First-line treatment and outcome of elderly patients with primary central nervous system lymphoma (PCNSL)--a systematic review and individual patient data meta-analysis.

BACKGROUND: To investigate prognosis and effects of first-line therapy in elderly primary central nervous system lymphoma (PCNSL) patients. PATIENTS AND METHODS: A systematic review of studies about first-line therapy in immunocompetent patients ≥60 years with PCNSL until 2014 and a meta-analysis of individual patient data from eligible studies and international collaborators were carried out. RESULTS: We identified 20 eligible studies; from 13 studies, we obtained individual data of 405 patients, which were pooled with data of 378 additional patients (N = 783). Median age and Karnofsky Performance Score (KPS) was 68 years (range: 60-90 years) and 60% (range: 10%-100%), respectively. Treatments varied greatly, 573 (73%) patients received high-dose methotrexate (HD-MTX)-based therapy. A total of 276 patients received whole-brain radiotherapy (median 36 Gy, range 28.5-70 Gy). KPS ≥ 70% was the strongest prognostic factor for mortality [hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.41-0.62]. After a median follow-up of 40 months, HD-MTX-based therapy was associated with improved survival (HR 0.70, 95% CI 0.53-0.93). There was no difference between HD-MTX plus oral chemotherapy and more aggressive HD-MTX-based therapies (HR 1.39, 95% CI 0.90-2.15). Radiotherapy was associated with an improved survival, but correlated with an increased risk for neurological side-effects (odds ratio 5.23, 95% CI 2.33-11.74). CONCLUSIONS: Elderly PCNSL patients benefit from HD-MTX-based therapy, especially if combined with oral alkylating agents. More aggressive HD-MTX protocols do not seem to improve outcome. WBRT may improve outcome, but is associated with increased risk for neurological side-effects. Prospective trials for elderly PCNSL patients are warranted.

Beyond high-dose methotrexate and brain radiotherapy: novel targets and agents for primary CNS lymphoma.

BACKGROUND: While there has been significant progress in outcomes for patients diagnosed with primary central nervous system (CNS) lymphoma (PCNSL), survival rates will likely plateau with the current armamentarium of agents used to treat these patients. Moreover, given that PCNSL increasingly impacts an older population, a significant proportion of patients are not eligible for intensive therapies such as high-dose chemotherapy or whole-brain radiation. There is a need for the development of novel agents, which target key survival pathways in order to continue to make progress in this disease. PATIENTS AND METHODS: We reviewed the key molecular pathways and genomic aberrations in PCNSL in order to identify candidate targets. We focused on molecules and pathways that have been identified and confirmed by more than one investigator or methodology. RESULTS: While PCNSL tumors usually express a BCL6+, MUM1+ 'activated, germinal center' immunophenotype, they exhibit multiple shared genetic properties with ABC-type diffuse large B-cell lymphomas. Candidate targets and pathways include NFkB, the B-cell receptor, the JAK/STAT pathway, IRF4, BCL-6 as well as PIM kinases. Elements of the tumor microenvironment that may be exploited therapeutically include chemokine pathways, as well as macrophage and T-cell responses. CONCLUSIONS: There is a significant need for developing novel therapies in PCNSL, given that an increasing proportion of patients are not eligible for high-dose chemotherapy and brain radiation is associated with detrimental cognitive side-effects. We provide an overview of potential drug targets and novel agents that may be integrated with existing strategies in order to make further progress in this disease.

Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma.

Bevacizumab is frequently used to treat patients with recurrent high-grade glioma (HGG), but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects and may work synergistically with VEGF inhibitors. We performed a phase I study to evaluate the safety and tolerability of the combination of orally administered panobinostat with bevacizumab in patients with recurrent HGG. Patients with recurrent HGG were treated on a 3 + 3 trial design. Patients received bevacizumab 10 mg/kg every other week in combination with oral panobinostat. The starting dose of panobinostat was 20 mg three times per week, weekly (cohort 1). Due to concerns for thrombocytopenia with the weekly dosing regimen, the protocol was amended to examine an every other week regimen. Cohort 2 received panobinostat 20 mg three times per week, every other week, and cohort 3 received 30 mg three times per week, every other week. Dose-limiting toxicity during the first 30 days was used to determine the maximum-tolerated dose. Twelve patients (median age 50, median KPS 90) with recurrent HGG were enrolled. One dose-limiting toxicity (DLT) (Grade 3 thrombocytopenia) was observed in cohort 1. No DLTs were observed in cohorts 2 and 3. The following grade 3 toxicities were seen in one patient each: thrombocytopenia, hypophosphatemia, esophageal hemorrhage, and deep venous thrombosis. There were no grade 4 or 5 toxicities. There were three patients with partial responses and seven with stable disease. The recommended doses for further study are oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. A phase II clinical trial in recurrent HGG is underway.

Repeatability of Standardized and Normalized Relative CBV in Patients with Newly Diagnosed Glioblastoma.

BACKGROUND AND PURPOSE: For more widespread clinical use advanced imaging methods such as relative cerebral blood volume must be both accurate and repeatable. The aim of this study was to determine the repeatability of relative CBV measurements in newly diagnosed glioblastoma multiforme by using several of the most commonly published estimation techniques. MATERIALS AND METHODS: The relative CBV estimates were calculated from dynamic susceptibility contrast MR imaging in double-baseline examinations for 33 patients with treatment-naïve and pathologically proved glioblastoma multiforme (men = 20; mean age = 55 years). Normalized and standardized relative CBV were calculated by using 6 common postprocessing methods. The repeatability of both normalized and standardized relative CBV, in both tumor and contralateral brain, was examined for each method with metrics of repeatability, including the repeatability coefficient and within-subject coefficient of variation. The minimum sample size required to detect a parameter change of 10% or 20% was also determined for both normalized relative CBV and standardized relative CBV for each estimation method. RESULTS: When ordered by the repeatability coefficient, methods using postprocessing leakage correction and ΔR2*(t) techniques offered superior repeatability. Across processing techniques, the standardized relative CBV repeatability in normal-appearing brain was comparable with that in tumor (P = .31), yet inferior in tumor for normalized relative CBV (P = .03). On the basis of the within-subject coefficient of variation, tumor standardized relative CBV estimates were less variable (13%-20%) than normalized relative CBV estimates (24%-67%). The minimum number of participants needed to detect a change of 10% or 20% is 118-643 or 30-161 for normalized relative CBV and 109-215 or 28-54 for standardized relative CBV. CONCLUSIONS: The ΔR2* estimation methods that incorporate leakage correction offer the best repeatability for relative CBV, with standardized relative CBV being less variable and requiring fewer participants to detect a change compared with normalized relative CBV.

Steroid myopathy in cancer patients.

We prospectively evaluated 15 adult cancer patients being treated with adrenocorticosteroids (steroids) to determine the frequency and time course of "steroid myopathy." Nine (60%) developed clinically detectable proximal muscle weakness that, in six, was severe enough to interfere with activities of daily living. Proximal muscle weakness developed within 15 days in eight of nine patients and was significantly related to the cumulative dose of steroid. Eight of nine patients with proximal muscle weakness, and two of six without such weakness, experienced a significant decline in respiratory function, leading to symptomatic dyspnea in four patients of the former group. In three patients who could be followed for more than 3 months off steroids, there was either improvement or resolution of the weakness and, when present, of the respiratory impairment. Steroid myopathy is a common complication among cancer patients receiving steroids. It can often affect respiratory function even when proximal limb muscles remain strong. Clinical recognition is important since steroid myopathy can lead to increased morbidity and may be reversible with reduction or discontinuation of steroids.

Advances in the therapy of primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin's lymphoma (NHL) confined to the nervous system. The management of PCNSL is quite different from the usual treatment of either primary brain tumors or systemic NHL. First-generation chemotherapy regimens used successfully in systemic NHL are ineffective in PCNSL, in large part due to the existence of the blood-brain barrier. Whole-brain radiation therapy (WBRT) results in high response rates but rapid relapse, and this treatment is associated with delayed neurotoxicity in patients with PCNSL. The addition of methotrexate-based chemotherapy has improved survival and lessened toxicity for this patient population. Fundamental issues that remain unresolved in PCNSL include identification of the optimal chemotherapy regimen for newly diagnosed and relapsed PCNSL, the role of WBRT and intrathecal chemotherapy in the treatment of PCNSL, and the optimal management of intraocular lymphoma. Finally, the optimal clinical study design for this rare disease has yet to be defined and implemented.

Solitary sciatic nerve lymphoma as an initial manifestation of diffuse neurolymphomatosis. Case report and review of the literature.

Solitary peripheral nerve lymphomas are exceedingly rare primary manifestations of diffuse peripheral nervous system or central nervous system (CNS) lymphomatosis. A 52-year-old man presented with progressive weakness in gastrocnemius and anterior tibial muscle function, which was associated with radiating pain in the right leg. Magnetic resonance imaging studies revealed a solitary fusiform tumor, extending from the sciatic nerve, at the level of the lesser trochanter of the femur, into the posterior tibial nerve below the popliteal fossa. Intraoperative gross examination found that the tumor diffusely expanded the nerve, but did not extend from or into surrounding muscle or tendons. The final histological diagnosis was a solitary extranodal lymphoma (Burkittlike high-grade B-cell lymphoma). Postoperative staging did not reveal evidence of lymphomatous involvement of other organs, but additional chemo- and radiotherapies were administered. Four months after the surgical biopsy, the patient presented with a right facial nerve palsy. The results of cytological examination of cerebrospinal fluid were positive for the presence of atypical lymphocytes, which was consistent with apparently progressive neurolymphomatosis; however, the results of radiological studies were negative for systemic progression. The patient underwent intrathecal chemotherapy followed by systemic myelosuppressive chemotherapy with bone marrow rescue, but died of respiratory failure while still receiving treatment. Postmortem examination revealed extensive lymphomatosis in the peripheral nerves and spinal nerve roots without evidence of cranial nerve, CNS, or other organ system involvement. The aggressive biological characteristics of these tumors, their management, and pertinent literature are reviewed.

Determination of procarbazine in human plasma by liquid chromatography with electrospray ionization mass spectrometry.

Procarbazine is a cytotoxic chemotherapeutic agent used in the treatment of lymphomas and brain tumors. Its pharmacokinetic behavior remains poorly understood even though more than 30 years have elapsed since the drug was approved for clinical use. To characterize the pharmacokinetics of procarbazine in brain cancer patients during a phase I trial, a method for determining the drug in human plasma by reversed-phase high-performance liquid chromatography (HPLC) with electrospray ionization mass spectrometry (ESI-MS) was developed and thoroughly validated. Plasma samples were prepared for analysis by precipitating proteins with trichloroacetic acid and washing the protein-free supernatant with methyl tert-butyl ether to remove excess acid. The solution was separated on a Luna C-18 analytical column using methanol-25 mM ammonium acetate buffer, pH 5.1 (22:78, v/v) as the mobile phase at 1.0 ml/min. A single-quadrupole mass spectrometer with an electrospray interface was operated in the selected-ion monitoring mode to detect the [M+H](+) ions at m/z 222.2 for procarbazine and at m/z 192.1 for the internal standard (3-dimethylamino-2-methylpropiophenone). Procarbazine and the internal standard eluted as sharp, symmetrical peaks with retention times (mean+/-S.D.) of 6.3+/-0.1 and 9.9+/-0.3 min, respectively. Calibration curves of procarbazine hydrochloride in human plasma at concentrations ranging from 0.5 to 50 ng/ml exhibited excellent linearity. The mean absolute recovery of the drug from plasma was 102.9+/-1.0%. Using a sample volume of 150 microl, procarbazine was determined at the 0.5 ng/ml (1.9 nM) lower limit of quantitation with a mean accuracy of 105.2% and an interday precision of 3.60% R.S.D. on 11 different days over 5 weeks. During this same time interval, the between-day accuracy for determining quality control solutions of the drug in plasma at concentrations of 2.0, 15 and 40 ng/ml ranged from 97.5 to 98.2% (mean+/-S.D., 97.9+/-0.4%) and the precision was 3.8-6.2% (mean+/-S.D., 5.1+/-1.2%). Stability characteristics of the drug were thoroughly evaluated to establish appropriate conditions to process, store and prepare clinical specimens for chromatographic analysis without inducing significant chemical degradation. The sensitivity achieved with this assay permitted the plasma concentration-time profile of the parent drug to be accurately defined following oral administration of standard doses to brain cancer patients.

Neuroimaging abnormalities with hypoglossal nerve palsies.

Seven patients with acute or chronic unilateral hypoglossal nerve lesions were evaluated by magnetic resonance imaging and computed tomography. In patients with acute to subacute tongue paralysis, the base of the ipsilateral side of the tongue appeared expanded and showed increased signal intensity on T2-weighted images. This appearance was suggestive of an infiltrative mass lesion within the tongue. These radiographic findings are due to the pathophysiological process of nerve injury and muscle denervation.

Neuroimaging abnormalities with hypoglossal nerve palsies.

Seven patients with acute or chronic unilateral hypoglossal nerve lesions were evaluated by magnetic resonance imaging and computed tomography. In the patients with acute to subacute paralysis of the tongue, the base of the ipsilateral side of the tongue appeared expanded with increased signal intensity on T2-weighted images. This appearance suggested an infiltrative mass lesion within the tongue. These radiographic findings are due to the pathophysiological process of nerve injury and muscle denervation.

Cognitive functions in primary central nervous system lymphoma: literature review and assessment guidelines.

BACKGROUND: Treatment-related neurotoxicity has been recognized as a significant problem in patients with primary central nervous system lymphoma (PCNSL) as effective treatment has increased survival rates. There is, however, a paucity of research on cognitive functions in this population. DESIGN: In a review of the literature, a total of 17 articles that described cognitive outcome in adult PCNSL patients were identified. RESULTS: The studies that assessed cognitive functions after whole-brain radiotherapy combined with chemotherapy reported cognitive impairment in most patients. Patients treated with chemotherapy alone had either stable or improved cognitive performance in most studies. Methodological problems, however, limited the ability to ascertain the specific contribution of disease and various treatment interventions to cognitive outcome. On the basis of the literature review, a battery of cognitive and quality-of-life (QoL) measures to be used in prospective clinical trials was proposed. The battery is composed of five standardized neuropsychological tests, covering four domains sensitive to disease and treatment effects (attention, executive functions, memory, psychomotor speed), and QoL questionnaires, and meets criteria for use in collaborative trials. CONCLUSION: The incorporation of formal and systematic cognitive evaluations in PCNSL studies will improve our understanding of treatment-related neurotoxicity in this population.

New treatment strategies for malignant gliomas.

Although survival in patients with malignant gliomas remains limited, there is renewed optimism with the emergence of novel treatment strategies. Cytotoxic agents such as temozolomide and CPT-11 have shown promising clinical activity. Biological treatments for brain tumors, including antisense oligonucleotides, gene therapy, and angiogenesis inhibitors, are also being evaluated in clinical trials. Delivery strategies have been developed to overcome challenges presented by the blood-brain barrier. These noteworthy treatments, alone or in combination, may ultimately prolong survival and enhance quality of life in this group of patients.

Primary nervous-system lymphoma.

Primary nervous-system lymphoma is a rare type of non-Hodgkin lymphoma, which is confined to the nervous system. This disease is managed quite differently from the usual treatment of either primary brain tumours or systemic non-Hodgkin lymphoma. Although whole-brain radiotherapy results in responses in more than 90% of cases, this treatment is associated with high relapse rates and with delayed neurotoxicity in elderly patients. First-generation chemotherapy regimens used successfully in systemic non-Hodgkin lymphoma (eg cyclo-phosphamide, adriamycin, vincristine, and prednisone) are ineffective in primary nervous-system lymphoma, partly because of the blood-brain barrier. Median survival of patients treated with radiotherapy alone or chemotherapy plus radiotherapy is similar, and ranges from 10 to 16 months. The addition of methotrexate-based chemotherapy has improved survival for these patients, extending median survival to more than 30 months. When used alone, methotrexate-based chemotherapy is associated with significantly fewer treatment-associated toxic effects. Leptomeningeal lymphoma and intraocular lymphoma are topics of particular relevance in primary nervous-system lymphoma and are addressed in this review.

Immunoadsorption therapy for paraneoplastic syndromes.

Paraneoplastic neurologic syndromes associated with systemic cancer are being increasingly recognized. Although these syndromes are thought to be immunologically mediated treatment with steroids, immunoglobulin and plasmapharesis has been disappointing. Based on our preliminary experience with the treatment of 6 cases of paraneoplastic neurologic syndromes with protein A immunoadsorption, an institutional, open-arm treatment protocol was established. Since our original report we have treated an additional 7 patients with this method. The 13 cases were accrued over a 2 year period and included 10 women and 3 men with an average age of 63. The paraneoplastic syndromes included 6 cases of cerebellar degeneration, 3 cases of opsoclonus/myoclonus, 3 cases of encephalomyelitis and 1 case of Lambert Eaton myasthenic syndrome. Primary cancers included 4 cases of small cell lung cancer, 2 cases of breast cancer, 2 cases of lymphoma and 1 each of acinic cell cancer, cholangiocarcinoma, Merkel cell cancer, pancreatic adenocarcinoma and rectal cancer. Anti-neuronal antibody status, cerebrospinal fluid and neuroimaging studies as well as cancer staging and treatment protocols were reviewed. Neurologic syndromes were clinically separated into component symptoms and signs for assessment of treatment effect. The treatment goal was a total of 6 sessions of protein A immunoadsorption given twice weekly. Twelve of 13 patients completed therapy and one patient developed cutaneous vasculitis during the second session with termination of treatment. Of the remaining patients 3/12 had a complete response of the primary clinical symptom/sign while 6/12 had a partial response for a total response rate of 9/12 (75%). Toxicity was limited to cutaneous vasculitis in 1 patient and an episode of hemisensory changes in another patient. Current treatment of paraneoplastic neurologic syndromes remains unsatisfactory. Despite the small number of patients in this report, protein A immunoadsorption is a promising therapy which deserves further study in a larger population of patients with paraneoplastic syndromes.

Chorea as a paraneoplastic complication of Hodgkin's disease.

Neurologic complications of Hodgkin's disease (HD) include both metastatic and non-metastatic involvement of the nervous system. There are at least five paraneoplastic syndromes associated with HD but chorea has not been described. We report the first choreiform disorder as a paraneoplastic complication of HD and only the second case of paraneoplastic chorea in the literature.