Harry Quon, Charles B. Simone, II, Keith A. Cengel, Jarod C. Finlay, Timothy C. Zhu, and Theresa M. Busch
The first report of cytotoxicity (in paramecium) observed by combining a drug (acridine) and visible light can be traced to the medical student Oscar Raab working in the laboratory of Herman von Tappeiner in 1900.1 This observation laid the foundation for the 1903 descriptions by von Tappeiner and Jesioneck who combined topical eosin and visible light for the treatment of a skin tumor.2 Modern investigations of photodynamic therapy (PDT) have since been attributed to Lipson et al.3 in 1960, with the discovery of hematoporphyrin derivative (HPD) by Samuel Schwartz,4 a water-soluble mixture of porphyrins and a series of preclinical and clinical investigations led by Dougherty et al.5
Despite its deep historical origins and modern research investigations dating back 40 years, the clinical application of PDT remains limited to specific clinical situations. In part, this has been due to the superficial depth of cytotoxicity achievable with past photosensitizers and light delivery techniques. It is also due to the complexity of its application, requiring familiarity with safe photosensitizer administration coupled with the technical requirements for effective light delivery and the optical expertise to prescribe and deliver an activating light energy in a selective manner.
Despite these disadvantages, there are several compelling reasons to evaluate PDT as a major therapeutic approach in the management of cancer. Central to this is its unique mechanism of action allowing for nonoverlapping toxicities with traditional cancer therapeutics. As such, PDT does not exclude the subsequent administration of these treatment modalities. Technical advances with interstitial light delivery techniques (and advancements in modeling its dosimetry6) along with the clinical development of photosensitizers capable of absorbing and being activated at longer wavelengths now offer the potential for more penetrating cytotoxicity.7 Unlike traditional chemotherapeutics and ionizing radiation therapy, there has also been a paucity of any long-term genotoxic effects with the use of PDT, an observation consistent with several in vitro studies.8–10 The explosion in our understanding of tumor biology and the influence of the microenvironment has also provided tremendous insights into the development of novel strategies to optimize the clinical efficacy of PDT, including its combination with biologic therapeutics. This also includes the potential for PDT to enhance the effects of traditional cancer therapeutics and its promising role to more effectively induce adaptive cell-mediated immunity.
TABLE 27.1 FACTORS AFFECTING THE EFFICACY OF PHOTODYNAMIC THERAPY
PRINCIPLES OF PHOTODYNAMIC THERAPY
Photosensitizers
PDT represents a treatment modality that combines the selective photochemical activation of photosensitizers with electromagnetic radiation in the visible energy range (i.e., light). Photosensitizers (PS) may be introduced into the cancer patient either systemically, topically, or injected locally, but it is its chemical structure that can significantly influence the effectiveness of a PDT treatment. These include influencing its biodistribution and subcellular localization along with how efficiently it absorbs light (referred to as its molar extinction coefficient) to generate reactive oxidative species (ROS), including singlet oxygen (referred to as its quantum yield) (Table 27.1). A PS with a low molar extinction coefficient will require large concentrations of the PS and light energy to be effectively delivered for photoactivation.
There are now a multitude of PS that have been generated with many under preclinical evaluation and several receiving regulatory approval for clinical application in the United States, European Union, and other countries. The first PS to receive regulatory approval was a semipurified preparation of HPD known as Photofrin (porfimer sodium). Porfimer sodium represents a complex mixture of hematoporphyrin oligomers whose chemical composition has been difficult to fully characterize and reproduce consistently. It has an absorption peak at 630 nm with a relatively low molar extinction coefficient, thus requiring large concentrations of drug and light energy (fluence) to be delivered. It has also been shown to have a prolonged risk of skin photosensitivity reflecting its relative lack of tumor selectivity; and while used routinely in clinical practice, these disadvantages have spurred ongoing PS development.
Several ideal characteristics have been well articulated in the area of PS development. These include a PS that has a well-established structure, ideally a pure compound with a constant composition and a stable shelf-life. Without light activation, it should have little toxicity and tumor specificity when administered. With light, a PS with spectral absorption peaks that demonstrate a high extinction coefficient will be more efficiently activated. However, it is not entirely clear if this is always desired. Strong PS absorption at a specific wavelength can further contribute to reduced light penetration, a phenomenon referred to as self-shielding. Moreover, potent PS such as temoporfin/m-THPC (Foscan) that thus require little drug and light for its efficient activation have been associated with significant complications necessitating even more vigilance to the light dosimetry (see below).11 The wavelengths of a photosensitizer’s absorption peaks also influences how the PS will be used clinically, with absorption at longer wavelengths (i.e., 700 nm range) offering deeper light penetration in human tissues. Lastly, some PS may undergo a process of photobleaching, whereby the PS in turn reacts with the singlet oxygen or other ROS created in the photoactivation process altering its ability to act as a PS. Typically, photobleaching decreases a photosensitizer’s reactivity, which may or may not be desirable depending on the context of its clinical application.
Structurally, photosensitizers are generally classified as porphyrin-based or nonporphyrins with the former sharing a common backbone that consists of the tetrapyrrole ring. Other structural backbones that have demonstrated photosensitizing capabilities include the presence of four phenol rings and polycyclic ring compounds based on the pyrrole ring especially the tetrapyrrollic PS. Extensive reviews are available regarding the specific physicochemical properties (i.e., primary structures, the presence of complexed heavy metals, and specific side chain substitutions) and the impact on its systemic biodistribution, cellular uptake, and photosensitizing properties.7 In general, the ability for hydrophobic compounds with two or less negative charges can still cross the plasma membrane. Otherwise, intracellular uptake is through active endocytosis. The charge of the hydrophobic PS can also influence where a PS localizes with cationic charges (positive), tending to localize to the mitochondria and anionic PS with a net charge of negative two or greater tending to localize in the lysosomes.12 Cationic PS localizing to the mitochondria have been suggested to be more effective in mediating direct cytotoxicity.13
Although tumor specificity is in part mediated by selective light administration and its natural energy attenuation, specific extracellular and intracellular PS delivery is felt to further contribute to this process. Human tissue studies in patients receiving porfimer sodium-mediated intraperitoneal PDT have confirmed PS selectivity, even if narrow.14 Systemically administered photosensitizers, especially those with the tetrapyrrole backbone, will associate with serum proteins, including albumin and low-density lipoproteins (LDL). The association with LDL proteins has been suggested to be a potential mechanism that may contribute to specific tumor localization.15 In this model, it has been proposed that tumor selectivity occurs due to a preferential up-regulation of LDL receptors in tumor cells due to the rapid plasma membrane turnover rate and the need for constituents in its biosynthesis. Alternatively, the functionally altered tumor vasculature resulting from overexpression of vascular endothelial growth factor16 and its impaired lymphatic clearance of the extravasated PS have also been advanced as a working model.17 Although this may lead to increased PS retention, the extracellular distribution of the PS can be inhomogeneous and can impact the effectiveness of a PDT treatment. Korbelik and Grosl18 demonstrated that direct tumor cell killing was a function of the distance from a tumor’s vascular supply. In turn, photosensitizers that tend to be located in the intravascular space can increase the effectiveness of PDT through mediating vascular damage and tumor infarction.19
The subcellular localization of a PS can similarly influence the mechanism of cellular injury and has been well studied and recently summarized.20 In general, photosensitizers that localize to the plasma membrane and lysosomes are likely to cause injury by necrosis. Those localizing to the mitochondria and endoplasmic reticulum are likely to initiate cell death by way of apoptosis.5,20,21 However, mitochondrial injury can also mediate a necrotic cell death with severe inner mitochondrial membrane damage.20
Most photosensitizers tend not to accumulate in the nucleus, possibly explaining the paucity of genotoxicity and observed carcinogenesis.8,22 Although DNA damage has been reported in cell culture experiments for various photosensitizers,8–10,23 especially for 5-aminolevulinic acid,23,24 efficient DNA repair has also been observed, suggesting that the damage may not be sufficient to overwhelm a cell’s repair capacity.10,25 As PDT can mediate cell death through non-DNA targets, the potential mutagenic effects of any DNA injury is likely to be further limited by its cell death.
FIGURE 27.1. Jablonski energy diagram following type II photosensitizer activation.
Photosensitizer Activation
Following photosensitizer administration, the drug–light interval (DLI) that is prescribed warrants consideration. Preclinical studies have demonstrated that varying the DLI can influence both the PS extracellular and intracellular localization.19,26 In general, longer DLI will promote PS extravasation and intracellular uptake, provided it has a sufficient long pharmacokinetic lifetime. However, this passive targeting of either the vascular (short DLI) or tumor compartment can be compounded by the lipophilicity of the PS and which proteins it associates with within the vasculature. It would also appear that targeting both the vascular and tumor compartment with repeat PS administration, combining both a short DLI and a long DLI, can further improve the effectively of PDT. However, the order of the repeat PS administration and activation may be particularly important. Prescribing an initial short DLI that targets the vasculature can create subsequent hypoxia that limits the efficacy of the repeat PS with a long DLI.19
PS activation involves the absorption of wavelength specific energy, causing specific changes in the electron energy states of the PS. Energy absorption can cause a PS electron to move from its ground state to a higher energy level or what is referred to as an excited energy state. While in the excited energy state, transition back to the ground state may occur, with energy released in the form of fluorescence or heat dissipation. Thus, some of the light absorbed by a PS may be re-emitted at a different wavelength, allowing for fluorescence detection of the PS or photodynamic diagnosis (PDD). Figure 27.1 demonstrates the Jablonski energy diagram that depicts the energy transitions that may occur with PDT. Two possible excited energy states may be possible: a singlet state (S1) or the triplet state (T1), which has a longer half-life. The distinction depends on the spin direction of the excited electron relative to its paired electron in the ground state. The triplet state has both electrons parallel to each other, and its ability to return to a ground state emitting fluorescence is impeded due to this spin direction.
Transition to the triplet state through a process referred to as intersystem crossing is critical to the generation of cytotoxic ROS. This is largely due to the longer half-life of the triplet state that increases the probability of interacting with a nearby organic molecule (i.e., in the plasma membrane), generating reactive anions or cations that in turn may react with molecular oxygen generating ROS (referred to as a type I reaction). Alternatively, a PS in its triplet state may directly transfer its energy to molecular oxygen to form an excited state singlet oxygen (1O2) (type II reaction). Both types of reactions may occur simultaneously, though direct singlet oxygen production is felt to be the dominant mechanism of cytotoxicity.27,28
Singlet oxygen within the cell has a limited half-life (estimated to be <0.04 μs) and thus a limited range of diffusion and activity (<0.02 μm).22,29 As such, PS cytotoxicity is limited to its extracellular and intracellular (commonly referred to as subcellular) localization and adjacent potential targets for reactivity.22 For example, photosensitizers that tend to biodistribute or favor being localized in the vasculature will favor an antivascular necrotic mechanism of injury. The specific subcellular localization offers an added degree of specificity to its cytotoxicity, as already described.
Physics of Light Dosimetry
Photodynamic therapy is inherently a dynamic process. All three principal components—photosensitizer, light, and oxygen—interact dynamically over the time period of a PDT prescription.5 As light interacts with human tissue, its energy distribution is influenced by surface reflection and with absorption and scatter at depth. Light scatter in human tissues can be affected by many factors. Tissue architecture, its geometry, and its heterogeneity at the histologic and cellular levels can contribute to photon scattering, limiting the energy deposited at depth. Thus, it is important to recognize that light scatter is likely to be different from one tissue type to another. Although this factor remains to be fully characterized such that it can be accounted for in the prescription of PDT, selecting longer wavelengths for photoactivation can help to reduce photon scatter, thus increasing light penetration.
The deposition of light, or its dosimetry, is determined by the light source characteristics and the tissue optical properties, both on the surface and at depth, in contrast to ionizing radiation. In turn, the tissue optical properties are influenced by the spatiotemporal distribution and concentration of both the photosensitizer and oxygen in the illuminated tissues. During illumination, the light dosimetry also dynamically changes as the photodynamic process consumes oxygen and can also alter the blood flow.30 For some photosensitizers, self-shielding can influence the light dosimetry at depth. Finally, the distribution of a photosensitizer may change as a result of photobleaching, a process whereby the photodynamic modification of the photosensitizer itself typically reduces its ability to further be photoactivated.
Quantifying the distribution of the light that is used in photoactivation is important oncologically and for quality assurance reasons, as in the practice of ionizing radiation. The ability to relate the treatment outcome to the effective light fluence and its rate of delivery (fluence rate) facilitates not only an understanding of its relationship to the treatment outcome but also to any potential toxicities, as areas of high fluence and fluence rates have been associated with treatment toxicities. Several approaches to quantifying light dosimetry may be outlined.
Explicit dosimetry refers to the prediction of a singlet oxygen dose on the basis of measurable quantities that contribute to the photodynamic effect.31 In clinical practice, the quantity most amenable to measurement is the PDT dose, defined as the light energy deposited to a photosensitizer. This quantity is proportional to the product of the absorption coefficient of the photosensitizer and light fluence. The absorption coefficient of the photosensitizer is, in turn, proportional to the photosensitizer concentration. PDT dose calculated in this way is a good predictor of outcome if one is operating in a drug- or light-limited situation when there is ample oxygen supply. To generally account for the oxygen effect, the concentration of reacted singlet oxygen (i.e., the concentration of reactions between singlet oxygen and molecular targets within the tumor cells) needs to be modeled as a function of PDT dose and tissue oxygenation. It has been shown that the reacted singlet oxygen concentration can be expressed as the integration of the product of the PDT dose rate and the photosensitizer’s singlet oxygen quantum yield.32
Implicit dosimetry refers to the use of photobleaching of the sensitizer as a measure of the light dose. For sensitizers where the photobleaching is mediated by singlet oxygen, it can be shown that on the microscopic scale, the fractional photobleaching is indicative of the concentration of singlet oxygen reactions induced by PDT.33 Although the relationship to tissue response is more complex, photobleaching has been shown to be predictive of response in animal models34 and used to design protocols for pain reduction during the treatment of patients.35
Accurate light dosimetry presents significant challenges in the clinic. Although it is relatively straightforward to measure the irradiance of light delivered to the surface of a tissue, the light absorbed by the sensitizer also includes the light scattered by tissue not too dissimilar from ionizing radiation. Unlike ionizing radiation, this scattered light contribution may also occur on a surface and is an important concept to consider in the practice of PDT. In hollow organs or any concave surface with surface secretions that further increase the reflective index, light can be reflected from one surface onto another surface, increasing the effective surface light fluence rate. This effect is often referred to as the integrating sphere effect. In the extreme case, multiple reflections can significantly magnify the fluence rate within a hollow organ. This integrating sphere effect has been extensively modeled in the case of bladder treatment.36 In complex concave mucosal surfaces such as in the head and neck, scattered light photons have been demonstrated to increase the effective fluence rate by factors of three- to fourfold.37,38
Light scattering can also occur within tissues, leading to a significant difference between the incident fluence rate that is delivered and the fluence rate within the tissue. In practice, the integrating sphere effect and multiple scattering within the tissue occur simultaneously. Accurate dosimetry requires accounting for both of these effects, ideally through real-time measurements using an isotropic light photon detector capable of capturing both directly incident and scattered light.39 A comparison of measurements using fiber-based isotropic detectors and photodiode detectors that capture only incident light indicated significant difference in the measured light dose with significant variation in the contribution from scattered light.40 Through measurements with a series of light sources and detectors, tissue optical properties can be assessed. However, PDT treatment can significantly change the optical properties. This requires the ability to assess the optical properties in real time for there to be effective feedback to compensate for the influence of varying light transmission on the deposited light dose within the target tissue.41,42 Recently, the first clinical experiences using an automated 18-channel system accommodating optical fibers for light delivery and monitoring was described in patients treated with temoporfin interstitial PDT.6
Biology of Photodynamic Therapy
Mechanisms of Tumor Cytotoxicity
Photodynamic therapy can induce cytotoxicity through all three death morphologies: apoptosis, autophagy, and necrosis. The multitude of signaling pathways (apoptotic and nonapoptotic) and the molecular interplay between various cell death pathways (balanced with the induction of pro-survival signals) that are activated with exposure of the cell to photodynamic oxidative stress have been the focus of intense investigations and the subject of a recent extensive review.43 Of these modes of cell death, apoptosis is a major pathway of PDT-mediated cytotoxicity and reflects the near ubiquitous ability of PDT to induce mitochondrial injury.44,45
Photodynamic therapy can also induce tumor cell injury through direct damage of the endothelial cells of the tumor vasculature. In turn, thrombus formation and the release of various vasoactive molecules, with an increase in the vascular permeability and deterioration of vascular status, ensue. Leukocyte infiltration further compounds this response, all contributing to secondary hypoxia46 with ischemic tumor death and tumor control.47 Preclinical studies also suggest that beyond direct tumor and vascular cytotoxicity, long-term tumor control can only occur in immunocompetent animals.48
Influence of the Tumor Microenvironment on the Photodynamic Therapy Response
As PDT is dependent on the presence and distribution of a photosensitizer, light, and oxygen, the normal tissue microenvironment within which a tumor is located can significantly determine the treatment response of the tumor to PDT. All three key PDT components are subject to effects from the tissue microenvironment. For example, tumor vascular density, permeability, or perfusion can affect photosensitizer delivery,49 which could undoubtedly contribute to the heterogeneities detected in photosensitizer levels among tumors within and among patients.50–52,53–54 Tumor-associated hypoxia can limit PDT-created damage.55,56–58 Even the distribution of the treatment light is affected by the microenvironment due to differences in the penetration of red light as a function of the oxygenation status of hemoglobin. Compared to deoxyhemoglobin, oxygenated hemoglobin is less absorptive of red light (630 or 650 nm), thereby allowing deeper light penetration in tissues with a higher proportion of oxygenated hemoglobin.59
Much research has been performed on the dependence, as well as the effects of, PDT on tumor oxygenation. With conventional photosensitizers, the photochemical process can consume tissue oxygen faster than its delivery, leading to a hypoxic state that limits PDT-mediated cytotoxicity.60,61–62 Even intratumor heterogeneities in tumor oxygenation can have consequences to PDT-mediated cytotoxicity. This has been shown in murine studies that identify the presence of more severe PDT-created hypoxia in the base of subcutaneous tumors accompanied by a relative protection of this area from clonogenic cell death.58
PDT-mediated vascular effects are another cause of hypoxia during PDT. These effects can take the form of PDT-triggered vasoconstriction.63 Additionally or alternatively, PDT can cause endothelial cell rounding, leading to intracellular gaps64 and activation of the coagulation cascade. Ischemia then results, as leukocyte and platelet aggregation with secondary thrombosis within the vessels can further alter the blood flow.63,65 Dynamic changes in tumor blood flow, including treatment-initiated decreases in the blood flow, have been observed for several photosensitizers including porfimer sodium, 5-aminolevulinic acid (5-ALA; Levulan), motexafin lutetium (Lutrin), verteporfin (Visudyne), palladium bacteriopherophorbide (Tookad), and 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH; Photochlor).63,66–72 In fact, PDT-triggered reductions in tumor blood flow during light delivery are not only therapy limiting, but also directly correlate with outcome measures. Yu et al.68 showed that the duration (long) and the slope (shallow) of the Photofrin-PDT–induced decrease in tumor blood flow correlated with the time-to-tumor regrowth (prolonged) in an animal. Similarly, Standish et al.73 and Pham et al.74 reported PDT-induced decreases in tumor blood flow and %StO2 (tissue hemoglobin oxygen saturation), respectively, correlated with necrosis development. These findings show the value in the development and application of noninvasive approaches to measure tumor blood flow during clinical applications of PDT.69,75,76 Thus, although PDT-induced ischemia can limit the effectiveness of PDT, in the setting of sufficient light and drug doses, the persistent ischemia that is induced can provide incremental cytotoxicity that can improve the effectiveness.47,77
Experimental strategies directed at modulating the vascular response to PDT are also consistent with the importance of its contribution to the PDT effect. For example, inhibitors of nitric oxide have been effective in increasing tumor and vascular damage to porfimer sodium or ALA-PDT in a protocol-dependent manner.78–80 Also, the vascular disrupting agent, vadimezan (5,6-dimethylxanthenone-4-acetic acid; DMXAA) has been successful in improving PDT responses when administered in such a way as to decrease tumor perfusion after illumination.70,81 It is even possible to deliver PDT in two fractions so that a vascular-damaging protocol follows one in which oxidative damage to tumor cells is the major cytotoxic mechanism.19 This approach has been studied in preclinical models using verteporfin as photosensitizer by first employing a longer interval between drug administration and light delivery to allow drug accumulation in the tumor cells, leading to direct light-induced cytotoxicity, followed by a second round of drug administration and light delivery that utilizes a short drug-light interval, which causes more extensive vascular damage due to drug localization in the blood vessels at the time of light delivery.19 Similar observations have been reported with the photosensitizer MV6401.26
Tumor Stress Response to Photodynamic Therapy
The oxidative stress initiated with PDT can induce the expression of genes that can mediate various modes of cell death as well as survival signals. Using c-DNA microarrays, the cellular effects of hypericin-mediated PDT was studied on the expression of a panel of genes involved in apoptosis, metabolism, and proliferation, among other cellular processes.82 Twenty-five genes were significantly up-regulated by PDT, including dual specificity phosphatase-1 (DUSP1), which can induce apoptosis; the stress response proto-oncogenes, FOSB and JUN, whose protein products dimerize to contribute to the transcription factor AP-1, another effector (both positive and negative) of apoptotic response; and MYC, which codes for the pro-apoptotic transcription factor c-myc. Among the genes down-regulated by PDT were THBS1, whose protein product thrombospondin-1 is an effector of cell interaction with the extracellular matrix, angiogenesis, apoptosis, and cell migration; ADAM10, which codes for a family of cell surface proteins with roles in epithelial cell–cell adhesion, migration, and proliferation; and several genes in the integrin family that mediate cell-to-cell and cell-to-matrix attachments, thereby facilitating signal transduction along pathways controlling apoptosis and metastasis, among other functions.82
In other studies, PDT-induced apoptosis was associated with activation of p38 in the mitogen-activated protein kinase (MAPK) family,83–85 which along with its other family members (including ERK and JNK) regulate cell proliferation, differentiation, and survival. Furthermore, expression of pro-apoptotic and anti-apoptotic proteins of the Bcl-2 family can also be modulated by PDT in a context-dependent matter, which depends on factors such as cell type and subcellular localization of photosensitizer.83,86,87 Similarly, PDT-induced expression and phosphorylation of survivin, capable of inhibiting apoptosis through inhibiting caspase-9, has also been an active area of investigation to therapeutically improve PDT cytotoxicity.88 Signal transduction in PDT-induced apoptosis, autophagy, and necrosis is an area of much and expanding interest, and for the interested reader, several comprehensive reviews43,89,90 are available on the current state of knowledge on this topic.
Immunologic Response to Photodynamic Therapy
The altered microenvironment generated by PDT can also serve to stimulate the host immune responses. Both the activation of an innate (nonspecific) and an adaptive antigen-specific immune response may be seen following PDT. These findings have raised considerable hopes that a localized treatment with PDT may lead to broader and possibly systemic oncologic benefits. For example, PDT-induced damage is associated with the local influx of neutrophils and other cell types, such as macrophages, natural killer cells, and dendritic cells, which contribute to local damage and inflammation while also initiating a broader systemic immune response.91 Both preclinical and clinical studies show this to be accompanied by the release of immune-modulating factors, such as interleukin (IL) 1-β, tumor necrosis factor (TNF)-α, IL-6, IL-10 and granulocyte colony-stimulating factor (G-CSF).92,93–94
The resulting activation of the innate immune response plays a major role in tumor control after PDT, and neutrophils are key to this process. In vitro studies demonstrate neutrophil adhesion to an extracellular matrix exposed by PDT-mediated endothelial cell damage.95 In vivo studies find neutrophils to attach to PDT-treated blood vessels,96 while various approaches toward depleting neutrophil influx into the PDT-treated tissues have been to the detriment of therapeutic outcome.97,98 In fact, a systemic neutrophilia is known to accompany PDT of various tumor types, sites, and photosensitization protocols.99–101 PDT can also activate the complement system with opsonization and fixation of the complement C3 protein to tumor cells, which also promotes a strong neutrophilia. This serves to not only target cells for destruction by the innate immune system but can induce the release of pro-inflammatory mediators further contributing to the migration of neutrophils.102
In addition to the induction of an innate immune response, PDT can also stimulate an adaptive cell-mediated immunity. In fact, these types of immune responses are intricately connected processes. It has been proposed that a critical aspect of PDT-induced adaptive immunity is the generation of a high antigen load with tumor cell death that is presented for adaptive immunity. Tumor cell death is further promoted by the strong neutrophilia through its release of lysosomal enzymes, including myeloperoxidase and the generation of further ROS. This strong neutrophilia also appears to be a critical factor for the development of PDT-induced adaptive immunity,103 as neutrophils degranulate and release a family of mediators referred to as alarmins. Alarmins are a critical link between the innate inflammatory response and adaptive immunity as they are capable of recruiting and activating the maturation of antigen-presenting dendritic cells.104 With a strong innate immune response, this antigen presentation can be more effectively recognized, inducing an adaptive cell-mediated immunologic response and memory.105
Dendritic cells (DCs) typically exist in the immature state within the tissue microenvironment actively surveying and capturing antigens then migrating and presenting these to T cells in adjacent draining lymph nodes. For dendritic cells to mature and affect adaptive immunity, the expression of costimulatory molecules that are involved in antigen-presentation to T cells is important. Several aspects of this innate response, including the strong neutrophilia103 and the release of damage-associated molecular patterns (DAMPs), consist of various markers of normal tissue injury. Among these, the extracellular release of heat shock protein-70 (HSP-70) and its association with tumor antigens by PDT-treated cells appears to be particularly effective in being recognized by DCs through surface receptors leading to their activation and maturation.106
HSPs, in particular HSP-70, have been a DAMP of particular interest in PDT for some time.107 HSPs are molecular chaperones crucial for proper protein folding. HSPs can facilitate cell survival during intracellular functioning, but become immunostimulatory when extracellular or membrane bound.108 In studies of PDT, HSP-70 is rapidly exposed on the surface of tumor cells treated in vitro,109 and its antibody-based blockage served to inhibit maturation of dendritic cells.110 Moreover, surface or extracellular expression of HSP-70 after PDT has been shown to correlate with curative outcome in temoporfin-treated murine tumors.111 Research in these and other aspects of PDT-generated antitumor immunity has spawned interest in the use of PDT to develop cancer vaccines, the history and progress of which have been recently reviewed.112
Vascular Response to Photodynamic Therapy
Despite the therapeutic benefits to be gained from PDT-created vascular damage and inflammation, it comes at a cost. In a post-PDT tumor microenvironment characterized by inflammatory infiltrates, cytokine overexpression, eicosanoid production, and hypoxia, there is a strong pro-angiogenic stimulus to support the growth of new tumor blood vessels.113 Such angiogenesis can counteract the intended effects of treatment by providing a means for delivery of oxygen and nutrients to tumor cells that escaped direct (oxidative) or secondary (vascular or immune-mediated) damage by PDT. Vascular endothelial growth factor (VEGF) is one of the most common angiogenic molecules whose expression is stimulated by PDT, and its increase has been measured following PDT with a variety of photosensitizers and tumor models.114–116 Moreover, studies of human tumors grown as murine xenografts find PDT to induce modest increases in host-derived (mouse) VEGF in addition to the increases in human VEGF that originate from the treated tumor.117,118 The molecular mechanisms of PDT-initiated increases in VEGF can include increases in hypoxia-inducible factor (HIF)-1α, a transcription factor that promotes the activation of many hypoxia-responsive genes such as VEGF,119,120 as well as activation of the p38 MAPK pathway.121 In the case of the latter, an inhibitor of p38 MAPK significantly attenuated the PDT-induced increase in VEGF.121
Cyclo-oxygenase (COX) 2 is another pro-angiogenic molecule that is up-regulated by PDT under a variety of treatment conditions.122,123–124 The COX-2 enzyme serves to catalyze the production of prostaglandin (PG) H2, a substrate for multiple eicosanoid mediators (including additional prostaglandins and thromboxane) known to contribute to PDT-created ischemia.125,126 The pro-angiogenic activity of COX-2 can be mediated through the enzyme’s role in production of PGE2, which in turn can promote increases in VEGF.113 Moreover, PDT-stimulated pro-inflammatory cytokines such as IL-1β and TNF-αmay also stimulate angiogenesis through a COX-2 dependent pathway. This is supported by findings that decrease in PGE2 after COX-2 inhibition is accompanied by a reduction in protein levels of IL-1β and TNF-α.127
Biologic Strategies to Improve Photodynamic Therapy Cytotoxicity
With a growing understanding of the biological and molecular mechanisms that underlie PDT-derived cytotoxicity has come the development of alternative, more effective approaches toward PDT delivery. These include the development of new targeted PS that exploit specific signatures or functions in diseased tissue in order to deliver, or even to activate, the PS.128 These are commonly referred to as PDT molecular beacons, where the PS and a singlet oxygen-quenching or -scavenging molecule are both coupled to a linker that can interact with a cancer-specific target.129 In this way, the PS photoactivity is silenced due to the proximity of the singlet oxygen-quenching molecule. The PS is only capable of being photoactivated when the linker interacts with the cancer-specific target, which results in physical separation of the singlet oxygen-scavenging molecule from the PS. Examples of novel targeted linker constructs include an antisense oligonucleotide complementary to a target messenger RNA that is conformationally restricted until the oligonucleotide interacts with its target.
Modulation of light delivery has also proven successful in mitigating the microenvironment limitations imposed by PDT. For example, lowering the fluence rate of light delivery can conserve tumor oxygenation during PDT, increasing direct tumor cell cytotoxicity as well as vascular and immune effects.56,58,97,130,131–132 Similarly, fractionation of the light with or without repeat administration of the PS before each light fraction has improved treatment response in various preclinical protocols46,133–134,135–138 and in early clinical studies.139 Without repeat PS administration, preclinical studies suggest that the light fractionation is improving oxygenation46 with more effective vascular injury138 and necrosis.134 The duration of the light that is first administered133 and the duration of time between each light fraction134 may be particularly important in improving the oxygen delivery between light fractions. When the PS has been readministered before the second light fraction, a short DLI has demonstrated improved tumor control in preclinical models through vascular targeting with various photosensitizers such as verteporfin,19MV6401,26 and m-tetrahydroxyphenylchlorin (mTHPC).140
As described above, PDT causes cytotoxic oxidative stress and induces the expression of pleiotropic pro-survival molecules such as COX-2.84 Understanding the mechanisms leading to pro-survival molecule induction is relevant to the design of more effective treatments. PDT in combination with various targeted agents designed to reduce the effect of the tumor stress response has demonstrated improved tumor responses in various preclinical models. Antiangiogenic agents lead to decreases in VEGF expression after PDT,115,141–143 along with improvements in tumor response.114,115,117,119,141–144 Inhibition of HSP increases the curative potential of PDT through decreased expression of angiogenic and pro-survival proteins in the treated tumors,145 while disruption of HSP-90 function in vitro leads to increases in PDT-induced apoptosis.88 The COX-2 pathway has also been targeted in combination with PDT and can improve therapeutic outcome through inhibition of post-PDT angiogenesis, as well as, under some circumstances, through increases in direct PDT cytotoxicity.127,146–148
PRACTICE OF PHOTODYNAMIC THERAPY
Light Delivery and Dosimetry
The ability to achieve PS activation is dependent on effective administration of light not only with a wavelength that matches the spectral absorption of the PS, but also on depositing a sufficient amount of energy to the target tissue (total fluence). Wavelengths >800 nm are unable to deposit sufficient energy to activate a PS. Delivering sufficient fluence is influenced not only by the technique of its administration (i.e., surface vs. interstitial), but also by the ability of the light energy to penetrate sufficiently at depth to treat the intended target volume. As light photons interact with human tissues, photons scatter and are absorbed by endogenous chromophores such as hemoglobin, myoglobin, melanin, and cytochromes. Hemoglobin is especially important to consider. Hemoglobin has spectral absorption peaks <600 nm (i.e., hemoglobin absorbs all colors except red), and its ability to absorb light energy is affected by its oxygenation status. Oxygenated hemoglobin is less likely to absorb between 600 and 800 nm compared to deoxygenated hemoglobin. Thus, most activating light that has been used for PDT has typically been between 600 and 800 nm, depending on the spectral absorption characteristics of the PS.
The rate at which the light energy is delivered (fluence rate) is also an important treatment factor that can affect the efficacy of PDT. It primarily affects the tissue microenvironment such as the vascular flow and oxygenation. In general, it is important to recognize that high fluence rates can rapidly consume and reduce the local oxygen levels such that it limits the efficacy of the remaining light fluence.149 Although the prescribed fluence rate is typically based on the power output of the light source, surface and internal scattering of light photons may result in areas of higher fluence rates. Strategies to reduce at least the surface scatter effect or to modify the prescribed power output of the light source should be considered (see below).
At present, the prescription of PDT typically used clinically remains limited to rudimentary power output calculations for surface illumination:
where the prescription dose is given in terms of the energy per unit area incident on the surface.
Various light delivery devices have been developed to perform PDT treatment. Most of them are fiber based. These include linear source, endotracheal-tube–modified point source, collimated light source, and flat-cut fiber (Fig. 27.2). The flat-cut and linear sources are suitable for inserting into the tissue for interstitial PDT application for the treatment of bulky tumors. The collimated light source is suitable for superficial treatment.
It is therefore helpful to recognize that various illumination techniques may be employed depending on the geometry of the target lesion that is to be treated. The most common clinical situation requires surface illumination, where several technical approaches may be considered. Where the geometry of the target lesion is flat or may be modified to be a near flat surface, the use of a light fiber with a diffusing lens at the tip of the fiber (i.e., microlens) offers the ability to achieve homogeneous light distribution across the surface target. Inhomogeneities due to different distances between points on the surface of the target and the light source can result in different fluence rates and the total light dose (fluence) that is effectively delivered. Unlike ionizing radiation, the surface scattering of photons due to surface concavities or reflective surfaces (i.e., any adjacent metal surfaces) can further increase the risk of high surface dose inhomogeneities. In a similar manner, surface convexities may create regions of shadowing that can create regions of low fluence and fluence rate. Areas of high light fluence (and its fluence rate) may also contribute to an increased risk of normal tissue complications.
When the target lesion is cylindrical, a cylindrical diffusing fiber with the light dose prescribed along its length has commonly been used. However, it is important to note that where the target surface is not rigid (i.e., esophagus), mucosal folds that are not in apposition to the light fiber may become underdosed. To reduce this risk, the cylindrical diffusing fiber can be placed within a balloon diffuser that can be expanded to increase its surface apposition with the mucosal surface. Similar considerations can be applied to spherical surface targets such as the mucosa of the bladder.
The use of a balloon diffuser may be helpful for certain complex three-dimensional surfaces, such as the lateral oral tongue and its adjacent floor of mouth where the surface to be treated can be molded in apposition to the balloon diffuser. In such situations, it is important to verify that the mucosal surface is in direct contact with the balloon’s surface before the light is delivered. Other strategies for such complex three-dimensional surfaces may include dividing the target volume into separate targets and individually treating each area with a microlens (patching technique). With this approach, it is important to bear in mind that areas of potential overlap, when illuminated, may increase the risk of normal tissue complications. Other surface illumination techniques under development include a light blanket that attempts to mold the light source to such complex three-dimensional surfaces.
Interstitial light fibers can also be placed when volume illumination is required. As with interstitial brachytherapy techniques, the geometry of the light fibers can significantly affect the overall distribution and amount of light that is delivered. Thus, the use of rigid templates guiding the insertion of the trocar needles (Fig. 27.3) can be very helpful in ensuring accurate interfiber spacing. These templates may be used to facilitate the advancement of rigid trocar needles whose track can then be replaced with light fibers. Alternatively, traditional low-dose rate after-loading plastic catheters may be used instead to allow the use of the needle track for both light detection fibers or treatment fibers where prescription is based on light dosimetry. The placement of the catheters can also facilitate several quality assurance measures. This can include verifying the geometry of the implant, allowing additional catheters to be placed or removed to optimize the geometry. It may also include verification or modification of the location of the light fiber in its catheter relative to the tumor volume.
Whether the optical properties of the tissue being treated are different by staging the placement of the implant and its illumination is not clear. However, where significant tissue trauma occurs with the placement of the implant, staging the illumination may offer some potential advantages especially where significant tissue bleeding with the introduction of the trocar needles has occurred. Other theoretical advantages may also include improved oxygenation of the implanted tissue, both improving the photosensitization process and reducing hemoglobin absorption of the activating light energy.
Although the optimal interstitial PDT prescription parameters remain to be defined, it is heartening to see successful interstitial light implants having been reported in patients. For such results to become generalizable, the development of a robust and easy-to-use dosimetry system will be needed that will facilitate characterizing the impact of different prescription factors (i.e., intercatheter distance, fluence rate) on normal tissue complications and oncologic results.
FIGURE 27.2. Various fiber-based light sources. These include a linear source (A), an endotracheal-tube modified point source (B), collimated light fiber (C), and a flat cut fiber (D).
Additional Technical Considerations
A significant property of the visible light energy used for photoactivation is its ability to reflect on a surface when light is delivered with a microlens technique. This can in turn increase the fluence and fluence rate delivered especially when the surface is concave and is often referred to as the integrating sphere effect. Strategies to minimize this may include manipulating the surface geometry to reduce concavities and convexities (which can reduce the fluence delivered), removing surface mucosal secretions, including the use of anticholinergics such as glycopyrrolate, and considering alternative illumination techniques, as already discussed. Where the target lesion lies adjacent to reflective metal surfaces that may be used in exposing and possibly flattening the target lesion, surface reflection may be reduced by placing dyed surgical towels over these surfaces. Alternatively, these metal surfaces may be coated with a dark pigment. Similarly, surface scatter may increase the light that is delivered to the adjacent normal skin or mucosa adjacent but outside of the target lesion. These areas may be protected by covering the surface with a dark pigmented towel or dye.
For small surface target lesions treated with a microlens technique, movement of the light fiber due to hand tremor can have a significant impact on the light dosimetry across a small surface area. For example, this is especially a concern when the glottic laryngeal mucosa is being illuminated while working down a laryngoscope. For these reasons, adding rigidity to the flexible light fiber by fixing it to a rigid stylet and immobilizing it with various commercially available fixation devices should be considered.
As discussed above, the mechanism of action for PDT is dependent on various microenvironment factors, such as blood flow and the effective tissue oxygenation. Practically, these principles require attention to the handling of the tissues to be treated and to not compromise its vascular supply, especially when exposing the surface for treatment. Surface cautery and vasoconstrictive agents used to control bleeding should be judiciously used if at all. This is particularly important when using strategies of tumor debulking to improve the depth of penetration with superficial illumination. For interstitial techniques, precise placement of the light fibers minimizing the use of multiple passages of the needle trocar should be considered. Whether the use of steroids to manage the potential adverse effects of PDT-induced edema (i.e., for airway management) adversely affects the immune response is not clear, but judicious use is recommended at this time.
FIGURE 27.3. Example of an interstitial tongue photodynamic therapy implant. A traditional interstitial brachytherapy implant using a template (A) to facilitate the placement of trocars guiding the insertion of hollow plastic catheters (B) that are modified for linear light sources (C).
CLINICAL PHOTODYNAMIC THERAPY
The clinical study of PDT has been an active area of investigation, despite only three PS being approved for clinical use in cancer management. These include porfimer sodium for the treatment of esophageal and lung cancers and superficial papillary bladder carcinomas, temoporfin for head and neck carcinomas, and ALA for skin actinic keratosis and basal cell carcinoma. These trials have generally established clinical activity and the potential for cure in the appropriate cancer application. Despite these efforts, rigorous clinical development of PDT is generally lacking and has not evaluated important comparative questions of its activity to established treatment modalities or, where more appropriate, its value as an adjunctive modality. In general, clinical investigations have also not established the optimal PDT treatment parameters. A systematic evaluation of the quality of evidence supporting PDT in clinical practice is outside the scope of this chapter, and the reader is referred to the recent systematic review by Fayter et al.150
Skin
The dermatologic applications of PDT are perhaps the most established and scientifically robust of all the anatomic sites for which PDT has been evaluated, with established consensus statements regarding its use.151 The success of PDT for skin malignancies is a testament to both its strengths and its weakness, with a multitude of randomized trials having been completed for various nonmelanomatous skin malignancies leading to its U.S. Food and Drug Administration (FDA) approval for the management of basal cell carcinomas and the premalignant nonhyperkeratotic actinic keratosis (AK).
PDT has been used extensively in the treatment of both premalignant and malignant skin tumors, typically with surface illumination.151,152 PDT of nonhyperkeratotic actinic keratosis, squamous cell carcinoma in situ (Bowen’s disease), and basal cell carcinoma (BCC) can be performed using systemically administered porfimer sodium or topically applied aminolevulinic acid (ALA) and ALA derivatives such as methyl-ALA (MAL). For example, in a placebo-controlled trial of PDT for AK, ALA-PDT showed a significantly superior complete response rate as compared to sham PDT using vehicle plus light of 89% versus 13% (p < .001).153 PDT for AK shows similar efficacy with less toxicity as compared to cryotherapy, topical 5-fluorouracil cream, or curettage. For example, a study in which 119 subjects with 1,501 AK lesions of the scalp and face were randomly assigned to receive MAL-PDT to either the left- or right-sided lesions, with cryotherapy used to treat the contralateral side.154 Twenty-four weeks after therapy, both treatment groups showed a high response rate (89% for MAL-PDT vs. 86% for cryotherapy; p = .2), but MAL-PDT showed superior cosmesis and patient preference. In contrast, the results for PDT of squamous cell carcinomas (SCC) of the skin using topical photosensitizers have been disappointing, with recurrence rates of >50%.151,152 Perhaps the most significant potential value of ALA-PDT may be its ability to prevent the development of nonmelanoma skin cancers in patients with AK, as recently demonstrated in a randomized trial of prophylactic ALA-PDT.155
Other indications for ALA-PDT include superficial and nodular BCC.156–158 In a large single institution series, high rates of local control (>90% complete response rate, <10% local failure at 3 to 5 years) can be achieved with PDT for superficial BCC. However, the response rate and local control rate for nodular BCC drops to 70% and 40%, respectively. In a multicenter randomized trial of MAL-PDT versus cryotherapy for superficial BCC, complete response rates at 3 months were 97% and 95%, with 22% and 20% 5-year recurrence rates for MAL-PDT and cryotherapy, respectively.159 In this study, the excellent to good cosmetic outcome was 89% for MAL-PDT and 50% for cryotherapy. However, when topical PDT is compared to surgery for BCC, topical ALA or MAL-PDT consistently shows a small increase in recurrence rate as compared to surgery for both superficial and nodular BCC. However, the cosmetic outcomes for PDT are typically superior to surgery with good to excellent cosmetic outcome in >90% of PDT patients with PDT and 60% to 70% with surgery. In summary, PDT can be an appropriate and effective treatment alternative to cryosurgery or surgical excision for selected BCC. PDT is currently approved in the United States, Canada, and the European Union for the treatment of AK and approved in the European Union and Canada for treatment of BCC.
Brain
Photodynamic therapy has primarily been evaluated as adjunctive therapy treating the surgical bed often combined with its use for PDD as a fluorescent guide to (surgical) resection (FGR). Yang et al.160 demonstrated that porfimer sodium fluorescence at 640 nm could be clearly visualized in the resection bed in patients with supratentorial gliomas not seen under white light. Biopsy of these areas of fluorescence confirmed the presence of residual tumor, demonstrating the concept of FGR. Similar high tumor specificity was also observed with hypericin-mediated FGR for glioblastoma multiforme (GBM)161 and protoporphyrin-IX (PpIX) fluorescence (that was produced following administration of the photosensitizer ALA) of the surgical bed in GBM patients.162 All biopsies of fluorescent tissue contained GBM.161,162 The oncologic benefits of FGF could not be clearly evaluated in a phase III study (n = 27) as all patients receiving ALA also had received porfimer sodium and received PDT to the surgical cavity. Eljamel et al.162 demonstrated that the mean survival significant increased with ALA-mediated FGR and porfimer sodium PDT (p < .01). However, in a phase III study of 322 patients with suspected malignant gliomas randomized to ALA-FGF or conventional surgery, Stummer et al.163 reported an improved progression-free survival (41% vs. 21%, respectively; p = .0003) following a median survival of 35.5 months. No significant increased complications have been observed with photosensitizer-based PDD and FGR.163
Further evidence in support of PDT activity for GBM particularly comes from several institutional experiences where PDT was used to treat the resection cavity for various histologies, including newly diagnosed164–165,166 and recurrent165 GBM and anaplastic astrocytoma (AA).164 Other histologies evaluated have also included malignant ependymomas167 and meningiomas.168 Muller and Wilson166 reported the results of a retrospective institutional review of adjuvant porfimer sodium PDT (mean fluence of 58 J/cm2 with only 18 patients receiving >100 J/cm2) in 96 patients with supratentorial gliomas. Of these 96 patients, 49 patients presented with either newly diagnosed (n = 12) or recurrent (n = 37) GBM; a median survival of 8.25 and 7.25 months was reported, respectively. In contrast, Stylli et al.165 reported a median survival of 14.3 and 14.9 months, respectively, with hematoporphyrin derivative (HpD)-mediated PDT. Though Muller and Wilson indicate that such differences may have been due to selection factors, they also suggest that this may be consistent with a dose–response effect, as Stylli et al. treated the majority of patients with 220 J/cm2 (60–260 J/cm2). Stylli et al. also observed a light-dose effect on overall survival for both GBM and AA. This has formed the basis for an ongoing randomized trial of low versus high light dose porfimer sodium–mediated PDT as adjuvant therapy following surgical resection for supratentorial gliomas.169
Head and Neck
The evaluation of PDT for head and neck malignancies has typically been for head and neck squamous cell carcinomas (HNSCC). Case reports or series have also demonstrated that PDT may have activity for other histologies such as Kaposi’s sarcoma and salivary gland malignancies such as adenoid cystic carcinomas.170 Although there have been significant numbers of clinical evaluations of PDT in the management of HNSCC, the vast majority represent single institutional experiences demonstrating activity either for definitive management or for palliation. Definitive management has typically evaluated surface illumination for premalignant dysplastic lesions or early primary invasive mucosa malignancies where the risk of nodal metastases was regarded as low. Common sites have included the oral cavity and the larynx with novel illumination techniques for the nasopharynx37 and base of tongue171having been reported.
Superficial premalignant mucosal lesions are attractive for PDT due to the ability to achieve wide-field mucosal ablation given the uncertainties that are commonly encountered in defining the peripheral extent of the lesion. For these reasons, treatment of the larynx is particularly attractive due to the defined nature of this anatomic site, where tissue-preserving therapies such as PDT can offer further function-preserving advantages. To date, clinical experience suggests that this treatment approach can be effective in obtaining a complete response for the treated lesion, but long-term follow-up is limited and has recently been extensively reviewed.172 However, this limitation is not dissimilar from other treatment modalities that have been used for mucosal dysplasia. To date, clinical experience has also included large retrospective reviews173 and several prospective studies of porfimer sodium,174temoporfin,175,176 and topical177 and systemic139 ALA that have demonstrated high complete response rates typically >80%. Further research efforts are needed to define both the long-term in-field and out-of-field relapses risks along with the risk of malignant transformation following PDT treatment.
PDT for the treatment of superficial invasive carcinomas has also been evaluated, typically with porfimer sodium and temoporfin, especially with the EU regulatory approval of temoporfin for the palliative management of HNSCC. Prospective studies of porfimer sodium174,178 and temoporfin179 have demonstrated complete response rates typically >80%, with both surface and interstitial illumination techniques used. Long-term in-field control rates have also been reported in approximately 70% to 90% of treated patients.178,179
The head and neck site has also been the main focus for the development of interstitial illumination techniques, offering an array of potential treatment possibilities. These include the ability to treat deeper invasive carcinomas where the risk of nodal metastases remains low, such as early tongue carcinomas (see Fig. 27.2) or the promise of less toxic salvage therapy,180 palliation of local–regional relapses that require tumor responses,181,182 and the treatment of benign tumors such as vascular malformations,183 which would otherwise require potentially debilitating surgery or the administration of radiotherapy. Lastly, a potential role for intraoperative PDT using porfimer sodium as adjuvant therapy following surgical resection for local–regionally recurrent HNSCC has been reported. With a minimum follow-up of 24 months, four of five treated patients were without local–regional recurrence with no wound complications noted.184
Thoracic
Since 1998, PDT has been FDA approved for the treatment of microinvasive endobronchial and advanced partially obstructing non–small cell lung cancer (NSCLC).185 Endobronchial light delivery has typically been used limiting treatment to central lesions with techniques under development to extend PDT to treat peripheral lesions.186 It has been used as definitive therapy in treating endobronchial, roentgenographically occult, or synchronous primary carcinomas where the bronchoscopically visible lesions are ≤1 cm in surface dimension with no extracartilaginous invasion. Less effective results have been observed when PDT is used to treat larger tumors without prior surgical debulking and has largely been used for palliative indications. PDT has also been investigated for malignant mesothelioma and pleural involvement by NSCLC with promising findings suggestive of activity and benefit.
Roentgenographically Occult Bronchogenic
Non–Small Cell Lung Cancer
Fewer than 1% of patients with roentgenographically occult bronchogenic carcinoma that are endoscopically visible but lack cartilaginous invasion have metastatic lymph node involvement, indicating a potential for a less invasive focal therapy to be curative.187 With demonstrated efficacy of PDT in this setting, it has emerged as a first-line therapy for roentgenographically occult lesions, particularly for tumors ≤1 cm that have no extracartilaginous invasion or lymph node involvement. Investigators from the National Kinki Central Hospital for Chest Diseases used PDT to treat roentgenographically occult bronchogenic carcinoma in 25 patients with 29 lesions.188 A complete remission was achieved in 72% of lesions, including 89% (17/19) of lesions ≤1 cm and 86% (18/21) of visible peripheral area lesions. In another series of 33 patients, with 40 roentgenographically occult carcinomas treated with PDT, a complete response was achieved in all lesions ≤1 cm (n = 32), but in only three of eight larger tumors.189 Among the 39 roentgenologically occult lesions treated at Osaka Prefectural Habikino Hospital with PDT, a complete response was achieved in 64% of lesions, more likely in superficially infiltrating than for nodular lesions (76% vs. 43%).190 Tohoku University Hospital investigators treated 48 medically operable patients with roentgenographically occult bronchogenic squamous cell carcinomas with tumor lengths of ≤1 cm with PDT, observing a complete response in 94% of patients and a 10-year overall survival rate of 71%.191
Radiographically Visible Early-Stage and
Endobronchial Non–Small Cell Lung Cancer
Similar to roentgenologically occult bronchogenic carcinomas, early-stage and endobronchial NSCLC can be effectively treated with PDT. Although often used for patients unsuitable for surgical resection, PDT has became an established alternative treatment modality to surgery for patients with early-stage, small central NSCLC lesions.
At Tokyo Medical University Hospital, 240 patients with 283 central lung cancer lesions were treated from 1980 to 1995 with PDT. The overall response rate was 99%, with a complete response in 40%. A complete response was achieved in 83% (79/95) of early-stage lesions, with a 94% (65/69) complete response rate for lesions <1 cm. Several institutional experiences also made similar observations of durable complete responses in over 75% of patients treated at a minimum of 12 months’ follow-up.192,193 However, the complete response rate fell to 54% (14/26) for lesions ≥1 cm and 38% (6/16) for lesions ≥2 cm (p = .00001).194 A more recent report from Tokyo Medical University Hospital demonstrated that among 93 patients treated with PDT for 114 central early-stage lung cancers, the complete response rate was higher for lesions <1 cm (77/83) than ≥1 cm (18/31; 93% vs. 58%; p < .001). The recurrence rate was 12% for lesions <1 cm with an initial complete response to PDT, and many recurrences could successfully be salvaged with additional PDT.195 In a review of 15 trials of 626 patients with 715 central early-stage bronchogenic cancers treated typically for surgery ineligibility patients, PDT-related toxicity was limited, with one PDT-related death (0.15%), photosensitivity skin reactions in 5% to 28%, respiratory complications in 0% to 18%, and nonfatal hemoptysis in 0% to 8%. A complete response was achieved in 30% to 100% of patients for a 2- to 120-month duration, and the 5-year overall survival was 61%.196
Synchronous multiple primary lung cancers occur in 1% to 15% of patients with lung malignancies and have been increasing in incidence due to improvements in imaging. These cases may warrant considerations for aggressive management. Incorporating PDT in the management of central lesions, especially when small in size, can significantly reduce the pulmonary morbidity. In a study of 22 patients with synchronous early lung cancers treated with PDT alone for each lesion (n = 11) or surgery for the more peripheral lesions and PDT for the more central lesions (n = 11), PDT achieved a complete response in all 39 central tumors at 2 months following therapy.197 All patients were alive with variable follow-up of up to 5 years.
Advanced-Stage Non–Small Cell Lung Cancer
For patients with locally advanced or metastatic NSCLC, PDT has most commonly been used for palliation. In a randomized trial comparing PDT to neodymium:yttrium-aluminum-garnet (Nd:YAG) laser therapy in the NSCLC patients with an obstructed airway, both PDT and Nd:YAG laser therapy were comparable with regard to symptom relief and response rates. The time to failure (p = .03) and the median survival (p = .007) were significantly longer in the cohort receiving PDT.198 In combination with radiotherapy, prolonged response of the luminal tumor mass may be observed and warrants further investigation.199,200
Preoperative PDT has been reported in several small institutional series of patients with NSCLC. Although small in numbers, these series have independently observed that preoperative PDT may help reduce the extent of definitive resection needed for locally advanced NSCLC by down-staging patients who would otherwise require a pneumonectomy to undergo lobectomy instead or to convert patients originally deemed inoperable to be surgical candidates.201–203 Okunaka et al.201 reported on the results of 26 patients with NSCLC treated with preoperative PDT alone for the purposes of reducing the extent of resection or converting inoperable disease to an operable status. These surgical goals were achieved in 85% of patients, with four of five originally inoperable patients converted to resectable, and 18 of 21 patients originally candidates only for pneumonectomy were able to undergo lobectomy. Ross et al.202 reported on 41 patients with locally advanced NSCLC treated with induction PDT and chemotherapy or radiation therapy. PDT induction allowed 57% of initially unresectable patients to undergo definitive surgical resection and 27% of those initially deemed in need of pneumonectomy to undergo lobectomy. Pathological down-staging occurred in 64%, and 46% of patients were alive at 3 years’ following therapy.
PDT may also be used as part of multimodality management for patients with NSCLC with pleural spread. A phase II trial of 22 such patients at the University of Pennsylvania assessed the oncologic outcome of patients treated with surgery, achieving either a complete resection (n = 17) or partial tumor debulking (n = 3) followed by hemithoracic pleural PDT (porfimer sodium) (n = 20) or PDT alone (n = 2).204 The 6-month local control rate for the cohort was 73.3% and the median overall survival was 21.7 months, suggesting promising activity.
Malignant Pleural Mesothelioma
The use of PDT to treat malignant pleural mesothelioma was pioneered at the National Cancer Institute in 1980s and has since become increasingly more integrated into multimodality therapy for mesothelioma.205 In a National Cancer Institute phase I trial, 54 patients with pleural malignancies isolated to one hemithorax were evaluated, including 40 patients with mesothelioma. Among the 42 patients who underwent optimal tumor debulking to ≤5 mm of residual tumor thickness followed by PDT, PDT was relatively well tolerated; toxicities included a patient with an empyema and a late hemorrhage, bronchopleural fistulas in two patients, and esophageal perforations in two patients. The median survival among mesothelioma patients was 10 months.206 In the perioperative period, however, intraoperative PDT for mesothelioma can be associated with acute bleeding, severe generalized vascular atherosclerosis, generalized edema, intrathoracic fluid accumulation, respiratory distress, and death.207
In a phase II study at Roswell Park Cancer Institute, 40 patients underwent extrapleural pneumonectomy or pleurectomy followed by intracavitary PDT.208 The median survival was significantly better for stages I and II patients (n = 13) than stages III and IV patients (n = 24; 36 months vs. 10 months; p < .0001). PDT dose was found to be an independent prognostic indicators for survival (p < .009).208 Dutch investigators treated 28 predominantly advanced-stage mesothelioma patients with pleuropneumonectomy followed by intraoperative PDT. Half of the patients in the cohort had persistent local tumor control for at least 9 months following PDT, and the median overall survival of the cohort was 10 months.207 At the University of Pennsylvania, 28 patients with malignant pleural mesothelioma, including 86% with stages III and IV disease, were treated from 2004 to 2008 with macroscopic complete resection and intraoperative PDT. Patients who underwent radical pleurectomy (n = 14) had a significantly improved median survival (not reached at a median follow-up of 2.1 years vs. 8.4 months; p = .009) compared with those who underwent modified extrapleural pneumonectomy.209
The only randomized phase III trial assessing the role of PDT in the management of malignant pleural mesothelioma involved 63 patients at the National Cancer Institute undergoing maximum debulking surgery, postoperative cisplatin, interferon α-2b, and tamoxifen with or without first-generation intraoperative intrapleural PDT (630 nm, porfimer sodium, 30 J/cm2 using intraoperative real-time light dosimetry).210 Most patients (79%) had stage III disease. The median survival for the 15 nonoptimally cytoreduced patients with >5 mm residual disease was 7.2 months, compared to 14.4 months for the remaining 48 patients. PDT did not influence the pattern of recurrence, median survival (14.1 vs. 14.4 months), or median progression-free time (8.5 vs. 7.7 months).210 Whether survival may have been improved with optimal debulking and PDT is not clear at this time.
Gastrointestinal Malignancies
Photodynamic Therapy for Malignancies
of the Gastrointestinal Tract
Of the gastrointestinal (GI) tract tumors that can be treated with PDT, Barrett’s esophagus (BE) with dysplasia and early-stage esophageal cancer are the best studied.211,212 Overholt et al.213 demonstrated in a multicenter randomized trial that PDT for premalignant BE can eliminate dysplastic cells and is associated with a lower incidence of development of invasive carcinoma. In this trial, 208 patients were randomly assigned to receive either PDT with proton pump inhibitor (PPI) or PPI alone in a two-to-one randomization schema. PDT-treated patients received porfimer sodium (2 mg/kg) 40 to 50 hours prior to the first light delivery. Areas of BE were exposed to 130 J/cm with 630 nm light using a cylindrical fiberoptic diffuser encased in an inflated esophageal balloon so that the fiber would be centered and the esophageal folds flattened. Ninety-six to 120 hours later, a repeat endoscopy was performed to assess response and an additional 50 J/cm could be given to areas of insufficient mucosal damage. If BE was found to persist on follow-up endoscopy, additional PDT treatments could be performed as described above to a maximum of three total treatments given at least 3 months apart. All patients (in both arms) received omeprazole therapy at a dose of 20 mg given twice daily. The results of this trial showed that PDT plus PPI was superior to PPI alone, both in terms of ablation of high-grade dysplasia (HGD) and progression to adenocarcinoma.
Updated 5-year results confirm the long-term benefits with a 50% relative risk reduction in the incidence of invasive carcinoma.214 At 5 years of follow-up, Overholt et al.213 demonstrated that 77% of patients treated with PDT-PPI showed ablation of HGD versus 39% of patients treated with PPI alone (p < .0001). More significantly, 15% of the patients in the PDT-PPI arm showed progression to cancer versus 29% of patients on the PPI arm (p < .006). The most serious toxicity of the PDT-PPI treatment was esophageal stricture, with the majority of cases successfully managed with esophageal dilatation. Mucosal injury prior to PDT and repeat PDT treatments appear to increase this risk.213,215 Cost-effectiveness analysis proposes suggest that PDT even when repeated is a relatively safe and effective management option of patients with BE-HGD.
PDT has also been studied in a variety of tumor types in the GI tract beyond the esophagus. Significant clinical efficacy has been observed in early studies of PDT for gastric,216 early duodenal, and ampullary cancers.217–219Promising results have been achieved in the treatment of cholangiocarcinomas (CC). Early case reports and pilot studies of PDT for CC demonstrated significant promise.220,221 In a randomized, controlled trial of stenting with or without PDT, the median survival of patients treated with PDT plus stenting was a remarkable 493 days compared with only 98 days in the stenting alone group.222 Other studies have shown similar results.223–225 Consequently, a multicenter clinical trial has been recently initiated to obtain regulatory approval in the United States and Canada.226
Other clinical applications of PDT in the GI tract have included unresectable pancreatic cancers227 and numerous reports using PDT to eliminate colon polyps as well as to palliate bulky colon and rectal cancers.219,228–230 In addition, PDT may have efficacy in treating hepatocellular carcinoma. Early results have been promising, and a phase III study is currently under way to evaluate the efficacy of Talaporfin-mediated PDT using interstitial LEDs compared with institution-specific standard treatment.231
Photodynamic Therapy for Intraperitoneal Malignancies
Peritoneal carcinomatosis presents a very difficult problem for standard cancer treatment modalities. The superficial nature of PDT combined with its ability to treat large surface areas lends itself to this particular problem. However, adequate and homogeneous light distribution to all peritoneal surfaces remains an ongoing technical challenge to date. In a phase I trial of 70 subjects with predominantly recurrent ovarian carcinomatosis, intraoperative PDT following maximal surgical debulking resulted in a 76% complete cytologic response rate with tolerable toxicity.232 In the follow-up phase II study, patients were enrolled and stratified according to cancer type (ovarian, gastrointestinal, or sarcoma) and given doses of porfimer sodium and light at the phase I defined maximally tolerated dose.233 Other than capillary leak syndrome and skin photosensitivity, the complication rates were similar to the complication rates typically observed after similarly extensive surgery in the absence of PDT.234 With a median follow-up of 51 months, the median failure-free survival and overall survival rates for the patients who received PDT were 3 months and 22 months in ovarian cancer patients and 3.3 months and 13.2 months in gastrointestinal cancer patients, respectively. Six months after therapy, the pathologic complete response rate was 3 of 33 (9.1%) and 2 of 37 (5.4%) for the patients with ovarian cancer and gastrointestinal cancer, respectively. These results in heavily pretreated patients suggest that PDT for peritoneal carcinomatosis may have clinical benefit, warranting further study.
Genitourinary Malignancies
Photodynamic Therapy for Prostate Carcinomas
The role of interstitial PDT for prostate adenocarcinoma has been investigated by several groups studying various PS including temoporfin,6,235 motexafin lutetium,52,233,236 and padoporfin.237 The majority of these phase I and II trials have been in patients with locally recurrent adenocarcinoma, where the standard management option has not been well defined, typically following failure of radiotherapy. Several important observations can be generalized. Of these, it is clear that traditional brachytherapy techniques can be adopted to administer diffusing light fibers with potentially effective light delivery and oncologic efficacy. Oncologically, the results would suggest that a dose–response relationship may exist with higher light doses delivered, increasing the probability of acute tissue injury with an increase in PSA in the first 24 hours posttreatment,52 pathologic complete response,238 and possibly a more durable PSA response.52 The early rise in PSA has been suggested to be a possible surrogate for treatment efficacy.52
At this time, the optimal light dose and other PDT prescription parameters remain to be determined for durable oncologic benefits to be realized. However, delivering a minimum and sufficient light fluence to 90% of the prostate may be important.238 This is further complicated by the significant inter- and intra-patient heterogeneity239,240 in the optical properties of the prostate that changes dynamically during the administration of the light.6 However, analysis of the heterogeneity in the tissue injury as assessed by magnetic resonance imaging demonstrates that light dosimetry may not be sufficient to completely predict for prostate and surrounding normal tissue injury, such as the risk of urorectal fistulas.241 That is, other factors such as the PS and oxygen concentrations and the effectiveness of the singlet oxygen generation along with unknown patient factors may be important and remain subjects of ongoing investigation.242 In the interim, careful attention to minimize trauma to the rectal wall235 and the light dosimetry for interstitial PDT remains important, and it may be prudent to establish a lower light fluence to the rectal wall as this tissue may have a lower intrinsic threshold for interstitial PDT injury.241
Photodynamic Therapy for Bladder Carcinomas
Bladder carcinomas are typically superficial and diffuse across the mucosa, lending to the application of intracavitary PDT. In fact, the first-generation photosensitizer hematoporphyrin and its derivative (HpD) was used as early as 1975, leading to the regulatory approval of the purified active component (porfimer sodium) for the treatment of recurrent superficial papillary carcinoma typically failing intravesical therapy such as bacille Calmette-Guérin (BCG). Several institutional experiences have demonstrated activity with HpD or porfimer sodium PDT to the whole bladder with high initial response rates of ≥70% with long-term (>2 years) control rates between 30% and 60%.243,244–245,246 These response rates are not too dissimilar to those observed with many intravesical agents, suggesting comparable activity that was recently supported in a recent multicenter randomized study comparing BCG to porfimer sodium PDT in patients with superficial (nonmuscle invasive) carcinoma.247 Bladder contracture due to fibrosis was observed to be a significant complication in the early experience of porfimer sodium PDT that was subsequently demonstrated could be reduced by measuring the light fluence on the surface accounting for both the incident and scattered light.248 Other strategies that reduced the risk of late bladder injury included porfimer sodium PDT with less penetrating light (514 nm),249 reducing the porfimer sodium and light dose administered,243 and the use of topical ALA, which is a more superficial photosensitizer with comparable outcomes suggested.250,251
CONCLUSION
A significant body of preclinical and clinical evidence supports the conclusion that PDT can have significant cancer cytotoxicity with cure possible in several clinical applications. There has been a tremendous body of advancement in the physics of light dosimetry, sophisticated PS development for photodiagnosis and photoactivation, and our understanding of the cellular and microenvironment effects of PDT. These offer an array of potential translational opportunities to advance both the indications and the efficacy of PDT both alone and in combination with traditional therapeutics.
ACKNOWLEDGMENTS
Harry Quon is a consultant with Pinnacle Biologics, and Theresa M. Busch is a consultant with Pharmacyclics, Inc. Support for the authors during the writing of this contribution was provided through grants R01-CA-129554, R01-CA-085831, and P01-CA-087971.
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