The Present and Future Role of PDT

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It is more than 25 years since photodynamic therapy (PDT)

was proposed as a useful tool in oncology, but the

approach is only now being used more widely in the clinic.

The understanding of the biology of PDT has advanced,

and efficient, convenient, and inexpensive systems of light

delivery are now available. Results from well-controlled,randomised phase III trials are also becoming available,

especially for treatment of non-melanoma skin cancer and

Barretts oesophagus, and improved photosensitising

drugs are in development. PDT has several potential

advantages over surgery and radiotherapy: it is

comparatively non-invasive, it can be targeted accurately,

repeated doses can be given without the total-dose

limitations associated with radiotherapy, and the healing

process results in little or no scarring. PDT can usually be

done in an outpatient or day-case setting, is convenient

for the patient, and has no side-effects. Two

photosensitising drugs, porfirmer sodium and temoporfin,

have now been approved for systemic administration, andaminolevulinic acid and methyl aminolevulinate have been

approved for topical use. Here, we review current use of

PDT in oncology and look at its future potential as more

selective photosensitising drugs become available.

Lancet Oncol2004 5: 497508

Photodynamic therapy (PDT) uses the combination of aphotosensitising drug and light (figure 1) to cause selectivedamage to the target tissue. An adequate concentration ofmolecular oxygen is also needed for tissue damage. If anyone of these components is absent, there is no effect, and theoverall effectiveness therefore requires careful planning of

both drug and light dosimetry. The drugs are generally givensystemically, but because the targeting process is mainlyachieved through precise application of the lightusuallyfrom a laser sourcethe effect is local rather than systemic.The local nature of the effect of PDT should be recognisedfrom the outset because it contributes to both thelimitations and the opportunities for PDT as a successfultreatment in cancer.

A limitation of PDT is that it cannot cure advanceddisseminated disease because irradiation of the whole bodywith appropriate doses is not possible (at least with currenttechnologies). Nevertheless, for advanced disease, PDT canimprove quality of life and lengthen survival. For early or

localised disease, PDT can be a selective and curative therapywith many potential advantages over available alternatives.A single treatment can eradicate disease and can have an

excellent cosmetic result (figure 2). Although the clinicalpotential of PDT has been recognised for more than25 years,1 it is only now starting to be used in the clinic.

PDT harnesses the energy of light to damage or destroytarget tissue (see panel). A sensitiser absorbs energy directly

from a light source, which it then transfers to molecularoxygen to create an activated form of oxygen called singletoxygen. It is this singlet oxygen that is the true cytotoxic agentand that reacts rapidly with cellular components2 to cause thedamage that ultimately leads to cell death and tumourdestruction. During this process, the sensitiser is regeneratedso that it acts catalytically, and many cycles of singlet-oxygenproduction can occur for each molecule of sensitiser.

ReviewPhotodynamic therapy

SBB is Yorkshire Cancer Research Professor of Biochemistry, EAB

is Clinical Database Co-ordinator, and IW is a research fellow; all at

the Centre for Photobiology and Photodynamic Therapy, School of

Biochemistry and Microbiology, University of Leeds, UK.

Correspondence: Prof Stanley Brown, Centre for Photobiology and

Photodynamic Therapy, School of Biochemistry and Microbiology,University of Leeds, Leeds, LS2 9JT, UK. Tel: +44 (0)113 233 3166.Fax: +44 (0)113 233 3017. Email: [email protected]

The present and future role of photodynamic

therapy in cancer treatment

Stanley B Brown, Elizabeth A Brown, and Ian Walker

Oncology Vol 5 August 2004 http://oncology.thelancet.com

Figure 1. Red light from a non-coherent lamp activates a topically

applied drug, killing cancer cells.

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Please refer to

the printed

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PDT uses several different mechanisms to destroytumours. A photosensitiser can target tumour cells directly,inducing necrosis or apoptosis.3 Alternatively, by thetargeting of tumour vasculature (or indeed of healthy

surrounding vasculature), the tumour can be starved ofoxygen-carrying blood. Thus, together with inflammatoryand immune responses, damage to the tumour can bemaximised by use of PDT.4

Practical considerationsAt a predetermined time after administration of the drug(called the drug-to-light interval), light is directed into thetumour and surrounding healthy tissue. The tumour isdestroyed rapidly, and any damage to healthy tissue healsover the following 68 weeks.

The targeting and selectivity of PDT is aided by severalfactors, the first of which is the delivery of light. By use ofmodern fibre-optic systems and various types of endoscopy,

light can be targeted accurately to almost any part of thebody. Singlet oxygen generated by the activated photosen-sitiser has a very short life, and is deactivated before it canescape from the cell in which it was produced, furtherassisting targeting.

Some photosensitising drugs can reach higherconcentrations in tumour tissue than in surrounding healthytissue. Although the exact mechanisms that drive thisprocess are not understood fully, the abnormal physiology oftumours (eg, poor lymphatic drainage, leaky vasculature,decreased pH,5 increased number of receptors for low-density lipoprotein, and abnormal stromal composition)might contribute to the selectivity of photosensitisers.6

Furthermore, the healing of healthy tissue after PDT is veryefficient, usually without scarring (figure 2). Even if healthytissue is damaged at the time of treatment, the cosmetic

result after 23 months is usuallyexcellentie, the effect of healing is

itself a type of selectivity.In the past 10 years, substantialadvances have been made in theunderstanding of the behaviour oflight in human tissues7,8 and in thedevelopment of equipment for lightdelivery for PDT. Light of adequatedose can now be delivered precisely tomost tumour sites (both internal andexternal), and PDT is now rarelyrejected because of difficulties indelivery of light. Generally, a lasersource is needed for internal treatmentby use of endoscopy or for interstitial

treamtent because lasers are the mostefficient way of channelling light intoone or more optical fibre. Forcutaneous or subcutaneous lesions, anon-laser source is usually effective.The power of the source is importantbecause it will determine treatmenttimes. However, achievement ofsufficient power is rarely difficult with

modern laser or non-laser sources, which have typicaltreatment times of 520 min.

One of the main advances has been the availability ofdiode lasers, which are small, portable, very reliable, and

inexpensive (about 20 000 or less) compared with earlierlasers for PDT. Diode lasers are ideal for routine use asclinical tools and need little technical expertise for use.However, because their wavelength is fixed and must bespecified for use with a particular photosensitiser, diodelasers are less useful for research in which differentphotosensitising drugs are being assessed. Many non-laserlight sources have also been developed, especially fortreatment of skin lesions. These non-laser sources can beeither various types of filtered lamps or, more recently, light-emitting diodes.9 In all cases, the light field produced needsto be uniform so that the dose delivered can be calculatedprecisely. As with most fixed-cost medical equipment, thereal cost of lasers for PDT depends on the intensity of their

use. A PDT laser that treats only one patient a week isexpensive, whereas the same laser that treats 2030 patients aweek gives a low cost per treatment.

PhotosensitisersSystemic sensitisers

Early preparations of photosensitisers for PDT were basedon a complex mixture of porphyrins called haemato-porphyrin derivative.10,11 Porfimer sodium was the first drug

Review Photodynamic therapy


Figure 2. Patient with Bowens disease before treatment with aminolevulinic acid PDT (A), and

2 months after treatment (B). The single treatment was shown by histological analysis to have

irradicated the lesion, which did not recur. The excellent healing after treatment is apparent.

Mechanisms by which photodynamic therapy harnesses

the energy of light to damage or destroy target tissue

Sensitiser + light Activated sensitiser

Activated sensitiser + oxygen

Sensitiser + activated (singlet) oxygenActivated oxygen + target Oxidised (damaged) target


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to receive approval for PDT and is based onhaematoporphyrin derivative, with some of the non-active

components removed. Although porfimer sodium is acomplex mixture, it is now used widely and remainsthe most common photosensitiser for treatment of non-dermatological tumours. The drug has been approvedfor use in advanced and early-stage lung cancers, superficialgastric cancer, oesophageal adenocarcinoma, cervicalcancer, and bladder cancer (and has been used on atrial basis for many other indications). The advantagesof porfimer sodium are that it: destroys tumourseffectively, is non-toxic in the absence of light, and canbe easily formulated in a water-soluble preparation forintravenous administration. As the first drug productto be approved, porfimer sodium has also highlightedthe fundamental safety and advantages of PDT as a

treatment option for cancer: the drug has been usedin thousands of patients for more than 20 years. Nolong-term safety issues have emerged, and it seems thatPDT can be used repeatedly without limit (ie, there areno lifetime dose limitations, as there can be withradiotherapy).

Despite the continuing effectiveness of porfimersodium, it has several disadvantages that could potentiallybe overcome in subsequent candidate compounds. The druginduces protracted skin photosensitivity,12 and the intialselectivity between tumour tissue and healthy tissue can below.13 Although reasonable selectivity is seen after23 months, this selectivity might be mainly the result of

selective healing of healthy tissue, rather than selective initialdamage by porfimer sodium. Furthermore, the timebetween administration of porfimer sodium and light istypically 4872 h, during which the patient must beprotected from light.

Much chemical and biological research has been doneover the past 20 years to identify new photosensitisers withimproved properties over porfimer sodium. However, mostof this work has been aimed at development ofphotosensitising drugs that are pure chemically and thatabsorb more strongly at longer wavelengths, rather thanplacing a high priority on development of improvedbiological properties. Table 1 shows the typical wavelengthof maximum absorption and the molar-absorption

coefficients for various photosensitising drugs.

With the exception of porfimer sodium, the only otherPDT drug currently approved for systemic use in cancer

treatment is temoporfin(table 1). A mixture of aluminium-sulphonated phthalocyanine has been used widely inRussia, but not in any other country. Temoporfin iseffective for the palliative treatment of head and neckcancer and was approved in Europe for this indication in2001. It is a very active photosensitiser and thus requires amuch lower dose of both the drug and light than doesporfimer sodium.10 Furthermore, temoporfin is a purecompound with a very strong absorption at 652 nm.However, like porfimer sodium, the drug is also associatedwith a pronounced and lengthy generalised skinphotosensitivity and can show little initial selectivity, withthe selective benefits arising later from selective healing ofhealthy tissue. Temoporfin also needs to be administered

up to 96 h before light is applied.Verteporfin (benzoporphyrin derivative) has been

developed for the treatment of macular degeneration(table 1).14,15 Although not indicated for cancer, this drug isone of the most useful ophthalmology drugs ever developedand thus might have lessons for the development of PDTdrugs for cancer. Verteporfin is cleared rapidly and does notinduce a generalised skin photosensitivity that lasts longerthan 24 h. Moreover, treatment with this drug is convenientfor patient and clinician: 10 min intravenous infusion,followed 15 min later by 83 s of laser light (690 nm) at600 mW/cm2.

Sensitisers for topical applicationNone of the systemically administered sensitisers shown intable 1 have been developed for topical application to treatskin lesions, despite many attempts. Furthermore,achievement of effective PDT through the injection ofphotosensitisers directly into the lesion has beenunsuccessful. In both cases, delivery of photosensitisers intosensitive subcellular sites, through binding to serumproteins, seems necessary for effective PDT.

All nucleated cells in the body contain the biochemicalapparatus needed to make haem for cytochromes andother haemoproteins (figure 3). The immediate precursorof haem (which is not a photosensitiser), isprotoporphyrin IX, which is a powerful photosensitiser.

The concentration of porphyrin that will support PDT can



Table 1. Types of photosensitising drugs

Class Approved drugs for photodynamic therapy Typical maximum Typical absorption

absorption (nm) coefficient*

Porphyrins Porfimer sodium 630 10 000

Protoporphyrin IX (eg, from methyl aminolevulinate

and aminolevulinic acid) 633 10 000

Chlorins Verteporfin (benzoporphyrin derivative) 690 35 000

Temoporfin (meta-tetrahydroxyphenylchlorin) 652 30 000

Bacteriochlorins None yet approved 740 32 000

Phthalocyanines Sulphonated aluminium phthalocyanine mixture

(approved in Russia) 680 110 000

Phenothiazinium compounds None yet approved 670 60 000

Texafrins None yet approved 734 42 000

*Absorption of light cm1 mol1 L1.


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be achieved by topical application of either aminolevulinicacid or methyl aminolevulinate to the site of a skin canceror precancerous lesion. This finding has led to approval ofaminolevulinic acid in the USA, and of methyl amino-levulinate in Europe.

PDT in clinical practiceThousands of patients have been given PDT over the past20 years but most trials have involved only a few patients,commonly have provided anecdotal data, and have not been

sufficiently convincing to persuade medical practitionersand health-service providers of the benefits of PDT asstandard treatment. This situation has partly been caused bydifficulties in establishing the optimum treatmentconditions for an approach that requires the setting ofseveral variables (ie, drug and light dose, and drug-to-lightinterval), as well as difficulties in skin photosensitivity andlow selectivity. However, greatly improved understanding ofthe tissue and cellular factors that control PDT4,16 andincreased experience in the clinic has led to much larger,better-controlled clinical trials and the approval of fourPDT drugs for cancer (table 2).

Hopper1 presented a comprehensive account of clinicaltrials on PDT up to 2000; several of which have contributed

to the approval of the drugs outlined in table 2. Table 3shows the scope of these trials. Here, we discuss subsequentand continuing clinical trials, and assesses the future of PDTin clinical practice.

Treatment of skin cancer

The very high incidence of skin cancer and the striking

rates of increase in white populations (up to 5% per year)17

place an increasing burden on both patients and healthservices. PDT already plays a substantial part in treatmentof non-melanoma skin cancer and will expand with newtrials and with approval of aminolevulinic acid fortreatment of actinic keratinosis in the USA, and of methylaminolevulinate for actinic keratinosis and basal-cellcarcinoma in Europe. Use of PDT for melanoma has not

yet been pursued substantially in any study partly becauseof the difficulty in achieving good penetration of lightthrough pigmented lesions, and partly because of ethicalconsiderations about the aggressive nature of the disease.

Non-melanoma skin cancer is very common andincludes both superficial and nodular basal-cell carcinoma,

superficial squamous-cell carcinoma, squamous-cellcarcinoma, and Bowens disease (squamous-cell carcinomain situ). Actinic (solar) keratoses are potentiallyprecancerous lesions that can progress to squamous-cellcarcinoma. Non-melanoma skin cancer is not usually life-threatening because it rarely metastasises and is treatedreadily. However, the treatment options have beenassociated with morbidity effects (eg, scarring), and thedrugs can be expensive (especially in view of the demandson the time of dermatologists and plastic surgeons). PDThas the potential to substantially decrease morbidity effectsand improve health economics.18

Intravenous administration of porfimer sodium19 or

temoporfin20,21

is effective in treatment of cutaneouslesions. However, systemic administration of these drugs isunlikely to be justified for large-scale treatment of localdisease (with the corresponding long periods ofphotosensitivity).

By contrast, use of PDT with topical applications ofeither aminolevulinic acid or methyl aminolevulinate issimple and convenient, without substantial systemic toxiceffects. A cream or solution that contains either drug isapplied to the lesion and secured under a dressing.Aminolevulinic acid is licensed in the USA for applicationas a solution for 1418 h, but in Europe (where the drug isunlicensed but widely used) it is usually applied as a creamfor 46 h. Methyl aminolevulinate is applied as a cream for

34 h, during which photosensitivity is generated. Thelicence given by the US Food and Drug Administration foruse of aminolevulinic acid requires use of blue light.However, red light is generally used in Europe to improve



Table 2. Approved photodynamic-therapy drugs for oncological indications

Chemical name Generic name Date and country of approval Indications

Haematoporphyrin derivative, Porfimer sodium First approved in 1995; now approved Advanced and early lung cancer,

polyhaematoporphyrin in more than 40 countries superficial gastric cancer,

oesophageal adenocarcinoma,

cervical cancer, and bladder cancer

Methyl-tetrahydroxyphenyl Temoporfin Approved in 2001 in European Union, Palliat ive head and neck cancer

chlorin Norway, and Iceland

5-aminolevulinic acid Aminolevulinic acid Approved in 1999 in USA Actinic keratosis

Methyl 5-aminolevulinate Methyl aminolevulinate Approved in 2001 in Europe Actinic keratosis, superficial basal-cell

carcinoma, and basal-cell carcinoma

OH

O

O

NH

NH

N

N

OH OOH O

Light

Protoporphyrin IX

H2N

Aminolevulinic acid

Porphobilinogen

Haem

Intermediate

products

Figure 3. A simplified scheme of the haem biosynthetic pathway. After

the accumulation of porphyrin, light of an appropriate wavelength(633 nm) can be administered to obtain a therapeutic response.


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penetration. Methyl aminolevulinate is always used withred light. The site of the lesion is usually irradiated for520 min. During the initial period of irradiation, the

patient might feel some discomfort or pain at the site. Thisdiscomfort does not usually need intervention, but localanaesthetic can be given if required.

Clinical use of aminolevulinic acid in non-melanomaskin cancer has been reviewed in the guidelines produced bythe British Photodermatology Group in 2002.18 At present,this unlicensed drug is available in Europe, but it is notknown how long this situation will be sustained.

The registration of aminolevulinic acid in the USA wasbased on two randomised, placebo-controlled investigator-blinded phase III trials that had identical designs (table 4).22,23

Patients with multiple actinic keratoses of the face and scalpwere randomly assigned either 20% aminolevulinic acid in

hydroalcoholic topical solution or vehicle (hydroalcoholictopical solution) only, followed by irradiation with blue light(417 nm, 10 mW/cm2 to a total fluence of 10 J/cm2). In oneof the trials (n=241),22 72% of patients in the treatmentgroup had a complete response, compared with 20% ofthose assigned placebo. The overall recurrence rate was 50%for the treatment group and 279% for placebo. In the othertrial (n=243),23 a complete response in the treatment groupwas seen in 128 of 166 patients (77%) at week 8 and in 133 of149 patients (89%) at week 12. In the group assigned vehicleonly, ten of 55 patients (18%) responded at week 8, andseven of 52 patients (13%) by week 12 (p0001 for bothgroups). These data thus confirmed that PDT withaminolevulinic acid is a safe and effective treatment for

actinic keratinosis.The development and approval of methyl amino-

levulinate has led to a licensed product for topical PDT forsuperficial and nodular basal-cell carcinomas, as well as foractinic keratinoses. Results from trials involving more than2500 patients in 14 countries have shown that this drug issafe and effective, with excellent cosmetic results.36 Afteradministration of methyl aminolevulinate, porphyrinaccumulates more in skin tumours than in healthy skin(figure 4). PDT with methyl aminolevulinate has beencompared with cryotherapy for superficial basal-cell carci-noma, and with excision surgery for nodular basal-cellcarcinoma, and with and . In one study,37 60 patients were

randomly assigned to PDT with methyl aminolevulinateand 58 patients to two freeze-thaw cycles of cryotherapy.Complete-response rates at 3 months were similar for both

groups (97% for PDT versus 95% for cryotherapy), but therate of recurrence at 12 months was less for the PDT group(8%) than for the cryotherapy group (16%). However, the

cosmetic outcome was more favourable for the groupassigned methyl aminolevulinate.

PDT with methyl aminolevulinate has also beencompared with cryotherapy in two randomised controlledstudies involving about 400 patients with actinickeratinoses.24,25 The results showed that one application ofmethyl aminolevulinate was equally as effective ascryotherapy, and that two applications were more effectivethan cryotherapy. In all cases, cosmetic outcome andsatisfaction were more favourable in the groups assignedmethyl aminolevulinate than in those assigned cryotherapy.

Gorlins syndrome is a rare disease in which patients areprone to develop several lesions of basal-cell carcinoma.

Although the number of patients is small, PDT withaminolevulinic acid has been used to treat patients with thisdisease,38 and leads to excellent healing and lack of scarring.Thus, topical PDT by use of licensed drugs seems set to havea major role in future routine treatment of non-melanomaskin cancer.

Localised disease and precancerous lesions

With the exception of skin cancer, PDT has so far not beenused widely for early or localised cancer, or for premalignantdisease. This finding is surprising, since PDT is a localtechnique and could potentially be curative. This situationcould change along with improvements in the availability ofscreening techniques to enable early detection of disease, and

the probable development of improved PDT drugs that donot have long-term skin photosensitivity or long drug-to-light intervals. Table 5 shows clinical trials involving morethan ten patients done since 2000 on PDT for treatment oflocalised disease.

Barretts oesophagus

This disease, widely regarded as a precursor ofadenocarcinoma of the oesophagus, is increasing in incidenceand is one of the most promising targets for use of PDT inearly disease. Trials of PDT with systemic (oral)aminolevulinic acid have shown encouraging results, withregeneration of healthy epithelium.4751 Most trials have been

small and non-randomised; however, in a prospectivedouble-blinded study by Ackroyd and co-workers39

36 patients with dysplastic Barretts oesophagus who were



Table 3. Summary of photodynamic therapy clinical trials up to 20001

Tumour type Photosensitisers Trials Patients (range)Premal ignant tumours (eg, Barretts oesophagus, Porfimer sodium, aminolevul inic acid, temoporfin, 8 5100

oral cavity, bladder) haematoporphyrin derivative

Cutaneous malignant tumours (eg, non-melanoma Porfimer sodium, aminolevulinic acid, temoporfin 9 16151

skin cancer, chest-wall recurrence of breast cancer)

Tumours of the head, neck, and oral cavity Porfimer sodium, temoporfin 7 14108

Lung, gastrointestinal, and other tumours Porfimer sodium, temoporfin 13 21218

Tumours managed with intraoperative and Porfimer sodium, temoporfin 4 554

adjunctive treatments (eg, pituitary)

Interstitial application (eg, pancreatic) Porfimer sodium, temoporfin 2 926


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receiving acid suppression with omeprazole were randomlyassigned either PDT with 30 mg/kg oral aminolevulinic acidplus laser endoscopy, or placebo plus laser endoscopy. In thegroup assigned aminolevulinic acid, 16 of 18 patientsresponded, with a median decrease in the area of Barrettsmucosa of 30% (range 060%). In the group assignedplacebo, a 10% decrease in area was seen in only two of18 patients. No dysplasia was seen in the treated area of anypatient in the PDT group, but persistent low-grade dysplasia

was seen in 12 patients (p


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sample taken at 2-cm intervals forsurveillance of disease progression.

A maximum of three courses of PDTwere given at least 90 days apart. At aminimum follow-up of 24 months,768% of patients in the PDT groupshowed ablation of all areas of high-grade dysplasia, compared with 386%of patients in the control group(p


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have a short drug-to-light interval to facilitate a single

treatment in the outpatient or day-patient clinic.

Advanced cancer

PTD has been used for various indications in which a cure isnot feasible, but where survival can be lengthened andquality of life improved. These indications are the mainnon-dermatological disorders for which licensed drugs areapproved. In advanced disease, the intrinsic advantages ofPDT are minimum invasiveness and that it does not restrictthe use of other subsequent treatments, includingretreatment with PDT. However, the imposition on apatient of a sustained skin photosensitivity should beweighed against the advantages PDT treatment has onquality of life. Table 6 shows the details of trials on use of

PDT for advanced cancer.

Lung cancer

Porfimer sodium is licensed for the reduction ofobstruction and palliation of symptoms for patients withcompletely or partially obstructing endobronchial non-small-cell lung cancer. Palliation is necessary becausepatients can die from obstruction of the airway before theysuccumb to the metastasising tumour.77 By maintainance ofthe airway, quality of life and survival can be improved.Trials in our group78 and elsewhere,6 with many patients(table 6), have shown clearly the benefits of PDT in terms ofquality of life and survival. Compared with alternatives,

PDT is easy to use, which is particularly beneficial fortreatment of smaller bronchi.79 However, there are alsofactors that have limited the use of PDT for advanced lung

cancer. The debulking of tumour and subsequent relief of

dyspnoea takes longer after PDT than after laser treatmentwith neodynium yttrium-aluminium-garnet (NdYAG),making PDT less suitable for patients with acute respiratorydistress.79 Another disadvantage of PDT with porfimersodium could be the apparent high cost (in excess of 1500per treatment for a patient who weights 75 kg), althoughalternative treatment methods might approach or exceedthis amount when calculated properly. Despite theselimitations, a review and meta-analysis80 of all relevantclinical trials concluded that bronchoscopic PDT wasbeneficial in the treatment of selected patients withadvanced lung cancer. Almost all the 636 patients treatedhad relief of symptoms, including improved ventilatoryfunction and relief of dyspnoea, with few adverse events.

Carcinoma of the oesophagus

Porfimer sodium is also licensed for palliation of patients withcompletely obstructing oesophageal cancer, or for patientswith partial obstruction of the oesophagus who cannot betreated satisfactorily with NdYAG laser therapy.1 Althoughpalliative control of obstruction is often necessary, survivalcan be short, and whether use of drugs that cause lengthenedskin photosensitivity (such as porfimer sodium andtemoporfin) is justified is debatable. This disorder is thusanother indication in which improved drugs with little or noskin photosensitivity could have a role.

Head and neck cancerTemoporfin was licensed in the European Union, Norway,and Iceland in 2001 as a local treatment for patients with



Table 5. Selected trials for localised cancer or precancerous conditions, 2000February, 2004

Condition Photosensitisers Treatment Trial type Patients Ref

Carcinoma of the lip Temoporfin Temoporfin (015 mg/kg) 96 h before Non-randomised phase II trial 25 20

20 J/cm2 light (652 nm)

Barretts oesophagus Aminolevulinic acid 30 mg/kg oral aminolevulinic acid Randomised, double blind, 36 39

or placebo 4 h before laser placebo controlled trial

endoscopy. Total light dose

60 J/cm2 (514 nm)

Barretts oesophagus Porfimer sodium 2 mg/kg porfimer sodium 4872 h Multicentre, partially blinded 208 40

before laser treatment (630 nm) randomised study

Cervical intraepithelial Aminolevulinic acid Topical application of 3% Randomised, double blind, 25 41

neoplasia aminolevulinic acid gel to cervix for placebo controlled trial

3 h, followed by 100 J/cm2 635 nm

laser light

Cervical intraepithelial Aminolevulinic acid Topical aminolevulinic acid Phase I/II trial 40 42

neoplasia (200 mg/mL) for 90 min before

50150 J/cm2 light (630 nm)

Dysplasia and early Porfimer sodium Porfimer sodium alone vs porfimer Randomised controlled trial 60 43cancer in Barretts sodium with oral prednisone, followed

oesophagus by 630 nm light

Barrett's oesophagus Aminolevulinic acid 30 mg/kg oral aminolevulinic Phase II trial 40 44

acid 4 h before laser endoscopy

Vulval intraepithelial Aminoleuvilinic acid 10 g of 10% aminolevulinic acid Phase II trial 15 45

neoplasia topically applied 23 h before

illumination. Light dose 120 J/cm2

(635 nm)

Vulval intraepithelial Aminolevulinic acid Topical aminolevulinic acid (20%) Phase II trial 25 46

neoplasia before treatment with laser light

at 100 J/cm2 (635 nm)


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advanced head and neck cancer who did not respond toprevious therapies, and who were unsuitable forradiotherapy or chemotherapy. PDT is an attractive optionfor treatment of cancers of the head and neck because of thegood cosmesis achieved and the accurate localisation oftherapy, limiting damage to organs in the head.61

Other applicationsSeveral other indications in advanced cancer, such as such asnon-resectable cholangiocarcinoma, have been investigated

in PDT trials, although approval for the drugs used has notyet been obtained.62 Data from a prospective randomisedcontrolled trial on non-resectable cholangiocarcinomashowed that PDT used in conjunction with plastic stentsimproved quality of life and survival, with a low rate ofadverse side-effects. Patients assigned PDT with porfimersodium had decreased serum concentrations of bilirubin,

increased scores in physical function, and decreasedsymptoms. The beneficial effects of PDT on the first39 patients enrolled in the trial were so great that it was



Table 6. Selected trials on photodynamic therapy for advanced cancer, 2000February, 2004

Tumour type Photosensitiser Treatment Trial Patients Ref

Brain Temoporfin Temoporfin (015 mg/kg) 96 h Phase II trial 25 61

before treatment. Light dose

20140 J/cm2 (652 nm)

Non-resectable Porfimer sodium Pat ients randomly assigned stent ing and Randomised prospective study 39 62

cholangiocarcinoma porfimer sodium (20 mg/kg) or stenting

alone. 48 h drug-to-light interval.

Light dose 180 J/cm2 (630 nm)

Mesothelioma Temoporfin Generally, 01 mg/kg temoporfin Phase I trial 26 63

6 days before surgery. Light dose

10 J/cm2 (652 nm)

Lung Haematoporphyrin Oral aminolevulinic acid (60 mg/kg), Non-randomised study 40 64

derivative and with 68 h drug-to-light interval

aminolevulinic acid (16 patients). Intravenous haematoporphyrin

derivative (2 mg/kg), with 48 h drug-to-light

interval (24 patients). Laser-light dose

100 J/cm2 (630 nm) for both groups

Lung Haematoporphyrin 2 mg/kg given intravenously 48 h before Prospective phase I/II trial to 30 65

derivative illumination. Light dose 300 J/cm2 determine effect of hyperbaric

oxygen

Lung or bronchus Haematoporphyrin 2 mg/kg given intravenously 48 h before Prospective, non-randomised 40 66

derivative illumination. Light dose 300 J/cm2 pilot study to determine effect of

hyperbaric oxygen

Head and neck Temoporfin Temoporfin 96 h before light interval, Retrospective study 25 67

followed by irradiation with 652 nm laser

light (20 J/cm2)

Head and neck Temoporfin Temoporfin 96 h before light interval, Prospective phase I/II trial 25 68

followed by irradiation with 652 nm laser

light (20 J/cm2).

Mean follow-up of 37 months

Intraperitoneal Porfimer sodium 25 mg/kg, with 48 h drug-to-light interval. Phase II trial 12 69

Intraperitoneal tumours resected and

analysed for presence of porfimer sodium

Intraperitoneal Porfimer sodium 25 mg/kg 48 h before treatment. Laser Phase II trial 56 70

light delivered to all intraperitoneal surfaces

Intraperitoneal Porfimer sodium 25 mg/kg 48 h before treatment (532 nm Phase II trial 11 71

or 630 nm light used)

Intraper itoneal Porfimer sodium 25 mg/kg 48 h before t reatment (630 nm Phase II t rial to invest igate systemic 65 72

laser light used) capillary leak syndrome, which

occurs after combination of surgery

and photodynamic therapy

Prostate Temoporfin 015 mg/kg 96 h before treatment Phase III trial 14 73

(652 nm laser, 100150 mW)

Oesophagus Aminolevulinic acid 60 mg/kg oral aminolevulinic acid 68 h Non-randomised 49 74

vs haematoporphyrin before illumination (22 patients); 2 mg/kg

derivative intravenous haematoporphyrin derivative

48 h before illumination (27 patients).

Light dose 300 J/cm2 of 630 nm laser light

Oesophagus Porfimer sodium 1520 mg/kg 48 h drug-to-light interval Non-randomised 77 75

before 630 nm laser light (300400 J/cm2)

Hilar bile-duct Porfimer sodium 20 mg/kg 14 days before treatment with Phase II trial 23 76

light (630 nm, 242 J/cm2)


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deemed unethical to continue with the randomisationprocedure. Use of PDT with temporforin in pancreatic

cancer is under development by Bown and colleagues81

toprovide an alternative treatment for this aggressive disease,which is commonly unresponsive to chemotherapy orradiotherapy. Other indications in which PDT is beingassessed include mesothelioma,63,82 and intraperitonealtumours.83,84

Why is PDT not a mainstream therapy inoncology, and what is its future?It is more than 25 years since PDT was first used inoncology. Since then, thousands of patients have beentreated. The approach has progressed slowly but surely, andfour drugs have now been licensed for general use. In somespecialties of medicine (eg, dermatological oncology and

ophthalmology), PDT is used widely; however, in otherspecialties its use remains marginal. Why has PDT notachieved a more sustained entry to the therapeutic scene inoncology, and will it become mainstream in future?

There are many answers to the first question, includingthe difficulty in the establishment of the optimum variablesfor a treatment that has several components, clinician andhospital resistance to a new approach, the capital cost ofsetting up a PDT centre, and the previous lack of inexpensiveand convenient light sources. However, the main answermust be that the existing combinations of drugs and lightsources in the applications in which they have been usedhave not established clear advantages over alternatives in

large controlled comparative randomised clinical trials. Thissituation is probably because the drugs have been effective inestablishing the viability and feasibility of PDT, but have notbeen optimum in terms of effectiveness. The development ofPDT could be compared with that of radiotherapy, whichhas been used for more than 50 years but is only nowapproaching optimum use. The competitive situation forPDT is even more acute because of the very existence ofradiotherapy.

The effectiveness of PDT with verteprofin for treatmentof macular degeneration (which does not lead to lengthenedskin photosensitivity, is selective, and has a very short drug-to-light interval) points the way to similar success inoncology. To date, most sensitiser development for cancer

treatment seems to have been driven chemically, rather thanbiologically or clinically, with a focus on improved opticalproperties: focus is needed on soving the problems of earlysensitisersie, sustained skin photosensitivity, lowselectivity, and inconveniently long drug-to-light intervals.Modification of the photosensitising moiety through itsphysicochemical properties or improved targeting byconjugation of the photosensitiser to moieties such asantibodies, polymers,85,86 and peptide scaffolds, mightovercome the present difficulties.87

In dermatological oncology, PDT is already a routinetreatment, and its use will continue to increase. For internallesions, inexpensive and convenient light sources are now

available. However, improved drugs that are more selectiveand that can be used conveniently and without sustainedskin photosensitivity are needed. If such drugs can be

developed, then the advantages of PDT in terms ofminimum invasion in the body, patient and practitionerconvenience, and health economics will ensure a substantial

future role for this type of treatment in oncology.

Conflict of interest

SBB is a consultant and minority shareholder in Photopharmica Ltd, acompany formed under the auspices of the University of Leeds, UK,which is involved in development of new-generation photosensitisers,for which SBB is named on several patent applications. These drugs arein the early stage of preclinical development in oncology and are notmentioned in the manuscript.

Acknowledgments

We thank Colin Hopper, Hugh Barr, and Colin Morton for advice andinformation about recent clinical trials. We thank Even Angell-Petersonfor permission to use figure 4 and Yorkshire Cancer Research, UK, forfinancial support.

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Search strategy and selection criteria

Published data up to 2000 were reviewed in a previous article in

The Lancet Oncology. More recent publications were identifiedby extensive searching of PubMed, Web of Science, and our

own reference base. Search terms included combinations of:

Photofrin, photodynamic therapy, PDT, 5-aminolaevulinic

acid, ALA, methyl 5-aminolaevulinate, MAL, Foscan,

porfimer sodium, temoporfin, and Metvix. Selection of

material focused on clinical applications that use recently

licensed drugs. Trials included in tables 46 were published

between 2000 and February, 2004, and included more than ten

patients.


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The Present and Future Role of PDT