Re-irradiation and bevacizumab in recurrent high-grade glioma: an effective treatment option.

Re-irradiation has been shown to be a meaningful option for recurrent high-grade glioma (HGG) patients. Furthermore, bevacizumab exerts certain activity in combination with chemotherapy/as monotherapy and was safely tested in combination with radiotherapy in several previous studies. To our knowledge, this is the largest cohort of patients treated with both re-irradiation and bevacizumab to date. After receiving standard radiotherapy (with or without TMZ) patients with recurrent HGG were treated with bevacizumab (10 mg/kg intravenously at d1 and d15) during re-irradiation. Median prescribed radiation dose during re-treatment was 36 Gy, conventionally fractionated. Datasets of 71 re-irradiated patients were retrospectively analyzed. Patients either received bevacizumab (N = 57) or not (N = 14; other substances (N = 4) and sole radiation (N = 10)). In patients receiving bevacizumab, both post-recurrence survival (PRS) (median 8.6 vs. 5.7 months; p = 0.003, log-rank test) and post-recurrence progression-free survival (PR-PFS, 5.6 vs. 2.5 months; p = 0.005, log-rank test; PFS-6 42.1 % for the bevacizumab group) were significantly increased which was confirmed by multivariate analysis. KPS, re-surgery, MGMT methylation status, sex, WHO grade, tumor volume and age were no significant predictors for neither PR-PFS nor PRS (univariate analysis). Re-irradiation with bevacizumab remains a feasible and highly effective treatment schedule. Studies on further salvage strategies and timing of sequential treatment options versus observation are warranted.

Re-irradiation in recurrent malignant glioma: prognostic value of [18F]FET-PET.

The aim of the present study is to determine new positron emission tomography (PET) imaging-related factors predictive of progression-free survival as well as survival in patients with recurrent malignant glioma (MG) prior to and after re-irradiation. Fifty-six patients with recurrent MG who underwent re-irradiation treatment and pretherapeutic dynamic [(18)F]-fluoroethyl-L-tyrosine (FET)-PET scan were retrospectively analyzed. The prognostic value of different parameters, such as biological tumor volume, maximal tumor uptake (SUV(max)/BG), mean tumor uptake (SUV(mean)/BG), as well as uptake kinetics, was evaluated. [(18)F]FET uptake kinetics was classified according to a five-point rating as category G(1-2) (strongly/mainly increasing kinetics), G(3) (mixed 1:1), or G(4-5) (mainly/strongly decreasing kinetics). Patients within the pretherapeutic kinetic group G(4-5) had significantly worse survival than the other two groups (p = 0.01). Multivariate analysis revealed that histologic grade, Karnofsky Performance Score (KPS), and kinetic group were independent significant predictors for survival after re-irradiation. The uptake kinetics of [(18)F]FET-PET is an independent determinant of overall and to a lesser extent also progression-free survival. Thus, [(18)F]FET-PET kinetics may provide valuable additional prognostic information for treatment decisions.

FET-PET assessed recurrence pattern after radio-chemotherapy in newly diagnosed patients with glioblastoma is influenced by MGMT methylation status.

BACKGROUND AND PURPOSE: The aim of the present study was to evaluate factors predicting the recurrence pattern determined by [(18)F]FET-PET imaging in patients with newly diagnosed glioblastoma after combined radio-chemotherapy treated according to the EORTC/NCIC trial. MATERIAL AND METHODS: Seventy-nine patients with newly diagnosed GBM treated with radiotherapy plus temozolomide (75 mg/m(2)/d) followed by adjuvant cyclic (5/28 days) temozolomide (150-200 mg/m(2)) were retrospectively analysed. Recurrence patterns were assessed by means of positron-emission-tomography with [(18)F]FET and additional MRI; in 54 patients MGMT methylation status was evaluated. RESULTS: Whilst 49.4% of the patients had an in-field recurrence, 12.6% an ex-field recurrence and 3.8% a recurrence at the field margin, 34.2% of the patients did not relapse during follow-up (median 595 days). Considering all patients included in this study, 41.5% (12/29) of the MGMT methylated population had no relapse, 37.9% (11/29) had an in-field-recurrence and 20.7% (6/29) an ex-field/marginal recurrence, whilst 28.0% (7/25) of the MGMT unmethylated population had no relapse, 64.0% (16/25) had an in-field-recurrence and 8.0% (2/25) an ex-field/marginal recurrence (p=0.15). CONCLUSIONS: After the administration of temozolomide concomitant with and adjuvant to radiotherapy in patients with glioblastoma, the pattern determined by [(18)F]FET-PET seems to be associated with MGMT methylation status.

Irradiation and bevacizumab in high-grade glioma retreatment settings.

PURPOSE: Reirradiation is a treatment option for recurrent high-grade glioma with proven but limited effectiveness. Therapies directed against vascular endothelial growth factor have been shown to exert certain efficacy in combination with chemotherapy and have been safely tested in combination with radiotherapy in a small cohort of patients. To study the feasibility of reirradiation combined with bevacizumab treatment, the toxicity and treatment outcomes of this approach were analyzed retrospectively. PATIENTS AND METHODS: After previous treatment with standard radiotherapy (with or without temozolomide) patients with recurrent malignant glioma received bevacizumab (10 mg/kg intravenous) on Day 1 and Day 15 during radiotherapy. Maintenance therapy was selected based on individual considerations, and mainly bevacizumab-containing regimens were chosen. Patients received 36 Gy in 18 fractions. RESULTS: The data of the medical charts of the 30 patients were analyzed retrospectively. All were irradiated in a single institution and received either bevacizumab (n = 20), no additional substance (n = 7), or temozolomide (n = 3). Reirradiation was tolerated well, regardless of the added drug. In 1 patient treated with bevacizumab, a wound dehiscence occurred. Overall survival was significantly better in patients receiving bevacizumab (p = 0.03, log-rank test). In a multivariate proportional hazards Cox model, bevacizumab, Karnovsky performance status, and World Health Organization grade at relapse turned out to be the most important predictors for overall survival. CONCLUSION: Reirradiation with bevacizumab is a feasible and effective treatment for patients with recurrent high-grade gliomas. A randomized trial is warranted to finally answer the question whether bevacizumab adds substantial benefit to a radiotherapeutic retreatment setting.

FET-PET for malignant glioma treatment planning.

BACKGROUND AND PURPOSE: The aim of this study was to compare MRI-based morphological gross tumour volumes (GTVs) to biological tumour volumes (BTVs), defined by the pathological radiotracer uptake in positron emission tomography (PET) imaging with (18)F-fluoroethyltyrosine (FET), subsequently clinical target volumes (CTVs) and finally planning target volumes (PTVs) for radiotherapy planning of glioblastoma. PATIENTS AND METHODS: Seventeen patients with glioblastoma were included into a retrospective protocol. Treatment-planning was performed using clinical target volume (CTV=BTV+20mm or CTV=GTV+20mm+inclusion of the edema) and planning target volume (PTV=CTV+5mm). Image fusion and target volume delineation were performed with OTP-Masterplan®. Initial gross tumour volume (GTV) definition was based on MRI data only or FET-PET data only (BTV), secondarily both data sets were used to define a common CTV. RESULTS: FET based BTVs (median 43.9 cm(3)) were larger than corresponding GTVs (median 34.1cm(3), p=0.028), in 11 of 17 cases there were major differences between GTV/BTV. To evaluate the conformity of both planning methods, the index (CTV(MRT)∩CTV(FET))/(CTV(MRT)∪CTV(FET)) was quantified which was significantly different from 1 (0.73 ± 0.03, p<0.001). CONCLUSION: With FET-PET-CT planning, the size and geometrical location of GTVs/BTVs differed in a majority of patients. It remains open whether FET-PET-based target definition has a relevant clinical impact for treatment planning.

Therapeutic options for recurrent malignant glioma.

BACKGROUND AND PURPOSE: Despite the given advances in neuro-oncology most patients with high grade malignant glioma ultimately fail locally or locoregionally. In parallel with improvements of initial treatment options, several salvage strategies have been elucidated and already entered clinical practice. Aim of this article is to review the current status of salvage strategies in recurrent high grade glioma. MATERIAL AND METHODS: Using the following MESH headings and combinations of these terms the pubmed database was searched: "Glioma", "Recurrence", "Neoplasm Recurrence, Local", "Radiosurgery", "Brachytherapy", "Neurosurgical Procedures" and "Drug Therapy". For citation crosscheck the ISI web of science database was used employing the same search terms. In parallel, the abstracts of ASCO 2008-2009 were analyzed accordingly. RESULTS: Currently the following options for salvage entered clinical practice: re-resection, re-irradiation (stereotactic radiosurgery, (hypo-)fractionated (stereotactic) radiotherapy, interstitial brachytherapy) or single/poly-chemotherapy schedules including new dose-intensified or alternative treatment protocols employing targeted drugs. Re-operation is associated with high morbidity and mortality, however, is an option in a highly selected patient cohort. Since toxicity has been overestimated, re-irradiation is an increasingly used option with precise fractionated radiotherapy being the most optimal technique. On average, time to secondary progression is in the range of several months. Conventional chemotherapy regimens also improve time to secondary progression; however the efficacy is only modest and treatment-related toxicities like myelo-suppression occur very frequently. Molecular targeted agents/kinases are undergoing clinical testing; however no final recommendations can be made. CONCLUSIONS: Currently, several re-treatment options with only modest efficacy exist. The relative value of each approach compared to other options is unknown as well as it remains open which sequence of modalities should be chosen.