Non-invasive loco-regional electro-hyperthermia (EHT) plus alkylating chemotherapy is occasionally used as salvage treatment in the relapse of patients with high-grade gliomas. Experimental data and retrospective studies suggest potential effects. However, no prospective clinical results are available. We performed a single-center prospective non-controlled single-arm Phase I trial. Main inclusion criteria were recurrent high-grade glioma WHO Grade III or IV, age 18-70, and Karnofsky performance score > or = 70. Primary endpoints were dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) with the combined regimen. Groups of 3 or 4 patients were treated 2-5 times a week in a dose-escalation scheme with EHT. Alkylating chemotherapy (ACNU, nimustin) was administered at a dose of 90 mg/m(2) on day 1 of 42 days for up to six cycles or until tumor progression (PD) or DLT occurred. Fifteen patients with high-grade gliomas were included. Relevant toxicities were local pain and increased focal neurological signs or intracranial pressure. No DLT occurred. In some patients, the administration of mannitol during EHT or long-term use of corticosteroids was necessary to resolve symptoms. Although some patients showed responses in their primarily treated sites, the pattern of response was not well defined. EHT plus alkylating chemotherapy is tolerable in patients with relapse of high-grade gliomas. Episodes of intracranial pressure were, at least, possibly attributed to EHT but did not cause DLTs. A Phase II trial targeting treatment effects is warranted on the basis of the results raised in this trial.

BackgroundAlthough Temozolomide is effective against glioblastoma, the prognosis remains dismal and new regimens with synergistic activity are sought for.MethodsIn this phase-I/II trial, pegylated liposomal doxorubicin (Caelyx™, PEG-Dox) and prolonged administration of Temozolomide in addition to radiotherapy was investigated in 63 patients with newly diagnosed glioblastoma. In phase-I, PEG-Dox was administered in a 3-by-3 dose-escalation regimen. In phase-II, 20 mg/m2 PEG-Dox was given once prior to radiotherapy and on days 1 and 15 of each 28-day cycle starting 4 weeks after radiotherapy. Temozolomide was given in a dose of 75 mg/m2 daily during radiotherapy (60 Gy) and 150-200 mg/m2 on days 1-5 of each 28-day cycle for 12 cycles or until disease progression.ResultsThe toxicity of the combination of PEG-Dox, prolonged administration of Temozolomide, and radiotherapy was tolerable. The progression free survival after 12 months (PFS-12) was 30.2%, the median overall survival was 17.6 months in all patients including the ones from Phase-I. None of the endpoints differed significantly from the EORTC26981/NCIC-CE.3 data in a post-hoc statistical comparison.ConclusionTogether, the investigated combination is tolerable and feasible. Neither the addition of PEG-Dox nor the prolonged administration of Temozolomide resulted in a meaningful improvement of the patient's outcome as compared to the EORTC26981/NCIC-CE.3 dataTrial registrationclinicaltrials.gov NCT00944801.

Objectives: Combined treatment approaches targeting tumor as well as other cells contributing to tumor progression may control chemorefractory malignancies. Methods: A phase II trial was initiated to analyze the activity of continuously administered pioglitazone and rofecoxib combined with low-dose chemotherapy (capecitabine or temozolomide) in patients with high-grade gliomas (glioblastoma or anaplastic glioma). Results: Fourteen patients were evaluable for response and toxicity. Major side effects were palmoplantar erythema, edema and motor neuropathy grade 3. Disease stabilizations lasting longer than 3 months were noted in 4 of 14 patients (29%). Clinical responses did not correspond to immunohistochemical staining for cyclooxygenase 2, peroxisome proliferator-activated receptor-γ and CD31. Discussion: The study demonstrates that this novel regimen is moderately active and well tolerated in patients with high-grade gliomas. As a comparably small proportion of patients responded, the regimen might only be suitable for a subset of highly selected patients.

Background: Recurrent malignant glioma has a dismal prognosis, and therapeutic options are scarce. After previous potentially encouraging reports on liposomal pegylated doxorubicin (PEG-DOX) in this setting, PEG-DOX was applied to patients with recurrent malignant glioma in an institutional series. Methods: In a retrospective analysis, 49 patients with recurrent high-grade glioma (WHO III, n = 18; WHO IV, n = 31) were treated with PEG-DOX (days 1 and 14/28, 20 mg/m², n = 26) alone or in combination with temozolomide (days 1–5/28, 200 mg/m², n = 23). The response rate, progression-free survival and overall survival were evaluated. Results: The rate of progression-free patients at 6 months after initiation of therapy was 27% (WHO III, 33%; WHO IV, 23%). The median overall survival (mOS) after initiation of PEG-DOX (monotherapy and combination therapy) was 8 months (WHO III, 16 months; WHO IV, 7 months). The mOS after initiation of PEG-DOX monotherapy was 8 months, and after initiation of combination therapy, 10 months. Both regimens were well tolerated, with the main side effect being hematologic toxicity (grade 1–2, 8%; grade 3–4, 18%). Conclusion: These data demonstrate the safety and moderate efficacy of PEG-DOX ± temozolomide therapy in recurrent malignant glioma. The potential of this nonalkylating chemotherapy should be further explored.

There is an urgent need for strategies maintaining remission in patients with malignant glioma. Maintenance therapy with high-dose cRA is feasible and well tolerated over long periods of time. A controlled clinical trial to test the efficacy of cRA as a maintenance treatment in malignant glioma is warranted.