Recurrence is a hallmark of malignant glioma, regardless of the therapy applied [6–10, 17]. Although PDT is a novel localized treatment for malignant glioma that can selectively kill tumor cells [14–16], it cannot completely prevent local recurrence [11, 12]. The prognosis of malignant glioma is unfortunately poor at recurrence, but its early detection can vastly improve the clinical course and patients’ management, such as reoperation, which might boost prognosis [18–22]. In this study, we found that a hyperintense signal on DWI as the post-PDT acute response helped to predict the local recurrence site. The PDT-irradiated area asymptomatically showed transient linear hyperintense signal on DWI. All local recurrences arose from the areas without this hyperintense signal on DWI that did not show the acute response on day 1 after PDT.
PDT exploits the tumor-selective accumulation of a photosensitizer and a photochemical reaction upon semiconductor laser irradiation. Singlet oxygen is generated and exerts an antitumor effect in the penetration depth of the semiconductor laser (5–7 mm) [11, 14]. The singlet oxygen exerts this antitumor effect without bystander effects because of its short migration distance (0.02–1 µm) and short lifetime (0.04–4 µs) [14, 24, 25]. Histopathologically, the effect of PDT is underpinned by direct tumor cell killing, including both apoptosis and necrosis [13, 26], tumor-associated vascular damage [27, 28], and activation of the immune response against tumor cells [29–31]. Because the PDT-induced cell damage and microcirculatory impairment leads to restricted diffusivity of water molecules, the PDT-irradiated area shows hyperintense signal on DWI and a decline in ADC values as the acute response [32]. All patients in this study exhibited linear hyperintense signal of about 5 mm in size on DWI at the surface of the resected cavity from day 1 after PDT, as we previously reported [23]. These characteristic changes asymptomatically disappeared in about 30 days.
About 80% of glioblastomas treated with the Stupp regimen develop local recurrence within 2 cm of the tumor margin [6–10, 17]. The extent of the glioblastoma resection is undoubtedly an independent prognostic factor [1–4]. However, Ellingson et al. reported that the postoperative residual contrast-enhancing tumor volume rather than extent of resection was a significant independent prognostic factor [33]. In line with this theory, PDT was added to maximal resection to kill as many tumor cells as possible around the resected cavity. Nitta et al. reported that PDT provided effective local control (local recurrence rate, 33%) and led to increased relative rates of distant recurrence or dissemination [11]. In our study, local recurrence was observed in only 33% of patients, indicating excellent local control, as in Nitta et al. However, PDT cannot completely control local recurrence, and the cause of PDT failure remains unclear. Several factors have been reported to contribute to PDT resistance, including overexpression of antioxidant enzyme, activation of drug efflux pumps, degeneration of photosensitizer, and increased DNA repair capacity in glioblastoma cells [34–38]. Our findings suggest that local recurrence after PDT occurred from the area with no acute response to PDT. This evidence supports the belief that PDT is locally effective in areas with an acute response on DWI. Clarification of the relationship between the area without an acute response to PDT and resistance to PDT would be an issue for future studies aimed at reducing PDT failure.
The acute response of malignant gliomas to PDT was detected as asymptomatic transient linear hyperintense signal on DWI. Interestingly, all local recurrences after PDT occurred from areas that did not show a hyperintense signal on DWI obtained on day 1 after PDT. This characteristic finding could help to predict the local recurrence site. By carefully observing the areas without hyperintense signal on DWI after PDT, we can detect recurrence earlier than ever. This would allow us to provide patients with greater opportunities for reoperation for resectable recurrence, which would undoubtedly improve their prognosis.
Nonetheless, our study also has several limitations. First, the study was conducted at a single institution. Second, the number of patients was small. However, the safety and effectiveness of PDT in our study was almost the same as in a phase II clinical trial and a previous report [11, 12]. Third, the image comparison after PDT and at recurrence had to manually consider the morphological changes in the brain. Fourth, we could not find a significant link between the hyperintense signal on DWI as an acute response after PDT and distant recurrence or dissemination. The patients with distant recurrence or dissemination tended to have an uninterrupted hyperintense signal on DWI obtained on day 1 after PDT. However, the difference was not clear enough to allow their discrimination from the local recurrence cases. Finally, this study could not fully examine other risk factors for recurrence in malignant glioma after PDT. The primary tumors of all disseminated cases were localized near the ventricles. Ventricle contact has been associated with poor outcomes [39], whereas subventricular zone contact has been associated with dissemination [40]. Ventricular entry during resection has been linked to dissemination [41], although the connection is controversial [42, 43]. Therefore, further studies using larger groups of patients and including these factors are needed to validate the recurrence pattern after PDT. Nevertheless, it was clinically important that the local recurrence in malignant gliomas after PDT occurred in the area without the hyperintense signal on DWI as an acute response to PDT. To our knowledge, this is the first study to show the usefulness of visually clear hyperintense signal on DWI in the monitoring of local recurrence after PDT in malignant glioma.