PHOTODYNAMIC DIAGNOSIS &
THERAPY
PHOTODYNAMIC DIAGNOSIS &
THERAPY
Attila L. Major, MD, PhD, PD
Presentation PlanPresentation Plan
• Introduction photomedicine• Photodetection (PDD)• Photodynamic Therapy (PDT)• Conclusion / Perspective
Photodynamic Principle Photodynamic Principle
• Use of a photo-enhancing or photo-sensitizing chemical to aid in the diagnosis or treatment of a target cell
• Use of a photo-enhancing or photo-sensitizing chemical to aid in the diagnosis or treatment of a target cell
HistoricalHistoricalHistorical19761976 J. F. KELLY + M. E. SNELL J. F. KELLY + M. E. SNELL -- FirstFirst clinicalclinical PDT PDT ofof aa
bladderbladder carcinomacarcinoma withwith HPD. (J. HPD. (J. UrolUrol., 115, 150, 1976).., 115, 150, 1976).
19781978 T. J. DOUGHERTY et al.T. J. DOUGHERTY et al.-- ClinicalClinical assessmentassessment ofof PDTPDT(Cancer (Cancer ResRes., 38, 2628, 1978).., 38, 2628, 1978).
! LASERS + OPTICAL FIBERS !! LASERS + OPTICAL FIBERS !
19931993 FirstFirst approvalapproval (by (by thethe canadiancanadian healthhealth agencyagency) ) ofof PDTPDTwithwith PhotofrinPhotofrin®® for for thethe prophylacticprophylactic treatmenttreatment ofofbladderbladder cancer.cancer.
Photophysical ProcessesPhotophysicalPhotophysical ProcessesProcesses
Fluorescence Fluorescence detectiondetection PhotodynamicPhotodynamic TherapyTherapy
S0
S1
S2
T1
AbsorptionAbsorption
FluorescenceFluorescence630 nm630 nm
700 nm700 nm630 nm630 nm
400 nm400 nm
Ene
rgy
ISCICIC
= 1ns= 1nsττ
PhosphorescencePhosphorescence
= 10µsτ = 250 nstd = 45 nm∆
Singlet Oxygenproduction
OO3322
**22
11OO
collision energytransfer
SpectroscopySpectroscopy
PhotosensitizersPhotosensitizers
• Porphyrins– Photofrin (PF) – "Aminolevulinic acid (ALA)", Protoporphyrin IX
(PpIX)• Chlorins
– m-Tetrahydroxyphenyl chlorin (mTHPC): Temoporfin (Foscan, Foslip)
– Benzoporphyrin derivative mono-acid (BPD): Verteporfin (Visudyne)
– Tin ethyl etiopurpurin (SnET2)• Phtalocyanines
Photofrin ApprovalPhotofrin Approval
• Superficial bladder cancer (Canada 1993)
• Early and late oesophageal and lung ca (Netherlands 1994)
• Advanced oesophageal ca (USA 1995)
• Early ca of stomach, oesophagus, lung, cervix and cervical dysplasia (Japan 1994)
Approvals of second generation photosensitizers
Approvals of second generation photosensitizers
• Temoporfin (Foscan, Biolitec) : PDT head and neck cancer (USA 2001)
• Meth-aminolaevulinate (Metvix, Galderma): PDT actinic keratosis, basal cell carcinoma (EU and Australia 2003)
• Hex-aminolaevulinate: PDD bladder cancer (Sweden 2004, EU 2005)
• Verteporfin (Visudyne, QLT, Novartis): macular degeneration of the retina (USA and EU 2002)
PHOTODETECTIONPHOTODETECTION
ProblematicFLUORESCENCE SPECTROSCOPY OF EXOGENOUS, EXOGENOUSLY-INDUCED AND ENDOGENOUS FLUOROPHORES FOR THE PHOTODETECTION AND PHOTODYNAMIC THERAPY OF CANCER. Early cancers are
easier to treatAdvanced cancerDifficult to treat
Early cancer are difficult to detect
MetastasesLocalized Radiography, endoscopy, MRI
ContrastEarly lesion /
normal surroundingMatthieu Zellweger, Février 2000
Principle of fluorescenceFLUORESCENCE SPECTROSCOPY OF EXOGENOUS, EXOGENOUSLY-INDUCED AND ENDOGENOUS FLUOROPHORES FOR THE PHOTODETECTION AND PHOTODYNAMIC THERAPY OF CANCER.
Fluorescent molecule
∆E > 0 ∆E < 0
ExcitationPhoton
Fluorescence photon
Matthieu Zellweger, Février 2000
Haem BiosynthesisHaem Biosynthesis
5-ALA synthase Uptake of exogenous 5-ALA
PBG Deaminase
Cytoplasma
Lower rate in Lower rate in tumourtumour cellscells
Higher rate in Higher rate in tumourtumour cellscells
CoproporphyrinogenCoproporphyrinogen IIIIII
UroporphyrinogenUroporphyrinogen IIIIII
PorphyrinogenPorphyrinogen55--ALAALA55--ALAALA
GyclineGycline++
succinylsuccinyl CoACoA
haemhaem
ProtoporphyrinProtoporphyrin IXIX
ProtoporphyrinogenProtoporphyrinogen IXIX
Feedback controlFeedback control
MitochondriaMitochondria
FeFe2+2+Ferrochelatase
Haem BiosynthesisHaem Biosynthesis
5-ALA synthase Uptake of exogenous 5-ALA
PBG Deaminase
Cytoplasma
Lower rate in Lower rate in tumourtumour cellscells
CoproporphyrinogenCoproporphyrinogen IIIIII
UroporphyrinogenUroporphyrinogen IIIIII
PorphyrinogenPorphyrinogen55--ALAALA55--ALAALA
GyclineGycline++
succinylsuccinyl CoACoA
haemhaem
ProtoporphyrinProtoporphyrin IXIX
ProtoporphyrinogenProtoporphyrinogen IXIX
Feedback controlFeedback control
MitochondriaMitochondria
FeFe2+2+Ferrochelatase
Higher rate in Higher rate in tumourtumour cellscells
Combined Diagnosis System
• White Light• ALA-Mode• Autofluorescence-Mode
• Rigid Telescopes• Fiberscopes• OP - Microscopes
P HOTODETECTION
Clinical Data
M. M. KriegmairKriegmair, ,
Ludwig Ludwig MaximilliansMaximillians--UniversityUniversity MunichMunich
Neurosurgery
Special FluorescenceMicroscopeCooperation w/ Carl Zeiss
Early Tumor Detectionwith Marker Substance
High grade Glioma
Stummer, Stummer, ReulenReulenMunichMunich--GroGroßßhadernhadern
Detection of Early Stage Bronchial Carcinomas (AF)
K. K. HHääuußßingeringer, F. , F. StanzelStanzel
AskleipiosAskleipios MunichMunich-- GautingGauting
PDD in GynaecologyPDD in Gynaecology
• Laparoscopic view of ovarian cancer after ip ALA-application
A
B
A. MajorA. Major
GenevaGeneva University HospitalUniversity Hospital
Light micrographs (A) andfluorescence (B) of a peritoneal
nodule (size < 0.5 mm) 6 hrafter ip ALA administration.
Magnification (C) of theperitoneal serosa (boxed area in
B) showing a thin layer oftumor matching with the
fluorescence
Light micrographs (A) andfluorescence (B) of a peritoneal
nodule (size < 0.5 mm) 6 hrafter ip ALA administration.
Magnification (C) of theperitoneal serosa (boxed area in
B) showing a thin layer oftumor matching with the
fluorescence
Major A. et al Gynecol Oncol 1996, 66 : 122-32.
0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
70.00%
80.00%
0-1st 0-2nd 0-3th 0-4th 0-5th
Other genital organs(vulva and vagina)
Cervix uteri
Corpus uteriBreast
Ovary
5-Year cumulative lethality of gynecologic malignancies in Geneva
Figure 1
Common sites of ovarian cancer metastases. Ovarian cancer spreads fast to the whole abdominal cavity by exfoliation
(stage III)
(stage IV)
Parenchymal
(stage III)
(stage Ic or IIc)
(stage Ib)
(stage IIa)
(stage IIb)
(stage IIa)
(stage IIIc)
(stage III)
(stage IV)
Epithelial Ovarian CancerEpithelial Ovarian CancerEpithelial Ovarian Cancer
• Fourth most frequent cause of “cancer-related” death
• 65% diagnosed with stage III-IV disease
• 80% chemo-sensitive (initial response)• 5 year survival rate: 15-20%• 50% of “cured” patients (negative second
look laparotomy) will recur
• Fourth most frequent cause of “cancer-related” death
• 65% diagnosed with stage III-IV disease
• 80% chemo-sensitive (initial response)• 5 year survival rate: 15-20%• 50% of “cured” patients (negative second
look laparotomy) will recur
Potential of In Vivo FluorescencePotential of In Vivo Fluorescence
• Staging laparotomy– 30% upstaged (Young RC, JAMA, 1983;
Zanetta G, Ann Oncol, 1998)• Second Look
– 50% recurrence of negative second-look after combination chemotherapy (DiSaia PJ, Mosby-Year Book, 1997)
Results of restaging laparotomies in women withapparent early stage ovarian carcinoma
Results of restaging laparotomies in women withapparent early stage ovarian carcinoma
Authors (year) Number ofpatients
FIGO stage atinitial surgery
% upstaged
Bagley 1973 5 I-II 60%
Young 1983 100 IA-IIB 31%
Helewa 1986 25 I 20-25%
Buchsbaum 1989 140 I-II 22,4%
Archer 1991 24 I-II 20,8%
Soper 1992 30 I-II 30%
Stier 1998 45 IA-IIB 16%
Leblanc 2000 28 I 21%
Survival by outcome of second lookSurvival by outcome of second look
neg second look
microsc pos
macrosc pos
Ovarian cancer PDD secondOvarian cancer PDD second--look look feasabilityfeasability StudyStudyStage III-IV ovarian + 6-8 cycles taxoid platinum chemotherapy
Clinical complete response
Second-look operation with white light and PDD. Retrospective DataNo second-look
Neg. second-look operationwith white and PDD.
Pos. second-look operationwith white light or PDD
Lesions < 1/2 cm via white or PDD or
microscopic disease
Macroscopic lesions > 1/2cm via
white or PDD
Second-linechemotherapy
Second linechemotherapy.
Survival data. Survival data. Survival data Retrospectivesurvival data.
CONCLUSIONSCONCLUSIONS
• Photodetection of ovarian cancer peritoneal implants, not visible by other methods, has been shown to be efficient and feasible in patients
• Survival advantage has to be demonstrated in clinical trials (second look and staging of first stage ovarian cancer)
PHOTODYNAMIC THERAPY PHOTODYNAMIC THERAPY
PHOTODYNAMIC THERAPYPHOTODYNAMIC THERAPY
Dye(PS)
Photons
DYE TOXICITYTOXICITY02
ACTIVATEDACTIVATED
Methaminolaevulinate (MAL) PDT in Aktinic Keratosis
TrondTrond WarloeWarloe
Radium Hospital OsloRadium Hospital Oslo
MAL-PDT in Basal Cell Carcinoma
TrondTrond WarloeWarloe
Radium Hospital OsloRadium Hospital Oslo
MAL-PDT in Basal Cell Carcinoma
TrondTrond WarloeWarloe
Radium Hospital OsloRadium Hospital Oslo
A. MajorA. Major
GenevaGeneva University HospitalUniversity Hospital
A. MajorA. Major
GenevaGeneva University HospitalUniversity Hospital
A. MajorA. Major
GenevaGeneva University HospitalUniversity Hospital
CONCLUSIONSCONCLUSIONS
• Photodynamic therapy (PDT) can be used efficiently in patient who were already treated with surgery, radiotherapy and chemotherapy
• PDT heals with better cosmetic results compared to other treatments (surgery, cryotherapy)
• PDT has no long term side effects and has no limitations to repeat it
Attila L. Major
Pierre-Marie TebeuBianca Mottironi
Magali ZeisserAnis Fekih
Frank Ludicke
Youri Popowski
FONDATION POURRECHERCHESMÉDICALES
FONDATION POURRECHERCHESMÉDICALES
Hubert van den Bergh
Georges Wagnières
Norbert LangeJean-Pierre Ballini
Autofluorescence (ENT)
Carcinoma of the left vocal cord,precancerous lesion right vocal cord
(bacterial growth)
Early Tumor Detectionwithout Marker Substance
K. Malzahn, C. Arens, H. GlanzK. Malzahn, C. Arens, H. Glanz
JustusJustus--LiebigLiebig--UniversityUniversity GiessenGiessen