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 [26–28]. 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). 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 [29–30]. Chemotherapies may induce TSA via disruptions in the salivary peroxidase system. As lactoferrin naturally balances salivary reduction-oxidation (redox) processes  and has been shown to reduce perception of metallic flavors when ingested , we investigated whether lactoferrin could improve subjective TSA among patients receiving chemotherapy. Our findings indicate that participants taking daily lactoferrin supplements for one month reported improvements in TSA, with further improvements over a subsequent washout period. Though 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 byproducts [6, 29–31].
Saliva serves a variety of complex functions  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 , 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  – 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 [29–30] 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. Though 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 , with mixed evidence regarding which treatments, combinations, and doses most significantly influence outcomes [7, 8, 35–36]. However, TSA and metallic flavor dysgeusia are particularly common among patients receiving platinum-based therapies . The observed differences between chemotherapy types raises 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 a possible precursor to chemotherapy-induced TSA but may also occur as a function of cancer itself [2, 37–38]. 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 . 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 [40–41], possibly through modulation of glutamatergic receptor activity within the microbiota-gut-brain axis . This litany of inflammatory phenomena also are noted as a consequence of cytotoxic substances such as chemotherapies . 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 . Previous reports  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 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 [10, 23], and may support patients with cancer in meeting nutritional requirements. In this study, change in FAACT A/CS scores from baseline to day 30 were not significant, which corresponds with lack of significant improvement in TSQ taste scores at day 30. Improvement in taste, smell, and composite TSA scores were 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, 35]. 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. Increasing sample size in future trials will allow examination of other variables of interest and may yield insights regarding the impact of different chemotherapies on TSA. Another potential limitation is the lack of objective assessments to evaluate TSA. Though 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. 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.