DOI: https://doi.org/10.21203/rs.3.rs-1692796/v1
Introduction: Side-effects during convection enhanced delivery (CED) are poorly understood. We intended to determine the frequency of side-effects during brain stem infusion and determine risk factors for side-effects persisting longer than 24 hours.
Methods: Children with a radiological diagnosis of brain stem diffuse midline glioma/Diffuse Intrinsic Pontine Glioma were treated on compassionate grounds with awake infusion of carboplatin and sodium valproate into the brain stem using the 4-catheter (2 trans-cerebellar 2 trans-frontal) chronic, intermittent Renishaw Drug Delivery System. We used change in the Pontine Neurological Observation Score (PONScore), a standardised neurological assessment tool, to identify side-effects during infusion. Recovery was determined by retrospective chart review.
Results: 55 infusions were performed in 8 children (3-11 years). Mean PONScore increased during infusion from 3.3 to 5.7 (p-value >0.001). One hundred and fifty-seven infusion-related side-effects were identified including headache (33/157) and limb weakness (49/157). Fifty-four side-effects persisted >24 hours. Side-effects that had occurred during a previous infusion and those that occurred during infusion via trans-cerebellar catheters were more likely to be persistent with OR 2.333 (95% CI 1.094-4.976; p-value =0.028) and 2.155 (1.029- 4.513; p-value=0.042) respectively. If infusion was stopped or titrated at onset rather than continued, the side-effect was less likely to persist >24 hours, OR 0.473 (95% CI 0.177-0.948; p-value=0.037). Most side-effects developed within the first three millilitre of infusion.
Conclusions: Side-effects during brainstem infusion are common, can be transient or persist longer than 24 hours. Neurological injury during infusion may be time dependent and accumulative rather than volume dependent.
Convection enhanced Delivery (CED) is a promising treatment for Brainstem Diffuse Midline Glioma (BS-DMG; previously Diffuse Intrinsic Pontine Glioma) (1). In CED one or more catheters are surgically implanted and, by continuous positive pressure infusion, drug is directly infused into the brain parenchyma – bypassing the blood brain barrier (BBB) achieving high intra-tumoural concentrations. (2, 3) This has particular theoretical advantages for treatment of BS-DMG, which is an unresectable lethal childhood brain tumour. BS-DMG is characterised by histone mutations leading to altered H3K27 function and widespread epigenetic dysregulation. Patients between 4-11 years present with progressive cerebellar signs, cranial neuropathy and ataxia, with imaging demonstrating expansion of the pons, often in the absence of contrast enhancement. Diagnosis occurs with 4-6 weeks of first symptom and has a median survival of 9 months, characterised by progressive neurological disability. Chemotherapy trials have failed for over 30 years. Radiotherapy remains the standard of care.
As such, CED is an exciting potential therapy for BS-DMG because of its ability to bypass the BBB and deliver chemotherapy to clinically relevant brain volumes. Several trials are underway (NCT03086616; NCT03566199; NCT01502917). The only trial published to date using CED in BS-DMG/DIPG is a landmark phase I dose escalation study delivering an 124I isotope conjugated to an tumour-targeting antibody (2) This study demonstrated that CED could achieve high intra-lesional dosing with negligible systemic exposure, and was well tolerated. Toxicity was defined according to the Criteria for Terminology Common Adverse Events (CTCAE) within 7 days of the infusion. In this non-randomised study, many of the adverse events may not have been CED-related and could be attributed to concomitant use of corticosteroids, such as hyperglycaemia, neutrophilia and lymphopenia. However, 25% of adverse events were neurological, suggesting local delivery of drugs causes local neurological side-effects. Szychot et al., 2021 described their experience of treating 13 patients on compassionate grounds with carboplatin and sodium valproate using the 4-catheter chronic, intermittent Renishaw Drug Delivery System. (3) The most common reported side effects were mild-moderate headache, transient facial weakness, dysarthria, ataxia, and/or unilateral weakness during infusion. Deficits were described as grade 1–2 mostly returning to pre-infusion baseline within 24 h of stopping infusion.
Quantification of toxicity in CED and BS-DMG is complex. Toxicity in CED can arise due to: 1. the effect of catheter implantation; 2. the infusion; or 3. the pharmacological action of the drug. The new or worsening neurological deficits occurring during infusion often improve after the infusion is stopped. However, the cause and recovery these deficits can be difficult to interpret. When infusion is stopped, local drug concentrations remain high. The patient’s clinical phenotype is superimposed on aftereffects of surgery (catheter implantation and/or biopsy) and may occur at different stages of a rapidly progressive disease. As such, neurological changes in BS-DMG patients occurring during CED may come and go, may persist, become permanent or even progress. Furthermore, neurological dysfunction cannot always be easily elicited in children; relying on subjective, and often opportunistic, examination. This is also compounded by the difficulties of performing a randomised controlled trials of CED in BS-DMG, which include the requirement of supra-specialist facilities to deliver treatment, the rarity of the disease, the absence of a good treatment options and the availability of alternative, and often well-publicized, experimental treatments inside and outside of clinical trials. Understanding causality in CED-related toxicity is therefore very challenging, requiring careful thought about how best to understand and reduce the side-effects of this emerging treatment. Szychot et al., 2021 described a novel patient evaluation system used to monitor side-effects during infusion. This patient evaluation system uses a standardised neurological assessment that elicited signs and symptoms of headache, ophthalmoplegia, bulbar dysfunction, paraesthesia, limb weakness and cerebellar dysfunction and amalgamated them into a numerical score, with increasing scores reflecting increasing disability. (3) This score, the Pontine Observational Neurology Score (PONScore) was found to have excellent intra-rater reliability that increased during infusion to reflect the accumulation of neurological signs and symptoms during infusion. (4) We hypothesised that the PONScore could be used to determine the frequency of side-effects in during infusion, and this would help better understand mechanisms of toxicity and likelihood of recovery.
Ethical approval
Treatment of patients using CED on compassionate grounds was approved by the institutional ethics committee and was compliant with the 1964 Helsinki declaration and its later amendments. Implantation of the drug delivery system was approved by the Medicines and Healthcare Regulatory Authority, United Kingdom. Parents were consented for the experimental nature of the treatment and the use of their child’s information for the development of the treatment and for scientific publication. Data was acquired from routinely collected information as part of their clinical treatment.
Pontine infusion
The technique of CED described herein has been described in detail. (3) In short, two trans- frontal and two trans-cerebellar catheters were inserted into the pons via the cerebral and cerebellar peduncles respectively. These catheters were connected to a bone-anchored transcutaneous drug administration port via sub-galeal tubing (Renishaw Drug Delivery System; Ren- ishaw Plc, Wooton-under-Edge, UK). Following implantation, patients would be recovered from anaesthetic and commence infusion within 72 hours of implantation. Patients would sit in bed connected to an infusion set connected by two-metre-long extension lines. Infusions would be continued until the onset of neurological symptoms to maximise the volume of tumour treated. Each treatment would typically consist of two infusions over two separate days and were repeated at 3–8 weekly intervals depending on patient fitness. (Figure 1) Infusion could be conducted using one or more catheters, these patients were infused on day one via trans-frontal catheter and on day two via trans-cerebellar catheters.
The PONScore
The development and validation of the PONScore have previously been described. (4) In brief, the PONScore is a 57-point scale that elicits the signs and symptoms of brainstem dysfunction arising during pontine infusion, with increasing scores reflecting greater degrees of severity.
Data Analysis
Data was available for 8 of the 13 patients described in the Sychot Cohort. (3) Data recorded during the routine care of patients was collected retrospectively from 55 pontine infusions. PONScores were measured by the attending nursing staff before infusion initiation and at every hour during infusion until the end. PONScores were inputted directly onto a computer database using critical care and anaesthesia information software, ICIP® (Phillips, Surrey), together with the infusion rates and volumes per catheter. Infusion-related side-effects were identified by increases in the PONScore. Side-effects detected using the PONScore were compared to the case notes. If a new side-effect identified during infusion by an increase in the PONScore and the deficit was documented in the patient chart (according to parent and patient interview, review of outpatient letters or clinical examination) more than 24 hours after the end of the infusion, the side-effect was defined as a persistent infusion-related side-effect. Transient infusion-related side-effects were defined as side-effects identified during infusion that were not present >24 hours following infusion. Data was analysed using Statistical Package for Social Science (Version 23; IBM, USA) was used for statistical analysis. Comparisons between PONScores were performed using t-test calculation. Correlation calculations were calculated using Spearman’s correlation co-efficient. Frequency of side-effects were determined at the time of onset. Infusion related side-effects were dichotomised into transient and persistent and logistic regression was performed to determine odds ratios (OR) for persistent side-effects. Statistical significance was defined as p-value <0.05.
55 infusions of carboplatin combined with sodium valproate were performed in 8 children (3-11 years; Table 1). Median PONScore at the start of each infusion was 2 (range 0-16). Pre-infusion baseline PONScores demonstrated weak (0.45) and moderate (0.63) correlations with numbers of infusions received and days since diagnosis respectively using Spearman correlation co-efficient calculations, both of which reached statistical significance (p-value<0.001). Mean PONScore increased during infusion from 3.3 to 5.7, which differed with statistical significance (p-value >0.001). PONScores identified 157 infusion-related side-effects during 55 pontine infusions, the most common of which were headache (33/157) and limb weakness (49/157) (Figure 2). The assessment of headache severity, which was derived from the Wong Baker Faces Scale, reported as hurting ‘a little’, ‘a little more’, ‘even more’ and ‘a whole lot’ in 17, 11, 4 and 1 cases respectively. (Figure 2). Side-effects ranged from cranial neuropathies, limb weakness and cerebellar signs, which occurred throughout infusion (Figure 2). The severity of change was usually only mild, indicated by an increase of one or two points of the PONScore (Figure 2). Transient and persistent neurological deficits were identified respectively in 70 and 54 cases respectively. Deficits that had occurred during a previous infusion and those that occurred during a trans-cerebellar infusion were more likely to be persistent with OR 2.333 (95% CI 1.094-4.976; p-value =0.028) and 2.155 (1.029- 4.513; p-value=0.042) respectively. If an infusion was stopped or titrated rather than continued, the deficit was less likely to be persistent, OR 0.473 (95% CI 0.177-0.948; p-value=0.037). Other factors such as maximum severity of deficit, increase in PONScore by >1, and duration of deficit during infusion longer than 3 hours trended toward increased risk of persistent deficit but failed to reach statistical significance. Deficits acquired after 3 mL of infusion tended toward reduced risk of becoming persistent; however, this did not reach statistical significance (Figure 4).
Table 1
Eight children with DIPG/BS-DMG receiving infusion of carboplatin and sodium valproate by intermittent, chronic Convection Enhanced Delivery using the Renishaw Drug Delivery System
|
Case |
Age at diagnosis (y) |
Biopsy |
Diagnosis to Implant (months) |
Number of pontine infusions studied |
|
1 |
10.6 |
- |
4.9 |
10 |
|
2 |
7.8 |
- |
7.9 |
1 |
|
3 |
6.9 |
- |
3.9 |
8 |
|
4 |
6.3 |
H3K27M |
3.3 |
4 |
|
5 |
10.7 |
H3K27M |
4.2 |
12 |
|
6 |
6 |
H3K27M |
4.9 |
6 |
|
7 |
3.6 |
H3K27M |
3.6 |
6 |
|
8 |
5.7 |
- |
6.5 |
8 |
Neurological signs and symptoms in 8 children during 55 pontine infusions of combined carboplatin and sodium valproate were systematically monitored using the PONScore. The PONScore increased during pontine infusion reflecting the accumulation of neurological signs and symptoms during infusion. The most common infusion-related side-effects were headache and limb weakness. Headache was mostly mild to moderate, while every patient developed at least a sign or symptoms of neurological dysfunction. 50/124 cases of infusion related side-effects identified using the PONScore persisted for >24 hours. Important predictors of persistent side-effects were recurrence of the side-effect during a previous infusion, infusion through transcerebellar catheters and continuation of infusion at the onset of side-effects, rather than stopping or reducing the rate of infusion.
There are several limitations to this analysis. The PONScore is in its developmental infancy and further studies are required to determine its reliability and validity as an outcome measure and its normative values are unknown. Nursing staff who performed the assessment were unblinded to the infusion volumes and parameters. There is also no understanding of what change in PONScore is clinically significant, and many detected side-effects may not reach a clinically meaningful threshold. The definition of recovery used retrospective chart review, and future prospective studies should consider using the same standardised neurological assessment tool, such as the PONScore, to quantify recovery. Due to differences in the number of infusions received prior to disease progression, infusions studied were not equally divided between all patients; and hence observed findings are skewed toward the patients who received the most infusions. However, despite these limitiations, this is the first attempt to use a standardised neurological assessment tool to describe the neurological changes during brain stem infusion and it makes important observations about the mechanisms of infusion related toxicity.
The description of symptomatology during infusion are corroborated by Souweidane’s et al., 2019 who describe a similar array of cranial neuropathies, limb weaknesses and long tract signs after brainstem infusion. (2) We cannot make comparisons regarding the frequency and severity of side-effects because Souweidene et al,. defined toxicity using CTCAE at a different time-point relative to infusion (7 days after infusion). (2) Szyshot et al., 2021 used clinical assessment to describe toxicity. Our findings are support their conclusion that neurological side-effect mostly resolved within 24 hours. (3) However, by using an increase in PONScore to identify side-effects, it appears a significant minority of infusion-related side-effects persist for longer than 24 hours. It is imperative that infusion-related side-effects are meticulously documented and their mechanisms understood.
Our findings demonstrate that side-effects occur during infusion. Equally it has been previously described how side-effects improve following cessation of infusion. (3) Taken together, it may be that the major source of infusion-related toxicity is due to the mechanical effects of infusion rather than direct pharmacotoxicity. Side-effects were more likely to become persistent if the infusion was continued rather than reduced or stopped at symptom onset. At the point of flow rate adjustment, local drug concentrations within the core of the distribution volume will remain stable up to 12-24 hours after adjustment. (5) The association between flow rate reduction and improved recovery suggests that infusion related side-effects are due to mechanical effects of infusion. Although, the effects of pontine infusion on interstitial pressure in treatment of BS-DMG are lacking, it is reasonable to assume that as infusion rate is reduced, interstitial pressure within the pons will also fall, or stabilise. It may be that infusion leads to increased interstitial pressure, which ultimately impairs locoregional perfusion. This may explain the variability in side-effects between patients. BS-DMG/DIPG are characterised by non-uniform, and sometimes reduced, perfusion, brought about by a hypercellular cytoarchitecture with irregular capillary networks. (6) Catheters in the same locations within the pons may elicit different side effects depending on the unique interactions between the effect of applied infusion pressures on local tumoural perfusion.
We also found that if an infusion related side-effect was observed during a previous infusion it is more likely to become persistent. This suggests infusion-related neurological injury is accumulative, and therefore reducing the risk of infusion-related side-effects is central to the future of the therapy. This theory is confounded by the interaction between numbers of infusions and time from diagnosis. However, considering that the infusion studied were performed prior to diagnosis of clinical and radiological progression, it is likely that infusion is an important contributory factor to the accumulation of neurological disability over time. Side-effects were also more likely to be persistent if acquired during infusion via trans-cerebellar versus trans-cerebral trajectories. Trans-cerebellar infusions were typically conducted on the second day of infusion, therefore, greater risk of side-effects may be due to the accumulative injury from the previous day. It could also be due to the anatomical arrangement of the catheters. Transcerebellar catheters are placed into the anterolateral pons containing corticospinal tracts and crossing ponto-cerebellar fibres, which may be more sensitive to distortion. High resolution tractography and perfusion mapping may help to direct catheters away from brain stem nuclei and tracts and critically ischemic tumour regions.
It is evident that infusion-related side-effects were not directly correlated to infusion volume. It is evident that 30% of the recorded deficits occurred <1mL infusion. Interestingly, fewer side-effects occurring at the end of infusion became persistent. The risk of persistent side-effects was increased if the infusion was continued (rather than stopped or reduced) and there was a non-significant tendency toward greater risk of persistent side-effects if the infusion was continued for ≥3 hours after deficit onset. This would suggest that the way in which the infusion is conducted is a key determinant of treatment-related side-effect profile. Performing the infusions awake, in such a way that patients can be constantly monitored and flow rates adjusted may be important avenues to achieve large volume infusions. Slowing down the ramping regime at the beginning of the infusion may also reduce critical pressures that could lead to infusion-related side-effects.
Regardless of the underlying cause of these side-effects, many of these hypotheses can only be tested in human subjects. As described, the neurological phenotype arising during pontine infusion is likely due to the interaction of catheter location, the morphology of fluid distribution and pathology of the underlying tumour, and the pharmacology of the drug. A reliable means of quantifying neurological change would be hard to achieve in an animal model, even with expert veterinary supervision. Without standardised neurological examination, addressing such questions will be impossible in human studies. In summary, we present findings from 55 pontine infusions in 8 children with BS-DMG/DIPG. Analysis of neurological signs and symptoms occurring during pontine infusion using the PONScore demonstrated that risk of persistent infusion-related side-effects were higher if the infusion was not immediately reduced and if the side-effect had occurred during prior infusions. If catheter flow was adjusted based on anatomical position some deficits would recover. This suggests that the neurological injury arising from pontine infusion is often localised, time dependent, accumulative rather than volume dependent, and ultimately modifiable. The study of interstitial pressure and perfusion and their interaction with neurological function may be central to development of the treatment.
The authors have nothing to declare
Funding
No specific funding was granted for this work
Conflicts of interest/Competing interests (include appropriate disclosures)
The authors report no conflict of interest
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Authors' contributions
MH conducted the work, collected and analysed the data and wrote the manuscript. SZ supervised the work and developed the manuscript.
Ethics approval
Ethics approval for treatment on compassionated grounds was granted by the institutional ethics committee
Acknowledgments
We are grateful to Professor Steven Gill for his pioneering work regarding multi-catheter awake pontine infusion. We also thank Dr Cornelia Hurter, Miss Ali Bienneman, Mr Will Singleton, Mr Neil Barua, Dr David Cronin, Dr James Morgan and Miss Marina Pitsika who played a vital role in developing this clinical treatment.
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