Marica B. Ericson

Pain caused by photodynamic therapy of skin cancer

Summary Pain resulting from photodynamic therapy (PDT) of skin cancer was investigated. The study included 69 lesions (60 patients) with different types of skin tumours or precursors. Protoporphyrin IX, which is produced by the topical application of δ‐aminolevulinic acid, was used as a photosensitizing agent. Twenty‐three of the lesions (19 patients) were examined with a fluorescence imaging system which demarcates the tumour area from the healthy skin and visualizes the contrast between the fluorescence from healthy skin and that from the tumour. EMLA® is used on all patients as part of our routine PDT protocol but despite this the major side‐effect of PDT is pain during treatment. There is a large variation in pain intensity experienced by the patients, as measured by a visual analogue scale (VAS). Patients with actinic keratoses experienced more pain than those with Bowens disease or basal cell carcinoma. The mean VAS score was higher when treating lesions located on the head than when treating lesions on the torso or the extremities. Also, treatment of large skin areas resulted in more pain than treatment of small areas, and men experienced more pain than women. The pain experienced by the patients did not correlate with treatment dose, Fitzpatrick skin type, age or fluorescence intensity.

Photodynamic therapy of actinic keratosis at varying fluence rates: assessment of photobleaching, pain and primary clinical outcome

Background  Although photodynamic therapy (PDT) is becoming an important treatment method for skin lesions such as actinic keratosis (AK) and superficial basal cell carcinoma, there are still discussions about which fluence rate and light dose are preferable. Recent studies in rodents have shown that a low fluence rate is preferable due to depletion of oxygen at high fluence rates. However, these results have not yet been verified in humans.

Review of photodynamic therapy in actinic keratosis and basal cell carcinoma

The number of non-melanoma skin cancers is increasing worldwide, and so also the demand for effective treatment modalities. Topical photodynamic therapy (PDT) using aminolaevulinic acid or its methyl ester has recently become good treatment options for actinic keratosis and basal cell carcinoma; especielly when treating large areas and areas with field cancerization. The cure rates are usually good, and the cosmetic outcomes excellent. The only major side effect reported is the pain experienced by the patients during treatment. This review covers the fundamental aspects of topical PDT and its application for treatment of actinic keratosis and basal cell carcinoma. Both potentials and limitations will be reviewed, as well as some recent development within the field.

Important factors for pain during photodynamic therapy for actinic keratosis

Photodynamic therapy (PDT) is an efficient treatment for actinic keratosis. A common problem, however, is pain. The aim of this study was to investigate pain during PDT for actinic keratosis. The possibility of using capsaicin cream for pain relief was also assessed. Pain was investigated during aminolaevulinic acid PDT in 91 patients. Size, redness, scaling and induration of the lesions were recorded. Maximum pain during treatment was registered, using a visual analogue scale (0-10). The pain-reducing efficacy of capsaicin was tested in a pilot study in six patients (10 lesions). These patients were pre-treated with capsaicin cream for one week before commencing PDT. Pain was found to be normally distributed around a mean value of visual analogue scale 4.6. Larger lesions gave more pain (p=0.001). The redness of the actinic lesions was found to be related to PDT-induced pain (p=0.01), the reduction of actinic area (p=0.007), and the cure rate (p=0.01). The redder the actinic area, the better the treatment outcome and the more pain experienced. Patients with the largest reduction in the actinic area experienced more pain (p=0.053). The most important factors for presence of pain seem to be the size and the redness of the lesion. No significant pain relief was experienced after pre-treatment with capsaicin.

Lipid cubic phases in topical drug delivery: visualization of skin distribution using two-photon microscopy.

The distribution of sulphorhodamine B (SRB), a fluorescent hydrophilic model drug, was investigated in human skin after passive diffusion using four different topical delivery systems. The delivery vehicles applied were two bicontinuous lipid cubic systems, a commercial ointment and water. The lipid cubic systems consisted of either monoolein (MO) or phytantriol (PT) and water. The formulations were applied on full-thickness human skin during 24 h. Thereafter the samples were investigated using two-photon microscopy (TPM). The TPM system consisted of an inverted microscope with a 40x water-immersion objective, laser scan-box, and a pulsed femtosecond titanium:sapphire laser operating at 780 nm. The fluorescence was detected using a 560 nm long-pass filter. Sequential optical sectioning was performed, resulting in images obtained at different tissue depths. TPM revealed that SRB mainly penetrates the skin via the intercellular lipid matrix. Samples exposed to the cubic phases showed a higher accumulation of SRB in micro-fissures, from which a fluorescent network of threadlike structures spread laterally in the tissue. These structures were also detected in some of the ointment samples, but not as frequent. The penetration of SRB into the stratum granulosum was deduced from the fluorescence of SRB present inside polygonal keratinocytes with cell nuclei. Higher SRB fluorescence was obtained in the outermost layer of the epidermis using the bicontinuous cubic phases, compared to when using the reference formulations. Thus, our results suggest that the dominating delivery route using the cubic phases is via micro-fissures caused by microscopic clustering of the keratinocytes in the skin. From these micro-fissures hydrophilic compounds, here modeled by SRB, can diffuse into the surrounding intercellular lipid matrix acting like a source for sustained release.

Bispectral fluorescence imaging of aggressive basal cell carcinoma combined with histopathological mapping: a preliminary study indicating a possible adjunct to Mohs micrographic surgery

Background  Fluorescence imaging is an attractive diagnostic technique for skin tumour demarcation with potential to move to clinical use. Bispectral fluorescence imaging combines skin autofluorescence with δ‐aminolaevulinic acid‐induced fluorescence. To evaluate the technique, fluorescence data must be compared with the histopathological extent of the tumour, which is the purpose of the current study.

Bioavailability of aminolaevulinic acid and methylaminolaevulinate in basal cell carcinomas: a perfusion study using microdialysis in vivo

Background  Photodynamic therapy is becoming a popular treatment for superficial nonmelanoma precancerous and cancerous lesions, showing excellent cosmetic results. Nevertheless, the reported cure rates vary and the transdermal penetration of drugs has been discussed as a limiting factor, particularly for treatment of nodular basal cell carcinoma (BCC).

A spectroscopic study of the photobleaching of protoporphyrin IX in solution

Abstract Photodynamic therapy (PDT) has developed into an important new clinical treatment for cancer during the past 30 years. The method is non-invasive and based on the photochemical activity of a photosensitising agent present in cells and tissues. In so-called ALA-PDT, protoporphyrin IX (Pp IX) is induced from aminolaevulinic acid (ALA) applied topically or systemically. It has been shown that Pp IX is photodegraded by a photo-oxidation process and that its photoproducts have a characteristic absorption band around 670 nm, as observed both in solution and in cells incubated with ALA. In this study, the involvement of oxygen in the photobleaching process was verified by studying the effect of oxygen depletion using the freeze–pump–thaw (FPT) method. A solution of Pp IX in dimethylformamide (DMF) was exposed to light in the wavelength region 600–700 nm (peak centred at 620 (±25) nm) both in the presence and in the absence of oxygen. The bleaching process was observed by absorbance and fluorescence measurements. Photobleaching was observed in the presence of oxygen, as verified by the build-up of a photoproduct absorbing at 670 nm. When the sample was deoxygenated with the FPT method, the photoproduct absorption peak at 670 nm was missing. These results confirm that the formation of photoprotopor-phyrin is a photo-oxidation process and that no photobleaching takes place in the absence of oxygen. When comparing our results to the studies carried out by N2 bubbling, the N2 bubbling seems to be insufficient to remove the oxygen completely from the solution.

Nerve blocks provide effective pain relief during topical photodynamic therapy for extensive facial actinic keratoses

Background.  Photodynamic therapy (PDT) is a first‐line therapeutic option for skin areas with multiple actinic keratoses (AKs). Its main drawback is the pain perceived during the irradiative phase, especially when treating field cancerization in the facial area. Effective pain‐relieving strategies are needed.

Fluorescence contrast and threshold limit: implications for photodynamic diagnosis of basal cell carcinoma

This study was designed to evaluate what application time of delta-5-aminolaevulinic acid (ALA) results in highest contrast between tumour and normal skin, in the interval 1-4 h, when using photodynamic diagnosis (PDD) of basal cell carcinomas (BCC) located on the face. Moreover, a value of the demarcation limit has been derived based on the fluorescence variation in normal skin adjacent to the tumour. Forty patients were included in the study, randomly allocated to four different groups with varying ALA application time in the range 1-4 h. The contrast, defined as the ratio between the fluorescence intensity in ALA-treated tumour tissue and normal skin, was calculated for each patient, and the mean values in each group were evaluated as a function of ALA application time. In addition, the fluorescence intensity variation in ALA-treated normal skin adjacent to the tumour was assessed. The results from this study show a peak of the mean contrast values after 3 h ALA application, but due to large interpatient variation, the mean contrast did not differ significantly in the interval 2-4 h. After 2 h ALA application, the fluorescence intensity variation in the normal ALA-treated skin was found to be at a maximum, which suggests that 2 h ALA application is not preferable when using PDD. Based on data of the fluorescence variation in ALA-treated normal skin after 3 and 4 h ALA application, a tolerance interval was calculated implying that values above 1.4 times the mean normal fluorescence indicate an abnormal condition. This tolerance limit agrees well with results obtained in a former study.