IECC v2.0.1 - System of Imaging Biomarkers

Introduction

Non-small cell lung carcinoma (NSCLC) is the most common subtype of lung cancer, and its management depends on correct staging by imaging. Since 2020 onwards, various radiological and nuclear medicine imaging biomarkers have been investigated to optimize diagnosis, prognosis and prediction of therapeutic response in NSCLC. The main modalities are computed tomography (CT), positron emission tomography with integrated CT (PET/CT) and magnetic resonance imaging (MRI). Each technique provides complementary information: CT provides anatomical details (tumor size, local invasion), PET/CT evaluates tumor metabolic activity and detects occult metastases, and MRI excels in soft tissue contrast (useful in certain situations such as brain metastases). The following compares these modalities in their diagnostic, prognostic and predictive applications, emphasizing imaging biomarkers such as SUVmax, MTV and TLG and their clinically significant values.

Imaging Modalities in NSCLC: CT, PET/CT and MRI

Computed Tomography (CT)

Chest CT is the initial cornerstone for diagnosis and anatomical staging of NSCLC. It allows characterization of the primary tumor in terms of location, size and relationship with adjacent structures, as well as identifying lymphadenopathy according to size criteria. However, its ability to differentiate malignant from reactive nodes is limited: the only practical criterion is diameter (a node >10 mm in short axis is considered suspicious). This results in CT having ~50% sensitivity and ~85% specificity for detecting mediastinal metastases using that 1 cm threshold. In a classic meta-analysis, CT showed sensitivities around 57–61% and specificities 77–82% for nodal involvement.

Key CT Performance Metrics: PubMed: CT Sensitivity NSCLC Studies

Positron Emission Tomography – CT (PET/CT)

FDG-PET/CT (fluorodeoxyglucose positron emission tomography integrated with CT) has revolutionized NSCLC staging by providing functional information about tumor glucose metabolism. Malignant pulmonary cells usually show intense FDG uptake, allowing distinction between malignant and benign lesions with high accuracy. For characterizing a solitary pulmonary nodule, PET/CT achieves ~95–97% sensitivity and ~78–94% specificity, far superior to CT alone. A meta-analysis reported ~96.8% sensitivity and ~77.8% specificity of PET for diagnosing malignant nodules.

PET/CT Performance Studies: PubMed: PET/CT Diagnostic Accuracy

Magnetic Resonance Imaging (MRI)

MRI has a more limited role in NSCLC, reserved for specific scenarios, but of great importance in them. It is not routinely used to evaluate the primary pulmonary tumor due to respiratory motion artifacts and lower resolution in aerated lung parenchyma. However, thoracic MRI is valuable for delineating extension to contiguous soft tissues. For example, in Pancoast tumors (pulmonary apex), MRI is superior to CT for defining brachial plexus, spinal column or subclavian vessel invasion, with studies reporting ~94% accuracy with MRI vs ~63% with CT in evaluating such apical invasion.

MRI Invasion Assessment: PubMed: MRI Pancoast Tumor Studies

Metabolic Biomarkers in PET: SUVmax, MTV and TLG

SUVmax (Standardized Uptake Value maximum)

SUVmax is the maximum standardized uptake value in the lesion, representing the highest FDG concentration in the tumor, normalized by injected dose and body weight. SUVmax is the most clinically widespread PET parameter due to its simplicity; it doesn't depend on delineating the entire tumor and has good inter-observer reproducibility. A threshold of ~2.5 in SUVmax is used to distinguish malignant from benign lesions in lung: a nodule with SUVmax >2.5–3 is considered suspicious for malignancy.

SUVmax Clinical Applications: PubMed: SUVmax Diagnostic Thresholds

MTV (Metabolic Tumor Volume)

MTV corresponds to the volume of tumor tissue with significant FDG uptake above a certain threshold. It is essentially the three-dimensional volume of metabolically active tumor. MTV is usually calculated by delineating the lesion in PET images, for example using a threshold of 40% of SUVmax or a determined absolute value. MTV reflects total metabolic tumor burden: extensive or multifocal tumors with high uptake will have elevated MTV. In patients with advanced NSCLC treated with anti-PD-1 immunotherapy, studies have identified that basal MTV >36.5 mL was associated with worse overall survival (OS).

MTV Prognostic Studies: PubMed: MTV Prognostic Value

TLG (Total Lesion Glycolysis)

TLG is a combined indicator that multiplies MTV by the mean SUV of that volume (TLG = MTV × SUV_mean), representing the total glycolytic activity of the entire tumor mass. In simple terms, TLG integrates how much tumor tissue there is (volume) and how intensely it takes up FDG on average, to quantify the total amount of glucose consumed by the tumor. A high TLG implies a voluminous and very hypermetabolic tumor. High TLG values have shown solid correlation with poor prognosis in multiple analyses.

TLG Prognostic Research: PubMed: TLG Survival Studies

Clinical Applications and Therapeutic Response Evaluation

Diagnostic and Staging Applications

The first application of imaging is to confirm the presence of malignancy in a suspicious pulmonary lesion (nodule or mass) and delimit its local extension. Here, PET/CT has shown notable advantages over CT alone. A pulmonary nodule >8–10 mm with high FDG uptake (SUVmax above ~2.5–4) strongly suggests cancer, with diagnostic sensitivity approaching 95%. PET/CT also helps distinguish viable tumor from atelectasis or surrounding scar: in central NSCLC with obstructive atelectasis, the tumor mass stands out metabolically on PET over the collapsed lung, better delimiting the extent of active tumor than conventional CT.

Staging Accuracy Studies: PubMed: PET/CT Staging Meta-analyses

Therapeutic Response Assessment

Response to treatment in NSCLC is traditionally evaluated with morphological criteria (CT, RECIST), but in recent years metabolic evaluation by PET has gained importance due to its ability to detect early functional changes. PET with FDG allows functional evaluation of whether active tumor persists after treatment, detecting changes in glycolytic uptake before size modification. For uniform criteria, PERCIST (PET Response Criteria in Solid Tumors) were developed, analogous to RECIST but based on SUV.

PERCIST Criteria Research: PubMed: PERCIST Response Studies

Prognostic and Predictive Applications

SUVmax as Prognostic Factor

Numerous studies have confirmed that elevated SUVmax in the primary tumor is associated with worse prognosis in NSCLC. This is interpreted because high SUVmax reflects a biologically more aggressive tumor (high proliferation, hypoxia, angiogenesis, etc.). For example, in patients with resected stage I NSCLC, those with high SUVmax have lower 5-year disease-free survival than those with low SUVmax, even if their tumors were the same size and pathological stage. A 2021 study identified SUVmax >6 as the optimal cutoff that separated two prognostic groups: patients with SUVmax >6 had significantly worse overall survival than those ≤6.

SUVmax Prognostic Studies: PubMed: SUVmax Prognostic Research

MTV and TLG as Survival Predictors

Since MTV and TLG quantify the total burden of active disease, their prognostic impact is often even greater than that of SUVmax alone. Recent meta-analyses have corroborated that high MTV and high TLG are associated with worse overall survival (OS) and progression-free survival (PFS) in NSCLC. For example, a 2022 review focused on patients with NSCLC treated with immunotherapy found that those with elevated baseline MTV had approximately twice the risk of early progression and death than those with low MTV, suggesting that tumor burden is critical for the success of immune treatments.

MTV/TLG Survival Meta-analyses: PubMed: MTV/TLG Meta-analyses

Imaging Biomarkers as Predictors of Response to Specific Therapies

Beyond general prognosis, imaging biomarkers can help anticipate who will respond better to certain treatments. In immunotherapy, several studies have indicated that patients with low metabolic tumor burden (low MTV, few hypermetabolic lesions) tend to have better and more prolonged responses to PD-1/PD-L1 inhibitors. Conversely, patients with very widespread metabolic disease (extremely high MTV, high TLG) often do not achieve durable benefit with immunotherapy, possibly due to an immunosuppressive microenvironment or resistant tumor clones.

Immunotherapy Response Prediction: PubMed: PET Immunotherapy Predictors