鞘内注射治疗实体瘤脑膜转移的临床研究进展

doi:10.19401/j.cnki.1007-3639.2024.07.009

摘要/Abstract

摘要：

脑膜转移（leptomeningeal metastasis，LM）是实体瘤患者的严重晚期并发症，常见于肺癌、乳腺癌及黑色素瘤患者中。近年来，由于诊断技术的进步，LM的诊出率逐渐上升。LM治疗的主要目标是维持患者的神经功能，改善生活质量，提高总生存率并延长无进展生存期。鞘内注射治疗是LM的主要治疗方法之一，能够直接将药物递送至蛛网膜下隙。传统的鞘内注射化疗药物包括甲氨蝶呤、阿糖胞苷及塞替哌等。随着新药研究的开展，多种化疗药物、靶向药物及免疫检查点抑制剂等也被尝试用于鞘内注射治疗。此外，不同的鞘内给药方式也给患者带来新希望。本文将对鞘内注射治疗LM的临床研究进展进行综述。

关键词: 脑膜转移, 鞘内注射, 化疗, 靶向治疗, 免疫治疗

Abstract:

Leptomeningeal metastasis (LM) is a serious late complication in patients with solid tumors, which is common in patients with lung cancer, breast cancer and melanoma. In recent years, due to the progress of diagnosis, the diagnosis rate of LM has gradually increased. The main goal of the therapy is to maintain neurological function, improve the quality of life and the overall survival rate, and prolong the progression-free survival time of patients. Intrathecal therapy is one of the main treatments for LM, which can deliver drugs directly to the subarachnoid space. The traditional intrathecal drugs are methotrexate, cytarabine and thiotepa. With the development of new research, a variety of chemotherapeutic drugs, targeted drugs and immune checkpoint inhibitors have also been used in intrathecal therapy. In addition, different ways of intrathecal administration also bring new hope to patients. This article reviewed the clinical research progress of intrathecal therapy in the treatment of LM.

Key words: Leptomeningeal metastasis, Intrathecal therapy, Chemotherapy, Targeted therapy, Immunotherapy

中图分类号:

R730.5

黄思捷, 康勋, 李文斌. 鞘内注射治疗实体瘤脑膜转移的临床研究进展[J]. 中国癌症杂志, 2024, 34(7): 695-701.

HUANG Sijie, KANG Xun, LI Wenbin. Clinical research progress of intrathecal therapy in the treatment of leptomeningeal metastasis[J]. China Oncology, 2024, 34(7): 695-701.

图/表 1

表1

鞘内注射药物比较"

Drug	Mechanism	Primary tumor	Dose	Course of treatment	Adverse events
MTX^[15-16]	Inhibit dihydrofolate reductase	Solid tumor	10-15 mg	Induction: twice weekly (for 4 weeks); Consolidation: once weekly (for 4 weeks); Maintenance: once a month	Myelosuppression, EHA, white matter lesions
Cytarabine^[15,22]	Inhibition of cellular DNA polymerization and synthesis	Solid tumor	25-100 mg	Induction: twice weekly (for 4 weeks); Consolidation: once weekly (for 4 weeks); Maintenance: once a month	Chemical meningitis, myelosuppression
Liposomal cytarabine^[15,22]	Inhibition of cellular DNA polymerization and synthesis		50 mg	Induction: once 2 weeks (for 8 weeks); Consolidation: every 4 weeks (for 24 weeks)
Thiotepa^{[15,23 -24]}	Prevent the synthesis of DNA, RNA and protein by cross-linking guanine base with DNA	Solid tumor	10 mg	Induction: twice weekly (for 4 weeks); Consolidation: once weekly (for 4 weeks); Maintenance: once a month	Myelosuppression
Pemetrexed^[26⇓-28]	Disrupt the normal metabolic process of folic acid dependence in cells	NSCLC	10-50 mg	Induction: twice weekly (for 2 weeks); Consolidation: once weekly (for 4 weeks); Maintenance: once a month	Myelosuppression, gastrointestinal reaction, chemical meningitis
Etoposide^[29⇓-31]	Hinder the repair of damaged DNA by interfering with DNA topoisomerase Ⅱ	Solid tumor	0.5 mg	Induction: daily (for 5 d), every other week (for 8 weeks); Consolidation: daily (for 5 d), every other week (for 4 weeks); Maintenance: daily (for 5 d), once a month	Chemical meningitis, chronic fatigue
GemCitabine^[33-34]	Inhibition of DNA polymerase and nucleotide reductase activity	Solid tumor	5-10 mg	Induction: twice weekly (for 6 weeks); Consolidation: once weekly (for 6 weeks); Maintenance: twice monthly for 4 months, then monthly thereafter	Neurotoxicity
Topotecan^[35-36]	Hinder the re-linking of broken DNA single-strand	Solid tumor	0.4 mg	Induction: twice weekly (for 6 weeks); Consolidation: once weekly (for 6 weeks); Maintenance: twice monthly for 4 months, then monthly thereafter	Chemical meningitis
Trastuzumab^[39]	HER2 receptor inhibitor	Breast cancer	80 mg	Induction: twice weekly (for 4 weeks); Consolidation: once weekly (for 4 weeks); Maintenance： 1-2 time every 2 weeks	Chemical meningitis, hydrocephalus
IL-2^[43]	Stimulate the production of interferon-γ and activate T cells	Melanoma	1.2 mU	Induction: daily for a week, then 2-3 time weekly for 3 weeks thereafter; Maintenance: 1-3 time monthly	Fever, cerebral edema

表1

参考文献 45

[1]	GANI C, MÜLLER A C, ECKERT F, et al. Outcome after whole brain radiotherapy alone in intracranial leptomeningeal carcinomatosis from solid tumors[J]. Al, 2012, 188(2): 148-153.
[2]	RHUN E L, 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.
[3]	HOU L, HAN W X, JIN J, et al. Clinical efficacy and safety of different doses of intrathecal methotrexate in the treatment of leptomeningeal carcinomatosis: a prospective and single-arm study[J]. Jpn J Clin Oncol, 2021, 51(12): 1715-1722.
[4]	HERRLINGER U, FÖRSCHLER H, KÜKER W, et al. Leptomeningeal metastasis: survival and prognostic factors in 155 patients[J]. J Neurol Sci, 2004, 223(2): 167-178. doi: 10.1016/j.jns.2004.05.008 pmid: 15337619
[5]	MONTES DE OCA DELGADO M, CACHO DÍAZ B, SANTOS ZAMBRANO J, et al. The comparative treatment of intraventricular chemotherapy by ommaya reservoir vs. lumbar puncture in patients with leptomeningeal carcinomatosis[J]. Front Oncol, 2018, 8: 509. doi: 10.3389/fonc.2018.00509 pmid: 30524956
[6]	RHUN E L, WELLER M, VAN DEN BENT M, et al. Leptomeningeal metastasis from solid tumours: EANO-ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up[J]. ESMO Open, 2023, 8(5): 101624.
[7]	HORBINSKI C, NABORS L B, PORTNOW J, et al. NCCN guidelines^® insights: central nervous system cancers, version 2.2022[J]. J Natl Compr Canc Netw, 2023, 21(1): 12-20.
[8]	NAYAK L, FLEISHER M, GONZALEZ-ESPINOZA R, et al. Rare cell capture technology for the diagnosis of leptomeningeal metastasis in solid tumors[J]. Neurology, 2013, 80(17): 1598-1605. doi: 10.1212/WNL.0b013e31828f183f pmid: 23553479
[9]	SUBIRÁ D, SIMÓ M, ILLÁN J, et al. Diagnostic and prognostic significance of flow cytometry immunophenotyping in patients with leptomeningeal carcinomatosis[J]. Clin Exp Metastasis, 2015, 32(4): 383-391.
[10]	PALMISCIANO P, WATANABE G, CONCHING A, et al. Intrathecal therapy for the management of leptomeningeal metastatic disease: a scoping review of the current literature and ongoing clinical trials[J]. J Neurooncol, 2022, 160(1): 79-100.
[11]	LI H Y, ZHENG S N, LIN Y J, et al. Safety, pharmacokinetic and clinical activity of intrathecal chemotherapy with pemetrexed via the ommaya reservoir for leptomeningeal metastases from lung adenocarcinoma: a prospective phase Ⅰ study[J]. Clin Lung Cancer, 2023, 24(2): e94-e104.
[12]	NAKAGAWA H, FUJITA T, KUBO S, et al. Ventriculolumbar perfusion chemotherapy with methotrexate and cytosine Arabinoside for meningeal carcinomatosis: a pilot study in 13 patients[J]. Surg Neurol, 1996, 45(3): 256-264. pmid: 8638223
[13]	GWAK H S, LIM H S, SHIN S H, et al. Ventriculolumbar perfusion chemotherapy for the treatment of leptomeningeal carcinomatosis: a phase Ⅰ study with pharmacokinetic data[J]. Am J Clin Oncol, 2013, 36(5): 491-499.
[14]	GWAK H S, JOO J, SHIN S H, et al. Ventriculolumbar perfusion chemotherapy with methotrexate for treating leptomeningeal carcinomatosis: a phase Ⅱ study[J]. Oncologist, 2014, 19(10): 1044-1045.
[15]	BEAUCHESNE P. Intrathecal chemotherapy for treatment of leptomeningeal dissemination of metastatic tumours[J]. Lancet Oncol, 2010, 11(9): 871-879. doi: 10.1016/S1470-2045(10)70034-6 pmid: 20598636
[16]	吴熙, 李峻岭, 肖建平, 等. 甲氨蝶呤鞘内注射化疗对肺癌脑膜转移的疗效分析[J]. 癌症进展, 2019, 17(8): 914-917.
	WU X, LI J L, XIAO J P, et al. Analysis of the efficacy of intrathecal methotrexate for leptomeningeal metastases from lung cancer[J]. Oncol Prog, 2019, 17(8): 914-917.
[17]	HITCHINS R N, BELL D R, WOODS R L, et al. A prospective randomized trial of single-agent versus combination chemotherapy in meningeal carcinomatosis[J]. J Clin Oncol, 1987, 5(10): 1655-1662. doi: 10.1200/JCO.1987.5.10.1655 pmid: 3309199
[18]	WANG N, BERTALAN M S, BRASTIANOS P K. Leptomeningeal metastasis from systemic cancer: review and update on management[J]. Cancer, 2018, 124(1): 21-35. doi: 10.1002/cncr.30911 pmid: 29165794
[19]	FOWLER M J, COTTER J D, KNIGHT B E, et al. Intrathecal drug delivery in the era of nanomedicine[J]. Adv Drug Deliv Rev, 2020, 165/166: 77-95.
[20]	RHUN E L, TAILLIBERT S, ZAIRI F, et al. A retrospective case series of 103 consecutive patients with leptomeningeal metastasis and breast cancer[J]. J Neurooncol, 2013, 113(1): 83-92.
[21]	RHUN E L, WALLET J, MAILLIEZ A, et al. Intrathecal liposomal cytarabine plus systemic therapy versus systemic chemotherapy alone for newly diagnosed leptomeningeal metastasis from breast cancer[J]. Neuro Oncol, 2020, 22(4): 524-538.
[22]	GAVIANI P, CORSINI E, SALMAGGI A, et al. Liposomal cytarabine in neoplastic meningitis from primary brain tumors: a single institutional experience[J]. Neurol Sci, 2013, 34(12): 2151-2157. doi: 10.1007/s10072-013-1358-0 pmid: 23525755
[23]	RHUN E L, TAILLIBERT S, DEVOS P, et al. Salvage intracerebrospinal fluid thiotepa in breast cancer-related leptomeningeal metastases: a retrospective case series[J]. Anticancer Drugs, 2013, 24(10): 1093-1097. doi: 10.1097/CAD.0000000000000010 pmid: 23962903
[24]	CHO K M, KIM Y J, KIM S H, et al. Salvage treatment with intracerebrospinal fluid thiotepa in patients with leptomeningeal metastasis after failure of methotrexate-based treatment[J]. Anticancer Res, 2015, 35(10): 5631-5638.
[25]	SUN J M, NAM M H, CHUNG J Y, et al. Safety and pharmacokinetics of intrathecal administration of pemetrexed in rats[J]. Cancer Chemother Pharmacol, 2011, 68(2): 531-538.
[26]	FAN C J, ZHAO Q Y, LI L, et al. Efficacy and safety of intrathecal pemetrexed combined with dexamethasone for treating tyrosine kinase inhibitor-failed leptomeningeal metastases from EGFR-mutant NSCLC-a prospective, open-label, single-arm phase 1/2 clinical trial (unique identifier: ChiCTR1800016615)[J]. J Thorac Oncol, 2021, 16(8): 1359-1368.
[27]	GENG D, GUO Q Q, HUANG S Y, et al. A retrospective study of intrathecal pemetrexed combined with systemic therapy for leptomeningeal metastasis of lung cancer[J]. Technol Cancer Res Treat, 2022, 21: 15330338221078429.
[28]	谢雨文, 徐婷, 程弯弯, 等. 经Ommaya囊侧脑室注射培美曲塞治疗非小细胞肺癌伴软脑膜转移的疗效及其影响因素[J]. 中华肿瘤防治杂志, 2023, 30(17): 1034-1039.
	XIE Y W, XU T, CHENG W W, et al. Efficacy and influencing factors on intrathecal chemotherapy with pemetrexed via the Ommaya reservoir for leptomeningeal carcinomatosis from non-small cell lung cancer[J]. Chin J Cancer Prev Treat, 2023, 30(17): 1034-1039.
[29]	FLEISCHHACK G, REIF S, HASAN C, et al. Feasibility of intraventricular administration of etoposide in patients with metastatic brain tumours[J]. Br J Cancer, 2001, 84(11): 1453-1459.
[30]	CHAMBERLAIN M C, TSAO-WEI D D, GROSHEN S. Phase Ⅱ trial of intracerebrospinal fluid etoposide in the treatment of neoplastic meningitis[J]. Cancer, 2006, 106(9): 2021-2027.
[31]	PARK M J. Prolonged response of meningeal carcinomatosis from non-small cell lung cancer to salvage intrathecal etoposide subsequent to failure of first-line methotrexate: a case report and literature review[J]. Am J Case Rep, 2015, 16: 224-227.
[32]	EGORIN M J, ZUHOWSKI E G, MCCULLY C M, et al. Pharmacokinetics of intrathecal gemcitabine in nonhuman primates[J]. Clin Cancer Res, 2002, 8(7): 2437-2442. pmid: 12114450
[33]	CHEN Y M, CHEN M C, TSAI C M, et al. Intrathecal gemcitabine chemotherapy for non-small cell lung cancer patients with meningeal carcinomatosis: a case report[J]. Lung Cancer, 2003, 40(1): 99-101.
[34]	BERNARDI R J, BOMGAARS L, FOX E, et al. Phase Ⅰ clinical trial of intrathecal gemcitabine in patients with neoplastic meningitis[J]. Cancer Chemother Pharmacol, 2008, 62(2): 355-361.
[35]	GROVES M D, GLANTZ M J, CHAMBERLAIN M C, et al. A multicenter phase Ⅱ trial of intrathecal topotecan in patients with meningeal malignancies[J]. Neuro Oncol, 2008, 10(2): 208-215.
[36]	SALGIA S, FLEMING G F, LUKAS R V. Leptomeningeal carcinomatosis from breast cancer treated with intrathecal topotecan with concomitant intravenous eribulin[J]. J Clin Neurosci, 2014, 21(7): 1250-1251. doi: 10.1016/j.jocn.2013.09.018 pmid: 24412296
[37]	STEMMLER H J, SCHMITT M, WILLEMS A, et al. Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier[J]. Anticancer Drugs, 2007, 18(1): 23-28.
[38]	BONNEAU C, PAINTAUD G, TRÉDAN O, et al. Phase I feasibility study for intrathecal administration of trastuzumab in patients with HER2 positive breast carcinomatous meningitis[J]. Eur J Cancer, 2018, 95: 75-84. doi: S0959-8049(18)30714-7 pmid: 29635147
[39]	KUMTHEKAR P U, AVRAM M J, LASSMAN A B, et al. A phase Ⅰ/Ⅱ study of intrathecal trastuzumab in human epidermal growth factor receptor 2-positive (HER2-positive) cancer with leptomeningeal metastases: safety, efficacy, and cerebrospinal fluid pharmacokinetics[J]. Neuro Oncol, 2023, 25(3): 557-565.
[40]	ZAGOURI F, SERGENTANIS T N, 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[J]. Breast Cancer Res Treat, 2013, 139(1): 13-22.
[41]	FIGURA N B, RIZK V T, MOHAMMADI H, et al. Clinical outcomes of breast leptomeningeal disease treated with intrathecal trastuzumab, intrathecal chemotherapy, or whole brain radiation therapy[J]. Breast Cancer Res Treat, 2019, 175(3): 781-788.
[42]	GLITZA I C, SMALLEY K S M, BRASTIANOS P K, et al. Leptomeningeal disease in melanoma patients: an update to treatment, challenges, and future directions[J]. Pigment Cell Melanoma Res, 2020, 33(4): 527-541.
[43]	GLITZA I C, ROHLFS M, GUHA-THAKURTA N, et al. Retrospective review of metastatic melanoma patients with leptomeningeal disease treated with intrathecal interleukin-2[J]. ESMO Open, 2018, 3(1): e000283.
[44]	FIGURA N B, RIZK V T, ARMAGHANI A J, et al. Breast leptomeningeal disease: a review of current practices and updates on management[J]. Breast Cancer Res Treat, 2019, 177(2): 277-294.
[45]	GLITZA OLIVA I C, FERGUSON S D, BASSETT R JR, et al. Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results[J]. Nat Med, 2023, 29(4): 898-905. doi: 10.1038/s41591-022-02170-x pmid: 36997799