Elsevier

The Lancet Oncology

Volume 1, Issue 4, December 2000, Pages 212-219
The Lancet Oncology

Review
Photodynamic therapy: a clinical reality in the treatment of cancer

https://doi.org/10.1016/S1470-2045(00)00166-2Get rights and content

Summary

Photodynamic therapy (PDT) is a minimally invasive treatment with great promise in malignant disease. It can be applied before, or after, chemotherapy, ionising radiation, or surgery, without compromising these treatments or being compromised itself. Unlike radiotherapy and surgery, it can be repeated many times at the same site. Response rates and the durability of response with PDT are as good as, or better than, those with standard locoregional treatments. Furthermore, there is less morbidity and better functional and cosmetic outcome. PDT is valuable for premalignant conditions such as mucosal dysplasia and carcinoma-in-situ. The excellent cosmetic outcome makes it valuable for skin lesions and for lesions of the head, neck, and oral cavity, where another advantage is that it has negligible effects on underlying functional structures. With endoscopic delivery of light to hollow structures, PDT has been successful in the treatment of early gastrointestinal cancers, such as oesophageal cancer, and lung cancer. The superficial effects of PDT can be exploited in the treatment of large areas such as the pleura and peritoneum, where curative radiation doses cannot be tolerated by underlying normal tissue. PDT is an ideal adjuvant therapy when surgical resection of solid tumours might leave behind residual microscopic disease. Interstitial light delivery, where light is fed directly into solid tumours, allows PDT to be used for large, buried tumours that would otherwise require extensive surgical resection.

Section snippets

Basics of PDT

The three fundamental elements of PDT are oxygen, a photosensitiser, and visible light (Figure 1). The photosensitiser is activated by the light and interacts with molecular oxygen to produce an excited state – reactive singlet oxygen. This moiety is highly cytotoxic, with a short lifetime (<0.04 μs) and a short radius of action (<0.02 μm). The direct cytotoxic activity and microvascular damage contribute to the destruction of tumour cells, which is manifested as swelling and formation of

Photosensitisers

Photosensitisers are probably incorporated directly into cellular membranes, but they do not seem to accumulate within cell nuclei. This conclusion is supported by observations that PDT is not mutagenic in vitro. There is evidence that photosensitisers are taken up and retained preferentially by neoplastic tissue, but as yet this effect is not sufficiently pronounced to allow a selective clinical response. The exception is in brain tumours, where the ratio of photosensitiser in tumour to normal

First-generation photosensitisers

Porfimer sodium was the first photosensitiser to receive approval, and it is now licensed for use in the oesophagus, lung, stomach, cervix, and bladder. However, it is only moderately active in tissue because the wavelength of light needed for activation (630 nm) penetrates tissue only slightly, and the absorption band at this wavelength is weak, therefore the depth of effect is limited to 0.5 cm. The efficiency of transfer of energy from light to cytotoxic products (quantum yield) is moderate

Second-generation photosensitisers

Second-generation synthetic photosensitisers have shorter periods of photosensitivity, longer activation wavelengths, and therefore increased depth of effect, higher yields of singlet oxygen, and better tumour selectivity. The groups that have been most actively investigated are the chlorins, texaphyrins, purpurins, and phthalocyanines.

The synthetic chlorin temoporfin is a very potent sensitiser (with a quantum yield of singlet oxygen of about 0.87) activated at 652 nm, with a residual

PDT in the treatment of malignant disease

Trials in many cancers have shown that PDT can achieve control rates similar to those achieved with the standard techniques of surgery and radiotherapy. The real advantages of PDT are the lower morbidity rates, improved functional and cosmetic outcome, and simplicity of the technique. PDT has therefore been investigated most extensively in disorders for which standard treatment has low efficacy or unacceptable side-effects. Examples include premalignant conditions and tumours that are

Treatment of premalignant conditions

Premalignant dysplastic lesions and non-invasive cancers are common in the mucosa of the aerodigestive and urinary tracts – for example, mucosal dysplasia of the oral cavity, Barrett's oesophagus associated with high-grade dysplasia, and carcinoma-in-situ of the lung and bladder. Treatment of a premalignant lesion before it becomes invasive is clearly desirable and preferable to treatment of a solid tumour. Eradication of the lesion at this stage will also minimise the risk of metastatic

Treatment of cutaneous malignant disease

Skin is readily accessible to treatment by light, and much experience has been gained with PDT for malignant disorders of the skin (Table 2). Most experience has been in the treatment of cutaneous basal-cell carcinoma with ALA and porfimer sodium, but there are also preliminary results in Bowen's disease and in chest-wall recurrences of breast cancer. In aqueous solution, ALA passes readily through abnormal but not normal keratin, thus inducing a degree of selective photosensitisation in

Cancers of the head, neck, and oral cavity

Skin and mucosal lesions in the head and neck region are difficult to treat satisfactorily with standard approaches. Surgery and radiotherapy, used alone or in combination, produce good success rates with excellent durability of response. However, the complex nature of this anatomical region means that control is commonly achieved at the expense of substantial functional disturbance and disfigurement or other long-lasting complications of radiotherapy, such as xerostomia and osteoradionecrosis.

Treatment of other malignant disease

Light can be delivered endoscopically to any hollow structure, such as the oesophagus or bronchial tree, thus avoiding major excision. PDT has been used successfully in the treatment of early gastrointestinal cancers and lung cancer (Table 4).

Furuse and colleagues21 reported complete response rates of 85% in patients with early-stage lung cancer, and Moghissi and co-workers22 found that PDT with porfimer sodium can be effective in the palliation of inoperable lung cancer, relieving obstruction

Intraoperative and adjunctive treatment of surface cancers

The superficial effects of PDT can be exploited in the treatment of large areas, such as the pleura and peritoneum. Cancers that arise in, or metastasise to, serosa are spread over large surface areas. Although surgical resection is possible to remove gross lesions, removal of microscopic disease is not feasible. Local recurrence or persistence is common in surgical resection of peritoneal carcinomatosis, malignant mesothelioma, and pleural carcinomas. Radiotherapy is limited by the inability

Interstitial treatment

PDT is not limited to the treatment of surface cancers, whether cutaneous or in hollow organs. Light can be delivered directly into solid tumours by feeding laser fibres through needles placed under image guidance in the tumour (Table 6). There is a clear parallel with the early days of interstitial radiotherapy, and the principles of fibre placement are similar to those of the Paris system. This type of treatment requires all light sources to be placed in an equidistant, parallel arrangement

Conclusion

Recent developments in photosensitisers and light delivery systems have substantially reduced treatment times and residual photosensitivity, while increasing the achievable depth of necrosis. Compared with standard approaches, PDT can achieve equivalent or greater efficacy in the treatment of many cancers, particularly in the head and neck and basal-cell carcinoma, with greatly reduced morbidity and disfigurement. The technique is simple, can commonly be carried out in outpatient clinics, and

Search strategy and selection criteria

Published data up to 1998 were already available to me for this review. More recent publications were identified through our own database of photodynamic therapy publications and PubMed. All preclinical and scientific papers and papers on non-malignant conditions (eg psoriasis, age-related macular degeneration) were excluded. Papers submitted on the same topic by the same group of investigators to several journals were reviewed to identify one in each case that was representative of the

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