Published online Sep 08, 2023.
https://doi.org/10.4048/jbc.2023.26.e40
Intrathecal Catheter for Chemotherapy in Leptomeningeal Carcinomatosis From HER2-Negative Metastatic Breast Cancer
,1
Lila Autier,2
Nathalie Lebrec,1
Valérie Seegers,3
Caroline Folliard,4
Anne Patsouris,2
Mario Campone,2
and Paule Augereau2
Abstract
Purpose
Most oncological treatments for leptomeningeal metastasis (LM) do not cross the blood-brain barrier (BBB). One therapeutic option is intrathecal (IT) chemotherapy. Both the brain-implanted Omaya reservoir and lumbar puncture (LP) are classic routes for IT chemotherapy delivery. An intrathecal catheter (IC) connected to a subcutaneous port is a recently developed option for the management of chemotherapy infusions. It is essential to evaluate the efficacy and safety of chemotherapy infusion using such device.
Methods
We conducted a retrospective monocentric study within Institut de cancerologie de l’Ouest at Angers, including all patients with advanced breast cancer (aBC) with LM implanted with an IT device for IT chemotherapy between January 2013 and May 2020. The primary endpoint was overall survival (OS) and secondary endpoints included surgical feasibility, patient safety, and progression-free survival (PFS). The catheter was inserted through an LP, the tip was positioned at the right level and connected to a subcutaneous port implanted under the skin of the anterior thoracic wall. IT chemotherapy is painless and easy for qualified nurses to administer on an outpatient basis.
Results
Thirty women underwent the implantation. No failures occurred during the procedure. A total of 77% of patients reported no complications after implantation. Only three complications required surgical treatment. The median number of IT chemotherapy courses per patient was 8 (range, 2–27). The tolerance profile for iterative IT chemotherapy was manageable in ambulatory care. With a median follow-up of 76.5 months (95% confidence interval [CI], 11.6–not available), the median OS was 158 days (95% CI, 87–235), and the median PFS was 116 days (95% CI, 58–174).
Conclusion
Infusing chemotherapy using an implanted catheter is an efficient option for managing IT chemotherapy with a good tolerance profile. Patient-reported outcomes for the evaluation of IT chemotherapy toxicity are currently being developed.
INTRODUCTION
Infiltration of the leptomeninges by metastatic carcinoma is a devastating evolution of advanced cancer, the prognosis of which remains poor despite state-of-the-art treatments.
Therapeutic advances have improved systemic control and overall survival (OS) in patients with advanced breast cancer (aBC), especially hormone receptor positive/human epidermal growth factor receptor-2 negative (HER2-) and HER2 positive (HER2+) breast cancer. Patients with leptomeningeal metastasis (LM), among an increasing number of patients with aBC (5%–20%), have limited therapeutic options in a drug sanctuary, especially those with aBC HER2−, and have poor short outcomes. The median OS of untreated patients with LM is 4–6 weeks [1].
Carcinomatous meningitis is responsible for extremely debilitating and painful symptoms that affect the quality of life. Treatment optimization, avoidance of pain related to treatment, and medical monitoring are fundamental in these patients [2].
As most oncological treatments do not cross the blood-brain barrier (BBB), one therapeutic option involves intrathecal (IT) cerebrospinal fluid (CSF) chemotherapy [3] (mainly methotrexate and thiotepa or methotrexate alone, +/− hydrocortisone, DepoCyte can also be used). CSF circulation is only pulsatile, and its pace is set by heartbeat and intrathoracic respiratory-induced pressure variations [4]. IT drug diffusion is limited, and the key factors in diffusion are the infusion level, drug volume, and flow rate [5].
Both the brain-implanted Omaya reservoir [6] and lumbar puncture (LP) are classic routes used for IT chemotherapy delivery. However, these routes have side effects that must be considered before deciding which means of treatment will ensure optimal care.
For instance, intraventricular administration requires brain surgery and can provoke transient aseptic chemical meningitis with severe neurological symptoms, requiring hospitalization and specific treatment. However, repeated LPs are uncomfortable for the patient. They may be technically challenging, and more hazardous with respect to drug delivery, as part of the medication may leak into the subdural or epidural space, even resulting in subtherapeutic concentrations of the drug.
Contrastingly, an IT catheter (IC) connected to a subcutaneous port has emerged in the last decade. This procedure is less invasive than repetitive LPs, easier to manage than an intraventricular device, and widely used and recommended for the treatment of refractory pain [7].
Studies have shown that this system allows the optimal delivery of drugs into the CSF, offering both remarkable efficacy and an easy-to-use refill system, making it easier to manage both patients and medical staff. Other studies investigating the distribution of different substances delivered by ICs, such as local anesthetics, opioids, and baclofen for spasticity, have indicated similar outcomes [8, 9].
Therefore, the use of this device for the treatment of carcinomatous meningitis may be an efficient option, and at Institut de cancerologie de l’Ouest in Angers, the procedure is routinely performed to administer IT chemotherapy to treat LM.
This study aimed to evaluate the efficacy and safety of intra-CSF chemotherapy for aBC using an IC connected to a subcutaneous port. The primary endpoint was OS, and the secondary endpoints were surgical feasibility, patient safety, and progression-free survival (PFS).
METHODS
Statement of study approval
The Angers University ethics committee of Angers (No. 2022-028) validated the study protocol and waived the requirement for written informed consent due to the retrospective nature of the study.
Cohort
We conducted a retrospective monocentric cohort study within Institut de cancerologie de l’Ouest in Angers in Angers, including all patients aged > 18 years undergoing treatment for aBC with LM and implanted with an IT device for IT chemotherapy between January 2013 and May 2020.
IC procedure
The procedure was performed in the operating theater under general anesthesia. The patients were placed in the lateral decubitus position. LP was performed using an interspinous approach using a 16G Tuohy needle supplied with a catheter puncture kit.
An IC (Ascenda® catheter; Medtronic, Minneapolis, USA) was then inserted, and its progression up the CSF is monitored under live fluoroscopy. Once the tip of the catheter was located at the correct level, its position was checked laterally to verify its location in the canal. Next, a vertical cutaneous incision was made opposite the puncture down to the aponeuroses, and a pocket was formed as layers of skin were peeled away. The catheter guide was then removed and the CSF must flow through the catheter end. Finally, the catheter was anchored using the device supplied with the manufacturer’s kit.
The physician then made an incision in the anterior thoracic wall down to the muscle aponeurosis and created a pocket of the same size as the diameter of the subcutaneous port (Celsite® 19G; B. Braun®, Melsungen, Germany). The catheter was then tunneled through the subcutaneous tissue from the spinal incision to the device pocket. The subcutaneous port was placed in the pocket and sutured. Finally, at the end of the procedure, the physician administered the first chemotherapy injection using a percutaneous needle (Figure 1).
Figure 1
Surgical implantation of intrathecal catheter.
After chemotherapy, infusions were administered by a qualified nurse in a sterile manner on an outpatient basis. A volume of CSF equivalent to the volume of chemotherapy injected (including the rinsing liquid) was first removed, and then the chemotherapy medication was infused very slowly (10 minutes) while monitoring for side effects such as headaches and pain.
Statistics
Quantitative data were summarized as mean, median, standard deviation, minimum, and maximum and were compared using analysis of variance. Categorical and binary variables were summarized as numbers and percentages and compared using the χ2 test. Kaplan-Meier method was used to estimate the OS. In this explorative study, a p-value lower than 0.05. was considered statistically significant. No imputation of missing data was planned.
RESULTS
Patient demographic characteristics
Thirty women diagnosed with LM (Figure 2) underwent implantation and received IT chemotherapy. Among them, three had a history of another cancer, two had a history of breast cancer, and one had developed signet ring cell carcinoma of the stomach.
Figure 2
Magnetic resonance imaging of leptomeningeal carcinomatosis. (A) Cerebellar leptomeningeal meningitis. (B) Lumbar leptomeningeal meningitis.
Patients with HER2+ status were not included in this study. This could be explained by the new European Society for Medical Oncology recommendations, which offer more systemic options for HER2+ patients with cerebral progression, with new TKI inhibitors (lapatinib and tucatinib) or conjugated antibody drugs (trastuzumab deruxtecan). Patients can also be included in a phase II trial of trastuzumab IT [10, 11, 12, 13, 14].
Seven patients had triple negative breast cancer subtype.
Only five of the women had metastatic cancer at diagnosis, whereas 29 had metastasis at LM diagnosis. LM was diagnosed based on the clinical symptoms and meningeal involvement seen on magnetic resonance imaging (MRI) (67%) and/or LP (57%) (Table 1).
Table 1
Patients’ characteristics
Only four patients had received fewer than two lines of previous LM treatment. Most patients who received chemotherapy received anthracyclines and taxanes. Capecitabine, bevacizumab, vinorelbine, and cisplatin were administered.
The number of chemotherapy sessions received depended on the time between aBC diagnosis and LM diagnosis. The median time between aBC diagnosis and LM was 1,628 days.
Hormonotherapy was administered to all 23 patients who were hormone receptor-positive. CDK4/6 inhibitors were added to nine patients because these treatments were recommended.
During LM diagnosis, 16 patients received systemic treatment, mostly myocytes and endoxan (Table 2) Among the 15 patients with cerebral parenchymatous lesions, only one refused cerebral radiotherapy.
Five patients had lesions discovered before LM and received radiotherapy before LM, and two patients received delayed whole brain radiotherapy because of secondary cerebral progression.
Four patients had spinal meningeal infiltration.
All patients received IT methotrexate (15 mg), thiosulfate, or hydrocortisone. One woman underwent received DepoCyte (Table 2). The scheduled dose of methotrexate was one injection every week for one month, completed by one injection every two weeks, and the DepoCyte schedule dose was one injection each week for one month, followed by an injection each month. The dose and frequency were adapted according to patient tolerance (Table 2).
IC management and safety
No failure occurred during the implantation procedures. Of all patients, 77% of them reported no complications after implantation. Transient headaches were observed on day 1 and rapidly resolved with analgesics. Only three complications required surgical treatment (one dislodgment, one infection and one lumbar hematoma) (Figure 3). No thrombosis, stenosis, fracture, or migration was observed during follow-up. After implantation, the catheter was not removed until the patient died. No pain was observed during the chemotherapy infusion. The tolerance profile for iterative IT chemotherapy was manageable in ambulatory care without treatment discontinuation owing to toxicity.
Figure 3
Tolerance profile post catheter implantation.
Treatment and efficacy
For all patients except one (IC implanted previously for pain management), the first treatment was started immediately during the surgical procedure. The median number of IT chemotherapy courses per patient was 8 (range, 2–27). (Figure 4)
Figure 4
Intrathecal chemotherapy courses per patient.
With a median follow-up of 76.5 months (95% confidence interval [CI], 11.6–not available), the median OS was 158 days (95% CI, 87–235). As of May 1, 2021, three patients were alive (Figure 5). The median PFS was 116 days (95% CI, 58–174).
Figure 5
Overall survival in days.
DISCUSSION
Management of carcinomatous meningitis associated with aBC remains challenging. A recent publication highlighted that breast cancer is one of the most common cancers worldwide for women [15]. This remains the most common etiology of LM. Treatment, including systemic treatment and radiotherapy, is not well defined and is mostly guided by expert opinion [16]. Several retrospective studies have demonstrated the benefits of IT therapy for OS [17, 18]. Commonly used agents include methotrexate (a folate antagonist), thiotepa (an alkylating agent), cytarabine (a pyrimidine analog), and sustained release liposomal cytarabine (DepoCyte®).
Treatment can be administered by LP or through a reservoir directly into the ventricular system through a catheter [18], but neither route is free of complications. The primary ones are aseptic meningitis characterized by sterile CSF pleocytosis and symptoms of meningitis seen in up to 43% of patients in Chamberlain et al.’s study [19], but also infectious meningitis (8%–24% of patients) for intraventricular devices [20]. Moreover, headaches or hazardous drug delivery are observed in approximately 10% of subdural or epidural deliveries using LP [21].
Studies have shown the superiority of intraventricular administration over LP delivery, suggesting a better distribution of treatment within the CSF with more homogeneous diffusion and a higher drug concentration compared with LP [22]. Because the IC also allows direct drug delivery to the CSF [23], IC should be an interesting device for IT chemotherapy, especially in cases of spinal meningeal infiltration.
The catheter tip can be positioned accurately from the lumbar position up to cervical height to improve diffusion, depending on the disease location. To date, no publications concerning the realization of LM treatment using ICs have been published; however, this device is widely and routinely used for pain management [24, 25]. Indeed, its tolerance and effectiveness have been demonstrated in comparison to comprehensive medical management [26].
Surgical procedure is also performed routinely with good tolerance profile.
The complications described in our study are those most frequently reported in the literature [19, 20, 21].
The PFS was difficult to obtain. We defined it using the MRI response assessment in neuro-oncology criteria when available or with clinical evolution; however, as clinical worsening was often synonymous with stopping additional examinations, the data was limited.
Regarding the median OS, we also found improved outcomes of 158 days (95% CI, 87–235) compared with those described in the recent Carausu et al.’s study (135 days [95% CI:,114–168]) [27], which can be linked either to an adjusted distribution of the treatment inside the CSF or to the simplicity and safety of IT chemotherapy administration, which facilitates patient compliance with the treatment.
The retrospective and monocentric nature of this study and its limited sample size are the most important limitations.
Finally, IT chemotherapy through an implanted catheter is an efficient, safe, and easy-to-manage option for IT chemotherapy in breast cancer patients with leptomeningeal meningitis. Further prospective studies are needed to confirm the improvement in quality of life using patient-reported outcomes in the evaluation of IT chemotherapy.
Conflict of Interest:The authors declare that they have no competing interests.
Data Availability:In accordance with the ICMJE data sharing policy, the authors have agreed to make the data available upon request.
Author Contributions:
Conceptualization: Dupoiron D, Augereau P.
Data curation: Dupoiron D, Autier L, Lebrec N, Seegers V, Folliard C, Patsouris A, Augereau P.
Formal analysis: Augereau P.
Investigation: Lebrec N, Patsouris A, Campone M, Augereau P.
Methodology: Dupoiron D, Seegers V.
Resources: Folliard C.
Software: Seegers V.
Validation: Autier L, Lebrec N, Seegers V, Patsouris A, Campone M, Augereau P.
Writing - original draft: Autier L, Seegers V, Augereau P.
Writing - review & editing: Dupoiron D, Folliard C, Patsouris A, Campone M.
References
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Montes de Oca Delgado M, Cacho Díaz B, Santos Zambrano J, Guerrero Juárez V, López Martínez MS, Castro Martínez E, et al. The comparative treatment of intraventricular chemotherapy by ommaya reservoir vs. lumbar puncture in patients with leptomeningeal carcinomatosis. Front Oncol 2018;8:509.
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Smith TJ, Staats PS, Deer T, Stearns LJ, Rauck RL, Boortz-Marx RL, et al. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol 2002;20:4040–4049.
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