Radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma

The purpose of this study is to evaluate the efficacy and toxicity of radiation therapy (RT) with concurrent temozolomide (TMZ) chemotherapy followed by adjuvant TMZ in children with diffuse intrinsic pontine glioma (DIPG). Newly diagnosed patients younger than 18 years with histologically proven DIPG were treated with focal radiotherapy to a dose of 54 Gy in 30 fractions along with concurrent daily TMZ (75 mg/m(2)/day). Four weeks after completing the initial RT-TMZ schedule, adjuvant TMZ (200 mg/m(2)/day, days 1-5) was given every 28 days up to six cycles. Responses/progressions were assessed by clinical and 2-monthly MRI follow-up studies. Between September 2005 and September 2009, 21 patients with newly diagnosed histologically confirmed DIPG were eligible for this study. Median age at diagnosis was 6.4 years (range 4-16 years). At last update in August 2010, 17 children have died, 1 child was alive with progressive disease and 3 with stable disease. Metastatic relapse was documented in the cerebral site in two patients and in spinal cord in two cases. The median time to progression was 7.5 months (range 28 days-14.5 months) and the median survival was 11.7 months (range 26 days-17.5 months). The 1-year PFS and the 1-year OS were 33 and 50%, respectively. Five patients presented radiological findings compatible with pseudoprogression during the treatment. Haematological toxicity (Grade III/IV thrombocytopenia and leucopenia) was the most commonly found and led to dose reductions of TMZ in 58% of the patients. TMZ with radiation therapy has not yielded any significant improvement in outcome of children with DIPG and is associated with higher toxicity compared with radiotherapy alone. Novel treatment modalities are needed to improve the outcome of these patients.     

End-of-life care of children with diffuse intrinsic pontine glioma

Although atypical meningioma recurs frequently in spite of total resection and/or radiotherapy, no consensus on optimal adjuvant management was found. However, several retrospective studies analysed the additional effect of adjuvant radiotherapy in atypical meningioma with inconsistent results. Therefrom, the purpose of this study was to evaluate prognostic factors influencing the recurrence/progression and progression-free survival (PFS) rates of atypical meningioma, particularly focused on the role of postoperative adjuvant radiotherapy. Between February 2001 and March 2015, 161 atypical meningioma resections were performed in our Department of Neurosurgery, of which, 128 cases underwent surgical treatment alone and 33 cases underwent surgery and radiotherapy. Kaplan–Meier analysis was used to provide median point estimates and PFS rates. The Cox-regression model was used in the univariate and multivariate analysis to identify significant factors associated with treatment. The extent of resection (Simpson grade I and II) significantly influenced the risk of recurrence (hazard ratio?=?1.8, CI (95%) 1.3–2.6, p-value?=?0.0004). There was no significant benefit for progression-free survival after adjuvant radiotherapy (hazard ratio?=?1.48, CI (95%) 0.76–2.86, p-value?=?0.22). Additionally, meningioma located at the anterior and posterior fossa showed a significantly longer PFS compared to other locations (p-value?=?0.03). Adjuvant postoperative radiotherapy had no significant impact on recurrence/progression rate or PFS. The extent of resection according to Simpson grade remains the most important prognostic factor associated with lower recurrence/progression rates and longer PFS in patients with atypical meningioma. The location of the tumours at the anterior or posterior fossa was an independent factor associated with improved PFS.     

Hypofractionated radiotherapy with temozolomide in diffuse intrinsic pontine gliomas: a randomized controlled trial

Journal of Neuro-Oncology - Diffuse intrinsic pontine glioma (DIPG) is the most common form of brainstem glioma. The present study was performed to assess if hypofractionated radiotherapy completed...     

Extended adjuvant temozolomide with cis-retinoic acid for adult glioblastoma

Objective

To determine the toxicity and effectiveness of 24 months of adjuvant temozolomide (tmz) with cis-retinoic acid (cra) for patients with glioblastoma.

Methods

This retrospective population-based review considered the charts of all patients diagnosed with glioblastoma in Manitoba and referred to a provincial cancer centre during 2002–2008. Consecutive patients came from a population-based referral centre and provincial cancer registry.All patients were treated according to the local standard of care with surgical resection followed by concurrent radiotherapy and tmz 75 mg/m² daily, followed by tmz 150–200 mg/m² for days 1–5, repeated every 28 days for up to 24 cycles, and cra 50 mg/m² twice daily for days 1–21, repeated every 28 days.The main outcome measures were safety, tolerability, and effectiveness of long-term tmz and cra.

Results

Of 247 patients diagnosed with glioblastoma in Manitoba during the study period, 116 started concurrent chemoradiotherapy, and 80 received adjuvant tmz. Of the patients who started concurrent chemoradiotherapy, 80 began adjuvant chemotherapy. Patients completed a median of 5.5 cycles of tmz and 3 cycles of cra. Grade 3 or 4 hematologic toxicity was noted in 16% of patients. Median overall survival was 15.1 months, and 26.7% of patients remained alive at 2 years.

Conclusions

Extended adjuvant tmz and cra is well tolerated. However, the population-based effectiveness of this regimen is similar to the clinical trial efficacy of 6 months of adjuvant tmz. Future studies in glioblastoma should incorporate duration of adjuvant chemotherapy into the study design.     

Proton magnetic resonance spectroscopy predicts survival in children with diffuse intrinsic pontine glioma

Patients with diffuse intrinsic pontine glioma (DIPG) face a grim prognosis with limited treatment options. Many patients will enroll on investigational trials though the role of chemotherapy or immunotherapy is unclear. Radiographic changes on conventional MRI are used to evaluate tumor response and progression, but are not predictive of outcome in these patients. More sensitive measures of tumor biology are needed to improve patient management. We evaluated changes in magnetic resonance spectroscopy (MRS) biomarkers in patients with DIPG. Thirty-eight patients were enrolled prospectively on an IRB-approved protocol, which included standard MRI, single voxel spectroscopy (SVS) and multi-slice multi-voxel spectroscopy (MRSI). Scans were performed at multiple time points during each patient’s clinical course, with a total of 142 scans. The prognostic values of Choline:N-acetylaspartate (Cho:NAA), Cho:Creatine (Cho:Cr) and the presence of lactate and lipids (+Lac/Lip) were evaluated. Cho:NAA and variance in Cho:NAA values among different voxels within a tumor were each predictive of shorter survival. This prospective study shows that MRS can be used to identify high-risk patients and monitor changes in tumor metabolism, which may reflect changes in tumor behavior.     

Prospective collection of tissue samples at autopsy in children with diffuse intrinsic pontine glioma

BACKGROUND:

Brain tissue obtained at autopsy has been used in research for non‐oncologic disorders. However, to the best of the authors' knowledge, this tool has never been systematically used in large investigational studies for cancer. A prospective, multicenter study was conducted to assess the feasibility of tissue collection at autopsy and its suitability for molecular analyses in children with diffuse intrinsic pontine glioma.

METHODS:

Tumor tissue was collected at the time of diagnosis, if clinically indicated, or at autopsy. Normal brain tissue was also collected at autopsy. The integrity of DNA and RNA was evaluated in all samples. Logistic data regarding autopsies were recorded. The feasibility of tissue collection at autopsy was assessed for patients treated at a single institution over a 43‐month period.

RESULTS:

Tumor samples were collected at the time of diagnosis (n = 3) or at autopsy (n = 38) at 29 centers across the United States; samples were obtained at diagnosis and autopsy in 2 cases. The median interval from death to autopsy was 7.7 hours. DNA and RNA with minimal or partial degradation, which were suitable for genome‐wide analysis, were obtained from 100% and 63% of tumor samples, respectively. At the coordinating institution, approximately 40% of parents consented to autopsy and 40% declined. During the study period, 12 autopsies were performed on patients who did not receive therapy at the coordinating center.

CONCLUSIONS:

Multicenter, biological studies based on tissue obtained at autopsy appear to be feasible in children with brain cancer. The current experience established a new paradigm for brain tissue collection, which may increase the potential for research studies in patients with cancer. Cancer 2010. © 2010 American Cancer Society.     

Hypofractionated radiotherapy followed by adjuvant chemotherapy with temozolomide in elderly patients with glioblastoma

Objectives The optimal treatment for elderly patients (age >70 years) with glioblastoma (GBM) remains controversial. We conducted a prospective trial in 43 consecutive elderly patients with GBM treated with hypofractionated radiotherapy (RT) followed by adjuvant temozolomide. Patients and methods Forty-three patients 70 years of age or older with a newly diagnosed GBM and a Karnofsky performance status (KPS) ≥ 60 were treated with hypofractionated RT (6 fractions of 5 Gy each for a total of 30 Gy over 2 weeks) followed by up to 12 cycles of adjuvant temozolomide (150–200 mg/m² for 5 days during each 28 day cycle). The HRQOL was assessed with the EORTC Quality of Life Questionnaire C30. The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), toxicity and quality of life. Results The median OS was 9.3 months and the median PFS was 6.3 months. The 6 and 12 month survival rates were 86% and 35%, respectively. The 6 and 12 month PFS rates were 55% and 12%, respectively. In multivariate analysis KPS was the only significant independent predictive factor of survival (P = 0.008). Neurological deterioration occurred during or after RT in 16% of patients and was resolved in most cases with the use of steroids. Grade 3–4 hematologic toxicity occurred in 28% of patients during the adjuvant chemotherapy treatment with temozolomide. The treatment had no negative effect on HRQOL, however, fatigue (P = 0.02) and constipation (P = 0.01) scales worsened over time. Conclusions Hypofractionated RT followed by temozolomide may provide survival benefit maintaining a good quality of life in elderly patients with GBM. It may represent a reasonable therapeutic approach especially in patients with less favourably prognostic factors.     

A twenty-year review of diagnosing and treating children with diffuse intrinsic pontine glioma in The Netherlands

Introduction: Children with diffuse intrinsic pontine glioma (DIPG) face a dismal prognosis, with a median overall survival of 9 months. Our aims are to determine the incidence of DIPG in the Netherlands and to identify points for improvement in clinical research, a prerequisite for increasing the chance to find a cure. Methods: We performed a population-based retrospective cohort study by evaluating all children diagnosed with DIPG in the Netherlands between 1990 and 2010. Results: The incidence of DIPG in the Netherlands corresponds with international literature. Between 1990 and 2010, a large heterogeneity of treatment schedules was applied and only a minority of patients was included in clinical trials. Discussion: Given the rarity of DIPG, we emphasize the need for (inter-)national trials to facilitate the identification of potentially effective therapeutics in the future. This can be supported by the recent development of a European DIPG registry enabling international study collaborations.     

弥漫性内生性脑桥胶质瘤基础与临床研究进展

弥漫性内生性脑桥胶质瘤（DIPG）是一种发生在脑干的高度侵袭性神经胶质瘤,在儿童期发病,约占儿科脑及中枢神经系统肿瘤发病率的10%~15%。DIPG 预后极差,仅有不到10%的患儿生存期超过2年。DIPG 的影像学表现非常典型,活检仅在非典型病例实施,治疗前的组织标本很少,限制了该病的分子生物学研究。近年来手术和分子分析技术的进展突飞猛进,活检的安全性大大提高,脑干活检的应用逐步纳入许多临床试验中,DIPG 的分子病理学研究及治疗将取得新的突破。     

Survival prediction model of children with diffuse intrinsic pontine glioma based on clinical and radiological criteria

Background

Although diffuse intrinsic pontine glioma (DIPG) carries the worst prognosis of all pediatric brain tumors, studies on prognostic factors in DIPG are sparse. To control for confounding variables in DIPG studies, which generally include relatively small patient numbers, a survival prediction tool is needed.

Methods

A multicenter retrospective cohort study was performed in the Netherlands, the UK, and Germany with central review of clinical data and MRI scans of children with DIPG. Cox proportional hazards with backward regression was used to select prognostic variables (P < .05) to predict the accumulated 12-month risk of death. These predictors were transformed into a practical risk score. The model''s performance was validated by bootstrapping techniques.

Results

A total of 316 patients were included. The median overall survival was 10 months. Multivariate Cox analysis yielded 5 prognostic variables of which the coefficients were included in the risk score. Age ≤3 years, longer symptom duration at diagnosis, and use of oral and intravenous chemotherapy were favorable predictors, while ring enhancement on MRI at diagnosis was an unfavorable predictor. With increasing risk score categories, overall survival decreased significantly. The model can distinguish between patients with very short, average, and increased overall survival (medians of 7.0, 9.7, and 13.7 mo, respectively). The area under the receiver operating characteristic curve was 0.68.

Conclusions

We developed a DIPG survival prediction tool that can be used to predict the outcome of patients and for stratification in trials. Validation of the model is needed in a prospective cohort.     

Retrospective evaluation of the outcomes of children with diffuse intrinsic pontine glioma treated with radiochemotherapy and valproic acid in a single center

Diffuse intrinsic pontine glioma is a pediatric oncologic disease with dismal prognosis and no effective treatment. Since 2007, our patients have been using valproic acid as prophylactic anticonvulsant. We have undertaken a retrospective study in order to evaluate the influence of valproate in the outcomes of children with this disease in our center. Patients were treated with weekly carboplatin and vincristine and received conformal radiotherapy, either concurrent or sequential. Event-free survival and overall survival of patients not treated with valproic acid were 6.5 and 7.8 months. Accelerated failure time model (a parametric multivariate regression test for time-to-failure data) showed a statistically significant superiority of the median event-free survival of treated patients (6.5 vs. 9.5 months in treated patients; HR 0.54–95 % CI 0.33–0.87; p < 0.05) and also of overall survival (7.8 vs. 13.4 months in treated patients; HR 0.60–95 % CI 0.37–0.98; p = 0.05).