Neoplastic Meningitis Due to Lung, Breast, and Melanoma Metastases.

BACKGROUND: Neoplastic meningitis, a central nervous system (CNS) complication of cancer metastatic to the meninges and cerebrospinal fluid (CSF), is relevant to oncologists due to the impact of the disease on patient quality of life and survival rates. METHODS: A review of the literature of articles published in English was conducted with regard to neoplastic meningitis. RESULTS: The incidence of neoplastic meningitis is increasing because patients with cancer are surviving longer in part because of the use of novel therapies with poor CNS penetration. Up to 5% of patients with solid tumors develop neoplastic meningitis during the disease course (breast cancer, lung cancer, and melanoma being the predominantly causative cancers). The rate of median survival in patients with untreated neoplastic meningitis is 1 to 2 months, although it can be as long as 5 months in some cases. Therapeutic options for the treatment of neoplastic meningitis include systemic therapy (cancer-specific, CNS-penetrating chemotherapy or targeted therapies), intra-CSF administration of chemotherapy (methotrexate, cytarabine, thiotepa) and CNS site-specific radiotherapy. Determining whom to treat with neoplastic meningitis remains challenging and, in part, relates to the extent of systemic disease, the neurological burden of disease, the available systemic therapies, and estimated rates of survival. CONCLUSIONS: The prognosis of neoplastic meningitis remains poor. The increasing use of novel, targeted therapies and immunotherapy in solid tumors and its impact on neoplastic meningitis remains to be determined and is an area of active research. Thus, well conducted trials are needed.

Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial.

Importance: Tumor-treating fields (TTFields) is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating electric fields to the tumor. Objective: To investigate whether TTFields improves progression-free and overall survival of patients with glioblastoma, a fatal disease that commonly recurs at the initial tumor site or in the central nervous system. Design, Setting, and Participants: In this randomized, open-label trial, 695 patients with glioblastoma whose tumor was resected or biopsied and had completed concomitant radiochemotherapy (median time from diagnosis to randomization, 3.8 months) were enrolled at 83 centers (July 2009-2014) and followed up through December 2016. A preliminary report from this trial was published in 2015; this report describes the final analysis. Interventions: Patients were randomized 2:1 to TTFields plus maintenance temozolomide chemotherapy (n = 466) or temozolomide alone (n = 229). The TTFields, consisting of low-intensity, 200 kHz frequency, alternating electric fields, was delivered (≥ 18 hours/d) via 4 transducer arrays on the shaved scalp and connected to a portable device. Temozolomide was administered to both groups (150-200 mg/m2) for 5 days per 28-day cycle (6-12 cycles). Main Outcomes and Measures: Progression-free survival (tested at α = .046). The secondary end point was overall survival (tested hierarchically at α = .048). Analyses were performed for the intent-to-treat population. Adverse events were compared by group. Results: Of the 695 randomized patients (median age, 56 years; IQR, 48-63; 473 men [68%]), 637 (92%) completed the trial. Median progression-free survival from randomization was 6.7 months in the TTFields-temozolomide group and 4.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.52-0.76; P < .001). Median overall survival was 20.9 months in the TTFields-temozolomide group vs 16.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76; P < .001). Systemic adverse event frequency was 48% in the TTFields-temozolomide group and 44% in the temozolomide-alone group. Mild to moderate skin toxicity underneath the transducer arrays occurred in 52% of patients who received TTFields-temozolomide vs no patients who received temozolomide alone. Conclusions and Relevance: In the final analysis of this randomized clinical trial of patients with glioblastoma who had received standard radiochemotherapy, the addition of TTFields to maintenance temozolomide chemotherapy vs maintenance temozolomide alone, resulted in statistically significant improvement in progression-free survival and overall survival. These results are consistent with the previous interim analysis. Trial Registration: clinicaltrials.gov Identifier: NCT00916409.

Chemotherapy-Related Neurotoxicity.

Chemotherapy may have detrimental effects on either the central or peripheral nervous system. Central nervous system neurotoxicity resulting from chemotherapy manifests as a wide range of clinical syndromes including acute, subacute, and chronic encephalopathies, posterior reversible encephalopathy, acute cerebellar dysfunction, chronic cognitive impairment, myelopathy, meningitis, and neurovascular syndromes. These clinical entities vary by causative agent, degree of severity, evolution, and timing of occurrence. In the peripheral nervous system, chemotherapy-induced peripheral neuropathy (CIPN) and myopathy are the two main complications of chemotherapy. CIPN is the most common complication, and the majority manifest as a dose-dependent length-dependent sensory axonopathy. In severe cases of CIPN, the dose of chemotherapy is reduced, the administration delayed, or the treatment discontinued. Few treatments are available for CIPN and based on meta-analysis, duloxetine is the preferred symptomatic treatment. Myopathy due to corticosteroid use is the most frequent cause of muscle disorders in patients with cancer.

Current Management of Adult Diffuse Infiltrative Low Grade Gliomas.

Diffuse infiltrative low grade gliomas (LGG) account for approximately 15 % of all gliomas. The prognosis of LGG differs between high-risk and low-risk patients notwithstanding varying definitions of what constitutes a high-risk patient. Maximal safe resection optimally is the initial treatment. Surgery that achieves a large volume resection improves both progression-free and overall survival. Based on results of three randomized clinical trials (RCT), radiotherapy (RT) may be deferred in patients with low-risk LGG (defined as age <40 years and having undergone a complete resection), although combined chemoradiotherapy has never been prospectively evaluated in the low-risk population. The recent RTOG 9802 RCT established a new standard of care in high-risk patients (defined as age >40 years or incomplete resection) by demonstrating a nearly twofold improvement in overall survival with the addition of PCV (procarbazine, CCNU, vincristine) chemotherapy following RT as compared to RT alone. Chemotherapy alone as a treatment of LGG may result in less toxicity than RT; however, this has only been prospectively studied once (EORTC 22033) in high-risk patients. A challenge remains to define when an aggressive treatment improves survival without impacting quality of life (QoL) or neurocognitive function and when an effective treatment can be delayed in order to preserve QoL without impacting survival. Current WHO histopathological classification is poorly predictive of outcome in patients with LGG. The integration of molecular biomarkers with histology will lead to an improved classification that more accurately reflects underlying tumor biology, prognosis, and hopefully best therapy.

Immunotherapy with CpG-ODN in neoplastic meningitis: A phase I trial.

TLR-9 agonists are immunostimulating agents that have antitumor effects in animal models. A phase I trial was conducted to define the safety profile of subcutaneous injections, combined with intrathecally administration of CpG-28, a TRL 9 agonist, in patients with neoplastic meningitis (NM). Cohorts of 3-6 patients with NM were treated for 5 weeks with escalating doses of CpG-28. The primary endpoint was tolerance. Secondary endpoints were progression free survival (PFS) and overall survival (OS). Twenty-nine patients were treated with CpG-28. The primary cancers were malignant glioma, lung carcinoma, breast cancer, melanoma or melanocytoma, ependymoma, and colorectal cancer. The median age was 56 years and median Karnovsky Performance status (KPS) was 70%. The treatment was well tolerated. Adverse effects that were possibly or probably related to the studied drug were grade 2 lymphopenia, anemia and neutropenia, local erythema at injection sites, fever and seizure. There were five serious adverse events: two confusions, two infections of ventricular devices and one grade 4 thrombopenia and neutropenia. The median PFS was 7 weeks and median OS was 15 weeks. Interestingly, the median survival was slightly (but not significantly) higher in the eight patients who were concomitantly treated with bevacizumab (19 weeks vs 15 weeks; P = 0.11). CpG-28 was well tolerated at doses up to 0.3 mg/kg subcutaneously and 18 mg intrathecally. Additional trials are warranted.

Tumor treating fields: a new standard treatment for glioblastoma?

PURPOSE OF REVIEW: Tumor treating fields (TTFields), an external therapeutic device with antimitotic properties, is a Food and Drug Administration approved treatment for recurrent glioblastoma (GBM) that has been reported to be efficacious in newly diagnosed GBM as well. RECENT FINDINGS: Preclinical data show that TTFields is an antimitotic agent that additionally augments response to alkylator-based chemotherapy. In a single study, nearly 15% of recurrent GBM treated with TTFields alone display durable responses. Responses may be delayed, sometimes after an initial progression, and are highly correlated to treatment compliance and to survival. In newly diagnosed GBM, a preplanned interim analysis of the phase III randomized trial (standard of care with or without TTFields) showed a statistically significant effect of TTFields resulting in a net gain of 3 months in both progression-free and overall survival. SUMMARY: TTFields is a novel noninvasive therapeutic option for recurrent GBM. The role of TTFields in newly diagnosed GBM will be adjudicated pending publication of the final results of the randomized EF-14 trial. If these results are compelling, this may result in accelerated approval and potentially a new standard of care for newly diagnosed GBM.

Venous thrombosis in patients with high-grade glioma.

PURPOSE OF REVIEW: High-grade glioma (HGG) patients are at particularly high risk of venous thromboembolism (VTE) occurrence and recurrence. VTE is associated with worsened survival in these patients. At present, the main challenge when prescribing anticoagulants in HGG patients is to address the risk of intracranial hemorrhage and provide the optimal treatment. RECENT FINDINGS: Here, we discuss the latest biological findings and their potential implications for better classification in daily practice and stratification of patients in future trials according to their risk of developing a VTE. SUMMARY: To help clinicians, international guidelines have been provided for cancer patients, but their implementation remains suboptimal. We report here the specificities of VTE management in HGG patients relative to other cancer patients. Particular aspects such as anticoagulation under targeted therapies, primary and secondary prophylaxis, and the role of new oral anticoagulants are discussed as well.

Complications related to the use of an intraventricular access device for the treatment of leptomeningeal metastases from solid tumor: a single centre experience in 112 patients.

Ventricular access devices (VAD) offer several advantages compared to intralumbar injections for the administration of intra-CSF agents in the treatment of leptomeningeal metastases (LM). However, there are few prospective studies reporting on complications with the use of VADs. All complications were prospectively collected that pertained to the implantation and use of a VAD in consecutive patients with solid tumor-related LM from June 2006 to December 2013. Clinical follow-up was every 2 weeks during the initial 2 months of treatment and then once monthly. Complete neuraxis MRI was performed at baseline and then every 2-3 months. A total of 112 patients (88 women) with a mean age of 51.1 years (range 26-73) were included. Primary cancers included breast (79 patients), lung (12) and melanoma (6). All patients were treated with intra-CSF liposomal cytarabine. 72 % of the patients received concomitant systemic and intra-CSF chemotherapy. The placement of the VAD was performed under local anesthesia in all cases. The mean operative time was 15 min and no perioperative complications were reported. The mean number of intraventricular injections per patient was 9.34 (range 1-47). A total of 11 complications in 11 patients were seen including 7 infections, 1 intracranial hemorrhage, 2 instances of symptomatic leukoencephalopathy and 1 catheter malpositioning. 8 complications required an operation and 1 complication was fatal. The use of a VAD is safe and may improve patients' comfort and compliance with LM-directed therapy.

Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial.

IMPORTANCE: Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly. OBJECTIVE: To evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS: After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis. INTERVENTIONS: Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up. RESULTS: The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004). CONCLUSIONS AND RELEVANCE: In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00916409.

CSF CA 15-3 in breast cancer-related leptomeningeal metastases.

UNLABELLED: The sensitivity of CSF cytology, the standard method for diagnosis of leptomeningeal metastases (LM), is low. Serum cancer antigen 15-3 (CA 15-3) is frequently used for the monitoring of patients with breast cancer (BC) and is a laboratory test available in most centers. The aim of the current study was to determine the feasibility of measuring CSF CA 15-3 and CA 15-3 CSF/serum ratio in patients with BC-related LM. Serum and CSF CA 15-3 values were evaluated in 20 BC patients with LM (Group 1), 20 patients with LM from other primary cancers (Group 2), 20 BC patients with parenchymal brain metastases only (Group 3) and 20 controls (Group 4). CSF and serum were collected on the same day. Serum and CSF CA 15-3 were assessed by an automatized immuno-enzymatic technology (TRACE(®) technology, KRYPTOR Automate, Brahms Society, France). In univariate analysis, BC patients with LM (Group 1) compared to other groups, a significantly elevated serum CA 15-3 (median 51 U/ml, range 12-2819) and CSF CA 15-3 (median 8.7 U/ml, range 0.1-251) was observed. Additionally, the CSF/serum ratio of CA 15-3 was significantly higher in this group of patients (median 0.18, range 0.002-4.40). Multivariate analysis identified a cut-off for CSF CA15-3 with 80 % sensitivity and 70 % specificity. CONCLUSIONS: The current study confirms the feasibility of determining CSF CA 15-3 using a widely available technology. Evaluation of the CSF CA 15-3 may be useful in the diagnosis and management of BC-related LM but further studies are needed.

Intracranial cystic lesions: a review.

Cysts and cystic-appearing intracranial lesions are common findings with routine cerebral imaging examination. These lesions often represent a challenge in diagnosis. Intracranial cystic lesions have wide pathologic and imaging spectra, of which some require an aggressive and tailored treatment, whereas many others remain asymptomatic and do not require follow-up or intervention. Intracranial cysts can be divided in non-neoplastic lesions that are often of developmental origin but comprise as well infectious cysts and neoplastic lesions that include benign cysts associated with low-grade tumors and cysts as a component of higher grade neoplasms. Reviewed are the pathology, origin, radiologic appearance, differential diagnosis, and therapeutic aspects of intracranial cystic lesions.

Rationale for the use of upfront whole brain irradiation in patients with brain metastases from breast cancer.

Breast cancer is the second most common cause of brain metastases and deserves particular attention in relation to current prolonged survival of patients with metastatic disease. Advances in both systemic therapies and brain local treatments (surgery and stereotactic radiosurgery) have led to a reappraisal of brain metastases management. With respect to this, the literature review presented here was conducted in an attempt to collect medical evidence-based data on the use of whole-brain radiotherapy for the treatment of brain metastases from breast cancer. In addition, this study discusses here the potential differences in outcomes between patients with brain metastases from breast cancer and those with brain metastases from other primary malignancies and the potential implications within a treatment strategy.

[Leptomeningeal metastases from solid tumors]. / Métastases leptoméningées des tumeurs solides.

The incidence of leptomeningeal metastases is increasing, due to the improvement of the management and the overall survival of cancer patients. Although the diagnosis may be sometimes difficult to assess, an early treatment before the setting of neurological deficits is required in order to improve the quality of life of the patients. The median survival of untreated patients is 4 to 6 weeks. Specific treatment may prolong survival by several months. The treatment requires a combination of chemotherapy and targeted therapies administrated systemically or via intra-cerebrospinal fluid route, surgery and radiotherapy. Patient management is specific but requires a multidisciplinary approach, which may vary according to the characteristics of meningeal disease, the characteristics of primary tumors, the general condition of patients and previous lines of treatments.

Salvage intracerebrospinal fluid thiotepa in breast cancer-related leptomeningeal metastases: a retrospective case series.

There is currently a paucity of data on salvage intracerebrospinal fluid (intra-CSF) chemotherapy in leptomeningeal metastases (LM). This report is a single-institution experience with salvage treatment in patients with breast cancer (BC) and LM. This retrospective cohort describes 24 consecutive patients with BC selected for a second-line of treatment for LM. The first line of LM treatment consisted of intra-CSF liposomal cytarabine in all patients combined with systemic therapy in 18 cases and radiotherapy in four cases. Second-line (salvage) treatment utilized intra-CSF thiotepa in all and systemic chemotherapy in nine patients. No patient received CNS-directed radiotherapy. The median Eastern Cooperative Oncology Group performance status at initiation of intra-CSF thiotepa treatment was 3 (range 1-4). The median progression-free survival and median survival following intra-CSF thiotepa was 3.1 months (range 3 days-2 years) and 4.0 months (range 6 days-2.5 years), respectively. The median overall survival from LM diagnosis was 9.5 months (range 1.3 months-2.7 years). No grade 3 or higher toxicity was observed. Recognizing the limits of a retrospective study, intra-CSF thiotepa has an acceptable toxicity profile and appears to be a reasonable option for selected BC patients.

Phase II study of intrathecal administration of trastuzumab in patients with HER2-positive breast cancer with leptomeningeal metastasis.

BACKGROUND: Patients with HER2-positive breast cancer (HER2 + BC) develop central nervous system metastases twice as often as patients with luminal HER2-negative breast cancer. Leptomeningeal progression results in a drastically altered prognosis with limited therapeutic options. This phase II study was conducted to assess the efficacy of intrathecal (IT) trastuzumab in HER2 + BC patients with leptomeningeal metastasis (LM), based on a phase I dose-escalation study that had determined the recommended weekly dose of 150 mg for phase II. METHODS: Eligible patients received weekly administrations of 150 mg of IT trastuzumab. The primary endpoint was clinical neurologic progression-free survival (LM-related-PFS) after 8 weeks. Overall survival (OS), toxicities, and quality of life (QoL) were secondary endpoints. RESULTS: Among the 19 enrolled patients, 16 (84%) had concomitant brain metastases, 15 of them had received prior radiotherapy to the brain. All patients had received at least one line of systemic anti-HER2 therapy. After 8 weeks, 14 patients (74%) were free of neurological progression. The median LM-related-PFS was 5.9 months and the median OS was 7.9 months. According to the QLQ-C30 and BN20 scales, the global health-related QoL status seemed preserved and no toxicity above grade 3 was observed. CONCLUSIONS: Conducting studies on patients with LM poses significant challenges and ethical dilemmas inherent to this population. Despite some limits, this phase II study's findings in terms of clinical neurologic response and QoL's control confirms weekly administration of 150 mg of IT trastuzumab as a valuable option for HER + BC patients with LM and support the interest for further investigations.

A multicenter prospective observational study of the conformity of temozolomide prescriptions in France.

CONTEXT: Temozolomide (TMZ) is approved for the treatment of high-grade gliomas such as glioblastoma (GBM) multiforme and refractory anaplastic astrocytoma, but it is also used in indications not mentioned in the summary of product characteristics (SPC). The main objective of this study was to evaluate the conformity of TMZ prescriptions to the French SPC and prescription guidebook. METHODS: We conducted a prospective observational study of all consecutive patients treated with TMZ in 21 French hospitals between September 2006 and February 2007, accounting for 39% of total TMZ consumption in France. The conformity of TMZ prescriptions was evaluated in terms of the indication, dosage, treatment duration, and combination with other treatments, with respect to the SPC and prescription guidebook. RESULTS: We enrolled 831 patients (median age, 56 years) who received a total of 5982 TMZ treatment cycles. TMZ was mainly prescribed to patients with newly diagnosed GBM (384 patients), GBM in progression/relapse (28 patients), or anaplastic astrocytoma in progression/relapse (19 patients). Prescriptions conformed to the SPC in 51.9% of cases and to the prescription guidebook in 91.5% of cases. Global conformity with the SPC, in terms of the dosage, treatment duration, and combination with other treatments, was 62% for newly diagnosed GBM treated with radiotherapy plus TMZ, 72% for TMZ maintenance monotherapy, and 66% for GBM and anaplastic astrocytoma in progression/relapse. CONCLUSION/DISCUSSION: In France, routine TMZ prescriptions conform to the SPC and practice guidebook. This is one of the largest studies of drug use in neuro-oncology in terms of the number of patients and cycles analyzed.

The Impact of Tumor Treating Fields on Glioblastoma Progression Patterns.

PURPOSE: Tumor-treating fields (TTFields) are an antimitotic treatment modality that interfere with glioblastoma (GBM) cell division and organelle assembly by delivering low-intensity, alternating electric fields to the tumor. A previous analysis from the pivotal EF-14 trial demonstrated a clear correlation between TTFields dose density at the tumor bed and survival in patients treated with TTFields. This study tests the hypothesis that the antimitotic effects of TTFields result in measurable changes in the location and patterns of progression of newly diagnosed GBM. METHODS AND MATERIALS: Magnetic resonance images of 428 newly diagnosed GBM patients who participated in the pivotal EF-14 trial were reviewed, and the rates at which distant progression occurred in the TTFields treatment and control arm were compared. Realistic head models of 252 TTFields-treated patients were created, and TTFields intensity distributions were calculated using a finite element method. The TTFields dose was calculated within regions of the tumor bed and normal brain, and its relationship with progression was determined. RESULTS: Distant progression was frequently observed in the TTFields-treated arm, and distant lesions in the TTFields-treated arm appeared at greater distances from the primary lesion than in the control arm. Distant progression correlated with improved clinical outcome in the TTFields patients, with no such correlation observed in the controls. Areas of normal brain that remained normal were exposed to higher TTFields doses compared with normal brain that subsequently exhibited neoplastic progression. Additionally, the average dose to areas of the enhancing tumor that returned to normal was significantly higher than in the areas of the normal brain that progressed to enhancing tumor. CONCLUSIONS: There was a direct correlation between TTFields dose distribution and tumor response, confirming the therapeutic activity of TTFields and the rationale for optimizing array placement to maximize the TTFields dose in areas at highest risk of progression, as well as array layout adaptation after progression.

Clinicopathological features of breast cancers predict the development of leptomeningeal metastases: a case-control study.

The incidence of leptomeningeal metastases (LM) in patients with breast cancer (BC) is increasing as a result of increased screening and improved patient survival. However, the median survival time after diagnosis of LM is between 5 weeks (without any treatment) and 5 months (for aggressively treated patients). In an attempt to identify clinicopathological risk factors for LM, we carried out a case-control study of 100 women with BC. Fifty patients with BC and LM were enrolled and an additional 50 patients with BC and no CNS metastases including leptomeningeal spread were selected as controls. Patients who had developed LM were selected between December 2006 and August 2008. The control group was matched for: age at diagnosis, year of diagnosis, and initiation of chemotherapy at BC diagnosis. The ILC type (P = 0.03), ER-negative (P = 0.01) and PR-negative status (P = 0.03), and initial M+ status at BC diagnosis (P = 0.008) tended to be more frequent in LM patients. These characteristics should lead to early appropriate assessments being performed in this targeted population when a neurological complaint appears, in order to detect LM as soon as possible.

Up-front temozolomide in elderly patients with anaplastic oligodendroglioma and oligoastrocytoma.

Optimal treatment of anaplastic oligodendroglial tumors (AOT) in elderly patients is debatable. We report a retrospective study of 44 consecutive patients aged 70 years or older [median age: 74 years; median Karnofsky performance status (KPS): 70] treated with up-front chemotherapy using temozolomide (TMZ) at conventional doses until tumor progression. O(6)-methylguanine-DNA methyltransferase promoter (MGMTP) methylation was assessed in 38 patients. Of the 41 evaluable patients, partial response (PR) was seen in 13 (32%) patients, 17 (41%) patients achieved stable disease, while the disease progressed in 11 (27%) patients. Median progression-free survival (PFS) and overall survival (OS) were 6.9 and 12.4 months, respectively. Hematotoxicity grades 3-4 occurred in nine patients (20%). MGMTP was methylated in 50% of patients and was associated with both longer PFS (8.7 versus 5.7 months, P = 0.01) and longer OS (16.1 versus 12.4 months, P = 0.05). The rate of responders to chemotherapy was similar in MGMTP-methylated (38%) and in MGMTP-unmethylated patients (31%), but duration of response was significantly longer in responders with methylated MGMTP than in responders with unmethylated MGMTP (16.1 versus 9.6 months, P = 0.0004). This study demonstrates that a substantial number of elderly patients with AOT can achieve prolonged survival with up-front chemotherapy using TMZ. Further investigation is needed to determine whether this treatment is preferable to initial radiation therapy.

Nitrosourea-based chemotherapy for low grade gliomas failing initial treatment with temozolomide.

There is a growing evidence of using Temozolomide as upfront therapy for progressive low grade gliomas. No data exist on the efficacy of nitrosoureas as an alternative to radiotherapy in those patients who progress after Temozolomide. We retrospectively reviewed 30 patients with median age of 46 years. Twenty-one patients had pure oligodendrogliomas. Thirteen patients had a non-enhancing tumor at progression after Temozolomide. The chromosomes 1p/19q were co-deleted in 5 cases and retained in 10 cases. Response rate was 10% (3 minor responses achieved in non-enhancing tumors). Tolerance was acceptable (17% grade III and IV myelosupression). Median PFS was 6.5 months. Median OS from start of salvage treatment was 23.4 months. Tumors without contrast enhancement demonstrated a better prognosis than those with contrast enhancement both in term of PFS (P = 0.0003) and OS (P = 0.0006). Chromosomes 1p/19q codeletion was not predictive for objective response to salvage treatment but correlated with a better PFS (P = 0.02). In conclusion, salvage NU chemotherapy provide disappointing results in TMZ-pretreated low grade gliomas (LGG), which should be treated in priority by conventional radiotherapy especially in LGG that display contrast enhancement at progression.