J Neurooncol (2009) 93:205212 DOI 10.

1007/s11060-008-9758-3

CLINICAL STUDY - PATIENT STUDY

Prognostic factors and clinical outcomes in patients with leptomeningeal metastasis from solid tumors
Fusako Waki Masashi Ando Atsuo Takashima Kan Yonemori Hiroshi Nokihara Mototaka Miyake Ukihide Tateishi Koji Tsuta Yasuhiro Shimada Yasuhiro Fujiwara Tomohide Tamura

Received: 15 April 2008 / Accepted: 17 November 2008 / Published online: 29 November 2008 Springer Science+Business Media, LLC. 2008

Abstract Background Leptomeningeal metastasis (LM) occurs in 415% of patients with solid tumors. Although the clinical outcomes in cancer patients have been improving recently, no standard treatment for LM has been established as yet. The purpose of this study was to identify the prognostic factors in patients with solid tumors with cytologically proven LM. Methods We retrospectively analyzed a series of 85 consecutive patients with cytologically proven LM who were treated between 1997 and 2005. Results The primary diseases were as follows; lung cancer (n = 36), breast cancer (n = 33), gastric cancer (n = 8), and others (n = 8). Forty-nine patients had brain metastasis at the time of diagnosis of the LM, and in 51 patients, MRI revealed meningeal dissemination in the
F. Waki (&) M. Ando K. Yonemori Y. Fujiwara Breast and Medical Oncology Division, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan e-mail: fohara@med.kagawa-u.ac.jp F. Waki Faculty of Medicine, Division of Hematology, Department of Internal Medicine, Kagawa University, Takamatsu, Japan A. Takashima H. Nokihara T. Tamura Thoracic Oncology Division, National Cancer Center Hospital, Tokyo, Japan M. Miyake U. Tateishi Diagnostic Radiology Division, National Cancer Center Hospital, Tokyo, Japan K. Tsuta Clinical Laboratory Division, National Cancer Center Hospital, Tokyo, Japan Y. Shimada Gastrointestinal Division, National Cancer Center Hospital, Tokyo, Japan

brain or spine. The performance status (PS) was 01 in 26 patients and 24 in 59 patients. Thirty-one patients, including 19 with breast cancer, four with lung cancer, ve with gastric cancer and three with other cancers, were treated by intrathecal (IT) chemotherapy. The response rate to the IT was 52% (95% condence interval (CI): 41.462.6%). The median survival was 51 days (range, 3759 days). A univariate analysis identied breast cancer, good PS (01), time to development of the LM ([1 year), and treatment by IT chemotherapy as being associated with a good prognosis, and multivariate analysis identied poor PS (HR: 1.72 (95% CI, 1.042.86) P = 0.04) and MRIproven LM (HR: 1.82 (95% CI, 1.112.98) P = 0.02) as being associated with a poor prognosis. Conclusion In patients with poor prognostic factors, such as poor PS or MRI-proven LM, palliative therapy might be the most suitable treatment strategy. Keywords Leptomeningeal metastasis Prognostic factor Intrathecal chemotherapy MRI Cancer

Introduction Leptomeningeal metastasis (LM) is a severe complication that occurs in 415% of all patients with solid tumors. The most common primary cancers, excluding hematological malignancies, are breast cancer, lung cancer, and melanoma [1]. Better systemic control of a cancer may delay the appearance of LM, however, once LM is established, the prognosis of the patients is poor and the median survival is around 8 weeks (range, 411 weeks) [2, 3]. LM is diagnosed based on the clinical features and the ndings on cerebrospinal uid (CSF) examination and

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neuroimaging studies, such as brain and spinal gadoliniumenhanced magnetic resonance imaging (Gd-MRI). Cytologic identication of malignant cells in the CSF is the gold standard for the diagnosis of LM. The specicity of the test is excellent and false-positive results are rare, nonetheless, less than adequate sensitivity, that is, a high frequency of falsenegative results, remains a problem for clinicians [4, 5]. MRI plays an important role in supporting the diagnosis and demonstrating the involved site, even in cytology-negative cases [68]. The relationship between the MRI ndings and prognosis has, however, not yet been reported. The indications of treatment for LM from a solid tumor are still controversial, as few prospective randomized trials of potential therapeutic strategies have been conducted. The results of previous studies are limited by the small sizes of the study samples and the focus on only one type of tumor [915]. Jayson reported that in breast cancer with LM, patients with a poor performance status (PS) should be treated symptomatically, while those with a good PS should receive more aggressive treatment [12]. On the other hand, Orland reported that intrathecal (IT) chemotherapy failed to yield any objective response or relief of the clinical symptoms [15]. Some studies have reported the PS, age, protein and/or lactate dehydrogenase (LDH) level in the CSF, and the sites of the metastasis as prognostic factors [9, 1214]. At our center, we diagnose LM based on the signs and symptoms of the patients and the ndings on CSF examination and/or imaging studies of the brain or spine. There is a tendency towards administering IT chemotherapy with or without radiation therapy (RT) to LM patients with a good PS, no major neurological decits and a chemosensitive primary disease, such as breast cancer. On the other hand, patients with a poor PS and bulky CNS disease causing serious neurological decits are considered for supportive care with or without RT to symptomatic sites. Otherwise, the modalities for the diagnosis and treatment interventions depend on the attending physicians, and no consensus or guideline exists yet for the diagnosis/treatment of LM. In the present study, we conducted a retrospective evaluation of our experience with 85 patients with cytologically proven LM to analyze the prognostic factors and most suitable potential treatment strategies for LM.

patients was extracted from electronic and paper medical records, and the imaging ndings were reviewed. An experienced cytopathologist (K.T.) diagnosed LM by the identication of malignant cells in the CSF. Imaging studies The images reviewed included CT scans (in three patients, all with contrast enhancement) and MR images (in 77 patients, all with contrast enhancement). The CT had been performed with one of two models of the equipment in all patients (Aquilion multislice CT scanner or X-Vigor, Toshiba Medical Systems, Tokyo, Japan) after injection of contrast (a total of 100 ml) at the rate of 1.0 ml/s. The scanning parameters were: axial single, 4- or 16-slice mode, section thickness 4.0 or 5.0 mm, 1.0 s/rotation, 120 kVp, 300 mA. The images were reconstructed using a standard algorithm without edge enhancement. MR imaging of the brain and spine had been performed using one of two models of 1.5-T systems (General Electric Medical Systems, Milwaukee, WI, or Toshiba Medical Systems, Tokyo, Japan). Using the spin-echo or fast spinecho technique, T1-weighted images (460600/1227 ms (TR/TE)) were obtained in the transverse plane, and T2-weighted images (3,5009,800/80112 ms (TR/TEeff); 812 echo train) were then obtained in the transverse and sagittal planes using the head or body coil. The images were obtained under the following imaging conditions: eld of view, 3240 cm; image matrix, 128 9 128256; slice thickness, 610 mm; intersection gap, 1.22.5 mm. Gadopentetate dimeglumine was then administered intravenously and T1-weighted images were obtained in the transverse and sagittal planes with fat suppression. Contrast-enhanced images were also obtained under the same imaging conditions as above. Image interpretation Two board-certied radiologists (M.M. and U.T.) reviewed the CT and MR images, and the ndings were reported based on consensus. The radiologic features assessed included the lesion location, tumor size, the lesion contours and margins, presence/absence of supercial linear sulcal, cisternal or dural enhancement, presence/absence of hydrocephalus, the signal characteristics on the T1and T2-weighted images, and the lesion homogeneity (homogeneous or heterogeneous). Tumor location was determined mainly in terms of whether the lesions were leptomeningeal or subpial metastases. The signal characteristics were described as isointense or hyperintense relative to the signal intensity of the normal spinal cord. Neurological examinations were performed at the time of the diagnosis.

Patients and methods Patients Between June 1997 and July 2005, 85 patients with solid tumors were diagnosed as having LM at the National Cancer Center Hospital, Tokyo. Information on these

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Treatment Treatment comprised intrathecal (IT) chemotherapy once weekly, mainly with methotrexate 1015 mg/body plus prednisolone, 20 mg, plus, in rare cases, AraC. Wholebrain radiotherapy (WBRT), at a total radiation dose of 30 Gy administered in 10 fractions, was administered for patients with severe symptoms arising from cranial nerve involvement caused by bulky disease. Patients with symptoms of intracranial hypertension were treated with steroids, glycerol and antiepileptic drugs, as palliative care. In addition, implantation of an intraventricular Ommaya reservoir was undertaken in some patients. Evaluation and statistical analysis Response criteria were dened as reported previously, with minor alterations [16]. Complete response (CR) was dened as clinical improvement, negative CSF cytology, and normalization of the CSF biochemistry. Partial response (PR) was dened as improved or stable clinical status, substantial ([50%) improvement in the CSF biochemistry and reduction of malignant cell counts (CSF cytology was not considered). Stable disease (SD) was dened as a stable clinical status and stable or marginally improved CSF biochemistry (CSF cytology was not considered). Progressive disease (PD) was diagnosed when none of the above criteria for response were met. Survival was calculated from the time of diagnosis of the LM until death or the last follow-up. Survival curves were estimated using the Kaplan-Meier method. Differences in survivals were tested using the logrank test. Cox proportional hazard models were used for the multivariate analysis to identify the variables inuencing the overall survival after the diagnosis of LM. The clinical variables were chosen by considering possible factors based on previous studies and our own experience [1113, 16, 17]. In the analyses for prognostic factors at the time of diagnosis, we performed univariate and multivariate analyses for these factors as follows: age at the time of diagnosis of the LM (\60 years vs. C60 years), gender (male versus female), primary disease (breast cancer versus other), rst relapse site (LM versus non-LM), interval from diagnosis of the primary to diagnosis of the LM (B1 year vs.[1 year), past history of WBRT (yes versus no), PS (01 vs. 24), meningeal enhancement on MRI or CT (yes versus no), brain metastasis on MRI or CT (yes versus no), cell count in the CSF (B100/3 vs.[100/3), and protein level in the CSF (B50 mg/dl vs.\50 mg/dl). We performed univariate analysis (logrank test) for factors of clinical interest related to the treatment of LM or brain metastasis: IT chemotherapy (yes versus no), response to IT

chemotherapy (yes versus no), WBRT (yes versus no), and implantation of an Ommaya reservoir (yes versus no). Data analysis was performed using the SPSS 12.0 J software (SPSS Inc., Chicago, IL), and two-sided P values of \0.05 were considered to denote signicance.

Results Patient characteristics Data from a total of 85 patients were included for the analysis. The patient characteristics at the time of diagnosis of the LM are shown in Table 1. There were 36 patients with lung cancer (42%), including ve with small cell lung cancer, 33 patients with breast cancer (39%), eight patients with gastric cancer (9%), and eight with other cancers (9%). The median age at the time of diagnosis of the LM was 59 years (range, 2283 years). Brain metastases had been detected in 14 patients (16%) before the diagnosis of LM. At the time of diagnosis of LM, 70 patients (82%) had metastatic disease at sites other than the CNS, including the lung, liver, skin, bones, lymph nodes, and other sites. Twelve patients (14%) had only brain metastasis and three patients developed LM without evidence of metastatic disease in other organs. Forty-four patients (52%) had undergone an operation for the primary tumor, and 65 patients (76%) had received chemotherapy for advanced disease or relapse, with the median number of chemotherapeutic regimens received of 1 (range, 05). Twelve patients (14%) had previously received WBRT for brain metastasis. Of these, one patient had undergone metastatectomy and another had undergone metastatectomy and radiosurgery in addition to WBRT. The median time from the diagnosis of the primary tumor to the diagnosis of LM was 446 days (range, 05,152 days). Thirty-seven patients were diagnosed to have LM within a year of the diagnosis of the primary tumor, and four patients were diagnosed with LM at the same time as the diagnosis of the primary tumor. Concerning the PS at the time of diagnosis of the LM, it was 01 in 26 patients (31%) and 24 in 59 patients (69%). Symptoms at the time of diagnosis of the LM The cerebral symptoms included headache (46 patients, 54%), nausea and vomiting (41, 48%), abnormal mental state (confusion) (29, 34%), and seizures (5, 6%). Symptoms of cranial nerve involvement included dizziness (22, 26%) and diplopia (14, 16%), and those of spinal cord involvement included leg weakness (24, 28%) and back pain/paralysis (15, 18%).

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208 Table 1 Patient characteristics N (%) Total patients Gender Male Female Age at diagnosis of LM (years) Primary site Lung Breast Gastric Esophagus Melanoma Ovarian Renal Primary unknown Metastasis site LM only Brain metastasis Past history Same time as LM Metastasis other than in CNS Past treatment of the primary disease Operation Chemotherapy Radiation therapy WBRT Number of chemotherapy regimens received in the past Interval from diagnosis of primary to diagnosis of LM LM within a year of diagnosis of the primary Performance status 01 24 26 (31) 59 (69) 44 (58) 65 (76) 38 (45) 12 (14) Median 1 (range, 05) 446 days (range, 05,152) 37 (44) 3 (4) 49 (58) 14 (16) 45 (53) 70 (82) 36 (42) 33 (39) 8 (9) 2 (2) 2 (2) 2 (2) 1 (1) 1 (1) 36 (42) 49 (58) Median 59 years (range, 2283) 85

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patients who had not undergone MRI or CT as patients not showing meningeal enhancement. Treatment of LM Thirty-one (36%) patients had received IT chemotherapy, including six who had also received WBRT; these patients comprised 19 of the 33 patients with breast cancer patients (58%), ve of the eight patients with gastric cancer (63%), 4 of the 36 patients with lung cancer (11%), two of the two patients with ovarian cancer (100%), and one patient with renal cancer (100%). The median number of IT chemotherapy sessions was 5 (range, 130) and the median duration of the therapy was 26 days (range, 1694 days). Nine patients (11%) received WBRT alone after the diagnosis of LM, including ve with breast cancer and four with lung cancer. Implantation of an intraventricular Ommaya reservoir was undertaken in 17 patients (20%), including 15 with breast cancer, and two with a ventriculoperitoneal shunt placed for hydrocephalus. None of the patients had received systemic chemotherapy. Forty-ve patients had received no treatment at all. Response rate to and toxicity of intrathecal chemotherapy The total response rate to IT chemotherapy, i.e., CR plus PR, was 52% (n = 16/31, CR: 6, PR 10, (95% CI: 41.462.6%)). When classied according to the site of the primary, it was 68% (13/19) in breast cancer patients, 50% (2/4) in lung cancer patients, and 20% (1/5) in gastric cancer patients. The neurologic toxicities and complications of IT chemotherapy included nausea/vomiting (n = 9), headache (n = 4), seizures (n = 1), confusion (n = 1), and delayed leukoencephalopathy (n = 2). One patient who had undergone implantation of an Ommaya reservoir experienced particularly severe recurrent vomiting. The two patients in whom leukoencephalopathy occurred (on day 694 and day 175, respectively) had received 30 and 14 sessions of IT chemotherapy, respectively, and the total doses of MTX in these patients were 220 and 210 mg, respectively. These two patients had not received WBRT either before or after the onset of LM. Survival The overall median survival after the diagnosis of LM was 51 days (range, 3759 days). The median survival for each tumor type was as follows: lung cancer, 43 days (range, 3375 days), breast cancer, 79 days (range, 13759 days) and other cancers, 30 days (range, 4523 days). Patients with breast cancer showed better survival times than patients with lung cancer (P = 0.04), however, there was no signicant

LM leptomeningeal metastasis, CNS central nervous system, WBRT whole-brain radiotherapy

Establishing the diagnosis of LM All the patients had undergone a lumbar puncture with or without neuroradiography and had a positive CSF cytology. Increase in the CSF cell counts was observed in 71 patients (84%) ([10/3) and increase of the CSF protein level ([40 mg/dl) was observed in 70 patients (82%). Seventy-seven patients (91%) had undergone MRI and three had undergone CT. Fifty-one patients (64%) showed characteristic MRI or CT ndings of LM and 45 patients (53%) showed brain metastasis. We included the ve

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209 Table 2 Univariate analysis Risk factor All Age \60 years C60 years Sex Male Female Primary site Lung cancer Breast cancer Other cancers First relapse site LM Non-LM B1 year [1 year Past history of WBRT Yes No Performance status 01 24 Yes No 26 59 51 34 120 41 45 67 0.3 0.09 0.005 14 71 85 41 0.3 36 33 16 5 80 37 48 43 79 30 312 45 39 69 0.01 0.02 * 36 49 36 79 0.001 48 37 56 47 0.6 N 85 Median survival (days) 51 P value

difference in the survival times between patients with breast cancer and those with other cancers (P = 0.1), or those with lung cancer and other cancers (P = 0.7). Figure 1 shows the Kaplan-Meier survival curves after the diagnosis of LM in patients with PS 01 as compared with those in patients with PS 24, with the median survival times in the two groups being 120 and 41 days, respectively (P \ 0.01). The survival period among patients who were diagnosed with LM within one year of the diagnosis of the primary was poor (median, 39 days; range, 4391), while the median survival among those who developed LM more than 1 year after the diagnosis of the primary was 69 days (range, 3759 days) (P = 0.01). The presence of brain metastasis at the time of diagnosis of the LM, and the tumor cell counts and protein levels in the CSF did not affect the survival. The following factors were identied by univariate analysis as good prognostic factors; female gender, LM as the rst relapse site, a long interval of more than 1 year between the onset of the primary tumor and the diagnosis of LM, and a good PS (01) (Table 2). Furthermore, patients who had received IT chemotherapy showed better survival times than those who had not, with a median survival time of 144 days vs. 39 days in the two groups, respectively (P B 0.01). Univariate analysis revealed that response to IT chemotherapy and implantation of an Ommaya reservoir were signicantly associated with better survival (Table 3). In the multivariate analysis, Cox proportional hazard regression identied signicant interaction of the survival with a poor PS (HR: 1.72 (95% CI, 1.042.86) P = 0.04) and association of the MRI or CT ndings of meningeal dissemination (HR: 1.82 (95% CI, 1.112.98) P = 0.02) with a poor survival (Table 4). Figure 2 shows the Kaplan-Meier survival curves for the patients who showed meningeal

Interval from diagnosis of primary to the diagnosis of LM

Meningeal enhancement on MRI or CT

Brain metastasis on MRI or CT Yes 45 59 No Cell count in CSF B100/3 [100/3 Protein level in CSF B50 mg/dl [50 mg/dl 27 58 75 45 59 26 67 42 40 42

0.06

0.4

LM leptomeningeal metastasis, WBRT whole-brain radiotherapy, MRI magnetic resonance imaging, CT computed tomography, CSF cerebrospinal uid * The P values were as follows: lung cancer versus breast cancer (P = 0.04), breast cancer and other cancers except lung cancer (P = 0.1) and lung cancer versus other cancers except breast cancer (P = 0.7)

enhancement on MRI or CT as compared with those for patients who did not show meningeal enhancement. Discussion LM is one of the most serious complications occurring in solid cancer patients. In general, several malignancies are

Fig. 1 Kaplan-Meier analysis of survival. The solid line indicates patients with a performance status of 01, and the dotted line indicates patients with PS of 24. The vertical bars indicate censored cases

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210 Table 3 Inuence of treatment-related factors on the survival (logrank test) Risk factor All IT Yes No Yes No WBRT Yes No Yes No 31 54 16 69 14 71 17 68 144 39 191 41 97 42 206 41 0.00001 0.3 0.0004 0.0001 N 85 Median survival (days) 51 P value

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Response to IT chemotherapy

Implantation of Ommaya reservoir

IT intrathecal, WBRT whole-brain radiotherapy Table 4 Multivariate analysis Risk factor Performance status (01 vs. 24) Meningeal enhancement on MRI or CT Hazard ratio (95% CI) 1.72 (1.042.86) 1.82 (1.112.98) P value 0.036 0.018

CI condence interval, MRI magnetic resonance imaging, CT computed tomography

Fig. 2 Kaplan-Meier analysis of survival. The solid line indicates patients with no meningeal enhancement on MRI or CT, and the dotted line indicates patients with positive ndings. The vertical bars indicate censored cases

known to be associated with a high risk of development of LM. In the present study, consistent with previous reports, LM was noted at a high frequency in lung cancer and breast

cancer patients [1]. LM from solid tumors is often associated with an advanced stage of systemic disease and often occurs with concomitant parenchymal brain metastasis. Surgical resection of brain metastasis, especially piecemeal resection of metastatic posterior fossa lesions, was associated with a risk of development of LM [18]. The present study included 12 patients (14%) with brain metastasis, two of whom had undergone surgery for brain metastasis before the diagnosis of LM. The optimal management strategy of LM in patients with solid tumors is controversial because of lack of evidence from randomized trials comparing specic treatments with best supportive care. In this retrospective study, we identied several prognostic factors in patients with LM. Previous studies have reported that PS is one of the most important prognostic factors in cancer patients with LM [12, 14, 15, 19]. Jayson et al. reported that IT chemotherapy was benecial in LM patients with a good PS [12]. The results of retrospective studies demonstrate a tendency towards the use of IT chemotherapy for LM patients with a good PS. In fact, in this retrospective study, we found that 58% of the patients with PS 01 and 27% of patients with PS 24 had received IT chemotherapy. This may inuence the results of statistical analysis of the prognostic factors. Although this study was a retrospective study and there could have been a selection bias, we consider from our results that it might be better to select patients for IT chemotherapy according to their PS. Although no study until date had examined the radiological factors in cases with LM for analysis of the prognostic factors, the present study showed that MRI-proven LM was a poor prognostic factor. MRI of the brain and spine with a T1-weighted gadolinium-enhanced sequence is a standard and sensitive method for the diagnosis of LM. In this study, 77 patients (91%) had undergone MRI at the time of diagnosis of LM, and 51 patients (66%) showed positive signs of LM on MRI, such as supercial linear sulcal, cisternal or dural enhancement, and hydrocephalus. The sensitivity of Gd-MRI for the diagnosis of LM has been reported to be 6671% [6, 7]. In addition, 31% of the patients with LM were diagnosed on the basis of the clinical features and abnormal neurological imaging ndings alone, despite negative CSF cytology [20]. Rodesch et al. reported that Gd-MRI is important for demonstrating the presence and extent of leptomeningeal seeding [8]. In addition to poor PS, the presence of MRI-proven evidence of LM may be useful to identify patients who may not benet from IT chemotherapy. Unfortunately, we did not perform imaging studies after therapy, because the usefulness of MRI for evaluation of the effects of treatment of LM has not yet been demonstrated. The type of the primary cancer has also been recognized as a major prognostic factor. Wasserstorm reported that 61% of breast cancer patients who received focal irradiation and

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intraventricular methotrexate showed neurological improvement or stabilization, and 15% were still alive at 1 year. In contrast, only 39% and 18%, respectively, of lung carcinoma and melanoma patients improved or remained stable, with a median survival of 34 months and 1-year survival rate of 0% [5]. Other studies have reported similar results [11, 21]. Our results are comparable to these reports; the response rates to IT chemotherapy was 68% in breast cancer patients, 50% in lung cancer patients and 20% in gastric cancer patients. Furthermore, the 1-year survival rate was 0% in non-breast cancer patients, except for one patient with ovarian cancer. As the survival outcomes have not improved over the past 25 years, it is essential to develop effective therapy for the management of LM. Although a denitive diagnosis of LM is made by cytopathologic examination of the CSF, CSF biochemistry is frequently useful for the assessment of LM. Some previous reports have suggested that the cell counts and protein level in the CSF may be prognostic factors for survival [5, 16]. However, our present study results did not support this suggestion. Several factors inuence the CSF biochemistry, including the site of sampling and obstruction of the CSF ow by tumor deposits [22]. Although prolongation of the survival times in cancer patients has been obtained with the development of various anticancer agents, no effective therapy for LM has been established as yet. The aim of treatment of LM is to palliate the symptoms and improve the quality of life. Some previous studies have shown that IT chemotherapy for LM in breast cancer patients did not yield either a neurological response or survival benet [15, 23]. Other previous studies, although retrospective in nature, have shown that patients with a good PS may be suitable candidates for more aggressive treatment [11, 12]. Not all patients are necessarily suitable candidates for aggressive CNS-directed therapy; in addition, few guidelines exist to guide appropriate choice of therapy. The guidelines of the National Comprehensive Cancer Network Practice recommend that patients should be stratied into poor risk and good risk groups. The poor-risk group includes patients with a low Karnofsky PS, multiple, serious, xed neurologic decits, extensive systemic disease with few treatment options, bulky CNS disease, and neoplastic meningitis related to encephalopathy [24]. Our results revealed that an additional consideration may be the extent of disease in the CNS, especially denitive radiological ndings of LM on MRI. The ndings of the present study suggest that MRI imaging, performed in addition to lumbar puncture for the diagnosis of LM, may also be useful for prediction of the prognosis. Early diagnosis and stratication of patients with LM are important to improve the survival and quality of life of these patients. IT chemotherapy may be benecial for patients with a good PS and negative MRI ndings,

while palliative therapy alone may be a better treatment approach for the other patients.

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