1. Department of General and Specialized Surgery, Fluminense Federal University, Rio de Janeiro, Brazil.
3. Service of Neurosurgery, Getulio Vargas Estate Hospital, Rio de Janeiro, Brazil.
4. Service of Anatomopathology, Fernando Magalhães Town Hospital, Rio de Janeiro, Brazil. 5Department of Pathology, Rio de Janeiro Federal University, UNIRIO, Rio de Janeiro, Brazil.
Aim: Glioblastoma multiforme (GBM), the most common and lethal primary brain tumor in adults, inevitably recurs despite standard of care, consisting of surgical resection, radiotherapy (RT), and alkylating temozolomide (TMZ). High content of the repair enzyme MGMT (O6-methylguanine-DNA methyltransferase) contributes to drug resistance and tumor recurrence. The monoterpene perillyl alcohol (POH) induces apoptosis and cytotoxicity of TMZ-resistant and TMZ-sensitive glioma cells independently of MGMT expression.
Case presentation: We report the case of an adult patient with non-resected inoperable recurrent GBM that was successfully treated with POH inhalation in combination with oral TMZ, after failing to respond to standard treatment. A 51-year-old white woman with a sudden, intense and refractory headache with no underlying cause showed brain image (MRI) with diffusely infiltrating lesion, prominent edema, and marked mass effect with midline shift, consistent with inoperable high-grade malignant glioma in the right temporal lobe. A complex histological feature, characterized by ischemic necrosis and glomeruloid microvascular proliferation, confirmed the diagnosis of malignant glioma. Immunohistochemical evaluation showed marked EGFR (epidermal growth factor receptor) staining; active proliferative status was confirmed by high Ki67 and p21 expression; there was strong p53 tumor suppressor labeling but faint cytoplasmic PTEN staining; expression of MLH1 and MSH6, two proteins associated with mismatch DNA repair and resistance to TMZ, was elevated. Indeed, 6 months after onset and despite specific treatment (RT+TMZ), this patient had tumor recurrence at same site. She developed adverse reactions including thrombocytopenia and resistance to alkylating TMZ, and was indicated for palliative treatment. The patient was then enrolled (December 2012) in the clinical trial for treatment with POH inhalation concomitant with 300 mg TMZ oral schedule during 5 days. MRI scans performed 3, 7, 12 and 24 months later (December 2012 to December 2014) revealed marked reduction of enhancing lesion without further recurrences.
Conclusion: Despite increased expression of DNA repair proteins supporting drug resistance, combined POH+TMZ therapy reduced tumor mass, halted tumor recurrence, and increased patient’s survival. This case highlights the therapeutic efficacy of combined POH intranasal administration with systemic TMZ in a patient with non-resected inoperable GBM, who failed prior therapy and was under supportive treatment.
Keywords: Perillyl alcohol, intranasal administration, glioblastoma multiforme, combination therapy, temozolomide, drug resistance