ABSTRACT
PURPOSE: To analyse feasibility, prognostic factors and patterns of recurrence after concurrent reirradiation and bevacizumab for recurrent high-grade gliomas. PATIENTS AND METHODS: Between 2009 and 2015, 35 patients (median 57-year-old; 21 men, 14 women) with WHO grade III (n=11) or grade IV (n=24) gliomas were included in this retrospective and consecutive single-centre study. All patients received bevacizumab (median number of treatments: 12) concomitant with reirradiation (median dose: 45Gy, median number of fractions: 18) for recurrence with median 22 months (range: 5.6-123.7 months) from first irradiation (median dose: 60Gy). RESULTS: The median follow-up was 9.2 months from reirradiation. The median overall survival from reirradiation was 10.5 months (95% confidence interval [95% CI]: 4.9-16.1) and the progression-free survival from reirradiation was 6.7 months (95% CI: 2.9-10.5). The median overall survival from initial diagnosis was 44.6 months (95% CI: 32-57.1). No grade 3 toxicity or above was reported. Prognostic factors significantly correlated with better overall survival in univariate analysis were: age at least 55 (P=0.024), initial surgery (P=0.003), and 2Gy equivalent dose (EQD2) at least 50Gy at reirradiation (P=0.046). Twenty-two patients bevacizumab-naïve at time of reirradiation had a significantly increased overall survival from reirradiation compared to patients treated with reirradiation after bevacizumab failure (17.7 vs. 5.4 months, P<0.001) as well as overall survival from initial diagnosis (58.9 vs. 33.5 months, P=0.006). This outcome was similar in patients with initial glioblastomas (P=0.018) or anaplastic gliomas (P=0.021). There was no correlation between overall survival and gross tumour volume or planning target volume, frontal localization, or number of salvage therapies before reirradiation (P>0.05). CONCLUSIONS: Concomitant reirradiation with bevacizumab in high-grade recurrent gliomas shows encouraging results in terms of survival and toxicities. Our data suggest that reirradiation should be favoured at initiation of bevacizumab, with EQD2 at least 50Gy.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Bevacizumab/therapeutic use , Brain Neoplasms/mortality , Brain Neoplasms/therapy , Chemoradiotherapy , Glioma/mortality , Glioma/therapy , Re-Irradiation , Adult , Age Factors , Aged , Brain Neoplasms/pathology , Female , Glioma/pathology , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/therapy , Prognosis , Radiotherapy Dosage , Retrospective Studies , Young AdultABSTRACT
A paradigm shift has occurred in the last decade from chemotherapy to targeted therapy for the management of many patients with advanced sarcoma. This work identifies a combination of targeted agents and doxorubicin that are effective against small cell sarcoma cell lines. Three small cell sarcoma cell lines were studied: RD18 (rhabdomyosarcoma), A204 (undifferentiated sarcoma) and TC 71 (Ewing's sarcoma). Each cell line was exposed to increasing concentrations of vorinostat (HDAC inhibitor), 17-DMAG (HSP90 inhibitor), abacavir (anti-telomerase) or sorafenib (tyrosine kinase inhibitor) alone, combined with one another, or combined with doxorubicin. Cell viability, cell cycle analysis and apoptosis were assessed by MTS assay, propidium iodide-Annexin V staining, and caspase 3/7 activity, respectively. The Chou and Talalay combination index (CI) was used to determine whether the effects were additive (CI = 1), synergistic (CI < 1) or antagonistic (CI > 1). In monotherapy, targeted agents achieved 30-90% reductions in viability, with the exception of abacavir. Dual-targeted combination therapies with vorinostat, sorafenib and 17-DMAG demonstrated synergy. Abacavir was antagonistic with every other drug and was not further studied. Both vorinostat and 17-DMAG synergized with doxorubicin, achieving 60% cell killing compared to 12% with doxorubicin alone. No synergy was observed for sorafenib with doxorubicin. The triple therapy vorinostat, 17-DMAG and doxorubicin did not show synergy, but increased the subG1 population at 24H, from 30% to 70% compared to monotherapies with an increase in apoptosis. This work provides evidence of synergy of combinations of vorinostat, 17-DMAG and sorafenib in small cell sarcoma. In addition to doxorubicin, these combinations enhance doxorubicin cytotoxicity at therapeutically relevant concentrations.
