Interleukin-6 as surrogate marker for imaging-based hypoxia dynamics in patients with head-and-neck cancers undergoing definitive chemoradiation—results from a prospective pilot trial,European Journal of Nuclear Medicine and Molecular Imaging

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Interleukin-6 as surrogate marker for imaging-based hypoxia dynamics in patients with head-and-neck cancers undergoing definitive chemoradiation—results from a prospective pilot trial
European Journal of Nuclear Medicine and Molecular Imaging ( IF 9.1 ) Pub Date : 2021-11-13 , DOI: 10.1007/s00259-021-05602-x
Alexander Rühle _{1,

2} , Nicole Wiedenmann _{1,

2} , Jamina T Fennell _{1,

2} , Michael Mix ₃ , Juri Ruf ₃ , Raluca Stoian _{1,

2} , Andreas R Thomsen _{1,

2} , Peter Vaupel _{1,

2} , Dimos Baltas _{1,

2} , Anca-L Grosu _{1,

2} , Nils H Nicolay _{1,

2}

Affiliation

Purpose

Intratumoral hypoxia increases resistance of head-and-neck squamous cell carcinoma (HNSCC) to radiotherapy. [¹⁸F]FMISO PET imaging enables noninvasive hypoxia monitoring, though requiring complex logistical efforts. We investigated the role of plasma interleukin-6 (IL-6) as potential surrogate parameter for intratumoral hypoxia in HNSCC using [¹⁸F]FMISO PET/CT as reference.

Methods

Within a prospective trial, serial blood samples of 27 HNSCC patients undergoing definitive chemoradiation were collected to analyze plasma IL-6 levels. Intratumoral hypoxia was assessed in treatment weeks 0, 2, and 5 using [¹⁸F]FMISO PET/CT imaging. The association between PET-based hypoxia and IL-6 was examined using Pearson’s correlation and multiple regression analyses, and the diagnostic power of IL-6 for tumor hypoxia response prediction was determined with receiver-operating characteristic analyses.

Results

Mean IL-6 concentrations were 15.1, 19.6, and 31.0 pg/mL at baseline, week 2 and week 5, respectively. Smoking (p=0.050) and reduced performance status (p=0.011) resulted in higher IL-6 levels, whereas tumor (p=0.427) and nodal stages (p=0.334), tumor localization (p=0.439), and HPV status (p=0.294) had no influence. IL-6 levels strongly correlated with the intratumoral hypoxic subvolume during treatment (baseline: r=0.775, p<0.001; week 2: r=0.553, p=0.007; week 5: r=0.734, p<0.001). IL-6 levels in week 2 were higher in patients with absent early tumor hypoxia response (p=0.016) and predicted early hypoxia response (AUC=0.822, p=0.031). Increased IL-6 levels at week 5 resulted in a trend towards reduced progression-free survival (p=0.078) and overall survival (p=0.013).

Conclusion

Plasma IL-6 is a promising surrogate marker for tumor hypoxia dynamics in HNSCC patients and may facilitate hypoxia-directed personalized radiotherapy concepts.

Trial registration

The prospective trial was registered in the German Clinical Trial Register (DRKS00003830). Registered 20 August 2015

中文翻译：

白细胞介素 6 作为头颈癌患者接受根治性放化疗的影像学缺氧动态的替代标志物——一项前瞻性试验的结果

目的

瘤内缺氧增加了头颈部鳞状细胞癌 (HNSCC) 对放射治疗的抵抗力。[ ¹⁸ F]FMISO PET 成像可实现无创缺氧监测，但需要复杂的后勤工作。^{我们使用 [ 18} F]FMISO PET/CT 作为参考，研究了血浆白细胞介素 6 (IL-6) 作为 HNSCC 中瘤内缺氧的潜在替代参数的作用。

方法

在一项前瞻性试验中，收集了 27 名接受根治性放化疗的 HNSCC 患者的系列血样，以分析血浆 IL-6 水平。^{使用 [ 18} F]FMISO PET/CT 成像在治疗第 0、2 和 5 周评估肿瘤内缺氧。使用 Pearson 相关性和多元回归分析检查基于 PET 的缺氧和 IL-6 之间的关联，并通过接受者操作特征分析确定 IL-6 对肿瘤缺氧反应预测的诊断能力。

结果

在基线、第 2 周和第 5 周时，平均 IL-6 浓度分别为 15.1、19.6 和 31.0 pg/mL。吸烟 ( p =0.050) 和体能状态降低 ( p =0.011) 导致 IL-6 水平升高，而肿瘤 ( p =0.427) 和淋巴结分期 ( p =0.334)、肿瘤定位 ( p =0.439) 和 HPV 状态( p =0.294) 没有影响。IL-6 水平与治疗期间的瘤内缺氧亚体积密切相关（基线：r = 0.775，p <0.001；第 2 周：r = 0.553，p = 0.007；第 5 周：r = 0.734，p<0.001)。在缺乏早期肿瘤缺氧反应的患者中，第 2 周的 IL-6 水平较高（p = 0.016）并预测早期缺氧反应（AUC = 0.822，p = 0.031）。第 5 周 IL-6 水平升高导致无进展生存期 ( p = 0.078) 和总生存期 ( p = 0.013) 降低。