Innovations and brief communications
Authors
Jun-Ho Choi1, *, Dongwook Oh2, *, Jae Hoon Lee3, Jin-hong Park4, Kyu-pyo Kim5, Seung Soo Lee6, Young-Joo Lee3, Young-Suk Lim2, Tae Jun Song2, Sang Soo Lee2, Dong-Wan Seo2, Sung Koo Lee2, Myung-Hwan Kim2, Do Hyun Park2
Institutions
Institutions are listed at the end of article.
submitted 29. October 2014 accepted after revision 31. March 2015
Background and study aims: New methods for the endoscopic selective ablation of locally advanced pancreaticobiliary malignancies as a minimally invasive approach are needed. Our aim was to examine the feasibility and safety of endoscopic ultrasonography (EUS)-guided photodynamic therapy (PDT) for local tumor control in patients with locally advanced pancreaticobiliary malignancies. Patients and methods: A chlorin e6 derivative and a flexible laser-light catheter were used to perform EUS-guided PDT in four patients with locally advanced pancreaticobiliary malignancies.
Results: EUS-guided PDT was technically feasible in all four patients with locally advanced pancreaticobiliary malignancies (two in the caudate lobe of the liver, one in the far distal bile duct, and one in the tail of the pancreas). No treatmentrelated complications occurred. The median volume of necrosis produced by PDT was 4.0 cm3 (range 0.7 – 11.3). Disease remained stable in all four patients during a median follow-up of 5 months (range 3 – 7). Conclusion: These preliminary data suggest that EUS-guided PDT with a second-generation photosensitizer and a flexible laser probe is feasible and safe.
Introduction
damage to healthy tissues and reducing skin photosensitivity to daylight [7]. Previous preliminary studies in animals demonstrated that endoscopic ultrasonography (EUS)guided PDT could be performed safely in the tail of the pancreas [8 – 10]. However, the stiffness of the laser-light catheter, caused by the quartz optic fiber, limited access to the head of the pancreas [9]. Recently, a flexible laser-light catheter with a diameter of 0.39 mm has become available for experimental use in PDT. Our aim was to examine the feasibility and safety of EUS-guided PDT with a second-generation photosensitizer and a flexible laser probe in patients with locally advanced pancreaticobiliary malignancies.
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1392150 Published online: 2015 Endoscopy © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X Corresponding author Do Hyun Park, MD, PhD Division of Gastroenterology Department of Internal Medicine University of Ulsan College of Medicine Asan Medical Center 88, Olympic-Ro 43-Gil Songpa-gu Seoul 138-736 South Korea Fax: +82-2-485-5782 [email protected]
!
Interest has been increasing in the use of locoregional treatments as part of a multimodality approach to the management of locally advanced pancreaticobiliary malignancies [1]. Photodynamic therapy (PDT) is a widely accepted way of producing selective tissue necrosis or apoptosis in patients with cholangiocarcinoma [2]. A firstgeneration photosensitizer – a hematoporphyrin derivative – has several drawbacks, which include prolonged photosensitivity of the skin lasting 1 to 3 months and a limited penetration depth of 4 to 6 mm [3]. Recently, interest in the clinical application of PDT with a novel second-generation photosensitizer – a chlorin e6 derivative – has appreciably increased [4 – 6]. The chlorin e6 derivative has an intensive absorption band at a longer wavelength, and this shift results in a deeper effective penetration of light in biological tissue [6, 7]. Other advantages over hematoporphyrintype photosensitizers are a much faster excretion rate and a high accumulation rate, preventing
* Jun-Ho Choi and Dongwook Oh contributed equally to this article.
Patients and methods !
Patients Patients with locally advanced pancreaticobiliary malignancies exhibiting local disease progression without metastasis after conventional chemoyradiotherapy were included in this study. Exclusion criteria were porphyria, a major blood vessel within the treatment area, and an Eastern Cooperative Oncology Group (ECOG) performance sta-
Choi Jun-Ho et al. Photodynamic therapy with a novel photosensitizer and a flexible laser-light catheter … Endoscopy
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Initial human experience of endoscopic ultrasoundguided photodynamic therapy with a novel photosensitizer and a flexible laser-light catheter
Innovations and brief communications
tus higher than 2. The study was approved by the institutional review board at Asan Medical Center, Seoul, South Korea. Written informed consent was obtained from all patients.
Flexible laser probe
Fig. 1 Endoscopic ultrasound-guided photodynamic therapy with a novel photosensitizer and a flexible laser-light catheter for locally advanced pancreaticobiliary malignancies. The probe is shown protruding from the tip of the 19-gauge needle, with the laser activated. A locking device on the needle is used to maintain positioning (inset).
Results !
Endoscopic ultrasound-guided photodynamic therapy A chlorin e6 derivative, Photolon (Belmedpreparaty, Minsk, Republic of Belarus), was administered intravenously at a dose of 2.5 mg/kg at 3 hours before illumination. Based on the previous literature [3], photoactivation at a 660-nm wavelength (UPLFDT; LEMT Research & Development Private Unitary Enterprise, Minsk, Republic of Belarus) was performed. The irradiation time was 330 seconds, the power density was 300 mW/cm, and the energy dose was 100 J/cm of diffuser length. Before each procedure, the laser-light probe was preloaded inside the needle and advanced until it was positioned within the " Fig. 1). After needle tip, then secured with the locking device (● EUS image acquisition, the 19-gauge FNA needle with the preloaded laser probe was inserted into the tumor via a transgastric or transduodenal approach. The needle was pulled back 10 to 20 mm over the fiber while a constant forward pressure was applied to advance the probe under EUS guidance, permitting the diffuser tip to be in direct contact with the tumor. This echo" Fig. 2 a). The genic laser probe is easily visible on EUS images (● laser probe within the tumor was securely positioned with the locking device. To ensure the integrity of the device, the cylindrical diffuser tip was positioned to expose no more than the total length of the diffuser from the tip of the needle. The tissue was then illuminated. This procedure was repeated with the same technique if important parts of the tumor had been missed. When the tumor length exceeded the diffuser length [12], a portion of the tumor length was illuminated first, and the procedure was then repeated with the same technique under EUS guidance. Care was taken to avoid overlapping treatment fields.
Post-procedure follow-up Interval computed tomography was performed at 3 days after PDT to evaluate safety and at 1 month after PDT to evaluate short-term efficacy by measuring the volume of ablated tumor. The total volume of PDT-induced necrosis was determined in all patients by means of volume rendering after segmentation of the area of necrosis on the computed tomographic scans.
EUS-guided PDT was performed in four patients with locally advanced pancreaticobiliary malignancies: two in the caudate lobe " Fig. 2 b), one in the far distal bile duct, and one in the tail of the (● pancreas. A multidisciplinary team consisting of a surgeon, a radiologist, an oncologist, a radiation oncologist, and endoscopists had recommended an alternative treatment modality for local tumor ablation in these patients because all were deemed unsuitable for surgery and had failed or could not toler" Table 1 shows the demoate prior chemoradiation therapy. ● graphic and clinical characteristics of the patients. The median tumor diameter before PDT was 2.9 cm (range 1.9 – 5.3). " Table 2. EUS-guided The treatment details are summarized in ● PDT consisting of two separate deliveries of interstitial laser light in a single session was feasible in all four patients (100 %). The needle and the exposed part of the PDT probe outside the needle but within the tumor were clearly visible throughout the proce" Fig. 2 a). The median procedure time was 28.5 minutes dure (● (range 25 – 32). No significant procedure-related adverse events, such as skin photosensitivity, bleeding, thrombosis, pancreatitis, and perforation, occurred after PDT. Laboratory tests revealed a normal hemogram and no significant changes in liver function and levels of pancreatic enzymes. In all cases, the contrast-enhanced computed tomographic scan obtained 3 days after PDT showed new areas of non-enhancement, con" Fig. 2 c). sidered to represent zones of PDT-induced necrosis (● The zones of necrosis were initially well defined. In the 4 weeks after PDT, the necrotic area of tumor healed safely, with no change in size observed on the follow-up computed tomographic scans " Fig. 2 d). The median volume of necrosis produced by EUS(● guided PDT was 4.0 cm3 (range 0.7 – 11.3). The disease remained stable in all patients during a median follow-up of 5 months (range 3 – 7).
Discussion !
This is the first in-human feasibility study of the EUS-guided application of PDT conducted in patients with locally advanced pancreaticobiliary malignancies. In our experience, PDT was suc-
Choi Jun-Ho et al. Photodynamic therapy with a novel photosensitizer and a flexible laser-light catheter … Endoscopy
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A custom-made flexible laser probe (quartz core with a diameter of 0.39 mm, polymer coating, and cylindrical diffuser tip 1 to 2 cm long; PhotoGlow, South Yarmouth, Massachusetts, USA) was used. The sheath of the probe is composed of a robust biocompatible polymer. The choice of diffuser length is based on the size of the tumor. The probe is compatible with a 19-gauge EUS-fine needle aspiration (FNA) needle (Cook Endoscopy, WinstonSalem, North Carolina, USA). A Luer lock on the proximal hub of the FNA needle is used to attach the needle to the probe. This prevents the probe from migrating inadvertently during the procedure and ensures a safe position of the probe within the needle [11]. The red and blue bars along the length of the probe, starting at the Luer lock connector, are used to determine how far the probe has been inserted; the red bar is the reference, at 0 mm; the first blue bar is at 10 mm, the second blue bar at 15 mm, and " Fig. 1, right the third blue bar at 20 mm from the connector (● upper inset).
Innovations and brief communications
Table 1 Demographic and clinical characteristics of four patients undergoing endoscopic ultrasound-guided photodynamic therapy (PDT) with a novel photosensitizer and flexible laser-light catheter for locally advanced pancreaticobiliary malignancies.
Patient
Age/sex
Diagnosis
Location
Reason for PDT
Tumor diameter, cm
Follow-up period, mo
1
72/M
CCa
Caudate lobe
Localized tumor progression following chemoradiotherapy
2.6
7.0
2
54/M
CCa
Caudate lobe
Localized tumor progression following chemoradiotherapy
5.3
4.0
3
78/M
CCa
Far distal bile duct
Inability to tolerate chemoradiotherapy and localized tumor progression
1.9
6.0
4
58/M
PCA
Tail of pancreas
Localized tumor progression following chemoradiotherapy
3.1
3.0
M, male; CCa, cholangiocarcinoma; PCA, pancreatic cancer.
cessfully applied under EUS guidance in all patients, and no significant complications or deaths related to the procedure were observed. In this study, a well-defined necrotic area was observed in all patients, and damage to adjacent normal tissue was avoided. Many vital structures are located in the vicinity of the pancreas and biliary tract; therefore, it is essential to ensure that PDT does not cause any unacceptable damage to the surrounding tissue [13]. EUS guidance may increase the safety of the application of PDT, and the use of color Doppler can reduce the risk of puncturing major vessels located between the gastric or duodenal wall and the target tumor. In this preliminary experience, EUS-guided PDT to deep-seated lesions was well tolerated. The development of a new, flexible laser-light catheter may overcome the main technical limitation of the EUS-guided procedure. Because the flexible design of the laser-light catheter makes it easy to maneuver the optic fiber, it may be used to treat lesions located in the head of the pancreas. Given the technical difficulty encountered in reaching the head of the pancreas in EUS-guided radio-frequency ablation [14], EUS-guided PDT with a flexible laser-light catheter may be a viable alternative. However, only
one lesion located in the far distal bile duct was included in the study. Thus, the current pilot study cannot confirm the technical feasibility of puncturing lesions of the pancreatic head from the second part of the duodenum, and this could represent a limitation. The level of energy delivered in this study was based on results from previous preliminary studies [3]. The volume of necrosis " Table 2), surrounding each treated area varied considerably (● and there are several plausible explanations for this finding. The tissue concentration of the photosensitizer may have differed in the patients, but real-time variations more likely were partly related to tissue and vascular perfusion around a diffuser fiber positioned interstitially within the mass [15]. To increase the effectiveness of ablation with EUS-guided PDT, two separate deliveries of laser light via EUS can be used to achieve confluent areas of necrosis in a tumor 10 mm in size. Then, EUS-guided PDT can be repeated if important areas of the tumor have been missed. Assuming spherical geometry, the median radius of the PDT-induced necrosis surrounding each site was approximately 8.3 mm (range 5.5 – 14.0) after two separate interstitial laser-light deliv-
Choi Jun-Ho et al. Photodynamic therapy with a novel photosensitizer and a flexible laser-light catheter … Endoscopy
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Fig. 2 Patient 1 was a 72-year-old man who had pathologically proven cholangiocarcinoma and had failed chemoradiotherapy. Local tumor progression in the caudate lobe could not be treated with surgical resection because of invasion of major vessels. a The tip of the cylindrical diffuser is protruding from the endoscopic ultrasound (EUS) needle. White arrow: tip of the laser probe. Green arrow: tip of the EUS needle. b Before treatment, arterial phase computed tomography demonstrates a low attenuation mass in the caudate lobe. c Computed tomographic scan obtained 3 days after photodynamic therapy shows new areas of non-enhancement. d Computed tomographic scan obtained 1 month after treatment shows a partially and progressively devascularized hypodense area.
Innovations and brief communications
Table 2
Patient
Details of endoscopic ultrasound-guided photodynamic therapy with two separate deliveries of interstitial laser light in a single session.
Access
Length of
Light
Energy
Laser-light
Procedure
Baseline
Median
Volume of necro-
diffuser
irradiation
dose, J/cm
deliveries
time, min
tumor
radius of
sis on computed
tip, cm
time, s*
diameter, cm
necrosis, cm
tomographicscan
per session, n
at 1 mo, cm3 1
Transgastric puncture
2
330
100
2
28
2.6
0.8
2.1
2
Transgastric puncture
2
330
100
2
25
5.3
1.4
11.3
3
Transduodenal puncture
1
330
100
2
32
1.9
0.55
0.7
4
Transgastric puncture
2
330
100
2
29
3.1
0.85
1.9
* Light irradiation time was 330 seconds in one interstitial endoscopic ultrasound-guided photodynamic therapy session.
Competing interests: None Institutions 1 Division of Gastroenterology, Department of Internal Medicine, Dankook University College of Medicine, Cheonan, South Korea 2 Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea 3 Department of Hepato-biliary and Pancreatic Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea 4 Department of Radiation Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea 5 Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea 6 Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
Acknowledgements !
The authors are grateful to Dongsung Pharmaceutical (Seoul, South Korea) for providing the Photolon chlorin e6 photosensitizer. The optical laser probe was kindly donated by Lightpharm Tech (Seoul, South Korea).
References 1 Halfdanarson TR, Haraldsdottir S, Borad MJ. Advances in systemic therapy for advanced pancreatobiliary malignancies. F1000Res 2013; 2: 105 2 Park do H, Lee SS, Park SE et al. Randomised phase II trial of photodynamic therapy plus oral fluoropyrimidine, S-1, versus photodynamic therapy alone for unresectable hilar cholangiocarcinoma. Eur J Cancer 2014; 50: 1259 – 1268 3 Ji W, Yoo JW, Bae EK et al. The effect of Radachlorin(R) PDT in advanced NSCLC: a pilot study. Photodiagnosis Photodyn Ther 2013; 10: 120 – 126 4 Istomin YP, Lapzevich TP, Chalau VN et al. Photodynamic therapy of cervical intraepithelial neoplasia grades II and III with Photolon. Photodiagnosis Photodyn Ther 2010; 7: 144 – 151 5 Copley L, van der Watt P, Wirtz KW et al. Photolon, a chlorin e6 derivative, triggers ROS production and light-dependent cell death via necrosis. Int J Biochem Cell Biol 2008; 40: 227 – 235 6 Kasuya K, Shimazu M, Suzuki M et al. Novel photodynamic therapy against biliary tract carcinoma using mono-L: -aspartyl chlorine e6: basic evaluation for its feasibility and efficacy. J Hepatobiliary Pancreat Sci 2010; 17: 313 – 321 7 Pietruska M, Sobaniec S, Bernaczyk P et al. Clinical evaluation of photodynamic therapy efficacy in the treatment of oral leukoplakia. Photodiagnosis Photodyn Ther 2014; 11: 34 – 40 8 Chan HH, Nishioka NS, Mino M et al. EUS-guided photodynamic therapy of the pancreas: a pilot study. Gastrointest Endosc 2004; 59: 95 – 99 9 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 – 961 10 Ayaru L, Wittmann J, Macrobert AJ et al. Photodynamic therapy using verteporfin photosensitization in the pancreas and surrounding tissues in the Syrian golden hamster. Pancreatology 2007; 7: 20 – 27 11 Konda VJ, Aslanian HR, Wallace MB et al. First assessment of needlebased confocal laser endomicroscopy during EUS-FNA procedures of the pancreas (with videos). Gastrointest Endosc 2011; 74: 1049 – 1060 12 Bown SG, Rogowska AZ, Whitelaw DE et al. Photodynamic therapy for cancer of the pancreas. Gut 2002; 50: 549 – 557 13 Ayaru L, Bown SG, Pereira SP. Photodynamic therapy for pancreatic and biliary tract carcinoma. Int J Gastrointest Cancer 2005; 35: 1 – 13 14 Kim HJ, Seo DW, Hassanuddin A et al. EUS-guided radiofrequency ablation of the porcine pancreas. Gastrointest Endosc 2012; 76: 1039 – 1043 15 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 – 1704
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eries. Therefore, EUS-guided PDT with chlorin e6 may be appropriate for deep-seated solid masses that range from 10 to 30 mm in size. To determine the optimal energy settings for delivering PDT to locally advanced pancreaticobiliary malignancies, however, larger clinical trials are needed. This pilot study is limited because it had a single-arm design and included a small number of patients. Therefore, a further study that includes a sufficient number of patients with long-term follow-up is required to confirm the results. In conclusion, in this preliminary experience, EUS-guided PDT was a feasible and relatively safe method for treating locally advanced cancers when the chlorin e6 photosensitizer and a flexible laser-light catheter were used. Although conclusions about quality of life or survival advantage cannot be based on the results of this pilot study, it was most encouraging that no treatment-related mortality or serious complications occurred, and that the procedure was well tolerated. These encouraging preliminary results may justify larger phase I/II clinical trials and aggressive multidisciplinary team discussions to assess EUSguided PDT as salvage treatment for selected patients with locally advanced cancers who are not surgical candidates and/or have failed chemoradiotherapy.
Authors
Jun-Ho Choi1, *, Dongwook Oh2, *, Jae Hoon Lee3, Jin-hong Park4, Kyu-pyo Kim5, Seung Soo Lee6, Young-Joo Lee3, Young-Suk Lim2, Tae Jun Song2, Sang Soo Lee2, Dong-Wan Seo2, Sung Koo Lee2, Myung-Hwan Kim2, Do Hyun Park2
Institutions
Institutions are listed at the end of article.
submitted 29. October 2014 accepted after revision 31. March 2015
Background and study aims: New methods for the endoscopic selective ablation of locally advanced pancreaticobiliary malignancies as a minimally invasive approach are needed. Our aim was to examine the feasibility and safety of endoscopic ultrasonography (EUS)-guided photodynamic therapy (PDT) for local tumor control in patients with locally advanced pancreaticobiliary malignancies. Patients and methods: A chlorin e6 derivative and a flexible laser-light catheter were used to perform EUS-guided PDT in four patients with locally advanced pancreaticobiliary malignancies.
Results: EUS-guided PDT was technically feasible in all four patients with locally advanced pancreaticobiliary malignancies (two in the caudate lobe of the liver, one in the far distal bile duct, and one in the tail of the pancreas). No treatmentrelated complications occurred. The median volume of necrosis produced by PDT was 4.0 cm3 (range 0.7 – 11.3). Disease remained stable in all four patients during a median follow-up of 5 months (range 3 – 7). Conclusion: These preliminary data suggest that EUS-guided PDT with a second-generation photosensitizer and a flexible laser probe is feasible and safe.
Introduction
damage to healthy tissues and reducing skin photosensitivity to daylight [7]. Previous preliminary studies in animals demonstrated that endoscopic ultrasonography (EUS)guided PDT could be performed safely in the tail of the pancreas [8 – 10]. However, the stiffness of the laser-light catheter, caused by the quartz optic fiber, limited access to the head of the pancreas [9]. Recently, a flexible laser-light catheter with a diameter of 0.39 mm has become available for experimental use in PDT. Our aim was to examine the feasibility and safety of EUS-guided PDT with a second-generation photosensitizer and a flexible laser probe in patients with locally advanced pancreaticobiliary malignancies.
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1392150 Published online: 2015 Endoscopy © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X Corresponding author Do Hyun Park, MD, PhD Division of Gastroenterology Department of Internal Medicine University of Ulsan College of Medicine Asan Medical Center 88, Olympic-Ro 43-Gil Songpa-gu Seoul 138-736 South Korea Fax: +82-2-485-5782 [email protected]
!
Interest has been increasing in the use of locoregional treatments as part of a multimodality approach to the management of locally advanced pancreaticobiliary malignancies [1]. Photodynamic therapy (PDT) is a widely accepted way of producing selective tissue necrosis or apoptosis in patients with cholangiocarcinoma [2]. A firstgeneration photosensitizer – a hematoporphyrin derivative – has several drawbacks, which include prolonged photosensitivity of the skin lasting 1 to 3 months and a limited penetration depth of 4 to 6 mm [3]. Recently, interest in the clinical application of PDT with a novel second-generation photosensitizer – a chlorin e6 derivative – has appreciably increased [4 – 6]. The chlorin e6 derivative has an intensive absorption band at a longer wavelength, and this shift results in a deeper effective penetration of light in biological tissue [6, 7]. Other advantages over hematoporphyrintype photosensitizers are a much faster excretion rate and a high accumulation rate, preventing
* Jun-Ho Choi and Dongwook Oh contributed equally to this article.
Patients and methods !
Patients Patients with locally advanced pancreaticobiliary malignancies exhibiting local disease progression without metastasis after conventional chemoyradiotherapy were included in this study. Exclusion criteria were porphyria, a major blood vessel within the treatment area, and an Eastern Cooperative Oncology Group (ECOG) performance sta-
Choi Jun-Ho et al. Photodynamic therapy with a novel photosensitizer and a flexible laser-light catheter … Endoscopy
Downloaded by: UPSTATE Medical University. Copyrighted material.
Initial human experience of endoscopic ultrasoundguided photodynamic therapy with a novel photosensitizer and a flexible laser-light catheter
Innovations and brief communications
tus higher than 2. The study was approved by the institutional review board at Asan Medical Center, Seoul, South Korea. Written informed consent was obtained from all patients.
Flexible laser probe
Fig. 1 Endoscopic ultrasound-guided photodynamic therapy with a novel photosensitizer and a flexible laser-light catheter for locally advanced pancreaticobiliary malignancies. The probe is shown protruding from the tip of the 19-gauge needle, with the laser activated. A locking device on the needle is used to maintain positioning (inset).
Results !
Endoscopic ultrasound-guided photodynamic therapy A chlorin e6 derivative, Photolon (Belmedpreparaty, Minsk, Republic of Belarus), was administered intravenously at a dose of 2.5 mg/kg at 3 hours before illumination. Based on the previous literature [3], photoactivation at a 660-nm wavelength (UPLFDT; LEMT Research & Development Private Unitary Enterprise, Minsk, Republic of Belarus) was performed. The irradiation time was 330 seconds, the power density was 300 mW/cm, and the energy dose was 100 J/cm of diffuser length. Before each procedure, the laser-light probe was preloaded inside the needle and advanced until it was positioned within the " Fig. 1). After needle tip, then secured with the locking device (● EUS image acquisition, the 19-gauge FNA needle with the preloaded laser probe was inserted into the tumor via a transgastric or transduodenal approach. The needle was pulled back 10 to 20 mm over the fiber while a constant forward pressure was applied to advance the probe under EUS guidance, permitting the diffuser tip to be in direct contact with the tumor. This echo" Fig. 2 a). The genic laser probe is easily visible on EUS images (● laser probe within the tumor was securely positioned with the locking device. To ensure the integrity of the device, the cylindrical diffuser tip was positioned to expose no more than the total length of the diffuser from the tip of the needle. The tissue was then illuminated. This procedure was repeated with the same technique if important parts of the tumor had been missed. When the tumor length exceeded the diffuser length [12], a portion of the tumor length was illuminated first, and the procedure was then repeated with the same technique under EUS guidance. Care was taken to avoid overlapping treatment fields.
Post-procedure follow-up Interval computed tomography was performed at 3 days after PDT to evaluate safety and at 1 month after PDT to evaluate short-term efficacy by measuring the volume of ablated tumor. The total volume of PDT-induced necrosis was determined in all patients by means of volume rendering after segmentation of the area of necrosis on the computed tomographic scans.
EUS-guided PDT was performed in four patients with locally advanced pancreaticobiliary malignancies: two in the caudate lobe " Fig. 2 b), one in the far distal bile duct, and one in the tail of the (● pancreas. A multidisciplinary team consisting of a surgeon, a radiologist, an oncologist, a radiation oncologist, and endoscopists had recommended an alternative treatment modality for local tumor ablation in these patients because all were deemed unsuitable for surgery and had failed or could not toler" Table 1 shows the demoate prior chemoradiation therapy. ● graphic and clinical characteristics of the patients. The median tumor diameter before PDT was 2.9 cm (range 1.9 – 5.3). " Table 2. EUS-guided The treatment details are summarized in ● PDT consisting of two separate deliveries of interstitial laser light in a single session was feasible in all four patients (100 %). The needle and the exposed part of the PDT probe outside the needle but within the tumor were clearly visible throughout the proce" Fig. 2 a). The median procedure time was 28.5 minutes dure (● (range 25 – 32). No significant procedure-related adverse events, such as skin photosensitivity, bleeding, thrombosis, pancreatitis, and perforation, occurred after PDT. Laboratory tests revealed a normal hemogram and no significant changes in liver function and levels of pancreatic enzymes. In all cases, the contrast-enhanced computed tomographic scan obtained 3 days after PDT showed new areas of non-enhancement, con" Fig. 2 c). sidered to represent zones of PDT-induced necrosis (● The zones of necrosis were initially well defined. In the 4 weeks after PDT, the necrotic area of tumor healed safely, with no change in size observed on the follow-up computed tomographic scans " Fig. 2 d). The median volume of necrosis produced by EUS(● guided PDT was 4.0 cm3 (range 0.7 – 11.3). The disease remained stable in all patients during a median follow-up of 5 months (range 3 – 7).
Discussion !
This is the first in-human feasibility study of the EUS-guided application of PDT conducted in patients with locally advanced pancreaticobiliary malignancies. In our experience, PDT was suc-
Choi Jun-Ho et al. Photodynamic therapy with a novel photosensitizer and a flexible laser-light catheter … Endoscopy
Downloaded by: UPSTATE Medical University. Copyrighted material.
A custom-made flexible laser probe (quartz core with a diameter of 0.39 mm, polymer coating, and cylindrical diffuser tip 1 to 2 cm long; PhotoGlow, South Yarmouth, Massachusetts, USA) was used. The sheath of the probe is composed of a robust biocompatible polymer. The choice of diffuser length is based on the size of the tumor. The probe is compatible with a 19-gauge EUS-fine needle aspiration (FNA) needle (Cook Endoscopy, WinstonSalem, North Carolina, USA). A Luer lock on the proximal hub of the FNA needle is used to attach the needle to the probe. This prevents the probe from migrating inadvertently during the procedure and ensures a safe position of the probe within the needle [11]. The red and blue bars along the length of the probe, starting at the Luer lock connector, are used to determine how far the probe has been inserted; the red bar is the reference, at 0 mm; the first blue bar is at 10 mm, the second blue bar at 15 mm, and " Fig. 1, right the third blue bar at 20 mm from the connector (● upper inset).
Innovations and brief communications
Table 1 Demographic and clinical characteristics of four patients undergoing endoscopic ultrasound-guided photodynamic therapy (PDT) with a novel photosensitizer and flexible laser-light catheter for locally advanced pancreaticobiliary malignancies.
Patient
Age/sex
Diagnosis
Location
Reason for PDT
Tumor diameter, cm
Follow-up period, mo
1
72/M
CCa
Caudate lobe
Localized tumor progression following chemoradiotherapy
2.6
7.0
2
54/M
CCa
Caudate lobe
Localized tumor progression following chemoradiotherapy
5.3
4.0
3
78/M
CCa
Far distal bile duct
Inability to tolerate chemoradiotherapy and localized tumor progression
1.9
6.0
4
58/M
PCA
Tail of pancreas
Localized tumor progression following chemoradiotherapy
3.1
3.0
M, male; CCa, cholangiocarcinoma; PCA, pancreatic cancer.
cessfully applied under EUS guidance in all patients, and no significant complications or deaths related to the procedure were observed. In this study, a well-defined necrotic area was observed in all patients, and damage to adjacent normal tissue was avoided. Many vital structures are located in the vicinity of the pancreas and biliary tract; therefore, it is essential to ensure that PDT does not cause any unacceptable damage to the surrounding tissue [13]. EUS guidance may increase the safety of the application of PDT, and the use of color Doppler can reduce the risk of puncturing major vessels located between the gastric or duodenal wall and the target tumor. In this preliminary experience, EUS-guided PDT to deep-seated lesions was well tolerated. The development of a new, flexible laser-light catheter may overcome the main technical limitation of the EUS-guided procedure. Because the flexible design of the laser-light catheter makes it easy to maneuver the optic fiber, it may be used to treat lesions located in the head of the pancreas. Given the technical difficulty encountered in reaching the head of the pancreas in EUS-guided radio-frequency ablation [14], EUS-guided PDT with a flexible laser-light catheter may be a viable alternative. However, only
one lesion located in the far distal bile duct was included in the study. Thus, the current pilot study cannot confirm the technical feasibility of puncturing lesions of the pancreatic head from the second part of the duodenum, and this could represent a limitation. The level of energy delivered in this study was based on results from previous preliminary studies [3]. The volume of necrosis " Table 2), surrounding each treated area varied considerably (● and there are several plausible explanations for this finding. The tissue concentration of the photosensitizer may have differed in the patients, but real-time variations more likely were partly related to tissue and vascular perfusion around a diffuser fiber positioned interstitially within the mass [15]. To increase the effectiveness of ablation with EUS-guided PDT, two separate deliveries of laser light via EUS can be used to achieve confluent areas of necrosis in a tumor 10 mm in size. Then, EUS-guided PDT can be repeated if important areas of the tumor have been missed. Assuming spherical geometry, the median radius of the PDT-induced necrosis surrounding each site was approximately 8.3 mm (range 5.5 – 14.0) after two separate interstitial laser-light deliv-
Choi Jun-Ho et al. Photodynamic therapy with a novel photosensitizer and a flexible laser-light catheter … Endoscopy
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Fig. 2 Patient 1 was a 72-year-old man who had pathologically proven cholangiocarcinoma and had failed chemoradiotherapy. Local tumor progression in the caudate lobe could not be treated with surgical resection because of invasion of major vessels. a The tip of the cylindrical diffuser is protruding from the endoscopic ultrasound (EUS) needle. White arrow: tip of the laser probe. Green arrow: tip of the EUS needle. b Before treatment, arterial phase computed tomography demonstrates a low attenuation mass in the caudate lobe. c Computed tomographic scan obtained 3 days after photodynamic therapy shows new areas of non-enhancement. d Computed tomographic scan obtained 1 month after treatment shows a partially and progressively devascularized hypodense area.
Innovations and brief communications
Table 2
Patient
Details of endoscopic ultrasound-guided photodynamic therapy with two separate deliveries of interstitial laser light in a single session.
Access
Length of
Light
Energy
Laser-light
Procedure
Baseline
Median
Volume of necro-
diffuser
irradiation
dose, J/cm
deliveries
time, min
tumor
radius of
sis on computed
tip, cm
time, s*
diameter, cm
necrosis, cm
tomographicscan
per session, n
at 1 mo, cm3 1
Transgastric puncture
2
330
100
2
28
2.6
0.8
2.1
2
Transgastric puncture
2
330
100
2
25
5.3
1.4
11.3
3
Transduodenal puncture
1
330
100
2
32
1.9
0.55
0.7
4
Transgastric puncture
2
330
100
2
29
3.1
0.85
1.9
* Light irradiation time was 330 seconds in one interstitial endoscopic ultrasound-guided photodynamic therapy session.
Competing interests: None Institutions 1 Division of Gastroenterology, Department of Internal Medicine, Dankook University College of Medicine, Cheonan, South Korea 2 Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea 3 Department of Hepato-biliary and Pancreatic Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea 4 Department of Radiation Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea 5 Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea 6 Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
Acknowledgements !
The authors are grateful to Dongsung Pharmaceutical (Seoul, South Korea) for providing the Photolon chlorin e6 photosensitizer. The optical laser probe was kindly donated by Lightpharm Tech (Seoul, South Korea).
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Choi Jun-Ho et al. Photodynamic therapy with a novel photosensitizer and a flexible laser-light catheter … Endoscopy
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eries. Therefore, EUS-guided PDT with chlorin e6 may be appropriate for deep-seated solid masses that range from 10 to 30 mm in size. To determine the optimal energy settings for delivering PDT to locally advanced pancreaticobiliary malignancies, however, larger clinical trials are needed. This pilot study is limited because it had a single-arm design and included a small number of patients. Therefore, a further study that includes a sufficient number of patients with long-term follow-up is required to confirm the results. In conclusion, in this preliminary experience, EUS-guided PDT was a feasible and relatively safe method for treating locally advanced cancers when the chlorin e6 photosensitizer and a flexible laser-light catheter were used. Although conclusions about quality of life or survival advantage cannot be based on the results of this pilot study, it was most encouraging that no treatment-related mortality or serious complications occurred, and that the procedure was well tolerated. These encouraging preliminary results may justify larger phase I/II clinical trials and aggressive multidisciplinary team discussions to assess EUSguided PDT as salvage treatment for selected patients with locally advanced cancers who are not surgical candidates and/or have failed chemoradiotherapy.
