Photodynamic therapy for cancer of the pancreas-The story so far

BACKGROUND AND OBJECTIVE: Pancreatic cancer has long been a leading cause of cancer death. Few patients are suitable for surgery and for those who are not, the response to treatment is generally poor. No more than about 10% survive for more than a year. Recent research has focused on focal treatment for local disease control. This review covers the development of one of the most promising options, photodynamic therapy (PDT). METHODS: This review covers pre-clinical and clinical studies. Laboratory work was designed to understand the effect of PDT on the normal pancreas and surrounding tissues and on transplanted cancers in the hamster pancreas to ensure safety prior to clinical application. Essentially all clinical studies have been undertaken in University College Hospital, London. Phase-I studies used the photosensitisers mTHPC and verteporfin in patients with localised but inoperable cancers. RESULTS: Laboratory results showed that normal pancreas, bile duct, liver, stomach and major blood vessels could tolerate PDT without any unacceptable effects on the structure and function of these organs. Necrosis that healed safely was documented in transplanted cancers. The clinical trials showed that focal necrosis could be produced in inoperable cancers with acceptable levels of complications, but considerable refinements of treatment delivery and monitoring are required before the technique will be ready for assessment in controlled clinical trials. CONCLUSIONS: PDT is showing promise for the minimally invasive treatment of localised pancreatic cancers, but it is still at an early stage of development. Much more work will be necessary to optimise techniques for applying PDT to these cancers and for combining it with other therapeutic options such as chemotherapy

NdYAG laser treatment of a glomus tympanicum tumour

Glomus tympanicum tumours are highly vascular tumours of the middle ear. Their removal by conventional surgical methods requires an extensive procedure in many cases, often with ossicular disarticulation to allow adequate exposure prior to the 'chaotic' and haemorrhagic event of tumour removal. This paper reports on the use of an NdYAG laser in a case of a large glomus tympanicum tumour. The laser facilitated a transcanal approach, avoided ossicular disarticulation and allowed accurate and almost bloodless ablation of the entire tumour.The NdYAG laser appears to be a very useful treatment modality in the management of these highly vascular tumours. Care should be taken to avoid accidental energy transmission to the cochlea

Oxygen monitoring during 5-aminolaevulinic acid induced photodynamic therapy in normal rat colon: comparison of continuous and fractionated light regimes

Comparative StudyJournal ArticleResearch Support, Non-U.S. Gov'tAuthor's post-print is subject to a Creative Commons Attribution Non-Commercial No Derivatives LicenseCurrently, the clinical use of 5-aminolaevulinic acid (ALA) induced protoporphyrin IX (PPIX) for photodynamic therapy (PDT) is limited by the maximum tolerated oral ALA dose (60 mg/kg). Attempts have been made to enhance this treatment modality without increasing the administered dose of ALA. One way to do this is through light dose fractionation, where the irradiation is interrupted at a particular point for a short period of time. This can produce up to three times more necrosis than with the same light dose delivered without a break. An oxygen microelectrode was employed to study the effect of continuous and fractionated light regimes on the level of oxygen in the colon of normal Wistar rats during ALA PDT. A rapid decline in pO2 occurred close to the irradiation fibre as soon as the light dose commenced. With the fractionated regime, a partial recovery in pO2 was observed during the dark interval which was reversed soon after the second light fraction commenced. We have shown that the level of tissue oxygen at the treatment site is affected differently when the light dose is fractionated, than when continuous illumination is employed. This factor may at least partially explain the difference in outcome of these two treatment regimes. Further, oxygen measurements might prove to be a useful way of monitoring PDT treatments if they can predict whether tissue is likely to be viable following treatment

Enhancing protoporphyrin IX-induced photodynamic therapy with a topical iron chelating agent in a normal skin model

PublishedArticle© Under License of Creative Commons Attribution 3.0 LicenseProtoporphyrin IX (PpIX)-induced photodynamic therapy (PDT) is being utilised within dermatological practice as a topical method of localised ablation of non-melanoma skin cancer/precancer. Standardised protocols have been implemented to good effect when the disease remains superficial but improvement is required to widen the application of this light activated drug therapy to treat thicker or acrally located conditions. As innate haem biosynthesis is exploited to accumulate the light sensitive PpIX from a topically applied inert prodrug (aminolaevulinic acid; ALA), this pathway can be further manipulated through the concurrent administration of an iron chelating agent to hyper-accumulate PpIX by temporarily reducing its iron dependent conversion to haem. A topical preparation of ALA was applied to normal rat skin with or without the hydroxypyridinone iron chelator, CP94. Image analysis quantification of tissue fluorescence following excision indicated that ALA plus CP94 produced 29.0% more fluorescence than ALA alone (p < 0.09), peaking at 5 hours. Furthermore, fluorescence spectroscopy of frozen skin samples from each treatment group were characteristic of PpIX (maxima 636 +/- 2 nm), indicating that topical CP94 administration elevated PpIX levels without significantly producing any other fluorescent species. When PDT efficacy was considered post irradiation, a substantial three-fold increase in effect was observed 4 days after treatment when the iron chelator CP94 was co-administered topically with the prodrug (p < 0.07). It has therefore been established that the hydroxypyridinone CP94, is topically active within normal rat skin, effectively chelating iron to elevate PpIX accumulation and thus improve PDT efficacy

Systematic review and meta-analysis of the growth and rupture rates of small abdominal aortic aneurysms: implications for surveillance intervals and their cost-effectiveness.

BACKGROUND: Small abdominal aortic aneurysms (AAAs; 3.0-5.4 cm in diameter) are usually asymptomatic and managed by regular ultrasound surveillance until they grow to a diameter threshold (commonly 5.5 cm) at which surgical intervention is considered. The choice of appropriate surveillance intervals is governed by the growth and rupture rates of small AAAs, as well as their relative cost-effectiveness. OBJECTIVES: The aim of this series of studies was to inform the evidence base for small AAA surveillance strategies. This was achieved by literature review, collation and analysis of individual patient data, a focus group and health economic modelling. DATA SOURCES: We undertook systematic literature reviews of growth rates and rupture rates of small AAAs. The databases MEDLINE, EMBASE on OvidSP, Cochrane Central Register of Controlled Trials 2009 Issue 4, ClinicalTrials.gov, and controlled-trials.com were searched from inception up until the end of 2009. We also obtained individual data on 15,475 patients from 18 surveillance studies. REVIEW METHODS: Systematic reviews of publications identified 15 studies providing small AAA growth rates, and 14 studies with small AAA rupture rates, up to December 2009 (later updated to September 2012). We developed statistical methods to analyse individual surveillance data, including the effects of patient characteristics, to inform the choice of surveillance intervals and provide inputs for health economic modelling. We updated an existing health economic model of AAA screening to address the cost-effectiveness of different surveillance intervals. RESULTS: In the literature reviews, the mean growth rate was 2.3 mm/year and the reported rupture rates varied between 0 and 1.6 ruptures per 100 person-years. Growth rates increased markedly with aneurysm diameter, but insufficient detail was available to guide surveillance intervals. Based on individual surveillance data, for each 0.5-cm increase in AAA diameter, growth rates increased by about 0.5 mm/year and rupture rates doubled. To control the risk of exceeding 5.5 cm to below 10% in men, on average a 7-year surveillance interval is sufficient for a 3.0-cm aneurysm, whereas an 8-month interval is necessary for a 5.0-cm aneurysm. To control the risk of rupture to below 1%, the corresponding estimated surveillance intervals are 9 years and 17 months. Average growth rates were higher in smokers (by 0.35 mm/year) and lower in patients with diabetes (by 0.51 mm/year). Rupture rates were almost fourfold higher in women than men, doubled in current smokers and increased with higher blood pressure. Increasing the surveillance interval from 1 to 2 years for the smallest aneurysms (3.0-4.4 cm) decreased costs and led to a positive net benefit. For the larger aneurysms (4.5-5.4 cm), increasing surveillance intervals from 3 to 6 months led to equivalent cost-effectiveness. LIMITATIONS: There were no clear reasons why the growth rates varied substantially between studies. Uniform diagnostic criteria for rupture were not available. The long-term cost-effectiveness results may be susceptible to the modelling assumptions made. CONCLUSIONS: Surveillance intervals of several years are clinically acceptable for men with AAAs in the range 3.0-4.0 cm. Intervals of around 1 year are suitable for 4.0-4.9-cm AAAs, whereas intervals of 6 months would be acceptable for 5.0-5.4-cm AAAs. These intervals are longer than those currently employed in the UK AAA screening programmes. Lengthening surveillance intervals for the smallest aneurysms was also shown to be cost-effective. Future work should focus on optimising surveillance intervals for women, studying whether or not the threshold for surgery should depend on patient characteristics, evaluating the usefulness of surveillance for those with aortic diameters of 2.5-2.9 cm, and developing interventions that may reduce the growth or rupture rates of small AAAs. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Discrete Event Simulation for Decision Modeling in Health Care: Lessons from Abdominal Aortic Aneurysm Screening

Markov models are often used to evaluate the cost-effectiveness of new healthcare interventions but they are sometimes not flexible enough to allow accurate modeling or investigation of alternative scenarios and policies. A Markov model previously demonstrated that a one-off invitation to screening for abdominal aortic aneurysm (AAA) for men aged 65 y in the UK and subsequent follow-up of identified AAAs was likely to be highly cost-effective at thresholds commonly adopted in the UK (£20,000 to £30,000 per quality adjusted life-year). However, new evidence has emerged and the decision problem has evolved to include exploration of the circumstances under which AAA screening may be cost-effective, which the Markov model is not easily able to address. A new model to handle this more complex decision problem was needed, and the case of AAA screening thus provides an illustration of the relative merits of Markov models and discrete event simulation (DES) models. An individual-level DES model was built using the R programming language to reflect possible events and pathways of individuals invited to screening v. those not invited. The model was validated against key events and cost-effectiveness, as observed in a large, randomized trial. Different screening protocol scenarios were investigated to demonstrate the flexibility of the DES. The case of AAA screening highlights the benefits of DES, particularly in the context of screening studies

New Photosensitizers for Photodynamic Therapy in Gastroenterology

Most applications of photodynamic therapy (PDT) in gastroenterology to date have used porfimer sodium as the photosensitizing agent. For destroying small lesions in the wall of the gastrointestinal tract in inoperable patients, it has proved to be most effective, but attempts to achieve circumferential mucosal ablation, as in the treatment of Barrett’s esophagus, have led to a high incidence of strictures, and all patients have cutaneous photosensitivity, which can last up to three months. Two new photosensitizers are of particular interest to gastroenterologists. PDT with metatetrahydroxyphenyl chlorin produces a similar biological effect as PDT with porfimer sodium, but the light doses required are much smaller, and cutaneous photosensitivity lasts only two to three weeks. Further, it can be used with percutaneous light delivery to destroy localized pancreatic cancers. The photosensitizing agent 5-amino levulinic acid, converted in vivo into the photoactive derivative protoporphyrin IX, sensitizes the mucosa much more than the underlying layers. This makes it feasible to destroy areas of abnormal mucosa without damaging the underlying muscle and is, therefore, better for treating Barrett’s esophagus. Detailed clinical studies are required to establish the real role of PDT with the use of these and other new photosensitizers

Photochemical internalisation of a macromolecular protein toxin using a cell penetrating peptide-photosensitiser conjugate.

Photochemical internalisation (PCI) is a site-specific technique for improving cellular delivery of macromolecular drugs. In this study, a cell penetrating peptide, containing the core HIV-1 Tat 48-57 sequence, conjugated with a porphyrin photosensitiser has been shown to be effective for PCI. Herein we report an investigation of the photophysical and photobiological properties of a water soluble bioconjugate of the cationic Tat peptide with a hydrophobic tetraphenylporphyrin derivative. The cellular uptake and localisation of the amphiphilic bioconjugate was examined in the HN5 human head and neck squamous cell carcinoma cell line. Efficient cellular uptake and localisation in endo/lysosomal vesicles was found using fluorescence detection, and light-induced, rupture of the vesicles resulting in a more diffuse intracellular fluorescence distribution was observed. Conjugation of the Tat sequence with a hydrophobic porphyrin thus enables cellular delivery of an amphiphilic photosensitiser which can then localise in endo/lysosomal membranes, as required for effective PCI treatment. PCI efficacy was tested in combination with a protein toxin, saporin, and a significant reduction in cell viability was measured versus saporin or photosensitiser treatment alone. This study demonstrates that the cell penetrating peptide-photosensitiser bioconjugation strategy is a promising and versatile approach for enhancing the therapeutic potential of bioactive agents through photochemical internalisation

Photodynamic therapy of malignant and premalignant lesions in patients with ’field cancerization‘ of the oral cavity

The management of patients with 'field cancerization' of the oral mucosa. with multicentric foci of invasion, presents a considerable problem for the head and neck surgeon. Surgical resection of synchronous or metachronous primary squamous cell carcinomas, along with adjacent premalignant lesions, is likely to be associated with considerable mutilation. Photodynamic therapy (PDT) has been shown to be of value in the treatment of superficial tumours in the upper aerodigestive tract, with excellent healing of treated areas. This study reports the use of PDT to treat 11 patients with 'field cancerization' occurring in the oral cavity. Six 'patients had multiple primary cancers and five had single primary tumours. All had associated areas of leukoplakia. Each received Photofrin 2 mg/kg 48 hours prior to photoirradiation with 50-100 J/cm2 red laser light by surface illumination. Six to eight weeks later treated areas in 10 of the 11 patients showed a complete response to PDT; one patient had areas of residual leukoplakia. Two patients developed further areas of leukoplakia or erythroplakia within 12 months but no patient has had evidence of recurrent invasive carcinoma in the treated areas. Longer term follow-up will be necessary to exclude further recurrence. It is concluded that PDT offers an effective repeatable treatment option, whether on its own or as an adjunct to local excision, for patients with 'field cancerization' of the oral cavity

Photodynamic therapy: Inception to application in breast cancer.

Photodynamic therapy (PDT) is already being used in the treatment of many cancers. This review examines its components and the new developments in our understanding of its immunological effects as well as pre-clinical and clinical studies, which have investigated its potential use in the treatment of breast cancer