Cetuximab is a chimeric IgG1 monoclonal antibody against epidermal growth factor receptor. It is approved by the European medical agency for the treatment of RAS wild-type metastatic colorectal cancer and metastatic squamous cell cancer of the head and neck. Few cases of aseptic meningitis, primarily associated with the first administration of cetuximab in patients with squamous cell cancer, have been reported. So far, there was only 1 case in a patient with metastatic colorectal cancer. We report on a 50-year-old Caucasian patient with metastatic rectum carcinoma who suffered from headache, fever, and neck stiffness 3 h after the first administration of cetuximab (400 mg/m2). CSF examination revealed an excessive pleocytosis with a white blood cell count of 2,433/µL. He was diagnosed with cetuximab-induced aseptic meningitis since clinical symptoms and CSF pleocytosis resolved within days, and further diagnostic workup revealed no infectious cause. Cetuximab-induced aseptic meningitis is a rare and severe drug reaction with predominance in treating squamous cell cancer of the head and neck. Clinical presentation and CSF findings suggest acute meningoencephalitis. In all reported cases, the course of the disease was benign and self-limited. Empiric antimicrobial and antiviral therapy are suggested until infectious causes can be ruled out. A lower dosage of cetuximab and a premedication including antihistamines and glucocorticosteroids may lower the risk of a re-occurrence if cetuximab therapy is continued.

© 2022 The Author(s). Published by S. Karger AG, Basel

Cetuximab is a chimeric IgG1 human/mouse monoclonal antibody against epidermal growth factor receptor. It is approved by the European medical agency for the treatment of metastatic squamous cell cancer of the head and neck and RAS wild-type metastatic colorectal cancer. In the palliative treatment of colorectal cancer, it may be used as a single agent and in combination with radiation therapy and chemotherapy (e.g., FOLFIRI [folinic acid, 5-fluorouracil, irinotecan]) [1, 2].

So far, few cases of aseptic meningitis associated with cetuximab application have been reported (see Table 1). Our MEDLINE analysis showed that most cases were associated with the first administration of cetuximab in patients with squamous cell cancer. Here, a higher dose (400 mg/m2) is administered, while in consecutive administrations, 250 mg/m2 is recommended. One case of aseptic meningitis was found in a patient with metastatic colorectal cancer after the 12th administration of cetuximab at the lower dosage (250 mg/m2) [3]. Even if clinical symptoms and CSF findings suggest severe bacterial meningitis, the course of cetuximab-induced aseptic meningitis is benign and self-limited within a few days.

Published cases of cetuximab-associated aseptic meningitis in patients with squamous cell cancer of the head and neck and colorectal cancer

We present a 50-year-old Caucasian man with metastatic rectum carcinoma. As first-line treatment, the patient was treated by low anterior resection and atypical liver resection of segments 4b/5. After R2 resection due to multiple bilobular hepatic filiae, a palliative first-line treatment was started. After determination of all RAS wild type within the IVOPAK II-study [4], the patient was offered weekly cetuximab in combination with FOLFIRI biweekly, following the dosing regimen of Van Cutsem et al. [5]. Before the first administration of cetuximab, 2 mg of clemastine iv was administered, following the usual protocol. No glucocorticosteroids were given. Hereafter, 860 mg cetuximab (400 mg/m2) was administered intravenously within 2 h. The patient presented no adverse side effects besides a mild flush during administration. Afterwards, he received an infusion of isotonic saline and was monitored for another hour. Then he was discharged without any clinical symptoms. However, 2 h later, the patient developed a severe headache, neck stiffness, and fever with a tympanic temperature of 39°. He immediately presented to our neurological emergency department.

Clinical examination revealed no focal neurological deficit. Cerebrospinal fluid (CSF) analysis revealed a severe polymorphonuclear neutrophil-predominant pleocytosis (87.8%) with a white blood cell (WBC) count of 2,433/µL. Further laboratory testing (including complete blood count, coagulation profile, and a comprehensive metabolic panel) remained unremarkable. Empirical broad-spectrum treatment was initiated, including ceftriaxone, ampicillin, aciclovir, and dexamethasone. He recovered from headaches, neck stiffness, and fever within 2 days. After 5 days, a repeated CSF analysis showed a complete recovery. After extensive viral and bacterial diagnostic workup (including assessment of herpes simplex type 1 and 2 [PCR], varicella zoster [PCR], human herpesvirus 6 and human herpesvirus 7, Epstein-Barr virus, cytomegalovirus, adenovirus, tick-borne encephalitis virus, Borrelia burgdorferi, Treponema pallidum, CSF cytology, and CSF culture/staining [bacterial and fungal]) remained unremarkable, antibiotic and antiviral therapy was discontinued. The patient and treating physicians decided to terminate the cetuximab treatment in a joint decision.

To estimate the probability of an adverse drug reaction (ADR), in this case, the Naranjo Score was applied. Following Naranjo et al. [6], the estimated probability for an ADR, in this case, was considered “probable” (Naranjo Score: 5, see Table 2).

ADR probability scale – Naranjo Score. To assess the probability of an ADR, following questionnaire was applied

We report on a case of clinically pronounced aseptic meningitis within hours after the first cetuximab treatment with a dosage of 400 mg/m2 in a patient with metastatic colorectal cancer, followed by fast and full recovery within 2 days. So far, few cases of aseptic meningitis related to a previous administration of cetuximab have been reported (see Table 1) [1, 3, 7-13].

Most patients showed mild clinical symptoms with headache and fever. However, some cases also reported encephalopathy and psychomotor slowing [9, 12]. CSF WBC count was elevated with a neutrophil-predominant cell profile (range: 302–4,100 WBC/μL) in all cases, which corresponds well to our case. So far, no associated bacterial superinfection was reported. In general, clinical symptoms occurred between one and 9 h after the administration of cetuximab. Most cases were reported in patients with squamous cell carcinoma of the head and neck after the first cetuximab application with a dosage of 400 mg/m2. Several studies on cetuximab application in colorectal cancer did not report aseptic meningitis as an adverse event [14-17]. The only reported case of aseptic meningitis in a patient with metastatic colon cancer was associated with the lower dose of 250 mg/m2. In contrast to all other reported cases, aseptic meningitis occurred after the 12th administration of cetuximab [3]. No premedication with glucocorticoids was reported before the respective cetuximab application (see Table 1). A timely standard empiric antimicrobial and antiviral therapy are suggested until an infectious cause is ruled out. All cases showed a self-limited course with complete recovery, irrespective of whether dexamethasone was added to the antimicrobial treatment. In six of the reported cases (50%), cetuximab was reintroduced at a lower dosage (250 mg/m2) after aseptic meningitis. Furthermore, a premedication with glucocorticosteroids was added before the consecutive cetuximab applications in all but 2 cases. In one of those 2 cases, there was a recurrence of aseptic meningitis within 4 weeks, showing a benign course [10]. In our case, the decision was made to discontinue the treatment with cetuximab to prevent further events of ADRs. FOLFIRI was continued.

The pathophysiological background of this rare adverse event remains unclear. However, it seems that aseptic meningitis is mainly related to the following three (risk) factors. (1) A higher dose of cetuximab is suggested as the first administration dose (initial dose 400 mg/m2 vs. subsequent dose 250 mg/m2) in the treatment of metastatic squamous cell carcinoma of the head and neck and metastatic colon carcinoma [1]; however, since there is only 1 case reported in metastatic colon carcinoma, it remains to be elucidated whether the dose-dependent risk also exists in patients with colorectal cancer. Furthermore, a clear association of symptom duration with cetuximab half-life (approx. 112 h) can also not be concluded from existing data since most patients seem to recovery within 48–96 h (see Table 1) after symptom onset. (2) The application of cetuximab in squamous cell cancer of the head and neck; (3) a premedication without glucocorticosteroids. Interestingly, panitumumab, a human IgG2 monoclonal antibody against epidermal growth factor receptor, was not reported to be associated with aseptic meningitis [18]. This might support the etiological hypothesis of an inflammatory response related to the chimeric (mouse/human) nature of cetuximab in terms of an antibody-dependent cell cytotoxicity effect [19]. In general, most of the above associations suggest an inflammatory response comparable to an allergic hypersensitivity reaction due to cetuximab antibodies crossing the blood-brain barrier [1, 13]. Comparable pathomechanisms have been reported in aseptic meningitis associated with intravenous immunoglobulin therapy [20]. Here, also dose-dependent effects have been described [21]. While some debate is still ongoing on whether a monoclonal antibody like cetuximab may be able to cross the blood-brain barrier due to its biochemical size; other reports describe a CSF antibody detection in a comparable setting [22] with a possible inflammatory reaction [23] affecting the CNS. Furthermore, the association of aseptic meningitis with cetuximab administration in squamous cell cancer of the head and neck, which in turn might be associated with certain virus infections, might also suggest a distinct inflammatory response [24]. Some authors suggest an involvement of interleukins in antibody-associated aseptic meningitis. An example may be the involvement of the interleukin-6 (IL-6) pathway, which was shown to be associated with aseptic meningitis related to the anti-IL-6-receptor antibody tocilizumab [25]. Interleukins may also play a role in tumor-associated processes of squamous cell carcinomas of the head and neck [26]. Furthermore, an association of IL-6-gene activation with the cetuximab-induced acneiform rash has been described in the treatment of squamous cell carcinoma of the head and neck, which is also supposed as a biomarker of the immunological response to cetuximab and related processes [19]. Thus, one may hypothetically propose an association of cytokine activation with cetuximab-associated aseptic meningitis. However, this could not be proven so far in this setting.

An inflammatory response seems likely in patients with aseptic meningitis after cetuximab administration. The risk of re-occurrence is generally low, especially if a lower cetuximab dosage is administered and a premedication with glucocorticosteroids is added. Thus, an anti-inflammatory premedication (including glucocorticosteroids) is proposed. However, pathophysiological mechanisms still need to be elucidated.

Cetuximab-associated aseptic meningitis is a rare side effect with a benign course despite pronounced initial symptoms and CSF findings. Nevertheless, immediate empiric antimicrobial and antiviral therapy are suggested until infectious causes are ruled out. A lower dose of cetuximab (250 mg/m2) and a premedication including glucocorticosteroids may be associated with a low risk of a re-occurrence of aseptic meningitis if cetuximab therapy is continued. Panitumumab may also represent a promising alternative treatment option since no aseptic meningitis associated with panitumumab treatment has been reported so far.

The study was conducted in accordance with the World Medical Association Declaration of Helsinki. Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patient provided his written informed consent to participate in this study. Written informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article.

The authors have no conflicts of interest to declare.

We acknowledge financial support by Deutsche Forschungsgemeinschaft and Friedrich-Alexander-Universität Erlangen-Nürnberg within the funding programme “Open Access Publication Funding.”

Bastian Volbers and Jakob Jäger: design of the work and drafting the manuscript. Axel Wein, Francesco Vitali, and Martin Uhl: acquisition of data and critical revision of the article for important intellectual content. Stefan Schwab, Tamara Brunner, and Maximilian Sprügel: interpretation of data and critical revision of the article for important intellectual content. Jakob Jäger, Maximilian Sprügel, Tamara Brunner, Martin Uhl, Stefan Schwab, Francesco Vitali, Axel Wein, and Bastian Volbers approved the final version.

All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.

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