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Radiation Oncology

Photodynamic Therapy in Oncology

^a Division of Experimental Therapy (H6) and ^b Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; ^c Faculty of Pharmaceutical Sciences, Division of Drug Toxicology, Utrecht University, Utrecht, The Netherlands

Key Words. Photodynamic therapy • Photofrin • Aminolevulinic acid • mTHPC

Correspondence: Fiona A. Stewart, Ph.D., Division of Experimental Therapy (H6), The Netherlands Cancer Institute/Antoni van Leeu-wenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Telephone: 31-20-512-2036; Fax: 31-20-512-2050; e-mail: f.stewart{at}nki.nl

Received January 13, 2006; accepted for publication August 10, 2006.

	LEARNING OBJECTIVES

Top Learning Objectives Abstract History of Photodynamic Therapy Principle of PDT Working Mechanism of PDT... Photosensitizers Light Application PDT as a Clinical... Future Perspectives Disclosure of Potential... References

 
After completing this course, the reader will be able to:

1. Discuss the safety and side effects of PDT.
   
2. Identify appropriate indications for PDT.
   
3. Explain the choice of PDT over other treatment modalities.
   

	ABSTRACT

Top Learning Objectives Abstract History of Photodynamic Therapy Principle of PDT Working Mechanism of PDT... Photosensitizers Light Application PDT as a Clinical... Future Perspectives Disclosure of Potential... References

 
Photodynamic therapy (PDT) is increasingly being recognized as an attractive, alternative treatment modality for superficial cancer. Treatment consists of two relatively simple procedures: the administration of a photosensitive drug and illumination of the tumor to activate the drug. Efficacy is high for small superficial tumors and, except for temporary skin photosensitization, there are no long-term side effects if appropriate protocols are followed. Healing occurs with little or no scarring and the procedure can be repeated without cumulative toxicity. Considering the efficacy and lack of long-term toxicity of PDT, and the fact that the first treatment of cancer with PDT was done more than 100 years ago, one might expect that this treatment had already become an established therapy. However, PDT is currently offered in only a few selected centers, although it is slowly gaining acceptance as an alternative to conventional cancer therapies. Here, we show the developmental steps PDT underwent and summarize the current clinical applications. The data show that, when properly used, PDT is an effective alternative treatment option in oncology.

	HISTORY OF PHOTODYNAMIC THERAPY

Top Learning Objectives Abstract History of Photodynamic Therapy Principle of PDT Working Mechanism of PDT... Photosensitizers Light Application PDT as a Clinical... Future Perspectives Disclosure of Potential... References

 
The first clinical application of photodynamic therapy (PDT) was described by von Tappeiner and Jesionek in 1903 [1], who applied eosin topically to basal cell carcinomas (BCCs) prior to illumination. von Tappeiner and Jodlbauer later defined PDT as the dynamic interaction among light, a photosensitizing agent, and oxygen resulting in tissue destruction [2]. It took another 70 years, however, before the possibilities of PDT for the treatment of cancer really became recognized.

In 1975 Dougherty et al. [3] reported that hematoporphyrin derivative (HpD) in combination with red light could completely eradicate mouse mammary tumor growth. Clinical trials were subsequently initiated with HpD to treat patients with bladder cancer and skin tumors [4, 5]. Following these successful studies, numerous trials were initiated involving a variety of cancers and photosensitizers. This resulted in the approval of PDT, using porfimer sodium (Photofrin^®; Axcan Pharma Inc., Mont-Saint-Hilaire, Canada), for the treatment of bladder cancer in Canada in 1993. Today, three more sensitizers are approved for clinical use—5-aminolevulinic acid (ALA, Levulan^®; DUSA Pharmaceuticals Inc., Wilmington, MA), the methyl ester of ALA (Metvix^®, Photocure ASA, Oslo, Norway), and meso-tetra-hydroxyphenyl-chlorin (mTHPC, temoporfin, Foscan^®; Biolitec Pharma Ltd., Dublin, Ireland)—and PDT is becoming an established treatment modality for localized cancers.

	PRINCIPLE OF PDT

Top Learning Objectives Abstract History of Photodynamic Therapy Principle of PDT Working Mechanism of PDT... Photosensitizers Light Application PDT as a Clinical... Future Perspectives Disclosure of Potential... References

 
PDT involves the administration of a photosensitizer followed by local illumination of the tumor with light of the appropriate wavelength to activate the specific drug. Activation of the photosensitizer upon absorption of the light transforms the drug from its ground state (¹PS) into an excited singlet state (¹PS^*, Fig. 1). From this state the drug may decay directly back to ground state by emitting fluorescence, which is a property that can be used clinically for photodetection. However, to obtain a therapeutic photodynamic effect, the photosensitizer must undergo electron spin conversion to its triplet state (³PS^*). In the presence of oxygen, the excited molecule can react directly with a substrate, by proton or electron transfer, to form radicals or radical ions, which can interact with oxygen to produce oxygenated products (type I reaction). Alternatively, the energy of the excited photosensitizer can be directly transferred to oxygen to form singlet oxygen (type II reaction), which is the most damaging species generated during PDT [6].

View larger version (6K): [in this window] [in a new window]   Figure 1. The principle of photodynamic therapy.

	WORKING MECHANISM OF PDT IN VIVO

Top Learning Objectives Abstract History of Photodynamic Therapy Principle of PDT Working Mechanism of PDT... Photosensitizers Light Application PDT as a Clinical... Future Perspectives Disclosure of Potential... References

Singlet oxygen is highly reactive and can diffuse only 0.01–0.02 µm during its brief lifetime. Therefore the sensitizer should be localized close to its target at the time of illumination. With the original aim of specific tumor cell killing, it was assumed that optimum response would be obtained for illumination at times when tumor drug levels were high relative to surrounding normal tissues. However, recent animal studies [8, 9] and clinical data [10] have shown that the concentration of sensitizer in the tumor at the time of illumination does not necessarily predict response to PDT. Plasma concentration at the time of illumination is a better indicator for PDT outcome [11–14]. This suggests that tumor cells may not always be direct targets of PDT, but they may be indirectly killed as a result of damage to other cell types, for example, vascular endothelial cells.

The relationship between the severity of PDT-induced vascular damage and tumor response has been well documented and results show that treatment schedules that fail to induce complete shutdown of vessels feeding a tumor will not result in long-term cure [13, 15–19]. Furthermore, inhibition of inflammatory responses and vasoconstriction decrease tumor response to PDT, whereas concomitant pharmacological inhibition of angiogenesis enhances the PDT response [11–14, 20–24]. All these studies demonstrate the importance of vascular-mediated damage in obtaining an effective tumoricidal effect after in vivo PDT.

The majority of evidence suggests that vascular sensitivity to PDT is a result of physiological factors, such as high local concentrations of both oxygen and photosensitizer in the blood vessels, rather than intrinsic sensitivity of endothelial cells. If the tumor vasculature is the primary target for PDT, the therapeutic benefit results from differences in vascular integrity between tumors and surrounding normal tissues rather than specific drug uptake in the tumor cells.

	PHOTOSENSITIZERS

Top Learning Objectives Abstract History of Photodynamic Therapy Principle of PDT Working Mechanism of PDT... Photosensitizers Light Application PDT as a Clinical... Future Perspectives Disclosure of Potential... References

 
The most ideal photosensitizer would be a chemically pure drug with preferential uptake in tumor, rapid clearance, and a strong absorption peak at light wavelengths >630 nm. We have compared the four clinically approved photosensitizers (Table 1) and give a brief summary of new photosensitizers under investigation.

View larger version (20K): [in this window] [in a new window]   Figure 2. Chemical structures of porfimer sodium (A), 5-aminolevulinic acid (ALA) and Metvix® (B), and meso-tetra-hydroxyphenyl-chlorin (mTHPC) (C), and absorption spectra of porfimer sodium and mTHPC (D). The relative absorption spectrum of ALA is comparable with that of porfimer sodium.

The second-generation photosensitizer ALA (Levulan^®) received approval for the treatment of cancerous lesions in 1999 (Fig. 2 and Table 2). ALA itself has no photosensitizing effect, but is a natural precursor of heme. This pathway ends with the conversion of protoporphyrin IX (PpIX), which has photosensitizing properties, into heme by ferrochelatase. Many tumor types have a lower ferrochelatase activity than normal tissue [26]. Therefore, upon administration of ALA, the capacity of ferrochelatase is overwhelmed, resulting in a buildup of PpIX in tumor cells [27]. The absorption spectrum for PpIX is very similar to that of porfimer sodium, and it is usually activated by light of 630 nm.

The use of ALA PDT has several advantages over PDT with porfimer sodium: there is a more rapid clearance (limiting skin photosensitivity to 1–2 days), it can be applied topically for the treatment of skin cancer and orally for cancer in the oral cavity or digestive tract, and greater tumor selectivity is achieved. The disadvantage of ALA is that it is strongly hydrophylic and therefore not able to enter cells easily. This led to the development of several alkyl esters of ALA that do penetrate the cell easier. The methyl ester of ALA (Metvix^®) was approved in the European Union (EU) in 2001 for the treatment of actinic keratosis and BCC.

mTHPC
The most recently approved photosensitizer for cancer is mTHPC (temoporfin, Foscan^®) (Fig. 2 and Table 2). Foscan^® was approved in 2001 in the EU for the palliative treatment of head and neck cancer. mTHPC is a much more potent photosensitizer than porfimer sodium or ALA, requiring light doses of only 10–20 J/cm² for tumor control [28–32]. Skin photosensitivity is also reduced to 2–4 weeks. Furthermore, mTHPC has an absorption peak at 652 nm, compared with 630 nm for both porfimer sodium and ALA, which slightly increases the tissue depth penetration of light.

New Photosensitizers
The search for new, third-generation photosensitizers is still ongoing, especially for drugs that can be activated with light of a longer wavelength, which provoke shorter generalized photosensitivity and have better tumor specificity. Although many new photosensitizers have already entered clinical trials, few results have been published. New photosensitizers already in clinical trials include tin ethyl etiopurpurin (SnET2), mono-L-aspartyl chlorin e6 (Npe6), benzoporphyrin derivative (BPD), and lutetium texaphyrin (Lu-Tex), which all have absorption bands at relatively high wavelengths (660, 664, 690, and 732 nm, respectively) and provoke only mild, transient skin photosensitivity. The few clinical studies published using these photosensitizers include phase I/II trials in which PDT was used for the treatment of cutaneous cancer [33–37], early squamous cell carcinoma of the lung [38], and recurrent prostate cancer using interstitial PDT[39]. Evaluation of the relative merits of these sensitizers and approval for general clinical use are awaited.

	LIGHT APPLICATION

Top Learning Objectives Abstract History of Photodynamic Therapy Principle of PDT Working Mechanism of PDT... Photosensitizers Light Application PDT as a Clinical... Future Perspectives Disclosure of Potential... References

 
Conventional, broad-spectrum light sources, such as arc lamps, can be used for activation of photosensitizers. These lamps are cheap and easy to use, but it is difficult to couple them to light delivery fibers without reducing their optical power. It is also difficult to calculate the effective delivered light dose, and power output is limited to a maximum of 1 W. Filters are also required to cut off UV radiation and infrared emission that can cause heating.

An important breakthrough in PDT was the development of lasers, which emit light of precise wavelengths in easily focused beams. Early lasers were expensive, large, immobile machines that required a level of technical support. Further developments in semiconductor diode technology resulted in cheaper systems, which are compact and portable while still retaining high power output. Most also contain an internal unit for dosimetric calculations and have built-in treatment programs, making them much more user friendly. However, diode lasers offer only a single output wavelength, limiting their versatility. Light emitting diodes (LEDs) are also available for clinical use. They are less expensive than the light sources described above, are small, and can provide a power output up to 150 mW/cm² at wavelengths in the range of 350–1,100 nm.

The development of optical fiber technology also plays an important role in PDT [40]. Successful PDT requires delivery of the light from source to target and a homogeneous light distribution. Optical fibers have been customized to meet the demands of illumination at different localizations. For superficial illumination of, for example, oral mucosa, optic fibers with a lens tip are used to spread the light over the target area. In hollow organs, for example, endobronchial, esophagus, and bladder, illumination is often performed with cylindrical diffusers combined with inflated balloons for uniform light distribution. Black coating of one side of the balloon is sometimes used to shield adjacent normal tissue areas for protection.

	PDT AS A CLINICAL APPLICATION FOR CANCER

Top Learning Objectives Abstract History of Photodynamic Therapy Principle of PDT Working Mechanism of PDT... Photosensitizers Light Application PDT as a Clinical... Future Perspectives Disclosure of Potential... References

 
For PDT, as for any new cancer therapy, it is important to identify the specific indications for this treatment and to evaluate its benefits and disadvantages relative to standard therapies. Before considering individual cancer types, there are some general conclusions that can be made.

PDT is a treatment requiring a single injection of drug followed after a certain time interval by single illumination. This is very often done on an outpatient basis. In comparison, typical curative radiotherapy regimes comprise daily irradiation for a total of 6–7 weeks (again on an outpatient basis). Chemotherapy schedules vary, but typically last for several months. Surgery, although a single procedure, requires general anesthesia and hospitalization for one to several weeks. Cost-effectiveness comparisons have been made for palliative treatment of head and neck cancer with PDT versus extensive surgery or chemotherapy [41, 42], and for PDT versus esophagectomy or endoscopic surveillance for patients with Barrett’s esophagus and high-grade dysplasia [43]. PDT proved both to be cost-effective and to provide increased life expectancy, compared with other treatment options for these conditions.

PDT is a local, rather than systemic, treatment; it is therefore suitable only for localized disease. Light of wavelengths used to excite current photosensitizers can provoke photochemically induced tissue necrosis up to a maximum of 10 mm [44]. This means that, for superficial illuminations, the indication for PDT as a primary treatment should be limited to small, accessible tumors. It can also be given in combination with debulking surgery for palliative treatment of larger tumors.

A big advantage of the limited light penetration is that this protects normal healthy tissue beneath the tumor from phototoxicity. Modern fiber-optic technology facilitates delivery of light, of the desired wavelength and fluence rate, to tumors located virtually anywhere in the body. Localized illumination, together with shielding of sensitive tissues at the margin of the field, enables specific tumor treatment without destruction of critical normal tissues outside the treated area. By contrast, surgery and radiotherapy of tumors located close to critical structures can be very mutilating and lead to loss of function. PDT has the advantage that, although there is severe ulceration of the illuminated area immediately after treatment, there is minimal long-term fibrosis, resulting in functional recovery without scarring (Fig. 3). PDT spares tissue architecture, providing a matrix for regeneration of normal tissue, because it does not damage subepithelial collagen and elastin and there is preservation of noncellular supporting elements [45, 46].

View larger version (79K): [in this window] [in a new window]   Figure 3. Basal cell carcinoma before (A) and 6 months after (B) meso-tetra-hydroxyphenyl-chlorin (mTHPC)-mediated photodynamic therapy. All lesions were cured. Scarring as a result of surgical excision of other lesions is also shown.

Bladder Cancer
HpDPDT was used to treat recurrent bladder cancer as early as 1975 [47]. This was also the first site to receive approval for porfimer sodium PDT in 1993. In the 1980s, several trials showed that PDT with HpD or porfimer sodium was effective for superficial, recurrent bladders cancers [48–52]. Initial response rates were very high (70%–100% at 3 months) with long-term response rates of 30%–60%, comparable with responses after transurethral resection or treatment with bacillus Calmette-Guerin. For whole-bladder PDT, there was, however, a very high incidence of side effects (urinary frequency, pain, and persistent reduction in bladder capacity), which prevented PDT from becoming an established clinical treatment for bladder cancer. These complications were associated with excessive light doses and nonuniform light delivery in the early studies. Nseyo et al. showed that, for standardized protocols using lower drug and light dose [53], or for illumination with less penetrating light of 514 nm, good tumor response rates could be achieved for superficial lesions without transmural bladder injury or treatment-related morbidity [54]. Whole-bladder PDT with green light and proper dosimetry remains an attractive treatment option for carcinoma in situ (CIS), although this has not been fully evaluated.

More recently, ALA has been used for recurrent superficial bladder cancer. ALA PDT given as a single treatment, or in combination with mitomycin C, resulted in complete response (CR) rates of 40%–52% at 18–24 months without persistent reduction in bladder capacity [55–57].

Skin Cancer
Skin cancers are ideally suited to PDT. In the first large clinical trial, CR rates of >85% were achieved for HpD followed by red light [4]. Since then, numerous other studies confirm that PDT achieves response rates for superficial skin cancers that are equivalent to those achieved by conventional methods (cryotherapy, surgical excision), but with less scarring [58].

For patients with only a few localized lesions, the use of a systemic photosensitizer may not be justified, because of the prolonged period of induced photosensitivity. By contrast, PDT using topical application of ALA or its ester Metvix^® is a very good alternative. ALA can be applied locally, a few hours before illumination of the tumor, and excellent CR rates (86%–100%) can be achieved for BCC [59]. The few recurrences that are seen seem to result from the failure of the ALA to penetrate the tumor; weak solutions of dimethylsulfoxide or desferrioxamine applied before ALA increases drug penetration and improves cure rates [60, 61]. ALA PDT can also be used to successfully treat Bowen’s disease, giving significantly higher CR rates (75%–88%) than 5-fluorouracil (50%) or cryotherapy (48%), provided that illumination is with penetrating red light [62–64]. One drawback of ALA PDT is that the first few minutes of illumination can be very painful. Local anesthesia or cold air can be used to alleviate this problem [65].

PDT with systemic photosensitizers (porfimer sodium or mTHPC) is more suitable for treatment of multiple lesions, particularly a large surface area with multiple small lesions suggestive of a field defect. The largest study, with porfimer sodium, included 1,400 superficial and nodular BCCs and resulted in a CR rate of 91% [66]. mTHPC PDT is also effective for multiple BCCs and has the advantage that treatment times are considerably shorter, because light doses of only 10–15 J/cm², instead of >200J/cm², are required. Generalized phototoxicity is also limited to a maximum of 2 weeks [67, 68].

Head and Neck Cancer
Early-stage carcinomas in the head and neck area are normally treated with surgery and/or radiotherapy, while, for advanced disease, chemoradiation is standard treatment. Cure rates are good, especially for early disease, but can be associated with high morbidity. Surgical excision requires a wide margin, which can cause functional damage to adjacent structures and result in swallowing and speech difficulties. Radiotherapy is associated with a risk of xerostomia, trismis, and even osteonecrosis. PDT is equally effective as curative surgery or radiotherapy for small superficial tumors or palliative treatment of recurrent disease but has the advantage of sparing tissue beneath the tumor, giving excellent long-term functional and cosmetic results [69, 70].

Early PDT studies on head and neck cancer patients used HpD or porfimer sodium and light doses of 100–200 J/cm², but nowadays mTHPC is more often used in combination with 10–20 J/cm². For early-stage primary tumors of the oral cavity or oropharynx, a CR rate of 85% at 1 year, decreasing to 77% at 2 years, is reported [69, 70], with an even higher CR rate of 96% for lip carcinoma [71].

Head and neck cancer patients have a lifetime risk of 20%–30% of developing second or multiple cancers after radical treatment of the primary. Repeated surgery is difficult because of progressive tissue loss and reirradiation may be impossible without exceeding tissue tolerance. By contrast, there is no cumulative tissue toxicity after PDT, which can also be used after either radiotherapy or surgery [72, 73]. mTHPC PDT treatment of second and multiple primary cancers resulted in CR rates of 67% for all tumors and 85% for T1 tumors. PDT can also be effective as a salvage treatment for recurrent head and neck cancer in patients who have failed conventional therapy [71, 72, 74].

For larger tumors, PDT can be given interstitially [75]. The response rates achieved are similar to those for other therapies, but PDT can also be used in patients who are unfit for further radiotherapy or surgery. Interstitial PDT is therefore a useful additional treatment for late-stage disease.

Esophageal Cancer
With a 5-year survival rate of only 12.5%, esophageal cancer has a very poor outcome [76]. Standard treatment is esophagectomy, but the high morbidity and mortality associated with this procedure led to the development of less invasive procedures, such as endoscopic mucosal resection, coagulation, and PDT. For PDT, illumination is given using flexible cylindrical diffusers that are placed via an endoscope near the tumor. Most often, a partially shielded balloon is inflated around the diffuser for protection of surrounding normal tissue and to facilitate uniform illumination.

The first studies with PDT in the esophagus were done as palliative treatment for obstructive tumors [77]. Subsequent studies confirmed the efficacy of PDT for such tumors [78, 79]. PDT is also effective as a curative treatment for small superficial tumors in the esophagus [80]. A CR rate of 87% at 6 months and a 5-year overall survival rate of 25% were achieved in a group of 123 patients treated with porfimer sodium–mediated PDT [81]. Comparable results were also obtained using mTHPC as the photosensitizer [82].

Despite the efficacy of PDT for esophageal cancer, side effects from treatment of this thin-walled, hollow organ can be severe. In addition to transient skin photosensitivity, stenosis, fistulas, and perforations have been reported in up to 57% of the patients treated with PDT using red light [79, 81, 82]. However, when mTHPC was used in combination with less penetrating green light, no fistulae or perforations were observed, whereas efficacy was not compromised [82]. Circumferential stricture of the esophagus following PDT can also be avoided by using 180° or 240° windowed light distributors, although no controlled trials have demonstrated better rates of stricture associated with the use of fiber centering devices such as balloons [82, 83].

Barrett’s Esophagus
PDT is especially suitable for treatment of the premalignant condition Barrett’s esophagus. This metaplastic tissue can progress from low-grade to high-grade dysplasia and ultimately to invasive adenocarcinoma. About 50% of all new esophageal cancers, which have very poor survival rates (see above), develop from Barrett’s esophagus; therefore, effective treatment of Barrett’s has major public health implications [84]. An international, multicenter prospective, randomized controlled trial using a blinded centralized pathology laboratory demonstrated that porfimer sodium PDT of Barrett’s esophagus can ablate Barrett’s high-grade dysplasia in 77%–96% of cases, compared with only 39% of cases for omeprazole therapy alone [85]. That study documented a significant reduction in the risk for esophageal cancer in patients treated with porfimer sodium PDT. Areas of persistent Barrett’s mucosa were detected in 58% of patients who were followed with a rigorous endoscopic surveillance biopsy protocol [86, 87]. Because this was a regulatory, phase III trial, no adjuvant endoscopic thermal ablation therapy was allowed. In clinical practice, these areas of persistent Barrett’s glandular mucosa are destroyed using an Nd:YAG (neodymium-doped yttrium aluminium garnet) laser or argon beam coagulation to prevent the development of recurrent dysplasia and/or carcinoma [88]. The combination of PDT with endoscopic mucosal resection has been shown to be almost as effective as esophagectomy (83% versus 100% CR rate at 1 year), but with much less morbidity [89] and a shorter hospital admission. It is important to emphasize the utility of porfimer sodium PDT in patients with Barrett’s high-grade dysplasia and esophageal carcinoma limited to the mucosa. Disease staging, therefore, is critically important in these patients, including the use of endoscopic ultrasound and contrast-enhanced computed tomography of the chest to look for signs of local advancement of disease. When carcinoma extends to the submucosa layer, then the risk for local metastasis increases dramatically. For patients who refuse surgery or are not candidates for surgery, endoscopic mucosal resection with fine-needle aspiration of adjacent lymph nodes is recommended for more complete histologic disease staging. Cancer progression beyond the submucosa implies locally advanced disease that will require chemoradiation therapy followed by surgical resection [90].

For PDT treatment of Barrett’s, as for esophageal cancer, strictures are the most important treatment-related toxicity, reported in 10%–50% of cases treated with systemic photosensitizers and red light. Because Barrett’s mucosa is not much deeper than the normal squamous-lined esophagus, the use of ALA PDT potentially offers an effective, but less toxic, alternative. Although complete remissions have been reported after 1 or 2 treatments, and recurrences can be retreated, comparative trials have found disappointing rates of ablation and subsquamous Barrett’s glands [86, 91–93]. Several cases of unexplained sudden death after ALA PDT were also reported at the recent International Photodynamic Association congress (Munich, Germany, June 2005). Less penetrating green light (514 nm) has also been successfully used in combination with ALA and porfimer sodium with correspondingly less effective rates of ablation [94, 95].

Endobronchial Cancer
Many publications have shown the therapeutic usefulness of PDT in different stages of endobronchial disease. Palliative treatment of obstructive cancer with HpD or porfimer sodium PDT was safe and resulted in symptom relief in almost all patients [96–99]. Side effects, in addition to skin photosensitivity, included cough, expectoration of necrotic debris, and dyspnea for a few days after PDT. Serious, or even fatal, hemorrhage was occasionally reported, but also occurs spontaneously in this disease and is therefore difficult to attribute to the PDT.

PDT has also been used as a curative treatment in early lung cancer. Overall 5-year survival rates were in the range of 56%–70% [97, 100, 101], with a disease-specific 5-year survival rate of 90% for CIS [97]. However, patients presenting with CIS are sparse, limiting the clinical impact of PDT for this disease. Another indication for endobronchial PDT is field cancerization or recurrence of tumors after resection or irradiation. These patients often have a limited pulmonary reserve and typically cannot withstand additional resection or extended radiation fields.

Other Applications
Although PDT already has proven value as a treatment option in the cancer types discussed above, it has great potential as a treatment for other types of cancer. For aggressive cancers with a poor prognosis and cancers in organs where other conventional treatments cause high morbidity, PDT is especially attractive, although publications demonstrating efficacy in large clinical trials are still scarce. Some of the most encouraging studies are summarized below.

Very promising results were seen in a prospective phase II study of patients treated with porfimer sodium–mediated PDT for nonresectable cholangiosarcoma [102]. Such patients generally have a median survival time of 3–6 months and receive only palliative treatment. Although PDT could not prevent progression of the disease, it did improve the median survival rate (74% at 6 months) and led to improvement in cholestasis and quality of life.

Porfimer sodium PDT has also shown efficacy in phase II trials against recurrent pituitary tumors [103] and in combination with debulking surgery for disseminated intraperitoneal disease [104], warranting further research.

mTHPC-mediated PDT was shown to be a safe and effective treatment for recurrent prostate cancer in a phase I trial [105, 106]. Efficacy with low morbidity has also been demonstrated for pancreatic cancer [107], which, if confirmed, could have major health implications, because the 1-year survival rate is currently only 10%.

Further studies must be done to confirm the true value of PDT as a new therapy for these and other types of cancer. The strengths of this treatment lie in its ability to destroy cancers without destroying normal tissue structures surrounding the tumor and that treatment can be repeated without cumulative toxicity. Furthermore, it has the advantage that it can be used for treatment of tumors that cannot be reirradiated or are not suitable for surgery. PDT using less penetrating green light is also very suitable for eradication of dysplasia, as shown for Barrett’s.

	FUTURE PERSPECTIVES

Top Learning Objectives Abstract History of Photodynamic Therapy Principle of PDT Working Mechanism of PDT... Photosensitizers Light Application PDT as a Clinical... Future Perspectives Disclosure of Potential... References

 
During the past 30 years, PDT has been employed in the treatment of many tumor types, and its effectiveness as a curative and palliative treatment is well documented. Especially for skin cancer, it is becoming an established therapy. But why is its role in other disciplines still marginal?

In general, it is difficult to persuade clinicians to use a new technique when standard treatments yield a high response rate. Although lasers have become much less expensive, the setup of a new PDT center remains costly. However, long-term comparisons show that PDT is cost-effective for palliative treatment of head and neck cancer and treatment of Barrett’s esophagus and high-grade dysplasia. The issue of cumbersome, difficult-to-use laser equipment has now been dealt with, and simple preprogrammed menus assist the physician with treatment. Therefore, the main drawback against using PDT as frontline therapy lies in the fact that large randomized trials have not yet been done.

Treatment regimens still have to be optimized and standardized for better therapeutic effectiveness. Severe side effects have been reported when using inappropriate PDT schedules, especially in hollow organs such as the esophagus and bladder. However, it is already clear that appropriate choices of drug type and dose, light wavelength, and drug–light interval can improve the efficacy and safety of PDT. Furthermore, careful attention to the physics and dosimetry of light will help to minimize toxicity.

Experimental demonstrations of the important contribution of vascular-mediated damage to tumor destruction, and the correlation seen between drug levels in the plasma at the time of illumination and PDT efficacy, might have clinical implications. If the vasculature, rather than tumor cells, is the main target for PDT damage, then optimal illumination times should be when the plasma drug levels are high. New clinical protocols could reduce drug–light intervals, and, if they show an improvement in outcome, then drug dose might also be decreased, which would result in less generalized phototoxicity.

Research into selective delivery of photosensitizers by conjugation to antibodies, use of liposomes as carrier and delivery systems, or new photosensitizers with a more specific tumor localization and faster clearance is also warranted.

It is also worthwhile to explore the possibilities of combining PDT with other therapies. In studies with mice, it has already been shown that the combination of PDT with doxorubicin [108, 109], mitomycin C [110, 111], modulators of the immune system [112–114], and inhibitors of angiogenesis [115–118] resulted in superior PDT responsiveness. As our understanding of the best ways to combine these therapies increases, it is to be expected that further improvements in the clinical application of PDT will be seen.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

Top Learning Objectives Abstract History of Photodynamic Therapy Principle of PDT Working Mechanism of PDT... Photosensitizers Light Application PDT as a Clinical... Future Perspectives Disclosure of Potential... References

 
The authors indicate no potential conflicts of interest.

	ACKNOWLEDGMENT

Top Learning Objectives Abstract History of Photodynamic Therapy Principle of PDT Working Mechanism of PDT... Photosensitizers Light Application PDT as a Clinical... Future Perspectives Disclosure of Potential... References

 
The authors are grateful to Robert van Veen, Chantal Appeldoorn, and Maurice Aalders for providing embedded figures.

	REFERENCES

Top Learning Objectives Abstract History of Photodynamic Therapy Principle of PDT Working Mechanism of PDT... Photosensitizers Light Application PDT as a Clinical... Future Perspectives Disclosure of Potential... References

 

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