British Journal of Plastic Surgery (1995), 48, 360-370 © 1995The British Association of Plastic Surgeons
BRITISH
JOURNAL
PLASTIC
OF
SURGERY
Photodynamic therapy of primary skin cancer: a review D. J. H. Roberts and F. Cairnduff
Centre for Photobiology and Photodynamic Therapy, UniversiO, o.f Leeds, Leeds, UK S U M M A R Y . The role of photodynamic therapy (PDT) in the treatment of primary non-melanoma skin cancer is examined. Prolonged systemic skin photosensitivity limits the usefulness of PDT using conventional photosensitisers such as Photofrin®-II. However in exceptional circumstances, such as multiple or widespread basal cell carcinomas, this therapy provides a useful and seemingly effective alternative mode of treatment. For Bowen's disease, PDT using topical 5-aminolaevulinic acid (ALA) yields high response rates and excellent cosmetic results. For large lesions and those in anatomically difficult sites or in poorly vascularised skin, ALA-based PDT can be considered the treatment of choice. Recent pharmacological and technological developments may further enhance the efficacy and convenience of photodynamic therapy, and make it more generally available in non-specialist centres.
A brief history of PDT
Photodynamic therapy (PDT) represents a new approach to the treatment of a number of malignant and non-malignant conditions and is currently undergoing Phase III trials for the treatment of lung, stomach, superficial bladder, cervical, and oesophageal cancers, and as an adjunct to resection in colo-rectal cancer. 1'2 In addition, it has been the subject of a much larger number of Phase I/II trials for diseases as diverse as alopecia, Barrett's oesophagus, psoriasis, mesothelioma and menorrhagia. In 1993, the Canadian government became the first to officially recognise P D T as a clinically useful (rather than experimental) therapeutic modality by granting approval for its use in the prophylaxis of papillary bladder cancer. Further approvals followed in 1994 in Canada, Europe and Japan. PDT has been extensively investigated for the treatment of primary skin cancers. Here, we will review this application of PDT in detail and, in particular, will examine critically whether PDT really does offer a useful alternative therapy for this group of diseases. Primary melanomas will not be considered because PDT is not a viable treatment for such lesions. In principle, PDT is very simple. An inactive drug, a photosensitiser, is administered to the patient by one of several routes and is allowed to accumulate in the tissue to be treated before being activated by the local application of visible light. The activated sensitiser reacts with molecular oxygen to produce highly reactive oxygen species which are ultimately responsible for the death of the treated tissue. In reality, however, this apparent simplicity is underlain by considerable biological, physical and, all too often, practical complexities, some of which we will consider further below. We will also look briefly at recent pharmacological and technological advances which may improve the performance of this novel modality and make it more accessible to non-specialist centres.
As noted by Daniell and Hill, :3the deepest foundations of P D T are to be found in ancient Greece, where the healing properties of light were first documented and where, under the auspices of the physician Herodotus, heliotherapy was born. However, the first experiments of the modern era were performed by a German medical student, Oscar Raab, who showed that acridine orange can lethally photosensitise Paramecia. ~ Shortly afterwards, Raab's Professor, Herman von Tappeiner, and a dermatologist, A. Jesionek, became the first to publish a clinical study of PDT s in which they showed that topically applied eosin activated by sunlight or an arc lamp could be an effective treatment for skin cancer. However, aside from a small confirmatory study, ~ it was then over 60 years before PDT was used to treat malignant disease again. In 1966, Lipson et al. T used haematoporphyrin derivative (HpD), a complex mixture of porphyrins derived from blood, as a photosensitiser for the photodynamic therapy of a single chest wall recurrence of breast cancer. Although a response was noted, the lesion was not cured and no further PDT was attempted. A similar single-case study, this time of bladder cancer treated with HpD and light, appeared in 19758 but it was not until 1976 that the first systematic clinical studies of PDT were initiated by Dougherty and colleagues at the Roswell Park Cancer Institute in Buffalo, U S A ? -t" This heralded an explosion of interest in P D T and over 10000 papers on the subject have now been published.
The mechanisms of PDT Figure 1 shows a patient undergoing photodynamic therapy for several areas of Bowen's disease (intra360
P h o t o d y n a m i c therapy o f primary skin cancer
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Figure I - - A 91-year-old woman being treated with topical ALA-PDT for several areas of Bowen's disease on the forehead. The patient had not received any prior treatment for these lesions. Light is being delivered from an ultra-high pressure xenon arc-based PDT illuminator. developed by the Laser Oncology Group, CRC Paterson Laboratories, Manchester) T M Figure 2 - - Examples of Bowen's disease before (A.
362 epidermal squamous cell carcinoma hi situ) located on the forehead. The three essential components of PDT, a photosensitiser, light and molecular oxygen in the tissue have been brought together and events that will lead to the death of the tumour cells are under way. These events may take the form of interactions between the highly reactive oxygen species generated by PDT and various components of the cells in which these species are formed. ~3-~8 The cellular damage induced in this way leads directly to tumour cell death. However, PDT also has marked effects on the vascular supply of tumours, causing rapid occlusion of the tumour vessels (and possibly those of the surrounding normal tissues) and depriving the tumour cells of nutrients and oxygenJ ~-'2 The relative importance of direct and indirect killing by PDT under different circumstances remains the subject of intense research. ~-'~
Practical considerations
Of the three essential components of PDT mentioned above, two, the photosensitiser and the tumour illumination, are major day-to-day considerations in tl~e clinical use of the treatment. In contrast, attempts at improving the effectiveness of PDT by manipulating tumour oxygen content have been made experimentally -~--~6but these have met with only limited success and, as yet, have no place in clinical PDT.
British Journal of Plastic Surgery
2. 5-amhwlaet, ulhTic acid/protoporphyrin IX. One of the most problematic aspects of PDT using HpD or P-II is that these agents exhibit a relatively slow rate of clearance from the skin. "-'N Consequently, patients receiving either drug systemically are rendered photosensitive and must remain out of sunlight or strong artificial light for 6 to 10 weeks after treatment to avoid severe sunburn. This problem seriously reduces the acceptability of this form of therapy, especially when other treatments are available and when the aim of the therapy is palliation rather than cure. A novel solution to this problem was first introduced by Kennedy et al. 45 Kennedy's technique exploits the haem biosynthesis pathway, and, in particular, the species immediately preceding haem, protoporphyrin IX (PplX). This compound, which appears to be an efficient photosensitiser, is not normally present within tissue at therapeutically useful concentrations. However, subverting the haem-dependent negative feedback control of the pathway can increase the intracellular concentration of PplX to potentially useful levels. This is achieved by the administration of 5aminolaevulinic acid (ALA), the first precursor of haem after the feedback control point. Because the resulting accumulation of PplX is relatively shortlived, any skin photosensitivity which may occur is resolved by 24 hours post-treatment. In addition, ALA can be applied to skin lesions topically (see below), completely eliminating generalised photosensitisation. Like HpD and P-II, PplX is usually activated with 630 nm light for PDT.
Photosensitisers 1. Haematoporphyrhl derivative and PhotofrhT¢-H. The most frequently used photosensitisers have been HpD and its more purified successor Photofrin'~-II (P-I'I; generic name: porfimer sodium). These materials are mixtures of non-metallic oligomeric porphyrins, containing up to eight porphyrin units per oligomer. 2;-2~ Initially, it was thought that such materials show specific uptake or retention by tumour tissue, :~°-:33holding out the promise of effective tumour killing with little or no collateral tissue damage. More recently, it has become clear that many normal tissues, especially those of the reticuloendothelial system, have a greater avidity for these agents than tumour tissue 3~-38 and that selectivity based on drug uptake or retention is often minimal. The development of photosensitisers with greater tumour-specificity is currently a major goal of PDT research. Drugs such as HpD and P-II are usually activated using light at 630 nm. Ironically, this wavelength coincides with the smallest of all the absorption peaks of these drugs. However, although lower wavelengths offer the potential of much greater light absorption by the sensitiser, tissue penetration by light decreases dramatically as the wavelength is reduced? "'4° It is for this reason that strenuous efforts are being made to develop new photosensitisers with strong absorption characteristics at wavelengths of 650 nm and upwards.
3. Others. Although most PDT for primary skin cancer to date has relied on the use of HpD, P-II or A L A , there are a number of other photosensitisers currently under development which may prove useful in the future. For skin cancer, one of the most interesting of these is benzoporphyrin derivative mono acid (BPD). 48 This agent combines a large absorption peak near 690 nm with just 3 to 5 days of cutaneous sensitivity following systemic administration, both major advances on P-II. In addition, as is the case with ALA-PDT, both drug and light can be given on the same day, whereas P-II therapy usually requires a 24 to 48 hour drug-to-light interval. Other promising sensitisers include m-tetrahydroxyphenylchlorin (mTHPC), ~ which is usually activated by light at 652 nm, and chlorin e~ aspartate ester (MACE) which absorbs near 660 nm. 48
Light sources 1. Lasers. Most pre-clinical and clinical studies of P D T to date have relied on laser sources to provide the light needed to activate the photosensitiser (for review, see reference 49). Unlike the output of conventional light sources, laser beams can be launched into single optical fibres very easily, enabling light to be delivered directly into large tumours via implanted applicators. ~°
C), 6 months (B) and 12 months (D) after topical ALA-basedPDT. The patient was a 75-year-oldwoman with multiple areas of disease. In view of her frailty, poor skin quality and the widespread nature of her disease, she had been referreddirectly ['orPDT and had not received any prior treatment.
Photodynamic therapy of primary skin cancer This also makes internal tumours that can be viewed endoscopically readily accessible to PDT. Such considerations are, however, of little importance for the treatment of primary skin mahgnancies, which are always treated by superficial illunaination (i.e. light is shone onto the lesion from above, as in Figure I, rather than being delivered into the lesion by a fibreoptic applicator) and which are always relatively easily accessible. The most popular lasers for PDT have been argon ion- and copper vapour-punaped dye laser systems. Such systems can be temperamental, are relatively expensive (many tens of thousands of pounds), require specialist support staff and are extremely bulky but they can produce 1-3 W of red light for use in PDT. In addition, their emission wavelength can be tuned within relatively wide limits, allowing the illumination to be precisely matched to one of the absorption peaks of the photosensitiser. However, it seems likely that such systems will eventually be displaced by laser diode arrays. These devices are very convenient, being easily carried, requiring only a single-phase supply, and having a minimal warm-up time (in contrast, a Cu-vapour laser needs 1 to 2 hours to warm up and half an hour to cool down). 3-4 W of light can be had at wavelengths between 670 and 690 nm and, compared to argon iota- and copper-pumped lasers, laser diode array-based systems are also relatively inexpensive. On the other hand, they are only tunable within narrow limits and versions suitable for PDT producing light in the 630 nm region are as yet unavailable. The prospect of new photosensitisers absorbing at longer wavelengths combined with powerful, convenient laser diode arrays is, however, a most exciting one. 2. Incoherent sources. Although their emission charac-
teristics make lasers the ideal source for PDT, their expense, inconvenience and support requirements have led to the use ofalternative light sources. This has been especially true in the treatment of primary skin cancer with ALA-based PDT, where the treatment parameters employed have been determined on a largely empirical basis and where the consequences of overdosing with light have been perceived as relatively insignificant. Most non-laser sources used to date have been built around commercially available incandescent or arc lamps. The most popular source has been the filtered slide projector in which light below about 600 nm is excluded, although unfiltered, white light versions have also been employed. More recently, however, attempts have been made to design sources with reasonably high output powers in relatively narrow wavelength bandwidths. Whitehurst et al., 51"5'-' for example, have described a highly portable short-arc xenon lamp producing 1-1.5 W of light in a 30 nm bandwidth centred on 630 nm. Indeed, the output of this source appears to be easily tunable over the range 400-1200 nm without any adverse effects on output power, thereby allowing its use with all the photosensitisers currently available or under development. Such devices, whether broad- or narrow-band, are likely to widen the acceptance of PDT for the
363 treatment of conditions such as primary non-melanoma skin cancer, as they can in effect turn these treatments into office procedures that can be undertaken with little training and without the costs of highly trained support staff.
PDT in the treatment of primary skin cancer
We have considered in some detail the drugs and light sources needed to undertake clinical PDT. However, the question remains as to just how effective this type of therapy is in the treatment of primary skin malignancies. Unfortunately. the literature in this area is littered with a large number of poor quality reports of very limited studies. Here, we have considered only the more complete reports although, as can be seen in Tables 1 and 3. even these do not, in general, provide the long-term follow-up data that are available for other treatment modalities. 1. H p D and P-H
The results of studies using PDT based on HpD, P-II and a similar material, Photosan-Ill, are summarised in Table I. Eight trials of PDT for basal cell carcinoma (BCC), four for Bowen's disease and four for invasive squamous cell carcinoma (SCC) are represented in these twelve studies. In all cases, the photosensitiser was given intravenously. There is considerable disparity in the findings of the eight trials involving BCC. Keller et al.,"" for example, observed 100% complete response (CR) which was maintained for 4 years. Similarly, Dougherty et al. 5:~ observed a 100% CR when assessments were done at 7-12 months after treatment. On the other hand, Pennington et al. ~: reported just 52 % initial CR with all lesions recurring within 6 months and Buchanan et al. '~:' observed 60 % initial CR (40 % partial response) followed by a 40% rate of recurrence. Similarly, Hintschich et al. '~' found that 100 % initial CR became 48 % recurrence within 3-20 months. Based on these response rates alone, it might be concluded that this form of PDT is either (i) a promising new treatment for BCC or (ii) such a poor treatment for this condition that to offer it would be ethically unacceptable. Indeed, it is the latter view that was adopted by Pennington et al?: when they cancelled their trial on ethical grounds. The reasons for this wide spread in the findings of different groups are far from clear. The very poor results of Pennington et al. ~ can probably be ascribed to the low dose of light employed (30 J cm-") and pulsed gold vapour lasers, such as that used by Buchanan et al., 59 may be less effective than continuous-wave argon ion-dye systems? 1 The largest study of PDT for the treatment of BCC published to date is the phase II trial undertaken at Roswell Park Cancer Institute in Buffalo. ~3 The findings of this investigation, which considered 151 lesions in 37 patients, suggested very good results with superficial and nodular BCC (50% and 16% of the lesions studied respectively) but poor results with morphoeic lesions (34% of lesions studied). 80% of their recurrences were of the morphoeic type, with only 4 %
364
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Photodynamic therapy of primary skin cancer Table 2 5 year recurrence rates for basal cell carcinomas treated by conventional modalities. Data obtained from Rowe et a l f l ~ Recurrence rate at 5 years TrealnWnl modalil.|'
(%)
Surgical excision Curettage and electrodesiccation Radiotherapy Cryotherapy All non-Moh's modalities Moh's micrographic surgery
10.1 (264/2606) 7.7 (274/3573) 8.7 (410/4695) 7.5 (20/269) 8.7 (968/11143) 1.0 (73/7670)
of the superficial or nodular types recurring (mean follow-up 29 months). In addition, only 11% of the lesions classed as complete responders 3 months after treatment were of the morphoeic variety. The obvious implication of this is that the outcome of a trial may depend heavily on the proportion of morphoeic lesions included. It is unfortunate, therefore, that most authors have not reported the histological subtypes of the lesions they have treated. A recently presented follow-up study from the Roswell Park group, in which 588 superficial and nodular BCC (in 9 patients with basal cell naevias syndrome) were treated with PDT using P-II, found a mean CR rate in adult patients of 95% (mean follow-up was 28 months, range 3-51 months) with generally excellent cosmetic results? ~ The conclusion to be drawn tentatively from this analysis is that PDT using agents such as P-II may be effective against superficial and nodular BCC 6a but that it is probably not suitable for the treatment of morphoeic lesions. Clearly, however, further properly designed studies would be required to reach any definitive conclusion and careful comparisons with other therapeutic modalities must be undertaken. As shown in Table 2, there are a variety of treatments already available for basal cell carcinoma and many of these have excellent complete response rates even after 5 years, s'' However, several of these alternatives (e.g. cryotherapy and Moh's surgery) are poorly suited to the treatment of multiple lesions or large areas of tumour. As Wilson et al. ~aconcluded, it is possible that PDT may have a role to play in such cases, given that many tens of lesions can be treated in a single sitting. Bowen's disease appears to respond well to photodynamic therapy using H p D or P-II. Three out of the four trials included in Table I reported 100% initial complete response, with the fourth finding 95 % CR and 5 % no response. Unfortunately, follow-up has been very limited and no details of outcome beyond 12 months have been published. An interesting attempt to reduce the generalised photosensitisation of patients given P-II (see above) was made by Robinson et al. ~8 in a single patient with 90 Bowen's lesions. This was based on a number of pre-clinical studies suggesting that, at least within certain boundaries, photosensitiser dose and light dose could be varied reciprocally without affecting the outcome of treatment. By reduc~'ng the dose of P-II from 2.0 to 1.0 mg kg -t, and compensating for this by doubling the light dose from 25 to 50 J cm-", it was
365 hoped that the skin sensitivity normally induced by P-II would be reduced in severity. Unfortunately, the CR rate observed dropped from 95 % to 50 %, with the other 50% of the lesions not responding at all. No reduction in skin sensitisation was observed. Invasive squamous cell carcinomas also appear to respond well to PDT. Only the results of Pennington et al., ~7 who, as we have already noted, used low doses of light, were obviously disappointing. Keller et al. 6'' reported 100% CR 4 years after therapy. However, the number of patients involved in all of these studies was very small, making it difficult to draw any sensible conclusions from the available data. To summarise, it appears that photodynamic therapy based on HpD or P-II may well be effective against superficial and nodular BCC, Bowen's disease, and possibly SCC, but not morphoeic BCC. For multiple or widespread lesions of the appropriate type, PDT probably does present a useful alternative therapy (it should be stressed that many patients in the trials shown in Tables 1 and 3 had already failed conventional therapy). However, its widespread acceptance as such is hindered by the problems of prolonged cutaneous photosensitivity already alluded to above.
2. A L A
Topical ALA-based PDT eliminates the problem of skin photosensitisation and can be given on an outpatient basis. Four studies of A L A - P D T for primary skin cancer have been published to date (Table 3). These included 5 trials for BCC, 3 for Bowen's disease and 2 for SCC. The results with nodular BCC (nBCC) have all been poor. Initial CR rates have varied from 10%, using a slide projector for illuminationfl 7 to 64% using a laser, e'J Neither of these compares well with the longterm results using standard treatments listed in Table 2. Photofrin-based treatments would be preferred for multiple or large areas of disease, despite the problem of cutaneous photosensitisation. Interestingly, Warloe et al. TM have recently reported that pre-treating nodular BCC with dimethylsulphoxide (DMSO) or including this material in the ALA cream can improve the response of these lesions markedly. An initial CR of 35 % (all nBCC) became 89 % (lesions < I mm thick) or 50% (lesions > l mm thick). These findings, if confirmed in a controlled trial, may indicate a useful direction for future research. Initial response rates for superficial BCC (sBCC) have varied between 87.5 % (assessed at I-2 months) and 100 % (assessed at 3 weeks). Wolfet al. '~7 reported a 2 % recurrence rate with a median follow-up of 7 months (range 3-12), whilst Svanberg et al.6afound no recurrences with follow-ups ranging from 6-14 months (no median follow-up time was given). In contrast, we have observed significantly higher rates of recurrence (43% at a median follow-up of 17 months; r a n g e = 4 - 2 1 months). Gs Interestingly, the median time to recurrence was 11 months. As a result, it is possible that the relatively low recurrence rates of Wolfet al. 6~and Svanberg et al. ~9were at least partially a result of inadequate follow-up times.
366
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Fig. 3 Figure3 - - Distribution of ALA-induced PplX in sBCC (a, b) and Bowen's disease (c, d). (a) and (c) are ultra-low light level micrographs of PplX fluorescence taken using a cryogenic charge-coupled device camera system and a helium-neon laser for fluorescence excitation. Comparison with the diagrammatic representations shown in (b) and (d) reveals that the areas of most intense PplX fluorescence (which appear white) are usually located in those areas of tumour immediately adjacent to the dermis in both types of lesion. Areas of relatively low PplX fluorescence (which appear black) include the dermis and the centres of relatively large islands of sBCC. Regions of intermediate fluorescence intensity are coloured according to the pseudocolour scale shown. Scale bars represent 100.urn (a. b) and 30,um (c, d). (Reprinted from International Photodynamics I, 1994, with permission.) B o w e n ' s disease a p p e a r s to r e s p o n d well to topical A L A - P D T . Initial c o m p l e t e response rates o f 9 0 100 % have been r e p o r t e d a n d recurrence rates a p p e a r to be relatively low. W e detected 9 % recurrence with an 18-month m e d i a n follow-up (range 7-22 m o n t h s ) ~s and no further recurrence has been o b s e r v e d in the 24 m o n t h s s u b s e q u e n t to this (some patients have been lost to follow-up, however). These findings are s u p p o r t e d by the o b s e r v a t i o n s o f S v a n b e r g et al. 69 ( 9 0 % initial C R , 0 % recurrence with 6 - 1 4 m o n t h s follow-up). O f p a r t i c u l a r interest are the excellent cosmetic results that A L A - P D T p r o d u c e s in Bowen's disease. 45'6~-~ In o u r own experience, this m o d a l i t y is very well suited to the t r e a t m e n t o f lesions located in
p o o r quality skin that would be difficult to treat a c c e p t a b l y with c o n v e n t i o n a l a p p r o a c h e s . F i g u r e 2 shows two before- a n d a f t e r - t r e a t m e n t e x a m p l e s o f the results that can be easily achieved using topical ALA-based PDT. It is not clear why the recurrence rate o f Bowen's lesions should be lower than that o f s B C C . Initially, we speculated that d r u g p e n e t r a t i o n m a y limit the efficacy o f A L A - P D T in B C C but not Bowen's disease, as the f o r m e r are likely to c o n t a i n cells lying in much deeper strata o f the skin, whilst Bowen's disease is, by definition, i n t r a e p i d e r m a l . 68 H o w e v e r , using u l t r a - l o w light level fluorescence m i c r o s c o p y to e x a m i n e the d i s t r i b u t i o n o f P p I X within Bowen's lesions a n d
368 sBCC, we found that PplX fluorescence was located mainly in those regions of tumour adjacent to the dermis in both types of lesion (Fig. 3) and that fluorescence did not appear to be limited by tumour depth. 7~We now consider it less likely that the depth of ALA penetration limits the treatment of sBCC and instead would suggest that poorly sensitised cells, in the centres of the "islands" or " c o r d s " of tumour which lie in the dermis, might survive PDT and be responsible for the later recurrences we have observed. This is less likely to occur in Bowen's disease, where cells with relatively low levels of PplX usually lie superficial to a band of more fluorescent cells located immediately adjacent to the dermis. As a result, any poorly sensitised cells in these lesions are probably sloughed coincidentally when the sensitised regions beneath them are illuminated. As is the case with P-lI-based therapy, very few invasive SCC have been treated with ALA-PDT, and further s~udies are required before even tentative conclusions can be drawn. To summarise, we believe that A L A - P D T cannot, without further development, be considered an effective therapy for BCC of either the superficial or nodular types. Presumably the same also applies to morphoeic BCC. However, this conclusion is based on our own findings 6a and requires confirmation by other workers. It would be interesting to compare our results with the longer-term follow-up data o f W o l f e t al. ~7and Svanberg et al. ~9 that must now be available. Unfortunately these have yet to be published. We do believe that A L A - P D T is an effective treatment for Bowen's disease. It is rapid and convenient, especially when a non-laser source is used, and can treat relatively large areas of disease at one sitting. It produces excellent cosmetic results, even in poorly vascularised skin that would be difficult to treat using more conventional modalities. We consider it to be the treatment of choice in patients with large areas of disease or disease in anatomically difficult sites.
Conclusion PDT does have a place in the treatment of skin malignancies. Therapy using intravenous Photofrin ~II should be considered when patients present with widespread multiple sBCC or nBCC. For these patients, the problem of prolonged skin photosensitisation may be outweighed by the convenience of treating many lesions in a single sitting. Topical ALAPDT should be considered for patients who have large areas of Bowen's disease, particularly in sites unsuitable for treatment with other modalities. If nonlaser light sources fulfil their present promise, then ALA-PDT at least may become an offce-based procedure readily available in non-specialist centres.
Acknowledgements The University of Leeds Centre for Photobiology and Photodynamic Therapy is funded by the Yorkshire Cancer Research Campaign, UK.
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British Journal of Plastic Surgery The Authors David J. H. Roberts, BSc, PhD, Senior Research Fellow. Centre for Photobiology and Photodynamic Therapy, Research School of Medicine. University of Leeds. Tunbridgc Building, Cookridge Hospital. Leeds LSI6 6QB. UK. Fiona Cairnduff, MA, MBBS, MRCP, FRCR, MD, Consultant Clinical Oncologist. Cookridge Hospital. Leeds. Correspondence to Dr D. J. H. Roberts. Paper received 20 February 1995. Accepted I I April 1995. after revision.