Cerebral Infarction as a Rare Adverse Event of Immune Checkpoint Inhibitors in Patients With Head and Neck Squamous Cell Carcinoma: A Case Series

Immune checkpoint inhibitors (ICIs) are a novel treatment option for treating head and neck squamous cell carcinoma (HNSCC). Among the immune-related adverse effects, cerebral infarction (CI) is a rare but fatal complication, and it has been reported in various cancers, except HNSCC. Herein, we describe three cases of patients diagnosed with HNSCC who experienced CI following ICI treatment. In addition, we conducted a comprehensive literature review on ICI-related thrombosis. Three patients with recurrent HNSCC were treated with nivolumab. Two patients had a history of CI, or heart disease, and were concurrently prescribed antithrombotic medications during nivolumab treatment. The number of nivolumab administrations varied from 1-25 before the onset of CI. All patients experienced worsening of neurological symptoms due to CI, irrespective of antithrombotic treatment, and they ultimately succumbed to the disease within 16-222 days following their initial ICI administration. ICIs may cause thromboembolisms, leading to CI. Based on our review of the literature, a history of thromboembolism or heart disease could be a risk factor for ICI-related thrombosis.


Introduction
Immune checkpoint inhibitors (ICIs) have emerged as a novel treatment option for patients diagnosed with head and neck squamous cell carcinomas (HNSCC).The activation of self-reactive immune cells has led to the emergence of multiple immune-related adverse events (irAEs), including dermatological and gastrointestinal effects.Excessive inflammation induces blood coagulation during severe infections.Similarly, nonspecific activation of immune cells by immunotherapy can possibly cause thromboembolism subsequent to blood coagulation.Supporting this hypothesis, several case reports have shown that the incidence rate of venous and arterial thromboembolic events with ICIs is 2.7%-12.9%and 1.1%-1.8%,respectively [1][2], which is comparable to that with cisplatin [3].Thus far, thromboembolisms following administration of ICIs in patients diagnosed with HNSCC have not been reported.Herein, we report three cases of patients diagnosed with HNSCC who experienced cerebral infarction (CI) after treatment with ICIs.

Case Presentation Case 1
A 67-year-old man initially presenting with a sore throat was referred to our hospital.He had a history of hypertension, diabetes, CI, and treatment for esophageal cancer with combined chemoradiotherapy (CCRT) received five years earlier.He had been receiving clopidogrel to prevent CI.Computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and laryngeal fiberscopy revealed the presence of an oropharyngeal tumor.Following a tumor biopsy, the patient was diagnosed with clinical stage IVa (T4aN0M0) right oropharyngeal cancer.
The patient was treated with cisplatin-based chemoradiotherapy.A PET scan acquired two months posttreatment revealed right neck lymph node metastasis; consequently, TS-1 was prescribed for 27 months.After 34 months of the initial treatment, left cervical and mediastinal lymph node metastases were observed.The patient underwent a regimen involving cisplatin, fluorouracil, and cetuximab, followed by paclitaxel and cetuximab for 19 weeks.Because the mediastinal lymph nodes were enlarged despite chemotherapy, the patient was initiated on nivolumab treatment.After receiving two courses of nivolumab over four days, the patient started experiencing numbness of the mouth and arms.An MRI scan revealed multiple new CIs (Figure 1).Despite receiving heparin and edaravone, his paralysis worsened, leading to the development of right hemiplegia and aphasia.The patient succumbed to CI at 114 days after nivolumab administration.

Case 2
A 75-year-old man with a history of aortic valve regurgitation and atrial fibrillation, managed with catheter ablation and rivaroxaban, sought medical attention for a sore throat and shortness of breath at a private clinic.Subsequently, he was referred to our department for treatment of a tumor in the right pyriform sinus.
Based on the biopsy and radiological findings, he was diagnosed with right hypopharyngeal cancer of clinical stage Ⅳb (T4aN3bM0).The patient was treated with CCRT using docetaxel and cisplatin.He developed metastases to the liver and vertebrae during CCRT, necessitating discontinuation of the treatment, and received palliative radiotherapy to address the vertebrae-related issues.
Following palliative radiotherapy, the patient was initiated on nivolumab.Consequently, he developed aphasia and right hemiplegia and was diagnosed with CI, as revealed through a brain MRI conducted six days after nivolumab administration (Figure 2).Following consultation with neurologists, the patient was initiated on edaravone.Despite these interventions, his general condition gradually worsened, and he succumbed to death after 16 days of nivolumab administration.

Case 3
A 62-year-old man visited a private clinic to seek medical attention for a headache.An MRI revealed a mass in the left maxillary sinus.Subsequently, he was referred to our department, where he was diagnosed with left maxillary sinus cancer of clinical stage Ⅳb (T4bN2bM0).The patient was treated with CCRT using docetaxel and cisplatin.However, due to the persistent local tumor, three courses of chemotherapy using cetuximab, cisplatin, and fluorouracil were administered.Following chemotherapy, the patient received 25 courses of nivolumab, resulting in the complete remission of the tumor.The patient developed disturbances in consciousness and weakness of the right upper and lower limbs 31 days after the last nivolumab administration.The patient was diagnosed with CI, and he succumbed to death 222 days after the initial nivolumab administration.

Discussion
The irAEs typically involve the skin, liver, renal system, and endocrine system.Although confirming thromboembolism as an irAE can be challenging, in this report, we have described three cases of CI following PD-1 blockade therapy.Recently, thrombosis associated with ICIs has been regarded as ICIassociated thrombosis (IAT) [4].Kunimasa   Among the included patients, 11 were men, and four were women (others were not specified).The median age of the patients was 70 (range: 48-82) years.Fourteen patients had lung cancer, and three patients had HNSCC (present cases).The most commonly used ICI was pembrolizumab in 10 cases, nivolumab in nine cases, and atezolizumab in two cases.Most patients developed CI after the first ICI administration (Figure 3).

Conclusions
We reported three cases of patients with HNSCC who developed CI following ICI treatment.Thromboembolic events, including CI, are rare but fatal irAEs.A prompt MRI examination is necessary to diagnose IAT when a patient develops neurological symptoms during ICI treatment.
obtained from the Asahikawa Medical University Institutional Review Board (#20054).Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

FIGURE 1 :
FIGURE 1: Findings of magnetic resonance imaging (MRI) in case 1 MRI scan reveals multiple cerebral infarctions (diffusion-weighted MRI scan), which developed four days after the second nivolumab administration.

FIGURE 2 :
FIGURE 2: Findings of magnetic resonance imaging (MRI) in case 2 MRI scan reveals multiple cerebral infarctions (diffusion-weighted MRI scan), which developed six days after the first nivolumab administration.

FIGURE 3 :
FIGURE 3: Administration of doses of immune checkpoint inhibitors (ICIs) until the onset of cerebral infarctionSummary of ICI doses in reported cases, including ours.The x-axis depicts the number of ICI treatments until the onset of cerebral infarction, and the y-axis depicts the number of reported cases.

TABLE 1 : Summary of reported cases of cerebral infarction following treatment with immune checkpoint inhibitors.
*N/A: Not applicable.