Abstract
Invasive grade III and IV malignant gliomas remain difficult to treat with a typical survival time post-diagnosis hovering around 16 months with only minor extension thereof seen in the past decade, whereas some improvements have been obtained towards five-year survival rates for which completeness of resection is a prerequisite. Optical techniques such as fluorescence guided resection (FGR) and photodynamic therapy (PDT) are promising adjuvant techniques to increase the tumor volume reduction fraction. PDT has been used in combination with surgical resection or alternatively as standalone treatment strategy with some success in extending the median survival time of patients compared to surgery alone and the current standard of care. This document reviews the outcome of past clinical trials and highlights the general shift in PDT therapeutic approaches. It also looks at the current approaches for interstitial PDT and research options into increasing PDT's glioma treatment efficacy through exploiting both physical and biological-based approaches to maximize PDT selectivity and therapeutic index, particularly in brain adjacent to tumor (BAT). Potential reasons for failing to demonstrate a significant survival advantage in prior PDT clinical trials will become evident in light of the improved understanding of glioma biology and PDT dosimetry.
Highlights
Malignant gliomas, which account for 2% of all cancer deaths worldwide, despite only accounting for 1% of all tumors, are highly invasive and di±cult to treat.[1]
In all of these studies the e®ect on normal brain structures is not reported and needs to be tested prior to considering these avenues for a future increase in the therapeutic index according to Eq (9) as required to treat the inltrating front of glioblastoma multiforme (GBM) clinically
While physical approaches to conrm photodynamic therapy (PDT) response to a particular treatment area have proven benecial in well-circumscribed tumors or situations where the clinical target volume (CTV) is delineated by organ boundaries, such as the prostate and skin, they are often inadequate in treating GBM beyond the resection boundary
Summary
Malignant gliomas, which account for 2% of all cancer deaths worldwide, despite only accounting for 1% of all tumors, are highly invasive and di±cult to treat.[1]. The pharmacokinetic-based selectivity of the various photosensitizers translate at least partially into a clinical impact and prolong the survival times in early clinical trials, but not to the extent anticipated based on the large di®erences in photosensitizer uptake initially observed in preclinical studies for ALA induced PpIX36,37 and in some clinical studies for Photofrin,[26] HpD25 and ALA induced PpIX30 reporting specic uptake ratio (SUR) of less than 10 In part, this is due to the intrinsic high sensitivity or low resilience of the normal tissue structures, particular astrocytes and neurons within the PDT treatmenteld as shown by Lilge and Wilson.[44,42] Neurological decits due to high radiant exposure [J cmÀ2] and high PDT dose, see below, are a limiting factor within the current PDT delivery concepts. Microinvasions, if left untreated, are the probable causes of GBM recurrence and need to be eradicated or minimized post-tumor resection[45] despite the fact that these microinvasions contribute only a minor fraction of the original tumor mass, essentially
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