Clinical study
Photodynamic therapy of brain tumours: evaluation of porphyrin uptake versus clinical outcome

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Abstract

The objective of this study was to investigate whether the level of the photosensitizer haematoporphyrin derivative (HpD) uptake measured in tissue samples taken from brain tumour patients was associated with survival post-treatment with photodynamic therapy (PDT). The mean HpD uptake in tumour tissue was significantly higher in glioblastoma multiforme than anaplastic astrocytoma. Recurrent tumours had a higher mean uptake compared to primary tumours, which was evident in all grades of tumour. Among patients with GBM, there was a significant association between greater HpD uptake and survival ( HR=0.26[0.12,0.59], p=0.001). There was also some evidence of a weak association between greater HpD uptake and survival among patients with AA, although the result was inconclusive ( HR=0.73[0.32,1.71], p=0.472).

Introduction

The biological hallmark of cerebral glioma is their extensive invasion into the brain. The best results with conventional treatments for high-grade glioma (glioblastoma multiforme – GBM), using surgery, radiotherapy and chemotherapy report a survival of less than one year.[1], [2] Tumours inevitably occur, due to conventional treatments being unable to destroy the invading glioma cells3 with most tumours recurring within or adjacent to the original tumour bed.4

Photodynamic therapy (PDT) is a form of localized adjuvant treatment. It involves a selective uptake of sensitizer by the cancer cell,5 followed by the irradiation of the tumour to activate the retained sensitizer causing selective tumour destruction6 mainly through oxidative reactions.7 In vivo studies have demonstrated that malignant cells retain haematoporphyrin derivative (HpD) selectively, and selective uptake of HpD by cerebral tumours has been demonstrated by experimental and clinical studies. Initial clinical studies of photodynamic therapy were disappointing.8 However, these studies often reported treatment of recurrent gliomas and doses of light irradiation that were 100-fold lower than those used in systemic tumours. This was done because of the fear of side-effects of photodynamic therapy at high doses and for the lack of availability of powerful light producing sources.

Studies in animal glioma models have demonstrated both tumour selectivity of HpD and a selective destruction of the tumours. We have reported the results of adjuvant photodynamic therapy, in the treatment of high-grade cerebral glioma using HpD photosensitizers.9

There are numerous variables in the administration of photodynamic therapy, including the type and composition of photosensitizer used,[10], [11], [12] the dose of photosensitizer administered, the relative uptake of the sensitizer into the tumour and the dosimetry of the light used to activate the sensitizer. In this study, we report the relationship of the uptake of the sensitizer HpD into the glioma and its relationship to the clinical outcome following PDT. In doing so, we recognize the many clinical and treatment variables that may have a more powerful influence on patient outcome, including the age of the patient, the Karnofsky performance status, the extent of tumour resection and the grade of the tumour.

Section snippets

Patient population

A total of 358 glioma patients have been treated with PDT at the Royal Melbourne Hospital since 1986. This study reports on the 104 patients resident in the state of Victoria that had both tumour samples analysed for HpD uptake and the clinical outcome confirmed by the Victorian Cancer Registry. Fifty eight of the patients were diagnosed with glioblastoma (GBM), while the remaining 46 were anaplastic astrocytoma (AA). The distribution is shown in Table 1. 58.82% of the patients were male,

Hpd uptake

The overall median HpD uptake for all tumour samples combined was 4.91 μg/g, ranging from 1.27 to 12.5 μg/g. The distribution profile is shown in Fig. 1. The average uptake in GBM (primary and recurrences) (6.19 μg/g) was greater than AA (4.44 μg/g).

The level of HpD uptake was associated with better prognosis across both grades of tumour combined ( HR=0.44[0.25,0.79], p=0.006). HRs calculated separately within each tumour grade showed a strong association between HpD uptake and survival

Discussion

The use of PDT as an adjuvant therapy has been investigated extensively, both experimentally and clinically in the treatment of a number of cancers. There have been several studies on its role in the treatment of malignant cerebral glioma since the first treatment by Perria in 1980.[8], [9], [19], [20], [21], [22] A direct comparison of these reported series is difficult as there are variations in the types of cerebral glioma treated, types and doses of photosensitizers, dose of light

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