Analysis of the Cytokine-Immunological Model of a Cancer-Related Symptom Cluster

描述（由申请人提供）：肝细胞癌（HCC）是全球癌症死亡的第二大原因，预计在未来十年内，美国HCC的发病率将增加，继发于感染丙型肝炎的人数增加。HCC通常出现在晚期，治疗仅提供关于生存的适度益处。因此，癌症相关症状和治疗副作用的管理对于维持健康相关生活质量（HRQL）和治疗依从性至关重要。在最近的NIH科学状态声明中，疼痛，疲劳和抑郁最近被报道为癌症最常见和最令人痛苦的症状。症状群的概念最近被引入肿瘤学领域，并提出了肿瘤免疫学理论模型，该模型表明癌症相关症状，包括疼痛-疲劳-抑郁三联征，可能具有共同的潜在生物学机制。我们有一个独特的机会来探索这一症状群，并在一项针对诊断为乙型肝炎（HBV）和丙型肝炎（HCV）相关HCC患者的这些癌症相关症状的干预措施的随机对照试验（RCT）中测试与相关细胞因子的相关性。我们计划前瞻性地评估标准治疗和随机对照试验干预组中这一症状三联征与相关细胞因子之间的关系。这项研究的具体目标是：（1）前瞻性地检查疼痛、疲劳和抑郁症状之间的患病率和关联及其作为聚类的协变，（2）前瞻性地表征每个个体症状的变化和/或其作为聚类的协变如何与免疫系统参数的变化相关联（白细胞介素[IL]-12，IL-5，IL-6，肿瘤坏死因子-1，干扰素-3和NK细胞数量的水平），和（3）前瞻性地确定症状和症状群的变化以及相关的免疫系统参数是否与HRQL相关。这项研究的结果将提供重要的信息，在诊断为HBV/HCV相关HCC的个体中，最常见的癌症相关症状之间的患病率和时间关系。这项研究的结果可能有助于开发行为和药理学干预措施，以更好地管理这些癌症相关症状。这些结果也可以为研究免疫和疾病进展在肝细胞癌中的作用的研究人员提供信息。拟议研究的目的是通过开展研究来了解癌症耐药性、易感性、启动、消退、进展和复发的生物学机制，从而达到NCI的目标。我们的目标也将通过提高我们对测量影响癌症护理质量、生存率和健康差异的环境、行为、社会文化和经济影响的能力的理解来实现NCI的目标。根据美国国立卫生研究院（NIH）的数据，被诊断患有癌症的人最常见和最难治疗的三种症状是疼痛、疲劳和抑郁。此时，卫生保健提供者独立评估和治疗这些症状。然而，最近提出了癌症相关症状的免疫模型。该理论表明，癌症相关症状可能具有相同的共同生物学原因，因此应开发其他治疗策略。我们有一个独特的机会来测试细胞因子免疫模型，作为一个更大的研究的一部分，该研究正在测试干预治疗癌症相关症状的有效性。拟议的研究（R21）将使我们能够评估可能与癌症相关症状群（抑郁，疼痛和疲劳）相关的免疫系统参数。更大的研究将使用随机对照试验设计来测试干预措施，这将使我们有机会研究这种癌症相关症状群与相关免疫系统标志物（例如，细胞因子）与被诊断患有肝细胞癌的个体进行比较，所述个体正在接受（1）标准护理（N = 111）或（2）旨在管理癌症相关症状的干预（N = 111）。拟议研究（R21）的主要重点是确定（1）这些癌症相关症状的患病率，（2）这些症状之间的时间和并发关系，（3）症状与免疫系统标志物（例如，细胞因子，NK细胞），和（4）这些症状对生活质量的影响。这项研究的结果将为可能有兴趣开发更好的行为和药理干预措施来治疗这些癌症相关症状的研究人员提供信息。该研究还可以提供关于免疫在已诊断为肝细胞癌的个体的疾病进展中的作用的额外信息。

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide and in the next decade the incidence of HCC is expected to increase in the U.S. secondary to the increasing number of individuals infected with hepatitis C. HCC often presents at advanced stages and treatment only provides modest benefits in regard to survival. As a result, management of cancer-related symptoms and treatment side effects is critical to maintain health related quality of life (HRQL) and adherence to treatment. In a recent NIH State-of-the-Science Statement, pain, fatigue, and depression were recently reported to be the most common and distressing symptoms of cancer. The concept of symptom clusters has been recently introduced in the field of oncology and the cytokine-immunological theoretical model has been proposed which suggests that cancer-related symptoms, including the pain-fatigue-depression triad, may have a common underlying biological mechanism. We have a unique opportunity to explore this symptom cluster and test the association to related cytokines in a randomized controlled trial (RCT) of an intervention targeting these cancer-related symptoms in people diagnosed with hepatitis B (HBV) and hepatitis C (HCV)-related HCC. We plan to prospectively assess the association between this symptom triad, and related cytokines, in both the standard of care and intervention arm of the RCT. The specific aims of the study are: (1) to prospectively examine the prevalence and association among pain, fatigue, and symptoms of depression and their covariation as a cluster, (2) to prospectively characterize how variation in each individual symptom and/or their covariation as a cluster are associated with changes in immune system parameters (levels of Interleukin [IL]-12, IL-5, IL-6, tumor necrosis factor-1, interferon-3, and NK cell number), and (3) to prospectively determine if changes in symptoms and symptom clusters, and related immune system parameters, are associated with HRQL. The results of this study will provide important information regarding the prevalence and temporal relationship amongst the most common cancer-related symptoms in individuals diagnosed with HBV/HCV-related HCC. The findings of this study may facilitate the development of behavioral and pharmacological interventions to better manage these cancer-related symptoms. The results may also inform researchers studying the role of immunity and disease progression in hepatocellular carcinoma. The aims of the proposed research meet the goals of the NCI by conducting research to understand the biological mechanisms underlying cancer resistance, susceptibility, initiation, regression, progression and recurrence. Our aims also will meet the goals of NCI by increasing our understanding of the ability to measure environmental, behavioral, sociocultural and economic influences that affect the quality of cancer care, survivorship, and health disparities.According to the National Institute of Health (NIH), the three most common and difficult to treat symptoms in people diagnosed with cancer are pain, fatigue, and depression. At this time, health care providers assess and treat these symptoms independently. However, recently the cytokine-immunological model of cancer-related symptoms was proposed. The theory suggests that cancer-related symptoms may have the same common biological cause and therefore other treatment strategies should be developed. We have a unique opportunity to test the cytokine- immunological model as part of a larger study that is testing the efficacy of an intervention to manage cancer-related symptoms. The proposed study (R21) would allow us to assess immune system parameters that may be related to this cancer-related symptom cluster (depression, pain, and fatigue). The larger study will test an intervention using a randomized controlled trial design, which will give us the opportunity to study the relationship between this cancer-related symptom cluster and related immune system markers (e.g., cytokines) with a individuals diagnosed with hepatocellular carcinoma who are either receiving the (1) standard of care (N=111), or (2) the intervention designed to manage cancer-related symptoms (N=111). The primary focus of the proposed study (R21) will be to determine (1) the prevalence of these cancer-related symptoms, (2) the temporal and concurrent relationship between these symptoms, (3) the association between the symptoms and immune system markers (e.g., cytokines, NK cell), and (4) the impact of these symptoms on quality of life. The results of this study will inform researchers who may be interested in developing better behavioral and pharmacological interventions to treat these cancer-related symptoms. The study may also provide additional information regarding the role of immunity in disease progression for individuals who have been diagnosed with hepatoceullar carcinoma.