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Photodynamic Therapy in Lung Cancer

Photodynamic Therapy in Lung Cancer

ABSTRACT: Photodynamic therapy (PDT) involves the use of photosensitizing agents that are selectively retained within tumor cells. The agents remain inactive until exposed to light of the proper wavelength. When activated by light, these compounds generate toxic oxygen radicals that result in tumor necrosis. In lung cancer, PDT can be used for both carcinoma in situ and for the treatment of unresectable disease with endobronchial obstruction. For patients with advanced disease, careful patient selection and integration of PDT with other interventional techniques are critical. Limited data suggest that PDT is comparable in efficacy to neodymium–yttrium-aluminum garnet (Nd-YAG) laser therapy, and some evidence indicates that it may be superior in terms of duration of response. For PDT to be used effectively, it should be integrated into a multimodality approach with chemotherapy and radiation. The optimal sequencing of these treatment modalities remains an area for further investigation. [ONCOLOGY 14(3):379-391, 2000]

Introduction

Photodynamic therapy (PDT) involves the use of
photosensitizing agents for the treatment of malignant disease. These
photosensitizing agents are infused intravenously and are selectively
retained within tumor cells. When exposed to light of the proper
wavelength, the photosensitizing agent is activated. This leads to
the formation of toxic oxygen radicals, which result in cell death.

Until recently, PDT for lung cancer had primarily been a research
tool. Several institutions worked with PDT in the 1980s, but its use
in the United States remained limited to the research setting.
Photodynamic therapy using the first FDA-approved photosensitizing
agent, porfimer sodium (Photofrin), is now available to US clinicians.

Photodynamic therapy has the potential to complement and improve the
approach to a variety of clinical problems. Potential applications
include carcinoma in situ, early-stage lung cancer in nonsurgical
candidates, advanced lung cancer, and tumors metastatic to the lung.
To properly assess the role of PDT in these settings requires careful
analysis of the mechanism of action and technique of PDT, a review of
clinical studies using PDT, and an exploration of how PDT may be
integrated into a multimodality approach.

Mechanism of Action

The concept of photochemical sensitization and subsequent cell death
is not a new one. Light was used for healing by the ancient Greeks,
and by 1900 photochemical reactions were used to kill paramecia.

Photodynamic therapy was initially used to treat skin cancers in the
early 1900s, leading to a variety of chemicals being developed to
promote photochemical cytotoxicity.[1] Among the agents used,
hematoporphyrin subsequently demonstrated the ability to be
selectively concentrated or preferentially

retained within malignant cells.[2,3] Hematoporphyrin derivatives
were later shown, first by Lipson et al and then by Gregorie et al,
to be retained in a large percentage of squamous cell carcinomas and
adenocarcinomas.[4-8] This led to the development of newer
hematoporphyrin derivatives with experimental applications, including
breast cancer and bladder cancer, and the use of PDT in an even wider
spectrum of malignancies.[9-13]

These pioneering studies highlighted the importance of several
factors related to the mechanism of PDT: membrane injury, delivery of
oxygen, the role of the immune and vascular systems, the importance
of the photosensitizer, and light dosimetry. Each of these factors is
critical to the mechanism of action of PDT and has potential clinical implications.

Membrane Injury

The basic mechanism of the cellular cytotoxicity of PDT seems to be
membrane damage. The plasma and mitochondrial membranes, in
particular, are targets of PDT because of the water-lipid partition
coefficient of the photosensitizing agents.[14-19] Porphyrin uptake
studies demonstrate initial binding of the photosensitizing agent
with the plasma membrane, with subsequent extension to the internal
cellular membranes.[20] Damage occurs after light activation and is
visible immediately. Initially, the damage is characterized by the
formation of multiple areas of membrane injury, or blebs. These
progress to form larger balloon-like areas.[16,21] Cellular division
and normal functions cease; this is followed by cell lysis.

Concurrent with damage to the plasma membrane is injury to other
internal cellular membranes, including the mitochondrial membrane,
nuclear membrane, Golgi apparatus, and endoplasmic reticulum.[18,22]
With mitochondrial injury comes inhibition of oxidative
phosphorylation and generation of adenosine triphosphate (ATP),
followed by a decrease in cellular ATP.[22,23] Using phosphate-31
spectroscopy to assess metabolic response to PDT, it can be shown
that the fall in ATP is dramatic, becoming virtually undetectable 2
to 4 hours after treatment.[24,25]

Although PDT results in nuclear membrane injury and DNA strand
breaks, it does not appear that DNA injury plays an important role in
cell death. Importantly, PDT has not been shown to be mutagenic in vitro.[16,19,26]

Delivery of Oxygen

In vitro, when oxygen is not present or is present in a concentration
of less than 2%, cells become resistant to PDT.[27,28] The
cytotoxicity of PDT is free radical–mediated via a type II
photooxidation reaction.[16,19] In type II reactions, light energy
excites and activates the photosensitizer, energy transfer occurs
from the sensitizer in its excited state to molecular oxygen, and
singlet oxygen species are generated.[29] The resulting free radical
generation leads to the membrane injury described above.

The importance of free radical–mediated injury is underscored by
the observation that scavengers of singlet oxygen, such as
1,3-diphenylisobenzofuran, reduce PDT-mediated cytotoxicity.[30] Low
oxygen concentrations have also been shown to lead to decreased
sensitivity to PDT in vitro, and tissue hypoxia models in animals
support this observation. Other investigators have suggested that
local tumor hypoxia may account for some cases of nonresponsiveness
to PDT.

Thus, all of the membrane injury described above is predicated on the
availability of an adequate concentration of oxygen to generate free radicals.

Role of the Immune and Vascular Systems

Part of the in vivo tumor destruction results from the effect of PDT
on the vasculature. The neovasculature of tumors may be a target for
PDT since these venous-derived vessels may not have sufficient
strength to remain patent in the face of high extravascular
pressures. Decreased flow occurs, leading to arteriolar and venular
stasis, arteriolar vasoconstriction, thrombosis of venules, and
increasing interstitial edema.[31,32]

In addition, other investigators have hypothesized and demonstrated
varying degrees of increased coagulation in the vascular bed
associated with PDT. Studies with nuclear magnetic resonance imaging
using in situ fluorine have shown that damage to the tumor
vasculature occurs prior to actual tumor necrosis.[33] Ben-Hur and
Orenstein demonstrated increased coagulation associated with injury
to the endothelium from PDT, with resultant red blood cell
agglutination and thrombus formation.[34]

Associated with this complex picture of free radical injury, vascular
injury, and coagulation is a concurrent immune response,
characterized by platelet and neutrophil activation.[16,35] This
immune activation results in the release of vasoactive compounds,
including arachidonic acid derivatives, such as prosta-glandins E2
and I2 and thromboxane. The potential contribution of
these mediators to cell death and tumor injury has been demonstrated
by the observation that cyclooxygenase inhibitors reduce the effect
of PDT on arterioles.[36]

Thus, in addition to oxygen-mediated free radical membrane injury and
ATP depletion, both direct vascular damage and immune-mediated injury
may contribute to cell death from PDT.

Photosensitizers

A wide variety of photosensitizing agents have been studied and
developed, including the chlorins, phthalocyanines,
tetraphenylporphine sulfate, porphines, rhodamine-123, and
porphyrin-based agents. The clinically significant aspects of
photosensitizers include their relative concentration in tumors,
their yield of singlet oxygen, the amount of tissue penetration
allowed, and their photostability/lability.

The only photosensitizing agent that has been approved by the
FDA—porfimer sodium (Photofrin)—belongs to the porphyrin-based
family of agents. Consequently, this discussion will focus on
porfimer sodium, although many of the comments apply to other agents
currently under investigation.

Selective retention or uptake of the photosensitizer by tumors allows
for a relatively high tumor-tissue concentration ratio. Most
sensitizers have a concentration ratio ranging from 2:1 to 5:1. The
selective tumor retention associated with the porphyrin-based agents
was initially reported by Figge in 1948.[2] Lipson and colleagues
subsequently demonstrated that derivatives of hematoporphyrin were
associated with an even higher tumor-tissue concentration ratio.[4-8]
This tumor-tissue ratio is highest at 24 to 48 hours after
intravenous injection.

However, Lipson and colleagues also demonstrated that fluorescence
could be detected within 3 hours of intravenous injection. This has
clinical importance in terms of how photoactive agents are used. When
employed for lung cancer treatment (ie, PDT), the time interval
between injection and light application is typically 48 to 72 hours.
When used in investigational studies for tumor detection and
localization, the 3-hour time interval is more useful.

The mechanism of selective retention and uptake of the porphyrins is
based on studies using murine models, which demonstrated that these
photosensitizers are accumulated and retained by endocytosis via the
vascular endothelium.[16,35,37] This is due, in part, to the
lipophilic nature of the compounds, previously described in relation
to their propensity to bind to cell membranes based on their
partition coefficient.

The distribution pattern of porphyrins after intravenous infusion
mirrors that of low-density lipoprotein receptors in the various
organs, with the greatest amount found in the liver, followed, in
descending order, by the adrenal glands, urinary bladder, pancreas,
kidney, spleen, stomach, bone, lung, heart, muscle, and brain.[38]
The serum half-life of photosensitizing agents in humans is 20 to 30
hours, but these compounds may persist in the skin at low levels of
2% to 5% for up to 4 to 6 weeks.[39]

The exact mechanism of selective retention of photosensitizing agents
remains an area of investigation. Possible theories include:
increased tumor uptake of low-density lipoprotein–associated
sensitizers; increased uptake by tumors due to their lower pH, and
the associated increase in water solubility of the sensitizer at low
pH; poor lymphatic drainage of tumors; tumor angiogenesis factors:
and changes within the stromal cells of tumors that increase uptake.[16,35]

As described above, the cytotoxicity of PDT is mediated via a complex
set of interactions, including photooxidative reactions. The
photosensitizer must be able to absorb photons of appropriate
wavelengths so as to become a triplet species. The light-excited
triplet state of the sensitizer transfers its energy to endogenous
state triplet oxygen to produce an excited state of molecular oxygen,
singlet oxygen. This is the type II photooxidation reaction described above.

Importantly, singlet oxygen can be generated with quantum energies as
low as 0.98 MeV, corresponding to a wavelength of 1,220 nm. However,
most available sensitizers work efficiently only at wavelengths up to
850 nm, with a quantum yield of 0.2 to 0.6 MeV.[40]

The differences in quantum yield appear to be related, or at least
affected by, the location of the sensitizer in the cells. In
addition, for any given quantum yield, lipophilic sensitizers, such
as porfimer sodium, seem to be more efficient than hydrophilic
sensitizers at similar quantum yields. Thus, while these
considerations may seem esoteric, they have direct clinical impact in
terms of efficacy.

Furthermore, the quantum energy used relates to the important
clinical issue of tissue penetration. The wavelength, as determined
by the quantum energy used, directly affects the maximum absorbance
capacity and depth of tissue penetration of the photosensitizing agent.

With respect to the porphyrin family of photosensitizers, the
absorption spectra demonstrate a peak at 405 nm. Use of this peak
allows for fluorescence of tumors to be used as a tumor marker.
However, for treatment (PDT), this wavelength of light is suboptimal,
since it is nearly completely absorbed within 1 mm of the surface.
Thus, a wavelength of 630 nm is used for PDT. This allows for
penetration to a depth of approximately 5 mm.

Obviously, the development of future photosensitizers will be greatly
affected by consideration of the quantum energies used, their
absorption spectra, and the resultant clinical consequences, in terms
of depth of penetration.

Finally, all photosensitizers can be destroyed by light, which may
have an impact on cytotoxicity. When exposed to light, a sensitizer
may generate enough energy to destroy tumor tissue but be destroyed
and lose its cytotoxic potential within normal cells, a process
described as photobleaching. This effect is an important
consideration, since it allows minimal damage to adjacent normal
tissue while selectively destroying tumor cells.

Light Dosimetry

The efficacy of PDT depends on accurate delivery of light to the area
to be treated. It is useful to think of PDT in terms of three
components: (1) the photosensitizer’s characteristics and
concentration at the tumor site (described above), (2) the rate of
energy delivery (power), and (3) the total energy delivered

With respect to the delivery of light, any source of light with the
appropriate characteristics could be used. In practice, laser light
is typically used because it offers the advantage of a uniform
spectrum and coherence. For lung cancer, the argon dye pump or
excimer laser is often used, although, in theory, any laser with the
proper wavelength and power could be employed. Important in vivo
considerations include the effect of dose rate delivery and total
energy delivery.

Although in vitro evidence has suggested that a high dose rate
(power) is associated with improved cytotoxicity, in vivo data have
demonstrated that lower dose rates may be more effective.[41,42] In a
study involving the treatment of human mesothelioma allografts in
nude mice, decreasing the light intensity from 200 to 50 mW/cm²
actually improved response. The investigators hypothesized that a
reduction in the fluence rate or fractionation

may paradoxically enhance the effect of treatment because of an
increase in singlet oxygen in regions of poor capillary flow.

Regardless of whether this is the only mechanism involved, what is
clearly important is the empiric observation that light dosimetry has
a clinical impact on response and side effects. Thus, controlled,
reproducible light dosimetry and the technology used to deliver it
are important considerations for PDT.

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