AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
Photodynamic Therapy: Fundamentals and Dosimetry
Timothy C Zhu1, Jarod C Finlay1, and Brian C Wilson2
Dept. of Radiation Oncology, University of Pennsylvania, Philadelphia, PA
Department of Medical Biophysics, University of Toronto, Toronto, CA
Abbreviations: AK, Actinic Keratosis; ALA, aminolevulinic acid; AMD, age-related macular
degeneration; BCC, Basal cell carcinoma; BPD-MA, benzoporphyrin derivative monoacid A, CNV,
Choroidal neovascularization; CW, continuous wave; FDA, Food and Drug Administration; Hb,
hemoglobin; HPD, hematoporphyrin derivative; ISC, Intersystem crossing; LED, light-emitting diode;
MLu, motexafin lutetium; mTHPC, meso-tetrahydroyphenol chlorin; PDT, Photodynamic therapy; PIT,
photoimunotherapy; PpIX, protoporphyrin IX; SCC, Squamous cell carcinoma;
I Introduction
Photodynamic therapy (PDT) is an emerging cancer treatment modality based on the interaction of light, a
photosensitizing drug, and oxygen.1 The photochemical reactions that result in photodynamic damage
can be characterized as either Type I or Type II reactions. In Type I reactions, the photosensitizer in its
excited state reacts directly with a substrate present in the tissue, leading to the generation of cytotoxic
free radicals.2, 3 The majority of sensitizers available for PDT utilize Type II photodynamic processes,
meaning that they accomplish their photodynamic effect through the production of singlet oxygen.2, 4
Singlet oxygen is a highly reactive excited state of the oxygen molecule. Direct optical excitation of
oxygen is forbidden by three molecular selection rules, and is practically impossible in living tissue. A
photosensitizer can act as an intermediate, allowing the formation of singlet oxygen, see below. The
energy level diagram shown in figure 1 summarizes the underlying physical processes involved in type-II
PDT. The process begins with the absorption of a photon by photosensitizer in its ground state, exciting it
to an excited stated. In general, both the ground state and this excited state are spectroscopic singlets (i.e.,
states with a spin multiplicity of 1). The sensitizer molecule can return to its ground state by emission of
a fluorescence photon, which can be used for fluorescence detection. Alternatively, the molecule may
convert to a triplet state (one with a spin multiplicity of 3), a process known as intersystem crossing
(ISC). A high intersystem-crossing yield is an essential feature of a good sensitizer. Once in its triplet
state, the molecule may undergo a collisional energy transfer with ground state molecular oxygen (type II)
or with the substrate (type I). In type II interaction, the photosensitzer returns to its ground state, and
oxygen is promoted from its ground state (a triplet state) to its excited (singlet) state. Since the sensitizer
is not consumed in this process, the same sensitizer molecule may create many singlet oxygen molecules.
Once the singlet oxygen is created, it reacts almost immediately with cellular targets in its immediate
vicinity. The majorities of these reactions are irreversible, and lead to consumption of oxygen. This
consumption of oxygen is efficient enough to cause measurable decreases in tissue oxygenation if the
incident light intensity is high enough. In addition to its reactions with cellular targets, singlet oxygen
may react with the sensitizer itself. This leads to its irreversible destruction (photobleaching).
Photobleaching can decrease the effectiveness of PDT by reducing the sensitizer concentration, however
it can also be useful for dosimetry.5 Because of its high reactivity, singlet oxygen has a very short lifetime
in tissue. However, a small fraction of the singlet oxygen produced may return to its ground state via
emission of a phosphorescence photon, which can be detected optically.6, 7
PDT has been approved by the US Food and Drug Administration for the treatment of microinvasive lung
cancer, obstructing lung cancer, and obstructing esophageal cancer. Studies have shown some efficacy in
the treatment of a variety of malignant and premalignant conditions including head and neck cancer,8, 9
AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
lung cancer,10-12 mesothelioma,13 Barrett’s esophagus,14, 15 prostate,16-18, and brain tumors.15, 19-21 Unlike
radiation therapy, PDT is a non-ionizing radiation that can be used repeatedly without cumulative longterm complications since it does not appear to target DNA.
There has been tremendous progress in photodynamic therapy dosimetry. The simplest clinical dose
prescription is to quantify the incident fluence (Joules/cm2) for patients treated with a given
photosensitizer injection per body weight. However, light dose given in this way does not take into
account the light scattering by tissue and usually underestimates light fluence rated. Techniques22, 23 have
been developed to characterize the tissue optical properties and the light fluence rate in-vivo. Other
optical spectroscopic methods24, 25 have been developed to characterize tissue absorption and scattering
spectra, which in term provide information about tissue oxygenation and drug concentration.
Fluorescence techniques26 can be used to quantify drug concentration and potentially photobleaching rate
of photosensitizers.
The objective of this paper is to present a brief review of the issues related to the application of
photodynamic therapy. In particular, we review the current start of art of techniques to quantify light
fluence, drug concentration, tissue oxygenation, and PDT efficiency.
II. Fundamentals of PDT dosimetry
To quantify the complex photodynamic effect, a dosimetric parameter called the "photodynamic dose" is
introduced.27 Patterson et al27 have described it as the number of photons absorbed by photosensitizing
drug per gram of tissue [ph/g]:
D = ∫ εc ⋅
φ (t ' ) 1
⋅ dt ' ,
hν ρ
where ρ is the density of tissue [g/cm3], φ is the light fluence rate [W/cm2], hν is the energy of a photon
[J/ph], c is the drug concentration in tissue [µM], ε is the extinction coefficient of the photosensitizer drug
[1/cm/µM]. “Photodynamic dose” is the dosimetric parameter most commonly documented. The logic in
this choice is that light fluence rate (φ), drug concentration (c), and exposure time (t) are parameters under
clinical control.
Due to photobleaching effect, the drug concentration is usually a function of light fluence Φ = φt. The
exact relationship between drug concentration and the light fluence should be determined by rate
equations based on molecular interactions.31-33 For purpose of illustration, one can assume an exponential
form between the drug concentration and light fluence, c = c0e-bφt, where the photobleaching rate b is a
constant28. One gets from Eq. 1:
εc 0 1
⋅ (1 − e −bφt ) .
ρhν b
Here we assume a constant light fluence rate φ. This equation illustrates that the PDT dose has an upper
limit for a given photosensitizer beyond that it cannot be increased by simply increasing the light fluence.
For photosensitizers with negligible photobleaching rate, i.e., bφt << 1, PDT dose is proportional to the
light fluence. Experimental determination of the margins of necrosis induced by a well-defined D can
specify the threshold dose (Dth).27, 29
AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
The “photodynamic dose” (D) does not consider the quantum yield (η) of oxidative radicals, the effect of
tissue oxygenation on η, or the fraction (f) of radicals that oxidize critical sites. The production of
oxidative radicals which are capable of damaging the tissue can be expressed 30 as:
[1 O2 ] = f ⋅ η ⋅ D ,
where f depends on the localization of the photosensitizer at the cell level and thus depends on the
photosensitizer and tissue types, the quantum yield η gives the number of singlet oxygen molecules
produced per an absorbed photon, which is a constant under ample oxygen supply. However, when
insufficient oxygen supply exists, η is also a function of the oxygen concentration, or pO2, in tissue. The
relationship between η and oxygen concentration can be derived from differential equations modeling the
reaction rates of oxygen and sensitizer in their various states.31-33 Based on our current understanding, the
PDT effect is directly proportional to the total concentration of reactions of singlet oxygen [1O2], with
biological targets which can be either calculated (Eq. 3) or indirectly measured in tissue via the local
[1O2] concentration.6, 7
III Photosensitizers
Various photosensitizer drugs have been developed. Although Type I photosensitizers have been
investigated for antimicrobial applications34, most available oncologic sensitizers achieve their cytotoxic
effect primarily via Type II reactions.
Table 1 lists several of the more widely used photosensitizers currently available. The first-generation
photosensitizer, haematoporphyrin derivative (HPD), is a mixture of porphyrin monomers and oligomers
that is partially purified to produce the commercially available product, porfimer sodium, marketed under
the tradename Photofrin®. Photofrin was approved for treatment of early stage lung cancer in 1998, and
for Barret's esophagus in 2003. The clinical applicability of Photofrin has been limited by two factors.
First, its absorption peak occurs at too short a wavelength (630 nm) to allow deep penetration in tissue.
Second, administration of photofrin results in cutaneous photosensitivity lasting up to 6 weeks.
These limitations have inspired the development of a second generation of photosensitizers with longerwavelength absorption peaks and more rapid clearance from skin. Among these was benzoporphyrin
derivative monoacid A (BPD-MA), or verteporfin. In preclinical trials, it was observed that verteporfin
preferentially targeted neovasculature. This selectivity has been exploited for the treatment of choroidal
neovascularization (CNV), an abnormal growth of vessels in the retina associated with age-related
macular degeneration (AMD), the leading cause of blindness in the developed world. Verteporfn was
approved in the US under the tradename Visudyne for CNV treatment in 2000.
Another development of note is the prodrug δ-aminolevulinic acid (ALA). Unlike other PDT drugs, ALA
itself is not a photosensitizer. When taken up by cells, however, it is converted by a naturally occurring
biosynthetic process into the photosensitizer protoporphyrin IX (PpIX). ALA can be applied topically,
and was approved by the FDA in 1999 for the treatment of actinic keratosis (AK). ALA has the
advantage that it clears from normal tissue within days and can be applied topically, so it causes almost no
systemic photosensitivity. In order to improve the uptake of ALA, two variants (methyl- and hexylaminolevulinate) have been developed. Methylaminolevulinate (m-ALA) has been approved for
treatment of AK under the name Metvix®. The hexyl variant (h-ALA), marketed as Hexvix®, has been
approved in the European Union for use in fluorescence cystoscopy. In this case, the preferential
accumulation of PpIX in tumors relative to normal bladder endothelium allows tumors to be differentiated
by their increased PpIX fluorescence.
AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
Other second-generation sensitizers include mTHPC (Foscan®), which has been investigated in clinical
trials for a variety of tumors and has been approved for palliative treatment in Europe, and Tookad® and
Motexafin Lutetium® (MLu), which are both currently undergoing Phase I trials for prostate cancer
treatment. This list is certainly not exhaustive. As understanding of the mechanisms of photosensitizer
uptake and preferential sensitization of tumors increases, drugs designed to increase selectivity and light
penetration while minimizing sensitization of normal tissue will continue to be developed.
Photoimunotherapy (PIT) is a promising approach to improving the selectivity of PDT agents.35-37 In PIT,
a sensitizer is conjugated to a monoclonal antibody, allowing it to target a particular molecular marker.
By choosing antibodies that target molecules selectively expressed by tumors, an increased tumor
selectivity can be achieved. This approach brings with it additional challenges, including the difficulty of
conjugating a sensitizer to an antibody without compromising the integrity of either molecule. PIT is still
in the early stages of development, however the initial results in animal and cell models are encouraging.
IV Light source and delivery devices
A. Light sources
Various light sources have been developed for photodynamic therapy. Most PDT procedures are carried
out at wavelengths between 600 and 850 nm, also called the “therapeutic window”, where the penetration
of light in tissue is the greatest and yet the photon energy (>1.5 eV) is high enough to cause
photoactivation.38 Because PDT requires intense light with preferably monochromic wavelength, laser is
the most common light source Early laser sources were very bulky argon-pumped dye systems. Solidstate lasers have been used lately, which can be made small enough to be transportable (see Fig. 2a). A
dye laser provides tunable wavelengths (see Fig. 2b). The current state of art laser is the diode laser,
which is very compact and have long lifetime but has slightly wider line width (~5 nm) (Fig. 3). Diode
lasers with high power of upto 15W are commercially available. One drawback of the diode laser is fixed
wavelength per diode module. New development in high power fiber lasers is advancing rapidly. They
will conceivably become the light source of choice in the futuret.39 Besides lasers, there are several other
light sources used in clinic: Broadband light sources, including various lamps and light-emitting diodes
(LED’s), which generate non-coherent light. Some common terms used to describe light sources as
described by AAPM TG5 are listed below:30
Continuous wave (cw): A source, which emits light continuously. Examples applicable to PDT are diode
lasers, LED’s, lamps and argon-pumped dye lasers.
Pulsed: A source which emits light as a series of pulses, for example, a dye laser pumped by a frequencydoubled Nd:YAG laser. Pulsed sources are characterized by their pulse repetition frequency (in Hz), the
pulse width (definition may vary), the pulse energy (typically in mJ), the peak power within a pulse (in
W), and the average power (in W). If the pulse energy is low enough, a pulsed source will produce the
same biological PDT effect as a cw source with the same average power.
Broadband: A source with a wide spectral output compared to typical laser line widths (less or greater?
than 1 nm).
Tunable: A source whose output wavelength may be adjusted – typically over a range of tens of
AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
Bandwidth: A term used to characterize the width of the source’s output spectrum. A variety of
definitions are used in practice. For example, the bandwidth of a laser source could be quoted as the
wavelength range over which the power is greater than 50% of the power at the peak wavelength.
B. Light delivery devices
Photodynamic therapy has been greatly facilitated by the development of optical fibers, which allows
light to be directed easily to deep-lying tissues, both within body cavities and interstitially. Figure 4
shows some common light delivery fiber optical devices used in photodynamic therapy (see details
1. Point sources
A fiber designed for intracavitary use, consisting of a small spherical scattering material at the fiber tip.
Ideally, such a fiber acts as a point source of illumination. For some special applications, such as PDT of
mesothelioma, lung, brain, and bladder cancers, it is preferable to create a uniform illuminating spherical
source with finite fluence rate at the sphere boundary. A balloon or a modified endotracheal tube filled
with intralipid solution is often used for this purpose (Fig. 4).
2. Linear sources
An optical fiber modified to emit light along some portion of its length. The “active” length may be
several centimeters. Such fibers are used in intralumenal treatments and may also be made robust enough
for interstitial implants.
3. Others
Often, a fiber fitted with a microlens in close proximity to the cleaved end is used. This design produces a
uniform circular field at a convenient distance from the fiber, and is often used for surface irradiation.
A good review of different types of light sources and methods of light fluence profile shaping can be
found in AAPM Monograph 19.40
V Light transport in tissue
A. Dosimetry Quantities
AAPM TG530 describes the dosimetric quantities used to characterize light in turbid medium based on
earlier definitions summarized by Star41:
Radiant energy (Q): Total energy emitted, transferred or received as electromagnetic radiation. SI unit
is J.
Radiant power (P): Power emitted, transferred or received as electromagnetic radiation. SI unit is W.
Energy radiance (L): Radiant power transported at a given field point in a given direction per unit solid
angle per unit area perpendicular to that direction. The SI unit is W m-2 sr-1. The radiance provides a
complete description of the light field and is the fundamental quantity in the radiative transport equation.
While important from a theoretical standpoint it is rarely measured directly.
AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
Energy fluence rate (φ): Ratio of total power incident on an infinitesimal sphere (containing the point of
interest) to the cross-sectional area of that sphere. It can also be defined as the integral of the radiance
over 4π solid angled. The SI unit is W m-2, although the unit mW cm-2 is still more common in PDT. The
fluence rate is the fundamental parameter in PDT dosimetry as it determines the local interaction rate of
photons. It can be measured using a specialized detector, which has an isotropic response.
Energy fluence (Φ): Total radiant energy incident on an infinitesimal sphere (containing the point of
interest) divided by the cross-sectional area of that sphere. SI unit is J m-2 but the unit J cm-2 is common
in PDT. Obviously, the fluence is the time integral of the fluence rated.
Irradiance (E): Radiant power incident on an infinitesimal surface element (containing the point of
interest) divided by the area of that element. The SI unit is W m-2 but the unit mW cm-2 is commonly
used in PDT. Note that the irradiance and the fluence rate have the same physical units (power per unit
area) but they are not the same quantity. The irradiance is defined for a particular surface whereas the
fluence rate can be defined and measured in free space or the interior of an object. Terms such as power
density, flux density and intensity, which have been used to describe the irradiance, should be avoided.
Radiant exposure (H): Radiant energy incident on an infinitesimal surface element (containing the point
of interest) divided by the area of that element. The SI unit is J m-2 but, in PDT, the unit J cm-2 is more
common. The radiant exposure is the time integral of the irradiance. The term “energy density” which
has been applied to this quantity should be avoided. The radiant exposure is specified for PDT treatments
using surface irradiation.
Among those quantities the most important quantity is the energy fluence (Φ) since this quantity is
directly associated with PDT dose. In a collimated beam, energy fluence = irradiance. However, in an
integrating sphere, energy fluence = 4* irradiance since irradiance takes into account the direction of light
B. Diffusion Approximation
The most widely used model of light transport in tissue is the radiative transport equation42. Because
analytic solutions to this equation exist for only very simple geometries, it is generally solved by a Taylor
expansion. A first-order expansion yields the commonly used diffusion approximation. In the near
infrared (NIR) region, tissue scattering dominates over tissue absorption, so that the diffusion
approximation is valid.38 Under diffusion approximation, the light fluence rate, φ, can be described as
∂φ (r , t )
= ∇ ⋅ D∇φ (r , t ) − vµ a φ (r , t ) + vS (r , t ) ,
where v is the speed of light in the turbid medium; D = v [3(µ s' + µ a )] is the photon diffusion coefficient; S is
an isotropic source term which gives the number of photons emitted at position r and time t per unit
volume per unit time.
Jacques showed that the light distribution using diffusion approximation is still not accurate in this
wavelength region, compared to Monte-Carlo simulation.43 This is especially true near the source, in the
so-called near-source field. Monte-Carlo simulation, however, is not suitable for real-time light fluence
calculation because of the long computing times required.44 To address this deficiency, several researchers
have investigated a 3rd-order approximation of the transport equation (P3 approximation) for a point
source to improve both the speed and accuracy of light fluence calculation.45-48
AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
VI PDT Dosimetry
The concept of explicit and implicit PDT dosimetry was introduced in the 1990s by Wilson et al.5
Explicit dosimetry refers to measurement of physical quantities that are well-defined, e.g. light fluence,
photosensitizer drug concentration, and tissue oxygenation. Because it is a well-defined physical
quantity, one may design methods to measure each quantity independently. Implicit dosimetry refers to
the use of a measurable quantity, such as the extent of sensitizer photobleaching, which is sensitive to
some or all of the factors influencing photodynamic efficacy but which does not require independent
measurements of each of these quantities.
A. Explicit dosimetry
From physics point of view, the explicit PDT dose is defined as the light energy deposited to
photosensitizer, i.e. it is proportional to the product of the absorption coefficient of the photosensitizer
and light fluence (Eq. 1). The absorption coefficient of the photosensitizer is, in turn, proportional to the
photosensitizer concentration. PDT dose calculated in this way is a good marker if one is operating in a
drug- or light- limiting regime when there is ample oxygen supply. However, if oxygen delivery is the
factor limiting PDT effect, singlet oxygen production rate (Eq. 3) is a better marker for predicting PDT
In-vivo light Dosimetry in PDT
Light is an important quantity that determines the outcome of PDT treatment. The light fluence (expressed
in J/cm2) is proportional to the light energy deposited in tissue. The total fluence in tissues is a function
not only of the incident light delivered by the laser but also of scattered light. Often clinical PDT
treatments are prescribed in terms of the incident light delivered from the laser rather than the total
fluence of light the tissues receive which is a combination of scattered and incident light. Substantial
differences in total fluence to tissues can be observed among patients if the clinician accounts only for
incident light.41, 49 Dosimetry systems using isotropic light detectors have been developed to measure both
incident and scattered light.50, 51 A 16-channel system developed at the University of Pennsylvania is
shown in Fig. 5. These systems should begin to allow clinical researchers to measure and therefore
prescribe a consistent total fluence to the tissues. Isotropic detectors are often used to measure the light
fluence rate directly (see Fig. 6).52 These detectors have the advantage of detecting light from all
directions vs. the flat photodiodes (Fig. 6) that can only detect light from normal incidencet.53
In vivo characterization of tissue optical properties
The measurement of light fluence rate in vivo is necessary but not sufficient to quantify light fluence rate
distribution. Volumetric determination of the light fluence rate in the entire treatment volume requires
accurate characterization of the in vivo tissue optical properties as input (µa, µs’ in Eq.4). Several
techniques have been developed to determine the optical properties in vivo.24, 54 Figure 7 shows measured
distribution of optical properties in human prostate.55 Clearly, there is a significant difference (up to 3
times) between optical properties measured in different locations, which will affect the light fluence
More advanced non-invasive technology such as diffuse optical tomography has shown promise for
determining the 3D distribution of optical properties (µa and µs’) in brain56 and breast57. However, this
technique can be applied to limited anatomic sites because of the limited tissue penetration depth, ~ 10
Quantification of drug concentration
Determination of drug concentration is important for PDT efficacy. Early PDT clinical protocols only
specify this quantity in terms of the amount of photosensitizer given to patient per body weight. Recent
in-vivo studies have show large variation of photosensitizer concentration in different tissue types, thus
AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
suggesting determination of this quantity in-vivo in the region of treatment directly.23, 55 To include the
drug concentration in the evaluation of PDT dose, in situ fluorescent58 or absorption25, 59-62 measurements of
photosensitizer can be made interstitially using optical fibers. Figure 8 shows measured distribution of
MLu drug concentration in prostate using absorption (Fig. 8a) and fluorescence (Fig. 8b) measurement.55
The results of the two methods agreed well for MLu drug concentration.55
Quantification of tissue oxygenation
Tissue oxygenation is known to affect PDT efficacy31, 63 in vitro. In addition, changes in tissue
oxygenation due to photochemical oxygen consumption during PDT have been observed directly,64, 65 and
indirectly through their effect on the photobleaching ratet.66, 67 Recent studies have shown that one can
determine the concentration of hemoglobin (Hb), HbO2, and H2O from absorption measurement.59-62
Figure 8a shows measured distribution of Hb and StO2 = HbO2/Hb measured in human prostate.55
B. Implicit dosimetry
Implicit dosimetry5 relies on a surrogate indicator of damage to measure the photodynamic effect, rather
than explicitly quantifying all the parameters needed to calculate the dose. One such mechanism is the
measurement of fluorescence photobleaching. In particular, if a sensitizer’s photobleaching and the
damage to tissue are both caused primarily by reactions with singlet oxygen, it is reasonable to assume
that the rate of photobleaching will be indicative of the rate of deposition of singlet oxygen-mediated
damage in tissue. In a simplified model, Georgakoudi et al. showed that the fraction of the initial
photosenstizer bleached could be related to the absolute concentration of reacted singlet oxygen in
tissue32. While oxygen transport, tissue heterogeneity, and light diffusion complicate the issue in vivo, the
correlation between photobleaching and PDT-induced damage holds in animal models 66, 68.
When designing a dosimetry protocol, it is important to remember that the usefulness of a particular
method or model depends on the drug, light fluence rate, and tissue being investigated. There is
experimental evidence that some sensitizers may photobleach by singlet oxygen-independent
mechanisms, in which case implicit dosimetry based on photobleaching will provide incorrect conclusions
concerning singlet oxygen dose.33 Different sensitizers may exhibit very different bleaching behaviors,
even in the same animal model.33, 67, 69 Furthermore, even if a sensitizer does bleach purely through singletoxygen mediated mechanisms, the relationship between photobleaching and clinical outcome will depend
on a host of factors, including cellular and vascular distribution and tumor selectivity, which may be drugand tissue-specific. Therefore, any implicit dosimetry method must be verified for the specific drug and
irradiation scheme being used before it can be implemented clinically.
VII PDT clinical protocols
Tables 2 and 3 list the current oncological PDT clinical trials listed by the NIH as ongoing in the US, and
the papers published since 2004 on clinical trial in PDT, as listed by PubMed. Trials investigating PDT
for cosmetic and ocular applications have not been included. While the majority of PDT trials and
approvals have been for cancers and other diseases of the skin, more recent studies have begun to expand
the range of diseases treated with PDT to include solid tumors of the head and neck, prostate, pancreas
and breast. As new drugs and new light delivery devices are developed, we can expect to see trials of
PDT for an increasing number of diseases that were previously considered inaccessible to PDT. These
sites generally involve the treatment of large, solid tumors, requiring illumination by intra-cavity or
interstitial light delivery devices. The wide variation in optical properties within and among tumors and
the variation in tumor geometry from patient to patient make accurate quantitative dosimetry even more
important in these cases. It is increasingly becoming appreciated that the PDT treatment of the future will
AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
incorporate real-time dosimetry and tissue optics monitoring into the light delivery system, allowing the
light distribution to be optimized as treatment progresses.
VIII Acknowledgment
The authors wish to thank members of the AAPM task group 5, especially Fred Hetzel and Steve Jacques,
for their contributions to establish methodology for PDT dosimetry.
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AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
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AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
P. Baas, L. Muller, Z. F.A.N., and et. al., "Photodynamic therapy as adjuvant therapy in surgically treated pleural
malignancies," Br J Cancer 76, 819-826 (1997).
M. Solonenko, T. C. Zhu, and T. G. Vulcan, "Commissioning of the isotropic light dosimetry system for photodynamic
therapy," Med Phys 26, 1124 (1999).
H. J. van Staveren, H. P. A. Marijnissen, M. C. Aalders, and W. M. Star, "Construction, Quality Assurance, and Calibrationof
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and S. M. Hahn, "Comparison between isotropic and nonisotropic dosimetry systems during intraperitoneal photodynamic
therapy," Lasers Surg Med 26, 292-301 (2000).
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properties of Normal Canine Prostate at 732 nm using motexafin lutetium-mediated photodynamic therapy," Photochem
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T. C. Zhu, J. C. Finlay, and S. M. Hahn, "Determination of the Distribution of light, optical properties, drug concentration,
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bowels, kidneys, and prostates," Phys. Med. Biol. 47, 857-873 (2002).
M. G. Nichols, and T. H. Foster, "Oxygen diffusion and reaction kinetics in the photodynamic therapy of multicell tumour
spheroids," Phys. Med. Biol. 39, 2161-2181 (1994).
B. J. Tromberg, A. Orenstein, S. Kimel, S. J. Barker, J. Hyatt, J. S. Nelson, and M. Berns, "In vivo tumor oxygen tension
measurements for the evaluation of the efficiency of photodynamic therapy," Photochem Photobiol 52, 375-385 (1990).
B. W. Henderson, T. M. Busch, L. A. Vaughan, N. P. Frawley, D. Babich, T. A. Sosa, J. D. Zollo, A. S. Dee, M. T. Cooper,
D. A. Bellnier, W. R. Greco, and A. R. Oseroff, "Photofrin photodynamic therapy can significantly deplete or preserve
oxygenation in human basal cell carcinomas during treatment, depending on fluence rate," Cancer Res. 60, 525-529 (2000).
D. J. Robinson, H. S. de Bruijn, N. van der Veen, M. R. Stringer, S. B. Brown, and W. M. Star, "Fluorescence
photobleaching of ALA-induced protoporphyrin IX during photodynamic therapy of normal hairless mouse skin: The effect of
light dose and irradiance and the resulting biological effect," Photochem. Photobiol. 67, 140-149 (1998).
J. C. Finlay, S. Mitra, and T. H. Foster, "In vivo mTHPC photobleaching in normal rat skin exhibits unique irradiancedependent features," Photochem Photobiol 75, 282-288 (2002).
D. J. Robinson, H. S. de Bruijn, N. van der Veen, M. R. Stringer, S. B. Brown, and W. M. Star, "Protoporphyrin IX
fluorescence photobleaching during ALA-mediated photodynamic therapy of UVB-induced tumors in hairless mouse skin,"
Photochem. Photobiol. 69, 61-70 (1999).
J. C. Finlay, D. L. Conover, E. L. Hull, and T. H. Foster, "Porphyrin bleaching and PDT-induced spectral changes are
irradiance dependent in ALA-sensitized normal rat skin in vivo," Photochem. Photobiol. 73, 54-63 (2001).
M. J. Shikowitz, A. L. Abramson, B. M. Steinberg, J. DeVoti, V. R. Bonagura, V. Mullooly, M. Nouri, A. M. Ronn, A.
Inglis, J. McClay, and K. Freeman, "Clinical trial of photodynamic therapy with meso-tetra (hydroxyphenyl) chlorin for
respiratory papillomatosis," Arch Otolaryngol Head Neck Surg 131, 99-105 (2005).
M. Hage, P. D. Siersema, K. J. Vissers, E. W. Steyerberg, J. Haringsma, E. J. Kuipers, and H. van Dekken, "Molecular
evaluation of ablative therapy of Barrett's oesophagus," J Pathol 205, 57-64 (2005).
M. Hage, P. D. Siersema, H. van Dekken, E. W. Steyerberg, J. Haringsma, W. van de Vrie, T. E. Grool, R. L. van Veen, H. J.
Sterenborg, and E. J. Kuipers, "5-aminolevulinic acid photodynamic therapy versus argon plasma coagulation for ablation of
Barrett's oesophagus: a randomised trial," Gut 53, 785-90 (2004).
M. Azab, D. S. Boyer, N. M. Bressler, S. B. Bressler, I. Cihelkova, Y. Hao, I. Immonen, J. I. Lim, U. Menchini, J. Naor, M. J.
Potter, A. Reaves, P. J. Rosenfeld, J. S. Slakter, P. Soucek, H. A. Strong, A. Wenkstern, X. Y. Su, and Y. C. Yang,
AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
"Verteporfin therapy of subfoveal minimally classic choroidal neovascularization in age-related macular degeneration: 2-year
results of a randomized clinical trial," Arch Ophthalmol 123, 448-57 (2005).
M. Wiedmann, F. Berr, I. Schiefke, H. Witzigmann, K. Kohlhaw, J. Mossner, and K. Caca, "Photodynamic therapy in
patients with non-resectable hilar cholangiocarcinoma: 5-year follow-up of a prospective phase II study," Gastrointest Endosc
60, 68-75 (2004).
M. Wiedmann, K. Caca, F. Berr, I. Schiefke, A. Tannapfel, C. Wittekind, J. Mossner, J. Hauss, and H. Witzigmann,
"Neoadjuvant photodynamic therapy as a new approach to treating hilar cholangiocarcinoma: a phase II pilot study," Cancer
97, 2783-90 (2003).
J. Webber, and D. Fromm, "Photodynamic therapy for carcinoma in situ of the anus," Arch Surg 139, 259-61 (2004).
D. Touma, M. Yaar, S. Whitehead, N. Konnikov, and B. A. Gilchrest, "A trial of short incubation, broad-area photodynamic
therapy for facial actinic keratoses and diffuse photodamage," Arch Dermatol 140, 33-40 (2004).
S. V. Sheleg, E. A. Zhavrid, T. V. Khodina, G. A. Kochubeev, Y. P. Istomin, V. N. Chalov, and I. N. Zhuravkin,
"Photodynamic therapy with chlorin e(6) for skin metastases of melanoma," Photodermatol Photoimmunol Photomed 20, 21-6
L. E. Rhodes, M. de Rie, Y. Enstrom, R. Groves, T. Morken, V. Goulden, G. A. Wong, J. J. Grob, S. Varma, and P. Wolf,
"Photodynamic therapy using topical methyl aminolevulinate vs surgery for nodular basal cell carcinoma: results of a
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H. Lui, L. Hobbs, W. D. Tope, P. K. Lee, C. Elmets, N. Provost, A. Chan, H. Neyndorff, X. Y. Su, H. Jain, I. Hamzavi, D.
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P. J. Lou, H. R. Jager, L. Jones, T. Theodossy, S. G. Bown, and C. Hopper, "Interstitial photodynamic therapy as salvage
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T. R. Nathan, D. E. Whitelaw, S. C. Chang, W. R. Lees, P. M. Ripley, H. Payne, L. Jones, M. C. Parkinson, M. Emberton, A.
R. Gillams, A. R. Mundy, and S. G. Bown, "Photodynamic therapy for prostate cancer recurrence after radiotherapy: a phase I
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S. G. Bown, A. Z. Rogowska, D. E. Whitelaw, W. R. Lees, L. B. Lovat, P. Ripley, L. Jones, P. Wyld, A. Gillams, and A. W.
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C. J. Kelty, R. Ackroyd, N. J. Brown, S. B. Brown, and M. W. Reed, "Comparison of high- vs low-dose 5-aminolevulinic
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AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
Table 1: An incomplete list of photosensitizers currently undergoing human clinical trials
clearance Sites
Approval excitation Drugtime
porfimer sodium
630 nm
4-6 weeks lung, Barret’s
405, 635
~2 days
Keratastick (FDA)
methyl aminolevulateMetvix
405, 635
3 hours
~2 days
hexyl aminolevulateHexvix
405 nm
~2 days
Detection of
bladder tumors
Verteporfin, 2000
689 nm
15 min
5 days
Phase I
652 nm
15 days
Head & Neck,
2001 (EU)
Motexafin Lutetium
MLu, Lutex, Phase I
732 nm
3 hours
Phase I
762 nm
~30 min ~2 hours
Taloporfin Sodium
chlorin e6)
Phase I &
II trials
664 nm
1 hour
CNV, Liver
& colorectal
Silicon pthalocyanine 4
Phase I
672 nm
24 to 36
AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
Light Sciences
Table 2: Current NIH listed on-going clinical PDT trials
Roswell Park Cancer
Case Western Reserve
Medical College of
University of
Eastern Virginia
Medical School
cutaneous lymphomas
AK, Skin Cancer
Brain tumors
recurrent prostate cancer
AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
Shikowitz 70
Table 3: Publications on clinical trials since 2004 by PubMed search
Hage 71, 72
Azab 73
Wiedmann 74, 75
Webber 76
Rhodes 79
Lui 80
Loning 84
Kelty 85
recurrent respiratory papillomatosis
Barret’s Esophagus
hilar cholangiocarcinoma
carcinoma in situ of the anus
multiple actinic keratoses
clorin e(6)
skin metastases from melanoma
methyl ALA
nodular BCC
nonmelanoma skin cancers
recurrent head and neck cancer, pancreas,
Ovarian carcinoma metastasis (detection
Barrett's esophagus
pituitary adenoma
oral squamous cell carcinoma
Sebaceous gland hyperplasia
Frei 89
metastatic lymph nodes in breast cancer
(detection only)
Etienne 90
Hopper 87
Gold 88
Ericson 91
Dragieva 92, 93
Cuenca 94
Cappugi 95
Barrett's esophagus
methyl ALA
AK and Bowen's disease
Breast cancer with Chest wall progression
Nodular BCC
AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
Reaction with
Energy transfer
to O2
Excitation, λex
Phosphorescence, λpl
Phosphorescence, λ = 1260 nm
Figure 1: Mechanism of action by Type II photosensitizer.
Figure 2: (a) LaserScope 40W KTP frequency-doubled Nd:YAG laser at wavelength of
532 nm and (b) LaserScope dye laser at tunable wavelengths 600 – 760 nm
AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
Figure 3: Diomed 2W diode laser at 732 nm
Figure 4: Various light delivery devices that are connected to an optical fiber (from left to
right): point source, microlens, cylindrically diffusing fiber, and modified endotracheal
point source.
AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
Photodiode SMA
Fiber cladding
Isotropic Probe
A/D with
Figure 5: Schematics of an in-vivo dosimetry system consists of isotropic detector,
photodiode, preamplifier, A/D converter, and PC control.
Figure 6: Light detectors used in photodynamic therapy: top raw for isotropic detectors,
1mm scattering tip and 0.3 mm scattering tip; bottom raw for flat photodiode detectors.
AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
RUQ: before PDT
RUQ: after PDT
LUQ: before PDT
RLQ: before PDT
RLQ: after PDT
µa (cm-1)
x (cm)
RUQ: before PDT
RUQ: after PDT
LUQ: before PDT
RLQ: before PDT
RLQ: after PDT
µeff (cm-1)
x (cm)
Figure 7: In-vivo distribution of (a) absorption and (b) effective attenuation coefficients
at 732 nm in the human prostate for patient #12. (Taken from Ref. 55).
AAPM Refresher Course (July 28, 2005) Photodynamic Therapy, Zhu et al
[Hb]t (µM)
StO2 (%)
MLu (ng mg-1) (X 10)
x (cm)
After PDT, from abs.
After PDT, from fl.
MLu (ng/mg)
x (cm)
Figure 8: In vivo distribution of (a) StO2, blood volume (µM), and MLu concentration
determined using the absorption spectra and (b) MLu concentration as determined by
absorption (triangles) and fluorescence (circles) measurements for RUQ in patient 13.
(Taken from Ref. 55)
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