clinical aspects of photodynamic therapy

Science Progress (2002), 85 (2), 131–150

Clinical aspects of photodynamictherapyHUGH BARR, CATHERINE KENDALL, JANELLE REYES-

GODDARD AND NICOLAS STONE

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

Keywords: photydynamic therapy, cancer

Introduction to PhotobiologyHumans in common with most other organisms are highly dependenton photobiology, with light driven reactions being one of the maincreative and destructive forces in the natural world. It appears eventsthat occurred some 2700 million years ago allowed our very fragileand highly complex survival.1,2 At that time cyanobacteria, otherprokaryotic bacteria and Archea, which were capable of light har-vesting (catalysed by photosensitisers such as chlorophyll) began toemerge.1 This allowed oxygenic photosynthesis, and created our

Correspondence to: Professor Hugh Barr, Department of Surgery, Cranfield PostgraduateMedical School in Gloucestershire, Gloucestershire Royal Hospital, Great Western Road,Gloucester GL1 3NN, UK. E-mail [email protected]

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highly reactive oxygen rich environment. These organisms lived anddeveloped in this highly combustible oxygen fuel tank. Thus thedevelopment of oxygenic photosynthesis required the organism tohave or import certain oxygen quenching proteins for protectionfrom these highly reactive species.3 If left unquenched the organismwould rapidly perish due to oxidation of vital molecules. We see theimportance of this at certain times when the loss of this protection ishighly evident, with subsequent toxic oxygen mediated photo-destruction. The massive cell destruction during autumnal senescenceis the clearest and most dramatic example. Clinical exploitation ofthese natural photo destructive mechanisms is the basis of clinicalphotodynamic therapy.4

Similar to the plants and photosynthetic organisms, eukaryoticcomplex multi-cellular organisms have a high degree of metabolicspecialisation with a requirement for oxygen and carbon species foroxidative phosphorylation. Yet the generation of reactive oxygen

132 Hugh Barr, Catherine Kendall, Janelle Reyes-Goddard, Nicolas Stone

Fig. 1. Simplified Jablonski diagram that demonstrates the reactive statesexploited during photodynamic therapy. The diagram depicts themolecular energy levels of the photosensitiser following excitation by aphoton of light. The photosensitiser in an initial singlet state (net electronspin is zero and paired in the ground state), absorbs energy from light toenter an excited singlet state that is short lived. Decay can occur byemission of light (fluorescence) or the molecule can undergo spininversion to a metastable triplet state (two unpaired electron spins). Thetriplet state has a longer lifetime and is generally the reactivephotosensitiser state involved in photodynamic action. In particular, thetriplet photosensitiser can react with ground state oxygen (which is atriplet) to produce singlet oxygen. This molecule is highly reactive and isthe toxic photoproduct produced during photodynamic therapy.

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species is an initiator of apoptosis and cell death. Eukaryotic cellshave therefore developed methods to resist oxidation. Evolutionarybiologists believe that cells overcame this problem by the endo-symbosis of mitochondria, a chloroplast like energy complexderived from cellular incorporation of primitive protobacteria.5 Themitochondria also contain natural photosensitisers called porphyrins,which are necessary for manufacture of the oxygen carrier haemo-globin and the energy transfer system involving the cytochromes.These are naturally generated or endogenous photosensitisers able toabsorb light and generate toxic oxygen species under certain circum-stances (Figure 1). Human cells have protective mechanisms againstthis toxic oxygen damage and cell death will only occur if a criticalthreshold of toxic oxygen species is reached and the protectivemechanisms associated with the mitochondria are overwhelmed.6This threshold effect is important since it can be exploited to allowpreservation of normal tissues. Some unfortunate individuals are afflicted with a disease in whichexcessive photosensitisers are generated by in-born errors of metab-olism. These disorders are called porphyrias and lead to excessiveaccumulation of porphyrin photosensitisers, which when activatedby light in the skin result in profound tissue damage overcoming thecells natural defences. These patients are exquisitely sensitive tolight; this is most evident in patients with acute intermittent por-phyria who are deficient of porphobilinogen deaminase (Figure 2).7This inherited disorder was highly prevalent in central Europe. Theafflicted individuals were exquisitely sensitive to light on the skinand developed excess body hair. In addition, the patients could havered teeth, be unable to venture out during daylight, and have mentaldisorders. It seems that this disease could be the derivation for themyths of vampires.

Historical considerationsThe use of light alone or in conjunction with a photosensitising agenthas a long and indeed ancient history. The civilisations based inChina, India, Egypt and Greece placed great emphasis on exposureto the sun to restore health. The ancient Indian civilisations (1000BC) discovered that administration of psoralens when combined withcareful exposure to sunlight could be used to treat the congenital anddisfiguring patchy loss of skin pigmentation called vitiligo. Thetechniques were further exploited in medieval Egypt and a variationof the treatment is still effective to allow skin repigmentation. It isunclear as to whether the ancients were able to differentiate this

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condition from the acquired depigmentation associated with cuta-neous leprosy.8 Certainly by the nineteenth century Niels Finsenrecognised the value of light therapy for the treatment of skin infec-tions including smallpox and pustular infectious eruptions. His andhis wife’s treatment of lupus vulgaris (cutaneous tuberculosis) withultraviolet light resulted in the award of the Nobel Prize forMedicine in 1903.

The discovery that an administered substance could render anorganism sensitive to light (photosensitivity) is attributed to OscarRaab working in Munich. In the winter of 1887–98, ProfessorHerman von Tappeiner set his student Raab to study the toxicity ofaniline dyes on paramecia. Raab recognised that the time to kill wasrelated to the intensity of light in the laboratory. Von Tappeiner


Fig. 2. Diagram to show the mechanism exploited for the generation ofthe photosensitiser protoporphyrin IX (PpIX), using the cell’s metabolicpathway for the production of haemoglobin. Derangement of this cycle isresponsible for the condition of porphyria. In order to generate PpIX,excess 5 aminolaevulinic acid is administered orally or by injection; 5-aminolaevulinic acid (5-ALA) being a precursor of haem. Anintracellular accumulation of the photosensitiser protoporphyrin IX(PpIX) is induced; since the synthesis of 5-ALA from glycine and succinyl-CoA is the first step in porphyrin biosynthesis, and the pathway is tightlyregulated by end product inhibition. If excess endogenous 5-ALA isadministered, then this regulation is bypassed and an intracellularaccumulation of the photosensitiser protoporphyrin IX (PpIX) istransiently induced.

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examined many other substances including chlorophyll and called thephenomenon “photodynamic action/photodynamische Erscheinung”.He demonstrated that a photosensitiser, light and molecular oxygenwere necessary. He also suggested that tumours could be treated andsome early clinical results were reported in 1905 in combinationwith the dermatologist Jesionek. They applied eosin to skin tumoursand 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 der-matitis in exposed areas of the skin. The most dramatic investigationof photosensitization was by Meyer-Betz who performed a famousSelbstversuch (self experimentation). He injected himself with aporphyrin compound (haematoporphyrin) and observed the effectsof sunlight on his skin. He published a series of photographs of him-self suffering from severe photosensitivity with gross facial oedemaand erthyema. He remained sensitive to sunlight for over 2 months.Campbell and Hill in series of experiments demonstrated the pro-found effect of photodynamic therapy on the microcirculation, withthe demonstration of thrombosis and vascular shutdown after photo-dynamic therapy. In Berlin during the Second World War, Auler andBanzer demonstrated that photosensitisers tended to localise intumour and malignant tissue. They injected animals with haemato-porphyrin and showed increases of fluorescence in animal cancers.Lipson in 1966 went on to treat a patient with a large cancer of thebreast following an injection of a derivative of haematoprphyrin(HpD). A filtered Xenon arc lamp was used for irradiation to activatethe photosensitiser in the tissue. The tumour did not disappear butthere 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 ofRadiation Biology at Roswell Park Memorial Institute, Buffalo,USA. He reported that the systemically injected porphyrin(haematoporphyrin) when activated by red light caused completeeradication of transplanted experimental tumours. He also confirmedthe preferential accumulation of the photosensitiser in malignant tissue.8,9 Subsequently, a patient at the Tokyo Medical College witha small upper bronchial squamous cell tumour, was treated in 1980at bronchosopy with photodynamic therapy. Irradiation was by usinga laser as the light source. The tumour was completely eradicated.Patients with large obstructing oesophageal cancers were similarlytreated by haematoporphyrin derivative photodynamic therapy.There was a very good improvement in the patient’s ability to swal-low and some suggestion of a prolongation of survival.


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Biology and photophysics of clinical photodynamictherapy

As stated in the introduction, the destruction of abnormal and dis-eased tissue after generating or administering a photosensitiser withthe direct application of light forms the basis of photodynamic therapy.The requirements are a photosenitiser, light, oxygen and a substrateto act upon. Each photosensitiser has a specific action spectrum thatis the wavelengths of light that are absorbed to produce an excitedelectronic state. The Jablonski diagram (Figure 1) demonstrates thereactions involved in the process. Light excites the ground state photo-sensitser to an excited singlet state. In this condition it is in a highlyreactive condition. However this state is short lived and can decay tothe ground state directly emitting light as fluorescence. In this case,the energy is lost and no photodynamic action can occur. This reac-tion can be useful medically since it forms the basis of laser-inducedphotosensitiser fluorescence as a method of cancer detection (photo-diagnosis). If a low dose of photosensitiser is given to patients withcancer and fluorescence is specifically excited, the malignant tissuecan be imaged or detected using spectral analysis and the establish-ment of a tumour demarcation function. This is calculated by dividingthe photosensitser fluorescence by the tissues natural autofluores-cence. Thus an imaging device can be produced to allow detection ofearly cancerous areas that are invisible to white light detection.

Photodynamic therapy and tissue destruction requires the excitedsinglet to undergo spin inversion (intersystem crossing) to themetastable triplet state. The triplet state has a longer lifetime and isgenerally the reactive state involved in photodynamic therapy. Themost usual subsequent action is for the activated triplet photosensitiserto transfer energy to ground state oxygen (which is a triplet) to pro-duce singlet oxygen. This molecule is highly reactive and cannot diffuse far before reacting with other molecules. Major biologicaltargets are membranes that undergo rupture and the cells aredestroyed. It has been recently demonstrated that most damage is tothe membranes around the mitochondria and the lysosomes. Theseorganelles liberate destructive proteins that induce subsequent cellulardestruction. Photosensitisers that target the outer plasma membraneare less effective. It is important again to emphasise that a criticallevel is required since the cells have developed mechanisms to with-stand this oxidative damage. Once these defences are overwhelmedthe cell are fatally wounded and necrosis or apoptosis is inevitable.It is important to note that the toxic photoproduct can also destroythe photosensitiser, a process called photodegradation. The relevance


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of this effect is apparent when we consider that several photosensi-tisers are retained in tumours longer than in their surrounding normaltissues. At certain times after administration there exists a concen-tration differential of 2–3:1 between the diseased cancerous tissueand adjacent normal structures. Selective tumour destruction can beachieved if the photosensitiser is administered in low dosage, sincethe photosensitiser is photodegraded (in normal tissue) by light irradiation before a critical lethal threshold photodynamic dose isreached. However, tumours that selectively retain a higher concen-tration of photosensitser are destroyed because this threshold photo-dynamic dose is achieved and cell death is inevitable. This selectiveeffect is restricted to very low dose and is, at present, not fullyexploited in many clinical situations.

It is also noticeable that some normal tissues are remarkably resis-tant to photodynamic therapy. They appear to have a naturally higherphotodynamic threshold. This is most apparent in the pancreas. Thenormal pancreatic acinar cell contains many mitochondria and isvery resistant to oxidative stress, the mitochondria being the ingested‘chloroplast’. 6 This appears essential since it produces such a cock-tail of digestive enzymes and must resist auto digestion. Malignantpancreatic cells have fewer mitochondria and thus fewer toxic oxy-gen quenching molecules, and are therefore much more sensitive tophotodynamic therapy. Selective necrosis of tumours with sparing ofnormal pancreatic tissue can be demonstrated in experimentallyinduced tumours.9 However, differential damage between normaland malignant tissue can be difficult to achieve and requires verycareful drug and light dosimetry. It is also possible to spare sur-rounding tissues using photodynamic therapy by targeting the lightdelivery very precisely to the area of disease. The clear attraction ofthis dual selectivity has been a major impetus for investigation ofthis technique.

The most commonly used method of photodynamic therapy is toadminister a photosensitiser, intravenously, orally or by local appli-cation to an area of abnormality and allow retention and accumulationin the tissue for a period of time prior to irradiation with appropriatewavelength light, usually from a laser. These externally adminis-tered photosensitisers tend to accumulate in rapidly growing tissue,blood vessels and the supporting tissue that grows with malignanttumours. Parenteral administration either by injection or by mouthdoes produce a period of general photosensitivity and accumulationis in stromal supportive tissue rather directly within growing cells.

The problem of targeting the photosensitiser to the rapidly grow-ing cells, and avoiding systemic photosensitisation may be over-


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come by using endogenous photosensitisation. This involves theexploitation 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 accumulatethe prodrugs required to generate the endogenous photosensitiser toa greater degree than the surrounding tissue. The generated photo-sensitiser tends to stay within the cells in whose mitochondria it wassynthesised. The metabolic pathway for porphyrin synthesis to generate haemoglobin and cytochromes is shown Figure 2. Thispathway is exploited to allow the generation of the photosensitiserprotoporphyrin IX. Following an excess oral administration of 5-aminolaevulinic acid (5-ALA), a precursor of haem, the negativefeedback loop is overcome and there follows an intracellular accumulation of the photosensitiser protoporphyrin IX (PpIX). Thesynthesis of 5-ALA from glycine and succinyl-CoA is the first stepin porphyrin biosynthesis and ultimately haem. This pathway istightly regulated by end product inhibition. If excess 5-ALA isadministered then this regulation is bypassed and an intracellularaccumulation of the photosensitiser protoporphyrin IX (PpIX) isinduced in the metabolically active cells (Figure 3). The level ofphotosensitisation is minimised to a few hours and the 5-ALA can beadministered orally dissolved in fruit juice. The photosensitiser isactivated in tissue using 633–635nm laser light from an appropriatelight source, usually a laser.

Clinical photodynamic therapy

OphthalmologyAge-related macular degeneration (AMD) is a leading cause ofblindness and loss of visual acuity in the older population in the UKand other Western Countries. The cause is not known and treatmentis very difficult. The patient is faced with deteriorating eyesight asthey become older. The area of the retina that is affect is the macularregion, which is most important for detailed vision. The fovea at thecentral part of the macula contains the photoreceptors necessary forhigh resolution. Abnormal vessels cause leakage of pigmenteddeposits in this region and also result in haemorrhage and retinaldetachment. The early changes can be seen on inspection of theretina when the sight is already deteriorating, with abnormal pig-ments already showing large deposits around the macula (Figure 4).Fluorescein angiography can demonstrated the early abnormal ves-sel formation, and Raman spectroscopy of the retina (Figure 5) candemonstrate an abnormal pattern of pigment deposition. Once the


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disease is detected at an early stage photodynamic therapy offers thepossibility of preventing deterioration and thus the maintenance ofvisual acuity. It appears that the target of therapy is the newly form-ing abnormally leaky and fragile blood vessels. Following intra-venous injection of the photosensitiser, a short delay is allowedbefore activation of the photosensitiser by light. This can be pre-cisely delivered to the area of disease through the front of the eye.Using this method most of the photosensitiser is still within theblood vessels, and activation seals them and causes vascularendothelial damage with vessel occlusion and destruction, prevent-ing 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 exudativeAMD.


Fig. 3. Histological picture of a squamous cell cancer, with an adjacentfluorescence false colour image to show the generation and accumulationof the photosensitiser (PpIX) following the administration of excess 5ALA.The highly cellular area of malignant tissue contains more PpIX. Thefalse colour scale is shown on the fluorescence image, with whiteindicating high fluorescence of PpIX and thus greater accumulation of thephotosensitiser. Decreasing fluorescence is indicated through blue, green,red and black, which indicates the lowest intensity with very littleaccumulation of photosensitiser.

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Fig. 4. A retinal image of exudates associated with age related maculardegeneration. The optic nerve is shown entering the retina with largeblood vessels radiating from the centre. The abnormal yellow areas orexudates are shown as distinct dots around an area of the retina (deep redarea) associated with precise vision called the macula. The accumulationof this yellow pigment ultimately will destroy vision.

Fig. 5. Raman spectroscopic scan of the retina. This is a method that will allow earlydetection of age related macular degeneration. Each peak represents a precisemolecular species and this scan indicates excess accumulation of the abnormalpigments associated with age related macular degeneration. This allows very earlymolecular detection before the exudates are grossly visible around the macula andvision is threatened.

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Skin diseasePhotodynamic therapy has returned as a very useful method to treatskin diseases and skin cancer, including superficial basal cell carci-noma (Figures 6 and 7), T-cell lymphoma, Bowen’s disease (earlyskin cancer) (Figures 9 and 10), actinic keratoses and acne. Treatmentis limited to superficial lesions since the penetration of surface illuminating light is limited. It is now apparent that the nature of thephotosensitiser is very important.10 In general, if ALA generatedPpIX is used a lesion of 0.2cm can be eradicated. Systemic par-enteral administration of a porphyrin derivative such as Photofrinallows areas up to 0.5cm to be treated. The most popular and satis-factory method is to use ALA photodynamic therapy. Topical 5aminolaevulinic acid in a carrier cream is applied to the abnormalarea and then irradiated with light after a few hours. The effects canbe remarkably effective (Figures 6–9). It is notable that the amountof scarring is minimal. A randomised clinical trial has shown thatphotodynamic therapy with ALA esters compared with simple sur-gical excision was equally effective in eradication of the tumour.Most notably the cosmetic result of photodynamic therapy wasclearly superior. The use of systemic parenterally administered photo-sensitisers is only useful for large area of disease.

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

CancerPhotodynamic therapy has attracted most interest as a method for thelocal eradication of cancer. The initial treatment of patients was oflarge areas of tumour that could not be treated by other means, or hadfailed conventional therapy following surgery, radiotherapy or


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Fig. 6. A superficial patch of early squamous cell carcinoma on theforehead of an elderly patient. Alternative treatment would have involvedextensive excision and reconstruction with a skin graft.

Fig. 7. The same area as in Fig. 6, 12 weeks after photodynamic therapy.The disease has been eradicated with minimal scarring. The treatmentwas performed without admission to hospital and minimal disruption tothe patient.

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chemotherapy. The treatment of advanced cancers is effective in palliation of some of the difficult symptoms associated with block-age of food or air passages. Palliation of malignant dysphagia (diffi-culty in swallowing) has proved very effective (Figure 10), allowingpatients greatly improved quality of life for the time remaining tothem.

It is now apparent that smaller areas of tumour can be treated verysuccessfully with the prospect of cure. In certain vulnerable areas ofthe body surgery is highly mutilating involving a great deal of normaltissue destruction. It is, of course, critical to detect these tumours asearly as possible. For example, patients who have had a previoussquamous cell carcinoma in the head and neck or the upper aero-digestive tract are at increased risk of developing a second cancer.Screening of those populations is resulting in increased detection ofvery early tumours; with 15–20% of patients develop a second cancer.Treatment of these patients can be difficult since they have often hadprevious surgery or radiotherapy and the tissue may not be able totolerate further irradiation, and surgery is associated with too great arisk. A large series of Chinese patients with such early screendetected cancers were treated with photodynamic therapy. Theyhave remained disease free after 21–32 months.9,10 Other investiga-tors have confirmed the effectiveness of photodynamic therapy forearly oesophageal cancer and cancer in the head and neck. Inparticular a very important retrospective series indicated that long-term survival was possible after photodynamic therapy using ahaematoporphyrin derivative and laser light at a wavelength of630nm for early squamous and adenocarcinoma.11 These patientswere 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 surgicalresection or radical radiotherapy. Combining the treatment withadditional chemotherapy and radiotherapy did not influence the survival.

Currently adenocarcinoma of the lower oesophagus and the gastro-oesophageal junction is at present reaching epidemic propor-tions in the West. The rate of rise is now greatest in England andWales. This is related to the increase in gastro-oesophageal refluxdisease (giving the symptoms of heartburn and indigestion) produc-ing a pre-malignant change in the lower oesophagus called Barrett’sor columnar lined oesophagus. Currently adenocarcinoma in Barrett’soesophagus has an incidence of 800 per 100,000. This can be com-pared with lung cancer in men over 65, where the incidence is 500per 100,000. The development of cancer in Barrett’s oesophagus is


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Fig. 8. This picture shows an extensive basal cell carcinoma behind theear before treatment with photodynamic therapy. These areas are difficultto treat and often very extensive plastic surgical reconstruction isrequired. It is also very difficult to be sure where the margins of thetumour are to allow all the abnormal area to be excised and repeatedsurgery may be necessary. Photodynamic therapy targets the treatmentand allows the marginal tumour to be eradicated.

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Fig. 9. The same area as in Fig. 8, 12 weeks after treatment. The cosmeticresult is excellent and the patient required one treatment withphotosensitiser applied to the skin followed by 15 minutes irradiation withred light from a laser. The patient was awake and was treated as a daycase.

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thought to follow a defined sequence from intestinal metaplasiathrough low and high-grade dysplasia and finally to invasive cancer.The presence of dysplasia is regarded as the best marker for malig-nant transformation in the epithelium. Photodynamic therapy fol-lowing endogenous photosensitisation with 5-ALA has beenreported for the treatment of high-grade dysplasia and metaplasia(Figure 11). There have been two major clinical studies of 5-ALAphotodynamic therapy for the ablation of high-grade dysplasia. Bothhave demonstrated eradication of the dysplasia and one seriesdemonstrated the successful eradication of T1 tumours that were less than 2mm in depth.4,12 There were no treatment associateddeaths, and therapy was performed as an outpatient. The alternativetherapy of radical oesophagectomy is associated with an operativemortality of up to 10%, requires intensive care and substantial timein hospital.

Recently great interest has been shown in the treatment of biliaryand pancreatic cancer. Bile duct or cholangiocarcinoma can be a relatively indolent tumour but treatment with surgery, radiotherapyand chemotherapy is very difficult. Aggressive surgical therapy isonly possible in a minority of patients with early cancers, and evenfollowing radical surgery, the median survival is only between 13and 20 months. Survival of patients with T3 and T4 tumours is limitedto between 300 and 420 days. A recent study of photodynamic therapy


Fig. 10. This patient presented with a very advanced oesophageal cancerwith no possibility of curative resection or therapy because of the extent ofthe disease and his general frailty with the presence of other cardiacabnormalities. The oesophagus is completely obstructed by thisoesophageal adenocarcinoma. The patient is unable to swallow liquidsand is in severe distress. After day case endoscopic photodynamic therapya large volume of the tumour has been destroyed, the food passage is openand the patient can now swallow.

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in patients with non-resectable cholangiocarcinoma (type III and IV)has proved to be highly informative. There was no 30-day mortalityand the median survival time was 439 days and one patient is alive at739 days.13 The remarkable lack of serious complications associatedwith experimental photodynamic therapy to the pancreas hasencouraged more detailed and clinical investigation. Twelve patientshave been treated with percutaneously inserted optical fibres and upto 6.5cm of necrosis has been induced without major morbidity. Twopatients are still alive at 16 and 17 months, and five patients havedied of disease progression.14

Photodynamic therapy is also becoming increasingly used to treatearly lung cancers in patients who have undergone previous resectionand are unsuitable for other forms of therapy. Lung cancer remains thecommonest cancer in men and at presentation 85% are unresectable.Virtually all patients referred for photodynamic therapy have had someother form of therapy. In a series of 100 patients treated with photo-dynamic therapy, the mean survival was 9 months. In patients withlocalised small tumours the survival was 29 months.15

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


Fig. 11. This pre-cancerous change (salmon pink area at the gastro-oesophageal junction) was found in a patient during a screeningprogramme. The patient has no symptoms but this area, if not removed,would degenerate into cancer over a period of months. After day caseendoscopic photodynamic therapy, the area has returned to normalepithelium, which does not have the potential to develop cancer.

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In the brain, the preservation of as much functioning tissue as possible is vital. Adjuvant therapy with photodynamic therapy isshowing promise. The neurosurgeon will resect as much of the visibletumour as possible since relapse is usually associated with a micro-scopic rest of malignant cells that cannot be identified in the tumourbed. Photodynamic therapy to the resection site is proving to be auseful method to reduce the incidence of local failure.

Infectious diseaseThe early use of photodynamic therapy for the treatment of infec-tions of the skin was displaced by the widespread introduction ofantibiotics. The situation is rapidly changing since the emergence ofmultiresistant bacterial strains. Other methods are being sought todestroy infecting bacteria. Helicobacter pylori is associated withupper gastrointestinal disease and cancer, and can on occasion bedifficult to eradicate. It is, however, very sensitive to photodynamictherapy.16 H.Pylori on the surface of the gastric mucosa is accessibleto 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 possi-bility that a light driven reaction ubiquitous in nature can beexploited to destroy diseased tissue. The widespread use in medicineis beginning after a long gestation and much work on the detailedunderstanding of the basic science. It now has an established role inthe treatment of eye and skin disease. These two areas illustrate theadvantages of targeted therapy that is repeatable and can be per-formed without admission to hospital and the use of expensive andincreasingly limited resources. The hope remains that it will havewidespread use for the treatment of cancers. However, exploitationof the advantages of this therapy has been slow for several reasons.First there is a natural conservatism and reluctance to subjectpatients to new concepts without overwhelming proof of efficacyover conventional treatment. Thus photodynamic therapy has beeninitially used for the treatment of desperate and very advanced cancers were other therapies have failed the patient. Photodynamictherapy has been the last resort. Secondly, for many years the con-cept of cancer treatment has involved radical therapy with extensivesurgical removal, large encompassing radiotherapy fields, or sys-temic chemotherapy. It is now becoming clear that if cancers are


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found at an early stage, local minimally invasive targeted therapysuch as photodynamic therapy may be very successful. This avoidsmutilating surgery and the inevitable normal tissue damage andcomplications associated with other therapies. Clinicians are nowactively seeking and screening for early cancers or pre-cancerouschanges. It is essential that the treatment offered these patients is notworse than the disease itself, which when detected may be causingno symptoms but has the potential to be lethal if progress is not inter-rupted.

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

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clinical aspects of photodynamic therapy

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