Fluorouracil/oxaliplatin

Author Information

An event is serious (based on the ICH definition) when the patient outcome is:

• * death

• * life-threatening

• * hospitalisation

• * disability

• * congenital anomaly

• * other medically important event

A 69-year-old man developed coronary vasospasm during treatment with fluorouracil. Additionally, he developed neutropenia during treatment with fluorouracil and oxaliplatin for colon adenocarcinoma.

The man, who had a history of hyperlipidaemia, osteoarthritis and coronary artery disease, had undergone coronary artery bypass graft at approximately 66 years of age. Three years later, at the age of 69 years, he underwent screening colonoscopy, following which he was diagnosed with mismatch repair-proficient KRAS wild-type colon adenocarcinoma of the transverse colon. He was subsequently enrolled into a clinical trial involving chemotherapy with FOLFOX, bevacizumab and immunotherapy (anti-PD-L1 antibody and tumour-targeted vaccine). Bevacizumab was subsequently withheld (reason unspecified); FOLFOX chemotherapy comprised IV oxaliplatin 85 mg/m ² over 2h concurrently with folinic acid [leucovorin], followed by the continuous administration of fluorouracil [5-fluorouracil] infusion 1200 mg/m ² daily for over 23h in 2 doses (total dose 2400 mg/m ²/cycle). Each chemotherapy cycle was repeated every 2 weeks. However, on on day 2 following fluorouracil initiation, he experienced rhinorrhoea, nausea, mild fever and severe headache. About 46h following fluorouracil initiation, he presented to the infusion department for the disconnection of the ambulatory infusion pump of fluorouracil. He received ondansetron for nausea, but without relief. His headaches worsened, and he stated that his headaches were similar to those experienced when he was diagnosed with coronary artery disease. His vital signs, physical examinations and cardiac tests including a chest X-ray and ECG were normal. However, his troponin-I level, which was normal earlier, was found elevated. His symptoms gradually subsided, and repeat ECG showed inferoposterior ischaemia. Serial ECGs and troponins were performed until normalisation. Echocardiogram showed normal left ventricular ejection fraction, along with equivocal inferior wall motion hypokinesis. A stress test with nuclear medicine exercise did not induce ischaemia. A nasopharyngeal wash showed positive results for coronavirus. Coronary vasospasm was diagnosed following evaluation of findings.

Hence, the man's therapy with fluorouracil was stopped for cycle 2, and he continued receiving oxaliplatin and immunotherapy. He tolerated cycle 2 without complications. Genetic testing for the dihydropyrimidine dehydrogenase gene (DYPD) showed no variants known to be associated with impaired catabolism of fluorouracil. After risk-benefit analysis, he expressed his desire to continue fluorouracil during cycle 3.

Therefore, the man resumed fluorouracil at a reduced dose (50% of the initial dose). He received nifedipine and isosorbide dinitrate prior to the administration of fluorouracil for prophylaxis against coronary vasospasm; these were continued for 24h following completion of the fluorouracil infusion. During cycle 4, the dose of fluorouracil was increased to 75% of the initial dose alongside nifedipine and isosorbide dinitrate. He experienced no complications throughout cycles 3 and 4. However, he later developed neutropenia [time to reaction onset not clearly stated]; therefore, during cycle 7, the dose of oxaliplatin was reduced, and he received growth factor support. Additionally, the dose of fluorouracil was decreased. During cycles 10 and 11, he developed signs of hypersensitivity to oxaliplatin, including mild hypoxaemia and transient tachycardia. Hence, oxaliplatin was stopped during cycle 12. After 12 cycles of chemotherapy, he started receiving maintenance therapy with capecitabine. After 13 days of initiation of capecitabine, he experienced jaw pain, which resolved on the same day [aetiology not stated]. After risk-benefit analysis, capecitabine was stopped permanently [outcomes not stated].

Author comment: "Infusional [fluorouracil] is a key component of therapy for [colon adenocarcinoma] but can induce coronary vasospasm during or after infusion." "[M]arrow suppression associated with FLOX can limit treatment."