5-Fluorouracil-Related Lactic Acidosis in a Patient with Colon Cancer.

Introduction
The combination of 5-fluorouracil (5-FU) and oxaliplatin is commonly used as chemotherapy for colorectal cancer, and various adverse effects of 5-FU have been documented (1). Although cases of encephalopathy due to hyperammonemia during FOLFOX therapy have been reported, lactic acidosis associated with 5-FU-based treatment remains rare (2-8). We present the clinical case of a 36-year-old woman who developed lactic acidosis during mFOLFOX6 and FOLFIRI therapy, and review the possible mechanisms underlying this metabolic abnormality.

Case Report
A 36-year-old Japanese woman was referred to our hospital with multiple liver tumors. Colonoscopy and computed tomography (CT) revealed a tumor in the sigmoid colon (Fig. 1A), and histological examination confirmed adenocarcinoma. The tumor was negative for microsatellite instability and BRAF V600E mutations. A KRAS codon 13 G13D mutation was detected. CT and magnetic resonance imaging (MRI) further revealed metastases to the liver, lungs, and brain (Fig. 1B-D). Due to concerns about tumor-induced obstruction, colostomy was performed. On postoperative day 16, mFOLFOX6 [oxaliplatin 85 mg/m2, folinic acid 200 mg/m2, 5-FU 400 mg/m2 (bolus), and 5-FU 2,400 mg/m2 (continuous infusion)] was initiated at 80% of the standard dose (5-FU 2,920 mg/body) to mitigate the risk of tumor lysis syndrome. Given the proximity to surgery, bevacizumab (Bmab) was excluded from the initial chemotherapy regimen. Two days after completing 5-FU administration, the patient experienced a loss of consciousness and convulsions. Head CT revealed no hemorrhage, but blood tests indicated lactic acidosis (pH, 7.137; lactate, 10 mmol/L) and hyperammonemia (143 μg/dL) (Table 1). The patient had no history of epilepsy. Although the levels of white blood cells, transaminases, and lactate dehydrogenase were elevated, no significant changes were observed in comparison to the pre-chemotherapy values. Furthermore, the serum levels of uric acid, potassium, phosphate, and calcium remained within normal limits, making the diagnosis of tumor lysis syndrome unlikely. The liver synthetic function and bilirubin levels were within the normal limits, and there was no evidence of liver failure. There was no concomitant use of biguanides or antiviral agents. Two sets of blood cultures were obtained, both of which were negative. The patient was admitted to the intensive care unit and treated with 125 mL of 7% sodium bicarbonate. Following treatment, her consciousness returned, seizures resolved, and acidosis improved (Fig. 2). Branched-chain amino acids and lactulose were administered for hyperammonemia and anticonvulsants were prescribed to prevent further seizures. No antibiotics were administered. From the second chemotherapy cycle onward, Bmab (215 mg/body) and thiamine (100 mg/day) were added. Chemotherapy was administered at 50% of the standard 5-FU dose during the second cycle and was increased to 100% by the fourth cycle, with no recurrence of acidosis, although a mild increase in lactate levels was noted. After the fourth cycle, a CT scan showed progression of the pulmonary and hepatic metastases, with marked hepatomegaly and a significant portion of the liver occupied by tumors. Consequently, the chemotherapy regimen was switched to Bmab + FOLFIRI [irinotecan 150 mg/m2, folinic acid 200 mg/m2, 5-FU 400 mg/m2 (bolus), and 5-FU 2,400 mg/m2 (continuous infusion)] with irinotecan administered at 80% of the standard dose. On the final day of 5-FU administration, although the patient had no subjective symptoms, acidosis and elevated lactate levels (pH 7.273, lactate 10.6 mmol/L) were observed. The ammonia levels were not measured. The acidosis resolved following the administration of 100 mL of 7% sodium bicarbonate. Subsequently, there was no recurrence of acidosis; however, the patient's overall condition gradually deteriorated, and she died on the fourth day after completing the treatment.

Ethics
The patient provided her informed consent for the publication of this case report. The Research Ethics Committee of the International University of Health and Welfare approved this report for publication (approval no. 24-TK-006).

Discussion
Lactic acidosis is a rare complication of cancer and is generally classified into two types: type A, caused by hypoxia, and type B, resulting from metabolic abnormalities unrelated to the oxygen supply. In this case, no circulatory failure or hypoxia was observed (124/78 mmHg, SpO2 98%), suggesting a type B lactic acidosis. Thiamine deficiency, which inhibits the oxidation of pyruvic acid to acetyl-CoA, leading to lactic acidosis, was not observed as the patient's blood thiamine level was normal. Hypotriglyceridemia is a potential risk factor for lactic acidosis due to impaired lipolysis and decreased adenosine triphosphate (ATP) production. However, the patient's triglyceride level was within the normal range. 5-FU has been linked to type B lactic acidosis (7,8) by reducing intracellular thiamine levels, impairing metabolism, and leading to lactate accumulation. Additionally, 5-FU disrupts the tricarboxylic acid cycle (9,10), reduces ATP production, and increases anaerobic glycolysis, which further contributes to lactate accumulation. Thus, 5-FU was believed to have induced lactic acidosis in this case. Although thiamine was administered from the second cycle of chemotherapy, lactic acidosis recurred. Tumor cells themselves produce lactate (11), and elevated lactate levels have been observed even prior to 5-FU administration. Furthermore, because lactate is metabolized and cleared by the liver, a reduced number of functional hepatocytes due to a high tumor burden may have contributed to lactate accumulation. Although thiamine supplementation is effective in preventing lactic acidosis, it is likely that thiamine supplementation alone would have been insufficient in this case due to the high hepatic tumor burden.
A loss of consciousness was observed in the patient. Reversible posterior leukoencephalopathy syndrome (RPLS) has been associated with 5-FU administration (12,13). Additionally, reduced ATP levels impair the urea cycle, leading to hyperammonemia (10,14), which can cause encephalopathy. Hyperammonemia was observed in this case; however, the symptoms resolved rapidly after the correction of acidosis with sodium bicarbonate. On the third day after the onset of lactic acidosis, brain MRI revealed no edematous changes in the occipital and parietal white matter characteristics of RPLS, and no abnormalities other than brain metastases were observed. Thus, RPLS and hyperammonemia were unlikely to be the primary causes. To further contextualize this case, we compared our case with previously reported cases of 5-FU-associated lactic acidosis. As shown in Table 2, although the patient characteristics and lactate levels varied among cases, lactic acidosis typically developed during or shortly after the administration of 5-FU, even at standard or reduced doses. Our patient shared several features with previously reported cases, including significant lactate elevation and a favorable response to supportive care. However, the recurrence of lactic acidosis despite thiamine supplementation is unique. This comparison highlights the importance of the early recognition and management of 5-FU-associated lactic acidosis, even in patients with atypical backgrounds. The loss of consciousness and convulsions were attributed to lactic acidosis. Seizures were also suspected to be related to brain metastasis, leading to the administration of anticonvulsants and the initiation of brain radiation therapy after the fourth chemotherapy cycle. In the present case, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) were considered in the differential diagnosis; however, the patient did not exhibit characteristic features such as recurrent headaches, vomiting, psychiatric symptoms, short stature, diabetes, hearing loss, or cardiomyopathy. The patient had no relevant family history. Dihydropyrimidine dehydrogenase (DPD) deficiency was also considered in the differential diagnosis; however, genetic testing was not performed.
In conclusion, this report describes a case of colon cancer complicated by lactic acidosis during 5-FU chemotherapy. Lactic acidosis should be recognized as a potential adverse effect of 5-FU. If lactic acidosis occurs, it is crucial to consider reducing the dosage of 5-FU or switching to a regimen that does not include 5-FU.

The authors state that they have no Conflict of Interest (COI).