ASCO 2013: bevacizumab and glioblastoma--a marriage dissolution?

The prognosis of patients affected by glioblastoma (GBM) is grim albeit the integrated therapeutic approaches now available. Standard surgery followed by chemoradiation median overall survival (OS) reaches 15 months in clinical trials. Despite primary treatment, recurrence is the rule in patients with GBM and for them OS ranges from 6 to 9 months. In recent years, the therapeutic scenario has been profoundly changed in view of the promising results obtained by bevacizumab (Avastin * *Avastin is a registered trade name of Bevacizumab, F. Hoffmann-La Roche Ltd, Basel, Switzerland. ), the most promising anti-angiogenesis agent, in two clinical trials. The results of both trials were presented at the last ASCO meeting in Chicago. Progression free survival was significantly improved with an acceptable safety and tolerability profile but surprisingly quality of life was preserved only in the AVAGlio trial. However, both studies showed that overall survival was not improved adding bevacizumab to temozolomide and radiotherapy.

Erlotinib: early clinical development in brain cancer.

INTRODUCTION: Glioblastoma (GBM) is the most common brain cancer in adults. It is also, unfortunately, the most aggressive type and the least responsive to therapy. Overexpression of EGFR and/or EGFRvIII is frequently found in GBM and is frequently associated with the more malignant phenotype of the disease and a poor clinical outcome. EGFR-targeted therapy represents a promising anti-GBM therapy. Two EGFR kinase inhibitors, gefitinib and erlotinib have been tested in clinical trials for malignant gliomas. However, the clinical efficacy of EGFR-targeted therapy has been only modest in GBM patients. AREAS COVERED: The authors provide an evaluation of erlotinib as a potential therapy for GBM. The authors highlight experiences drawn from clinical trials and discuss the challenges, which include the insufficient penetration through the blood-brain barrier (BBB) and chemoresistance. EXPERT OPINION: Malignant brain tumours have a very complex signalling network that is not only driven by EGFR. This complexity dictates tumour sensitivity to EGFR-targeted therapies. Alternative kinase signalling pathways may be involved in parallel with the inhibited target, so that a single target's inactivation is not sufficient to block downstream oncogenic signalling. The use of nanocarriers offers many opportunities, such as the release of the drug to specific cells or tissues, together with the ability to overcome different biological barriers, like the BBB.

Protracted low dose of oral vinorelbine and temozolomide with whole-brain radiotherapy in the treatment for breast cancer patients with brain metastases.

PURPOSE: The management of brain metastases (BM) from breast cancer (BC) needs to be improved, and new therapeutic strategies are urgently requested. In this view, we have evaluated the efficacy, tolerability, and safety of concurrent low protracted dose of temozolomide (TMZ), metronomic oral vinorelbine (VNB), and radiotherapy in BC women with previously untreated BM. METHODS: Thirty-six patients with newly diagnosed BM were treated with TMZ orally administered at a dose of 75 mg/m(2) during whole-brain radiotherapy, followed by 4 weeks off-therapy and a subsequent administration of oral 70 mg/m(2) VNB fractionated in days 1, 3, and 5, weekly for three consecutive weeks plus TMZ at 75 mg/m(2) on days 1-21, all every 4 weeks for up to 12 additional cycles. The primary end point was the evaluation of the objective response rate (ORR). RESULTS: Three complete responses and 16 partial responses have been achieved with an ORR of 52 % (95 % CI 38-67 %) that exceeded the target activity per study design. The median progression-free survival and overall survival were 8 and 11 months, respectively. The schedule appeared to be well tolerated, and side effects were generally mild. The functional assessment of cancer therapy-breast (FACT-B) analysis showed a significant positive change during the study. CONCLUSIONS: In conclusion, the treatment was safe and a significant number of objective responses were observed with a significant improvement in quality of life demonstrated by FACT-B. On the basis of the present results, a large randomized trial is warranted in BC patients with previously untreated BM.

Trigeminal neuralgia and persistent trigeminal artery.

We report a case of trigeminal neuralgia caused by persistent trigeminal artery (PTA) associated with asymptomatic left temporal cavernoma. Our patient presented unstable blood hypertension and the pain of typical trigeminal neuralgia over the second and third divisions of the nerve in the right side of the face. The attacks were often precipitated during physical exertion. MRI and Angio-MRI revealed the persistent carotid basilar anastomosis and occasionally left parietal cavernoma. After drug treatment of blood hypertension, spontaneous recovery of neuralgia was observed and we planned surgical treatment of left temporal cavernoma.

A new schedule of fotemustine in temozolomide-pretreated patients with relapsing glioblastoma.

In the present study we investigated the feasibility and effectiveness of a new biweekly schedule of fotemustine (FTM) in patients with recurrent glioblastoma, after at least one previous treatment. The primary endpoint was progression-free survival at 6 months; secondary objectives were clinical response, overall survival, disease-free survival, and toxicity. Forty patients (median age 52.8 years; median Karnofsky Performance Status at progression 90) underwent second-line chemotherapy with FTM. Selected patients were previously treated with a standard radiotherapy course with concomitant temozolomide (TMZ). After tumor relapse or progression proven by magnetic resonance imaging (MRI), all patients underwent chemotherapy with FTM, given intravenously at dose of 80 mg/m(2) every 2 weeks for five consecutive administrations (induction phase), and then every 4 weeks at 80 [DOSAGE ERROR CORRECTED] mg/m(2) as maintenance. A total of 329 infusions were administered; the median number of cycles administered was 8. All patients completed the induction phase, and 29 patients received at least one maintenance infusion. Response to treatment was assessed using MacDonald criteria. One complete response [2.5%, 95% confidence interval (CI): 0-10%], 9 partial responses (22.5%, 95% CI: 15-37%), and 16 stable diseases (40%, 95% CI: 32-51%) were observed. Median time to progression was 6.7 months (95% CI: 3.9-9.1 months). Progression-free survival at 6 months was 61%. Median survival from beginning of FTM chemotherapy was 11.1 months. The schedule was generally well tolerated; the main toxicities were hematologic (grade 3 thrombocytopenia in two cases). To the best of our knowledge, this is the first report specifically dealing with the use of a biweekly induction schedule of FTM. The study demonstrates that FTM has therapeutic efficacy as single-drug second-line chemotherapy with a favorable safety profile.

Use of a collagen biomatrix (TissuDura) for dura repair: a long-term neuroradiological and neuropathological evaluation.

PURPOSE: The aim of this study was to evaluate the clinical, neuroradiological, and neuropathological outcomes of patients treated with equine collagen foil (TissuDura) as a dura mater substitute during cranial and spinal neurosurgical procedures. MATERIALS AND METHODS: All patients treated at the Department of Neurosurgery of the Second University of Naples with TissuDura between 2005 and 2009 were included. Dural reconstruction was performed using TissuDura, overlaid 1 cm over the dural defect with additional fixation using fibrin glue. No surgical sutures were used. Patients underwent postoperative contrast-enhanced magnetic resonance scans at 1 week, 1 month, and 1 year after surgery to detect any cerebrospinal fluid (CSF) leaks, infections, inflammations, or CSF circulation in the surgical region. RESULTS: Dural reconstruction was performed in 74 patients, including 50 patients with tumors, two with C2 neurinoma, two with acoustic neurinoma, six with Chiari I malformation, two with severe head injury, and 12 requiring spinal surgery. Clinical and neuroradiological findings were normal and no signs of graft rejection or CSF leaks at postoperative follow-up were observed. In two cases of atypical meningioma, re-operation of the dural reconstruction was performed after 1 year. No adherences between brain and neodura were detected, and histopathological investigations demonstrated dural regeneration. CONCLUSIONS: Following dural reconstructions with TissuDura without surgical sutures, no local toxicity or complications were observed for up to 1 year. TissuDura demonstrated elasticity, non-reactivity, and good adaptability. The overlay technique using fibrin glue was simple and fast. Future studies and longer follow-up are needed to confirm the efficacy of TissuDura.

Cranial reconstruction using bioabsorbable calcified triglyceride bone cement.

BACKGROUND: We report our experience on 6 cases of cranial reconstruction using bioabsorbable calcified triglyceride KRYPTONITE Bone Cement (Doctors Research Group). METHODS: Six patients underwent cranial reconstruction during the surgical removal of a supratentorial tumor between September 2008 and November 2009 at our department. In 5 patients, we performed the cranial reconstruction using KRYPTONITE Bone Cement and cranial fixations; in the remaining patient, we avoided cranial fixation systems or other bone sutures to obtain good aesthetic results in the frontal supraorbital region. Preoperatively and 7 days and 12 months after surgery, patients were assessed using craniocerebral magnetic resonance imaging and computed tomography (CT). RESULTS: We observed that this bone cement was an injectable liquid for up to 8 minutes after mixing, it became adhesive at 8 to 15 minutes, and it was then shaped for use. Brain and dural reconstructions were not protected when this bone cement was being poured into the craniotomy site because of the minimal exothermal reaction. After 8 minutes, additional expansion is limited to 10%; therefore, we took heightened awareness of the amount of cement needed to fill the bone defect. In all patients, postoperative craniocerebral CT scanning, at 7 days, showed perfect alignment of the craniotomical bone and optimal filling of bone defects. No complications occurred, and aesthetic result was good. Twelve months after surgery, craniocerebral CT scanning showed bioabsorbability and osteoconductivity of this cement. CONCLUSIONS: KRYPTONITE Bone Cement is a nonthermal conducting, radiopaque, nonmagnetic, lightweight, simple to prepare, and easily applicable and molded material. Moreover, it has adhesive, bioabsorbable, and osteoconductive properties. To our knowledge, we present the first case of cranial reconstruction using this cement without cranial fixation systems.

Surgery, radiotherapy and temozolomide in treating high-grade gliomas.

Temozolomide (TMZ) a recent, oral, second generation alkylating agent is a chemotherapeutic with demonstrated efficacy for the treatment of high-grade gliomas. The efficacy of TMZ has been demonstrated in both pre-clinical and phase I and II studies. The goal of this study is to determine the activity and safety of temozolomide in improving overall survival (OS), progression-free survival (PFS) and health-related quality of life (HQL) in patient with malignant gliomas treated by surgery, radiotherapy and temozolomide. Twelve patients with newly diagnosed glioblastoma (GBM), and anaplastic astrocytoma (AA) were studied. The mean follow-up period was 12 months. The overall response rate for all histological groups was 33% (4 patients), 6 patients (50%) showed a stabilization of disease. The median progression-free survival (PFS) and overall survival (OS) was respectively 8.35 and 14.1 months; time to progression was 36 week ranging from 20 to 46 In all patients, treatment with temozolomide was associated with improvement of performance status including the patient showing disease progression; Karnofski score improved in all patients by a minimum of 10, with a median of 20 at 6 months. No patient stopped the treatment due to side-effects, no major adverse events were recorded. In two cases of glioblastoma, we observed complete response and after three years, the quality of life is optimal. Surgery allows to establish a histopathological diagnosis, to improve signs and symptoms which are attributable to intracranial hypertension or tumour topography, and to reduce the number of target cells for adjunctive therapies. Radiotherapy improves survival and TMZ chemotherapy that is given after radiotherapy adds survival benefit for patients. Because of its favourable pharmacokinetic and pharmacodynamic properties and improved tolerability. Temozolomide appears to be an ideal, first-line, single-agent, with a safe profile and demonstrated HQL benefits in patients with high-grade gliomas.