Photodynamic therapy within edematous brain tissue: considerations on sensitizer dose and time point of laser...

Photosensitizer is known to spread with vasogenic edema fluid arising from a cerebral lesion (Neurosurg 33:1075-1082, 1993), which may be essential for sensitizing malignant cells outside the main tumor mass. The present experiments seek to elucidate whether resultant necrosis of perifocal brain tissue after laser irradiation follows a corresponding time pattern and whether damage depends on the photosensitizer dose. Male Wistar rats were anaesthetized with chloralhydrate for venous cannulation, craniotomy and focal cold lesion in order to induce vasogenic edema. Simultaneously, Photofrin II (PF II) was administered at a dose of 5 mg kg-1. The animals were re-anaesthetized after either 4, 12 or 24 h for the irradiation of lesion and perifocal tissue with 200 J cm-2 of laser light (630 nm). The brains of other animals were irradiated 4 h after cold lesion with 200 J cm-2 after receiving either 0, 2.5 or 5 mg kg-1 PF II (all groups: n = 6). Resultant necrosis was assessed planimetrically in serial coronal cryosections of brains perfusion fixed 24 h after irradiation. Necrosis was significantly enhanced with irradiation 4 h after cold lesion and photosensitizer (avg. area +/- SD: 4.3 +/- 0.7 mm2) compared with lesion only (0.84 +/- 0.2 mm2). Maximal necrosis (6.3 +/- 1.6 mm2) occurred with irradiation 12 h after lesion, whereas necrosis was only slightly increased with irradiation at 24 h (2.8 +/- 0.4 mm2). Furthermore, the area of necrosis was dependent on the sensitizer dose (0 mg kg-1: 0.7 +/- 0.3 mm2, 2.5 mg kg-1: 2.09 +/- 0.2 mm2, 5 mg kg-1: 4.3 +/- 0.7 mm2; all differences p < 0.05). Therefore, to prevent unwanted side-effects such as necrosis of edematous but otherwise healthy, peritumoral tissue in the treatment of malignant cerebral tumors by PDT, tribute should be paid to the possibility of time and dose dependent sensitization of the perifocal tissue after i.v. administration of photosensitizer.