Exercise prehabilitation in colorectal cancer: establishing mechanisms of adaptation to advance optimisation and stratification.

肠癌，如结肠癌或直肠癌，是死亡的主要原因，特别是在60岁以上的人中。然而，如果及早发现，这些癌症也提供了治愈性治疗的机会。然而，从癌症诊断到切除手术的时间需要不到31天，这限制了患者为手术做身体准备的机会。尽管手术通常是成功的，但癌症的负担（一些患者可能已经潜伏了很长一段时间）和手术的生理损害各自对手术恢复产生负面影响，具有短期和长期后果（例如，住院时间延长和恢复正常活动受阻）。心肺适应性（CRF;心脏和肺的适应性）下降以及骨骼肌质量和功能的丧失，这两者都可以通过不同类型的运动训练来增强，每一种都强烈地导致不良的临床（即，手术并发症和总存活率）和以患者为中心（即，这些患者的生活质量。然而，尽管有这些知识，为什么这些方面的生理学下降与结直肠癌的基础机制，以及结直肠癌如何影响对运动训练的反应仍然未知。因此，本提案的第一个目的是研究结直肠癌患者与性别和年龄匹配的对照组相比，心肺和骨骼肌生物学的多个方面。第二个目标是围绕外科手术的“预防”。在术前阶段进行锻炼，是对抗心肺系统有害变化的一种手段。有希望的是，以前的研究表明，心肺适应可以在不到31天的时间内通过高强度间歇训练（HIIT）实现。然而，值得注意的是，HIIT（也不是传统的有氧运动（即，长时间的中等强度慢跑或骑自行车））似乎不能有力地增强结肠直肠癌患者的骨骼肌质量或功能，这是在准备手术时达到最佳身体状况的主要障碍。为了解决这个问题，我们提出了一个试验的HIIT与HIIT加阻力运动训练（（RET;重量为基础的训练），我们将称为ReHIIT）在结直肠癌患者。我们假设将RET添加到HIIT中将通过实现肌肉质量和CRF的增加而带来重大益处，并将使用统计方法对此进行测试，从而将这两个单独方面的改善结合起来，以给出“整体健康”改善的数值。至关重要的是，我们还将对肌肉、血液和尿液样本进行实验室研究，以确定结直肠癌患者心肺和骨骼肌状态下降的潜在机制，以及结直肠癌对预防有效性的影响。这些实验室研究将包括以下测量：i）肌肉蛋白质周转（即，细胞生长和分解），ii）血管重塑，和iii）循环蛋白质。我们还将建立数学模型来预测哪些患者可能对任何一种类型的预防（HIIT或ReHIIT）做出最佳反应，以帮助为未来的个性化医疗方法提供信息。

Bowel cancers, such as colon or rectal, are a leading cause of death, especially in those over the age of 60 years. However, if caught early, these cancers also present an opportunity for curative treatment. There is however a required period of less than 31 days from diagnosis of cancer to resection with curative intent, and this limits the window of opportunity to physically prepare patients for their surgery. Despite often successful surgery, the burden of cancer (which some patients may have been harbouring for a long time) and the physiological insult of surgery each negatively impact surgical recovery with both short- and long-term consequences (e.g., increased hospital length of stay and hampered return to normal activities, respectively). Declines in cardiorespiratory fitness ((CRF); the fitness of the heart and lungs) and losses of skeletal muscle mass and function, both of which can be enhanced through different types of exercise training, each contribute strongly to poor clinical (i.e., surgical complications and overall survival) and patient-centred (i.e., quality of life) outcomes in these patients. However, despite this knowledge, the underpinning mechanisms of why these aspects of physiology decline with colorectal cancer, and how colorectal cancer impacts responses to exercise training remain unknown. As such, a first aim of this proposal is to investigate multiple facets of cardiorespiratory and skeletal muscle biology in patients with colorectal cancer compared to sex and age-matched controls. The second aim surrounds surgical "prehabilitation". Constituting exercise in the preoperative period, prehabilitation is a means by which to counter deleterious changes in the cardiorespiratory system. Promisingly, previous research has shown that cardiorespiratory adaptation can be achieved in less than 31-days with an exercise modality known as high-intensity interval training (HIIT). Notably however, HIIT (nor traditional aerobic exercise (i.e., prolonged moderate intensity jogging or cycling)) does not appear able to robustly enhance skeletal muscle mass or function in colorectal cancer patients and this is a major barrier to achieving optimal physical condition in preparation for surgery. To address this, we propose a trial of HIIT versus HIIT plus resistance exercise training ((RET; weights-based training), which we will call ReHIIT) in colorectal cancer patients. We hypothesise that adding RET to HIIT will present major benefits by achieving gains in both muscle mass and CRF, and will test this using a statistical method whereby improvements in these two separate aspects are combined to give a numerical value of improvement in 'overall health'. Crucially, we will also conduct laboratory investigations of muscle, blood and urine samples to determine the underlying mechanisms of declines in cardiorespiratory and skeletal muscle status with colorectal cancer, and the impact of colorectal cancer on the effectiveness of prehabilitation. These laboratory investigations will include measures of: i) muscle protein turnover (i.e., cell growth and breakdown), ii) blood vessel remodelling, and iii) circulating proteins. We will also build mathematical models to predict which patients will likely best respond to either type of prehabilitation (HIIT or ReHIIT) to help inform future personalised-medicine approaches.