Photo Dynamic therapy

Presenter:- Dr.Vijay.P.Raturi

Moderator :- Mr. Teerthraj Sir

JR-2 ,king George Medical College Deptt of Radiation Oncology

Histortical Background

1st report of Cytotoxicity (in Paramecium) observed by combining drug (acridine ) & visible light was seen by Oscar Raab( Medical student) working in Hermann von tappiener in 1900.

Von tappiener & Jesioneck combined topical eosin and visible light in t/t of skin cancer(1903)

Discovery of hematoporphyrins by Samuel schwartz in 1960

Clinical application of PDT remain limited to specific situations

Principle of PhotoDynamic Therapy

• T/t modality that combines the selective photochemical activation of PS with EMR in visible energy range (i:e light )

• PS may be introduced into pt either - Systemically, - Optically or - Injected locally

Photosensitizer

• PS & it chemical structure influence the effectiveness of PDT

• Molar efficient coefficient ( how efficiently it absorbs the light) Quantum yield( generate ROS including singlet oxygen)

• 1st PS to recieve regulatory approval was Photofrin (porfimer sodium)

• Selectivity to tumor cells

• Photostability

• Biological stability

• Photochemical efficiency

• No cytotoxicity in absence of light

• Strong absorption – 600-800 nm

• Good tissue penetration

Photosensitizing Agents:Requirements

J. of Photochemistry and Photobiology A: Chemistry 2002, 153, 245. Photochemistry and Photobiology 2001, 74, 656.

Type of Cancer t/td with PDT

• Porfimer sodium, BPD verteporfin - Cancer of the esophagus, Barrett esophagus, non-small cell lung cancer or endobronchial cancer.

• Aminolevulinic acid (ALA or Levulan), Methyl ester of ALA (Metvixia® cream) - actinic keratosis (AK),basal cell carcinoma

• Temoporfin :- used in head & neck cancere

Photochemistry and Photobiology 2001, 74, 656. Int. J. Cancer 2001, 93, 720.

• 2nd generation

• Improved red light absorption

• 25-30 times more potent than HpD

• More selective toward tumor cells

• Most active photosensitizer with low drug and light doses

• Not granted approval

Photosensitizing Agents:Meta-tetra(hydroxyphenyl)porphyrins (mTHPP)

Jabonski energy diagram

Physics of light dosimetry

• Its a dynamic interaction over the period of time.

•The deposition of light or its dosimetry is determined by the light source characteristic and tissue optical properties at surface and at depth

• PDT dose :- product of absorption coefficient of PS * light fluence

Light delivering devices

• Various light delivering devices have been developed for PDT , most of them are fibre based a> linear based

b> endotracheal tube modified

c> collimated light source

d> flat cut fiber

• Various illumination technique may be used depending on geometry of the target lesion ,M.c clinical situation require surface illumination.

• Use of balloon diffuser may be helpful for complex 3D surfaces eg:- lateral tongue & it adjacent floor of mouth where the surface treated can be moulded in apposition to the balloon diffuser.

• Other strategy for complex 3D surface :- a> Patching b> Light blanket

Intersitial PDT

Placement of trocar guiding the insertion of plastic caths Using templates

Linear ligth sources

• its used for when volume illumination is required

Techinical consideration

• Light that is reflected on the surface during delivery increase the fluence and fluence rate especially when the surface is concave a.k.a integrating sphere effect .

• Strategy:- to minimise the surface geometry either concavity or convaxity

• Using anticholinergic such as glycopyrolate to decrease the mucosal secretion

• When target lesion lie adjacent to reflective metal surface ,dyed surgical towel should be placed above it.

• Hand tremor have significant impact on delivery ,so using rigid stylet during treatment cause immobilization.

Factors affecting the efficacy of PDT

A> Photosensitizer (PS) :- efffective of tumor vasculature - extra and intracellular location of PS - PS extinction coefficient - quantum yield - PS photobleaching

B> Light :- drug-light interval - fluence - fluence rate

C> Microenvironment :- oxygenation , status of immune system

D> Tumor response :- interaction between pro-apoptotic & pro-survival signals, angiogenic response

Steps in Systemically infused PS

First, the porfimer sodium(photo sensitiser) is administered intravenously into the cancer patient.

It travels through the bloodstream and is absorbed by every cell in the body (both the normal and the cancerous cells).

The normal cells get rid of porfimer sodium in a couple of days.But a lot of the drug stays in the cancer and normal skin cells.

Porfimer sodium is activated or turned on by light (visible/infra red) after 2-3 days of administering it into the body

This gives normal cells to get rid of the drug.

The doctor directs a laser light at the area of cancer cells through a thin fiber optic glass strand.

LASER used is a low power light so it does not burn.It gives minimal or no pain.

Depending on the size of the tumor,the light is given from 5-40 minutes.

Any dead tissue left in the treated are is removed after 4-5 days. T/tcan be repeated.

Steps in Locally applied PS

ALA is a topical drug applied directly on skin to treat actinic keratosis (a pre malignant condition).

Applied directly on face or scalp (unlike porfimer sodium,this does not reach other body parts).

After 14-15 hours of application of the drug,doctor passes BLUE LIGHT onto the area for 15 minutes.

Area may become red,scaly and crusty for almost 4 weeks before healing.

If the lesion does not go away completely,it can be treated again after 8 weeks.

Biology of PDT

• Mechanism of tumor cytotoxicity

• Influence of tumor micro enviroment on the PDT response

• Tumor stress response to PDT

• Immunologic response to PDT

• Vascular response to PDT

Mechanisms Of PDT Cytotoxicity

Indirect–

Changes in tumor

microenvironment

- Anti-vascular effects

- Anti-tumor immune

response

Direct-

Direct tumor cell killing due

to

macromolecule damage

- apoptosis

- necrosis

Indirect Cytotoxicity

Anti-vascular Effects

- Vessel leakage - Vasocontriction - Thrombosis

strongly dependent on— photosensitizer used & time

interval between the administration of photosensitizer & light

Anti-tumor Immune Response

- release of pro-inflammatory cytokines - fixation of complement - release of tumor associated

antigens

Practice of photodynamic therapy

• PS activation depends on effective adminsitration of light & depositing a sufficient amount of energy to the target tissue (total fluence)

• Most activationg light that has been used for PDT has typically been between 600 – 800nm depending on spectrum of absorption.

• Fluence rate:- Rate at which light energy is delivered ,its an imp t/t factor that affect efficacy & it primarily affect vascular flow & oxygenation.

• Prescription of PDT ( power output calculation of surface illumination )

Incident irradiation( mW/cm2)= power (mW)/Area (cm2)

Time(t) required = prescription dose (J/cm2)/irradiation *1000

Clinical aplication of PDT in Skin lesions

• Skin :- Basal cell ca , premalignant non hyperkeratotic actinic keratosis typicaly with surface illumination

• large institutinal series has shown high rate of LC ( >90% CR , <10% failure rate) for superficical BCC.

• PDT is appropriate alternative to cryosurgery and excision for BCC

• PDT is current approved in USA & european conuntry for t/t of actinic keratosis & BCC

Clinical aplication of PDT in brain

• PDT has been primarily been evaluted as adjunctive therapy treating surgical bed often combined with it use as PDD as a guide surgical resection

• Several institutional experience where PDT is used to treat the resection cavity for various histologies including GBM & AA

• Sylli et al observed a light dose effect on OS for GBM & AA

Clinical aplication of PDT in head & neck cancer

• Vast majority of single instituinal experience demonstrated its effectiveness either for definite Mx or for palliation

• Used for premalignant dysplastic lesion or early primary invasive mucosal Ca where the risk of nodal mets is low ( mucosal lesion are attractive for PDT as wide field ablation can be achieved)

• T/t of larynx with PDT due to defined nature of anatomic site, where PDT can offer function preservation.

• prospective studies with Porfimer sodium & Temoporfin have demonstrated CR >80%

Clinical aplication of PDT in thoracic malignancy

• PDT has been FDA approved for t/t of microinvasive endobronchial and advanced partially obstructed NSCLC .

• Endobronchial light delivery is typicaly been used to t/t central lesion.

• PDT has been used as definitive therapy in treating endobronchial, occult or primary carcinoma where the bronchoscopically visible lesions are <1 cm in surface dimension with no extracartilaginous involvement.

• PDT has also been investigated for malignant mesothelioma

Clinical aplication of PDT in GI malignancy

• BE with dysplasia and early stage oesophageal cancer are best studied.

• Overholt et al demonstrated in randomized trial that PDT for premalig BE can eliminate dysplastic cell & is asso with lower incidence of development of invasive Ca

• Trial comparing PDT + PPI vs PPI- result showed that PDT + PPI was superior both inb term of ablation of high grade dysplasia & progresion to adenoca.

• It has no long term side effects when used properly,its not genotoxic

• It’s less invasive than surgery.

• It usually takes only a short time and is most often done as an outpatient.

• It can be targeted very precisely.

• Unlike radiation, PDT can be repeated many times at the same site if needed.

• There’s little or no scarring after the site heals.

• It often costs less than other cancer treatments.

• PDT is currently used in a number of medical fields, including oncology (cancer), dermatology (skin), and cosmetic surgery.

Advantages

• Drugs makes the skin and eyes sensitive to light for approximately 6 weeks after treatment.(Thus, patients are advised to avoid direct sunlight and bright indoor light for at least 6 weeks.)

• However, PDT can cause burns, swelling, pain, and scarring in nearby healthy tissue.

• Other side effects include coughing, painful breathing, trouble swallowing, stomach pain, or shortness of breath; these side effects are usually temporary.

S/E & Complication

• The light needed to activate most photosensitizers cannot pass through more than about one third of an inch of tissue (1 centimeter).

• For this reason, PDT is usually used to treat tumors on or just under the skin or on the lining of internal organs or cavities.

• PDT is also less effective in treating other tumors, because the light cannot pass far into these tumors.

• PDT is a local treatment and generally cannot be used to treat cancer that has spread (metastasized).

Disadvantage of PDT

Conclusion

• PDT can have significant cancer cytotoxicity with cure possible in several clinical applications( supourted by preclinical & clinical evidence)

• There has been tremendous advancement in the physics of light dosimetry,PS development for PDG & Photoactivation & our understanding of cellular & microenviroment effect of PDT

• Potential oppurtunities to advance both the indication & efficacy of PDT both alone & in combination with traditional therapeutics

Thank You