A total of 187 patients satisfying the eligibility criteria were diagnosed with LM at Memorial Sloan-Kettering Cancer Center over these 3 years of 564 patients screened for this study; only 6 (3%) were included on the basis of the physician's clinical judgment. Of these 187 patients, 150 had solid tumors and 37 had hematologic cancers (). The median age was 56 years (range, 19–87 years) and the median KPS was 70 (range, 10–100). There were more women (n = 137, 73%); the largest number of patients had breast cancer (n = 65, 35%) followed by lung cancer, lymphoma, leukemia, and melanoma. The median time from diagnosis of the primary tumor to diagnosis of LM was 1.6 years (range, 0–22.6 years) in the entire population. However, patients with solid tumors had a median time interval of 2.0 years (range, 0–22.6 years), in contrast to 11 months (range, 0–7.7 years) for those with hematologic primaries (p = 0.004). At LM diagnosis, 121 (81%) patients with solid tumors had known metastatic disease and 30 (81%) with hematopoietic tumors had active disease. Only 14 (9%) patients with solid tumors and 6 (16%) with hematopoietic tumors were considered free of disease prior to their LM diagnosis. A total of 109 patients (58%) had previous or current brain metastases, 105 (70%) with solid tumors and 4 (11%) with hematopoietic tumors.
Table 1 Patient and tumor characteristics
The clinical picture of LM classically involves symptoms and signs referable to multiple levels of the neuraxis. Only 2% of the cohort had no clinical features at diagnosis; 2 patients had leukemia, 1 was found to have LM during prophylactic intrathecal chemotherapy and 1 to have LM on a screening MRI, and 2 patients had non-small cell lung cancer with incidentally found LM on MRI done for known brain metastases. Thirty-four percent of patients had symptoms or signs referable to one compartment of the CNS (cerebral, posterior fossa, or spine), 39% to 2 compartments, and 25% to all 3. Headache, confusion, nausea/vomiting, diplopia, cerebellar dysfunction, back pain, and leg weakness were the most common findings.
Of the 187 patients, the diagnosis of LM was established by imaging in 53%, by CSF cytology in 23%, and by both methods in 24%. Not every patient had all tests performed. A total of 177 (95%) had MRI of at least 1 segment of the CNS, while 102 (55%) underwent cytologic analysis; 1 patient with solid tumor was diagnosed solely by cranial CT (figure e-1 and table e-1 on the Neurology
® Web site at www.neurology.org
). The proportion of patients undergoing CSF analysis was higher in those with hematopoietic tumors than solid tumors (100% vs 43%). The proportion of patients undergoing MRI was high in both groups, 96% in solid tumors and 89% in hematologic cancers. Imaging was diagnostic for LM in 143 of 177 patients (81%) who had an MRI; 88 of 102 patients (86%) had a positive CSF cytology. For patients with solid tumors, neuroimaging was positive for LM in 88% and CSF was positive in 85% of those tested. In contrast, only 48% of patients with hematopoietic tumors had positive neuroimaging for LM, while 89% had a positive CSF cytologic analysis.
Cytology vs MRI.
Ninety-three patients had both MRI of at least 1 segment and CSF analysis (). LM was confirmed by both positive cytology and MRI results in 45 patients (48%). In 34 of 93 patients (37%), the diagnosis was established only by the demonstration of malignant cells in the CSF, while the diagnosis was made by neuroimaging alone in 14 of 93 patients (15%). The distribution of diagnostic tools used to confirm LM was marginally different between primary tumor types (p = 0.08). Both diagnostic tests were positive for LM in 55% of solid tumor patients compared with only 36% of hematopoietic patients. Cytology alone was positive more frequently in patients with hematopoietic tumors compared to solid tumors (52% vs 28%). In contrast, positive neuroimaging alone was uncommon in both solid and hematopoietic tumor patients (17% vs 12%).
Table 2 Comparison of diagnostic tools
Of the 48 patients who underwent both cytologic evaluation and MRI of the entire neuraxis (brain and total spine) at diagnosis, 35 had solid tumors and 13 had hematopoietic tumors. Of these patients, only 54% had concordant positive results on both diagnostic tests (). Twenty-one percent of patients had positive MRI results but negative CSF cytology, while 25% had a negative MRI but positive CSF cytology. In patients with solid tumors, the rate of positive MRI scans was incrementally higher, whereas in patients with hematopoietic tumors the rate of positive CSF cytology results was slightly higher (p = 0.42). True sensitivity and specificity could not be calculated, as all patients had a positive result on at least one of the studies.
A total of 102 patients underwent some degree of CSF analysis, of which cytology was malignant in 76 and suspicious in 12. Only 5 patients had completely normal CSF (defined as negative cytology, leukocytes ≤5 per mm3
, protein ≤50 mg/dL, glucose ≥40 mg/dL, and opening pressure ≤20 cm water); of these, 4 had breast cancer and one had leukemia. Four other patients had cytology samples taken from ventricular rather than lumbar fluid; other CSF characteristics in these patients were not analyzed due to differing normal values in ventricular vs lumbar fluid.2
Overall, cytology was abnormal in 86% of patients, while leukocytes were elevated in 64%, protein was elevated in 59%, and glucose was decreased in 31% (table e-2). Opening pressure was measured in only 32 patients, but was elevated in 50%. Leukocytosis was seen more often in hematopoietic tumors, while elevated protein, low glucose, and elevated opening pressure were seen more often in solid tumors.
Of the 187 LM patients, 28 (15%) received supportive care alone, all but one of whom had solid tumors. There were 67 patients (36%) who received initial treatment with radiotherapy alone, 46 (25%) chemotherapy alone, and 36 (19%) combined radiation and chemotherapy. Treatment was unknown in 10 patients (5%). Chemotherapy was intrathecal in 26% of patients, combined intrathecal and systemic in 4%, and systemic only in 14%. Just over 40% of all patients received whole brain radiotherapy, while 19% received radiotherapy to the spine. Of note, 42% of patients with solid tumors had previously received cranial radiotherapy for brain metastases, of whom 97% received whole brain radiotherapy, and 3% received stereotactic radiosurgery. Intrathecal chemotherapy was used more often in patients with hematopoietic tumors than in those with solid tumors; 46% of patients with hematopoietic tumors received intrathecal methotrexate while 32% received cytarabine in either regular or liposomal form. Of patients with solid tumors, only 11% received intrathecal methotrexate and 4% received some form of intrathecal cytarabine. Approximately 20% of patients in each group received systemic chemotherapy.
Survival and prognostic factors.
Of the 187 patients with LM, 177 (95%) had died at last follow-up. Median overall survival for the entire cohort was 2.4 months (95% confidence interval [CI] 1.9–3.1) (). Median overall survival for patients with solid tumors was 2.3 months (95% CI 1.7–2.6) compared with 4.7 months (95% CI 2.7–6.8) for patients with hematopoietic tumors (p = 0.0006; ). Median survival of patients with breast cancer was 2.8 months, comparable to those with lung cancer at 2.2 months. Patients with other solid tumors fared worse. Leukemia patients survived a median of 5.8 months, and lymphoma patients 4.6 months. There were no differences in overall survival seen within the solid (p = 0.09) or hematopoietic (p = 0.32) patient populations. Twenty patients had no active disease prior to their diagnosis of LM; these patients survived a median of 3.8 months vs a median survival of 2.4 months in patients known to have active disease (p = 0.18). We were unable to confirm their systemic disease status, as staging was often not completed once LM was diagnosed.
Figure 1 Overall survival of the entire cohort of 187 patients
Figure 2 Survival of patients following diagnosis of leptomeningeal metastasis by tumor type
Twenty patients survived longer than 12 months (range 12.6 to 66.3 months); of these, 10 had hematopoietic tumors (6 leukemia and 4 lymphoma) and 10 had solid tumors (4 breast, 4 lung, 1 bladder, and 1 carcinoma of unknown primary). Of the 6 leukemia patients, none died of progressive LM: 3 were alive, 2 died of systemic disease, and 1 died of methotrexate leukoencephalopathy. No clear difference could be found between these 20 patients and the remainder of the cohort with regard to extent of disease at LM diagnosis, the presence of previous or concurrent brain metastases, symptoms at diagnosis, or treatment provided.
Elevated intracranial pressure (ICP) was present in 48 patients (26%), as determined by an elevated opening pressure (>20 cm water) on lumbar puncture (16 patients), diagnosis of hydrocephalus,3
placement of or recommendation for a ventriculoperitoneal (VP) shunt,7
or other symptoms or signs consistent with elevated ICP.22
The median overall survival of patients with a diagnosis of elevated ICP was 1.7 months, while it was 2.9 months for those without the diagnosis (p
= 0.02). All but 3 of the patients with elevated ICP had solid tumors.
After univariate Cox regression analysis, 20 patients were removed from the multivariate analysis because they were missing variable information, resulting in 167 patients included in the final analysis (). Univariate analysis demonstrated an association between initial KPS, primary tumor type, and elevated ICP with overall survival. Initial KPS and primary tumor type continued to be significant in the multivariate analysis. Gender became significant in multivariate analysis, but was not in univariate analysis; there was an interaction seen between gender and tumor type. When comparing women with hematopoietic tumors to men with hematopoietic tumors, men had a higher risk of death (hazard ratio 3.1 [95% CI 1.4–6.9], p = 0.005). When comparing women with solid tumors to men with solid tumors, men had a higher risk of death (hazard ratio 1.5 [95% CI 1.0–2.3], p = 0.04), perhaps related to the different tumor types in each group.
Table 3 Univariate and multivariate Cox regression analysis