Fadel Michael G, Murray James, Woodfield Georgia, Belluomo Ilaria, Laponogov Ivan, Parker Aaron, Converso Valerio, Ellis James K, Wheatstone Pete, Hepburn Julie, Groves Chris, Monahan Kevin, Saunders Brian P, Španěl Patrik, Veselkov Kirill, Cross Amanda J, Kontovounisios Christos, Sharples Linda D, Hanna George B
Department of Surgery and Cancer, Hammersmith Hospital Campus, Imperial College London, Du Cane Road, London, W12 0NN, UK.
Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.
BMC Cancer. 2025 Jul 29;25(1):1230. doi: 10.1186/s12885-025-14520-2.
Colorectal cancer (CRC) is the fourth most common cancer in the United Kingdom. The five-year survival rate from CRC is only 10% when discovered at a late stage, but can exceed 90% if diagnosed early. Symptoms related to CRC can be non-specific, and therefore the decision to refer for a colonoscopy can be challenging. Breath analysis potentially offers a simple and quick method to detect CRC specific volatile organic compounds (VOCs) in breath. This protocol describes the COBRA2 study which aims to develop and validate the clinical prediction model (CPM) in the detection of CRC based on the breath test. An exploratory comparison between the breath test and faecal immunochemical test (FIT) will also be carried out to assess whether combining both tests improves diagnostic performance.
The COBRA2 study is a multicentre, case-control development and validation study. Breath samples will be collected from participants attending hospital for a planned colonoscopy (control group) or from participants with histologically confirmed colorectal adenocarcinoma (CRC group). A total of 720 participants (470 controls, 250 CRC) will be recruited. All participants will maintain a clear fluid diet for a minimum of 4-6 h prior to sampling, which will take place at outpatient clinics to avoid bowel preparation. The FIT result will be recorded where available. Breath samples will be analysed using gas chromatography-mass spectrometry to identify the VOCs present. Relationships between VOCs of interest and presence of CRC will be explored, and the CPM will be developed using statistical and machine learning methods. We will also assess whether incorporating FIT into the CPM improves diagnostic performance. The CPM will be subsequently validated in an independent sample of up to 250 participants (125 controls, 125 CRC) using the same case-control design and the potential clinical utility of decision rules for triaging will be assessed. If successful, broad validation in an unselected target population of symptomatic patients is required.
The non-invasive breath test may provide direct patient benefit through earlier and accurate detection of CRC, and higher patient acceptability. It can help ensure timely secondary care referral, potentially translating to improved curative treatment and survival for patients.
The study is registered with ClinicalTrials.gov (NCT05844514).
结直肠癌（CRC）是英国第四大常见癌症。结直肠癌若在晚期发现，其五年生存率仅为10%，但如果早期诊断，生存率可超过90%。与结直肠癌相关的症状可能不具有特异性，因此决定是否进行结肠镜检查具有挑战性。呼气分析可能提供一种简单快速的方法来检测呼出气体中结直肠癌特异性挥发性有机化合物（VOCs）。本方案描述了COBRA2研究，其目的是开发并验证基于呼气测试检测结直肠癌的临床预测模型（CPM）。还将对呼气测试和粪便免疫化学测试（FIT）进行探索性比较，以评估两种测试相结合是否能提高诊断性能。
COBRA2研究是一项多中心、病例对照的开发和验证研究。将从计划进行结肠镜检查的住院参与者（对照组）或组织学确诊为结直肠腺癌的参与者（CRC组）中采集呼气样本。总共将招募720名参与者（470名对照，250名CRC患者）。所有参与者在采样前至少4 - 6小时需保持清淡流食，采样将在门诊进行以避免肠道准备。如有FIT结果也将记录。呼气样本将使用气相色谱 - 质谱法进行分析以识别其中存在的VOCs。将探索感兴趣的VOCs与CRC存在之间的关系，并使用统计和机器学习方法开发CPM。我们还将评估将FIT纳入CPM是否能提高诊断性能。随后将使用相同的病例对照设计在多达250名参与者（125名对照，125名CRC患者）的独立样本中验证CPM，并评估分诊决策规则的潜在临床效用。如果成功，需要在有症状患者的未选择目标人群中进行广泛验证。
非侵入性呼气测试可能通过更早、准确地检测结直肠癌以及更高的患者接受度为患者带来直接益处。它有助于确保及时转诊至二级护理，可能会改善患者的治愈性治疗和生存率。
该研究已在ClinicalTrials.gov注册（NCT05844514）。
