Certas programmable shunt valves with a "virtual off" for intrathecal chemotherapy delivery in infants with high-grade CNS tumors and hydrocephalus

doi:10.21203/rs.3.rs-4157739/v1

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Certas programmable shunt valves with a "virtual off" for intrathecal chemotherapy delivery in infants with high-grade CNS tumors and hydrocephalus

https://doi.org/10.21203/rs.3.rs-4157739/v1

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Introduction

Current chemotherapy protocols for treatment of embryonal brain tumors in infants may recommend administration of intrathecal chemotherapy, either by a lumbar tap or via an Ommaya reservoir. Children with concurrent hydrocephalus and shunts may have subtherapeutic levels of chemotherapy in the CSF due to constant CSF drainage to extra-CNS compartments. We present our experience in delivery of chemotherapy to young children via programmable valves.

Results

A retrospective analysis of infants with CNS malignancies together with hydrocephalus treated with a shunt and a programmable valve (CERTAS™ Plus Programmable Valves - Integra Life Sciences) was conducted. Five infants 1.1-3 years of age (mean age 2 years) were included. Pathologies included two atypical rhabdoid teratoid tumors, two medulloblastomas, and one metastatic rhabdomyosarcoma. Intrathecal injections were conducted in an outpatient setting unless hospitalization was required for other reasons. 4 children did not require sedation, one child was noncompliant and required sedation. 67 chemotherapeutic administrations were performed directly through the valve while set on a high opening pressure (setting 8) for several hours (35 hydrocortisone + cytarabine, 32 topotecan). There were no infections, leaks, or major complications. One child required a wound revision due to exposure of the proximal catheter related to extremely thin skin. One patient experienced a “stuck” setting of the valve.

Conclusions

Programmable ventriculoperitoneal valves are a safe method for delivery of chemotherapy in infants. This technique may potentially have an added value for children with concurrent shunts, and may also obviate the need for an additional ventricular access device (such as an Ommaya reservoir).

intrathecal

chemotherapy

programmable valve

hydrocephalus

high-grade tumor

pediatric brain tumor

Current protocols for high-risk embryonal tumors (i.e., medulloblastoma and ATRT) advocate direct administration of chemotherapy to the ventricular system in addition to systemic chemotherapy. The conventional mode of administration is either by lumbar puncture or insertion of an Ommaya reservoir^1,2. IT (intrathecal) chemotherapy medications frequently include methotrexate, ARA-C, topotecan, and hydrocortisone. IT delivery may also be utilized for experimental therapies such as Car-T cell therapy, radio-immunotherapy, or antibiotics.

Typically, infants with high-grade tumors such as embryonal tumors have concurrent hydrocephalus and a ventriculoperitoneal shunt. When administering IT drugs with a shunt, some of the drugs will inevitably drift to the abdomen, thus lowering the CSF level of these drugs and reducing their efficacy³. Prior studies describing on-off or high-resistant valves used to enable IT injection while avoiding drug level reduction have been reported only rarely, and these valves were usually placed concurrently with an additional Ommaya reservoir for the IT injection^4–6. Some valve systems were connected linearly with an Ommaya system⁷. Programmable magnetic ventriculo-peritoneal shunts were originally designed for better control of hydrocephalus by enabling valve pressure adjustments to optimize CSF drainage rate. Rarely have programmable valves been used for drug administration^3,8.

We report our experience using a programmable valve as a port for IT chemotherapy injection, as well as to temporarily decrease CSF drainage.

Following an IRB approval, we retrospectively collected data on infants younger than 3 years of age with programmable valves that were used for IT treatment. Patient and caregiver approval were waived.

Since January 2019, we have been routinely inserting programmable valves for infants with high-grade CNS tumors and hydrocephalus who undergo a shunt placement. We use the CODMAN® CERTAS® Plus Small Programmable Valve (Integra). This valve has 8 settings which may be set by an external magnetic device. Opening pressure settings range between 25-215mmH₂O, with an additional “virtual off” setting, set at an opening pressure of 400mmH₂O⁹. There are 2 subtypes – with and without a siphon-guard component. The CERTAS® Plus is designed to withstand unintended pressure setting changes due to external magnetic influences, up to and including a 3-T MRI.

The integrated reservoir is placed proximal to the valve mechanism, and there is no unidirectional component between the reservoir and the ventricular catheter. Thus, there is minimal resistance between the reservoir and the ventricle when injecting media through it, and when the valve is set at “virtual off”, the media is anticipated to solely reach the ventricle and not the distal component of the shunt.

Intrathecal chemotherapy injection

Procedures were performed in an outpatient setting unless hospitalization was required for other reasons. Only one child required sedation due to noncompliance. Prior to administration of chemotherapy, the magnetic shunt was adjusted to “virtual off” to minimize the CSF drainage, and remained closed for 3-4 hours after injection. Maximal volume of injected fluid was 3cc.

Using a sterile technique, the valve is tapped using a 23G butterfly needle. A few cc of CSF are aspirated and sampled, followed by injection of the chemotherapeutic drug, then flushed by 1cc of CSF. Children were discharged an hour after re-setting the shunt to the preprocedural baseline setting.

The goal of this study is to describe the safety of this technique, as well as patient outcomes.

Statistical analysis

As this is a small series, no statistical analyses are described.

Five infants aged 1.1-3 years (mean 2 years) with high-grade CNS tumors were included between 2019-2023 (Table 1). The pathological diagnoses included ATRT (N=2), medulloblastoma (N=2), and metastatic rhabdomyosarcoma (N=1). 67 IT chemotherapeutic administrations were performed using the programmable valve. 35 included IT cytosine arabinoside (ARA-C) with hydrocortisone, and 32 included topotecan.

There were no infections, leaks, or major complications. One child had somnolence and fever due to a viral disease, and one child encountered valve-setting malfunction (valve was stuck at the setting of “6” with no clinical implications). One child required wound revision due to exposure of the proximal catheter, related to extremely thin skin. The same child at one point had clinical and radiological shunt over-drainage, solved by increasing the valve settings.

Four children are alive, with a maximal follow up of five years. One girl with metastatic rhabdomyosarcoma died of disease during treatment. There were no late effects related to IT chemotherapy.

We report on a small series of 5 infants with concurrent high-grade CNS tumor and hydrocephalus, treated by IT CT injections to a programmable valve with a “virtual off” mode. Our results show that the technique is simple and safe. The most significant complication was 1 instance of the valve being "stuck" on one specific setting, with no ability to reprogram it. Despite the fact that the valve was stuck on a high-pressure setting, the child did not develop hydrocephalus. Although not of clinical significance in this case, and although we are unable to state the reason for this complication, it is important to note since it may pose significant risks. Possible causes of this malfunction may include being secondary to the external effect of an MRI system, or secondary to an internal effect, such as a small blood clot introduced during injection. The Certas valves are intended to withstand external electromagnetic fields up to (and including) 3 Tesla. Nevertheless, these children often undergo repeated MRI scans, and thus, despite the safety profile of the valve, we cannot exclude this as a cause.

Burger et al. described 2 cases of children with an “on-off” valve who were undergoing injection of CT⁵. They closed the valve for 24 hours following the injection, to maximize CSF distribution of the drugs. Their system consisted of 1 intracranial catheter, with several parts, including a Rickham reservoir, in addition to the valve system. Czech et al. described 8 cases using an “on-off” system, which was closed for 2 hours following the IT injection¹⁰. Kramer et al. increased a programmable valve setting for 6 hours following injections of radioimmunotherapy⁸. Zada et al. increased the valve pressure for 4 hours following injection, and measured the distribution of a tracer injected concurrently with the chemotherapy⁶. Lin et al. have published a series on IT CT injection using an Ommaya connected to an “on-off” shunt system⁷. They closed the system for 2-6 hours following the injection. However, one of the limitations of the “on-off” valves is the inadvertent closure of the valve, which may lead to life threatening conditions^10,11.

Over recent years, use of an “on-off” valve has decreased, replaced by magnetic programmable valves. McThenia et al. reported on 15 cases using 6 different magnetic programmable valve models, evaluating drug distribution to the peritoneum at 2-4 hours and 24 hours after injecting In-111-DTPA³. In their model, McThenia et al. increased the valve pressure to the maximal setting for about 4-5 hours, and compared the distribution of the marker at 2-4 hours and 24 hours after IT injection. Their findings suggest that there does exist some peritoneal spread, although the number of cases per valve model, as well as heterogeneity in pathology, valve settings, ages, and other variables, does not enable identification of any clear advantage of one model over another.

The current series describes using the valve as a port of injection, with no need for an additional Ommaya reservoir. As stated, most prior series have placed a separate injection port.

Limitations

Our series is small and heterogenous; therefore we are unable to statistically prove efficacy or safety of the proposed technique. The time period of valve closure was chosen arbitrarily (3-4 hours); the pharmacokinetics of the drugs was not studied. It is therefore unknown how much of the drug level in the CSF was effective over time. Despite virtually closing the valve, drug distribution may not resemble that of IT drug distribution via a lumbar tap or an Ommaya injection, as these children have CSF pathway obstruction, or malabsorption. Thus, the CSF bulk flow is not equal to that of a child with no hydrocephalus.

Children with high grade brain tumors and hydrocephalus with a VP shunt may benefit from the use of a Certas programmable valve, which may enable direct IT injection to the valve, sparing the need for an additional port, while temporarily “closing” the valve, reducing drug level reduction due to CSF shunting. This technique can be utilized even in small infants, with a high safety profile and minimal complications.

Peyrl, A. et al. Safety of Ommaya reservoirs in children with brain tumors: A 20-year experience with 5472 intraventricular drug administrations in 98 patients. J Neurooncol 120, 139–145 (2014).
Kramer, K. et al. A phase II study of radioimmunotherapy with intraventricular 131I-3F8 for medulloblastoma. Pediatr Blood Cancer 65, (2018).
McThenia, S. S. et al. Quantifying intraventricular drug delivery utilizing programmable ventriculoperitoneal shunts as the intraventricular access device. J Neurooncol 157, 457–463 (2022).
Palejwala, S. K. et al. Use of a stop-flow programmable shunt valve to maximize CNS chemotherapy delivery in a pediatric patient with acute lymphoblastic leukemia. Surg Neurol Int 5, (2014).
Burger, M. C. et al. Ventriculoperitoneal shunts equipped with on-off valves for intraventricular therapies in patients with communicating hydrocephalus due to leptomeningeal metastases. J Clin Med 7, (2018).
Zada, G. & Chen, T. C. A novel method for administering intrathecal chemotherapy in patients with leptomeningeal metastases and shunted hydrocephalus: Case report. Neurosurgery 67, (2010).
Lin, N. et al. Benefit of ventriculoperitoneal cerebrospinal fluid shunting and intrathecal chemotherapy in neoplastic meningitis: A retrospective, case-controlled study. Clinical article. J Neurosurg 115, 730–736 (2011).
Kramer, K., Smith, M. & Souweidane, M. M. Safety profile of long-term intraventricular access devices in pediatric patients receiving radioimmunotherapy for central nervous system malignancies. Pediatr Blood Cancer 61, 1590–1592 (2014).
Czosnyka, Z., Pickard, J. D. & Czosnyka, M. Hydrodynamic properties of the Certas hydrocephalus shunt: Laboratory investigation. J Neurosurg Pediatr 11, 198–204 (2013).
Czech, T., Reinprecht, A., Dietrich, W., Hainfellner, J. A. & Slavc, I. Reversible occlusion shunt for intraventricular chemotherapy in shunt- dependent brain tumor patients. Pediatr Hematol Oncol 14, 375–380 (1997).
Hertle, D. N. et al. Reversible occlusion (on-off) valves in shunted tumor patients. Neurosurg Rev 34, 235–242 (2011).

Table 1 is available in the Supplementary Files section.

No competing interests reported.

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Certas programmable shunt valves with a "virtual off" for intrathecal chemotherapy delivery in infants with high-grade CNS tumors and hydrocephalus

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Abstract

Introduction

Methods

Results

Discussion

Conclusion

References

Tables

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Supplementary Files

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