Optical Diagnosis and Treatment in Barretts Esophagus

1
Optical Diagnosis and Treatmentin Barretts
Esophagus

• Dr Laurence Lovat
• National Medical Laser Centre
• University College London, UK

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Esophageal Cancer Rates (Men, Age Standardised
Mortality/105)
20 10 0
USA
US SEER data, 2004
3
Esophageal Cancer Rates (Men, Age Standardised
Mortality/105)
20 10 0
London UK USA
Thames Cancer Registries US SEER data, 2004
4
Esophageal Cancer Rates (Men, Age Standardised
Mortality/105)
20 10 0
Scotland NW UK London UK USA
Scottish, NW UK, Thames Cancer Registries US
SEER data, 2004
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The Questions

• How do we prevent death from esophageal
  adenocarcinoma?
• How do we detect patients at risk?
• How do we best treat patients?

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The Questions

• How do we prevent death from esophageal
  adenocarcinoma?
• How do we detect patients at risk?
• How do we best treat patients?

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Detecting patients at risk

• 80 of cases of esophageal adenocarcinoma arise
  within Barretts esophagus
• Screening
• Endoscopy
• Invasive
• Not of proven value
• Less invasive techniques
• Nothing proven

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Detecting patients at risk

• Surveillance
• Lifetime risk of cancer lt10
• Need to target high risk groups

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Markers of Risk
Acid reflux, Bile acids, Cytokines
Cell Cycle G1-S G2, apoptosis
Cell Interactions adhesion, catenins
?
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Cancer Risk in Presence of Aneuploidy or
Tetraploidy gt6
All patients without HGD at baseline
RR25
Years
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p16, p53, ploidy Biomarker Panel Progression to
EA
Biomarker panel (9pLOH, 17pLOH, abnormal ploidy)
Dysplasia grade Seattle Criteria
4 Biopsies per 1-2 cm plus Targeted Biopsies
HGD
Probability of Cancer
ltHGD
Time (months)
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Endoscopic Detection of HGD
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Morphological Changes in HGD
200 mm
Non-dysplastic intestinal metaplasia High
grade dysplasia
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Elastic Scattering Spectroscopy(Optical biopsy)

• Point measurement
• Wavelength dependence
• Scattering efficiency of tissue
• Sensitive to morphological changes
• Size, shape and density of nuclei mitochondria
• cellular density

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Elastic Scattering Spectroscopy
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Optical Biopsy
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Elastic Scattering Spectra
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Elastic Scattering Barretts Oesophagus
V1V3 vs V4V5 Sensitivity 92 Specificity
70 Negative predictive value gt99
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ESS Optical Biopsies

• Perform 17 random biopsies
• OR
• 17 optical measurements and 7 biopsies

• Model
• 92 dysplasia sites detected
• Negative test gt99.5 reliable

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Taking Optical Biopsy Forward

• Detecting patients at high risk who do NOT have
  dysplasia
• Can OB detect patients at risk

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Detecting Field Change Effect

• Animal model of colon cancer
• Aberrant crypt foci is the first visible change
• ESS detects fingerprint of microarchitectural
  abnormalities BEFORE aberrant crypt foci visible
• ( Roy et al, Gastroenterology (2004) 126 1071)
• Human Colorectal Cancer Risk Stratification
• 37 patients
• Colonoscopy in those with/without previous
  adenomas
• Similar findings to animal models
• ( Roy et al, DDW 2005)

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The Questions

• How do we prevent death from esophageal
  adenocarcinoma?
• How do we detect patients at risk?
• How do we best treat patients?

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Treatment for HGD in Barretts Oesophagus

• Oesophagectomy
• Morbidity 40 Mortality 5
• Elderly patients
• Need for minimally invasive therapy

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Mucosal Ablation

• Thermal (hot/cold)
• Laser
• MPEC
• Cryotherapy
• Photochemical (PDT)

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The Ideal of Mucosal Ablation

• Selective mucosal
• destruction
• Ambulatory therapy
• No side effects Strictures Photosensitivity Acu
  te Hypotension Buried glands

Thermal Photofrin ALA PDT PDT No No Yes Yes Mayb
e No10 minutes 20 minutes 40 mins
2-5 30 0 None 2-3 months 1
day No No Yes Frequent Rare Very rare
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Courtesy Professor H Barr, Gloucester
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Courtesy Professor H Barr, Gloucester
Oesophageal strictures 25
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PDT Results Barretts Esophagus

• ALA for HGD and T1 Ca in Barretts
• 66 patients (35 HGD)
• Median follow up 37 months
• (Pech GI Endoscopy 2005)
• Disease Strictures
• Free
• HGD 89
• 0
• T1 Ca 68

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Results (ALA)

• From October 1999
• 75 patients treated
• (most after 2002)
• All had high grade dysplasia (V4)
• 3 studies
• High dose ALA (60mg/kg)
• Light dose ranging (low, medium, high light dose)
• RCT ALA 30 mg/kg with red v green light
• RCT ALA 60 mg/kg with red v green light

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ALA 60 mg/kg (high dose)Red Light at various
doses
Log Rank P 0.008
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ALA 30 mg/kg (low dose)Red v Green Light
Log Rank P 0.07
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Rescue with high dose ALAand various light doses
Log Rank P 0.03
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ALA PDT

• 75 patients treated
• Best regime 80 clearance HGD at 2 years
• Toxicity (all at 60mg/kg)
• 4 patients severe hypotension
• (prevented by rehydration and avoiding
  psychotropic drugs)
• 3 patients aspiration pneumonia
• 8 patients transient fever
• 2 patients asymptomatic jaundice, cleared in 5
  days

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ALA PDT

• Looks promising but there are toxicity issues

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Foscan Mucosal Selectivity
3.5
3.0
2.5
SELECTIVITY RATIO Between MUCOSA AND MUSCLE
2.0
1.5
1.0
0.5
0.0
4 hours
24 hours
4 days
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Verteporfin photosensitiser(2mg/kg, activated at
15 minutes)

• 430 nm or 690 nm
• Experiments to assess
• Effects on pancreas

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Duodenal PDT Histology
Mucosal ulceration
Loop of duodenum
Normal duodenum
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Duodenal collagen resistant to damage
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The Ideal of Mucosal Ablation

• Selective mucosal
• destruction
• Ambulatory therapy
• No side effects Strictures Photosensitivity Acu
  te Hypotension Buried glands

Verteporfin PDT Yes? Yes? 15
minutes 0? None? No? Very rare?
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Conclusions

• Optical methods might be developed to detect
  patients at highest risk
• New PDT approaches to treat HGD in BE
• Can optical methods be used to assess the outcome
  of PDT?