1 Cryotherapy, Brachytherapy & Photodynamic Therapie R Eberhardt Thoraxklinik am...

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Cryotherapy, Brachytherapy Cryotherapy, Brachytherapy & Photodynamic Therapie& Photodynamic Therapie

R EberhardtR Eberhardt

Thoraxklinik am Universitätsklinikum HeidelbergThoraxklinik am Universitätsklinikum HeidelbergInternistische Onkologie der Thoraxtumoren - ThoraxchirurgieInternistische Onkologie der Thoraxtumoren - Thoraxchirurgie

R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH

International Bronchoscopy Course/Istanbul 2006

2R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH

Thoraxklinik Heidelberg gGmbH

1885 tuberculosis hospital1885 tuberculosis hospitalsince 1972 rebuild as a clinic forsince 1972 rebuild as a clinic forlung and thoracic diseaseslung and thoracic diseases


► 4.000 – 5.000 procedures/year

► all interventional procedures

► Endobronchial Ultrasound

► Thoracoscopy in LA

Thoraxklinik Heidelberg gGmbH


Photodynamic therapy - PDT

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Photodynamic therapyPhotodynamic therapy



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based on the dye-sensitized photooxidation of based on the dye-sensitized photooxidation of biological matter in the target tissue/tumorbiological matter in the target tissue/tumor

ligthligth photosensitizerphotosensitizer oxygenoxygen

the light and the chemical interaction leads to the light and the chemical interaction leads to necrosis of the tumornecrosis of the tumor

PDT: photodynamic therapyPDT: photodynamic therapy



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ideal photosensitizerideal photosensitizer

► high uptake in malignant tumorshigh uptake in malignant tumors► low uptake in benign tissuelow uptake in benign tissue► low phototoxicitylow phototoxicity► safe profilesafe profile► effective cytotoxicity at appropiate effective cytotoxicity at appropiate

wavelengthwavelength► stable and easy to prepare and to stable and easy to prepare and to

administrateadministrate


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PhotofrinPhotofrin®®

• 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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sensitizer concentrationsensitizer concentration

► drug is cleared from the most organs within 72 drug is cleared from the most organs within 72 hourshours

► it is retained in malignant cells it is retained in malignant cells andand skin skin

► concentration depends on concentration depends on : :

► sensitizersensitizer ► tumortumor► timetime


Photofrin®

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Absorption spectrum Absorption spectrum

► peak absorption atpeak absorption ata wavelength of 405 nma wavelength of 405 nm

► light (405nm) completelylight (405nm) completelyabsorbed at the tissue surfaceabsorbed at the tissue surface

► using wavelength of 630 nmusing wavelength of 630 nm

► penetration depth of penetration depth of 5-10 mm can be achieved5-10 mm can be achieved

Wavelength (nm)



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11stst stepstep: i.v.-injec: i.v.-injecttiioonn

22ndnd stepstep: : illuminationillumination

33rdrd stepstep: : cytotoxic effectscytotoxic effects



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IlluminationIllumination

to activate the sensitizer at the target tissue



Wilson 1986, Dougherty 1991

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absorption and diffusion depend on:

• tissue• liver: poor penetration• brain: high penetration

• photosensitizer



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microlens fibresfor small tumors and carcinoma in situ



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interstitial diffusing fibresfor big and obstructive tumors




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► time of illuminationtime of illumination 5- 30 minutes5- 30 minutes

► Clean up-BronchoscopyClean up-Bronchoscopy after 1-3 Tageafter 1-3 Tage

► 2. PDT during 2-7 days possible2. PDT during 2-7 days possible




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Photodynamic therapyPhotodynamic therapy

Indications are visible malignant tumors for:

• cure

• palliation


Data Photodynamic therapy - PDT

* not visible in CT-Scan / **modified to Sutedja T 1996* not visible in CT-Scan / **modified to Sutedja T 1996

Occult lung cancer* 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


Data Photodynamic therapy - PDT

Hayata Y et al. Lasers Med Sci 1996Hayata Y et al. Lasers Med Sci 1996

PDT – Early CancerPDT – Early Cancermaximal 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)



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Photodynamic TherapyPhotodynamic Therapyresults (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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Early CancerEarly Cancer


EBUS – Early Cancer

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Early CancerEarly Cancer





Miyazu Y et al., Am J Respir Crit Care Med, 2002



Miyazu Y et al., Am J Respir Crit Care Med, 2002


data Photodynamic therapy - PDT

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alternative to surgical alternative to surgical resectionresection

well tolerated und cost-well tolerated und cost-effectiveffectiv

potentially curative potentially curative treatmenttreatment



Carrol et al. Eur J Cancer Clin Oncol 1986;22:1352-56Carrol et al. Eur J Cancer Clin Oncol 1986;22:1352-56

Ernst et al. Respir Crit Care Med 2004; 169: 1278-1297Ernst et al. Respir Crit Care Med 2004; 169: 1278-1297

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► 57% 57% of the patients with non surgical tumors and of the patients with non surgical tumors and 36% 36% of of total will total will die for local problemsdie for local problems

► 20-30% of patients with lung cancer will develope 20-30% of patients with lung cancer will develope CAO and up to 40% of lung cancer deaths may be CAO and up to 40% of lung cancer deaths may be attributed tp locoregional diseaseattributed tp locoregional disease

PDT: for palliativePDT: for palliative



12 articles, 636 patients12 articles, 636 patients indication: severe bronchial obstructionindication: severe bronchial obstruction histology: mostly NSCLChistology: mostly NSCLC symptom relief: almost all patients (> 90%) symptom relief: almost all patients (> 90%) main complication: sunburn (- 28%)main complication: sunburn (- 28%) fatal complication: haemoptysis (< 3%)fatal complication: haemoptysis (< 3%) PDT is safe and effectivePDT is safe and effective

Advanced stage lung cancerAdvanced stage lung cancer

Moghissi K, Dixon K; Eur Respir J 2003; 22: 535-541.Moghissi K, Dixon K; Eur Respir J 2003; 22: 535-541.



Lam et al; Proc Spie Proc 1991: pp20-28Lam et al; Proc Spie Proc 1991: pp20-28

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RadiotRadiothheraperapyy versus PDT versus PDT

► 41 patients41 patients► pdt+rdt: repermeabilization: 70% of pat.pdt+rdt: repermeabilization: 70% of pat.► rdt only: repermeabilization: 10% of pat.rdt only: repermeabilization: 10% of pat.► no response: 20% of pat.no response: 20% of pat.

PDT: for palliativePDT: for palliative



Diaz-Jimenez JP et al. Eur Respir J 1999; 14(4): 800-5Diaz-Jimenez JP et al. Eur Respir J 1999; 14(4): 800-5

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31 patients31 patients

► airway obstruction >75% in 77,4%airway obstruction >75% in 77,4%

► 14 PDT 14 PDT ► 17 ND-YAG-Laser resection17 ND-YAG-Laser resection

PDT versus Nd-YAG-LaserPDT versus Nd-YAG-Laser



Diaz-Jimenez JP et al. Eur Respir J 1999; 14(4): 800-5Diaz-Jimenez JP et al. Eur Respir J 1999; 14(4): 800-5

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► effectiveness similiareffectiveness similiar► safety comparablesafety comparable► Nd:YAG Nd:YAG

better initial responsebetter initial response faster reobstruction faster reobstruction

► PDT PDT longer time until treatment failurelonger time until treatment failure longer medial survival (295 : 95 days)longer medial survival (295 : 95 days) but: differences in tumor stage between the groupsbut: differences in tumor stage between the groups

PDT versus Nd-YAG-LaserPDT versus Nd-YAG-Laser



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IndicationsIndications

• dysplasia: no formal indication

• carcinoma in situ: prior

• microinvasive carcinoma : optional

• invasive carcinoma : palliative



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LimitationsLimitations

• size and location of tumor

• 48h waiting after injection

• 2-3 days for tumoral necrosis

• phototoxicity



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ContraindicationsContraindications

specifics:previous pneumonectomyinvasion of big vesselsbilateral obstructión main carina

general:porfiria or porfirin allergyleucos < 2.000platelets < 100.000 TP > 1,5 of normal



Moghissi K, Dixon K; Eur Respir J 2003; 22: 535-541.Moghissi K, Dixon K; Eur Respir J 2003; 22: 535-541.

ComplicationsComplications

• dyspnea*• worsening obstruction*• fever 20%• massive haemorrhage 2,2%• minors 0,5%• sun light photosensitivity 5-28%

* usually resolved after clean-upbronchoscopy



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EstimationEstimation• effectiv in relatively non invasive, limited and effectiv in relatively non invasive, limited and superficial lesions with visible margins superficial lesions with visible margins

• suitable in: suitable in: • Carcinoma in situCarcinoma in situ• microinvasive cancermicroinvasive cancer• severe dysplasiasevere dysplasia

• clear indication in inoperable patientsclear indication in inoperable patients

• debatetable as first-line, when surgery is debatetable as first-line, when surgery is refusedrefused


Brachytherapy

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BrachytherapyBrachytherapy

IridiumIridium192192 HDR HDR endobronchial irradiationendobronchial irradiation


Brachytherapy

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high dose rate (HDR) = > 2 Gy/min

Iridium192 half-life = 74,5 days

dose 15 – 47 Gy (messured in 10mm)

1– 5 sessions

duration 1 – 10 min

1 cm

30

Gy

7.5

Gy

3.3

Gy

3cm


Brachytherapy

American Brachytherapy Society Brachytherapy for Carcinoma of the Lung, Oncology 2001

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Enforcement 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


Brachytherapy

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Brachytherapy

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blind-tipped catheterblind-tipped catheter

After After loading loading techniquetechnique


data Brachytherapy

Chella-A et al, Lung Cancer 2000

Nd-YAG vs. Nd-YAG+Brachytherapie

• N = 29 randomized/NSCLC Nd-YAG

Nd-YAG + EBBT p

N 15 14

FEV1 (ml) + 810 + 890 n.s.

Stenosis (Speiser‘s index) - 3,4 - 4,2 n.s.

Survival (month) 7,4 10,3 n.s.

Time to progression (month) 2,2 7,5<0,0

5

Numbers of interventional treatments (n) 15 3 <0,0

5


data Brachytherapy

External Radiation +/- Brachytherapy 2x 4,8 Gy -

randomized•

p = 0.42 p = 0.007

survival . time to progression

Huber-RM et al, Int J Radiation Oncology Biol Phys 1997


data Brachytherapy

Brachytherapie – Early cancer

Author 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%


PDT plus Brachytherapy

Freitag L, Ernst A, Thomas M, Prenzel R, Wahlers B, Macha HNFreitag L, Ernst A, Thomas M, Prenzel R, Wahlers B, Macha HNThorax 2004; 59:790-793Thorax 2004; 59:790-793

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Sequential photodynamic therapy (PDT) and high dose Sequential photodynamic therapy (PDT) and high dose brachytherapy for endobronchial tumour control in brachytherapy for endobronchial tumour control in

patients with limited bronchogenic carcinomapatients with limited bronchogenic carcinoma

PDT PDT 2 mg/kg Photofrin® i.v.

HDR-BrachytherapieHDR-Brachytherapieafter 5 – 6 weeksIridium 192 - 4 Gy weekly up to 20 Gy

Follow UpFollow UpBronchoscopy every 3 month



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PDTPDT• CR 75 %

Brachytherapy 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 Follow Up • all patients are living after 24 month (3-46 all patients are living after 24 month (3-46 month )month )Freitag L, Ernst A, Thomas M, Prenzel R, Wahlers B, Macha HNFreitag L, Ernst A, Thomas M, Prenzel R, Wahlers B, Macha HN

Thorax 2004; 59:790-793Thorax 2004; 59:790-793

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• results are surprisingly goodresults are surprisingly good

• long time survival and tumor controll seems to long time survival and tumor controll seems to bebe better than PDT or EBBT alone better than PDT or EBBT alone

• no severe complicationsno severe complications

• prospective randomized study necessaryprospective randomized study necessaryFreitag L, Ernst A, Thomas M, Prenzel R, Wahlers B, Macha HNFreitag L, Ernst A, Thomas M, Prenzel R, Wahlers B, Macha HNThorax 2004; 59:790-793Thorax 2004; 59:790-793

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Sequential photodynamic therapy (PDT) and high Sequential photodynamic therapy (PDT) and high dose brachytherapy for endobronchial tumour dose brachytherapy for endobronchial tumour control in patients with limited bronchogenic control in patients with limited bronchogenic

carcinomacarcinoma


Brachytherapy

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Complications Complications

• acute bronchitis

• fistula

• stenosis

• fatal/letal hemorhaghe• up to 42 %• risk factors:

• infiltration of the big vessels• upper Lobe• external beam radiation prior


Brachytherapy

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• Endoluminal and intramural tumorsEndoluminal and intramural tumors

• Complementary to other endoscopic Complementary to other endoscopic treatmentstreatments

• local long time response local long time response

• Possible after ERTPossible after ERT

• Outpatient basisOutpatient basis


Brachytherapy

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• Delayed effect (weeks)Delayed effect (weeks)

• Several sessionsSeveral sessions

• No emergenciesNo emergencies

• ExpensiveExpensive


Cryotherapy

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CryotherapyCryotherapy


Cryotherapy

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► Liquid nitrous oxide NLiquid nitrous oxide N22O (-80O (-8000C)C)

► Ice ball (-40Ice ball (-4000C)C)

► flexible/rigid probeflexible/rigid probe

► tissue freezingtissue freezing► selective cellular necrosisselective cellular necrosis► elimination of vascularizationelimination of vascularization


Cryotherapy

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physical effectphysical effect immediateimmediate freezing and recrystallization freezing and recrystallization

of water on thawingof water on thawing celluar dehydrationcelluar dehydration

vascular effectvascular effect results in tissue ischemia results in tissue ischemia

from vasoconstrictionfrom vasoconstriction platelet aggregationplatelet aggregation increased blood viscosityincreased blood viscosity


Cryotherapy

Joule-Thompson effectJoule-Thompson effect

Cryo-probeCryo-probe

high pressure

atmosphericpressurecooling

effect


Cryotherapy

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CryoprobeCryoprobe


Cryotherapy

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The effects of freeze injury depend on the

► rate of freezing and rewarming

► effect depends on rapidity of freezing and thawingeffect depends on rapidity of freezing and thawing rapid coolingrapid cooling slow thawingslow thawing

► the lowest temperature achievedthe lowest temperature achieved

► number of sessionsnumber of sessions

► cryosensitivity of the tissue (water content)


Cryotherapy

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cryosensitive cryosensitive cryorestistantcryorestistant

► skin► mucous

membranes► nerve cells► granulation tissue► vascular

endothelium

► nerve sheats► fibrous tissue► connective tissue► cartilage► fat tissue


Cryotherapy

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How to do it ...How to do it ...

CryoproCryoprobebe

IceballIceball


Cryotherapy

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How to do it ...How to do it ...

• Cryoprobe Cryoprobe

o IceballIceball


Cryotherapy

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IndicationsIndications

► AblationAblation malignant tumorsmalignant tumors benigne tumorsbenigne tumors stent-over-growthstent-over-growth

► curable intent in early lung cancer curable intent in early lung cancer

► bleedingbleeding

► foreign bodysforeign bodys

► recanalizationrecanalization immediately ?immediately ?


Cryotherapy

Cryotherapy in advanced Cryotherapy in advanced bronchial carcinomabronchial carcinoma

► 33 patients/81 sessions33 patients/81 sessions improvement in lung function 58%improvement in lung function 58% relief of bronchial obstruction 77%relief of bronchial obstruction 77%Walsh DA et al. Thorax 1990Walsh DA et al. Thorax 1990

► 172 patients/344 sessions172 patients/344 sessions improvement in dyspnoe 50,5%improvement in dyspnoe 50,5% 10% increase in Karnofsky index all over10% increase in Karnofsky index all overAsimakopoulus G Chest 2005Asimakopoulus G Chest 2005


Cryotherapy

Cryotherapy in early superficial Cryotherapy in early superficial bronchogenic carcinomabronchogenic carcinoma

► 35 patients35 patients► 41 cancers41 cancers

► complete response in 91%complete response in 91%► recurrence rate of 28% within 4 yearsrecurrence rate of 28% within 4 years► long term response of 63%long term response of 63%

► results comparable to PDT?? results comparable to PDT??

Deygas N Chest 2001; 120: 26-31Deygas N Chest 2001; 120: 26-31


Cryotherapy

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RecanalizationRecanalization


Cryotherapy

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RecanalizationRecanalization


Cryotherapy

Central airway obstruction and respiratory Central airway obstruction and respiratory failurefailure

ContraindicationContraindication

NO NO

CRYO !CRYO !


Cryotherapy

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AdvantagesAdvantages

► No risk of perforation No risk of perforation

► No risk of firing No risk of firing

► CheapCheap

► Very easy to learnVery easy to learn

contact modecontact mode tactile feed-backtactile feed-back


Cryotherapy

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Limits and DrawbacksLimits and Drawbacks

► Delayed effect – no emergencies Delayed effect – no emergencies

► Depth of effect is limited – several sessionsDepth of effect is limited – several sessions

► Cannot achieve vaporisation of tissue Cannot achieve vaporisation of tissue

► Coagulation of highly vascularised tissue is notCoagulation of highly vascularised tissue is not achieved as quickly as with the laser or with achieved as quickly as with the laser or with electrocautery electrocautery

► Section of webs (PITS) is impossibleSection of webs (PITS) is impossible

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Early cancerEarly cancer


Data inhomogenous, but ...Data inhomogenous, but ...

if operableif operable resectionresection if not or refusedif not or refused PDTPDT if largerif larger PDT + brachytherapyPDT + brachytherapy alternativesalternatives cryotherapycryotherapy

brachytherapy, brachytherapy, electrocauteryelectrocautery



central airway obstruction

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immediate effectimmediate effect• Laser ResectionLaser Resection• ElectrocauteryElectrocautery• Argon Plasma CoagulationArgon Plasma Coagulation• Cryotherapy?Cryotherapy?

delayed effectdelayed effect• BrachytherapyBrachytherapy• Photodynamic therapyPhotodynamic therapy• CryotherapyCryotherapy

advanced lung canceradvanced lung cancer



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LaserLaser

APCAPC

BrachytheraBrachytherapypy


PDTPDT

StentsStents

+ 0 +++ 0 ++

++ 0 ++++ 0 ++

0 +++ ++0 +++ ++

endoluminal extraluminal endoluminal extraluminal mixedmixed




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► no randomized trialsno randomized trials

► the best therpeutic approach will be the best therpeutic approach will be thethe combination of several treatment combination of several treatment approaches approaches

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Thank you for your attention …Thank you for your attention …


[email protected]



[email protected]



Cryotherapy

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Cooling agentsCooling 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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n = 95, unbehandelte Patienten mit NSCLC, Stadium I - IIIB 30 oder 60 Gy perkutan ± 2 x 7,5 Gy endoluminal

randomisiert

Langendijk-JA et al, Radiotherapy and Oncology 2001

Brachytherapie + externe Radiatio

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PDT und Brachytherapie bei PDT und Brachytherapie bei limitiertem BClimitiertem BC

► zwischen 4/95 und 11/98 32 Patientenzwischen 4/95 und 11/98 32 Patienten► mit mit

► primärem inoperablen Bronchialkarzinom (n=15) primärem inoperablen Bronchialkarzinom (n=15) ► oder einem Rezidiv (n=17)oder einem Rezidiv (n=17)► begrenzt auf zentrale Atemwegebegrenzt auf zentrale Atemwege

CT und CT und Bronchoskopie mit Weißlicht und Autofluoreszenz sowieBronchoskopie mit Weißlicht und Autofluoreszenz sowie Biopsien vom Tumor und den GrenzenBiopsien vom Tumor und den Grenzen

► Ausdehnung nach Länge, Weite und Erhabenheit über Ausdehnung nach Länge, Weite und Erhabenheit über die Oberflächedie Oberfläche

► histologisch ganz überwiegend Plattenepithelkarzinome histologisch ganz überwiegend Plattenepithelkarzinome (30 von 32)(30 von 32)


Brachytherapy

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