Lactoferrin supplementation for taste and smell abnormalities among patients receiving cancer chemotherapy

Abstract

Purpose

Taste and smell abnormalities (TSA) are common in patients receiving chemotherapy and may lead to altered nutritional intake, treatment withdrawal, and impaired quality of life. Lipid peroxidation in the oral cavity is one cause of TSA. Lactoferrin (LFN), an iron-binding salivary protein, reduces production of lipid oxidation byproducts and has been shown to reduce perception of unpleasant flavors. To assess the feasibility of LFN as a treatment for TSA, we conducted pilot investigations among patients with cancer who self-reported TSA following onset of chemotherapy. The primary objective was to assess change in subjective taste and smell perception from baseline to completion of 30 days of LFN supplementation.

Methods

Patients were treated with 750 mg LFN daily for 30 days and followed for an additional 30 days without LFN. TSA was measured via the taste and smell questionnaire (TSQ) including taste (score 0–10), smell (score 0–6), and composite scores (0–16) (0 = no TSA) at baseline, day 30, and day 60.

Results

A total of 26 patients enrolled; 19 remained on study at day 30 and 17 at day 60. Baseline mean TSQ scores were 6.5 (taste), 3.1 (smell), and 9.6 (composite). By day 30, mean composite TSQ score improved by 1.7 (p = 0.018); taste and smell improved by 0.6 (p = 0.062) and 1.1 (p = 0.042), respectively. From baseline to day 60, mean composite TSQ score improved by 3.8 (p < 0.0001); taste and smell improved by 1.9 (p = 0.001) and 1.8 (p = 0.003).

Conclusions

Further evaluation of LFN is warranted to determine its value for improving self-reported TSA among patients receiving chemotherapy.

Introduction

Cancer-related taste and smell abnormalities (TSA) are poorly understood despite their considerable impact on patients [1, 2]. Among individuals receiving chemotherapy, a majority report altered taste and smell perception [3, 4] that frequently manifests as reduced taste (ageusia), taste distortions (dysgeusia), and perception of metallic and/or unpleasant flavors [1]. Although TSA may be acute following a variety of cancer treatments, patients commonly report chronic TSA that can persist for years following treatment completion [4]. These disruptions diminish hedonic pleasure of eating and may profoundly impact quality of life, social relationships, psychological and emotional function, and nutrition (e.g., food aversion, malnutrition) [1, 2]. Importantly, eating is about more than supplying nutrition to the body—it is a fundamental component of the social landscape that provides connection with culture and community. Disinterest in eating as a function of TSA stands to impair physical and emotional well-being and may be particularly distressing within the context of cancer. Additional research is warranted to understand cancer-related TSA and identify prevention and treatment strategies.

Taste and smell are interconnected chemosensory systems that work synergistically to allow perception of flavors and chemical stimuli (e.g., food) [5]. Although taste and smell qualities may be uniquely altered based on differences in cancer site and treatment regimens [6], patients who develop TSA following chemotherapy commonly describe persistent metallic and/or bitter flavors. Mechanisms responsible for these phenomena remain unclear, but may be partially attributed to metal-induced lipid oxidation in the oral cavity and volatile chemical oxidative by-products, which produce strong metallic odors and flavors [6]. Even during chemotherapy administration, patients often describe metallic and bitter flavors, as chemical compounds (or their metabolites) enter saliva and the oral cavity to directly impact taste receptors [7]. Such alterations can remain for hours or many months. Given that chemotherapies target rapidly dividing cell characteristic of cancers, other cells may be damaged as sequelae of chemotherapy. Therefore, gustatory and olfactory receptor cells, which proliferate every 7–10 days, are particularly vulnerable to cytotoxic insults [7]. Although rapid regeneration of these receptors may facilitate recovery of chemosensory function [8], long-lasting TSA can contribute substantially to unintended weight loss, malnutrition [9], morbidity, and mortality [9, 10].

Changes in taste and smell can occur as a function of micronutrient deficiency [11], poor oral health, and altered saliva production, all of which are interconnected and routinely observed among patients undergoing chemotherapy. Among the many pharmacologic and behavioral interventions proposing to mitigate TSA (e.g., amifostine, Synsepalum dulciifcum, zinc, dietary counseling, education), the micronutrient zinc [5, 12–14] has received the most attention due to its role in taste perception and oral health. Randomized, placebo-controlled studies evaluating zinc for prevention or treatment of TSA [5], however, indicate zinc is no more beneficial than placebo and may be more relevant for promoting oral health and stimulating salivary secretions than for repairing cancer-related TSA.

Despite a growing number of investigational therapies, a recent systematic review [15] concluded that no studies definitively have demonstrated efficacy for improving TSA in any population. However, authors noted preliminary evidence supporting lactoferrin supplementation as a potential treatment among patients with cancer undergoing chemotherapy [16], as it may reduce harmful by-products of lipid oxidation that could otherwise damage taste and smell receptors.

Lactoferrin

Cytotoxic chemotherapies may disrupt integrity of the salivary peroxidase system and induce deregulated production of aldehydes and ketones that yield metallic odors and perception of off flavors [6]. If unmitigated, this disrupted system can promote oxidative stress within the oral cavity and damage chemosensory structures. Lactoferrin, an ironbinding transferrin protein, may relieve metallic dysgeusia through chelation of unbound iron compounds (Fe²⁺) produced via lipid oxidation [17]. In laboratory settings, lactoferrin has shown efficacy in eliminating the perception of metallic flavor induced by a ferrous solution when subsequently used as an oral rinse [6]. Building upon this work and frequently reported metallic dysgeusia among patients receiving chemotherapies, we hypothesized that lactoferrin supplementation would reduce subjective perceptions of TSA among patients undergoing chemotherapy.

Objectives

To assess the feasibility of lactoferrin supplementation as a treatment for self-reported TSA among patients receiving chemotherapy, we conducted two methodologically identical pilot investigations among patients receiving different types of chemotherapy treatments; we subsequently pooled data from the pilots. The primary objective was to assess change in subjective taste and smell perception from baseline to completion of 30 days of lactoferrin supplementation. We also investigated the impact of lactoferrin on change in appetite. Following a subsequent 30-day washout period in which patients did not take lactoferrin, data were collected on day 60 to assess persistence of outcomes. Our prior publication describes a proteomic analysis of salivary protein and mineral profiles among these same participants [16].

Methods

The first pilot study included patients receiving platinum-based chemotherapy regimens; the second expanded eligibility to patients with any type of cancer receiving any type of chemotherapy. Studies were approved by the Institutional Review Boards of Wake Forest Baptist Medical Center (CCCWFU#98,112) and Virginia Tech (IRB#14–880) and registered with www.clinicaltrials.gov (NCT01596634; NCT01941810). Across studies, 26 patients reporting TSA after receiving chemotherapy were recruited via convenience sampling by their oncologists at Wake Forest Baptist Comprehensive Cancer Center. Eligible patients had normal taste perception prior to receiving chemotherapy and had at least 1 month of chemotherapy planned following enrollment. Any dose or schedule of chemotherapy was allowed so long as patients self-reported TSA that (1) had developed since the initiation of chemotherapy or (2) had subjectively worsened since initiating current chemotherapy (in the event of pre-existing TSA from prior chemotherapy). Individuals were excluded if undergoing inpatient induction therapy for acute leukemia; hospitalized for marrow or peripheral blood stem cell transplantation; life expectancy was less than 3 months; unable to produce sufficient saliva (2 mL in 20 min); diagnosed as HIV + ; pregnant; diagnosed and untreated for gastrointestinal reflux disease or diabetes mellitus; allergic to milk and/or iron; diagnosed with active oral infection; or diagnosed with active mucositis. All eligible participants provided informed consent, completed baseline assessments, and received lactoferrin supplements.

Demographic data were collected at baseline (i.e., age, sex, diagnosis, chemotherapy history, treatment schedules, tobacco use, and concurrent medications and supplements), along with height and weight to determine body surface area.

Eastern Cooperative Oncology Group (ECOG) performance status [18]

ECOG performance status, a standard criterion for grading cancer impact, was obtained at baseline. ECOG performance status is graded from 0 to 5: “0” represents patients able to carry on all pre-disease performance without restriction, “4” represents patients unable to provide self-care, and “5” represents those who are deceased.

Lactoferrin treatment

Following completion of baseline assessments, participants were given 90 lactoferrin tablets (Bioferrin 2000, 250 mg tablets; Jarrow Formulas Inc, Los Angeles, CA) and instructed to take one tablet three times daily for the next 30 days followed by a 30-day washout period. All patients were instructed to refrain from taking additional tablets or other medications to relieve TSA symptoms. Data were collected over 60 days: at baseline (day 0) prior to lactoferrin supplementation, following the 30-day supplement period (day 30), and after completion of a 30-day washout period (day 60). Patients received diaries to track lactoferrin intake.

Taste and Smell Questionnaire (TSQ)

Subjective taste and smell function were assessed via the Taste and Smell Questionnaire, which has been used to evaluate chemosensory function in patients with AIDS [19] and in our prior investigations among patients with malignant brain tumors [20, 21]. Participants rated their taste and smell perception as “insignificant,” “mild,” “moderate,” “severe,” or “incapacitating.” The TSQ yields a taste complaint score (0–10) corresponding with changes in taste perception across nine questions; 1 point was added for each taste complaint and, for a single item assessing severity of taste abnormality, 2 points were added for a rating of “severe” or “incapacitating.” A smell complaint score (0–6) was generated by adding 1 point for a positive response to each of five questions addressing changes in smell perception. On one item assessing severity of smell abnormality, 2 points were assigned to a rating of “severe” or “incapacitating.” A composite chemosensory complaint score (0–16) was calculated as the sum of all scores. Higher scores indicate greater degree of complaint.

Brief Smell Identification Test (B-SIT) [22]

The B-SIT is a 12-item version of the University of Pennsylvania Smell Identification Test (UPSIT), a validated tool for detecting loss of sense of smell that includes 12 well-known cross-cultural odorants embedded on scent strips. Olfactory scores are determined as the number of odorants correctly identified, with higher scores representing better performance. Olfactory dysfunction is defined as correctly identifying fewer than 9 odorants.

Functional Assessment of Anorexia/Cachexia Treatment Anorexia/Cachexia Subscale (FAACT A/ CS) [23]

The FAACT A/CS, a validated 12-item self-report measure, assessed nutrition-related quality of life and factors associated with appetite during the previous week. For each item, patients provided ratings via a 5-point Likert scale (“not at all” to “very much”); scores of negatively worded items were reversed (e.g., “My interest in food drops as soon as I begin eating”). Summed scores range from 0 to 48; lower scores indicate less appetite. For the assessment of anorexia among patients with cancer, evidence suggests an optimal cut-off score of ≤ 37 [23].

Statistical methods

To determine the effect of lactoferrin on self-reported TSA in patients receiving chemotherapy, TSQ scores from each assessment were tested separately via paired t-tests to determine significance of change from baseline to day 30 and from baseline to day 60.

Linear regression models determined covariates associated with change. Repeated measures models assessed change over time using longitudinal measures, and contrasts assessed individual pair-wise differences. Other contrasts included change between baseline and day 60 and between day 30 and day 60 to determine if scores returned to baseline levels. An unstructured covariance matrix modeled within-patient correlations over time. Due to limited sample size, additional covariance structures (e.g., compound symmetry, autoregressive, and toeplitz) were assessed using Bayesian information criterion to reduce the number of estimated parameters. These same analyses assessed changes in B-SIT and FAACT.

Results

Patient characteristics

Twenty-six adult patients presenting for chemotherapy for various malignancies were enrolled and completed baseline assessments. Participant characteristics are reported in Table 1.

Table 1.

Baseline demographic characteristics of study sample

Characteristic	N = 26
Sex	N (%)
Female	12 (46)
Male	14 (54)
Age (years)	Mean ± SD 60.4 ± 11.2 (range 32–79)
Race	N (%)
Ethnicity	23 (88)
Non-Hispanic White	1 (4)/2 (8)
Hispanic White
African American
Cancer diagnosis	N (%)
Brain	3 (11.4)
Breast	5 (19)
Colorectal	8 (30.4)
Liver	1 (3.8)
Lymphoma	2 (7.7)
Multiple myeloma	1 (3.8)
Mycosis fungoides	1 (3.8)
Pancreatic	4 (15.2)
Unspecific neoplasm	1 (3.8)
Chemotherapy type	N (%)
Platinum*	13 (50)
Non-platinum**	13 (50)
Body surface area (BSA)	Mean ± SD/1.86 ± 0.28 (range 1.43–2.55)
Smoking status/Never smoked/Former smoker/Current smoker	N (%)/9 (35)/13 (50)4 (15)

^*Platinum-based chemotherapies: cisplatin, oxaliplatin.

^**Non-platinum-based chemotherapies: bevacizumab, bortezomib, capecitabine, cyclophosphamide, doxorubicin, etoposide, gemcitabine, irinotecan hydrochloride, lenalidomide, methotrexate, paclitaxel, pertuzumab, rituximab, sorafenib, tamoxifen, temozolomide, trastuzumab, vincristine.

Effect of lactoferrin on taste and smell abnormalities

Baseline mean taste (0–10 scale), smell (0–6 scale), and TSQ composite scores (sum of taste and smell, 0–16 scale) for the 26 enrolled patients were 6.5, 3.1, and 9.6, respectively, such that higher scores indicate greater degree of sensory complaint. Analyzable data were available for 19 patients who completed primary assessments after 30 days of lactoferrin supplementation and 17 patients who also completed post-washout assessments on day 60. Outcome analyses were conducted for the 17 patients who completed both the 30-day and 60-day assessments (Fig. 1). From baseline to day 30, taste scores improved by 0.6 units (p = 0.062), smell scores significantly improved by 1.1 units (p = 0.042), and composite TSQ scores significantly improved by 1.7 units (p = 0.018). Of those who completed both day 30 and day 60 assessments (n = 17), taste and smell scores significantly improved by 1.9 (p = 0.001) and 1.8 (p = 0.003), respectively, and composite scores improved from baseline by 3.8 units (p < 0.0001). Decreasing scores indicate improved chemosensory function. All significant differences exceeded a change of 0.5 standard deviation units, supporting generic standards for what would be considered a minimal clinically important difference or the smallest difference in taste and smell scores that would be perceived as beneficial to patients.

Fig. 1.

Taste, smell, and composite TSA abnormality scores at baseline, after 30 days lactoferrin supplementation and 30 days post-lactoferrin supplementation. Note: Decreasing scores indicate improvement in subjective evaluation of taste and smell function

FAACT A/CS

FAACT A/CS scores did not change significantly from baseline to day 30. From day 30 to day 60, scores increased significantly by 5.13 units (p = 0.007), from 30.32 to 35.45, indicating improvement in overall appetite. Among the 17 patients completing day 60 assessments, 76% reported improvement and 35% resolved anorexia based on the established cut off score of 37. In response to FAACT A/CS item, “my interest in food drops as soon as I begin to eat,” scores decreased significantly by 0.76 units (p = 0.05) from day 30 to day 60, indicating an increased interest in eating.

Change in B-SIT scores

At baseline, mean B-SIT score was 9.85 and 27% of patients met B-SIT criteria for smell abnormality (i.e., correctly identified fewer than 9 scents). Mean scores decreased from baseline to day 30 (9.1, p = 0.48) at which point 57% of the remaining sample (n = 19) met the criteria for smell abnormality. Individuals who dropped out by day 30 had a higher mean baseline B-SIT score (11.14). From day 30 to day 60, mean scores remained unchanged (9.1, p = 0.78), and 47% of the remaining sample (n = 17) met the criteria for smell abnormality. Changes in B-SIT scores were not statistically significant.

Platinum versus non‑platinum chemotherapy type

When grouped by type of chemotherapy received (platinum-based versus non-platinum), patients receiving non-platinum therapies (n = 13) reported higher baseline abnormality scores for taste (6.78 ± 1.48), and composite TSQ (10.14 ± 1.88), and lower abnormality score for smell (3.36 ± 2.02) compared to those receiving platinum-based therapies (6.17 ± 1.11, 5.13 ± 1.8, and 4.75 ± 2. 66 respectively; n = 13) (Fig. 2a, b, c). Among non-platinum patients who completed day 30 and day 60 assessments (n = 8), patients demonstrated greater magnitude of change from baseline to day 60 for taste (− 2.0, p = 0.01) and composite scores (− 4.33, p = 0.009), with significant changes in taste, smell, and composite TSQ scores across all time points.

Fig. 2.

a Change in TSQ taste scores based on chemotherapy type. b Change in TSQ smell scores based on chemotherapy type. c Change in TSQ total composite scores based on chemotherapy type.

Attrition

Among the 13 enrolled patients receiving platinum-based therapies, eight completed day 30 and day 60 assessments. Among the 13 patients receiving non-platinum therapies who enrolled, eleven completed assessments on day 30 and nine on day 60 (Table 2).

Table 2.

Number of patients that remained enrolled and completed assessments at each time point based on chemotherapy type

Chemotherapy type	Baseline (n = 26)	Day 30 (n = 19)	Day 60 (n = 17)
Platinum-based	13	8	8
Non-platinum	13	11	9

Nine patients completed chemotherapy prior to trial completion. On day 30, two platinum-based patients no longer were receiving chemotherapy. By day 60, seven additional patients no longer were receiving chemotherapy, five from the platinum-based group and two from the non-platinum group. Among the patients who dropped out, disease progression and severe chemotherapy-related toxicities were cited most frequently as reasons for attrition. No lactoferrin-related toxicities were observed or reported by any participants.

Discussion

Among patients receiving chemotherapy, taste and smell changes occur frequently (68–100%) across studies, cancer types (e.g., head, neck, lung, breast), and treatment regimens [24–26]. Our trial was designed to contribute to the literature regarding TSA among patients receiving chemotherapy. In our previously reported salivary proteomic analysis, patients undergoing chemotherapy had significantly higher baseline salivary iron concentrations compared to healthy controls (p = 0.033) [16]. These findings suggest that salivary mineral and heavy metal content may play a role in taste and smell perception and supports the hypothesis that the salivary peroxidase system may influence chemosensory perception among patients receiving chemotherapy.

Lactoferrin and the salivary peroxidase system

Compared to healthy subjects, increased salivary lipid oxidation has been observed among patients with cancer, including those receiving chemotherapy or radiation [27, 28]. Chemotherapies may induce TSA via disruptions in the salivary peroxidase system. As lactoferrin naturally balances salivary reduction–oxidation (redox) processes [29] and has been shown to reduce perception of metallic flavors when ingested [6], we investigated whether lactoferrin could improve subjective TSA among patients receiving chemotherapy. Our findings indicate that participants taking daily lactoferrin supplements for 1 month reported improvements in TSA, with further improvements over a subsequent washout period. Although additional research is needed, these improvements may be attributable to reduction in salivary iron due to lactoferrin’s ability to attenuate production of lipid oxidation by-products [6, 27–29].

Saliva serves a variety of complex functions [30] including (a) defense from microorganisms and toxins via the peroxidase system and (b) perception of flavors via transport of tastants to taste buds. Lipid oxidation in the oral cavity is essential to protect against bacteria and regulate oral microbiota [31], but must be balanced by salivary antioxidants to prevent uncontrolled formation of reactive oxygen species (ROS). When impaired, lipid oxidation in the oral cavity yields volatile aldehydes and ketones that prompt perception of metallic flavors [6]—a perception commonly reported among patients with cancer. In the presence of Fe²⁺ (unbound iron compounds), lipid oxidation increases and promotes formation of hydroxyl radicals (highly reactive ROS). When the peroxidase system and its redox balance are deregulated due to exogenous factors (e.g., chemotherapies, exposure to heavy metals), this may lead to ROS accumulation, reduction in saliva’s antioxidant capacity, oxidative stress, and damage to oral tissues and taste receptors. However, in the presence of iron-binding chelators that scavenge free radicals, such as lactoferrin, lipid oxidation is attenuated and may help repair redox balance [27, 28] and reduce metallic flavor perception. Further study will determine how chemotherapies may interfere with taste, smell, and the salivary peroxidation system, and whether lactoferrin supplementation is an effective intervention across varying cancer types, treatments, and TSA. Recognizing the complexity of chemosensory processes and the many pathways through which TSA may occur, additional mechanisms may explain chemosensory disturbances among patients with cancer.

Differences based on platinum versus non‑platinum chemotherapy type

Baseline data indicate significant differences in TSA when patients were grouped by chemotherapy type, such that non-platinum patients reported greater magnitude of change in taste, smell, and composite TSQ scores across all time points. It is possible that the mechanisms, severity, and persistence of TSA may differ across treatments, along with responsiveness to lactoferrin supplementation. Although some patients completed chemotherapy treatment during the trial, which may have influenced improvements, chemotherapy-induced TSA often persists for months following chemotherapy cessation.

Taste and smell abnormalities have been linked with both chemotherapy and radiotherapy [32], with mixed evidence regarding which treatments, combinations, and doses most significantly influence outcomes [7, 33–35]. However, TSA and metallic flavor dysgeusia are particularly common among patients receiving platinum-based therapies [35]. The observed differences between chemotherapy types raise questions about the extent to which different chemotherapies might exert differential impact on TSA and whether they operate via different mechanisms.

Lactoferrin and anti-inflammatory activity

Even a cursory review of the literature linking TSA to cancer and chemotherapies supports a multifactorial etiology where inflammation and damage to taste receptors and neurons variably leads to chemosensory dysfunction. Inflammation is not only a possible precursor to chemotherapy-induced TSA but may also occur as a function of cancer itself [2, 36, 37]. The proliferation of cancer cells and corresponding release of pro-inflammatory factors support a sustained and systemic inflammatory state that has been linked to dysgeusia via disruption in taste cell differentiation, lifespan, and renewal [38]. Circulating inflammatory markers may also act within the central nervous system to modulate areas responsible for chemosensory function. Emerging evidence further suggests that inflammation may disrupt oral and gut microbiota to alter taste [39, 40], possibly through modulation of glutamatergic receptor activity within the microbiota–gut–brain axis [41]. This litany of inflammatory phenomena also is noted as a consequence of cytotoxic substances such as chemotherapies [34]. Relevant to our findings, lactoferrin’s anti-inflammatory and immune-modulatory properties may function to improve TSA by inhibiting cytokine production in the oral cavity and within the gastrointestinal tract [42]. Previous reports [43] have identified lactoferrin’s defense against various infections, oxidative stress, and extreme inflammation, noting its anticancer functions. Innate to the immune system, lactoferrin is synthesized and released into exocrine fluids (e.g., saliva, tears, colostrum, vaginal fluids), transports plasma iron, regulates signaling pathways to impart cytotoxic effects on cancer cells, suppresses production of pro-inflammatory factors, and improves production of anti-inflammatory factors. Future studies should explore mechanisms of TSA not only as a function of chemotherapy but also as a consequence of cancer-related inflammation, as differences in mechanisms may inform interventions for reducing TSA burden.

Lactoferrin and appetite

Impaired taste and smell frequently contribute to reduced pleasure from eating and are known to influence poor appetite and nutrition. In turn, reduced dysgeusia is associated with improved appetite and enjoyment from eating [9, 21] and may support patients with cancer in meeting nutritional requirements. In this study, change in FAACT A/CS scores from baseline to day 30 was not significant, which corresponds with lack of significant improvement in TSQ taste scores at day 30. Improvement in taste, smell, and composite TSA scores was later observed from day 30 to day 60, which may have influenced marginal improvement in “interest in eating” over that same interval. Among patients undergoing chemotherapy, prior studies confirm that experimental enhancement of chemosensory function may improve nutrition [6, 34]. However, it is unclear whether improvements in “interest in eating” and TSA from days 30 to 60 are due to lactoferrin supplementation or chemotherapy cessation. Improvements in TSA and FAACT A/CS scores from day 30 to day 60 could therefore be attributed to natural resolution of taste, smell, and appetite factors. Should future studies confirm the efficacy of lactoferrin for improving TSA and appetite, lactoferrin could potentially reduce risk for anorexia and cachexia among patients undergoing chemotherapy.

Limitations

This pilot investigation was designed to assess feasibility of lactoferrin as a potential TSA therapy. Although sample size was small with limited statistical power and high attrition, many interesting findings emerged meriting further examination in appropriately powered investigations. Owing to this trial’s pragmatic nature, factors contributing to attrition were not adequately assessed. More rigorous observations of adherence and attrition should be integrated into future investigations to ensure that attrition bias is adequately addressed, as there may be differential rates of attrition based on the type of chemotherapy treatment received. Increasing sample size in future trials also will allow examination of other variables of interest and may yield insights regarding the impact of different chemotherapies on TSA, and within the context of a larger trial, stratifying the sample by diagnosis and medication type will assist in understanding potential differences in development of TSA between groups. Additionally, implementing a randomized controlled trial with an expanded cohort and more robust assessments and adherence checks will enhance the ability to address confounding bias and reduce potential for distorting the measure of association between lactoferrin supplementation and changes in taste and smell outcomes. Inclusion of more robust assessments of medication and supplement use will also allow for further exploration of the impact of drug interactions and polypharmacy in the relationship between chemotherapy and TSA.

As it relates to confounding bias and measures of association, other limitations should be noted and considered in future work. This pilot study did not include routine assessments of oral health or oral hygiene, both of which are known to influence taste disturbance. Although our exclusion criteria likely assisted in preventing participation among patients with active oral inflammation, there is strong rationale for assessing gum disease and oral hygiene within the context of future studies in order to control for potential confounding. This study also lacked objective assessments to evaluate TSA. Although objective measures may be more sensitive to functional changes that might otherwise be subjectively undetectable, we contend that patient reports provide more meaningful evaluations of TSA that are more relevant to nutrition and quality of life as well as clinical practice contexts emphasizing the primacy of patients’ own perceptions. Aligned with this, additional and more in-depth assessments of taste disturbances and the qualitative nature of taste alteration may yield valuable insights to bridge gaps in the understanding of how different chemotherapies differentially impact TSA. Furthermore, recognizing this trial’s lack of diversity, future studies should pursue health equity relevant designs that support engagement of diverse patient samples to enhance generalizability and reduce health disparities.

Despite these limitations, our results suggest lactoferrin potentially could serve as an effective dietary supplement to reduce TSA among patients receiving chemotherapy. Confirmation of these findings requires exploration within the context of a more robust randomized controlled trial and would benefit from inclusion of longer treatment and followup periods. Additionally, given the importance of saliva in the maintenance of oral health and its role in supporting taste and smell function, future work also should include assessments of saliva production and specific salivary biomarkers.