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

描述(申请人提供)：肝细胞癌是全球第二大癌症死亡原因，预计在未来十年，由于感染丙型肝炎的人数增加，美国肝细胞癌的发病率将上升。肝细胞癌通常出现在晚期，治疗对生存的好处不大。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的生活质量(HRQL)和坚持治疗至关重要。在NIH最近的一份科学状况声明中，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。最近在肿瘤学领域引入了症状簇的概念，并提出了细胞因子-免疫学理论模型，认为与癌症相关的症状，包括疼痛-疲劳-抑郁三联体，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，并在一项随机对照试验(RCT)中测试与相关细胞因子的相关性，该试验针对诊断为乙肝(乙肝)和丙型肝炎(丙型肝炎)相关肝癌的患者进行了针对这些癌症相关症状的干预。我们计划前瞻性地评估这种症状三联症和相关细胞因子在随机对照试验的标准护理和干预方面的相关性。该研究的具体目的是：(1)前瞻性地检查疼痛、疲劳和抑郁症状以及它们之间的相关性作为一个簇，(2)前瞻性地表征每个单独症状的变化和/或它们作为一个簇的协变性如何与免疫系统参数(白介素12、IL-5、IL-6、肿瘤坏死因子-1、干扰素-3和NK细胞数量)的变化相关联，以及(3)前瞻性地确定症状和症状组的变化以及相关的免疫系统参数是否与HRQL相关。这项研究的结果将为诊断为乙肝病毒/丙型肝炎相关肝细胞癌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提供重要信息。这项研究的发现可能有助于开发行为和药物干预措施，以更好地管理这些癌症相关症状。这一结果也可能为研究免疫和肝细胞癌疾病进展的作用的研究人员提供信息。这项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、退化、进展和复发的生物学机制，从而达到NCI的目标。我们的目标也将达到NCI的目标，通过增加我们对衡量环境、行为、社会文化和经济影响的能力的理解，这些影响影响癌症护理、生存和健康差异的质量。根据美国国家卫生研究所(NIH)的数据，在被诊断为癌症的人中，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细胞因子-免疫学模型。这一理论表明，癌症相关症状可能有相同的共同生物原因，因此应该开发其他治疗策略。作为一项更大规模研究的一部分，我们有一个独特的机会来测试细胞因子免疫模型，该研究正在测试控制癌症相关症状的干预措施的有效性。拟议的研究(R21)将使我们能够评估可能与这种癌症相关症状群(抑郁、疼痛和疲劳)相关的免疫系统参数。这项更大规模的研究将使用随机对照试验设计测试干预措施，这将使我们有机会研究这一癌症相关症状群和相关免疫系统标记物(例如细胞因子)与接受(1)治疗标准(N=111)或(2)旨在管理癌症相关症状的干预措施(N=111)的肝细胞癌患者之间的关系。拟议研究(R21)的主要焦点将是确定(1)这些癌症相关症状的患病率，(2)这些症状之间的暂时和同时存在的关系，(3)这些症状与免疫系统标记物(如细胞因子、NK细胞)之间的联系，以及(4)这些症状对生活质量的影响。这项研究的结果将为那些可能有兴趣开发更好的行为和药物干预措施来治疗这些癌症相关症状的研究人员提供信息。这项研究还可能提供关于免疫在已被诊断为肝细胞癌的个体的疾病进展中的作用的更多信息。

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.