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EUS-guided interstitial brachytherapy of the pancreas: a feasibility study
EUS-guided interstitial brachytherapy of the pancreas: a feasibility study Siyu Sun, MD, Lu ¨ Qingjie, MD, Guo Qiyong, MD, Wang Mengchun, MD, Qin Bo, MD, Xu Hong, MD Shenyang, China
Background: Intraoperative interstitial brachytherapy has been effective when used at laparotomy to improve local control in locally advanced pancreatic cancer. Our aim in this study was to investigate the feasibility and the safety of EUS-guided brachytherapy of the pancreas in a porcine model. Methods: A modified 18-gauge needle with radioactive seeds was inserted, under EUS guidance, into the pancreas. The radioactive seeds were implanted into the tissue by the needle. After 14 days of clinical observation, the animals were euthanized, and the tissue response to brachytherapy was examined. Observations: All the seeds were successfully implanted, and no migration occurred. Localized tissue necrosis and fibrosis was achieved in the pancreas, without significant complication. One pig had mild hyperlipasemia. Biochemical parameters were normal in the remaining pigs. Conclusions: EUS-guided implantation of radioactive seeds is a safe, simple, and minimally invasive technique for interstitial brachytherapy.
Interstitial brachytherapy (IBT) has been considered as a useful method for local control of pancreatic malignant tumors.1,2 Clinically, the technique also has been used to control malignancies of the prostate, the breast, the brain, the tongue, and the rectum.3-7 After radioactive seed placement, the target tissue is exposed to gamma rays, which produce localized tissue injury and tumor ablation. Intraoperative IBT has been effective when used at laparotomy to improve local control in advanced pancreatic cancer. The recent development of linear-array EUS technology has expanded the clinical utility of EUS by enabling image-guided biopsy and fine-needle therapy.8-13 If the radioactive seeds could be implanted by EUS, they may offer a new palliative therapy for surgically unresectable malignant pancreatic tumors. We undertook this preliminary animal study to determine whether placement of radioactive seeds can be performed safely, with EUS guidance, in the porcine pancreas. The protocol was approved by the Subcommittee on Research Animal Care at the Second Hospital of China Medical University.
Copyright ª 2005 by the American Society for Gastrointestinal Endoscopy 0016-5107/$30.00 doi:10.1016/j.gie.2005.06.050
respiratory parameters were monitored throughout the procedures. The operator wore a lead apron. A lineararray echoendoscope (EG3630; Pentax Precision Instruments, Orangeburg, NY), with a 2.4-mm working channel then was inserted into the esophagus and passed to the proximal stomach. EUS was completed to identify the location and the structure of the pancreas in the pigs, and EUS images were captured via a computer. Because there was no tumor in the pancreas of the pigs, we identified an area in the head or the body of the pancreas (devoid of the main pancreatic duct or large vessels) to simulate a tumor for IBT. The pancreatic tail in the pig was too small to select as a suitable area. We selected a small area that was suitable to implant 4 seeds. A therapy plan for seed implantation was made in the selected area on the EUS images. The distance between any two seeds and between any seed and the border of the pancreas was designed to be more than 5 mm. The iodine I 125 radioactive seeds (33 MBq; China Institute of Atomic Energy, Beijing, China) were 4.5 mm long and 0.84 mm thick. A seed was easily inserted into the lumen of the tip of a modified needle, which was a normal 22-gauge needle body (Hancke/Vilmann needle; MediGlobe GmbH, Achenmu ¨hle, Germany) with a 2.5-cmlong, 18-gauge needle tip attached to the distal end (Fig. 1). The 18-gauge needle tip had a 0.85-mm lumen. When the seed was inserted into the lumen, the friction between the seed and the lumen was 0.2 N. The seed did not move from the modified needle until it was ejected by advancing the core of the 22-gauge needle. The needle assembly with a radioactive seed was advanced through the gastric wall into the pancreas under
www.giejournal.org
Volume 62, No. 5 : 2005 GASTROINTESTINAL ENDOSCOPY 775
MATERIAL AND METHODS Six healthy farm swine, weighing 30 to 40 kg, were administered halothane (1% to 2%) through an endotracheal tube, with 100% oxygen as the carrier. Cardiac and
EUS-guided interstitial brachytherapy
Sun et al
Capsule Summary What is already known on this topic d
Intraoperative, interstitial brachytherapy is used to improve control of locally advanced pancreatic cancer.
What this study adds to our knowledge d
Figure 1. An iodine I 125 radioactive seed (arrow) was easily inserted into the tip of a modified needle; when the core of the needle is advanced, the seed is released and implanted into the tissue.
continuous sonographic guidance. When the core of the needle was advanced, the seed was pushed out of the modified needle and implanted into the tissue (Fig. 2). The modified needle assembly then was removed, reloaded with another seed, and the aforementioned implantation procedure was repeated until all seeds were implanted into the target site. This process was repeated in each of the 6 pigs according to the treatment plan. The endoscopist was committed to placement of the seed once the modified needle was placed within the pancreas. During all the procedures, the operator radiation absorbed dose was measured by the BIRM personal thermoluminescence (TL) dosimeter (LiF:Mg,Cu,P TL Detector; Institute of Radiation Medicine Academy of Military Medical Sciences, Beijing, China) worn on the neck and on the hand. After the treatment, the animals were observed for 14 days for clinical signs of acute pancreatitis (loss of appetite, altered consciousness, and irritability). EUS was performed on all pigs 7 and 14 days after the implantation. Prior studies of IBT have found tissue damage to be maximal at 14 days.14 Routine blood tests, serum amylase, and lipase levels were obtained at baseline; immediately after IBT; and on days 2, 7, and 14 after implantation. After 14 days of observation, the animals were euthanized by intravenous injection of pentobarbital (100 mg/kg). All animals underwent a postmortem to exclude an intra-abdominal hemorrhage, a pancreatic fistula, or peritonitis. Liver, stomach, duodenum, left kidney, and adrenal glands were excised for observation of a surrounding tissue response to IBT. Under radiographic guidance, the pancreas was excised and incised on the plane where the seeds were placed (Fig. 3). For gross pathologic analysis, the visible region of necrosis was measured with calipers in fresh tissue before preservation in 10% formalin. The locations of the seeds were observed to estimate seed migration. H&E stained slides obtained from the representative sections were evaluated for IBT-associated findings. The 776 GASTROINTESTINAL ENDOSCOPY Volume 62, No. 5 : 2005
In a pilot animal study from China, EUS-guided implantation of radioactive seeds was feasible, safe, and caused tissue necrosis and fibrosis in healthy porcine pancreas.
extent of necrosis induced by IBT and the intensity of the inflammation of parenchyma adjacent to the targeted area were assessed by one pathologist (L.Q.). All specimens were examined and fixed within an hour of the pig’s euthanasia.
RESULTS All pigs tolerated the procedure well. The pigs awoke from treatment anesthesia without undue delay. The initial EUS appearance of the pancreas in the pigs was not significantly different from that seen in humans. The radioactive seed was visualized as a linear hyperechoic structure. When a seed was implanted, the hyperechoic structure was placed into the tissues from the distal needle tip. The tip of the modified needle was rigid and sharp; therefore, the procedure of the EUS-guided placement of 4 seeds for each pig was completed within 10 minutes without technical difficulty. All attempts to place seeds were successful. No seeds were misplaced. The personal TL dosimeters on the endosonographer were collected and processed after the implantations were completed on all 6 pigs. The absorbed effective doses to the surgeon’s neck and hand were 0.10 to 0.32 mSv. The average effective doses to the surgeon’s neck and hand for individual implantation procedures were 0.017 to 0.053 mSV. During the 14-day post-IBT observation period, there were no clinical signs of peritoneal bleeding, infection, or acute pancreatitis (i.e., no change in appetite, consciousness, or irritability). Repeat EUS was performed on all the pigs on the 7th and 14th day after implantation. On day 7, there was a slightly irregular, heterogeneous hypoechoic intrapancreatic lesion around the hyperechoic structure of the seeds in all pigs. The median diameter of the lesion was 3.2 cm (range 2.8-3.5 cm). The lesion became larger and appeared more heterogeneous on day 14. The median diameter of the lesion was 3.8 cm (range 3.2-4.0 cm). The surrounding pancreas was sonographically normal, and there was no free intraperitoneal fluid. Baseline red blood cell, white blood cell, blood platelet count, serum amylase, and lipase levels were www.giejournal.org
Sun et al
EUS-guided interstitial brachytherapy
Figure 2. EUS appearance of radioactive seed implantation. A, Needle (arrow) was inserted into the pancreas. B, The seed (arrow) was released from the needle and implanted into the tissue. C, The radioactive seed (arrows) in the tissue was visualized as a linear hyperechoic structure. D, Fourteen days after implantation, a slightly irregular, heterogeneous hypoechoic intrapancreatic focus around the hyperechoic structure of the seed is visible (arrows).
5.42 1012/L G 0.4 1012/L, 1.82 1010/L G 0.32 1010/L, 8.4 1011/L G 1.6 1011/L, 6110 G 1200 U/L, and 2.6 G 1.6 U/dL, respectively. Immediately after the operation, enzyme levels were unchanged. Forty-eight hours after ablation, one pig had a 62% elevation in serum amylase level, with a normal serum lipase level. By day 7 after the operation, serum amylase and lipase levels were at baseline in all pigs. By day 14, red blood cell, white blood cell, blood platelet count, serum amylase, and lipase levels were 5.92 1012/L G 0.5 1012/L, 1.89 1010/L G 0.41 1010/L, 7.4 1011/L G 1.7 1011/L, 6230 G 1410 U/L and 2.9 G 1.8 U/dL, respectively. The fluctuations of the biochemical parameters were not significant (p O 0.05). After euthanasia, no ecchymosis was observed on the surface of the pancreas or the stomach in all animals. There was no blood or fluid in the abdominal cavity of the pigs. The pancreata were excised and incised on the plane where the seeds were placed. In total, there were 24 seeds in the pancreata of the 6 pigs. No seed migration www.giejournal.org
was found. All seeds were identified and removed. The pancreatic tissue around the seeds became white and rigid (Fig. 4A). Histopathologic examination confirmed the 3.5- to 4.5-cm areas filled with necrotic tissues and surrounding fibrotic tissues composed of granulation tissue, macrophages, and debris (Fig. 4B). There was mild inflammation surrounding the areas. The pancreatic tissue that was 5 cm away from the focus and the tissue of surrounding organs appeared normal.
DISCUSSION IBT has been used to treat various cancers, including those of the prostate, the breast, the brain, and the tongue.3-7 In addition, IBT has been effective when used at laparotomy to improve local control in advanced pancreatic cancer.1,2,15,16 The utilization of intraoperative IBT has proven effective in palliating obstructive Volume 62, No. 5 : 2005 GASTROINTESTINAL ENDOSCOPY 777
EUS-guided interstitial brachytherapy
Sun et al
Figure 3. Radiograph of the excised pancreas. The 4 seeds are visible (arrows).
symptoms with minimal morbidity. Although the US-guided percutaneous interstitial implantation of iodine I 125 seeds in cancer therapy has been reported, the difficulty and the accuracy of the percutaneous implantation is disputed. EUS-guided puncture is the most accurate and the most minimally invasive interventional method for treating pancreatic carcinoma. Recently, EUS-guided gene therapy, immunotherapy, radiofrequency, and photodynamic therapy of pancreatic cancer have been reported.9-13 Given that this technology allows precise targeting, its use to direct the safe implantation of radioactive seeds may provide a new method for interstitial brachytherapy of pancreatic cancer. This represents a logical advance in the evolution of EUS as a therapeutic tool. EUS was used in the present study to guide implantation of radioactive seeds by a modified needle to assess the feasibility and the safety of EUS-guided, low-dose brachytherapy of the porcine pancreas. An experienced endosonographer encountered no technical difficulty in performing this procedure, including the targeting of pancreatic tissue and the release of the radioactive seeds into the pancreas. There was no significant immediate or delayed complication. One pig had mild hyperamylasemia. Localized necrosis and fibrosis in the pancreas were induced by IBT. Radiation exposure to the operator appeared to be minimal. The average effective doses to the endoscopist’s neck and hand for an individual implantation was 0.017 to 0.053 mSV. By using the highest measured exposure during one implantation in this preliminary study, an endoscopist could perform 377 implantations of 4 seeds yearly before the annual exposure limit of 20 mSV/y (as stipulated by the International Commission on Radiological Protection) would be reached. Moreover, operator dose can be substantially reduced when the implantation is performed more proficiently and additional protective
measures (e.g., additional lead shielding) are used. We believe that the protocol as described above for EUS-guided implantation of radioactive seeds should be considered safe for operators. This study demonstrates the technical feasibility of EUS-guided implantation of radioactive seeds in the porcine pancreas. This technique appears to be well tolerated. This technique should be further evaluated for use in humans. EUS-guided IBT may ultimately be used for palliation of unresectable malignant tumors of the pancreas. Potential clinical uses of this technique also could include treatment of malignant abdominal or mediastinal lesions. The present study has significant limitations. Further studies of safety and efficacy are necessary. Development of a reliable implantation technique for use in humans is essential. A delivery system that would allow detailed
778 GASTROINTESTINAL ENDOSCOPY Volume 62, No. 5 : 2005
www.giejournal.org
Figure 4. Histopathologic appearance of pancreatic tissue after brachytherapy. A, In the gross pathologic specimen, the tissue on the section plane with the seed (arrow) became rigid and white. B, Histopathologic section from the center of the treatment focus shows the necrotic tissue (arrow) and the surrounding fibrotic tissue (H&E, orig. mag. 200).
Sun et al
placement and removal of seeds before final release would be ideal. However, in this preliminary study with rudimentary equipment, our success rate was excellent. We hope to proceed with additional investigations on the application of this technique to humans with unresectable pancreatic lesions. ACKNOWLEDGMENTS We thank the Education Department of Liaoning Province and Shenyang Science and Technique Bureau for their support.
REFERENCES 1. Takacsi-Nagy Z, Varga J, Poller I, et al. Successful treatment of a T1 cancer of the pancreatic head with high dose rate brachytherapy and external radiotherapy. Hepatogastroenterology 2002;49:844-6. 2. Bodner WR, Hilaris BS, Mastoras DA. Radiation therapy in pancreatic cancer: current practice and future trends. J Clin Gastroenterol 2000; 30:230-3. 3. Sakurai H, Mitsuhashi N, Harashima K, et al. CT-fluoroscopy guided interstitial brachytherapy with image-based treatment planning for unresectable locally recurrent rectal carcinoma. Brachytherapy 2004;3: 222-30. 4. Hannoun-Levi JM, Houvenaeghel G, Ellis S, et al. Partial breast irradiation as second conservative treatment for local breast cancer recurrence. Int J Radiat Oncol Biol Phys 2004;60:1385-92. 5. Merrick GS, Butler WM, Wallner KE, et al. Permanent interstitial brachytherapy for clinically organ-confined high-grade prostate cancer with a pretreatment PSA ! 20 ng/mL. Am J Clin Oncol 2004;27:611-5. 6. Viola A, Major T, Julow J. The importance of postoperative CT image fusion verification of stereotactic interstitial irradiation for brain tumors. Int J Radiat Oncol Biol Phys 2004;60:322-8.
www.giejournal.org
EUS-guided interstitial brachytherapy 7. Takacsi-Nagy Z, Polgar C, Oberna F, et al. Interstitial high-dose-rate brachytherapy in the treatment of base of tongue carcinoma. Strahlenther Onkol 2004;180:768-75. 8. Soetikno RM, Chang K. Endoscopic ultrasound-guided diagnosis and therapy in pancreatic disease. Gastrointest Endosc Clin N Am 1998;8: 237-47. 9. Chang KJ, Nguyen PT, Thompson JA. 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. 10. Krinsky ML, Binmoeller KF. EUS-guided investigational therapy for pancreatic cancer. Gastrointest Endosc 2000;52(Suppl 6):S35-8. 11. Hecht JR, Bedford R, Abbruzzese JL, et al. A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma. Clin Cancer Res 2003;9:555-61. 12. Chan HH, Nishioka NS, Mino M, et al. EUS-guided photodynamic therapy of the pancreas: a pilot study. Gastrointest Endosc 2004;59:95-9. 13. Goldberg SN, Mallery S, Gazelle GS, et al. EUS-guided radiofrequency ablation in the pancreas: results in a porcine model. Gastrointest Endosc 1999;50:392-401. 14. Tashchereau R, Roy R, Pouliot J. Relative biological effectiveness enhancement of a 125I brachytherapy seed with characteristic X rays from its constitutive materials. Med Phys 2002;29:1397-420. 15. Bodner WR, Hilaris BS. Brachytherapy and pancreatic cancer. Semin Surg Oncol 1997;13:204-7. 16. Order SE, Siegel JA, Principato R, et al. Selective tumor irradiation by infusional brachytherapy in nonresectable pancreatic cancer: a phase I study. Int J Radiat Oncol Biol Phys 1996;36:1117-26.
Received January 22, 2005. Accepted June 29, 2005. Current affiliations: The Second Hospital, China Medical University, Shenyang; The Third Hospital of Fushun, Fushun; The First Hospital, Jilin University, Jilin, China. Reprint requests: Siyu Sun, MD, The Second Hospital, China Medical University, Sanhao St 36. Shenyang, Liaoning Province, China 110004.
Volume 62, No. 5 : 2005 GASTROINTESTINAL ENDOSCOPY 779
Background: Intraoperative interstitial brachytherapy has been effective when used at laparotomy to improve local control in locally advanced pancreatic cancer. Our aim in this study was to investigate the feasibility and the safety of EUS-guided brachytherapy of the pancreas in a porcine model. Methods: A modified 18-gauge needle with radioactive seeds was inserted, under EUS guidance, into the pancreas. The radioactive seeds were implanted into the tissue by the needle. After 14 days of clinical observation, the animals were euthanized, and the tissue response to brachytherapy was examined. Observations: All the seeds were successfully implanted, and no migration occurred. Localized tissue necrosis and fibrosis was achieved in the pancreas, without significant complication. One pig had mild hyperlipasemia. Biochemical parameters were normal in the remaining pigs. Conclusions: EUS-guided implantation of radioactive seeds is a safe, simple, and minimally invasive technique for interstitial brachytherapy.
Interstitial brachytherapy (IBT) has been considered as a useful method for local control of pancreatic malignant tumors.1,2 Clinically, the technique also has been used to control malignancies of the prostate, the breast, the brain, the tongue, and the rectum.3-7 After radioactive seed placement, the target tissue is exposed to gamma rays, which produce localized tissue injury and tumor ablation. Intraoperative IBT has been effective when used at laparotomy to improve local control in advanced pancreatic cancer. The recent development of linear-array EUS technology has expanded the clinical utility of EUS by enabling image-guided biopsy and fine-needle therapy.8-13 If the radioactive seeds could be implanted by EUS, they may offer a new palliative therapy for surgically unresectable malignant pancreatic tumors. We undertook this preliminary animal study to determine whether placement of radioactive seeds can be performed safely, with EUS guidance, in the porcine pancreas. The protocol was approved by the Subcommittee on Research Animal Care at the Second Hospital of China Medical University.
Copyright ª 2005 by the American Society for Gastrointestinal Endoscopy 0016-5107/$30.00 doi:10.1016/j.gie.2005.06.050
respiratory parameters were monitored throughout the procedures. The operator wore a lead apron. A lineararray echoendoscope (EG3630; Pentax Precision Instruments, Orangeburg, NY), with a 2.4-mm working channel then was inserted into the esophagus and passed to the proximal stomach. EUS was completed to identify the location and the structure of the pancreas in the pigs, and EUS images were captured via a computer. Because there was no tumor in the pancreas of the pigs, we identified an area in the head or the body of the pancreas (devoid of the main pancreatic duct or large vessels) to simulate a tumor for IBT. The pancreatic tail in the pig was too small to select as a suitable area. We selected a small area that was suitable to implant 4 seeds. A therapy plan for seed implantation was made in the selected area on the EUS images. The distance between any two seeds and between any seed and the border of the pancreas was designed to be more than 5 mm. The iodine I 125 radioactive seeds (33 MBq; China Institute of Atomic Energy, Beijing, China) were 4.5 mm long and 0.84 mm thick. A seed was easily inserted into the lumen of the tip of a modified needle, which was a normal 22-gauge needle body (Hancke/Vilmann needle; MediGlobe GmbH, Achenmu ¨hle, Germany) with a 2.5-cmlong, 18-gauge needle tip attached to the distal end (Fig. 1). The 18-gauge needle tip had a 0.85-mm lumen. When the seed was inserted into the lumen, the friction between the seed and the lumen was 0.2 N. The seed did not move from the modified needle until it was ejected by advancing the core of the 22-gauge needle. The needle assembly with a radioactive seed was advanced through the gastric wall into the pancreas under
www.giejournal.org
Volume 62, No. 5 : 2005 GASTROINTESTINAL ENDOSCOPY 775
MATERIAL AND METHODS Six healthy farm swine, weighing 30 to 40 kg, were administered halothane (1% to 2%) through an endotracheal tube, with 100% oxygen as the carrier. Cardiac and
EUS-guided interstitial brachytherapy
Sun et al
Capsule Summary What is already known on this topic d
Intraoperative, interstitial brachytherapy is used to improve control of locally advanced pancreatic cancer.
What this study adds to our knowledge d
Figure 1. An iodine I 125 radioactive seed (arrow) was easily inserted into the tip of a modified needle; when the core of the needle is advanced, the seed is released and implanted into the tissue.
continuous sonographic guidance. When the core of the needle was advanced, the seed was pushed out of the modified needle and implanted into the tissue (Fig. 2). The modified needle assembly then was removed, reloaded with another seed, and the aforementioned implantation procedure was repeated until all seeds were implanted into the target site. This process was repeated in each of the 6 pigs according to the treatment plan. The endoscopist was committed to placement of the seed once the modified needle was placed within the pancreas. During all the procedures, the operator radiation absorbed dose was measured by the BIRM personal thermoluminescence (TL) dosimeter (LiF:Mg,Cu,P TL Detector; Institute of Radiation Medicine Academy of Military Medical Sciences, Beijing, China) worn on the neck and on the hand. After the treatment, the animals were observed for 14 days for clinical signs of acute pancreatitis (loss of appetite, altered consciousness, and irritability). EUS was performed on all pigs 7 and 14 days after the implantation. Prior studies of IBT have found tissue damage to be maximal at 14 days.14 Routine blood tests, serum amylase, and lipase levels were obtained at baseline; immediately after IBT; and on days 2, 7, and 14 after implantation. After 14 days of observation, the animals were euthanized by intravenous injection of pentobarbital (100 mg/kg). All animals underwent a postmortem to exclude an intra-abdominal hemorrhage, a pancreatic fistula, or peritonitis. Liver, stomach, duodenum, left kidney, and adrenal glands were excised for observation of a surrounding tissue response to IBT. Under radiographic guidance, the pancreas was excised and incised on the plane where the seeds were placed (Fig. 3). For gross pathologic analysis, the visible region of necrosis was measured with calipers in fresh tissue before preservation in 10% formalin. The locations of the seeds were observed to estimate seed migration. H&E stained slides obtained from the representative sections were evaluated for IBT-associated findings. The 776 GASTROINTESTINAL ENDOSCOPY Volume 62, No. 5 : 2005
In a pilot animal study from China, EUS-guided implantation of radioactive seeds was feasible, safe, and caused tissue necrosis and fibrosis in healthy porcine pancreas.
extent of necrosis induced by IBT and the intensity of the inflammation of parenchyma adjacent to the targeted area were assessed by one pathologist (L.Q.). All specimens were examined and fixed within an hour of the pig’s euthanasia.
RESULTS All pigs tolerated the procedure well. The pigs awoke from treatment anesthesia without undue delay. The initial EUS appearance of the pancreas in the pigs was not significantly different from that seen in humans. The radioactive seed was visualized as a linear hyperechoic structure. When a seed was implanted, the hyperechoic structure was placed into the tissues from the distal needle tip. The tip of the modified needle was rigid and sharp; therefore, the procedure of the EUS-guided placement of 4 seeds for each pig was completed within 10 minutes without technical difficulty. All attempts to place seeds were successful. No seeds were misplaced. The personal TL dosimeters on the endosonographer were collected and processed after the implantations were completed on all 6 pigs. The absorbed effective doses to the surgeon’s neck and hand were 0.10 to 0.32 mSv. The average effective doses to the surgeon’s neck and hand for individual implantation procedures were 0.017 to 0.053 mSV. During the 14-day post-IBT observation period, there were no clinical signs of peritoneal bleeding, infection, or acute pancreatitis (i.e., no change in appetite, consciousness, or irritability). Repeat EUS was performed on all the pigs on the 7th and 14th day after implantation. On day 7, there was a slightly irregular, heterogeneous hypoechoic intrapancreatic lesion around the hyperechoic structure of the seeds in all pigs. The median diameter of the lesion was 3.2 cm (range 2.8-3.5 cm). The lesion became larger and appeared more heterogeneous on day 14. The median diameter of the lesion was 3.8 cm (range 3.2-4.0 cm). The surrounding pancreas was sonographically normal, and there was no free intraperitoneal fluid. Baseline red blood cell, white blood cell, blood platelet count, serum amylase, and lipase levels were www.giejournal.org
Sun et al
EUS-guided interstitial brachytherapy
Figure 2. EUS appearance of radioactive seed implantation. A, Needle (arrow) was inserted into the pancreas. B, The seed (arrow) was released from the needle and implanted into the tissue. C, The radioactive seed (arrows) in the tissue was visualized as a linear hyperechoic structure. D, Fourteen days after implantation, a slightly irregular, heterogeneous hypoechoic intrapancreatic focus around the hyperechoic structure of the seed is visible (arrows).
5.42 1012/L G 0.4 1012/L, 1.82 1010/L G 0.32 1010/L, 8.4 1011/L G 1.6 1011/L, 6110 G 1200 U/L, and 2.6 G 1.6 U/dL, respectively. Immediately after the operation, enzyme levels were unchanged. Forty-eight hours after ablation, one pig had a 62% elevation in serum amylase level, with a normal serum lipase level. By day 7 after the operation, serum amylase and lipase levels were at baseline in all pigs. By day 14, red blood cell, white blood cell, blood platelet count, serum amylase, and lipase levels were 5.92 1012/L G 0.5 1012/L, 1.89 1010/L G 0.41 1010/L, 7.4 1011/L G 1.7 1011/L, 6230 G 1410 U/L and 2.9 G 1.8 U/dL, respectively. The fluctuations of the biochemical parameters were not significant (p O 0.05). After euthanasia, no ecchymosis was observed on the surface of the pancreas or the stomach in all animals. There was no blood or fluid in the abdominal cavity of the pigs. The pancreata were excised and incised on the plane where the seeds were placed. In total, there were 24 seeds in the pancreata of the 6 pigs. No seed migration www.giejournal.org
was found. All seeds were identified and removed. The pancreatic tissue around the seeds became white and rigid (Fig. 4A). Histopathologic examination confirmed the 3.5- to 4.5-cm areas filled with necrotic tissues and surrounding fibrotic tissues composed of granulation tissue, macrophages, and debris (Fig. 4B). There was mild inflammation surrounding the areas. The pancreatic tissue that was 5 cm away from the focus and the tissue of surrounding organs appeared normal.
DISCUSSION IBT has been used to treat various cancers, including those of the prostate, the breast, the brain, and the tongue.3-7 In addition, IBT has been effective when used at laparotomy to improve local control in advanced pancreatic cancer.1,2,15,16 The utilization of intraoperative IBT has proven effective in palliating obstructive Volume 62, No. 5 : 2005 GASTROINTESTINAL ENDOSCOPY 777
EUS-guided interstitial brachytherapy
Sun et al
Figure 3. Radiograph of the excised pancreas. The 4 seeds are visible (arrows).
symptoms with minimal morbidity. Although the US-guided percutaneous interstitial implantation of iodine I 125 seeds in cancer therapy has been reported, the difficulty and the accuracy of the percutaneous implantation is disputed. EUS-guided puncture is the most accurate and the most minimally invasive interventional method for treating pancreatic carcinoma. Recently, EUS-guided gene therapy, immunotherapy, radiofrequency, and photodynamic therapy of pancreatic cancer have been reported.9-13 Given that this technology allows precise targeting, its use to direct the safe implantation of radioactive seeds may provide a new method for interstitial brachytherapy of pancreatic cancer. This represents a logical advance in the evolution of EUS as a therapeutic tool. EUS was used in the present study to guide implantation of radioactive seeds by a modified needle to assess the feasibility and the safety of EUS-guided, low-dose brachytherapy of the porcine pancreas. An experienced endosonographer encountered no technical difficulty in performing this procedure, including the targeting of pancreatic tissue and the release of the radioactive seeds into the pancreas. There was no significant immediate or delayed complication. One pig had mild hyperamylasemia. Localized necrosis and fibrosis in the pancreas were induced by IBT. Radiation exposure to the operator appeared to be minimal. The average effective doses to the endoscopist’s neck and hand for an individual implantation was 0.017 to 0.053 mSV. By using the highest measured exposure during one implantation in this preliminary study, an endoscopist could perform 377 implantations of 4 seeds yearly before the annual exposure limit of 20 mSV/y (as stipulated by the International Commission on Radiological Protection) would be reached. Moreover, operator dose can be substantially reduced when the implantation is performed more proficiently and additional protective
measures (e.g., additional lead shielding) are used. We believe that the protocol as described above for EUS-guided implantation of radioactive seeds should be considered safe for operators. This study demonstrates the technical feasibility of EUS-guided implantation of radioactive seeds in the porcine pancreas. This technique appears to be well tolerated. This technique should be further evaluated for use in humans. EUS-guided IBT may ultimately be used for palliation of unresectable malignant tumors of the pancreas. Potential clinical uses of this technique also could include treatment of malignant abdominal or mediastinal lesions. The present study has significant limitations. Further studies of safety and efficacy are necessary. Development of a reliable implantation technique for use in humans is essential. A delivery system that would allow detailed
778 GASTROINTESTINAL ENDOSCOPY Volume 62, No. 5 : 2005
www.giejournal.org
Figure 4. Histopathologic appearance of pancreatic tissue after brachytherapy. A, In the gross pathologic specimen, the tissue on the section plane with the seed (arrow) became rigid and white. B, Histopathologic section from the center of the treatment focus shows the necrotic tissue (arrow) and the surrounding fibrotic tissue (H&E, orig. mag. 200).
Sun et al
placement and removal of seeds before final release would be ideal. However, in this preliminary study with rudimentary equipment, our success rate was excellent. We hope to proceed with additional investigations on the application of this technique to humans with unresectable pancreatic lesions. ACKNOWLEDGMENTS We thank the Education Department of Liaoning Province and Shenyang Science and Technique Bureau for their support.
REFERENCES 1. Takacsi-Nagy Z, Varga J, Poller I, et al. Successful treatment of a T1 cancer of the pancreatic head with high dose rate brachytherapy and external radiotherapy. Hepatogastroenterology 2002;49:844-6. 2. Bodner WR, Hilaris BS, Mastoras DA. Radiation therapy in pancreatic cancer: current practice and future trends. J Clin Gastroenterol 2000; 30:230-3. 3. Sakurai H, Mitsuhashi N, Harashima K, et al. CT-fluoroscopy guided interstitial brachytherapy with image-based treatment planning for unresectable locally recurrent rectal carcinoma. Brachytherapy 2004;3: 222-30. 4. Hannoun-Levi JM, Houvenaeghel G, Ellis S, et al. Partial breast irradiation as second conservative treatment for local breast cancer recurrence. Int J Radiat Oncol Biol Phys 2004;60:1385-92. 5. Merrick GS, Butler WM, Wallner KE, et al. Permanent interstitial brachytherapy for clinically organ-confined high-grade prostate cancer with a pretreatment PSA ! 20 ng/mL. Am J Clin Oncol 2004;27:611-5. 6. Viola A, Major T, Julow J. The importance of postoperative CT image fusion verification of stereotactic interstitial irradiation for brain tumors. Int J Radiat Oncol Biol Phys 2004;60:322-8.
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Received January 22, 2005. Accepted June 29, 2005. Current affiliations: The Second Hospital, China Medical University, Shenyang; The Third Hospital of Fushun, Fushun; The First Hospital, Jilin University, Jilin, China. Reprint requests: Siyu Sun, MD, The Second Hospital, China Medical University, Sanhao St 36. Shenyang, Liaoning Province, China 110004.
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