A phase Ⅱ trial of comprehensive treatment based on radiotherapy in leptomeningeal metastasis
Yang Siran1, Liu Qingfeng1, Xiao Jianping1, Zhang Hongmei1, Bi Nan1, Zhang Ye1, Ma Yuchao1, Wang Kai1, Chen Xuesong1, Zhao Ruizhi1, Wu Xi2, Li Junling3, Yi Junlin1, Wang Shulian1, Li Yexiong1
1Department of Radiation Oncology,2Department of General,3Department of Internal Medicine, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Abstract：Objective To evaluate the efficacy and safety of comprehensive treatment based on radiotherapy for patients with leptomeningeal metastases (LM) in this prospective study. Methods A total of 93 patients diagnosed with LM admitted to our hospital undergoing whole brain radiotherapy (WBRT) or craniospinal irradiation (CSI) with or without simultaneous boost from 2014 to 2017 were enrolled. The dynamic changes of clinical signs and symptoms, enhanced magnetic resonance imaging (MRI), cerebrospinal fluid cytology and liquid biopsy detection were recorded. The primary endpoint was overall survival (OS),the secondary endpoints were local control (LC), intracranial progress-free survival (IPFS), brain metastasis specific survival (BMSS) and toxicity. Results The major primary disease was non-small cell lung cancer. The whole cohort received WBRT with boost (40 Gy in 20 fractions (f) for WBRT and 60Gy in 20 f for boost), focal radiation to LM, WBRT and CSI (40 Gy in 20 f or 50Gy in 25 f for WBRT and 36 Gy in 20 f for CSI). For 20 patients, tumor cells were identified and intrathecal chemotherapy was performed. Sixty-three patients received target therapy. The median follow-up time was 33.8 months. The 1-year OS, LC and IPFS was 62.4%, 77.2% and 52.6%, respectively. The median survival time was 15.9 months, and the median BMSS was 42.2 months.Treatment-related grade 3–4 adverse events were rare and only 8 cases was observed to have grade 3 hematological toxicity. Conclusion Reasonable comprehensive treatment including precise radiotherapy, intrathecal chemotherapy and targeted therapy can be well tolerated and prolong the survival time of LM patients.
Yang Siran,Liu Qingfeng,Xiao Jianping et al. A phase Ⅱ trial of comprehensive treatment based on radiotherapy in leptomeningeal metastasis[J]. Chinese Journal of Radiation Oncology, 2020, 29(9): 744-750.
[1] Chamberlain M, Soffietti R, Raizer J, et al. Leptomeningeal metastasis:a response assessment in neuro-oncology critical review of endpoints and response criteria of published randomized clinical trials[J]. Neuro Oncol, 2014, 16(9):1176-1185. DOI:10.1093/neuonc/nou089. [2] 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[J]. Ann Oncol, 2017, 28(Suppl 4):iv84-iv99. DOI:10.1093/annonc/mdx221. [3] 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]. J Thorac Oncol, 2012, 7(2):382-385. DOI:10.1097/jto.0b013e3182398e4f. [4] Kuiper JL, Hendriks LE, van der Wekken AJ, et al. Treatment and survival of patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastasis:a retrospective cohort analysis[J]. Lung Cancer, 2015, 89(3):255-261. DOI:10.1016/j.lungcan.2015.05.023. [5] Kunimasa K, Mimura C, Kotani Y. Erlotinib is effective for leptomeningeal carcinomatosis due to disease flare after osimertinib treatment failure[J]. J Thorac Oncol, 2017, 12(7):e93-e94. DOI:10.1016/j.jtho.2017.02.025. [6] Gaye E, Geier M, Bore P, et al. Intra-cranial efficacy of brigatinib in an ALK-positive non-small cell lung cancer patient presenting leptomeningeal carcinomatosis[J]. Lung Cancer, 2019, 133(1):1-3. DOI:10.1016/j.lungcan.2019.04.013. [7] Soffietti R, Abacioglu U, Baumert B, et al. Diagnosis and treatment of brain metastases from solid tumors:guidelines from the European Association of Neuro-Oncology (EANO)[J]. Neuro Oncol, 2017, 19(2):162-174. DOI:10.1093/neuonc/now241. [8] Gani C, Muller AC, Eckert F, et al. Outcome after whole brain radiotherapy alone in intracranial leptomeningeal carcinomatosis from solid tumors [J]. Strahlenther Onkol, 2012, 188(2): 148-153. DOI: 10.1007/s00066-011-0025-8. [9] Gwak HS, Joo J, Shin SH, et al. Ventriculolumbar perfusion chemotherapy with methotrexate for treating leptomeningeal carcinomatosis:a phase Ⅱ study[J]. Oncologist, 2014, 19(11):1044-1045. DOI:10.1634/theoncologist.2014-0199. [10] Du C, Hong R, Shi Y, et al. Leptomeningeal metastasis from solid tumors:a single center experience in Chinese patients[J]. J Neurooncol, 2013, 115(3):285-291. DOI:10.1007/s11060-013-1228-x. [11] Lee S, Ahn HK, Park YH, et al. Leptomeningeal metastases from breast cancer: intrinsic subtypes may affect unique clinical manifestations[J]. Breast Cancer Res Treat, 2011, 129: 809-817. DOI: 10.1007/s10549-011-1682-0. [12] Wolf A, Donahue B, Silverman JS, et al. Stereotactic radiosurgery for focal leptomeningeal disease in patients with brain metastases[J]. J Neurooncol, 2017, 134(1):139-143. DOI:10.1007/s11060-017-2497-6. [13] Miyakawa A, Shibamoto Y, Takemoto S, et al. Low-dose gamma knife radiosurgery plus whole-brain radiation therapy for patients with 5 or more brain metastases with or without meningeal dissemination[J]. Int J Clin Oncol, 2019, 24(2):161-167. DOI:10.1007/s10147-018-1339-7. [14] El Shafie RA, Böhm K, Weber D, et al. Palliative radiotherapy for leptomeningeal carcinomatosis–analysis of outcome, prognostic factors, and symptom response[J]. Front Oncol, 2019, 8(7):641. DOI:10.3389/fonc.2018.00641. [15] Schiopu SR, Habl G, Haefner M, et al. Helical tomotherapy in patients with leptomeningeal metastases[J]. Cancer Manag Res, 2019, 11(3):401-409. DOI:10.2147/cmar. S185414. [16] Yang JCH, Kim SW, Kim DW, et al. Osimertinib in patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer and leptomeningeal metastases:the BLOOM study[J]. J Clin Oncol, 2020, 38(6):538-547. DOI:10.1200/JCO.19.00457. [17] Ahn MJ, Chiu CH, Cheng Y, et al. Osimertinib for patients with leptomeningeal metastases associated with EGFR T790M-positive advanced NSCLC:the AURA leptomeningeal metastases analysis[J]. J Thorac Oncol, 2020, 15(4):637-648. DOI:10.1016/j.jtho.2019.12.113. [18] Pan Z, Yang G, He H, et al. Concurrent radiotherapy and intrathecal methotrexate for treating leptomeningeal metastasis from solid tumors with adverse prognostic factors:A prospective and single-arm study[J]. Int J Cancer, 2016, 139(8):1864-1872. DOI:10.1002/ijc.30214. [19] Hendriks LEL, Bootsma G, Mourlanette J, et al. Survival of patients with non-small cell lung cancer having leptomeningeal metastases treated with immune checkpoint inhibitors[J]. Eur J Cancer, 2019, 116(7):182-189. DOI:10.1016/j.ejca.2019.05.019.
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