Daria Harlamova, BS1; Zachariah Taylor, DO2; Benjamin E. Jacobs, MD3; David B. Cahn, DO, MBS, FACOS4
1Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania
2 Department of Urology, Main Line Health, Philadelphia, Pennsylvania
3 Department of Hematology Oncology, Alliance Cancer Specialists, Media, Pennsylvania
4 Department of Urology, MidLantic Urology, Media, Pennsylvania
KEYWORDS:
Bladder cancer; immunotherapy; Guillain-Barre syndrome
Abstract
As nivolumab becomes more prevalent in the treatment of urothelial carcinoma, the need for additional data on immune-related adverse events and their management is apparent. The use of nivolumab has been associated with mild side effects such as pruritus, diarrhea, and fatigue, but less common but more serious neurologic side effects, such as Guillain-Barré syndrome, are not well described in the literature. This report presents the diagnostic process for Guillain-Barré syndrome following nivolumab induction for muscle-invasive urothelial carcinoma of the bladder, including the treatment method, clinical course, and associated literature review, to characterize standard therapy and patient outcomes.
The programmed cell death 1 protein (PD-1) receptor is expressed on T cells and diminishes the immune response upon binding to its ligands, programmed cell death 1 ligand 1 (PD-L1) and PD-L2, on antigen-presenting cells. Immune checkpoint inhibitors are antibodies that have transformed cancer treatment by targeting a malignant tumor cell’s ability to use PD-L1 to evade the immune response.1 Nivolumab is a fully human monoclonal immunoglobulin G4 immune checkpoint inhibitor against PD-1 expressed on T cells. Its use has been US Food and Drug Administration approved for urothelial carcinoma as an adjuvant treatment for adult patients who are at high risk of recurrence after radical resection (ie, stage T3-T4, ypT2, or node-positive disease) as frontline therapy in combination with cisplatin and gemcitabine or after platinum-containing chemotherapy.2
Although proven to be an effective therapy for a variety of cancers, nivolumab also presents with unique immune-related adverse events (irAEs). The most common AEs for nivolumab, as evaluated by the CheckMate 274 trial, were pruritus (23.1%), fatigue (17.4%), and diarrhea (16.8%).2 Neurologic AEs were not reported in this trial, but a recent review of the literature estimated that neurologic toxicity occurs in 1% to 5% of patients treated with immune checkpoint inhibitors.3 A 2019 pharmacovigilance database study found that immune checkpoint inhibitors were associated with neuromuscular junction dysfunction, noninfectious encephalitis and myelitis, peripheral neuropathy (with Guillain-Barré syndrome being the most common), and noninfectious meningitis.4
The relationship between nivolumab and Guillain-Barré syndrome is well documented in the treatment of melanoma and lung cancer,5,6 but only 1 other case of Guillain-Barré syndrome following nivolumab treatment for muscle-invasive urothelial carcinoma has been reported to date.7 Although this report presents a similar case, there are important distinctions between the 2 rare cases.
The 2019 case involved urothelial carcinoma treated with cystectomy and adjuvant chemotherapy, which eventually led to recurrent disease and lung metastases. In contrast, our case involves the avoidance of chemotherapy altogether. This is an important case to report because it indicates that nivolumab-induced Guillain-Barré syndrome in the treatment of urothelial bladder carcinoma is not isolated. With the increasing number of indications and subsequent use of nivolumab for urologic malignancies, urologists and urologic oncologists need to be aware of the potential neurologic side effects, the necessity for expedited recognition, and immediate treatment to potentially prevent devastating outcomes.
A 73-year-old man with a history of paroxysmal atrial fibrillation, stage 3 chronic kidney disease, and iron deficiency anemia was diagnosed with muscle-invasive urothelial carcinoma of the bladder and a nearly obstructing right colon mass. He was not a candidate for neoadjuvant cisplatin chemotherapy, and he underwent robot-assisted radical cystoprostatectomy, bilateral pelvic lymph node dissection, right hemicolectomy, and creation of an ileal conduit urinary diversion. Final pathology revealed pT3N1 urothelial carcinoma of the bladder, incidental Gleason score 1 adenocarcinoma of the prostate with perineural invasion, and tubular adenoma of the colon.
After his recovery from surgery, the patient was started on adjuvant nivolumab immunotherapy, receiving 3 cycles of 240 mg intravenous nivolumab. Two days after the third dose, he began experiencing lower extremity weakness that prevented ambulation, followed by progressive upper extremity weakness and areflexia. Upon hospital admission, a magnetic resonance imaging scan of the cervical, thoracic, and lumbar spine showed enhancement of the nerves (Figure 1), predominantly in the lumbar spine, including the cauda equina nerve roots. A subsequent lumbar puncture revealed an elevated cerebrospinal fluid protein level (>600 mg/L) with normal cerebrospinal fluid cell counts (albuminocytologic dissociation), confirming Guillain-Barré syndrome.
The patient was started on methylprednisolone 1 g daily for 5 days, along with intravenous immunoglobulin 0.4 g/kg/d for 5 days. Because of a lack of clinically significant improvement, he then underwent plasma exchange therapy, which also did not result in clinically significant neurologic improvement. Unfortunately, his clinical course has been complicated by multiple hospital admissions for sepsis and acute decompensation, necessitating inpatient rehabilitation. He currently remains bedbound and receives home care.
Although PD-1 inhibitors are commonly used in melanoma and various forms of lung cancer, the use of nivolumab in the treatment of urothelial carcinoma remains in its early stages. The most common irAEs of nivolumab include pruritus, fatigue, diarrhea, and rash. These are mild compared with the typical side effects of PD-1 and PD-L1 inhibitors, such as hypothyroidism, arthritis, and pneumonitis, which have been well described with nivolumab.8 Aside from a 2019 case report by Kyriazoglou et al,7 we present the only other case of nivolumab-induced Guillain-Barré syndrome after treatment for urothelial carcinoma of the bladder.
A literature search of the PubMed database using the keywords nivolumab and Guillain-Barré syndrome yielded 31 results: 19 case reports or series, 2 retrospective studies, and 10 review articles. Table 1 lists the clinical characteristics of patients treated solely with nivolumab, with or without adjuvant chemotherapy. Studies were excluded if they reported treatment with multiple immune checkpoint inhibitors. The median (IQR) number of treatment cycles at the time of Guillain-Barré syndrome diagnosis was 4 (3.00-6.75) cycles.
Interestingly, both Tanaka et al9 and Nukui et al10 described a change from an initial Guillain-Barré syndrome diagnosis to chronic inflammatory demyelinating polyneuropathy and multiple cranial neuropathy with demyelinating polyradiculoneuropathy, respectively, based on response to treatment. McNeill et al11 described a Miller Fisher variant of Guillain-Barré syndrome characterized by a triad of ophthalmoplegia, ataxia, and areflexia.
Nine of 10 patients were treated with intravenous immunoglobulin, 6 received concurrent steroid therapy, 1 received plasma exchange, 1 received pyridostigmine, and 1 received only steroid pulse therapy. Five patients experienced resolution of symptoms, 2 experienced partial resolution, 1 required chronic steroids, and 2 patients died. Although neurologic AEs from immune checkpoint inhibitors are uncommon, the consequences of late diagnosis can be fatal. This finding underscores the importance of maintaining a low threshold for hospitalization and the need to fine-tune treatment regimens.
Our case demonstrates the potentially devastating complications of immunotherapy. Although the oncologic benefits are well defined, caution should be exercised in prescribing these medications. Lifethreatening irAEs can result in exclusion from further cancer therapy because of permanent changes in functional status, which is a life-altering consequence.
Risk factors for developing irAEs have not been well characterized in the literature because studies typically focus on specific cancer types, immune checkpoint inhibitors, or side effects. A 2022 review published in Frontiers in Immunology by Chennamadhavuni et al12 identified various risk factors associated with irAEs, grouped into 3 categories: patient specific (eg, demographics, medical history, social history, or medication use), tumor specific (eg, higher disease burden), and agent specific (eg, combination with chemotherapy).
This case report and review of the literature highlights the importance of a thorough medical and social history, medication review, and consideration of the aggressiveness of the malignancy for any urologist starting patients on PD-L1 inhibitors. In addition, there remains a need to identify risk factors for neurologic side effects in urologic cancers so that practicing urologists are better equipped to treat this patient population, ultimately resulting in better patient outcomes.
Immune-related AEs can be devastating for patients. Because of the rarity of these complications, no prospective trials have been conducted to determine the best treatment for irAEs associated with immune checkpoint inhibitors. Because the Food and Drug Administration is increasingly approving immune checkpoint inhibitors for the treatment of urologic cancers, a deeper understanding is needed to determine which patients are at the highest risk of these complications and how to facilitate these patients’ full recovery.
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Published: June 23, 2025. Conflict of Interest Disclosures: None.
Funding/Support: No funding was received for this study.
Author Contributions: All authors were involved in study conception and design, data analysis and interpretation, drafting the manuscript, and critically revising the draft for intellectual content. All authors approved the final version of the article to be published and agree to be accountable for all aspects of the work.
Data Availability Statement: Data sources are available upon reasonable request to the corresponding author.
Citation: Harlamova D, Taylor Z, Jacobs BE, Cahn DB. Nivolumab-induced Guillain-Barré syndrome in the treatment of urothelial carcinoma. Rev Urol. 2025;24(2):e107-e111.
Corresponding author: Daria Harlamova, 626 Lukens Ave, Upper Darby, PA 19082 (dh1439@pcom.edu)