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EUS Guided Anti Tumor Therapyversion0
 

EUS Guided Anti Tumor Therapyversion0

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

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

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    EUS Guided Anti Tumor Therapyversion0 EUS Guided Anti Tumor Therapyversion0 Presentation Transcript

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