Colin Hopper

Photodynamic therapy: a clinical reality in the treatment of cancer

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.

Photodynamic therapy using 5-aminolevulinic acid for premalignant and malignant lesions of the oral cavity.

Premalignant changes in the mouth, which are often widespread, are frequently excised or vaporized, whereas cancers are treated by excision or radiotherapy, both of which have cumulative morbidity. Photodynamic therapy (PDT) is another option that produces local tissue necrosis with light after prior administration of a photosensitizing agent. This heals with remarkably little scarring and no cumulative toxicity. This article describes the use of PDT with the photosensitizing agent 5‐aminolevulinic acid (ALA) for premalignant and malignant lesions of the mouth.

Stromal features are predictive of disease mortality in oral cancer patients

Worldwide, approximately 405 000 cases of oral cancer (OSCC) are diagnosed each year, with a rising incidence in many countries. Despite advances in surgery and radiotherapy, which remain the standard treatment options, the mortality rate has remained largely unchanged for decades, with a 5‐year survival rate of around 50%. OSCC is a heterogeneous disease, staged currently using the TNM classification, supplemented with pathological information from the primary tumour and loco‐regional lymph nodes. Although patients with advanced disease show reduced survival, there is no single pathological or molecular feature that identifies aggressive, early‐stage tumours. We retrospectively analysed 282 OSCC patients for disease mortality, related to clinical, pathological, and molecular features based on our previous functional studies [EGFR, αvβ6 integrin, smooth muscle actin (SMA), p53, p16, EP4]. We found that the strongest independent risk factor of early OSCC death was a feature of stroma rather than tumour cells. After adjusting for all factors, high stromal SMA expression, indicating myofibroblast transdifferentiation, produced the highest hazard ratio (3.06, 95% CI 1.65–5.66) and likelihood ratio (3.6; detection rate: false positive rate) of any feature examined, and was strongly associated with mortality, regardless of disease stage. Functional assays showed that OSCC cells can modulate myofibroblast transdifferentiation through αvβ6‐dependent TGF‐β1 activation and that myofibroblasts promote OSCC invasion. Finally, we developed a prognostic model using Cox regression with backward elimination; only SMA expression, metastasis, cohesion, and age were significant. This model was independently validated on a patient subset (detection rate 70%; false positive rate 20%; ROC analysis 77%, p < 0.001). Our study highlights the limited prognostic value of TNM staging and suggests that an SMA‐positive, myofibroblastic stroma is the strongest predictor of OSCC mortality. Whether used independently or as part of a prognostic model, SMA identifies a significant group of patients with aggressive tumours, regardless of disease stage. Copyright

Interstitial photodynamic therapy as salvage treatment for recurrent head and neck cancer.

Interstitial photodynamic therapy (IPDT) is a technique for applying photodynamic therapy (PDT) to internal tumours using light delivered via fibres inserted percutaneously. This phase I–II study assessed the safety and efficacy of IPDT for patients with persistent or recurrent head and neck cancer unsuitable for further treatment with surgery, radiotherapy or chemotherapy, recruited for ‘last hope’ salvage treatment. Patients were sensitised with 0.15 mg kg−1 mTHPC (meso-tetrahydroxyphenyl chlorin) 4 days prior to light delivery from fibres inserted directly into the target tumour (20 J per site at 652 nm) under image guidance. In all, 45 patients were treated. Nine achieved a complete response. Five are alive and free of disease 10–60 months later. Symptomatic relief (mainly for bleeding, pain or tumour debulking) was achieved in a further 24. The median survival (Kaplan–Meier) was 16 months for the 33 responders, but only 2 months for the 12 nonresponders. The only serious complication was a carotid blow out 2 weeks after PDT. No loss of function was detected in nerves encased by treated tumours. Interstitial photodynamic therapy provides worthwhile palliation with few complications and occasional long-term survivors for otherwise untreatable advanced head and neck cancers. It is a treatment option worth adding to those available to integrated head and neck oncology teams.

Photodynamic therapy using mTHPC for malignant disease in the oral cavity

Photodynamic therapy (PDT) produces local tumor necrosis, on activation of a previously administered sensitizer with non‐thermal light of an appropriate wavelength. It is attractive for treating tumors of the mouth as tissue healing is particularly good. We describe the use of the photosensitizing agent meta tetrahydroxyphenyl chlorin (mTHPC, Foscan®) for PDT of oral cancer, including patients with field cancerization. Nineteen patients with histologically confirmed oral cancer (8 with field change disease) and one with severe dysplasia, were sensitised with mTHPC intravenously. Activation was carried out 72–96 hr later with laser light at 652 nm using a range of light doses. The results were assessed clinically and histologically. Multiple biopsies were taken during the ulcerative stages to look at the effects of PDT and after healing to assess the overall treatment result. All single lesions up to stage T3 cleared after one PDT treatment (total of 6 patients). Three out of 6 T4 tumours were also cleared. Lesions in patients with field change disease did less well, only 9 of 14 T1 and T2s clearing, including 4 that required extra treatments with a higher light dose. Most healed very well, but tongue tethering was seen in 1 patient and another had necrosis in normal areas due to light scattering within the mouth. PDT using mTHPC is a promising new treatment for patients with oral cancer. Int. J. Cancer 73:25–32, 1997.

Proliferative verrucous leukoplakia: a report of ten cases.

A particularly aggressive form of oral leukoplakia that commences with a hyperkeratosis, spreads to become multifocal and verruciform in appearance, and later becomes malignant has been termed proliferative verrucous leukoplakia. Ten patients with persistent multifocal verruciform white patches were investigated. Lesions were often bilateral and affected predominantly mandibular alveolar and buccal mucosa. At first biopsy no lesion was graded higher than a verrucous hyperplasia, but subsequently all patients had squamous cell carcinoma, and two patients have died of their disease. Lesions were managed with surgery, carbon dioxide laser, and photodynamic therapy. The patients presented here confirm the existence of proliferative verrucous leukoplakia as a clinicopathologic entity. Careful examination of the whole mouth is essential when a hyperplastic white patch is seen to check for possible proliferative verrucous leukoplakia. Early aggressive treatment must then be started, and regular long-term review is crucial.

Clinical outcomes of photodynamic therapy for head-and-neck cancer

Head-and-neck cancers not only carry poor prognoses, but also reduced quality of life for the patients. Disease control is often achieved at the expense of substantial functional loss and disfigurement. Photodynamic therapy (PDT) is particularly well suited to the treatment of head-and-neck-tumors because it has little effect on underlying functional structures and has an excellent cosmetic outcome. Studies in the past decades have shown that PDT is of similar efficacy as traditional measures in the treatment of early-stage head-and-neck cancers with an overall response rate of 85%–100%, with up to 75% of the complete responses sustained at 2 years after PDT. For advanced head-and-neck cancers, studies were also conducted to evaluate the palliative effects of PDT. Overall, a 58%–70% palliative benefit can be observed in these patients. Using interstitial PDT, the median survival of the patients with recurrent unresectable head-and-neck cancers can be improved to 14 months (cf. 226 days by using surface illumination PDT). PDT is thus a therapeutic option that may prove a useful addition to the armamentarium of the integrated head and neck oncology team.

Photodynamic therapy : An effective, but non-selective treatment for superficial cancers of the oral cavity

It has often been claimed that photodynamic therapy (PDT) produces selective destruction of small cancers without affecting the adjacent normal tissue. The objective of our work was to treat small cancers of the oral cavity with PDT and subsequently excise the treated areas for histological studies of tumour and adjacent normal tissue exposed to the same light dose. Eleven patients with histologically proven T1NO oral squamous‐cell carcinomas were treated with PDT, using Photofrin as a sensitiser. The tumours plus a surrounding cuff of normal tissue were exposed to 50 J/cm2 non‐thermal laser light at 630 nm delivered by surface illumination and the treated areas subsequently excised. Histological staining and image analysis were used to determine the nature and extent of injury. No macroscopic distinction was evident between tumour and normal tissue exposed to light. Histologically, replacement of superficial epithelium, tumour and connective tissue with a fibrinous necrotic slough was seen. There was also loss of endothelium from small vessels, with haemorrhage and thrombosis. Preservation of subepithelial collagen and elastin was demonstrated with EVG staining. No evidence of selective tumour necrosis was found. Although depth of injury was variable, full thickness mucosal necrosis occurred in all cases.Int. J. Cancer 71: 937‐942, 1997.

In vitro examination of suspicious oral lesions using optical coherence tomography

We compared findings of optical coherence tomography (OCT) with histopathological results of suspicious oral lesions to assess the feasibility of using OCT to identify malignant tissue. Thirty-four oral lesions from 27 patients had swept-source frequency-domain OCT. Four variables were assessed (changes in keratin, epithelial, and sub-epithelial layers, and identification of the basement membrane) and from this we calculated whether or not there were architectural changes. These data were then compared with histopathological results. Two clinicians, who were unaware of the clinical and histopathological diagnoses, decided whether biopsy was necessary. The basement membrane was recognised in only 15 oral lesions. OCT could identify diseased areas but could not provide a diagnosis or differentiate between lesions. The two clinicians, who recommended biopsy agreed in all cases. This pilot study confirms the feasibility of using OCT to identify architectural changes in malignant tissues.

Photodynamic therapy of normal rat arteries after photosensitisation using disulphonated aluminium phthalocyanine and 5-aminolaevulinic acid

Photodynamic therapy of cancer exposes adjacent arteries to the risk of injury and the possibility of haemorrhage and thrombosis. The nature of photodynamic injury to normal arteries has not been satisfactorily defined, and the ability of arteries to recover with time is unclear. To clarify these issues, we have investigated the effects of PDT on rat femoral arteries, using a second-generation photosensitiser, disulphonated aluminium phthalocyanine, and a new method of photosensitisation, using endogenous synthesis of protoporphyrin IX following systemic administration of 5-aminolaevulinic acid (ALA). Pharmacokinetic studies of sensitiser fluorescence were carried out to determine peak levels of sensitiser. Subsequently photodynamic therapy at times corresponding to maximal fluorescence was performed using two light doses, 100 and 250 J cm-2. The nature of injury sustained and recovery over a 6 month period was investigated. Three days following PDT, all vessels treated showed complete loss of endothelium, with death of all medial smooth muscle cells, leaving an acellular flaccid artery wall. No vascular occlusion, haemorrhage or thrombosis was found. A striking feature was the lack of inflammatory response in the vessel wall at any time studied. Re-endothelialisation occurred in all vessels by 2 weeks. The phthalocyanine group showed repopulation of the media with smooth muscle cells to be almost complete by 3 months. However, the ALA group failed to redevelop a muscular wall and remained dilated at 6 months. Luminal cross-sectional area of the ALA-treated group was significantly greater than both control and phthalocyanine groups at 6 months. All vessels remained patent. This study indicates that arteries exposed to PDT are not at risk of catastrophic haemorrhage or occlusion, a finding that is of significance for both the local treatment of tumours and the use of PDT as an intraoperative adjunct to surgery for the ablation of microscopic residual malignant disease.