Metronomic photodynamic therapy (mPDT) for intracranial neoplasm: physiological, biological, and dosimetry considerations

Abstract

Metronomic photodynamic therapy (mPDT), a procedure in which both the photosensitizer and light are delivered continuously so that the individual doses overlap pharmacologically is introduced. The fundamental hypothesis in mPDT is that by providing therapy at low fluence over extended periods of time, there is potential for improved selectivity in tumor cell kill through non necrotic pathways. This is especially important in the treatment of malignant brain tumors, in which selectivity between damage to tumor cells versus normal brain tissue is critical. Previous studies have shown that low-dose PDT using aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) can induce apoptosis in tumor cells without causing necrosis in either tumor or normal brain tissue nor apoptosis in the latter. However, in order to achieve tumor control, multiple PDT treatments, such as hyper fractionation or metronomic delivery, are required, where the frequency and duration of the treatment are determined by the levels of apoptosis achieved in relationship to tumor cell doubling times. mPDT poses two substantial technical challenges: extended delivery of ALA and implantation of interstitial devices for extended light delivery at a sufficiently high enough density to achieve low fluence exposure to the brain adjacent to tumor or the entire hemisphere. In a rat model we evaluated the feasibility of delivering sustained ALA administration via the drinking water for up to 10 days without loss of PPIX selectivity. Post mortem quantitative spectrofluorimetry of tumor, normal brain and other tissues demonstrates a 4 times higher PPIX concentration in the 9L gliosarcoma model without noticeable toxicity. Light sources and delivery devices based either on laser diode or light emitting diode (LED) coupled to an implanted optical fiber were shown to be feasible. The maximum permissible spacing of cylindrical isotropic emitters is determined using known apoptotic indices and the necrosis threshold value for white matter. Preliminary evidence of selective apoptosis of tumor under these conditions is presented.