Efficacy of temozolomide as adjuvant chemotherapy after postsurgical radiotherapy alone for glioblastomas

Objectives

The aim of this study was to assess the efficacy of adjuvant TMZ chemotherapy for newly diagnosed GBM patients who were treated with surgery followed by radiotherapy alone.

Material and methods

Between January 2003 and April 2005, 59 consecutive GBM patients underwent radiation therapy after surgical resection and subsequently received TMZ chemotherapy. For the comparative analysis, we selected 60 clinically matched GBM patients who underwent radiotherapy followed by nitrosourea-based chemotherapy (NUBC), at the same institution between June 1995 and April 2005. The study cohort was divided into two groups, those with adjuvant TMZ treatment and with NUBC.

Results

59 patients with adjuvant TMZ treatment were assigned to the treatment group and 60 patients with NUBC to the control group. The median overall survival for the treatment group was 18.2 months (95% CI, 11.7–24.7 months), compared with the survival of 14.5 months (95% CI, 11.2–17.7 months) for the control group (p = 0.019). The progression-free survival for the treatment group was 5.6 months (95% CI, 4.4–6.7 months), while the control group showed progression-free survival of 3.3 months (95% CT, 3.2–6.0 months) (p = 0.030). Uni- and multivariate analysis revealed that extent of surgical resection, age ≥55 years and postoperative KPS were significantly associated with survival.

Conclusion

Adjuvant TMZ chemotherapy provided a clinically relevant benefit of survival, as compared with NUBC. Thus, we suggest that adjuvant TMZ chemotherapy may be effective even for patients who did not receive concomitant chemoradiotherapy for GBM.     

Neuropathological postmortem evaluation of BNCT for GBM

BACKGROUND: Thirty patients with glioblastoma multiforme (GBM) were treated by boron neutron capture therapy (BNCT) at the Studsvik facility in Sweden, in a clinical trial exploring a procedure in which 900 mg p-boronophenylalanine (BPA) per kilo body weight was infused in 6 h. OBJECTIVE: The present study was designed to assess tumor efficacy and radiation damage to the brain for the seven patients in the Studsvik trial that were available for postmortem neuropathological examination. METHOD: Whole brain slices containing the initial tumor site and other regions showing pathological changes were chosen for microscopy and selected areas were studied by immunological methods. RESULTS: Local control of GBM was observed in all cases. Conclusive evidence for radiation induced brain damage was not found. CONCLUSION: Using a novel procedure for BPA infusion, BNCT achieves local control of GBM for minimum tumor doses as low as 15 wGy, allowing treatment with very low concomitant doses to surrounding healthy tissues.     

BNCT for recurrent intracranial meningeal tumours - case reports

OBJECTIVES: The investigation was designed to explore the efficacy of boron neutron capture therapy (BNCT) as treatment for recurrent intracranial meningeal tumours. MATERIALS AND METHODS: Three patients with meningeal tumours, recurring after initial surgery, radiation therapy and several reoperations, were evaluated for treatment with BNCT by determination of the accumulation of boronophenylalanine fructose (BPA-F) in tumour and in surrounding tissue. Two of these patients were subsequently treated by BNCT. RESULTS: The present results indicate that BNCT could be effective in prolonging time to recurrence, and thus in extending survival time, for patients with recurrent intracranial meningeal tumours. CONCLUSIONS: BNCT is potentially an effective radiation treatment modality for malignant intracranial meningeal tumours, which could increase progression-free survival, thus reducing the need for additional surgical interventions. Indications for BNCT would be even larger if recurrent grade II meningiomas could be treated, as indicated by the results of the boron uptake study.     

Hypo-fractionated IMRT for patients with newly diagnosed glioblastoma multiforme: A 6 year single institutional experience

Objectives

Glioblastoma (GBM) is the most common malignant primary brain tumour in adults. Surgery and radiotherapy constitute the cornerstones for the therapeutic management of GBM. The standard treatment today is maximal surgical resection followed by concomitant chemo-radiation therapy followed by adjuvant TMZ according to Stupp protocol. Despite the progress in neurosurgery, radiotherapy and oncology, the prognosis still results poor.In order to reduce the long time of standard treatment, maintaining or improving the clinical results, in our institute we have investigated the effects of hypo-fractionated radiation therapy for patients with GBM.

Patients and methods

Sixty-seven patients affected by GBM who had previously undergone surgical resection (total, subtotal or biopsy) were enrolled between October 2005 and December 2011 in a single institutional study of hypo-fractionated intensity modulated radiation therapy (IMRT) followed or not by adjuvant chemotherapy with TMZ (6–12 cycles). The most important eligibility criteria were: biopsy-proven GBM, KPS ≥ 60, age ≥ 18 years, no previous brain irradiation, informed consensus. Hypo-fractionated IMRT was delivered to a total dose of 25 Gy in 5 fractions prescribed to 70% isodose. Response to treatment, OS, PFS, toxicity and patterns of recurrence were evaluated, and sex, age, type of surgery, Karnofsky performance status, Recursive Partitioning Analysis (RPA) classification, time between surgery and initiation of radiotherapy were evaluated as potential prognostic factors for survival.

Results

All patients have completed the treatment protocol. Median age was 64.5 years (range 41–82 years) with 31 females (46%) and 36 males (54%). Median KPS at time of treatment was 80. The surgery was gross total in 38 patients and subtotal in 14 patients; 15 patients underwent only biopsy.No grade 3–4 acute or late neurotoxicity was observed. With median follow-up of 14.9 months, the median OS and PFS were 13.4 and 7.9 months, respectively.

Conclusions

The hypo-fractionated radiation therapy can be used for patients with GBM, resulting in favourable overall survival, low rates of toxicity and satisfying QoL. Future investigations are needed to determine the optimal fractionation for GBM.     

Rechallenge with temozolomide in patients with recurrent gliomas

Temozolomide (TMZ) is the standard of care for patients with newly diagnosed glioblastoma (GBM) as well as those with recurrent anaplastic glioma (AG) and GBM. It has become common practice to re-expose patients to TMZ who had been previously treated with TMZ, or to switch patients to alternative dosing regimens of TMZ when there are signs of relapse or progress on standard TMZ therapeutic regimens. To date, however, there is a scarcity of data on the efficacy of this therapeutic strategy, currently referred to as TMZ rechallenge. We have conducted a retrospective review of patients with recurrent glioma rechallenged with TMZ. Patients experiencing progressive disease (PD) during TMZ therapy who were rechallenged with alternative TMZ regimens and patients rechallenged after stable disease in a TMZ-free interval were evaluated separately. A total of 90 rechallenges were identified in 80 patients. The progression-free survival at 6 months (PFS-6) was 48% in patients with AG (12/25) and 27.7% in those with GBM (14/47). The PFS-6 was 16.7% in AG and 26.3% in GBM for patients switched during TMZ and 57.9 and 28.6% in patients rechallenged after a TMZ-free interval of at least 8 weeks. Relevant hematological toxicity (NCI-CTC grade 3–5) was observed in 22 of 90 rechallenges, and relevant non-hematological in ten of 90 rechallenges. Temozolomide was well tolerated and generated promising PFS-6 in patients who had previously failed TMZ, regardless if they progressed during TMZ treatment, or if they were rechallenged after a TMZ-free interval. These results suggest that the TMZ rechallenge strategy warrants further investigation in a prospective randomized trial.     

Intraventricular pentosan polysulphate in human prion diseases: an observational study in the UK

Background, purpose and methods:  This observational study assessed the effect of continuous intraventricular infusion of pentosan polysulphate (PPS) in seven patients at different clinical centres in the UK.
Results:  Complications of intraventricular catheterization were frequent. PPS was well-tolerated over a wide dose range (11–110  μ g/kg/day) during the 6-month study. Four patients were assessed for the entire study period: one remained stable, two showed minimal deterioration and one progressed significantly.
Conclusion:  Mean survival of all patients was longer than reported values for natural history of specific prion disorders. Possible reasons for these findings are explored.     

Continuous Low-Dose Temozolomide Chemotherapy and Microvessel Density in Recurrent Glioblastoma

Objective

The purpose of this study was to evaluate the clinical efficacy of continuous low-dose temozolomide (TMZ) chemotherapy for recurrent and TMZ-refractory glioblastoma multiforme (GBM) and to study the relationship between its efficacy and microvessel density within the tumor.

Methods

Thirty patients who had recurrent GBM following Stupp''s regimen received TMZ daily at 50 mg/m²/day until tumor progression between 2007 and 2013. The median duration of continuous low-dose TMZ administration was 8 weeks (range, 2-64).

Results

The median progression-free survival (PFS) of continuous low-dose TMZ therapy was 2 months (range, 0.5-16). At 6 months, PFS was 20%. The median overall survival (OS) from the start of this therapy to death was 6 months (95% CI : 5.1-6.9). Microvessel density of recurrent tumor tissues obtained by reoperation of 17 patients was 22.7±24.1/mm² (mean±standard deviation), and this was lower than that of the initial tumor (61.4±32.7/mm²) (p-value=0.001). It suggests that standard TMZ-chemoradiotherapy reduces the microvessel density within GBM and that recurrences develop in tumor cells with low metabolic burden. The efficacy of continuous low-dose TMZ could not be expected in recurrent GBM cells in poor angiogenic environments.

Conclusion

The efficacy of continuous low-dose TMZ chemotherapy is marginal. This study suggests the need to develop further treatment strategies for recurrent and TMZ-refractory GBM.     

Optical platelet aggregometry does not appear useful as a means of assessing the risk of recurrent vascular events in aspirin-treated patients

Objectives –  To investigate whether the results of optical platelet aggregometry indicate the risk of recurrent ischemic events.
Materials and methods –  Cerebro- and cardiovascular patients taking aspirin for at least 30 days were studied retrospectively. Ischemic vascular events occurring prior to testing and the presence of vascular risk factors were recorded.
Results –  241 subjects were included. Among the 78 patients (32.4%) who displayed recurrent vascular episodes, the age (62.5 ± 10.6 vs. 58.4 ± 11.6, P  = 0.009) and the proportion of hypertensives (80.8% vs. 68.1%, P  = 0.040) were significantly higher when compared with the participants who exhibited single events. The degree of platelet aggregation did not differ significantly between the patients with and those without recurrent episodes. Logistic regression analysis identified only age (OR 1.033, 95% CI 1.008–1.058, P  = 0.010), and not aggregation values, as a risk condition for recurrent vascular episodes.
Conclusions –  Results of optical platelet aggregometry were not indicative of the risk of recurrent vascular events. The role of conventional risk factors appeared to be more important.     

Long-term assessment of oxcarbazepine in a naturalistic setting: a retrospective study

Background –  New antiepileptics seem to be better tolerated by patients. The retention rate of an antiepileptic would be a useful indicator of its practical usefulness.
Aims –  To assess the long-term outcome of oxcarbazepine (OXC) in a naturalistic setting by determining the retention rate.
Methods –  This is a retrospective study. All epilepsy patients treated with OXC at a tertiary care epilepsy center during a period of 3.5 years were included in this study. Retention rates of OXC at 1 and 3 years were estimated for each cohort group using Kaplan–Meier estimates and corresponding 95% confidence intervals.
Results –  A total of 98 patients were studied. OXC was used as monotherapy in 14 (14.3%) and as add-on therapy in 84 (85.7%). The mean daily dose was 947 ± 492 mg and 60% received ≤900 mg/day. Using the Kaplan–Meier survival analysis, the retention rates of OXC at 1 and 3 years were estimated to be 0.853 (0.749–0.956) and 0.737 (0.570–0.904), respectively.
Conclusions –  OXC is well tolerated by patients as both monotherapy and add-on therapy.     

Efficacy of concomitant and adjuvant temozolomide in glioblastoma treatment. A multicentre randomized study

Background and purposeThe common treatment in patients with newly diagnosed glioblastoma multiforme is the ultimately radical surgical removal of the tumour combined with radiotherapy. This study compared safety and efficacy of radiotherapy alone with radiotherapy combined with temozolomide (TMZ) given before, during, and after radiotherapy.Material and methodsThe patients operated on for glioblastoma multiforme during the first 21 postoperative days were randomly assigned to the group treated with radiotherapy alone (involved-field radiotherapy in 2 Gy fractions daily five times a week up to the total of 60 Gy over 6 weeks of treatment) or to the group treated with radiotherapy and TMZ, initially in the dose of 200 mg/m² during 5 postoperative days and after 23 days followed by 75 mg/m² of body surface area daily, 7 days a week (from the first to the last day of radiotherapy). On completion of radiotherapy, five complementary courses of TMZ were introduced (150–200 mg/m² for 5 days, repeated every 28 days). The primary outcome measure was overall survival.ResultsFifty-eight patients from 3 centres were included in the study. The mean age of patients was 55 years and all the patients underwent a surgical procedure of glioblastoma removal. The mean overall survival in the group treated with TMZ was 16.0 months, whereas in the group with radiotherapy alone the overall survival reached 12.5 months. 24-month survival reached 23% in patients treated with TMZ and 6.7% in those who received radiotherapy only. Haematological complications of third or fourth degree were present in 10% of patients treated with radiotherapy and TMZ.ConclusionsThe introduction of TMZ before, during and after radiotherapy for newly diagnosed glioblastoma multiforme gives clinically and statistically significant improvement of survival with unremarkably increased toxicity of the treatment.     

Hippocampal volumes and diffusion-weighted image findings in children with prolonged febrile seizures

Objectives –  To assess hippocampal volumes (HV) and signal changes on diffusion-weighted imaging (DWI) within 5 days of prolonged febrile seizures (PFS) and compare them with the PFS duration and EEG.
Methods –  We studied 12 children (mean age: 32 ± 21 months, range 10 months–5 years) within 5 days of a first episode of PFS (a seizure or series of seizures lasting for 30 min or longer, without return of consciousness between the seizures). The HV measurements were carried out using high-resolution magnetic resonance imaging and signal intensity abnormalities were evaluated visually on DWI. HV in patients were compared with those of 13 neurologically normal controls (mean age 31 ± 16 months, range 15 months–5 years). HV abnormalities correlated with PFS duration. HV and DWI abnormalities were compared with EEG abnormalities.
Results –  Seizure duration ranged from 40 to 95 min. In seven out of twelve patients, seizures were refractory and lasted for 60 min or longer despite intravenous infusion of diazepam. In the patients with PFS for 60 min or longer, HV were significantly larger than that of controls. In all patients, there was a positive correlation between HV and seizure duration. DWI showed hyperintensity in unilateral hippocampus in three patients with intractable seizures, ipsilateral thalamus in two, and cingulate in one. EEG showed abnormalities in temporal areas ipsilateral to the DWI abnormalities in these patients.
Conclusions –  Large HV and hippocampal hyperintensity on DWI were seen in patients with refractory PFS. Our results suggest that medically refractory PFS lasting for 60 min or longer may cause structural changes in limbic structures that could promote later epileptogenesis.     

Lamotrigine in bipolar disorder: efficacy during pregnancy

Objective:  Clinical management of bipolar disorder (BPD) patients during pregnancy is a major challenge. The high risk of bipolar depression during pregnancy encourages consideration of lamotrigine (LTG). We therefore compared recurrence risks among pregnant women with BPD treated with LTG to those discontinuing mood stabilizer therapies.
Methods:  We compared risks and weeks to new DSM-IV illness-episodes among 26 initially clinically stable pregnant women diagnosed with DSM-IV BPD who continued LTG treatment to those discontinuing all mood stabilizer treatment during pregnancy.
Results:  The risk of new illness-episodes with LTG was 30% versus 100% after discontinuing mood stabilizers, and survival-computed time-to-25%-recurrence was 28.0 versus 2.0 weeks (χ² = 17.3, p < 0.0001; hazard ratio = 12.1; 95% confidence interval = 1.6–91.7).
Conclusions:  Discontinuing mood stabilizer treatment presents high risks of illness-recurrence among pregnant women diagnosed with BPD. LTG may afford protective effects in pregnancy, and its reported fetal safety compares favorably to other agents used to manage BPD.     

Postmortem neuropathological features secondary to boron neutron capture therapy for glioblastoma multiforme

This postmortem study of 12 patients with glioblastoma multiforme (GBM) treated with boron neutron capture therapy (BNCT) employing an epithermal neutron beam and p-boronophenylalanine describes the neuropathological findings in patients receiving a relatively high radiation dose to the tumor, but a relatively low radiation dose to the normal brain. In addition to a standardized neuropathology panel of sections, we used individual treatment dosimetry maps to select sections along the projected maximum radiation beam pathway. We found that the normal neuroparenchyma exposed to the highest radiation dose exhibited a single instance of radiation-induced focal venular fibrinoid necrosis and a single instance of multifocal demyelination. Semiquantitative analysis of pretreatment neurosurgical and postmortem tumor samples revealed only two radiation ascribed histopathological findings to be particular to therapy, fibrinoid necrosis and vascular hyalinization. In this relatively small series of cases we found an unexpectedly high frequency of cases (3 of 12) with neurodegenerative histopathology (Lewy bodies, neurofibrillary tangles, and neuritic senile plaques), which appeared, by distribution, to be independent of the radiation beam. Two of these patients were over 70 yr of age. One was only 41. Our findings suggest an acceptable radiation-induced level of neurotoxicity at the lower doses employed, but raise the possibility of unexpected boron neurodegenerative toxicity.     

MGMT gene promoter methylation in pediatric glioblastomas

Purpose  

Relatively few studies have been performed on molecular properties of pediatric glioblastoma multiforme (GBM). Methylation of DNA repair gene O⁶-methylguanine-DNA methyltransferase (MGMT) promoter region has been associated with favorable prognosis and prolonged survival in adult GBM patients treated with temozolomide (TMZ). We explored the frequency of MGMT gene promoter methylation in pediatric glioblastomas and compared it with the known molecular alterations in p53.     

Temozolomide: therapeutic limitations in the treatment of adult high-grade gliomas

Temozolomide-based chemotherapy represents an incremental improvement in the treatment of patients with high-grade gliomas. Notwithstanding a survival benefit in a subset of patients with high-grade gliomas, temozolomide (TMZ; Temodar?, Schering-Plough Pharmaceuticals, NJ, USA) is the primarily palliative treatment for the vast majority of patients. Indeed, for patients with newly diagnosed glioblastoma, the median increase in survival for treatment with TMZ and radiotherapy is only 2.5 months compared with radiotherapy alone. Additionally, recent studies suggest that 60-75% of patients with glioblastoma derive no benefit from treatment with TMZ. For the treatment of recurrent anaplastic gliomas, more than 50% of patients fail TMZ treatment with cancer progression at 6 months, demonstrating that TMZ is only a modestly effective chemotherapy. In addition, 15-20% of patients treated with TMZ develop clinically significant toxicity, which can leave further treatment unsafe. Despite the availability of TMZ, there is still a substantial need for a chemotherapeutic agent that is more effective and safe. In fact, there still remains a significant unmet need for more effective treatments of high-grade gliomas (improved palliation or cure), whether that treatment be by surgery, radiotherapy, chemotherapy or any yet to be developed type of treatment, such as 'targeted therapies'.     

Hereditary neuropathy with liability to pressure palsies: description of seven patients without known family history

Objectives –  Hereditary neuropathy with liability to pressure palsies (HNPP) is an inherited disorder resulting in a polyneuropathy with particular involvement at sites of entrapment, and is often underdiagnosed or misdiagnosed. We report findings on seven patients referred for evaluation of focal mononeuropathies or polyneuropathies of undetermined etiology, in whom we established a diagnosis of HNPP.
Materials and methods –  We retrospectively reviewed clinical, electrophysiological and laboratory data for patients diagnosed with HNPP over a 4-year period at our institution.
Results –  All patients had transient or recurrent neurological symptoms, some with residual deficits. No patients had a family history of any neuropathy. Electrodiagnostic studies revealed abnormal conduction findings at symptomatic and asymptomatic sites. Testing for the Peripheral Myelin Protein ( PMP22 ) deletion was positive in all patients.
Conclusions –  A high index of clinical suspicion and thorough electrodiagnostic evaluation can lead to correct diagnosis of HNPP, despite the absence of a positive family history.     

Hypokalemic thyrotoxic periodic paralysis: clinical characteristics and predictors of recurrent paralytic attacks

Background and purpose:  To study the clinical characteristics of hypokalemic thyrotoxic periodic paralysis (hoTPP) and identify the predictors of recurrent paralytic attacks before achieving the euthyroid status.
Methods:  We retrospectively analyzed 45 hoTPP patients who were admitted during the 7-year study period.
Results:  A tendency towards male predominance was observed among the 45 patients (91.1%, 41/45). The mean onset age was 32.9 ± 10.0 years (range: 16–54 years). No significant differences were observed in the onset age between male and female patients. Precipitating factors included rest/sleep at night, hot weather, upper respiratory tract infections (URIs), and excessive physical activities. Atypical weakness was observed in nine (20%, 9/45) patients. One patient initially diagnosed with sporadic periodic paralysis eventually developed hoTPP.
Discussion:  In provocative tests, hypokalemia was not a consistent finding during paralytic attacks. Before achieving the euthyroid status, the rate of recurrent attacks was as high as 62.2%, and peaked in the first 3 months after hoTPP was diagnosed. Patients with URIs exhibited a higher incidence of recurrent paralytic attacks than those without (odds ratio = 13.00; 95% confidence interval = 1.08–156.08; P  =   0.04).     

Metabolic syndrome and three of its components as risk factors for recurrent ischaemic stroke presenting as large-vessel infarction

Background and purpose:  Although a clear protocol for reduction of recurrent ischaemic stroke (RIS) has been established, few studies have compared the stroke subtype distribution and risk factors between RIS and first-ever stroke (FES).
Methods:  This one-year hospital-based study enrolled 587 FES and 475 RIS patients. Patients were categorized into four stroke subtypes according to a modified TOAST stroke subtype classification system. Risk factor profiles were compared between the two major stroke groups and between the corresponding four subtypes to discriminate the significant risk factors for RIS.
Results:  A multivariate regression analysis identified hypertension (OR, 1.87; 95% CI, 1.34–2.62), diabetes mellitus (DM) (OR, 1.57; 95% CI, 1.22–2.02), low high-density lipoprotein (LHDL) (OR, 1.43; 95% CI, 1.08–1.88) and older age as significant RIS risk factors. The significance of the former three RIS factors was further recognized in its large-vessel subtype. Moreover, metabolic syndrome was significantly more common in the recurrent stroke group ( P  = 0.01), including its large-vessel subtype ( P  = 0.04). Progressively increasing odds ratios from 1.49 to 2.02, in accordance with increased number of diagnostic components of metabolic syndrome for recurrent large-vessel ischaemic stroke, were noted.
Conclusions:  Metabolic syndrome likely plays a crucial role in the development of RIS, including large-vessel infarction in modern-day Taiwan.     

Long-term safety and efficacy of zonisamide in patients with refractory partial-onset epilepsy

Objectives –  To investigate whether zonisamide remains effective and well tolerated in the treatment of refractory partial epilepsy during long-term treatment and with flexible dosing in clinical practice.
Materials and methods –  Patients with refractory partial epilepsy who completed a fixed-dose, randomized, double-blind clinical trial were recruited in an open-label extension study with adjustment of zonisamide and other antiepileptic drug dosage according to the treating physician's usual clinical practice.
Results –  An intention-to-treat analysis of 317 patients showed that zonisamide was well tolerated with a predictable safety profile. Patient retention rates at 1, 2 and 3 years were 65.3%, 44.5% and 28.8%, respectively. Zonisamide treatment was associated with a maintained reduction in seizure frequency, with some patients achieving prolonged periods of seizure freedom.
Conclusions –  Flexible dosing with zonisamide demonstrated a good safety profile and sustained efficacy in the long-term adjunctive treatment of refractory partial epilepsy.