Concurrent tumor lysis syndrome and 5-fluorouracil encephalopathy during the first cycle of zolbetuximab plus mFOLFOX6 for CLDN18.2-positive gastric cancer: a case report

Abstract

The safety data on zolbetuximab, a new CLDN18.2-targeting antibody for advanced gastric cancer (AGC), are still exiguous. We report herein a 75-year-old, male patient with CLDN18.2-positive, HER2-negative AGC with weight loss, massive nodal disease, and peritoneal carcinomatosis-related obstructive uropathy. First-line zolbetuximab plus mFOLFOX6 triggered grade 2 nausea, which was followed on day 3 by tumor lysis syndrome (TLS) and 5-fluorouracil (5-FU)-induced hyperammonemic encephalopathy. Discontinuation of 5-FU and supportive care consisting of hydration and rasburicase led to rapid clinical improvement. Chemotherapy, which was resumed after a dosage adjustment, achieved tumor shrinkage and resolved the hydronephrosis. To the best of our knowledge, the present study is the first to describe concurrent TLS and 5-FU-induced encephalopathy during the administration of a zolbetuximab-based regimen and highlights the need for proactive prophylaxis against TLS and for controlling nausea in AGC patients with a high tumor burden, baseline renal impairment, and cachexia.

Introduction

Claudin‑18.2 (CLDN18.2) is a gastric tight‑junction protein that becomes aberrantly exposed on the tumor cell surface when a malignant transformation disrupts epithelial polarity and junctional integrity [1, 2]. Approximately 40% of gastric and gastro‑esophageal junction (GEJ) adenocarcinomas across ethnicities and disease stages express CLDN18.2 [3].

Zolbetuximab, a first-in-class monoclonal antibody directed against CLDN18.2, received regulatory approval in Japan in June 2024 for first-line use in combination with fluoropyrimidine/platinum doublets in patients with CLDN18.2-positive, HER2-negative, advanced gastric and GEJ cancer. The pivotal, phase III SPOTLIGHT and GLOW trials demonstrated a statistically significant improvement in progression-free and overall survival as a result of administering zolbetuximab-containing regimens [4, 5]. A pooled analysis of both trials confirmed these survival benefits [6]. However, there was no notable increase in the objective response rate (ORR) (48% vs. 48% and 42.5% vs. 40%, respectively) [4, 5]. In contrast, the earlier, phase 2 FAST study had shown a 14% increase in the ORR of patients receiving zolbetuximab plus chemotherapy than of those receiving chemotherapy alone (39% vs. 25%) [7]. Despite these encouraging findings, the precise contribution of zolbetuximab to tumor shrinkage remains uncertain, and real-world safety data are still scarce.

Tumor lysis syndrome (TLS) and 5-fluorouracil (5-FU)-induced encephalopathy are both rare complications of solid malignancies [8–10]. Only a few case reports have described TLS occurring in the context of gastric cancer [11–13]. Furthermore, 5-FU-related neurotoxicity is typically attributed to hyperammonemia or dihydropyrimidine dehydrogenase (DPD) deficiency [14, 15], both of which are often exacerbated by renal dysfunction [16]. To the best of our knowledge, the co-occurrence of TLS and 5-FU encephalopathy has not previously been reported either in gastric cancer patients receiving zolbetuximab plus mFOLFOX6 or in any other clinical setting.

Herein, we present the first report of unresectable, CLDN18.2-positive gastric cancer with massive nodal involvement and peritoneal carcinomatosis-associated renal dysfunction, which led to the development of TLS and 5-FU encephalopathy following the first cycle of zolbetuximab plus mFOLFOX6.

Case report

A 75-year-old, male patient initially presented with complaints of upper abdominal discomfort, reduced oral intake, and weight loss with a body mass index of 16.3. Upper gastrointestinal endoscopy revealed a large, Borrmann type 3 advanced gastric cancer (approximately 7 cm in size) in the upper to middle third of the stomach. Esophageal invasion was also suspected (Fig. 1). A biopsy of the lesion confirmed moderately to poorly differentiated adenocarcinoma. Immunohistochemical analysis of a biopsy specimen demonstrated that the expression of mismatch repair proteins was intact. The HER2 score, PD-L1 combined positive score using clone 22C3, and CLDN18.2 expression was 0,  ≥10, and positive (≥75%), respectively (Fig. 2). Microsatellite instability testing (FALCO kit) confirmed microsatellite stability. The initial contrast-enhanced computed tomography (CT) demonstrated gastric wall thickening in the antrum and extensive lymphadenopathy extending from the para-aortic area to the right common iliac artery, with the largest lymph node measuring 6 cm in diameter. A small amount of ascites was also noted, along with right-sided hydronephrosis and hydroureter suggesting peritoneal dissemination (Fig. 3a1, a2). These findings led to the diagnosis of stage IVB gastric cancer (cT3N + M1 [LYM, PER]) based on the criteria of the Japanese Gastric Cancer Association (JGCA) classification, 15th edition, which corresponded to T3N3bM1 (Stage IV) in the Union for International Cancer Control (UICC) staging system, 8th edition.

Fig. 1.

Upper gastrointestinal endoscopy before chemotherapy. Endoscopy revealed an ulcerated lesion extending from the cardia to the lesser curvature of the lower gastric body

Fig. 2.

Histopathological and immunohistochemical findings. (a) Hematoxylin and eosin-stained section demonstrating features of a moderately to poorly differentiated adenocarcinoma. (b) Immunohistochemical staining for HER2 was negative, indicating no overexpression. (c) Immunohistochemistry found strong, membranous CLDN18.2 expression indicating positive expression

Fig. 3.

Serial CT images demonstrating disease progression and the treatment response. (Left column) Abdominal lymph node metastases; (Right column) Right-sided hydronephrosis. Top row (a1, a2): Initial CT showing extensive lymphadenopathy (a1) with mild, right-sided hydronephrosis (a2). Middle row (b1, b2): CT at hospital admission revealed further lymph node enlargement (b1) with worsening hydronephrosis (b2). Bottom row (c1, c2): Post-treatment CT demonstrated a marked reduction in lymph node size (c1) and improvement of the hydronephrosis (c2)

The patient was urgently admitted for anorexia and deteriorating renal function secondary to urinary tract obstruction. Laboratory findings demonstrated elevated serum creatinine and lactate dehydrogenase (LDH) indicating disease progression. Non-contrast CT performed at admission revealed further enlargement of the abdominal lymph nodes, which was consistent with a progressive, metastatic disease. Compression of the right ureter led to worsening hydronephrosis and deterioration of the renal function (Fig. 3b1, b2). To reduce the urinary tract obstruction, a right percutaneous nephrostomy was performed.

Zolbetuximab plus mFOLFOX6 was administered as the first-line chemotherapy. The patient received a comprehensive premedication protocol consisting of intravenous chlorpheniramine, dexamethasone, palonosetron, aprepitant, and olanzapine. The infusion of zolbetuximab (800 mg/m²) was initiated at an initial rate of 140 mg/m²/hr. Fifteen minutes later, grade 1 abdominal pain and grade 2 nausea developed (according to Common Terminology Criteria for Adverse Events [CTCAE], version 5.0). The abdominal pain was alleviated with supportive therapy, but the nausea persisted. Nevertheless, the infusion was completed without interruption. The rate was successfully escalated incrementally to a final rate of 400 mg/m²/h, allowing the full planned dose to be administered. On day 3 of the first cycle, altered mental status (grade 3) developed concomitantly with hyperammonemia, elevated AST (grade 3), elevated ALT (grade 2), hyperkalemia (grade 3), hyperuricemia (grade 3), and elevated creatinine (grade 1). Based on the Cairo-Bishop criteria [17], the concurrent hyperkalemia, hyperuricemia, hyperphosphatemia, and acute kidney injury established the diagnosis of clinical TLS (Table 1). Head CT, brain magnetic resonance imaging, and cerebrospinal fluid analysis findings were unremarkable. The altered mental status was thought to have stemmed from hyperammonemia secondary to 5-FU-induced encephalopathy. After 5-FU was discontinued, the patient was treated with intravenous fluids and rasburicase. By the following day, the patient’s mental status had improved, and his serum ammonia had markedly declined. The uric acid value normalized, and the potassium and creatinine values showed marked improvement (Fig. 4).

Table 1.

Laboratory data at key time points

Laboratory parameter	On admission	Day 3 (TLS Diagnosis)	Day 4 (Post-treatment)
Uric acid (mg/dL)	3.3	10.4	0.2
Potassium (mEq/L)	5.1	6.3	4.7
Calcium (mg/dL)	9.7	9.8	8.1
Phosphorus (mg/dL)	3.8	5.4	4.6
Creatinine (mg/dL)	1.00	1.76	1.4
LDH (U/L)	1316	2509	2305

TLS, Tumor lysis syndrome, LDH, Lactate dehydrogenase

Fig. 4.

Clinical course during the initial phase of first-line chemotherapy. Time course of clinical laboratory parameters and level of consciousness during the initial days of chemotherapy with zolbetuximab (Zol) plus mFOLFOX6 (5-fluorouracil [5-FU], leucovorin [LV], and oxaliplatin [L-OHP]). Shortly after treatment initiation, the patient experienced electrolyte abnormalities, hepatic enzyme elevation, and hyperammonemia, which were consistent with tumor lysis syndrome (TLS) and 5-FU-induced hyperammonemic encephalopathy. Grade 3 impairment of consciousness developed on day 3 in parallel with a peak in ammonia (NH₃), uric acid (UA), potassium (K), AST, and LDH levels. Rasburicase and intravenous fluids were administered. By day 4, the ammonia level and consciousness status had markedly improved. The markers continued to decline. Left nephrostomy had been performed prior to chemotherapy. 5-FU, 5-fluorouracil; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Cre, creatinine; K, potassium; LDH, lactate dehydrogenase; L-OHP, oxaliplatin; LV, leucovorin; NH₃, ammonia; TLS, tumor lysis syndrome; UA, uric acid; Zol, zolbetuximab; Cre, creatinine; K, potassium; LDH, lactate dehydrogenase; UA, uric acid; AST, aspartate aminotransferase; ALT, alanine aminotransferase; NH₃, ammonia

After the resolution of both TLS and encephalopathy, a discussion was held with the patient and his family to determine the subsequent treatment strategy through a shared decision-making process. Given the significant tumor shrinkage observed after the first cycle, which indicated a profound response to the regimen, it was concluded that the potential therapeutic benefits of continuing treatment outweighed the risks. Therefore, the decision was made to proceed with a dose-reduced regimen under careful monitoring. The second chemotherapy cycle was begun approximately three weeks after the start of the first cycle. The second cycle omitted the bolus administration of 5-FU and reduced the continuous infusion by 50%. After two cycles of chemotherapy, follow-up contrast-enhanced CT demonstrated a reduction in the gastric wall thickening and a marked decrease in the size of multiple, metastatic lymph nodes. The right-sided hydronephrosis and hydroureter had also improved (Fig. 3c1, c2), and the serum creatinine level was normal. The patient was discharged after approximately 6 weeks of hospitalization. Given the improvement in his renal function and tumor burden, the nephrostomy tube was removed. He is now receiving outpatient chemotherapy with the same regimen (with modified 5-FU dosing), which he has been able to tolerate well.

Discussion

TLS occurs predominantly in the context of hematological malignancies, such as leukemia and malignant lymphoma, which are characterized by rapid, cellular turnover and high sensitivity to cytotoxic agents. In contrast, TLS is rarely observed in solid tumors with an overall incidence estimated at 1–5% and an average of 3.6%. In gastric cancer specifically, the incidence of TLS remains unclear, with only sporadic case reports available [11–13]. Established risk factors include high tumor burden pre-existing renal dysfunction, and elevated LDH levels [18, 19]. Our patient indeed presented with a high tumor burden—evidenced by multiple lymph node metastases and peritoneal dissemination—and an elevated baseline LDH level, placing him at increased risk. Gastric cancer typically has a modest response rate of approximately 40–50% to standard chemotherapy regimens without molecularly targeted agents [4, 5, 20, 21], and the risk of TLS is generally considered low. Moreover, past studies have reported that adding zolbetuximab failed to produce a significant improvement in the therapeutic response [4, 5]. In the present case, however, disease progression on imaging studies and a tendency for the LDH value to rise indicated an increasing tumor burden and accelerated proliferation. While the specific contribution of zolbetuximab to improving the patient’s condition remains uncertain, its combination with chemotherapy may have elicited a strong, antitumor response, which then triggered TLS.

Pretreatment, renal function is also a significant factor in assessing the TLS risk. In our case, peritoneal metastasis likely contributed to obstructive uropathy, which in turn resulted in the baseline, post-renal dysfunction. CLDN18.2 is more frequently expressed in diffuse, Lauren-type gastric cancer, a subtype often associated with peritoneal dissemination [22–24]. Accordingly, proactive prophylaxis against TLS should be considered when starting zolbetuximab therapy in combination with chemotherapy for patients with these high-risk features.

In addition to TLS, gastrointestinal toxicity appeared to have significantly influenced the patient’s renal function. Zolbetuximab is commonly associated with gastrointestinal adverse events. In two pivotal trials, SPOTLIGHT and GLOW, patients receiving zolbetuximab-containing regimens exhibited a notably high incidence of nausea and vomiting. Nausea was reported in 68.5% (GLOW) to 82% (SPOTLIGHT), and vomiting occurred in 66.1% (GLOW) to 67% (SPOTLIGHT), of the patients [4, 5]. An integrated analysis of these two studies interestingly demonstrated that nausea and vomiting most commonly occurred during the initial zolbetuximab infusion and affected 58% and 43% of the patients, respectively, with the incidence of both adverse events declining substantially with subsequent infusions [25]. Furthermore, this analysis indicated that a slower infusion rate and the concomitant use of multiple antiemetics helped mitigate the nausea and vomiting [25]. In the present case, however, the inability to control nausea completely despite the administration of NK1 receptor antagonists, corticosteroids, H1 receptor antagonists, and olanzapine underscored the challenge of managing this adverse effect. Grade 2 nausea, which emerged immediately after zolbetuximab administration and persisted for some time, led to a reduction in oral intake, exacerbation of dehydration, and consequent impairment of the renal function.

It is likely that multiple factors in the present case converged to impair 5-FU clearance, thereby precipitating hyperammonemic encephalopathy. First, renal dysfunction is a risk factor of hyperammonemia during fluorouracil therapy [16]. As mentioned above, the post-renal obstruction due to peritoneal metastasis resulted in our patient’s baseline renal dysfunction. This was further exacerbated by TLS-induced acute kidney injury and prerenal hypovolemia secondary to persistent anorexia following zolbetuximab administration. The underlying, renal impairment may have predisposed the patient to impaired clearance of 5-FU and its metabolites, thereby resulting in metabolic complications. A previous study reported that α-fluoro-β-alanine (FBAL), a fluorouracil metabolite, may increase 5-FU-related toxicity in patients with renal impairment by its tendency to accumulate [26]. Second, the key role played by skeletal muscle in ammonia metabolism suggested that the patient’s pre-treatment cachexia may have further impaired ammonia clearance [27, 28]. Together, these factors likely acted synergistically to elevate the risk of altered consciousness status during 5-FU administration. Dihydropyrimidine dehydrogenase (DPD) deficiency is a known risk factor for severe 5-FU-related toxicities. However, testing for this condition was not performed in the present case. In Japan, DPD testing is not covered by national health insurance and is not routinely conducted, partly because its reported prevalence among the Japanese population is extremely low—approximately 0.7% [29]. The optimal strategy for re-challenging with 5-FU after an episode of encephalopathy remains unclear. However, several case reports have described successful and safe continuation of therapy with a dose reduction to 50–80% [10, 30]. Guided by this precedent, we decided to resume treatment by omitting the 5-FU bolus and reducing the continuous infusion dose by 50%.

To the best of our knowledge, the present report is the first to document a case of TLS co-occurring with 5‑FU‑associated encephalopathy during the first cycle of zolbetuximab plus mFOLFOX6 therapy. This case underscores the importance of heightened vigilance when administering cytotoxic chemotherapy with zolbetuximab in patients with advanced gastric cancer, particularly those with a high tumor burden, renal dysfunction, and cachexia. Early recognition and prevention of TLS, along with aggressive management of gastrointestinal toxicity and close monitoring for signs of encephalopathy, are essential for improving outcomes in this setting.

Author contributions

T. Tamura and Y. Kanemasa drafted the manuscript. T. Tamura, Y. Kanemasa, Y. Masuda, N. Kanai, K. Ishimine, T. Sawabe, M. Mino, A. Takahara, S. Nakamura, T. Okuya, Y. Yagi, S. Matsuda, S. Horiguchi, and T. Shimoyama participated in the patient’s treatment. All the authors have read and approved the final manuscript.

Funding

None.

Data availability

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

Declarations

Conflicts of interest

The authors declare no conflicts of interest.

Informed consent for publication

Informed consent was obtained from the patient for the publication of this report and the use of the accompanying images.

Human rights statement

This study was conducted in accordance with the Ethical Principles for Medical Research Involving Human Subjects as outlined in The Declaration of Helsinki.