SEARCH

SEARCH BY CITATION

Keywords:

  • neoplastic meningitis;
  • cerebrospinal fluid cytology;
  • survival;
  • prognostic variables

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. References

BACKGROUND:

This retrospective comparison evaluated survival in 2 well-matched cohorts of patients with neoplastic meningitis (NM) presenting with or without positive cerebrospinal fluid (CSF) cytology.

METHODS:

Two patient cohorts were studied: 42 individuals with (Group A) and 42 without (Group B) positive CSF cytology. Groups were matched with respect to age; primary tumor; Karnofsky performance status; site of NM disease (cranial nerves or spinal cord); treatment (radiotherapy and chemotherapy; systemic and intraventricular); and absence of CSF compartmentalization, NM-related encephalopathy, and neuroradiographic bulky central nervous system disease. Primary tumor histology included breast (28 patients), non-Hodgkin lymphoma (14 patients), nonsmall cell lung cancer (14 patients), melanoma (12 patients), and others (16 patients). NM at presentation revealed cranial neuropathy (40 patients) or spinal cord dysfunction (58 patients). Radiotherapy was administered to 69 patients (whole brain only in 14 patients [7 each in Groups A and B], restricted spine only in 51 patients [25 in Group A and 26 in Group B], and both whole brain and restricted spine in 4 patients [2 each in Groups A and B]). All patients received intraventricular chemotherapy and 60 (30 each in Groups A and B) received concurrent tumor-specific systemic chemotherapy.

RESULTS:

The median, 3-month, 6-month, and 12-month survival rates for patients with NM were not significantly different between those patients with positive CSF cytology (18 weeks, 83%, 33%, and 9.5%, respectively) and those without positive CSF cytology (20 weeks, 90.5%, 40.5%, and 9.5%, respectively). All patients demonstrated progressive disease and died of either NM or systemic cancer.

CONCLUSIONS:

In patients with NM who were matched for known prognostic variables, the presence or absence of CSF cytology did not appear to influence survival. Cancer 2009. © 2009 American Cancer Society.

Neoplastic meningitis (NM) is a frequent complication of systemic cancer, reported to occur in approximately 5% of all patients with cancer.1-4 However, deciding whom to treat is problematic for several reasons. In nearly 75% of patients with NM, evidence of progressive systemic cancer is apparent.1-4 Furthermore, approximately one-third of patients with NM have coexistent bulky central nervous system (CNS) metastases defined by neuraxis neuroradiography, a previously documented predictor of poor survival in patients with NM.1-4 In addition, another one‒third of patients with NM have evidence of cerebrospinal fluid (CSF) compartmentalization by radioisotope ventriculography, another prognostic variable creported to be predictive of survival.3 In patients with persistent obstruction to CSF flow, survival is curtailed compared with patients without CSF obstruction. In a recent study, NM-related performance as measured by the Karnofsky performance status (KPS) was found to be independently predictive of survival in patients with NM. Lastly, in patients with NM-related encephalopathy (approximately 15% of all patients with NM), survival is poor compared with patients without encephalopathy. The current study compared patients with NM matched for recognized prognostic variables with respect to the presence or absence of positive CSF cytology. This study demonstrated that, when treated, patients with negative CSF cytology and NM have outcomes that are not significantly different from patients with positive CSF cytology and NM.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. References

Study Population

This institutional review board-approved study comprised 2 groups of patients. Group A (n = 42 patients; Patients 1-42 in Table 1) included patients with a diagnosis of NM and positive CSF cytology who were seen between August 1990 and January 2007. During this period, 150 patients with a diagnosis of NM with positive CSF cytology were seen. For each patient in Group A, a patient with NM (defined by a clinical syndrome consistent with NM in a patient with known cancer, abnormal CSF profile [protein, glucose, cell count, or opening pressure], and neuroradiography consistent with NM) and negative CSF cytology (in each patient at least 2 large-volume CSF cytology samples were obtained) was matched with respect to age, sex, tumor histology, extent of disease (absent CSF compartmentalization and CNS bulky disease), site of NM disease (cranial nerve or spine), treatment, KPS, and absence of NM-related encephalopathy. This patient group comprised Group B (Patients 43-84 in Table 1).

Table 1. Patient Characteristics
Patient No.Age, Years/ SexKPSTumor Histology/ CSF Cytology ResultActive or Measurable Systemic DiseaseNeurologic PresentationNM-directed TreatmentSurvival, wk
Cranial NerveSpinal CordRadio therapyChemo therapy
BrainSpineSystemicCSF
  1. KPS indicates Karnofsky performance status; CSF, cerebrospinal fluid; NM, neoplastic meningitis; W, woman; +, positive; M, man; NSCLC, nonsmall cell lung cancer; SCLC, small cell lung cancer; NHL, non-Hodgkin lymphoma; PCNSL, primary central nervous system lymphoma; −, negative.

162/W70Breast/++++ +++14
259/M100NSCLC/+ ++   +17
354/W80Breast/++ + +++15
465/W90Breast/+  + + +58
560/M90NSCLC/+++   ++12
661/M80SCLC/+ +    +12
758/M70Melanoma/++ + +++8
867/W100Breast/+  + + +52
954/W100Breast/+ +    +54
1056/M70Melanoma/++ + +++9
1160/M80NSCLC/++ + +++11
1278/M80Prostate/++ + +++32
1358/W90Breast/+ + +  +56
1456/M90Colon/++ + +++10
1556/M100NHL/++++ +++24
1658/W100NHL/+++ ++++22
1768/W70Breast/++ + +++18
1859/M70NHL/+ + +  +15
1948/W80Breast/+++ + ++16
2032/M90Testicular/++ + +++14
2152/M90NHL/++ + +++12
2244/M100Medulloblastoma/+ +    +18
2338/M70Ependymoma/+  + + +13
2448/M80PCNSL/+ + +  +26
2562/W90NHL/++ + +++28
2668/W80Breast/++++ +++22
2769/M90NSCLC/+++ + ++12
2855/W100Breast/++ + +++28
2960/M90Melanoma/+++++ ++11
3053/M80Melanoma/++ + +++10
3139/W70Breast/+++ + ++32
3261/W70Breast/++ + +++20
3352/M70NSCLC/+++   ++16
3454/M90Melanoma/++++ + +16
3557/M80NSCLC/+  + + +20
3658/W100Breast/++ + +++32
3756/M70NHL/+  + + +24
3846/M80NHL/++++++++42
3946/W90Breast/++ +  ++27
4050/M70NSCLC/+++    +20
4152/M70Melanoma/++ + + +11
4266/M100Colon/++ + + +22
4361/W70Breast/−+++ +++16
4458/M90NSCLC/− ++   +17
4553/W90Breast/−+ + +++16
4666/W90Breast/−  + + +60
4761/M90NSCLC/−++   ++12
4862/M90SCLC/− +    +14
4957/M80Melanoma/−+ + +++8
5066/W100Breast/−  + + +55
5155/W100Breast/− +    +59
5257/M80Melanoma/−+ + +++10
5361/M90NSCLC/−+ + +++12
5479/M90Prostate/−+ + +++33
5557/W100Breast/− + +  +60
5655/M100Colon/−+ + +++9
5755/M90NHL/−+++ +++27
5857/W90NHL/−++ ++++24
5967/W80Breast/−+ + +++20
6059/M80NHL/− + + ++18
6147/W90Breast/−++  +++20
6231/M100Testicular/−+ + +++16
6351/M90NHL/−+ + +++17
6443/M90Medulloblastoma/− +    +20
6537/M80Ependymoma/−  + + +14
6649/M80PCNSL/− + +  +30
6761/W90NHL/−+ + +++31
6867/W80Breast/−+++ +++24
6970/M90NSCLC/−++ + ++13
7054/W90Breast/−+ + +++31
7159/M80Melanoma/−++++ ++12
7252/M70Melanoma/−+ + +++11
7340/W80Breast/−++ + ++34
7460/W80Breast/−+ + +++23
7551/M80NSCLC/−++   ++17
7655/M90Melanoma/−+++ + +17
7758/M80NSCLC/−  + + +21
7859/W100Breast/−+ +++++33
7957/M70NHL/−  + + +26
8047/M80NHL/−+++ +++43
8148/W80Breast/−+ +  ++30
8251/M70NSCLC/−++ +  +22
8354/M70Melanoma/−+ + + +13
8467/M90Colon/−+ + + +24

The 84 patients (52 males and 32 females) ranged in age from 31 to 84 years (median, 57 years). KPS at the time of diagnosis of NM ranged from 70 to 100 (median, 90). In 6 patients (7.1%; 3 each from Groups A and B), NM was diagnosed at the time of initial systemic tumor presentation. In the 78 remaining patients, NM was diagnosed 5 to 32 months (median, 15 months) after initial tumor presentation. Forty patients had cranial nerve involvement (20 in each group), and 58 patients had NM-related spinal cord disease (29 in each group). In 24 patients (12 each from Groups A and B), the primary tumor was in remission (ie, recurrence manifested as isolated NM); therefore, only regional chemotherapy and limited-field CNS radiotherapy were used. Thirty patients in each group had active or measurable systemic disease in which a variety of tumor-specific systemic chemotherapies were used in addition to regional chemotherapy and limited-field CNS radiotherapy. Seven patients in each group (a total of 14 patients) initially had evidence of CSF flow obstruction; however, after site of CSF flow obstruction radiotherapy, normal CSF flow was restored in all. Radiotherapy was administered to 63 patients (whole brain only in 14 patients [7 each in Groups A and B], restricted spine only in 51 patients [25 in Group A and 26 in Group B], and both whole brain and restricted spine in 4 patients [2 each in Groups A and B]).

All patients underwent placement of an intraventricular catheter and reservoir, after which the extent of NM disease was evaluated as previously described.1-4 All patients received intraventricular chemotherapy after the completion of involved-field radiotherapy, as previously described.3

Statistical Methods

Equality of baseline characteristics of the 2 groups was tested with contingency tables and the chi-square test for categoric variables (sex, site of NM disease, extent of disease, and treatment) and 1-way analysis of variance for continuous variables (age and KPS). Kaplan-Meier plots and the log-rank test were used to evaluate the association of survival as a function of CSF cytology.5-7

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. References

There were no statistically significant differences between the group characteristics: age, sex, tumor histology, site of NM disease, extent of disease, and NM-related treatment. All patients in Group B (n = 42) had negative CSF cytology. Whole‒brain radiotherapy was administered to 9 patients and 27 patients received involved-field spinal radiotherapy in Group B. By contrast, all patients in Group A (n = 42) had positive CSF cytology. Nine patients were treated with whole‒brain radiotherapy and 28 received involved-field spinal cord radiotherapy in Group A.

No treatment-related deaths occurred. Eighteen of 84 patients (21%) developed grade 3 or 4 neutropenia or thrombocytopenia, 6 of whom required hospitalization for antibiotic treatment of neutropenic fever on at least 1 occasion and 8 of whom required platelet transfusions on at least 1 occasion (grading determined according to the National Cancer Institute Common Toxicity Criteria v. 3.0). All instances of grade 3 or 4 myelosuppression were believed to be a consequence of coadministered systemic chemotherapy. CNS treatment-related toxicity included intraventricular catheter infections (3 of 84 patients; 3.5%) and multiple episodes of chemically induced aseptic meningitis (44 of 84 patients; 52%).

Survival did not significantly vary (P = .51) between the groups (Group A: median, 18 weeks; range, 8-58 weeks [95% confidence interval (95% CI), 14.78-21.52]; Group B: median, 20 weeks; range, 8-60 weeks [95% CI, 14.71-25.29]). A Kaplan-Meier survival plot demonstrates (Fig. 1) no difference in survival as a function of CSF cytology. There was a trend toward improved 3-month and 6-month survival in patients with negative CSF cytology compared with patients with positive CSF cytology (90.5% vs 83.3% at 3 months; 40.5% vs 33.3% at 6 months); however, no difference was noted with regard to 12-month survival (9.5% in both groups). The cause of death (determined by the investigator) also did not differ between patient groups, with 60% of Group A patients dying of progressive leptomeningeal disease compared with 65% of Group B patients.

thumbnail image

Figure 1. Survival in neoplastic meningitis as a function of cerebrospinal fluid (CSF) cytology. The solid line indicates CSF-negative cytology (median overall survival, 20 weeks); dashed line, CSF-positive cytology (median overall survival, 18 weeks).

Download figure to PowerPoint

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. References

In patients with NM, deciding whom to treat is challenging. The majority of patients have end-stage cancer, often have coexistent bulky CNS disease, and present with pleomorphic neurologic signs and symptoms making disease recognition challenging. Furthermore, because the NM affects the entire neuraxis, evaluation requires craniospinal neuroradiography. Finally, the optimum treatment of NM uses intraventricular chemotherapy, thereby requiring patients to undergo a neurosurgical procedure.1-4, 8-16 For all of these reasons, deciding which patients with NM to treat is clinically and economically relevant.

Several clinical characteristics define patients for whom standard NM-directed treatment is ineffective. These characteristics include patients with limited survival due to advanced systemic cancer and patients who, after discussion of the clinical implications of NM, decline further treatment. In patients with NM and impaired performance status (as defined by a KPS < 70) and thus no longer independent in activities of daily living, survival is poor, suggesting supportive care is more appropriate for this subset of patients. In addition, prior studies have suggested 3 additional patient groups in whom NM-directed treatment is of limited benefit. In 1 group of patients, bulky subarachnoid or parenchymal CNS metastatic disease is predictive of limited survival. In the second group of patients, radiotherapy‒resistant interruption of CSF flow, as defined by radioisotope CSF flow study, predicts for limited survival.2 In the third group, NM-related encephalopathy also is predictive of poor survival. The National Comprehensive Cancer Network (NCCN) guidelines regarding the treatment of NM stratify patients into good‒risk and poor‒risk groups.17 Poor risk is defined by a low KPS; multiple, serious, fixed neurologic deficits; and extensive systemic disease with few treatment options. Separating NM patients into CSF-positive and CSF-negative cohorts and determining outcomes based on similar treatment to our knowledge has never formally been evaluated. In addition, prior randomized trials have included only patients with positive CSF cytology, selecting for 1 group of patients with NM. In what to our knowledge is the only autopsy study of patients with NM diagnosed by postmortem pathology, CSF cytology was negative for 50% to 60% of all patients believed antemortem to have NM.18 In addition, this study suggested that nearly 5% of all patients with solid tumor cancer are determined to have NM postmortem.18-20 This finding suggests that NM is more common than appreciated and not infrequently associated with negative CSF cytology.

The results of the current study suggest that the response (as defined by median, 3-month, 6-month, and 12-month survival) to NM-directed therapy is similar in patients matched for prognostic variables with or without positive CSF cytology. These results, although admittedly based on a retrospective analysis and in comparatively small number of patients, suggest that NM without positive CSF cytology has prognostic significance and demonstrate a survival that is similar to that of patients with positive CSF cytology when treated with intra-CSF chemotherapy and radiotherapy. A larger prospective trial validating the results of the current study would substantiate that patients with negative CSF cytology and NM-compatible clinical and neuroradiographic findings should be considered for NM-directed clinical trials. NM is often underdiagnosed and consequently undertreated; at least 1 explanation is provided by the results of this study suggesting that NM may be diagnosed in patients with negative cytology and clinical and neuroradiographic findings consistent with NM. By tailoring NM-directed therapies to appropriate patients with NM, including patients with negative CSF cytology, clinicians may more confidently provide palliative therapy for this challenging disease.

References

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. References
  • 1
    Glantz MJ,Jaeckle KA,Chamberlain MC, et al. A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res. 1999; 5: 3394-3402.
  • 2
    Chamberlain MC,Kormanik, PA. Prognostic significance of 111Indium- DTPA CSF flow studies in leptomeningeal metastases. Neurology. 1996; 46: 1674-1677.
  • 3
    Chamberlain MC,Dirr L. Involved field radiotherapy and intra-Ommaya methotrexate/ara-C in patients with AIDS-related lymphomatous meningitis. J Clin Oncol. 1993; 11: 1978-1993.
  • 4
    Freilich RJ,Krol G,DeAngelis LM. Neuroimaging and cerebrospinal fluid cytology in the diagnosis of leptomeningeal metastasis. Ann Neurol. 1995; 38: 51-57.
  • 5
    Log Rank Test (2xK tables). In: Miller RGJr, ed. Survival Analysis. New York: John Wiley & Sons; 1981: 114-118.
  • 6
    SAS Institute Inc. SAS Version 8. Cary, NC: SAS Institute Inc; 1999.
  • 7
    Epicenter Software. Epilog Window: Epicenter Software. Pasadena, Calif: Epicenter Software; 1999.
  • 8
    Chamberlain MC,Kormanik P. Prognostic significance of co-existent bulky metastatic central nervous system disease in patients with leptomeningeal metastases. Arch Neurol. 1997; 54: 1364-1368.
  • 9
    Glantz M,Jaeckle KA,Chamberlain MC, et al. A randomized trial of a slow-release formulation of cytarabine for the treatment of lymphomatous meningitis. J Clin Oncol. 1999; 17: 3110-3116.
  • 10
    Mason WP,Yeh SD,DeAngelis LM. 111Indium-diethylenetriamine pentaacetic acid CSF flow studies predict distribution of intrathecally administered chemotherapy and outcome in patients with leptomeningeal metastases. Neurology. 1998; 50: 438-448.
  • 11
    Sherman AM,Jaeckle K,Meyers CA. Pretreatment cognitive performance predicts survival in patients with leptomeningeal disease. Cancer. 2002; 95: 1311-1316.
  • 12
    Glantz MJ,Chamberlain MC,Walters BC. Diagnosis and outcome measures in trials for neoplastic meningitis: a review of the literature and clinical experience. Neurosurg Focus. 1998; 4: 1-7.
  • 13
    Grossman SA,Finkelstein DM,Ruckdeschel JC, et al. Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. J Clin Oncol. 1993; 11: 561-569.
  • 14
    Hitchins RN,Bell DR,Woods RL, et al. A prospective randomized trial of single agent, versis combination chemotherapy in meningeal carcinomatosis. J Clin Oncol. 1987; 5: 1655-1662.
  • 15
    Glantz MJ,Hall WA,Cole BF, et al. Diagnosis, management, and survival of patients with lemptomeningeal cancer based on CSF flow studies. Cancer. 1995; 75: 2919-2931.
  • 16
    Chamberlain MC,Tsao-Wei D. Neoplastic meningitis-related encephalopathy: prognostic significance. Neurology. 2005; 63: 2159-2161.
  • 17
    Brem SS,Bierman PJ,Black P, et al. Central nervous system cancers: clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2005; 3: 644-690.
  • 18
    Glass JP,Melamed M,Chernik NL, et al. Malignant cells in cerebrospinal fluid (CSF): the meaning of a positive CSF cytology. Neurology. 1979; 29: 1369-1375.
  • 19
    Boyle R,Thomas M,Adams JH. Diffuse involvement of the leptomeninges by tumour-a clinical and pathological study of 63 cases. Postgrad Med J. 1980; 56: 149-158.
  • 20
    Chamberlain MC. Cytologically negative carcinomatous meningitis: usefulness of CSF biochemical markers. Neurology. 1993; 50: 1173-1175.