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Endoscopic ultrasound guided tumor directed therapy and cyst ablation
Author’s Accepted Manuscript Endoscopic Ultrasound Guided Tumor Directed Therapy and Cyst Ablation Seyfettin Koklu, Omer Basar, William R. Brugge
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To appear in: Techniques in Gastrointestinal Endoscopy Cite this article as: Seyfettin Koklu, Omer Basar and William R. Brugge, Endoscopic Ultrasound Guided Tumor Directed Therapy and Cyst Ablation, Techniques in Gastrointestinal Endoscopy, http://dx.doi.org/10.1016/j.tgie.2017.10.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Endoscopic Ultrasound Guided Tumor Directed Therapy and Cyst Ablation Seyfettin Koklu, M.D. Department of Gastroenterology Middle East 19 May Hospital, Ankara, Turkey Email: [email protected] Phone: +90(0312) 478 28 28 Fax: +90(0312) 479 93 40 Cell: +90(505) 256-3305
Omer Basar, M.D. Pancreas Biliary Center, Gastrointestinal Unit Massachusetts General Hospital E-mail: [email protected] Phone: +1(857) 724-0972 Fax: +1(617) 724-5997 Cell: +1(857) 350-5600
William R. Brugge, M.D. Professor of Medicine, HMS Director, Pancreas Biliary Center Gastrointestinal Unit Massachusetts General Hospital E-mail: [email protected] Phone: +1(617) 724-0578 Fax: +1(617) 724-5997 Cell: +1(617) 308-3532
ESummary Endoscopic ultrasonography (EUS) has become an interventional procedure for the diagnosis and treatment of various gastrointestinal and pancreatic tumors. Because of the unique anatomic location of the pancreas, EUS-guided therapies offer substantial promise for the delivery of targeted treatments. This article reviews the recent EUSguided various therapeutic methods for pancreatic cyst and tumor ablation, especially focusing on cystic neoplasms. Key words: Endoscopic ultrasonography, EUS-guided fine needle aspiration, pancreas, fine needle injection, ethanol, pancreatic cyst, radiofrequency ablation, brachytherapy, photodynamic therapy, fiducial placement, laser therapy, antitumor agent.
Introduction Endoscopic ultrasonography (EUS) has revolutionized the diagnosis and management of a broad range of disorders. It provides real-time imaging and has the potential to ablate cysts and tumors. EUS-guided fine needle based therapy provides a minimally invasive approach for treating benign and potentially malignant lesions, pain management and controlling local tumor growth. It represents an attractive alternative therapeutic approach to the morbidity of surgical intervention. A majority of EUS-guided procedures are used for management of pancreatic disorders. EUS-guided tumor directed therapy and cyst ablation include direct and indirect applications of antitumor or ablative agents 1. Ethanol injection, radiofrequency ablation, brachytherapy, photodynamic therapy and laser ablation are direct EUS-guided methods 2-6. Indirect methods include fine needle injection of antitumor agent including chemotherapeutic and biological agents and placement of fiducial markers 7-9. 1. EUS-guided Pancreatic Cyst Ablation Estimated prevalence of pancreatic cysts (PCs) is around 2% in the general population and increases with age 10. With improvement in imaging techniques including computerized tomography (CT) and magnetic resonance imaging (MRI), diagnoses of PCs are also increasing. PCs may be non-neoplastic or neoplastic, and neoplastic PCs may need therapeutic intervention. Although surgery is the mainstay of the treatment, pancreas surgery has significant rates of morbidity and mortality and hence, EUS-guided cyst ablation becomes an option. The decision on which PCs may be candidates for EUSguided pancreatic cyst ablation remain unclear. 2. With the success of percutaneous ethanol application for cyst and tumor ablation, EUS-guided ethanol lavage has been investigated for the treatment of PCs 11, 12. Ethanol is cytotoxic and causes cell membrane lysis, rapid protein denaturation and vascular blockage 13. To improve the success of ethanol ablation,
paclitaxel, a chemotherapeutic agent, has been injected into the PC 14. With the viscous nature of paclitaxel, it remains within the cyst cavity and improves the local cytotoxic effect of ethanol. EUS-guided ethanol lavage of PCs employs techniques based on fine needle aspiration of the pancreas. Prophylactic antibiotic administration is recommended. Before injection of ablative agents into a cystic lesion, complete or partial evacuation of the fluid contents of the cyst is required. It may be difficult to aspirate the highly viscous fluid of mucinous cysts. Furthermore, there will be a dead space of approximately 0.8 mL in the aspiration needle. Hence, larger cysts that are more than 10 mm in diameter are ideal for lavage. Usually, a 22 or 25-gauge aspiration needle is used. Once the needle is placed within the cyst, the ablative agent is injected under ultrasound monitoring. Swirls of aerated liquid are readily observed with ultrasound, and the distribution can be easily determined during the procedure. In many cases, ablative therapy is provided with a lavage of ethanol, in and out of the cyst over several minutes. At the end, ethanol is completely removed. If used, paclitaxel is then injected, but not removed from the cyst. Unilocular cysts with a diameter of 10 to 20 mm are easily treated in one or two lavage sessions. On the other hand, larger and more complex cysts require multiple sessions 15. The end point of ethanol lavage is elimination of the cyst as evidenced by cross-sectional imaging. The clinical success of EUS-guided ethanol ablation of PCs is controversial. Several studies have reported 33% to 79% complete cyst resolution after one or sequential ethanol lavages with and without paclitaxel injection 14, 16. On the other hand, a study by Gomez et al reported 9% complete resolution of the PCs treated with ethanol lavage in 23 prospectively followed patients (mean duration of follow-up was 40 months) 17. Currently, Choi et al reported the long-term results of 164 patients who were treated with EUS-guided PC ablation using ethanol and paclitaxel. The study is the largest published series and patients were followed prospectively (median 72 months). Complete resolution was 72% and almost all (98.3%) of the PCs remained in remission after complete resolution was achieved 18. The different success rates may be due to differences in methods such as ethanol concentration and volume, use of ethanol alone or in combination with paclitaxel, sample size and prospective or retrospective nature of the studies. Besides, most of the studies did not include a control group. In some cysts, the type or the diagnosis could not have been identified based on only imaging findings. The technical detail of the procedure, proposed indications and most suitable cyst types are not standardized yet. EUS-guided ethanol lavage seems to be safe. Mild pancreatitis and several non-specific post-procedural symptoms have been reported 19. The frequency of adverse event is less than 10% and mostly mild and self-limited 20. Overall, the preliminary studies showed the feasibility and safety of EUSguided alcohol and paclitaxel injection into PCs. It inhibits or slows down the growth of the cyst, and complete ablation can be achieved. EUS-guided PC ablation may be promising therapeutic method for patients who are not good candidates for surgery or who refuse surgery, asymptomatic cysts that increased in size and cysts with a low potential for malignancy 19. EUS-guided radiofrequency ablation, injection of other chemotherapeutic agents/immunotherapy with or without ethanol lavage may be therapeutic options in the near future.
2. EUS-Guided Ethanol Ablation of Solid Tumors EUS-guided ethanol injection therapy was first applied to liver metastases 21. Subsequently it was used for gastrointestinal stromal tumor and adrenal metastasis 22, 23. With confirming safety and feasibility of EUS-guided ethanol injection to pancreas in initial animal experiments 24, 25, Jurgensen et al reported first successful result of EUS-guided ethanol ablation in a patient with insulinoma 26. Clinical and radiological regression in insulinomas and other pancreatic neuroendocrine tumors have been reported in subsequent case series 27-31. Frequencies of adverse events were low and include mild pancreatitis, minor bleeding and pseudocyst formation. Overall, the results demonstrate that EUS-guided alcohol ablation is a safe and feasible treatment method for insulinoma and other pancreatic neuroendocrine tumors especially in patients who are poor candidates for surgery. However, the amount of alcohol, the number of sessions and the needle type need to be standardized 1. 3. EUS-Guided Ethanol Ablation of Other Tumors Success of EUS-guided ethanol injection has been reported in several organ tumors other than pancreas including stomach, liver and adrenal glands 21-23, 3235. Complete resolution of a 4 cm gastrointestinal stromal tumor in the stomach after EUS-guided alcohol injection has been reported 22. At a single session, 1.5 ml of 95% ethanol was injected under EUS guidance and at two years follow-up there was complete remission of the lesion. EUS-guided ethanol injection may also cause total or subtotal resolution of hepatocellular carcinoma 32, 33.Decrement of tumor size in solid liver metastases have been reported in single or multiple sessions of EUS-guided alcohol injection 21, 34, 35. DeWitt et al reported complete resolution of metastatic lymph nodes after EUS-guided alcohol ablation without complication 36. 4. EUS-Guided Chemotherapy Injection Chemotherapeutic agents may be delivered to the tumors directly or via feeding vessels to overcome the drawbacks of systemic pharmacological therapy. In a study, EUS-guided intratumoral gemcitabine was administered once prior to the conventional multimodality therapy in 36 patients with locally advanced or metastatic pancreatic cancer 7. There was no procedure-related complication or significant adverse event. Four patients (20%) with stage III unresectable tumor were downstaged and became resectable. EUS-guided direct injection of chemotherapeutic agents into the hepatic artery or portal vein may deliver enhanced efficacy and decrease systemic toxicities 37, 38. In patients with liver metastasis, the efficacy of EUS-guided hepatic intra-arterial 5-Fluoracil/5-Fluorodeoxymidine injections was compared to interventional radiology administration in a clinical trial 37. The response and survival rates were comparable between the two groups, whereas EUS group was superior in respect to median duration of hospitalization and the complication rate. A current study has documented the efficacy of EUS-guided portal injection chemotherapy (irinotecan, doxorubicin and paclitaxel) in an animal model 38. Although the data are limited,
EUS-guided intra-arterial or portal vein injection of chemotherapy appears to be safe and feasible in patients with metastatic liver disease. 5. EUS-Guided Radiofrequency Ablation Radiofrequency ablation (RFA) works by the induction of thermal injury to the target tissue through the use of electromagnetic energy resulting in coagulative necrosis 39. The procedural technique used for RFA is based on the EUS guidance of a needle catheter into the target lesion (Figure 1). Four different RFA probes have been reported for the pancreas 1. In recent clinical studies, the Habib EUS RFA probe (Habib catheter, Emcision Ltd, London) was used to apply EUS-guided RFA to the pancreas. EUS-RFA is a minimally invasive and safe method. It provides localized tissue necrosis ranging from 1 to 3 cm from the needle catheter 40. Initially RFA was used for the treatment of abdominal tumors including hepatocellular carcinoma and liver metastases 41. The first use of EUS-RFA in the pancreas was reported in 1999 in an animal model 42. Since the pancreas is a highly thermosensitive organ, EUS-RFA experience is limited in human studies. A recent review reported the results of 42 patients with pancreas tumors including adenocarcinoma, neuroendocrine tumor and PCs who underwent EUS-RFA 3. For the 7 patients with pancreatic ductal carcinoma, the post-procedure imaging after 3 to 6 months showed a decrease in size of the lesion in two patients, whereas the lesions were unchanged in the rest of the patients. The procedure was well tolerated in all patients and no complication was detected except for one patient with mild pancreatitis that resolved with conservative management 43. Another study reported by the same group included 8 patients with a neoplastic lesion (six PCs and two neuroendocrine tumors) located at the head of the pancreas 44. Of the six patients with PCs (four had a mucinous cyst, one had a intraductal papillary mucinous neoplasm and one had a microcystic adenoma), two patients showed complete resolution of the cysts and three patients showed a half reduction in size on the postprocedure imaging after 3 to 6 months. Only one patient needed a repeated EUSRFA procedure. There was no adverse event within 48 hours of the procedure. In a recent study, EUS-RFA was used in 6 patients with unresectable pancreatic cancer 45. The procedure was performed successfully in all patients and only 2 patients experienced mild abdominal pain. However, they did not evaluate long-term survival results. A prototype 19-gauge internally cooled needle electrode was applied to 3 patients with a symptomatic pancreatic insulinoma in another recent study 46. All patients had rapid symptom relief with biochemical improvement and remained symptom free at 11 to 12 months of follow-up. No procedure-related adverse event was reported. A commercial cool-tipped cryotherm device was designed and tested for pancreatic ablation 47. A flexible bipolar ablation probe combining RFA and cryotechnology was used to induce the foci of complete pancreatic ablation. In the first human clinical trial, the flexible bipolar ablation probe was successfully applied under EUS guidance in 16 of 22 (72.8%) patients with advanced pancreatic carcinoma 48. In six patients, it failed because of excessive resistance of the gastrointestinal wall and of the tumor.
Overall, EUS-RFA seems to be a feasible and safe treatment modality for various pancreatic tumors. However, further prospective comparative studies are still needed to demonstrate the safety and overall survival benefit before widespread use in clinical practice. 6. EUS-Guided Brachytherapy Brachytherapy in the form of small seeds or beads has been used for various malignant diseases. Its advantage is limited radiation toxicity. Iodine (I125) or palladium (Pd103) can be used. As an advantage, Iodine has slower delivery rate (half-life is 60 days for iodine and 17 days for palladium). Through an 18-G EUS needle, multiple small radioactive seeds can be placed into the pancreatic lesion. Clinical studies have reported the efficacy and safety of EUS-guided brachytherapy 4, 49, 50. Similarly, promising results in left-sided liver tumors were reported in a recent study 51. Also, EUS-guided brachytherapy has been used successfully in head and neck malignancies and esophagus cancer with low adverse event rates 52, 53. 7. EUS-Guided Photodynamic Therapy Photodynamic therapy utilizes a photosensitizing molecule (hematoporphyrin derivative as a first and chlorin e6 derivative as a second-generation photosensitizer) and a light source to activate the administered drug 5. It is an accepted method for the treatment of various cancers including pancreatobiliary malignancies. Chlorin e6 derivative has advantages over hematoporphyrin derivative regarding deeper effective penetration of light and much faster excretion rate as well (Figure 2). Preliminary animal studies demonstrated the safety of EUS-guided photodynamic therapy 54. Choi et al reported the first in-human feasibility of the method performed in 4 patients with locally advanced pancreatobiliary malignancies 5. 8. EUS-Guided Laser Ablation Laser ablation has been used for liver tumors 55, 56. Laser ablation was safe in an animal model study 6. To date, only one case has been reported on the use of EUS-guided laser ablation for human pancreas 57. The patient had recurrent pancreatic neuroendocrine tumor and radiological resolution was achieved after single session of EUS-guided laser application. 9. EUS-Guided Fiducial Placements By EUS guidance, small radiopaque markers are placed into the periphery of a malignant lesion to facilitate better targeting of radiation therapy 9. Fiducial placement is performed by using 19-G or 22-G EUS needles. To enable correct positioning, both fluoroscopic and ultrasonographic visualization may be used. EUS- guided fiducial placement seems to be safe and effective. For pancreatic malignancies, high technical and clinical success rates (85-90%) and only few minor adverse events have been reported 9, 58, 59. Moreover, the technique has been adopted to facilitate intraoperative localization (tattooing) of pancreatic tumors in patients undergoing enucleation or other resection procedures 60, 61.
10. EUS-Guided Injection of Novel anti-tumoral agents Several biological agents have been tested by EUS-fine needle injection for pancreatic and esophageal cancers (Table 1). A phase I clinical trial demonstrated the feasibility and safety of EUS-guided injection of sensitized culture of lymphocytes in patients with pancreas cancer 62. Eight patients with unresectable pancreatic adenocarcinoma underwent EUS-guided lymphocyte cytoimplants. The median survival was 13.2 months. Two of 8 patients had partial and one had minor response. As an adverse event, there was low-grade fever in seven patients. EUS-guided delivering antitumor viral therapy is another novel technique 63. An E1B-55-kDa gene-deleted replication-selective adenovirus, ONYX-015 (dl1520), preferentially replicates in malignant cells and causes cell death. In a clinical trial, twenty-one patients with locally advanced pancreas adenocarcinoma or with metastatic disease underwent eight sessions of EUS-guided injection of ONYX015 over 8 weeks. Intravenous gemcitabine was added in the final four sessions. At the end, two patients had partial regressions, two had minor responses, six had stable disease, and 11 had progressive disease. Dendritic cells, potent antigen-presenting cells, were used in experimental studies as a vaccine therapy against various cancers. In a study, seven patients with advanced pancreatic cancer that were refractory to gemcitabine therapy received repeated EUS-guided intratumoral injection of immature dendritic cells 64. There was no clinical toxicity. Median survival was 9.9 months which was similar to previous chemotherapy studies. In another trial, the method was combined with gemcitabine in 5 patients with advanced pancreatic cancer 65. One patient had a partial response and two patients had prolonged stable disease. The median survival time was 15.9 months. There were no serious treatment-related adverse events during the study period. Tumor necrosis factor (TNFerade) is a second-generation replication-deficient adenovirus vector. It expresses human TNF-alpha gene, which is regulated by a chemoradiation-inducible promoter. In a multicenter study, TNFerade was applied to 50 locally advanced pancreatic cancers by EUS-guidance (n = 27) or percutaneous injections (n = 23) for 5 weeks in combination with 5-fluorouracil and radiation 8. The higher-dose group (n = 11) had better outcomes when compared to the lowerdose group (n = 30). At high-dose, five patients became surgically resectable and four of those had pathologically negative margins; three patients survived more than 24 months. The overall outcomes were comparable among EUS-guided and percutaneous route groups. The adverse events were mild and well tolerated. On the other hand, in a comparative study including 187 locally advanced pancreatic cancer, TNFerade arm could not show superiority for prolonging survival when compared to standard of care arm 66. In another study, EUS-guided or direct endoscopic injection of TNFerade was combined with standard chemoradiotherapy before surgery in 24 patients with locally advanced resectable esophageal cancer 67. The combination was associated with long survival but frequent adverse events including thromboembolic events. BC-819 is a DNA plasmid. It provides the expression of diphtheria-toxin gene under the control of H19 regulatory sequences. Since pancreatic cancer overexpresses the H19 gene, BC-819 was used in a clinical trial 68. Intratumoral injection of BC819 was performed by computerized tomography (n:3) or EUS (n:6) guidance. Two patients who underwent chemotherapy or chemoradiotherapy following BC-819
injection had downstaging. Three of 6 patients in the EUS group had partial responses. There were no clinical adverse events. The results of these initial studies were promising, however, randomized controlled trials are still needed to confirm the benefits of these novel treatments. Conclusion With the advances in diagnostic tools, the prevalence of pancreatic cysts and solid lesions has increased. EUS-guided ethanol ablation is a safe and feasible method for treatment of pancreas cysts and neuroendocrine tumors. We need more data about the efficacy of EUS-guided therapeutic methods on tumor ablation including radiofrequency ablation, photodynamic therapy, brachytherapy, laser therapy and injection of antitumor agents. Delivery of antitumoral agents via EUS seems to be an effective treatment for pancreatic cancer. Conflict of interest: None
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60. Law JK, Singh VK, Khashab MA, Hruban RH, Canto MI, Shin EJ, et al. Endoscopic ultrasound (EUS)-guided fiducial placement allows localization of small neuroendocrine tumors during parenchymal-sparing pancreatic surgery. Surg Endosc 2013;27:3921-6. 61. Okuzono T, Kanno Y, Nakahori M, Aoki H, Sato S, Matsuda T, Chonan A. Preoperative endoscopic ultrasonography-guided tattooing of the pancreas with a minuscule amount of marking solution using a newly designed injector. Dig Endosc 2016;28:744-8. 62. Chang KJ, Nguyen PT, Thompson JA, Kurosaki TT, Casey LR, Leung EC, Granger GA.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. 63. Hecht JR, Bedford R, Abbruzzese JL, Lahoti S, Reid TR, Soetikno RM, et al. A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX015 with intravenous gemcitabine in unresectable pancreatic carcinoma. Clin Cancer Res 2003;9:555-61. 64. Irisawa A, Takagi T, Kanazawa M, Ogata T, Sato Y, Takenoshita S, et al. Endoscopic ultrasound-guided fine-needle injection of immature dendritic cells into advanced pancreatic cancer refractory to gemcitabine: a pilot study. Pancreas. 2007;35:189-90. 65. Hirooka Y, Itoh A, Kawashima H, Hara K, Nonogaki K, Kasugai T, et al. A combination therapy of gemcitabine with immunotherapy for patients with inoperable locally advanced pancreatic cancer. Pancreas. 2009;38:e69-e74. 66. Herman JM, Wild AT, Wang H, Tran PT, Chang KJ, Taylor GE, et al. Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. J Clin Oncol. 2013;31:886-94. 67. Chang KJ, Reid T, Senzer N, Swisher S, Pinto H, Hanna N, et al. Phase I evaluation of TNFerade biologic plus chemoradiotherapy before esophagectomy for locally advanced resectable esophageal cancer. Gastrointest Endosc 2012;75:1139-46. 68. Hanna N, Ohana P, Konikoff FM, Leichtmann G, Hubert A, Appelbaum L, et al. Phase 1/2a, dose-escalation, safety, pharmacokinetic and preliminary efficacy study of intratumoral administration of BC-819 in patients with unresectable pancreatic cancer. Cancer Gene Ther 2012;19:374-81. Figure Legends: Figure 1: EUS-Guided Radiofrequency Ablation of a cystic pancreatic neuroendocrine tumor. (displayed with the permission of Dr. Romano Sassatelli, Reggio Emilia, Italy) Figure 2: Photodynamic therapy of pancreas in an experimental setting
TABLE Table: EUS-guided novel antitumor agents Authors
Underlying Disease
Anti-tumoral Agent
Number of Patients
Chang et al62
Pancreas cancer
Lymphocyte cytoimplants
8
Results
Adverse Event
Partial response in 2 patients
Fever
Minor response in 1 patient Hecth et al63
Pancreas cancer
ONYX-015 + gemcitabine
21
Partial response in 2 patients
Sepsis in 2 patients
minor response in 2 patients stable disease in 6 patients Irisawa et al64
Pancreas cancer
Dendritic cells
7
No benefit on survival
None
Hirooka et al65
Pancreas cancer
Dendritic cells + gemcitabine
5
Partial response in 1 patient
None
Stable disease in 2 patients Hecht et al8
Pancreas cancer
TNFerade + chemoradiotherapy
50
Downstaging at higher doses
Mild
Herman et al66
Pancreas cancer
TNFerade + chemoradiotherapy
187
No benefit on survival
Minimal
Chang et al67
Esophageal cancer
TNFerade + chemoradiotherapy
24
Longer survival
Fatique, fever, nausea, vomiting, esophagitis; thromboemboli in higher döşe
Hanna et al68
Pancreas cancer
BC-819
9
Downstaged in 2 patients
Asymptomatic lipase elevation
Partial response in 3 patients
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PII: DOI: Reference:
S1096-2883(17)30065-7 http://dx.doi.org/10.1016/j.tgie.2017.10.003 YTGIE50545
To appear in: Techniques in Gastrointestinal Endoscopy Cite this article as: Seyfettin Koklu, Omer Basar and William R. Brugge, Endoscopic Ultrasound Guided Tumor Directed Therapy and Cyst Ablation, Techniques in Gastrointestinal Endoscopy, http://dx.doi.org/10.1016/j.tgie.2017.10.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Endoscopic Ultrasound Guided Tumor Directed Therapy and Cyst Ablation Seyfettin Koklu, M.D. Department of Gastroenterology Middle East 19 May Hospital, Ankara, Turkey Email: [email protected] Phone: +90(0312) 478 28 28 Fax: +90(0312) 479 93 40 Cell: +90(505) 256-3305
Omer Basar, M.D. Pancreas Biliary Center, Gastrointestinal Unit Massachusetts General Hospital E-mail: [email protected] Phone: +1(857) 724-0972 Fax: +1(617) 724-5997 Cell: +1(857) 350-5600
William R. Brugge, M.D. Professor of Medicine, HMS Director, Pancreas Biliary Center Gastrointestinal Unit Massachusetts General Hospital E-mail: [email protected] Phone: +1(617) 724-0578 Fax: +1(617) 724-5997 Cell: +1(617) 308-3532
ESummary Endoscopic ultrasonography (EUS) has become an interventional procedure for the diagnosis and treatment of various gastrointestinal and pancreatic tumors. Because of the unique anatomic location of the pancreas, EUS-guided therapies offer substantial promise for the delivery of targeted treatments. This article reviews the recent EUSguided various therapeutic methods for pancreatic cyst and tumor ablation, especially focusing on cystic neoplasms. Key words: Endoscopic ultrasonography, EUS-guided fine needle aspiration, pancreas, fine needle injection, ethanol, pancreatic cyst, radiofrequency ablation, brachytherapy, photodynamic therapy, fiducial placement, laser therapy, antitumor agent.
Introduction Endoscopic ultrasonography (EUS) has revolutionized the diagnosis and management of a broad range of disorders. It provides real-time imaging and has the potential to ablate cysts and tumors. EUS-guided fine needle based therapy provides a minimally invasive approach for treating benign and potentially malignant lesions, pain management and controlling local tumor growth. It represents an attractive alternative therapeutic approach to the morbidity of surgical intervention. A majority of EUS-guided procedures are used for management of pancreatic disorders. EUS-guided tumor directed therapy and cyst ablation include direct and indirect applications of antitumor or ablative agents 1. Ethanol injection, radiofrequency ablation, brachytherapy, photodynamic therapy and laser ablation are direct EUS-guided methods 2-6. Indirect methods include fine needle injection of antitumor agent including chemotherapeutic and biological agents and placement of fiducial markers 7-9. 1. EUS-guided Pancreatic Cyst Ablation Estimated prevalence of pancreatic cysts (PCs) is around 2% in the general population and increases with age 10. With improvement in imaging techniques including computerized tomography (CT) and magnetic resonance imaging (MRI), diagnoses of PCs are also increasing. PCs may be non-neoplastic or neoplastic, and neoplastic PCs may need therapeutic intervention. Although surgery is the mainstay of the treatment, pancreas surgery has significant rates of morbidity and mortality and hence, EUS-guided cyst ablation becomes an option. The decision on which PCs may be candidates for EUSguided pancreatic cyst ablation remain unclear. 2. With the success of percutaneous ethanol application for cyst and tumor ablation, EUS-guided ethanol lavage has been investigated for the treatment of PCs 11, 12. Ethanol is cytotoxic and causes cell membrane lysis, rapid protein denaturation and vascular blockage 13. To improve the success of ethanol ablation,
paclitaxel, a chemotherapeutic agent, has been injected into the PC 14. With the viscous nature of paclitaxel, it remains within the cyst cavity and improves the local cytotoxic effect of ethanol. EUS-guided ethanol lavage of PCs employs techniques based on fine needle aspiration of the pancreas. Prophylactic antibiotic administration is recommended. Before injection of ablative agents into a cystic lesion, complete or partial evacuation of the fluid contents of the cyst is required. It may be difficult to aspirate the highly viscous fluid of mucinous cysts. Furthermore, there will be a dead space of approximately 0.8 mL in the aspiration needle. Hence, larger cysts that are more than 10 mm in diameter are ideal for lavage. Usually, a 22 or 25-gauge aspiration needle is used. Once the needle is placed within the cyst, the ablative agent is injected under ultrasound monitoring. Swirls of aerated liquid are readily observed with ultrasound, and the distribution can be easily determined during the procedure. In many cases, ablative therapy is provided with a lavage of ethanol, in and out of the cyst over several minutes. At the end, ethanol is completely removed. If used, paclitaxel is then injected, but not removed from the cyst. Unilocular cysts with a diameter of 10 to 20 mm are easily treated in one or two lavage sessions. On the other hand, larger and more complex cysts require multiple sessions 15. The end point of ethanol lavage is elimination of the cyst as evidenced by cross-sectional imaging. The clinical success of EUS-guided ethanol ablation of PCs is controversial. Several studies have reported 33% to 79% complete cyst resolution after one or sequential ethanol lavages with and without paclitaxel injection 14, 16. On the other hand, a study by Gomez et al reported 9% complete resolution of the PCs treated with ethanol lavage in 23 prospectively followed patients (mean duration of follow-up was 40 months) 17. Currently, Choi et al reported the long-term results of 164 patients who were treated with EUS-guided PC ablation using ethanol and paclitaxel. The study is the largest published series and patients were followed prospectively (median 72 months). Complete resolution was 72% and almost all (98.3%) of the PCs remained in remission after complete resolution was achieved 18. The different success rates may be due to differences in methods such as ethanol concentration and volume, use of ethanol alone or in combination with paclitaxel, sample size and prospective or retrospective nature of the studies. Besides, most of the studies did not include a control group. In some cysts, the type or the diagnosis could not have been identified based on only imaging findings. The technical detail of the procedure, proposed indications and most suitable cyst types are not standardized yet. EUS-guided ethanol lavage seems to be safe. Mild pancreatitis and several non-specific post-procedural symptoms have been reported 19. The frequency of adverse event is less than 10% and mostly mild and self-limited 20. Overall, the preliminary studies showed the feasibility and safety of EUSguided alcohol and paclitaxel injection into PCs. It inhibits or slows down the growth of the cyst, and complete ablation can be achieved. EUS-guided PC ablation may be promising therapeutic method for patients who are not good candidates for surgery or who refuse surgery, asymptomatic cysts that increased in size and cysts with a low potential for malignancy 19. EUS-guided radiofrequency ablation, injection of other chemotherapeutic agents/immunotherapy with or without ethanol lavage may be therapeutic options in the near future.
2. EUS-Guided Ethanol Ablation of Solid Tumors EUS-guided ethanol injection therapy was first applied to liver metastases 21. Subsequently it was used for gastrointestinal stromal tumor and adrenal metastasis 22, 23. With confirming safety and feasibility of EUS-guided ethanol injection to pancreas in initial animal experiments 24, 25, Jurgensen et al reported first successful result of EUS-guided ethanol ablation in a patient with insulinoma 26. Clinical and radiological regression in insulinomas and other pancreatic neuroendocrine tumors have been reported in subsequent case series 27-31. Frequencies of adverse events were low and include mild pancreatitis, minor bleeding and pseudocyst formation. Overall, the results demonstrate that EUS-guided alcohol ablation is a safe and feasible treatment method for insulinoma and other pancreatic neuroendocrine tumors especially in patients who are poor candidates for surgery. However, the amount of alcohol, the number of sessions and the needle type need to be standardized 1. 3. EUS-Guided Ethanol Ablation of Other Tumors Success of EUS-guided ethanol injection has been reported in several organ tumors other than pancreas including stomach, liver and adrenal glands 21-23, 3235. Complete resolution of a 4 cm gastrointestinal stromal tumor in the stomach after EUS-guided alcohol injection has been reported 22. At a single session, 1.5 ml of 95% ethanol was injected under EUS guidance and at two years follow-up there was complete remission of the lesion. EUS-guided ethanol injection may also cause total or subtotal resolution of hepatocellular carcinoma 32, 33.Decrement of tumor size in solid liver metastases have been reported in single or multiple sessions of EUS-guided alcohol injection 21, 34, 35. DeWitt et al reported complete resolution of metastatic lymph nodes after EUS-guided alcohol ablation without complication 36. 4. EUS-Guided Chemotherapy Injection Chemotherapeutic agents may be delivered to the tumors directly or via feeding vessels to overcome the drawbacks of systemic pharmacological therapy. In a study, EUS-guided intratumoral gemcitabine was administered once prior to the conventional multimodality therapy in 36 patients with locally advanced or metastatic pancreatic cancer 7. There was no procedure-related complication or significant adverse event. Four patients (20%) with stage III unresectable tumor were downstaged and became resectable. EUS-guided direct injection of chemotherapeutic agents into the hepatic artery or portal vein may deliver enhanced efficacy and decrease systemic toxicities 37, 38. In patients with liver metastasis, the efficacy of EUS-guided hepatic intra-arterial 5-Fluoracil/5-Fluorodeoxymidine injections was compared to interventional radiology administration in a clinical trial 37. The response and survival rates were comparable between the two groups, whereas EUS group was superior in respect to median duration of hospitalization and the complication rate. A current study has documented the efficacy of EUS-guided portal injection chemotherapy (irinotecan, doxorubicin and paclitaxel) in an animal model 38. Although the data are limited,
EUS-guided intra-arterial or portal vein injection of chemotherapy appears to be safe and feasible in patients with metastatic liver disease. 5. EUS-Guided Radiofrequency Ablation Radiofrequency ablation (RFA) works by the induction of thermal injury to the target tissue through the use of electromagnetic energy resulting in coagulative necrosis 39. The procedural technique used for RFA is based on the EUS guidance of a needle catheter into the target lesion (Figure 1). Four different RFA probes have been reported for the pancreas 1. In recent clinical studies, the Habib EUS RFA probe (Habib catheter, Emcision Ltd, London) was used to apply EUS-guided RFA to the pancreas. EUS-RFA is a minimally invasive and safe method. It provides localized tissue necrosis ranging from 1 to 3 cm from the needle catheter 40. Initially RFA was used for the treatment of abdominal tumors including hepatocellular carcinoma and liver metastases 41. The first use of EUS-RFA in the pancreas was reported in 1999 in an animal model 42. Since the pancreas is a highly thermosensitive organ, EUS-RFA experience is limited in human studies. A recent review reported the results of 42 patients with pancreas tumors including adenocarcinoma, neuroendocrine tumor and PCs who underwent EUS-RFA 3. For the 7 patients with pancreatic ductal carcinoma, the post-procedure imaging after 3 to 6 months showed a decrease in size of the lesion in two patients, whereas the lesions were unchanged in the rest of the patients. The procedure was well tolerated in all patients and no complication was detected except for one patient with mild pancreatitis that resolved with conservative management 43. Another study reported by the same group included 8 patients with a neoplastic lesion (six PCs and two neuroendocrine tumors) located at the head of the pancreas 44. Of the six patients with PCs (four had a mucinous cyst, one had a intraductal papillary mucinous neoplasm and one had a microcystic adenoma), two patients showed complete resolution of the cysts and three patients showed a half reduction in size on the postprocedure imaging after 3 to 6 months. Only one patient needed a repeated EUSRFA procedure. There was no adverse event within 48 hours of the procedure. In a recent study, EUS-RFA was used in 6 patients with unresectable pancreatic cancer 45. The procedure was performed successfully in all patients and only 2 patients experienced mild abdominal pain. However, they did not evaluate long-term survival results. A prototype 19-gauge internally cooled needle electrode was applied to 3 patients with a symptomatic pancreatic insulinoma in another recent study 46. All patients had rapid symptom relief with biochemical improvement and remained symptom free at 11 to 12 months of follow-up. No procedure-related adverse event was reported. A commercial cool-tipped cryotherm device was designed and tested for pancreatic ablation 47. A flexible bipolar ablation probe combining RFA and cryotechnology was used to induce the foci of complete pancreatic ablation. In the first human clinical trial, the flexible bipolar ablation probe was successfully applied under EUS guidance in 16 of 22 (72.8%) patients with advanced pancreatic carcinoma 48. In six patients, it failed because of excessive resistance of the gastrointestinal wall and of the tumor.
Overall, EUS-RFA seems to be a feasible and safe treatment modality for various pancreatic tumors. However, further prospective comparative studies are still needed to demonstrate the safety and overall survival benefit before widespread use in clinical practice. 6. EUS-Guided Brachytherapy Brachytherapy in the form of small seeds or beads has been used for various malignant diseases. Its advantage is limited radiation toxicity. Iodine (I125) or palladium (Pd103) can be used. As an advantage, Iodine has slower delivery rate (half-life is 60 days for iodine and 17 days for palladium). Through an 18-G EUS needle, multiple small radioactive seeds can be placed into the pancreatic lesion. Clinical studies have reported the efficacy and safety of EUS-guided brachytherapy 4, 49, 50. Similarly, promising results in left-sided liver tumors were reported in a recent study 51. Also, EUS-guided brachytherapy has been used successfully in head and neck malignancies and esophagus cancer with low adverse event rates 52, 53. 7. EUS-Guided Photodynamic Therapy Photodynamic therapy utilizes a photosensitizing molecule (hematoporphyrin derivative as a first and chlorin e6 derivative as a second-generation photosensitizer) and a light source to activate the administered drug 5. It is an accepted method for the treatment of various cancers including pancreatobiliary malignancies. Chlorin e6 derivative has advantages over hematoporphyrin derivative regarding deeper effective penetration of light and much faster excretion rate as well (Figure 2). Preliminary animal studies demonstrated the safety of EUS-guided photodynamic therapy 54. Choi et al reported the first in-human feasibility of the method performed in 4 patients with locally advanced pancreatobiliary malignancies 5. 8. EUS-Guided Laser Ablation Laser ablation has been used for liver tumors 55, 56. Laser ablation was safe in an animal model study 6. To date, only one case has been reported on the use of EUS-guided laser ablation for human pancreas 57. The patient had recurrent pancreatic neuroendocrine tumor and radiological resolution was achieved after single session of EUS-guided laser application. 9. EUS-Guided Fiducial Placements By EUS guidance, small radiopaque markers are placed into the periphery of a malignant lesion to facilitate better targeting of radiation therapy 9. Fiducial placement is performed by using 19-G or 22-G EUS needles. To enable correct positioning, both fluoroscopic and ultrasonographic visualization may be used. EUS- guided fiducial placement seems to be safe and effective. For pancreatic malignancies, high technical and clinical success rates (85-90%) and only few minor adverse events have been reported 9, 58, 59. Moreover, the technique has been adopted to facilitate intraoperative localization (tattooing) of pancreatic tumors in patients undergoing enucleation or other resection procedures 60, 61.
10. EUS-Guided Injection of Novel anti-tumoral agents Several biological agents have been tested by EUS-fine needle injection for pancreatic and esophageal cancers (Table 1). A phase I clinical trial demonstrated the feasibility and safety of EUS-guided injection of sensitized culture of lymphocytes in patients with pancreas cancer 62. Eight patients with unresectable pancreatic adenocarcinoma underwent EUS-guided lymphocyte cytoimplants. The median survival was 13.2 months. Two of 8 patients had partial and one had minor response. As an adverse event, there was low-grade fever in seven patients. EUS-guided delivering antitumor viral therapy is another novel technique 63. An E1B-55-kDa gene-deleted replication-selective adenovirus, ONYX-015 (dl1520), preferentially replicates in malignant cells and causes cell death. In a clinical trial, twenty-one patients with locally advanced pancreas adenocarcinoma or with metastatic disease underwent eight sessions of EUS-guided injection of ONYX015 over 8 weeks. Intravenous gemcitabine was added in the final four sessions. At the end, two patients had partial regressions, two had minor responses, six had stable disease, and 11 had progressive disease. Dendritic cells, potent antigen-presenting cells, were used in experimental studies as a vaccine therapy against various cancers. In a study, seven patients with advanced pancreatic cancer that were refractory to gemcitabine therapy received repeated EUS-guided intratumoral injection of immature dendritic cells 64. There was no clinical toxicity. Median survival was 9.9 months which was similar to previous chemotherapy studies. In another trial, the method was combined with gemcitabine in 5 patients with advanced pancreatic cancer 65. One patient had a partial response and two patients had prolonged stable disease. The median survival time was 15.9 months. There were no serious treatment-related adverse events during the study period. Tumor necrosis factor (TNFerade) is a second-generation replication-deficient adenovirus vector. It expresses human TNF-alpha gene, which is regulated by a chemoradiation-inducible promoter. In a multicenter study, TNFerade was applied to 50 locally advanced pancreatic cancers by EUS-guidance (n = 27) or percutaneous injections (n = 23) for 5 weeks in combination with 5-fluorouracil and radiation 8. The higher-dose group (n = 11) had better outcomes when compared to the lowerdose group (n = 30). At high-dose, five patients became surgically resectable and four of those had pathologically negative margins; three patients survived more than 24 months. The overall outcomes were comparable among EUS-guided and percutaneous route groups. The adverse events were mild and well tolerated. On the other hand, in a comparative study including 187 locally advanced pancreatic cancer, TNFerade arm could not show superiority for prolonging survival when compared to standard of care arm 66. In another study, EUS-guided or direct endoscopic injection of TNFerade was combined with standard chemoradiotherapy before surgery in 24 patients with locally advanced resectable esophageal cancer 67. The combination was associated with long survival but frequent adverse events including thromboembolic events. BC-819 is a DNA plasmid. It provides the expression of diphtheria-toxin gene under the control of H19 regulatory sequences. Since pancreatic cancer overexpresses the H19 gene, BC-819 was used in a clinical trial 68. Intratumoral injection of BC819 was performed by computerized tomography (n:3) or EUS (n:6) guidance. Two patients who underwent chemotherapy or chemoradiotherapy following BC-819
injection had downstaging. Three of 6 patients in the EUS group had partial responses. There were no clinical adverse events. The results of these initial studies were promising, however, randomized controlled trials are still needed to confirm the benefits of these novel treatments. Conclusion With the advances in diagnostic tools, the prevalence of pancreatic cysts and solid lesions has increased. EUS-guided ethanol ablation is a safe and feasible method for treatment of pancreas cysts and neuroendocrine tumors. We need more data about the efficacy of EUS-guided therapeutic methods on tumor ablation including radiofrequency ablation, photodynamic therapy, brachytherapy, laser therapy and injection of antitumor agents. Delivery of antitumoral agents via EUS seems to be an effective treatment for pancreatic cancer. Conflict of interest: None
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TABLE Table: EUS-guided novel antitumor agents Authors
Underlying Disease
Anti-tumoral Agent
Number of Patients
Chang et al62
Pancreas cancer
Lymphocyte cytoimplants
8
Results
Adverse Event
Partial response in 2 patients
Fever
Minor response in 1 patient Hecth et al63
Pancreas cancer
ONYX-015 + gemcitabine
21
Partial response in 2 patients
Sepsis in 2 patients
minor response in 2 patients stable disease in 6 patients Irisawa et al64
Pancreas cancer
Dendritic cells
7
No benefit on survival
None
Hirooka et al65
Pancreas cancer
Dendritic cells + gemcitabine
5
Partial response in 1 patient
None
Stable disease in 2 patients Hecht et al8
Pancreas cancer
TNFerade + chemoradiotherapy
50
Downstaging at higher doses
Mild
Herman et al66
Pancreas cancer
TNFerade + chemoradiotherapy
187
No benefit on survival
Minimal
Chang et al67
Esophageal cancer
TNFerade + chemoradiotherapy
24
Longer survival
Fatique, fever, nausea, vomiting, esophagitis; thromboemboli in higher döşe
Hanna et al68
Pancreas cancer
BC-819
9
Downstaged in 2 patients
Asymptomatic lipase elevation
Partial response in 3 patients