Efficacy and safety of intravenous administration of high-dose selenium for preventing chemotherapy-induced peripheral neuropathy in gastric cancer patients receiving adjuvant oxaliplatin and capecitabine after gastrectomy: a retrospective pilot study

Abstract

Purpose

Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting toxicity associated with oxaliplatin-based chemotherapy in gastric cancer patients. Recent studies suggest that high-dose intravenous selenium may exert neuroprotective effects in patients receiving platinum-based chemotherapy.

Methods

This pilot study analyzed patients with stage III gastric adenocarcinoma who underwent gastrectomy between January and December 2024. A total of 28 patients receiving adjuvant capecitabine plus oxaliplatin (XELOX) chemotherapy were included and divided into two groups: one receiving chemotherapy alone (non-selenium: n=17) and the other receiving an intravenous injection of selenium (2,000 μg/day) before chemotherapy (selenium: n=11). CIPN severity was assessed after the first chemotherapy cycle and at the completion of chemotherapy using standardized grading criteria.

Results

Baseline clinicopathological characteristics, including age, sex, body mass index, preoperative comorbidities, extent of resection, operation time, and hospital stay, were comparable between groups. No adverse events related to high-dose selenium administration were observed. There were no significant differences in chemotherapy-related adverse events, such as hand-foot syndrome, nausea, vomiting, diarrhea, and loss of appetite, between the two groups. While CIPN severity was similar between groups after the first chemotherapy cycle, by the end of chemotherapy, the selenium group exhibited significantly lower paresthesia severity compared to the non-selenium group (P<0.0001).

Conclusion

High-dose intravenous selenium appears to be a safe and potentially effective intervention for reducing paresthesia associated with oxaliplatin-based chemotherapy. Further large-scale prospective studies are warranted to validate these findings and establish optimal dosing guidelines.

INTRODUCTION

Gastric cancer is the fifth most common cancer and the fourth leading cause of cancer-related mortality worldwide [1]. Surgical resection with D2 lymph node dissection is the standard treatment for advanced gastric cancer. Two large-scale prospective randomized trials [2,3] demonstrated that adjuvant chemotherapy significantly improves survival compared to surgery alone. Among them, the CLASSIC trial, which evaluated the capecitabine and oxaliplatin (XELOX) regimen in South Korea, China, and Taiwan, confirmed its efficacy even in advanced stages. Consequently, oral pyrimidine-based doublet regimens, such as XELOX, have become a preferred treatment option for stage III gastric cancer [4].

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and often irreversible condition that significantly impacts the quality of life (QoL) of cancer patients undergoing chemotherapy. It manifests as a dose-limiting neurotoxicity, most commonly associated with oxaliplatin, a key component of the XELOX regimen [5]. CIPN presents as sensory disturbances, motor deficits, and neuropathic pain, often necessitating dose reduction or discontinuation of chemotherapy, thereby compromising treatment efficacy and overall survival outcomes [6,7].

Emerging evidence suggests that selenium, an essential trace element, may mitigate oxidative stress and inflammation, both implicated in the pathogenesis of CIPN. Selenium’s antioxidative properties, particularly in its high-dose intravenous form, have shown promise in preclinical models for neuroprotection [8,9]. Sodium selenite pentahydrate, a bioavailable form of selenium, has demonstrated safety in clinical settings, justifying further exploration of its efficacy in CIPN prevention [10].

This study aims to evaluate the safety and efficacy of high-dose intravenous selenium in preventing CIPN among gastric cancer patients receiving adjuvant XELOX chemotherapy following gastrectomy.

METHODS

Patients

Patients diagnosed with gastric adenocarcinoma who underwent gastrectomy between January and December 2024 at Seoul St. Mary’s Hospital, with final pathology confirming stage III disease, were included in this study. At our institution, unless contraindicated, adjuvant chemotherapy is initiated within 2 months after surgery, with most stage III patients receiving the XELOX regimen. Patients were eligible for inclusion if they met the following criteria: (1) aged 20–70 years; (2) histologically confirmed gastric adenocarcinoma; (3) curative gastrectomy with confirmed stage III disease; (4) received adjuvant chemotherapy with the XELOX regimen; (5) Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; (6) no concurrent diseases significantly affecting survival; (7) adequate baseline hematologic, renal, and hepatic function prior to chemotherapy; and (8) complete medical records documenting chemotherapy administration and CIPN assessment. Patients were excluded if they (1) had pre-existing peripheral neuropathy or neurological disorders before chemotherapy, (2) received additional neuroprotective agents apart from selenium, (3) had a history of allergic reactions to selenium compounds, or (4) had missing or incomplete CIPN evaluation records. A total of 28 patients were included, with 11 in the selenium group and 17 in the non-selenium group. All patients received 6–8 cycles of chemotherapy, and the selenium group received selenium injections prior to chemotherapy administration. Clinicopathological characteristics, including surgical and postoperative outcomes, were compared. This study was approved by the Seoul St. Mary’s Hospital Data Review Board (2025319-029) and Institutional Review Board (KC25RASI0225).

Assessment of adverse events

CIPN was assessed based on clinical documentation of neurological examinations, symptom reports, and standardized neuropathy grading scales (World Health Organization [WHO]-CIPN and Common Terminology Criteria for Adverse Events [CTCAE] version 5.0) (Table 1). Selenium-related adverse events were identified through medical records documenting laboratory abnormalities or clinical toxicities.

Table 1.

Assessment of chemotherapy-induced peripheral neuropathy

Factors	Grade 0	Grade 1	Grade 2	Grade 3	Grade 4
Paresthesia	No symptom	Presence of paresthesia and/or decreased DTR (no requirement of medication)	Severe paresthesia (improved with medication, tolerable without medication)	Intolerable paresthesia (intolerable without medication)	Life-threatening consequence urgent intervention indicated (death related to overdose of medication)
Pain	NRS 0	NRS 1–3	NRS 4–6	NRS 7–9	NRS 10
Motor function	No weakness	Normal ADL	Limiting instrumental ADL and/or light muscle weakness	Limiting self-care ADL and/or marked muscle weakness	Life-threatening consequence: urgent intervention indicated

DTR, deep tendon reflex; NRS, numerical rating scale; ADL, activity of daily living.

Objectives

The primary outcome was to determine whether high-dose selenium administration significantly reduces the severity of CIPN symptoms, including paresthesia, pain, and motor dysfunction, compared to the control group. The secondary outcome was to evaluate the safety profile of high-dose intravenous selenium, including the incidence of selenium-related toxicity.

Treatment

Experimental group (selenium group)

Sodium selenite pentahydrate 2,000 μg/40 mL (GC Selenium, Green Cross Wellbeing, Ltd.) was administered intravenously over 2 hours before each chemotherapy cycle. Patients received 6–8 cycles of oral capecitabine (1,000 mg/m² twice daily on days 1–14 of each cycle) plus intravenous oxaliplatin (130 mg/m² on day 1 of each cycle). Dose reductions or interruptions were permitted to manage serious adverse events.

Control group (non-selenium group)

Patients received 6–8 cycles of oral capecitabine and intravenous oxaliplatin using the same regimen as the selenium group but without selenium administration.

Statistical analysis

All statistical analyses were performed using SAS (Version 9.4, SAS Institute). A significance level of P<0.05 was considered statistically significant. CIPN symptoms and adverse events were compared before chemotherapy, during the first cycle, and after completion. Hematology and blood chemistry were evaluated at these three time points. Within-group comparisons were conducted using paired t tests, while between-group comparisons utilized two-sample t tests.

RESULTS

Study population

Among the 28 enrolled patients, 21 (75.0%) were male and seven (25.0%) were female, with a mean age of 57.1 years (Table 2). There were no significant differences between the groups in terms of age, sex, body mass index, comorbidities, or performance status. Preoperative laboratory findings and operative outcomes, including operation time, blood loss, and hospital stay, were also comparable between the two groups.

Table 2.

Baseline characteristics of patients and operative data

Characteristic	Selenium (n=11)	Non-selenium (n=17)	P-value
Sex			0.8232
Male	8	13
Female	3	4
Age (yr), mean±SD	55.2±12.6	58.9±7.4	0.3351
BMI (kg/m2), mean±SD	23.7±2.5	25.4±2.5	0.0960
Comorbidity			0.7740
Yes	4	7
No	7	10
ECOG			0.3713
0	11	16
1	0	1
Approach			0.4127
Open	0	1
Laparoscope + robot	11	16
Resection			0.3147
TG	6	6
STG + PG	5	11
LN dissection			0.7475
D1+	1	1
D2	10	16
Anastomosis			0.2328
B-I	3	9
B-II + RY	7	8
Double tract	1	0
Operation time (min), mean±SD	183.6±25.0	177.1±34.6	0.5912
Estimated blood loss (min), mean±SD	60.9±39.1	76.5±46.8	0.3689
Hospital stay (day), mean±SD	7.9±1.7	8.5±3.5	0.5872

SD, standard deviation; BMI, body mass index; ECOG, Eastern Cooperative Oncology Group performance status; TG, total gastrectomy; STG, subtotal gastrectomy; PG, proximal gastrectomy; LN, lymph node; B-I, Billroth I; B-II, Billorth II; RY, Roux en Y.

Adverse events of chemotherapy

We evaluated the frequency of the most commonly observed chemotherapy-induced adverse events, including hand-foot syndrome, nausea with vomiting, diarrhea, and loss of appetite (Table 3). The severity of each event was graded in accordance with the CTCAE version 5.0, and intergroup comparisons were performed to assess differences in severity. No significant differences was observed between the selenium and non-selenium groups (Fig. 1). Dose reduction due to side effects was required in 19 of 28 patients (67.9%). Additionally, no differences were observed between the two groups in blood test results, including leukopenia, liver dysfunction, or kidney dysfunction (Fig. 2).

Table 3.

Adverse events reported by patients

	Selenium (n=11)				Non-selenium (n=17)
	After 1st cycle		After finish		After 1st cycle		After finish
	All grades	Grade 3 or 4	All grades	Grade 3 or 4	All grades	Grade 3 or 4	All grades	Grade 3 or 4
Nausea & vomiting	8 (72.7)	2 (18.2)	10 (90.9)	3 (27.3)	15 (88.2)	5 (29.4)	15 (88.2)	3 (17.6)
Diarrhea	7 (63.6)	0	11 (100)	1 (9.1)	12 (70.6)	0	16 (94.1)	0
Hand-foot syndrome	2 (18.2)	0	11 (100)	1 (9.1)	6 (35.3)	0	11 (64.7)	0
Loss of appetite	11 (100)	0	11 (100)	2 (18.2)	17 (100)	2 (11.8)	17 (100)	2 (11.8)
Peripheral neuropathy	11 (100)	0	11 (100)	0	17 (100)	0	17 (100)	0

Values are presented as number (%).

Fig. 1.

Chemotherapy-induced adverse events in patients. Relationship between selenium consumption and chemotherapy side effect score in all patients’ post-gastrectomy. The figure presents the mean±standard deviation of patients’ chemotherapy side effect score. The data were analyzed using a two-paired t test. HFS, hand-foot syndrome; N_V, nausea and vomiting; D, diarrhea.

Fig. 2.

Laboratory tests in patients. Relationship between selenium consumption and laboratory test results in all patients’ post-gastrectomy. The figure presents the mean±standard deviation of patients’ hematology. Each panel represents level in (A) white blood cell (WBC), (B) creatinine, (C) aspartate aminotransferase (AST), and (D) alanine aminotransferase (ALT). The data were analyzed using a two-paired t test.

Extent of peripheral neuropathy

Peripheral neuropathy was observed in all 28 patients, but no severe cases (grade 3 or higher) were reported. Symptoms were assessed in three categories: paresthesia, pain, and motor function, and the average grades for each were compared. After the first chemotherapy cycle, CIPN severity was similar between groups. However, by the end of chemotherapy, paresthesia severity was significantly lower in the selenium group (1.091 in the selenium group vs. 1.765 in the non-selenium group, P<0.0001) (Fig. 3).

Fig. 3.

CIPN symptoms score of the total patients. Relationship between selenium consumption and CIPN symptoms of all patients’ post-gastrectomy. The figure presents the mean±standard deviation of all patients’ total CIPN symptom scores. The data were analyzed using a two-paired t test. CIPN, chemotherapy-induced peripheral neuropathy.

Safety of high-dose selenium

No specific adverse effects associated with high-dose selenium administration were observed.

DISCUSSION

This study investigated whether high-dose intravenous selenium administration could prevent CIPN associated with oxaliplatin-based chemotherapy. Symptom severity was assessed using the WHO-CIPN criteria and CTCAE, converted into scores, and compared between the two groups. Although no severe grade 3 or 4 cases were observed, CIPN occurred in all patients. The majority of participants developed acute symptoms, such as paresthesia, within 2–3 days following oxaliplatin administration, with symptoms improving within a week.

To evaluate the impact of selenium, we compared symptom severity between the selenium-treated and non-treated groups. After the first chemotherapy cycle, paresthesia severity did not differ significantly between the groups. However, after 6–8 cycles, paresthesia severity increased in the non-selenium group but decreased in the selenium-treated group, resulting in a statistically significant difference.

We further analyzed CIPN severity based on sex. Among male patients, a significant difference in CIPN scores was observed following chemotherapy, whereas no such difference was noted in female patients (Fig. 4).

Fig. 4.

CIPN symptoms score according to sex. Relationship between selenium consumption and CIPN symptoms in male and female patients’ post-gastrectomy. The figure presents the mean±standard deviation of all patients’ total CIPN symptom scores. Each panel represents level in (A) male and (B) female CIPN symptoms score. The data were analyzed using a two-paired t test. CIPN, chemotherapy-induced peripheral neuropathy.

In addition to paresthesia, CIPN symptoms such as pain and motor dysfunction were assessed; however, no significant differences were found between the two groups.

Oxaliplatin-induced neurotoxicity manifests in both acute and chronic phases. Acute neuropathy occurs in approximately 90% of patients, typically peaking immediately after oxaliplatin infusion and resolving within a week. This condition presents as paresthesia, dysesthesia, and cramping of the extremities [11]. In contrast, chronic CIPN is cumulative, dose-dependent, and among the most common dose-limiting adverse events of oxaliplatin-based chemotherapy [12]. Approximately one-third of patients experience chronic CIPN 6 months or more after chemotherapy, significantly impacting long-term QoL and underscoring the need for effective treatment strategies [13].

Given the limited therapeutic options for CIPN, the neuroprotective potential of selenium has attracted significant interest. Selenium, an essential trace element, plays a critical role in antioxidant defense and neuroprotection through its incorporation into selenoproteins [14]. The pathogenesis of CIPN involves oxidative stress, mitochondrial dysfunction, and inflammatory cytokine activation, all contributing to neuronal damage [15]. Therefore, selenium’s antioxidant and anti-inflammatory properties have been explored as a potential intervention to prevent CIPN in chemotherapy patients [16].

However, low-dose oral selenium may not be effective in preventing CIPN. Several studies in cancer patients undergoing chemotherapy have failed to demonstrate a protective effect with low-dose oral selenium supplementation [17,18]. In contrast, high-dose intravenous selenium has shown promising results with acceptable toxicity levels. Studies administering intravenous selenium at doses ranging from 3,200 to 7,200 μg/day reported minimal adverse events [19,20]. In the study conducted by Tan et al. [21], the most frequently observed grade 3 toxicity symptoms associated with selenium doses up to 5,000 μg included restlessness and pain. Although most selenium-related toxicities were not severe, some symptoms such as garlic odor, brittle nails and hair, and gastrointestinal discomfort were reported [19]. While there is no standardized threshold for defining high-dose selenium administration, previous studies have administered doses ranging from 3,000 to 5,000 μg. In contrast, the recommended daily intake of selenium is typically between 100 and 200 μg. Our dosage reference was based on a recent Korean study, in which 2,000 μg was designated as a high dose of selenium [22]. In our study, no definitive selenium-related toxicities were observed.

In this study, we aimed to evaluate whether intravenous administration of high-dose selenium attenuates the severity of CIPN. Furthermore, a subgroup analysis was performed to identify potential clinically relevant factors, including sex, presence of complications, alcohol consumption, and smoking status. Among these variables, sex demonstrated a statistically significant difference, with a notable disparity observed between male and female patients. However, previous studies have not reported sex-based differences in the neuroprotective effects of selenium on CIPN, and there is currently no definitive evidence to account for this observation. It is plausible that the absence of a significant effect in female patients may be attributable to the limited sample size within this subgroup in the present study.

In addition to male patients, statistically significant differences were also observed among patients without comorbidities and those without a history of alcohol consumption. However, no significant intergroup difference was observed based on smoking status. The relevant data is summarized in the supplement figures. Given that this was a pilot study with a limited sample size, primarily focused on assessing the potential effect of selenium administration on CIPN severity, we considered multivariate analysis using individual clinical variables to be of limited value. Additionally, we investigated whether high-dose selenium administration impacts chemotherapy dose reduction. We assessed the number of participants who experienced a reduction of more than 20% in chemotherapy dosage. In the selenium group, eight patients (73%) had a dose reduction, while in the non-selenium group, 11 patients (65%) experienced a reduction; however, this difference was not statistically significant.

To our knowledge, this is the first study to evaluate the safety and efficacy of high-dose intravenous selenium in reducing paresthesia associated with oxaliplatin-based chemotherapy.

Despite these promising findings, our study has certain limitations. The optimal measurement of CIPN remains a topic of debate, as physician-reported grading does not always correlate with patient-reported symptoms and functional impairment [23]. Additionally, quantitative neurological testing is impractical for routine clinical use and may not fully capture the patient’s symptom burden. The heterogeneity of CIPN assessment methods highlights the need for a standardized approach to evaluating CIPN in clinical practice.

In conclusion, high-dose intravenous selenium appears to be a safe intervention and may help reduce paresthesia associated with oxaliplatin-based chemotherapy in patients with gastric cancer. However, further large-scale, multi-center trials are required to confirm selenium’s efficacy in CIPN prevention and establish optimal dosing guidelines. Additionally, long-term follow-up studies should assess whether selenium provides sustained neuroprotection beyond chemotherapy completion. If validated, selenium could become an integral component of CIPN management, improving chemotherapy adherence and enhancing patient QoL.