwww.giejournal.org
ture site) was 7 to 10 mm apart from the previous site based on the expected region of necrosis produced by each treatment. A porfimer sodium dose of 1 mg/kg14,15 was used for the first 6 patients, which increased to 2 mg/kg for the last 6 patients.6,8 Treatment application time per site was either 125 or 250 seconds, and therefore total treatment energy for one or both procedures varied between 150 and 300 J (Table 1). After EUS, patients remained in recovery without oral intake for at least 2 hours. If required analgesics or antiemetics were given. If symptoms were well controlled, the patient was given water to drink. If symptoms were minimal or successfully treated, the patient was discharged. Samples for assessing serum amylase and lipase levels were taken before discharge. Gemcitabine and nab-paclitaxel therapy. Chemotherapy with gemcitabine and nab-paclitaxel was initiated after the conclusion of PDT therapy on treatment day 21 (which was also called cycle 1, day 1). Gemcitabine was administered intravenously over 30 minutes at a dose of 1000 mg /m2. Nab-paclitaxel was administered intravenously over 30 minutes at a dose of 125 mg/ m2 before the administration of gemcitabine. Both medications were given on day 1, day 8, and day 15 of a 28-day treatment cycle and were continued until disease progression or unacceptable toxicity. Volume
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TABLE 1. Treatment protocol for EUS-PDT for 12 patients (3 patients per cohort)
Cohort number (3 patients per cohort)
Photofrin dose (mg/kg)
Energy per site (J)
Maximal number of sites treated per EUS
Power output (mW)
Treatment application time per site (seconds)
Maximal total energy (J) of each EUS treatment
1
1
50
3
400
125
150
2
1
100
3
400
250
300
3
2
50
3
400
125
150
4
2
100
3
400
250
300
PDT, Photodynamic therapy; mW, milliwatts; J, joules.
Figure 2. Fiber with a 1.0cm cylindrical light diffuser passed through a locking device on the proximal side of a 19-gauge needle until about 1.5 cm of the fiber exited the tip of the FNA needle.
Criteria for treatment modifications and suggested guidelines for the management of toxicities related to nab-paclitaxel and/or gemcitabine were standardized for the study protocol, but these general guidelines were modified at the discretion of the investigator based on best clinical judgement at that time. Toxicities related to nab-paclitaxel and/or gemcitabine were managed according to standard medical practice. Once the toxicity resolved to the required level, nab-paclitaxel and/or gemcitabine were restarted. Dose escalation of nab-paclitaxel and/or gemcitabine was not allowed once a dose was reduced. If nab-paclitaxel and/or gemcitabine treatment was delayed for >28 days despite supportive treatment per standard clinical practice or more than 2 dose reductions (gemcitabine <600 mg/m2, nab-paclitaxel <75 mg/m2) were required, nab-paclitaxel and/or gemcitabine treatment was discontinued.
Radiology examinations All studies were reviewed by a single experienced gastrointestinal radiologist who reported tumor size, dimensions, vascular involvement, and degree of necrosis if present. CT was performed using Brilliance-64 (64channel) or Brilliance-40 (40-channel) CT scanners (Philips 4 GASTROINTESTINAL ENDOSCOPY Volume
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Figure 3. Fiber and FNA needle exiting the echoendoscope adjacent to the ultrasound transducer.
Medical Systems, Best, Netherlands) without oral contrast. Intravenous contrast was given only with an estimated glomerular filtration rate of more than 30 mL/min/1.73 m2). A dose of 120 mL of iopamidol (Isovue-370, Bracco Diagnostics, Princeton, NJ) was given at a rate of 4 mL/second using a power injector (CT Envision, Medrad Inc, Pittsburg, Pa) followed by flushing with 20 mL of saline solution. The abdomen (dome of the diaphragm to iliac crests) was imaged in the pancreatic parenchymal and venous phases, timed at 35 and 70 seconds, respectively, after the start of intravenous contrast injection.
Adverse events Adverse events occurring from porfimer sodium infusion, laser light application, CT, MRI, chemotherapy, and surgery (if performed) were evaluated. These were further classified as follows: (1) expected versus unexpected; (2) serious adverse event (SAE) versus important but not serious adverse event; (3) no reasonable possibility (where a medical condition or other cause for the event is identified); and (4) reasonable possibility. SAEs were considered to be any undesirable sign, symptom, or medical condition that was fatal, life-threatening, required inpatient hospitalization 24 hours, resulted in persistent or significant disability/incapacity, or was medically significant and www.giejournal.org
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TABLE 2. Baseline demographics, tumor characteristics, and EUS-PDT procedure
Cohort
Age (years)/ gender
Tumor location
Maximal tumor diameter (mm)
Vascular involvement by tumor*
Clinical TN stagey
Number of sites treated in tumor by PDTy
Site of puncturez
Serum amylase (U/L) before/after PDTx
1
1
69/M
Head
51
CAx1, PV1, SV1, SMA1
T4N0
3
Stomach
28/26
2
1
63/F
Body
50
CAx3, PV1, SA3, SMA3, SMV1
T4N1
3
Stomach
89/30
3
1
67/F
Neck
39
PV1, SMA3, SMV1
T4N0
3
Stomach
62/50
4 5
2
78/M
Body, tail
24
CAx1, HA1, SA1
T4N1
2
Stomach
24/24
2
71/M
Head
42
SMV1
T3N1
3
Duodenum
612/157
6
2
66/M
Head
39
PV1, SV1, SMA1
T4N1
3
Duodenum
43/26
7
3
67/M
Head, neck
56
PV3, SMA3, SMV3
T4N1
3
Duodenum
48/50
8
3
58/F
Head, neck
28
GDA1, PV1, SV1
T3N0
3
Stomach
17/18
9
3
60/M
Head, neck
65
HA2, PV2
T3N1
2
Stomach
59/35
10
4
71/M
Body, tail
65
CAx1, HA1, SA1
T4N1
3
Stomach
48/49
11
4
76/M
Body
45
CAx1, SA1, SV1
T4N0
3
Stomach
63/57
12
4
63/F
Head, neck
38
SMV1
T3N1
3
Duodenum
25/28
Patient
PDT, Photodynamic therapy; M, male; CAx, celiac axis; PV, portal vein; SV, splenic vein; SMA, superior mesenteric artery; F, female; SA, splenic artery; SMV, superior mesenteric vein; GDA, gastroduodenal artery; HA, hepatic artery. *Vessels names are abbreviated. Invasion, adherence, and abutment by CT scan are assigned a value of 1, 2, and 3, respectively, after the vessel name. yTumors assigned a tumor (T) and nodal (N) staging system according to the AJCC 8th Edition Cancer Staging System. zA maximum of 3 punctures were made per patient. xPost-PDT serum amylase (normal, 30-110 U/L) samples were drawn 2 hours after EUS-PDT.
which the investigator regarded as serious based on judgement. Adverse event intensity was assessed by investigators according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0, and ranged from grade 1 (mild), 2 (moderate), 3 (severe), or 4 (lifethreatening/disabling). Death (grade 5) was considered the outcome of an event and assigned a grade 4 severity. For EUS-PDT, adverse events were graded as possibly, probably, or definitively related to either endoscopy alone or EUS-PDT from the time period extending from the PDT until 1 week later. If any of the first 3 study patients undergoing EUS-PDT had any of the following adverse events requiring hospitalization for 5 days (acute pancreatitis, infected pancreatic necrosis, abdominal pain, retroperitoneal or gastrointestinal bleeding requiring transfusion or additional procedure, new gastrointestinal symptoms) or if any bowel perforation occurred, then an additional 3 patients were required to be accrued to that dose level. If 2 of the first 3 or 6 patients in any cohort experienced an adverse event related to EUS-PDT, then further enrollment was halted and the study terminated or amended to evaluate lower treatment doses. Dose escalation to a new 3person cohort proceeded only after the last patient (3 or 6 patients, depending on the incidence of adverse events) was followed for 2 weeks after the last EUS-PDT treatment.
Measurement of effect The primary objective of this phase 1 study was to determine the safety of increasing total energy and number of apwww.giejournal.org
plications sites treated for EUS-guided PDT for LAPC in humans and was evaluated as described above. The principal secondary endpoint of image-defined volume of tumor necrosis produced by EUS-PDT before chemotherapy was evaluated by CT or MRI 18 days after treatment. The volume of necrosis was measured by the formula d1 d2 d3/2, where d is the maximal diameter of tumor necrosis in 1 of the 3 dimensions. The percentage necrosis was the volume of tumor non-enhancement divided by the volume of whole tumor and was manually calculated by the radiologist by measuring necrotic and non-necrotic tumor area on each axial slice. Automatic segmentation software was not used for these calculations. Imaging was performed every 2 to 3 months thereafter to evaluate for further changes to the tumor dimensions while on systemic chemotherapy. Additional secondary study objectives of tumor stabilization or surgical downstaging were also assessed by cross-sectional imaging after EUS-PDT. If the necrosis produced by treatment was able to remove tumor adherence or involvement of a major abdominal blood vessel (ie, portal vein, superior mesenteric artery), then repeat surgical consultation was obtained to consider surgery if feasible. When surgery was performed, type of operation and presence of distant metastases, if any, were evaluated. Pathology was categorized as a complete or incomplete response, and margins were assessed as R0 (negative margins), R1 (microscopic residual cancer), R2 (macroscopically visible cancer). The final objective of survival was assessed by follow-up visits or phone calls. Volume
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TABLE 3. Change in tumor necrosis, chemotherapy, and follow-up after PDT
Cohort
Baseline volume tumor necrosis (cm3)
1
1
0
0
0
0
5
0
5
Death
321
2
1
0
0
0
0
0
1
1
Death
31
3
1
7.9
17.8
78
88
0
7
7
Death
323
4
2
0
1
0
28
2
5
7
Alive
1147
5
2
0
0
0
0
0
2
2
Death
352
6
2
0
0
0
0
0
6
6
Death
499
7
3
2.4
1.8
3
3
0
6
6
Death
232
8
3
0
9.4
0
58
0
1
1
Death
519
9
3
2.1
93.9
8
48
0
0
0
Death
39
10
4
0
9
0
48
0
2
2
Alive
342
11
4
0
0
0
0
0
2
2
Alive
287
12
4
0
1.7
0
33
0
2
2
Alive
30
Patient
Percentage Cycles of Time until Volume of Baseline tumor percentage tumor gemcitabineTotal death or last necrosis after tumor necrosis Cycles of nabcycles of follow-up PDT (cm3) necrosis after PDT gemcitabine paclitaxel chemotherapy Outcome (days)
PDT, Photodynamic therapy.
Statistics Descriptive statistics consisted of means standard deviations or medians with ranges for continuous variables, and simple proportions for dichotomous variables. Twosided paired t tests were used to test for change in tumor necrosis volume and percentage of tumor necrosis from baseline to post EUS-PDT and the change in CA 19-9 with treatment. Progression-free (PFS) and overall survival (OS) medians and 95% confidence intervals were estimated using the Kaplan-Meier method. All statistical analyses were performed using SAS v9.4 (Cary, NC).
RESULTS Study population Between August 2013 and June 2017, 16 patients were screened and 12 (mean age, 67 6 years; 8 male) were enrolled. Baseline patient demographics, tumor characteristics, and results of the EUS-PDT procedure are shown in Table 2. Mean axial, coronal, and sagittal tumor dimensions were 40.8 15.7 mm, 37.8 10.1 mm, and 34.4 10.5 mm, respectively. Maximal diameter was 45.2 12.9 mm. Tumors were located in the head and/or neck (n Z 8) or the body and/or tail (n Z 4).
EUS-PDT All patients successfully underwent all intended EUS-PDT treatments. Needle puncture was transgastric in 8 (67%) and transduodenal in 4 (33%). In 10 (83%), 3 intratumoral treatments were performed, whereas 2 treatments were used in 2 (17%). Compared with baseline tests, cross-sectional imaging performed 18 days after EUS-PDT showed increased volume and percentage of tumor necrosis 6 GASTROINTESTINAL ENDOSCOPY Volume
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(Table 3) in 6 of 12 (50%) patients including 4 of 6 (67%) in the last 2 cohorts (Figs. 4 and 5). Mean overall increase (n Z 12) in the volume and percentage of necrosis was 10 26 cm3 (P Z .20) and 18% 22% (P Z .016), respectively.
Follow-up after PDT A median of 2 (range, 0-7) chemotherapy cycles were successfully completed (Table 3). By the RECIST criteria, the best response to treatment was progressive disease in 6, stable disease in 3, partial response in 1, and not evaluable in 2. Surgical resection was performed in 2 patients. One in cohort 2 (number 4) had a 2.4-cm tumor at the body/tail junction with invasion of the celiac, hepatic, and splenic arteries. This patient underwent EUS-PDT, 7 rounds of chemotherapy, and distal pancreatectomy without vascular resection or reconstruction. Baseline CT showed no tumor necrosis but showed 28% necrosis on the first CT after PDT. Pathology showed a pathologic complete response. The second patient in cohort 4 (number 10) had a 6.5-cm tumor at the body/tail junction also with invasion of the celiac, hepatic, and splenic arteries. This patient underwent EUSPDT, 2 rounds of chemotherapy, and distal pancreatectomy without vascular resection or reconstruction. Baseline CT showed no tumor necrosis but showed 48% necrosis on the first CT after PDT. Pathology showed a residual 2-mm well-differentiated T1N0 adenocarcinoma with negative margins (R0 resection). Treatment with EUS-PDT did not change mean CA 19-9 values between baseline and before chemotherapy (P Z .30).
Adverse events There were 4 grade 1 or grade 2 adverse events related to porfimer sodium including sunburned hands from sun www.giejournal.org
DeWitt et al
EUS-guided PDT for locally advanced pancreatic cancer
Dose of Photofrin = 1 mg/kg
Dose of Photofrin = 2 mg/kg
88
Percent Tumor Necrosis
80
78
58
60
48 48 40 33 28 20 8 0
000 0
000 0 0
3 0
0 3 0 0 0
Post PDT Baseline
Baseline
Post PDT
Time Period 100 Joules
150 Joules
200 Joules
300 Joules
Figure 4. Change in percentage tumor necrosis by porfimer sodium dose and total energy delivered.
exposure (n Z 1), nausea (n Z 1), photosensitivity (n Z 1), and skin hyperpigmentation (n Z 1). One patient had increased fatigue (grade 2) after endoscopy, but there were no SAEs related to porfimer sodium, endoscopy, or EUS-PDT. Specifically, no patient developed pancreatitis, infection, bleeding, bowel obstruction, or bowel perforation after endoscopy. Of the 14 grade III or IV toxicities from gemcitabine, the most frequent were neutropenia (37%), fatigue (18%), and anemia (18%). Of the 12 grade III and IV toxicities from nab-paclitaxel, the most frequent were neutropenia (30%) and anemia (20%). Eight SAEs occurred in 7 patients, all of which required hospitalization (Table 4). Seven patients with SAEs were discharged after hospitalization and 1 died during the hospitalization.
Survival Median follow-up from PDT to last contact with patient alive on protocol or to death was 10.5 months (range, 137.4 months). Four patients were still alive with a median follow-up of 315 days (range, 30-1147 days). Median PFS and OS were 2.6 months (95% CI, 0.7-not estimable) and 11.5 months (95% CI, 1.1-16.9), respectively. The KaplanMeier plot for time to death after photosensitizer administration is shown in Figure 6.
DISCUSSION The current phase 1 study represents the first case-series description of EUS-PDT for treatment-naïve pancreatic cancer www.giejournal.org
in humans. We found that EUS-PDT for locally advanced pancreatic ductal adenocarcinoma using the photosensitizer porfimer sodium is technically feasible and may be performed without SAEs related to porfimer sodium administration, endoscopy, or EUS-PDT. These findings further suggest that EUS-PDT is safe as previously shown in a healthy porcine model using the photosensitizers porfimer sodium14 and verteporfin.15 Furthermore, our study replicates the safety of PDT found in previous human trials that used fibers placed by duodenoscopy into ampullary tumors11 or percutaneously via needles placed into pancreatic cancer.12,13 Adverse events related to the photosensitizer or treatment noted in these human studies included skin photosensitivity11 and duodenal obstruction.13 Similar to animal and human studies,11-15 we noted in 6 of 12 patients that cross-sectional imaging after EUS-PDT produced increasing pancreatic tumor necrosis. As we hypothesized, necrosis was greatest in cohorts 3 and 4; 4 of 6 patients had tumor necrosis after therapy. These 2 cohorts received the higher dose of photosensitizer (2 mg/kg) and a maximum total of 150 J or 300 J per treatment. Two patients in the last cohort had no increased tumor necrosis after therapy. It has been postulated that differences in pharmacokinetics and tumor biology (ie, vascular perfusion) may account for the differences in observed responses to PDT treatment.13 Porfimer sodium, the photosensitizer used in the current study, has been used extensively and successfully in gastroenterology for treatment of early malignant or dysplastic Barrett’s esophagus,6,7 palliation of dysphagia Volume
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Figure 5. A 57-year-old woman with jaundice and 4.7-cm pancreatic head cancer (patient 8, cohort 3). Baseline tumor showed no pancreatic necrosis. Porfimer sodium 2 mg/kg was given intravenously followed 2 days later by 3 transgastric PDT treatments of 50 J each (150 J total).
TABLE 4. Serious adverse events observed during the trial
Subject 1
SAE
Hospitalization
Attribution to porfimer sodium or EUS-PDT
Attribution to chemotherapy
Toxicity grade Unexpected
Ascites, nausea
Yes
No
Possible, gemcitabine
2
No
Outcome Resolved and discharged
2
Nausea, vomiting
Yes
No
No
3
Yes
Death
5
Pulmonary emboli
Yes
No
No
3
Yes
Resolved and discharged
8
Pneumonia, sepsis
Yes
No
No
3
No
Resolved and discharged
8
Thrombocytopenia
Yes
No
No
4
No
Resolved and discharged
9
Jaundice, malaise, fatigue
Yes
No
No
4
No
Resolved with sequelae and discharged
10
Nausea
Yes
No
Probable, gemcitabine and nab-paclitaxel
3
No
Resolved and discharged
12
Dizziness, dysarthria, hallucinations
Yes
No
No
2
Yes
Resolved and discharged
SAE, Serious adverse event; PDT, photodynamic therapy.
in esophageal cancer or palliation of biliary obstruction, and recurrent cholangitis from inoperable cholangiocarcinoma.8,9 However, the pharmacology of the drug requires treatment 20 to 50 hours after injection and the long elimination half-life (about 3 weeks) causes photosensitivity to remain for up to 1 month. These properties are similar to the photosensitizer meso-tetrahydroxyphenylchlorin, which was used by Bown et al12 for treatment of pancreatic cancer. Patients in our study were counseled extensively about these risks, which likely accounts for the absence of SAEs from photosensitivity. Huggett et al13 used the second-generation photosensitizer verterporfin in a recent phase 1/2 study of PDT using percutaneously placed fibers. The short half-life of verteporfin permits treatment only 1 to 2 hours after administration, and patients are photosensitive for only 7 days. There are 8 GASTROINTESTINAL ENDOSCOPY Volume
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currently no comparative trials between photosensitizers in pancreatic cancer in humans; therefore, the clinical benefit of one agent over the other apart from differences in photosensitivity is unknown. Two patients in our study underwent surgery after an increase in tumor necrosis of 28% to 48% after PDT and further tumor downstaging during chemotherapy. The first patient had an R0 resection and was alive more than 3 years after PDT. Previous trials have also had patients undergo R0 resections after PDT.12,13 The second patient had a residual 3-mm T1N0 tumor. It is difficult to postulate the contribution of PDT alone to surgical downstaging, but both patients had significant necrosis from PDT treatment before starting chemotherapy. Choi et al16 described the first use of EUS-PDT in a single patient with pancreatic tail cancer that had progressed www.giejournal.org
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EUS-guided PDT for locally advanced pancreatic cancer
1.0 Survival Probability
and produces measurable image-defined tumor necrosis. Chemotherapy after EUS-PDT may occasionally lead to tumor downstaging to permit attempted surgical resection. Phase 2 studies with porfimer sodium and additional studies using EUS with other photosensitizers is warranted.
Product-Limit Survival Estimate With Number of Subjects at Risk Censored
0.8 0.6 0.4
REFERENCES 0.2
0.0 At Risk
12 0
7 1 1 20 10 30 Months to Death from Photofrin Administration
0 40
Figure 6. Kaplan-Meier plot for time to death after photosensitizer administration.
despite chemotherapy. These authors used a 19-gauge needle, 2-cm diffuser fiber, and a chlorin e6 photosensitizer. Treatment produced a 0.85-cm region of necrosis without adverse events. The current study used linear EUS and a flexible 19-gauge needle to deliver the diffuse fiber used for PDT. We found that transgastric puncture and fiber delivery to tumors in the body and tail were technically easier than transduodenal puncture of pancreatic head tumors. Furthermore, imaging of pancreatic head tumors smaller than 35 mm with metallic biliary stents was challenging. Nevertheless, treatment was technically successful in all patients. Development of a fiber that can be delivered with a 22gauge needle will likely make treatment easier. The use of EUS-FNA needles to deliver a diffuser fiber for PDT in pancreatic cancer stands in contrast to previous studies that used percutaneous needles for fiber delivery. Although endoscopy requires sedation, our procedures required less than 30 minutes to complete, and real-time imaging of the needle and fiber permits assurance that treatment is properly positioned. Although percutaneous delivery is likely more uncomfortable than endoscopy, it does permit use of simultaneous diffuser fibers to enhance the area of treatment.13 Because EUS appears to be the ideal modality to deliver therapy to pancreatic tumors, EUS-guided injection17-21 and ablation22 of pancreatic cancer are feasible. However, it is unclear whether delivery of ablation to pancreatic tumors to induce necrosis may improve survival.18 The principal study limitation is the use of EUS-PDT in highly selected, functional patients with treatment-naïve locally advanced pancreatic adenocarcinoma. The safety of EUS-PDT using porfimer sodium in patients with previously treated cancer, other histologic types of pancreatic cancer, or at energy doses not used in this study is not known. In conclusion, EUS-PDT using the photosensitizer porfimer sodium in patients with LAPC appears to be safe www.giejournal.org
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68:7-30. 2. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369: 1691-703. 3. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25. 4. Fogel EL, Shahda S, Sandrasegaran K, et al. A multidisciplinary approach to pancreas cancer in 2016: a review. Am J Gastroenterol 2017;112:537-54. 5. Sheng C, Pogue BW, Wang E, et al. Assessment of photosensitizer dosimetry and tissue damage assay for photodynamic therapy in advanced-stage tumors. Photochem Photobiol 2004;79:520-5. 6. Overholt B, Lightdale C, Wang K, et al. Photodynamic therapy (PDT) with porfimer sodium for the ablation of high-grade dysplasia in Barrett’s esophagus (BE): international, partially blinded randomized phase III trial. Gastrointest Endosc 2005;62:488-98. 7. Ackroyd R, Brown NJ, Davis MF, et al. Photodynamic therapy for dysplastic Barrett’s oesophagus: a prospective, double blind, randomised, placebo controlled trial. Gut 2000;47:612-7. 8. Ortner ME, Caca K, Berr F, et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology 2003;125:1355-63. 9. Kahaleh M, Mishra R, Shami VM, et al. Unresectable cholangiocarcinoma: comparison of survival in biliary stenting alone versus stenting with photodynamic therapy. Clin Gastroenterol Hepatol 2008;6:290-7. 10. Liu CD, Kwan D, Saxton RE. Hypericin and photodynamic therapy decreases human pancreatic cancer in vitro and in vivo. J Surg Res 2000;93:137-43. 11. Abulafi AM, Allardice JT, Williams NS, et al. Photodynamic therapy for malignant tumours of the ampulla of Vater. Gut 1995;36:853-6. 12. Bown SG, Rogowska AZ, Whitelaw DE, et al. Photodynamic therapy for cancer of the pancreas. Gut 2002;50:549-57. 13. Huggett MT, Jermyn M, Gillams A, et al. Phase I/II study of verteporfin photodynamic therapy in locally advanced pancreatic cancer. Br J Cancer 2014;110:1698-704. 14. Mino M, Lauwers GY, Puricelli WP, et al. EUS-guided photodynamic therapy of the pancreas: a pilot study. Gastrointest Endosc 2004;59: 95-9. 15. Yusuf TE, Matthes K, Brugge WR. EUS-guided photodynamic therapy with verteporfin for ablation of normal pancreatic tissue: a pilot study in a porcine model (with video). Gastrointest Endosc 2008;67:957-61. 16. Choi JH, Oh D, Lee JH, et al. Initial human experience of endoscopic ultrasound-guided photodynamic therapy with a novel photosensitizer and a flexible laser-light catheter. Endoscopy 2015;47:1035-8. 17. Levy MJ, Alberts SR, Bamlet WR, et al. EUS-guided fine-needle injection of gemcitabine for locally advanced and metastatic pancreatic cancer. Gastrointest Endosc 2017;86:161-9. 18. Hecht JR, Farrell JJ, Senzer N, et al. EUS or percutaneously guided intratumoral TNFerade biologic with 5-fluorouracil and radiotherapy for first-line treatment of locally advanced pancreatic cancer: a phase I/II study. Gastrointest Endosc 2012;75:332-8. 19. Nishimura M, Matsukawa M, Fujii Y, et al. Effects of EUS-guided intratumoral injection of oligonucleotide STNM01 on tumor growth,
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histology, and overall survival in patients with unresectable pancreatic cancer. Gastrointest Endosc 2018;87:1126-31. 20. Chang KJ, Nguyen PT, Thompson JA, et al. Phase I clinical trial of allogeneic mixed lymphocyte culture (cytoimplant) delivered by endoscopic ultrasound-guided fine-needle injection in patients with advanced pancreatic carcinoma. Cancer 2000;88:1325-35.
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21. Hirooka Y, Kasuya H, Ishikawa T, et al. A phase I clinical trial of EUSguided intratumoral injection of the oncolytic virus, HF10 for unresectable locally advanced pancreatic cancer. BMC Cancer 2018;18:596. 22. Arcidiacono PG, Carrara S, Reni M, et al. Feasibility and safety of EUSguided cryothermal ablation in patients with locally advanced pancreatic cancer. Gastrointest Endosc 2012;76:1142-51.
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