DOI: 10.31038/CST.2020541

Abstract

Background: Predominantly used in external beam radiotherapy (EBRT) are intensity modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3DCRT). However, the superiority between these two techniques remains inconclusive. This study aim to evaluate the late clinical toxicity of cervical cancer patients treated with intensity-modulated radiation therapy (IMRT) compared to three-dimensional conformal radiation therapy (3D-CRT) and dosimetrically compare the planning target volume (PTV) plan of 3D-CRT to the PTV plan of IMRT based on target coverage and bladder and rectum doses at different volumes.

Methods and Materials: From September 2011 – December 2015, 146 patients with International Federation of Gynaecology and Obstetrics (FIGO) stage IB2-IIB squamous cell carcinoma of the cervix were analysed retrospectively. The patients received EBRT of 50 Gy in 25 fractions of the whole pelvic delivered with IMRT or 3D-CRT. Seventy-five (75) patients received 3D-CRT and seventy-one (71) patients received IMRT.

Results: The 2 years’ overall survival (OS) was 92% in the IMRT group and 88% in the 3D-CRT group (p-value = 0.073). The disease-free survival outcome (DFS) was 83% and 80% in IMRT and 3D-CRT group respectively (p-value). Acute genitourinary (GU) and gastrointestinal (GI) toxicity were lower in IMRT patients compared to 3D-CRT patients (GU, 21.1% vs. 37.3%, p-value = 0.179; GI, 46.5% vs. 49.3%, p-value = 0.436). The mean coverage of the prescribed dose in IMRT and 3D-CRT techniques was 50.02 ± 0.10 Gy and 50.10 ± 0.23 Gy respectively with a non-significant p-value of 0.005 for 95 percent (D₉₅) of the PTV. Also, the mean coverage of 5% (D₅) of the PTV was 52.66 ± 0.39 Gy and 53.89 ± 0.76 Gy of the prescribed dose in IMRT and 3D-CRT techniques respectively with a significant p-value of 0.0001.

Conclusion: Patients treated with IMRT had a lower dose to bladder and rectum, a lesser rate of late toxicity and comparable clinical outcome than 3D-CRT. We admonish larger sample size studies and longer follow-up in subsequent studies to affirm our results.

Keywords

Cervical cancer; IMRT; 3D-CRT; Rectum; Bladder

Introduction

Cancer has become a significant public health problem in China since 2010 due to increasing incidence and mortality, making it the number one cause of death in the country [1,2]. External beam radiotherapy (EBRT) is a vital method of treatment for cervical cancer management. Most often than not EBRT and brachytherapy in addition to chemotherapy are often used when treating and managing locally advanced cancer of the cervix. The primary goal of EBRT is in the delivering of maximum radiation to the malignant tissue, with minimum radiation to healthy organs. This treatment can be noxious, and about 20-25% of patients are reported to have severe side effects [3]. Hence, reliable dose-response knowledge in malignant lesions and organs at risk (OAR) is therefore very vital. Before advancement into new treatment planning and imaging technique, most cervical cancer patients were treated using 2D (Two-dimensional) planning. In 2D treatment planning, the contour of the patient is captured with x-ray using lead wire, and bony landmarks and is transcribed on a graph paper sheet with an identified reference point, [4] which results in the target volume being inadequately uncovered. With the limitation of 2D planning, 3D treatment planning and conformal radiotherapy became the standard for EBRT in the 90ths [5]. This treatment planning uses computer tomography (CT) scan images with patients required to be positioned in the planning set-up and requires a computerised treatment planning system (TPS). 3D-CRT is a form of EBRT which uses computers and unique imaging technologies to optimize the radiation beams precisely in other to reduce radiation to surrounding healthy tissues; and was started to be used for effective management of patients since it could give a maximum target coverage and also has the tendency for dose optimization to normal healthy tissues. It makes use of several high photon beams to amply deliver a high dose to a centrally located target volume with minimum dose to superficial structures in the pelvis. Intensity-modulated radiation therapy (IMRT) allows radiation to be more precisely shaped to fit the target volume by using heterogeneous fluences beams from different directions thereby optimises high radiation dose to the target volume and also limiting the amount of radiation received by the normal healthy organs. With IMRT, the beam intensity is able to be optimised as it orients around the patients using computer algorithms [6]. The ‘inverse method’ in treatment planning forms the basis of this process hence able to generate significant dose gradients in the adjacent structures and target volume to accomplish dose-volume prescription [7]. In IMRT, many beams with varying intensity levels are used in treating the tumour while 3D-CRT uses uniform intensity radiation beams hence the constraint of the latter is evident whenever a tumour is wrapped around an organ. Many experts indicated that IMRT is capable of reducing doses to the bone marrow, rectum and bowel and are linked with reduced levels of haematological, gastrointestinal (GI) and genitourinary (GU) toxicity compared to conventional radiation therapy. Nevertheless, these studies were usually defined by small sample sizes and the absence of clinical outcome data. Additionally, brachytherapy patients were involved in their selection criteria and this could influence toxicity. Retrospective reviews comparing IMRT and 3D-CRT technique for cervical cancer patients treated by radiotherapy are deficient, and also there has been inconsistency finding in dose to OAR. The purpose of this study was to analyse retrospectively the clinical toxicity of cervical cancer patients treated with IMRT compared to 3D-CRT and secondly, to compare the PTV plans of 3D-CRT to the PTV plan of IMRT on the basis of target coverage and doses to bladder and rectum at different volumes.

Materials and Methods

Patient Selection

146 stage IB2-stage IIB cervical cancer patients were treated from September 2011-December 2015. The eligibility criteria were [8]:

I.     Biopsy confirmation of squamous cell carcinoma or adenocarcinoma.

II.    Cytological /histological diagnosis of cervical cancer.

III.   No previous surgery, chemotherapy or radiation.

IV.   No evidence of distance metastasis.

V.    KPS performance score 70-80.

Pre-Treatment Evaluation

The pre-treatment workup included a comprehensive medical history, vagina-recto-abdominal examination. Radiological studies like CT-scan of the abdomen-pelvis, chest x-ray and MRI in a few selected patients. Laboratory studies included a complete blood count (CBC), Liver function test (LFT), Blood Chemistries, BUN/Cr, SCC blood test. The clinical-stage was defined according to the International Federation of Obstetrics & Gynaecology (FIGO) staging system.

CT-Simulation

All patients were immobilised with a thermoplastic sheet and underwent CT simulation for planning in a supine position. Philips CT scanner was used for simulation and 3 mm slice images of the abdomen and pelvis area were obtained. The Pinnacle treatment planning system (TPS) (Version 9.2) was used for planning and target contouring.

Treatment Planning

The clinical target volume (CTV) and organs at risk (OAR) were contoured using the concept and definition of volume targets from ICRU reports [9,10]. The gross tumour volume (GTV) and clinical target volume (CTV) were contoured on each single axial CT slice. The CTV included palpable tumour and areas expected to be affected with subclinical tumours. Therefore, the CTV included the pelvic lymph node (external, internal and common iliac), cervix, vagina upper section and uterus. A margin of 10 mm was generated around the CTV to define the planning target volume (PTV). Four fields (two lateral and PA-AP fields) with zero-degree (0°) couch angle were used to generate the 3D-CRT plans (Figure 1). The isocenter was positioned at the PTV’s geometric centre. 10 megavolt (MV) photon energy was used for all plans to improve coverage of PTV and reduce dose to the skin. The beam aperture was shaped to the PTV in each beam’s eye view and a margin of 0.5 cm in all directions accounting for the beam penumbra. The PTV was prescribed a total dose of 50 Gy (2Gy per fraction). The bladder and rectum were protected with a 4-cm central shield after 40 Gy. IMRT plans were generated using 10 megavolt energy with six coplanar fields (Figure 2). Patients had whole pelvic radiotherapy prescribe to 50 Gy with either 3D-CRT or IMRT in 1.8-2 Gy per fractions from Monday – Friday. Chemotherapy involving cisplatin (25 mg/m²) was given concurrently to all patients from second to fifth week during radiotherapy treatment. None of the patients received high dose rate-intracavitary brachytherapy.

Figure 1: Shows the 4-field beam arrangement and isodose curve in 3D-CRT.

Figure 2: Shows the beam arrangement and isodose curve in IMRT technique.

Plan Evaluation

All plans were passed and accepted after more than 95% of the PTV received more than 95% of the dose prescribed (PD). The dose-volume histograms (DVHs) were used in evaluating the PTV coverage, rectum and bladder between 3D-CRT and IMRT plans. The parameter analysed for bladder and rectum included D₁₅D₅₀D₈₀ (dose to 15%, 50% and 80% of organ volume) while PTV coverage was based on D₅ and D₉₅ (Dose to 5% and 95% of the PTV respectively). The conformity index (CI) and homogeneity index (HI) was calculated in both techniques using the formulae below.

HI_95% = D₅/D₉₅; where D₅ is the minimum dose of 5% of the target volume indicating the maximum dose, and D₉₅ is the maximum dose of 95% of the target volume indicating the minimum dose. The Homogeneity Index (HI) is an accurate method for analysing the homogeneity of the target volume dose distribution. HI, therefore, demonstrates in all terminology the ratio between both the minimum and maximum dose in the target volume and the lower value demonstrates a more homogeneous distribution of the dose within this volume.

The ideal value is 1, and it increases as the plan become less homogeneous.

CI_95% = Total volume receiving 95% of prescribed dose/planning target volume. The ideal value is 1.

Statistical Analysis

All statistical analyses were carried out using SPSS 18, and a substantial difference in each set of dosimetric variables was determined using an independent sample test and chi-square. The rate of survival was evaluated after treatment was completed. The Kaplan – Meier method was used to calculate overall survival (OS) and disease-free survival (DFS). With the aid of the log-rank test, the significance of the difference was analyzed and a p-value < 0.05 was considered significant statistically.

Follow-Up

One month after treatment, patients had a gynaecological examination and pelvic CT/MRI. Afterwards, they were followed at a regular interval of 3 months for the first 2 years and at an interval of 6 months thereafter and then once a year. Version 3.0 of the Common Terminology Criteria for Adverse Events (CTCAE) was used in evaluating chronic and acute toxicity.

Results

Characteristics and Treatment of patients

146 stage IB2-stage IIB cervical cancer patients were treated from September 2011-December 2015. Seventy-five (75) were treated with 3D-CRT and the median age was 50 years (range, 39-68). Seventy-one (71) were also treated with IMRT and the median age was 53 years (range, 32-78). The squamous cell carcinoma histology type was seen in one hundred and thirty-seven (137, 93.8%) patients and nine (9, 6.2%) patients with adenocarcinoma. Table 1 shows a summary of the patients’ characteristics.

Table 1: Patients clinical characteristics.

Dose-Volume Histogram (DVH) Outcomes

The 95% PTV mean value was 50.02 ± 0.10 Gy and 50.10 ± 0.23 Gy of the prescribed dose in IMRT and 3D-CRT techniques respectively with a significant p-value of 0.005. Also, the mean coverage of 5% of the PTV was 52.66 ± 0.34 Gy and 53.89 ± 0.76 Gy of the prescribed dose in IMRT and 3D-CRT techniques respectively with a significant p-value of 0.001. Hence the target coverage was esteemed satisfactory and appropriate in both groups.

The HI mean value was 1.052 ± 0.008 and 1.083 ± 0.021 in IMRT and 3D-CRT plans respectively, and the p-value 0.001, indicates the statistical significance of HI in both plans. The CI mean value was 1.330 ± 0.103 and 1.109 ± 0.214 in IMRT and 3D-CRT plans respectively, with a significant 0.001 p-value. Table 2 shows the outcomes of the CI, HI and target coverage in both treatment technique.

Table 2: Outcomes of the CI, HI and target coverage in both treatment technique.

The dose received by 15% (D₁₅), 50% (D₅₀) and 80% (D₈₀) of the bladder in IMRT was 51.30Gy, 46.79 Gy and 38.69 Gy respectively while that of 3D-CRT was also 52.96 Gy, 51.30 Gy and 41.95 Gy at D₁₅, D₅₀ and D₈₀ respectively. The dose difference between these two techniques at D₁₅, D₅₀ and D₈₀ was highly significant with p-value 0.0001 at all level. Furthermore, dose received by 15% (D₁₅), 50% (D₅₀) and 80% (D₈₀) of the rectum in IMRT was 51.04 Gy, 48.82 Gy and 43.72 Gy respectively while that of 3D-CRT was also 52.24 Gy, 50.99 Gy and 48.08 Gy at D₁₅, D₅₀ and D₈₀ respectively. The dose difference between these two techniques at D₁₅, D₅₀ and D₈₀ was highly significant with p-value 0.001 at all level. Table 3 shows the detailed values of rectum and bladder dose at D₁₅, D₅₀ and D₈₀.

Table 3: Summary of rectum and bladder dose.

Survival Outcome and Failure Patterns

The 2 years’ overall survival (OS) was 92% in the IMRT group and 88% in the 3D-CRT group with a non-significate p-value of 0.073 and the median follow-up time was 28 months. The disease-free survival outcome (DFS) was 83% and 80% in IMRT and 3D-CRT group respectively. Locoregional failure was noticed in 5 patients. Three (3) from the 3D-CRT group and 2 from the IMRT group. Distant metastasis was observed in one patient in the three-dimensional conformal radiotherapy group in addition to the locoregional failure. Six (6) death rate was recorded during the follow-up, two (2) from the IMRT group and 4 from the 3D-CRT group. The causes of death were pulmonary embolism (1 patient), heart failure (3 patients) and natural death (2).

Clinical Toxicity Outcome

Table 4 shows the percentage of patients with acute genitourinary (GU), haematological and gastrointestinal (GI) toxicity and their grades. Less acute genitourinary (GU) and gastrointestinal (GI) toxicity were noticed in the IMRT patients compared to the 3D-CRT patients (p-value = 0.436 and 0.179 respectively). None of the patients experienced grade 4 genitourinary (GU) and gastrointestinal (GI) toxicity in both groups. Two patients in the IMRT category developed oedema while 12 patients in the 3D-CRT category experienced the same effect. None significant statistical difference was noticed between the two groups when the various clinical toxicity was considered.

Table 4: Clinical toxicity between IMRT and 3D-CRT.

Discussion

Previous epidemiological studies have shown that most cervical cancer patients mostly report to the hospital in advance stages of the disease. The public, accepted management for locally advanced cervical cancer (LACC) is brachytherapy with concurrent cisplatin chemoradiotherapy. Conventional radiotherapy continues to be the golden standard for LACC. There has been a reduction in the clinical outcomes and toxicities of IMRT compared with 3D-CRT from preliminary studies. The utilisation of IMRT for gynaecologic tumours including locally advanced cervical cancer has upsurge over these years even though there is insufficient retrospective randomised data to support its usage. From our results, both techniques attained the desired target coverage since 95% of the PTV had above 95% of the prescribed dose (PD). Also, there was better CI, HI and PTV coverage in IMRT compared to 3D-CRT because IMRT uses computer optimised intensity beams and multiple beam angles. Secondly, by using computer algorithms, the intensity of the beam can be optimised in IMRT as it orients around the patient, therefore, allowing radiation to be more precisely shaped to fit the target volume. The results of previous studies, when compared to this present study, confirmed that both IMRT and 3D-CRT are useful in PTV coverage hence no difference in our PTV coverage when compared with previous studies. Van De Bunt et al. [11] reported that IMRT is superior to conformal and conventional treatment in sparing critical organs with ample target volume coverage and also stated that IMRT remains superior after EBRT of 30 Gy regardless of internal organ movement and tumour deterioration.

Mell et al. [12], reported IMRT that there was a reduction in doses to the bone marrow and small bowel when patients were treated with IMRT. A study by Naik et al. [13], reported that doses to organ volume of bladder and rectum were reduced in IMRT patients compared to 3D-CRT. Fiorino et al. [14] concluded that IMRT was superior regarding bowel sparing for doses above 30Gy and also a correlation exists between toxicity and the amount of radiation received by an organ. Central target volume boost is possible with IMRT for patients whom brachytherapy is not possible due to a reduction in doses to OAR thereby allowing higher dose up to 66-70 Gy to be delivered using IMRT. Retrospective studies have accounted that decrease in dose to healthy organs may present a clinical benefit in clinical toxicities reduction. Jereczek – Fossa et al. [15] examined 317 postoperative endometrium carcinoma patients and reported that there was a statistically significant correlation between late and acute bowel reactions. The morbidity and complications among cervical cancer patients after a long-term treatment survivor was assessed by Kamal et al. [16] and reported that the rate of obstruction of the small intestines was comparable in IMRT and 3D-CRT with no significant p-value in both groups. Ajeet et al. [17] reported grade 2 diarrhoea, tenesmus and constipation in patients treated with 3D-CRT compared to a lower grade in IMRT patients. Avinash et al. [18] concluded that there were no differences in both techniques when the grade of haematological toxicities was considered every week even though there was a statistically significant difference between IMRT and 3D-CRT during the second week when the total count and Neutrophils count were assessed. Our results showed that less acute genitourinary (GU) and gastrointestinal (GI) toxicity was noticed in the IMRT patients compared to the 3D-CRT patients (p-value = 0.436 and 0.179 respectively). None of the patients experienced grade 4 genitourinary (GU) and gastrointestinal (GI) toxicity in both groups. Two patients in the IMRT category developed oedema while 12 patients in the 3D-CRT category experienced the same effect. In general, lower clinical toxicities were observed in the IMRT patients than the 3D-CRT patients even though there wasn’t any statistical significance between the two techniques.

Past studies [19-27] in postoperative patients treated with IMRT have normally shown suitable survival outcomes. Chen et al. [28] analyzed 35 patients receiving four-field radiation therapy and 33 patients receiving intensity-modulated radiotherapy and concluded that IMRT improved locoregional control. An update of the study of the Gynaecologic Oncology Group showed 3-year overall survival and progression-free survival rates of 88% and 86% respectively in stage IB cervical cancer patients. Results from the Radiation Therapy Oncology Group 0418 study, involving 48 patients showed an estimated 2-year OS and DFS rates of 94.6% and 86.9% respectively with a median follow-up duration of 2.68 years. In Folkert et al. [29] studies involving 34 patients, the 3 years OS was 91.1% and the 5 years DFS was 91.2%. Our findings were similar to this study.

Our study’s major limitation is the short follow-up period. Furthermore, using bone marrow-sparing methods could reduce the higher rates of haematological toxicity recorded in treated patients with intensity-modulated radiotherapy. In addition, more focus should be given to the target margin in order to leave an adequate margin in IMRT planning for PTV expansion.

Conclusion

In conclusion, patients treated with IMRT had a lower dose of bladder and rectum, a lesser rate of clinical toxicity and comparable clinical outcome than 3D-CRT. We admonish larger sample size studies and longer follow-up in subsequent studies to affirm our results.

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DOI: 10.31038/CST.2020534

Abstract

Background: Cellular immunotherapy with autologous T cells genetically engineered to express chimeric antigen receptors is emerging as a promising new class of immunotherapeutic agents, however may cause unique symptoms of neuro-toxicity, such as toxic encephalopathic state with symptoms of confusion and delirium, and occasionally seizures and cerebral oedema.

Case presentation: Hereby, we report a case of a 4-year-old boy, with B-cell precursor acute lymphoblastic leukemia and refractory CNS involvement, which was treated with CAR T-cells. The patient developed severe encephalopathy, high fever and seizures, and was treated with steroids and anticonvulsants. Nevertheless, the patient rapidly deteriorated and developed diffused brain oedema and herniation of cerebellar tonsils. Unfortunately, the patient showed no neurological improvement and suffered brain death.

Conclusion: Neurotoxicity is an important and common complication of CAR-T cell therapies. Usually, severe neurological symptoms are manageable in most patients, which respond to standard interventions. Early detection of neurological deterioration is of paramount importance, and pediatric intensivists should consider pre-emptive management for brain oedema, even prior to radiological evidence. Randomized prospective studies of treatment algorithms are urgently needed to improve patient monitoring and management.

Keywords

Chimeric antigen receptors (CAR), cytokine-release syndrome (CRS), Immune effector cell-associated neurologic syndrome (ICANS), Neurotoxicity

Background

Cellular immunotherapy with autologous T cells genetically engineered to express chimeric antigen receptors (CARs) is emerging as a promising new class of immunotherapeutic agents in relapsed and refractory B-cell malignancies [1,2]. As CAR T-cell therapies become more widely used, recognition of their unique toxicities, which are distinct from those seen with traditional chemotherapies, monoclonal antibodies, and small-molecule targeted therapies, is of the utmost importance [1]. The two most commonly observed toxicities with CAR-T-cell therapies are: 1) cytokine-release syndrome (CRS), characterized by high fever, hypotension, hypoxia, and/or multiorgan toxicity; and 2) Immune effector Cell-Associated Neurologic Syndrome (ICANS), which may occur in more than 60% of patients treated with CAR T-cells [2]. ICANS is typically characterized by a toxic encephalopathic state with symptoms of confusion and delirium, and occasionally seizures and cerebral oedema, and can occur with or after CRS [1] with peak incidence occurring 4–6 days after infusion [3-5]. About 20% of patients will present severe neurotoxicity [5], and grade 5 fatal neurotoxicity has been described in clinical studies in adults treated with CD19-directed CAR T-cells, with an incidence of up to 3% [4]. Hereby, we are the first to present an extreme form of neurotoxicity in a young child, resulting in brain oedema and death.

Case Presentation

We report a case of a 4-year-old boy, with B-cell precursor acute lymphoblastic leukemia (ALL) with CNS involvement. Due to high risk relapse/refractory disease he was enrolled on a clinical trial using CD19 CAR T-cells. The patient developed CRS on day +3 (grade 1), and due to encephalopathy, high fever and seizures he was transferred to pediatric intensive care (PICU) on day 5 of CAR-T treatment. Prior to transfer to PICU, due to a clinical diagnosis of ICANS grade 3, he was commenced on dexamethasone, on top of Levetiracetam prophylaxis (started on day -3). Following this event, a brain CT was performed and was normal, showing no intracranial bleeding or oedema. EEG revealed general encephalopathy. Following repeated tonic-clonic seizures despite increase in the Levetiracetam dose and steroids treatment, he was loaded with phenytoin as well as a few midazolam boluses to stop the seizures. During the first 24 hours in PICU, the patient remained stable, encephalopathic, however maintained GCS of 8-10. The following day (+6) a brain MRI was performed under general anesthesia, showing high T2-FLAIR signal involving the hemispheral sub-cortical white matter, hippocampi and capsule externa, in addition to high signal in the thalami bilateral. Furthermore, there were cortical areas with diffusion strain which correlate with ICANS. The patient was extubated and returned to PICU drowsy but responsive. Upon returning from MRI the patient had a sudden acute deterioration, with apneic episode and GCS which dropped to 3, therefore was immediately intubated. An urgent repeat CT brain was performed revealing diffused brain oedema with developing herniation of cerebellar tonsils (Figure 1). During the next 24 hours he received mannitol, hypertonic saline, and noradrenaline to maintain proper cerebral perfusion pressure and reduction of oedema, he was started on broad spectrum antibiotics and anti-viral empiric therapy for possible meningo-encephalitis, as well as pulse methylprednisolone and tocilizumab. Unfortunately, the patient showed no neurological improvement and had absent brain stem reflexes and anisocoric pupils. SPECT was performed showing absent flows which correlates with brain death.

Figure 1: CT/MRI findings.

Discussion

We describe a young child with relapse ALL that was commenced on CAR-T therapy and very rapidly, after 5 days of treatment, developed severe ICANS presenting as encephalopathy and seizures. He received the acceptable treatment with anti-epileptic drugs and steroids, unfortunately suffered from very extreme and rare complication of CAR-T treatment as of brain oedema, followed by tonsillar herniation and death. The oedema itself may have risen as the sequelae of some other underlying process, and in our patient might have been main cause of the neurological deterioration. Neurotoxicity is an important and common complication of CAR-T cell therapies. Acute neurologic signs and/or symptoms occur in a significant proportion of patients with clinical manifestations that include headache, confusion, delirium, language disturbance, seizures and rarely, acute cerebral oedema. The mechanisms that lead to neurotoxicity remain unknown, but data from patients and animal models suggest there is compromise of the blood-brain barrier, associated with high levels of cytokines in the blood and cerebrospinal fluid, as well as endothelial activation [6]. This cytokine production is correlated to early onset of severe CRS, or may be associated with expansion and activation of CAR T-cells that lead to a direct parenchymal CAR T-cell infiltration [5]. Such toxicities have also been observed in patients treated with other redirected-T-cell therapies and bispecific T-cell-engaging antibodies [1]. Gust et al., [4] described a potential mechanism for the cases of diffuse and often fatal cerebral oedema, with findings of widespread endothelial activation as well as findings of meningeal inflammation from a mouse model of CAR T-cell neurotoxicity [7]. Toxicity may also be primarily mediated by the inflammatory cytokine surge that accompanies CAR-T cell expansion in the marrow, rather than the CAR-T cells themselves [6].

The management of ICANS remains an area of active investigation. Therapy rests upon symptomatic management, seizure control, and corticosteroids. Despite the widespread use of corticosteroids, it is unknown to what degree they influence CAR T cell–mediated anticancer effects [2]. Presently, corticosteroids and tocilizumab are the mainstays of treatment for both CRS and neurotoxicity [1]. However, treatment with tocilizumab for CRS causes serum IL-6 to rise, which may predispose to more severe neurotoxicity [6]. In sicker patients with depressed level of consciousness, dexamethasone should be added and seizures need to be ruled out and controlled. In the sickest patients who are unarousable, with status epilepticus, motor weakness or diffuse cerebral oedema, or when brain MRI identifies focal or diffuse oedema, high dose methylprednisolone should be started. Anakinra (anti-interleukin-1 receptor antagonist) has been anecdotically proposed [5,6]. Although symptoms could present at virtually any time within the first few weeks after CAR T-cell infusion, patients who developed early CRS are more likely to develop severe neurotoxicity. Severe neurotoxicity represents a negative prognostic factor for overall survival with potential therapy-related mortality and underline the importance of rigorous monitoring of these patients [2]. Usually, ICANS is manageable in most patients, although some require monitoring and treatment in the intensive-care setting. It is thus imperative that clinicians remain vigilant in their workup and management of all neurological symptoms, especially those that deviate from the expected course of recovery and responsiveness to standard interventions. The role of intensivists is crucial and PICU specialists may help anticipate the risk for developing organ dysfunction or sepsis, based on patient’s frailty, immunity and comorbid conditions. After CAR-T infusion, when patients develop subacute fever and mild organ derangement, early PICU admission is recommenced. PICU intensivists should consider early management for brain oedema with possible intubation and secure airway, hyperosmolar therapy, and raising the cerebral perfusion pressure by vasoactive support. All of these measures should be considered at a very early stage of ICANS, even prior to radiological evidence, as most if not all patients will have brain oedema to some degree at presentation with encephalopathy. Diabetes ketoacidosis is a similar example where an inflammatory state associated with an immune and systemic inflammatory response results in disruption in the integrity of brain capillaries tight junctions which causes capillary permeability and brain oedema [8]. Our problem in clinical practice is that we are unable to quantify BBB function in real time during the acute course of ICANS treatment. Hence, from a pragmatic perspective, recognizing and providing preemptive treatment is paramount for pediatric intensivists.

Conclusion

Early detection of neurological deterioration is of paramount importance after CAR-T cell treatment, and PICU intensivists should consider early management for brain oedema, even prior to radiological evidence. Randomized prospective studies of treatment algorithms are urgently needed to improve patient monitoring and management.

List of Abbreviations

CAR: Chimeric antigen receptors

CRS: Cytokine-Release Syndrome

ICANS: Immune Effector Cell-Associated Neurologic Syndrome

ALL: Acute Lymphoblastic Leukemia

PICU: Pediatric Intensive Care

Declarations

• Ethics approval and consent to participate.
• Consent for publication – there is an ethical approval and consent to participate by the local IRB committee.
• Availability of data and materials – all data was described in references.
• Competing interests – no competing interests.
• Funding – no funding.
• Authors’ contributions – RKL wrote the manuscript with the help of EJ. Initiated, supervised and finally edited and approved by GP. All authors read and approved the final manuscript.
• Acknowledgements – not applicable.

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