Michael Scordo Gunjan L. Shah Jonathan U. Peled Elaina V. Preston Marissa L. Buchan Joel B. Epstein Andrei Barasch Sergio A. Giralt
Introduction
Taste disturbance, known as dysgeusia, is an oftenreported yet underappreciated sequela of cancer therapy that can markedly affect patients’ quality of life (QoL). Although dysgeusia is not unique to recipients of hematopoietic cell transplantation (HCT), this complication may be most pertinent in the early post-transplantation period, when direct conditioning regimen-related mucosal injury impairs taste and flavor perception and alters nutritional absorptive capacity, and when myelosuppression and delayed immune recovery affect mucosal immunity and oropharyngeal microbiome biodiversity. Although transplantation physicians often find themselves discussing taste disturbances with their patients, the pathophysiology of dysgeusia is poorly understood, and to our knowledge, has not been widely evaluated in prospective HCT clinical trials. In this report, we review normal taste function and how it is evaluated, discuss unique transplantation-related factors that contribute to dysgeusia, and examine potentially novel strategies for studying and mitigating dysgeusia in this patient population.
Review of Taste Function
At its fundamental level, the sense of taste has evolved to allow an individual to appraise ingested items as nutritious food or noxious material. It also allows one to derive satisfaction and pleasure from the experience of eating. As such, taste plays a critical role in both nutritional status and QoL. Human flavor perception is a highly regulated and multicomponent sensorial system that involves neuronal pathways, the sense of olfaction, and adequate saliva production. At the time of food consumption, salivary enzymes dissolve taste molecules that are delivered to taste receptors. Multiple taste receptor cells contained within taste buds of the tongue, palate, and oropharynx function as neuroreceptors.
Causes of Taste Disorders in Patients with Cancer
Taste disorders in patients with cancer are often have multiple etiologies. Patients with head and neck cancer undergoing multimodal treatment with surgery, chemotherapy, and radiotherapy (RT) are the most well-studied population. A 75% to 100% incidence of taste disturbances in this population has been reported in several series, with some patients describing taste changes even before the start of treatment, suggesting a direct impact of the tumor. In a mouse model in which taste buds were disrupted by radiation exposure, the primary mechanism of taste disturbance after RT was direct injury to taste receptor progenitor cells that impeded normal cell turnover.
Unique Aspects of Taste Disturbances in Patients
Undergoing HCT
Conditioning regimens
The contributors to dysgeusia may differ between recipients of autologous stem cell transplantation (ASCT) and recipients of allogeneic HCT (allo-HCT). Early taste disturbances after ASCT are largely caused by direct conditioning regimen-related oral mucosal and salivary gland injury from chemotherapy with or without RT. A patient’s underlying disease often dictates the choice of conditioning regimen,
which in turn variable affects the severity and duration of dysgeusia and decreased saliva production. The most common indications for ASCT are multiple myeloma and non-Hodgkin lymphoma, for which high-dose melphalan and combination chemotherapy regimens, such as carmustine, etoposide, cytarabine, and melphalan (BEAM), are widely used. A recent retrospective analysis of patients with lymphoma
and myeloma receiving a BEAM-like regimen and highdose melphalan, respectively, identifified both combination chemotherapy conditioning regimens and the development of oral mucositis as independent risk factors for dysgeusia. Patients with myeloma who received oral preventive cryotherapy before high-dose melphalan therapy were at less risk of significant taste disturbances. No other patient or transplantation characteristics were found to modulate the risk
of developing dysgeusia.
Dysgeusia and malnourishment
Taste disturbances can have profound, objective effects on dietary intake and certain indicators of nutritional status after HCT, such as albumin. Hypoalbuminemia is a reflection of multiple factors, including liver synthetic function, the in- flammatory cytokine milieu, and losses through proteinuria or protein-losing enteropathy, with nutritional status representing only one key component.
Similarly, by decreasing the desire for oral intake, dysgeusia likely affects other surrogate measures of nutritional status after HCT, such as weight loss and body mass index (BMI). Patients considered malnourished based on these surrogate measures after HCT have inferior overall survival. It should be noted that although weight and BMI are often used as surrogates of nutritional state, they imperfectly reflect the full biological assessment of nourishment. This may be particularly true as we develop a more robust understanding of the role of cardiopulmonary health, muscle mass, and physical conditioning on post-transplantation recovery and outcomes.
Immune recovery
By influencing appetite and nutritional intake, dysgeusia also indirectly impacts immunity, given the wellrecognized relationships between malnutrition and weight
loss, impaired healing, and ineffective innate and adaptive immune responses. In the early post-transplantation period, immune recovery represents a critical step in avoiding life-threatening infections and risk of disease relapse. The thymus maintains effective immune function, and thymicatrophy from malnourishment suppresses T cell maturation and function. This is particularly relevant in older adults, who naturally have thymic involution with advancing age, and in the context of conditioning regimen- and GVHDrelated thymic injury after HCT. Nutritional formulas designed to improve immune responses, also known as immunonutrition, have been studied in multiple populations, including critically ill patients, with mixed and sometimes negative results. Interestingly, anorexia during infection is a widely recognized phenomenon thought by some to represent an adaptive response that up-regulates and improves autophagy in immune and nonimmune cells. Whether optimal timing of our nutritional efforts could maximize immune function after allo-HCT requires further inquiry.
The unique role of the microbiome
Patients undergoing allo-HCT represent a distinctive group in which to study the intestinal microbiota, given their intense nutritional disturbances and antibiotic exposures. Conditioning regimens result in marked colonic mucosal injury, which allows for resulting gut translocation of microorganisms or their products, such as lipopolysaccharide, as well as poor nutritional intake and dysgeusia.
QoL
Only a few studies to date have quantifified the symptom burden of dysgeusia. Prospectively examined physical, emotional, and social function in 56 patients in their fifirst year after HCT and found that 20% of patients reported dysgeusia that impacted QoL. Campagnaro et al. Prospectively evaluated the symptom burden of patients undergoing high-dose melphalan-based ASCT within the first 30 days using the M.D. Anderson Symptom Inventory— Blood and Marrow Transplantation (MDASI-BMT), and found that the most common early post-transplantation symptoms included fatigue, weakness, anorexia/nausea, diarrhea, and insomnia. Importantly, these symptoms were associated with decreased frequency of physical activity and QoL. Although many of the toxicities in this prospective study are interrelated, dysgeusia likely contributed in part to these
symptom clusters presents a summary of selected published trials of dysgeusia and related factors after HCT.
Assessment of Taste Dysfunction
A detailed patient history assessing the onset and quality of symptoms, medication review, and a comprehensive head and neck physical examination are invaluable tools in identifying the etiology of taste disturbances. Commercially available kits, such as the University of Pennsylvania Smell Identification Test (UPSIT), have been used to evaluate the contribution of olfactory disturbances to dysgeusia. Relevant laboratory testing for electrolyte disturbances and for hepatic and renal function also may be indicated in certain cases; for example, hyperuricemia is known to be associated with appetite suppression. Given the importance of flavor on QoL and adequate nutritional intake, it is essential to integrate both subjective and
objective data when assessing dysgeusia after HCT. In whole-mouth gustometric testing, the patient first rinses his or her mouth with room temperature water. Then small amounts of specific chemical reagents at various concentrations that test the 5 taste senses are swished around the mouth or applied directly throughout the tongue and mouth by soaked filter paper/applicators or droppers. Similarly, spatial taste testing allows the tester to compare taste changes in different areas of the oral cavity. Given the known contributions of salivation on taste disturbances, additional complementary patient evaluations include salivary measurements, which objectively estimate the stimulated and unstimulated salivary flow rate.
Prevention and Treatment
There are no specific and effective treatments for patients with dysgeusia. Several published studies of zinc supplementation have demonstrated modest improvements in taste disturbances, particularly in patients with as an important factor in taste management. Potential additional approaches for dysgeusia may include treatment trials of megestrol, cannabinoids, and Synsepalum dulcificum (socalled “miracle berry”), which have shown limited evidence of benefit. Studies of these agents in patients undergoing HCT are needed.
Conclusions and Future Directions
Dysgeusia in patients undergoing HCT is a complex syndrome. A better understanding of its etiology and pathobiology, as well as the preventative or therapeutic strategies that could be developed, likely will have a major positive
impact on QoL and possibly on other outcomes, such as NRM. As our biological understanding of contributing factors in dysgeusia broadens and deepens, we need innovative and multimodal studies that incorporate our growing knowledge of the interactions between host and microbiota, nutrition and dietary intake, personalized approaches to conditioning regimen administration, immune recovery, and novel
preventive strategies, such as photomodulation with lowlevel laser light therapy. This will open the door to impactful prospective studies that attempt to minimize confounding variables by selecting homogeneous patient populations, diseases, and conditioning platforms. The prospective strategies chosen must include patient-reported outcomes data and should evaluate whether the studied approach is clinically and economically effective. High-quality data from welldefined and carefully selected patient populations may be applicable across HCT platforms and may inform strategies to reduce the incidence, severity, and symptom burden of dysgeusia. Moreover, the information gained through this work also may be relevant in the care of patients undergoing cytotoxic therapy for other malignancies.
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