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