Tonic-clonic Seizures During Chemotherapy Regimen in Gastric Cancer: A Case Report

Lupu Crinela-Alina1, Blag Dorel1, Burz Claudia1, 2

1) Institute of Oncology Prof. Dr. I. Chiricuta Cluj Napoca; 2) The “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj Napoca

Introduction

Chemotherapy is a systemic drug therapy of cancer, in which cytostatics interfere with the cell’s metabolism by creating a cytolysis. Anticancer drugs generally act on targets involved in cell proliferation. Tumors are characterized by a high growth fraction, which explains the preferential effect of cytostatics on tumor cells. The lack of absolute specifics on tumor tissue trains a degree of toxicity on normal tissues, particularly those with rapid turnover (bone marrow, mucous membranes, skin, and gonads).

The term chemotherapy was first introduced by Paul Ehrlich in the late 19th century. His first research regarding color marking allowed the implementation of new methods for tracking cells and microbes. As a researcher, he founded modern hematology and the study of leukemia.

casE rEport

Journal of Radiotheraphy & Medical OncologySeptember 2014 Vol. 20 No 1: 20-23Address for correspondence: Claudia Burz Ion Chiricuta Oncology Institute 34-36 Republicii Str 400015 Cluj-Napoca, Romania Email: cburz@yahoo.fr

Due to late diagnosis, gastric cancer remains a severe disease, with a 5-year survival of 15% for all stages. Surgery is the only curative treatment. Radiotherapy and chemotherapy used as neoadjuvant or adjuvant regimens, alone or in combination, have yielded encouraging results. Regarding metastatic gastric cancer a slow but indisputable progress of palliative chemotherapy has been` observed. The main chemotherapy regimens used for the advanced stages of the disease are ECF (epirubicin, cisplatin, 5 fluorouracil), EOX (epirubicin, oxaliplatin, capecitabine), DCF (docetaxel, cisplatin, 5 fluorouracil), FOLFOX (5 fluorouracul, folinic acid, oxaliplatin), XELOX (oxaliplatin, capecitabine), with an inclination towards EOX due to low toxicity and overall survival improvement. Chemotherapy is a systemic treatment which causes a large number and a variety of side effects to the body. The toxicity limits the dose and rate of cytostatic administration. In this study we report a case of a 34 year old patient, without a personal history of pathologic disease, who developed seizures after the 4th EOX cycle for gastric cancer. After eliminating other causes through cerebral CT and IRM scans, lumbar puncture and neurological examination, it was considered that the seizures were caused by the chemotherapeutic drugs Epirubicin or Oxaliplatin.

Key words: gastric cancer; EOX chemotherapy; tonic-clonic seizures

Case report

A 34 year old patient attended the Oncology Institute “Prof. Dr. Ion Chiricuta” in January 2014 with diagnosis of gastric signet ring cell carcinoma operated pT3N3M0, stage III B.

Pre-treatment management consisted of:• Esophagogastroduodenoscopy that revealed an

ulcerated lesion at the great gastric curvature with a 3/2 cm diameter.

• CT of the abdomen:- Circumferentially thickened stomach wall in the lower gastric body and antrum (including both curvatures) with a variable depth (2 cm maximum), an eccentric luminal stenosis and irregular contour.- Multiple homogenous masses in the celiac sides, small gastric curvature, periantral – to 24 mm axial diameter, and mesenteric – to 11 mm axial diameter. - Increased densification of adjacent peri-gastric fat, without any noticeable abnormalities in the abdomen. - A dense subpleural micronodule in the middle lobe of the right lung (3.5 cm).

• Electrocardiogram: normal relations.• Chest radiograph: normal relations.

Tonic-clonic seizures during chemotherapy regimen in gastric cancer 21

The patient underwent surgery at the University Emergency Hospital Bucharest (November 2013). An exploratory laparotomy was initially performed and a voluminous gastric tumour with multiple large epigastric lymph nodes was discovered. The extemporaneous histologic examination highlighted metastasis of signet ring cell carcinoma. Surgical intervention was then performed practicing subtotal gastrectomy with the following histopathologic diagnosis: G3 gastric adenocarcinoma with areas of signet ring cell carcinoma, ulcerated and infiltrated through serous. pT3N3 G3 stage III B.

The patient was then referred to the IOCN for specialized treatment.

The patient arrived with a good health status without subjective complaints and slight postoperative weight decrease and without a personal history of pathologic disease. Physical examination: no palpable lymph nodes, without organomegaly, abdominal scar. Laboratory tests: normal CBC, normal LFT, normal kidney function tests. Normal cardiovascular examination.

Following the clinical examination and laboratory tests, adjuvant chemotherapy with EOX protocol was decided, at every 3 weeks, with the following dosage:

- Epirubicin50 mg/mp = 100 mg, iv day 1;- Oxaliplatin 130 mg/mp = 260 mg, iv day 1;- Capecitabine 1000 mg/mp = 2000 mg,po daily.Between January and March 2014 the patient received 3

EOX cycles and presented gastrointestinal toxicity (nausea and vomiting 3-4 days post-infusion) and neurotoxicity (paresthesias in hands). He showed weight gain.

In March 13 2014 the patient returned for cycle 4 EOX. At arrival: good health status, mentioning influenza and fever a few days before. Normal physical examination. Laboratory tests: normal CBC, normal kidney function tests, slight hepatic cytolysis. The 4th EOX cycle was initiated with good immediate tolerability.

In the evening, the patient ended the chemotherapy session. He experienced somnolence, temporo-spatial disorientation and headache. The on-duty doctor was called, who suspected brain metastases and administered depletive treatment. The patient was retained for evolution monitoring.

During the night, the patient evidenced vomiting, psychomotor agitation, disorientation, aggressiveness evolving in seizures and status epilepticus due to which he was transferred to intensive care. At takeover, in the intensive care, the patient was unconscious, cyanotic, showed trismus, hypersalivation, tonic-clonic seizures with no response to the specific medication, cold skin, vomiting with secretions aspiration. Blood presure = 90/60 mmHg, heart rate = 110/min, SpO2 = 70%, fever 390C. Lung auscultation: crackles and bronchial rales. An acid-base and fluid resuscitation treatment, antibiotics, corticosteroids, mannitol, antiacids, antithrombotics, parenteral nutrition was established.

On the cultures of pulmonary secretions and blood cultures, colonies of Candida Krusei and Staphiloccocus

epidermitis, Corynebacterium spp developed that caused a change in the antibiotic treatment according to antibiogram.

During hospitalization in the intensive care unit the patient was investigated, in order to elucidate the seizures causes, for:

- Cerebral and thoracic CT scan: no pathological changes; aspect of aspiration pneumonia.

- Lumbar puncture: negative cellularity, smear and culture.

- Cerebral IRM with ivcontrast: normal brain structures.- Neurological examination: normal EEG.Given the exclusion of other causes it was considered

that the seizures were caused by the chemotherapeutic drugs Epirubucin or Oxaliplatin.

The patient’s evolution was positive being discharged in a good health.

Discussions

Up to 90% of gastric cancers occur randomly, an important causal role being the environmental factors such as the diet or infections with Helicobacter pylori. The remaining 10% shows the familial forms of gastric tumours. Lauren’s classification is the most commonly used and divides adenocarcinomas in two categories: intestinal form and diffuse type. Hereditary gastric cancer appears to have a diffuse growth pattern and is less correlated with environmental factors (1)

The diffuse type of gastric cancer is characterized by the appearance of small malignant cells, poorly differentiated, dispersed or in nests, infiltrating the gastric wall and thickening its lining without forming a distinct mass and without any precursor lesion present. In some histological types the volume of intracytoplasmatic mucin compress the nucleus against the periphery of the cell, giving the classical signet ring appearance (2).

Its incidence has increased, appearing more often in young people. Unlike similar stage of intestinal types, it has a worse prognosis.

Subtotal gastrectomy with negative resection margins and regional lymphadenectomy is the treatment of choice, potentially curative, and also the best palliative method. Combined treatment using preoperative chemotherapy and/or radiation, perioperative chemotherapy or postoperative chemo-radiotherapy with surgery may reduce the risk of recurrence (3).

Single chemotherapeutic agents have low response rates. Combining several agents bring higher response rates but it is more toxic and more costly. The chemotherapy regimen of epirubicin, oxaliplatin and capecitabine (EOX) showed less toxicity and an improvement in overall survival. The dosage schedule for EOX is as follows:

- Epirubicin 50 mg/mp iv on day 1;- Oxaliplatin 130 mg/mp iv on day 1,- Capecitabine 625 mg/mp/dose twice daily days 1 to 2.1.

22 Lupu et al

Cycles are repeated every 21 days.Some toxicity is natural due to the insufficient specificity

of cytostatic for tumor cells, but without these side reactions chemotherapy may not be effective. Common toxicity to all substances manifests as hematologic (leukopenia with neutropenia) and gastrointestinal toxicity (nausea and vomiting) (4,5).

Epirubicin is an anthracycline antitumor antibiotic used in breast and gastric cancers. Among the most common adverse reactions reported to the FDA include neutropenia (3.08%), pyrexia (2.51%), febrile neutropenia (2.36%), vomiting (1.77%), and nausea (1.61%). Cardiotoxicity is a known side effect of epirubicin. The most feared cardiac toxicity is cardiomyopathy with congestive heart failure with a higher risk after a total dose of 900 mg/mp (6).

Seizures are rare (0.2%). Percent (%) represents percentage of the adverse event to all adverse events reported for the drug. According to the FDA Adverse Event Reporting System (AERS) the age of persons who developed seizures was over 40 years, with a higher frequency in people over 60 years. Most affected were females. Most of them were taking pharmorubicin for breast cancer (6-8).

In the eHealthMe study published in March 2014 from FDA and social media support, among 1435 people who had adverse reactions to epirubicin, only 3 had seizure disorders. Seizures occurred over a month but less than 6 months from initiating the treatment. The patient’s age was between 40 and 49 years old. Main conditions involved were liver cancer, therapeutic embolization, breast cancer. Other used drugs were ethyl ester of iodinated poppy-seed oil fatty acid, gelatin, optiray, uromitexan and 5 fluorouracil (6-11).

Oxaliplatin is an alkylating agent used in colorectal, pancreatic and gastric cancers. The most common side reactions are anorexia, nausea, vomiting, mild to moderate myelosuppression, LFT abnormalities. Occasionally mild nephrotoxicity, headache and allergic reactions may occur. The toxicity leading to dose-limiting include acute dysesthesias in the hands, feet, perioral area or throat, triggered or aggravated by cold, and persistent peripheral sensory neuropathy characterized by paresthesias, dysesthesias, hypesthesia and proprioception deficits. Also the dose should be reduced for renal dysfunction (12).

At doses >200 mg/mp headaches, balance disorders, seizures, delirium, neurophatymay occur. A non-convulsive encephalopathy was also reported for cisplatin therapeutic doses. It has not been established yet whether these symptoms are reversible or not. An explanation could be the affecting of the dorsal root ganglion and axonal degradation (13,14).

Overdose symptoms are represented by agitation, disorientation, lack of coordination, renal insufficiency, electrolyte abnormalities, seizures, pancreatitis. There is no specific antidote for cisplatin. The time until adverse reactions of overdose can occur can be grouped in time slots from hours to days: nausea and vomiting; days: acute

renal insufficiency, electrolyte abnormalities, peripheral neuropathy, pancreatitis (uncommon), seizures (rare); days to weeks: myelosuppression, chronic renal insufficiency, ototoxicity (15).

Another type of neuropathy induced by oxaliplatin is reversible posterior leukoencephalopathy syndrome (RPLS), a rare condition that affects the brain. Seizures, headache, altered mental function, visual impairment, hypertension could be symptoms of RPLS. Nerve problems may start with the first treatment, up to 2 day after treatment. The diagnosis is confirmed by brain imaging (16).

Other central and peripheral nervous system disorders after using oxaliplatin may be loss of deep tendon reflexes, dysarthria, Lhermitte‘s sign, cranial nerve palsies, fasciculation, and convulsions (17,18).

Conclusions

The study presents the case of a patient, without a personal history of pathologic disease, who developed seizures after the 4th EOX cycle for gastric cancer. After eliminating other causes through cerebral CT and IRM scan, lumbar puncture and neurological examination, it was considered that the seizures were caused by the chemotherapeutic drugs Epirubucin or Oxaliplatin.

According to literature, convulsions rarely occur after epirubicin use (0.2%), but may occur at doses >200 mg/mp of oxaliplatin and may indicate an overdose.

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