Multifocal glioblastoma multiforme: prognostic factors and patterns of progression

PURPOSE: To assess the progression patterns in patients with multifocal glioblastoma multiforme who had undergone whole brain radiotherapy (WBRT), the historical standard, versus three-dimensional conformal radiotherapy, and to identify predictive treatment and pretreatment factors. METHODS AND MATERIALS: The records of 50 patients with multifocal glioblastoma multiforme treated with RT were reviewed. Univariate analyses were performed using survival methods and the Cox proportional hazards regression method. Multivariate analyses were performed using the Cox proportional hazards regression method. RESULTS: The mean age was 61 years, and 71% had a Karnofsky performance status (KPS) score of > or =70. Of the 50 patients, 32% underwent WBRT and 68%, three-dimensional conformal RT. Progression was local in all evaluable patients, as determined by imaging in 38 patients and early neurologic progression in 12. The median time to progression (TTP) was 3.1 months, and the median survival time (MST) was 8.1 months. The significant independent predictors of TTP on multivariate analysis were a KPS score <70 (p = 0.001), the extent of surgery (p = 0.040), a radiation dose <60 Gy (p = 0.027), and the lack of chemotherapy (p = 0.001). The significant independent predictors of a reduced MST were a KPS score <70 (p = 0.022) and the absence of salvage surgery (p = 0.011) and salvage chemotherapy (p = 0.003). CONCLUSION: Local progression was observed in all patients. On multivariate analysis, no significant difference was found in the TTP or MST between three-dimensional conformal radiotherapy and WBRT. The KPS was a consistent independent predictor of both TTP and MST. On the basis of the progression pattern, we do not recommend WBRT as a mandatory component of the treatment of multifocal glioblastoma multiforme.     

BCNU for recurrent glioblastoma multiforme: efficacy,toxicity and prognostic factors

Background  

The prognosis for patients with recurrent glioblastoma is still poor with a median survival between 3 and 6 months. Reports about the application of carmustine (BCNU), one of the standard chemotherapeutic drugs in the treatment of newly diagnosed glioblastoma, in the recurrent situation are rare.     

Treatment outcome of patients with recurrent glioblastoma multiforme: a retrospective multicenter analysis

According to the recently updated World Health Organization (WHO) classification (2016), grade II–III astrocytomas are divided into IDH-wildtype and IDH-mutant groups, the latter being significantly less aggressive in terms of both progression-free and total survival. We identified a small cohort of WHO grade II–III astrocytomas that harbored the IDH1 R132H mutation, as confirmed by both immunohistochemistry and molecular sequence analysis, which nonetheless had unexpectedly rapid recurrence and subsequent progression to glioblastoma. Among these four cases, the mean time to recurrence as glioblastoma was only 16 months and the mean total survival among the three patients who have died during the follow-up was only 31 months. We hypothesized that these tumors had other, unfavorable genetic or epigenetic alterations that negated the favorable effect of the IDH mutation. We applied genome-wide profiling with a methylation array (Illumina Infinium Human Methylation 450k) to screen for genetic and epigenetic alterations in these tumors. As expected, the methylation profiles of all four tumors were found to match most closely with IDH-mutant astrocytomas. Compared with a control group of four indolent, age-similar WHO grade II–III astrocytomas, the tumors showed markedly increased levels of overall copy number changes, but no consistent specific genetic alterations were seen across all of the tumors. While most IDH-mutant WHO grade II–III astrocytomas are relatively indolent, a subset may rapidly recur and progress to glioblastoma. The precise underlying cause of the increased aggressiveness in these gliomas remains unknown, although it may be associated with increased genomic instability.     

Isolation of cancer stem cells from adult glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common adult primary brain tumor and is comprised of a heterogeneous population of cells. It is unclear which cells within the tumor mass are responsible for tumor initiation and maintenance. In this study, we report that brain tumor stem cells can be identified from adult GBMs. These tumor stem cells form neurospheres, possess the capacity for self-renewal, express genes associated with neural stem cells (NSCs), generate daughter cells of different phenotypes from one mother cell, and differentiate into the phenotypically diverse populations of cells similar to those present in the initial GBM. Having a distinguishing feature from normal NSCs, these tumor stem cells can reform spheres even after the induction of differentiation. Furthermore, only these tumor stem cells were able to form tumors and generate both neurons and glial cells after in vivo implantation into nude mice. The identification of tumor stem cells within adult GBM may represent a major step forward in understanding the origin and maintenance of GBM and lead to the identification and testing of new therapeutic targets.     

Limited impact of prognostic factors in patients with recurrent glioblastoma multiforme treated with a bevacizumab-based regimen

Bevacizumab has demonstrated activity in patients with recurrent glioblastoma. However, the impact of prognostic factors associated with recurrent glioblastoma treated with cytotoxic agents has not been determined in patients treated with bevacizumab. To analyze the prognostic factors and clinical benefits of bevacizumab and irinotecan treatment in patients with recurrent glioblastoma. This monocentric study retrospectively analyzed all patients with recurrent glioblastoma who were treated with at least one cycle of bevacizumab and irinotecan at our institution from April 2007 to May 2010. Multivariate analysis was used to analyze prognostic factors for overall survival (OS) from the initiation of bevacizumab administration. Among the 100 patients that were identified (M/F: 65/35), the median age was 57.9 years (range: 18–76). Karnofsky Performance Status (KPS) was <70 in 44 patients and ≥70 in 56 patients; 83 % of the patients were on steroids. The median tumor area was 2012 mm². The median progression free survival was 3.9 months (CI 95 %: 3.4–4.3). The median OS was 6.5 months (CI 95 %: 5.6–7.4). Multivariate analysis revealed that OS was affected by KPS (p = 0.024), but not by gender, age, steroid treatment, number of previous lines of treatment, tumor size, or time from initial diagnosis. KPS was improved in 30 patients, including 14/44 patients with an initial KPS <70. The median duration of maintained functional independence (KPS ≥70) was 3.75 months (CI 95 %: 2.9–4.6). The median OS from initial diagnosis was 18.9 months (CI 95 %: 17.5–20.3). In patients with recurrent glioblastoma treated with bevacizumab, KPS was revealed as the only factor to impact OS. The clinical benefits associated with this regimen appear valuable. A positive impact of bevacizumab administration on OS of patients with glioblastoma multiforme is suggested.     

Treatment of recurrent glioblastoma multiforme with GliaSite brachytherapy

PURPOSE: In this study, we assess the efficacy of GliaSite brachytherapy in the treatment of patients with recurrent glioblastoma multiforme (GBM). METHODS AND MATERIALS: Between 1999 and 2004, 24 patients with recurrent glioblastoma multiforme were treated with the GliaSite Radiation Therapy System (RTS). The GliaSite is an inflatable balloon catheter that is placed in the resection cavity at the time of surgical resection. Low-dose-rate radiation is then delivered locally by temporarily inflating the balloon with an aqueous solution of organically bound (125)I (Iotrex [sodium 3-((125)I)-iodo-4-hydroxybenzenesulfonate]). Patients at the Johns Hopkins Hospital with recurrent GBM, who were previously treated with surgery and external beam radiotherapy, underwent surgical resection followed by GliaSite balloon implantation. Subsequently, the patients received radiation therapy using the GliaSite to a mean dose of 53.1 Gy. Ten patients were male, and 14 patients were female. The mean age was 48.1 years. All patients had pathologically confirmed recurrent GBM. The median Karnofsky performance status (KPS) was 80. Median follow-up time was 21.8 months. RESULTS: At the time of analysis, 18 patients (75%) had died; 6 patients (25%) were alive. Median survival from diagnosis for all patients was 23.3 months. Median survival after GliaSite brachytherapy was 9.1 months. Patients with a KPS > or =70 had a median survival of 9.3 months, whereas patients with a KPS <70 had a median survival of 3.1 months (p < 0.003). Survival was not significantly different between patients receiving 45 Gy and patients receiving a dose greater than 45 Gy. Acute side effects were minor, consisting of mild nausea and/or headache. One patient developed a wound infection. No incidents of meningitis were observed. Late sequelae were rare, but 2 incidents of symptomatic radiation necrosis were observed. One patient developed transient expressive aphasia. CONCLUSIONS: GliaSite radiotherapy confers a prolongation of survival in patients with recurrent glioblastoma multiforme compared to historical controls with recurrent GBM. GliaSite therapy leads to a favorable survival outcome of 9.3 months in patients with KPS > or =70, but only 3.1 months in patients with KPS <70. Favorable survival is observed for patients within each recursive partitioning analysis class. Treatment with GliaSite is safe and generally well tolerated. Additional data are needed to fully assess the therapeutic benefit of GliaSite brachytherapy for recurrent GBM.     

Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is rare but is one of the most aggressive human malignancies. Several prognostic factors have been observed in patients with ATC, and some experts advocate aggressive multimodal therapy in selected patients. However, it is unclear whether such an approach significantly improves survival. The authors analyzed prognostic factors and treatment outcomes in patients with ATC reported in the National Cancer Institute's Surveillance, Epidemiology, and End Results data base. METHODS: The cohort consisted of 516 patients with ATC reported to 12 population-based cancer registries between 1973 and 2000. Demographic, pathologic, and treatment data were used for univariate and multivariate survival analyses. RESULTS: The mean patient age at diagnosis was 71.3 years, and there were 171 men and 345 women. Eight percent of patients had intrathyroidal tumors, 38% had extrathyroidal tumors and/or lymph node invasion, and 43% of patients had distant metastasis. The average tumor size was 6.4 cm (range, 1-15 cm). Sixty-four percent of patients underwent surgical resection of their primary tumor, and 63% received external beam radiotherapy. The overall cause-specific mortality rate was 68.4% at 6 months and 80.7% at 12 months. Univariate analysis showed that age < 60 years, female gender, intrathyroidal tumor, external beam radiotherapy, surgical resection, and combined surgical resection of tumor and radiotherapy were associated with a lower cause-specific mortality. On multivariate analysis, only age < 60 years, an intrathyroidal tumor, and the combined use of surgical and external beam radiation therapy were identified as independent predictors of lower cause-specific mortality. CONCLUSIONS: Although most patients with ATC had an extremely poor prognosis, patients < 60 years old with intrathyroidal tumors survived longer. Surgical resection with external beam radiotherapy for ATC was associated with lower cause-specific mortality.     

3-D conformal radiotherapy with concomitant and adjuvant temozolomide for patients with glioblastoma multiforme and evaluation of prognostic factors

Background

The aim of the retrospective study was to evaluate the outcome and prognostic factors of newly diagnosed glioblastoma patients who received 3-D conformal radiotherapy (RT) combined with concomitant and/or adjuvant temozalamide (TMZ) postoperatively.

Patients and methods

Fifty patients with glioblastoma multiforme were treated with 3-D conformal RT combined with concomitant and/or adjuvant TMZ postoperatively. Median age was 57 years (range, 12–79) and median Karnofsky performance status (KPS) was 70 (range, 40–100). A multivariate Cox regression model was used to test the effect of age, sex, KPS, extent of surgery, tumour dimension (<5cm vs. ≥5cm), full dose RT (≥60 Gy vs. <60 Gy), concurrent TMZ and adjuvant TMZ treatment (adjuvant therapy plus 6 cycles of TMZ group versus <6 cycles of TMZ group) on the overall survival.

Results

The median follow up time was 10 months (range 3–42). One- and 2-year overall survival rates were 46% and 20%, respectively. The prognostic factors important for the overall survival were a full dose RT (≥60 Gy) (p=0.005) and the application of adjuvant TMZ for 6 cycles (p=0.009).

Conclusions

The results of our study confirm the efficiency of RT plus concomitant and adjuvant TMZ, with an acceptable toxicity in patients. We suggest that at least 6 cycles of adjuvant TMZ should be administered to obtain a benefit from the adjuvant treatment.     

Imaging glioblastoma multiforme

Glioblastoma multiforme are infiltrative lesions that have a high degree of heterogeneity, both within and between different patients. Imaging is critical for all phases in the evaluation and treatment of these lesions, but has been limited in providing information that is reliable enough to stratify patients into groups with uniform behavior and to predict outcome. Although magnetic resonance imaging is the method of choice for visualizing anatomic features of the lesion, its results are ambiguous in terms of defining the functional characteristics of the lesion and distinguishing tumor from treatment induced necrosis. Recent advances in magnetic resonance have made possible the routine acquisition of physiological data such as perfusion- and diffusion-weighted images and of metabolic data such as water suppressed proton spectroscopic images. These provide quantitative measurements that are more closely related to the biological properties of the tumor and reflect changes in tumor vascularity, cellularity and proliferation that are associated with tumor progression. As the molecular properties that influence invasion and neoplastic transformation are elucidated, it is critical that noninvasive imaging techniques are available for investigating new therapies and tailoring treatment to individual patient characteristics. The data obtained from patients with glioblastoma multiforme have already demonstrated that these new magnetic resonance techniques are able to contribute to diagnosis, characterization of malignant potential, treatment planning and assessment of response to therapy.     

Outcome and prognostic factors in cerebellar glioblastoma multiforme in adults: a retrospective study from the Rare Cancer Network

PURPOSE: The aim of this study was to assess the outcome in patients with cerebellar glioblastoma (GBM) treated in 15 institutions of the Rare Cancer Network. METHODS AND MATERIALS: Data from a series of 45 adult patients with cerebellar GBM were collected in a retrospective multicenter study. Median age was 50.3 years. Brainstem invasion was observed in 9 (20%) patients. Radiotherapy (RT) was administered to 36 patients (with concomitant chemotherapy, 7 patients). Adjuvant chemotherapy after RT was administered in 8 patients. Median RT dose was 59.4 Gy. Median follow-up was 7.2 months (range, 3.4-39.0). RESULTS: The 1-year and 2-year actuarial overall survival rate was 37.8% and 14.7%, respectively, and was significantly influenced by salvage treatment (p = 0.048), tumor volume (p = 0.044), extent of neurosurgical resection (p = 0.019), brainstem invasion (p = 0.0013), additional treatment after surgery (p < 0.001), and completion of the initial treatment (p < 0.001) on univariate analysis. All patients experienced local progression: 8 and 22 had progression with and without a distant failure, respectively. The 1- and 2-year actuarial progression free survival was 25% and 10.7%, respectively, and was significantly influenced by brainstem invasion (p = 0.002), additional treatment after surgery (p = 0.0016), and completion of the initial treatment (p < 0.001). On multivariate analysis, survival was negatively influenced by the extent of surgery (p = 0.03) and brainstem invasion (p = 0.02). CONCLUSIONS: In this multicenter retrospective study, the observed pattern of failure was local in all cases, but approximately 1 patient of 4 presented with an extracerebellar component. Brainstem invasion was observed in a substantial number of patients and was an adverse prognostic factor.     

Hypofractionated radiotherapy for elderly or younger low-performance status glioblastoma patients: outcome and prognostic factors

PURPOSE: To evaluate the outcome for elderly or younger poor prognosis glioblastoma patients treated with hypofractionated radiotherapy (HypoRT). METHODS AND MATERIALS: Retrospective review at The University of Texas M. D. Anderson Cancer Center identified 59 glioblastoma patients (median age 65 years) treated with HypoRT between 1988 and 2001 with 50 Gy given at 2.5 Gy/fraction/day in 20 fractions within 4 weeks. Classification was according to the Radiation Therapy Oncology Group recursive partitioning analysis and was Class IV in 11, V in 29, and VI in 19. Surgery consisted of gross total resection (n = 16), subtotal resection (n = 28), and biopsy only (n = 13). Two patients were treated presumptively on the basis of radiographic findings. Chemotherapy was given either as part of the initial treatment (n = 15) or for progression (n = 9). RESULTS: The median survival time for the entire study population was 7 months, and the median progression-free survival was 3.9 months. The median survival time for patients with Class IV, V, and VI was 11, 7, and 5 months, respectively. Concordance was found with Radiation Therapy Oncology Group-established recursive partitioning analysis class survival. Steroid requirements were not increased during RT compared with preoperatively and immediately postoperatively. Late complications of HypoRT were limited to 3 cases of radiation necrosis suggested by MRI, 2 of which were pathologically confirmed. CONCLUSION: HypoRT consisting of 50 Gy in 4 weeks can be used for selected GBM patients to reduce the overall treatment time of conventional RT by 33-39% without apparent increased toxicity or decrement in survival.     

Treatment for glioblastoma multiforme: current guidelines and Canadian practice

Purpose

Our survey aimed to document variability in the practice patterns of Canadian radiation oncologists treating high-grade brain tumours.

Materials and Methods

A 20-question survey was developed to address various aspects of treatment:

• Guidelines used
• Types of fusion protocols used
• Number of treatment phases
• Margins for volume delineation
• Dose constraints

The survey was sent to Canadian radiation oncologists currently treating the central nervous system (cns) as one of their primary sites.

Results

We attained a 56% response rate from radiation oncologists across Canada treating cns sites. In their practice, 14% of respondents reported following guidelines from the European Organisation for Research and Treatment of Cancer; 32%, from the Radiation Therapy Oncology Group; and 56%, centre-specific guidelines. Single-phase treatment was reported by 60% of clinicians, and two-phase or multi-phase treatments, by 37%. For clinicians treating in single phase, margins from the gross treatment volume (gtv) to the planning treatment volume (ptv) included 0.5 cm (6%), 1 cm (6%), 1.5 cm (25%), 2.0 cm (56%), 2.5 cm (25%), and 3 cm (12.5%), with some respondents selecting more than one standard margin. For clinicians treating in multiple phases, margins from gtv to ptv in phase 2 included 1 cm (10%), 2.0 cm (40%), 2.5 cm (30%), and 3.0 cm (20%). Variability was also observed in dose constraints to critical structures. All respondents trimmed their margins to bony structures.

Conclusions

Our survey shows considerable variation in the current treatment by Canadian radiation oncologists of high-grade brain tumours, especially with respect to guidelines followed, number of phases, and overall volume treated. Further studies are thus required to establish the evidence for optimal radiation volumes and phases, especially as brain tumour treatments evolve in the age of mr imaging and chemotherapy.     

Bevacizumab in glioblastoma multiforme

Bevacizumab is a humanized IgG1 monoclonal antibody that selectively binds with high affinity to human VEGF and neutralizes VEGF' s biologic activity. Malignant gliomas are characterized by extensive microvascular proliferation and produce VEGF. Preclinical data indicate that angiogenesis is essential for the proliferation and survival of malignant glioma cells. Promising response rates, progression-free survival rates at 6 months and median overall survival in patients with recurrent glioblastoma multiforme (GBM) have been reported with bevacizumab, both in retrospective analyses and in prospective Phase II studies. In the pivotal randomized but noncomparative Phase II trial, a non-negligible percentage of patients survived beyond 1 and 2 years after the start of bevacizumab administration. However, randomized Phase III trial data on bevacizumab in recurrent GBM are lacking. Currently, bevacizumab is being studied in combination with temozolomide and radiation in previously untreated GBM patients in two large randomized Phase III trials.     

Primary cerebellar glioblastoma multiforme

Summary Glioblastoma multiforme in adults arising in the cerebellum is a rare tumor, well documented in only 13 cases in the literature. We report a fourteenth case, an 80-year-old female, and reassess the clinical and CT aspects of this tumor based on a review of the world's literature. The median age of patients is 53 years with a median survival of three months, which is less than adult cerebral hemisphere malignant gliomas.     

Current management of glioblastoma multiforme

Glioblastoma multiforme is the most common primary brain tumor in adults. Despite major research efforts and progress in neuroimaging, neurosurgery, and radiation and medical oncology, the overall survival of patients with this disease has changed little over the past 30 years. Surgery and radiation therapy remain critical components in the care of patients with glioblastoma multiforme. Treatment with chemotherapy has been hampered by the apparent resistance of these tumor cells to available agents and challenges in delivering agents to the tumor cells. The blood-brain barrier can restrict entry of some agents and the effect of antiepileptic drugs inducing hepatic P450 can significantly affect the pharmacology of a wide range of antineoplastic agents. As a result, new agents and novel approaches are required. Translational research efforts should: (1) pursue a broad research agenda until productive avenues are identified; (2) quantify the delivery of novel agents to the malignant brain tumor cells; (3) determine the maximum tolerated dose (MTD) and preliminary efficacy data on novel agents before initiating combination therapies; (4) optimize trial designs; and (5) improve psychosocial and supportive care for patients with this devastating illness.