First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

BACKGROUND: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma. METHODS: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). RESULTS: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. CONCLUSIONS: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.

Correction to: First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.

Proton therapy for atypical meningiomas.

We report clinical outcomes of proton therapy in patients with World Health Organization grade 2 (atypical) meningiomas. Between 2005 and 2013, 22 patients with atypical meningiomas were treated to a median dose of 63 Gy (RBE) using proton therapy, as an adjuvant therapy after surgery (n = 12) or for recurrence or progression of residual tumor (n = 10). Six patients had presumed radiation-induced meningiomas, but none had received prior radiotherapy for their meningioma. The median follow-up time after radiation was 39 months (range 7-104) and all patients remain alive at last follow-up. The 5-year estimate of local control was 71.1% (95% CI 49.3-92.9%). The 5-year estimate of local control was 87.5% following a radiation dose >60 Gy (RBE), compared to 50.0% for ≤ 60 Gy (RBE) (p = 0.038). The 5-year estimate of neuraxis dissemination was 5% (95% CI 0-14.6%) and 6.2% (95% CI 0-18.2%) for metastases outside of the central nervous system. Radiation necrosis was observed in one patient with a history of prior cranial irradiation. Fractionated proton therapy was associated with favorable tumor control rates for grade 2 meningiomas. Prospective studies are needed to define the optimal radiation dose for high-grade meningiomas.

Neurotoxicity of cancer chemotherapy.

Neurologic dysfunction is a common side effect of many chemotherapy drugs. For several agents, neurotoxicity is common, severe, and can be dose-limiting. As the list of newer chemotherapy agents and systemic "targeted therapies" grows, so does the number and variety of potential neurotoxicities. This is a review of the clinical features of chemotherapy-induced syndromes involving the central and peripheral nervous systems.

Disseminated choroid plexus papillomas in adults: A case series and review of the literature.

Choroid plexus papillomas (CPPs) are uncommon, usually intraventricular, low-grade tumors, accounting for less than 1% of all intracranial neoplasms and 2-4% of brain tumors in children. Dissemination of CPPs to multiple levels of the neuraxis has been seldom observed. Thus far, only 26 adult patients have been reported in the English language literature. With some exceptions, disseminated CPPs have been observed in adults and involved multiple sites along the cerebrospinal fluid pathways. Occasionally, intraparenchymal extension has been documented, and secondary involvement of the suprasellar region has been reported in only five patients. Postoperative treatment of CPPs has not been standardized. Most recommended therapies have been extrapolated from a series of atypical papillomas or carcinomas of the choroid plexus in children. We herein report a series of three patients of disseminated choroid plexus papillomas providing additional insights into this relatively rare entity.

Anti-Hu antibody neuropathy: a clinical, electrophysiological, and pathological study.

OBJECTIVE: The objective is to report the clinical, electrophysiological, and histopathological features of 16 patients with anti-Hu antibody neuropathy. METHODS: Clinical and electrophysiological data in 16 patients (11 females and 5 males) with positive anti-Hu antibody and nerve biopsy data in 9 cases were analyzed. RESULTS: Cancer was detected in 11 patients, including 9 with small-cell lung cancer. Classical paraneoplastic subacute sensory neuronopathy (SSN) and/or encephalomyelitis (EM) was observed in 7 patients (44%), including 5 with SSN. The most common clinical feature was sensory-motor neuropathy (SMN), accounting for 50% of cases. Though sensory nerve conduction abnormality was the prominent feature in 14 (88%) cases, sensory and motor nerve conduction was abnormal in all cases. Motor nerve conduction findings were typical of axonal degeneration. The most common nerve conduction pattern was that of SMN, with a sensory neuronopathy pattern being observed in only 3 cases. Sural nerve biopsy in 9 patients showed axonal degeneration in all cases and inflammatory cells in 4 cases. CONCLUSIONS: Classical sensory neuronopathy is rarer than expected, both clinically and electrophysiologically. Motor involvement is not uncommon and motor nerve conduction abnormality is frequently seen. A diverse clinical and electrophysiological, and histopathological spectrum was observed in this neuropathy. SIGNIFICANCE: New guidelines for the selection of patients for anti-Hu antibody test are recommended.

Remote neurologic manifestations of cancer.

Paraneoplastic disorders may affect any part of the central or peripheral nervous systems. Although relatively uncommon, these disorders are a significant cause of neurologic morbidity for cancer patients. At least some paraneoplastic syndromes are believed to be caused by an autoimmune reaction against shared tumor-neural antigens. This article summarizes the clinical features of paraneoplastic disorders, the current evidence for autoimmunity, and guidelines for diagnosis and treatment.

Neurologic complications of lung cancer.

Neurologic complications of lung cancer are a frequent cause of morbidity and mortality. Tumor metastasis to the brain parenchyma is the single most common neurologic complication of lung cancer, of any histologic subtype. The goal of radiation therapy and in some cases surgical resection for patients with brain metastases is to improve or maintain neurologic function, and to achieve local control of the brain lesion(s). Metastasis of lung cancer to the spinal epidural space requires urgent evaluation and treatment. Early diagnosis and modern surgical and radiotherapy techniques improve neurologic outcome for most patients. Leptomeningeal metastasis is a less common but ominous occurrence in patients with lung cancer. Lung carcinomas can also occasionally metastasize to the brachial plexus, skull base, dura, or pituitary. Paraneoplastic neurologic disorders are uncommon but important complications of lung carcinoma, and are generally the presenting feature of the tumor. Paraneoplastic disorders are believed to be caused by an autoimmune humoral or cellular attack against shared "onconeural" antigens. The most frequent paraneoplastic disorders in patients with lung cancer are Lambert-Eaton myasthenic syndrome, and multifocal paraneoplastic encephalomyelitis, both mainly occurring in association with small-cell lung carcinoma. There is a variety of other paraneoplastic disorders affecting the central and peripheral nervous systems. Some affected patients have a good neurologic outcome, while others are left with severe permanent neurologic disability.

Should the cost of care for patients with glioblastoma influence treatment decisions?

This article presents the case of a patient with recurrent glioblastoma who questions whether he can or should pay for treatment with bevacizumab. There are differing views on the physician's role in dealing with cost and cost-effectiveness issues for patients, but it is becoming increasingly unrealistic for physicians to disregard the cost of cancer care when making treatment recommendations. Physicians need to be able to address cost issues in order to allow individual patients to make the best informed decision about what treatment option is the most beneficial and the "best value" for them.

The neurologic side effects of chemotherapeutic agents.

Neurologic dysfunction is a common side effect of many chemotherapy drugs. For several agents neurotoxicity is common, severe, and can be dose limiting. As the list of newer chemotherapy agents and systemic targeted therapies grows, so does the number and variety of potential neurotoxicities. This article reviews the clinical features of chemotherapy-induced syndromes involving the central and peripheral nervous systems.

Neurotoxicity of radiation therapy.

Direct or incidental exposure of the nervous system to therapeutic irradiation carries the risk of symptomatic neurologic injury. Central nervous system toxicity from radiation includes focal cerebral necrosis, neurocognitive deficits, and less commonly cerebrovascular disease, myelopathy, or the occurrence of a radiation-induced neoplasm. Brachial or lumbosacral plexopathy are the most common syndromes of radiation toxicity affecting the peripheral nervous system. This article focuses on the clinical features, diagnosis, and management options for patients with radiation neurotoxicity.

Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme.

PURPOSE: Cilengitide, an inhibitor of alphavbeta3 and alphavbeta5 integrin receptors, demonstrated minimal toxicity and durable activity across a wide range of doses administered to adults with recurrent glioblastoma multiforme (GBM) in a prior phase I study. The current multicenter phase II study was conducted to evaluate the activity and safety of cilengitide in GBM patients at first recurrence. PATIENTS AND METHODS: Eligible patients were randomly assigned to receive either 500 or 2,000 mg of cilengitide twice weekly on a continuous basis. Patients were assessed every 4 weeks. The primary end point was 6-month progression-free survival (PFS) rate. Secondary end points included PFS, overall survival (OS), and radiographic response, as well as quality-of-life and pharmacokinetic assessments. RESULTS: Eighty-one patients were enrolled, including 41 on the 500-mg arm and 40 on the 2,000-mg arm. The safety profile of cilengitide was excellent, with no significant reproducible toxicities observed on either arm. Antitumor activity was observed in both treatment cohorts but trended more favorably among patients treated with 2,000 mg, including a 6-month PFS of 15% and a median OS of 9.9 months. CONCLUSION: Cilengitide monotherapy is well tolerated and exhibits modest antitumor activity among recurrent GBM patients. Additional studies integrating cilengitide into combinatorial regimens for GBM are warranted.

Immunotherapy for paraneoplastic neurological disorders.

Paraneoplastic disorders may affect any part of the central or peripheral nervous systems. Although relatively uncommon, these disorders are a significant cause of severe neurological disability among cancer patients. Most, if not all, neurological paraneoplastic disorders are believed to be autoimmune diseases in which an antitumour immune response also attacks neurons that express shared neuronal tumour antigens. Affected patients often have one or more circulating antineuronal antibodies, which serve as a diagnostic marker for the paraneoplastic condition, and in some cases are the direct mediators of neuronal injury. The exact immunopathogenesis and relative contributions of humoral or cellular immune effectors for most paraneoplastic syndromes are not well understood. Some patients have a gratifying neurological response to tumour treatment and/or immunotherapy, especially if the diagnosis is made early and treatment is initiated promptly. Unfortunately, many patients are left with severe and permanent neurological deficits despite aggressive treatment. This review summarises the current understanding of the clinical immunology of paraneoplastic disorders, and outlines immunotherapy options and outcomes.

Update on paraneoplastic syndromes.

PURPOSE OF REVIEW: This review discusses the varied clinical spectrum of neurologic paraneoplastic disorders, describes recent advances in our understanding of autoimmunity in these disorders, and outlines a practical clinical approach to patient management. RECENT FINDINGS: Paraneoplastic disorders may affect any part of the central or peripheral nervous system. Although relatively uncommon, these disorders are a significant cause of severe and permanent neurologic disability. Syndromes such as limbic encephalitis or opsoclonus-myoclonus should always raise suspicion of a paraneoplastic condition, but any paraneoplastic syndrome can also occur in patients without a neoplasm. Most neurologic paraneoplastic disorders are thought to be caused by an autoimmune reaction directed against 'onconeural' antigens expressed by neurons and tumor cells. Some syndromes such as Lambert-Eaton myasthenic syndrome and neuromyotonia are clearly mediated by autoantibodies. Much less is known about the immunopathogenesis of syndromes that affect the central nervous system, although a growing body of evidence implicates cellular immune effectors in causing neuronal injury. Many patients have circulating antineuronal antibodies, which can be useful in identifying a neurologic disorder as paraneoplastic and in finding the associated neoplasm. Early diagnosis of the neurologic disorder and prompt initiation of tumor treatment probably increase the likelihood of neurologic improvement. SUMMARY: Neurologists must be able to recognize the clinical manifestations of neurologic paraneoplastic disorders, and to distinguish them from other causes of neurologic dysfunction in cancer patients. Early diagnosis of paraneoplastic syndromes maximizes the likelihood of a favorable oncologic and neurologic outcome.

Low-Grade Gliomas in Adults.

Adult patients with a magnetic resonance scan suggestive of a supratentorial low-grade glioma should generally undergo at least a stereotactic biopsy to confirm the diagnosis and rule out an anaplastic glioma or a non-neoplastic lesion. Early tumor treatment should be given to patients with newly diagnosed low-grade gliomas who are over age 50 years, those who have headaches or neurologic deficits other than seizures, or those whose neuroimaging studies show tumor growth or mass effect. For younger patients presenting with seizures and no other neurologic symptoms, it is reasonable to defer therapy until there is clinical or radiographic tumor progression. When it is judged that intervention is necessary, patients should undergo the maximal surgical tumor resection, which preserves or improves neurologic function. For younger (<50 years) astrocytoma patients with a good tumor resection, radiation may be deferred until tumor progression. Early radiation should be given to astrocytoma patients who are older than 50 years of age at diagnosis (regardless of the type of surgery) or to younger patients who are judged to require early intervention but who are not candidates for aggressive surgical resection. The radiation dose for low-grade glioma should be 4500 to 5000 cGy, preferably with three-dimensional conformal ports. The same guidelines for management apply to patients with low-grade oligodendroglioma or oligoastrocytoma, except that chemotherapy is a reasonable alternative to radiation when it is judged that treatment other than surgical resection is required.

Neurologic paraneoplastic syndromes.

Paraneoplastic disorders can affect any part of the central or peripheral nervous system. Although relatively uncommon, these disorders are a significant cause of severe neurologic disability among cancer patients. Many paraneoplastic disorders are believed to be caused by an autoimmune response directed against shared neural tumor antigens. This article summarizes the clinical features, possible autoimmune pathophysiology, and management issues for patients with paraneoplastic disorders.

Neurotoxicity of cancer chemotherapy.

Neurological dysfunction is a common side effect of many chemotherapy drugs. For several agents neurotoxicity is common, severe, and can be dose-limiting. This is a review of the clinical features of chemotherapy-induced syndromes involving the central and peripheral nervous systems.