Validated imaging biomarkers as decision-making tools in clinical trials and routine practice: current status and recommendations from the EIBALL* subcommittee of the European Society of Radiology (ESR)

deSouza, Nandita M.; Achten, Eric; Alberich-Bayarri, Angel; Bamberg, Fabian; Boellaard, Ronald; Clément, Olivier; Fournier, Laure; Gallagher, Ferdia; Golay, Xavier; Heussel, Claus Peter; Jackson, Edward F.; Manniesing, Rashindra; Mayerhofer, Marius E.; Neri, Emanuele; O’Connor, James; Oguz, Kader Karli; Persson, Anders; Smits, Marion; van Beek, Edwin J. R.; Zech, Christoph J.

doi:10.1186/s13244-019-0764-0

Insights into Imaging

Table 3 Imaging biomarkers for disease response assessment (semi-quantitative and quantitative) with examples of current evidence for their use that would support decision-making

From: Validated imaging biomarkers as decision-making tools in clinical trials and routine practice: current status and recommendations from the EIBALL* subcommittee of the European Society of Radiology (ESR)

	Biomarker	SemiQ/Q	Disease	Question answered	Utility of biomarker	Data from	Potential decision for
Non-malignant disease	Volumetric high resolution CT density (quantitative interstitial lung disease, QILD)	Q	Scleroderma	Response to cyclophosphamide	24-month changes in QILD scores in the whole lung correlated significantly 24-month changes in forced vital capacity (ρ = − 0.37), diffusing capacity (ρ = − 0.22) and breathlessness (ρ = − 0.26) [164]	Single centre	Continue, change or stop treatment
Non-malignant disease	Left Ventricular ejection fraction LVEF	Q	Pulmonary hypertension Myocardial ischaemia/infarction	Right and left cardiac sufficiency Improvement in cardiac function	Increases in 6-min walk distance were significant correlated with change in right ventricular ejection fraction and left ventricular end-diastolic volume [165] Monitoring cardiac function [166]	Multicentre Multicentre	Continue, change or stop treatment
Malignant disease	RECIST/morphological volume	Q	Cancer	Response	Current guidelines for response assessment [167]	Multicentre	Continue, change or stop treatment
	PERCIST/metabolic volume [168]	Q	Cancer	Response	Current guidelines for response assessment	Multicentre	Continue, change or stop treatment
	Scoring systems for disease burden	SQ	Multiple sclerosis Rheumatoid arthritis	Reduction in disease burden	Effects on MRI lesions over 6–9 months predict the effects on relapses at 12–24 months) [169] International consensus on scoring system [170]	Meta-analysis Review	Continue, change or stop therapy
	DSC-MRI	SQ (rCBV)	Brain cancer	Differentiation of treatment effects and tumour progression	In 2 meta-analyses MRI had high pooled sensitivities and specificities: 87% (95% CI, 0.82–0.91) to 90% (95% CI, 0.85-0.94) sensitivity and 86% (95% CI, 0.77–0.91) to 88% (95% CI, 0.83-0.92) specificity [171, 172]	Meta-analysis	Decision to treat
	¹⁸F FDG-SUV_max [173]	Q	Multiple cancer types	Response to therapy	Rectal cancer-pooled sensitivity, 73%; pooled specificity, 77%; pooled AUC, 0.83 [174] Intratreatment low SUV_max (persistent low or decrease of ¹⁸F-FDG uptake) predictive of loco-regional control in head and neck cancer [175]	Meta-analysis Meta-analysis	Continue, change or stop therapy
	Deauville or RECIL score on ¹⁸ F-FDG-PET	SQ	Lymphoma	CR, PR, SD or PD [176]	Assessment of tumour burden in lymphoma clinical trials can use the sum of longest diameters of a maximum of three target lesions [177]	Multicentre	Continue, change or stop therapy
	Targeted agents HER2 PSMA	SQ	Breast cancer [178] Prostate cancer [179]	Reduction in tumour cells expressing these antigens	Tumour receptor specific Effects of treatment on receptor expression	Single centre studies, review	Continue, change or stop therapy
	ADC [117]	SQ Q	Rectal cancer Breast cancer	Response to neoadjuvant chemotherapy Response to neoadjuvant chemotherapy	Additional value in both the prediction and detection of (complete) response to therapy compared with conventional sequences alone [180] After 12 weeks of therapy, change in ADC predicts complete pathologic response to neoadjuvant chemotherapy (AUC = 0.61, p = 0.013) [181]	Review Multicentre	Continue, change or stop therapy, proceed to surgery
	CT perfusion/blood flow	Q	Oesophageal cancer	Response to chemoradiotherapy	Multivariate analysis identified blood flow as a significant independent predictor of response [182]	Single centre	Further treatment
	DCE-MR parameters	Q	Multiple cancer types	Response to therapy	Particular benefit in assessing therapy response to antiangiogenic agents [183]	Review	Change therapeutic strategy
	CT density HU	Q	Gastrointestinal stromal tumours	Response to chemotherapy	Decrease in tumour density of > 15% on CT had a sensitivity of 97% and a specificity of 100% in identifying PET responders versus 52% and 100% by RECIST [184]		Continue, change or stop therapy

Biomarkers used visually in the clinic are given in italics, and those that are used quantitatively are in bold
Abbreviations: ADC apparent diffusion coefficient, APT amide proton transfer, AUC area under curve, BI-RADS breast imaging reporting and data systems, CBV cerebral blood volume, CoV coefficient of variation, CR complete response, CT computerised tomography, DCE dynamic contrast enhanced, DFS disease-free survival, DOTATOC DOTA octreotitide, DOTATATE DOTA octreotate, DSC dynamic susceptibility contrast, ECG electro cardiogram, FDG fluorodeoxyglucose, FLT fluoro thymidine, HR hazard ratio, HU Hounsfield unit, ICC intraclass correlation, IQR interquartile range, LVEF left ventricular ejection fraction, MRF magnetic resonance fingerprinting, MRI magnetic resonance imaging, MTR magnetisation transfer ratio, NCCN National Comprehensive Cancer Network, OS overall survival, pCT perfusion computerised tomography, PERCIST positron emission tomography response criteria in solid tumours, PD progressive disease, PFS progression-free survival, PPV positive predictive value, PI-RADS prostate imaging reporting and data systems, PR partial response, PSMA prostate-specific membrane antigen, RECIL response evaluation in lymphoma, RECIST response evaluation criteria in solid tumours, ROC receiver operating characteristic, SD stable disease, SUV standardised uptake value, SWE shear wave elastography, US ultrasound

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