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Clinical aspects of photodynamic therapy

HUGH BARR, CATHERINE KENDALL, JANELLE REYESGODDARD AND NICOLAS STONE

Photodynamic therapy is a method for local destruction of tissue or organisms by generating toxic oxygen and other reactive species using light absorbed by an administered or an endogenously generated photosensitiser. It is a highly promising treatment for patients with cancer. More recently it has found increasing use as a method of therapy for non-cancerous illnesses. It depends on the exploitation of natural and vital reactions widespread in nature that have driven and preserved life on this planet. Following administration of a photosensitiser or its precursor there is an accumulation or retention in areas of cancer and disease relative to adjacent normal tissue. The photosensitiser is inactive until irradiated by light, following which cellular destruction occurs. The clear attraction of this method is the possibility of some targeting of the disease by drug and by the area irradiated. This explanation although oversimplified has been the reason for the scientific and clinical interest in photodynamic therapy. An understanding of evolutionary photobiology is enormously helpful to understand disease response and clinical outcomes.

Keywords: photydynamic therapy, cancer

Introduction to Photobiology

Humans in common with most other organisms are highly dependent on photobiology, with light driven reactions being one of the main creative and destructive forces in the natural world. It appears events that occurred some 2700 million years ago allowed our very fragile and highly complex survival.At that time cyanobacteria, other prokaryotic bacteria and Archea, which were capable of light harvesting (catalysed by photosensitisers such as chlorophyll) began to
emerge.This allowed oxygenic photosynthesis, and created our highly reactive oxygen rich environment. These organisms lived and developed in this highly combustible oxygen fuel tank. Thus the development of oxygenic photosynthesis required the organism to have or import certain oxygen quenching proteins for protection from these highly reactive species. If left unquenched the organism would rapidly perish due to oxidation of vital molecules.We see the importance of this at certain times when the loss of this protection is highly evident, with subsequent toxic oxygen mediated photodestruction. The massive cell destruction during autumnal senescence is the clearest and most dramatic example. Clinical exploitation of these natural photo destructive mechanisms is the basis of clinical photodynamic therapy.

Similar to the plants and photosynthetic organisms, eukaryotic complex multi-cellular organisms have a high degree of metabolic specialisation with a requirement for oxygen and carbon species for oxidative phosphorylation. Yet the generation of reactive oxygen species is an initiator of apoptosis and cell death. Eukaryotic cells have therefore developed methods to resist oxidation. Evolutionary biologists believe that cells overcame this problem by the endosymbosis of mitochondria, a chloroplast like energy complex derived from cellular incorporation of primitive protobacteria. The mitochondria also contain natural photosensitisers called porphyrins, which are necessary for manufacture of the oxygen carrier haemoglobin and the energy transfer system involving the cytochromes. These are naturally generated or endogenous photosensitisers able to absorb light and generate toxic oxygen species under certain circumstances (Figure 1). Human cells have protective mechanisms against this toxic oxygen damage and cell death will only occur if a critical threshold of toxic oxygen species is reached and the protective
mechanisms associated with the mitochondria are overwhelmed. This threshold effect is important since it can be exploited to allow preservation of normal tissues.

Figure 1

Some unfortunate individuals are afflicted with a disease in which excessive photosensitisers are generated by in-born errors of metabolism. These disorders are called porphyrias and lead to excessive accumulation of porphyrin photosensitisers, which when activated by light in the skin result in profound tissue damage overcoming the cells natural defences. These patients are exquisitely sensitive to light; this is most evident in patients with acute intermittent porphyria who are deficient of porphobilinogen deaminase (Figure 2). This inherited disorder was highly prevalent in central Europe. The afflicted individuals were exquisitely sensitive to light on the skin and developed excess body hair. In addition, the patients could have red teeth, be unable to venture out during daylight, and have mental disorders. It seems that this disease could be the derivation for the myths of vampires.

Figure 2

Historical considerations

The use of light alone or in conjunction with a photosensitising agent has a long and indeed ancient history. The civilisations based in China, India, Egypt and Greece placed great emphasis on exposure to the sun to restore health. The ancient Indian civilisations (1000 BC) discovered that administration of psoralens when combined with careful exposure to sunlight could be used to treat the congenital and disfiguring patchy loss of skin pigmentation called vitiligo. The
techniques were further exploited in medieval Egypt and a variation of the treatment is still effective to allow skin repigmentation. It is unclear as to whether the ancients were able to differentiate this condition from the acquired depigmentation associated with cutaneous leprosy. Certainly by the nineteenth century Niels Finsen recognised the value of light therapy for the treatment of skin infections including smallpox and pustular infectious eruptions. His and his wife’s treatment of lupus vulgaris (cutaneous tuberculosis) with ultraviolet light resulted in the award of the Nobel Prize for Medicine in 1903.

The discovery that an administered substance could render an organism sensitive to light (photosensitivity) is attributed to Oscar Raab working in Munich. In the winter of 1887–98, Professor Herman von Tappeiner set his student Raab to study the toxicity of aniline dyes on paramecia. Raab recognised that the time to kill was related to the intensity of light in the laboratory. Von Tappeiner examined many other substances including chlorophyll and called the phenomenon “photodynamic action/photodynamische Erscheinung”. He demonstrated that a photosensitiser, light and molecular oxygen were necessary. He also suggested that tumours could be treated and some early clinical results were reported in 1905 in combination with the dermatologist Jesionek. They applied eosin to skin tumours
and exposed them to white light with some response. Subsequently, the parenteral administration of eosin by the French neurologist, J. Prime, as a treatment for epilepsy resulted in a light induced dermatitis in exposed areas of the skin. The most dramatic investigation of photosensitization was by Meyer-Betz who performed a famous Selbstversuch (self experimentation). He injected himself with a porphyrin compound (haematoporphyrin) and observed the effects of sunlight on his skin. He published a series of photographs of himself suffering from severe photosensitivity with gross facial oedema and erthyema. He remained sensitive to sunlight for over 2 months. Campbell and Hill in series of experiments demonstrated the profound effect of photodynamic therapy on the microcirculation, with the demonstration of thrombosis and vascular shutdown after photodynamic therapy. In Berlin during the Second World War, Auler and Banzer demonstrated that photosensitisers tended to localise in tumour and malignant tissue. They injected animals with haematoporphyrin and showed increases of fluorescence in animal cancers. Lipson in 1966 went on to treat a patient with a large cancer of the breast following an injection of a derivative of haematoprphyrin (HpD). A filtered Xenon arc lamp was used for irradiation to activate the photosensitiser in the tissue. The tumour did not disappear but there was encouraging objective evidence of response.

There were sporadic reports of photodynamic therapy, but T.J. Dougherty established the modern era working at the Division of Radiation Biology at Roswell Park Memorial Institute, Buffalo, USA. He reported that the systemically injected porphyrin (haematoporphyrin) when activated by red light caused complete
eradication of transplanted experimental tumours. He also confirmed the preferential accumulation of the photosensitiser in malignant tissue. Subsequently, a patient at the Tokyo Medical College with a small upper bronchial squamous cell tumour, was treated in 1980 at bronchosopy with photodynamic therapy. Irradiation was by using a laser as the light source. The tumour was completely eradicated. Patients with large obstructing oesophageal cancers were similarly treated by haematoporphyrin derivative photodynamic therapy. There was a very good improvement in the patient’s ability to swallow and some suggestion of a prolongation of survival.

Biology and photophysics of clinical photodynamic therapy

As stated in the introduction, the destruction of abnormal and diseased tissue after generating or administering a photosensitiser with the direct application of light forms the basis of photodynamic therapy. The requirements are a photosenitiser, light, oxygen and a substrate to act upon. Each photosensitiser has a specific action spectrum that is the wavelengths of light that are absorbed to produce an excited electronic state. The Jablonski diagram (Figure 1) demonstrates the
reactions involved in the process. Light excites the ground state photosensitser to an excited singlet state. In this condition it is in a highly reactive condition. However this state is short lived and can decay to the ground state directly emitting light as fluorescence. In this case, the energy is lost and no photodynamic action can occur. This reaction can be useful medically since it forms the basis of laser-induced photosensitiser fluorescence as a method of cancer detection (photodiagnosis). If a low dose of photosensitiser is given to patients with cancer and fluorescence is specifically excited, the malignant tissue can be imaged or detected using spectral analysis and the establishment of a tumour demarcation function. This is calculated by dividing the photosensitser fluorescence by the tissues natural autofluorescence. Thus an imaging device can be produced to allow detection of early cancerous areas that are invisible to white light detection.

Photodynamic therapy and tissue destruction requires the excited singlet to undergo spin inversion (intersystem crossing) to the metastable triplet state. The triplet state has a longer lifetime and is generally the reactive state involved in photodynamic therapy. The most usual subsequent action is for the activated triplet photosensitiser to transfer energy to ground state oxygen (which is a triplet) to produce singlet oxygen. This molecule is highly reactive and cannot diffuse far before reacting with other molecules. Major biological targets are membranes that undergo rupture and the cells are destroyed. It has been recently demonstrated that most damage is to the membranes around the mitochondria and the lysosomes. These organelles liberate destructive proteins that induce subsequent cellular
destruction. Photosensitisers that target the outer plasma membrane are less effective. It is important again to emphasise that a critical level is required since the cells have developed mechanisms to withstand this oxidative damage. Once these defences are overwhelmed the cell are fatally wounded and necrosis or apoptosis is inevitable. It is important to note that the toxic photoproduct can also destroy the photosensitiser, a process called photodegradation. The relevance of this effect is apparent when we consider that several photosensitisers are retained in tumours longer than in their surrounding normal tissues. At certain times after administration there exists a concentration differential of 2–3:1 between the diseased cancerous tissue and adjacent normal structures. Selective tumour destruction can be achieved if the photosensitiser is administered in low dosage, since the photosensitiser is photodegraded (in normal tissue) by light irradiation before a critical lethal threshold photodynamic dose is reached. However, tumours that selectively retain a higher concentration of photosensitser are destroyed because this threshold photodynamic dose is achieved and cell death is inevitable. This selective effect is restricted to very low dose and is, at present, not fully
exploited in many clinical situations.

It is also noticeable that some normal tissues are remarkably resistant to photodynamic therapy. They appear to have a naturally higher photodynamic threshold. This is most apparent in the pancreas. The normal pancreatic acinar cell contains many mitochondria and is very resistant to oxidative stress, the mitochondria being the ingested ‘chloroplast’. This appears essential since it produces such a cocktail of digestive enzymes and must resist auto digestion. Malignant
pancreatic cells have fewer mitochondria and thus fewer toxic oxygen quenching molecules, and are therefore much more sensitive to photodynamic therapy. Selective necrosis of tumours with sparing of normal pancreatic tissue can be demonstrated in experimentally induced tumours. However, differential damage between normal and malignant tissue can be difficult to achieve and requires very careful drug and light dosimetry. It is also possible to spare surrounding
tissues using photodynamic therapy by targeting the light delivery very precisely to the area of disease. The clear attraction of this dual selectivity has been a major impetus for investigation of this technique.

The most commonly used method of photodynamic therapy is to administer a photosensitiser, intravenously, orally or by local application to an area of abnormality and allow retention and accumulation in the tissue for a period of time prior to irradiation with appropriate wavelength light, usually from a laser. These externally administered photosensitisers tend to accumulate in rapidly growing tissue, blood vessels and the supporting tissue that grows with malignant tumours. Parenteral administration either by injection or by mouth does produce a period of general photosensitivity and accumulation is in stromal supportive tissue rather directly within growing cells. The problem of targeting the photosensitiser to the rapidly growing cells, and avoiding systemic photosensitisation may be overcome by using endogenous photosensitisation. This involves the exploitation of the increased metabolic activity that may be the ‘Achilles heel’ of the rapidly growing and dividing cells of cancer. These cells have voracious needs for metabolites; they accumulate the prodrugs required to generate the endogenous photosensitiser to a greater degree than the surrounding tissue. The generated photosensitiser tends to stay within the cells in whose mitochondria it was synthesised. The metabolic pathway for porphyrin synthesis to generate haemoglobin and cytochromes is shown Figure 2. This pathway is exploited to allow the generation of the photosensitiser
protoporphyrin IX. Following an excess oral administration of 5-aminolaevulinic acid (5-ALA), a precursor of haem, the negative feedback loop is overcome and there follows an intracellular accumulation of the photosensitiser protoporphyrin IX (PpIX). The synthesis of 5-ALA from glycine and succinyl-CoA is the first step in porphyrin biosynthesis and ultimately haem. This pathway is tightly regulated by end product inhibition. If excess 5-ALA is administered then this regulation is bypassed and an intracellular accumulation of the photosensitiser protoporphyrin IX (PpIX) is induced in the metabolically active cells (Figure 3). The level of
photosensitisation is minimised to a few hours and the 5-ALA can be administered orally dissolved in fruit juice. The photosensitiser is activated in tissue using 633–635 nm laser light from an appropriate light source, usually a laser.

Figure 3

Clinical photodynamic therapy

Ophthalmology

Age-related macular degeneration (AMD) is a leading cause of blindness and loss of visual acuity in the older population in the UK and other Western Countries. The cause is not known and treatment is very difficult. The patient is faced with deteriorating eyesight as they become older. The area of the retina that is affect is the macular region, which is most important for detailed vision. The fovea at the central part of the macula contains the photoreceptors necessary for high resolution. Abnormal vessels cause leakage of pigmented deposits in this region and also result in haemorrhage and retinal detachment. The early changes can be seen on inspection of the retina when the sight is already deteriorating, with abnormal pigments already showing large deposits around the macula (Figure 4).
Fluorescein angiography can demonstrated the early abnormal vessel formation, and Raman spectroscopy of the retina (Figure 5) can demonstrate an abnormal pattern of pigment deposition. Once the disease is detected at an early stage photodynamic therapy offers the possibility of preventing deterioration and thus the maintenance of visual acuity. It appears that the target of therapy is the newly forming abnormally leaky and fragile blood vessels. Following intravenous injection of the photosensitiser, a short delay is allowed before activation of the photosensitiser by light. This can be precisely delivered to the area of disease through the front of the eye. Using this method most of the photosensitiser is still within the blood vessels, and activation seals them and causes vascular endothelial damage with vessel occlusion and destruction, preventing leakage of abnormal pigments. The treatment is simple to perform in the ophthalmology clinic and is easily repeatable. Clinical trials have demonstrated that it is particular effective at limiting visual loss in the group of patients with wet or exudative AMD.

Figure 4 and 5

Skin disease

Photodynamic therapy has returned as a very useful method to treat skin diseases and skin cancer, including superficial basal cell carcinoma (Figures 6 and 7), T-cell lymphoma, Bowen’s disease (early skin cancer) (Figures 9 and 10), actinic keratoses and acne. Treatment is limited to superficial lesions since the penetration of surface illuminating light is limited. It is now apparent that the nature of the photosensitiser is very important. In general, if ALA generated PpIX is used a lesion of 0.2cm can be eradicated. Systemic parenteral administration of a porphyrin derivative such as Photofrin allows areas up to 0.5cm to be treated. The most popular and satisfactory method is to use ALA photodynamic therapy. Topical 5 aminolaevulinic acid in a carrier cream is applied to the abnormal area and then irradiated with light after a few hours. The effects can be remarkably effective (Figures 6–9). It is notable that the amount of scarring is minimal. A randomised clinical trial has shown that photodynamic therapy with ALA esters compared with simple surgical excision was equally effective in eradication of the tumour. Most notably the cosmetic result of photodynamic therapy was clearly superior. The use of systemic parenterally administered photosensitisers is only useful for large area of disease.

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Cardiovascular disease

Blockage of arteries by atherosclerotic disease is one of the major causes of death in the world. Increasingly efforts are being made to treat the disease within the blood vessel by endoluminal techniques. It may seem paradoxical to consider photodynamic therapy in view of the previous discussion on inducing vascular occlusion in the eye. However, the effect on the microcirculation is very different from the effect exploited in the treatment of large vessel obstruction. If a large artery develops narrowing, balloon dilation is often a very effective procedure to reopen it. The effectiveness of the procedure is often limited because of early reocclusion by excessive growth of the vessel lining (intimal hyperplasia). This effect can be reduced by immediate intravascular photodynamic therapy applied directly to the area after dilatation.

Cancer

Photodynamic therapy has attracted most interest as a method for the local eradication of cancer. The initial treatment of patients was of large areas of tumour that could not be treated by other means, or had failed conventional therapy following surgery, radiotherapy or chemotherapy. The treatment of advanced cancers is effective in palliation of some of the difficult symptoms associated with blockage of food or air passages. Palliation of malignant dysphagia (difficulty in swallowing) has proved very effective (Figure 10), allowing patients greatly improved quality of life for the time remaining to them.

It is now apparent that smaller areas of tumour can be treated very successfully with the prospect of cure. In certain vulnerable areas of the body surgery is highly mutilating involving a great deal of normal tissue destruction. It is, of course, critical to detect these tumours as early as possible. For example, patients who have had a previous squamous cell carcinoma in the head and neck or the upper aerodigestive tract are at increased risk of developing a second cancer. Screening of those populations is resulting in increased detection of very early tumours; with 15–20% of patients develop a second cancer. Treatment of these patients can be difficult since they have often had previous surgery or radiotherapy and the tissue may not be able to tolerate further irradiation, and surgery is associated with too great a risk. A large series of Chinese patients with such early screen detected cancers were treated with photodynamic therapy. They have remained disease free after 21–32 months. Other investigators have confirmed the effectiveness of photodynamic therapy for early oesophageal cancer and cancer in the head and neck. In particular a very important retrospective series indicated that longterm survival was possible after photodynamic therapy using a haematoporphyrin derivative and laser light at a wavelength of 630 nm for early squamous and adenocarcinoma. These patients were treated with photodynamic therapy because they had other diseases that precluded any other form of therapy. The five-year cancer specific survival was 74%, which was as effective as surgical resection or radical radiotherapy. Combining the treatment with additional chemotherapy and radiotherapy did not influence the survival.

Currently adenocarcinoma of the lower oesophagus and the gastro-oesophageal junction is at present reaching epidemic proportions in the West. The rate of rise is now greatest in England and Wales. This is related to the increase in gastro-oesophageal reflux disease (giving the symptoms of heartburn and indigestion) producing a pre-malignant change in the lower oesophagus called Barrett’s or columnar lined oesophagus. Currently adenocarcinoma in Barrett’s oesophagus has an incidence of 800 per 100,000. This can be compared with lung cancer in men over 65, where the incidence is 500 per 100,000. The development of cancer in Barrett’s oesophagus is thought to follow a defined sequence from intestinal metaplasia through low and high-grade dysplasia and finally to invasive cancer. The presence of dysplasia is regarded as the best marker for malignant transformation in the epithelium. Photodynamic therapy following endogenous photosensitisation with 5-ALA has been reported for the treatment of high-grade dysplasia and metaplasia (Figure 11). There have been two major clinical studies of 5-ALA photodynamic therapy for the ablation of high-grade dysplasia. Both have demonstrated eradication of the dysplasia and one series demonstrated the successful eradication of T1 tumours that were less than 2mm in depth. There were no treatment associated deaths, and therapy was performed as an outpatient. The alternative therapy of radical oesophagectomy is associated with an operative mortality of up to 10%, requires intensive care and substantial time in hospital.

Figure 11

Recently great interest has been shown in the treatment of biliary and pancreatic cancer. Bile duct or cholangiocarcinoma can be a relatively indolent tumour but treatment with surgery, radiotherapy and chemotherapy is very difficult. Aggressive surgical therapy is only possible in a minority of patients with early cancers, and even following radical surgery, the median survival is only between 13 and 20 months. Survival of patients with T3 and T4 tumours is limited to between 300 and 420 days. A recent study of photodynamic therapy in patients with non-resectable cholangiocarcinoma (type III and IV) has proved to be highly informative. There was no 30-day mortality and the median survival time was 439 days and one patient is alive at 739 days. The remarkable lack of serious complications associated with experimental photodynamic therapy to the pancreas has encouraged more detailed and clinical investigation. Twelve patients have been treated with percutaneously inserted optical fibres and up to 6.5cm of necrosis has been induced without major morbidity. Two patients are still alive at 16 and 17 months, and five patients have died of disease progression. Photodynamic therapy is also becoming increasingly used to treat early lung cancers in patients who have undergone previous resection and are unsuitable for other forms of therapy. Lung cancer remains the commonest cancer in men and at presentation 85% are unresectable. Virtually all patients referred for photodynamic therapy have had some other form of therapy. In a series of 100 patients treated with photodynamic
therapy, the mean survival was 9 months. In patients with localised small tumours the survival was 29 months.

Superficial cancer of the bladder is another attractive target for photodynamic therapy. It is widely distributed within the lining of the bladder, and is often very difficult to differentiate from surrounding normal unaffected tissue. Methods have been developed for total bladder irradiation. Using ALA as a photosenitiser can
reduce the main complication of excessive deep damage to the bladder muscle resulting in a non-compliant bladder.

In the brain, the preservation of as much functioning tissue as possible is vital. Adjuvant therapy with photodynamic therapy is showing promise. The neurosurgeon will resect as much of the visible tumour as possible since relapse is usually associated with a microscopic rest of malignant cells that cannot be identified in the tumour bed. Photodynamic therapy to the resection site is proving to be a useful method to reduce the incidence of local failure.

Infectious disease

The early use of photodynamic therapy for the treatment of infections of the skin was displaced by the widespread introduction of antibiotics. The situation is rapidly changing since the emergence of multiresistant bacterial strains. Other methods are being sought to destroy infecting bacteria. Helicobacter pylori is associated with upper gastrointestinal disease and cancer, and can on occasion be difficult to eradicate. It is, however, very sensitive to photodynamic
therapy. H.Pylori on the surface of the gastric mucosa is accessible to topical photosensitiser application and to endoscopic light delivery. This technique has not yet entered the clinical arena.

Conclusions

Photodynamic therapy is a beautiful concept, presenting the possibility that a light driven reaction ubiquitous in nature can be exploited to destroy diseased tissue. The widespread use in medicine is beginning after a long gestation and much work on the detailed understanding of the basic science. It now has an established role in the treatment of eye and skin disease. These two areas illustrate the advantages of targeted therapy that is repeatable and can be performed without admission to hospital and the use of expensive and increasingly limited resources. The hope remains that it will have widespread use for the treatment of cancers. However, exploitation of the advantages of this therapy has been slow for several reasons. First there is a natural conservatism and reluctance to subject patients to new concepts without overwhelming proof of efficacy over conventional treatment. Thus photodynamic therapy has been initially used for the treatment of desperate and very advanced cancers were other therapies have failed the patient. Photodynamic therapy has been the last resort. Secondly, for many years the concept of cancer treatment has involved radical therapy with extensive surgical removal, large encompassing radiotherapy fields, or systemic chemotherapy. It is now becoming clear that if cancers are found at an early stage, local minimally invasive targeted therapy such as photodynamic therapy may be very successful. This avoids mutilating surgery and the inevitable normal tissue damage and complications associated with other therapies. Clinicians are now actively seeking and screening for early cancers or pre-cancerous changes. It is essential that the treatment offered these patients is not worse than the disease itself, which when detected may be causing no symptoms but has the potential to be lethal if progress is not interrupted.

There is no doubt that the long scientific gestation of photodynamic therapy will allow useful patient treatments in the future.

 

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