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As with any other type of therapy, during administration of PDT in addition to obtaining the maximal possible treatment benefit the safety of the patient must be constantly ensured. Some adverse events and reactions may result independently in significant deterioration of health and may be categorized as serious vs. minor, predictable vs. unpredictable, and treatment-related vs. possibly unrelated vs. definitely unrelated. Adverse events must be also examined with regard to factors unique to PDT, that is, related to the photosensitizer, light, and photochemical reactions [6, 21].

Both PDD and PDT are considered sufficiently safe techniques. In a survey of adverse reactions in 42 patients with gastrointestinal cancer who received oral 5-ALA at a dose of 30–60 mg/kg, nausea and vomiting were observed in 15 and 5% of cases, respectively; all were noted within 2–3 h after drug ingestion and lasted for only a very short time [34]. Within 120 h no abnormalities were noted in the laboratory tests, including CBC, urea nitrogen, and serum electrolytes. A few patients had minor liver dysfunction, but no causal relationship with 5-ALA administration could be identified; moreover, all parameters had returned to normal by 2 months after treatment [34]. In a phase I–II study of high-dose PDT with HpD in 23 malignant brain tumors, Kaye et al. [35] noted no evidence of increased cerebral edema or other therapy-related complications, including hematological, hepatic and renal dysfunction, and no increase in the toxicity of postoperative FRT. In a series of 112 patients with various brain tumors treated with Photofrin^® PDT Muller and Wilson [28] observed complications in 25% of cases. Death, postoperative hemorrhage, neurological impairment, deep venous thrombosis, infection, and light sensitivity (hand burns, facial erythema, facial pruritus), were marked in 2.7, 2.7, 6.2, 3.6, 3.6, and 3.6% of patients, respectively. However, the majority of major complications were seemingly related to tumor resection, but not to photo-irradiation [28]. Eljamel et al. [6] reported their experience with more than 365 PDD/PDT procedures using both 5-ALA and Photofrin^® in 150 brain tumor patients. Adverse events were encountered in 7 cases (4.7%). Deep venous thrombosis developed in 3 (2%) and in all of them Photofrin^® had been used, while no one case of that complication was noted after administration of 5-ALA. Serious skin photosensitivity reactions occurred in 2 patients (1.3%) owing to non-adherence to light protection, and it was considered to have been avoidable had precautions been taken. Cerebral edema occurred after Photofrin^® PDT in 2 patients (1.3%) with recurrent tumors, both of whom required treatment. This complication was not noted after PDT of newly diagnosed neoplasms. Rupture of the balloon diffuser for PDT and necrosis of the previously irradiated skin flap with cerebrospinal fluid (CSF) leak occurred in 1 patient each (0.7%). Overall, these side effects were not different from those encountered during standard brain tumor therapy [6].

In patients with malignant gliomas infiltrating eloquent brain structures or spinal cord, a question remains is whether PDT can selectively eradicate the neoplasm without postoperative neurological deterioration. As mentioned above, in our series 11 of 13 patients harboring such high-risk tumors had either unchanged or improved neurological status after incomplete resection combined with Photofrin^® PDT. Schmidt et al. [36] evaluated PDT in 20 patients with recurrent malignant brain neoplasms located near functionally important brain areas. Neurotoxicity in the form of ataxia and facial palsy was noted in 1 case each. However, these complications might be caused by tumor resection, or result from damage sustained by normal brain tissues during optical fiber insertion and were not associated with photo-irradiation itself. Of note, in their series no side effects were noted in 2 cases of brainstem gliomas. The authors concluded that the toxicity profile in their patients was within the acceptable range [36]. These results indicate that Photofrin^® PDT is unlikely to cause severe and/or irreversible damage to normal brain tissue and can be applied safely even to critically located tumors [10, 37].

Most of the complications associated with PDT are actually caused by tumor resection and are not unique to photo-irradiation. Certainly, photosensitivity reactions of the skin and retina should be considered as minor predictable treatment-related adverse events. Their negative consequences can be easily avoided with appropriate protective measures. Moreover, in the majority of patients excessive photosensitivity fully resolves within 4 days after photosensitizer administration and at most lasts approximately 2 weeks [31]. Of note, the incidence and magnitude of adverse effects associated with PDT are much lower as compared with FRT and chemotherapy.