Transcript Endobronchialer Ultraschall

International Bronchoscopy Course/Istanbul 2006
Cryotherapy, Brachytherapy &
Photodynamic Therapie
R Eberhardt
Thoraxklinik am Universitätsklinikum Heidelberg
Internistische Onkologie der Thoraxtumoren - Thoraxchirurgie
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Pneumologie Thoraxklinik Heidelberg gGmbH
Thoraxklinik Heidelberg gGmbH
1885 tuberculosis hospital
since 1972 rebuild as a clinic for
lung and thoracic diseases
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Pneumologie Thoraxklinik Heidelberg gGmbH
Thoraxklinik Heidelberg gGmbH
► 4.000 – 5.000
procedures/year
► all interventional
procedures
► Endobronchial Ultrasound
► Thoracoscopy in LA
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
Photodynamic therapy
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
PDT: photodynamic therapy
based on the dye-sensitized photooxidation of biological
matter in the target tissue/tumor
ligth
photosensitizer
oxygen



the light and the chemical interaction leads to necrosis of
the tumor
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
ideal photosensitizer
►
►
►
►
►
►
high uptake in malignant tumors
low uptake in benign tissue
low phototoxicity
safe profile
effective cytotoxicity at appropiate wavelength
stable and easy to prepare and to administrate
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
Photofrin®
• porfimer sodium
• the only one on market
• dosification:
•
Photofrin® 2 mg/kg
•
wash out 48 h
•
tumor-to-normal tissue ratio
is maximal at 24-48 hours
•
illumination 100-800 mW
(400mW/cm length of diffuser for 500 sec.)
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
sensitizer concentration
►
drug is cleared from the most organs within 72 hours
►
it is retained in malignant cells and skin
►
concentration depends on :
►
►
►
sensitizer
tumor
time
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photofrin®
Absorption spectrum
►
peak absorption at
a wavelength of 405 nm
►
light (405nm) completely
absorbed at the tissue surface
►
using wavelength of 630 nm
►
penetration depth of
5-10 mm can be achieved
Wavelength (nm)
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
PDT: photodynamic therapy
1st step: i.v.-injection
2nd step: illumination
3rd step: cytotoxic effects
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
Illumination
to activate the
sensitizer at
the target tissue
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
Illumination
absorption and diffusion depend on:
•
tissue
•
photosensitizer
•
•
liver: poor penetration
brain: high penetration
Wilson 1986, Dougherty 1991
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
Illumination
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
Illumination
microlens fibres
for small tumors
and carcinoma in situ
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
Illumination
interstitial diffusing fibres
for big and obstructive
tumors
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
PDT: photodynamic therapy
► time of illumination
 5- 30 minutes
► Clean up-Bronchoscopy
 after 1-3 Tage
► 2. PDT during 2-7 days possible
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
Photodynamic therapy
Indications are visible malignant tumors for:
• cure
• palliation
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Data
Photodynamic therapy - PDT
Occult lung cancer*
**
Lesions
Results
CR (%)
Survival
Month
Monnier et al., 1990
16
69
3-60
Okunaka et al., 1991
27
98
38
Edell and Cortese, 1992
14
71
7-49
Furuse et al., 1993
59
83
14-32
Inamura et al., 1994
39
64
4-169
Sutedja et al., 1994
39
72
2-95
Cortese et al., 1997
21
53
12
* not visible in CT-Scan / **modified to Sutedja T 1996
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Data
Photodynamic therapy - PDT
PDT – Early Cancer
maximal extent
lesions
CR (%)
superficial type (123 lesions, 110 patients)
< 0,5 cm
64
61 (95)
< 1 cm
25
22 (88)
< 2,0 cm
20
9 (45)
> 2,0 cm
14
6 (43)
nodular type (45 lesions, 43 patients)
< 0,5 cm
29
27 (93)
< 1,0 cm
9
6 (67)
> 1,0 cm
7
1 (14)
Hayata Y et al. Lasers Med Sci 1996
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
Photodynamic Therapy
results (145 Pat., 191 tumors)
Stadium 0
99
Stadium IA
56
Squamos cell carcinoma
98%
CR
86%
Tumor size < 1 cm*
95%
Tumor size ≥ 2 cm
46%
Distal end visible+
92%
Distal end not visible
*/+
.
67%
98%
Recurences
13%
Long term response
75%
Mathur PN et al. Chest 2003; 123:176S-180S
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Pneumologie Thoraxklinik Heidelberg gGmbH
EBUS – Early Cancer
Early Cancer
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Pneumologie Thoraxklinik Heidelberg gGmbH
EBUS – Early Cancer
Early Cancer
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Pneumologie Thoraxklinik Heidelberg gGmbH
EBUS – Early Cancer
Miyazu Y et al., Am J Respir Crit Care Med, 2002
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Pneumologie Thoraxklinik Heidelberg gGmbH
EBUS – Early Cancer
Miyazu Y et al., Am J Respir Crit Care Med, 2002
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Pneumologie Thoraxklinik Heidelberg gGmbH
data
Photodynamic therapy - PDT
alternative to surgical resection
well tolerated und cost-effectiv
potentially curative treatment
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
PDT: for palliative
►
57% of the patients with non surgical tumors and 36% of
total will die for local problems
►
20-30% of patients with lung cancer will develope CAO and
up to 40% of lung cancer deaths may be attributed tp
locoregional disease
Carrol et al. Eur J Cancer Clin Oncol 1986;22:1352-56
Ernst et al. Respir Crit Care Med 2004; 169: 1278-1297
.
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Photodynamic therapy - PDT
Advanced stage lung cancer







12 articles, 636 patients
indication: severe bronchial obstruction
histology: mostly NSCLC
symptom relief: almost all patients (> 90%)
main complication: sunburn (- 28%)
fatal complication: haemoptysis (< 3%)
PDT is safe and effective
Moghissi K, Dixon K; Eur Respir J 2003; 22: 535-541.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
PDT: for palliative
Radiotherapy versus PDT
41 patients
► pdt+rdt: repermeabilization: 70% of pat.
► rdt only: repermeabilization: 10% of pat.
► no response: 20% of pat.
►
Lam et al; Proc Spie Proc 1991: pp20-28
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
PDT versus Nd-YAG-Laser
31 patients
►
airway obstruction >75% in 77,4%
14 PDT
► 17 ND-YAG-Laser resection
►
Diaz-Jimenez JP et al. Eur Respir J 1999; 14(4): 800-5
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
PDT versus Nd-YAG-Laser
► effectiveness similiar
► safety comparable
► Nd:YAG
 better initial response
 faster reobstruction
► PDT
 longer time until treatment failure
 longer medial survival (295 : 95 days)
 but: differences in tumor stage between the groups
Diaz-Jimenez JP et al. Eur Respir J 1999; 14(4): 800-5
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
Indications
• dysplasia: no formal indication
• carcinoma in situ: prior
• microinvasive carcinoma : optional
• invasive carcinoma : palliative
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
Limitations
•
size and location of tumor
•
48h waiting after injection
•
2-3 days for tumoral necrosis
•
phototoxicity
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
Contraindications
specifics:
previous pneumonectomy
invasion of big vessels
bilateral obstructión main carina
general:
porfiria or porfirin allergy
leucos < 2.000
platelets < 100.000
TP > 1,5 of normal
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
Complications
•
•
•
•
•
•
dyspnea*
worsening obstruction*
fever 20%
massive haemorrhage 2,2%
minors 0,5%
sun light photosensitivity 5-28%
* usually resolved after clean-upbronchoscopy
Moghissi K, Dixon K; Eur Respir J 2003; 22: 535-541.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Photodynamic therapy - PDT
Estimation
• effectiv in relatively non invasive, limited and
superficial lesions with visible margins
• suitable in:
• Carcinoma in situ
• microinvasive cancer
• severe dysplasia
• clear indication in inoperable patients
• debatetable as first-line, when surgery is refused
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Brachytherapy
Brachytherapy
.
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Iridium192 HDR
endobronchial irradiation
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Pneumologie Thoraxklinik Heidelberg gGmbH
Brachytherapy
Brachytherapy
high dose rate (HDR) = > 2 Gy/min
Iridium192 half-life = 74,5 days
1 cm
dose 15 – 47 Gy (messured in 10mm)
1– 5 sessions
duration 1 – 10 min
.
3cm
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Pneumologie Thoraxklinik Heidelberg gGmbH
Brachytherapy
Enforcement
dose (HDR) palliative intent (10mm):
only Brachytherapy: 4 x 6 Gy or 3 x 7,5 Gy or 2 x 10 Gy
Brachytherapy for Boost: 4 x 4 Gy or 3 x 5 Gy or 2 x 7,5 Gy
> sufficient distance between probe and tissue
> radiation > 2cm over proximal and distal end
American Brachytherapy Society
Brachytherapy for Carcinoma of the Lung, Oncology 2001
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Brachytherapy
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Brachytherapy
After loading
technique
blind-tipped catheter
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
data
Brachytherapy
Nd-YAG vs. Nd-YAG+Brachytherapie
Nd-YAG
Nd-YAG
+ EBBT
15
14
+ 810
+ 890
n.s.
- 3,4
- 4,2
n.s.
Survival (month)
7,4
10,3
n.s.
Time to progression (month)
2,2
7,5
<0,05
Numbers of interventional treatments (n)
15
3
<0,05
N = 29 randomized/NSCLC
•
N
FEV1 (ml)
Stenosis (Speiser‘s index)
p
Chella-A et al, Lung Cancer 2000
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Pneumologie Thoraxklinik Heidelberg gGmbH
data
Brachytherapy
External Radiation +/- Brachytherapy
2x 4,8 Gy - randomized
•
p = 0.42
survival
p = 0.007
.
time to progression
Huber-RM et al, Int J Radiation Oncology Biol Phys 1997
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data
Brachytherapy
Brachytherapie – Early cancer
Author
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Year
modus
n
follow up
[Jahre]
CR
Rezidiv
Edell
1990
PDT
21
2
71%
48%
Edell
1993
PDT
58
5
84%
39%
Imamura
1994
PDT
29
2
64%
36%
Lam
1998
PDT
102
5
78%
44%
Tredaniel
1994
EBBT
29
2
Perol
1997
EBBT
19
1
83%
25%
Marsiglia
2000
EBBT
34
2
85%
35%
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Pneumologie Thoraxklinik Heidelberg gGmbH
PDT plus Brachytherapy
Sequential photodynamic therapy (PDT) and high dose
brachytherapy for endobronchial tumour control in patients
with limited bronchogenic carcinoma
PDT
2 mg/kg Photofrin® i.v.
HDR-Brachytherapie
after 5 – 6 weeks
Iridium 192 - 4 Gy weekly up to 20 Gy
Follow Up
Bronchoscopy every 3 month
Freitag L, Ernst A, Thomas M, Prenzel R, Wahlers B, Macha HN
Thorax 2004; 59:790-793
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
PDT plus Brachytherapy
PDT
• CR 75 %
Brachytherapy
• 31/32 Pat. without histological proof of tumor
• response rate 97 %
• recurrence in 6/32 (19 %)
• than lokal therapy or external radiation allowed
Follow Up
• all patients are living after 24 month (3-46 month )
.
Freitag L, Ernst A, Thomas M, Prenzel R, Wahlers B, Macha HN
Thorax 2004; 59:790-793
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
PDT plus Brachytherapy
Sequential photodynamic therapy (PDT) and high dose
brachytherapy for endobronchial tumour control in
patients with limited bronchogenic carcinoma
• results are surprisingly good
• long time survival and tumor controll seems to be
better than PDT or EBBT alone
• no severe complications
• prospective randomized study necessary
.
Freitag L, Ernst A, Thomas M, Prenzel R, Wahlers B, Macha HN
Thorax 2004; 59:790-793
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Brachytherapy
Complications
• acute bronchitis
• fistula
• stenosis
• fatal/letal hemorhaghe
• up to 42 %
• risk factors:
• infiltration of the big vessels
• upper Lobe
• external beam radiation prior
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Brachytherapy
Brachytherapy
•
Endoluminal and intramural tumors
•
Complementary to other endoscopic treatments
•
local long time response
•
Possible after ERT
•
Outpatient basis
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Brachytherapy
Brachytherapy
• Delayed effect (weeks)
• Several sessions
• No emergencies
• Expensive
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Cryotherapy
Cryotherapy
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Cryotherapy
Cryotherapy
► Liquid nitrous oxide N2O (-800C)
► Ice ball (-400C)
► flexible/rigid probe
► tissue freezing
► selective cellular necrosis
► elimination of vascularization
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Cryotherapy
Cryotherapy
physical effect
 immediate
 freezing and recrystallization
of water on thawing
 celluar dehydration
vascular effect
 results in tissue ischemia
from vasoconstriction
 platelet aggregation
 increased blood viscosity
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Cryotherapy
Cryo-probe
Joule-Thompson effect
high pressure
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cooling
effect
atmospheric
pressure
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Pneumologie Thoraxklinik Heidelberg gGmbH
Cryotherapy
Cryoprobe
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Cryotherapy
The effects of freeze injury
depend on the
► rate of freezing and rewarming
► effect depends on rapidity of freezing and thawing
 rapid cooling
 slow thawing
► the lowest temperature achieved
► number of sessions
► cryosensitivity of the tissue (water content)
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Cryotherapy
cryosensitive
►
►
►
►
►
skin
mucous membranes
nerve cells
granulation tissue
vascular endothelium
cryorestistant
►
►
►
►
►
nerve sheats
fibrous tissue
connective tissue
cartilage
fat tissue
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Cryotherapy
How to do it ...
Cryoprobe
Iceball
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Cryotherapy
How to do it ...
•
Cryoprobe
o
Iceball
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Cryotherapy
Indications
►



Ablation
malignant tumors
benigne tumors
stent-over-growth
►
curable intent in early lung cancer
►
bleeding
►
foreign bodys
►
recanalization immediately ?
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Cryotherapy
Cryotherapy in advanced
bronchial carcinoma
► 33
patients/81 sessions
 improvement in lung function 58%
 relief of bronchial obstruction 77%
Walsh DA et al. Thorax 1990
► 172
patients/344 sessions
 improvement in dyspnoe 50,5%
 10% increase in Karnofsky index all over
Asimakopoulus G Chest 2005
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Pneumologie Thoraxklinik Heidelberg gGmbH
Cryotherapy
Cryotherapy in early superficial
bronchogenic carcinoma
►
►
35 patients
41 cancers
►
complete response in 91%
recurrence rate of 28% within 4 years
long term response of 63%
►
results comparable to PDT??
►
►
Deygas N Chest 2001; 120: 26-31
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Cryotherapy
Recanalization
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Cryotherapy
Recanalization
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Cryotherapy
Contraindication
Central airway obstruction and respiratory failure
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Pneumologie Thoraxklinik Heidelberg gGmbH
Cryotherapy
Advantages
►
No risk of perforation
►
No risk of firing
►
Cheap
►
Very easy to learn


contact mode
tactile feed-back
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Cryotherapy
Limits and Drawbacks
►
Delayed effect – no emergencies
►
Depth of effect is limited – several sessions
►
Cannot achieve vaporisation of tissue
►
Coagulation of highly vascularised tissue is not
achieved as quickly as with the laser or with
electrocautery
►
Section of webs (PITS) is impossible
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
International Bronchoscopy Course/Istanbul 2006
Early cancer
Data inhomogenous, but ...




R Eberhardt
if operable
if not or refused
if larger
alternatives
resection
PDT
PDT + brachytherapy
cryotherapy
brachytherapy,
electrocautery
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Pneumologie Thoraxklinik Heidelberg gGmbH
central airway obstruction
advanced lung cancer
immediate effect
• Laser Resection
• Electrocautery
• Argon Plasma Coagulation
• Cryotherapy?
delayed effect
• Brachytherapy
• Photodynamic therapy
• Cryotherapy
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
central airway obstruction
advanced lung cancer
Laser
+
0
++
++
0
++
0
+++
++
APC
Brachytherapy
Cryotherapy
PDT
Stents
endoluminal
extraluminal
mixed
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
central airway obstruction
advanced lung cancer
►
no randomized trials
►
the best therpeutic approach will be the
combination of several treatment
approaches
.
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International Bronchoscopy Course/Istanbul 2006
Thank you for your attention …
[email protected]
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Pneumologie Thoraxklinik Heidelberg gGmbH
International Bronchoscopy Course/Istanbul 2006
[email protected]
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Pneumologie Thoraxklinik Heidelberg gGmbH
Cryotherapy
Cooling agents
► Chlorofluoracarbons (CFCs)
 damage the ozone layer
► Carbon dioxide (CO2)
 CO2 snow obstructs the cryoprobe
► Lliquid nitrogen (LN2)
► Nitrous oxide (NO2)
 commonest used agent
.
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Pneumologie Thoraxklinik Heidelberg gGmbH
Brachytherapie + externe Radiatio
n = 95, unbehandelte Patienten mit NSCLC, Stadium I - IIIB
30 oder 60 Gy perkutan ± 2 x 7,5 Gy endoluminal
randomisiert
76
Langendijk-JA et al, Radiotherapy and Oncology 2001
PDT und Brachytherapie bei
limitiertem BC
► zwischen
4/95 und 11/98 32 Patienten
► mit
► primärem
inoperablen Bronchialkarzinom (n=15)
► oder einem Rezidiv (n=17)
► begrenzt auf zentrale Atemwege
 CT und
 Bronchoskopie mit Weißlicht und Autofluoreszenz sowie
 Biopsien vom Tumor und den Grenzen
► Ausdehnung
nach Länge, Weite und Erhabenheit über die
Oberfläche
► histologisch ganz überwiegend Plattenepithelkarzinome (30 von
32)
77
Brachytherapy
.
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