EUS Guided Anti Tumor Therapyversion0


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An overview of the advances in Endoscopic Oncology using Interventional Endoscopic Ultrasound

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EUS Guided Anti Tumor Therapyversion0

  1. 1. EUS Guided Anti-Tumor Therapy: Past, Present and Future Shivakumar Vignesh, MD Endoscopic Oncologist Moffitt Cancer Center
  2. 2. Outline <ul><li>Therapeutic capabilities of EUS </li></ul><ul><li>Role of EUS Prior to Endoscopic Mucosal Resection </li></ul><ul><li>Rationale for local therapy, Agents used </li></ul><ul><li>EUS-guided therapy for: </li></ul><ul><ul><li>Pancreatic Cystic Neoplasms </li></ul></ul><ul><ul><li>Pancreatic adenocarcinoma </li></ul></ul><ul><li>EUS-guided Fiducial placement for Image Guided Radiotherapy </li></ul><ul><li>EUS-guided Brachytherapy </li></ul><ul><li>EUS-guided Vascular Interventions </li></ul><ul><li>Future Possibilities: PDT/RF/Cryotherapy, HIFU, NOTES, Contrast, Nanoparticles </li></ul>
  3. 3. Therapeutic Capabilities of EUS <ul><li>Large therapeutic channel </li></ul><ul><li>Doppler, real-time needle visualization </li></ul><ul><li>One-step diagnosis and therapy </li></ul><ul><li>Fine Needle Injection: </li></ul><ul><ul><li>Intralesional tattooing/ chemotherapy </li></ul></ul><ul><ul><li>Placement of fiducials and brachytherapy </li></ul></ul><ul><ul><li>Pseudocyst/Abscess drainage </li></ul></ul><ul><li>EUS-guided Biliary and Pancreatic drainage (EURCP) </li></ul>
  4. 4. E ndoscopic M ucosal R esection <ul><li>EUS guided Saline injection prior to EMR (Sun et al., 2002) </li></ul><ul><li>Complete resection >90 % </li></ul><ul><li>Path upgraded or downgraded (~30%) </li></ul><ul><li>Complete local remission achieved in 95% (3 yr f/u) </li></ul><ul><li>5-year survival rate was 79 % </li></ul>T1 sm3 T1m1
  5. 5. EUS-guided Biliary and Pancreatic drainage EUS-Pancreatic drainage EUS-Biliary Drainage <ul><li>ERCP fails in 3-12% of cases </li></ul><ul><li>Percutaneous drainage has a 20% complication rate </li></ul><ul><li>EUS-FNI with contrast injection; methylene blue </li></ul><ul><li>Direct EUS-drainage and Rendezvous feasible </li></ul>
  6. 6. EUS-guided Celiac Plexus Neurolysis For Unresectable Pancreatic Cancer <ul><li>5 ml of Bupivacaine, 10ml of 98% alcohol </li></ul><ul><li>Celiac ganglia visualized on EUS </li></ul><ul><li>Pain relief in 94% with direct intraganglionic injection; n=36 (Levy et al, Am J Gastroenterol. 2008;103:98-103) </li></ul><ul><li>Safe, well tolerated and cost-effective </li></ul><ul><li>Predictors of poor response: Age <45, pancreatic surgery </li></ul>Fenestrated Needle
  7. 7. Rationale for Local Anti-tumor therapy <ul><li>Need to change the paradigm </li></ul><ul><ul><li>Poor survival with current therapy </li></ul></ul><ul><ul><li>Systemic multi-drug therapy poorly tolerated </li></ul></ul><ul><ul><li>Increasing population with high surgical risk </li></ul></ul><ul><li>High intratumoral drug levels </li></ul><ul><li>Low circulating level  fewer adverse effects </li></ul><ul><li>EUS-FNI is safe, minimally invasive and precise </li></ul>
  8. 8. Agents Used for EUS-Guided Ablation <ul><li>Ethanol ablation </li></ul><ul><ul><li>Cystic Pancreatic Tumor (CPT), Insulinoma, hepatic and adrenal metastasis, GIST </li></ul></ul><ul><li>Allogeneic mixed lymphocyte culture (Cytoimplant) </li></ul><ul><li>Gene Therapy </li></ul><ul><ul><li>Gene-deleted replication-selective adenovirus (ONYX-015) </li></ul></ul><ul><ul><li>Adenovector with a radiation-inducible promoter, carrying the human TNF- α gene (TNFerade) </li></ul></ul><ul><li>Polymerized Paclitaxel (Oncogel) </li></ul><ul><ul><li>Pancreatic Cystic tumors, Solid Tumors Esophageal Cancer (Ongoing) </li></ul></ul><ul><ul><li> (Chang et al. Cancer. 2000;88:1325–1335; Hecht et al. Clin Cancer Res. 2003;9:555–561; Chang et al. GIE. 2004;59:AB-92; Nat Clin Pract Gastroenterol Hepatol. 2008;5(2):107-11;Farrell et al, GIE 2006;63:AB93;Jurgensen et al, GIE 2006;63:1059-62; Barclay et al, GIE 2002;55:266-70;Artifon et al, GIE2007 ;66(6):1201-5;Gunter et al, GIE 2003;57(1):113-5;Oh et al, GIE 2008 Apr;67(4):636-42;Vukelja et al, Anti-Cancer Drugs. 18(3):283-289) </li></ul></ul>
  9. 9. EUS-FNI for Cystic Pancreatic Tumors (CPT) <ul><li>Rationale: </li></ul><ul><ul><li>Unpredictable malignant potential </li></ul></ul><ul><ul><li>High morbidity of pancreatic resection </li></ul></ul><ul><li>Ethanol injected into pig pancreas results in concentration-dependent focal tissue necrosis without complications (Matthes et al., Gastrointest Endosc. 2007) </li></ul><ul><li>FNI of Paclitaxel polymer (OncoGel) provides therapeutic drug concentrations in porcine pancreas (Gastrointest Endosc. 2007) </li></ul>
  10. 10. EUS-FNI for CPT in Humans <ul><li>Ethanol lavage of CPT; n=25 (Gan et al, GIE 2005;61:746-752) </li></ul><ul><ul><li>Epithelial ablation in all patients </li></ul></ul><ul><ul><li>Complete cyst resolution at 6 mos in 35% </li></ul></ul><ul><li>A Prospective, Randomized, Double blind study of Ethanol versus saline lavage of CPT; n=39 (Dewitt et al, Gastrointest Endosc. 2007;65:AB106) </li></ul><ul><ul><li>Cyst diameter reduction ≥ 25% in 61% receiving ethanol and 17% receiving saline lavage </li></ul></ul><ul><ul><li>Complete resolution in 22% </li></ul></ul><ul><li>Ethanol + Paclitaxel lavage for CPT; n=14 (Oh et al, Gastrointest Endosc. 2008;67:636-42) </li></ul><ul><ul><li>11/ 14 patients showed complete resolution at ≥6 months </li></ul></ul><ul><ul><li>Complications included abdominal pain (n = 1) and focal pancreatitis (n = 1) </li></ul></ul>
  11. 11. EUS Guided Ethanol Injection for Ablation of Mucinous Cysts
  12. 12. EUS-FNI Of TNFerade™ For Pancreatic Cancer Chang KJ et al . (2008) Endoscopic ultrasound delivery of an antitumor agent to treat a case of pancreatic cancer Nat Clin Pract Gastroenterol Hepatol 5: 107–111 doi:10.1038/ncpgasthep1033 Pancreatic mass shrinking with ► injections of TNFerade EUS-FNA negative 1 month after therapy EUS-FNI of TNFerade
  13. 13. EUS-FNI TNFerade: Result in 1 patient   Resected pancreas with no residual tumor Chang KJ et al . (2008) Endoscopic ultrasound delivery of an antitumor agent to treat a case of pancreatic cancer. Nat Clin Pract Gastroenterol Hepatol 5: 107–111 doi:10.1038/ncpgasthep1033 Tumor measurements relative to weeks of TNFerade TM treatment Complete pathologic response <ul><li>2 cases of pancreatitis </li></ul><ul><li>1 case of ascending cholangitis reported </li></ul>
  14. 14. Phase 2/3, Randomized, Trial using TNFerade™ Combined with Chemoradiation in Locally Advanced Pancreatic Cancer Data presented at the ASCO 2007 meeting <ul><li>Indication: First-line therapy, concurrent with 5-FU and RT, and followed by maintenance gemcitabine or gemcitabine/erlotinib, for patients with locally advanced pancreatic cancer (LAPC) </li></ul><ul><li>Patient population: Newly diagnosed, unresectable, LAPC. Patients with metastatic disease excluded </li></ul><ul><li>Groups: TNFerade+SOC versus SOC (Total n=330; 2:1 rand) </li></ul><ul><li>Interim analysis ( n=51) </li></ul><ul><ul><li>Median survival: 19.3 months in the TNFerade + SOC arm and 11.1 months for patients receiving standard of care alone </li></ul></ul><ul><ul><li>Tumor Response: No significant difference between the groups </li></ul></ul><ul><ul><li>Adverse events: No significant difference between the groups </li></ul></ul>
  15. 15. Image Guided Radiotherapy: EUS-Guided Fiducial Placement <ul><li>An FNA needle loaded with radio-opaque, metal markers (fiducials) is precisely directed into a tumor with EUS </li></ul><ul><li>Successfully used for abdominal and pelvic tumors; mediastinal nodes </li></ul><ul><li>Technique shown to be simple, safe and effective </li></ul><ul><li>Rare: mild pancreatitis, abdominal pain, migration </li></ul><ul><li>EUS-guided implantation of a micro-particulate form of brachytherapy (32P BioSilicon) shown to be feasible & safe </li></ul><ul><ul><li>Patel SN, Mira JG, Amerduri A, Berg M. Endoscopic ultrasound guided placement of fiducials for the treatment of pancreatic cancer. Am J Gastroenterol. 2006; </li></ul></ul><ul><ul><li>Siwar Albashir, Gastrointestinal Endoscopy April 2008.EUS Guided Fiducial Placement for Cyberknife Treatment of Pancreatic Cancer </li></ul></ul><ul><ul><li>Michael K. Sanders EUS-Guided Fiducial Placement for Stereotactic Radiosurgery in Pancreatic Cancer GIE April 2008 </li></ul></ul><ul><ul><li>Pishavian A, EUS-guided fiducial placement for CyberKnife radiotherapy of mediastinal and abdominal malignancies GIESeptember 2006 </li></ul></ul>
  16. 16. EUS-Guided Fiducial Placement: Esophageal Cancer
  17. 17. EUS-Guided Fiducial Placement: Rectal Cancer
  18. 18. EUS-guided Interstitial Brachytherapy <ul><li>Porcine Pancreas feasibility study  No complications ( Sun et al., EUS-guided interstitial brachytherapy of the pancreas: a feasibility study, GIE 62 (2005), 775–779) </li></ul><ul><li>Pancreatic Cancer </li></ul><ul><ul><ul><li>In combination with systemic chemotherapy, n=22, stage II, III& IV, median of 10 (I-125) seeds per patient. Significant drop in pain score, fever, seed migration ( Jin Z Endoscopy. 2008 Apr;40(4):314-20) </li></ul></ul></ul><ul><ul><ul><li>Brachytherapy alone, n=15, stage III&IV, mean of 22 (I-125) seeds per patient. Pain relief in 1/3 rd ; 3 cases of mild pancreatitis ( Sun S Endoscopy. 2006 Apr;38(4):399-403) </li></ul></ul></ul><ul><ul><ul><li>EUS-guided implantation of a liquid/micro-particulate form of brachytherapy (32P BioSilicon™) (Meenan et al, GIE 2007) </li></ul></ul></ul><ul><li>Recurrent squamous esophageal cancer in perigastric lymph nodes </li></ul><ul><ul><li>(JJ Lah et al, EUS-guided brachytherapy, Gastrointest Endosc 62 (2005), pp. 805–808) </li></ul></ul><ul><li>Head and neck cancers, n= 39 </li></ul><ul><ul><li>( Maier W , J Laryngol Otol 1999; 113:41-8) </li></ul></ul><ul><li>Rectal Cancer </li></ul><ul><ul><li>(Doniec et al. Rectal EUS guided HDR-brachytherapy in patients with anal and peri-anal malignancies. Gastrointest Endosc. 2000;51:AB-106) </li></ul></ul>
  19. 19. EUS Guided Angiotherapy <ul><li>5 cases of refractory bleeding from pancreatic pseudoaneurysm, Dieulafoy lesion, GIST: </li></ul><ul><ul><li>Alcohol/ Cyanoacrylate/ thrombin injected </li></ul></ul><ul><ul><li>into the bleeding vessel </li></ul></ul><ul><ul><li>No rebleeding or complications </li></ul></ul><ul><ul><li>(Levy et al, Am J Gastroenterol. 2008 Feb;103(2):352-9; Roach et al, Endoscopy 2005; </li></ul></ul><ul><ul><li>37: 876-878) </li></ul></ul><ul><li>Cyanoacrylate for gastric varices ( Romero-Castro GIE. 2007 Aug;66:402-7) </li></ul><ul><li>Portal vein intervention </li></ul><ul><ul><li>Embolization with Enteryx ( Matthes et al Acta Gastroenterol Belg. 2005;68:412–415) </li></ul></ul><ul><ul><li>Catheterization and pressure measurement in pigs (Lai et al, Gastrointest Endosc. 2004;59:280–283) </li></ul></ul><ul><li>Selective vascular injection ( Aorta, Celiac & Splenic arteries, Splenic and Portal vein) was performed safely in pigs (Magno et al, GIE 2006, 63; AB267) </li></ul>
  20. 20. EUS-Guided Radiofrequency Ablation (RFA) and Photodynamic Therapy (PDT) <ul><li>A retractable umbrella shaped electrode array was used to safely perform EUS-RFA of the liver & pancreas in pigs </li></ul><ul><li>( Varadarajulu et al, EUS-Guided RFA Using a Prototype Retractable Needle Electrode Array; Goldberg et al. EUS-guided radiofrequency ablation in the porcine pancreas: GIE. 1999;50:392–401) </li></ul><ul><li>EUS-PDT of the pancreas feasible and safe in pigs (Chan et al. The use of endoscopic ultrasound (EUS)-guided PDT in the ablation of the pancreas: A pilot study GIE 2003;57:AB242) </li></ul><ul><li>EUS-PDT with Verteporfin for ablation of pig pancreas (Yusuf et al, Gastrointest Endosc. 2008;67:957-61) </li></ul>
  21. 21. High Intensity Focused Ultrasound (HIFU) <ul><li>Does not affect surrounding tissue </li></ul><ul><li>Activates anti-tumor immunity (Cd4) </li></ul><ul><li>Used for Prostate Cancer, studied for cancers of breast, liver, kidney and pancreas </li></ul><ul><li>Pilot study (n=8) in unresectable Pancreatic cancer </li></ul><ul><ul><li>All experienced pain relief, within 48 hours of HIFU </li></ul></ul><ul><ul><li>Tumor size regressed by ~40% , mean survival ~1 year </li></ul></ul><ul><ul><li>No reported side effects </li></ul></ul><ul><li>(Wu, et al. Feasibility of US-guided High-Intensity Focused Ultrasound Treatment in Patients with Advanced Pancreatic Cancer: Initial Experience. Radiology. 2005; 236:1034-1040 </li></ul>
  22. 22. Interventional EUS: Future possibilities <ul><li>Contrast EUS directed targeted biopsy and ablation </li></ul><ul><li>Chemo-embolization </li></ul><ul><li>Cryotherapy </li></ul><ul><li>EUS combined with NOTES </li></ul><ul><li>Multifunctional nanoparticles, Si-RNA </li></ul><ul><ul><li>Drug/ gene carriers </li></ul></ul><ul><ul><li>Ultrasound contrast agents </li></ul></ul><ul><ul><li>Ultrasound mediated drug delivery </li></ul></ul>