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

Abstract 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

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Dynamics of tumor hypoxia assessed by 18F-FAZA PET/CT in head and neck and lung cancer patients during chemoradiation: Possible implications for radiotherapy treatment planning strategies

Radiotherapy and Oncology ◽

10.1016/j.radonc.2014.10.010 ◽

2014 ◽

Vol 113 (2) ◽

pp. 198-203 ◽

Cited By ~ 47

Author(s):

Vikram R. Bollineni ◽

Michel J.B. Koole ◽

Jan Pruim ◽

Charlotte L. Brouwer ◽

Erwin M. Wiegman ◽

...

Keyword(s):

Lung Cancer ◽

Head And Neck ◽

Cancer Patients ◽

Treatment Planning ◽

Tumor Hypoxia ◽

Radiotherapy Treatment Planning ◽

Lung Cancer Patients ◽

Pet Ct ◽

Planning Strategies ◽

Radiotherapy Treatment

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Assessment of tumor hypoxia by 62Cu-ATSM PET/CT as a predictor of response in head and neck cancer: a pilot study

Annals of Nuclear Medicine ◽

10.1007/s12149-011-0471-5 ◽

2011 ◽

Vol 25 (5) ◽

pp. 339-345 ◽

Cited By ~ 59

Author(s):

Yumiko Minagawa ◽

Kazuya Shizukuishi ◽

Izumi Koike ◽

Choichi Horiuchi ◽

Kei Watanuki ◽

...

Keyword(s):

Head And Neck Cancer ◽

Pilot Study ◽

Head And Neck ◽

Neck Cancer ◽

Tumor Hypoxia ◽

Pet Ct

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PD-0135: Dynamics of tumor hypoxia assessed by 18F-FAZA PET/CT in head and neck and lung cancer patients during chemoradiatioN

Radiotherapy and Oncology ◽

10.1016/s0167-8140(15)30240-1 ◽

2014 ◽

Vol 111 ◽

pp. S53

Author(s):

V.R. Bollineni ◽

M.J.B Koole ◽

J. Pruim ◽

E.M. Wiegman ◽

H.J.M. Groen ◽

...

Keyword(s):

Lung Cancer ◽

Head And Neck ◽

Cancer Patients ◽

Tumor Hypoxia ◽

Lung Cancer Patients ◽

Pet Ct

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A prospective trial comparing FDG ‐ PET / CT and CT to assess tumor response to cetuximab in patients with incurable squamous cell carcinoma of the head and neck

Cancer Medicine ◽

10.1002/cam4.294 ◽

2014 ◽

Vol 3 (6) ◽

pp. 1493-1501 ◽

Cited By ~ 10

Author(s):

Douglas Adkins ◽

Jessica Ley ◽

Farrokh Dehdashti ◽

Marilyn J. Siegel ◽

Tanya M. Wildes ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Fdg Pet ◽

Tumor Response ◽

Prospective Trial ◽

Pet Ct ◽

Fdg Pet Ct

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Phase 2 Prospective Trial of Triphasic PET/CT: Primary Site Inflammation Versus Cancer at 3 Months After Completion of Radiation for Head and Neck Squamous Cell Carcinoma

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2014.05.1787 ◽

2014 ◽

Vol 90 (1) ◽

pp. S596

Author(s):

T. Chang ◽

C. Anderson ◽

M. Marquardt ◽

W. Sun ◽

M. Graham ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Prospective Trial ◽

Primary Site ◽

Neck Squamous Cell Carcinoma ◽

Phase 2 ◽

Pet Ct

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Early Analysis of a Phase 2 Prospective Trial Evaluating Accuracy of Triphasic PET/CT After RT for Head and Neck Squamous Cell Carcinoma

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2013.06.247 ◽

2013 ◽

Vol 87 (2) ◽

pp. S95-S96

Author(s):

C.M. Anderson ◽

M. Marquardt ◽

M. Graham ◽

A. Button ◽

B. Smith ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Prospective Trial ◽

Neck Squamous Cell Carcinoma ◽

Phase 2 ◽

Early Analysis ◽

Pet Ct

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Erythropoietin receptor is not a surrogate marker for tumor hypoxia and does not correlate with survival in head and neck squamous cell carcinomas

Radiotherapy and Oncology ◽

10.1016/j.radonc.2005.06.030 ◽

2005 ◽

Vol 76 (2) ◽

pp. 213-218 ◽

Cited By ~ 20

Author(s):

Ilse J. Hoogsteen ◽

Wenny J.M. Peeters ◽

Henri A.M. Marres ◽

Paul F.J.W. Rijken ◽

Franciscus J.A. van den Hoogen ◽

...

Keyword(s):

Head And Neck ◽

Squamous Cell ◽

Tumor Hypoxia ◽

Surrogate Marker ◽

Squamous Cell Carcinomas ◽

Erythropoietin Receptor

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Relevance of Human Papillomaviruses in Head and Neck Cancer—What Remains in 2021 from a Clinician’s Point of View?

Viruses ◽

10.3390/v13061173 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1173

Author(s):

Markus Hoffmann ◽

Elgar Susanne Quabius

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Gold Standard ◽

Clinical Relevance ◽

Hpv Vaccination ◽

Surrogate Marker ◽

Human Papillomaviruses ◽

Point Of View ◽

Prevalence Rates ◽

Hpv Status

Human papillomaviruses (HPV) cause a subset of head and neck cancers (HNSCC). HPV16 predominantly signs responsible for approximately 10% of all HNSCC and over 50% of tonsillar [T]SCCs. Prevalence rates depend on several factors, such as the geographical region where patients live, possibly due to different social and sexual habits. Smoking plays an important role, with non-smoking patients being mostly HPV-positive and smokers being mostly HPV-negative. This is of unparalleled clinical relevance, as the outcome of (non-smoking) HPV-positive patients is significantly better, albeit with standard and not with de-escalated therapies. The results of the first prospective de-escalation studies have dampened hopes that similar superior survival can be achieved with de-escalated therapy. In this context, it is important to note that the inclusion of p16INK4A (a surrogate marker for HPV-positivity) in the 8th TMN-classification has only prognostic, not therapeutic, intent. To avoid misclassification, highest precision in determining HPV-status is of utmost importance. Whenever possible, PCR-based methods, still referred to as the "gold standard”, should be used. New diagnostic antibodies represent some hope, e.g., to detect primaries and recurrences early. Prophylactic HPV vaccination should lead to a decline in HPV-driven HNSCC as well. This review discusses the above aspects in detail.

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18F-FMISO-PET Hypoxia Monitoring for Head-and-Neck Cancer Patients: Radiomics Analyses Predict the Outcome of Chemo-Radiotherapy

Cancers ◽

10.3390/cancers13143449 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3449

Author(s):

Montserrat Carles ◽

Tobias Fechter ◽

Anca L. Grosu ◽

Arnd Sörensen ◽

Benedikt Thomann ◽

...

Keyword(s):

Treatment Outcome ◽

Head And Neck ◽

Disease Progression ◽

Multiple Testing ◽

Validation Cohort ◽

Tumor Hypoxia ◽

Texture Feature ◽

Time Points ◽

Pet Ct ◽

Initial Cohort

Tumor hypoxia is associated with radiation resistance and can be longitudinally monitored by 18F-fluoromisonidazole (18F-FMISO)-PET/CT. Our study aimed at evaluating radiomics dynamics of 18F-FMISO-hypoxia imaging during chemo-radiotherapy (CRT) as predictors for treatment outcome in head-and-neck squamous cell carcinoma (HNSCC) patients. We prospectively recruited 35 HNSCC patients undergoing definitive CRT and longitudinal 18F-FMISO-PET/CT scans at weeks 0, 2 and 5 (W0/W2/W5). Patients were classified based on peritherapeutic variations of the hypoxic sub-volume (HSV) size (increasing/stable/decreasing) and location (geographically-static/geographically-dynamic) by a new objective classification parameter (CP) accounting for spatial overlap. Additionally, 130 radiomic features (RF) were extracted from HSV at W0, and their variations during CRT were quantified by relative deviations (∆RF). Prediction of treatment outcome was considered statistically relevant after being corrected for multiple testing and confirmed for the two 18F-FMISO-PET/CT time-points and for a validation cohort. HSV decreased in 64% of patients at W2 and in 80% at W5. CP distinguished earlier disease progression (geographically-dynamic) from later disease progression (geographically-static) in both time-points and cohorts. The texture feature low grey-level zone emphasis predicted local recurrence with AUCW2 = 0.82 and AUCW5 = 0.81 in initial cohort (N = 25) and AUCW2 = 0.79 and AUCW5 = 0.80 in validation cohort. Radiomics analysis of 18F-FMISO-derived hypoxia dynamics was able to predict outcome of HNSCC patients after CRT.

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