Introduction

Nausea and vomiting represent among the most debilitating symptom complexes in patients with advanced malignancies of the gastrointestinal (GI) tract, with prevalence rates ranging from 30% to 70% depending on tumor location and disease stage.1 A systematic review by Hardy and Davis confirmed that nausea affects up to 68% of palliative patients in the terminal stage.2 The 2023 MASCC/ESMO guidelines recognize control of these symptoms as a priority in palliative care.3

These symptoms substantially impair quality of life and lead to significant clinical consequences, including fluid and electrolyte imbalances, dehydration, and progressive cachexia.4 Uncontrolled vomiting limits the possibility of oral food and medication intake, complicating symptomatic therapy.5 Effective control of gastrointestinal symptoms is a key component of integrated palliative care.6

The pathophysiology of nausea and vomiting in advanced GI cancer is complex and multifactorial. Unlike chemotherapy-induced nausea and vomiting (CINV), which is predominantly mediated through serotonergic pathways, symptoms in incurable patients often arise from hepatic dysfunction activating the chemoreceptor trigger zone through accumulation of toxic metabolites, neurogenic mechanisms involving the vomiting center, or mechanical obstruction and gastroparesis.3,7 Metabolic disturbances such as hypercalcemia and uremia further complicate the clinical picture.8

International NCCN 2024 and ASCO guidelines primarily focus on prevention and treatment of chemotherapy-induced symptoms.9 Although these protocols effectively address CINV, their applicability for incurable patients with non-chemotherapy-related nausea remains limited.10 Specific recommendations for palliative patients require further development.11

Metoclopramide is widely used for gastroparesis due to its prokinetic properties and dopamine D2 receptor blockade.12 However, its effectiveness varies across different etiologies of nausea, and the risk of extrapyramidal side effects requires careful monitoring.13 Several other agents are used empirically in palliative nausea and vomiting, including haloperidol, a potent D2 antagonist;14 olanzapine, a multi-receptor antagonist with growing evidence in refractory nausea;15,16 and levomepromazine, a broad-spectrum phenothiazine.17 Chlorpromazine, also a phenothiazine, has demonstrated effectiveness in refractory and neurogenic vomiting through multimodal receptor antagonism (D2, H1, and muscarinic receptors).14 We selected chlorpromazine for the neurogenic phenotype because its broad receptor coverage targets central emetic mechanisms, and because it is routinely available and inexpensive in our setting, making the findings directly applicable to comparable resource-constrained palliative services; haloperidol, olanzapine, and levomepromazine remain reasonable comparators for future trials. Ondansetron and other 5-HT3 receptor antagonists remain effective for symptoms related to hepatic dysfunction.18,19

Despite the availability of these agents, few studies have directly compared mechanism-based antiemetic selection with standard empirical treatment in incurable GI cancer patients. The aim of this study was to compare outcomes of standard antiemetic therapy with individualized, pathophysiology-based treatment, with particular focus on the neurogenic and hepatic subgroups.

Materials and Methods Study Design and Setting

A prospective observational cohort study was conducted at the Palliative Medicine Department of Kyiv City Clinical Oncological Center, a tertiary-level healthcare facility, from January 2022 to December 2024. The study was conducted in accordance with the principles of the Declaration of Helsinki and reported in accordance with the STROBE guidelines for observational studies. The study protocol was approved by the Ethics and Academic Integrity Committee of Shupyk National Healthcare University of Ukraine (Protocol No. 6/10, November 21, 2024) during the ongoing data collection period. In accordance with Ukrainian institutional regulations, a separate prospective ethics application is not required for non-interventional observational studies conducted within standard clinical practice. This observational study involved no experimental interventions; all treatments represented standard clinical care. Ethics review was conducted during the study period rather than prior to enrollment due to the administrative constraints imposed by the ongoing armed conflict in Ukraine, which significantly disrupted institutional processes. All participants provided written informed consent prior to inclusion.

Participants

One hundred patients with histologically confirmed incurable malignancies of the GI tract and clinically significant nausea were included. Admission to the specialized palliative care department is determined by national performance-status-based eligibility criteria; consequently, the accessible source population consisted almost exclusively of patients in advanced or terminal stages with limited expected survival. To maximize the available sample within this constraint, all consecutively eligible patients admitted during the study period were screened for inclusion. Inclusion criteria were: age ≥18 years; confirmed diagnosis of advanced/metastatic GI cancer; presence of nausea and/or vomiting not related to active anticancer therapy; Eastern Cooperative Oncology Group (ECOG) performance status 2–4; expected survival >2 weeks. Exclusion criteria were: active chemotherapy or radiation therapy within 2 weeks; severe cognitive impairment; contraindications to study medications; nausea primarily attributed to intestinal obstruction requiring surgical intervention. Patients with functional bowel obstruction (intestinal atony) were excluded from this analysis. Patient flow, including screening, exclusions, and allocation to the mechanism-based subgroups, is summarized in Figure 1.

Figure 1 Patient flow diagram. *Exclusion criteria: active chemo/radiotherapy within 2 weeks; severe cognitive impairment; contraindications to study medications.

Treatment Allocation and Groups

Treatment allocation was based on clinical assessment of the predominant pathophysiological mechanism of nausea, performed by the treating palliative care physician at admission. This represents a pragmatic, non-randomized design reflecting real-world clinical decision-making. Patients were allocated to two groups:

Standard Therapy Group (n=41)

Metoclopramide 10 mg intramuscularly or intravenously three times daily combined with dexamethasone 4–8 mg intravenously once or twice daily. This group included patients for whom the treating physician chose the standard empirical protocol regardless of the suspected predominant mechanism.

Individualized Therapy Group (n=59)

Patients received one of the following regimens based on the clinically assessed predominant mechanism: (1) Ondansetron 8 mg IV or PO once or twice daily plus dexamethasone 4–8 mg for hepatic-related nausea (n=46); (2) Chlorpromazine 12.5–25 mg IM once or twice daily plus dexamethasone 4–8 mg for neurogenic vomiting (n=13).

Hepatic-related nausea was defined clinically as nausea in the setting of hepatic metastases with biochemical evidence of hepatic dysfunction (elevated bilirubin, transaminases, or alkaline phosphatase). Neurogenic vomiting was defined as persistent nausea and vomiting without clear hepatic or obstructive etiology, often presenting as central-pattern emesis (not temporally related to meals, associated with headache or raised intracranial pressure signs when present).

Outcome Measures

The primary outcome was clinical improvement, defined as ≥50% reduction in VAS score for nausea and/or ≥50% reduction in daily vomiting frequency at day 7. Nausea intensity was assessed using a 10-cm Visual Analog Scale (VAS; 0 = no nausea, 10 = worst imaginable nausea), administered verbally or via paper scale by the treating physician or nurse. All patients reported clinically significant nausea at baseline, with natural variability in severity reflected by standard deviations >0. Vomiting frequency was recorded as episodes per 24 hours. Assessments were performed at baseline (day of admission, before treatment initiation) and after 7 days of treatment.

Statistical Analysis

Statistical analysis was performed using SPSS version 26.0. Quantitative variables are presented as mean ± standard deviation (M±SD) and compared using Student’s t-test for independent samples (between groups) and paired t-test (within groups). Categorical variables were compared using χ2 test or Fisher’s exact test when expected cell counts were <5. For the key subgroup comparison, the absolute difference in improvement rates is reported with 95% confidence intervals (CI) calculated using the Newcombe method. No a priori sample-size or power calculation was performed, as this was an exploratory observational cohort enrolling all consecutively eligible admissions; the achieved sample therefore represents a convenience sample limited by the size of the eligible source population. Multivariable adjustment was not performed because the number of outcome events in the mechanism-based subgroups (eg, chlorpromazine n=13) was too small to support a stable multivariable model without substantial risk of overfitting; unadjusted estimates are therefore reported, and the potential for residual confounding is acknowledged A two-sided p-value <0.05 was considered statistically significant.

Results Baseline Characteristics

The study included 100 patients (51 males, 49 females) with a mean age of 70.2±10.5 years (range 28–89). Primary tumor locations were: colon (n=35, 35.0%), pancreas (n=23, 23.0%), stomach (n=19, 19.0%), rectum (n=13, 13.0%), liver (n=5, 5.0%), and biliary tract (n=5, 5.0%). Hepatic metastases were present in 67 patients (67.0%).

Baseline characteristics were comparable between groups (Table 1). Mean age was 70.8±9.8 years in the standard group and 69.8±11.0 years in the individualized group (p=0.634). ECOG performance status was similar (3.8±0.4 vs 3.8±0.4; p=0.635). Baseline VAS scores (7.7±0.9 vs 7.6±0.8; p=0.747) and baseline vomiting frequency (4.0±1.1 vs 3.9±0.8 episodes/day; p=0.783) did not differ significantly between groups. The proportion of patients with hepatic metastases was higher in the individualized group (78.0% vs 51.2%), reflecting the mechanism-based allocation.

Table 1 Baseline Characteristics of Study Participants

Primary Outcomes

Both groups demonstrated significant improvement in nausea severity from baseline to day 7 (paired t-test: standard group t=16.26, p<0.001; individualized group t=17.19, p<0.001). In the standard therapy group, clinical improvement was achieved in 31 patients (75.6%), with mean VAS decreasing from 7.7±0.9 to 4.3±1.5 (p<0.001). In the individualized therapy group, clinical improvement was achieved in 52 patients (88.1%), with mean VAS decreasing from 7.6±0.8 to 4.5±1.5 (p<0.001). The difference in overall improvement rates between groups did not reach statistical significance (χ2=1.88; p=0.171) (Table 2).

Table 2 Comparison of Treatment Outcomes Between Groups

Subgroup Analysis by Mechanism

In the neurogenic subgroup, chlorpromazine (individualized group, n=13) achieved a higher improvement rate than metoclopramide (standard group, n=20): 100% (13/13; 95% CI 77.2–100%) vs 55.0% (11/20; 95% CI 34.2–74.2%); absolute difference 45.0% (95% CI 15.2–65.8%, Newcombe method); Fisher’s exact test, p=0.005. Although the confidence interval excludes zero, its width reflects the small subgroup size, and the estimate should be interpreted as exploratory. Post-treatment VAS scores were significantly lower with chlorpromazine (4.2±0.6 vs 5.5±0.8; p<0.001). The mean VAS reduction was 4.0±0.9 with chlorpromazine compared to 2.5±1.1 with standard therapy (Table 3).

Table 3 Subgroup Analysis by Nausea Mechanism

In the hepatic subgroup, both treatment approaches were effective. Standard therapy (metoclopramide, n=21) achieved an improvement rate of 95.2% compared to 84.8% with individualized therapy (ondansetron, n=46); this difference was not statistically significant (Fisher’s exact test, p=0.419). Post-treatment VAS scores were significantly lower in the standard therapy group (3.2±1.1 vs 4.5±1.7; p=0.002); however, the clinical significance of this difference remains unclear given the comparable improvement rates.

Adverse Events

Adverse events were not systematically assessed using a standardized reporting tool. However, no treatment discontinuations due to adverse effects were recorded during the 7-day observation period. Sedation, a known side effect of chlorpromazine, was observed clinically but was mild and manageable in all cases. Extrapyramidal symptoms were not observed in any patient during the study period. A detailed safety analysis was beyond the scope of this study and represents a limitation.

Discussion

This prospective observational study compared standard empirical antiemetic therapy with individualized, mechanism-based treatment in 100 incurable patients with GI tumors. The overall improvement rates did not differ significantly between groups. In an exploratory subgroup analysis, chlorpromazine was associated with a higher improvement rate than metoclopramide for neurogenic nausea and vomiting (100% vs 55.0% improvement; p=0.005); given the small, non-randomized subgroup, this association should be regarded as hypothesis-generating rather than as confirmation of superiority.

The overall improvement rate of 75.6% in the standard therapy group suggests that metoclopramide-dexamethasone combination is a reasonable empirical first-line regimen for many palliative patients. However, this masks important heterogeneity in response across different mechanisms. In patients with neurogenic vomiting, nearly half (45%) did not respond to metoclopramide, whereas all patients treated with chlorpromazine achieved clinical improvement. This is consistent with the pharmacological profile of these agents: metoclopramide acts primarily through dopamine D2 blockade and prokinetic effects, whereas chlorpromazine provides broader receptor coverage including D2, H1, and muscarinic antagonism, which may be more effective against central vomiting mechanisms.14

The effectiveness of chlorpromazine for neurogenic vomiting (100% improvement rate) aligns with previous reports. Hasuo et al found that intravenous chlorpromazine was effective in terminal cancer patients for delirium-associated symptoms including nausea, with response rates influenced by baseline clinical characteristics18 Similarly, Saudemont et al, in their systematic review of antipsychotic antiemetics in palliative medicine, highlighted the broad receptor activity of agents such as olanzapine as a pharmacological basis for their efficacy in refractory nausea, a property shared by chlorpromazine through its multimodal receptor antagonism.15

An unexpected finding was that standard metoclopramide-based therapy appeared to perform well in the hepatic subgroup (95.2% improvement), compared to ondansetron-based therapy (84.8%). While this difference was not statistically significant (p=0.419), it suggests that metoclopramide’s combination of prokinetic and antiemetic properties may provide benefit even in hepatic-related nausea, possibly through addressing concurrent gastroparesis often present in these patients.12 Although post-treatment VAS was statistically lower in the standard group (p=0.002), the clinical significance of this finding is uncertain given comparable improvement rates. This observation warrants further investigation in controlled studies.

The study was conducted at a tertiary-level palliative care facility, and patients were enrolled consecutively upon admission, forming a real-world cohort. This pragmatic design enhances the external validity and clinical applicability of our findings, though it also introduces inherent limitations.

Limitations

Several limitations should be acknowledged. First, the non-randomized, observational design introduces potential selection bias and confounding by indication. The allocation to treatment groups was based on clinical judgment, and patients in the individualized group had a higher prevalence of hepatic metastases (78.0% vs 51.2%), reflecting the mechanism-based allocation. Second, the study was conducted at a single center, which may limit generalizability. Third, the 7-day follow-up period is short and does not capture longer-term outcomes, durability of response, delayed effects, or symptom fluctuations. Fourth, the assessment of nausea mechanism was based on clinical judgment rather than a validated diagnostic algorithm, of which none currently exists for this distinction in palliative practice, introducing inter-observer variability and limiting reproducibility. Fifth, the neurogenic subgroup was small (n=33, of whom only 13 received chlorpromazine), and the observed 100% response rate to chlorpromazine should be interpreted as exploratory and hypothesis-generating rather than as evidence of established superiority. Sixth, no multivariable analysis was performed to adjust for potential confounders, including the imbalance in hepatic metastases between groups; as noted, the subgroup event counts were too small to support stable multivariable modelling, so residual confounding cannot be excluded. Seventh, adverse events were not systematically assessed using standardized tools, precluding a formal safety comparison. Finally, quality of life assessment using validated instruments was not included. Multi-center randomized controlled trials with larger sample sizes, longer follow-up, and systematic safety monitoring are needed to confirm these findings.

Conclusions

In this prospective observational study of 100 incurable patients with GI tumors, both standard and individualized antiemetic approaches were effective overall, with no statistically significant difference in the primary endpoint. In an exploratory subgroup analysis, chlorpromazine was associated with higher improvement rates than metoclopramide for neurogenic nausea and vomiting (100% vs 55.0%; p=0.005). Given the observational, non-randomized design and the small subgroup, these findings are hypothesis-generating and do not establish causal superiority. They suggest that identifying the predominant pathophysiological mechanism of nausea may help guide antiemetic selection, particularly when a neurogenic etiology is suspected. Adequately powered randomized controlled trials are warranted to determine whether mechanism-based antiemetic therapy improves outcomes in palliative oncology.

Data Sharing Statement

The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.

Ethics Approval

The study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Ethics and Academic Integrity Committee of Shupyk National Healthcare University of Ukraine (Protocol No. 6/10, November 21, 2024) during the ongoing data collection period. In accordance with Ukrainian institutional regulations, a separate prospective ethics application is not required for non-interventional observational studies conducted within standard clinical practice, as no experimental interventions or deviations from routine care were involved. This study involved only standard clinical care with no experimental interventions. Ethics review was conducted during the study period due to administrative constraints imposed by the ongoing armed conflict in Ukraine. All participants provided written informed consent prior to inclusion.

Consent to Participate

All participants provided written informed consent prior to enrollment.

Consent for Publication

Not applicable. No individual patient data are presented.

Acknowledgments

The authors thank the medical staff of the Palliative Medicine Department of Kyiv City Clinical Oncological Center for their assistance in patient care and data collection.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Disclosure

The authors declare no conflicts of interest.

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