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  Table of Contents  
Year : 2018  |  Volume : 55  |  Issue : 4  |  Page : 413-414

Creatinine kinase elevation and peripheral neuropathy during nivolumab treatment of a patient with metastatic renal cell carcinoma

Department of Medical Oncology, Ataturk University Faculty of Medicine, Erzurum, Turkey

Date of Web Publication28-Feb-2019

Correspondence Address:
Melih Simsek
Department of Medical Oncology, Ataturk University Faculty of Medicine, Erzurum
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_151_18

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 » Abstract 

We report elevation of creatinine kinase (CK), which is an uncommon adverse event related to treatment with nivolumab. Nivolumab is a monoclonal antibody against programmed cell death-1 and an effective agent in metastatic renal cell carcinoma (RCCa). Here, we report a case of 58 year-old male receiving nivolumab as fourth-line treatment for metastatic RCCa. The patient was admitted to our clinic with pelvic pain and weakness in his legs. Elevated CK level was noted and he was hospitalized. About 1 mg/kg methylprednisolone was initiated and nivolumab was discontinued. On the second day of his hospitalization, left facial palsy occurred. After his neuropathy improved and CK level normalized, the patient was discharged. Neurological immune-related adverse events are very rare with nivolumab but can be serious.

Keywords: Nivolumab, renal cell carcinoma, creatinine kinase

How to cite this article:
Simsek M, Bilici M, Tekin SB. Creatinine kinase elevation and peripheral neuropathy during nivolumab treatment of a patient with metastatic renal cell carcinoma. Indian J Cancer 2018;55:413-4

How to cite this URL:
Simsek M, Bilici M, Tekin SB. Creatinine kinase elevation and peripheral neuropathy during nivolumab treatment of a patient with metastatic renal cell carcinoma. Indian J Cancer [serial online] 2018 [cited 2022 Jul 4];55:413-4. Available from:

 » Introduction Top

Immune regulatory monoclonal antibodies inhibiting immunological check points like the T-lymphocyte-associated antigen 4 (CTLA4) and the programmed cell death-1 (PD-1) receptor pathways have been developed in recent years.[1] Nivolumab is a monoclonal antibody against PD-1 and has demonstrated a durable response in advanced malignancies such as malignant melanoma, non-small cell lung cancer, and renal cell carcinoma (RCCa).[2],[3] Nivolumab was first approved by FDA in 2015 for metastatic RCCa. However, the optimal duration of treatment with anti-PD-1 agents is unknown. The majority of immune-related adverse events (IrAEs) were observed in the first 6 months of treatment, but toxicity may occur later with ongoing therapy.[4] The most common IrAEs due to immune checkpoint inhibitors are interstitial pneumonitis, colitis, vitiligo, autoimmune hepatitis, and endocrine dysfunction.[4] Here, we report a case of 58 year-old man with metastatic RCCa who was treated with nivolumab as fourth-line treatment.

 » Case Report Top

The patient was 52 years old at diagnosis and 58 years old at the time of neuropathic adverse event was evaluated for hematuria and a right renal mass was detected with ultrasonography. He had no comorbidities. He had smoked two packs of cigarettes per day for 20 years and had no alcohol consumption. On January 2012, right radical nephrectomy was performed and pathology was revealed as T1N0Mx clear cell RCCa. On February 2012, multiple metastases in lungs, liver, and bones were determined on computerized tomography. The Memorial Sloan Kettering Cancer Center Score for RCCa of our patient was calculated as 2 and fell into intermediate risk group. After palliative radiotherapy for bone metastasis, interferon-alpha-2b was initiated. Because of insurance conditions in our country in 2012, powerful agents like sunitinib and pazopanib could not be used as first-line treatment unless there was intolerance to interferon or there was disease progression under interferon treatment. Because of intolerance, interferon-alpha-2b was discontinued and sunitinib treatment was initiated on March 2012. On May 2014, progression in bone lesions occurred, and after second-line palliative radiotherapy, everolimus with a dose of 10 mg/day was initiated. After 1 year of everolimus treatment initiation, progression of bone lesions and lung metastasis was seen with positron emission tomography on March 2015. After third-line palliative radiotherapy for bone lesions, axitinib treatment was initiated. In December 2015, there was progression and we applied to early access for nivolumab. Nivolumab 3 mg/kg per body weight (total dose of 225 mg) was initiated on April 2016 and was administered intravenously every 14 days. After 10 weeks from the initial dose, the patient was admitted to our clinic to receive his sixth cycle of treatment with complaints of pelvic pain and weakness in his legs. Glucose level was 94 mg/dL, creatinine 1.3 mg/dL, AST 55 U/L, ALT 33 U/L, total bilirubin 1.9 mg/dL, direct bilirubin 1 mg/dL, CRP 113 mg/L, TSH 82, LDH 533 U/L, total protein 8.4 g/dL, albumin 3.5 g/dL, and creatinine kinase 2440 U/L (reference value for CK from Ataturk University, Medical School Hospital, for males is 38–174 U/L). After first evaluation, we hospitalized the patient. A rapid onset of symmetrical motor weakness in the legs and left peripheral facial palsy occurred on the second day of his hospitalization. Bilateral hypoesthesia, hypoalgesia, and deep sensory disturbance on thighs were determined with neurological examination. The plantar reflex and the tone of legs were normal. Neurology specialist considered a diagnosis of facial palsy caused by lower motor neuron (LMN) deficit. Higher mental status of the patient was normal. There was grade 1–2 neurological dysfunction. Analysis of CSF was not suggested after evaluation of neurology specialist. After first evaluation of the patient by neurology department, no association with any neurological diseases was determined. As a consequence, the situation was considered to be immune-related. Because most of the immune checkpoint inhibitor-related adverse events are treated with a corticosteroid, and the suggested standard dose of methylprednisolone for managing the grade 1–2 IrAEs caused by immunotherapies is 1–2 mg/kg/day, we initiated methylprednisolone with a dose of 1 mg/kg/day. Nivolumab treatment was discontinued. No evidence of metastasis, ischemic, and/or hemorrhagic events was found in magnetic resonance imaging (MRI) of brain. Lumbar spinal MRI showed pathological compression fracture due to bone metastasis at L1 vertebral corpus. There were no compressive myelopathy signs at the time of MRI and the complaints of the patient were resolving. After neurological complaints and signs of the patient were resolved, the patient was discharged from our clinic and transferred to clinic of orthopedics for surgery of pathological compression fracture.

 » Conclusion Top

In recent years, anti-PD-1 monoclonal antibodies have shown significant clinical benefits in many different cancer types. Nivolumab is one of these agents and had shown clinical efficacy in RCCa. Clinical improvement with nivolumab treatment in patients with RCCa often occurs at first response assessment and durable responses are observed thereafter. However, there is no defined optimal duration of treatment with nivolumab in metastatic RCCa. Although it has clinical benefit, immune-related toxicities due to nivolumab are not uncommon. Here, we aimed to discuss an immune-related neuropathy due to nivolumab treatment that was not reported so common.

The majority of adverse events reported with anti-PD1 and anti-CTLA4 monoclonal antibodies have been grade 2 or lower, and reversible. The incidence of grade 3–5 toxicities across different cohorts in Keynote-001[5] and Keynote-006[6] was reported as 13%. These toxicities include pneumonitis (<1%), fatigue (<1%), colitis (<1–3%), diarrhea (<1–3%), hypophysitis (<1%), hypothyroidism (<1%), nausea (<1%), and arthralgia (<1%).

Neurological IrAEs seem to be rare with both ipilimumab and nivolumab treatments. The incidence of neurological IrAEs in phase II and III trials was reported as 0.1% for ipilimumab.[7] Neurological disorders due to ipilimumab treatment have been reported in six case reports.[8],[9] The most common immune-related toxicities which were reported in less than 1.0% of the patients receiving nivolumab were uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain–Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, and sarcoidosis. Reports suggest that although neurological irAEs are rare for both ipilimumab and nivolumab, they can become severe or even fatal.[8],[9] Therefore, early diagnosis and proper intervention are very important for both previously identified IrAEs and neurological IrAEs. Most of the IrAEs were treated with steroids and intravenous immunoglobulin (IVIg) therapies. Similarly, the majority of reported cases of neurological disorder associated with ipilimumab or nivolumab have been treated with either a steroid or IVIg.[8],[9]

Although durable responses with immunotherapeutic agents in different types of cancers were reported, they are not without toxicities. The relationship between the toxicities and tumor response is not clear yet. Because of this, further studies are needed to elucidate this correlation more accurately. It is very important to monitor the patients on anti-PD-1 treatments to determine the risks of toxicity, its severity, and reversibility.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 » References Top

Postow M, Callahan MK, Wolchok JD. Beyond cancer vaccines: A reason for future optimism with immunomodulatory therapy. Cancer J 2011;17:372-8.  Back to cited text no. 1
Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-35.  Back to cited text no. 2
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803-13.  Back to cited text no. 3
DiGiacomo AM, Biagioli M, Maio M. The emerging toxicity profiles of anti-CTLA-4 antibodies across clinical indications. Semin Oncol 2010;37:499-507.  Back to cited text no. 4
Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial. Lancet 2014;384:1109-17.  Back to cited text no. 5
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015;372:2521-32.  Back to cited text no. 6
Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 2015;33:1889-94.  Back to cited text no. 7
Bot I, Blank CU, Boogerd W, Brandsma D. Neurological immune related adverse events of ipilimumab. Pract Neurol 2013;13:278-80.  Back to cited text no. 8
Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S. Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. Neuro Oncol 2014;16:589-93.  Back to cited text no. 9


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