Routine double treatments of superficial basal cell carcinomas using aminolaevulinic acid-based photodynamic therapy.

BACKGROUND: Superficial basal cell carcinomas of the skin (sBCC) often respond poorly to single-treatment aminolaevulinic acid-based photodynamic therapy (ALA-PDT), with a number of reports indicating a relapse rate of 50% or more. OBJECTIVES: To determine whether a second treatment at seven days can improve the response. METHODS: Twenty-six lesions were treated twice with ALA-PDT, with an interval of 7 days between the two treatment sessions. RESULTS: We observed a complete response rate of 100% 1 month after treatment. Only one lesion relapsed (16 months post-PDT), a relapse rate of 4% (median follow up 27 months; range 15-45 months). Cosmetic results were excellent. CONCLUSIONS: We consider routine double treatments with ALA-PDT to be an effective approach to the management of sBCC, particularly those located in anatomically difficult, or cosmetically sensitive, sites.

Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen.

The assessment of angiogenesis in breast cancer is of importance as a key indicator of survival and response to therapy. Circulating vascular endothelial growth factor (VEGF) measurements may provide a less subjective analysis than microvessel density (MVD) or immunohistochemical analysis of VEGF expression; however, most studies have used serum, which is now known to largely reflect platelet-derived VEGF concentrations. This study examined for the first time both plasma (VEGFp) and serum (VEGFs) VEGF concentrations in 201 blood samples from pre- and postmenopausal healthy controls and from patients with benign breast disease, localized breast cancer, breast cancer in remission, or metastatic breast cancer and related these to other clinicopathological markers. VEGFp but not VEGFs concentrations of patients with localized disease were significantly elevated compared with normal controls (P = 0.016). Patients with metastatic disease had higher VEGFp and VEGFs levels than normal controls (P < 0.001, P = 0.044 respectively), and higher VEGFp, but not VEGFs, than patients with benign disease (P = 0.009) and patients with localized disease (P = 0.004). However, the highest VEGFp and VEGFs concentrations were seen in patients in remission compared with normal controls (P < 0.001 and P = 0.008, respectively). VEGFp concentrations in patients in remission were also higher than in patients with benign disease (P = 0.01) or patients with localized disease (P = 0.005). Tamoxifen treatment was significantly associated with higher circulating and platelet-derived VEGF levels. Circulating VEGF did not correlate with any clinicopathological factor, including MVD or VEGF expression. VEGF expression was significantly correlated with estrogen receptor status and inversely correlated with tumor grade. MVD correlated with tumor size. Tamoxifen-induced increases in VEGF may be important in clinical prognosis or associated pathologies.

Photodynamic therapy of primary skin cancer: a review.

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.

Response of a rodent fibrosarcoma to photodynamic therapy using 5-aminolaevulinic acid or polyhaematoporphyrin.

The effects of 5-aminolaevulinic acid (ALA)-based photodynamic therapy (PDT) on the growth of an intradermal rat fibrosarcoma have been determined following topical, intravenous, or intratumour application of ALA. The pattern of tumour growth was identical following each type of therapy and we conclude that the efficacy of ALA-PDT is independent of the route of drug administration, at least in this tumour system. We have also compared the efficacy of interstitial ALA-based PDT with similar therapy using a conventional photosensitizer, polyhaematoporphyrin (PHP). ALA-PDT was less effective than PHP-based therapy at inhibiting the growth of a subcutaneous rat fibrosarcoma at light doses over 300 J. It is suggested that protoporphyrin IX photo-bleaching may limit the effectiveness of treatment, whilst the more bleach-resistant PHP may continue to be effective at higher light doses.

The response of a rodent fibrosarcoma to combined treatment with photodynamic therapy and radiotherapy.

The response of a rodent fibrosarcoma to photodynamic therapy (PDT), radiotherapy (RT) or combined PDT and RT was examined. PDT used intravenous polyhaematoporphyrin (PHP) and interstitial illumination with 630 nm light (300 or 400J). RT was given as an external beam of gamma-rays (15, 20 or 25 Gy). Both PDT and RT induced a significant delay in tumour growth when applied alone. PHP given alone, without subsequent illumination, did not alter the response of the tumour to RT. The effect of combining PDT and RT was dependent on the dose of light administered, but not, in most cases, on either the radiation dose or the sequence in which the two treatments were given. Using 300J of light, all combined treatments produced additive tumour growth delays. In contrast, sub-additive tumour responses were observed following most combined treatments using 400J of light.

Modulation of the response of a rodent fibrosarcoma to photodynamic therapy by hyperbaric-oxygen treatment.

The ability of hyperbaric oxygen (HBO) treatment to modulate the response of a rodent fibrosarcoma to interstitial photodynamic therapy (PDT) using 630 nm light and intravenous polyhaematoporphyrin (PHP) was examined. Application of HBO for 30 min immediately prior to PDT resulted in a light dose-dependent increase in tumour growth retardation, maximum effect (+227%) being observed with 100J light, and no enhancement being seen at or above 400J. Application of HBO during or immediately after PDT had no effect on response. Reducing the interval between giving PHP and administering light from the usual 48 h to just 1 h increased the efficacy of PDT even in the absence of HBO pre-treatment. Under these circumstances, application of HBO did not realise any further increase in tumour response at any light dose. Our findings suggest that manipulation of tumour oxygenation may be able to improve the outcome of PDT under some circumstances, but that careful consideration of other treatment variables, such as light dose and drug-to-light interval, may provide similar, more easily achievable, improvements in efficacy.

Superficial photodynamic therapy with topical 5-aminolaevulinic acid for superficial primary and secondary skin cancer.

Between January 1991 and December 1992 a phase I trial of superficial photodynamic therapy (PDT) using topical application of 5-aminolaevulinic acid (ALA) was undertaken to treat Bowen's disease, superficial basal cell carcinomas (BCCs) and metastatic skin secondaries from breast (adenocarcinoma) or pinna (squamous cell carcinoma). Promising results were obtained with 36 areas of Bowen's disease, with a complete response rate of 89% at a median follow-up of 18 months. The treatment of BCCs was less successful, with 50% complete responses in 16 lesions at a median follow-up of 17 months. Metastatic nodules responded poorly. The treatment was well tolerated and discomfort during light irradiation could be reduced by prior application of 'Emla' cream. Lesions wept for 1-2 weeks following treatment and healed over a period of approximately 2 months. For large areas of Bowen's disease, particularly in anatomically difficult areas and in elderly patients, PDT using ALA may constitute a single simple alternative outpatient treatment to existing therapies. Further work is required to improve the results with BCCs.

Tumor vascular shutdown following photodynamic therapy based on polyhematoporphyrin or 5-aminolevulinic Acid.

The effects of photodynamic therapy (PDT) based on polyhaematoporphyrin (PHP) or 5-aminolaevulinic acid (ALA) on the tumour vascular perfusion (TVP) of a rat fibrosarcoma were examined using an (RbCl)-Rb-86 extraction technique. Both forms of therapy induced large and highly significant reductions in TVP, countering the previous suggestion that ALA-PDT has no vascular effects. Ultrasensitive digital imaging fluorescence microscopy indicated that ALA-induced PpIX was distributed relatively evenly throughout the tumour. Use of Hoechst 33342 as a vascular marker revealed that PpIX was also present in cells lining the tumour microvascular spaces, contrary to previous findings.

Phase I trial and pharmacokinetics of trimelamol (N2,N4,N6-trihydroxymethyl-N2,N4,N6-trimethylmelamine).

Trimelamol is an analogue of hexamethylmelamine and pentamethylmelamine which does not require metabolic activation and is sufficiently soluble to allow parenteral administration. A Phase I trial has been performed at the Royal Marsden Hospital in which two schedules of administration have been evaluated, a single i.v. infusion repeated every 3 weeks and 3 daily doses repeated every 3 weeks. Pharmacokinetic analysis was performed at all dose levels on both schedules and a linear correlation was demonstrated between dose and area under the curve. Myelosuppression was dose limiting for single dose administration with a maximum tolerated dose of 2400 mg/m2. Median leukocyte nadirs at 1800, 2100, and 2400 mg/m2 were 3.2, 2.6, and 1.5 x 10(9)/liter. Thrombocytopenia and anemia also occurred but were not dose limiting. Doses greater than 1500 mg/m2 caused WHO grade 3 nausea and vomiting but no acute sedation. Three day administration appeared to be less myelosuppressive, giving a maximum tolerated dose of 1000 mg/m2. Median leukocyte nadirs at 800, 900, and 1000 mg/m2 daily for 3 days were 3.0, 2.3, and 1.5 x 10(9)/liter. Nonhematological toxicities were also less marked on the fractionated schedule. Antitumor effects were observed including 1 complete and 9 partial responses. Demonstration of activity in ovarian cancer has led to further evaluation in this disease using the 3-day schedule at a dose of 800 mg/m2 daily for 3 days.

High dose versus low dose medroxyprogesterone acetate: a randomized trial in advanced breast cancer.

One hundred and twenty-four patients with advanced breast cancer were randomly allocated to treatment with either low dose (300 mg/day) or high dose (1000 mg/day) oral medroxyprogesterone acetate. The objective response rate was 24% for both treatment groups. For premenopausal patients, responses were achieved in two out of four on low dose and three out of six on high dose therapy (overall 5 out of 10 responders). No significant differences in response were seen in relation to previous endocrine therapy or site of disease. Both treatments were associated with a high incidence of bone pain relief (43 and 52%) but a low objective response rate (13%) in bone. Median response duration (10 vs. 11 months) and survival (13 vs. 11 months) were not significantly different for the two treatments. Both treatments were in general well tolerated, but toxicity was greater with the high dose treatment. Low dose oral medroxyprogesterone acetate is as effective as high dose therapy in the treatment of advanced breast cancer, and is cheaper and less toxic.