The relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study

doi:10.1016/j.ejca.2004.08.012

European Journal of Cancer

Volume 40, Issue 18, December 2004, Pages 2726-2733

https://doi.org/10.1016/j.ejca.2004.08.012 Get rights and content

Abstract

To assess the benefit of intraventricular chemotherapy, patients with leptomeningeal metastasis (LM) from breast cancer were randomised to treatment including intraventricular (IT) chemotherapy (n = 17) or to non-intrathecal (non-IT) treatment (n = 18). Appropriate systemic therapy and involved field radiation therapy (RT) were given in both arms. Intention-to-treat analysis showed neurological improvement or stabilisation in 59% of the IT and in 67% of the non-IT group, with median time to progression of 23 weeks (IT) and 24 weeks (non-IT). Median survival of IT patients was 18.3 weeks and 30.3 weeks for non-IT patients (difference 12.9 weeks; 95% Confidence Interval (CI) −5.5 to +34.3 weeks; P = 0.32). Neurological complications of treatment occurred in 47% (IT) vs 6% (non-IT) (P = 0.0072). In conclusion, standard systemic chemotherapy with involved field RT for LM from breast cancer is feasible. Addition of intraventricular chemotherapy does not lead to survival benefit or improved neurological response, and is associated with an increased risk of neurotoxicity.

Introduction

Leptomeningeal metastasis (LM) causes serious morbidity and without specific treatment presumably leads to death within 4–6 weeks [1], [2], [3]. Standard treatment consists of intraventricular administration of Methotrexate (MTX) in combination with involved field radiotherapy (RT). Promising results of such intensive treatment with responses in more than half of the patients and a median overall survival of 6 or 7 months have been observed in patients with LM from breast cancer [2], [4]. However, lower response rates and a median survival of only 1–4 months were seen in more recent studies, with most patients dying of progressive leptomeningeal disease [5], [6], [7], [8], [9], [10], [11]. Additionally, intraventricular (IT) treatment is associated with neurotoxic side-effects [8], [12], [13].

In a previous study, we observed neurological improvement and prolonged survival in some patients with LM from breast cancer who had been treated without IT chemotherapy. Outcome appeared to be more dependent on patient- and disease-related characteristics than on the intensity of treatment [8]. Presently, the role of intensive treatment in the management of LM from breast cancer is unclear, as there are no controlled studies comparing IT therapy with non-IT treatment.

We therefore designed a multicentre study to evaluate, in a randomised design, the efficacy of IT for breast cancer patients with LM. Aims of the study were to assess neurological response, survival and cause of death, and the toxicity of treatment.

Section snippets

Patients and methods

Patients with LM from breast cancer, who met the eligibility criteria and gave their informed consent, were stratified according to prognostic factors and randomised to receive either

1.
intraventricular MTX, appropriate systemic therapy and, if necessary, RT to clinically relevant sites, or
2.
appropriate systemic therapy and, if necessary, RT to clinically relevant sites, but without intrathecal chemotherapy.

Patient characteristics (Table 1)

Between May 1991 and July 1998, 35 patients were entered into the trial, 22 patients during the first 3 years, and 13 patients during the subsequent 4 years. It appeared difficult to obtain the patient’s consent after information about randomisation between standard intensive treatment including insertion of an Ommaya reservoir with its possible complications or non-IT treatment. This became even more problematic over the years when clinical practice and other studies confirmed our previous

Discussion

Patients treated with IT chemotherapy for LM from breast cancer may have a better outcome when they also receive systemic chemotherapy [7], [8], [13]. It is possible that LM tumour deposits can be reached and treated by cytostatic drugs through their own permeable tumour blood vessels [19], [20]. Moreover, non-randomised studies show that the outcome after standard systemic chemotherapy and involved field RT is similar to that following treatment including IT chemotherapy, but without the

Conflict of interest statement

None declared.

Acknowledgements

Participating institutions and investigators include The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital Amsterdam (W. Boogerd; J.J. van der Sande; N.K. Aaronson; A.A.M. Hart), Dr. Daniël den Hoed Cancer Clinic Rotterdam (M.J. van den Bent; Ch. J. Vecht), Atrium Medical Center Heerlen (P.J. Koehler), Free University Medical Center Amsterdam (J.J. Heimans), Academic Medical Center Groningen (H. Haaxma-Reiche), Academic Medical Center Amsterdam (P.J.M. Bakker), Slotervaart Hospital

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Leptomeningeal disease (LMD) is clinically detected in 5% to 10% of patients with solid tumors and is a source of substantial morbidity and mortality. Prognosis for this entity remains poor and treatments are palliative. Radiation therapy (RT) is an essential tool in the management of LMD, and a recent randomized trial demonstrated a survival benefit for proton craniospinal irradiation (CSI) in select patients. In the setting of this recent advance, we conducted a review of the role of RT in LMD from solid tumors to evaluate the evidence basis for RT recommendations.
In November 2022, we conducted a comprehensive literature search in PubMed, as well as a review of ongoing clinical trials listed on ClinicalTrials.gov, to inform a discussion on the role of RT in solid tumor LMD. Because of the paucity of high-quality published evidence, discussion was informed more by expert consensus and opinion, including a review of societal guidelines, than evidence from clinical trials.
Only 1 prospective randomized trial has evaluated RT for LMD, demonstrating improved central nervous system progression-free survival for patients with breast and lung cancer treated with proton CSI compared with involved-field RT. Modern photon CSI techniques have improved upon historical rates of acute hematologic toxicity, but the overall benefit of this modality has not been prospectively evaluated. Multiple retrospective studies have explored the use of involved-field RT or the combination of RT with chemotherapy, but clear evidence of survival benefit is lacking.
Optimal management of LMD with RT remains reliant upon expert opinion, with proton CSI indicated in patients with good performance status and extra-central nervous system disease that is either well-controlled or for which effective treatment options are available. Photon-based CSI traditionally has been associated with increased marrow and gastrointestinal toxicities, though intensity modulated RT/volumetric-modulated arc therapy based photon CSI may have reduced the toxicity profile. Further work is needed to understand the role of radioisotopes as well as combined modality treatment with intrathecal or central nervous system penetrating systemic therapies.
Pharmacotherapy for leptomeningeal disease in breast cancer
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Clinical data supporting the best therapeutic approach in leptomeningeal disease (LMD; also known as leptomeningeal metastases or leptomeningeal carcinomatosis) are lacking. Despite the development of new agents and increasing incidence of central nervous system metastases, patients with LMD are often excluded from clinical trials in breast cancer, with very few conducted specifically in LMD. Consequently, current evidence may not provide an accurate reflection of real-world clinical practice. This review aims to provide further insight into the treatment strategies for patients with breast cancer and LMD. We explore differences between clinical and real-world studies, considering inclusion criteria, levels of evidence for LMD diagnosis, and time between diagnosis of LMD and LMD-specific treatment initiation. Patient prognosis is poor; median overall survival is limited to several months, with approximately 10 % of patients alive at 12 months. Efficacy results have been reported for various systemic and intrathecal agents in LMD to date. Systemic therapies under investigation for LMD in breast cancer include tucatinib, trastuzumab deruxtecan, and paclitaxel trevatide; trastuzumab is the main intrathecal agent currently under investigation. Recent trials investigating systemic or intrathecal therapies are typically small, single-arm studies, and most are restricted to patients with human epidermal growth factor receptor 2-positive breast cancer. Moreover, the variability among inclusion criteria and response assessment tools makes the interpretation of results difficult. Large retrospective cohorts with various inclusion criteria and treatment regimens provide some real-world data. However, there remains an urgent need for randomised clinical trials which include patients with LMD across all breast cancer subtypes.
Leptomeningeal metastasis from solid tumours: EANO–ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up <sup>☆</sup>
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The role of involved-field radiation therapy (IFRT) and intrathecal chemotherapy (IC) in leptomeningeal metastasis (LM) from solid tumors was gradually underestimated in the era of targeted therapy. This study was aimed to investigate the safety and effectiveness of concurrent IFRT and intrathecal methotrexate (MTX)/cytarabine (Ara-C) for LM, particularly for those who developed LM while receiving targeted therapy.
Enrolled patients were given induction IC first and then concurrent treatment, which consisted of IFRT (40 Gy total; 2 Gy/f) and IC (MTX 15 mg or Ara-C 50 mg, once per week). Primary endpoint was clinical response rate (RR). Secondary endpoints were safety and overall survival (OS).
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Concurrent IFRT and intrathecal MTX or Ara-C was proved to be a feasible treatment option with an acceptable safety profile for LM from a common tumor entity.
Engineering metalloporphyrin-integrated nanosystems for targeted sono-/chemo- dynamic therapy of leptomeningeal carcinomatosis through intrathecal administration
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Leptomeningeal carcinomatosis (LMC) is a severe complication of cancers that markedly shortens survival and lowers the quality of patients’ life, and it still lacks adequate therapeutic programs. Nanomedicine-mediated therapy has recently presented promising to treat malignant tumors, whereas it remains challenging to deliver nanomedicines for high-efficacy LMC treatment owing to the existence of brain-related delivery barriers. Herein, a novel and effective strategy of combined sonodynamic/chemodynamic therapy (SDT/CDT) of LMC by intrathecal injection of a tumor-targeted metalloporphyrin-integrated nanosystem (MOF@MP-RGD) is developed for the first time. Thereinto, intrathecal administration can directly transport such nanosystems into the cerebrospinal fluid (CSF) around the brain and spinal cord to overcome the brain-related barriers for improving delivery. By building of the orthotopic LMC model, the nanosystems are demonstrated to be effectively accumulated in the LMC area post intrathecal administration due to the arginine-glycine-aspartate (RGD) active targeting, and subsequently excreted out of the body by metabolism process. In vivo evaluations reveal the desirable LMC tumor inhibition and survival prolongation of the combined SDT/CDT based on such biocompatible nanosystems, that is superior to the clinically-used chemotherapeutic drug. Therefore, the combination of intrathecal delivery and nanomedicine-mediated therapy holds great potential for clinical LMC treatment.
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View all citing articles on Scopus

^☆: The study was supported by a grant from the Dutch Cancer Society (CKVO 90.12).

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The relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study☆

Abstract

Introduction

Section snippets

Patients and methods

Patient characteristics (Table 1)

Discussion

Conflict of interest statement

Acknowledgements

Cancer Treat Rev

Meningeal carcinomatosis. Clinical manifestations

Arch Neurol

Intraventricular methotrexate therapy of leptomeningeal metastases from breast carcinoma

Neurology

Diagnosis and treatment of leptomeningeal carcinomatosis from solid tumours: experience with 90 patients

Cancer

A prospective trial of single agent versus combination chemotherapy in meningeal carcinomatosis

J Clin Oncol

Randomised prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis

J Clin Oncol

Clinical outcome in aggressively treated meningeal carcinomatosis

Arch Neurol

Meningeal carcinomatosis in breast cancer: prognostic factors and influence of treatment

Cancer

Leptomeningeal metastases from solid tumours

Cancer

A randomised controlled trial comparing intrathecal sustained – release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumours

Clin Cancer Res

Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine

Br J Cancer

Complications associated with Ommaya reservoirs in patients with cancer: the Princess Margaret Hospital experience and a review of the literature

Arch Intern Med

Leptomeningeal meetastases: analysis of 31 patients with sustained off-therapy responses following combined-modality therapy

Neurology

Neuroimaging and cerebrospinal fluid cytology in the diagnosis of leptomeningeal metastasis

Ann Neurol