Cerebrospinal fluid circulating tumor cells as a quantifiable measurement of leptomeningeal metastases in patients with HER2 positive cancer.

PURPOSE: The CellSearch® system has been used to identify circulating tumor cells (CTCs) in cerebrospinal fluid (CSF) to diagnose leptomeningeal metastasis (LM) in patients with epithelial cancers. Using this system, we prospectively explored sequential CSF CTC enumeration in patients with LM from HER2+ cancers receiving intrathecal (IT) trastuzumab to capture dynamic changes in CSF CTC enumeration. METHODS: CSF from patients enrolled in an IRB-approved phase I/II dose escalation trial of IT trastuzumab for LM in HER2+ cancer (NCT01325207) was obtained on day 1 of each cycle and was evaluated by the CellSearch® platform for CTC enumeration. The results were correlated with CSF cytology from the same sample, along with clinical and radiographic response. RESULTS: Fifteen out of 34 patients with HER2+ LM were enrolled in CSF CTC analysis; 14 were women. Radiographic LM was documented in 14 (93%) patients; CSF cytology was positive in 6 (40%) and CSF CTCs were identified in 13 (87%). Median CSF CTC was 22 CTCs (range 0-200 +) per 3 ml. HER2/neu expression analysis of CTCs was performed in 8 patients; 75% had confirmed expression of HER2/neu positivity in CSF and HER2/neu expression was absent in 25%. Four of 10 patients received 7 or more cycles of IT trastuzumab; in 3 of these patients, increase in CSF CTCs enumeration from baseline was detected 2-3 months prior to changes seen on MRI, and while CSF cytology remained negative. CONCLUSION: Our study demonstrates that enumeration of CSF CTCs may provide dynamic, quantitative assessment of tumor burden in the central nervous system compartment during treatment for LM and prior to changes on MRI or CSF cytology. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01325207; registered March 29th, 2011.

Phase 1 lead-in to a phase 2 factorial study of temozolomide plus memantine, mefloquine, and metformin as postradiation adjuvant therapy for newly diagnosed glioblastoma.

BACKGROUND: Repurposed memantine, mefloquine, and metformin have putative anticancer activity. The objective of this phase 1 study was to determine the maximum tolerated doses (MTDs) of combinations of these agents with temozolomide (TMZ). METHODS: Adults with newly diagnosed glioblastoma who completed chemoradiation were eligible. The patients were assigned to receive doublet, triplet, or quadruplet therapy with TMZ combined with mefloquine, memantine, and/or metformin. Dose-limiting toxicities (DLTs) were determined, using a 3 + 3 study design. RESULTS: Of 85 enrolled patients, 4 did not complete cycle 1 (the DLT observation period) for nontoxicity reasons, and 81 were evaluable for DLT. The MTDs for doublet therapy were memantine 20 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For triplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For quadruplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 500 mg twice daily. DLTs included dizziness (memantine) and gastrointestinal effects (metformin). Lymphopenia was the most common adverse event (66%). From study entry, the median survival was 21 months, and the 2-year survival rate was 43%. CONCLUSIONS: Memantine, mefloquine, and metformin can be combined safely with TMZ in patients with newly diagnosed glioblastoma.

Differentiation of 2-hydroxyglutarate enantiomers and its lactones by gas chromatography/electron ionization tandem mass spectrometry.

RATIONALE: 2-Hydroxyglutarate (2-hg) exists as enantiomers and can readily undergo cyclization to its lactone. Gas chromatography/electron ionization mass spectrometry (GC/EI-MS) has been used to separate 2-hg enantiomers in bodily fluids but the assay cannot simultaneously measure cyclic and acylic 2-hg enantiomers. Furthermore, the assignment of ion structures was not verified by complementary MS data. METHODS: GC/EI-MS and product ion analysis were used to obtain MS and MS/MS spectra of 2-hg, deuterated and 13 C-labeled 2-hg, and 2-hg lactone. Ion structures and EI fragmentation mechanisms were determined by fragmentation pattern and isotopologue comparisons. Using the EI data, a GC/MS/MS assay was developed to separate and detect 2-hg enantiomers and 2-hg lactone enantiomers in blood and urine using a cyclodextrin capillary column. RESULTS: A new ion structure was predicted for the 85 m/z fragment than what was previously hypothesized, and the 117 m/z ion was the only fragment unique to the linear 2-hg compound. MS/MS data suggested that the majority of the fragments were the result of secondary fragmentation. Finally, separation of serum and urine 2-hg and 2-hg lactone enantiomers was achieved, and the acyclic 2-hg compound was found to be the major compound detected, though the amount of lactone detected was considerable in a number of samples. CONCLUSIONS: Unique EI fragmentation pathways for both 2-hg and the 2-hg lactone have been described. Subsequently, the GC/MS/MS assay presented herein has significant potential as a novel clinical assay as it separates and detects both 2-hg enantiomers and the 2-hg lactone enantiomers, a capability which has not been previously demonstrated by any other assay to date.

A phase I/II study of intrathecal trastuzumab in human epidermal growth factor receptor 2-positive (HER2-positive) cancer with leptomeningeal metastases: Safety, efficacy, and cerebrospinal fluid pharmacokinetics.

BACKGROUND: Patients with human epidermal growth factor receptor 2-positive (HER2-positive) cancers have a high incidence of central nervous system (CNS) spread, but unfortunately systemic trastuzumab which targets the HER2 receptor has little CNS penetration. The purpose of this study was to determine the maximum-tolerated dose of intrathecal trastuzumab and its efficacy in patients with HER2-positive leptomeningeal disease (LMD). METHODS: This multicenter study enrolled 34 LMD patients in a combined phase I/II study in treating patients with intrathecal trastuzumab. Any HER2-positive histology was allowed in the phase I; the phase II was limited to HER2-positive breast cancer. RESULTS: Intrathecal trastuzumab was well-tolerated, with one dose limiting toxicity of grade 4 (arachnoiditis) occurring at the 80 mg twice weekly dose. The recommended phase II dose was 80 mg intrathecally twice weekly. Twenty-six patients at dose level 80 mg were included in evaluation for efficacy: partial response was seen in 5 (19.2%) patients, stable disease was observed in 13 (50.0%), and 8 (30.8%) of the patients had progressive disease. Median overall survival (OS) for phase II dose treated patients was 8.3 months (95% CI 5.2-19.6). The phase II HER2-positive breast cancer patients median OS was 10.5 months (95% CI 5.2-20.9). Pharmacokinetic (PK) studies were limited in the setting of concurrent systemic trastuzumab administration, however, did show stable cerebrospinal fluid (CSF) concentrations with repeated dosing suggest that trastuzumab does not accumulate in the CSF in toxic concentrations. CONCLUSION: This study suggests promise for potentially improved outcomes of HER-positive LMD patients when treated with intrathecal trastuzumab while remaining safe and well-tolerated for patients.

Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial.

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).

Phase 2 trial of irinotecan and thalidomide in adults with recurrent anaplastic glioma.

BACKGROUND: Therapeutic options for patients with anaplastic gliomas (AGs) are limited despite better insights into glioma biology. The authors previously reported improved outcome in patients with recurrent glioblastoma treated with thalidomide and irinotecan compared with historical controls. Here, results of the AG arm of the study are reported, using this drug combination. METHODS: Adults with recurrent AG previously treated with radiation therapy, with Karnofsky performance score ≥70, adequate organ function and not on enzyme-inducing anticonvulsants were enrolled. Treatment was in 6-week cycles with irinotecan at 125 mg/m(2) weekly for 4 weeks followed by 2 weeks off, and thalidomide at 100 mg daily increased to 400 mg/day as tolerated. The primary endpoint was progression-free survival rate at 6 months (PFS-6), and the secondary endpoints were overall survival (OS) and response rate (RR). RESULTS: In 39 eligible patients, PFS-6 for the intent-to-treat population was 36% (95% confidence interval [CI] = 21%, 53%), median PFS was 13 weeks (95% CI = 6%, 28%) and RR was 10%(95% CI = 3%, 24%). Radiological findings included 2 complete and 2 partial responses and 17 stable disease. Median OS from study registration was 62 weeks, (95% CI = 51, 144). Treatment-related toxicities (grade 3 or higher) included neutropenia, diarrhea, nausea, and fatigue; 6 patients experienced venous thromboembolism. Four deaths were attributable to treatment-related toxicities: 1 from pulmonary embolism, 2 from colitis, and 1 from urosepsis. CONCLUSIONS: The combination of thalidomide and irinotecan did not achieve sufficient efficacy to warrant further investigation against AG, although a subset of patients experienced prolonged PFS/OS. A trial of the more potent thalidomide analogue, lenalidomide, in combination with irinotecan against AG is currently ongoing.

Infigratinib in Patients with Recurrent Gliomas and FGFR Alterations: A Multicenter Phase II Study.

PURPOSE: FGFR genomic alterations (amplification, mutations, and/or fusions) occur in ∼8% of gliomas, particularly FGFR1 and FGFR3. We conducted a multicenter open-label, single-arm, phase II study of a selective FGFR1-3 inhibitor, infigratinib (BGJ398), in patients with FGFR-altered recurrent gliomas. PATIENTS AND METHODS: Adults with recurrent/progressive gliomas harboring FGFR alterations received oral infigratinib 125 mg on days 1 to 21 of 28-day cycles. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate by Response Assessment in Neuro-Oncology criteria. Comprehensive genomic profiling was performed on available pretreatment archival tissue to explore additional molecular correlations with efficacy. RESULTS: Among 26 patients, the 6-month PFS rate was 16.0% [95% confidence interval (CI), 5.0-32.5], median PFS was 1.7 months (95% CI, 1.1-2.8), and objective response rate was 3.8%. However, 4 patients had durable disease control lasting longer than 1 year. Among these, 3 had tumors harboring activating point mutations at analogous positions of FGFR1 (K656E; n = 2) or FGFR3 (K650E; n = 1) in pretreatment tissue; an FGFR3-TACC3 fusion was detected in the other. Hyperphosphatemia was the most frequently reported treatment-related adverse event (all-grade, 76.9%; grade 3, 3.8%) and is a known on-target toxicity of FGFR inhibitors. CONCLUSIONS: FGFR inhibitor monotherapy with infigratinib had limited efficacy in a population of patients with recurrent gliomas and different FGFR genetic alterations, but durable disease control lasting more than 1 year was observed in patients with tumors harboring FGFR1 or FGFR3 point mutations or FGFR3-TACC3 fusions. A follow-up study with refined biomarker inclusion criteria and centralized FGFR testing is warranted.

Combination of 6-thioguanine, capecitabine, and celecoxib with temozolomide or lomustine for recurrent high-grade glioma.

We evaluated the efficacy of temozolomide (TMZ) or lomustine (CCNU) in combination with 6-thioguanine, capecitabine, and celecoxib for the treatment of recurrent high-grade glioma. Forty-three patients with recurrent glioblastoma and 31 patients with recurrent anaplastic glioma (AG) were enrolled in this open-label, non-comparative study. Patients previously treated with TMZ received CCNU while all others received TMZ; all patients received 6-thioguanine, capecitabine, and celecoxib. Endpoints were 12-month progression-free survival (PFS) for patients with AG, 6-month PFS for patients with glioblastoma, duration of PFS, and MRI-based objective response rates. Results from the TMZ and CCNU treatment arms were combined in the final analysis because there was no statistically significant difference between them. Thirty-eight patients with glioblastoma were treated with the lomustine-based regimen, and five received the TMZ-based regimen. For the 43 glioblastoma patients, the objective response rate was 12 and 33% had stable disease; the 6-month PFS was 14% and median overall survival 32 weeks. For the 31 AG patients, the combined objective response rate was 26 and 42% had stable disease; the 12 month PFS was 44%. Treatment was reasonably well tolerated with hematological toxicity common and more frequent with CCNU than TMZ. The combination therapy with 6-thioguanine, capecitabine and celecoxib plus CCNU or TMZ does not appear to be more effective than other alkylating agent schedules for patients with recurrent glioblastoma. The combination, however, is promising for patients with recurrent high-grade AG.

High-grade gliomas.

OPINION STATEMENT: High-grade gliomas (HGGs) should be treated with maximal, safe surgical resection followed by 57-60 Gy of partial-field external beam or intensity-modulated radiotherapy to a 2 cm margin surrounding the resection cavity. The standard of care for newly diagnosed glioblastoma includes concurrent temozolomide (TMZ) during radiotherapy and adjuvant TMZ for six or more cycles. The optimal role of chemotherapy in anaplastic gliomas is unresolved. Carefully selected patients with anaplastic gliomas can be treated with combination chemotherapy (procarbazine, lomustine, vincristine; PCV) or TMZ as initial therapy after surgical resection, adjuvant therapy after radiotherapy, or at recurrence in patients with anaplastic glioma. Patients with recurrent glioblastoma can be treated with intravenous bevacizumab or dose-intense regimens of TMZ, but selection of optimal candidates for either therapy is unresolved. Other currently available targeted biologic agents are not part of routine management of patients with HGGs. Combination therapeutic trials of antiangiogenic and other targeted agents are ongoing in patients with HGGs. The way forward for patients with HGGs will involve treatments targeting the molecular abnormalities that are important to tumor initiation and growth. All patients with HGGs should be evaluated for clinical trial eligibility at diagnosis and upon recurrence.

Tonsillar pseudotumor: complications of chronically-administered temozolomide.

The current standard of care for patients with Glioblastoma multiforme (GBM) is surgery, followed by radiation in combination with Temozolomide (TMZ), followed by adjuvant TMZ. The most appropriate length of treatment of adjuvant TMZ after the completion of radiation is unclear. We present the case of a 45 year old female with GBM who received adjuvant TMZ on an experimental study for 24 1-month cycles (150 mg/M(2) 7 days on/7 days off continuously-a higher TMZ dose than standard). After 24 months on study she was stable without GBM regrowth, but presented with a right tonsil and pharynx mass consistent with a new primary malignancy. Tonsillar biopsy was positive for Epstein-Barr virus, Cytomegalovirus and Herpes Simplex Virus, but no tumor. This case highlights the risks and possible complications of immunosuppression associated with long term TMZ use.

Biology and therapy of neoplastic meningitis.

Neoplastic meningitis (NM) occurs in 5% to 8% of cancer patients, commonly as an end-stage process in previously metastatic disease. As newer therapeutics extend patient survival by maintaining long-term control of systemic malignancies, the incidence of NM is likely to rise. This can be expected both because of a change in the natural history of the underlying disease and the generally poor penetrance of many newer anticancer drugs into the central nervous system, thereby creating a sanctuary site for malignant cells. Currently available treatments have provided limited benefit in overall survival in NM, although long-term survival does occur. Because of the morbidity occasionally associated with treatment, prognostic indicators are being analyzed to identify patients who may benefit from systemic and/or intrathecal therapy before making the decision to initiate treatment. Additionally, because of the relative insensitivity of traditional cerebrospinal fluid analysis, new markers of NM are being investigated. This endeavor is being aided by ongoing research into the underlying biology of the metastatic process.

Known and emerging biomarkers of leptomeningeal metastasis and its response to treatment.

Leptomeningeal metastasis (LM) is the metastatic dissemination of malignant cells to the leptomeninges and the subarachnoid space of the CNS, affecting approximately 8% of all cancer patients. Cerebrospinal fluid cytology is currently the gold standard for diagnosis of LM and assessment of treatment response, but it has relatively low sensitivity. Thus, specific biomarkers of LM may allow for earlier diagnosis and treatment. This article reviews known tumor markers for LM and describes recent work to find LM-specific markers, such as angiogenesis-related proteins. Novel methods of protein profiling that may aid this search are also described; these methods still need to be standardized and validated to gain widespread acceptance. Nevertheless, we anticipate that future biomarkers will have not only the potential to detect LM, but to predict its progression and response to treatment.

A Bayesian adaptive randomized phase II multicenter trial of bevacizumab with or without vorinostat in adults with recurrent glioblastoma.

BACKGROUND: Bevacizumab has promising activity against recurrent glioblastoma (GBM). However, acquired resistance to this agent results in tumor recurrence. We hypothesized that vorinostat, a histone deacetylase (HDAC) inhibitor with anti-angiogenic effects, would prevent acquired resistance to bevacizumab. METHODS: This multicenter phase II trial used a Bayesian adaptive design to randomize patients with recurrent GBM to bevacizumab alone or bevacizumab plus vorinostat with the primary endpoint of progression-free survival (PFS) and secondary endpoints of overall survival (OS) and clinical outcomes assessment (MD Anderson Symptom Inventory Brain Tumor module [MDASI-BT]). Eligible patients were adults (≥18 y) with histologically confirmed GBM recurrent after prior radiation therapy, with adequate organ function, KPS ≥60, and no prior bevacizumab or HDAC inhibitors. RESULTS: Ninety patients (bevacizumab + vorinostat: 49, bevacizumab: 41) were enrolled, of whom 74 were evaluable for PFS (bevacizumab + vorinostat: 44, bevacizumab: 30). Median PFS (3.7 vs 3.9 mo, P = 0.94, hazard ratio [HR] 0.63 [95% CI: 0.38, 1.06, P = 0.08]), median OS (7.8 vs 9.3 mo, P = 0.64, HR 0.93 [95% CI: 0.5, 1.6, P = 0.79]) and clinical benefit were similar between the 2 arms. Toxicity (grade ≥3) in 85 evaluable patients included hypertension (n = 37), neurological changes (n = 2), anorexia (n = 2), infections (n = 9), wound dehiscence (n = 2), deep vein thrombosis/pulmonary embolism (n = 2), and colonic perforation (n = 1). CONCLUSIONS: Bevacizumab combined with vorinostat did not yield improvement in PFS or OS or clinical benefit compared with bevacizumab alone or a clinical benefit in adults with recurrent GBM. This trial is the first to test a Bayesian adaptive design with adaptive randomization and Bayesian continuous monitoring in patients with primary brain tumor and demonstrates the feasibility of using complex Bayesian adaptive design in a multicenter setting.

Diagnostic tools for neoplastic meningitis: detecting disease, identifying patient risk, and determining benefit of treatment.

Three methods are routinely used to diagnose neoplastic meningitis (NM): clinical signs and symptoms, cerebrospinal fluid (CSF) cytology, and magnetic resonance imaging (MRI) of the brain and spine. Clinical manifestations are often subtle or may be ascribed to other cancer complications, eg, treatment-related disorders or brain parenchymal metastases. CSF cytology has a high specificity (>95%), but its sensitivity is generally less than 50%. MRI sensitivity and specificity vary with the type of primary cancer; overall, MRI findings consistent with leptomeningeal disease are detected in fewer than 50% of NM patients. While most clinicians evaluate CSF cytology along with MRI and the clinical examination, underdiagnosis is a major problem, since many patients are both cytologically and radiographically negative. Failure to consider NM in the differential diagnosis magnifies the problem of underdiagnosis. CSF flow cytometry is particularly promising for evaluating NM from hematologic cancers, with a diagnostic sensitivity many fold greater than conventional cytology. Research has focused on identifying biochemical markers of tumor cells in the CSF. For example, molecules involved in CNS penetration (eg, matrix metalloproteinases and cathepsins), tumor cell tropism (eg, chemokines CXCL8 and CCL18), and angiogenesis (eg, vascular endothelial growth factor) are elevated in the CSF of patients with NM. Evidence that some tumor types are more likely to infiltrate the CNS also has stimulated research into primary tumor markers predictive of CNS metastases. At present, there is no tumor marker or patient characteristic that reliably predicts the development of NM, and diagnosis still relies on suggestive signs and symptoms, positive CSF cytology, or a consistent MRI-all late manifestations of NM. Until techniques capable of detecting NM early are developed, increased awareness of the disease and standardized evaluation are likely to have the greatest impact on improving diagnosis and implementing earlier treatment.

Biomarkers of disease: cerebrospinal fluid vascular endothelial growth factor (VEGF) and stromal cell derived factor (SDF)-1 levels in patients with neoplastic meningitis (NM) due to breast cancer, lung cancer and melanoma.

BACKGROUND: Breast cancer, lung cancer and melanoma metastasize to the meninges in 5-15% of patients. The identification of specific biomarkers of disease may allow for earlier diagnosis and treatment. Preclinical evidence suggests the possible relevance of SDF-1 and VEGF in the homing and neoangiogenesis of metastases. We chose to measure these molecules in the cerebrospinal fluid (CSF) of melanoma, breast, and lung cancer patients being evaluated for neoplastic meningitis (NM). MATERIALS AND METHODS: We collected CSF from patients with these cancers who were being evaluated for possible NM. CSF was assayed for SDF-1 and VEGF levels using Enzyme-linked Immunosorbent Assay (ELISA) assays. RESULTS: CSF samples from 89 patients met criteria for analysis, including 41 with breast cancer, 35 with lung cancer and 13 with melanoma. Twenty-five percent (22/89) of all samples were positive for malignant cells; 8/41 (20%) from breast cancer, 10/35 (29%) from lung cancer and 4/13 (31%) from melanoma. CSF VEGF levels were available from 83 patients, and were elevated (>20 pg/ml) in 15/22 (68%) of patients with positive CSF cytology and normal (<20 pg/ml) in 59/61 (97%) of patients with negative CSF cytology. The two patients with negative CSF cytology who also had elevated CSF VEGF levels had MRI evidence of NM. CSF SDF-1 levels were available from 81 patients, and were elevated (>950 pg/ml) in 11/18 (61%) of patients with positive CSF cytology and normal (<950 pg/ml) in 57/63 (90%) of patients with negative CSF cytology. CONCLUSIONS: Elevated CSF levels of VEGF are sensitive and highly specific for the diagnosis of NM from breast cancer, lung cancer and melanoma, and may serve as a useful biomarker of NM in high risk patients. CSF SDF-1 levels add little to the diagnostic information provided by CSF VEGF. Evaluation of CSF VEGF levels as a trigger for early treatment in high risk breast cancer, lung cancer and melanoma patients at risk for NM, is warranted.

Liquid biopsy in central nervous system metastases: a RANO review and proposals for clinical applications.

Liquid biopsies collect and analyze tumor components in body fluids, and there is an increasing interest in the investigation of liquid biopsies as a surrogate for tumor tissue in the management of both primary and secondary brain tumors. Herein we critically review available literature on spinal fluid and plasma circulating tumor cells (CTCs) and cell-free tumor (ctDNA) for diagnosis and monitoring of leptomeningeal and parenchymal brain metastases. We discuss technical issues and propose several potential applications of liquid biopsies in different clinical settings (ie, for initial diagnosis, for assessment during treatment, and for guidance of treatment decisions). Last, ongoing clinical studies on CNS metastases that include liquid biopsies are summarized, and recommendations for future clinical studies are provided.

Prognostic factors and outcomes in patients with leptomeningeal melanomatosis.

The purpose of this study was to describe a cohort of patients with leptomeningeal melanomatosis (LM) and to determine prognostic factors for outcomes in these patients. The primary hypothesis was that more extensive burden of CNS metastasis at the time of diagnosis of LM (as evidenced by imaging of the CNS parenchyma and meninges and cerebrospinal fluid [CSF] cytology status [positive versus negative]) correlates with poorer outcomes. The records of all patients with LM treated at M. D. Anderson Cancer Center between 1944 and 2002 were reviewed. Information on clinical course and outcomes was gathered. Univariate and multivariate analyses were performed on 110 patients using Cox proportional hazards regression analysis to examine the effects of possible predictive factors on survival. The overall median survival from LM diagnosis was 10 weeks, with a 95% confidence interval (CI) of 8-14 weeks. Eighty-six (78.2%) patients had cutaneous primary lesions, and 23 (20.9%) had melanoma of unknown primary site. The primary hypothesis was not proven. Neither the presence of parenchymal CNS metastases, nor greater imaging evidence of LM, nor positive CSF cytology at diagnosis correlated with survival outcomes. Univariate analyses revealed possible predictors of longer survival, including the presence of supratentorial or spinal LM on imaging at diagnosis versus its absence and any treatment of LM, whereas elevated serum lactate dehydrogenase at the time of LM diagnosis predicted shorter survival. Multivariate analysis revealed that a history of a primary melanoma lesion originating on the trunk predicted shorter survival after LM diagnosis (hazard ratio [HR] = 2.0, 95% CI = 1.0-3.8, p = 0.035), and treatment with intrathecal chemotherapy predicted longer survival (HR = 0.5, 95% CI = 0.4-0.8, p = 0.0036). The positive result with respect to treatment is unreliable due to the inability to remove treatment selection bias from the analysis. This retrospective analysis confirmed the dismal prognosis associated with LM. The amount of CNS tumor burden at the time of diagnosis of LM did not inversely correlate with survival outcomes, contrary to our hypothesis.

Phase II trial of irinotecan and thalidomide in adults with recurrent glioblastoma multiforme.

This phase II study aimed at determining the efficacy and safety of irinotecan combined with thalidomide in adults with recurrent glioblastoma multiforme (GBM) not taking enzyme-inducing anticonvulsants (EIACs). Adult patients (> or =18 years) with recurrent GBM with up to three relapses following surgery and radiation therapy were eligible for this trial. The primary end point was rate of progression-free survival at 6 months (PFS-6); secondary end points were response rate, overall survival, and toxicity. Patients were treated in 6-week cycles with 125 mg/m(2) irinotecan weekly for 4 weeks followed by 2 weeks off treatment and 100 mg of thalidomide daily increased as tolerated to 400 mg/day. Of 32 evaluable patients, 8 (25%) were alive and progression free at 6 months. The median PFS was 13 weeks. One patient experienced a complete response, one a partial response, and 19 stable disease. Median overall survival time from entry into the study was 36 weeks, and the 1-year survival rate was 34%. Adverse events (grade 3 or 4) included diarrhea, abdominal cramps, lymphopenia, neutropenia, and fatigue. Two of the four deaths that occurred were possibly due to treatment-related toxicity. The combination of irinotecan, a cytotoxic agent, and thalidomide, an antiangiogenic agent, shows promising activity against recurrent GBM in patients not receiving EIACs and warrants further study. The results also provide support for similar strategies using combination therapies with newer targeted antiangiogenic agents to generate effective therapies against malignant gliomas.

A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies.

To determine the therapeutic efficacy (13-week and 26-week CNS progression-free survival [PFS], response rate, and overall survival) and safety of intraventricular (IVent) topotecan in patients with neoplastic meningitis (NM), we conducted a phase II, open-label, nonrandomized, single-arm trial of IVent topotecan in patients with NM using 400 mug of topotecan IVent twice weekly for 6 weeks, followed by evaluation with imaging, cerebrospinal fluid (CSF), and physical examinations. In the absence of disease progression, patients were then treated with IVent topotecan weekly for 6 weeks, twice monthly for 4 months, and monthly thereafter. Sixty-two patients (23 males and 39 females) were enrolled from April 2001 through March 2006. Median age and KPS at enrollment were 56 (range 5-83) and 80 (range 60-100), respectively. Primary cancers included breast (19), lung (13), CNS (14), and others (16). Forty patients (65%) completed the 6-week induction period, among whom 13 (21%) had CSF clearance of malignant cells. Kaplan-Meier estimates of PFS at 13 and 26 weeks were 30% (95% confidence interval [CI], 20%-45%) and 19% (95% CI, 11%-34%). Overall median survival (50 deaths) was 15 weeks (95% CI, 13-24 weeks). The most common side effect was chemical meningitis in 32% of patients (5% grade 3); 32% experienced no drug side effects. IVent topotecan is well tolerated, but provides no added benefit over other IVent therapies. Because of its modest side effect profile, combining IVent topotecan with other IVent or systemic interventions should be considered.