Brachial Plexitis during Maintenance Atezolizumab after Palliative Radiotherapy for Cervical Spine Metastasis in Lung Cancer

Abstract

We present the case of a patient with lung cancer who developed brachial plexitis following treatment with immunochemotherapy, which included atezolizumab and palliative radiotherapy for a metastatic cervical spine tumor. This case highlights the importance of considering immune-related adverse events (irAEs) when initiating immune checkpoint inhibitor therapy, in addition to other recognized causes such as radiation, tumor compression and invasion, and paraneoplastic syndromes. While brachial plexitis has been reported as an irAE associated with programmed cell death 1 (PD-1) antibodies, this is the first report associated with the administration of programmed cell death ligand 1 (PD-L1) antibodies.

Introduction

Lung cancer treatment typically involves a combination of local therapies, such as surgery and radiation, along with systemic therapies, including chemotherapy, immunotherapy, and targeted molecular therapies, which can be used either individually or in combination. Recently, immune checkpoint inhibitors (ICIs) have been used increasingly frequently as a form of immunotherapy owing to their potential to achieve long-term effects. However, these drugs are associated with a variety of immune-related adverse events (irAEs). These irAEs can range from mild to life-threatening and can affect various organs and systems, including the nervous system. Nervous system irAEs include myasthenia gravis, myositis, peripheral neuropathy such as Guillain-Barre syndrome, and encephalitis/meningitis. These adverse events are often challenging to recognize because of their nonspecific symptoms (1).

We herein report a case of brachial plexitis, a rare peripheral neuropathy that developed during treatment of stage IV epidermal growth factor receptor (EGFR)-mutated lung cancer. The patient initially presented with non-specific symptoms of shoulder pain, which ultimately progressed to the right upper extremity and diaphragmatic paralysis. Although radiation-induced injury is considered a potential factor, we believe that irAEs were the most likely cause in this case.

Case Report

Two years prior to the most recent presentation, a 74-year-old never-smoking woman presented with complaints of neck pain but no other symptoms. Computed tomography (CT) revealed nodal shadows in the left lower lobe of the lung and multiple bone metastases, including a lesion at C5; however, no neurological symptoms were observed. A CT-guided biopsy of a tumor in the iliac bone confirmed a diagnosis of thyroid transcription factor 1-positive, EGFR-mutated (L858R and S768I) lung adenocarcinoma (cT1cN1M1c-Stage IVB) with moderate programmed cell death ligand 1 (PD-L1) expression (20%). The medical history of the patient included post-ablation ventricular fibrillation with no other medications or a history of autoimmune disease.

Initial treatment included osimertinib and palliative radiation therapy for C5 lesions (stereotactic radiotherapy 20 Gy/fraction) 1 month after the first visit (Fig. 1), followed by systemic therapy with carboplatin and pemetrexed. The disease progressed, and afatinib was administered, followed by erlotinib in combination with bevacizumab. Nonetheless, the disease continued to progress over the next 16 months. Four courses of induction immunochemotherapy with atezolizumab, bevacizumab, carboplatin, and paclitaxel were subsequently administered, which resulted in a partial response. This was followed by two courses of maintenance therapy with bevacizumab and atezolizumab. At 22 months post-diagnosis, the patient developed right shoulder pain, limited range of motion, and flexion contracture in the right upper limb. The patient was subsequently admitted to the hospital for the evaluation and control of shoulder pain. She had been vaccinated twice against SARS-CoV-2 two years ago, experiencing no major side effects, and had no recent infection episodes prior to hospitalization.

Figure 1.

Palliative radiotherapy plan for C5 cervical metastases, axial (A), sagittal (B), coronal (C).

Upon admission, the patient's vital signs were normal. A physical examination revealed triangular muscle weakness (right, 2; left, 5 on the Manual Muscle Testing scale), attenuated right-sided deep tendon reflexes in the biceps and triceps brachii, and impairments in right shoulder flexion and abduction measured at 0° and 30°, respectively (Fig. 2). Cranial nerve testing and sensory examination results were normal, and motor strength in the lower limbs was preserved. Laboratory tests showed a normal complete blood count and normal blood chemistry, with a C-reactive protein level of 0.32 mg/dL, indicating no significant inflammation. Although the levels of the tumor markers carcinoembryonic antigen (125.6 ng/mL) and carbohydrate antigen 19-9 (58.2 U/mL) were elevated, they decreased following the initiation of immunochemotherapy. The progastrin-releasing peptide level, indicative of small cell transformation, was within the normal range.

Figure 2.

Motor deficits in the right upper limb of the patient. (A) Right shoulder flexion is limited to 0°, and (B) right shoulder abduction is restricted to 30°.

Immunological tests were negative for various antibodies associated with autoimmune diseases, such as vasculitis or peripheral neuropathy, including antinuclear antibodies, rheumatoid factor, anti-cyclic citrullinated peptide antibody, anti-SS-A antibody, myeloperoxidase anti-neutrophil cytoplasmic antibody, proteinase-3-anti-neutrophil cytoplasmic antibodies, and anti-ganglioside antibodies. Screening for anti-neuronal antibodies associated with paraneoplastic neurological syndromes and anti-glycolipid antibodies, suggestive of autoimmune neuropathies, also yielded negative results. Nerve conduction velocity studies showed a decreased frequency of F-waves in the median and ulnar nerves, predominantly on the right side.

Magnetic resonance imaging (MRI) revealed no tumor invasion of the brachial plexus. However, diffusion-weighted (DWI) MR neurography, three-dimensional (3D)-short τ inversion recovery (STIR), and a fused DWI and 3D-STIR image showed a high signal intensity in the brachial plexus, indicating bilateral inflammation (Fig. 3). A spinal fluid analysis was normal, with cytology classified as Class I, showing no malignant cells. Chest fluoroscopy revealed right diaphragmatic elevation and reduced movement, consistent with diaphragmatic paralysis (Supplementary material). Consequently, the patient was diagnosed with bilateral (right-dominant) brachial plexitis involving the C4-C7 regions.

Figure 3.

Magnetic resonance imaging (MRI) reveals a high signal in the superior nerve trunk of the brachial plexus on diffusion-weighted (DWI) MR neurography (A), three-dimensional (3D)-short τ inversion recovery (STIR) (B), and a fused DWI and 3D-STIR image (C).

Treatment included steroid pulse therapy (methylprednisolone 1,000 mg daily for 3 days) and intravenous immunoglobulin, considering the possibility of a neurological irAE, with late radiotherapy complications as a potential contributing factor. This was followed by a tapering regimen of prednisolone 50 mg/day (1 mg/kg/day). Although the pain improved, upper limb and diaphragmatic paralysis persisted. Due to the decline in the performance status and cancer progression, the focus of care shifted toward symptom management and comfort, with an emphasis on palliative measures, ultimately leading to death three months after admission.

Figure 4.

The clinical course of the patient from the diagnosis of lung cancer to the onset of brachial plexitis.

Discussion

Brachial plexitis is an inflammation of the brachial plexus that presents as multiple mononeuropathy. Although symptoms vary depending on the nerves involved, it often presents with severe pain, followed by paralysis and significant muscle atrophy in one upper extremity. It is sometimes clinically understood as neuralgic amyotrophy and is synonymous with the well-known Parsonage-Turner syndrome. Early manifestations include nonspecific pain and complicated diagnosis. Research has shown that 43.5% of brachial plexitis cases are related to infection, and 90% of patients experience pain as the initial symptom, with symptoms varying depending on the affected site (2).

In the present case, we considered several potential factors for brachial plexus disorder: local factors such as radiation and tumor invasion, and systemic factors such as idiopathic irAEs, paraneoplastic nerve syndrome, and post-infection immune responses. A high dose per fraction is a risk factor for radiotherapy-induced brachial plexitis. The acceptable total radiation dose to the brachial plexus is 60-66 Gy (3), and the median time to the symptom onset is 10 months (4). In the present case, the radiation dose was low, comprising only a single fraction of 20 Gy; therefore, it is unlikely that radiation alone caused this disorder.

Only five previously reported cases of brachial plexitis occurred in patients receiving ICIs: two pembrolizumab cases, one nivolumab case, and two nivolumab and ipilimumab combination therapies. These are caused by programmed cell death 1 (PD-1) inhibitors and anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibodies. Among the 4 cases with a clearly documented onset, symptoms appeared in 1 case at 8 months after the initial administration and in another case 11 months later; both of these cases involved a combination of ipilimumab and nivolumab. In contrast, the symptoms in the two cases after the ninth infusion were associated with nivolumab monotherapy and pembrolizumab monotherapy (5-7). Consistent with previous reports, our patient developed symptoms after a sixth infusion of atezolizumab. Patients who describe motor weakness or neuropathy during treatment with ICIs should be evaluated for nerve conduction deficits using electrodiagnostics such as EMG and nerve conduction studies and imaging (8).

In addition, there have been reports of radiation-induced pulmonary organ damage exacerbated by irAEs, and radiation-induced damage to parenchymal cells, vasculature, and interstitium has been proposed to drive immune cell mobilization and activation, chronic inflammation, and fibrosis (9, 10). This mechanism may also be applied to peripheral nerve and plexus damages. Paraneoplastic neurological syndrome has been reported in small-cell lung cancer, breast cancer (11), and Hodgkin's lymphoma (12); however, it was considered unlikely in this case because of negative anti-neuronal antibodies and elevated tumor markers suggestive of small-cell transformation.

In conclusion, this case highlights a rare instance of brachial plexitis occurring during treatment of EGFR-positive lung cancer. The early diagnosis is difficult because of nonspecific shoulder pain. Despite considering various pathologies, the final diagnosis was a neurogenic irAE related to the anti-PD-L1 antibody (atezolizumab), with radiation neuropathy associated with C5 palliative irradiation as a possible contributing factor. Clinicians should be aware of the potential for brachial plexitis as a rare neurological irAE in cancer patients undergoing treatment with immune checkpoint inhibitors, particularly when presenting with shoulder pain and upper limb weakness.

The next of kin of the patient presented in this report consented to the submission of this paper.

The authors state that they have no Conflict of Interest (COI).

Supplementary Material

Chest fluoroscopy video

Demonstrates right diaphragmatic elevation and reduced movement, consistent with diaphragmatic paralysis.