Continuous low-dose temozolomide and celecoxib in recurrent glioblastoma

Even after gross tumor resection and combined radiochemotherapy, glioblastomas recur within a few months. Salvage therapy often consists of rechallenging with temozolomide in a dose-intensified schedule. Previously, low-dose metronomic temozolomide in combination with cyclo-oxigenase 2 inhibitors has had a beneficial effect as first-line treatment for glioblastoma. We report our experience with this procedure in recurrent glioblastomas after standard treatment. From June 2007 to April 2009, 28 patients with recurrent glioblastoma received continuous low-dose temozolomide of 10 mg/m² twice daily and 200 mg celecoxib. Before therapy the recurrent tumor was resected in 19 of 28 patients. Microvessel density (MVD) was determined by immunohistochemistry in 19 patients, and MGMT promoter methylation status, using the pyrosequencing method, was determined in 17 patients. In 14/28 patients, positron emission tomography with [F-18]-fluoroethyl)-l-tyrosine (FET-PET) was performed. Tumor progression was defined by the Macdonald criteria on MRI every 8–12 weeks or by clinical deterioration. The median time to progression was 4.2 months. Progression-free survival (PFS) after 6 months was 43%. Except for a lymphopenia in one patient, there was no grade 3 or 4 toxicity. PFS did not correlate with MVD or MGMT status. A high FET uptake correlated with tumor control after 6 months under therapy (P = 0.041, t-test). Low-dose continuous temozolomide in combination with celecoxib seems to have activity in recurrent glioblastoma without relevant toxicity. High FET uptake correlated with a better outcome under metronomic therapy.     

Glioblastoma treatment using perphenazine to block the subventricular zone’s tumor trophic functions

We present here a potential new treatment adjunct for glioblastoma. Building on murine studies, a series of papers appeared recently showing that therapeutic irradiation of the ipsilateral subventricular zone (SVZ) retards growth of more peripherally growing cortical glioblastomas in humans, suggesting a tumor trophic function for the SVZ. Further studies showed that SVZ cells migrate out towards a peripheral glioblastoma. Dopamine signaling through D3 subtype receptor indirectly drives this centrifugal migration in humans. Since psychiatry has several drugs with good D3 blocking attributes, such as fluphenazine, or perphenazine, we suggest that adding one of these D3 blocking drugs to current standard treatment of resection followed by temozolomide and irradiation might prolong survival by depriving glioblastoma of the trophic functions previously subserved by dopaminergic signaling on SVZ cells.     

A phase II study of extended low-dose temozolomide in recurrent malignant gliomas.

Temozolomide is an effective agent in the treatment of recurrent malignant gliomas. The standard dosage is 150-200 mg/m2 per day for 5 days in a 28-day cycle. A prior phase I study established a chronic daily temozolomide dose that significantly increased the total dose administered and suggested a superior response rate. In a prospective phase II trial, we treated 35 patients with recurrent malignant gliomas with temozolomide 75 mg/m2 per day for 42 consecutive days in a 70-day cycle. Median age was 55 years (range, 27-73 years) and median Karnofsky performance score was 70 (range, 60-90). Twenty-eight (79%) patients had glioblastoma multiforme, 3 (9%) anaplastic astrocytoma, 2 (6%) anaplastic oligodendroglioma, and 2 (6%) anaplastic oligoastrocytoma. All but one had prior radiotherapy, and 27 had prior chemotherapy. There were 2 partial (anaplastic astrocytoma) and 3 minor (glioblastoma multiforme) radiographic responses; 17 patients had progressive disease at the end of the first cycle. In 55 cycles of temozolomide, there were 8 episodes of asymptomatic drug-related grade 3 toxicity: 6 lymphopenia, 1 neutropenia, and 1 thrombocytopenia. Median progression-free survival and overall survival were 2.5 and 8.7 months (2.3 and 7.7 months in glioblastoma multiforme patients). At 6 months, progression-free survival and overall survival rates were 27% and 67% (19% and 60% in glioblastoma multiforme). Quality of life scores did not change significantly during treatment. We conclude that the extended low-dose schedule of temozolomide is well tolerated in heavily pre-treated patients; however, our results do not support an improved rate of response or survival.     

ACNU-based chemotherapy for recurrent glioma in the temozolomide era

No standard of care for patients with recurrent glioblastoma has been defined since temozolomide has become the treatment of choice for patients with newly diagnosed glioblastoma. This has renewed interest in the use of nitrosourea-based regimens for patients with progressive or recurrent disease. The most commonly used regimens are carmustine (BCNU) monotherapy or lomustine (CCNU) combined with procarbazine and vincristine (PCV). Here we report our institutional experience with nimustine (ACNU) alone (n = 14) or in combination with other agents (n = 18) in 32 patients with glioblastoma treated previously with temozolomide. There were no complete and two partial responses. The progression-free survival (PFS) rate at 6 months was 20% and the survival rate at 12 months 26%. Grade III or IV hematological toxicity was observed in 50% of all patients and led to interruption of treatment in 13% of patients. Non-hematological toxicity was moderate to severe and led to interruption of treatment in 9% of patients. Thus, in this cohort of patients pretreated with temozolomide, ACNU failed to induce a substantial stabilization of disease in recurrent glioblastoma, but caused a notable hematotoxicity. This study does not commend ACNU as a therapy of first choice for patients with recurrent glioblastomas pretreated with temozolomide.     

A randomized phase II trial of standard dose bevacizumab versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma

Antiangiogenic therapy can rapidly reduce vascular permeability and cerebral edema but high doses of bevacizumab may induce selective pressure to promote resistance. This trial evaluated the efficacy of low dose bevacizumab in combination with lomustine (CCNU) compared to standard dose bevacizumab in patients with recurrent glioblastoma. Patients (N?=?71) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 1:1 to receive bevacizumab monotherapy (10 mg/kg) or low dose bevacizumab (5 mg/kg) in combination with lomustine (90 mg/m²). The primary end point was progression-free survival (PFS) based on a blinded, independent radiographic assessment of post-contrast T1-weighted and non-contrast T2/FLAIR weighted magnetic resonance imaging (MRI) using RANO criteria. For 69 evaluable patients, median PFS was not significantly longer in the low dose bevacizumab?+?lomustine arm (4.34 months, CI 2.96–8.34) compared to the bevacizumab alone arm (4.11 months, CI 2.69–5.55, p?=?0.19). In patients with first recurrence, there was a trend towards longer median PFS time in the low dose bevacizumab?+?lomustine arm (4.96 months, CI 4.17–13.44) compared to the bevacizumab alone arm (3.22 months CI 2.5–6.01, p?=?0.08). The combination of low dose bevacizumab plus lomustine was not superior to standard dose bevacizumab in patients with recurrent glioblastoma. Although the study was not designed to exclusively evaluate patients at first recurrence, a strong trend towards improved PFS was seen in that subgroup for the combination of low dose bevacizumab plus lomustine. Further studies are needed to better identify such subgroups that may most benefit from the combination treatment.     

Afatinib,an irreversible ErbB family blocker,with protracted temozolomide in recurrent glioblastoma: A case report

There are few effective treatments for recurrent glioblastoma multiforme (GBM). We present a patient with recurrent GBM who achieved a prolonged response to treatment with afatinib, an irreversible ErbB family blocker, plus temozolomide. A 58-year-old female patient was diagnosed with multifocal primary GBM. After surgical resection, first-line therapy comprised radiotherapy and temozolomide. Following disease progression after 3 temozolomide cycles, the patient entered a phase I/II clinical trial of afatinib (20–40 mg daily for 28 days) plus temozolomide (50 mg/m² every 21/28 days). Next-generation sequencing analysis of the brain tumor specimen was performed. At the last assessment, 63 treatment cycles had been completed and the patient had survived for ~5 years since recurrence. Significant disease regression was observed after 5 cycles and was maintained during long-term follow-up. Adverse events were consistent with the known tolerability profile of afatinib and were managed by treatment interruption/dose reduction. The patient had several epidermal growth factor receptor (EGFR) aberrations, including gene amplification and EGFRvIII positivity. Three somatic mutations were identified, including an unprecedented extracellular-domain substitution (D247Y). The patient has survived ~6-fold longer than normally expected in patients with recurrent GBM. The complex EGFR genotype may underlie sustained response to afatinib plus temozolomide.     

Nonsurgical treatment of recurrent glioblastoma

Standard treatment for glioblastoma multiforme is surgery followed by radiotherapy and chemotherapy, generally with temozolomide. However, disease recurs in almost all patients. Diagnosis of progression is complex given the possibility of pseudoprogression.The Response Assessment in Neuro-Oncology criteria increase the sensitivity for detecting progression. Most patients will not be candidates for new surgery or re-irradiation, and anticancer drugs are the most common approach for second-line treatment, if the patient’s condition allows. Antiangiogenics, inhibitors of the epidermal growth factor receptor, nitrosoureas, and re-treatment with temozolomide have been studied in the second line, but a standard therapy has not yet been established. This review considers currently available medical treatment options for patients with glioblastoma recurrence.     

Phase I trial of dose-escalating metronomic temozolomide plus bevacizumab and bortezomib for patients with recurrent glioblastoma

The average survival time for patients with recurrent glioblastoma is between 5 and 9 months. Phase I and II trials have shown a modest survival benefit with combination temozolomide and other chemotherapeutics. We conducted a phase I trial of dose-escalating temozolomide with bevacizumab and the proteasome inhibitor bortezomib for patients with recurrent disease. Three groups of three patients were scheduled to receive daily doses of temozolomide at 25, 50, and 75 mg/m². Fixed doses of bortezomib and bevacizumab were given at standard intervals. Patients were monitored for dose-limiting toxicities (DLT) to determine the maximum-tolerated dose (MTD) of temozolomide with this regimen. No DLT were seen in the first two groups (25 and 50 mg/m² temozolomide). One patient in the 75 mg/m² group experienced a grade 4 elevation of ALT and three more patients were accrued for a total of six patients at that dose level. No other DLT occurred, thus making 75 mg/m² the MTD. Progression-free survival was 3.27 months for all patients and mean overall survival was 20.75 months. The MTD of temozolomide was 75 mg/m² in combination with bevacizumab and bortezomib for recurrent glioblastoma. Only one patient experienced a severe (Grade 4) elevation of ALT. This study will provide the framework for further studies to elicit effectiveness and better determine a safety profile for this drug combination.     

肿瘤治疗电场在脑胶质母细胞瘤治疗中的现状与前景

肿瘤治疗电场是一种新的治疗方法,其通过低强度、中等频率的交变电场干扰肿瘤细胞有丝分裂,从而抑制肿瘤细胞增殖。在治疗复发胶质母细胞瘤患者的临床试验中,肿瘤治疗电场治疗组受试者与经验化疗组受试者相比生存期数据无显著性差异。而在治疗新发胶质母细胞瘤患者的临床试验中,肿瘤治疗电场联合替莫唑胺组受试者与替莫唑胺组受试者相比,生存期显著延长。鉴于肿瘤治疗电场在这两项Ⅲ期临床试验中的优异表现,其被美国国立综合癌症网络（NCCN）指南纳入复发和新发胶质母细胞瘤患者的一线治疗,其产品现已在美国、日本、以色列、中国香港获批准上市。本文对肿瘤治疗电场在脑胶质母细胞瘤治疗中的现状与前景进行综述。      

CUSP9* treatment protocol for recurrent glioblastoma: aprepitant,artesunate, auranofin,captopril, celecoxib,disulfiram, itraconazole,ritonavir, sertraline augmenting continuous low dose temozolomide

CUSP9 treatment protocol for recurrent glioblastoma was published one year ago. We now present a slight modification, designated CUSP9*. CUSP9* drugs- aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, sertraline, ritonavir, are all widely approved by regulatory authorities, marketed for non-cancer indications. Each drug inhibits one or more important growth-enhancing pathways used by glioblastoma. By blocking survival paths, the aim is to render temozolomide, the current standard cytotoxic drug used in primary glioblastoma treatment, more effective. Although esthetically unpleasing to use so many drugs at once, the closely similar drugs of the original CUSP9 used together have been well-tolerated when given on a compassionate-use basis in the cases that have come to our attention so far. We expect similarly good tolerability for CUSP9*. The combined action of this suite of drugs blocks signaling at, or the activity of, AKT phosphorylation, aldehyde dehydrogenase, angiotensin converting enzyme, carbonic anhydrase -2,- 9, -12, cyclooxygenase-1 and -2, cathepsin B, Hedgehog, interleukin-6, 5-lipoxygenase, matrix metalloproteinase -2 and -9, mammalian target of rapamycin, neurokinin-1, p-gp efflux pump, thioredoxin reductase, tissue factor, 20 kDa translationally controlled tumor protein, and vascular endothelial growth factor. We believe that given the current prognosis after a glioblastoma has recurred, a trial of CUSP9* is warranted.     

Temozolomide in combination with irinotecan for treatment of recurrent malignant glioma

The prognosis for patients with recurrent malignant glioma is poor. Both temozolomide and irinotecan have been shown to be active in this disease. A study was performed combining temozolomide 200 mg/m2 daily for 5 days and irinotecan 125 mg/m2 on days 6, 13, and 20 initially (Schedule A) and then changed to (Schedule B) temozolomide 200 mg/m2 daily for 5 days and irinotecan 350 mg/m2 on day 6. Each cycle was 28 days. All patients with recurrent tumor had to complete two cycles of therapy to be evaluable. Six cycles of treatment were provided for all responders. Thirty-two patients were treated, 6 with schedule A, 24 with schedule B, and 2 initially schedule A and then switched to schedule B. Eighteen patients (56%) had glioblastoma and 14 patients and anaplastic glioma (AOA 8, anaplastic astrocytoma 4, AO 2). Eighty-three percent (15/18) of patients with glioblastoma responded (complete response [CR] 2, partial response [PR] 3, stable disease [SD] 10). Median duration of response was 24 weeks, and 6-month progression-free survival (PFS) was 39% (7/18). Fourteen patients with anaplastic glioma were treated and all responded (CR 3, PR 2, SD 9). Median duration of response was 29 weeks and 6-month PFS was 71% (10/14). Grade IV leukopenia occurred in one patient and grade IV thrombocytopenia in two patients. Two patients were admitted to the hospital for neutropenic fever. Nonhematologic toxicity was mild and mostly gastrointestinal. These results demonstrate a favorable response and low toxicity with combined irinotecan and temozolomide therapy and warrant further clinical evaluation.     

Phase I study of temozolomide in relapsed/refractory acute leukemia.

PURPOSE: To determine the dose-limiting toxicity and maximum-tolerated dose of temozolomide in patients with acute leukemia. PATIENTS AND METHODS: Twenty patients (16 with acute myelogenous leukemia, two with acute lymphoblastic leukemia, and two with chronic myelogenous leukemia in blastic phase) received 43 cycles of temozolomide. Patients began treatment at two different dose levels: 200 mg/m(2)/d for 7 days or 200 mg/m(2)/d for 9 days. RESULTS: Prolonged aplasia was the dose-limiting toxicity, and the maximum-tolerated dose was 7 days of temozolomide. Overall treatment was well tolerated: hospitalization was required in only nine of 43 courses, and there were no treatment-related deaths. Two patients obtained a complete response, and two others met criteria for complete response except for platelet recovery. Overall, nine of 20 patients had a significant decrease in bone marrow blasts after temozolomide treatment. CONCLUSION: Temozolomide was well tolerated and had significant antileukemic activity when administered as a single agent. Further studies of temozolomide in hematologic malignancies are indicated.     

Recurrent malignant glioma in adults

Opinion statement Meaningful palliation is possible for selected patients with recurrent malignant glioma (glioblastoma multiforme, anaplastic astrocytoma, anaplastic oligodendroglioma, or anaplastic mixed oligoastrocytoma) using aggressive treatment. Although long-term disease-free survival occurs in fewer than 10% of patients, most who achieve such survival have been treated for multiple recurrences. Surgical resection with the placement of lomustine-releasing wafers is the only therapy proven in randomized trials to be beneficial for recurrent malignant gliomas. Reoperation is indicated when local mass effect limits the quality of life. Reoperation may make other treatments more effective by removing treatment-resistant hypoxic cells and thereby prolonging high-quality survival. Combination chemotherapy (including procarbazine and a nitrosourea) provides dramatic benefit for many recurrent anaplastic or aggressively behaving oligodendrogliomas and anaplastic mixed oligoastrocytomas. For other recurrent malignant gliomas, single-agent cytotoxic chemotherapy (eg, intravenous lomustine or platinums, oral carmustine, temozolomide, or procarbazine) appears to provide equivalent results and better quality of life at a lower cost than do the combinations of cytotoxic drugs. A randomized phase II trial demonstrates that temozolomide provides longer progression-free survival and better quality of life than standard-dose procarbazine in patients with recurrent glioblastoma multiforme. Because benefits of available cytotoxic chemotherapy for anaplastic astrocytoma and glioblastoma are small, participation in clinical trials is appropriate for most patients. Reirradiation (using stereotactic or three-dimensional conformal techniques with or without concomitant cytotoxic chemotherapy) as radiation sensitization can prolong high-quality survival in selected patients. Specific examples include radiosurgery with the gamma knife or with linear accelerators, intracavitary radiation with the newly US Food and Drug Administration-approved GliaSite (Proxima Therapeutics, Alpharetta, GA) radiation therapy system, low dose rate permanent-seed brachytherapy, and high dose rate stereotactic brachytherapy. Dexamethasone (used for the shortest time in the lowest effective doses) can provide symptomatic benefits. Osmotic diuretics such as mannitol reduce cytotoxic edema more rapidly.     

Combined salvage therapies for recurrent glioblastoma multiforme: evaluation of an interdisciplinary treatment algorithm

Glioblastoma multiforme patients presenting with recurrence following multimodality therapy have limited palliative treatment options when the major modalities of therapy including surgery, radiochemotherapy and adjuvant chemotherapy have been exhausted. The authors introduce a clinical and radiological indication-solving algorithm and provide outcome rates of a glioblastoma recurrence cohort. Sixty six consecutive adult patients with recurrent glioblastoma who underwent a combined scheme of salvage treatments consisting of reoperation, high dose rate (HDR) brachytherapy and chemotherapy were included in this prospective study and were compared to a historical control group of 24 recurrent glioblastoma patients who have been treated with intensive temozolomide chemotherapy as the only treatment modality. Median follow-up was 32 months (range 28–36 months). Median survival was 9 months for the entire cohort after salvage treatment and can be translated into a 3-month improvement in survival compared to the control group of patients with glioblastoma recurrence treated with temozolomide alone (P = 0.043). Toxicity and adverse events of reoperation, HDR brachytherapy combined with chemotherapy were quite favourable compared to intensive temomozolomide chemotherapy as the only treatment. Our experience suggests that a combined salvage treatment plan appears to be both feasible and effective and can be considered in selected patients affected by recurrent high grade gliomas. The authors’ clinical and radiological indication-solving algorithm may assist in providing the best possible salvage treatment for this difficult population.     

A pilot study of metronomic temozolomide treatment in patients with recurrent temozolomide-refractory glioblastoma

Frequent regular administration of chemotherapeutic agents at low doses, known as 'metronomic chemotherapy', can increase the anti-angiogenic activity of the drugs, as has been confirmed by several other experimental tumor models. The aim of this pilot study was to evaluate the efficacy and safety of metronomic temozolomide (TMZ) treatment in twelve consecutive patients with recurrent TMZ-refractory glioblastoma. The patients were administered by metronomic treatment schedule (continuous low-dose chemotherapy) with TMZ at a daily dose of 40 mg/m(2). The median overall survival (OS) and progression-free survival (PFS) from the start of metronomic treatment were 11.0 months (95% CI, 5.2-10.5 months) and 6.0 months (95% CI, 0-12.3 months), respectively. During the follow-up period, complete response (CR) was not achieved in any patient, partial response (PR) in 2, and stable disease (SD) in 5 patients. Estimated PFS (CR+PR+SD) was 58.3% at 3 months. Grade III/IV toxicity according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) was not found. These results suggest that the change of chemotherapeutic schedule from conventional to metronomic treatment overcomes the chemo-resistance in patients with recurrent TMZ-refractory glio-blastoma without any major toxicity.     

Phase II study of Thalidomide in the treatment of recurrent glioblastoma multiforme

Treatment options and prognosis remains poor for patients with recurrent glioblastoma multiforme. These tumors are highly vascularised and over express angiogenic factors such as vascular endothelial growth factor and may potentially be responsive to antiangiogenic therapies. We present the results of a phase II trial of Thalidomide, an antiangiogenic agent, in the treatment of recurrent glioblastoma multiforme. Patients were treated with 100mg/day of Thalidomide, increased at weekly intervals by 100mg to a maximum tolerated dose of 500mg/d.Forty-two patients were enrolled, with 38 patients being assessable for response and 39 for toxicity. Two patients (5%) achieved a partial response and 16 (42%) had stable disease. The median survival was 31 weeks and the 1-year survival was 35%. Patients who had a partial response or stable disease had either a stabilisation or improvement in quality of life scores or performance status. Overall Thalidomide was well tolerated with no grade 4 toxicities and no treatment related deaths. The median maximum tolerated dose was 300mg/day. The most common toxicity was fatigue to which patients developed tachyphylaxis. There was no correlation demonstrated with plasma vascular endothelial growth factor levels and response or survival.Thalidomide is a well-tolerated drug that may have some activity in the treatment of recurrent glioblastoma. Optimum dosing with antiangiogenic agents is currently under investigation. Chronic low dose therapy may be required to see conventional responses or improvements in time to progression. The dose required to achieve optimal biological impact may be better defined once we have established reliable surrogate endpoints.     

Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment.

PURPOSE: Glioblastomas are treated by surgical resection followed by radiotherapy [X-ray therapy (XRT)] and the alkylating chemotherapeutic agent temozolomide. Recently, inactivating mutations in the mismatch repair gene MSH6 were identified in two glioblastomas recurrent post-temozolomide. Because mismatch repair pathway inactivation is a known mediator of alkylator resistance in vitro, these findings suggested that MSH6 inactivation was causally linked to these two recurrences. However, the extent of involvement of MSH6 in glioblastoma is unknown. We sought to determine the overall frequency and clinical relevance of MSH6 alterations in glioblastomas. EXPERIMENTAL DESIGN: The MSH6 gene was sequenced in 54 glioblastomas. MSH6 and O(6)-methylguanine methyltransferase (MGMT) immunohistochemistry was systematically scored in a panel of 46 clinically well-characterized glioblastomas, and the corresponding patient response to treatment evaluated. RESULTS: MSH6 mutation was not observed in any pretreatment glioblastoma (0 of 40), whereas 3 of 14 recurrent cases had somatic mutations (P = 0.015). MSH6 protein expression was detected in all pretreatment (17 of 17) cases examined but, notably, expression was lost in 7 of 17 (41%) recurrences from matched post-XRT + temozolomide cases (P = 0.016). Loss of MSH6 was not associated with O(6)-methylguanine methyltransferase status. Measurements of in vivo tumor growth using three-dimensional reconstructed magnetic resonance imaging showed that MSH6-negative glioblastomas had a markedly increased rate of growth while under temozolomide treatment (3.17 versus 0.04 cc/mo for MSH6-positive tumors; P = 0.020). CONCLUSIONS: Loss of MSH6 occurs in a subset of post-XRT + temozolomide glioblastoma recurrences and is associated with tumor progression during temozolomide treatment, mirroring the alkylator resistance conferred by MSH6 inactivation in vitro. MSH6 deficiency may therefore contribute to the emergence of recurrent glioblastomas during temozolomide treatment.     

Canadian recommendations for the treatment of recurrent or progressive glioblastoma multiforme

Recommendation 1: Multidisciplinary ApproachTo optimize treatment outcomes, the management of patients with recurrent glioblastoma should be individualized and should involve a multidisciplinary team approach, including neurosurgery, neuropathology, radiation oncology, neuro-oncology, and allied health professions.Recommendation 2: ImagingThe standard imaging modality for assessment of recurrent glioblastoma is Gd-enhanced magnetic resonance imaging (mri). Tumour recurrence should be assessed according to the criteria set out by the Response Assessment in Neuro-Oncology Working Group. The optimal timing and frequency of mri after chemoradiation and adjunctive therapy have not been established.Recommendation 3: Pseudo-progressionProgression observed by mri after chemoradiation can be pseudo-progression. Accordingly, treated patients should not be classified as having progressive disease by Gd-enhancing mri within the first 12 weeks after the end of radiotherapy unless new enhancement is observed outside the radiotherapy field or viable tumour is confirmed by pathology at the time of a required re-operation. Adjuvant temozolomide should be continued and follow-up imaging obtained.Recommendation 4: Repeat SurgerySurgery can play a role in providing symptom relief and confirming tumour recurrence, pseudo-progression, or radiation necrosis. However, before surgical intervention, it is essential to clearly define treatment goals and the expected impact on prognosis and the patient's quality of life. In the absence of level 1 evidence, the decision to re-operate should be made according to individual circumstances, in consultation with the multidisciplinary team and the patient.Recommendation 5: Re-irradiationRe-irradiation is seldom recommended, but can be considered in carefully selected cases of recurrent glioblastoma.Recommendation 6: Systemic TherapyClinical trials, when available, should be offered to all eligible patients. In the absence of a trial, systemic therapy, including temozolomide rechallenge or anti-angiogenic therapy, may be considered. Combination therapy is still experimental; optimal drug combinations and sequencing have not been established.     

Standards of care for treatment of recurrent glioblastoma—are we there yet?

Newly diagnosed glioblastoma is now commonly treated with surgery, if feasible, or biopsy, followed by radiation plus concomitant and adjuvant temozolomide. The treatment of recurrent glioblastoma continues to be a moving target as new therapeutic principles enrich the standards of care for newly diagnosed disease. We reviewed PubMed and American Society of Clinical Oncology abstracts from January 2006 to January 2012 to identify clinical trials investigating the treatment of recurrent or progressive glioblastoma with nitrosoureas, temozolomide, bevacizumab, and/or combinations of these agents. At recurrence, a minority of patients are eligible for second surgery or reirradiation, based on appropriate patient selection. In temozolomide-pretreated patients, progression-free survival rates at 6 months of 20%–30% may be achieved either with nitrosoureas, temozolomide in various dosing regimens, or bevacizumab. Combination regimens among these agents or with other drugs have not produced evidence for superior activity but commonly produce more toxicity. More research is needed to better define patient profiles that predict benefit from the limited therapeutic options available after the current standard of care has failed.     

Cytotoxic and apoptotic effects of bortezomib and gefitinib compared to alkylating agents on human glioblastoma cells

Glioblastoma is a malignant astrocytic tumor with a median survival of about 12 months for which new therapeutic strategies are required. We therefore examined the cytotoxicity of anticancer drugs with different mechanisms of action on two human glioblastoma cell lines expressing various levels of EGFR (epidermal growth factor receptor). Apoptosis induced by these anticancer agents was evaluated by flow cytometry. The cytotoxicity of alkylating drugs followed a dose-effect curve and cytotoxicity index values were lower with carboplatin than with BCNU and temozolomide. Anti-EGFR gefitinib (10 microM) cytotoxicity on DBTRG.05-MG expressing high levels of EGFR was significantly higher than on U87-MG expressing low levels of EGFR. Carboplatin and temozolomide cytotoxicity was potentiated with the addition of gefitinib on DBTRG.05-MG. Among the anticancer agents tested, the proteasome inhibitor bortezomib was the most cytotoxic with very low IC50 on the two cell lines. Moreover, all anticancer drugs tested induced apoptosis in a concentration-dependent manner. Bortezomib proved to be a more potent inductor of apoptosis than gefitinib and alkylating agents. These results show the efficacy of bortezomib and of the association between conventional chemotherapy and gefitinib on glioblastoma cells and therefore suggest the interest of these molecules in the treatment of glioblastoma.