J Korean Neurosurg Soc.  2021 Jul;64(4):631-643. 10.3340/jkns.2020.0300.

Cerebrospinal Fluid Profiles and Their Changes after Intraventricular Chemotherapy as Prognostic or Predictive Markers for Patients with Leptomeningeal Carcinomatosis

Affiliations
  • 1Neuro-oncology Clinic, National Cancer Center, Goyang, Korea
  • 2Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea
  • 3Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, Goyang, Korea
  • 4Biostatistics Collaboration Team, National Cancer Center, Goyang, Korea

Abstract


Objective
: Here, we evaluated whether cerebrospinal fluid (CSF) profiles and their changes after intraventricular chemotherapy for leptomeningeal carcinomatosis (LMC) could predict the treatment response or be prognostic for patient overall survival (OS) along with clinical factors.
Methods
: Paired 1) pretreatment lumbar, 2) pretreatment ventricular, and 3) posttreatment ventricular samples and their CSF profiles were collected retrospectively from 148 LMC patients who received Ommaya reservoir installation and intraventricular chemotherapy. CSF profile changes were assessed by calculating the differences between posttreatment and pretreatment samples from the same ventricular compartment. CSF cell counts were further differentiated into total and other based on clinical laboratory reports.
Results
: For the treatment response, a decreased CSF ‘total’ cell count tended to be associated with a ‘controlled’ increase in intracranial pressure (ICP) (p=0.059), but other profile changes were not associated with either the control of increased ICP or the cytology response. Among the pretreatment CSF profiles, lumbar protein level and ventricular cell count were significantly correlated with OS in univariable analysis, but they were not significant in multi-variable analysis. Among CSF profile changes, a decrease in ‘other’ cell count showed worse OS than ‘no change’ or increased groups (p=0.001). The cytological response was significant for OS, but the hazard ratio of partial remission was paradoxically higher than that of ‘no response’.
Conclusion
: A decrease in other cell count of CSF after intraventricular chemotherapy was associated with poor OS in LMC patients. We suggest that more specific CSF biomarkers of cancer cell origin are needed.

Keyword

Cerebrospinal fluid; Spinal puncture; Injections, Intraventricular; Meningeal carcinomatosis; Prognosis

Figure

  • Fig. 1. Flow diagram of patient selection. LMC : leptomeningeal carcinomatosis, CSF : cerebrospinal fluid.

  • Fig. 2. Interaction plot depicting changes in the (A) total cell count, (B) other cell count, and (C) protein level between pretreatment and posttreatment ventricular CSF samples. After the intraventricular chemotherapy, total cell count and ‘other cell count’ were decreased significantly (to mean 7.8 and 2.6 cells/mm3, respectively). In contrast to the CSF cell count, the CSF protein level was significantly increased after the treatment (to 48.2 mg/dL, p=0.014). See details in the Results section. CSF : cerebrospinal fluid.

  • Fig. 3. Kaplan-Meier plot of patient overall survival according to variables that were significant in the multivariable analysis : (A) age (<60 vs. ≥60 years), (B) rounds of intraventricular methotrexate administration (<5 vs. ≥5), (C) CSF cytology conversion, and (D) change in the CSF cell count (other). MTX : methotrexate, CSF : cerebrospinal fluid.


Reference

References

1. Ahn JH, Lee SH, Kim S, Joo J, Yoo H, Lee SH, et al. Risk for leptomeningeal seeding after resection for brain metastases: implication of tumor location with mode of resection. J Neurosurg. 116:984–993. 2012.
Article
2. An YJ, Cho HR, Kim TM, Keam B, Kim JW, Wen H, et al. An NMR metabolomics approach for the diagnosis of leptomeningeal carcinomatosis in lung adenocarcinoma cancer patients. Int J Cancer. 136:162–171. 2015.
Article
3. Balm M, Hammack J. Leptomeningeal carcinomatosis. Presenting features and prognostic factors. Arch Neurol. 53:626–632. 1996.
4. Boogerd W, Hart AA, van der Sande JJ, Engelsman E. Meningeal carcinomatosis in breast cancer. Prognostic factors and influence of treatment. Cancer. 67:1685–1695. 1991.
Article
5. Boogerd W, van den Bent MJ, Koehler PJ, Heimans JJ, van der Sande JJ, Aaronson NK, et al. The relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study. Eur J Cancer. 40:2726–2733. 2004.
Article
6. Bruna J, González L, Miró J, Velasco R, Gil M, Tortosa A, et al. Leptomeningeal carcinomatosis: prognostic implications of clinical and cerebrospinal fluid features. Cancer. 115:381–389. 2009.
7. Chamberlain MC. Radioisotope CSF flow studies in leptomeningeal metastases. J Neurooncol. 38:135–140. 1998.
8. Chamberlain MC. Leptomeningeal metastasis. Curr Opin Oncol. 22:627–635. 2010.
Article
9. Chamberlain MC, Glantz M, Groves MD, Wilson WH. Diagnostic tools for neoplastic meningitis: detecting disease, identifying patient risk, and determining benefit of treatment. Semin Oncol. 36(4 Suppl 2):S35–S45. 2009.
Article
10. Chamberlain MC, Kormanik P. Carcinoma meningitis secondary to nonsmall cell lung cancer: combined modality therapy. Arch Neurol. 55:506–512. 1998.
Article
11. Chamberlain MC, Kormanik PA, Glantz MJ. A comparison between ventricular and lumbar cerebrospinal fluid cytology in adult patients with leptomeningeal metastases. Neuro Oncol. 3:42–45. 2001.
Article
12. Clamon G, Doebbeling B. Meningeal carcinomatosis from breast cancer: spinal cord vs. brain involvement. Breast Cancer Res Treat. 9:213–217. 1987.
Article
13. de Azevedo CR, Cruz MR, Chinen LT, Peres SV, Peterlevitz MA, de Azevedo Pereira AE, et al. Meningeal carcinomatosis in breast cancer: prognostic factors and outcome. J Neurooncol. 104:565–572. 2011.
Article
14. Fizazi K, Asselain B, Vincent-Salomon A, Jouve M, Dieras V, Palangie T, et al. Meningeal carcinomatosis in patients with breast carcinoma. Clinical features, prognostic factors, and results of a high-dose intrathecal methotrexate regimen. Cancer. 77:1315–1323. 1996.
Article
15. Freilich RJ, Krol G, DeAngelis LM. Neuroimaging and cerebrospinal fluid cytology in the diagnosis of leptomeningeal metastasis. Ann Neurol. 38:51–57. 1995.
Article
16. Gauthier H, Guilhaume MN, Bidard FC, Pierga JY, Girre V, Cottu PH, et al. Survival of breast cancer patients with meningeal carcinomatosis. Ann Oncol. 21:2183–2187. 2010.
Article
17. Glantz MJ, Hall WA, Cole BF, Chozick BS, Shannon CM, Wahlberg L, et al. Diagnosis, management, and survival of patients with leptomeningeal cancer based on cerebrospinal fluid-flow status. Cancer. 75:2919–2931. 1995.
Article
18. Glass JP, Melamed M, Chernik NL, Posner JB. Malignant cells in cerebrospinal fluid (CSF): the meaning of a positive CSF cytology. Neurology. 29:1369–1375. 1979.
Article
19. Gleissner B, Chamberlain MC. Neoplastic meningitis. Lancet Neurol. 5:443–452. 2006.
Article
20. Grossman SA, Krabak MJ. Leptomeningeal carcinomatosis. Cancer Treat Rev. 25:103–119. 1999.
Article
21. Groves MD, Glantz MJ, Chamberlain MC, Baumgartner KE, Conrad CA, Hsu S, et al. A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies. Neuro Oncol. 10:208–215. 2008.
Article
22. Gwak HS, Joo J, Kim S, Yoo H, Shin SH, Han JY, et al. Analysis of treatment outcomes of intraventricular chemotherapy in 105 patients for leptomeningeal carcinomatosis from non-small-cell lung cancer. J Thorac Oncol. 8:599–605. 2013.
Article
23. Gwak HS, Joo J, Shin SH, Yoo H, Han JY, Kim HT, et al. Ventriculolumbar perfusion chemotherapy with methotrexate for treating leptomeningeal carcinomatosis: a phase II study. Oncologist. 19:1044–1045. 2014.
Article
24. Harstad L, Hess KR, Groves MD. Prognostic factors and outcomes in patients with leptomeningeal melanomatosis. Neuro Oncol. 10:1010–1018. 2008.
Article
25. Herrlinger U, Förschler H, Küker W, Meyermann R, Bamberg M, Dichgans J, et al. Leptomeningeal metastasis: survival and prognostic factors in 155 patients. J Neurol Sci. 223:167–178. 2004.
Article
26. Hitchins RN, Bell DR, Woods RL, Levi JA. A prospective randomized trial of single-agent versus combination chemotherapy in meningeal carcinomatosis. J Clin Oncol. 5:1655–1662. 1987.
Article
27. Hyun JW, Shin HS, Kim SH, Kong SY, Yoo H, Gwak HS, et al. CYFRA 21-1 levels in cerebrospinal fluid as a putative therapeutic monitoring biomarker for patients with leptomeningeal carcinomatosis: a pilot study. Cancer Biomark. 28:81–89. 2020.
Article
28. Jayson GC, Howell A. Carcinomatous meningitis in solid tumours. Ann Oncol. 7:773–786. 1996.
Article
29. Lee JS, Melisko ME, Magbanua MJ, Kablanian AT, Scott JH, Rugo HS, et al. Detection of cerebrospinal fluid tumor cells and its clinical relevance in leptomeningeal metastasis of breast cancer. Breast Cancer Res Treat. 154:339–349. 2015.
Article
30. Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, et al. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol. 16:e270–e278. 2015.
Article
31. Morris PG, Reiner AS, Szenberg OR, Clarke JL, Panageas KS, Perez HR, et al. Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy. J Thorac Oncol. 7:382–385. 2012.
Article
32. Nakagawa H, Kubo S, Murasawa A, Nakajima S, Nakajima Y, Izumoto S, et al. Measurements of CSF biochemical tumor markers in patients with meningeal carcinomatosis and brain tumors. J Neurooncol. 12:111–120. 1992.
Article
33. Shim Y, Gwak HS, Kim S, Joo J, Shin SH, Yoo H. Retrospective analysis of cerebrospinal fluid profiles in 228 patients with leptomeningeal carcinomatosis : differences according to the sampling site, symptoms, and systemic factors. J Korean Neurosurg Soc. 59:570–576. 2016.
Article
34. Singh SK, Agris JM, Leeds NE, Ginsberg LE. Intracranial leptomeningeal metastases: comparison of depiction at FLAIR and contrast-enhanced MR imaging. Radiology. 217:50–53. 2000.
Article
35. Singh SK, Leeds NE, Ginsberg LE. MR imaging of leptomeningeal metastases: comparison of three sequences. AJNR Am J Neuroradiol. 23:817–821. 2002.
36. Taillibert S, Laigle-Donadey F, Chodkiewicz C, Sanson M, Hoang-Xuan K, Delattre JY. Leptomeningeal metastases from solid malignancy: a review. J Neurooncol. 75:85–99. 2005.
Article
37. Teplyuk NM, Mollenhauer B, Gabriely G, Giese A, Kim E, Smolsky M, et al. MicroRNAs in cerebrospinal fluid identify glioblastoma and metastatic brain cancers and reflect disease activity. Neuro Oncol. 14:689–700. 2012.
Article
38. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 92:205–216. 2000.
39. Tu Q, Wu X, Le Rhun E, Blonski M, Wittwer B, Taillandier L, et al. CellSearch technology applied to the detection and quantification of tumor cells in CSF of patients with lung cancer leptomeningeal metastasis. Lung Cancer. 90:352–357. 2015.
Article
40. Twijnstra A, van Zanten AP, Hart AA, Ongerboer de Visser BW. Serial lumbar and ventricle cerebrospinal fluid lactate dehydrogenase activities in patients with leptomeningeal metastases from solid and haematological tumours. J Neurol Neurosurg Psychiatry. 50:313–320. 1987.
Article
41. Waki F, Ando M, Takashima A, Yonemori K, Nokihara H, Miyake M, et al. Prognostic factors and clinical outcomes in patients with leptomeningeal metastasis from solid tumors. J Neurooncol. 93:205–212. 2009.
Article
42. Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer. 49:759–772. 1982.
Article
43. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 28:1963–1972. 2010.
Article
44. Yap HY, Yap BS, Rasmussen S, Levens ME, Hortobagyi GN, Blumenschein GR. Treatment for meningeal carcinomatosis in breast cancer. Cancer. 50:219–222. 1982.
Article
45. Yousem DM, Patrone PM, Grossman RI. Leptomeningeal metastases: MR evaluation. J Comput Assist Tomogr. 14:255–261. 1990.
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