5.1 Introduction

Photodynamic reaction is a process that involves the interaction between light and a photosensitizer (PS) in a biological environment. Currently, this modality has been applied as a local treatment for cancer and also for infections caused by bacteria, fungi, or virus [1]. The first biological photodynamic action was reported by Oscar Raab in 1900, when he observed that the toxicity of acridine hydrochloride against Paramecium caudatum was dependent on the amount of light, thus publishing the first article on photodynamic effects of chemical compounds [2].

Later, the first clinical applications of the technique with the use of eosin as PS and light were applied for the treatment of lupus vulgaris, syphilis, psoriasis, and superficial skin cancer [3]. Although in all these potential findings, around 1928 with the emergence of antibiotics age, the further development and investigation of the inactivation photodynamic effect were significantly decreased [4].

The photodynamic action occurs when the PS in its fundamental state (S₀) is excited by light with a well-suited wavelength to an electronic excited state and, later, through an intercrossing system process, to a triplet excited state (T₁). After that, there are two possible reactions, type I reaction (via free radical formation) and type II (via singlet oxygen formation), depending on the PS characteristics. The photodynamic reactions and the biological targets are summarized in Fig. 5.1.

In the type I reaction, the PS excited can interact with the biological substrate (BS) transferring electrons or deducting a hydrogen atom, as the Eqs. (5.1) and (5.2), while, in the type II reaction, the PS excited can react with molecular oxygen (³O₂) producing the singlet oxygen (¹O₂ ) that is a reactive oxygen species, according to the Eq. (5.3):

(5.1)

(5.2)

(5.3)

These reactions result in toxic products responsible for the biological target’s damage, and it is highly unlikely that microorganisms and cells acquire resistance to the treatment, which is a significant advantage when compared to the antibiotics mechanisms.

When the photodynamic reactions are used to treat cancer, the technique is known as photodynamic therapy (PDT). PDT is also used in non-oncological lesions as in wet age-related macular degeneration, acne, psoriasis, and atherosclerosis [5–7]. Depending on the PS localization, the cell death in PDT can be caused by necrosis when the PS is mainly located in the plasma membrane, by apoptosis if it is localized in the mitochondria or lysosomes, and by autophagia if it is held in the endoplasmic reticulum [8].

PDT allows a localized treatment since the PSs accumulate preferentially in the target cells, and it is possible to perform local irradiation [9, 10]. This selectivity is another significant advantage when PDT is compared to the other cancer treatments, once it can preserve healthy cells and tissues. The main disadvantage of PDT is the limited light penetration, which results in a limited tumor necrosis. This technique can only be used for superficial tumors; in bulky tumors, as of head and neck cancers (HNC), the combination of PDT with surgery and radiation therapy, or multiple sessions, is usually needed. Other related disadvantages are pain during the irradiation procedure mainly only using the topical PDT, and with the systemic PDT, the skin photosensitivity can last for weeks or months. Nevertheless, analgesics and anti-inflammatory can be prescribed by the physician based on patient needs; there is no reported evidence of adverse effects of PDT in combination with these drugs.

The light source for the irradiation is chosen depending on the region to be treated. For internal organs, the irradiation is mainly applied by a laser with optical fiber to achieve the desired location. In contrast, to perform an external treatment is possible to irradiate using laser or light-emitting diode (LED) systems [11, 12]. The typical light parameters range from 80 to 200 mW/cm² with total delivered dose from 80 to 150 J/cm². Hence the irradiation takes from 10 to 30 min to be completed. Figure 5.2 shows examples of light sources for treatment by photodynamic reactions. For superficial basal cell carcinoma (BCC) lesions, some groups have presented sunlight as an alternative PDT light source. The procedure using the sun as a light source is known as daylight PDT and has been used in numerous studies [13–16]. But here, consideration must be performed, since the dosimetry cannot be well-controlled, due to high variability associated with the meteorological conditions.

As PDT is based on simple concepts, it could be used in any type of well-oxygenated lesion for which it is possible to deliver PS and light. However, in practice, it is not that simple. Due to the limitation imposed by light penetration, dark lesions, such as melanoma or pigmented basal cell carcinoma, are not adequate for PDT. Also, bulky or internal tumors are challenges for sufficient and uniform irradiation. For a useful treatment with PDT, it is essential to afford enough amounts of light and drug, ensuring precise dosimetry for each application [17].

5.2 Photodynamic Therapy in Facial Lesions

The main malignant lesions in the facial skin are superficial and nodular basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), whereas the primary nonmalignant lesions are actinic cheilitis, psoriasis, actinic and seborrheic keratosis, Bowen’s disease (squamous cell carcinoma in situ), and sebaceous hyperplasia. PDT can be applied as an alternative to the traditional treatments to all these facial lesions, with the advantages of having better cosmetic results in comparison with surgery, for example. The photosensitizer can be applied intravenously or topically. The systemic delivery of the PS is recommended for more aggressive types of cancer or internal diseases. Beil et al. reviewed relevant results of PDT using systemic PS delivery to PDT treatment of head and neck cancers (HNC), though there is a significant side effect of the systemic application, the prolonged photosensitivity, during weeks depending on the PS.

When the PS is topically applied, we call it topical PDT. The most used prodrugs for topical PDT are 5-aminolevulinic acid (ALA) and methyl aminolevulinate (MAL). ALA is a precursor in the biosynthesis of the endogenous protoporphyrin IX (PpIX). Due to metabolic changes in altered cells, they present the behavior to produce more PpIX and have a different pharmacokinetics time of its elimination. The steps of PpIX formation after topical cream application are summarized in Fig. 5.3. After the cream application, the prodrug molecule (e.g., ALA) reaches the mitochondria, where the PpIX is synthesized and thus converted into heme to produce hemoglobin molecules. To avoid exceeding heme molecules to be converted back to ALA by negative feedback autoregulation, the ALA vehicle cream contains ferrochelatase inhibitors (such as ethylenediaminetetraacetic acid, EDTA) to interrupt heme formation at PpIX step and allow PpIX accumulation in cells. Abnormal cells show characteristics that interfere with the clearance of the accumulated PpIX. Thus, although the mechanisms are not clearly elucidated, it is observed that those cells usually take much longer time to completely clear the extra PpIX molecules when compared to normal cells [18].

Topical PDT is a simple procedure, it can be performed in an ambulatory setting, and after the treatment, the patient receives instructions related to pain control and post-procedure care.

The BCC is considered a nonmetastatic type of cancer. It is the most incident non-melanoma skin cancer, affecting mainly the head and neck regions [19, 20]. The surgical procedure is the standard protocol applied, though there are elder patients with comorbidities that prevent the surgery or even cases that the removal can compromise anatomic structures. Regarding a better cosmetic outcome and less invasive treatment, PDT has been widely applied in non-melanoma skin cancer treatment [21, 22], including BCC [23, 24] with similar success to the surgery. When the BCC lesion is less than 2 mm in thickness, the topical PDT is preferred. Figure 5.4 presents a BCC lesion treated with systemic PS (Photogem—hematoporphyrin derivative) administration; also its follow-up is 30 and 180 days after PDT.

For squamous cell carcinoma, PDT can be indicated but only using the systemic photosensitizer administration. This is a more invasive cancer and requires a higher PDT dose to be treated. The planning of the PDT irradiation must consider the tumor site, thickness, and optical properties, mainly absorbance.

Cutaneous melanoma is not a current indication for PDT, due to its high visible light absorbance. The PDT is inefficient to this pigmented lesion since the light will be absorbed in the first cell layers, resulting in reduced light penetration and no PDT response in depth. Another issue is because melanoma is highly invasive, and PDT has no effect at a distance, i.e., no photodynamic response will occur away from the irradiated tissue.

In the literature, several studies can be found showing the success of PDT in the treatment of nonmalignant lesions as actinic cheilitis [14, 25–28], psoriasis [6, 29], actinic and seborrheic keratosis [13, 30, 31], Bowen’s disease [32–34], sebaceous hyperplasia [35, 36].

When a patient with facial lesion is referred to be treated with topical PDT, the lesion is usually scarified, to remove crusts and a particular layer of stratum corneum, allowing a better permeation and penetration of both cream and light. The cream containing the PpIX precursor is then applied on the lesion as a layer about 1 mm thick, and an occlusive bandage is placed on the lesion to keep the cream in place and to avoid undesired light exposure during the drug-light interval. After about 3 h, the bandage is removed, and the lesion is cleaned with gauze and is ready to receive irradiation. Figure 5.5 shows the steps of a typical clinical PDT procedure for skin cancer using topical medication. The lesion morphology with the white light image, followed by the widefield fluorescence images before the cream application (endogenous fluorescence), after 3 h of incubation (the red color corresponds to the PpIX fluorescence), and after the irradiation (PpIX consumption). White light images also represent the appearance of the treated region 7 and 30 h after PDT.

5.3 Photodynamic Therapy of Head and Neck Cancers

HNC consists in an anatomically and histopathologically diverse group of malignancies located in about 35 different sites of the region but mainly in the lips, mouth, pharynx, larynx, salivary glands, paranasal sinuses, and skin of the head and neck [37]. Their treatment is a clinical challenge since it affects important structures, such as vital nerves, vessels and tracks, and the ones essential for basic sensations. Additionally, the overall survival rates have remained unchanged for many decades, and significant increases in it have been achieved only recently. In the United States, 5-year survival increased from 54.7% in 1992–1996 to 65.9% in 2002–2006 [38, 39].

Standard treatments include surgery and chemoradiotherapy. Surgical resection is still controversial, with opinions divided between a conservative and observative approach and a traditional one, in which large margins are employed to try to prevent recurrences [40, 41]. On the contrary, radiation exposure in the tissues surrounding the tumor due to radiotherapy results in short- and long-term consequences such as xerostomia, mucositis, taste loss, radiation caries, trismus, dental decay, dysphagia, and, occasionally, osteoradionecrosis and the formation of scar tissue. However, even in cases that present excellent cure rates, their long-term sequelae substantially and negatively impact the quality of life [41]. Additionally, there are cases of recurrence after surgery and chemoradiotherapy in which the tumor site is not easily accessible [42].

In that context, PDT has emerged as an alternative treatment that could improve the quality of life of patients, as it protects surrounding tissues and results in excellent cosmetic outcomes , as well as provides a way to treat inaccessible tumors via interstitial PDT with local fibers [42, 43]. In the mid-1980s, there were initial clinical trials in head and neck tumors restricted to advanced disease patients with poor prognosis. Still, good results in a small number of patients were reported [44–49]. Since then, several types of tumors have been treated with PDT [50]. PDT for HNC can be indicated as a curative treatment, when the lesion volume can be entirely irradiated, or as a palliative technique; in this case, aiming to control or decrease the tumor size is indicated in combination with the radiotherapy and surgery.

There are good reviews on the topic, Civantos et al. reported an overall view focusing on clinical application of the past 30 years of PDT experience in HNC treatment regarding mechanisms of action, available data, and historical development [50]. Gondivkar et al. also presented a recent review on the subject, focused on protocols, details, and results obtained in 1985–2015, covering 26 studies and a total of 988 patients [51]. They reported complete response following PDT of oral potentially malignant lesions in 27% of these studies and 16–100% in HNC patients.

5.3.1 Protocols and Determining Factors in the Outcome

Diverse protocols have been used in preclinical and clinical trials, comprising wavelengths from 585 to 660 nm, fluence rates, photosensitizers, and incubation times. Light sources reported include light-emitting diodes (LEDs), dye lasers, and diode lasers, with power densities in the interval of 50–500 mW/cm². Photosensitizers (PSs) used in clinical trials varied from hematoporphyrin derivatives, Photofrin, aminolevulinic acid (ALA), meta-tetra(hydroxyphenyl)chlorin, choline e6, Photosan, and Foscan. It could be employed in a gel, cream, or emulsion form when applied topically, or intralesionally and intravenously. The PS choice is mostly based on regulatory agencies approval, cancer type, and site and tumor volume, which correlates to light penetration required. The PS doses employed and the time between application and irradiation vary widely, the last one ranging from 24 to 96 h for intravenous administrations and 1–5 h for topical application [51]. Many parameters in PDT, combined with the intrinsic heterogeneity of tumors, limit the comparison and advances in the modality since it becomes difficult to isolate the dependence of successful outcomes with a variable. Some factors that are known to impact the treatment are briefly described next.

5.3.2 Lesion Size and Appearance

Tumor volume and appearance are crucial factors for determining PDT results. However, most of the studies fail to correlate them with treatment outcome. As pointed out by Gondivkar et al., the recurrence differences between the results from Selvam et al., Grant et al., and Jerjes et al. (0%, 36%, and 19%, respectively) suggest that dysplasia, type, volume, and surface of the lesion could impact the effectiveness of the therapy [47, 52, 53]. Future investigations are needed to determine the influence of these factors in PDT.

5.3.3 Dosimetry

As mentioned before, light dose, or fluence rate , is one of the leading protocol parameters, and it has a significant role in determining the success or failure of PDT. Light distribution is hugely affected by spatial and temporal diversity in the optical properties of the tissue, which impacts the light dose delivered in the tumor volume. Therefore, it is known that advances in dosimetry lead to better clinical outcomes [50]. The total delivered dose is dependent on the number of PDT employed. However, its effectiveness also depends on the number of PDT sessions. Hosokawa et al. reported no additional effect of the second or third PDT compared to a single one, in the treatment of 33 patients with head and neck squamous cell carcinoma [43].

5.3.4 Site

The success of PDT is highly dependent on the anatomical tumor site and type . For example, subgroup analysis from the study of Karakullukcu identified that lesions from the oral tongue and floor of mouth have more favorable outcomes relative to other oral cavity sites, the oropharynx, or the nasal cavity [54]. In 2015, Cerrati et al. reviewed the PDT literature for oral cavity cancer comparing it with surgical treatment. They found no statistical difference between the groups concerning local control and recurrences [55]. For lip squamous cell carcinomas, PDT is also very efficient, especially for field cancerization cases, in which leukoplakia and erythroplakia compromise large areas of the lip surface [56]. However, PDT should not be the single therapeutic modality of tumors with more than 3 mm of invasion depth, as additional treatment of the neck would be essential [50].

There is proper evidence that suggests that PDT would be an alternative to endoscopic resection for treating superficial lesions of early-stage larynx cancer . A study of Shafirstein et al. reported complete response in 68% of the 29 patients treated with PDT using HPPH as a PS [57]. As mentioned before, it presents the advantage of minimal normal tissue destruction. Nevertheless, there are no available data on the quality of life of PDT patients compared to conventional approaches [50].

Interstitial PDT (iPDT) is performed for bulky tumors or cancer sites thicker than 5 mm. PS is given via intravenous or intralesional administration, and light is delivered using fibers. The main advantage of iPDT is the possibility of protecting and sparing nerves and essential structures that often surround the tumor, preventing severe functional deficiencies caused by surgery and chemoradiotherapy. PDT also helps in the preservation of elastin and collagen fibers, when compared to other treatment modalities, which may reduce the risks of thrombosis or rupture of normal arteries [38]. It is also a useful option for a palliative measure and treatment of recurrent tumors [38, 58, 59]. The main groups investigating iPDT uses are from the University College London, who uses ultrasound to guide the laser fibers, and a group from the Netherlands Cancer Institute, who uses computer tomography and magnetic resonance imaging-guided catheters and cylindrical diffusers [50].

A summary of the main advantages and disadvantages of PDT is presented in Table 5.1.

Table 5.1

Summary of the main advantages and disadvantages of PDT

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