Intrathecal chemotherapy in the complex treatment of children with parameningeal rhabdomyosarcoma with intracranial spread and/or leptomeningeal metastasis
https://doi.org/10.21294/1814-4861-2026-25-1-28-45
Abstract
Introduction. Parameningeal rhabdomyosarcoma with intracranial spread is a highly aggressive pediatric malignancy with a high risk of leptomeningeal metastasis. Historically, central nervous system (CNS) involvement was considered an incurable condition with a survival rate of no more than 10–20 %. The bloodbrain barrier is the primary barrier to the penetration of most drugs and the creation of effective concentrations. Therefore, the search for effective and non-toxic methods for controlling leptomeningeal metastases is one of the most pressing challenges in pediatric oncology. Intrathecal chemotherapy (ITCT) delivers cancer drugs directly into the cerebrospinal fuid, bypassing the BBB. It enables high concentrations of medication to directly target cells, reducing systemic toxicity.
The purpose of the study was to evaluate the effcacy and safety of intrathecal chemotherapy in a multidisciplinary approach to the treatment of children with parameningeal rhabdomyosarcoma with intracranial spread and/or leptomeningeal metastasis, and to improve survival rates in this cohort of children.
Material and Methods. The study included 21 patients with a histologically verifed diagnosis of parameningeal rhabdomyosarcoma with intracranial spread and/or leptomeningeal metastasis, who received treatment at the L.A. Durnov Research Institute of Pediatric Oncology and Hematology of the Russian Academy of Medical Sciences from 2021 to 2024. The study was approved by the local ethics committee.
Results. With a 34.3-month median follow-up, the overall 2-year survival rate was 65 %. This indicates the effectiveness of early tumor control by overcoming the blood-brain barrier. The overall 2-year survival rate was signifcantly higher in both the prophylactic and therapeutic frst-line intrathecal chemotherapy groups than in the relapse group (80 % vs 20 %, p<0.05) and signifcantly exceeded the median survival time of 4–6 months reported by other authors [1]. The toxicity profle of ITCT was favorable, with no cases of severe neurotoxicity.
Conclusion. Intensive intrathecal chemotherapy in the combination treatment of children with parameningeal rhabdomyosarcoma with intracranial extension and/or leptomeningeal metastasis is an effective and safe method for treating and preventing CNS tumor cell infltration. This therapy can signifcantly improve survival of patients with extremely unfavorable prognosis.
About the Authors
A. D. Rodina
N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
Russian Federation
Russian Federation
Anastasia D. Rodina, MD, Researcher, Pediatric Oncologist, Oncology Department No. 3 (Chemotherapy for Head and Neck Tumors), Research Institute of Pediatric Oncology and Hematology named after Academician L.A. Durnov
24, Kashirskoe highway, Moscow, 115478
V. G. Polyakov
N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia;
Russian Medical Academy of Continuing Professional Education, Ministry of Health of Russia;
Pirogov Russian National Research Medical University, Ministry of Health of Russia;
N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
Russian Federation
Russian Federation
Vladimir G. Polyakov, MD, DSc, Professor, Academician of the Russian Academy of Sciences, Advisor to the Director, Research Institute of Pediatric Oncology and Hematology named after Academician L.A. Durnov; Head of the Department of Pediatric Oncology named after Academician L.A. Durnov; Professor, Department of ENT Diseases of the Pediatric Faculty; Professor, Department of Postgraduate Education for Physicians, Department of Professional Education
24, Kashirskoe highway, Moscow, 115478;
2/1, building 1, Barrikadnaya St., Moscow, 125993;
1, Ostrovityanova St., Moscow, 117997;
24, Kashirskoe highway, Moscow, 115478
A. S. Krylov
N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
Russian Federation
Russian Federation
Alexander S. Krylov, MD, PhD, Head of the Radionuclide Diagnostics Department No. 1, Radionuclide Diagnostics and Therapy Department, Research Institute of Clinical and Experimental Radiology
24, Kashirskoe highway, Moscow, 115478
A. L. Kashanina
N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
Russian Federation
Russian Federation
Alexandra L. Kashanina, MD, Radiologist, Department of X-ray Diagnostic, Research Institute of Pediatric Oncology and Hematology named after Academician L.A. Durnov
24, Kashirskoe highway, Moscow, 115478
T. V. Gorbunova
N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia;
Pirogov Russian National Research Medical University, Ministry of Health of Russia;
N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
Russian Federation
Russian Federation
Tatyana V. Gorbunova, MD, PhD, Chief Physician, Research Institute of Pediatric Oncology and Hematology; Senior Researcher, Oncology Department No. 3 (Chemotherapy for Head and Neck Tumors), Research Institute of Pediatric Oncology and Hematology named after Academician L.A. Durnov; Assistant, Department of ENT Diseases, Faculty of Pediatrics; Department of Postgraduate Education for Physicians, Department of Professional Education
24, Kashirskoe highway, Moscow, 115478;
1, Ostrovityanova St., Moscow, 117997;
24, Kashirskoe highway, Moscow, 115478
S. R. Varfolomeeva
N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia;
Russian Medical Academy of Continuing Professional Education, Ministry of Health of Russia;
N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
Russian Federation
Russian Federation
Svetlana R. Varfolomeeva, MD, DSc, Professor, Director, Research Institute of Pediatric Oncology and Hematology named after Academician L.A. Durnov; Professor, Department of Pediatric Oncology named after Academician L.A. Durnov; Professor, Department of Postgraduate Education for Physicians, Department of Professional Education
24, Kashirskoe highway, Moscow, 115478;
2/1, building 1, Barrikadnaya St., Moscow, 125993;
24, Kashirskoe highway, Moscow, 115478
References
1. Pentheroudakis G., Pavlidis N. Management of leptomeningeal malignancy. Expert Opin Pharmacother. 2005; 6(7): 1115–25. doi: 10.1517/14656566.6.7.1115.
2. Thakkar J.P., Kumthekar P., Dixit K.S., Stupp R., Lukas R.V. Leptomeningeal metastasis from solid tumors. J Neurol Sci. 2020; 411: 116706. doi: 10.1016/j.jns.2020.116706.
3. Rodina A.D., Polyakov V.G., Gorbunova T.V., Krylov A.S., Kashanina A.L., Merkulov O.A., Varfolomeeva S.R. Risk of leptomeningeal metastasis in children with parameningeal rhabdomyosarcoma with intracranial extension. Russian Journal of Pediatric Hematology аnd Oncology. 2022; 9(4): 27–36. (in Russian). doi: 10.21682/2311-1267-2022-9-4-27-36. EDN: BVAVXX.
4. Postovsky S., Ash S., Ramu I.N., Yaniv I., Zaizov R., Futerman B., Elhasid R., Ben Barak A., Hali A., Ben Arush M.W. Central nervous system involvement in children with sarcoma. Oncology. 2003; 65(2): 118–24. doi: 10.1159/000072336.
5. Wang N., Bertalan M.S., Brastianos P.K. Leptomeningeal metastasis from systemic cancer: Review and update on management. Cancer. 2018; 124(1): 21–35. doi: 10.1002/cncr.30911.
6. Pruitt A.A. CNS infections in patients with cancer. Continuum (Minneap Minn). 2012; 18(2): 384–405. doi: 10.1212/01. CON.0000413665.80915.c4.
7. Raney R.B., Meza J., Anderson J.R., Fryer C.J., Donaldson S.S., Breneman J.C., Fitzgerald T.J., Gehan E.A., Michalski J.M., Ortega J.A., Qualman S.J., Sandler E., Wharam M.D., Wiener E.S., Maurer H.M., Crist W.M. Treatment of children and adolescents with localized parameningeal sarcoma: experience of the Intergroup Rhabdomyosarcoma Study Group protocols IRS-II through-IV, 1978–1997. Med Pediatr Oncol. 2002; 38(1): 22–32. doi: 10.1002/mpo.1259.
8. Raney R.B.Jr., Tefft M., Newton W.A., Ragab A.H., Lawrence W.Jr., Gehan E.A., Maurer H.M. Improved prognosis with intensive treatment of children with cranial soft tissue sarcomas arising in nonorbital parameningeal sites. A report from the Intergroup Rhabdomyosarcoma Study. Cancer. 1987; 59(1): 147–55. doi: 10.1002/1097-0142(19870101)59:1<147::aidcncr2820590129>3.0.co;2-8.
9. Pellerino A., Bertero L., Rudà R., Soffetti R. Neoplastic meningitis in solid tumors: from diagnosis to personalized treatments. Ther Adv Neurol Disord. 2018; 11: 1756286418759618. doi: 10.1177/1756286418759618.
10. Wang X., Yao C., Quan L., Zhou J. A review on intrathecal administration of medications for leptomeningeal metastases in solid tumors. Front Pharmacol. 2025; 16: 1472945. doi: 10.3389/fphar.2025.1472945.
11. Pan Z., Yang G., He H., Zhao G., Yuan T., Li Y., Shi W., Gao P., Dong L., Li Y. Concurrent radiotherapy and intrathecal methotrexate for treating leptomeningeal metastasis from solid tumors with adverse prognostic factors: a prospective and single-arm study. Int J Cancer. 2016; 139(8): 1864–72. doi: 10.1002/ijc.30214.
12. Fulton D.S., Levin V.A., Gutin P.H., Edwards M.S., Seager M.L., Stewart J., Wilson C.B. Intrathecal cytosine arabinoside for the treatment of meningeal metastases from malignant brain tumors and systemic tumors. Cancer Chemother Pharmacol. 1982; 8(3): 285–91. doi: 10.1007/BF00254052.
13. Cho K.M., Kim Y.J., Kim S.H., Kim J.W., Lee J.O., Han J.H., Lee K.W., Kim J.H., Kim C.Y., Bang S.M., Kim I.A., Kim J.S., Lee J.S. Salvage treatment with intracerebrospinal fuid thiotepa in patients with leptomeningeal metastasis after failure of methotrexate-based treatment. Anticancer Res. 2015; 35(10): 5631–38.
14. Le Rhun E., Wallet J., Mailliez A., Le Deley M.C., Rodrigues I., Boulanger T., Lorgis V., Barrière J., Robin Y.M., Weller M., Bonneterre J. Intrathecal liposomal cytarabine plus systemic therapy versus systemic chemotherapy alone for newly diagnosed leptomeningeal metastasis from breast cancer. Neuro Oncol. 2020; 22(4): 524–38. doi: 10.1093/neuonc/noz201.
15. Blaney S.M., Heideman R., Berg S., Adamson P., Gillespie A., Geyer J.R., Packer R., Matthay K., Jaeckle K., Cole D., Kuttesch N., Poplack D.G., Balis F.M. Phase I clinical trial of intrathecal topotecan in patients with neoplastic meningitis. J Clin Oncol. 2003; 21(1): 143–47. doi: 10.1200/JCO.2003.04.053.
16. Pajtler K.W., Tippelt S., Siegler N., Reichling S., Zimmermann M., Mikasch R., Bode U., Gnekow A., Pietsch T., Benesch M., Rutkowski S., Fleischhack G. Intraventricular etoposide safety and toxicity profle in children and young adults with refractory or recurrent malignant brain tumors. J Neurooncol. 2016; 128(3): 463–71. doi: 10.1007/s11060-016-2133-x.
17. Kwon B.S., Cho Y.H., Yoon S.K., Lee D.H., Kim S.W., Kwon D.H., Lee J.C., Choi C.M. Impact of clinicopathologic features on leptomeningeal metastasis from lung adenocarcinoma and treatment efcacy with epidermal growth factor receptor tyrosine kinase inhibitor. Thorac Cancer. 2020; 11(2): 436–42. doi: 10.1111/1759-7714.13296.
18. Kumthekar P.U., Avram M.J., Lassman A.B., Lin N.U., Lee E., Grimm S.A., Schwartz M., Sonabend A.M., Stupp R., Chen F., D’Andrea K., Jin L., Zhang H., Zhang J., Dittmar M., Getch T., McCarthy K., Gradishar W., Khan S.A., Mulcahy M., Borson S., Savone M., Cristofanilli M. A phase I/II study of intrathecal trastuzumab in human epidermal growth factor receptor 2-positive (HER2-positive) cancer with leptomeningeal metastases: safety, efcacy, and cerebrospinal fuid pharmacokinetics. Neuro Oncol. 2023; 25(3): 557–65. doi: 10.1093/neuonc/noac195.
19. Glitza Oliva I.C., Ferguson S.D., Bassett R. Jr., Foster A.P., John I., Hennegan T.D., Rohlfs M., Richard J., Iqbal M., Dett T., Lacey C., Jackson N., Rodgers T., Phillips S., Duncan S., Haydu L., Lin R., Amaria R.N., Wong M.K., Diab A., Yee C., Patel S.P., McQuade J.L., Fischer G.M., McCutcheon I.E., O’Brien B.J., Tummala S., Debnam M., Guha-Thakurta N., Wargo J.A., Carapeto F.C.L., Hudgens C.W., Huse J.T., Tetzlaff M.T., Burton E.M., Tawbi H.A., Davies M.A. Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results. Nat Med. 2023; 29(4): 898–905. doi: 10.1038/s41591-022-02170-x.
20. Holdaway M., Ablyazova F., Huda S., D’Amico R.S., Wong T., Shani D., Ben-Shalom N., Boockvar J.A. First in-human intrathecal delivery of bevacizumab for leptomeningeal spread from recurrent glioblastoma: rationale for a dose escalation trial. J Neurooncol. 2023; 164(1): 231–37. doi: 10.1007/s11060-023-04412-5.
21. Ju Y., Wang J., Sun S., Jiao S. Nimotuzumab treatment and outcome analysis in patients with leptomeningeal metastasis from nonsmall cell lung cancer. J Cancer Res Ther. 2016; 12(s): 181–85. doi: 10.4103/0973-1482.200596.
22. Carausu M., Carton M., Darlix A., Pasquier D., Leheurteur M., Debled M., Mouret-Reynier M.A., Goncalves A., Dalenc F., Verret B., Campone M., Augereau P., Ferrero J.M., Levy C., Fumet J.D., LefeuvrePlesse C., Petit T., Uwer L., Jouannaud C., Larrouquere L., Chevrot M., Courtinard C., Cabel L. Breast cancer patients treated with intrathecal therapy for leptomeningeal metastases in a large real-life database. ESMO Open. 2021; 6(3): 100150. doi: 10.1016/j.esmoop.2021.100150.
23. Kazakova L.L., Zhukov N.V. Disseminirovannoe porazhenie mozgovyh obolochek pri rabdomiosarkome parameningeal’noj lokalizacii. Pediatric hematology/oncology and immunopathology. 2019; 18(4): 90–98. (in Russian). doi: 10.24287/1726-1708-2019-18-4-90-98. EDN: ARAVCS.
24. Rodina A.D., Gorbunova T.V., Merkulov O.A., Ivanova N.V., Polyakov V.G. Clinical observations of changes in the nasal cavity microbiome in children with malignant tumors of parameningeal localization during chemoradiotherapy. Pediatrics. Journal named after G.N. Speransky. 2021; 100(1): 144–53. (in Russian). doi: 10.24110/0031-403X-2021-100-1-144-153. EDN: CWAAZK.
Supplementary files
|
|
1. Fig. 1. Results of brain tomoscintigrams with 99mTc-pertechnetate of patient P. diagnosed with alveolar parameningeal rhabdomyosarcoma with intracranial extension, leptomeningeal metastases in the brain. Stage IV. T2вN0M1. IRS IVa. Tomograms in axial (a) and frontal (b) projections before starting treatment show focally increased distribution of radiopharmaceuticals in the projection of the primary tumor parameningeally on the left (common nasal meatus, maxillary sinus, left orbit and middle cranial fossa) – red arrows. There are signs of damage to the meninges by contact in the left middle cranial fossa. CT scans after 9 cycles of chemotherapy, 6 cycles of intrathecal chemotherapy, and craniospinal irradiation (total dose: 36 Gy) to the area of the primary tumor (total dose: 50.4 Gy) according to the CWS 2014 protocol (group of metastatic sarcomas) show a slightly increased distribution of the radiopharmaceuticals in the projection of the primary tumor parameningeally on the left in the axial (c) and frontal (d) projections. Compared with the initial study, a marked positive trend is observed. Note: created by the authors | |
| Subject | ||
| Type | Other | |
View
(243KB)
|
Indexing metadata ▾ | |
|
|
2. Fig. 2. Frequency of tumor metastases to different anatomical sites at the time of diagnosis. Note: created by the authors | |
| Subject | ||
| Type | Other | |
View
(161KB)
|
Indexing metadata ▾ | |
|
|
3. Fig. 3. Patient R. diagnosed with alveolar parameningeal rhabdomyosarcoma with intracranial spread, lymph node metastases on the right of the neck. Stage -III. T2bN1M0. IRS IIIa. Before starting treatment – tomograms in axial (a) (b) and sagittal (c) projections; after completing treatment – tomograms in axial (d) (e) and sagittal (f) projections. Note: created by the authors | |
| Subject | ||
| Type | Other | |
View
(449KB)
|
Indexing metadata ▾ | |
|
|
4. Fig. 4. Patient P. diagnosed with embryonal parameningeal rhabdomyosarcoma with intracranial spread, lymph node metastases, leptomeningeal metastases of the spine. Stage IV. T2вN1M1. IRS IVa. Before starting treatment – tomograms in frontal (a), axial (b) and sagittal (c) projections; after completing treatment – tomograms in frontal (d), axial (e) and sagittal (f) projections. Note: created by the authors | |
| Subject | ||
| Type | Other | |
View
(426KB)
|
Indexing metadata ▾ | |
|
|
5. Fig. 5. Patient T. diagnosed with embryonal parameningeal rhabdomyosarcoma with intracranial spread. Stage – Т2bN0M0 IRSIII. Relapse I. Before starting anti-relapse treatment – tomograms in axial (a), frontal (b) projections; after treatment –tomograms in frontal (d) and sagittal (e) projections, cytological picture (c) (f) of cerebrospinal fluid. Note: created by the authors | |
| Subject | ||
| Type | Other | |
View
(427KB)
|
Indexing metadata ▾ | |
|
|
6. Fig. 6. Overall 2-year survival rates in patients with parameningeal rhabdomyosarcoma with intracranial spread and/or leptomeningeal metastasis depending on the status of the central nervous system. Note: created by the authors | |
| Subject | ||
| Type | Other | |
View
(255KB)
|
Indexing metadata ▾ | |
|
|
7. Fig. 7. Overall 2-year survival rates in patients with parameningeal rhabdomyosarcoma with intracranial extension and/or leptomeningeal metastasis. Note: created by the authors | |
| Subject | ||
| Type | Other | |
View
(209KB)
|
Indexing metadata ▾ | |
Review
For citations:
Rodina A.D., Polyakov V.G., Krylov A.S., Kashanina A.L., Gorbunova T.V., Varfolomeeva S.R. Intrathecal chemotherapy in the complex treatment of children with parameningeal rhabdomyosarcoma with intracranial spread and/or leptomeningeal metastasis. Siberian journal of oncology. 2026;25(1):28-45. (In Russ.) https://doi.org/10.21294/1814-4861-2026-25-1-28-45
Views:
271
JATS XML
Email this article 
