Fig. 11.1
Type I and type II reactions in PDT (“photodynamic reaction”). Schematic Jablonski diagram showing PDT’s mechanism of action. Following light absorption, the PS reaches an excited singlet state (PS*). After an intersystem crossing, photosensitizer in a triplet excited state (3PS*) can react in two ways: (1) it reacts with biomolecules through a hydrogen atom transfer to form radicals, which react with molecular oxygen to generate ROS (type I reaction); (2) 3PS* can react directly with oxygen through energy transfer, generating singlet oxygen (1O2) (type II reaction). PS photosensitizer, PS* excited singlet, 3 PS* excited triplet singlet, ROS reactive oxygen species, 1 O 2 singlet oxygen, that ultimately produce tissue destruction
Singlet oxygen produces in cell membranes, cytoplasm, and organelles peroxidative reactions leading to damage and cell death.
The PS used in clinical and experimental studies accumulate selectively in abnormal or proliferation cells, such as cancer cells or tumor tissues. Its photoactivation produces a specific tissue ablation [4]. After intravenous injection, the photosensitizer can be found in the liver, spleen, kidney, bone marrow, and tumor tissue. Normal organs remove quickly this substance, but in tumoral cells it remains inside for more than 48 h.
The destruction process is quite complex, but basically the damage of a specific subcellular targets depends on the location of the photosensitizer, due to the reduced capacity of migration of oxygen. Photofrin ® , for instance, is accumulated in the mitochondria and once activated causes apoptosis. Other PS have empathy for determinate organelles, like lysyl chlorin p6 for lysosomes and porphyrin for membranes. The damage that PDT produces in cell membranes can be observed with in few minutes after light exposure: edema, blistering, ruptured vesicles containing enzymes, reduction of active cell transport, plasmatic membrane depolarization producing more photosensitizer income, increased chromate permeability, and ATPase inhibition [1].
Light delivery can be enhanced by using wavelengths from 600 to 800 nm within the optical window [5] to activate PS, which passes from a basal energy level to a “singlet” state. The “singlet PS” can return to its basal state emitting a photon and producing the fluorescence phenomenon or can go to a longer excitement level and more stable state called “triplet PS.” To return to its ground state, triplet PS can take two ways reacting with different substances. Triplet PS can react directly with oxygen through energy transfer, generating singlet oxygen with cell toxicity properties through a type II reaction (most common). Or it can react with biomolecules (i.e., lipids, proteins, and nucleic acids) through type I reaction. This reaction transfers hydrogen atoms and generates free radicals and radical ions (radical type depends on the target biomolecule) which along with oxygen result in reactive oxygen species (ROS) generation.
ROS and singlet oxygen have a high reactivity but a short half-life. Due to this, PDT directly affects only those biological substrates that are close to the region where these species are generated, usually within a 20 nm radius [6].
The balance between these two processes (type I and II reaction) depends on the nature of PS being used, the concentrations of oxygen and substrate, and affinity of the PS with the substrate. Both types of reactions result in cell death, but in general, under hypoxic conditions primarily a photodynamic reaction type I occurs, while in oxygenated conditions type II reactions prevail. Schematic Jablonski diagram showing PDT’s mechanism of action is represented in Fig. 11.1 [7, 8].
PDT cytotoxic effects on tumor cells can be reached by indirect and direct mechanism. Indirect effect leads to changes in the tumor microenvironment as anti-vascular effect (vasoconstriction, thrombosis, or vessel leakage) and antitumor immune response (release pro-inflammatory cytokines and tumor-associated antigens or fixation of complement). Direct cell killing is due to macromolecule damage with apoptosis and necrosis process. Apoptotic cell death tends to predominate in the most PDT-sensitive cell lines at lower light/photosensitizer doses, and the necrotic mechanism tends to predominate at higher light/photosensitizer doses.
Tumor destruction is based on three steps: (1) PS is distributed in all the cells after the intravenous injection. (2) Because of the differences in the vasculature and lymphatic drainage and the uptake of photosensitizer, PS is selectively retained in tumor cells and interstitial tissue. In a couple of days, PS concentration is higher in the tumor than in the surrounding tissues. (3) The photosensitizing substance absorbs the light energy and produces a photodynamic reaction [9].
Antitumor activity of inflammatory cells and immune reactions are triggered by the sensitized tumor. These two reactions contribute to more complete tumor destruction. But there are some factors that limit it, such as the uneven distribution of the PS agent inside the tumor or oxygen availability.
Likewise, some drugs affect the final result of photodynamic therapy, such as Adriamycin [10] and corticosteroids [11, 12], both enhancing the effects of PDT.
Animal studies by Diaz-Jimenez et al. have shown that the photodynamic reaction, even when it starts almost immediately after exposure to light, continues to act slowly over a rather long time. “In vivo” model showed that tumor cells transplanted immediately after treatment were able to be implanted and to reproduce, while those transplanted 24 h after treatment were not [13].
Technique
Administration of PS can be oral or topical or by a slow intravenous injection (3–5 min), which is the most used modality for lung cancer treatment. Dose and window period until bronchoscopy are variable depending on the PS. The PS should be preferably excited by light of a wavelength included in the therapeutic window between 600 and 800 nm, which has greater capacity for tissue penetration. Photofrin ® is used at a dose of 2 mg/kg 48 h before bronchoscopy, and Npe6 is administered at doses of 40 mg/m² 4 h before.
Bronchoscopy is performed under topical anesthesia or conscious sedation. The tumoral area is illuminated for 500 s with a 630 nm wavelength laser light with nonthermal effect such as the argon-dye laser or diode laser (Fig. 11.2). Forty-eight hours after treatment, one or several clean-up bronchoscopies should be performed to remove viscous debris and detritus from the tumor process destruction to avoid complications such as infection, respiratory distress, or respiratory failure [14].
Fig. 11.2
Diode laser of 630 nm
Two types of light fiber can be used: front light microlens fiber (Fig. 11.3) or 360° diffusing light cylindrical fiber (Fig. 11.4). The microlenses are used for small and superficial tumors such as “in situ” carcinomas. The cylindrical fiber is appropriate for parallel bronchial lumen tumors, tumors that involve small branches of the bronchial tree and in exophytic tumors more than 5 mm in size. It’s also useful for large tumors in which the fiber is inserted directly inside the tumor. Current protocols use a power of 200–400 mW/cm² to apply a total light dose of 100–200 J/cm² in a treatment time of 500 s [5]. In addition to argon-dye and diode lasers, other types have been used such as gold vapor laser, copper-dye laser, laser-dye excimer, and yttrium aluminum garnet (YAG) laser with a crystal of potassium titanyl phosphate laser and an optical parametric oscillator [6].
Fig. 11.3
Microlens fiber
Fig. 11.4
Cylindrical fiber
Photosensitizers: Past and Present
The correct choice of PS is important for a successful response to PDT treatment. PS must be nontoxic for the cells in the absence of light exposure and should be selectively retained by the target (malignant) cells. Ideally, PS should be able to induce an immunogenic response over treated cells such as changes of surface glycoproteins receptors and consequently activate a cascade of immunologic cells response and malignant cells death [15].
Most of PS were first derived from a molecule called hematoporphyrin. Hematoporphyrins are tetrapyrrolic pigments, whose base is the porphyrin molecule, formed by four pyrrolic units linked by four methylic bridges.
Hematoporphyrin is obtained from the blood by two consecutive steps. In a first step, hemin is obtained by treating blood with sulfuric acid, hydrochloric acid, and alcohol. In a second step, the extracted iron is used to obtain crystallized hematoporphyrin. This crystallized form of hematoporphyrin is quite impure.
In 1961 Lipson, Baldes, and Olsen at the Mayo Clinic treated hematoporphyrin by several recrystallization processes, and they obtained a new and pure compound suitable for human use called hematoporphyrin derivative (HpD) [16, 17]. In 1983, Dougherty describes a new component from the HpD called dihematoporphyrin ether or ethyl 8 (DHE), which seemed to have the ability to sensitize tumors [18]. Tetrafenilsulfonato (TPPS) is another well-known PS but not used in clinical practice due to its neurotoxicity and slow serum elimination [19].
At the beginning of the 1980s, PDT was specially used to treat early-stage squamous cell lung cancer, but currently more than 3000 different locations and histological types have been treated in over 32 countries [20]:
- (a)
Porfimer Sodium (Photofrin ® ) : It is the most extensively studied photosensitizer. In January 1998, the Food and Drug Administration approved in the USA the use of Photofrin® (porfimer sodium) for PDT in patients with microinvasive lung tumor who are ineligible for surgery or radiotherapy [21]. The palliation use of certain tumors was approved in 1997.
Photofrin® and its predecessor, hematoporphyrin derivative, are obtained by complex mixtures of esters from hematoporphyrin. The cytotoxic effect for PDT is limited by the maximum penetration capacity of the laser at 630 nm wavelength light. This wavelength has the highest power to penetrate tissue from 3 to 5 mm.
Following treatment, there is a systemic photosensitivity period that can last up to 6 weeks. Patients should avoid sunlight exposure, artificial light, heat sources, or other strong light sources during the treatment and posttreatment period [4].
- (b)
Benzoporphyrin Derivate (BPD) : It is a second generation PS. Chemically, is a hydrophobic molecule with a maximum absorbing peak at 690 nm, higher than the absorption of the hemoglobin. So it is not attenuated by the blood and has a maximum tissue penetration. Furthermore, BPD is quickly accumulated in the target tissue allowing a PDT treatment from 30 to 150 min after intravenous injection. It is also rapidly cleared from the body. Photosensibility of the skin does not extend more than few days [4].
5-Aminolevulinic Acid (ALA) : Endogenous photosensitization induced by ALA is a new approach for photodynamic therapy and tumors detection. It consists in a biosynthetic reaction to produce endogenous porphyrins heme and particularly protoporphyrin IX, which is a very effective photosensitizer that accumulates in mucosal surfaces, such as the skin, conjunctiva, and oral, rectal, vaginal, endometrial, and ureteral mucosa [1]. It has been used with acceptable results to treat superficial tumors of the skin, such as the basal cell carcinoma, squamous cell carcinoma, and adenocarcinoma. Residual photosensitivity after treatment lasts about 48 h.
ALA has been also applied orally and by aerosol inhalation via jet nebulizer, showing that both modalities were well tolerated, allowing tumor visualization, and after oral administration it was possible to perform photodynamic therapy. At 5 and 12 weeks after PDT, marked reduction in tumor volume and recanalization of the bronchus were observed bronchoscopically, with no associated adverse effects [22].
ALA fluorescence can be used in detection of bladder lesions, early-stage “in situ” lung carcinoma, and malignant gliomas.
N-Aspartyl Chlorin E6 (NPE6) : It is a second generation PS that stands out for its excellent antitumor effects and rapid skin clearance in laboratory animals. Npe6 has a longer absorption band (664 nm) than Photofrin®, so it has a slight advantage in deep tumors treatment. The administered dose is 40 mg/m² and laser power density needed is 100 J/cm². Adverse effects are minimal, cutaneous photosensitivity disappears within 2 weeks after administration. It is approved by the Japanese authorities (Japan Ministry of Health, Labor and Welfare) since 2004 for lung cancer treatment. In 2010 it was approved for advanced lung cancer treatment.
Chlorins have been extensively investigated for their potential to treat oral cancer. Extensive cellular damage and complete tumor regression within a week treatment have been reported [23]. Although chlorins exhibit good water solubility and stability, aqueous solutions did not represent the best delivery system in many tumors such as oral cavity or endobronchial tumors. A combination to a mucoadhesive delivery system shows to increase the absorption in the target tissue and improves the overall outcomes [24]. Recently, PS incorporation to nanoparticles prepared from human serum albumin or hyaluronic acid brings new perspectives and challenges to this field [25]. Due to their submicron size, nanoparticles as PS delivery system have numerous advantages such as protection against enzymatic PS degradation, control of PS release allowing a constant and uniform concentration into target cells, and the ability to penetrate target cells [26].
- (c)
Others Photosensitizers: Tin etiopurpurin, SnET2 (Purlytin); lutetium texaphyrin (Lu-Tex); benzoporphyrin derivative monoacid ring A (BPD-MA); mesotetra (hydroxyphenyl) chlorin, mTHPC (Foscan), that are under investigation.
- (d)
Table 11.1: Summary of main photosensitizers.
Table 11.1
Summary of main photosensitizers
Photosensitizer/generic name | Commercial name | Administration formulation | Approved indications/clinical trials | Skin photosensitivity |
|---|---|---|---|---|
Hematoporphyrin derivatives (HpD)/porfimer sodium | Photofrin® | IV/topic/powder for solution Wavelength: 630 nm | Esophageal cancer, high-grade dysplasia in Barrett’s esophagus, gastric and cervical dysplasia, bronchial, bladder, and lung cancer | 1–3 months |
Benzoporphyrin derivative monoacid ring A (BPD-MA)/verteporfin | Visudyne® | IV/liposomes | Age-related macular degeneration | 3–5 days |
Meso-tetra(hydroxyphenyl)chlorin (mTHPC)/temoporfin | Foscan® | IV/solution in ethanol and propylene glycol Wavelength, 652 nm | Palliative advanced head and neck cancer/squamous cell carcinoma | Up to 6 weeks |
Tinethyletiopurpurin (SnET2)/rostaporfin | Purlytin® | IV/lipid emulsion | Clinical trials: skin, prostate, and metastatic breast cancer, Kaposi’s sarcoma, and age-related macular degeneration | 2–3 weeks |
Lutetium texaphyrin/motexafin lutetium | Lutrin® | IV/powder for solution | Clinical trials: skin and breast cancer | 1–2 days |
5-Aminolevulinic acid (5-ALA) | Levulan® | Topical/oral/IV/powder for solution/cream | Active keratosis. Clinical trials: basal cell carcinoma, esophageal, gastrointestinal, lung, and non-melanoma skin cancer | 1–2 days |
Methyl aminolevulinate | Metvix® | Topical/cream | Active keratosis, basal cell carcinoma, Bowen’s disease. Clinical trials: acne | Uncommon |
Hexylaminolevulinate (HAL) | Hexvix® | Topical powder for solution/gel | Bladder cancer diagnosis. Clinical trials: rectal adenoma and cancer diagnosis, cervical dysplasia | Uncommon |
Indications and Contraindications
Different tumors treated by PDT include cancers of the digestive tract, lesions of the head and neck, lung cancer, cervix and bladder cancer, and skin cancer, among others. PDT treatment is based on a standard dose of the drug, on a specific light source (nonthermal laser), and on a specific drug-light interval. However, clinical outcomes vary extremely due to many variables: power and duration of light exposure, tissue oxygenation and vascular supply within the tumor; and finally, metabolism of the PS in a particular patient [27]. Summary of curative and palliative indications of photodynamic therapy in the management of patients with non-small cell carcinoma [28] is represented in Table 11.2.
- A.
Curative PDT Indications
Curative PDT indications are:
- 1.
Carcinoma in situ (this is first-line indication).
- 2.
Microinvasive and limited to the bronchial wall non-small cell lung cancer:
- (a)
Early-stage intraluminal and central tumors following definitive surgery or radiation therapy
- (b)
Roentgenographically occult central tumors
- (c)
Synchronous primary carcinomas
- (a)
- 3.
Recurrence of operated non-small cell lung carcinoma (stump area) or treated by radiotherapy.
- 4.
Severe dysplasia.
Patient’s selection should be cautious taking into account area and depth of tumoral extent. The Japanese Lung Cancer Society defines the criteria of early central lung tumor selection [29]: (1) subsegmentary bronchus location as distal limit, (2) tumor margins must be identified bronchoscopically, (3) tumor size less than 2 cm in its greatest dimension, and (4) squamous cell carcinoma is proven histologically. It also defines three types of lesions according to the endoscopic appearance: flat lesions, nodular lesions, and early polypoid lesions. It has been shown that lesions protruding (nodular or polypoid) tend to invade the bronchial wall in more depth than the flat-type lesions. Flat lesions <1 mm in diameter and visible distal margins were carcinoma in situ in more than 90% of the times, suggesting to be the ideal indication [30, 31].
- 1.
- B.
Curative PDT Contraindications
Contraindications for curative PDT are:
- 1.
Porphyria or porphyrins allergy
- 2.
Main vessel infiltration (high risk of bleeding)
- 3.
Tracheoesophageal or bronchopleural fistula
- 4.
Carcinoma in situ with lymph node involvement
- 5.
Extrinsic compression or submucosal infiltration
- 1.
- C.
Palliative PDT Indications
Palliative PDT indications are:
- 1.
To improve endobronchial obstruction caused by any type of tumors: all histological types, primary and metastatic, have responded to treatment [1, 9, 32, 33]. Small cell tumor is not included among the histologic types that can benefit from this treatment mainly because it is known that these tumors respond well to chemotherapy and because they present more as infiltrative tumors than obstructive masses.
- 2.
- 3.
Some authors have suggested to use PDT for inoperable patients making them candidates for surgical treatment [34] or to reduce tumoral extension in order to perform a less aggressive surgery [35, 36]. Review of available data on this indication, published by four authors [37–40], shows results of 106 responses on 111 patients treated. Recently, PDT has been used at the Tokyo Medical University Hospital as preoperative therapy in 26 patients, reducing the extension of non-small cells tumor and/or converting patients in operable candidates. Four of the 5 patients originally inoperable became operable, and 18 of the 21 patients originally candidates for pneumonectomy were eligible for less invasive surgery such as lobectomy [36].
- 4.
To treat recurrence in the surgical stump. Historically, survival of these patients is around 9 months. McCaughan and Williams have observed 5-year survivals of similar cases treated repeatedly with PDT [9]. Some authors [13] disagree with this view and discourage application of PDT for the treatment of recurrence in the surgical stump, mainly due to the difficulty of managing laser light distally to the surgical suture.
- 5.
PDT causes thrombosis of small vessels and can be used to control bleeding, regardless of location or cause of the bleeding. The amount of bleeding was recorded before, during, and after treatment with PDT, and there was statistically a significant reduction of bleeding during and after treatment [9]. PDT has been described as effective in the palliative treatment of patients with uncontrollable life-threatening hemoptysis [41].
- 6.
In case of non-small cell lung cancer with pleural dissemination, patients can be treated by PDT following a complete surgical resection.
- 7.
As with malignant pleural mesothelioma, PDT may be utilized as part of multimodality management. In fact, PDT can be used for non-small cell lung cancer with pleural spread. In a phase II trial with pleural spread and clinical T4 non-small cell lung cancer, 20 patients underwent surgery that was followed by pleural PDT, and in only 2 patients, PDT was practiced alone. After 6 months of control, the rate of survival was 73.3%, and median overall survival was 21.7 months, compared with 6–9 months for similar patients based on historical controls [42].
- 1.
- D.
Palliative PDT Contraindications
Palliative PDT contraindications are:
- 1.
Tumoral lesions that obstruct the tracheal lumen in more than 50%, compromize of the main carina or patients with pneumonectomy. PDT causes inflammatory reaction, and airway edema worsens airway obstruction that can go from partial to complete, putting life at risk.
- 2.
Erosion or invasion of vascular structures. When there is infiltration of the tracheobronchial wall or vascular structures, the use of PDT may cause perforation and/or fatal bleeding.
- 3.
Submucosal infiltration or extrinsic compression: PDT is not effective in these cases.
- 4.
Airway acute obstruction. PDT does not relieve airway obstruction immediately, and therefore patients presenting acute obstructive symptoms are not candidates for this treatment and should be treated with Nd-YAG laser or diode laser for rapid desobstruction.
- 5.
Porphyria, allergy, or hypersensitivity to the porphyrin.
- 6.
Leukocyte count less than 2000/mm³, thrombocyte count less than 100,000/mm³, or prothrombin time upper than1.5 normal limit.
- 1.
Summary of curative and palliative indications of photodynamic therapy in the management of patients with non-small cell carcinoma |
|---|
Definitive therapy for early-stage central endobronchial tumors |
Definitive therapy for early-stage locally recurrent central tumors following definitive surgery or radiation therapy |
Definitive therapy for roentgenographically occult central tumors |
Definitive therapy for synchronous primary carcinomas |
Palliation to reduce endobronchial luminal obstruction and tumor stenosis, improve performance status and respiratory function, and resolve acute hemoptysis and poststenotic pneumonia |
Neoadjuvant therapy to reduce the extent of surgical resection (pneumonectomy → lobectomy) |
Neoadjuvant therapy to convert originally inoperable patients to surgical candidates |
Treatment of locally advanced disease as part of multimodality therapy |
Treatment of disease with pleural spread as part of multimodality therapy |
PDT Advantages, Disadvantages, and Complications
Advantages of PDT for cancer treatment are:
Minimally invasive procedure.
Short treatment time
Outpatient treatment
Can be repeated at the same location.
Little or no scar after healing
Fewer adverse effects
Lower cost treatment
Disadvantages of PDT for cancer treatment are:
Photosensitivity after treatment
Efficacy of the treatment depending on patient selection, photosensitizer selection and accurate light delivery to the tumoral site.
Complications of PDT for cancer treatment are:
Fever (approximately 20%).
Skin and eye photosensitivity (from 4 to 6 weeks). Sun exposure, sources of light, or intense heat (halogen lights, dryers, etc.) should be avoided.
Adverse reactions to photosensitizing substance.
Dyspnea due to airway edema and accumulated secretions. Thus, cleanup bronchoscopy is recommended.
Atelectasis or respiratory failure due to mucus and secretions accumulations.
Infections: bronchitis and post-obstructive pneumonia.
Massive hemoptysis.
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