Photodynamic therapy (PDT) is a site-specific tumour treatment involving the intravenous (i.v.) administration of a photosensitizing agent. The photosensitizer is subsequently activated in the presence of oxygen by non-thermal light of a specific wavelength matched to its absorption peak. This results in tissue death.
In head and neck oncology, PDT is licensed for the treatment of advanced head and neck carcinoma. The photochemical tissue destruction permits tumour debulking while maintaining normal tissue architecture, so that re-epithelialization can occur with minimal scarring. PDT can be used to treat non-malignant head and neck conditions such as oral epithelial dysplasia, lymphangioma and neurofibroma. It also has a role in the treatment of other malignancies, e.g. skin, bronchial, gynaecological and in non-malignant conditions such as Barrett’s oesophagus and age-related macular degeneration [1,2].
The most commonly used photosensitizing agent in oncology is meso-tetrahydroxyphenyl chlorine (mTHPC, Foscan®; Biolitec Pharmaceuticals Ltd., Ireland), which has the greatest depth of effect when activated by a light of 652 nm. Most photosensitizers bind to cellular membranes. After i.v. injection, they enter the cellular interstitial space and bind initially to the external plasma membrane. They gradually enter the cell and, after a few hours, are found diffusely throughout the cytoplasm.
By 96 h after administration, the time of light administration, they are bound to intracellular membranes of the internal plasma membrane, the mitochondria, the nuclear membrane, and to a lesser extent the Golgi complex and the endoplasmic reticulum.
Although more drug is retained by tumour compared with normal tissue, this difference is insufficient to produce a selective effect, and there will be some tissue necrosis wherever sufficient light reaches the tissue. However, by shielding normal tissue and exposing the treatment site to light from a diode laser, localized effects are achieved. Tissue necrosis is caused by the production of oxygen free radicals (type I mechanism) or by the formation of intracellular singlet oxygen (type II mechanism), which causes tissue death by intracellular oxygenation and vascular shutdown mechanisms. The light can be delivered through fibre-optic light bundles placed either within the tissues (interstitial PDT) (Fig. 1) or externally (surface PDT) . Light penetration of tissue is wavelength dependent, with longer wavelengths penetrating deeper into tissues; thus, although a drug might have another absorption peak at 420 nm (blue light), the utilized 652 nm wavelength (red light) produces a greater depth of effect.
Other photosensitizers used in the head and neck area include profimer sodium (Photofrin®; Axam Pharma, Quebec, Canada) and aminolaevulinic acid (ALA). Profimer sodium is a first generation photosensitizer that is injected intravenously; 48 h after infusion, the tumour tissue is activated at 630 nm wavelength. Profimer sodium is relatively selectively retained by cancer cells for unknown reasons. Tumour cell death is caused by oxygen-radical production and tumour microvascular shutdown, and undefined immunological mechanism most likely due to intense inflammatory response .
On the other hand, ALA is an intrinsic photosensitizer. It has no photosensitizing properties but is converted in situ to a photosensitizer, protoporphyrin IX. The exact rate of protoporphyrin accumulation in any tissue depends on metabolic turnover and the capacity of the cell line for haeme synthesis. Cancer cells accumulate protoporphyrin IX more actively than normal cells do. ALA is activated at 635 nm of light, with peak tumour fluorescence occurring 3–5 h after administration. In actinic keratosis, ALA may be activated by a blue light spectrum (around 400 nm wavelength).
Light is delivered to the tumour tissue bed using a diode laser with silicone quartz fibre-optic cables. The distal end of the quartz fibres is modified to obtain an optimal uniform geometric light delivery to the tissues. The fibre tips used in the head and neck area are a microlens and a cylindrical diffuser. The microlens tip distributes the light in a uniform circle and illuminates superficial tissue surfaces. Cylindrical diffuser tips distribute light 360° along the axis of the fibre. The wavelength of light used depends on the type of the photosensitizer utilized (e.g. 652 nm for mTHPC, 635 nm for ALA, 630 nm for profimer sodium). The total light dose (J cm−2) and the dose rate (mW cm−2) to be administered to the tumour tissue are a predetermined number based on clinical trials for each specific photosensitizer and tumour type to be treated.
The length of each session depends on the total treatment surface area as well as the photosensitizer used. We have utilized a beam splitter allowing us to treat four sites simultaneously, thus reducing the total treatment time. In addition, extra time is needed for accurate placement of fibres into treatment sites in cases of interstitial PDT, especially when computed tomography or magnetic resonance imaging is needed for localization. PDT can be carried out under local anaesthesia. In some cases, however, optimal surgical access or adequate patient comfort may only be provided under general anaesthesia.
The patient population undergoing PDT for maxillofacial conditions may prove challenging for the anaesthetist. PDT is mainly used in advanced inoperable head and neck cancer that is no longer suitable for other treatment modalities  (Fig. 2), and the majority of patients have already had extensive surgery and radiotherapy. PDT is also indicated for the debulking of non-malignant conditions such as neurofibromas, lymphangiomas or haemangiomas, which cause cosmetic or mass effect problems. Both patient groups might have challenging airways and necessitate the presence of an experienced anaesthetist and access to the specialist airway equipment. In addition, the patients are often elderly, poorly nourished, heavy smokers and drinkers with multiple medical co-morbidities. A thorough preoperative assessment is necessary. A close working relationship and good communication with the maxillofacial team is essential when planning perioperative care.
The treatment itself causes very little bleeding or soiling of the upper airway. General anaesthesia is often only needed to ensure access to the treatment site and immobility, which allow accurate tissue placement of the needles through which the light fibre bundles are passed. It is not mandatory to perform endotracheal intubation, and a reinforced laryngeal mask airway with a throat pack is often adequate. PDT is used for the treatment of laryngeal tumours. In these cases, standard anaesthetic techniques allowing surgical access to the larynx will be required.
When endotracheal intubation is necessary, it is important to remember that a standard laryngoscope emits 1500 lux and an intubating fibrescope emits 50 000 lux. These levels are very much higher than the 400 lux that photosensitized patients can tolerate without burning. Prolonged or repeated attempts at endotracheal intubation using a laryngoscope or fibrescope could lead to upper airway burns and this must be considered when formulating an anaesthetic plan. To date, our institution has performed many fibre-optic endotracheal intubations in PDT patients without any incidents, but this is not an appropriate patient group on which airway management techniques are taught to very junior anaesthetists.
Skin photosensitivity and burns
After the i.v. injection of mTHPC, patients experience generalized tissue photosensitivity. Every patient is given written instructions about the gradual re-exposure to light over a 3-week period. Maximal light exposure of 100 lux (60 W light bulb) is permitted on day 1 after sensitization, increasing by increments of 100 lux per day until complete clearance of the photosensitizer from the system after 3 weeks. On the day of treatment, all patients are exposed to indoor light. Gradual re-exposure to daylight is important from day 14 onwards. Precautions should be taken by covering the exposed skin areas to avoid burns when going outside.
The anaesthetic and surgical implications of generalized photosensitivity are very important. The anaesthetic room, theatre and recovery areas must be minimally illuminated. When transferring patients to and from the theatre, their exposed skin must be covered (Fig. 3). Anaesthesia and surgery in these conditions can be challenging. Establishing i.v. access, intubation, airway control and interpretation of physical signs (e.g. cyanosis) can be difficult in a darkened environment. Red filters can be placed on the theatre’s main operating lights to reduce the risk of light of the activation wavelength penetrating through, thus causing burns at non-operative sites.
Burns associated with pulse oximetry have been reported (Fig. 4). The pulse oximeter transmits red light, which can burn photosensitized skin. Its duration of use at any one site must not exceed 10 min. The effect is cumulative so that each digit can be used only once. When handing over to the recovery staff, it is important to note the sites that have already been used and it may be necessary to monitor saturation intermittently.
Safety goggles/red light filtration
There is a risk of ocular damage to staff and theatre personnel during PDT as during conventional laser therapy. Wavelength-specific safety goggles are necessary during PDT. When mTHPC, profimer or ALA is used, the goggles are blue and selectively filter out red light impairing the visualization of anything red. Any parameter displayed on a monitor in red (conventionally invasive and non-invasive blood pressure) becomes difficult to recognize (Fig. 5a,b). To improve safety, it is advisable to reconfigure this to a different colour, e.g. white. Similarly, black writing on a red background will be illegible. After the recent changes in our drug-labelling system, the identification of neuromuscular blocking drug labels is difficult when wearing these goggles. In fact, all colours are slightly altered so that drug recognition by label colour is unreliable and extra vigilance is required to avoid drug errors (Fig. 6).
PDT can be very painful. Per-operatively, the activation of the fibre-optic light bundles during PDT can be intensely stimulating. Postoperatively, tissue necrosis, oedema and breakdown caused by PDT result in moderate to severe pain. This may be immediate or may take up to 48 h to develop. The unpredictable severity and time onset of pain coupled with the fact that many patients will be on long-term opiates makes successful pain control a challenge. A multi-disciplinary team approach to pain management is essential with careful preoperative planning.
A balanced analgesia regimen, consisting of paracetamol, non-steroidal anti-inflammatory drugs (e.g. diclofenac sodium) and i.v. opiates is recommended, combined with the liberal administration of local anaesthesia wherever possible. Per-operatively, remifentanil can be used to cover the intense treatment stimulus. In opiate-tolerant patients, drugs such as clonidine are particularly useful. Some patients benefit from a patient-controlled analgesia (PCA) delivery system or i.v. infusion of opiates necessitating an appropriate postoperative environment, e.g. a high dependency unit.
Postprocedure airway management
Tissue necrosis, sloughing, oedema and swelling at the treatment site may occur immediately or 24–48 h postprocedure. This is of particular importance when PDT is used to manage head and neck conditions (e.g. carcinoma, dysplasia, lymphangioma), and depending on tumour site and extent of treatment there may be a postoperative risk of airway swelling and compromise. A joint decision must be made by anaesthetist and surgeon on intra and postoperative airway management. It is occasionally necessary to perform a pre-procedural tracheostomy to cover the treatment period.
PDT is a rapidly developing technique that is being increasingly integrated into the treatment strategy of oncology teams and is also gaining acceptance for many non-malignant conditions. Despite the potential adverse effects associated with systemic photosensitizing agents, extensive benefits have been shown following PDT [4,5]. With the increasing use of PDT more photosensitized patients will present for surgery in both elective and emergency settings. Following these simple guidelines, PDT can be safely and effectively carried out in the operating theatre environment.
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