Median OS at 19.3 weeks in our current analysis compares favorably to that in previously published analyses in patients with LC: for LC from non-small-cell lung cancer, two relatively large analyses, including 125 and 149 patients, have been published by Morris et al6 and Lee et al,13 respectively. Median OS estimates were 12.9 and 15.0 weeks in those cohorts that received heterogeneous treatment regimens, including WBRT and RT to the involved regions and differing combinations with ITC and/or systemic chemotherapy. A small subgroup of patients, for whom the administration of EGFR-TKIs was indicated, showed a favorable median OS of up to 14 months.6 Similar analyses for breast cancer patients have been recently reviewed by Kak et al.56 In several mid-sized cohorts of between 60 and 100 patients, median OS estimates of 10–16 weeks could be achieved.7,57–59Therapeutic modalities comprised mostly ITC with methotrexate and second-line thiotepa, although Le Rhun et al described a reasonably sized cohort of 103 patients treated with liposomal cytarabine as a first-line therapy, achieving a median OS of 16.3 weeks.12 Overall results for breast cancer are thus comparable to those previously discussed for lung cancer.

A recent publication by Brower et al assessed the outcome of 124 patients with LC from heterogeneous solid tumors, including unfavorable histologies such as small-cell lung-cancer.14 In this unselected patient collective, median OS at 9.2 weeks was slightly inferior to the works mentioned before.14 In our analysis, no statistical significance could be found for the impact of primary histology and in view of the recently discussed works, this is possibly due to the limited number of patients.

In the published literature, as well as our current analysis, survival seems to be highly dependent on patient selection. This is demonstrated most clearly in clinical performance manifesting itself as a central and consistent prognostic factor throughout the great majority of publications available on the subject of LC.13–16,60–62 Our analysis is in agreement with that body of literature in confirming the prognostic value of the KPI. For a more comprehensive assessment of the patients’ neurologic function, the NFS scale has proven a useful tool with independent prognostic significance. Its key value lies in providing functional quantification to a reasonable extent and summarizing the neurologic symptoms for better comparability. Several recent publications have confirmed the role and applicability of the NFS for the clinical assessment of baseline status and treatment outcome in patients with CNS metastases.30,63 Age at LC diagnosis was identified as another prognostic factor in our analysis and in this, consistency can be found with the widely established recursive partitioning analysis (RPA) and graded prognostic assessment (GPA) indices for the prognostic evaluation of CNS metastases.64–66 The statistically significant identification of these factors despite the limited number of patients in the current analysis emphasizes their decisiveness and suggests that it is, in fact, a very select subgroup of patients that may benefit from CSI as a palliative measure. Furthermore, this implies that rigorous patient selection, based on thorough clinical assessment, and interdisciplinary decision making are necessary to choose the best treatment approach after LC diagnosis.

Continue Reading

Limitations of the current study include its retrospective nature and the small number of patients, as well as a possible selection bias, owing to the fact that CSI for the palliative treatment of LC is not an approach generally recommended by the current guidelines. Consequently, it was decided upon on an individual basis for each patient in this group and for differing reasons, including mostly young age, good performance and clinically estimated benefit. Furthermore, the very small number of patients receiving ITC in our cohort permits no assessment of the effect ITC may have had on survival. Analogously, in the era of targeted therapies with proven efficacy inside the CNS,67,68 comparative data with this form of treatment would be warranted.


To the best of our knowledge, this is the larger of only two cohorts in the current literature, for which the specific effect of CSI in the palliative treatment of LC has been evaluated. We could demonstrate treatment feasibility and potential therapeutic value in carefully selected patients, alleviating preexisting symptoms or delaying neurologic deterioration. OS after CSI was comparable to rates described in the current literature for patients with LC. To achieve a reasonable toxicity profile, the use of modern irradiation techniques, such as helical IMRT, is warranted. Patient selection should be done on an individual basis, taking into account prognostic factors such as age, clinical performance, neurologic function and the availability of systemic treatment options.

Ethics approval

Ethics approval for the study and a waiver of written informed consent, as applicable to the retrospective in-house research, were granted by the Heidelberg University ethics committee on April 12, 2018 (#S-172/2018). Patient confidentiality was maintained by anonymizing patient data to remove any identifying information.

Rami A El Shafie,1,2 Karina Böhm,1,2 Dorothea Weber,3 Kristin Lang,1,2 Fabian Schlaich,1,2 Sebastian Adeberg,1,2 Angela Paul,1,2,4 Matthias F Haefner,1,2 Sonja Katayama,1,2 Florian Sterzing,1,2,5 Juliane Hörner-Rieber,1,2 Sarah Löw,6 Klaus Herfarth,1,2,4 Jürgen Debus,1,2,4,7 Stefan Rieken,1,2,4 Denise Bernhardt1,2

1Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg 69120, Germany; 2National Center for Radiation Oncology (NCRO), Heidelberg Institute for Radiation Oncology (HIRO), Heidelberg 69120, Germany; 3Institute of Medical Biometry and Informatics (IMBI), Heidelberg University Hospital, Heidelberg 69120, Germany; 4Heavy Ion Therapy Center (HIT), Heidelberg University Hospital, Heidelberg 69120, Germany; 5Department of Radiation Oncology, Klinikum Kempten, Kempten 87439, Germany; 6Department of Neurology, University Hospital of Heidelberg, Heidelberg 69120, Germany; 7German Cancer Research Center (DKFZ), Heidelberg 69120, Germany


This work received indirect financial support by Heidelberg University young investigator grants to RAES, DB and JHR.


The authors report no conflicts of interest in this work.


1. Kesari S, Batchelor TT. Leptomeningeal metastases. Neurol Clin. 2003;21(1):25–66.

2. Kaplan JG, Desouza TG, Farkash A, et al. Leptomeningeal metastases: comparison of clinical features and laboratory data of solid tumors, lymphomas and leukemias. J Neurooncol. 1990;9(3):225–229.

3. Le Rhun E, Weller M, Brandsma D, et al. EANO–ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours. Ann Oncol. 2017;28(Suppl 4):iv84–iv99.

4. Clarke JL, Perez HR, Jacks LM, Panageas KS, Deangelis LM. Leptomeningeal metastases in the MRI era. Neurology. 2010;74(18):1449–1454.

5. Umemura S, Tsubouchi K, Yoshioka H, et al. Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama Lung Cancer Study Group. Lung Cancer. 2012;77(1):134–139.

6. Morris PG, Reiner AS, Szenberg OR, et al. Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy. J Thorac Oncol. 2012;7(2):382–385.

7. Lara-Medina F, Crismatt A, Villarreal-Garza C, et al. Clinical features and prognostic factors in patients with carcinomatous meningitis secondary to breast cancer. Breast J. 2012;18(3):233–241.

8. Nugent JL, Bunn PA, Matthews MJ, et al. CNS metastases in small cell bronchogenic carcinoma: increasing frequency and changing pattern with lengthening survival. Cancer. 1979;44(5):1885–1893.

9. Yap HY, Yap BS, Tashima CK, Distefano A, Blumenschein GR. Meningeal carcinomatosis in breast cancer. Cancer. 1978;42(1):283–286.

10. Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer. 1982;49(4):759–772.

11. Grossman SA, Krabak MJ. Leptomeningeal carcinomatosis. Cancer Treat Rev. 1999;25(2):103–119.

12. Le Rhun E, Taillibert S, Zairi F, et al. A retrospective case series of 103 consecutive patients with leptomeningeal metastasis and breast cancer. J Neurooncol. 2013;113(1):83–92.

13. Lee SJ, Lee JI, Nam DH, et al. Leptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors. J Thorac Oncol. 2013;8(2):185–191.

14. Brower JV, Saha S, Rosenberg SA, Hullett CR, Ian Robins H. Management of leptomeningeal metastases: prognostic factors and associated outcomes. J Clin Neurosci. 2016;27:130–137.

15. Ozdemir Y, Yildirim BA, Topkan E. Whole brain radiotherapy in management of non-small-cell lung carcinoma associated leptomeningeal carcinomatosis: evaluation of prognostic factors. J Neurooncol. 2016;129(2):329–335.

16. Gwak HS, Joo J, Kim S, et al. Analysis of treatment outcomes of intraventricular chemotherapy in 105 patients for leptomeningeal carcinomatosis from non-small-cell lung cancer. J Thorac Oncol. 2013;8(5):599–605.

17. Grossman SA, Finkelstein DM, Ruckdeschel JC, Trump DL, Moynihan T, Ettinger DS. Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. Eastern Cooperative Oncology Group. J Clin Oncol. 1993;11(3):561–569.

18. Hitchins RN, Bell DR, Woods RL, Levi JA. A prospective randomized trial of single-agent versus combination chemotherapy in meningeal carcinomatosis. J Clin Oncol. 1987;5(10):1655–1662.

19. 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(11):3394–3402.

20. Kwon J, Chie EK, Kim K, et al. Impact of multimodality approach for patients with leptomeningeal metastases from solid tumors. J Korean Med Sci. 2014;29(8):1094.

21. Bernier V. Technical aspects in cerebrospinal irradiation. Pediatr Blood Cancer. 2004;42(5):447–451.

22. Schiopu SR, Habl G, Häfner M, et al. Craniospinal irradiation using helical tomotherapy for central nervous system tumors. J Radiat Res. 2017;58(2):238–246.

23. Tsang DS, Murphy ES, Ezell SE, Lucas JT, Tinkle C, Merchant TE. Craniospinal irradiation for treatment of metastatic pediatric low-grade glioma. J Neurooncol. 2017;134(2):317–324.

24. Hermann B, Hültenschmidt B, Sautter-Bihl ML. Radiotherapy of the neuroaxis for palliative treatment of leptomeningeal carcinomatosis. Strahlenther Onkol. 2001;177(4):195–199.

25. Kumar N, Miriyala R, Thakur P, et al. Impact of acute hematological toxicity on treatment interruptions during cranio-spinal irradiation in medulloblastoma: a tertiary care institute experience. J Neurooncol. 2017;134(2):309–315.

26. Zong-Wen S, Shuang-Yan Y, Feng-Lei D, et al. Radiotherapy for adult medulloblastoma: evaluation of helical tomotherapy, volumetric intensity modulated arc therapy, and three-dimensional conformal radiotherapy and the results of helical tomotherapy therapy. Biomed Res Int. 2018;2018:1–8.

27. Wang K, Meng H, Chen J, Zhang W, Feng Y. Plan quality and robustness in field junction region for craniospinal irradiation with VMAT. Phys Med. 2018;48:21–26.

28. Seravalli E, Bosman M, Lassen-Ramshad Y, et al. Dosimetric comparison of five different techniques for craniospinal irradiation across 15 European centers: analysis on behalf of the SIOP-E-BTG (radiotherapy working group). Acta Oncol. 2018;57(9):1240–1249.

29. Farace P, Bizzocchi N, Righetto R, et al. Supine craniospinal irradiation in pediatric patients by proton pencil beam scanning. Radiother Oncol. 2017;123(1):112–118.

30. Bezjak A, Adam J, Barton R, et al. Symptom response after palliative radiotherapy for patients with brain metastases. Eur J Cancer. 2002;38(4):487–496.

31. National Institutes of Health NCI. Common Terminology Criteria for Adverse Events v4.0 (CTCAE). Available from: Published 2010. Accessed December 19, 2016.

32. Rief H, Bischof M, Bruckner T, et al. The stability of osseous metastases of the spine in lung cancer – a retrospective analysis of 338 cases. Radiat Oncol. 2013;8(1):200.

33. Scharp M, Hauswald H, Bischof M, Debus J, Combs SE. Re-irradiation in the treatment of patients with cerebral metastases of solid tumors: retrospective analysis. Radiat Oncol. 2014;9(1):4.

34. Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials. 1996;17(4):343–346.

35. Bower M, Waxman J. Central nervous system cancers. In: Lecture Notes Oncology. PA, USA: National Comprehensive Cancer Network; V2 2018:96–97.

36. Sandberg DI, Bilsky MH, Souweidane MM, Bzdil J, Gutin PH. Ommaya reservoirs for the treatment of leptomeningeal metastases. Neurosurgery. 2000;47(1):49–54.

37. Groves MD, Glantz MJ, Chamberlain MC, et al. A multicenter Phase II trial of intrathecal topotecan in patients with meningeal malignancies. Neuro Oncol. 2008;10(2):208–215.

38. Chamberlain MC, Tsao-Wei DD, Groshen S. Phase II trial of intracerebrospinal fluid etoposide in the treatment of neoplastic meningitis. Cancer. 2006;106(9):2021–2027.

39. Zagouri F, Sergentanis TN, Bartsch R, et al. Intrathecal administration of trastuzumab for the treatment of meningeal carcinomatosis in HER2-positive metastatic breast cancer: a systematic review and pooled analysis. Breast Cancer Res Treat. 2013;139(1):13–22.

40. Bauman G, Yartsev S, Coad T, Fisher B, Kron T. Helical tomotherapy for craniospinal radiation. Br J Radiol. 2005;78(930):548–552.

41. Sterzing F, Schubert K, Sroka-Perez G, Kalz J, Debus J, Herfarth K. Helical tomotherapy. Strahlenther Onkol. 2008;184(1):8–14.

42. Sharma DS, Gupta T, Jalali R, Master Z, Phurailatpam RD, Sarin R. High-precision radiotherapy for craniospinal irradiation: evaluation of three-dimensional conformal radiotherapy, intensity-modulated radiation therapy and helical TomoTherapy. Br J Radiol. 2009;82(984):1000–1009.

43. Hong JY, Kim GW, Kim CU, et al. Supine linac treatment versus tomotherapy in craniospinal irradiation: planning comparison and dosimetric evaluation. Radiat Prot Dosimetry. 2011;146(1–3):364–366.

44. Kunos CA, Dobbins DC, Kulasekere R, Latimer B, Kinsella TJ. Comparison of helical tomotherapy versus conventional radiation to deliver craniospinal radiation. Technol Cancer Res Treat. 2008;7(3):227–233.

45. Sugie C, Shibamoto Y, Ayakawa S, et al. Craniospinal irradiation using helical tomotherapy: evaluation of acute toxicity and dose distribution. Technol Cancer Res Treat. 2011;10(2):187–195.

46. Peñagarícano J, Moros E, Corry P, Saylors R, Ratanatharathorn V. Pediatric craniospinal axis irradiation with helical tomotherapy: patient outcome and lack of acute pulmonary toxicity. Int J Radiat Oncol Biol Phys. 2009;75(4):1155–1161.

47. Petersson K, Gebre-Medhin M, Ceberg C, et al. Haematological toxicity in adult patients receiving craniospinal irradiation – indication of a dose-bath effect. Radiother Oncol. 2014;111(1):47–51.

48. Myers PA, Mavroidis P, Papanikolaou N, Stathakis S. Comparing conformal, arc radiotherapy and helical tomotherapy in craniospinal irradiation planning. J Appl Clin Med Phys. 2014;15(5):12–28.

49. Mascarin M, Giugliano FM, Coassin E, et al. Helical tomotherapy in children and adolescents: dosimetric comparisons, opportunities and issues. Cancers. 2011;3(4):3972–3990.

50. Hansen AT, Lukacova S, Lassen-Ramshad Y, Petersen JB. Comparison of a new noncoplanar intensity-modulated radiation therapy technique for craniospinal irradiation with 3 coplanar techniques. Med Dosim. 2015;40(4):296–303.

51. Sarkar B, Munshi A, Manikandan A, et al. A low gradient junction technique of craniospinal irradiation using volumetric-modulated arc therapy and its advantages over the conventional therapy. Cancer Radiother. 2018;22(1):62–72.

52. Macewan I, Chou B, Moretz J, Loredo L, Bush D, Slater JD. Effects of vertebral-body-sparing proton craniospinal irradiation on the spine of young pediatric patients with medulloblastoma. Adv Radiat Oncol. 2017;2(2):220–227.

53. Giantsoudi D, Seco J, Eaton BR, et al. Evaluating intensity modulated proton therapy relative to passive scattering proton therapy for increased vertebral column sparing in craniospinal irradiation in growing pediatric patients. Int J Radiat Oncol Biol Phys. 2017;98(1):37–46.

54. Yock TI, Yeap BY, Ebb DH, et al. Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a Phase 2 single-arm study. Lancet Oncol. 2016;17(3):287–298.

55. Farace P, Vinante L, Ravanelli D, Bizzocchi N, Vennarini S. Planning field-junction in proton cranio-spinal irradiation – the ancillary-beam technique. Acta Oncol. 2015;54(7):1075–1078.

56. Kak M, Nanda R, Ramsdale EE, Lukas RV. Treatment of leptomeningeal carcinomatosis: current challenges and future opportunities. J Clin Neurosci. 2015;22(4):632–637.

57. Gauthier H, Guilhaume MN, Bidard FC, et al. Survival of breast cancer patients with meningeal carcinomatosis. Ann Oncol. 2010;21(11):2183–2187.

58. Rudnicka H, Niwińska A, Murawska M. Breast cancer leptomeningeal metastasis – the role of multimodality treatment. J Neurooncol. 2007;84(1):57–62.

59. Boogerd W, Hart AA, van der Sande JJ, Engelsman E. Meningeal carcinomatosis in breast cancer. Prognostic factors and influence of treatment. Cancer. 1991;67(6):1685–1695.

60. Morris Z, Whiteley WN, Longstreth WT, et al. Incidental findings on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ. 2009;339:b3016.

62. de Azevedo CR, Cruz MR, Chinen LT, et al. Meningeal carcinomatosis in breast cancer: prognostic factors and outcome. J Neurooncol. 2011;104(2):565–572.

61. Gani C, Müller AC, Eckert F, et al. Outcome after whole brain radiotherapy alone in intracranial leptomeningeal carcinomatosis from solid tumors. Strahlenther Onkol. 2012;188(2):148–153.

63. Bernhardt D, Bozorgmehr F, Adeberg S, et al. Outcome in patients with small cell lung cancer re-irradiated for brain metastases after prior prophylactic cranial irradiation. Lung Cancer. 2016;101:76–81.

64. Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997;37(4):745–751.

65. Sperduto PW, Berkey B, Gaspar LE, Mehta M, Curran W. A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys. 2008;70(2):510–514.

66. Sperduto PW, Kased N, Roberge D, et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol. 2012;30(4):419–425.

67. Grommes C, Oxnard GR, Kris MG, et al. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol. 2011;13(12):1364–1369.

68. Goss G, Tsai CM, Shepherd FA, et al. CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two Phase II trials. Ann Oncol. 2018;29(3):687–693.

Source: Cancer Management and Research

Originally published January 17, 2019.