Optimizing Treatment of Prostate Cancer in Men living with HIV

摘要 癌症是感染艾滋病毒(PWH)和前列腺癌的老年人发病率和死亡率的主要原因 现在是PWH中最常见的癌症之一。尽管如此，前列腺癌仍然是研究最少的。 在艾滋病毒的背景下，肿瘤的自然病史和临床结果。我们的发现表明，艾滋病毒 感染与快速癌变、不良治疗事件增加和死亡率升高有关 风险。然而，关于艾滋病毒对治疗选择的影响(与积极监测相比)的数据非常有限。 关于关键的短期和长期结果，包括癌症控制、生活质量和死亡率，特别是对PWH 临床上有局限性前列腺癌(最常见的诊断阶段)。其中包括毒性方面的权衡。 治疗方式之间的概况和肿瘤学控制，以及非癌症死亡的竞争风险 原因。量化不同管理策略对本地化企业的下游危害和好处 前列腺癌对于辅助决策、最大限度地提高治疗效益和减少危害至关重要。尽管 迫切需要，局限性前列腺癌的治疗从未在#年艾滋病毒的背景下被调查过 临床试验，并从未感染艾滋病毒的人的临床试验中推断结果是不合适的，因为 治疗并发症和耐受性的差异。此外，独特的艾滋病毒相关因素可能在很大程度上 前列腺癌自然病史、合并症、功能状态、第二原发癌风险、生命 预期，和生活质量。该项目将确定HIV在局限性前列腺癌中的作用。 历史和结果。我们将合成一种疾病模拟，用于进行比较 评估常见的治疗途径，以指导治疗决策。我们的具体目标是：(一) 评估免疫功能障碍和特定的ART方案对a)主动监测(AS)低风险的影响 疾病和中高风险疾病的最终治疗，以及b)结果和不良治疗 PWH中前列腺癌所有阶段的事件；(2)创建和验证微观模拟模型(HIV 前列腺癌治疗[HIPR-T])局限性前列腺的自然病史和治疗结果 和(3)使用HIPR-T模型来比较优化的AS和 在PWH的整个生命周期内对局限性前列腺癌进行最终的治疗。为了实现这些目标，我们将利用 来自具有代表性的大型艾滋病毒/癌症队列(3,000名前列腺癌幸存者)和经过验证的艾滋病毒的数据 自然历史模拟框架。我们将合成并验证一种新的前列腺癌-HIV模拟 AS模型捕获、治疗启动和最终治疗结果。然后，我们将使用增强的模型 评估治疗局限性前列腺癌的最佳治疗方法，以最大限度地提高生存和质量。 生活的一部分。这项研究的发现将改变早期前列腺癌的临床决策过程。 癌症，最大限度地受益和减少危害，减少不确定性和治疗差异，并将 威尔斯亲王前列腺癌的治疗建议。

SUMMARY Cancer is a leading cause of morbidity and mortality among aging people with HIV (PWH) and prostate cancer is now one of the most common cancers among PWH. Despite this, prostate cancer remains the least studied tumor in terms of its natural history and clinical outcomes in the context of HIV. Our findings suggest that HIV infection is associated with rapid carcinogenesis, increased adverse treatment events, and elevated mortality risk. However, there are very limited data on the impact of HIV on treatment selection (versus active surveillance) on key short- and long-term outcomes, including cancer control, quality of life, and mortality particularly for PWH with clinically localized prostate cancer (the most commonly diagnosed stage). These include tradeoffs in toxicity profiles and oncologic control among therapeutic modalities, as well as competing risks of death from non-cancer causes. Quantifying the downstream harms and benefits of different management strategies for localized prostate cancers is critical to aid decision-making, maximize treatment benefits, and reduce harms. Despite compelling need, treatment of localized prostate cancer has never been investigated in the context of HIV in clinical trials, and extrapolating results from clinical trials in HIV uninfected persons is inappropriate due to differences in treatment complications and tolerability. Furthermore, unique HIV-related factors may substantially alter prostate cancer natural history, comorbidities, functional status, risk of second primary cancers, life expectancy, and quality of life. This project will determine the role of HIV on localized prostate cancer natural history and outcomes. We will synthesize a disease simulation that will be used to perform comparative assessment of common treatment pathways to guide treatment decision-making. Our Specific Aims are: (1) To evaluate the impact of immune dysfunction and specific ART regimens on a) active surveillance (AS) for low-risk disease, and definitive treatment for intermediate- and high-risk disease and b) outcomes and adverse treatment events for all stages of prostate cancer among PWH; (2) To create and validate a microsimulation model (HIv Prostate Treatment [HIPR-T]) of prostate cancer natural history and treatment outcomes for localized prostate cancer in PWH; and (3) To use the HIPR-T model to compare the benefits vs harms of optimized AS and definitive treatment for localized prostate cancer over the lifetime of PWH. To achieve these aims, we will use data from large, representative HIV/cancer cohorts (>3,000 PWH prostate cancer survivors) and a validated HIV natural history simulation framework. We will synthesize and validate a novel prostate cancer-HIV simulation model capturing AS, treatment initiation and definitive therapy outcomes. Then, we will use the enhanced model to assess the optimal management of PWH with localized prostate cancer that will maximize survival and quality of life. The findings from this study will transform the clinical decision-making process for early-stage prostate cancer, maximize benefits and reduce harms, reduce uncertainties and treatment disparities, and will inform treatment recommendations for managing prostate cancer among PWH.