Download Photodynamic Therapy in Cancer Treatment

Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
Photodynamic Therapy in Cancer Treatment
RCT summary for professionals
1. Abstract ................................................................................................................................ 3
2. What is it? ............................................................................................................................ 4
2.1 Introduction ...................................................................................................................4
2.2 Principles of photodynamic therapy .............................................................................5
2.2.1 Biological mechanisms of PDT ...............................................................................5
2.2.2 Basic components of PDT ......................................................................................7
2.2.2.1 Photosensitizers ............................................................................................... 7
2.2.2.2 Light sources and delivery ................................................................................9
2.2.3 Treatment monitoring ........................................................................................... 10
2.2.3.1 Dosimetry .........................................................................................................10
2.2.3.2 Optical imaging .................................................................................................11
2.3 Advantages and limitations of photodynamic therapy .................................................11
2.4 Mechanisms of synergies ............................................................................................. 13
2.4.1 Combinations of photodynamic therapy with standard therapies .....................13
2.4.2 Novel strategies in photodynamic therapy ......................................................... 14
2.4.2.1 Nanotechnology in PDT ...............................................................................14
2.4.2.2 PDT-mediated immune response ................................................................ 16
3. Does it work? ....................................................................................................................... 17
3.1 Introduction ...................................................................................................................17
3.2 Clinical applications of photodynamic therapy per anatomical location .....................18
3.2.1 Anal cancer ..........................................................................................................18
3.2.2 Barrett’s esophagus ............................................................................................. 18
3.2.3 Bile duct cancer ...................................................................................................19
3.2.4 Bladder cancer .....................................................................................................20
3.2.5 Brain cancer .........................................................................................................21
3.2.6 Cancer of the lower genital tract.........................................................................22
3.2.7 Esophageal cancer ............................................................................................... 23
3.2.8 Eye cancer............................................................................................................25
3.2.9 Head and neck cancer ......................................................................................... 25
3.2.10 Lung cancer........................................................................................................27
3.2.10.1 PDT in early stage lung cancer ...................................................................27
3.2.10.2 PDT in advanced lung cancer .....................................................................28
3.2.10.3 PDT in other lung cancer indications ......................................................... 29
3.2.11 Prostate cancer ..................................................................................................30
3.2.12 Skin cancer .........................................................................................................30
3.2.12.1 Actinic keratosis ......................................................................................... 31
3.2.12.2 Bowen’s disease ........................................................................................ 32
3.2.12.3 Basal cell carcinoma ..................................................................................33
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 1 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
4. Is it safe? ............................................................................................................................. 34
4.1 Does photodynamic therapy has any complications or side effects? ........................... 34
4.2 Contraindications for using photodynamic therapy .....................................................35
5. Conclusions .......................................................................................................................... 35
6. References............................................................................................................................ 36
6.1 Scientific publications ....................................................................................................37
6.2 Books ............................................................................................................................. 53
6.3 Professional Societies/Organizations ............................................................................54
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 2 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
1. Abstract
Photodynamic therapy (PDT) is a medical treatment that uses the combination of a drug, a
photosensitive molecule called a photosensitizer, and visible light of an appropriate
wavelength (generally in the red to deep red, between 600-800 nm) to activate the drug.
PDT involves a two-step procedure that consists of administering either locally or
systemically the photosensitizer, which is retained selectively by malignant tissue, followed
by local irradiation of the tissue which eventually results in a series of photochemical
reactions forming high-energy oxygen molecules. These reactions occurring in the
immediate locale of the light-absorbing photosensitizers mediate cellular toxicity in the
tumor and associated vasculature and induction of a local inflammatory reaction. PDT has
been under study for several decades and is now an emerging treatment modality for a
range of primarily malignant conditions. It is generally used as either a primary treatment or
as an adjunctive treatment alongside surgery or chemotherapy. PDT is under clinical
investigation for the treatment of cancers of mainly head and neck, skin, esophagus, lung,
gastrointestinal and genital tract, bladder, prostate and brain. Recent systematic reviews
revealed that PDT can be considered as an option in the treatment of malignant and
premalignant non-melanoma skin lesions. It is also useful in the treatment of Barrett’s
esophagus and unresectable cholangiocarcinoma. In general, the advantages of PDT over
classical chemotherapy or radiotherapy rely on lower long-term morbidity, improved
functional and cosmetic outcome, the possibility of repeated treatments either alone or as
adjuvant therapy. A perceived limitation of PDT, however, is that it is a localized therapy and
has little benefit in widespread disease. Current research is focused on the development of
photosensitizers that would be more powerful and more specifically target cancer cells.
Ongoing research exploiting the property of PDT to stimulate the host’s anti-tumor immunity
might expand the rather selective therapeutic applications of PDT to disseminated disease.
This review will address the basic principles of PDT and summarizes its current clinical status.
Keywords: photodynamic therapy, PDT
This text is written by Erik Cabuy (RCT) and reviewed by Prof. Patrizia Agostinis (Cell Death
Research and Therapy Unit, Department of Cellular and Molecular Medicine KU Leuven, KU
Leuven, Leuven, Belgium) and by Prof. Peter de Witte (Laboratory of Pharmaceutical Biology,
KU Leuven, Leuven, Belgium).
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 3 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
2. What is it?
2.1 Introduction
The first attempts to use photosensitizing drugs dates back to ancient Egypt, India, and
Greece, where psoralen-containing plant extracts and light were applied to treat psoriasis
and vitiligo (Daniell and Hill, 1991). The concept of photodynamic therapy dates from the
early days of the twentieth century. The use of an applied photosensitizing agent in
combination with light to treat disease may be attributed to Raab who as a medical student
unintentionally destroyed paramecia that had been incubated in a fluorescent dye when
strong light was introduced (Raab, 1900). The term photodynamic effect was coined by Von
Tappeiner in 1904 to describe oxygen-dependent chemical reactions induced by
photosensitization and eventually, by the early 1900s brought photodynamic therapy to the
clinic (Jodlbauer and Von Tappeiner, 1904; Jesionek and Von Tappeiner, 1905). The modern
explosion of interest in PDT dates from the discovery of hematoporphyrin derivative (HpD)
by Lipson and Baldes (Lipson and Baldes, 1960), and was fueled by pioneering studies in both
basic science and clinical application by Dougherty (1974) and co-workers (1978; 1979).
Although the application of the principles of photodynamic effect to patients’ treatment and
what became photodynamic therapy (PDT) was practiced in 1960s and 1970s, clinical trials
were only started in the 1980s, following successful synthesis of clinically usable
photosensitizers (drugs) and the manufacturing of light sources (Mitton and Ackroyd, 2008).
PDT belongs to the light induced therapies. Unlike other phototherapies, PDT employs a
sensitizing agent that when activated by an appropriate wavelength and intensity of light, in
the presence of oxygen, will lead to toxic photodynamic reactions that may cause direct
cancer cell killing and disrupt of the tumor vasculature (Allison et al., 2004). On the other
hand, the use of light to cause damage to diseased cells through localized heat generation is
referred to as photothermal therapy (PTT). PTT including derivatives hereof such as laser
immunotherapy will not be covered in this review. Phototherapy thus distinguishes itself
from PDT by lack of oxygen dependence. From the point of view of biological response, PDT
is fundamentally different from other cancer therapies. Unlike ionizing radiation, PDT
achieves its cytotoxic effects primarily though damage to molecular targets other than DNA.
The specific subcellular targets damaged by PDT depend on the photosensitizer’s localization
within the cell, which varies among photosensitizers and cell types. PDT can be ranked
among cancer therapies (including cryotherapy, hyperthermia, and focused ultrasound
ablation) producing a chemical and physical insult in tumor tissue perceived by the host as
localized acute trauma. PDT in particular is a promising approach to cancer treatment
because of the absence of systemic toxicity of the drug in the absence of light irradiation,
the possibility to irradiate the tumor selectively, the opportunity of treating multiple lesions
simultaneously, and the ability to retreat a tumor to improve the response. It has particular
appeal in oncology because the use of chemotherapy, ionizing radiation, or surgery does not
preclude the use of PDT, and all of these approaches can be used in a patient who has
received PDT. Despite these advantages PDT remains unknown to many oncologists.
PDT has been investigated most extensively in disorders for which standard treatment has
low efficacy or unacceptable side-effects. Examples include premalignant conditions and
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 4 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
tumors that are inaccessible by surgery or would be associated with unacceptably high
morbidity. PDT is approved for clinical use in a number of countries worldwide for the
elimination of early stage malignancies, palliation of symptoms, and reduction of obstruction
in patients with late stage tumors. Researchers continue to study ways to improve the
effectiveness of PDT and expand it to other cancers. Clinical trials are under way to evaluate
the use of PDT for cancers of the skin, cervix, head and neck, esophagus, lung,
gastrointestinal and genital tract, bladder, prostate, and brain. Other research is focused on
the development of photosensitizers that are more powerful, more specifically target cancer
cells, and are activated by light that can penetrate tissue and treat deep or large tumors.
Researchers are also investigating ways to improve equipment and the delivery of the
activating light. The purpose of this review is to outline the principles by which PDT ablates
tumor tissue within the human body, including limitations, mechanisms of synergies, and
patient outcomes are presented.
2.2 Principles of photodynamic therapy
2.2.1 Biological mechanisms of PDT
PDT is a treatment modality involving the topic or systemic administration of a
photosensitizing compound. Currently, it is believed that most photosensitizers (PSs) travel
intravenously as complexes of serum proteins (Allison et al., 2008). At this small size they
may not generally be recognized by the reticulo-endothelial system, though PS may still
undergo uptake by the Kupfer cells of the liver. The PSs are then taken up preferentially by
rapidly proliferating tissue, such as tumor tissue, although the mechanisms of this
phenomenon are not well understood (Nowis et al., 2005a). This may be through a
mechanism similar or identical to the low-density lipoprotein receptor. Leaky neovasculature
will also allow for enhanced permeability and accumulation of the PS in the tumor region
(Allison et al., 2010). PDT drugs in their free state need to be lipophilic to pass through
cellular membranes and reach subcellular sites sensitive to the initial oxidative damage that
will subsequently destroy cells (Wang et al., 2011a). The PS can be localized in various
organelles such as mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus and
plasma membranes and this sub-cellular location governs much of the signaling that occurs
after PDT (Mroz et al., 2011a). A period of time is required to permit photosensitizer uptake
ranging from a few minutes up to several days. The PS is then activated at a specific
wavelength of non-thermal monochromatic light and in the presence of oxygen, produces
reactive oxygen species (ROS). The accumulative presence of these cytotoxic photoproducts
starts a cascade of molecular and biochemical events resulting in cell death via apoptotic or
necrotic mechanisms (Dougherty et al., 1998; Buytaert et al. 2007). The use of a focused
non-ionizing light beam for drug activation instigates selective killing of tumor cells.
Sometimes the destruction of tumor cells is manifested as swelling and formation of necrotic
tissue. The damaged/killed tissue eventually sloughs away (or is resorbed), and there is
normal healing of the treated site. The antitumor effects of PDT derives from 3 inter-related
mechanisms: direct cytotoxic effects on tumor cells, damage to the tumor vasculature, and
induction of a robust inflammatory reaction that can lead to the development of systemic
immunity (Olivo et al., 2010). Each of these mechanisms will be described briefly.
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 5 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
Unique to PDT is the generation of an oxygen dependent photodynamic reaction. Following
the absorption of light (photons), the sensitizer is transformed from its ground state (singlet
state) into a relatively long-lived electronically excited state (triplet state) via a short-lived
excited singlet state (Henderson and Dougherty, 1992). The triplet state can undergo two
different reactions. First it can undergo electron transfer to form radicals that interact with
oxygen to produce oxygenated products, which effectively oxidize the cellular components
at locations where they have been produced (Calzavara-Pinton et al., 2007). Alternatively, it
transfers its energy directly to ground-state triplet oxygen to form singlet oxygen (1O2),
thought to be the main mediator of PDT. The first alternative is called type I reaction, the
second type II reaction. PDT-generated reactive oxygen species (ROS) subsequently lead to
severe oxidative stress causing damage to different intracellular membranes/organelles in
the treated cells and consequently lead to cell death. The lifetime of singlet oxygen is on the
order of microseconds and is limited to approximately 200 nm in diffusional range (Hopper,
2000). Consequently, 1O2-mediated oxidative damage will occur in the immediate vicinity of
the subcellular site of photosensitizing molecule localization during light exposure. Tissue
damage is therefore restricted to the penetration depth of the light used to activate the
photosensitizer. Different cell death modalities activated by PDT have been described such
as those involved in apoptosis (self-killing), cell death associated with autophagy (i.e. selfeating) and necrosis (Nowis et al., 2005b; Garg et al., 2010; Mroz et al., 2011a). To achieve
the desired therapeutic effect, this procedure should leave the surrounding healthy tissue
unharmed, and thus production of ROS should be spatially limited to the tumor tissue.
PDT also damages the tumor-associated vasculature. The shutdown of tumor vessels may
lead to local depletion of nutrients and oxygen and therefore trigger secondary PDT related
necrosis. Apart from direct cell killing and damage to the tumor vasculature, PDT can also
activate the host’s immune response against the tumors (Korbelik, 1996; Dougherty et al.,
1998; Dolmans et al., 2003; Korbelik et al., 2005; Castano et al., 2006; Gollnick and Brackett,
2010; Mroz et al., 2010; Mroz et al., 2011b). Numerous preclinical and clinical observation
studies have demonstrated the immuno-stimulatory capability of PDT, however, the precise
molecular mechanisms underlying PDT-induced antitumor immunity are not well defined.
PDT would alter the tumor microenvironment by stimulating the release or expression of
various pro-inflammatory and acute phase response mediators from the PDT-treated site
(Cecic and Korbelik, 2002; Gollnick et al., 2003; Cecic et al., 2006; Korbelik et al., 2008). PDT
thereby prompts a powerful acute inflammatory response, causing accumulation of
neutrophils and other inflammatory cells in large numbers at the treated site and attack
tumor cells (Krosl et al., 1995; Cecic et al. 2006). Studies reported infiltration of lymphocytes,
leukocytes and macrophages into PDT-treated tissue, indicating that PDT has the capability
to activate the immune response. Several preclinical studies demonstrated that PDT is able
to control the growth of tumors present outside the treatment field (e.g. Kabingu et al.,
2007), although others have failed to demonstrate control of distant disease after PDT (e.g.
Thong et al., 2008). While it is possible that the intracellular site of action of the
photosensitizer and type of cell death that ensues following its light-activation may influence
the immunogenic properties of the target cells (Garg et al., 2012), different studies
highlighted that compromising the host immune system has a negative impact on tumor
cure rates (Korbelik, 2006).
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 6 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
PDT-mediated anti-tumor immune responses are reviewed in Agostinis et al. (2011) and
Mroz et al. (2011b).
The combination of all three PDT mechanisms may lead to long-term tumor control via antitumor action against both the primary and metastatic tumors (Dolmans et al., 2003; Castano
et al., 2006; Gollnick and Brackett, 2010). The relative contribution of these mechanisms
depends to a large extent on the type and dose of PS used, the time between PS
administration and light exposure, total light dose and its fluence rate, tumor oxygen
concentration, and perhaps other still poorly recognized variables (Agostinis et al., 2011). All
of these factors are interdependent (Dolmans et al., 2003). Thus the choice of optimal
combinations of these parameters is crucial for successful PDT.
2.2.2 Basic components of PDT
While clinically relatively simple to perform, in reality PDT is a complex interaction requiring
numerous components to be available both in time and space. Here we will review the key
components of current PDT i.e. the photosensitizers and light sources.
2.2.2.1 Photosensitizers
Photosensitizers (PSs) are critical to the successful eradication of malignant cells and
numerous first and second-generation photosensitizers have been tested both clinically and
in vitro over the past years. The properties of an ideal photosensitizer should include (Moan,
1990b): a minimal dark toxicity, selective accumulation in target tissue, a short time interval
between administration and maximal accumulation in target tissue, rapid excretion from the
body to give minimal systemic toxicity, a high quantum yield of ROS production, which is
often mediated by singlet oxygen and a high extinction coefficient in the 600-800 nm range,
where light penetration into tissue is maximal, and where the photons still have enough
energy to produce 1O2. However, such an ideal photosensitizer has not been found yet. To
date, several PSs are commercially available and some of them are approved for the
treatment for oncologic indications. Most of the PSs used in cancer therapy are based on a
tetrapyrrole structure, similar to that of the protoporphyrin contained in hemoglobin, and
are derivatives of porphyrins, chlorines and bacteriochlorins (Allison and Sibata, 2010a).
Photosensitizers are generally classified as porphyrins and non-porphyrins. Porphyrin-based
photosensitizers are also often classified as a first, second, and third generation PS.
The first PS used clinically in PDT was hematoporphyrin derivative (HpD). Its purified fraction
porfimer sodium later became known as Photofrin. Photofrin and HpD are first-generation
photosensitizers. They are known to have two major drawbacks. One is the time taken
(typically 48 hours) for tissues to accumulate sufficient levels of PS to allow irradiation. The
second is the time taken for PS concentration to fall below clinically active levels. Persistent
levels will typically last for many weeks, causing photosensitivity of the skin. Photofrin,
however, does not appear to concentrate in connective tissue, allowing for superior tissue
healing even in heavily pretreated anatomy (Allison and Sibata, 2010a).
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 7 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
Many of the limitations of first generation PSs have been at least partially overcome by the
development of second generation photosensitizers. These second generation PSs have
various structures including porphyrins, expanded porphyrins, chlorophyll derivatives and
dyes (Allison and Sibata, 2010a). They demonstrate higher absorption in the 650-800 nm
range where tissue penetration is optimal and have higher extinction coefficients of
absorption in the red than the first generation compounds, shorter tissue accumulation time
and lower toxicity. Prolonged skin photosensitization, a problem that essentially hampered
the broad implementation of PDT, has been nearly eliminated by the development of second
generation PSs. The two main compounds in use are 5-aminolaevulinic acid (ALA) and its
methyl ester (MAL). Both are precursors of an endogenous photosensitizer, protoporphyrin
IX (PpIX), which is expressed in all nucleated mammalian cells but at very low level, below
those which would cause photosensitivity. After application of ALA or MAL to a skin tumor or
lesion the pro-drug is taken up into abnormal cells and converted via the heme cycle to PpIX.
The rate limiting step of ferrochelatase results in accumulation of PpIX in abnormal cells,
with relatively less accumulation in surrounding normal skin (Ibbotso, 2010). Administration
of sufficient ALA or MAL results in a rapid elevation (for a few hours) of PpIX levels, meaning
that illumination can take place. Following this there is also rapid systemic clearance of ALAinduced PpIX, within 24 hours. Tetra (m-hydroxyphenyl) chlorin (mTHPC, Foscan) is another
second generation photosensitizer, a pure synthetic chlorin compound, which is activated by
652 nm light. The major advantages of mTHPC are a short duration of skin photosensitivity
(15 days), a high quantum yield for singlet oxygen, and depth of tumor necrosis of up to 10
mm in preclinical models. PSs such as Indocyanine green (ICG) are being explored as an
alternative PDT agent for melanoma (Mamoon et al., 2009).
In recent times much work has been done on developing new PS, and at the present time
there is such a great number of potential PSs for PDT that it is difficult to decide which ones
are suitable for which particular disease or application. Side effects of the present PSs and
their specificities are the main reasons for designing new drugs for specific neoplastic
conditions. Also, PSs require amphylicity, the ability both to travel unhindered through the
blood system and then to localize and be introduced into the target tissue. Most of the
second generation PSs are hydrophobic and can aggregate very easily in aqueous media
which can affect their photophysical, chemical and biological properties. Therefore, third
generation photosensitizers are mainly characterized by the drug delivery approach, by
conjugation to carrier molecules to target the PS to the target cells, resulting in minimized
accumulation in healthy tissues (Josefsen and Boyle, 2008). To obtain higher tumor
localization, several tumor-targeting molecule photosensitizer conjugates were developed
such as a monoclonal antibody directed against tumor-associated antigens (Ogura et al.,
2012), oligonucleotides (Chernonosov, 2005), proteins (Huang et al., 2006), peptides
(Sibrian-Vazquez et al., 2007), cyclodextrins (Kralova et al., 2006), and epidermal growth
factors (Savitsky et al., 2000). Other means such as encapsulation of PSs in liposomes
(Guelluy et al., 2010) to enhance specificity are currently in research. A particularly
promising conjugate is based on a PS attached to a chemotherapeutic agent. The PS and
chemotherapeutic agents accumulate in the tumor membrane and via illumination lead to
PDT as well as release (photolysis) of the chemotherapeutic agent (Bednarski et al., 2007;
Noguchi et al., 2008). The conjugates might be an antibody, imaging agent, or perhaps a
biodegradable nanoparticle (see 2.4.2.1).
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 8 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
The PS can be administered systemically, locally, or topically to a patient bearing a lesion,
followed after some time by the illumination of the lesion with visible light. The mechanisms
involved in the selective uptake and retention of photosensitizers by tumor cells are not yet
fully understood. The specific subcellular targets damaged by PDT depend on the PS’s
localization within the cell, which varies among photosensitizers and cell lines. Very few PSs
have been rigorously tested for clinical application and only a handful have passed clinical
trials to allow for regulatory approval for patient treatment. Furthermore, some PSs have
passed regulatory approval in some countries, but not others, and are therefore unavailable
for patients (Allison et al., 2010). For an overview of photosensitizers see the clinical review
of Allison and Sibata (2010a).
2.2.2.2 Light sources and delivery
The primary requirement for the light source and delivery devices for photodynamic therapy
is to achieve adequate light illumination throughout the target tissue volume. This means
having the total optical power at the appropriate wavelength for activation of the
photosensitizer and optimum penetration into the target tissue and the corresponding
diffusion of the spatial distribution of that power with the size and shape of the tumor or
illumination volume (Mang, 2008). PDT became popular after the invention of the laser,
which allowed the production of monochromatic and coherent light that could be easily
coupled into optical fibers. An advantage of using lasers is that their light can be focused into
fiber systems and led to otherwise inaccessible locations, such as urinary bladder, digestive
tract or brain. Larger lesions can be treated with interstitial therapy, in which case multiple
laser fibers are inserted directly into the depth of the tumor through needles positioned
under image guidance. In addition to facilitating the treatment of thick and deeply lying
tumors, interstitial light delivery via multiple fibers allows for the treatment of irregularly
shaped lesions while sparing normal surrounding tissue. However, sometimes PDT demands
a homogeneous light distribution over an extensive surface area such as when treating
Barrett’s esophagus. In recent years, LED technology has come to the forefront of PDT.
These tiny light sources can now easily fit though scopes and biopsy channels for deep tissue
illumination. They can also be designed for easy surface illumination such as for skin cancer
through various arrays. The advance here is the highly portable energy source, for example,
battery power, which is self-contained. Now the patient can be mobile during illumination.
This allows for the realization of prolonged outpatient illumination as well as metronomic
repeated illumination (Bisland et al., 2004). However, the wavelength generated is not
amiable to manipulation and therefore have to be matched for a chosen photosensitizer.
Currently, most PDT procedures are performed with optical fibers which allow light to be
directed easily to deliver irradiation to desired regions without the requirement of a straight
light path. By attaching diffuse scattering tips of various geometrical shapes at the exit end
of the fiber, point, linear, and planar light sources can be produced. The wavelength of light
used for PDT is typically in the wavelength range between 600-800 nm, the so called
therapeutic window. In this wavelength range, the energy of each photon is high enough to
excite the photosensitizer and yet is low enough so that the light has sufficient penetration
into the tissue (Zu and Finlay, 2008). The interaction of light with tissue is incompletely
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 9 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
understood but in theory, wavelengths approaching 700-800 nm will penetrate tissue to
about 1 cm while wavelength closer to 600 nm penetrate to about 0.5 cm (Plaetzer et al.,
2009). Blue light thus penetrates least efficiently through tissue, whereas red and deep red
radiations penetrate more deeply. The interval between the sensitizer administration and
light exposure is also another key factor in determining PDT efficacy. Fractionated drug-dose
PDT regimens (i.e. metronomic PDT) were reported to result in a superior therapeutic effect
compared to single-dose regimens and were able to induce long-term tumor growth control
(Dolmans et al., 2002). For instance, light fractionation using a 2 hour dark interval
significantly enhanced the clinical response of superficial basal cell carcinoma to ALA PDT (de
Haas et al., 2006). For non-cutaneous lesions light is generally delivered in a single curative
fraction due to the technical difficulties in delivering low dose and prolonged or intermittent
(metronomic) illumination with commercially available light sources (Wilson and Patterson,
2008).
2.2.3 Treatment monitoring
2.2.3.1 Dosimetry
To successfully ablate lesions without undue normal tissue injury is the goal of PDT
dosimetry (Allison and Sibata, 2010a). To achieve this reliably and consistently requires
reproducible dose parameters. A myriad of variables affects the clinical outcome of PDT and
many attempts have been made to create a real time system of dosimetry that evaluates
these variables and generates appropriate treatment parameters (Allison and Sibata, 2010a).
The primary requirement when treating lesions with PDT is to ensure that sufficient,
homogenous light is delivered to the target tissue in the presence of an optimal tissue
concentration of photosensitizer. This is referred to as the photodynamic dose. The light
dose to a particular patient will depend on type of tissue (e.g. vascularity), applicator and on
the number of sequential fiber placements needed to treat the entire volume of the target
tissue. Since PDT works via the interaction between a photosensitizing drug, PS-activating
light and tissue oxygen, the outcome following PDT is dependent on the parameters used
during the treatment. Parameters that can affect the outcome include the intracellular
distribution of the PS, the PS and light doses, the time interval between PS administration
and light activation, the light fluence rate and the duration of light treatment (Olivo et al.,
2010). The fluence rate (the rate at which the PS-activating light is delivered) is known to be
one of the key parameters in PDT that can be varied to modulate the PDT outcome (Olivo et
al., 2010). Given the enormous challenge of measuring these factors and including them in
the practice of dosimetry for each patient, in the clinical setting the physician treating the
patient can, in practice, ignore all of these factors to save two critical therapeutic
components; the administered drug dose and the total light dose delivered. The physician
must ensure that the appropriate amount of light is delivered to the target site and that the
energy and time that light is delivered exceeds a value which has been determined by prior
clinical trials and is in accordance with standard approved light doses (Mang, 2008).
Currently, the use of drug dose and light dose as well as Drug application to Illumination
Interval (DLI) are the crude means employed to optimize therapy (Allison and Sibata, 2010a;
Olivo et al., 2010).
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 10 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
2.2.3.2 Optical imaging
Often, it is difficult to clinically discriminate neoplastic regions from normal tissue by
appearance in microsurgeries, irrespective of the cancer type. However some of the light
absorbed by photosensitizers is re-emitted at a different wavelength, a process known as
fluorescence. The fact that most photosensitizers are also fluorescent as well as
photochemically active means that imaging and detection strategies can be applied in PDT
protocols. These techniques are known as photo(dynamic) detection or diagnosis and may
be used alongside PDT. The technique of photodiagnosis (PD) relies on this differential
accumulation of photosensitizer within abnormal tissues. PD may thus be carried out to
detect otherwise hidden disease such as dysplasia, to delineate tumor borders, or to
visualize disease in inaccessible areas. This phenomenon has been clinically applied in
detecting neoplasms in the brain, esophagus, bladder, uterus, and skin. This technique
exploits PS-induced differences in fluorescent signatures between normal and tumor tissues
(Krammer and Plaetzer, 2008). Numerous studies show an improved ability to accurately
remove the tumor and conserve normal tissue (Allison and Sibata, 2008). This has already
been demonstrated to be feasible for cutaneous tumors and bladder cancer (Berger et al.,
2003; Szeimies et al., 2008). Analyzing the fluorescence region aids in estimating
preoperative states or postoperative residual tumor. Changes in fluorescence may be a part
of an accurate real time PDT dosimetry system that allows the operator to determine if
treatment was sufficient for lesion destruction during therapy (Wilson and Patterson, 2008).
Further, fluorescent signatures of malignant or premalignant lesions may be distinct enough
to allow for optical diagnosis instead of histological diagnosis (Brown et al., 2004).
2.3 Advantages and limitations of photodynamic therapy
PDT has the advantage of dual selectivity, due to the preferential localization of the
photosensitizer by the malignant tissue and restriction of photoactivation to the tumor site
due to localized light irradiation. In addition, the evident advantage of PDT over other
conventional cancer treatments such as chemotherapy and radiotherapy is its minimal side
effects, no drug resistance and reduced toxicity that allows for repeated treatment (Dolmans
et al., 2003; Wang et al., 2011a). Another benefit of PDT as compared to chemotherapy or
radiation therapy is that PDT does not seem to be carcinogenic (Allison and Sibata, 2010a);
mutations that confer resistance to chemotherapy or radiation therapy do not limit the
efficacy of PDT. None of the clinically approved PSs accumulate in cell nuclei, limiting DNA
damage that could be carcinogenic or lead to the development of resistant clones. An
additional advantage of PDT is that it can induce a form of programmed cell death called
apoptosis, which is not associated with the destructive effects of necrotic cell death. This
means that cancer cells dying in response to PDT by apoptosis, do not spill out their
intracellular content, thereby preventing major inflammatory reactions and damage to the
surrounding stromal components. Scar formation is minimal and the native tissue that
replaces the cancer cells maintains its normal functions limiting the functional loss
significantly (Karakullukcu et al., 2011). PDT thus has the ability to preserve the anatomic
and functional integrity of many organs such as the tongue, bladder or larynx (Dolmans et
al., 2003). PDT also offers the ability to treat diseased tissue not reachable by surgery. As has
been shown by many clinical studies PDT delivers excellent cosmetic results, scarring being
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 11 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
an exception. Excellent cosmetic outcomes make PDT suitable in particular for patients with
skin cancers (especially non melanoma skin cancer). There are no significant changes in
tissue temperature, and the preservation of connective tissue leads to minimal fibrosis,
allowing retention of functional anatomy and mechanical integrity of hollow organs
undergoing PDT. Selected patients with inoperable tumors, who have exhausted other
treatment options, can also achieve improvement in quality of life with PDT. The fact that a
rapid cyto- and vasculotoxic reaction ensues with visible tumor destruction and sparing of
normal tissue makes this therapy appealing to both patient and clinician. Moreover, PDT can
be applied alone or in combination as an adjuvant therapeutic modality with chemotherapy,
surgery, radiotherapy and immunotherapy (Juarranz et al., 2008; Ortel et al., 2009) (see 2.4).
Finally, many PDT procedures can be performed in an outpatient or ambulatory setting,
thereby not only alleviating costs, but also making the treatment patient-friendly. All of
these properties have led to PDT receiving increased support from preclinical research
although PDT is not widely available as compared to operating rooms and radiation centers.
However as often discussed, disadvantages of PDT do exist. The majority of currently
approved photosensitizing agents lack a complete selectivity and localization of the
photosensitizer in tumors vs. normal tissue (Mang, 2008). In this respect, PDT has also been
criticized by proponents of near infrared photo-immunotherapy (e.g. Mitsunaga et al., 2011)
for that the PS accumulation and selective recognition of target tissue is still not high enough
for many clinical applications. PDT is also less effective in treating poorly oxygenated large
tumors. Most wavelengths of light cannot penetrate through more than 1-2 cm of tissue
using standard laser and LED technology, thus limiting application of PDT to the treatment of
tumors on or under the skin, or on the lining of some internal organs or cavities. One way
around this limitation is to use hollow needles to get the light into deeper tissues. Highpowered LED technology combined with photosensitizers which excites at 750-800 nm
would await further development to achieve a greater depth of light penetration.
Paradoxically, the highly localized nature of PDT is also one of its current limitations, because
the treatment is ineffective against metastatic lesions, which are the most frequent cause of
death in cancer patients. Another limitation of PDT is the variability of photosensitizer
concentration observed in systemically photosensitized tissues, mainly due to differences of
the tissue architecture, cell lines, and pharmacokinetics (Vollet-Filho et al., 2010). If the local
concentration is lower than estimated for the application, only an insufficient photodynamic
effect will be achieved, and the targeted lesion will not be completely treated. This is a
relevant issue when dealing with malignant lesions because recurrence frequently worsens a
patient’s clinical condition (Vollet-Filho et al., 2010). Another parameter that can limit direct
tumor-cell destruction is the availability of oxygen within the tissue that is targeted by PDT.
It is known that most solid tumors contain regions with low oxygen concentration due to
poor vasculature and this may lead to low PDT efficiency. Systemic administration of the
photosensitizer leads to a period of unwanted residual photosensitivity that must be
managed until the drug is eliminated.
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 12 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
2.4 Mechanisms of synergies
2.4.1 Combinations of photodynamic therapy with standard therapies
One approach which is being explored for the enhancement of the effectiveness of PDT
involves the combination of a different therapeutic modality such as surgery, chemotherapy
and radiotherapy (Luksiene et al., 2006; Khdair et al., 2009; Postiglione et al., 2011).
Combinations of various therapeutic modalities with non-overlapping toxicities are among
the commonly used strategies to improve the therapeutic index of treatments in modern
oncology. However, there have been few recent studies on combinations of PDT with
standard antitumor regimens published to date. PDT can be used in combination with
surgery as a neoadjuvant, adjuvant, or repetitive adjuvant treatment, preferably
fluorescence image-guided (see 2.2.3.2) to confine illumination to the most suspicious
lesions. For instance, curettage of the hyperkeratotic or crusty surface or debulking of a
nodular basal cell carcinoma could be regarded as surgical approaches that can be combined
with subsequent PDT very well. Also the reduction of tumor size by PDT to simplify surgical
removal is a useful approach in specific cases (Sidoroff and Thaler, 2010).
PDT has been successfully combined with radiotherapy and chemotherapy (see ref. in
Agostinis et al., 2011). During the last twenty years of research, radiotherapy has been
combined with PDT, although conflicting results have been reported (Berg et al., 1995;
Luksiene et al., 1999; Takahashi and Misawa, 2008; 2009). PDT does not interfere with
radiotherapy which means for example that radiotherapy can still be used if PDT was
ineffective in a given patient (Sidoroff and Thaler, 2010). More recently, Weinberg et al.
(2010) reviewed the outcome of combined PDT and high dose rate brachytherapy (HDR) for
patients with symptomatic obstruction from endobronchial non-small cell lung cancer. The
authors concluded that combined HDR/PDT treatment for endobronchial tumors is well
tolerated and can achieve prolonged local control with acceptable morbidity when PDT
follows HDR and when the spacing between treatments is 1 month or less.
Several recent studies have examined the usefulness of PDT combination with local
chemotherapy. Zhang et al. (2007) conducted a pilot study in 140 patients to evaluate the
efficacy of PDT combined with local chemotherapy using 5-fluorouracil (5-FU) for the
palliative treatment of advanced esophagocardiac cancer. Long-term follow-up (up to 36
months) showed that the mean survival time of combined treatment group was longer than
that of the PDT group. Local administration of 5-FU can improve PDT efficacy and prolong
survival according to these authors. A study by Li et al. (2010) investigated the effect of
Photofrin PDT combined with chemotherapy (5-FU and DDP) on advanced esophageal
cancer, compared with PDT or chemotherapy alone. All the 90 patients were followed up for
2 years. It was concluded that PDT combined with chemotherapy for advanced esophageal
cancer is superior to PDT alone and chemotherapy alone. Another example of combined
therapy use is topical imiquimod or topical 5-FU; both have been shown to be effective in
non-melanoma skin cancer (Sidoroff and Thaler, 2010). In general, PDT can be used either
before or after surgery, ionizing radiation, or chemotherapy without compromising these
treatments or being compromised itself (Hopper, 2000; Agostinis et al., 2011). As yet these
combinations have not been studied much in patients.
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 13 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
2.4.2 Novel strategies in photodynamic therapy
As most current photosensitizers used in PDT do not display significant tumor tissue
selectivity, there is a need for designing improved targeted delivery as we have seen in
2.2.2.1. To enhance selectivity and overall efficacy of PDT, third-generation photosensitizers
are being designed and developed (Josefsen and Boyle, 2008), by improving the existing
photosensitizers, adding specific moieties and using delivery vehicles to specifically target
these compounds (Sharman et al., 2004). Targeted-PDT via receptor specific synthetic
peptides has been researched in the recent years to achieve a certain degree of selectivity
by site-specifically confining the PS, and thereby increasing the efficacy of PDT (Olivo et al.,
2010). Several other approaches to improve PDT outcome are currently under preclinical
investigation such as nanoparticle based drug delivery; vascular and anti-angiogenesis
targeted PDT and PDT-mediated immune response are in preclinical research. In addition,
molecular beacons as fluorescent probes with target specificity and 2-photon PDT are
interesting developments. In 2-photon PDT, short (approximately 100 femtosecond) laser
pulses with very high peak power are used, so that 2 light photons are absorbed
simultaneously by the PS. Because each photon only contributes one-half of the excitation
energy, near-infrared light can be used to achieve deeper tissue penetration (Agostinis et al.,
2011). Also, certain compounds activated by low-intensity ultrasound (sonosensitizers) have
been combined with PDT which is named sonodynamic photodynamic therapy (SPDT) (Wang
et al., 2011b). However, only two major developments in PDT will be discussed hereafter.
2.4.2.1 Nanotechnology in PDT
Nanoparticles (NPs) may offer a versatile platform for PDT drug delivery by targeting and
with additional advantages such as enhanced light penetration.
For PDT drug delivery, a photosensitizer is encapsulated or immobilized on the nanoparticle
surface using covalent or non-covalent interactions. The use of nanoparticles for molecular
transport is advantageous for providing an inert environment which protects the drug from
recognition and clearance before reaching the target. The same argument has been used for
the development of other transport vectors (including micelles, liposomes, dendrimers, and
polymer based NPs) for drug stabilization until reaching the tumor target (Doane and Burda,
2012). In addition, the advantage of this approach would be the targeted delivery of the
photosensitizer to the tumor site in a more selective manner and with low toxicity, rendering
minimal damage to the normal tissues (Bechet et al., 2008). In this approach, NPs can be
used as drug carriers where the drug is either dissolved in the matrices or adsorbed on the
surface of the cell. This approach has been gaining attention in recent years because of the
tunability of size, surface characteristics and high drug loading capability of the
nanoparticles. NPs can increase the solubility of hydrophobic drugs and offer the benefits of
hydrophilicity and proper size to accumulate in the tumor tissue. Selective accumulation may
be improved by the modification of the surface area using other ligands, which offers an
attractive strategy to increase drug delivery to cancer cells and thereby keeping them away
from healthy tissue sensitive to the toxic effect (Chatterjee et al., 2008; Kozlowska et al.,
2009). NP encapsulated photosensitive drugs have a variety of advantages. Due to their
small sizes they are not removed from the body by the reticulo-endothelial system which
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 14 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
leads to longer half-life times. They have a strong ability to protect encapsulated agents, are
compatible with biological systems, and their surface can easily be modified with functional
groups such as antibodies or other ligands to improve selectivity (Roy et al., 2003; Kateb et
al. 2011). Several types of nanomaterials for encapsulating PS have now been studied for
drug delivery. Such nanomaterials are: lipids, polymers, protein, dendrimers, metallic or
silicon nanoparticles, quantum dots (Oba, 2007; Dhankhar et al., 2010), and upconversion
nanoparticles (Wang et al., 2011a). Also, the use of carbon nanotubes as a new
photosensitizer for PDT is another area of research currently under investigation. NPs can be
biodegradable polymer based, such as chitosan (Lee et al., 2009) and poly lactic acid derived
(Zeisser-Labouebe et al., 2009) or inorganic particles such as silica (Roy et al., 2003) or gold
(Wieder et al., 2006) and quantum dots (Yaghini et al., 2009).
In addition to targeting, a nanoparticle based approach can have advantages such as,
increasing light penetration which is crucial for an effective PDT. To overcome this limitation,
NPs for 2-photon PDT (Gao et al., 2006) have been developed. Two-photon absorption
induced excitation uses two photons of lower energy (red shift, IR region) to produce an
excitation that would otherwise be produced by the absorption of single photon of high
energy (blue shift). Hence this method facilitates deeper penetration of light into tumor
tissues compared to the single photon PDT drugs. This feature has been used in the
treatment of gliomas as these tissues need higher penetration power. In another approach,
up-conversion phosphors for the ceramic-based NPs have been utilized by Ungun et al.
(2009) for PDT. Up-conversion phosphors are ceramic materials with a rare earth atom in the
crystalline matrix. These absorb light in the near IR region and up convert to emit shorter
wavelength light that activates the attached PS (Chatterjee et al., 2008). Advantages are that
the power required to excite these particles is 107 times less than the intensities needed for
two photon excitation of conventional organic dyes and they are resistant to
photobleaching. Another example is the combined use of PDT and magneto-hyperthermia
using magnetic nanoparticles (Gu et al., 2005; Primo et al., 2008). This is related to a
hyperthermia approach that combines PDT and photothermal therapy (PTT) (Kah et al.,
2008), in which photothermal agents can selectively heat the local environment (Barakat,
2009). This relies on materials where, after light absorption of the photothermal agent,
mainly non-radiative decay channels are used, which results in overheating of the area
around the light absorbing species. A typical example is the use of gold nanoshells
conjugated to anti-epidermal growth factor receptor as a photothermal agent and PDT using
hypericin as the photosensitizer, which proved to be an effective treatment strategy
compared to conventional PDT or PTT alone (Kah et al., 2008). A combination nanoparticle
for both PDT and chemotherapy (based on doxorubicin and methylene blue bound to
aerosol OT alginate nanoparticles) was used to overcome drug resistance problems in
chemotherapy (Khdair et al., 2009). Likewise, approaches for a combination of radiotherapy
and nanoparticle PDT have been developed. Here, scintillation or persistent luminescence
nanoparticles with bound PS are used. Upon exposure to ionizing radiation such as X-rays,
the nanoparticles emit scintillation or persistent luminescence, which, in turn, activates the
photosensitizers (Zhao et al., 2009).
However, also attention has to be given to the potential drawbacks of such systems. These
may include prolonged tissue exposure, yet unknown long term effects, stability (Muthu and
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 15 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
Feng, 2009), alteration of the photophysical properties of the PS. In fact, many toxic effects
of nanoparticles have been noted. These ranges from increased inflammation, to lung tumor
induction, impairment of cardiac function, higher levels of oxidative stress, platelet
aggregations and others (Radomski et al., 2005; Medina et al., 2007).
2.4.2.2 PDT-mediated immune response
A large body of evidence suggests that PDT-induced inflammatory reaction is a critical factor
for activating host anti-tumor immunity. It is reported that during and after PDT, proinflammatory damage formed in cellular membranes and the blood vessel walls of treated
tumors start to recruit neutrophils, mast cells, monocytes and macrophages (Chen and
Huang, 2006). In addition to its direct photo-cytotoxicity, PDT seems to induce a variety of
host immune responses under certain doses and treatment conditions (reviewed in Castano
et al., 2006; Gollnick and Brackett, 2010). While immune responses may be seen as a
secondary effect of PDT in cancer treatment, an active immunological stimulation can
produce synergistic effects and further enhance overall therapeutic efficacy. Recent studies
have further delineated the mechanisms of PDT-induced immune responses and the
rationale of combining PDT and immunotherapy to achieve better therapeutic effects.
It is now widely accepted that there is a pronounced activation of the immune system after
PDT for cancer in both animal models and also in patients. Both experimental and clinical
studies suggest that anti-tumor immunity may be responsible for eliminating minimal
residual tumors and preventing metastases (Chen and Huang, 2006). Several studies have
shown that local PDT treatment can lead to the induction of systemic anti-tumor immunity
(Castano et al., 2006; Gollnick and Brackett, 2010) and an ability to combat distant disease
(Kabingu et al., 2007; Thong et al., 2007; 2008). In a recent clinical study, it was reported that
basal cell carcinoma (BCC) patients who underwent PDT showed an increased systemic
immune response to a BCC associated tumor antigen compared to patients who underwent
surgical removal of the tumors (Kabingu et al., 2009). Garg et al. (2012) found that after PDT,
dying cancer cells undergo immunogenic apoptosis characterized by phenotypic maturation
and functional stimulation of dendritic cells as well as induction of a protective antitumor
immune response. It is possible that the activation of a specific and systemic host immune
response could result not only in further destruction of remaining tumor cells but also in the
control of metastases. For instance, Thong et al. (2007) reported clinical observation of a
PDT-activated immune response against distant untreated angiosarcoma lesions. Following
PDT of lesions in the head and neck region, new lesions appeared on both upper limbs,
whereupon the main cluster of lesions on the right upper limb were treated with PDT. The
untreated lesions on the right and left upper limbs underwent spontaneous remission 2
months and 4 months after PDT, respectively. This was the first clinical case in which
untreated distant tumors were observed to regress following PDT. Thus a local treatment of
tumors may lead to a systemic immune response against tumors outside of the treatment
field. In recent years, there has been a growing interest on this aspect of PDT-mediated
tumor destruction (Dolmans et al., 2003; Castano et al., 2005; Gollnick and Brackett, 2010).
There is at present a rather optimistic view on the possibility of developing effective antitumor immunotherapy, although only very little has yet reached the stage of clinically
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 16 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
proven efficacy. However, there is no agreement on the molecular and cellular determinants
of the effect and more importantly on how to improve it. Because of the infrequency and
generally unsatisfactory nature of the observable immune response after PDT, a
considerable amount of work has gone into testing strategies designed to administer some
sort of immunostimulant or adjuvant in combination with PDT to increase the frequency or
strength of the anti-tumor immune response. Large and diverse arrays of therapies that
combine PDT and an immunostimulant have been tested but there is no agreement on
which is best and which could be clinically applied. Many new studies show that
immunoadjuvants such as e.g. glycated chitosan (GC) can facilitate leukocyte infiltration.
Experimental data indicated that the combination of PDT and immunoadjuvants, such as GC,
could significantly increase the survival of tumor-bearing animals. T-cell responses (CD4 and
CD8) have been observed and these have been shown to be tumor specific and to lead to
memory immunity. Other reports have demonstrated the activation of neutrophils, NK cells
and macrophages after PDT (Mroz et al., 2011b). It would be safe to conclude that photoimmunotherapy awaits further evaluation and despite significant advances in specific
delivery of photosensitizer, still remains an experimental approach.
3. Does it work?
3.1 Introduction
This section highlights recent outcomes of photodynamic therapy (PDT). The purpose is to
summarize the clinical feasibility and efficacy of PDT for each anatomical tumor location.
Evidence for its efficacy comes from published research studies and clinical trials. Main focus
is on phase 2 and 3 randomized controlled clinical trials if available. Over 140 clinical trials
are registered in the ClinicalTrials.gov (access May 2012, conditions: the different cancer
types; interventions: photodynamic or PDT). An electronic search of the Medline, Embase,
Cochrane Library, CancerLit, and ClinicalTrials.gov databases was undertaken between
February 2012 and May 2012. Two sets of keywords were used for the search strategy. One
was for the PDT interventions, the other set was for each cancer type per anatomical
location. In vitro and animal studies, as well as case reports and abstracts have been
omitted, including studies published before 2005, however, review studies generally go
further back in time. Case reports have been mostly omitted mainly because they are based
on an individual patients profile hence results cannot be generalized. PDT applications in
experimental research of breast, liver, ovarian, cutaneous T-cell lymphoma, bone or rectal
cancer and in the treatment of vascular malformations (e.g. Jerjes et al., 2011d) will not be
covered either. Thus these selection criteria would benefit the rationale for rating the
efficacy of PDT based on what is available in clinical practice today.
A systematic review of PDT in the treatment of pre-cancerous skin conditions, Barrett's
esophagus and cancers of the biliary tract, brain, head and neck, lung, esophagus and skin
was conducted by Fayter et al. (2010). This review presents data till May 2009. More
recently, an eloquent general overview was given by Agostinis et al. (2011). A systematic
analysis of the literature per anatomical cancer location, however, is limited due to lack of
optimal PDT parameters (illumination conditions or PS dose) that could be comparable
among these studies as well as variation in PDT technique including photosensitizer choice
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 17 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
which makes comparison difficult. There is also considerable heterogeneity among the
studies with regard to both outcome measurements used and follow-up times reported. The
major endpoint of these studies though, has been response rates. Cosmetic outcome,
tolerability (pain) and patient’s preferences have been secondary endpoints in some of these
trials. Only a few adequately powered randomized controlled trials have been performed to
date. The clinical trials mentioned hereafter have tended to focus on patients who have not
responded to the usual treatment, but more recent research is now assessing the
effectiveness of PDT as a first-line intervention. PDT has been approved by several
authorities such as the National Institute for Clinical Excellence (NICE).
3.2 Clinical applications of photodynamic therapy per anatomical location
3.2.1 Anal cancer
There are only a small number of clinical reports on PDT for the treatment of cancer in the
anal region. Most recently, Allison et al. (2010d) examined the treatment and outcome of
Photofrin based PDT in a cohort of patients with anal cancer who failed locally despite
chemoradiation (n=6) and two patients with positive margins of resection after excision of
small T(1) squamous cell anal cancers who refused further surgery or chemoradiation. At the
drug dose and light dose employed lesion ablation is possible as is retention of a functioning
sphincter. All patients completed PDT without incident and all have maintained local control
of disease in the anal region for the length of follow-up (18-48 months). Photofrin Given the
good outcomes presented the authors suggested that PDT may be an option for sphincter
sparing salvage therapy and perhaps an upfront treatment for early stage disease.
3.2.2 Barrett’s esophagus
The application of PDT in the gastrointestinal tract has been divided into 2 groups: PDT of
the esophagus (see 3.2.7) and beyond i.e. Barrett’s esophagus. PDT has been used to treat
high grade dysplasia (HGD) in Barrett’s epithelium, and both early and advanced esophageal
carcinomas (Gray and Fullarton, 2007). A randomized, phase 3 trial of porfimer sodiummediated PDT for Barrett’s esophagus and high-grade dysplasia has been performed by the
International Photodynamic Group for High-Grade Dysplasia in Barrett’s Esophagus
(Overholt et al., 2007). Patients were randomized to treatment with omeprazole (70
patients) or omeprazole with PDT (138 patients). At 5 years, PDT was significantly more
effective than omeprazole alone in eliminating high-grade dysplasia (77% vs. 39%). A
secondary endpoint of preventing progression to cancer showed a significant difference with
approximately one-half the likelihood of cancer occurring in the PDT arm (15% vs. 29%).
There was also a significantly longer time to progression to cancer favoring PDT. On the basis
of this trial, it appears that PDT with porfimer sodium in addition to omeprazole is more
effective than omeprazole alone at producing long-term ablation of HGD and
slowing/preventing progression to cancer. It is based upon these data that the US FDA
approved porfimer sodium-mediated PDT for patients with Barrett’s esophagus and highgrade dysplasia who do not undergo surgery.
PDT using 5-aminolaevulinic acid (ALA PDT) may be a more attractive alternative to PDT with
porfimer sodium for the treatment of HGD in Barrett's esophagus because of the shorter
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 18 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
duration of light photosensitivity and low risk of esophageal stricture formation. Published
results, however, show marked variation in its efficacy, and optimum treatment parameters
have not been defined. One trial found that patients with HGD receiving high-dose ALA PDT
(60 mg/kg) and high-dose red light (1,000 J/cm) had a significant decrease in cancer risk
compared with treatment groups with lower doses of photosensitizer and/or lower light
doses at 36 months (3% risk vs. 24% risk). Red light was associated with lower rates of
adenocarcinoma than green light (8% vs. 45%) (MacKenzie et al., 2007). Also, Mackenzie et
al. (2009) investigated how the dose of ALA and the color of the illuminating light influenced
the biological effect. Twenty-seven patients were enrolled into a randomized controlled trial
of red versus green (635 nm or 512 nm) laser light activation for the eradication of HGD with
ALA PDT in Barrett's esophagus. A further 21 patients were subsequently treated with the
most effective regimen. Patient's receiving ALA at 30 mg/kg relapsed to HGD more than
those receiving 60 mg/kg. Additionally, for those treated with ALA 60 mg/kg, red laser light
was more effective than green laser light. 21 patients who were subsequently treated with
this optimal regimen demonstrated an eradication rate of 89% for HGD and a cancer-free
proportion of 96% at 36 months' follow-up. Using an ALA dose of 60 mg/kg activated by
1,000 J/cm red laser light, the authors found that ALA PDT was an effective treatment for
HGD in Barrett's esophagus.
NICE reported in 2010 that current evidence on the efficacy of PDT for patients with
Barrett’s esophagus with HGD is adequate, provided that patients are followed up in the
long term. There are no major safety concerns, although there is a risk of esophageal
stricture, and photosensitivity reactions are common. This procedure may be used in
patients with Barrett’s esophagus with HGD provided that normal arrangements are in place
for clinical governance, consent and audit (NICE, 2010). A Cochrane review, however,
concluded that radiofrequency ablation has significantly fewer complications than PDT and is
efficacious at eradicating both dysplasia and Barrett esophagus (Rees et al., 2010).
3.2.3 Bile duct cancer
Bile duct cancer or cholangiocarcinoma (CC) is emerging as an important treatment
indication for PDT (Allison et al., 2009a). Intervention is aimed at tumor removal if possible,
but mainly at biliary drainage. The majority of patients with hilar CC has irresectable disease
and requires palliation to alleviate symptoms and prevent biliary sepsis. Chemotherapy and
radiotherapy have proven to be ineffective. Palliative biliary drainage by either percutaneous
or endoscopic insertion of endoprostheses improves quality-of-life by reducing pruritus,
cholangitis, and pain, but has been reported to improve survival time only slightly (Tomizawa
and Tian, 2012). NICE reported in 2005 that current evidence on the safety and efficacy of
PDT for bile duct cancer does not appear adequate for this procedure to be used without
special arrangements for consent and for audit or research (NICE, 2005). More recently,
there have been several promising reports of the outcomes of PDT as an advanced palliative
strategy for CC, which have noted significant improvements in quality of life and survival
after PDT and stenting. PDT is usually given alongside biliary stenting following endoscopic
retrograde cholangiopancreatography (ERCP) rather than as a stand-alone treatment (Fayter
et al., 2010).
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 19 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
In a large study of 184 patients with hilar CC, Witzigmann et al. (2006) concluded that PDT
plus stenting, employed in a subset of 68 patients, was superior to stenting alone with
survival nearly doubling to 12 months. Successful drainage was achieved in 75% of PDT plusstent patients versus 39% receiving stents alone. Similarly, Kahaleh et al. (2008) reported
that the addition of Photofrin PDT to stenting alone achieved a 16.2 month vs. 7.4 month
survival advantage. Oral ALA has been tried for CC as well. A small phase 1/2 study of Foscan
for non-resectable biliary strictures from CC or recurrent stent occlusion achieved a median
survival of 8 months (Pereira et al., 2007). However, Foscan with the applied drug dose/light
dose combination appears to have significant acute morbidity and mortality.
Fuks et al. (2009) aimed to assess the accuracy of PDT in a single center. Fourteen selected
patients, with jaundice related to unresectable CC, underwent Photofrin PDT and biliary
stenting (with or without chemotherapy). No severe toxicity was noted. PDT improved the
Karnofski index in 64% of cases. The median survival time was 13.8 months and the 3-, 6and 12-month survival rates were 85%, 77% and 77%, respectively. When combined with
biliary drainage and chemotherapy, PDT appears to be an effective treatment for
unresectable CC, with low morbidity and mortality, a significant improvement in survival and
better quality of life. On the basis of these results, the authors believe that PDT should
become an integral part of the palliative treatment of CC, in combination with biliary
drainage and effective chemotherapy.
A prospective clinical cohort study evaluated the efficacy of radical curative surgery (10
patients), stenting combined with chemotherapy (17 patients) and stenting combined with
Photofrin PDT (23 patients) in 50 consecutive patients treated for hilar CC over a 5-year
period (Quyn et al., 2009). Actual 1-year survival was 80%, 12% and 75%, respectively. Mean
survival after resection was 1278 days. Mean survival was 173 days after stenting and
chemotherapy and 512 days after stenting and PDT. Patient survival was significantly longer
in the first and the last group of patients. This prospective clinical cohort study has
demonstrated that radical surgery and palliative Photofrin PDT are associated with an
increased survival in patients with hilar CC. Similarly, a study by Cheon et al. (2012) aimed to
determine long-term outcomes and factors associated with increased survival after PDT
compared with endoscopic biliary drainage alone in patients presenting with advanced hilar
CC. A retrospective analysis of the institutional database was conducted. Of the 232 patients
identified, 72 (31%) were treated with PDT and 71 (31%) were treated with endoscopic
biliary drainage alone. PDT with stenting resulted in longer median survival than stenting
alone (9.8 months vs. 7.3 months). Early PDT after diagnosis and multiple PDT treatments
were shown to have survival benefits. In addition, metal stent patency was longer in patients
receiving PDT. Tomizawa and Tian (2012), who conducted an electronic search for available
scientific literature published between 1991 and 2010 for PDT in treatment of unresectable
CC, concluded that although accumulated data and local expertise are limited, PDT can be
regarded as a standard palliative therapy for unresectable CC. Overall, PDT improves
survival, jaundice and quality of life, is well tolerated and can be repeated without losing its
efficacy (Ortner, 2011).
3.2.4 Bladder cancer
Bladder cancers, which are often superficial and multifocal, can be assessed and debulked
endoscopically. In addition, the geometry of the bladder should allow for improved and
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 20 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
homogeneous delivery of light. These factors would make superficial bladder cancer an
attractive target for PDT (Agostinis et al., 2011). In general, early response rates to PDT have
been observed in approximately 50% to 80% of patients, with longer term (1-2 years)
durable responses noted in 20% to 60% of patients (Agostinis et al., 2011).
Studies combining intravesical immunotherapies such as Bacillus Calmette-Guérin (BCG) or
chemotherapies such as mitomycin C with PDT showed that these therapies may
significantly enhance the PDT responsiveness of bladder tumors (Skyrme et al., 2005; Pinthus
et al., 2006). A randomized controlled study compared a single Photofrin-mediated PDT with
multiple BCG treatments (induction plus maintenance) and found that these therapies are
equivalent in durable treatment response. Jocham et al. (2009) designed a multicenter
phase 3 study to compare the efficacy of BCG instillations and PDT in the treatment of
patients with intermediate and high-risk non-muscle invasive bladder cancer (NMIBC). All
patients were centrally randomized after transurethral resection (TUR) to receive BCG
induction and maintenance therapy or a single PDT with Photofrin. 124 patients (63 PDT
group, 61 BCG group) were enrolled at 7 institutions. Each patient had a follow-up for 2
years. No statistically significant differences were demonstrated between the two therapy
arms with respect to recurrence-free survival after randomization. After intention-to-treat
analysis and after as-treated analysis, the estimated median recurrence-free survival periods
were 24.9 (BCG) versus 16.6 months (PDT) and 25.8 (BCG) versus 14.7 (PDT) months,
respectively. A single PDT with Photofrin in intermediate and high-risk NMIBC patients could
not be shown to be superior to BCG maintenance therapy.
Lee et al. (2010) evaluated PDT using chlorin e6-polyvinylpyrrolidone (Ce6-PVP) as a bladder
sparing therapy for high-risk NMIBC refractory to intravesical BCG therapy. Patients with
recurrent NMIBC after induction intravesical BCG therapy were treated with PDT. Five
patients underwent PDT; one patient received intravenous Ce6-PVP, while the rest received
intravesical Ce6-PVP. There were three patients with primary CIS of the bladder and two
with T1 high grade TCC and CIS of the bladder. At a median follow-up of 29 months, two
patients were disease free, two patients developed recurrence and one patient progressed
to muscle invasive disease. There were no immediate adverse effects. Despite being a small
pilot study, intravesical Ce6-PVP mediated PDT is a feasible bladder sparing treatment option
for recurrent high risk NMIBC in selected individuals.
Despite these promising results, PDT for bladder cancer remains largely investigational with
limited use. PDT for bladder cancer is approved in Canada and in some EU nations but has
not been approved by the US FDA.
3.2.5 Brain cancer
PDT has been used very little in the treatment of malignant brain tumors. It has been used in
addition to radiotherapy and/or chemotherapy, and is normally preceded by photodynamic
diagnosis (PD; see also 2.2.3.2) to identify tumor tissue. Photodynamic techniques such as
PD, fluorescence-guided tumor resection (FGR) and PDT are currently undergoing clinical
investigations as adjuvant treatment for malignant brain tumors (Kostron, 2010). Besides
many clinical phase 1/2 trials for PDT for malignant brain tumors, there are only few
controlled clinical trials following tumor resection. The initial trials provided encouraging
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 21 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
results, and the authors concluded that PDT can be used as an adjuvant therapy in patients
with brain tumors (Agostinis et al., 2011). Currently, photosensitizers (PSs) are being
evaluated both as intraoperative diagnostic tools by means of PD and FGR as well as during
PDT as an adjunctive therapeutic modality. All 3 approaches take advantage of the higher
uptake of PS by the malignant cells and are used intraoperatively. Recently published trials
that employed PD, FGR, and PDT provided encouraging results, but the initial delay in tumor
progression did not translate to extended overall survival. Stylli et al. (2005) reported the
results of a total of 375 patients treated with HpD mediated PDT following surgical resection.
Among the 375 patients, the majority consisted of those with newly diagnosed (138
patients) and recurrent (140 patients) glioblastoma multiforme (GBM). Additional
histological types included newly diagnosed (41 patients) and recurrent (46 patients)
anaplastic astrocytoma (AA). In the follow-up, the mean survival for both types of GBM was
between 14.3 and 14.9 months, and approximately 28% to 41% of patients survived more
than 2 years. For AA, the mean survival was between 66.6 and 76.5 months and 57% to 73%
of patients survived more than 3 years. Eljamel et al. (2008) performed a prospective
randomized controlled trial to evaluate ALA and Photofrin FGR and repetitive PDT in GBM.
They recruited 27 patients; 13 were in the study group and 14 were in the control group. The
mean survival of the study group was 52.8 weeks compared to 24.6 weeks in the control
group. There were no differences in complications or hospital stay between the two groups.
The mean time to tumor progression was 8.6 months in the study group compared to 4.8
months in the control group. Apparently, ALA and Photofrin fluorescence-guided resection
and repetitive PDT offered a worthwhile survival advantage without added risk to patients
with GBM. Lyons et al. (2012) reviewed the impact of PDT in conjunction with intraoperative
radiotherapy. Patients received standard therapy (ST), ST + PDT or ST + PDT + IORT (intraoperative radiotherapy). Thirty of 73 patients received PDT and the remaining did not. The
mean survival of PDT patients was significantly longer than those had ST alone (62.9 weeks
vs. 20.6 weeks). IORT on its own did not make a significant difference to survival. However
the average survival for patients who received PDT + IORT was substantially higher than
those who received PDT alone (79 weeks vs. 39.7 weeks). PDT in high grade glioma was
statistically significant, therapeutic modality and its effects were further improved by IORT.
In summary, there is limited evidence available on PDT for brain cancer and no definitive
statements can currently be made. Fluorescence-guided resection with repeated ALA PDT
may possibly have some effectiveness, but whether PDT has any role in treating brain
cancer, using current technologies, is a subject needing further debate (Fayter et al., 2010).
It remains to be seen whether PDT for brain tumors remains a palliative or, at most, an
alternative treatment modality.
3.2.6 Cancer of the lower genital tract
PDT is evaluated in different fields in gynecology. Recently, PDT was proposed as a promising
and highly selective therapeutic method for the treatment of cervical intraepithelial
neoplasia (CIN). CIN is associated with genital human papillomavirus (HPV) infection and
represents the precursor of cervical cancer. Soergel et al. (2008) suggested that PDT using a
topical precursor of photoactive porphyrins may be a non-invasive alternative with minimal
side effects for treating CIN. They assessed the feasibility and response rate of PDT with
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 22 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
hexaminolevulinate (HAL) in CIN and HPV infection. Twenty four patients with a CIN 2 or 3 or
a persistent CIN 1 and a positive high-risk HPV-DNA test were included. HAL-thermogel was
topically applied to the cervix, followed by illumination of both ecto- and endocervical canal
using a PDT laser and a special light catheter. Fifteen out of the 24 patients (63%) had a
complete response and a HPV remission 6 months after treatments. The remission rates
were 71%, 50%, and 71% for CIN 1, 2 and 3. HAL PDT seems to be a non-invasive, repeatable
procedure for CIN and cervical HPV infection with minimal side effects which can be
performed on an outpatient basis. A study by Soergel et al. (2010) aims at evaluating the
effect of HAL and methylaminolevulinate (MAL) PDT on cervical tissue. Twenty-five patients
underwent 1-2 PDT cycles for CIN 1-3 applying topical HAL and MAL. No macroscopic
changes of the cervix were encountered and histological evaluation revealed no signs of
apoptosis, necrosis, irritation, vascular changes and fibroses 6 months after PDT. HAL and
MAL PDT do not leave any sustained damage in normal cervical tissue. This is important
because cervical insufficiency or stenosis may have implications on pregnancy and cervical
cancer screening. Istomin et al. (2010) tested in clinics a previously developed novel organsaving approach for the treatment of CIN using PDT with the photosensitizer Photolon
applied in women of a childbearing age with CIN 2 and 3. All 112 patients had been observed
at least during 1-year follow-up period after PDT. A complete response was revealed in 104
(92.8%) of treated women. In 3 months after treatment a complete eradication of the HPV
infection was shown in 47 (53.4%) from 88 patients who have been infected with HPV of a
highly oncogenic strain before PDT. PDT with Photolon is suggested as an alternative
approach for the treatment of CIN which can be recommended for women of childbearing
age. The simplicity of the procedure as well as its therapeutic efficacy defines the
reasonability of its introduction into the clinical practice as a new organ-saving method for
the treatment of patients with CIN (Istomin et al., 2010).
Limited data reviewed in the original guidelines suggested that topical ALA PDT could be
effective in the treatment of vulval intraepithelial neoplasia (VIN). Topical PDT offers
therapeutic benefit in VIN (Morton et al., 2008). Zawislak et al. (2009) appraised in a study
PDT as a treatment method for VIN using a novel bioadhesive patch to deliver ALA. Twentythree patients with VIN lesions underwent PDT. Most patients (52%) reported a
symptomatic response, with normal pathology restored in 38% of lesions.
PDT has recently also been added to the list of treatment modalities used for patients with
penile intraepithelial neoplasia. In a study by Paoli et al. (2006) lesions initially responded to
PDT in 7 out of 10 patients. Four of these patients presented no recurrences during a mean
follow-up of 35 months, and were completely cleared after 2-8 treatments. Three patients
presented recurrences after treatment but no patient developed invasive penile cancer
(mean follow-up 46.5 months).
3.2.7 Esophageal cancer
PDT was first introduced as a palliative treatment for esophageal cancer but it is now also
used as a first-line treatment for patients with early esophageal cancer (Gray and Fullarton,
2007). The treatment objective in early-stage esophageal cancer is cure, whereas in
advanced cancer it continues to be a palliative option. PDT can be used alone or in
combination with a range of other therapies for curative and palliative purposes.
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 23 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
NICE reported in 2006 that the evidence on safety of PDT for early-stage esophageal cancer
appears to be adequate. They further state that PDT appears to be efficacious in reducing
tumor bulk in carefully selected patients with small early-stage tumors. However, the
current evidence is of poor quality and relates only to short-term outcomes; it is therefore
not adequate to support the use of this procedure without special arrangements for
consent, audit and clinical governance (NICE, 2006). Also, current evidence on the safety and
efficacy of palliative PDT for advanced esophageal cancer is of poor quality but appears
adequate to support the use of this procedure to relieve symptoms in patients with a poor
prognosis (NICE, 2007). To illustrate some of the findings in early stage esophageal cancer, a
study by Craig et al. (2007) described the use of Photofrin PDT as an alternative to surgery in
28 patients medically unfit for esophagectomy. 18 of 28 patients had an initial complete
response 8 weeks post procedure. Nine patients were non-responders. 7/18 complete
responders remained disease free for a mean follow-up period of 1166 days. 11/18
developed recurrent local disease treated with further PDT with a median survival of 770
days. Fourteen patients had EUS staging which accurately predicted response: all T1N0
patients (9/14) had initial complete response to treatment although 5/9 have required
further PDT. All remain disease free at a mean follow up of 1103 days. No patients with
T2/3N0 disease had complete response to treatment. The major complication of PDT
encountered was stricture formation which occurred in 50% of cases and required a median
of five dilations. Filonenko et al. (2008) performed PDT in 48 esophageal cancer patients
using photosensitizers (Photogem, Photosens, Radachlorin, Alasens) and equipment
developed in Russia. Complete regression was observed in 77% of esophageal cancer lesions,
partial regression was in 23%. The median of survival of esophageal cancer patient was 4.6
years. Lecleire et al. (2008) compared retrospectively the results and the complications rate
of PDT between consecutive patients treated in primary intent for a superficial esophageal
cancer versus patients treated by Photofrin PDT for a local recurrence after
chemoradiotherapy (CRT). 40 consecutive patients were treated by PDT for a superficial
esophageal cancer, 25 (group 1) in primary intent and 15 (group 2) for a local recurrence
after CRT. In group 1, 19 out of 25 patients (76%) were successfully treated versus 8 out of
15 patients (53%) in group 2. Severe complications were significantly more frequent in
patients treated after a prior CRT. PDT as a salvage therapy in patients with a local
recurrence after CRT for esophageal cancer tended to be less efficient than in first-line
treatment. Of interest is a retrospective single center study evaluating the effect of an
individualized multimodal palliative treatment in 250 patients (Lindenmann et al., 2012). The
treatment included PDT in 171 cases (in 118 as first measure), stenting in 124 (38),
endoscopic dilatation in 83 (24), endoluminal brachytherapy in 92 (20), feeding enterostomy
in 40 (14), external radiation in 67 (23), chemotherapy in 57 (29), and palliative resection in 3
patients. Distant metastases and nodal positivity were connected with a significantly
reduced survival. If PDT was used in the first place, median survival was 50.9 months
compared to 17.3 months if other options were used as initial modality. PDT, if used as initial
endoluminal treatment in patients without gross tumor infiltration into the mediastinum,
the great vessels or the tracheo-bronchial tree, enables a considerable beneficial effect in
the palliative setting.
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 24 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
3.2.8 Eye cancer
Successful PDT applications to conjunctival squamous cell carcinoma (SCC) have been
reported in a few patients (Barbazetto et al., 2004; Sears et al., 2008, Cekiç et al., 2011).
Barbazetto et al. (2004) described the use of PDT with verteporfin to conjunctival SCC in 3
patients. Sears et al. (2008) reported the case of a patient with conjunctival in situ SCC who
received ocular PDT. Although the patient was unable to complete the course of laser
treatment and subsequently underwent excision of the lesion, regression of the neoplasm
was observed. PDT seems to be advantageous with regard to treatment morbidity compared
with excision, cryotherapy, or radiation and may be useful in some cases of extensive ocular
surface squamous neoplasia that is less than invasive (Cekiç et al., 2011).
3.2.9 Head and neck cancer
Conventional treatments (surgery, radiotherapy) in head and neck cancer patients have
proven to achieve at times significant and permanent disfigurement and disability. It would
seem then that a minimally invasive local therapy such as PDT would be an ideal substitute
for select patients (Allison et al., 2009b). PDT in the treatment of head and neck cancer,
which is used with either curative or palliative intent, is normally a stand-alone treatment,
but can be used in combination with other treatments. It is particularly well suited to the
treatment of lesions of the head, neck, and oral cavity because it has little effect on
underlying functional structures and has an excellent cosmetic outcome (Hopper, 2000).
Hence, the management of head and neck cancer has been the focus of significant study in
the past years seeking to improve local-regional disease control rates while striving to
preserve function in these anatomical locations. Multiple institutions have published small
series of results demonstrating the efficacy of PDT. The technique has been successfully
employed to treat early carcinomas of the oral cavity, pharynx, and larynx, preserving
normal tissue and vital functions of speech and swallowing (Jerjes et al., 2010). For select
patients without nodal metastases or those at very low risk for nodal metastases, including
patients with in situ disease, early lip, superficial T1N0M0 cancers and early vocal cord
lesions, PDT as currently practiced, can be highly successful (Allison et al., 2009b). Very
select patients who have symptomatic local failure are another distinct cohort who may also
potentially be palliated, so long as the light source can be appropriately placed (Allison et al.,
2009b) or with advanced cancer of the head and neck, who have exhausted other treatment
options, can also achieve improvement in quality of life with PDT (Nyst et al., 2009).
However, to date there is not a single prospective phase 3 curative intent randomized trial
comparing PDT versus conventional treatments in head and neck cancer patients.
Copper et al. (2007) assessed meta-tetrahydroxy-phenyl chlorine (mTHPC)-mediated PDT in
the management of second or multiple primary tumors in the head and neck. A total of 27
patients with 42 second or multiple primary head and neck tumors were treated by PDT.
Twenty-eight of 42 tumors were cured (67%). Cure rates for stage I or in situ disease were
85% vs. 38% for stage 2/3. Cure rates for PDT of the multiple primary head and neck tumors
were lower than previously described for first primaries. In another study, Photofrinmediated PDT was assessed for the treatment of 30 patients with diffuse field cancerization
and Tis-T2N0M0 SCC of the oral cavity and oropharynx in patients not amenable to or that
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 25 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
have failed conventional head and neck cancer treatment (Schweitzer and Somers, 2010).
Twenty-four of 30 patients (80%) have demonstrated complete remission in a follow-up of 3144 months. Eleven of 24 patients were cancer disease free at 2 years. The authors came to
conclude that PDT provides a surgical oncologic modality for potentially curative treatment
of early stage oral cavity and oropharyngeal malignancies either as a primary modality or for
treatment in patients that have previously failed surgery and/or radiation therapy. In
addition, Karakullukcu et al. (2011) analyzed the institutional experience of early stage oral
cavity and oropharynx neoplasms (Tis-T2) to identify the success rates for each subgroup
according to T stage, primary or non-primary treatment and subsites. In total, 170 patients
with 226 lesions were treated with PDT. From these lesions, 95 are primary neoplasms, 131
were non-primaries (recurrences and multiple primaries). The overall response rate was
90.7% with a complete response rate of 70.8%. Subgroup analysis identified oral tongue,
floor of mouth sites with more favorable outcome. PDT thus seems to have more favorable
results with certain subsites and with previously untreated lesions.
Jerjes et al. (2011a) conducted a prospective clinical study to evaluate the outcome following
ultrasound guided interstitial PDT (US-iPDT) of tumors in the head and neck. One hundred
and ten patients underwent US-iPDT using mTHPC (Foscan) as the photosensitizing agent.
Following treatment, patients were followed-up for a mean of 26 months. Four out of five
patients who presented with visual problems reported improvement after treatment. Also,
27/32 reported improvement of breathing. Improvement of swallowing was reported by
30/37 patients; while speech improvement was evident in 22/29 patients and 43/52
reported reduction in the disfigurement caused by their pathology. Clinical assessment
showed that nearly half of the patients had good response to the treatment and 5 became
disease free. Moderate clinical response was reported by 39 patients. This study provided
further evidence that PDT is a useful modality in the management of these pathologies that
are otherwise resistant to conventional treatments, and with minimal side effects. A study
by the same group on T1/T2 oral cancer showed that 3 rounds of PDT are as successful as
surgery in terms of mortality with minimal morbidity (Jerjes et al., 2011b). This study
assessed the oncological outcomes following surface illumination mTHPC PDT of oral
squamous cell carcinoma in 38 patients. Pathological analysis revealed that 12 patients had
well differentiated SCC, 16 moderately differentiated and 10 had poorly differentiated
cancer. At last clinic review post-PDT, 26/38 patients showed complete normal clinical
appearance of their oral mucosa in the primary tumor site. Recent surgical biopsies from the
study cohort showed that 17 had normal mucosa, five with hyperkeratinization, 10 with
dysplastic changes and six showed recurrent SCC. The overall recurrence was 15.8% and the
5 year survival was 84.2%. Death from loco-regional and distant disease spread was
identified in three patients. The authors concluded that mTHPC PDT is a comparable
modality to other traditional interventions in the management of low-risk tumors of the oral
cavity. Morbidity following PDT is far less when compared to the three conventional
modalities: surgery, radiotherapy, and chemotherapy. Yet another study by the same group
evaluated the outcome following US-iPDT of stage IV tongue base carcinoma patients (Jerjes
et al., 2011c). Twenty-one patients were treated for advanced and/or recurrent tongue base
cancer using mTHPC. Two-thirds of the patients had not been offered further conventional
therapeutic options apart from palliative treatment. Following treatment, patients were
followed-up for a mean of 36 months. Nine of the 11 patients who presented with breathing
problems reported improvement after treatment. Also, 19 of the 21 patients reported
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 26 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
improvement of swallowing; improvement of speech was reported by 11 of 13 patients.
Clinical assessment showed that more than half of the patients had good response to the
treatment and about a third reported moderate response. Radiological assessment
comparing imaging 6-week post-PDT to the baseline showed stable pathology with no
change in size in four patients, minimal response in seven patients, moderate response in six
patients, and significant response in two patients. Eight patients died; four of which due to
loco-regional disease; and two from distant tumor spread. This study concludes that PDT is a
successful palliative modality in the treatment of advanced and/or recurrent tongue base
carcinoma.
3.2.10 Lung cancer
PDT is increasingly being utilized to treat thoracic malignancies. It is a treatment option for
patients with localized endobronchial cancer that is unsuitable for surgical resection and for
patients with inoperable non-small cell lung cancer (NSCLC), which have a poor prognosis.
PDT is intended to reduce the bulk of the tumor, therefore reducing symptoms caused, for
example, by bronchial obstruction. PDT may also be employed to downstage disease as part
of surgery or to treat surgical margins post resection (Agostinis et al., 2011). It can be
repeated if necessary, and can be used alongside other lung cancer treatments. NICE
reported in 2004 and 2005 that evidence on the safety and efficacy of PDT for localized
inoperable endobronchial cancer and for advanced bronchial carcinoma appears adequate
to support the use of this procedure. The use of PDT for both early-stage or advanced NSCLC
has several advantages over other therapies. The technique has a relatively favorable side
effect profile when compared to other treatment modalities like surgery, external beam
radiation therapy, or endobronchial brachytherapy. PDT for lung cancer is particularly useful
for patients with advanced disease in whom PDT is used as a palliation strategy and for
patients with early central lung cancer when patients are unable to undergo surgery. PDT is
considered to be more specific and lesion-oriented compared with other available modalities
and produces less collateral damage, and therefore fewer complications (Agostinis et al.,
2011). Multiple peer reviewed publications have shown the efficacy of PDT for
endobronchial obstructing lesions, early stage and minimally invasive endobronchial tumors
and in particular in situ and dysplastic lesions.
3.2.10.1 PDT in early stage lung cancer
For early-stage disease, PDT is primarily employed as an endobronchial therapy to treat
endobronchial or roentgenographically occult tumors (Simone et al., 2012). PDT can be
considered as well for the curative treatment of early central lung cancer, especially for
tumors 1 cm or less in diameter and provided there is no imaging evidence of extrabronchial involvement (Du Rand et al., 2011). Kato et al. (2006) reporting on 264 early
lesions treated with Photofrin found a 81% complete response rate and a 95% 5 year disease
specific survival rate. Usuda et al. (2007) employed NPe6 for both PDT and PD and noted a
92% complete response (CR) for 38 lesions. In a study by Corti et al. (2007) 40 patients with
early (T1N0M0) medically inoperable lesions (n=12) or recurrent carcinoma in situ following
previous treatment for invasive lung cancer (n=28) were treated with PDT and achieved a
72% overall complete response rate, with similar complete response rates for Tis lesions and
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 27 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
T1 lesions (73% vs. 69%). The median overall survival for the cohort was 91 months, patients
with Tis lesions demonstrating a longer median survival (120 vs. 36 months). Moghissi and
Dixon (2008) investigated the practice and results of PDT in early central lung cancer based
on the review of the literature and personal experience. Fifteen articles (626 patients/715
lesions) were selected. PDT was typically employed for patient ineligibility for operation, and
porfimer sodium photosensitizer followed by bronchoscopic laser illumination after an
interval of 48-72 hours was the most common treatment course. PDT-related death
occurred in 1 patient (0.15%), whereas adverse events included photosensitivity skin
reactions in 5-28%, respiratory complications in 0-18%, and non-fatal hemoptysis in 0-8%. A
complete response was achieved in 30-100% of patients for 2-120 months. The overall 5year survival rate was estimated to be 61% which is only slightly inferior to that achieved by
surgical resection in a similar stage of disease according to the authors. More recently, Endo
et al. (2009) treated 48 medically operable patients with roentgenographically occult
bronchogenic squamous cell carcinomas with bronchoscopic longitudinal tumor lengths of
≤1 cm with PDT. A complete response was achieved in 94% of patients, and the 5-year and
10-year overall survival rates for the cohort were 81% and 71%, respectively. Ali et al. (2011)
treated 16 centrally located early lung carcinomas with PDT and achieved a complete
response in 88% of lesions, but 29% of lesions that completely responded were subsequently
found to recur within 12 months of PDT administration. Usuda et al. (2010a) employed NPe6
to treat 91 endobronchial lesions. Lesions less than 1 cm (n=70) achieved CR in 94% of cases.
Lesions greater than 1 cm achieved CR in 90% of cases, though the majority of these cases
had undergone debulking just prior to PDT. The authors felt that NPe6 PDT may be more
versatile than Photofrin as the longer wavelength of treatment (664 nm) may allow for
improved outcomes to larger lesions. NPe6 which would have a stronger antitumor effect
than Photofrin, however, showed similar treatment outcome even for large tumors >1.0 cm
in diameter (Ikeda et al., 2011).
3.2.10.2 PDT in advanced lung cancer
A range of options are available to help alleviate symptoms for patients with advanced lung
cancer. These include brachytherapy, electrocautery, laser therapy, PDT (Cardona et al.,
2008) as well as cryotherapy. For patients with advanced-stage NSCLC, PDT can be used to
palliate obstructing endobronchial lesions, as a component of definitive multi-modality
therapy, or to increase operability or reduce the extent of operation required (Simone et al.,
2012). Ross et al. (2006) treated 41 patients with locally advanced NSCLC, including 78% with
stage III disease, received induction PDT and chemotherapy and/or radiation therapy. PDTbased induction allowed 57% of patients initially deemed unresectable to undergo definitive
surgical resection and 27% initially deemed in need of pneumonectomy to undergo
lobectomy, pathological downstaging in 64%, and a pathologic complete response in 18%
undergoing surgery. Overall, 46% of patients were alive at 3 years following therapy, and the
mean survival was greatest in patients undergoing lobectomy (35.9 months) and shortest in
those unable to undergo surgery after multi-modality therapy (14.7 months). Moghissi et al.
(2007) reviewed Photofrin PDT in early central lung cancer in subjects not eligible for
surgery. Indications for bronchoscopic PDT were recurrence or metachronous endobronchial
lesions following previous treatment with curative intent in 10 patients (11 lesions),
ineligibility for surgery because of poor cardiorespiratory function in 8 patients (9 lesions)
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 28 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
and declined consent to operation in 3 patients. 29 treatments were performed in 21
patients (23 lesions). All patients expressed satisfaction with the treatment and had a
complete response of variable duration. Six patients died at 3-103 months (mean 39.3),
three of which were not as a result of cancer. Fifteen patients were alive at 12-82 months.
The authors concluded that bronchoscopic PDT in early central lung cancer can achieve long
disease-free survival and should be considered as a treatment option in those ineligible for
resection. More recently, Weinberg et al. (2010) reviewed the outcome of combined PDT
and high dose rate brachytherapy (HDR) for patients with symptomatic obstruction from
endobronchial NSCLC in nine patients. Combined HDR/PDT treatment for endobronchial
tumors was well tolerated and can achieve prolonged local control with acceptable
morbidity when PDT follows HDR and when the spacing between treatments is 1 month or
less.
3.2.10.3 PDT in other lung cancer indications
Patients with pleural dissemination of NSCLC may also be treated with intraoperative PDT
following macroscopically complete surgical resection (Simone et al., 2012). A phase 2 trial
of porfimer sodium-mediated PDT was performed to investigate the efficacy of combined
surgery and PDT for patients with either recurrent or primary NSCLC with pleural spread, the
majority of whom had N2 lymph node involvement and bulky pleural disease (Friedberg,
2009). In this study, local control of pleural disease at 6 months was achieved in 11 of 15
patients (73%) and the median overall survival for all 22 patients was 21.7 months. These
results are highly encouraging in this population of patients and suggest that additional
investigation in this area is warranted (Agostinis et al., 2011).
Employing auto fluorescence bronchoscopy, Usuda et al. (2010b) identified 22 patients with
multiple early lesions. These individuals were treated either by PDT alone or PDT in some
lesions and surgical resections in others. All patients achieved complete response. The
authors contend that PDT alone is a potentially curative option. Similarly Jung et al. (2011)
analyzed a cohort of 32 patients treated by pneumonectomy, lobectomy, more limited
surgery or PDT. PDT was able to ablate most lesions. These authors felt that PDT may be the
optimal option. Sokolos et al. (2010) evaluated the outcome of 104 patients with multiple
early tumors. PDT alone was able to ablate all lesions less than 1 cm in size. These reports
confirm that PDT alone for this cohort of patients may provide acceptable local control and
disease free survival. Minnich et al. (2010) conducted a retrospective cohort study of a
prospective database. 133 symptomatic patients were treated with PDT for endobronchial
lung lesions of varying histologies. Indications for intervention were NSCLC in 89 patients,
metastatic airway lesions in 31 patients, small cell disease in 4 patients, benign disease in 7
patients, other or unknown in 2 patients. PDT was best used for bloody tumors that block
the tracheobronchial tree, even in severely debilitated patients with profound shortness of
breath from advanced malignancy who fail conventional core-out or laser treatments. It
allowed for significant improvements in dyspnea in 74% of patients.
Malignant pleural mesothelioma (MPM) is a cancer of the pleura that, similar to NSCLC with
pleural spread, has no currently available curative options. A recent study of macroscopically
complete, lung-sparing surgical debulking followed by intraoperative porfimer sodiummediated PDT for patients with locally advanced MPM found a median survival that had not
been reached with a 2.1-year median follow-up in patients after radical pleurectomy with
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 29 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
PDT (Friedberg and Cengel, 2010). Friedberg et al. (2011) reviewed the results of patients
who underwent a macroscopic complete resection, by two different surgical techniques, and
intraoperative PDT as a treatment for MPM. 28 patients with MPM underwent macroscopic
complete resection, 14 by modified extrapleural pneumonectomy (MEPP) and 14 by radical
pleurectomy (RP) and intraoperative PDT. Stage III/IV disease was present in 12 of 14
patients, with 50% or more with +N2 disease. The median overall survival for the MEPP
group was 8.4 months, but has not yet been reached for the RP group at a median follow-up
of 2.1 years. In addition to the inherent advantages of sparing the lung, RP plus PDT yielded
a superior overall survival than MEPP plus PDT in this series. The overall survival for the RP
plus PDT group was, for unclear reasons, superior to results reported in many surgical series,
especially for a cohort with such advanced disease. Given these results, the authors believe
RP plus PDT is a reasonable option for appropriate patients pursuing a surgical treatment for
MPM.
In summary, PDT is effective in the curative treatment of early stage lung cancer, in tumor
debulking and palliation of symptoms in tracheobronchial obstruction from NSCLC. It is
effective in the palliation of advanced tracheobronchial lung cancer, although adverse
events including hemoptysis can occur (Du rand et al., 2011).
3.2.11 Prostate cancer
Currently, PDT is being explored as a treatment option for localized prostate cancer. In a
report of temeporfin-mediated PDT as a first-line therapy, 6 patients with organ-confined,
Gleason score 6 prostate cancer were treated with 4 to 8 interstitial fibers with implants
designed to cover only the areas of the prostate with biopsy proven disease (Moore et al.,
2006). Four of these patients had a second PDT session due to biopsy confirmed persistent
disease at 3 months of follow-up. Although the treatment was relatively well tolerated, and
all patients showed evidence of necrosis on post-procedure imaging or biopsy, all 6 patients
had biopsy confirmed residual disease after PDT. Another group has studied in a phase 1 trial
motexafin lutetium (MLu) as a photosensitizer for PDT of the prostate (Du et al., 2006; Patel
et al., 2008). Also, vascular targeted PDT using padoporfin-mediated PDT has been studied in
recurrent prostate cancer (Weersink et al., 2005; Trachtenberg et al., 2007). In a phase 1
trial, 24 patients after definitive radiotherapy for prostate adenocarcinoma were treated
with padoporfin-mediated PDT using 2 interstitial fibers (Trachtenberg et al., 2007). This
study demonstrated that vascular-targeted PDT could be safely performed in this patient
population. In the follow-up phase 2 study, 28 patients were treated with increasing light
doses (Trachtenberg et al., 2008). After 6 months of follow-up, less residual cancer was
noted on biopsy as the light dose increased, however, toxicities were significant.
3.2.12 Skin cancer
Extensive experience has been gained with PDT for pre-malignant and malignant disorders of
the skin. Most experience has been in the treatment of actinic keratosis and cutaneous basal
cell carcinoma but there are also preliminary results in Bowen's disease and squamous cell
carcinoma. Topically active agents are preferred in the treatment of dermatological cancers
and pre-cancerous conditions, as most systemic photosensitizers produce prolonged
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 30 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
generalized photosensitivity. In addition to high clinical response rates, the cosmetic
outcome is excellent, and in controlled studies patients preferred PDT compared to other
therapy options (Braathen et al., 2007; Morton et al., 2008; Babilas et al., 2010; Christensen
et al., 2010; Kleinpenning et al., 2010; Sidoroff and Thaler, 2010). NICE and NCCN indeed
reported that there is adequate evidence of efficacy of PDT for the treatment of actinic
keratosis (AK), Bowen’s disease (BD) and basal cell carcinoma (BCC) to support its use for
these conditions. According to the British Association of Dermatologists (BAD) Guidelines
(update 2008), multicenter randomized controlled studies now demonstrate high efficacy of
topical PDT for AK, BD, superficial BCC and efficacy in thin nodular BCC, while confirming the
superiority of cosmetic outcome over standard therapies (e.g. cryotherapy, surgical
excision). Long term follow-up studies are also now available, indicating that PDT has
recurrence rates equivalent to other standard therapies in BD and superficial BCC, but with
lower sustained efficacy than surgery in nodular BCC. PDT can reduce the number of new
lesions developing in patients at high risk of skin cancer and may have a role as a preventive
therapy (Morton et al., 2008). However, the results of PDT for squamous cell carcinoma
(SCC) of the skin using topical PSs have been disappointing, with recurrence rates of greater
than 50% (NICE, NCCN). According to a recent Cochrane review, there is a clear need for
well-designed randomized studies in order to improve the evidence base for the
management of this condition (Lansbury et al., 2010).
PDT is being utilized at NCCN institutions for premalignant or superficial low-risk lesions on
any location on the body. In patients with low-risk shallow cancers, such as SCC in situ
(Bowen’s disease) or low risk superficial BCC, a topical therapy such as PDT may be
considered (NCCN). Guidelines for practical use of MAL PDT in non-melanoma skin cancer
have been published by the Norwegian PDT group (Christensen et al., 2010). It should be
clear that the skill set of the operator very often will make a tremendous difference in the
chance of achieving outstanding outcome with regard to treatment of cutaneous disease
(Allison and Sibata, 2010b). In the definitive setting, PDT is currently approved in the United
States, Canada, and the European Union (EU) for the treatment of AK and approved in the
EU and Canada for the treatment of BCC. The role of PDT in primary and metastatic
melanoma is so far quite limited. As melanoma has a propensity for regional and systemic
spread any local therapy is of limited value to the majority of patients (Allison and Sibata,
2010b). Recent findings of PDT for the treatment of AK, BD and BCC will be highlighted.
3.2.12.1 Actinic keratosis
Current national and international guidelines recommend the treatment of actinic keratoses
(AKs) in order to prevent their potential progression into SCC (Stockfleth and Kerl, 2006;
Braathen et al., 2007; de Berker et al., 2007). Of interest is however that AKs are classified by
others as in situ SCC anyway (Röwert-Huber et al., 2007). Several therapeutic options are
available, although PDT and imiquimod are the treatments of choice for patients with
multiple AK and field cancerization, as both are effective in treating wide areas of skin with
excellent cosmetic results (Serra-Guillén et al., 2012).
According to the guidelines devised by international experts from the International Society
for Photodynamic Therapy in Dermatology in 2005, PDT was highly suited for AK treatment,
leading to high cure rates (complete response of around 90% after 2 sessions) as well as
good-to-excellent esthetic results (>84%) (Braathen et al., 2007). The French Dermatology
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 31 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
Recommendations Association (aRED) also recognizes PDT as an effective treatment option
for multiple AK or AK in areas of skin with poor healing (Bonerandi et al., 2011). In the open,
multicenter, clinical trial by Morton et al. (2006a) 1,501 AK cases of the face and scalp in 119
patients were treated, and intra-individual MAL PDT was compared with cryotherapy. The
percentage rate of complete AK regression at 12 weeks in the per protocol (PP) population
was better for PDT (86.9%) than for cryotherapy (76.2%), with similar results observed at 24
weeks (89.1% vs. 86.1%). Cosmetic results for PDT in the PP population were also better
according to patients and assessors alike (Morton et al., 2006a; 2008). Similarly, PDT versus
cryotherapy which used ALA as the photosensitizer utilized a standardized cryotherapy
protocol and reported complete clinical clearance rates at 12 weeks to be significantly better
for patients treated with ALA PDT than with cryotherapy (89% vs. 77%) (Hauschild et al.,
2009). Also Szeimies et al. (2010) evaluated the efficacy and safety of PDT of AK with a new
stable nano-emulsion-based ALA i.e. BF-200 ALA. The study was performed as a randomized,
multicenter, double-blind, placebo-controlled, inter-individual, two-armed trial with BF-200
ALA and placebo. A total of 122 patients with four to eight mild to moderate AK lesions on
the face and/or the bald scalp were included. PDT with BF-200 ALA was superior to placebo
PDT. Also Dirschka et al. (2011) demonstrated in a randomized trial of 600 patients that BF200 ALA is superior to the registered MAL medication. Serra-Guillén et al. (2012) sought to
determine whether PDT or imiquimod provides a better clinical and histologic response in
patients with AK and whether sequential use of both was more efficacious than each
separately. 105 patients were randomly assigned into three treatment groups: PDT only;
imiquimod only; or sequential use of PDT and imiquimod. This study concluded that
sequential application of PDT and imiquimod provides a significantly better clinical and
histologic response in the treatment of AK than PDT or imiquimod monotherapy for patients
with multiple AK or field cancerization on the face or scalp.
3.2.12.2 Bowen’s disease
Bowen's disease (BD) is also known as squamous cell carcinoma in situ (SCC in situ). Topical
PDT is an effective therapy for BD, with equivalence to cryotherapy and equivalence or
superiority to topical 5-FU. Cosmetic outcome is superior to standard therapy. Topical PDT
offers particular advantages for large/multiple patch disease and for lesions at poor healing
sites (Morton et al., 2008). Topical PDT should achieve clearance rates of 86-93%, with up to
18% recurrence at 3-5 year follow-up (Ibbotson, 2010).
In a large randomized controlled trial (n=225) comparing topical MAL PDT with either
cryotherapy or 5-FU, estimated lesion sustained response at 12 months following treatment
was 80% for PDT, 67% for cryotherapy and 69% for 5-FU and superior cosmetic outcome
with PDT (Morton et al., 2006b). Cosmetic outcome at 3 months was good or excellent in
94% of patients treated with MAL-PDT vs. 66% with cryotherapy and 76% with fluorouracil,
and was maintained at 12 months. Thus topical PDT proved to be at least as effective as
cryotherapy and 5-FU and with superior cosmetic outcome. Calzavara-Pinton et al. (2008)
assessed MAL PDT for the treatment of BD and SCC. In total, 112 lesions of BD and SCC in 55
subjects were treated in an outpatient setting. The overall complete response rates were
73.2% at 3 months and 53.6% at 2 years. The maximal diameter of the lesion was a predictor
of relapse at 24 months of treatment outcome. MAL PDT may represent a valuable, effective
and well tolerated treatment option with good cosmetic outcome for superficial, wellThis document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 32 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
differentiated BD and microinvasive SCC. In contrast, its use for superficial SCCs with a
microinvasive histological pattern and for nodular, invasive lesions, particularly if poorly
differentiated keratinocytes are present should be avoided. In the study by López et al.
(2011), the overall response rate of BD was 90% at 3 months after MAL PDT and decreased
to 87% at the 12-month follow-up. Recent guidelines suggest that PDT is an effective
treatment for BD (Christensen et al., 2010).
3.2.12.3 Basal cell carcinoma
Other indications for PDT include superficial and nodular BCC. Evidence-based guidelines
support the use of topical PDT in the treatment of BCC, particularly low risk, superficial
lesions (Braathen et al., 2007; Morton et al., 2008). PDT may be considered where cosmetic
outcomes are of a high priority and/or the lesion is too large for surgery (NICE, 2006). It
appears to be useful in the short-term, especially for people who wish to avoid scarring.
However, long-term follow-up is needed according to a Cochrane review (Bath-Hextall et al.,
2006).
Szeimies et al. (2008) compared the efficacy and cosmetic outcome of topical MAL PDT with
excision surgery for superficial BCC over a 1-year period. In this multicenter, randomized,
controlled, open study, 196 patients were treated with either MAL PDT (n=100) or surgery
(n=96). Similar high efficacy rates were seen at 12 months for the two treatment arms with
9.3% recurrence for PDT and no recurrences in the surgery group. However, superior
cosmetic outcome was reported with PDT. Basset-Seguin et al. (2008) performed a
multicenter, randomized study comparing PDT using topical MAL PDT with cryotherapy for
treatment of superficial BCC. A total of 118 randomized patients were treated; 60 patients
with MAL PDT and 58 patients with cryotherapy. Complete response rates at 3 months were
97% and 95%, respectively. There was no difference in 5-year recurrence rates with either
treatment (20% with cryotherapy vs. 22% with MAL PDT). However, more patients had an
excellent cosmetic outcome with MAL PDT (60% vs. 16% with cryotherapy). PDT resulted in
statistically better cosmetic appearance when compared with cryotherapy at both 3-month
and 5-year follow-up points. These results provide evidence to support the use of MAL PDT
as an effective, non-invasive, selective treatment for superficial BCC with favorable cosmesis.
However, topical PDT has limitations in the treatment of thick skin tumors. Christensen et al.
(2009) evaluated the effect of pre-PDT deep curettage on tumor thickness in thick (>2mm)
BCC. At 3-month follow-up, complete tumor response was found in 93% and the cosmetic
outcome was rated excellent or good in 100% of cases. Deep curettage significantly reduces
BCC thickness and may with topical PDT provide a favorable clinical and cosmetic short-term
outcome.
Topical MAL PDT is also effective in nodular BCC (nBCC), although with a lower efficacy than
excision surgery, and may be considered in situations where surgery may be suboptimal
(Morton et al., 2008). Other studies have shown that the cosmetic outcome with MAL PDT is
superior to surgery in nodular BCC (Szeimies et al. (2008). A multicenter controlled study
showed estimated sustained response rates of 76% and 96% when comparing MAL PDT and
surgery respectively for nodular BCC, with recurrence rates of 14% and 4% respectively at 5
years (Rhodes et al., 2007). Furthermore, in a smaller study topical PDT was shown to be
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 33 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
inferior to surgery for nBCC (Berroeta et al., 2007). Mosterd et al. (2008) have shown that,
despite curettage and cautery 3 weeks before fractionated ALA PDT, 30% recurrence rates
were seen when treating nodular BCCs compared with only 2% following surgery. In another
randomized, double blinded study of nBCC the complete response rates were higher with
MAL PDT than with placebo (73% vs. 27%) (Foley et al., 2009).
In summary, PDT can be an appropriate and effective treatment alternative to cryosurgery
or surgical excision for selected patients with BCC (Agostinis et al., 2011). However, when
topical PDT is compared with surgery for BCC, topical PDT with ALA or MAL consistently
shows an increase in the recurrence rate compared with surgery for both superficial and
nodular BCC. In the treatment of primary nBCC, excision surgery is preferred over PDT
following this treatment regimen.
4. Is it safe?
4.1 Does photodynamic therapy has any complications or side effects?
In essence PDT is ablating a lesion and creating a wound that needs to heal. For small
superficial therapies this process may occur in a fairly mild form with minimal pain, wound
healing or other cosmetic and functional issues. However, for larger tumor volumes or
located deeper within the body specific complications may occur depending on tumor
location. Pain is currently the main limiting factor for cutaneous PDT (Apalla et al., 2010;
Attili et al., 2011). However, the number of patients reporting significant pain and having to
stop treatment because of this varies considerably. Maximal pain usually occurs in the early
part of irradiation during PDT and then gradually reduces. Pain is restricted to the
illuminated area and may reflect nerve stimulation and/or tissue damage. A range of
techniques has been used in an attempt to reduce PDT-related pain, including local
anesthesia and cooling the skin with fans or sprayed water (Morton et al., 2008). Arits et al.
(2010) reported a slightly higher pain score in patients treated for skin cancer during the
follow-up PDT session. Lindeburg et al. (2007) also found that the follow-up PDT session was
experienced more painful by the patients compared to the first PDT session.
Other side effects of PDT include long-lasting skin photosensitivity and occasional systemic
and metabolic disturbances (Castano et al., 2004). The photosensitizers are said to be
essentially inert, therefore, application should be well tolerated unless the patient is allergic
to the drug. However, once applied with PS the patient is photosensitive almost immediately
so photosensitivity precautions are critical to prevent improper and unwanted PDT. For
topically applied PS this means a local bandage to prevent local light exposure. For systemic
PS this translates to avoiding direct sunlight for various lengths of time depending on the PS
employed. For instance, the use of systemic photosensitizers such as Photofrin or Foscan is
associated with generalized photosensitivity to visible light which can be prolonged over
weeks to months (Ibbotson, 2010). Thus, patients are advised to avoid direct sunlight and
bright indoor light for at least 6 weeks. While this side effect pales in comparison to those
experienced by patients receiving extensive surgical procedures, radiation therapy,
chemotherapy and combinations thereof and though it is generally manageable it remains a
concern and can cause significant problems particularly in non-compliant patients (Mang,
2008). Nevertheless, current evidence suggests that there are no major safety concerns
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 34 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
associated with PDT for non-melanoma skin tumors (including premalignant and primary
non-metastatic skin lesions) (NICE, 2006). Although the used photosensitizer porfimer
sodium is selectively retained in tumor tissue compared to normal tissue at a ratio of at least
2:1, the drug does accumulate to significant levels in the skin and in the reticuloendothelial
system, especially of the liver and spleen (Lindenmann et al., 2012). Importantly, PDT has
not been reported to produce second malignant neoplasms, and PDT typically does not
compromise future treatment options for patients in need of additional definitive therapy.
Because PDT is a cold photochemical process (Hopper, 2000), there is no tissue heating, and
connective tissues such as collagen and elastin are largely unaffected. There is therefore
much less risk to the integrity of underlying structures than with thermal ablation techniques
and surgery. Other complications specifically occurring per tumor type are addressed in 3.2
and in the scientific literature.
4.2 Contraindications for using photodynamic therapy
No clear evidence was found implying that PDT should definitely not be used for certain
clinical conditions except a few. Contraindications to PDT include a history of porphyria and
allergy to active ingredients of the applied photosensitizer (Hohwy et al., 2007). In some
cases patients whose pulmonary capacity is limited may not be candidates for PDT as well.
Other contraindications of PDT include tumors known to be eroding into a major blood
vessel in or adjacent to the illumination site; a planned surgical procedure within the next 30
days; coexisting ophthalmic disease likely to require slit-lamp examination within the next 30
days and existing therapy with a photosensitizing agent (see ref. in Jerjes et al., 2011b).
Cutaneous illumination gives a very vigorous response in the entire illumination field often
with tissue slough. While this may heal in previously untreated patients, those whose
illumination fields overlap as well as, operated upon or irradiated regions, have significant
chronic tissue healing issues. Again, PDT will not be offered to these individuals due to this
morbidity risk (Allison and Sibata, 2010b). In studies published about the use of topical PDT
in dermatology to date there has been no evidence of increased phototoxicity or adverse
effects in immunosuppressed patients (Ibbotson, 2010).
5. Conclusions
Photodynamic therapy (PDT) relies on the presence of a photosensitizing agent (PS) which,
once activated by light of the appropriate wavelength, generates cytotoxicity. This is an
inherently complex process that depends on multiple variables including the chemical and
photochemical properties of the PS, the PS dosage and delivery vehicle, the drug-light time
interval, the wavelength, energy dose, power density and pulse structure of the light, and
the oxygenation state of the tissue. However, the technique in itself is simple, can commonly
be carried out in outpatient clinics, and is highly acceptable to patients. PDT is currently
most accepted in the treatment of malignant and pre-malignant non-melanoma skin lesions.
In this review we found evidence of effectiveness for the treatment of actinic keratosis and
basal cell carcinoma. It is also useful in the treatment of Barrett’s esophagus and
unresectable cholangiocarcinoma. Its acceptance into mainstream clinical practice is
exemplified by approval for its use in several conditions for instance by NICE. Although the
clinical results mentioned in 3.2 attest PDT an important role in the treatment of selected
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 35 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
cancer patients, it is remarkable that this therapeutic modality is not being generally offered
to patients with these diseases. The small number of randomized clinical trials in patients
and insufficient reporting on study methods and treatment outcomes do not enable us to
draw conclusions regarding PDT efficacy and safety in the remaining cancers described ad
hoc. However, we did not find any clear evidence implying that PDT should definitely not be
used for certain clinical conditions; rather there are a number of uncertainties that require
further investigation.
Compared with standard approaches PDT can achieve equivalent or greater efficacy in the
treatment of certain cancers, particularly in the head and neck and basal-cell carcinoma,
with greatly reduced morbidity and disfigurement. The advantages of PDT compared with
surgery, chemotherapy, or radiotherapy are reduced long-term morbidity and the fact that
PDT does not compromise future treatment options for patients with residual or recurrent
disease. The excellent cosmetic outcome makes it valuable for skin lesions and lesions of the
head, neck, and oral cavity. With endoscopic delivery of light to hollow structures, PDT has
been successful in the treatment of early gastrointestinal cancers, such as esophageal
cancer, and lung cancer. However, PDT is not yet a front-line therapy for most indications,
presumably owing to the lack of large randomized clinical trials. It remains in many cases an
alternative or palliative treatment or is used within the context of a clinical trial. We do not
yet fully know the effectiveness of PDT in relation to other treatments and optimal
parameters for PDT do not appear to be firmly established. There are no randomized phase
3 trials comparing PDT with other treatment modalities. Thus for most treatments, it is
premature to state whether PDT is superior, equivalent, or inferior to other ablative
treatments. Researchers continue to study ways to improve the effectiveness of PDT and
expand it to other cancers. In the future, it is likely that PDT will continue to be used as a
stand-alone modality or in combination with chemotherapy, surgery or other new strategies.
Other ways to improve PDT include the development of new photosensitizers, as well as the
optimization of PDT protocols such as fractionation of light or drugs. Well-designed clinical
trials that involve selectively localized photosensitizers and convenient light sources may
improve the prospects for the use of PDT in cancer. As PDT treatment is not available in all
centers at the moment, patients should be referred to a specialized center that conducts
PDT.
6. References
6.1 Scientific publications
Agostinis P, Berg K, Cengel KA, Foster TH, Girotti AW, Gollnick SO, Hahn SM, Hamblin MR,
Juzeniene A, Kessel D, Korbelik M, Moan J, Mroz P, Nowis D, Piette J, Wilson BC, Golab J.
Photodynamic therapy of cancer: an update. CA Cancer J Clin. 2011;61(4):250-81.
Ali AH, Takizawa H, Kondo K, Nakagawa Y, Toba H, Khasag N, Kenzaki K, Sakiyama S,
Mohammadien HA, Mokhtar EA, Tangoku A. Follow-up using fluorescence bronchoscopy for
the patients with photodynamic therapy treated early lung cancer. J Med Invest 2011;58:4655.
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 36 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
Allison RR, Downie GH, Cuenca R, Hu XH, Childs CJH, Sibata CH. Photosensitizers in clinical
PDT. Photodiag Photodyn Ther. 2004;1:27-42.
Allison RR, Mota HC, Bagnato VS, Sibata CH. Bio-nanotechnology and photodynamic therapy
- state of the art review. Photodiagnosis Photodyn Ther. 2008;5(1):19-28.
Allison RR, Zervos E, Sibata CH. Cholangiocarcinoma: an emerging indication for
photodynamic therapy. Photodiagnosis Photodyn Ther. 2009;6(2):84-92.
Allison RR, Sibata C, Gay H. PDT for cancers of the head and neck. Photodiagnosis Photodyn
Ther. 2009;6(1):1-2.
Allison RR, Bagnato VS, Sibata CH. Future of oncologic photodynamic therapy. Future Oncol.
2010;6(6):929-40.
Allison RR, Sibata CH. Oncologic photodynamic therapy photosensitizers: a clinical review.
Photodiagnosis Photodyn Ther. 2010 Jun;7(2):61-75.
Allison RR, Sibata CH. Photodynamic therapy: mechanism of action and role in the treatment
of skin disease. G Ital Dermatol Venereol. 2010;145:491-507.
Allison R, Moghissi K, Downie G, Dixon K. Photodynamic therapy (PDT) for lung cancer.
Photodiagnosis Photodyn Ther. 2011;8(3):231-9.
Apalla Z, Sotiriou E, Chovarda E, Lefaki I, Devliotou-Panagiotidou D, Ioannides D. Skin cancer:
preventive photodynamic therapy in patients with face and scalp cancerization. A
randomized placebo-controlled study. Br J Dermatol 2010;162:171-75.
Arits AH, van de Weert MM, Nelemans PJ, Kelleners-Smeets NW. Pain during topical
photodynamic therapy: uncomfortable and unpredictable. J Eur Acad Dermatol Venereol.
2010;24(12):1452-7.
Attili SK, Dawe R, Ibbotson S. A review of pain experienced during topical photodynamic
therapy - our experience in Dundee. Photodiagnosis Photodyn Ther. 2011;8(1):53-7.
Babilas P, Schreml S, Landthaler M, Szeimies RM. Photodynamic therapy in dermatology:
state-of-the-art. Photodermatol Photoimmunol Photomed 2010;26:118-32.
Barakat NS. Magnetically modulated nanosystems: a unique drug-delivery platform.
Nanomedicine 2009;4:799-812.
Barbazetto IA, Lee TC, Abramson DH. Treatment of conjuntival squamous cell carcinoma
with photodynamic therapy. Am. J. Ophthalmol. 2004;138:183-89.
Basset-Seguin N, Ibbotson SH, Emtestam L, Tarstedt M, Morton C, Maroti M, CalzavaraPinton P, Varma S, Roelandts R, Wolf P. Topical methyl aminolaevulinate photodynamic
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 37 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
therapy versus cryotherapy for superficial basal cell carcinoma: a 5 year randomized trial.
Eur J Dermatol. 2008;18(5):547-53.
Bath-Hextall FJ, Perkins W, Bong J, Williams HC. Interventions for basal cell carcinoma of the
skin. Cochrane Database of Systematic Reviews 2007, Issue 1.
Bechet D, Couleaud P, Frochot C, Viriot ML, Guillemin F, Barberi-Heyob M. Nanoparticles as
vehicles for delivery of photodynamic therapy agents. Trends Biotechnol 2008;26(11):61221.
Bednarski PJ, Mackay FS, Sadler PJ. Photoactivatable platinum complexes. Anticancer Agents
Med. Chem. 2007;7(1):75-93.
Berg K, Luksiene Z, Moan J, Ma LW. Combined treatment of ionizing radiation and
photosensitization by 5-aminolevulinic acid-induced protoporphyrin IX, Radiat. Res.
1995;142:340-46.
Berroeta L, Clark C, Dawe RS, Ibbotson SH, Fleming CJ. A randomized study of minimal
curettage followed by topical photodynamic therapy compared with surgical excision for
low-risk nodular basal cell carcinoma. Br J Dermatol 2007;157:401-3.
Bisland SK, Lilge L, Lin A, Rusnov R, Wilson BC. Metronomic photodynamic therapy as a new
paradigm for photodynamic therapy: rationale and preclinical evaluation of technical
feasibility for treating malignant brain tumors. Photochem Photobiol 2004;80:22-30.
Bonerandi JJ, Beauvillain C, Caquant L, Chassagne JF, Chaussade V, Clavère P, Desouches C,
Garnier F, Grolleau JL, Grossin M, Jourdain A, Lemonnier JY, Maillard H, Ortonne N, Rio E,
Simon E, Sei JF, Grob JJ, Martin L; French Dermatology Recommendations Association
(aRED). Guidelines for the diagnosis and treatment of cutaneous squamous cell carcinoma
and precursor lesions. J Eur Acad Dermatol Venereol. 2011;Suppl 5:1-51.
Braathen LR, Szeimies RM, Basset-Seguin N, Bissonnette R, Foley P, Pariser D, Roelandts R,
Wennberg AM, Morton CA; International Society for Photodynamic Therapy in Dermatology.
Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an
international consensus. Journal of the American Academy of Dermatology 2007;56(1):12543.
Brown SB, Brown EA, Walker I. The present and future role of photodynamic therapy in
cancer treatment. Lancet Oncol 2004;5(8):497-508.
Buytaert E, Dewaele M, Agostinis P. Molecular effectors of multiple cell death pathways
initiated by photodynamic therapy. Biochim Biophys Acta. 2007;1776(1):86-107.
Calzavara-Pinton PG, Venturini M, Sala R. Photodynamic therapy: Update 2006. Part 2.
Clinical results. J Eur Acad Dermatol Venereol 2007;21:439-51.
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 38 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
Calzavara-Pinton PG, Venturini M, Sala R, Capezzera R, Parrinello G, Specchia C, Zane C.
Methylaminolaevulinate-based photodynamic therapy of Bowen's disease and squamous
cell carcinoma. Br J Dermatol. 2008;159(1):137-44.
Cardona AF, Reveiz L, Ospina EG, Ospina V, Yepes A. Palliative endobronchial brachytherapy
for non-small cell lung cancer. Cochrane Database Syst Rev 2008;(2):CD004284.
Castano AP, Demidova TN, Hamblin MR, Mechanisms in photodynamic therapy: part one photosensitizers, photochemistry and cellular localization. Photodiagnosis Photodyn Ther.
2004;1:279-93.
Castano AP, Demidova TN, Hamblin MR, Mechanisms in photodynamic therapy: part two cellular signaling, cell metabolism and modes of cell death. Photodiagnosis Photodyn Ther.
2005;2:1-23.
Castano AP, Mroz P, Hamblin MR. Photodynamic therapy and anti-tumour immunity. Nat
Rev Cancer. 2006 Jul;6(7):535-45.
Cecic I, Korbelik M. Mediators of peripheral blood neutrophilia induced by photodynamic
therapy of solid tumors. Cancer Lett. 2002;183:43-51.
Cecic I, Stott B, Korbelik M. Acute phase response-associated systemic neutrophil
mobilization in mice bearing tumors treated by photodynamic therapy. Int
Immunopharmacol. 2006;6:1259-66.
Cekiç O, Bardak Y, Kapucuoğlu N. Photodynamic therapy for conjunctival ocular surface
squamous neoplasia. J Ocul Pharmacol Ther. 2011;27(2):205-7.
Chatterjee DK, Fong LS, Zhang Y. Nanoparticles in photodynamic therapy: an emerging
paradigm. Adv Drug Deliv Rev 2008;60:1627-37.
Cheng WR, Huang Z. Biophotonics and immune responses – Highlights from a new SPIE
photonics west conference (BIOS 2006). Photodiagnosis Photodyn Ther. 2006;3:184-89.
Cheon YK, Lee TY, Lee SM, Yoon JY, Shim CS. Longterm outcome of photodynamic therapy
compared with biliary stenting alone in patients with advanced hilar cholangiocarcinoma.
HPB (Oxford). 2012;14(3):185-93.
Christensen E, Skogvoll E, Viset T, Warloe T, Sundstrøm S. Photodynamic therapy with 5aminolaevulinic acid, dimethylsulfoxide and curettage in basal cell carcinoma: a 6-year
clinical and histological follow-up. Journal of the European Academy of Dermatology and
Venereology 2009;23(1):58-66.
Christensen E, Warloe T, Kroon S, Funk J, Helsing P, Soler AM, Stang HJ, Vatne O, Mørk C.
Guidelines for practical use of MAL-PDT in non-melanoma skin cancer. J Eur Acad Dermatol
Venereol 2010;24:505-12.
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 39 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
Copper MP, Triesscheijn M, Tan IB, Ruevekamp MC, Stewart FA. Photodynamic therapy in
the treatment of multiple primary tumours in the head and neck, located to the oral cavity
and oropharynx. Clin Otolaryngol. 2007;32(3):185-9.
Corti L, Toniolo L, Boso C, Colaut F, Fiore D, Muzzio PC, Koukourakis MI, Mazzarotto R,
Pignataro M, Loreggian L, Sotti G. Long-term survival of patients treated with photodynamic
therapy for carcinoma in situ and early non-small-cell lung carcinoma. Lasers Surg Med.
2007;39(5):394-402.
Craig C, Gray J, Macpherson M, Hodgson H, Zammit M, Fullarton G. Porfimer sodium
photodynamic therapy in the treatment of early oesophageal carcinoma. Photodiagnosis
Photodyn Ther. 2007;4(4):244-48.
Daniell MD, Hill JS. A history of photodynamic therapy. Aust N Z J Surg. 1991;61(5):340-8.
Doane TL, Burda C. The unique role of nanoparticles in nanomedicine: imaging, drug delivery
and therapy. Chem Soc Rev. Chem Soc Rev. 2012;41(7):2885-911.
De Berker D, McGregor JM, Hughes BR. Guidelines for the management of actinic keratoses.
Br J Dermatol 2007;156:222-30.
de Haas ER, Kruijt B, Sterenborg HJ, Martino Neumann HA, Robinson DJ. Fractionated
illumination significantly improves the response of superficial basal cell carcinoma to
aminolevulinic acid photodynamic therapy. J Invest Dermatol. 2006;126(12):2679-86.
Dhankhar R, Vyas SP, Jain AK, Arora S, Rath G, Goyal AK. Advances in novel drug delivery
strategies for breast cancer therapy, Artif. Cells Blood Substit. Biotechnol. 2010;38:230-49.
Dolmans DE, Kadambi A, Hill JS, Flores KR, Gerber JN, Walker JP, Borel Rinkes IH, Jain RK,
Fukumura D. Targeting tumor vasculature and cancer cells in orthotopic breast tumor by
fractionated photosensitizer dosing photodynamic therapy. Cancer Res. 2002;62(15):428994.
Dolmans DEJGJ, Fukumura D, Jain RK. Photodynamic therapy for cancer. Nature Reviews
Cancer 2003;3(5):380-87.
Dougherty TJ. Activated dyes as antitumor agents. J Natl Cancer Inst 1974;52:1333-6.
Dougherty TJ, Kaufman JE, Goldfarb A, Weishaupt KR, Boyle D, Mittleman A. Photoradiation
therapy for the treatment of malignant tumors. Cancer Res 1978;38:2628-35.
Dougherty TJ, Lawrence G, Kaufman JH, Boyle D, Weishaupt KR, Goldfarb A. Photoradiation
in the treatment of recurrent breast carcinoma. J Natl Cancer Inst 1979;62:231-7.
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 40 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
Dougherty TJ, Henderson BW, Gomer CJ, Jori G, Kessel D, Korbelik M, Moan J, Peng Q.
Photodynamic therapy. J. Natl Cancer Inst. 1998;90(12):889-905.
Du KL, Mick R, Busch TM, Zhu TC, Finlay JC, Yu G, Yodh AG, Malkowicz SB, Smith D,
Whittington R, Stripp D, Hahn SM. Preliminary results of interstitial motexafin lutetiummediated PDT for prostate cancer. Lasers Surg Med. 2006;38:427-34.
Du Rand IA, Barber PV, Goldring J, Lewis RA, Mandal S, Munavvar M, Rintoul RC, Shah PL,
Singh S, Slade MG, Woolley A. BTS Interventional Bronchoscopy Guideline Group. Summary
of the British Thoracic Society guidelines for advanced diagnostic and therapeutic flexible
bronchoscopy in adults. Thorax. 2011;66(11):1014-5.
Eljamel MS, Goodman C, Moseley H. ALA and Photofrin fluorescence-guided resection and
repetitive PDT in glioblastoma multiforme: a single centre Phase III randomised controlled
trial. Lasers Med Sci. 2008;23(4):361-7.
Endo C, Miyamoto A, Sakurada A, Aikawa H, Sagawa M, Sato M, et al. Results of long-term
follow-up of photodynamic therapy for roentgenographically occult bronchogenic squamous
cell carcinoma. Chest 2009;136:369-75.
Fayter D, Corbett M, Heirs M, Fox D, Eastwood A. A systematic review of photodynamic
therapy in the treatment of pre-cancerous skin conditions, Barrett's oesophagus and cancers
of the biliary tract, brain, head and neck, lung, oesophagus and skin. Health Technol Assess.
2010;14(37):1-288.
Filonenko EV, Sokolov VV, Chissov VI, Lukyanets EA, Vorozhtsov GN. Photodynamic therapy
of early esophageal cancer. Photodiagnosis Photodyn Ther. 2008;5(3):187-90.
Foley P, Freeman M, Menter A, Siller G, El-Azhary RA, Gebauer K, Lowe NJ, Jarratt MT,
Murrell DF, Rich P, Pariser DM, Oseroff AR, Barnetson R, Anderson C, Kossard S, Gibson LE,
Tope WD. Photodynamic therapy with methyl aminolevulinate for primary nodular basal cell
carcinoma: results of two randomized studies. International Journal of Dermatology
2009;48(11):1236-45.
Friedberg JS. Photodynamic therapy as an innovative treatment for malignant pleural
mesothelioma. Semin Thorac Cardiovasc Surg. 2009;21:177-87.
Friedberg JS, Cengel KA. Pleural malignancies. Semin Radiat Oncol. 2010;20:208-14.
Friedberg JS, Mick R, Culligan M, Stevenson J, Fernandes A, Smith D, Glatstein E, Hahn SM,
Cengel K. Photodynamic therapy and the evolution of a lung-sparing surgical treatment for
mesothelioma. Ann Thorac Surg. 2011;91(6):1738-45.
Fuks D, Bartoli E, Delcenserie R, Yzet T, Celice P, Sabbagh C, Chatelain D, Joly JP, Cheron N,
Dupas JL, Regimbeau JM. Biliary drainage, photodynamic therapy and chemotherapy for
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 41 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
unresectable cholangiocarcinoma with jaundice. J Gastroenterol Hepatol. 2009;24(11):174552.
Gao D, Agayan RR, Xu H, Philbert MA, Kopelman R. Nanoparticles for two-photon
photodynamic therapy in living cells. Nano Lett. 2006;6:2383-86.
Garg AD, Nowis D, Golab J, Agostinis P. Photodynamic therapy: Illuminating the road from
cell death towards anti-tumour immunity. Apoptosis 2010;15:1050-71.
Garg AD, Krysko DV, Verfaillie T, Kaczmarek A, Ferreira GB, Marysael T, Rubio N, Firczuk M,
Mathieu C, Roebroek AJ, Annaert W, Golab J, de Witte P, Vandenabeele P, Agostinis P. A
novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer
cell death. EMBO J. 2012;31(5):1062-79.
Gollnick SO, Evans SS, Baumann H, Owczarczak B, Maier P, Vaughan L, Wang WC, Unger E,
Henderson BW. Role of cytokines in photodynamic therapy-induced local and systemic
inflammation. Br J Cancer 2003;88:1772-79.
Gollnick SO, Brackett CM. Enhancement of anti-tumor immunity by photodynamic therapy.
Immunol. Res. 2010;46:216-226.
Gray J, Fullarton G. The current role of photodynamic therapy in oesophageal dysplasia and
cancer. Photodiagn Photodyn Ther 2007;4:151-9.
Gu H, Xu K, Yang Z, Chang CK, Xu B. Synthesis and cellular uptake of porphyrin decorated iron
oxide nanoparticles - a potential candidate for bimodal anticancer therapy. Chem Commun
2005:4270-2.
Hauschild A, Stockfleth E, Popp G, Borrosch F, Brüning H, Dominicus R, Mensing H, Reinhold
U, Reich K, Moor AC, Stocker M, Ortland C, Brunnert M, Szeimies RM. Optimization of
photodynamic therapy with a novel self-adhesive 5-aminolaevulinic acid patch: results of
two randomized controlled phase III studies. Br J Dermatol 2009;160:1066-74.
Henderson BW, Dougherty TJ. How does photodynamic therapy work? Photochem.
Photobiol. 1992;55:145-57.
Hohwy T, Andersen KE, Sølvsten H, Sommerlund M. Allergic contact dermatitis to methyl
aminolevulinate after photodynamic therapy in 9 patients. Contact Dermatitis 2007;57:3213.
Hopper C. Photodynamic therapy: a clinical reality in the treatment of cancer. Lancet Oncol.
2000;1:212-19.
Huang JD, Lo PC, Chen YM, Lai JC, Fong WP, Ng DKP. Preparation and in vitro photodynamic
activity of novel silicon (IV) phthalocyanines conjugated to serum albumins. J. In org.
Biochem. 2006;100:946-51.
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 42 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
Ikeda N, Usuda J, Kato H, Ishizumi T, Ichinose S, Otani K, Honda H, Furukawa K, Okunaka T,
Tsutsui H. New aspects of photodynamic therapy for central type early stage lung cancer.
Lasers Surg Med. 2011;43(7):749-54.
Istomin YP, Lapzevich TP, Chalau VN, Shliakhtsin SV, Trukhachova TV. Photodynamic therapy
of cervical intraepithelial neoplasia grades II and III with Photolon. Photodiagnosis Photodyn
Ther. 2010;7(3):144-51.
Jesionek A, Von Tappeiner H. On the treatment of skin cancers with fluorescent substances.
Arch Klin Med 1905;82:223-7.
Jerjes W, Upile T, Akram S, Hopper C. The surgical palliation of advanced head and neck
cancer using photodynamic therapy. Clin Oncol (R Coll Radiol). 2010;22:785-91.
Jerjes W, Upile T, Alexander Mosse C, Hamdoon Z, Morcos M, Morley S, Hopper C.
Prospective evaluation of 110 patients following ultrasound-guided photodynamic therapy
for deep seated pathologies. Photodiagnosis Photodyn Ther. 2011;8(4):297-306.
Jerjes W, Upile T, Hamdoon Z, Alexander Mosse C, Morcos M, Hopper C. Photodynamic
therapy outcome for T1/T2 N0 oral squamous cell carcinoma. Lasers Surg Med
2011;43(6):463-9.
Jerjes W, Upile T, Hamdoon Z, Abbas S, Akram S, Mosse CA, Morley S, Hopper C.
Photodynamic therapy: the minimally invasive surgical intervention for advanced and/or
recurrent tongue base carcinoma. Lasers Surg Med 2011;43(4):283-92.
Jerjes W, Upile T, Hamdoon Z, Mosse CA, Akram S, Morley S, Hopper C. Interstitial PDT for
Vascular Anomalies. Lasers in Surgery and Medicine. 2011;43:357-65.
Jocham D, von Wietersheim J, Pflüger H, Steiner H, Doehn C, Büttner H, Böhle A, Kausch I.
BCG versus photodynamic therapy (PDT) for nonmuscle invasive bladder cancer-a
multicentre clinical phase III study [in German]. Aktuelle Urol. 2009;40:91-99.
Jodlbauer A, Von Tappeiner H. On the participation of oxygen in the photodynamic effect of
fluorescent substances. Münch Med Wochenschr 1904;52:1139-41.
Josefsen LB, Boyle RW. Photodynamic therapy: novel third generation photosensitizers one
step closer? Br J Pharmacol 2008;154(1):1-3.
Juarranz A, Jaén P, Sanz-Rodríguez F, Cuevas J, González S. Photodynamic therapy of cancer.
Basic principles and applications. Clin Transl Oncol 2008;10:148-54.
Jung Jung EJ, Lee JH, Jeon K, Koh WJ, Suh GY, Chung MP, Kim H, Kwon OJ, Shim YM, Um SW.
Treatment outcomes for patients with synchronous multiple primary non-small cell lung
cancer. Lung Cancer. 2011;73(2):237-42.
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 43 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
Kabingu E, Vaughan L, Owczarczak B, Ramsey KD, Gollnick SO. CD8+ T cell-mediated control
of distant tumours following local photodynamic therapy is independent of CD4 + T cells and
dependent on natural killer cells. Br J Cancer 2007;96:1839-48.
Kabingu E, Oseroff AR, Wilding GE, Gollnick SO. Enhanced systemic immune reactivity to a
Basal cell carcinoma associated antigen following photodynamic therapy. Clin Cancer Res.
2009;15(13):4460-6.
Kah JCY, Wan RCY, Wong KY, Mhaisalkar S, Sheppard CJR, Olivo M. Combinatorial treatment
of photothermal therapy using gold nanoshells with conventional photodynamic therapy to
improve treatment efficacy: an in vivo study. Lasers Surg Med 2008;40:584-9.
Kahaleh M, Mishra R, Shami VM, Northup PG, Berg CL, Bashlor P, Jones P, Ellen K, Weiss GR,
Brenin CM, Kurth BE, Rich TA, Adams RB, Yeaton P. Unresectable cholangiocarcinoma:
comparison of survival in biliary stenting alone versus stenting with photodynamic therapy.
Clin Gastroenterol Hepatol 2008;6:290-7.
Karakullukcu B, van Oudenaarde K, Copper MP, Klop WM, van Veen R, Wildeman M, Bing
Tan I. Photodynamic therapy of early stage oral cavity and oropharynx neoplasms: an
outcome analysis of 170 patients. Eur Arch Otorhinolaryngol. 2011;268(2):281-8.
Kateb B, Chiu K, Black KL, Yamamoto V, Khalsa B, Ljubimova JY, Ding H, Patil R, Portilla-Arias
JA, Modo M, Moore DF, Farahani K, Okun MS, Prakash N, Neman J, Ahdoot D, Grundfest W,
Nikzad S, Heiss JD. Nanoplatforms for constructing new approaches to cancer treatment,
imaging, and drug delivery: what should be the policy? Neuroimage. 2011;54 Suppl 1:S10624.
Kato H, Usuda J, Okunaka T, Furukawa K, Honda H, Sakaniwa N, Suga Y, Hirata T, Ohtani K,
Inoue T, Maehara S, Kubota M, Yamada K, Tsuitsui H. Basic and clinical research on
photodynamic therapy at Tokyo Medical University Hospital. Lasers Surg Med 2006;38:3715.
Khdair A, Handa H, Mao G, Panyam J. Nanoparticle-mediated combination chemotherapy
and photodynamic therapy overcomes tumor drug resistance in vitro, Eur. J. Pharm.
Biopharm. 2009;71:214-22.
Kleinpenning MM, Van de Kerkhof PC, Gerritsen RM. The clinical efficacy of topical methylaminolevulinate photodynamic therapy in moderate to severe actinic keratoses of the face
and scalp. J Dermatolog Treat 2010;21:252-57.
Korbelik M. Induction of tumor immunity by photodynamic therapy. J. Clin. Laser Med. Surg.
1996;14:329-34.
Korbelik M, Sun J, Cecic I. Photodynamic therapy-induced cell surface expression and release
of heat shock proteins: relevance for tumor response. Cancer Res. 2005;65:1018-26.
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 44 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
Korbelik M. PDT-associated host response and its role in the therapy outcome. Lasers Surg
Med. 2006;38(5):500-8.
Korbelik M, Cecic I, Merchant S, Sun J. Acute phase response induction by cancer treatment
with photodynamic therapy. Int J Cancer 2008;122:1411-417.
Kozlowska D, Foran P, MacMahon P, Shelly MJ, Eustace S, O’Kennedy R. Molecular and
magnetic resonance imaging: the value of immunoliposomes. Adv Drug Deliv Rev
2009;61:1402-11.
Kralova J, Synytsya A, Pouckova P, Koc M, Dvorak M, Kral V. Novel porphyrin conjugates with
a potent photodynamic antitumor effect: Differential efficacy of mono- and bisbetacyclodextrin derivatives in vitro and in vivo. Photochem. Photobiol. 2006;82:432-38.
Krammer B, Plaetzer K. ALA and its clinical impact, from bench to bedside. Photochem.
Photobiol. Sci. 2008;7:283-89.
Krosl G, Korbelik M, Dougherty GJ. Induction of immune cell infiltration into murine SCCVII
tumour by photofrin-based photodynamic therapy. Br J Cancer 1995;71:549-55.
Lansbury L, Leonardi-Bee J, Perkins W, Goodacre T, Tweed JA, Bath-Hextall FJ. Interventions
for non-metastatic squamous cell carcinoma of the skin. Cochrane Database of Systematic
Reviews 2010, Issue 4.
Lecleire S, Di Fiore F, Antonietti M, Ben-Soussan E, Hochain P, Lerebours E, Michel P,
Ducrotté P. Nonoperable patients with superficial esophageal cancer treated by
photodynamic therapy after chemoradiotherapy have more severe complications than
patients treated in primary intent. Am J Gastroenterol. 2008;103(9):2215-9.
Lee SJ, Park K, Oh YK, Kwon SH, Her S, Kim IS, Choi K, Kim H, Lee SG, Kim K, Kwon IC. Tumor
specificity and therapeutic efficacy of photosensitizer-encapsulated glycol chitosan-based
nanoparticles in tumor-bearing mice. Biomaterials 2009;30:2929-39.
Lee LS, Thong PS, Olivo M, Chin WW, Ramaswamy B, Kho KW, Lim PL, Lau WK. Chlorin e6polyvinylpyrrolidone mediated photodynamic therapy - A potential bladder sparing option
for high risk non-muscle invasive bladder cancer. Photodiagnosis Photodyn Ther.
2010;7(4):213-20.
Li LB, Xie JM, Zhang XN, Chen JZ, Luo YL, Zhang LY, Luo RC. Retrospective study of
photodynamic therapy vs photodynamic therapy combined with chemotherapy and
chemotherapy alone on advanced esophageal cancer. Photodiagnosis Photodyn Ther.
2010;7(3):139-43.
Lindeburg KE, Brogaard HM, Jemec GB. Pain and photodynamic therapy. Dermatology
2007;215:206-08.
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 45 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
Lipson RL, Baldes EJ. The photodynamic properties of a particular hematoporphyin
derivative. Arch Dermatol 1960;82:508.
Luksiene Z, Kalvelyte A, Supino R. On the combination of photodynamic therapy with ionizing
radiation, J. Photochem. Photobiol. 1999;52:35-42.
Luksiene Z, Juzenas P, Moan J. Radiosensitization of tumours by porphyrins. Cancer Lett.
2006;40-47.
Lyons M, Phang I, Eljamel S. The effects of PDT in primary malignant brain tumours could be
improved by intraoperative radiotherapy. Photodiagnosis Photodyn Ther. 2012;9(1):40-5.
Mackenzie G, Selvasekar C, Jamieson N, Mosse C, Thorpe S, Novelli M, Bown S, Lovat L. Low
incidence of esophageal adenocarcinoma following optimal regimen of ALA PDT for high
grade dysplasia in Barrett’s esophagus. Gastrointest Endosc 2007;65:A132.
Mackenzie GD, Dunn JM, Selvasekar CR, Mosse CA, Thorpe SM, Novelli MR, et al. Optimal
conditions for successful ablation of highgrade dysplasia in Barrett’s oesophagus using
aminolaevulinic acid photodynamic therapy. Lasers Med Sci 2009;24:729-34.
Mamoon AM, Gamal-Eldeen AM, Ruppel ME, Smith RJ, Tsang T, Miller LM. In vitro efficiency
and mechanistic role of indocyanine green as photodynamic therapy agent for human
melanoma. Photodiagnosis Photodyn Ther. 2009;6(2):105-16.
Medina C, Santos-Martinez MJ, Radomski A, Corrigan OI, Radomski MW. Nanoparticles:
pharmacological and toxicological significance. Br J Pharmacol 2007;150:552-8.
Minnich DJ, Bryant AS, Dooley A, Cerfolio RJ. Photodynamic laser therapy for lesions in the
airway. Ann Thorac Surg. 2010;89(6):1744-8.
Mitton D, Ackroyd R. A brief overview of photodynamic therapy in Europe. Photodiagnosis
Photodyn Ther. 2008;5(2):103-11.
Moghissi K, Dixon K, Thorpe JAC, Stringer MR. Photodynamic therapy in early central lung
cancer: a treatment option for patients ineligible for surgical resection. Thorax 2007;65:3915.
Moghissi K, Dixon K. Update on the current indications, practice and results of photodynamic
therapy (PDT) in early central lung cancer (ECLC). Photodiag Photodyn Ther 2008;5:10-8.
Moore CM, Nathan TR, Lees WR, Mosse CA, Freeman A, Emberton M, Bown SG.
Photodynamic therapy using meso tetra hydroxy phenyl chlorin (mTHPC) in early prostate
cancer. Lasers Surg Med. 2006;38:356-63.
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 46 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
Morton C, Campbell S, Gupta G, Keohane S, Lear J, Zaki I, Walton S, Kerrouche N, Thomas G,
Soto P; AKtion Investigators. Intraindividual, right-left comparison of topical methyl
aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses:
a multicentre, randomized controlled study. Br J Dermatol. 2006;155(5):1029-36.
Morton C, Horn M, Leman J, Tack B, Bedane C, Tjioe M, Ibbotson S, Khemis A, Wolf P.
Comparison of topical methyl aminolevulinate photodynamic therapy with cryotherapy or
Fluorouracil for treatment of squamous cell carcinoma in situ: Results of a multicenter
randomized trial. Arch Dermatol. 2006;142(6):729-35.
Morton CA, McKenna KE, Rhodes LE. British Association of Dermatologists Therapy
Guidelines and Audit Subcommittee and the British Photodermatology Group. Guidelines for
topical photodynamic therapy: update. Br J Dermatol. 2008;159(6):1245-66.
Mosterd K, Thissen MR, Nelemans P, Kelleners-Smeets NW, Janssen RL, Broekhof KG,
Neumann HA, Steijlen PM, Kuijpers DI. Fractionated 5-aminolaevulinic acid-photodynamic
therapy vs. surgical excision in the treatment of nodular basal cell carcinoma: results of a
randomized controlled trial. British Journal of Dermatology 2008;159(4):864-70.
Mroz P, Szokalska A, Wu MX, Hamblin MR. Photodynamic therapy of tumors can lead to
development of systemic antigen-specific immune response. PLoS One. 2010;5(12):e15194.
Mroz P, Yaroslavsky A, Kharkwal GB, Hamblin MR. Cell Death Pathways in Photodynamic
Therapy of Cancer. Cancers 2011;3:2516-39.
Mroz P, Hashmi JT, Huang YY, Lange N, Hamblin MR. Stimulation of anti-tumor immunity by
photodynamic therapy. Expert Rev. Clin. Immunol. 2011;7:75-91.
Muthu MS, Feng S-S. Pharmaceutical stability aspects of nanomedicines. Nanomedicine
2009;4:857-60.
National Institute for Health and Clinical Excellence (NICE). Photodynamic therapy for
advanced bronchial carcinoma. (Interventional Procedure Guidance: IPG087). NICE, 2004.
URL: http://guidance.nice.org.uk/IPG087.
National Institute for Health and Clinical Excellence (NICE). Photodynamic therapy for bile
duct cancer (IPG134). NICE, 2005. URL: http://guidance.nice.org.uk/IPG134.
National Institute for Health and Clinical Excellence (NICE). Photo-dynamic therapy for early
oesophageal cancer (IPG200). NICE, 2005. URL: http://guidance.nice.org.uk/IPG200.
National Institute for Health and Clinical Excellence (NICE). Photodynamic therapy for
localised
inoperable
endobronchial
cancer
(IPG137).
NICE,
2006.
URL:
http://guidance.nice.org.uk/IPG137.
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 47 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
National Institute for Health and Clinical Excellence (NICE). Photodynamic therapy for
nonmelanoma skin tumours (including premalignant and primary non-metastatic skin
lesions) (Interventional
Procedure
Guidance:
IPG155). NICE,
2006. URL:
http://guidance.nice.org.uk/IPG155.
National Institute for Health and Clinical Excellence (NICE). Palliative photodynamic therapy
for advanced oesophageal cancer (Interventional Procedure Guidance: IPG206). NICE, 2007.
URL: http://guidance.nice.org.uk/IPG206
National Institute for Health and Clinical Excellence (NICE). Photodynamic therapy for
Barrett's oesophagus. (Interventional Procedure Guidance: IPG350). NICE, 2010. URL:
http://guidance.nice.org.uk/IPG350
Noguchi M, Skwarczynski M, Prakash H, Hirota S, Kimura T, Hayashi Y, Kiso Y. Development
of novel water-soluble photocleavable protective group and its application for design of
photoresponsive paclitaxel prodrugs. Bioorg. Med. Chem. 2008;16(10):5389-97.
Nowis D, Stokłosa T, Legat M, Issat T, Jakóbisiak M, Gołąb J. The influence of photodynamic
therapy on the immune response. Photodiagnosis Photodyn. Ther. 2005;2:283-98.
Nowis D, Makowski M, Stoklosa T, Legat M, Issat T, Golab J. Direct tumor damage
mechanisms of photodynamic therapy. Acta Biochim. Pol. 2005; 52:339-52.
Nyst HJ, Tan IB, Stewart FA, Balm AJ. Is photodynamic therapy a good alternative to surgery
and radiotherapy in the treatment of head and neck cancer? Photodiagnosis Photodyn. Ther.
2009;6(1):3-11.
Oba T. Photosensitizer Nanoparticles for Photodynamic Therapy. Current Bioactive
Compounds 2007;3:239-51.
Ogura SI, Hagiya Y, Tabata K, Kamachi T, Okura I. Improvement of tumor localization of
photosensitizers for photodynamic therapy and its application for tumor diagnosis. Curr Top
Med Chem. 2012;12(3):176-84.
Olivo M, Bhuvaneswari R, Lucky SS, Dendukuri N, Thong PSP. Targeted therapy of cancer
using photodynamic therapy in combination with multi-faceted anti-tumor modalities.
Pharmaceuticals 2010;3:1507-29.
Ortel B, Shea CR, Calzavara-Pinton P. Molecular mechanisms of photodynamic therapy. Front
Biosci 2009;14:4157-72.
Overholt BF, Wang KK, Burdick JS, Lightdale CJ, Kimmey M, Nava HR, Sivak MV Jr, Nishioka N,
Barr H, Marcon N, Pedrosa M, Bronner MP, Grace M, Depot M; International Photodynamic
Group for High-Grade Dysplasia in Barrett's Esophagus. Five-year efficacy and safety of
photodynamic therapy with Photofrin in Barrett’s high-grade dysplasia. Gastrointest Endosc
2007;66:460-8.
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 48 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
Paoli J, Ternesten Bratel A, Löwhagen GB, Stenquist B, Forslund O, Wennberg AM. Penile
intraepithelial neoplasia: results of photodynamic therapy. Acta Derm Venereol.
2006;86(5):418-21.
Patel H, Mick R, Finlay J, Zhu TC, Rickter E, Cengel KA, Malkowicz SB, Hahn SM, Busch TM.
Motexafin lutetium-photodynamic therapy of prostate cancer: short- and long-term effects
on prostate-specific antigen. Clin Cancer Res. 2008;14:4869-76.
Pereira SP, Ayaru L, Rogowska A, Mosse A, Hatfield AR, Bown SG. Photodynamic therapy of
malignant biliary strictures using meso-tetrahydroxyphenylchlorin. Eur J Gastroenterol
Hepatol 2007;19(6):479-85.
Pinthus JH, Bogaards A, Weersink R, Wilson BC, Trachtenberg J. Photodynamic therapy for
urological malignancies: past to current approaches. J Urol. 2006;175:1201-07.
Plaetzer K, Krammer B, Berlanda J, Berr F, Kiesslich T. Photophysics and photochemistry of
photodynamic therapy: fundamental aspects. Lasers Med Sci 2009;24(2):259-68.
Postiglione I, Chiaviello A, Palumbo G. Enhancing photodynamyc therapy efficacy by
combination therapy: dated, Curr. Oncoming Strateg. Cancers 2011;3(2):2597-2629.
Primo FL, Rodrigues MM, Simioni AR, Lacava ZG, Morais PC, Tedesco AC. Photosensitizerloaded magnetic nanoemulsion for use in synergic photodynamic and magnetohyperthermia
therapies of neoplastic cells. J Nanosci Nanotechnol 2008;8:5873-7.
Quyn AJ, Ziyaie D, Polignano FM, Tait LS. Photodynamic therapy is associated with an
improvement in survival in patients with irresectable hilar cholangiocarcinoma. HPB. 2009;
11(7):570-77.
Raab O. On the effect of fluorescent substances on infusoria (German). Z Biol 1900;39:524.
Radomski A, Jurasz P, Alonso-Escolano D, et al. Nanoparticle induced platelet aggregation
and vascular thrombosis. Br J Pharmacol 2005;146:882-93.
Rees JRE, Lao-Sirieix P, Wong A, Fitzgerald RC. Treatment for Barrett's oesophagus. Cochrane
Database of Systematic Reviews 2010, Issue 1. Art.
Rhodes LE, de Rie MA, Leifsdottir R, Yu RC, Bachmann I, Goulden V, Wong GA, Richard MA,
Anstey A, Wolf P. Five-year follow-up of a randomized, prospective trial of topical methyl
aminolevulinate photodynamic therapy vs surgery for nodular basal cell carcinoma. Arch
Dermatol. 2007;143(9):1131-6.
Ross P Jr, Grecula J, Bekaii-Saab T, Villalona-Calero M, Otterson G, Magro C. Incorporation of
photodynamic therapy as an induction modality in non-small cell lung cancer. Lasers Surg
Med 2006;38:881-9.
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 49 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
Roy I, Ohulchanskyy TY, Pudavar HE, Bergey EJ, Oseroff AR, Morgan J, Dougherty TJ, Prasad
PN. Ceramic-based nanoparticles entrapping water-insoluble photosensitizing anticancer
drugs: a novel drug-carrier system for photodynamic therapy. J. Am. Chem. Soc. 2003;125:
7860-65.
Röwert-Huber J, Patel MJ, Forschner T, Ulrich C, Eberle J, Kerl H, Sterry W, Stockfleth
E.Actinic keratosis is an early in situ squamous cell carcinoma: proposal for reclassification.
Br J Dermatol 2007;156(Suppl 3):8-12.
Savitsky AA, Gukasova NV, Gumanov SG, Feldman NB, Luk’yanets EA, Mironov AF,
Yakubovskaya RI, Lutsenko SV, Severin SE. Cytotoxic action of conjugates of R-fetoprotein
and epidermal growth factor with photoheme, chlorines, and phthalocyanines. Biochemistry
(Moscow), 2000; 65:732-36.
Schweitzer VG, Somers ML. PHOTOFRIN-mediated photodynamic therapy for treatment of
early stage (Tis-T2N0M0) SqCCa of oral cavity and oropharynx. Lasers Surg Med.
2010;42(1):1-8.
Sears KS, Rundle PR, Mudhar HS, Rennie IG. The effect of photodynamic therapy on
conjuntival in situ squamous cell carcinoma - a review of the histopathology. Br. J.
Ophthalmol. 2008;92:716-17.
Serra-Guillén C, Nagore E, Hueso L, Traves V, Messeguer F, Sanmartín O, Llombart B,
Requena C, Botella-Estrada R, Guillén C. A randomized pilot comparative study of topical
methyl aminolevulinate photodynamic therapy versus imiquimod 5% versus sequential
application of both therapies in immunocompetent patients with actinic keratosis: Clinical
and histologic outcomes. J Am Acad Dermatol. 2012;66(4):e131-7.
Sharman WM, van Lier JE, Allen CM. Targeted photodynamic therapy via receptor mediated
delivery systems. Adv. Drug Deliv. Rev. 2004;56(1):53-76.
Sibrian-Vazquez M, Ortiz J, Nesterova IV, Fernandez-Lazaro F, Sastre-Santos A, Soper SA,
Vicente MG. Synthesis and properties of cell-targeted Zn(II)-phthalocyanine-peptide
conjugates. Bioconjugate Chem. 2007;18:410-20.
Sidoroff A, Thaler P. Taking treatment decisions in non-melanoma skin cancer – the place for
topical photodynamic therapy (PDT). Photodiagnosis Photodyn Ther 2010;7:24-32.
Simone CB, Friedberg JS, Glatstein E, Stevenson JP, Sterman DH, Hahn SM, Cengel KA.
Photodynamic therapy for the treatment of non-small cell lung cancer. J Thorac Dis.
2012;4(1):63-75.
Skyrme RJ, French AJ, Datta SN, Allman R, Mason MD, Matthews PN. A phase-1 study of
sequential mitomycin C and 5-aminolaevulinic acid-mediated photodynamic therapy in
recurrent superficial bladder carcinoma. BJU Int. 2005;95:1206-10.
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 50 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
Soergel P, Wang X, Stepp H, Hertel H, Hillemanns P. Photodynamic therapy of cervical
intraepithelial neoplasia with hexaminolevulinate. Lasers Surg Med 2008;40(9):611-5.
Soergel P, Loehr-Schulz R, Hillemanns M, Landwehr S, Makowski L, Hillemanns P. Effects of
photodynamic
therapy
using
topical
applied
hexylaminolevulinate
and
methylaminolevulinate upon the integrity of cervical epithelium. Lasers Surg Med.
2010;42(9):624-30.
Stockfleth E, Kerl H. Guidelines for the management of actinic keratoses. Eur J Dermatol
2006;16:599-606.
Stylli SS, Kaye AH, MacGregor L, Howes M, Rajendra P. Photodynamic therapy of high grade
glioma-long term survival. J Clin Neurosci. 2005;12:389-98.
Szeimies RM, Ibbotson S, Murrell DF, Rubel D, Frambach Y, de Berker D, Dummer R,
Kerrouche N, Villemagne H; Excilight Study Group. A clinical study comparing methyl
aminolevulinate photodynamic therapy and surgery in small superficial basal cell carcinoma
(8-20 mm), with a 12‑month follow-up. J. Eur. Acad. Dermatol. Venereol. 2008;22(11): 130211.
Szeimies RM, Radny P, Sebastian M, Borrosch F, Dirschka T, Krähn-Senftleben G, Reich K,
Pabst G, Voss D, Foguet M, Gahlmann R, Lübbert H, Reinhold U. Photodynamic therapy with
BF-200 ALA for the treatment of actinic keratosis: results of a prospective, randomized,
double-blind, placebo-controlled phase III study. Br J Dermatol. 2010;163(2):386-94.
Takahashi J, Misawa M. Analysis of potential radiosensitizing materials for X-ray induced
photodynamic therapy, NanoBiotechnology 2008;3(2):116-26.
Takahashi J, Misawa M. Characterization of reactive oxygen species generated by
protoporphyrin IX under X-ray irradiation, Radiat. Phys. Chem. 2009;78:889-98.
Thong PS, Ong KW, Goh NS, Kho KW, Manivasager V, Bhuvaneswari R, Olivo M, Soo KC.
Photodynamic-therapy activated immune response against distant untreated tumours in
recurrent angiosarcoma. Lancet Oncol 2007;8:950-52.
Thong PS, Olivo M, Kho KW, Bhuvaneswari R, Chin WW, Ong KW, Soo KC. Immune response
against angiosarcoma following lower fluence rate clinical photodynamic therapy. J Environ
Pathol Toxicol Oncol 2008;27:35-42.
Tomizawa Y, Tian J. Photodynamic therapy for unresectable cholangiocarcinoma. Dig Dis Sci.
2012;57(2):274-83.
Trachtenberg J, Bogaards A, Weersink RA, Haider MA, Evans A, McCluskey SA, Scherz A,
Gertner MR, Yue C, Appu S, Aprikian A, Savard J, Wilson BC, Elhilali M. Vascular targeted
photodynamic therapy with palladium-bacteriopheophorbide photosensitizer for recurrent
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 51 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
prostate cancer following definitive radiation therapy: assessment of safety and treatment
response. J Urol. 2007;178:1974-79.
Trachtenberg J, Weersink RA, Davidson SR, Haider MA, Bogaards A, Gertner MR, Evans A,
Scherz A, Savard J, Chin JL, Wilson BC, Elhilali M. Vascular-targeted photodynamic therapy
(padoporfin, WST09) for recurrent prostate cancer after failure of external beam
radiotherapy: a study of escalating light doses. BJU Int. 2008;102:556-62.
Ungun B, Prud'homme RK, Budijon SJ, Shan J, Lim SF, Ju Y, Austin R. Nanofabricated
upconversion nanoparticles for photodynamic therapy. Opt. Express 2009;17:80-86.
Usuda J, Tsutsui H, Honda H, Ichinose S, Ishizumi T, Hirata T, et al. Photodynamic therapy for
lung cancers based on novel photodynamic diagnosis using talaporfin sodium (NPe6) and
autofluorescence bronchoscopy. Lung Cancer 2007;58:317-23.
Usuda J, Ichinose S, Ishizumi T, Hayashi H, Ohtani K, Maehara S, et al. Outcome of
photodynamic therapy using NPe6 for bronchogenic carcinomas in central airways >1.0 cm
in diameter. Clin Cancer Res 2010;16:2198-204.
Usuda J, Ichinose S, Ishizumi T, Hayashi H, Ohtani K, Maehara S, Ono S, Kajiwara N, Uchida O,
Tsutsui H, Ohira T, Kato H, Ikeda N. Management of multiple primary lung cancer in patients
with centrally located early cancer lesions. J Thorac Oncol 2010;5:62-8.
Vollet-Filho JD, Caracanhas MA, Grecco C, Ferreira J, Kurachi C, Bagnato VS. Nonhomogeneous liver distribution of photosensitizer and its consequence for photodynamic
therapy outcome. Photodiagnosis Photodyn Ther. 2010;7(3):189-200.
Von Tappeiner H, Joldlbauer A. On the effect of photodynamic (fluorescent) substances on
protozoa and enzymes. Arch Klin Med. 1904;80:427-87.
Wang C, Tao H, Cheng L, Liu Z. Near-infrared light induced in vivo photodynamic therapy of
cancer based on upconversion nanoparticles. Biomaterials. 2011;32(26):6145-54.
Wang X, Zhang W, Xu Z, Luo Y, Mitchell D, Moss RW. Sonodynamic and Photodynamic
Therapy in Advanced Breast Carcinoma: A Report of 3 Cases. Integrative Cancer Therapies.
2011;8(3):283-87.
Weersink RA, Bogaards A, Gertner M, Davidson SR, Zhang K, Netchev G, Trachtenberg J,
Wilson BC. Techniques for delivery and monitoring of TOOKAD (WST09)-mediated
photodynamic therapy of the prostate: clinical experience and practicalities. J Photochem
Photobiol B. 2005;79(3):211-22.
Weinberg BD, Allison RR, Sibata C, Parent T, Downie G. Results of combined photodynamic
therapy (PDT) and high dose rate brachytherapy (HDR) in treatment of obstructive
endobronchial non-small cell lung cancer (NSCLC). Photodiagnosis Photodyn Ther.
2010;7(1):50-8.
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 52 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
Wieder ME, Hone DC, Cook MJ, Handsley MM, Gavrilovic J, Russell DA. Intracellular
photodynamic therapy with photosensitizer-nanoparticle conjugates: cancer therapy using a
'Trojan horse'. Photochem. Photobiol. Sci. 2006;5:727-34.
Wilson BC, Patterson MS. The physics, biophysics and technology of photodynamic therapy.
Phys Med Biol 2008;53(9):R61-109.
Witzigmann H, Berr F, Ringel U, Caca K, Uhlmann D, Schoppmeyer K, Tannapfel A, Wittekind
C, Mossner J, Hauss J, Wiedmann M. Surgical and palliative management and outcome in
184 patients with hilar cholangiocarcinoma: palliative photodynamic therapy plus stenting is
comparable to r1/r2 resection. Ann Surg 2006;244:230-9.
Yaghini E, Seifalian AM, MacRobert AJ. Quantum dots and their potential biomedical
applications in photosensitization for photodynamic therapy. Nanomedicine (Lond)
2009;4:353-63.
Zawislak A, Donnelly RF, McCluggage WG, Price JH, McClelland HR, Woolfson AD, Dobbs S,
Maxwell P, McCarron PA. Clinical and immunohistochemical assessment of vulval
intraepithelial neoplasia following photodynamic therapy using a novel bioadhesive patchtype system loaded with 5-aminolevulinic acid. Photodiagnosis Photodyn Ther. 2009;6(1):2840.
Zeisser-Labouebe M, Delie F, Gurny R, Lange N. Benefits of nanoencapsulation for the
hypercin-mediated photodetection of ovarian micrometastases. Eur. J. Pharm. Biopharm.
2009;71:207-13.
Zhang NZ, Zhu Y, Pan W, Ma WQ, Shao AL. Photodynamic therapy combined with local
chemotherapy for the treatment of advanced esophagocardiac carcinoma. Photodiagnosis
Photodyn Ther. 2007;4:60-64.
Zhao B, Yin J, Bilski PJ, Chignell CF, Roberts JE, He Y. Enhanced photodynamic efficacy
towards melanoma cells by encapsulation of Pc4 in silica nanoparticles. Toxicol Appl
Pharmacol 2009;241:163-72.
6.2 Books
Photodynamic Therapy with ALA: A Clinical Handbook (Comprehensive Series in
Photochemical & Photobiological Sciences). Roy Pottier (Editor), Barbara Krammer (Editor),
Herbert Stepp (Editor), Reinhold Baumgartner (Editor). Royal Society of Chemistry, 2006
edition
Procedures in Cosmetic Dermatology Series: Photodynamic Therapy. Mitchel Goldman.
Saunders; 2007 edition
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 53 of 54
Cabuy E. Reliable Cancer Therapies. Energy-based therapies. 2012;3(2):1-54.
Advances in Photodynamic Therapy: Basic, Translational and Clinical (Engineering in
Medicine & Biology) Michael R. Hamblin (Editor), Pawel Mroz (Editor) Artech House
Publishers; 2008 edition
Photodynamic Therapy: Methods and Protocols (Methods in Molecular Biology) Charles J.
Gomer (Editor) Humana Press; 2010 edition
6.3 Professional Societies/Organizations
European Society for Photodynamic Therapy in Dermatology (www.euro-pdt.com)
European Platform for Photodynamic Medicine (http://www.eppm-photomedicine.org)
International Photodynamic Association (http://sites.pcmd.ac.uk/ipa)
This document provided by Reliable Cancer Therapies (RCT) does not replace a medical consultation. Material in this document may not be
reproduced in any form without explicit permission. For permission, please contact RCT at [email protected]
Page 54 of 54