Reassessing Patterns of Response to Immunotherapy with PET: From Morphology to Metabolism.

Cancer demands precise evaluation and accurate and timely assessment of response to treatment. Imaging must be performed early during therapy to allow adjustments to the course of treatment. For decades, cross-sectional imaging provided these answers, showing responses to the treatment through changes in tumor size. However, with the emergence of immune checkpoint inhibitors, complex immune response patterns were revealed that have quickly highlighted the limitations of this approach. Patterns of response beyond tumor size have been recognized and include cystic degeneration, necrosis, hemorrhage, and cavitation. Furthermore, new unique patterns of response have surfaced, like pseudoprogression and hyperprogression, while other patterns were shown to be deceptive, such as unconfirmed progressive disease. This evolution led to new therapeutic evaluation criteria adapted specifically for immunotherapy. Moreover, inflammatory adverse effects of the immune checkpoint blockade were identified, many of which were life threatening and requiring prompt intervention. Given complex concepts like tumor microenvironment and novel therapeutic modalities in the era of personalized medicine, increasingly sophisticated imaging techniques are required to address the intricate patterns of behavior of different neoplasms. Fluorine 18-fluorodeoxyglucose PET/CT has rapidly emerged as one such technique that spans both molecular biology and immunology. This imaging technique is potentially capable of identifying and tracking prognostic biomarkers owing to its combined use of anatomic and metabolic imaging, which enables it to characterize biologic processes in vivo. This tailored approach may provide whole-body quantification of the metabolic burden of disease, providing enhanced prediction of treatment response and improved detection of adverse events. ©RSNA, 2020.

Theranostics in Nuclear Medicine: Emerging and Re-emerging Integrated Imaging and Therapies in the Era of Precision Oncology.

Theranostics refers to the pairing of diagnostic biomarkers with therapeutic agents that share a specific target in diseased cells or tissues. Nuclear medicine, particularly with regard to applications in oncology, is currently one of the greatest components of the theranostic concept in clinical and research scenarios. Theranostics in nuclear medicine, or nuclear theranostics, refers to the use of radioactive compounds to image biologic phenomena by means of expression of specific disease targets such as cell surface receptors or membrane transporters, and then to use specifically designed agents to deliver ionizing radiation to the tissues that express these targets. The nuclear theranostic approach has sparked increasing interest and gained importance in parallel to the growth in molecular imaging and personalized medicine, helping to provide customized management for various diseases; improving patient selection, prediction of response and toxicity, and determination of prognosis; and avoiding futile and costly diagnostic examinations and treatment of many diseases. The authors provide an overview of theranostic approaches in nuclear medicine, starting with a review of the main concepts and unique features of nuclear theranostics and aided by a retrospective discussion of the progress of theranostic agents since early applications, with illustrative cases emphasizing the imaging features. Advanced concepts regarding the role of fluorine 18-fluorodeoxyglucose PET in theranostics, as well as developments in and future directions of theranostics, are discussed. ©RSNA, 2020 See discussion on this article by Greenspan and Jadvar.

Tumor glycolytic profiling through 18F-FDG PET/CT predicts immune checkpoint inhibitor efficacy in advanced NSCLC.

Background: A significant proportion of patients with non-small-cell lung cancer (NSCLC) do not respond to immune checkpoint inhibitors (ICIs). Since metabolic reprogramming with increased glycolysis is a hallmark of cancer and is involved in immune evasion, we used 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) to evaluate the baseline glycolytic parameters of patients with advanced NSCLC submitted to ICIs, and assessed their predictive value. Methods: 18F-FDG PET/CT results in the 3 months before ICIs treatment were included. Maximum standardized uptake values, whole metabolic tumor volume (wMTV), and whole-body total lesion glycolysis (wTLG) were evaluated. Cutoff values for high or low glycolytic categories were determined using receiver-operating characteristic curves. Progression-free survival (PFS) and overall survival (OS) were evaluated. Patients with a complete response and a matching group with resistance to ICIs underwent immunohistochemistry analysis. An unsupervised k-means clustering model integrating programmed cell death ligand 1 (PD-L1) expression, glycolytic parameters, and ICIs therapy was performed. Results: In all, 98 patients were included. Lower baseline 18F-FDG PET/CT parameters were associated with responses to ICIs. Patients with low wMTV or wTLG had improved PFS and OS. High wTLG, strong tumor expression of glucose transporter-1, and lack of responses were significantly associated. Patients with low glycolytic parameters benefited from ICIs, regardless of chemotherapy. Conversely, those with high parameters benefited from the addition of chemotherapy. Patients with higher wTLG and lower PD-L1 were associated with progression and worse survival to ICIs monotherapy. Conclusions: Glycolytic metabolic profiles established through baseline 18F-FDG PET/CT are useful biomarkers for evaluating ICI therapy in advanced NSCLC.

Whole Skeletal Mean SUV Measured on 18F-NaF PET/CT Studies as a Prognostic Indicator in Patients with Bone Metastatic Breast Cancer.

In this work we assessed the association between the whole skeletal mean standardized uptake value (SUV) measured on 18F-NaF PET/CT studies and the overall survival (OS) of bone metastatic breast cancer patients. Methods: We retrospectively analyzed 176 patients with breast cancer and bone metastatic disease who performed 18F-NaF PET/CT studies. The outcomes of the patients (dead or alive) were established based on the last information available on their files. The mean and maximum SUVs were measured in a whole skeletal volume of interest (wsVOI). The wsVOI was defined based on the CT component of the PET/CT study using Hounsfield Units thresholds. The wsVOI was then applied on the 18F-NaF PET image. Univariate analyses were performed to assess the association of the SUVs with OS. We also analyzed the association of the age of the patients, the presence of visceral metastatic disease, histological subtypes, presence of hormone receptors, human epidermal growth factor receptor 2 expression and the creatinine, CA15-3 and alkaline phosphatase (ALP) levels with OS. The variables statistically significant in the univariate analyses were included in a multivariate cox regression survival analysis. Results: In the univariate analyses there were associations of the mean and maximum whole skeletal SUVs, estrogen receptor status and the CA15-3 and ALP levels with OS. In the multivariate analysis, all the variables that were statistically significant in the univariate analysis but the CA15-3 were associated with OS. Conclusion: In patients with bone metastatic breast cancer, the whole skeletal mean SUV is an independent predictor of overall survival.

Comparison of the Variability of SUV Normalized by Skeletal Volume with the Variability of SUV Normalized by Body Weight in 18F-Fluoride PET/CT.

Our objective was to test the hypothesis that variability in SUV normalized by skeletal volume (SV) in 18F-fluoride (18F-NaF) PET/CT studies is lower than variability in SUV normalized by body weight (BW). Methods: The mean SUV (SUVmean) was obtained for whole skeletal volume of interest (wsVOI) in 163 selected 18F-NaF PET/CT studies. These studies were performed to investigate bone metastases and were considered to have normal results. SUVmean was calculated with normalization by BW (BW SUVmean), with normalization by SV (SV SUVmean), and without normalization (WN SUVmean). The total SV for each patient was also estimated on the basis of the wsVOI defined on the CT component of the PET/CT study. SUVmean variability for each patient was estimated as the absolute value of the difference between the SUVmean for the patient and the mean of the SUVmean for the whole group of patients, divided by the mean of the SUVmean for the whole group of patients. The variabilities of SUVmean calculated by the 3 methods were compared using a paired 1-tailed Wilcoxon test. Results: The mean variability for the BW, SV, and WN SUVmean was 0.16, 0.13, and 0.16, respectively. There were statistically significant differences between SV and BW SUVmean variability (P = 0.03) and between SV and WN SUVmean variability (P < 0.01). There was no statistically significant difference between BW and WN SUVmean variability (P = 0.4). Conclusion: In patients with normal 18F-NaF PET/CT results, SV SUVmean presents lower variability than BW SUVmean.