Journal of Cancer Research and Practice

CASE REPORT
Year
: 2020  |  Volume : 7  |  Issue : 3  |  Page : 127--129

Gemcitabine/cisplatin/pembrolizumab-induced posterior reversible encephalopathy syndrome


Yuh- Ching Gau, Hui- Ching Wang, Hui- Hua Hsiao, Yi- Chang Liu 
 Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

Correspondence Address:
Dr. Yuh- Ching Gau
Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Sanmin District, Kaohsiung City 80756
Taiwan

Abstract

Posterior reversible encephalopathy syndrome (PRES) is a syndrome related to endothelial dysfunction and disorder in cerebral autoregulation. The clinical manifestations include seizures, headache, mental alteration, and visual disturbance. The causes of PRES are diverse and include renal failure, transfusion, transplantation, endocrine disorders, autoimmune diseases, and cytotoxic and immunosuppressive agents. Various anti-cancer drugs such as gemcitabine and platinum can also cause PRES, and a few case reports have discussed the effect of immunotherapy on PRES. In this article, we present a case who developed PRES after receiving gemcitabine, cisplatin, and pembrolizumab. We also review previous cases with gemcitabine/cisplatin- and immunotherapy-induced PRES. Most of these cases had a good clinical outcome, the resolution of neurologic signs varied from days to weeks.



How to cite this article:
Gau YC, Wang HC, Hsiao HH, Liu YC. Gemcitabine/cisplatin/pembrolizumab-induced posterior reversible encephalopathy syndrome.J Cancer Res Pract 2020;7:127-129


How to cite this URL:
Gau YC, Wang HC, Hsiao HH, Liu YC. Gemcitabine/cisplatin/pembrolizumab-induced posterior reversible encephalopathy syndrome. J Cancer Res Pract [serial online] 2020 [cited 2020 Dec 3 ];7:127-129
Available from: https://www.ejcrp.org/text.asp?2020/7/3/127/294020


Full Text



 Introduction



Posterior reversible encephalopathy syndrome (PRES) was first introduced in 1996 as a syndrome related to disorders of cerebral autoregulation and endothelial damage. The pathophysiology involves the breakdown of the blood–brain barrier leading to interstitial extravasation of plasma and macromolecules.[1] Clinical manifestations include seizures, headache, mental alteration, and visual disturbance. The causes of PRES are very diverse and include renal failure, transfusion, transplantation, endocrine disorders, autoimmune diseases, and cytotoxic and immunosuppressive agents.[2] Various anticancer drugs including gemcitabine and platinum can also cause PRES; however, few case reports have discussed immunotherapy-related PRES. Herein, we present a case with gemcitabine/cisplatin/pembrolizumab-induced PRES and accomplish a review of the literature. Ethical approval for this study was obtained from our hospital, and we informed both the patient and the patient's family about this study and obtained written informed consent (T-KMUH-17043).

 Case Report



This 59-year-old female denied any previous systemic diseases and had an Eastern Cooperative Oncology Group performance status of 0–1. She had felt low back pain for 2 months (since February 2018). Urothelial carcinoma with multiple lung and bone metastases was diagnosed after a series of examinations. Spinal magnetic resonance imaging (MRI) disclosed multiple pathological fractures in bilateral hip bones, right acetabulum, and multiple vertebral bodies. She received image-guided radiotherapy to spinal metastatic lesions with a total dose of 3000 cGy/10fx from April 2018 to May 2018. Her low back pain worsened after spinal radiation, so she received laminectomy and tumor removal surgery. We started immunotherapy (pembrolizumab 100 mg on day 1) combined with gemcitabine and cisplatin (GC, gemcitabine 1000 mg/m2 on days 1, 8, and 15, and cisplatin 60 mg/m2 on day 1, for 3 weeks) at the end of May 2018. An interim bone scan showed a dramatic improvement. However, she had nausea, abdominal discomfort, severe headache with a hypertensive emergency, and visual disturbance during the fifth cycle of chemotherapy on September 21, 2018. An initial brain computed tomography showed no intracranial lesions and an ophthalmology examination was normal. She suffered a tonic-clonic seizure with a loss of consciousness for 2 min. Hours later, she became drowsy and lethargic. There were no abnormal findings in blood tests, and cortisol level, thyroid function, and ammonia level were within normal ranges. Brain MRI revealed abnormal cortical and subcortical lesions at bilateral parieto-occipital lobes, compatible with PRES [Figure 1]. She received an anti-convulsion agent (levetiracetam) and also had a nicardipine pump for the hypertensive emergency. Her blood pressure returned to normal range after 2 days, and nicardipine pump was gradually tapered and discontinued. One day later, her visual disturbance recovered completely and she had clear consciousness. No seizure episodes occurred afterward. After 1 week, she was discharged without neurologic sequela.{Figure 1}

 Discussion



PRES is a neurological disorder with a (sub) acute onset characterized by various neurological symptoms, which may include headache, impaired visual acuity or visual field deficits, disorders of consciousness, confusion, seizures, and focal neurological deficits.[3] In a majority of patients, the clinical presentation includes elevated arterial blood pressure and may involve a hypertensive emergency. For patients with malignancy, PRES is usually encountered after multi-drug chemotherapy, especially during combination high-dose chemotherapy. The reported drugs include cytarabine, cisplatin, gemcitabine, tiazofurine, bevacizumab (Avastin), and some kinase inhibitors.[4] Few case reports have mentioned the relationship between immunotherapy and PRES. Immune checkpoint inhibitors currently approved by the Food and Drug Administration include ipilimumab (an anti-CTLA-4 monoclonal antibody); pembrolizumab and nivolumab (programmed death-1 (PD-1) antibodies), and atezolizumab, durvalumab, and avelumab (programmed death ligand-1 (PD-L1) antibodies).[5] In one mini-review discussing immune checkpoint inhibitor-related central nervous system (CNS) toxicity, 15 cases developed encephalopathies (ipilimumab monotherapy [9 of 15 cases, 60%], simultaneous or sequential use of ipilimumab with an anti-PD-1 antibody [3 of 15 cases, 20%], and anti-PD-1 monotherapy [3 of 15 cases, 20%]).[6]

The efficacy of pembrolizumab has been proven in melanoma, renal cell carcinoma, urothelial carcinoma, and non-small-cell lung cancer (NSCLC). The adverse events associated with pembrolizumab are related to an increase in immune response and include rash, pneumonitis, colitis, hepatitis, hypophysitis, nephritis, and hypothyroidism.[7] Immune-related adverse effects in neurological complications can involve both the CNS and peripheral nervous system, and the presentations range from nonspecific symptoms to clinical syndromes, including chronic inflammatory demyelinating polyneuropathy, transverse myelitis, meningitis, limbic encephalitis, and PRES.[8] The possible explanation for the association between PRES and immune checkpoint inhibitors may be the immune activation of damaged vascular endothelial cells caused by cytokine-mediated inflammatory responses.[9] Whether GC combined with pembrolizumab increases the risk of PRES is unclear.

We reviewed previous cases with gemcitabine, GC, and gemcitabine/immunotherapy-induced PRES [Table 1].[3],[9],[10],[11],[12] The initial presentations included headache, consciousness disturbance, and convulsions. Most of these cases had good clinical outcomes with full-recovery, and the resolution of neurologic signs occurred within weeks, which is consistent with previously documented cases of PRES. One 68-year-old man with advanced NSCLC with bone metastasis who received the GC regimen combined with nivolumab developed PRES after 16 days after the last dose of nivolumab, and he was successfully treated with supportive care and antihypertensive agents.[13] Another case report regarding monotherapy with pembrolizumab involved a 26-year-old woman with relapsed Hodgkin lymphoma after hematopoietic stem cell transplantation who developed PRES 10 days after her first dose of pembrolizumab.[9] Another interesting case report was a 64-year-old-woman who had advanced lung adenocarcinoma and was treated with an anti-programmed cell death-1 ligand 1 antibody (durvalumab) and vascular endothelial growth factor 2 antibody (ramucirumab) after receiving first-line cisplatin–pemetrexed and subsequently developed PRES.[11] The complexity of diseases themselves and immune reaction effects on the brain–blood barrier could be possible explanations for PRES. In summary, to recognize PRES properly, identifying the causative agent and removing offending factors is important. Robust data regarding the relationship between PRES and immunotherapy are lacking in the literature. Further investigations are needed to provide more information about immunotherapy and its association with PRES.{Table 1}

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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