Endoscopic Therapy for Barretts: Resect, Burn or Freeze

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Endoscopic Therapy for Barretts Resect, Burn or
Freeze?
Ram Chuttani, M.D. Director of Endoscopy
and Chief, Interventional Gastroenterology Beth
Israel Deaconess Medical Center Assistant
Professor of Medicine Harvard Medical School
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Barrett Classification and Management

• Non-dysplastic IM
• Surveillance every 1-3 years
• Detect progression to dysplasia or adenocarcinoma
• LGD (low grade dysplasia)
• Surveillance every 6-12 months
• Detect progression to HGD or adenocarcinoma
• HGD (high grade dysplasia) and CIS (carcinoma
  in-situ)
• Treated like invasive adenocarcinoma
• Standard of care is esophagectomy (EMR for purely
  focal disease)
• PDT is an option at some institutions

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Esophagectomy

• Mortality4-7 (Expert centers 1-2)
• Early Morbidity 25
• Late Morbidity gt50

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How to ablate ?

• Argon Plasma Coagulation
• Multipolar Electrocagulation
• Heater Probe
• Lasers
• PDT
• Radio-frequency Ablation
• Cryotherapy

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Who to ablate ?

• HGD Poor surgical candidate-Yes Good
  surgical candidate- Focal (incidence of Ca
  7)-Yes Diffuse (incidence of Ca 36)- No
  Flat (incidence of Ca 13)- Yes
  Nodular (incidence of Ca 63)- No
• LGD- YES
• Non Dysplastic Barretts ?

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Colonic Polyp vs. Intestinal Metaplasia

• Ries LAG, et al. (eds). SEER Cancer Statistics
  Review, 1975-2004, National Cancer Institute.
  Bethesda, MD, http//seer.cancer.gov/csr/1975_2004
  /, based on November 2006 SEER data submission,
  posted to the SEER web site, 2007.
• Winawer SJ, et al. Prevention of colorectal
  cancer by polypectomy. The National Polyp Study
  Workgroup. N Engl J Med. 19933291977-81.
• Sharma P, Falk GW, Weston AP, Reker D, Johnston
  M, Sampliner RE. Dysplasia and Cancer in a Large
  Multicenter Cohort of Patients with Barretts
  Esophagus. Clin Gastroenterol Hepatol
  20064566-572.

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What is ablation?

• Implies destruction and, ultimately, removal
• Mechanismheating of tissue to the point of
  vaporization and/or coagulation
• Endpoint is irreversible cell injury and,
  ultimately, cell death

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Human Esophagus
Controlling ablation depth avoids stricture
Ablation Target
Muscularis mucosae(Ablation Target Depth)
G
G
Submucosa with esophageal glands
EMR Depth
Muscularis propria
Surgical Depth
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HALO Electrode Technology

• High power
• Rapid delivery (very short on time)
• Energy density control
• Tight electrode spacing

MagnifiedElectrode
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• HGD Esophagectomy
• Surg Endo, April 2007
• Dosing study HGD
• HGD BE epithelium targeted
• 10-12-14 J/cm2
• 2x-3x-4x
• HGD can be eliminated at 12 and 14 J/cm2
• No submucosal injury, even at high doses
• First HGD dosing trial
• Led to IRB approval for subsequent HGD ablation
  trials

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AIM Clinical Trial

• Sharma VK, Fleischer DE, Wang KK, Overholt B,
  Lightdale C, Kimmey M, Reymunde A, Santiago N,
  Chuttani R, Pleskow D, Chang K

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Methods

• Non-dysplastic IM
• AIM-I (n32)
• Pilot dosimetry phase
• Dose escalation of energy density (6-12 J/cm2)
• AIM-II (n70)
• Effectiveness phase
• 10 J/cm2 delivered twice per session (2x)
• 1, 3, 6, 12 mo EGD with bx
• Focal ablation (HALO90) offered after 1 year
• EGD biopsy at 2.5 years

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• AIM Trial (1 year)
• GIE, Feb 2007
• Two phase trial
• Dosing phase (n32)
• 6,8,10,12 J/cm2 (1x)
• Efficacy phase (n70)
• 10 J/cm2 (2x)
• 70 CR-IM at 1 year
• No strictures
• No buried glands
• 6000 biopsy fragments

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• AIM-II Trial (2.5 year extended follow-up)
• GIE, in-press 2008 (Fleischer, et al.)
• After 1 year data collected
• HALO90 applied for visible disease / confirmed IM
• Biopsy at 2.5 years
• CR-IM 98.4 (60/61 patients)
• 1,000 biopsies collected
• no strictures or buried glands

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• HGD Registry (1 year)
• GIE (in-press)
• (Ganz, et al.)
• 142 patients, 16 centers
• HGD (median 6 cm)
• HALO360 only
• 12 J/cm2 (2x)
• Results
• 92 patients
• follow-up 12 months
• CR for HGD 90
• no focal ablation
• 1 mild stricture, 1.1
• no buried glands

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• RFA for HGD/CA (AMC I II)
• (Bergman et al., Endoscopy, 2008)
• RFA combined with EMR effective for HGD early
  cancer
• 13 of 23 pts had prior EMR for visible
  abnormalities
• After 14 month average follow-up
• 100 CR-D and CR-IM
• No strictures
• No buried glands in gt800 bx

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• AIM LGD Trial
• (Sharma, et al., Endoscopy, 2008)
• RFA effective for LGD
• Baseline LGD confirmed in 10 patients by 2
  pathologists over 2 endoscopy sessions
• At 2 year follow-up
• 100 CR-dysplasia
• 90 CR-IM
• No strictures
• No buried glands in gt200 bx fragments

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EURO-II Multi-center Trial

• 10 center (n100) follow-on to EURO-I
• /- EMR followed by RFA for HGD/CA

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Malignant Degeneration in BE
Intestinal metaplasia LGIN HGIN carcino
ma
p16 loss p53 loss aneuploidy
AMC Marker Study
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Conclusions

• RFA results in restoration of normal appearing
  neosquamous mucosa that shows no oncogenetic
  alterations as present before treatment.
• This suggests that the neosquamous epithelium has
  no residual malignant potential.
• RFA may indeed be a permanent cure for Barretts
  associated neoplasia.

AMC Marker Study
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BARRx RF Ablation Summary

• Ablation with circumferential and focal device
  results in CR for IM and dysplasia in 85-98 of
  patients
• Elimination of abnormal genetic markers
• Preservation of esophageal function
• Safety profile
• Cost-effectiveness studies completed comparing
  ablation to life-long surveillance
• Evaluations of focal device underway for other
  disease states (GAVE, radiation proctitis,
  hemostasis)

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Cryotherapy

• Device and Technique for Use
• Mechanism of Action
• Results

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Technique of Cryotherapy Ablation

• Visually directed, non-contact method using low
  pressure liquid nitrogen spray(3 5 psi)

• 7-French catheter through working channel of
  standard endoscope

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Technique of Cryotherapy Ablation

• Modified orogastric tube (cryodecompression tube)
  placed to vent esophagus and stomach during
  procedure

• Treatment session freeze (10-20 seconds) then
  thaw (45 seconds) cycles. Sessions repeated every
  4-6 weeks until lesion ablated

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Patient Preparation

• High dose proton pump inhibitor for one week
• NPO after midnight

Sedation

• Moderate sedation (fentanyl, midazolam)or
• Monitored anesthesia care (propofol)

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Disease States Being Treated

• Barretts esophagus, LGD
• Barretts esophagus, HGD
• Intramucosal cancer
• T1N0 cancer
• T2 (palliative)
• Squamous cell carcinoma
• Squamous dysplasia

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Dosimetry
0.5 mm
4 x 10 seconds Lamina Propria to shallow
Submucosal injury
3 x 20 seconds Submucosal injury

• Depth of injury controlled by
• Length of tissue freeze time
• Repetitions of freeze/thaw cycles

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Mechanism of action - immediate

• Protein denaturation
• Extracellular ice
• Intracellular ice

• Cell membrane disruption
• Continued hypothermia

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Mechanism of action - delayed

• Vasoconstriction
• Vascular stasis
• Anoxia, necrosis
• Reactive vasodilation
• Increased permeability
• Platelet aggregation
• Thrombosis, necrosis

Rapid freezing
Cell death
Slow thaw

• Apoptosis programmed cell death
• Possible cellular immunity against tumor cells

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Tissue Injury Immediate Effects
Intact epithelium Submucosal hemorrhage
Minimal inflammation
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Tissue Injury Delayed Effect
Day 2
Day 14
Day 28
Blister
Normal
Necrosis Inflammation
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Results

• Significant success in treatment of various GI
  lesions in complex high-risk patient populations
• gt300 patients treated, gt800 CSA procedures
• Typically 3-4 treatments per patient
• Treatment of Barretts esophagus, LGD, HGD, IMCA,
  T1N0, T2N0, squamous dysplasia and squamous cell
  carcinoma

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First Human Trial
Johnston MH, et al. Gastrointest Endosc. 2005
62(6)842
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CryoSpray Ablation of HGD/IMCA

• 32 patients enrolled and treated
• 20 completed treatment 12 under treatment
• Average segment length 5 cm (1 12 cm)
• Age 71 yr (IQR 63 88)
• 4.3 CSA sessions (IQR 2.8 8.0)

CR PR CR/PR Failed
Months 16 HGD 7 8 15 (94) 1 11 4 IMCA
1 2 3 (75) 1 9
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Treatment Results High-Grade Dysplasia/Intramucos
al Carcinoma
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Treatment Results High-Grade Dysplasia/Intramucos
al Carcinoma
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CryoSpray Ablation of Early Stage Esophageal
Cancer
Greenwald and Cash. DDW 2007
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CryoSpray Ablation of Early Stage Esophageal
Cancer
Greenwald and Cash. DDW 2007
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Endoscopic Cryotherapy AblationAdverse Events
(137 procedures at U. Md.)
Stricture 2 (6). Less common nausea (4),
abdominal bloating (4), headache (2), fever
(1) and hiccoughs (1)
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Endoscopic Cryotherapy AblationSummary

• Unique mechanism of action
• Safe and well-tolerated
• Physician controlled depth of injury
• Successful in eliminating high-grade dysplasia
  and intramucosal cancer
• Useful in treatment of nodules and raised
  lesions, including locally advanced tumors

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Thank You!