FLOT: 5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel

DPD: Dihydropyrimidine Dehydrogenase

EEG: Electroencephalogram

PRES: Posterior Reversible Leukoencephalopathy Syndrome

Perioperative chemotherapy became the standard of care in resectable gastric cancer [1]. The most common used regimen is the FLOT as it has shown improved overall survival compared to other regimens [2]. It consisted of continuous infusion of 5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel. Central neurologic toxicity (seizure, confusion, somnolence, cerebellar ataxia…) is a rare side effect of these drugs. We, herein, report a case of generalized tonic seizures in a patient following the first injection of FLOT.

A 73-year-old woman with recently diagnosed stage IIA (T2 N1 M0) dMMR gastric adenocarcinoma was admitted to our hospital for the first injection of FLOT. The patient had a good performance status. Her medical records included diabetes, dyslipidemia and coronaropathy. She was taking bisoprolol, furosemid, atorvastatin, acetylsalicylic acid and insulin injections. The assessment of dihydropyrimidine dehydrogenase (DPD) function returned normal. The first dose of chemotherapy was administered after premedication with corticosteroids and antihistamines. The patient was discharged home with prophylactic growth factors.

Four days later, she presented to the emergency room with asthenia and diarrhea. Accompanying family members revealed that the patient developed, early in the morning, 3 separate generalized tonic seizures with ocular revulsion that lasted less than 2 minutes and followed by full recovery. There was no urinary incontinence or post?ictal confusion. The patient denied any previous personal or family history of seizures.

On admission, blood pressure was 140/80 mmHg, heart rate 83 pulse/minute, oxygen saturation 96 %, temperature 36,5 °C and capillary blood glucose 220 mg/dl. Neurologic examination revealed no abnormalities. Laboratory workup including complete blood count, serum electrolytes, renal and hepatic function and troponin was normal. Diarrhea ceased after taking loperamide. Brain imaging (computed tomography and magnetic resonance) did not demonstrate any sign of metastases, recent hemorrhage or infarction. A cardiac assessment including holter monitoring showed no abnormalities. An electroencephalogram (EEG) done 48 hours after the seizures was unremarkable (Figure 1). No subsequent seizures were observed. Considering the dMMR status, the medical team opted to discontinue chemotherapy and refer the patient for surgery.

Figure 1:  Normal electroencephalogram in our case.

The most common cause of seizure in cancer patients is brain metastasis. Other less frequent causes that can explain this neurological symptom are systemic infections, metabolic disorders and cancer treatment [3].

In our case, after excluding other potential causes, chemotherapy appears to be the most likely factor leading to seizures. In fact, chemotherapy-induced seizures are relatively uncommon but can occur, particularly with certain drugs (Ifosfamide, Etoposide, L-Asparginase…) or in patients with several comorbidities.

Drugs used in the FLOT regimen are rarely responsible for central neurologic toxicity. Regarding Docetaxel, there have been no documented cases of seizures.

Continuous 5-Fluorouracil infusion can cause neurotoxicity during or shortly after drug administration [4, 5]. DPD deficiency represented a major risk factor. Symptoms consisted mainly of encephalopathy, cerebellar syndrome. Seizures have been rarely reported [4-9]. Elevated ammonium levels supported the causality of 5-Fluorouracil 9. In their study including 30 patients with 5-Fluorouracil induced hyperammonaemic encephalopathy, Boilève et al reported that neurologic disorders occurred 2 days after 5-Fluorouracil infusion (with seizures in 53 %) 6. Computed tomography, brain magnetic resonance and EEG showed no abnormalities respectively in 91 %, 41 % and 23 % 6.

Our patient manifested delayed neurologic toxicity (4 days after chemotherapy) with no signs of confusion or ataxia. Ammonium levels have not been assessed.

Oxaliplatin is a platinum derived drug. Its ability to cross the blood brain barrier is limited. However, in combination with other cytotoxic drugs, Oxaliplatin may cause endothelial injuries that weakness the brain endothelial wall resulting in central neurologic toxicity. Oxaliplatin induced seizures are generally associated with posterior reversible leukoencephalopathy syndrome (PRES). It is a rare condition that can involve various neurological (headache, altered mental status, seizures) and visual symptoms with high blood pressure [10]. It can, indeed, occur in normotensive patients. Brain magnetic resonance is essential for the diagnosis of PRES typically showing bilateral symmetric subcortical vasogenic edema [11]. PRES has been reported under chemotherapy with FLOT after a delay of 2 months with permanent neurologic sequelae [12]. However, in our case, neuroimaging showed no signs of PRES.

To our knowledge, 3 cases of Oxaliplatin induced seizures in the absence of PRES have been published. The first case was reported by Rahal et al [13]. A 50-year-old man with mixed adenoneuroendocrine carcinoma developed tonico-clonic seizures during the third cycle of FOLFOX (5-Fluorouracil, Leucovorin and Oxaliplatin) with no signs of PRES. He became seizure free after switching from Oxaliplatin to Irinotecan. The second case involved a 26-year-old man with metastatic colorectal cancer. The patient manifested generalized seizures following cytoreductive surgery with intraperitoneal Oxaliplatin [14]. Brain imaging was normal. The third patient was a 74-year-old woman with colorectal cancer [15]. A status epilepticus occurred 2 days after Oxaliplatin administration. Blood pressure was normal and brain magnetic resonance showed no signs of metastasis or PRES. All three cases reported favorable outcomes, with no seizure recurrence.

Our patient experienced isolated seizures without any other neurologic accompanying symptoms. She had no electrolyte abnormalities and no signs of infection. EEG and brain imaging excluded any epileptic disorder, metastasis or PRES. We believe that Oxaliplatin is the most likely culprit of this toxicity.

This case sheds light on the likelihood of seizures occurring in the absence of PRES following the FLOT regimen. Clinicians should be aware of this rare side effect to provide informative guidance to their patients, ultimately aiming to prevent adverse outcomes.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Competing Interests

• Conflict Of Interest: The authors declare that they have no conflict of interest
• Financial Interests: none
• Non-Financial Interests: none

Compliance with Ethical Standards

• Statement of Human and Animal Rights or ethical approval: This is an observational study. For this type of study ethical approval is not required
• Acknowledgments: The authors have no acknowledgments to declare
• Consent to participate and to publish: Informed consent has been appropriately obtained

Data Transparency

All authors are sure that all data and materials support their published claims and comply with field standard

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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