[Show abstract][Hide abstract] ABSTRACT: Available treatments for recurrent glioblastoma (GBM) are inadequate, and median survival is approximately 6 months. Ipilimumab
(ipi) is an immune modulator that inhibits CTLA-4 and is active in refractory melanoma, including brain metastases. We retrospectively
reviewed records of patients treated with ipi for recurrent GBM, and explored safety, response, and survival using Kaplan-Meier
methodology. There were 10 patients (6 men), median age 55 years (range 41-65). All received prior radiotherapy and temozolomide,
and 9 received prior bevacizumab. Ipi (3mg/kg/dose) was administered for 1st (1), 2nd (4), 3rd (4), or 6th (1) recurrence.
Bevacizumab was administered concurrently to all patients to reduce corticosteroid requirements that can blunt ipi effect.
Other concurrent therapies included GM-CSF (8), nitrosoureas (5), carboplatin (1), temozolomide (1), or lapatinib (1). Corticosteroids
(dexamethasone, 0.75 - 4.0 mg/day) were administered concurrently in 4. All patients were evaluated for toxicity. One experienced
fever, elevated LDH, and transaminitis. One experienced rash and fatigue. There were no other significant toxicities, specifically
no endocrinopathies or electrolyte abnormalities. Responses included stable disease (5) and progressive disease (5). Median
progression-free survival (PFS) was 2.8 months and overall survival (OS) was 5.1 months, although 5 patients remain alive.
Results were the same for those (9) treated for bevacizumab-refractory disease. Historical control suggests results are similar
in bevacizumab-failure patients treated with salvage chemotherapy (PFS 1-3 moths, OS 4-6 months), and superior to those in
patients who receive no further treatment following progression on bevacizumab. Comparison of immunologic effects in pre-ipi
and post-ipi tumor tissue for one case is underway. Ipi can be administered safely to patients with GBM concurrently with
GM-CSF, bevacizumab, nitrosoureas, and other therapies. In patients treated for bevacizumab-refractory disease, ipi may prolong
PFS and OS as compared to historical controls. Concurrent bevacizumab may reduce corticosteroid requirements. Treatment earlier
in the disease course merits investigation.
[Show abstract][Hide abstract] ABSTRACT: Melanoma has a high propensity to metastasize to the brain. In patients with brain metastases (BM) survival is limited, neurologic morbidity is high, with seizure incidence reported up to 67%. Current guidelines recommend against antiepileptic drug prophylaxis (AED PPX) in patients without a history of seizure. We reviewed our experience with melanoma BM to determine the efficacy of AED PPX in the era of second generation AED and to delineate risk factors associated with development of seizures. We reviewed records of all patients treated at Memorial Sloan-Kettering Cancer Center with melanoma and BM between May 2006 and October 2008. Seizure risk was studied relative to BM characteristics at diagnosis and AED PPX. We identified 109 patients. Median age was 61 years (range 29-91); 56% had no neurologic symptoms at diagnosis. On neuroimaging, 94% (102/109) had cortical lesions, 60% (65/109) had more than one supratentorial lesion, 54% (59/109) had hemorrhage. Seizure led to diagnosis of BM in 13% (14/109); 20% (22/109) developed seizures later. On univariate analysis among patients without a seizure at diagnosis, AED-PPX was significantly associated with decreased risk of seizure (P = 0.03) with 3-month seizure rate of 0% compared to 17% without AED-PPX. Hemorrhage (P < 0.001) and multiple supratentorial metastases (P = 0.03) were associated with increased seizure risk. Melanoma patients with multiple supratentorial BM and hemorrhage may have an increased risk of seizure. AED PPX may be effective in selected patients, and should be addressed in a randomized controlled trial.
No preview · Article · Feb 2012 · Journal of Neuro-Oncology
[Show abstract][Hide abstract] ABSTRACT: Glioblastoma (GBM) is a highly vascular tumor dependent on angiogenesis through the vascular endothelial growth factor (VEGF) signaling cascade. Inhibition of VEGF signaling is an important therapeutic strategy. We report our experience with bevacizumab (BEV), a VEGF targeting antibody, following failure of a VEGF receptor targeting tyrosine kinase inhibitor (TKI). We retrospectively identified patients treated on clinical trials with VEGFR-TKIs for recurrent GBM followed by BEV at next recurrence. Survival was estimated by the Kaplan-Meier method. Fourteen patients were identified (six women; median age 57). All received VEGFR-TKIs (sunitinib 11, cediranib 2, sorafenib 1) then BEV at next recurrence. There were no radiographic responses to VEGFR-TKIs; best response was stable disease in 50% (7/14). Patients received BEV alone (21%, 3/14) or in combination with chemotherapy (79%, 11/14). On BEV, 29% (4/14) had a partial response, and 36% (5/14) stabilized. Of evaluable patients, 42% (5/12) had neurological improvement and 56% (5/9) reduced corticosteroid requirement. Median survival on BEV was 7.8 months (95% CI 4.0-15.8), median progression-free survival (PFS) was 4.0 months (95% CI 1.6-10.5), and the 6-month PFS rate was 29% (95% CI 9-52). Our radiographic and survival outcomes with BEV following progression after VEGFR-TKIs are similar to data from studies of BEV as initial salvage therapy, although our sample size was small. Prior exposure to VEGFR-TKIs may not preclude response to BEV, but sensitivity to BEV may be lower following more robust VEGFR inhibition.
No preview · Article · Dec 2011 · Journal of Neuro-Oncology
[Show abstract][Hide abstract] ABSTRACT: Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor approved for recurrent glioblastoma (GBM), metastatic breast, colorectal and non-small-cell lung cancers (NSCLC). There has been a potentially increased risk of intracranial hemorrhage (ICH) in patients receiving bevacizumab.
We retrospectively identified patients with ICH who received bevacizumab between 1 January 2001 and 10 January 2009.
We identified 1024 patients with ICH, 4191 patients who received bevacizumab and 12 (0.3%) who met both our criteria. There were eight women and four men with a median age of 66 years. Primary cancers were ovarian (n = 3), NSCLC (n = 3), colon (n = 1), angiosarcoma (n = 1) and GBM (n = 4). Intracranial tumors were present in 9 of the 12 patients; the remaining three (25%) had no evidence of intracranial pathology. Two hundred and fifty-seven patients with these same primary pathologies and brain tumors were treated with bevacizumab; ICH was seen in nine (3.7%), which was comparable to the 3.6% frequency seen in comparable patients not receiving bevacizumab.
ICH with bevacizumab treatment in this population is rare and does not appear to increase its frequency over the baseline rate of ICH in a comparable population. Most bevacizumab-related ICH occurs into central nervous system tumors but spontaneous hemorrhages were seen.
Full-text · Article · May 2011 · Annals of Oncology
[Show abstract][Hide abstract] ABSTRACT: Contemporary cancer research has led to unparalleled advances in therapeutics and improved survival. Even as treatment options continue to improve, quality of life should remain a priority. Headache drastically impacts the quality of life of patients with cancer and has a wide etiological scope, making diagnosis a challenge. Intracranial mass lesions are only one cause; others include extracranial tumors, paraneoplastic processes, and the consequences of diagnostic and therapeutic interventions used in cancer care. Fortunately, cancer-related headache is treatable, but a sound understanding of the variable etiologies is crucial to appropriate diagnostic evaluation and treatment. In this review, we highlight the important causes of headache in the patient with cancer, and consider the epidemiology, pathophysiology, clinical course, and treatment options for each.
No preview · Article · Oct 2010 · Current Pain and Headache Reports
[Show abstract][Hide abstract] ABSTRACT: Seizures are a common complication of metastatic brain tumors (MBT), affecting approximately 27-50% of all patients during the course of their illness. Treatment of tumor-induced seizures is often inadequate with traditional antiepileptic drugs (AED) due to a variety of factors, including activation of glutamatergic NMDA receptors, alterations of neuronal input pathways, and tumor growth. Levetiracetam (LEV) is a 2nd generation non-enzyme inducing AED with a novel mechanism of action, binding to neuronal synaptic vesicle protein SV2A, that has been previously shown to reduce seizure activity in patients with primary brain tumors. Due to its unique mechanism of action, it has been postulated that LEV may also be effective in controlling seizures from MBT. A retrospective chart review was performed of all Neuro-Oncology Center patients with MBT who had received LEV for seizure control. Thirteen patients were reviewed with a median age of 55.1 years (range: 34-70). Six patients had breast cancer, five had lung cancer, and two had melanoma. LEV was used as an add-on AED in seven patients (54%) and as monotherapy in six patients (46%), with a median dose of 1,000 mg/day (range: 500-3,000). The baseline median seizure frequency was one ictal event every other day. After the addition of LEV, the median seizure frequency was reduced to 0 per week. The seizure frequency was reduced to less than 50% of the pre-LEV baseline in 100% of patients (P=0.0002, Sign test), with 10 patients (77%; confidence interval: 46-95%) noting complete seizure control. The most common adverse event was somnolence and headache, noted in 3 of 13 patients (23%). LEV was very effective and well tolerated in MBT patients with seizures and should be considered for add-on therapy or as a substitute AED for monotherapy.
Full-text · Article · Oct 2007 · Journal of Neuro-Oncology
[Show abstract][Hide abstract] ABSTRACT: Seizures are a common complication of primary (PBT) and metastatic (MBT) brain tumors, affecting approximately 50% of all patients during the course of their illness. Anti-convulsant therapy of these tumor-induced seizures is often inadequate with conventional anti-epileptic drugs (AEDs), due to a variety of factors, including activation of glutaminergic NMDA receptors, immune-mediated neuronal damage, and anatomic alterations of neuronal input pathways. Levetiracetam (LEV) is a new AED with a novel mechanism of action, which includes reducing the Ca++ current through neuron-specific, high voltage activated Ca++ channels (n-type). Because of this unique mechanism, it has been postulated that LEV may be effective in controlling tumor-induced seizures. A retrospective chart review was performed of all patients who had received LEV for seizure control. Forty-one patients were reviewed (22 female, 19 male), with a median age of 47.5 years (range 25-81). There were 34 patients with PBT and 7 with MBT. LEV was used as an add-on AED in 33 patients and as monotherapy in eight patients, with a median dose of 1500 mg/day (range 500-3500). The baseline median seizure frequency for the cohort was 1 per week. After the addition of LEV and follow-up for a minimum of 4 weeks, the median seizure frequency was reduced to 0 per week (59% of patients noted complete seizure control). Overall, the seizure frequency was reduced in 90% of patients (P<0.0001; Sign test). The most common toxicity was somnolence, noted in 37% of patients. LEV was very effective and well tolerated in brain tumor patients with seizures, and should be considered for add-on therapy to current AEDs, or as a substitute anti-convulsant for monotherapy.
No preview · Article · May 2006 · Journal of Neuro-Oncology