UCSF

Dyspnea is defined as “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity”. Dyspnea occurs in approximately 10% to 70% of oncology patients. This broad range in its prevalence rates suggests that dyspnea has a large amount of inter-individual variability. In addition, the risk factors for dyspnea in patients with cancer are likely to be multifactorial. This variability makes it difficult to characterize the “dyspnea experience” of oncology patients and determine factors associated with this symptom. Consequently, dyspnea decreases oncology patients’ quality of life and, in some cases, overall survival. Yet, definitive interventions do not exist. Therefore, the aims of this dissertation research were to: 1) develop the Multifactorial Model of Dyspnea in Patients with Cancer; 2) systematically review studies published since 2009 that evaluated for dyspnea in patients with cancer; 3) identify subgroups of patients with distinct shortness of breath profiles in a sample of outpatients receiving chemotherapy and evaluate for differences in a variety of demographic, clinical, and symptom characteristics; and 4) determine the most influential perturbed inflammatory pathways between patients with and without dyspnea.

In terms of Aim 1, a conceptual paper provides an overview of the physiology of normal breathing; the pathophysiology of dyspnea; and factors that contribute to dyspnea in oncology patients. Specific factors that were included in the Multifactorial Model of Dyspnea in Patients with Cancer were: person, clinical, and cancer-related factors, as well as respiratory muscle weakness, co-occurring symptoms, and stress. While this paper provides a summary of the evidence on the mechanisms and factors associated with dyspnea in patients with cancer, the paucity of research on this symptom suggests numerous areas for investigation. This paper concludes that progress will not be made in the effective management of dyspnea without increased knowledge of its associated risk factors and underlying mechanisms.

In terms of Aim 2, in a systematic review, 117 studies were identified that evaluated for dyspnea in patients with cancer. This systematic review summarized the prevalence, intensity, distress, and impact of dyspnea in oncology patients and identified research gaps. Across these studies, the intensity of dyspnea was the most common symptom dimension that was evaluated followed by impact and distress. Depression and anxiety were the most common symptoms that co-occurred with dyspnea. Future research studies need to use valid and reliable multidimensional measures. In addition, given the paucity of studies on mechanism(s) that underlie dyspnea in patients with cancer, future research is warranted to determine specific biomarkers for dyspnea.

In terms of Aim 3, in outpatients receiving their second or third cycle of chemotherapy, four distinct shortness of breath profiles were identified (None [70.5%]; Decreasing [8.2%]; Increasing [7.8%], High [13.5%]). Findings suggest that risk factors for membership in High class include history of smoking, self-reported diagnosis of lung disease, having lung cancer, and receipt of a higher number of cancer treatments. In terms of symptom dimensions, patients in the High class reported more frequent and severe shortness of breath. In addition, compared to None class, patients in the other three classes reported higher occurrence rates for chest tightness and difficulty breathing. Compared to None class, patients in the Decreasing and High classes reported higher occurrence rates for cough. Regarding the impact of shortness of breath, compared to None class, patients in the High class reported poorer physical, psychological, and social functioning.In addition, we evaluated associations between shortness of breath and global, cancer-specific, and cumulative life stress, as well as resilience and common co-occurring symptoms. Compared to None class, patients in the Decreasing and High classes had higher global and cancer-specific stress scores. Patients in the High class reported higher occurrence rates for several adverse childhood experiences. In addition, our findings suggested that compared to None class, patients in the Decreasing and High classes had higher depression, anxiety, and morning fatigue scores and lower morning energy and cognitive function scores.

In terms of Aim 4, given the paucity of research on underlying mechanism(s) for dyspnea in patients with cancer and the potential contribution of inflammatory mechanisms, whole transcriptome gene expression and pathway impact analyses were done to evaluate for associations between this symptom and perturbations in inflammatory pathways. Among 73 significantly perturbed Kyoto Encyclopedia of Genes and Genomes signaling pathways, 29 were related to inflammatory mechanisms. Findings from this study provide preliminary support for the hypothesis that pulmonary and systemic inflammation contribute to the occurrence of dyspnea in patients receiving chemotherapy.

To evaluate the interconnections between and among these inflammatory pathways, an unweighted knowledge network was created using the specific pathway maps. Three centrality measures (i.e., betweenness, closeness, degree) were calculated to gain insights into the structural importance of each node. The mitogen-activated protein kinase (MAPK) signaling pathway node had the highest closeness, betweenness, and degree scores. The next ten pathways with the highest centrality scores were: Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway; apoptosis, phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway, natural killer (NK)-cell mediated cytotoxicity, neutrophil extracellular trap (NET) formation, nuclear factor kappa light chain enhancer of activated B cells (NF-kappa B) signaling pathway, cytokine-cytokine receptor interaction, nucleotide-binding and oligomerization domain (NOD)-like receptor signaling pathway, Forkhead box O (FoxO) signaling pathway, and chemokine signaling pathway. In addition, five common respiratory disease-related pathways, that may share mechanisms with cancer-related dyspnea, were perturbed. These findings warrant validation. This dissertation concludes with implications for clinical practice and future research.