[18F]FDG-PET-CT compared with CT for persistent or recurrent neutropenic fever in high-risk patients (PIPPIN): a multicentre, open-label, phase 3, randomised, controlled trial,The Lancet Haematology

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[18F]FDG-PET-CT compared with CT for persistent or recurrent neutropenic fever in high-risk patients (PIPPIN): a multicentre, open-label, phase 3, randomised, controlled trial
The Lancet Haematology ( IF 24.7 ) Pub Date : 2022-06-28 , DOI: 10.1016/s2352-3026(22)00166-1
Abby Douglas ₁ , Karin Thursky ₂ , Timothy Spelman ₃ , Jeff Szer ₄ , Ashish Bajel ₅ , Simon Harrison ₆ , Shio Yen Tio ₁ , Olivia Bupha-Intr ₇ , Michelle Tew ₈ , Leon Worth ₁ , Benjamin Teh ₁ , Lynette Chee ₄ , Ashley Ng ₉ , Dennis Carney ₄ , Amit Khot ₅ , Gabrielle Haeusler ₁ , Michelle Yong ₁₀ , Jason Trubiano ₁₁ , Sharon Chen ₁₂ , Rodney Hicks ₁₃ , David Ritchie ₄ , Monica Slavin ₁₄

Affiliation

National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Department of Health Services Research and Implementation Science, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia; National Centre for Antimicrobial Stewardship, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
Department of Health Services Research and Implementation Science, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Burnet Institute, Melbourne, Victoria, Australia.
Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia; Department of Clinical Haematology, Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, Melbourne, Victoria, Australia.
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia; Department of Clinical Haematology, Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, Melbourne, Victoria, Australia.
National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia; Department of Clinical Haematology, Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, Melbourne, Victoria, Australia.
Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Department of Health Services Research and Implementation Science, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Centre for Health Policy, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
Department of Clinical Haematology, Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, Melbourne, Victoria, Australia.
National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia; Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research, NSW Health Pathology, Westmead Hospital, Westmead, New South Wales, Australia; The Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, New South Wales, Australia.
Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Department of Health Services Research and Implementation Science, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia; Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne, Victoria, Australia.

Background

Management of neutropenic fever in high-risk haematology patients is challenging; there are often few localising clinical features, and diagnostic tests have poor sensitivity and specificity. We aimed to compare how [¹⁸F]flurodeoxyglucose ([¹⁸F]FDG)-PET-CT scans and conventional CT scans affected the guidance of antimicrobial management and the outcomes of patients with persistent or recurrent neutropenic fever.

Methods

We did a multicentre, open-label, phase 3, randomised, controlled trial in two tertiary referral hospitals in Australia. We recruited adults aged 18 years or older who were receiving conditioning chemotherapy for haematopoietic stem-cell transplantation or chemotherapy for acute leukaemia and had persistent (>72 h) or recurrent (new fever beyond 72 h of initial onset interspersed with >48 h defervescence) neutropenic fever. Exclusion criteria were pregnancy, allergy to iodinated contrast, or estimated glomerular filtration rate of less than 30 mL/min. Patients were randomly assigned by computer-generated randomisation chart (1:1) to [¹⁸F]FDG-PET-CT or conventional CT. Masking was not possible because of the nature of the investigation. Scans were done within 3 days of random assignment. The primary endpoint was a composite of starting, stopping, or changing the spectrum (broadening or narrowing) of antimicrobial therapy—referred to here as antimicrobial rationalisation—within 96 h of the assigned scan, analysed per protocol. This trial is registered with clinicaltrials.gov, NCT03429387, and is complete.

Findings

Between Jan 8, 2018, and July 23, 2020, we assessed 316 patients for eligibility. 169 patients were excluded and 147 patients were randomly assigned to either [¹⁸F]FDG-PET-CT (n=73) or CT (n=74). Nine patients did not receive a scan per protocol, and two participants in each group were excluded for repeat entry into the study. 65 patients received [¹⁸F]FDG-PET-CT (38 [58%] male; 53 [82%] White) and 69 patients received CT (50 [72%] male; 58 [84%] White) per protocol. Median follow up was 6 months (IQR 6–6). Antimicrobial rationalisation occurred in 53 (82%) of 65 patients in the [¹⁸F]FDG-PET-CT group and 45 (65%) of 69 patients in the CT group (OR 2·36, 95% CI 1·06–5·24; p=0·033). The most frequent component of antimicrobial rationalisation was narrowing spectrum of therapy, in 28 (43%) of 65 patients in the [¹⁸F]FDG-PET-CT group compared with 17 (25%) of 69 patients in the CT group (OR 2·31, 95% CI 1·11–4·83; p=0·024).

Interpretation

[¹⁸F]FDG-PET-CT was associated with more frequent antimicrobial rationalisation than conventional CT. [¹⁸F]FDG-PET-CT can support decision making regarding antimicrobial cessation or de-escalation and should be considered in the management of patients with haematological diseases and persistent or recurrent high-risk neutropenic fever after chemotherapy or transplant conditioning.

Funding

National Health and Medical Research Council Centre of Research Excellence (APP1116876), Melbourne Health foundation, Gilead Research Fellowship grants supported this study.

中文翻译：

[18F]FDG-PET-CT 与 CT 比较高危患者持续性或复发性中性粒细胞减少性发热 (PIPPIN)：一项多中心、开放标签、3 期、随机、对照试验

背景

高危血液病患者中性粒细胞减少性发热的管理具有挑战性；通常很少有局部临床特征，诊断测试的敏感性和特异性较差。我们旨在比较 [ ¹⁸ F] 氟脱氧葡萄糖([ ¹⁸ F]FDG)-PET-CT 扫描和常规 CT 扫描如何影响抗菌药物管理的指导以及持续性或复发性中性粒细胞减少性发热患者的预后。

方法

我们在澳大利亚的两家三级转诊医院进行了一项多中心、开放标签、3 期、随机对照试验。我们招募了年龄在 18 岁或以上的成年人，他们正在接受造血干细胞移植的预处理化疗或急性白血病的化疗，并且有持续性（>72 小时）或复发性（新发发热超过初始发病 72 小时并穿插>48 小时退热）中性粒细胞减少症。排除标准是妊娠、对碘造影剂过敏或估计肾小球滤过率低于 30 mL/min。患者通过计算机生成的随机图表 (1:1) 随机分配到 [ ¹⁸F]FDG-PET-CT 或常规 CT。由于调查的性质，无法进行掩蔽。扫描在随机分配后 3 天内完成。主要终点是在指定扫描后 96 小时内开始、停止或改变抗菌治疗范围（扩大或缩小）的复合终点（此处称为抗菌合理化），按方案分析。该试验在clinicaltrials.gov注册，NCT03429387，并且已经完成。

发现

在 2018 年 1 月 8 日至 2020 年 7 月 23 日期间，我们评估了 316 名患者的资格。169 名患者被排除，147 名患者被随机分配至 [ ¹⁸ F]FDG-PET-CT (n=73) 或 CT (n=74)。9 名患者没有按照方案接受扫描，每组中有 2 名参与者被排除重复进入研究。根据方案， 65 名患者接受了 [ ¹⁸ F]FDG-PET-CT（38 [58%] 男性；53 [82%] 白人）和 69 名患者接受 CT（50 [72%] 男性；58 [84%] 白人）。中位随访时间为 6 个月（IQR 6-6）。^{[ 18} ] 65 名患者中有 53 名 (82%) 发生了抗生素合理化F]FDG-PET-CT 组和 CT 组 69 名患者中的 45 名 (65%) (OR 2·36, 95% CI 1·06–5·24; p=0·033)。^{抗生素合理化最常见的组成部分是缩小治疗范围，[ 18} F]FDG-PET-CT 组65 名患者中有 28 名（43%），而CT 组 69 名患者中有 17 名（25%）（或2·31, 95% CI 1·11–4·83；p=0·024)。