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1 Cryotherapy, Brachytherapy & Photodynamic Therapie R Eberhardt Thoraxklinik am Universitätsklinikum Heidelberg Internistische Onkologie der Thoraxtumoren.

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Presentation on theme: "1 Cryotherapy, Brachytherapy & Photodynamic Therapie R Eberhardt Thoraxklinik am Universitätsklinikum Heidelberg Internistische Onkologie der Thoraxtumoren."— Presentation transcript:

1 1 Cryotherapy, Brachytherapy & Photodynamic Therapie R Eberhardt Thoraxklinik am Universitätsklinikum Heidelberg Internistische Onkologie der Thoraxtumoren - Thoraxchirurgie R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH International Bronchoscopy Course/Istanbul 2006

2 2 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Thoraxklinik Heidelberg gGmbH 1885 tuberculosis hospital since 1972 rebuild as a clinic for lung and thoracic diseases

3 3 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH ► ► – procedures/year ► ► all interventional procedures ► ► Endobronchial Ultrasound ► ► Thoracoscopy in LA Thoraxklinik Heidelberg gGmbH

4 4 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Photodynamic therapy - PDT. Photodynamic therapy

5 5 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Photodynamic therapy - PDT. 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 PDT: photodynamic therapy

6 6 R Eberhardt 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

7 7 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH. 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 hours illumination mW (400mW/cm length of diffuser for 500 sec.) Photodynamic therapy - PDT

8 8 R Eberhardt 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

9 9 R Eberhardt 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)

10 10 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Photodynamic therapy - PDT. 1 st step: i.v.-injection 2 nd step: illumination 3 rd step: cytotoxic effects PDT: photodynamic therapy

11 11 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH. Illumination to activate the sensitizer at the target tissue Photodynamic therapy - PDT

12 12 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Wilson 1986, Dougherty Illumination absorption and diffusion depend on: tissue liver: poor penetration brain: high penetration photosensitizer Photodynamic therapy - PDT

13 13 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH. Illumination Photodynamic therapy - PDT

14 14 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH. Illumination microlens fibres for small tumors and carcinoma in situ Photodynamic therapy - PDT

15 15 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH. Illumination interstitial diffusing fibres for big and obstructive tumors Photodynamic therapy - PDT

16 16 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Photodynamic therapy - PDT. ► time of illumination  minutes ► Clean up-Bronchoscopy  after 1-3 Tage ► 2. PDT during 2-7 days possible PDT: photodynamic therapy

17 17 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Photodynamic therapy - PDT.

18 18 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Photodynamic therapy - PDT.

19 19 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Photodynamic therapy - PDT. Photodynamic therapy Indications are visible malignant tumors for: cure palliation

20 20 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Data Photodynamic therapy - PDT * not visible in CT-Scan / **modified to Sutedja T 1996 Occult lung cancer* **LesionsResults CR (%) Survival Month Monnier et al., Okunaka et al., Edell and Cortese, Furuse et al., Inamura et al., Sutedja et al., Cortese et al.,

21 21 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Data Photodynamic therapy - PDT Hayata Y et al. Lasers Med Sci 1996 PDT – Early Cancer maximal extentlesionsCR (%) superficial type (123 lesions, 110 patients) < 0,5 cm6461 (95) < 1 cm2522 (88) < 2,0 cm209 (45) > 2,0 cm146 (43) nodular type (45 lesions, 43 patients) < 0,5 cm2927 (93) < 1,0 cm96 (67) > 1,0 cm71 (14)

22 22 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Photodynamic therapy - PDT. Photodynamic Therapy results (145 Pat., 191 tumors) Stadium 099 Stadium IA56 Squamos cell carcinoma98% CR86% Tumor size < 1 cm*95% Tumor size ≥ 2 cm46% Distal end visible+92% Distal end not visible67% */+98% Recurences13% Long term response75% Mathur PN et al. Chest 2003; 123:176S-180S

23 23 Early Cancer R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH EBUS – Early Cancer

24 24 Early Cancer R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH EBUS – Early Cancer

25 25 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH EBUS – Early Cancer Miyazu Y et al., Am J Respir Crit Care Med, 2002

26 26 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH EBUS – Early Cancer Miyazu Y et al., Am J Respir Crit Care Med, 2002

27 27 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH data Photodynamic therapy - PDT. alternative to surgical resection well tolerated und cost-effectiv potentially curative treatment

28 28 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Photodynamic therapy - PDT Carrol et al. Eur J Cancer Clin Oncol 1986;22: Ernst et al. Respir Crit Care Med 2004; 169: ► 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 PDT: for palliative

29 29 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Photodynamic therapy - PDT  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 Advanced stage lung cancer Moghissi K, Dixon K; Eur Respir J 2003; 22:

30 30 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Photodynamic therapy - PDT Lam et al; Proc Spie Proc 1991: pp Radiotherapy versus PDT ► 41 patients ► pdt+rdt: repermeabilization: 70% of pat. ► rdt only: repermeabilization: 10% of pat. ► no response: 20% of pat. PDT: for palliative

31 31 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Photodynamic therapy - PDT Diaz-Jimenez JP et al. Eur Respir J 1999; 14(4): patients ► airway obstruction >75% in 77,4% ► 14 PDT ► 17 ND-YAG-Laser resection PDT versus Nd-YAG-Laser

32 32 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Photodynamic therapy - PDT Diaz-Jimenez JP et al. Eur Respir J 1999; 14(4): ► 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 PDT versus Nd-YAG-Laser

33 33 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Photodynamic therapy - PDT. Indications dysplasia: no formal indication carcinoma in situ: prior microinvasive carcinoma : optional invasive carcinoma : palliative

34 34 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Photodynamic therapy - PDT. Limitations size and location of tumor 48h waiting after injection 2-3 days for tumoral necrosis phototoxicity

35 35 R Eberhardt 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 < platelets < TP > 1,5 of normal

36 36 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Photodynamic therapy - PDT Moghissi K, Dixon K; Eur Respir J 2003; 22: Complications dyspnea* worsening obstruction* fever 20% massive haemorrhage 2,2% minors 0,5% sun light photosensitivity 5-28% * usually resolved after clean-upbronchoscopy

37 37 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Photodynamic therapy - PDT. Estimation effectiv in relatively non invasive, limited and superficial lesions with visible margins suitable in: suitable in: Carcinoma in situ Carcinoma in situ microinvasive cancer microinvasive cancer severe dysplasia severe dysplasia clear indication in inoperable patients clear indication in inoperable patients debatetable as first-line, when surgery is refused debatetable as first-line, when surgery is refused

38 38 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Brachytherapy. Brachytherapy Iridium 192 HDR endobronchial irradiation

39 39 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Brachytherapy. Brachytherapy high dose rate (HDR) = > 2 Gy/min Iridium 192 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

40 40 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Brachytherapy American Brachytherapy Society Brachytherapy for Carcinoma of the Lung, Oncology 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

41 41 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Brachytherapy.

42 42 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Brachytherapy. blind-tipped catheter After loading technique

43 43 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH 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 N1514 FEV1 (ml) n.s. Stenosis (Speiser‘s index)- 3,4- 4,2n.s. Survival (month)7,410,3n.s. Time to progression (month)2,27,5<0,05 Numbers of interventional treatments (n) 153 <0,05

44 44 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH data Brachytherapy External Radiation +/- Brachytherapy 2x 4,8 Gy - randomized p = 0.42p = survival.time to progression Huber-RM et al, Int J Radiation Oncology Biol Phys 1997

45 45 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH data Brachytherapy Brachytherapie – Early cancer AuthorYearmodusnfollow up [Jahre] CRRezidiv Edell1990PDT21271%48% Edell1993PDT58584%39% Imamura1994PDT29264%36% Lam1998PDT102578%44% Tredaniel1994EBBT292 Perol1997EBBT19183%25% Marsiglia2000EBBT34285%35%

46 46 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH PDT plus Brachytherapy Freitag L, Ernst A, Thomas M, Prenzel R, Wahlers B, Macha HN Thorax 2004; 59: 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 Gy weekly up to 20 Gy Follow Up Bronchoscopy every 3 month

47 47 R Eberhardt 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 ) 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:

48 48 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH PDT plus Brachytherapy. results are surprisingly good results are surprisingly good long time survival and tumor controll seems to be better than PDT or EBBT alone long time survival and tumor controll seems to be better than PDT or EBBT alone no severe complications no severe complications prospective randomized study necessary prospective randomized study necessary Freitag L, Ernst A, Thomas M, Prenzel R, Wahlers B, Macha HN Thorax 2004; 59: Sequential photodynamic therapy (PDT) and high dose brachytherapy for endobronchial tumour control in patients with limited bronchogenic carcinoma

49 49 R Eberhardt 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

50 50 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Brachytherapy. Brachytherapy Endoluminal and intramural tumors Endoluminal and intramural tumors Complementary to other endoscopic treatments Complementary to other endoscopic treatments local long time response local long time response Possible after ERT Possible after ERT Outpatient basis Outpatient basis

51 51 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Brachytherapy. Brachytherapy Delayed effect (weeks) Several sessions Several sessions No emergencies No emergencies Expensive Expensive

52 52 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Cryotherapy. Cryotherapy

53 53 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Cryotherapy. Cryotherapy ► Liquid nitrous oxide N 2 O (-80 0 C) ► Ice ball (-40 0 C) ► flexible/rigid probe ► tissue freezing ► selective cellular necrosis ► elimination of vascularization

54 54 R Eberhardt 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

55 55 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Cryotherapy Joule-Thompson effect Cryo-probe high pressure atmospheric pressure cooling effect

56 56 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Cryotherapy. Cryoprobe

57 57 R Eberhardt 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)

58 58 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Cryotherapy. cryosensitive cryorestistant ► ► skin ► ► mucous membranes ► ► nerve cells ► ► granulation tissue ► ► vascular endothelium ► ► nerve sheats ► ► fibrous tissue ► ► connective tissue ► ► cartilage ► ► fat tissue

59 59 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Cryotherapy. How to do it... CryoprobeIceball

60 60 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Cryotherapy. How to do it... Cryoprobe Cryoprobe o Iceball

61 61 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Cryotherapy. Indications ► Ablation  malignant tumors  benigne tumors  stent-over-growth ► curable intent in early lung cancer ► bleeding ► foreign bodys ► recanalizationimmediately ?

62 62 R Eberhardt 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

63 63 R Eberhardt 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

64 64 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Cryotherapy. Recanalization

65 65 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Cryotherapy. Recanalization

66 66 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Cryotherapy Central airway obstruction and respiratory failure Contraindication NO CRYO !

67 67 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Cryotherapy. Advantages ► No risk of perforation ► No risk of firing ► Cheap ► Very easy to learn  contact mode  tactile feed-back

68 68 R Eberhardt 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

69 69 Early cancer R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Data inhomogenous, but...  if operableresection  if not or refusedPDT  if largerPDT + brachytherapy  alternativescryotherapy brachytherapy, electrocautery International Bronchoscopy Course/Istanbul 2006

70 70 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH central airway obstruction. immediate effect Laser Resection Laser Resection Electrocautery Electrocautery Argon Plasma Coagulation Argon Plasma Coagulation Cryotherapy? Cryotherapy? delayed effect Brachytherapy Brachytherapy Photodynamic therapy Photodynamic therapy Cryotherapy Cryotherapy advanced lung cancer

71 71 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH central airway obstruction. LaserAPCBrachytherapyCryotherapyPDTStents endoluminal extraluminal mixed endoluminal extraluminal mixed advanced lung cancer

72 72 R Eberhardt 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

73 73 Thank you for your attention … R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH International Bronchoscopy Course/Istanbul 2006

74 74 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH International Bronchoscopy Course/Istanbul 2006

75 75 R Eberhardt 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

76 76 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

77 77 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)

78 78 R Eberhardt Pneumologie Thoraxklinik Heidelberg gGmbH Brachytherapy.


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