Treatment and prevention of secondary CNS lymphoma.

Central nervous system (CNS) involvement in non-Hodgkin lymphoma is a serious, potentially preventable complication that can occur in 5 to 10% of patients. Its occurrence is directly correlated with pathologic aggressiveness and ranges from less than 3% in the indolent, less-aggressive histologies to as high as 50% in the very aggressive ones such as Burkitt lymphoma. Aggressive treatment once detected can improve neurologic outcome, but because it is often associated with contemporaneous systemic relapse, is rarely associated with long-term survival. Preventing its occurrence, therefore, remains an important goal of initial treatment. Despite there being some suggestive evidence that the addition of systemic rituximab and several intracerebrospinal fluid chemotherapy regimens may have decreased the incidence of CNS involvement, both optimal selection of those patients who should receive prophylaxis as well as the best prophylactic regimen remain active areas of investigation.

Lipid-associated sialoprotein in the cerebrospinal fluid: association with brain malignancies.

BACKGROUND: Changes in the glycosylation process by tumor cells result in larger amounts of sialoproteins on their surface compared with normal cells. Sialoproteins then are released into the surrounding environment primarily by shedding or cell lysis. In the current study, the authors attempted to evaluate whether lipid-associated sialoprotein (LSP) in the cerebrospinal fluid (CSF) can distinguish patients with primary and metastatic brain tumors from those without brain tumors as well as determine response to treatment. METHODS: CSF samples were obtained from a tissue bank. The concentration of LSP was determined after chloroform:methanol extraction followed by protein precipitation. One-way analysis of variance and Scheffe pairwise comparisons were used for statistical analysis. RESULTS: The CSF of neurologically normal controls, patients with a normal leukocyte count (< or = 5/microl), and patients with various neurologic disorders or systemic tumors without central nervous system (CNS) malignancies contained similar levels of LSP. The CSF from patients with a normal leukocyte count and newly diagnosed primary or metastatic brain tumors contained on average 3.7-fold higher levels of LSP compared with CSF from patients without CNS tumors (P = 0.0001). The CSF from patients with brain tumors with progressive disease not responding to treatment contained high levels of LSP comparable to the levels found in newly diagnosed patients. The CSF from treatment-responsive patients contained decreased levels of LSP similar to that found in control patients. CONCLUSIONS: The LSP in CSF may be a useful marker with which to determine the presence of intracranial malignancies and assess response to treatment.

Adult medulloblastoma: multiagent chemotherapy.

In this study, the records of 17 adult patients with medulloblastoma treated with craniospinal radiation and 1 of 2 multiagent chemotherapy protocols were reviewed for progression-free survival, overall survival, and toxicity, and the patients were compared with each other and with similarly treated children and adults. Records of patients treated at 3 institutions were reviewed. Seventeen medulloblastoma patients (11 female, 6 male) with a median age of 23 years (range, 18-47 years) were treated with surgery, craniospinal radiation (CSRT) plus local boost, and 1 of 2 adjuvant chemotherapy regimens. All tumors were infratentorial (10 in 4th ventricle and 7 in left or right hemisphere). Ten patients presented with hydrocephalus, and 7 of them were shunted. Eight patients had gross total resection, 7 had subtotal resection (>50% removed), and 2 had partial resection (<50% removed). Postoperatively, 3 patients had positive cytology and 3 had positive spinal MRI. Five patients were classified as good risk and 12 were classified as poor risk (Chang staging system). Ten patients were treated with the "Packer protocol," consisting of CSRT plus weekly vincristine followed by 8 cycles of cisplatin, lomustine, and vincristine. Seven patients were treated with the Pediatric Oncology Group (POG) protocol, consisting of alternating courses of cisplatin/etoposide and cyclophosphamide/vincristine, followed by CSRT. Eight of 17 patients relapsed, with all 8 relapsing at the primary site. Other relapse sites included the leptomeninges (5), bone (1), and brain (1). The estimated median relapse-free survival (Kaplan-Meier) for all patients was 48 months (95% confidence interval, >26 months to infinity). Median relapse-free survival for patients on the Packer protocol was 26 months, and for those on the POG regimen was 48 months (P = 0.410). Five of 10 on the Packer protocol were relapse-free, while 4 of 7 were relapse-free on the POG regimen. Two patients relapsed during chemotherapy and 6 relapsed after completing all therapy at 18, 18, 26, 30, 40, and 48 months. The estimated median survival of all patients was 56 months (95% confidence interval, 27 to infinity) with 11 patients alive; for the Packer protocol, median survival was 36 months, and for the POG protocol, it was 57 months (P = 0.058). The hazard ratio was 0 (95% confidence interval, 0 to infinity). Toxicity during the Packer protocol was moderately severe, with only 1 of 10 patients able to complete all therapy. Two patients had severe abdominal pain during CSRT + vincristine, and 5 had peripheral neuropathy during vincristine therapy. Hearing loss (>20 dB) occurred in 7, neutropenia (<500 microl) in 6, thrombocytopenia (<50,000 microl) in 6, nephrotoxicity (>25% decrease by creatinine clearance) in 2, and decreased pulmonary function (diffusing capacity for carbon monoxide decrease >40%) in 1. On the POG protocol, only 1 patient had persistent nausea and vomiting, 2 had peripheral neuropathy, and 3 had hearing deficit (>20 dB) or tinnitus. The POG and Packer protocols did not have a statistically significant difference in relapse-free or overall survival because of the small sample size. The POG protocol seemed to have less nonhematologic toxicity. Adults on the Packer protocol appeared to have shorter median survival and greater toxicity than did children. To know whether adding adjuvant chemotherapy to craniospinal radiation in adult therapy increases relapse-free and overall survival, we must await the results of a larger randomized controlled clinical trial.

A comparison between ventricular and lumbar cerebrospinal fluid cytology in adult patients with leptomeningeal metastases.

Leptomeningeal metastases (LMs) are common metastatic complications, occurring in at least 5% of patients with disseminated cancer. Cerebrospinal fluid (CSF) cytology remains the standard for diagnosis and assessment of treatment response, but may be inadequate. Our objective was to compare ventricular and lumbar CSF cytology in patients who had cytologically proven LM and were receiving intra-CSF chemotherapy. Sixty patients with LM, positive lumbar CSF cytology documented at diagnosis, limited extent of CNS disease, and no evidence of CSF flow obstruction were treated with a variety of intra-CSF chemotherapies. All patients underwent a single simultaneous ventricular and lumbar CSF sampling (mean volume of CSF per site examined, 10 ml) to assess response to therapy at either 1 or 2 months after treatment initiation. Ventricular CSF cytology was positive in 44 patients (73%), 35 of whom were also positive by lumbar CSF cytology. Lumbar CSF cytology was positive in 45 patients (75%), of which 35 were also positive by ventricular CSF cytology. Samples were negative at both ventricular and lumbar sites in 6 patients (10%). Paired CSF cytologies were discordant in 19 (32%) patients. The lumbar cytology was negative in 9, whereas the ventricular cytology was positive (lumbar false-negative rate of 17%); the ventricular cytology was negative in 10, whereas the lumbar cytology was positive (ventricular false-negative rate of 20%). In the presence of spinal signs or symptoms of LM, the lumbar CSF cytology was more likely to be positive than was the ventricular (odds ratio = 2.86; 95% confidence interval, 0.86-9.56). Conversely, in the presence of cranial signs or symptoms, the ventricular CSF cytology was more likely to be positive than was the lumbar (odds ratio = 2.71; 95% confidence interval, 0.76-9.71). In this cohort of patients, whose LM was documented initially by positive lumbar CSF cytology, ventricular and lumbar CSF samples obtained during treatment had similar false-negative rates, depending on the site of clinical or radiologic disease. This suggests that both lumbar and ventricular sites must be sampled when assessing treatment response. If clinical or radiographic disease is present only at 1 site, then CSF from that site is more likely to be positive than is CSF obtained from the more distant site.

Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine.

DepoCyte is a slow-release formulation of cytarabine designed for intrathecal administration. The goal of this multi-centre cohort study was to determine the safety and efficacy of DepoCyte for the intrathecal treatment of neoplastic meningitis due to breast cancer. DepoCyte 50 mg was injected once every 2 weeks for one month of induction therapy; responding patients were treated with an additional 3 months of consolidation therapy. All patients had metastatic breast cancer and a positive CSF cytology or neurologic findings characteristic of neoplastic meningitis. The median number of DepoCyte doses was 3, and 85% of patients completed the planned 1 month induction. Median follow up is currently 19 months. The primary endpoint was response, defined as conversion of the CSF cytology from positive to negative at all sites known to be positive, and the absence of neurologic progression at the time the cytologic conversion was documented. The response rate among the 43 evaluable patients was 28% (CI 95%: 14-41%); the intent-to-treat response rate was 21% (CI 95%: 12-34%). Median time to neurologic progression was 49 days (range 1-515(+)); median survival was 88 days (range 1-515(+)), and 1 year survival is projected to be 19%. The major adverse events were headache and arachnoiditis. When drug-related, these were largely of low grade, transient and reversible. Headache occurred on 11% of cycles; 90% were grade 1 or 2. Arachnoiditis occurred on 19% of cycles; 88% were grade 1 or 2. DepoCyte demonstrated activity in neoplastic meningitis due to breast cancer that is comparable to results reported with conventional intrathecal agents. However, this activity was achieved with one fourth as many intrathecal injections as typically required in conventional therapy. The every 2 week dose schedule is a major advantage for both patients and physicians.

Neoplastic meningitis.

Neoplastic meningitis is recognized clinically in 4% to 7% of patients with extraneural cancer, but it remains dramatically under-diagnosed. The frequency of neoplastic meningitis is increasing because of heightened clinical suspicion, improved neuroimaging techniques, and longer survival in patients with extraneural cancer Longer survival allows residual tumor cells within central nervous system sanctuary sites time to become symptomatic. Affected patients may present with cerebral, cranial nerve, or spinal signs and symptoms, depending on the specific sites of central nervous system (CNS) involvement. Magnetic Resonance Imaging (MRI) seems to be sensitive for detecting metastatic deposits along the neuraxis. However, metastases at a microscopic level are below the resolution of MRI scanning. As a result, the standard diagnostic test for neoplastic meningitis remains the cytologic identification of malignant cells in cerebrospinal fluid (CSF). Although CSF cytology is useful, malignant cells are not detected in as many as one third of patients who have compelling clinical or radiographic evidence of neoplastic meningitis. Novel assays are being tested that may enhance the early identification of malignant cells in CSF. Currently, the diagnosis occurs generally after the onset of neurologic manifestations and heralds a rapidly fatal course for most patients. By the time symptoms appear, most tumors have disseminated widely within the CNS, due to cortical irritation, compression of nervous system structures, or obstruction of CSF flow. At this stage surgery, cranial irradiation, and chemotherapy are rarely, if ever, curative. The goals of treatment are to improve or to stabilize the neurologic status of patients and to prolong survival. A major problem in treating neoplastic meningitis is that the entire neuraxis must be treated. If only symptomatic areas are treated, reseeding of the neuraxis with tumor cells will occur. Therefore, intrathecal chemotherapy remains a mainstay of therapy. Currently, four therapeutic agents are available for intrathecal treatment: methotrexate, ara-C, sustained-release ara-C (DepoCyt; Chiron Therapeutics, San Francisco, CA), and thiotepa. Unfortunately, intrathecal chemotherapy does not treat bulky disease in the subarachnoid space, and often is slow to stabilize progressive neurologic deficits. For these reasons, radiation therapy to sites of symptomatic disease and sites of bulky disease on imaging studies is recommended. High dose intravenous methotrexate may be as effective as intrathecal methotrexate. Alternative approaches (which offer less toxicity, enhanced therapeutic effect, and prolonged survival) are being investigated.

Delirium in patients with cancer at the end of life.

PURPOSE: Delirium is a common and distressing syndrome seen in patients with advanced cancer. Behavioral manifestations of delirium, such as agitation, may result in medical intervention, stress to family caregivers, and inpatient hospice admission. The purpose of this study was to examine the frequency, characteristics, and presumed causes of delirium in patients with advanced cancer. DESCRIPTION OF STUDY: Records of all patients with cancer who were admitted to an inpatient hospice facility in 1995 were reviewed retrospectively (N = 210). Patients were classified as delirious based on the clinical judgment of the admitting physician. RESULTS: Delirium was the third most common reason for admission (20%). Male gender (P = .04) and the presence of a primary or metastatic brain tumor (P = .03) were significant risk factors for delirium, while advanced age and primary or metastatic liver, lung, or bone cancer were not. Resolution of the agitation, the most disruptive symptom of delirium, occurred in 69% of patients before death or discharge. CLINICAL IMPLICATIONS: Delirium is common in hospice patients with cancer and is an important cause of family distress and increased cost of care. The recognition of early clinical signs and predisposing factors should facilitate prompt diagnosis. Appropriate intervention is usually successful in alleviating the most distressing symptoms of delirium.

A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors.

Standard treatment for neoplastic meningitis requires frequent intrathecal (IT) injections of chemotherapy and is only modestly effective. DepoCyt is a sustained-release formulation of cytarabine that maintains cytotoxic concentrations of the drug in the cerebrospinal fluid (CSF) for more than 14 days after a single 50-mg injection. We conducted a randomized, controlled trial of DepoCyt versus methotrexate in patients with solid tumor neoplastic meningitis. Sixty-one patients with histologically proven cancer and positive CSF cytologies were randomized to receive IT DepoCyt (31 patients) or IT methotrexate (30 patients). Patients received up to six 50-mg doses of DepoCyt or up to sixteen 10-mg doses of methotrexate over 3 months. Treatment arms were well balanced with respect to demographic and disease-related characteristics. Responses occurred in 26% of DepoCyt-treated and 20% of methotrexate-treated patients (P = 0.76). Median survival was 105 days in the DepoCyt arm and 78 days in the methotrexate arm (log-rank P = 0.15). The DepoCyt group experienced a greater median time to neurological progression (58 versus 30 days; log-rank P = 0.007) and longer neoplastic meningitis-specific survival (log-rank P = 0.074; median meningitis-specific survival, 343 versus 98 days). Factors predictive of longer progression-free survival included absence of visible central nervous system disease on neuroimaging studies (P<0.001), longer pretreatment duration of CSF disease (P<0.001), history of intraparenchymal tumor (P<0.001), and treatment with DepoCyt (P = 0.002). The frequency and grade of adverse events were comparable between treatment arms. In patients with solid tumor neoplastic meningitis, DepoCyt produced a response rate comparable to that of methotrexate and significantly increased the time to neurological progression while offering the benefit of a less demanding dose schedule.

Concurrent chemotherapy and radiotherapy in patients with brain tumors.

Because treatment for most brain tumors remains inadequate, there has been a sustained interest in using concurrent chemotherapy and radiotherapy to improve local control, prolong overall survival, and reduce treatment-related toxicity. Unfortunately, many currently available radiosensitizers are either ineffective against brain tumors or have a reduced ability to cross the blood-brain barrier when administered systemically. Many agents also have overlapping toxicities with cranial irradiation or enhance the toxicity of radiation in a way that potentially compromises care. Finally, the addition of chemotherapy to cranial irradiation complicates the assessment of tumor response. Despite these barriers, trials with a number of promising agents are currently under way. These trials have already provided crucial insights into the pharmacokinetics, clinical pharmacology, and practical management of brain tumor patients with concurrent chemotherapy and radiotherapy. These findings should rapidly lead to the safer and more effective use of combined-modality therapy in patients with central nervous system cancer.

Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis.

PURPOSE: To evaluate the efficacy and safety of a slow-release formulation of cytarabine (DepoCyt; Chiron Corp, Emeryville, CA, and Skye Pharma, Inc, San Diego, CA) that maintains cytotoxic concentrations of cytarabine (ara-C) in the CSF of most patients for more than 14 days. PATIENTS AND METHODS: Twenty-eight patients with lymphoma and a positive CSF cytology were randomized to receive DepoCyt 50 mg once every 2 weeks or free ara-C 50 mg twice a week for 1 month. Patients whose CSF cytology converted to negative and who did not have neurologic progression received an additional 3 months of consolidation therapy and then 4 months of maintenance therapy. All patients received dexamethasone 4 mg orally bid on days 1 through 5 of each 2-week cycle. RESULTS: The response rate was 71% for DepoCyt and 15% for ara-C on an intent-to-treat basis (P =.006). All of the patients on the DepoCyt arm but only 53% of those on the ara-C arm were able to complete the planned 1-month induction therapy regimen. Time to neurologic progression and survival trend in favor of DepoCyt (median, 78.5 v 42 days and 99.5 v 63 days, respectively; P >.05). DepoCyt treatment was associated with an improved mean change in Karnofsky performance score at the end of induction (P =.041). The major adverse events on both arms were headache and arachnoiditis, which were often caused by the underlying disease. CONCLUSION: DepoCyt injected once every 2 weeks produced a high response rate and a better quality of life as measured by Karnofsky score relative to that produced by free ara-C injected twice a week.

The role of paclitaxel in the treatment of primary and metastatic brain tumors.

The rationale for the use of paclitaxel to treat brain tumors includes impressive activity in a wide array of chemotherapy-resistant solid tumors, in vitro and in vivo evidence of cytotoxicity against primary brain tumors, and a paucity of effective alternative agents. A review of published studies evaluating paclitaxel alone or in combination with other chemotherapeutic agents suggests that paclitaxel alone is not highly active against newly diagnosed or recurrent glioblastoma multiforme. However, additional prospective trials are warranted to evaluate the efficacy of paclitaxel plus conventional cranial irradiation or stereotactic radiosurgery. Single-agent paclitaxel appears to be active against gliomas with an oligodendroglial component and may prove useful both as a component of initial therapy and for recurrent disease. Activity against anaplastic gliomas and brain metastases also should be explored. With radiation, a weekly paclitaxel administration schedule is particularly appealing from pharmacologic, safety, and dose-intensity perspectives. In addition, the dose of paclitaxel must be increased in patients who are concurrently receiving medications that induce the P-450 drug metabolizing system. Primary and metastatic brain tumors constitute a very difficult problem in oncology. Future investigations should be directed at evaluating paclitaxel-based chemotherapy regimens in selected brain tumor types, combining paclitaxel with stereotactic radiosurgery, and determining the importance of other proposed mechanisms of action of paclitaxel (eg, inhibition of angiogenesis and tumor invasion).

National survey on prophylactic cranial irradiation: differences in practice patterns between medical and radiation oncologists.

PURPOSE: Prophylactic cranial irradiation (PCI) in the treatment of small cell lung cancer (SCLC) patients remains controversial in the oncology community because of its potential for long-term toxicity and unproven survival benefit in randomized trials. A national survey of 9176 oncologists was conducted to characterize the use of PCI with regard to physician demographics, patient characteristics, and oncologists' beliefs. METHODS: Data was collected via a questionnaire letter survey. Biographical data, treatment patterns, and clinical impressions were analyzed by the generalized linear model and generalized estimating equations method. RESULTS: There were 1231 responders overall (13.4% of those surveyed), including 628 (51%) radiation oncologists (RO), 587 (48%) medical oncologists (MO), 8 (0.6%) surgical oncologists, and 8 (0.6%) from other oncology subspecialties. Of respondents, 74% overall recommend PCI in limited-stage patients, including 65% of MO and 82% RO (p = 0.001). Of responders who recommend PCI in limited-stage patients, 67% do so only after complete response to initial therapy. Only 30% of respondents recommend PCI for extensive-stage SCLC patients (p = 0.001), and 94% of these recommend PCI only when those patients have a complete response after initial therapy. Interestingly, 38% of responding MO feel that PCI improves survival of limited-stage patients, but only 11% believe PCI improves quality of life. Of the RO, 48% believe PCI improves survival in limited-stage SCLC, and 36% feel PCI improves quality of life (p < 0.05 and p < 0.01, respectively). MO responders believe PCI causes late neurological sequelae more often than do RO responders (95% vs. 84%, p < 0.05), with impaired memory (37%), chronic fatigue (19%), and loss of motivation (13%) as most commonly seen side effects. Only 1.5% overall, however, routinely obtain neuropsychiatric testing in PCI patients, and 42% overall never obtain them. CONCLUSION: Results confirm that oncologic subspecialists have statistically significant differences in opinion regarding the use of PCI. However, these differences may not translate into large differences in clinical practice. Most oncologists continue to recommend PCI in limited-stage SCLC patients, despite many believing PCI may not provide a survival advantage nor improve quality of life.

Unexpected in vitro chemosensitivity of malignant gliomas to 4-hydroxyperoxycyclophosphamide (4-HC).

To individually tailor chemotherapy for patients with malignant gliomas according to tumor chemosensitivity, a rapid assay system which can be performed with a high success rate is needed. The fluorescent cytoprint assay (FCA) can assess multiple chemotherapeutic agents using small (approximately 500 cells) tumor aggregates very quickly (approximately 1 wk). Tissue samples from 51 patients with malignant gliomas obtained either at time of initial diagnosis (n = 34) or at recurrence were assayed using this method. The assay success rate approached 90% in those culture samples which were histologically verified as tumor. A meaningful number of agents could be tested both on samples obtained by stereotactic biopsy (median, 5) and on specimens from more extensive resections (median, 6). One hundred ninety-three FCAs were performed on a samples obtained from 36 patients. In only twenty six assays (14%) was an agent deemed sensitive (> 90% cell kill) to a chemotherapeutic agent. Sixty-two percent of sensitive FCAs were observed in tumors tested against the activated analog of cyclophosphamide, 4-hydroxyperoxycyclophosphamide (4-HC), where a sensitivity rate (# samples sensitive/total tested against agent) of 64% (95 % CI, 36.6-77.9%) was noted. This rate was significantly higher than with any other agent tested (p = 0.012, two sided McNemar's test) and was not affected by age, histology or disease status. We conclude that: (1) the FCA represents a feasible method for quickly assaying tumors for sensitivity to multiple chemotherapeutic agents; and (ii) malignant gliomas may be particularly sensitive to 4-HC.

High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary?

PURPOSE: Standard treatments for neoplastic meningitis are only modestly effective and are associated with significant morbidity. Isolated reports suggest that concurrent systemic and intrathecal (i.t.) therapy may be more effective than i.t. therapy alone. We present our experience, which includes CSF and serum pharmacokinetic data, on the use of high-dose (HD) intravenous (i.v.) methotrexate (MTX) as the sole treatment for neoplastic meningitis. PATIENTS AND METHODS: Sixteen patients with solid-tumor neoplastic meningitis received one to four courses (mean, 2.3 courses) of HD (8 g/m2 over 4 hours) i.v. MTX and leucovorin rescue. Serum and CSF MTX concentrations were measured daily. Toxicity, response, and survival were retrospectively compared with a reference group of 15 patients treated with standard i.t. MTX during the same time interval. RESULTS: Peak methotrexate concentrations ranged from 3.7 to 55 micromol/L (mean, 17.1 micromol/L) in CSF and 178 to 1,700 micromol/L (mean, 779 micromol/L) in serum. Cytotoxic CSF and serum MTX concentrations were maintained much longer than with i.t. dosing. Toxicity was minimal. Cytologic clearing was seen in 81% of patients compared with 60% of patients treated intrathecally (P = .3). Median survival in the HD i.v. MTX group was 13.8 months versus 2.3 months in the i.t. MTX group (P = .003). CONCLUSION: HD i.v. MTX is easily administered and well tolerated. This regimen achieves prolonged cytotoxic serum MTX concentrations and CSF concentrations at least comparable to those achieved with standard i.t. therapy. Cytologic clearing and survival may be superior in patients treated with HD i.v. MTX. Prospective studies and a reconsideration of the use of i.t. chemotherapy for patients with neoplastic meningitis are warranted.

Specific matrix metalloproteinase profiles in the cerebrospinal fluid correlated with the presence of malignant astrocytomas, brain metastases, and carcinomatous meningitis.

BACKGROUND: Detection in tumor tissue of specific matrix metalloproteinases (MMPs), particularly gelatinases A and B, correlates with the grade and aggressiveness of primary and metastatic brain tumors. The ability to detect these enzymes in the cerebrospinal fluid (CSF) would be a minimally invasive method of evaluating brain tumors. METHODS: CSF from 66 patients with white blood cell counts of < or = 5 microL were analyzed for the presence of gelatinolytic activity by zymography. Twenty-nine patients had malignant astrocytomas, 10 had brain metastases from systemic malignancies, 4 had systemic cancer not involving the central nervous system, 4 had nonmalignant neurologic diseases, and 19 were healthy controls. Fifteen CSF samples had positive cytologies. The zymographic results were retrospectively correlated with clinical information and CSF cytologic data. RESULTS: CSF from all patients with malignant astrocytomas or brain metastases contained precursor gelatinase A (pMMP2) and precursor gelatinase B (pMMP9), whereas control CSF contained only pMMP2. All patients with positive CSF cytologies had activated MMP2. A similar correlation was observed between the presence of activated MMP9 and positive CSF cytology. CONCLUSIONS: The precursor and activated forms of gelatinases A and B can be detected in the CSF of patients with primary and metastatic brain tumors. The distribution of gelatinase activity in CSF distinguishes patients with malignant gliomas or brain metastases from those without brain tumors, and distinguishes patients with meningeal carcinomatosis from those without CSF spread of tumor, regardless of their brain tumor status. Analysis of MMPs in the CSF may be a sensitive technique for diagnosing CNS tumors and provide an early indication of tumor recurrence. This technique may also provide longitudinal information that would be useful in evaluating ongoing treatment and predicting tumor behavior.

Cerebrospinal fluid cytology in patients with cancer: minimizing false-negative results.

BACKGROUND: Detection of malignant cells on cytologic examination of the cerebrospinal fluid (CSF) is the diagnostic gold standard for leptomeningeal carcinomatosis. The absence of cells is a primary endpoint for most therapeutic trials. Unfortunately, false-negative results are common. Practical strategies are necessary to remedy this problem. METHODS: Four physician-dependent variables (CSF sample volume, site of CSF sampling, processing time, and frequency of CSF sampling) were identified, and their contributions to the false-negative rate of CSF cytology were evaluated prospectively in 39 patients with leptomeningeal carcinomatosis. Retrospective data were analyzed to estimate the importance of these variables in daily practice. RESULTS: False-negative CSF cytology results correlated with small CSF volume (P < 0.001), delayed processing (P < 0.001), not obtaining CSF from a site of symptomatic or radiographically demonstrated disease (P = 0.02), and sampling fewer than two times (P < 0.001). In 1 year, 97% of CSF specimens at the study institution were of inadequate volume; >25% were processed too slowly. CONCLUSIONS: False-negative CSF cytology results are common, but can be minimized by: 1) withdrawing at least 10.5 mL of CSF for cytologic analysis; 2) processing the CSF specimen immediately; 3) obtaining CSF from a site of known leptomeningeal disease; and 4) repeating this procedure once if the initial cytology is negative.

Diagnosis and outcome measures in trials for neoplastic meningitis: a review of the literature and clinical experience.

Innovative approaches to the treatment of neoplastic meningitis are being widely tested. Unfortunately, research on diagnostic strategies and outcome measures on which any advances in treatment ultimately depend, has not been avidly pursued. A critical review of the literature on neoplastic meningitis published since 1978 was undertaken by using MEDLINE and other English language databases. All articles addressing the issues of diagnostic or response criteria were included. Randomized clinical trials (RCTs) were emphasized. Prospectively collected data from the authors' institution correlating the results of cerebrospinal fluid (CSF) cytological examinations with Karnofsky Performance Scale (KPS) score are also discussed. Twenty-six studies (representing 1208 patients) fulfilled search criteria. Only three were RCTs. Cerebrospinal fluid cytology was the sole diagnostic criterion in two-thirds of studies. The results of CSF cytological examination alone or in combination with other clinical or laboratory endpoints constituted the primary outcome measure in 85%. Few studies attempted to address known deficiencies in the reliability and validity of these measures, and correlation between measures was poor. Quality of life was never used as a primary outcome measure. All currently available measurements, including CSF cytology, biochemistry, immunological, and molecular markers, neuroimaging studies, clinical examination, and survival, suffer from poor sensitivity and/or specificity, and often correlate poorly with each other. Although CSF cytological examination, performed according to a rigorous, research-supported protocol, may be the optimum diagnostic and outcome measure at this time, additional research is a prerequisite for any further advances in the clinical care of patients with neoplastic meningitis.

Prophylactic cranial irradiation in small cell lung cancer: rationale, results, and recommendations.

The utility of prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC) constitutes one of the longest running debates in oncology. Despite dozens of prospective and retrospective studies and decades of individual experience, a consensus has been reached on only two issues: (1) when administered to all patients with SCLC, PCI decreases the likelihood of developing brain metastases by about half, but (2) PCI does not significantly prolong survival. Uncertainty persists over many critical questions, including whether, when, and how to administer PCI; whether identifiable subgroups of patients benefit more tangibly from PCI; how frequent and severe the long-term side effects of PCI are; whether withholding treatment until brain metastases are diagnosed is clinically responsible and cost effective; and how newer forms of treatment for brain metastases should be integrated into the picture. In this review, we discuss the epidemiology and natural history of brain metastases in patients with SCLC, the results of studies examining the efficacy of PCI, data on the early and late toxicities of PCI, and the status of alternative therapies for patients with brain metastases from SCLC. Based on this information, an approach to newly diagnosed patients is suggested, and recommendations for future study are made.