State-of-the-Art Therapy for Glioblastoma Multiforme

2 February 2009

State-of-the-Art Therapy for Glioblastoma Multiforme

A report by:

Henry S. Friedman, MD, James B. Powell, Jr. Professor of Neuro-Oncology
David A. Reardon, MD, Associate Professor of Pediatrics and Surgery
Last Updated: 2/2/2009

Cliccare qui per aprire il file pdf.

Source VirtualTrials

Awake craniotomy and intraoperative magnetic resonance imaging: patient selection, preparation, and technique.

19 January 2009

Nabavi A, Goebel S, Doerner L, Warneke N, Ulmer S, Mehdorn M.

Department of Neurosurgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. nabavia@...

OBJECTIVES: Intraoperative magnetic resonance imaging (iMRI) has been reported to augment radical brain tumor resection. "Awake craniotomy" is a technique to conserve function during brain tumor surgery. We report on the combination of these 2 techniques, with special emphasis on potential adverse effects, caveats, and patient preparation. METHODS: Thirty-four patients had 38 awake craniotomies with cortical stimulation within an integrated MRI-operating room with a 1.5-T unit. Thirty-two lesions were left hemispheric, 6 on the right side. RESULTS: Preparation for iMRI per patient amounted to 20 to 25 minutes, in addition to scan time. The procedure was well tolerated by all patients. Thirty-two stated that they would undergo this procedure again, if necessary. Four underwent a second "awake" surgery in the iMRI for recurrent disease. Intraoperative MRI had no adverse effect, such as seizures. Cortical stimulation could be performed without restrictions outside the 5-gauss line. CONCLUSIONS: The combination of iMRI and awake craniotomy is demanding but well tolerated by patients. Careful preoperative evaluation is essential to ensure compliance. There is no adverse effect through iMRI on the awake patient or the results of cortical stimulation. Since the introduction of the iMRI in our department in 2005, all awake craniotomies were done in this setting. The implementation of these 2 techniques into our procedures is demanding, and necessitates thorough preparation but has broadened our basis for surgical decision making. However, to substantiate our positive perception, more clinical data are being compiled.

PMID: 19148035 [PubMed - in process]

Commento Personale: Interessante sapere che in questa struttura tedesca è disponibile da alcuni anni la iMRI, una tecnica eccellente di neurochirurgia che permette al neurochirurgo di avere una risonanza in tempo reale. Questo fattore rende possibile una craniotomia più radicale possibile, fattore che, sebbene non sia risolutivo nel GBM, è comunque in grado di aggiungere tre mesi in più di sovravvivenza. La Germania presenta altre due strutture particolarmente all'avanguardia nei tumori cerebrali: il Dr. Westphal ad Amburgo e il Dr. Jurgen Debus ad Heidelberg, probabilmente la struttura di radioterapia più avanzata d'Europa. In caso di recidiva suggerisco quindi di valutare una seconda craniotomia in Germania con la iMRI, oppure valutando trattamenti di radioterapia stereotassica (SRS) affiancata ad eventuali trattamenti chemioterapici in sperimentazione. Al momento gli studi più interessanti, ai quali parteciperei senza esitazione se fossi stato diagnosticato di una prima recidiva di GBM, sono i seguenti:

Ketogenic Diet for Recurrent Glioblastoma

Effect of NovoTTF-100A in Recurrent Glioblastoma Multiforme (GBM)

Phase III: Cediranib in Combination With Lomustine Chemotherapy in Recurrent Glioblastoma.

Source p Magn Reson Imaging. 2009 Jan;19(4):191-6

Efficacy of intracerebral delivery of Carboplatin in combination with photon irradiation for treatment of F98 glioma-bearing rats 

1 February 2009

Rousseau J, Barth RF, Moeschberger ML, Elleaume H.

Institut National de la Santé et de la Recherche Médicale U836, Equipe 6, Grenoble, France.

PURPOSE: To evaluate the efficacy of prolonged intracerebral (i.c.) administration of carboplatin by means of ALZET osmotic pumps, in combination with radiotherapy for the treatment of intracranial F98 glioma in rats. METHODS AND MATERIALS: Seven days after stereotactic implantation of F98 glioma cells into the brains of Fischer rats, carboplatin was administrated i.c. by means of ALZET pumps over 6 days. Rats were treated at the European Synchrotron Radiation Facility with a single 15-Gy X-ray dose, either given alone or 24 h after administration of carboplatin. RESULTS: Untreated rats had a mean survival time (MST) +/- SE of 23 +/- 1 days, compared with 44 +/- 3 days for X-irradiated animals and 69 +/- 20 days for rats that received carboplatin alone, with 3 of 13 of these surviving >195 days. Rats that received carboplatin followed by X-irradiation had a MST of >142 +/- 21 days and a median survival time of >195 days, with 6 of 11 rats (55%) still alive at the end of the study. The corresponding percentage increases in lifespan, based on median survival times, were 25%, 85%, and 713%, respectively, for carboplatin alone, radiotherapy alone, or the combination. CONCLUSIONS: Our data demonstrate that i.c. infusion of carboplatin by means of ALZET pumps in combination with X-irradiation is highly effective for the treatment of the F98 glioma. They provide strong support for the approach of concomitantly administering chemo- and radiotherapy for the treatment of brain tumors.

PMID: 19147017 [PubMed - indexed for MEDLINE]

Commento Personale: Questo studio è propedeutico ad una possible introduzione nei prossimi anni di sperimentazioni nei nuovi diagnosticati combinata di carboplatino locoregionale (magari in wafer similari a quelli di carmustina del Gliadel) e radioterapia.

Source Int J Radiat Oncol Biol Phys. 2009 Feb 1;73(2):530-6

Topotecan in combination with radiotherapy in unresectable glioblastoma: a phase 2 study

13 January 2009

Lesimple T, Riffaud L, Frappaz D, Ben Hassel M, Gédouin D, Bay JO, Linassier C, Hamlat A, Piot G, Fabbro M, Saïkali S, Carsin B, Guégan Y.

Department of Medical Oncology, Centre Eugène Marquis, CS44229, 35042 Rennes Cedex, France, lesimple@....

Improving glioblastoma multiforme (GBM) treatment with radio-chemotherapy remains a challenge. Topotecan is an attractive option as it exhibits growth inhibition of human glioma as well as brain penetration. The present study assessed the combination of radiotherapy (60 Gy/30 fractions/40 days) and topotecan (0.9 mg/m(2)/day on days 1-5 on weeks 1, 3 and 5) in 50 adults with histologically proven and untreated GBM. The incidence of non-hematological toxicities was low and grade 3-4 hematological toxicities were reported in 20 patients (mainly lymphopenia and neutropenia). Partial response and stabilization rates were 2% and 32%, respectively, with an overall time to progression of 12 weeks. One-year overall survival (OS) rate was 42%, with a median OS of 40 weeks. Topotecan in combination with radiotherapy was well tolerated. However, while response and stabilization concerned one-third of the patients, the study did not show increased benefits in terms of survival in patients with unresectable GBM.

PMID: 19139825 [PubMed - as supplied by publisher]

Source J Neurooncol. 2009 Jan 13

Association Between Hyperglycemia and Survival in Patients With Newly Diagnosed Glioblastoma

12 January 2009

Derr RL, Ye X, Islas MU, Desideri S, Saudek CD, Grossman SA.

Division of Endocrinology and Metabolism; and the Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD.

PURPOSE: Hyperglycemia has been associated with poor outcomes in many disease states. This retrospective study assessed the association between hyperglycemia and survival in patients with newly diagnosed glioblastoma multiforme (GBM). PATIENTS AND METHODS: Between 1999 and 2004, before the standard use of temozolomide, 191 patients were accrued onto New Approaches to Brain Tumor Therapy CNS Consortium trials with similar eligibility criteria. Time-weighted mean glucose and mean glucocorticoid dose were calculated for each patient using all values collected regularly in follow-up. The primary outcome was survival. RESULTS: Mean glucose levels ranged between 65 and 459 mg/dL. These were divided into quartiles: quartile one (< 94 mg/dL), quartile two (94 to 109 mg/dL), quartile three (110 to 137 mg/dL), and quartile four (> 137 mg/dL). Median survival times for patients in quartiles one, two, three, and four were 14.5, 11.6, 11.6, and 9.1 months, respectively. The association between higher mean glucose and shorter survival persisted after adjustment for mean daily glucocorticoid dose, age, and baseline Karnofsky performance score (KPS). Compared with patients in the lowest mean glucose quartile, those in quartile two (adjusted hazard ratio [HR], 1.29; 95% CI, 0.85 to 1.96), quartile three (adjusted HR, 1.35; 95% CI, 0.89 to 2.06), and quartile four (adjusted HR, 1.57; 95% CI, 1.02 to 2.40) were at progressively higher risk of dying (P = .041 for trend). CONCLUSION: In these patients with newly diagnosed GBM and good baseline KPS, hyperglycemia was associated with shorter survival, after controlling for glucocorticoid dose and other confounders. The effect of intensive management of glucocorticoid-related hyperglycemia on survival deserves additional study in patients with GBM.

PMID: 19139429 [PubMed - as supplied by publisher]

Commento Personale: Un altro studio che dimostra come controllare l'iperglicemia sia un aspetto fondamentale per aumentare le probabilità di sopravvivenza nel malato di glioblastoma. In precedenza abbiamo già visto quali sono le terapie di medicina alternativa complementare che andrebbero somministrate ai pazienti.

Source J Clin Oncol. 2009 Jan 12

High-dose radiotherapy to 78 Gy with or without temozolomide for high grade gliomas

14 January 2009

Watkins JM, Marshall DT, Patel S, Giglio P, Herrin AE, Garrett-Mayer E, Jenrette JM 3rd.

Department of Radiation Oncology, Medical University of South Carolina, 169 Ashley Avenue, MSC 318, Charleston, SC, 29425, USA.

Objectives: To describe outcomes associated with high-dose radiotherapy with and without temozolomide for high grade central nervous system (CNS) neoplasms. Methods Retrospective chart review of 60 patients diagnosed with malignant glioma treated with >/=70 Gy radiotherapy. Results Median age at diagnosis was 52 years, and 52 patients had astrocytomas (38 glioblastomas). Median prescribed radiotherapy dose was 78 Gy (range 70-80), and 29 patients received concurrent temozolomide. Eighty-six percent completed the planned course treatment. Three patients experienced RTOG grade 3 acute CNS toxicity; late brain necrosis was suspected in four patients. Overall median survival was 13 months (range 2-83). Within glioblastoma patients, temozolomide provided a statistically significant survival improvement over no chemotherapy (median survival 12.7 vs. 7.5 months; P = 0.0058). Conclusions High dose conformal radiotherapy to >/=70 Gy with chemotherapy for high-grade CNS neoplasms appears safe but survival remains suboptimal. Within glioblastoma patients, temozolomide provided statistically significant survival improvement over no chemotherapy.

PMID: 19142584 [PubMed - as supplied by publisher]

Commento Personale: Questo studio mette in risalto come, anche aumentando la dose di radioterapia alla prima diagnosi (dai 54/60Gy standard ai 78Gy) non si ottengano miglioramenti sulla sopravvivenza. Appare quindi inutile richiedere dosaggi più elevati in sede di prima radioterapia.

Source J Neurooncol. 2009 Jan 14

Grape seed extract inhibits VEGF expression via reducing HIF-1{alpha} protein expression.

8 January 2009

Lu J, Zhang K, Chen S, Wen W.

Division of Molecular Medicine.

Grape Seed Extract (GSE) is a widely consumed dietary supplement that has anti-tumor activity. Here we have investigated the inhibitory effect of GSE on the expression of vascular endothelial growth factor (VEGF) and the mechanism underlying this action. We found that GSE inhibited VEGF mRNA and protein expression in U251 human glioma cells and MDA-MB-231 human breast cancer cells. GSE inhibited transcriptional activation of the VEGF gene through reducing protein but not mRNA expression of hypoxia-inducible factor 1alpha (HIF-1alpha). The inhibitory effect of GSE on HIF-1alpha expression was mainly through inhibiting HIF-1alpha protein synthesis rather than promoting protein degradation. Consistent with this result, GSE suppressed phosphorylation of several important components involved in HIF-1alpha protein synthesis, such as Akt, S6 kinase and S6 protein. Furthermore, in the MDA-MB-231 tumor, we found that GSE treatment inhibited the expression of VEGF and HIF-1alpha and the phosphorylation of S6 kinase without altering the subcellular localization of HIF-1alpha, correlating with reduced vessel density and tumor size. Depletion of polyphenol with polyvinylpyrrolidone (PVPP) abolished the inhibitory activity of GSE, suggesting a water soluble fraction of polyphenol in GSE is responsible for the inhibitory activity. Taken together, our results indicate that GSE inhibits VEGF expression by reducing HIF-1alpha protein synthesis through blocking Akt activation. This finding provides new insight into the mechanisms of anti-cancer activity of GSE and reveals a novel molecular mechanism underlying the anti-angiogenic action of GSE.

PMID: 19131542 [PubMed - as supplied by publisher]

Commento Personale: Esistono, in natura, diversi prodotti in grado di inibire il VEGF e molti di questi sono erbe cinesi. In particolare suggerisco di valutare terapeuticamente la somministrazione ai malati di GBM di prodotti che, oltre ad inibire il VEGF, inibiscono anche altri path importanti. Fra questi suggerisco la Curcuma, la Camellia sinensis (Green Tea), il Quercetin e il Ginkgo Biloba. In particolare ho trattato questo argomento in uno specifico thread che invito tutti a leggere. La curcuma è senz'altro un elemento che non dovrebbe mancare in alte dosi (almeno 10.000mg/gg) in ogni piano di battaglia intergrato terapeutico.

Source Carcinogenesis. 2009 Jan 8

NOVEL DEVICE SHOWN TO BENEFIT SURVIVAL FOR BRAIN CANCER

22 January 2009

Newly published data show that the Novo-TTF device combined with standard chemotherapy (temozolomide) demonstrated a three-fold increase in time to progression (TTP) and a five-fold increase in overall survival (OS) for patients with newly diagnosed glioblastoma multiforme (GBM), when compared to historical controls. This study of the Novo-TTF, a non-invasive medical device that uses low intensity alternating electric fields to destroy cancer cells was published in BMC Medical Physics in January.

In the pilot trial, 10 patients with newly diagnosed GBM were treated with combination therapy of standard chemotherapy and the Novo-TTF device.  The study showed that combination therapy prolonged TTP by nearly 30 months and increased survival by more than 25 months compared to historical results of patients receiving standard chemotherapy alone. According to updated pilot data recently presented at the annual Society for Neuro-Oncology meeting late last year, eight of the 10 patients were still alive 49 months after the study began. Patients in the study did not experience any device-related, systemic, adverse events.

"We are excited about the publication of these pilot study results as they indicate the potential effect the Novo-TTF device may have on chemotherapy in the treatment of newly diagnosed GBM," said Eilon Kirson, MD, Medical Director, NovoCure Ltd. "many patients with GBM do not live beyond 12 months on standard therapy, but these data show that the Novo-TTF device combined with chemotherapy may enhance its efficacy and lead to much longer survival."

The study also included an initial In vitro study that showed the Novo-TTF device enhanced the efficacy of standard chemotherapy (temozolomide) treatment when applying both treatments together to GBM cells in culture. Data from these studies were recently presented during the annual Society for Neuro-Oncology meeting in November 2008.

The Novo-TTF device disrupts cancer cell proliferation and tumor growth by generating low intensity, intermediate frequency, alternating electric fields within a tumor.  These electric fields exert forces on polar structures within the dividing cancer cells that prevent tumor growth.  In pre-clinical and clinical studies to date, the electric fields have shown no effect on non-dividing, healthy cells in the same region, suggesting that the device can treat cancer without harming surrounding tissue, unlike chemotherapies that are typically associated with high toxicity resulting in serious side effects.  The Novo-TTF is currently an investigational medical device and is not yet FDA approved.

NovoCure recently published data from its human pilot study for patients with later stage GBM tumors that recurred after surgery and radiation.  The results of this study preliminarily indicate that the Novo-TTF more than doubled the median overall survival rates for recurrent GBM patients relative to historical data.

NovoCure is currently conducting a Phase III clinical trial at more than 20 centers in the US and Europe for patients with recurrent GBM and is planning to launch a Phase III clinical trial to evaluate Novo-TTF treatment in combination with standard chemotherapy in patients with newly diagnosed GBM in 2009.  Please refer to www.novocuretrial.com or call 1 (800) 978-0265 for more information on the ongoing trial.

STUDY DETAILS

The in vitro study looked at the effects of TTFields alone and in combination with DTIC, a precursor of MTIC (the active metabolite of temozolomide) in human GBM cells. The results demonstrated that, when applied together with DTIC, TTFields drastically increased the sensitivity of GBM cells in culture to DTIC.

The open-label, single-arm prospective pilot clinical trial evaluated the efficacy and safety of the Novo-TTF device in combination with standard chemotherapy (temozolomide). Twenty patients were enrolled in the trial, 10 patients with newly diagnosed GBM were treated with combination therapy and 10 patients with recurrent GBM were treated with the device alone as salvage therapy. The results of the study were compared to concurrent and historical control outcomes of standard chemotherapy when given alone. All patients were followed on a monthly basis and received treatment with the device for up to 18 months. The primary endpoints were feasibility, toxicity, time to disease progression and overall survival. No device-related, systemic, adverse events were noted throughout treatment with the Novo-TTF device. A mild to moderate skin irritation appeared beneath the device electrodes in all patients.

Median time to disease progression was 155 weeks in the 10 patients treated with combined standard chemotherapy and the Novo-TTF device, compared to 31 weeks in concurrent control patients treated with standard chemotherapy alone. Half of patients were still progression-free at the end of the trial. Median overall survival was reported at 39 months at the time of publication and was recently updated by the company to be greater than 49 months in the combination trial, compared to 14.7 months reported for historical controls.

Commento Personale: In Europa ricordo a tutti che questo metodo di cura dai significativi risultati ottenuti è oggi disponibile in sperimentazione in diversi Paesi (Austria, Israele, Republica Ceka, Francia ma suggerisco di rivolgersi o in Germania o in Svizzera contattando direttamente Manfred Westphal o Roger Stupp). Senz'altro da considerare come una delle prime alternative terapeutiche alle inutili fotemustina ed alle altre nitrosuree. Purtroppo molti medici, la quasi totalità, non conoscono l'esistenza di queste sperimentazioni pertanto quando farete domande li troverete molto probabilmente impreparati a qualsiasi giudizio in merito.

Source VirtualTrials

Short delay in initiation of radiotherapy may not affect outcome of patients with glioblastoma

10 February 2009

Blumenthal DT, Won M, Mehta MP, Curran WJ, Souhami L, Michalski JM, Rogers CL, Corn BW.

Departments of Oncology, Tel Aviv Medical Center, Tel Aviv, Israel. deborahblumenthal@...

PURPOSE: To analyze the Radiation Therapy Oncology Group (RTOG) database of patients with glioblastoma and appraise whether outcome was influenced by time to initiation of radiation therapy (RT). PATIENTS AND METHODS: From 1974 through 2003, adult patients with histologically confirmed supratentorial glioblastoma were enrolled onto 16 RTOG studies. Of 3,052 enrolled patients, 197 patients (6%) were either initially rendered ineligible or had insufficient chronologic data, leaving a cohort of 2,855 patients for the present analysis. We selected four patient groups based on the interval from surgery to the start of RT: <or= 2 weeks, 2 to 3 weeks, 3 to 4 weeks, more than 4 weeks to the protocol eligibility limit of 6 weeks. Survival times were estimated by the Kaplan-Meier method. Multivariate analysis incorporated variables of time interval, recursive partitioning analysis (RPA) class, and treatment regimen. RESULTS: No decrement in survival could be identified with increasing time to initiation of RT. Among our four temporal groupings, median survival time was unexpectedly and significantly greater in the group with the longest interval (> 4 weeks) than in those with the shortest delay (<or= 2 weeks): respectively, 12.5 months versus 9.2 months (P < .0001). On multivariate analysis, with overall survival as the end point, time interval more than 4 weeks and lower RPA class were both significant predictors of improved outcome. Treatment regimen was not a significant factor. CONCLUSION: There is no evident reduction in survival by delaying initiation of RT within the relatively narrow constraint of 6 weeks. An unanticipated yet significantly superior outcome was identified for patients for whom RT was delayed beyond 4 weeks from surgery.

PMID: 19114694 [PubMed - in process]

Commento Personale: Interessante studio che ha comparato la sopravvivenza dei malati di GBM a seconda dell'inizio della radioterapia post prima craniotomia. Spesso capita, causa code, di iniziare tardi la radioterapia esterna (WBRT). Generalmente viene suggerito dai medici di non superare i 40gg dalla craniotomia ma capita che, per disguidi o impegni delle macchine, talvolta si superi questo range temporale. Questo studio, ad ogni modo, dimostra che anticipare la radioterapia o ritardarla anche fino a sei settimane dalla prima craniotomia non produce impatti significativi sulla sopravvivenza. Anzi, al contrario di quanto potrebbe sembrare, ritardarla nel range dai 28/42gg (in questo studio) ha prodotto una maggiore sopravvivenza (12.5 vs. 9.2 mesi nei primi 28gg).

Source J Clin Oncol. 2009 Feb 10;27(5):733-9. Epub 2008 Dec 29

Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma.

29 December 2008

Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA.

Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-8200, USA.

PURPOSE: To evaluate single-agent activity of bevacizumab in patients with recurrent glioblastoma. PATIENTS AND METHODS: Patients with recurrent glioblastoma were treated with bevacizumab 10 mg/kg every 2 weeks. After tumor progression, patients were immediately treated with bevacizumab in combination with irinotecan 340 mg/m(2) or 125 mg/m(2) every 2 weeks, depending on use of enzyme-inducing antiepileptic drugs. Complete patient evaluations were repeated every 4 weeks. RESULTS: Forty-eight heavily pretreated patients were accrued to this study. Thromboembolic events (12.5%), hypertension (12.5%), hypophosphatemia (6%), and thrombocytopenia (6%) were the most common drug-associated adverse events. Six patients (12.5%) were removed from study for drug-associated toxicity (five thromboembolic events, one bowel perforation). Thirty-four patients (71%) and 17 patients (35%) achieved radiographic response based on Levin and Macdonald criteria, respectively. Median progression-free survival (PFS) was 16 weeks (95% CI, 12 to 26 weeks). The 6-month PFS was 29% (95% CI, 18% to 48%). The 6-month overall survival was 57% (95% CI, 44% to 75%). Median overall survival was 31 weeks (95% CI, 21 to 54 weeks). Early magnetic resonance imaging response (first 96 hours and 4 weeks) was predictive of long-term PFS, with the Levin criteria being more predictive than Macdonald criteria. Of 19 patients treated with bevacizumab plus irinotecan at progression, there were no objective radiographic responses. Eighteen patients (95%) experienced disease progression by the second cycle, and the median PFS was 30 days. CONCLUSION: We conclude that single-agent bevacizumab has significant biologic and antiglioma activity in patients with recurrent glioblastoma.

PMID: 19114704 [PubMed - in process

Commento Personale: Questo studio mette in risalto un aspetto chiave che sta capitando recentemente in Italia. Se utilizziamo l'avastin in combinazione con l'irinotecan (ma anche da solo) alla terza recidiva oramai ... è troppo tardi! La sua efficacia è pari a zero "Of 19 patients treated with bevacizumab plus irinotecan at progression, there were no objective radiographic responses". Quindi o si insiste con i medici per ottenere l'Avastin già a partire dalla prima recidiva oppure diventa inutile applicarlo, eventualmente, dopo una seconda linea di fotemustina. I risultati ottenuti da questo studio sia per PFS-6 sia per sopravvivenza mediana sono però stati decisamente inferiori a quelli pubblicati in altri studi. Questo studio ha registrato, stranamente, anche una migliore risposta nelle persone più vecchie rispetto a quelle giovani.

Source J Clin Oncol. 2009 Feb 10;27(5):740-5. Epub 2008 Dec 29

Early clinical and neuroradiological worsening after radiotherapy and concomitant temozolomide in patients with glioblastoma: Tumour progression or radionecrosis?

29 December 2008

Peca C, Pacelli R, Elefante A, Del Basso De Caro ML, Vergara P, Mariniello G, Giamundo A, Maiuri F.

Department of Neurological Sciences, Neurosurgical Clinic, University Federico II, Naples, Italy.

OBJECTIVES: This study investigates the diagnosis and management of patients with resected brain glioblastomas who presented early clinical and neuroradiological worsening after the completion of the Stupp protocol. Its aim is to discuss the occurrence of early radionecrosis. METHODS: Fifty patients with brain glioblastoma treated by surgical resection and Stupp protocol were reviewed; 15 among them (30%) had early clinical and neuroradiological worsening at the 6-month follow-up. The MR spectroscopy and surgical findings of these patients are reviewed. RESULTS: MR spectroscopy was in favour of tumour recurrence in 14 among 15 patients and showed radionecrosis in one. Among 10 patients who were reoperated on, 7 had histologically verified tumour recurrence or regrowth, whereas in 3 histopathology showed necrosis without evidence of tumour. The 7 patients with tumour progression had prevalence of focal neuroradiological signs (6/7) and a survival of 7.5-12 months (median survival 10 months). The 4 patients with early radionecrosis (including one patient who was not reoperated on) had clinical worsening with mental deterioration, confusion and ataxia, and MR spectroscopy positive for tumour recurrence in 3. Three were alive 24-30 months after the end of the radiotherapy, whereas one died at 40 months. CONCLUSION: Early radionecrosis after the Stupp protocol is not a rare event due to the radiosensitization effect of temozolomide. This phenomenon may predict a durable response to radiotherapy. MR spectroscopy may simulate tumour recurrence. A correct diagnosis is necessary to avoid useless reoperations and incorrect withdrawal of temozolomide.

PMID: 19117668 [PubMed - as supplied by publisher]

Commento Personale: E' paradossale ma, questo studio ci indica che avere radionecrosi significa avere una sopravvivenza superiore alla mediana storica.

Source Clin Neurol Neurosurg. 2008 Dec 29

An exploratory survival analysis of anti-angiogenic therapy for recurrent malignant glioma

29 November 2009

Norden AD, Drappatz J, Muzikansky A, David K, Gerard M, McNamara MB, Phan P, Ross A, Kesari S, Wen PY.

Division of Neuro-Oncology, Department of Neurology, Brigham and Women's Hospital, 75 Francis St, Boston, MA, 02115, USA, anorden@....

Recent clinical trial results suggest that anti-angiogenic therapy may be effective against recurrent malignant glioma. Though these treatments prolong progression-free survival, the extent to which they prolong overall survival is unknown. We pooled data from 34 patients treated at a single institution on phase II clinical trials of bevacizumab and cediranib, and we compared these data to 18 patients treated on clinical trials of cytotoxic chemotherapies. In univariate and multivariate analyses, treatment group was a significant predictor of progression-free but not overall survival. Median progression-free survival was 8 vs. 22 weeks in patients treated with cytotoxic as compared to anti-angiogenic therapy (P = 0.01). Median overall survival was nearly identical in the two groups (39 vs. 37 weeks). The results of this exploratory analysis suggest that anti-angiogenic therapy may fail to prolong overall survival in patients with recurrent malignant glioma. If this conclusion proves correct, progression-free survival may be an inappropriate endpoint for phase II trials of anti-angiogenic therapies.

PMID: 19043778 [PubMed - as supplied by publisher]

Commento Personale: Questo studio (sebbene piccolo), molto interessante ed importante perchè fa riferimento all'utilizzo di due farmaci anti-VEGF promettenti nel GBM come l'avastin e il cediranib, dimostra come in realtà questi farmaci siano in grado di dare ottime risposte a breve (PFS-6) ma divenire sostanzialmente similari ad altri farmaci chemioterapici standard in tema di sopravvivenza (nell'abastract non si fà riferimento a quali). In realtà ritengo, per esperienza di studi letti, che la sopravvivenza che si ottiene con gli anti-angiogenetici possa spingersi mediamente fino a 9/10 mesi dalla recidiva (se assunto come seconda linea in modo tempestivo) rispetto ai 6/7 mesi delle nitrosuree. In tal senso credo che l'Avastin o il Cediranib siano due alternative terapeutiche senz'altro da preferire al Muphoran, alla Carmustina o ai recenti farmaci anti-EGFR (erlotinib, gefitinib).

Source J Neurooncol. 2008 Nov 29

Two gene mutations linked to common types of brain cancers known as gliomas

19 February 2009

Scientists at the Johns Hopkins Kimmel Cancer Center and Duke University Medical Center have linked mutations in two genes, IDH1 and IDH2, to nearly three-quarters of several of the most common types of brain cancers known as gliomas.

Among the findings: people with certain tumors that carry these genetic alterations appear to survive at least twice as long as those without them.

Further research on the genes could also lead to more precise diagnosis and treatments, they said.

Reporting in the Feb. 19 issue of the New England Journal of Medicine, scientists say they looked for IDH1 and IDH2 gene alterations in material taken from 500 brain tumors and 500 non-central nervous system cancers. They located changes in the IDH1 gene in more than 70 percent of three common types of gliomas: low-grade astrocytomas, oligodendrogliomas, and secondary glioblastomas. The changes occurred within a single spot along a string of thousands of genetic coding letters. Some of the brain cancers that did not have alterations in IDH1 had equivalent mutations in another closely related gene, IDH2.

"For patients with these types of common brain tumors, mutations of IDH1/IDH2 are the most frequent genetic alterations yet identified," says D. Williams Parsons, M.D., Ph.D., visiting professor in pediatric oncology at Johns Hopkins and assistant professor at Baylor College of Medicine.

Further analysis of their data showed that glioblastoma and anaplastic astrocytoma patients carrying the mutations survived longer than those who did not, and note that additional studies of how the gene works may reveal why this occurs. The median survival for glioblastoma patients with mutations in either IDH1 or IDH2 was 31 months versus 15 months for those lacking the mutations. Anaplastic astrocytoma patients carrying the mutations were found to have a median survival of 65 months as compared with 20 months for those who did not. The scientists say that they could not compare survival data in oligodendroglioma patients because there were too few tumors that did not carry the mutations.

"Gliomas with IDH1/IDH2 mutations clearly make up a clinically and biologically distinct subgroup of brain cancers that may benefit from targeted therapies in the future," says Parsons.

IDH1, which stands for isocitrate dehydrogenase 1, was first spotted last year in results from a genomewide scan of brain cancer mutations led by the Johns Hopkins scientists. At the time, the scientists linked mutations in the IDH1 gene to roughly 12 percent of glioblastomas (or glioblastoma multiforme), the most lethal form of glioma.

Add to this the newly discovered mutations occurring in lower grade astrocytomas and oligodendrogliomas, and Parsons estimates that 6,000 adults and children with brain cancer per year in the U.S. could be affected.

"Pathologists may find it useful to determine IDH1/IDH2 status to help identify and classify these cancers," says Parsons. He added that proper diagnosis is essential because treatments differ within types of gliomas, as well as other forms of brain cancer.

"New treatments could be designed to target the enzymatic activity that is altered by these mutations," says Victor Velculescu, M.D., Ph.D., associate professor and director of cancer genetics at the Ludwig Center at Johns Hopkins.

"The mutations appear to occur very early in the progression of these cancers, perhaps at the stem cell level," adds Bert Vogelstein, M.D., Clayton Professor and co-director of the Ludwig Center aH1t Johns Hopkins and a Howard Hughes Medical Institute investigator.

Mutations were found by a standard technique of amplifying sections of the IDH1 and IDH2 genes through polymerase chain reaction (PCR), a process that replicates bits of DNA to levels that can be detected by sensitive computer equipment.

Yan, Parsons, Jones, Kinzler, Velculescu, Vogelstein, and Bigner are eligible for royalties received by Johns Hopkins University on sales of products related to research described in this article, under licensing agreements between the University and Beckman Coulter. These agreements are being managed in accordance with policies at the Johns Hopkins University.

Source News-Medical.Net

An International Case-Control Study of Adult Diet and Brain Tumor Risk: A Histology-Specific Analysis by Food Group

18 February 2009

Terry MB, Howe G, Pogoda JM, Zhang FF, Ahlbom A, Choi W, Giles GG, Little J, Lubin F, Menegoz F, Ryan P, Schlehofer B, Preston-Martin S.

Columbia University, New York, NY.

PURPOSE: Existing studies of diet and adult brain tumors have been limited by small numbers in histology-specific subgroups. Dietary data from an international collaborative case-control study on adult brain tumors were used to evaluate associations between histology-specific risk and consumption of specific food groups. METHODS: The study included 1548 cases diagnosed between 1984 and 1991 and 2486 control subjects from 8 study centers in 6 countries. Of the 1548 cases, 1185 were gliomas, 332 were meningiomas, and 31 were other tumor types. Dietary consumption was measured as average grams per day. RESULTS: We found inverse associations between some vegetable groups and glioma risk, the strongest for yellow-orange vegetables (odds ratio [OR], 0.7, 95% confidence interval [CI], 0.5-0.9 for the 4th vs. 1st quartile of consumption, p for trend<0.001), and the association was limited to specific glioma subtypes. There was no association with cured meat. Non-cured meat was associated with a modest increase in glioma risk (OR, 1.3; 95% CI, 1.0-1.7 for 4th quartile vs. 1st quartile, p for trend=0.01). We also found positive associations between egg, grain, and citrus fruit consumption and glioma but not meningioma risk. CONCLUSIONS: Our study suggests that selected dietary food groups may be associated with adult gliomas and its subtypes but not meningiomas.

PMID: 19216998 [PubMed - as supplied by publisher]

Source Ann Epidemiol. 2009 Mar;19(3):161-171

An International Case-Control Study of Maternal Diet During Pregnancy and Childhood Brain Tumor Risk: A Histology-Specific Analysis by Food Group

18 February 2009

Pogoda JM, Preston-Martin S, Howe G, Lubin F, Mueller BA, Holly EA, Filippini G, Peris-Bonet R, McCredie MR, Cordier S, Choi W.

USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA.

PURPOSE: Maternal dietary data from an international collaborative case-control study on childhood brain tumors were used to evaluate associations between histology-specific risk and consumption of specific food groups during pregnancy. METHODS: Nine study centers from seven countries contributed 1218 cases and 2223 controls. Most cases were diagnosed between 1982 and 1992 and ranged in age from 0 to 19 years. Dietary consumption was measured as average grams per day. RESULTS: Foods generally associated with increased risk were cured meats, eggs/dairy, and oil products; foods generally associated with decreased risk were yellow-orange vegetables, fresh fish, and grains. The cured meat association was specific to astrocytomas (odds ratio [OR] range=1.8-2.5 across astrocytoma subtypes for 4(th) vs. 1(st) quartile of consumption, p trends </= 0.03) and ependymomas (OR, 2.0; 95% confidence interval (CI), 0.4-2.9 for 4(th) vs. 1(st) quartile; p trend=0.03) and was similar in magnitude to previously reported ORs relating maternal cured meat consumption to increased astroglial risk. Other histology-specific associations were decreased risk of anaplastic astrocytomas from cruciferous vegetables (OR, 0.4; 95% CI, 0.3-0.7 for 4(th) vs. 1(st) quartile; p trend<0.0001), decreased risk of astroglial tumors from fresh fish (OR, 0.6; 95% CI, 0.5-0.9 for 4(th) vs. 1(st) quartile; p trend=0.008), and increased risk of medulloblastoma from oil products (OR, 1.5; 95% CI, 1.0-2.2 for 4(th) vs. 1(st) quartile; p trend=0.005). CONCLUSIONS: These results suggest the need for dietary analysis not only by brain tumor histology, but also by specific foods within a broad food group.

PMID: 19216997 [PubMed - as supplied by publisher]

Commento Personale: Da un altro punto di vista possiamo anche dire che molto probabilmente nei bambini figli di malati di tumori cerebrali, in particolare astrocitomi, una alimentazione ricca di pesce e crucifere è altamente consigliata per ridurre i rischi di malattia.

Source Ann Epidemiol. 2009 Mar;19(3):148-160

Is There A Brain Tumor Virus?

9 January 2009

In 2002, UCSF neurosurgeon Charles Cobbs published a novel finding in a prominent cancer journal: nearly all of the two-dozen brain tumors he had analyzed were teeming with a common herpes virus called cytomegalovirus, or CMV. Normally, CMV is harmless-it lies dormant in roughly 80 percent of the population-but in Cobbs's tumor samples, the virus appeared to be actively replicating, even as it remained dormant in nearby healthy tissue. "When I first saw the data, I couldn't sleep for a week," says Cobbs. "I kept asking myself, 'can this be?'" If his findings were correct, they might shed light on the causes of brain cancer, or better yet, provide a new target for battling-maybe even preventing-the disease.

But by 2004, at least two labs had tried and failed to replicate Cobbs's results. That might have been the end of the story, were it not for the young neurosurgeon's audacity. Convinced that his methodology was better than his colleagues, he offered to show both research teams his technique. One group, led by Duke University neuro-oncologist Duane Mitchell, accepted. Last year they published the first peer-reviewed confirmation of Cobbs's work. "We have enough evidence now to say that this merits serious attention," says Mitchell. As the journal Science wrote last week, a flurry of papers exploring a possible link between CMV and brain cancer have caught the attention of at least some experts, spurring the first conference on the subject last October and touching off a handful of clinical trials.

The findings have opened a new avenue of inquiry for one of the most intractable cancers-Glioblastoma Multiforme, an aggressive brain tumor, diagnosed in 10,000 new patients every year and fatal in virtually all cases. (Sen. Ted Kennedy was stricken with the disease last year). The alleged link between CMV and brain cancer may also represent the latest reversal of a decades-old consensus that generally speaking, viruses don't cause cancer. While some scientists are urging caution in interpreting this growing body of evidence, others say that a bias against "cancer-virus" research highlights a major flaw in the way science works. Ideas that challenge the conventional wisdom are often shunned in favor of "safer" hypotheses that stand a better chance of gaining acceptance and securing research dollars. "The powers that be are really opposed to funding this kind of research," says Cobbs who is now at California Pacific Medical Center. "They would rather put their money on more discreet projects where the outcomes are clear."

To be fair, the history of cancer-virus research is littered with false starts and embarrassing missteps. In 1926, a Danish scientist scored a Nobel Prize for showing that parasitic worms cause stomach cancer; it was later discovered that the "tumors" were actually lesions, triggered by vitamin deficiency. In the early 1970s scientists still believed that many if not most human cancers were triggered by some sort of infection. Famed HIV scientist Robert Gallo spent years at the National Cancer Institute trolling for the viral culprit, but most of his studies were never replicated and by the end of the decade, the hypothesis had been abandoned. "You have to tread carefully with findings like these," says Robert Weinberg, a biology professor and cancer researcher at MIT. "The majority of these claims tend to go up in smoke."

Today we know that at least three cancers are virus-induced: cervical cancer (Human Papiloma Virus, or HPV), liver cancer (Hepatitis B), and lymphoma (Epstein-Barr virus). But many questions still need answers before scientists can add brain cancer and CMV to that list. Chief among them is whether the virus actually triggers tumor growth. Cobbs thinks this may be the case, but he says the virus's influence is probably indirect. "It's not like a typical virus-disease relationship," he says. "The cancer may stem from chronic inflammation that is triggered by the virus and persists for years and years." If he's right, scientists may one day be able to develop a vaccine that prevents brain cancer by targeting CMV, much like Merck's Gardasil protects against cervical cancer by inoculating against certain strains of HPV.

Other researchers hypothesize that rather than induce tumor formation, CMV might simply abet their growth. Studies have shown that the virus promotes angiogenesis-the creation of an extra blood supply that tumors need to survive and grow.

Even if CMV doesn't cause brain tumors, the virus promises to be a useful target for future glioblastoma therapies. Mitchell's team is testing a vaccine made from immune cells that have been trained to attack CMV proteins. While the trial is too small to be conclusive, the vaccine, which enhanced immune responses against CMV, did extend patients' median survival time from 15 to more than 20 months. Meanwhile, Swedish researchers have just completed a clinical trial of the anti-CMV medication Valcyte to see if it can prevent the recurrence of brain tumors that have been surgically removed. The data is being tabulated now; if it looks good, Roche may eventually launch a large-scale study (il Valcyte, o valganciclovir, è disponibile in Italia e più "abili" potrebbero ricrearsi la stessa sperimentazione in corso in Svezia con la supervisione di un medico, qui trovate tutte le indicazioni per la sua applicazione, ndr)

To make real progress, however, scientists will need funding. Cobbs says that he has had a dozen or so grant proposals on CMV-glioblastoma research rejected by the National Cancer Institute and other funding agencies. "People from NCI have said that we need to prove CMV causes brain cancer before they fund us," says Cobbs. "It's putting the cart before the horse."

Source Newsweek

ImmunoCellular Therapeutics' Cancer Vaccine Demonstrates Immune Response against Brain Cancer

23 December 2008

ImmunoCellular Therapeutics, Ltd. (IMUC), a biotechnology company, presented preliminary, promising clinical data from a Phase I trial, evaluating ICT-107, the company's dendritic cell-based cancer vaccine product candidate for the treatment of glioblastoma. ICT-107 was well tolerated, and no significant adverse events were reported. These data were reported at the Society for Neuro-Oncology 13th Annual Scientific Meeting in Las Vegas, Nevada.

The Phase I clinical trial of ICT-107 was conducted to evaluate the safety and tolerability of the cancer vaccine in patients with glioblastoma, the most common and malignant type of brain cancer. The trial enrolled 19 patients and was conducted at Cedars-Sinai Medical Center. Of the 19 patients enrolled, seventeen patients are still alive, with eight patients surviving at least one year after the surgery that preceded their vaccine treatment. Ten patients were evaluated for immune responses, and five of them had a significant immune response to at least one tumor-associated antigen. Patients demonstrating an immune response are exhibiting a trend toward longer overall survival. IMUC expects to present additional follow-up data on this trial at a medical meeting in 2009.

"We are encouraged by these preliminary data from ICT-107, and while we are cautious due to their preliminary nature, we are pleased that 42 percent of patients remain alive one year after the surgery that preceded their vaccine treatment. Our clinical goal with ICT-107 is to stimulate a cancer-specific immune response, so we were encouraged to see that 50 percent of the patients evaluated had a tumor-specific immune response," stated Surasak Phuphanich, M.D., the principal investigator of the trial and a senior author of the presentation at the meeting.

"Glioblastoma remains a large unmet medical need across all age groups, and I am optimistic that an immune-based therapy such as ICT-107 or our cancer stem cell vaccine product candidate, ICT-121, may someday provide additional survival benefit to this patient population," stated Manish Singh, Ph.D. "Our next goal is to advance ICT-121, which we expect to enter the clinic as a non patient-specific ("off the shelf") vaccine in the second quarter of 2009. IMUC is strategically reviewing how to best move forward with our various vaccine cancer and molecular antibody programs in light of our limited resources and the difficulty for biotech companies to access additional capital under current market conditions. We look forward to completing the analysis of the data from the Phase I trial of our dendritic cell-based vaccine as an important part of this strategic review."

About ICT-107

ICT-107 is IMUC's patient-specific therapeutic cancer vaccine product candidate that consists of dendritic cells—immune system cells responsible for presenting antigens (immune system targets) to the immune system—which are obtained from the patient's blood and "programmed" with tumor antigens which in turn provide a target for the immune system. The immune system should then be armed to seek and destroy any remaining glioblastoma cells.

Source Businesswire

How Glioblastoma Tumor Cells Use The Body's Protection

8 December 2008

Glioblastoma is one of the most common but also most aggressive brain tumors, almost invariably leading to death in a short time. It consists of different cell types and their precursors, complicating successful treatment. To fight the driving force of the tumor - the tumor stem cells - scientists have been trying to initiate apoptosis in these cells. However, Dr. Ana Martin-Villalba (German Cancer Research Center, DKFZ, Heidelberg, Germany) suspects that the activated apoptosis program accelerates the progress of the disease. "The tumor growth declines when apoptosis is blocked," she reported at the conference "Brain Tumor 2008" at the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Germany.

Glioblastomas grow like corals and form filigran branches into nearby, healthy brain tissue. For that reason it is very difficult for neurosurgeons to remove the tumor entirely because the risk of damaging healthy tissue is too high. Moreover, glioblastomas are resistant to conventional therapies which normally activate the body's apoptosis program.

This programmed cell death is a vital process. It plays an important role during development but also in the adult organism. Together with its partner CD95L, the molecular switch CD95 ensures that sick or abnormal cells are removed. Once activated, CD95 triggers a chain of different signals which in the end lead to the death of the damaged cell. Until recently, scientists were convinced that triggering apoptosis in brain tumors was a useful tool for not only killing the tumor but also the cells of its origin - the tumor stem cells.

The scientist from Heidelberg could show that CD95 as well as its partner CD95L is active in the tumor cells. However, the cells do not die. "Instead, the signal stimulates the tumor cells to migrate into neighboring, healthy brain regions," Dr. Martin-Villalba explained. For instance, it activates the protein MMP which "drills" its way into the brain tissue. "Contrary to our expectations," the neuroscientist said, "what we find when we activate apoptosis in the tumor cells is that we help them spread into healthy nerve tissue."

In experiments with mice, the researchers could already show that the tumor proliferates less aggressively when they block CD95L with an antibody, thus inhibiting the activation of programmed cell death. "With this changed perspective, we hope to develop new ideas for tumor therapy in the future," Dr. Martin-Villalba said.

Altogether, about 180 scientists and clinicians from Europe and the USA came to the two-day conference, which ended this Friday afternoon. The organizers were the MDC, the Charité - Universitätsmedizin Berlin, and HELIOS Kliniken GmbH, Berlin, a private clinic in Berlin-Buch.

Barbara Bachtler

Press and Public Affairs

Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch

Robert-Rössle-Straße 10; 13125 Berlin; Germany

www.mdc-berlin.de

Source MedicalNewsToday

CHMP Recommends Approval In The European Union (EU) For New Options For Patients With Certain Primary Brain Tumors

9 December 2008

Schering-Plough Corporation announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) has issued a positive opinion recommending approval of the intravenous (IV) formulation of TEMODAL(R) (temozolomide) as an alternative to the already approved oral form of temozolomide in the EU. The CHMP also has issued a positive opinion recommending approval of a sachet packaging presentation for TEMODAL Capsules. This new presentation was created to provide greater patient convenience and flexibility.

TEMODAL Capsules are a chemotherapy agent approved in the EU for treatment of patients with newly diagnosed glioblastoma multiforme (GBM) concomitantly with radiotherapy and subsequently as monotherapy, and for patients with malignant gliomas, such as GBM or anaplastic astrocytoma (AA), showing recurrence or progression after standard therapy. The CHMP recommendation serves as the basis for a European Commission approval of the IV formulation of TEMODAL and the sachet presentation of TEMODAL Capsules. In the US, temozolomide, marketed as TEMODAR(R) Capsules, is approved for the treatment of adult patients with newly diagnosed GBM concomitantly with radiotherapy and then as maintenance treatment, as well as for refractory AA, ie, patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.

"TEMODAL is a well recognized, effective treatment for patients in Europe with malignant gliomas, but is only available orally. Upon approval, the IV formulation of TEMODAL can provide patients in the EU with an important alternative route of administration, and the sachet presentation can offer flexibility and a more convenient form of packaging," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "These two new options demonstrate Schering-Plough's commitment to providing effective treatments in a variety of presentations for specific patient needs and for patient convenience."

About temozolomide

TEMODAL (temozolomide), a cytotoxic agent, is currently approved in oral form as 5mg, 20mg, 100mg, 140mg, 180mg and 250mg capsules in Europe. Cytotoxic agents are designed to impact the replication of cells that divide rapidly, such as those in tumors. TEMODAL was initially approved in the European Union (EU) in 1999 for the treatment of patients with malignant glioma, such as GBM or AA, showing recurrence or progression after standard therapy. In June 2005, TEMODAL received marketing approval in the EU for the treatment of patients with newly diagnosed GBM concomitantly with radiotherapy and subsequently as monotherapy treatment. The TEMODAL IV formulation reviewed by the CHMP was developed for cancer patients who are unable to take TEMODAL Capsules and has shown bioequivalence to the oral product. The sachet packaging presentation for TEMODAL Capsules was created to provide greater patient convenience and flexibility.

Schering-Plough has received a Complete Response Letter from the U.S. Food and Drug Administration for the TEMODAR IV formulation and is working with the agency to address outstanding questions. TEMODAR capsules (temozolomide) received accelerated approval from the U.S. Food and Drug Administration (FDA) for adult patients with refractory AA in 1999 and full approval in March 2005 for refractory AA, ie, patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine, and for the treatment of newly diagnosed GBM concomitantly with radiotherapy and then as maintenance treatment.

Source Medical News Today

Nimustine (ACNU) Plus Teniposide (VM26) in Recurrent Glioblastoma

18 February 2009

Nimustine (ACNU) Plus Teniposide (VM26) in Recurrent Glioblastoma

M. Glas^a, T. Hundsberger^{c, d}, M. Stuplich^a, D. Wiewrodt^b, D. Kurzwelly^a, B. Nguyen-Huu^c, K. Rasch^a, U. Herrlinger<sup>a

a</sup>Department of Neurology, Clinical Neurooncology Unit, University of Bonn, Bonn, and Departments of
^bNeurosurgery and
^cNeurology, University of Mainz, Mainz, Germany;
^dDepartment of Neurology, Kantonsspital St. Gallen, St. Gallen, Switzerland

Background: In a previous trial (NOA-01), the combination of nimustine and teniposide showed efficacy in previously untreated glioblastoma (GBM). After establishing temozolomide as standard first-line therapy in GBM patients, the nimustine (ACNU)/teniposide (VM-26) combination has been employed as salvage chemotherapy for recurrent GBM. However, data on the toxicity and efficacy of this regimen in recurrent GBM are lacking. Patients and Methods: In two neurooncological centers, all patients with recurrent GBM treated with nimustine (90 mg/m², day 1/42) and teniposide (45-70 mg/m², days 1-3/42) were analyzed retrospectively for progression-free survival (PFS), overall survival (OS) and toxicity. Results: Thirty-five patients (median age 51 years, range 25-71 years) were identified. Six months after chemotherapy initiation, PFS was 29% and the median OS 6 months; 23% of patients were alive 1 year after initiation of nimustine-teniposide chemotherapy. Grade 4 hematotoxicity was observed in 12 of 35 patients (34%) and in 14 of 83 evaluable chemotherapy courses (17%). Conclusions: The benefit of the nimustine-teniposide combination is moderate in patients with recurrent GBM. The data support the efficacy of the nimustine-teniposide chemotherapy, but the rate of high-grade hematotoxicity is increased.

Copyright © 2009 S. Karger AG, Basel

Commento Personale: Questa particolare combinazione di farmaci non ha prodotto, nella recidiva di GBM post Temodal, una risposta particolarmente importante offrendo sostanzialmente risultati similari alle nistrosuree standard. 

Source Oncology 2009;76:184-189

Blood Pressure Compound May Benefit Brain Tumor Patients

19 February 2009

A widely used blood pressure medication may be the key to preventing brain function loss common after radiation treatment, according to a newly published study by researchers at Wake Forest University Baptist Medical Center. The findings offer the hope of an improved quality of life for cancer patients.

Using a rat model, the study drew on a hypothesis from previous studies that a compound similar to the anti-hypertensive drug losartan can prevent the cognition loss that has been closely-associated with radiation therapy for brain tumor treatment.

The findings, recently published in the International Journal of Radiation Oncology, Biology, Physics, appear to validate the hypothesis in rats and researchers are optimistic that the same theory could easily be applied in a human clinical trial setting because the drug used has a long-established safety profile in patients who have taken it to treat high blood pressure.

"We need to kill cancer cells but also prevent or reduce treatment-related side effects," said Mike E. Robbins, Ph.D., a professor in the department of radiation oncology at the Brain Tumor Center of Excellence, part of Wake Forest University School of Medicine. "One very interesting feature of this compound is that it has never shown any pro-tumor effects. If anything, it appears to have anti-tumor properties. We're very close to having a compound that will protect the normal brain from cognitive injury as a result of radiation and, at the same time, we may very well increase the likelihood of curing brain cancer patients of their tumors."

Researchers have theorized from previous studies that radiation may lead to the overproduction of angiotensin II (Ang II), a peptide that has been associated with decline of brain function. By blocking the binding of Ang II to the Ang type I receptor in patients receiving radiation, researchers hypothesized that they could prevent or hinder cognitive decline. Anti-hypertensive drugs, such as losartan, have been effective in preventing or minimizing radiation-induced injury in the lungs and kidneys, Robbins said, so testing them in the brain was an obvious next step.

The study involved three groups of 80 rats. Each group was divided in half to either receive radiation or no treatment. Then, each of those halves was divided into two more groups: one that received L-158,809, the compound similar to losartan, in its drinking water, and one group that received plain drinking water. The rats that received the drug received it before, during and for different time intervals – 14, 28 or 54 weeks – post-radiation.

In addition, a small group of rats continued to receive the drug for only five weeks after radiation. Researchers found that administering L-158,809 before, during and for as little as five weeks after radiation either prevents or lessens the severity of radiation-induced cognitive impairment.

"The extent of cognitive impairment experienced by patients who undergo radiation therapy varies in terms of how it is recognized," Robbins said. "Sometimes the patient realizes that their short-term memory is fading or that they've lost the ability to multi-task. Instead of waking up in the morning and having a clear idea of what needs to get done that day, patients finds themselves having to write things down. They just can't keep thoughts in their brain. Sometimes it's a friend or partner that realizes the impairment, but once it is noticed, it is not going to improve. Cognitive decline resulting from radiation is not stable. It is a chronic, progressive condition."

An estimated 170,000 patients undergo radiation therapy annually to treat primary or metastatic brain tumors. At least 50 percent of adult patients who undergo the treatment and live six months or more post-radiation experience some level of cognitive decline. In children, the effect is even greater, Robbins said. "All will have some form of cognitive impairment if they are long-term survivors and, thankfully, with today's technology, most children will survive long-term.

"This study provides hope that we may be able to take a drug that has been prescribed to millions of individuals with essentially very little morbidity and give it to cancer patients and stop them from experiencing cognitive impairment as a result of brain radiation. These drugs are routinely prescribed for the treatment of hypertension, are well-tolerated and exhibit anti-tumor effects," Robbins said. "They appear to be ideal for future clinical trials because they offer the promise of improving the quality of life for brain tumor patients."

Co-researchers on the study, funded by the National Cancer Institute, were Valerie Payne, B.S., Ellen Tommasi, B.S., Debra I. Diz, Ph.D, Fang-Chi Hsu, Ph.D., William R. Brown, Ph.D., Kenneth T. Wheeler, Ph.D., John Olson, M.S. and Weiling Zhao, Ph.D., all of Wake Forest University School of Medicine.

Commento Personale: Nel carcinoma in vitro sembra che si ottenga un migliore risultato nell'inibire il VEGF e ridurre la massa tumorale applicando un'altro farmaco similare, il perindopril. L'autore di questa scoperta conclude la sua ricerca dicendo: "In summary, we have shown here that the ACE inhibitor perindopril significantly inhibits tumor growth and angiogenesis along with suppression of the VEGF level. Several drugs, such as thalidomide, are now used in the clinical trials as antiangiogenic agents against cancer. Because perindopril is also already used widely in clinical practice without serious side effects, it may also be applicable as an anticancer agent, thus providing a new strategy for cancer therapy"

Source www.HealthNewsDigest.com

Trapianto di staminali embrionali causa tumori benigni in ragazzo di 17 anni

18 February 2009

I ricercatori che si usano le cellule staminali devono risolvere un problema di sicurezza dopo quanto accaduto a un ragazzo di 17 anni. Affetto da una rara malattia genetica, dopo essere stato curato nel 2001 con il trapianto di cellule staminali embrionali a Mosca, quattro anni fa ha sviluppato tumori benigni al cervello e alla spina dorsale. A parlarne e' la rivista 'Plos medicine'. Secondo i medici israeliani che hanno rimosso le formazioni cancerose, queste sono nate delle cellule staminali. Alcuni ricercatori temono che questa terapia possa involontariamente trasmettere virus o altre patologie alle persone che le ricevono. Il ragazzo in questione, curato per una malattia nota come Atassia Telangiectasia o sindrome di Louis-Bar, che attacca la regione cerebrale del movimento e della parola, ha ricevuto tre serie di iniezioni di staminali embrionali nel cervello e nel fluido che circonda la spina dorsale. Nei quattro anni successivi al trattamento e' stato visitato per mal di testa frequenti e i medici dello Sheba Medical Centre di Tel Aviv gli hanno trovato due tumori, uno nel cervello e l'altro nella spina dorsale, nello stesso punto in cui erano state fatte le iniezioni. L'anno successivo e' stato rimosso il tumore benigno alla spina dorsale, scoprendo cosi' che conteneva cellule che non potevano essere state prodotte dai tessuti del paziente, e che probabilmente erano nate da quelle staminali trapiantate. Secondo i medici le cellule derivate dal donatore possono aver fatto 'scoppiare' i tumori nel paziente perche' le persone affette da questa malattia spesso hanno un sistema immunitario piu' debole. 'Non e' chiaro se la terapia con le cellule staminali abbia aiutato le sue condizioni genetiche, ma cio' non significa che la ricerca sulle staminali debba essere abbandonata. Si deve fare di piu' per la sicurezza'.

Source Aduc Salute