Radiotherapy and radiation oncology play a key role in the clinical management of patients suffering from oncological diseases. In clinical routine, anatomic imaging such as contrast-enhanced CT and MRI are widely available and are usually used to improve the target volume delineation for subsequent radiotherapy. Moreover, these modalities are also used for treatment monitoring after radiotherapy. However, some diagnostic questions cannot be sufficiently addressed by the mere use standard morphological imaging. Therefore, positron emission tomography (PET) imaging gains increasing clinical significance in the management of oncological patients undergoing radiotherapy, as PET allows the visualization and quantification of tumoral features on a molecular level beyond the mere morphological extent shown by conventional imaging, such as tumor metabolism or receptor expression. The tumor metabolism or receptor expression information derived from PET can be used as tool for visualization of tumor extent, for assessing response during and after therapy, for prediction of patterns of failure and for definition of the volume in need of dose-escalation. This review focuses on recent and current advances of PET imaging within the field of clinical radiotherapy / radiation oncology in several oncological entities (neuro-oncology, head & neck cancer, lung cancer, gastrointestinal tumors and prostate cancer) with particular emphasis on radiotherapy planning, response assessment after radiotherapy and prognostication.

PET with O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) has reached increasing clinical significance for patients with brain neoplasms. For quantification of standard PET-derived parameters such as the tumor-to-background ratio, the background activity is assessed using a region of interest (ROI) or volume of interest (VOI) in unaffected brain tissue. However, there is no standardized approach regarding the assessment of the background reference. Therefore, we evaluated the intra- and inter-reader variability of commonly applied approaches for clinical 18F-FET PET reading. The background activity of 20 18F-FET PET scans was independently evaluated by 6 readers using a (i) simple 2D-ROI, (ii) spherical VOI with 3.0 cm diameter, and (iii) VOI consisting of crescent-shaped ROIs; each in the contralateral, non-affected hemisphere including white and gray matter in line with the European Association of Nuclear Medicine (EANM) and German guidelines. To assess intra-reader variability, each scan was evaluated 10 times by each reader. The coefficient of variation (CoV) was assessed for determination of intra- and inter-reader variability. In a second step, the best method was refined by instructions for a guided background activity assessment and validated by 10 further scans. Compared to the other approaches, the crescent-shaped VOIs revealed most stable results with the lowest intra-reader variabilities (median CoV 1.52%, spherical VOI 4.20%, 2D-ROI 3.69%; p < 0.001) and inter-reader variabilities (median CoV 2.14%, spherical VOI 4.02%, 2D-ROI 3.83%; p = 0.001). Using the guided background assessment, both intra-reader variabilities (median CoV 1.10%) and inter-reader variabilities (median CoV 1.19%) could be reduced even more. The commonly applied methods for background activity assessment show different variability which might hamper 18F-FET PET quantification and comparability in multicenter settings. The proposed background activity assessment using a (guided) crescent-shaped VOI allows minimization of both intra- and inter-reader variability and might facilitate comprehensive methodological standardization of amino acid PET which is of interest in the light of the anticipated EANM technical guidelines.

NETTER-1 trial demonstrated high efficacy and low toxicity of four cycles of Peptide Receptor Radionuclide Therapy (PRRT) in patients with metastasized NET. The present study evaluates the outcome of further PRRT cycles in the so called salvage setting in patients after initial response to four therapy cycles and later progression. Thirty five patients (pat.) (25 male, 10 female, 63 ± 9 years) with progressive, metastasized NET (23 small intestinal, 5 lung, 4 CUP, 1 rectal, 1 gastric and 1 paraganglioma) were included. All patients previously received 4 PRRT cycles with 177Lu-DOTATATE and showed initial response. SPECT based dosimetry was applied to determine kidney and tumor doses. Therapy response was evaluated using 68Ga-DOTATATE PET/CT (with high dose CT), CT alone or MRI (RECIST 1.1), toxicity was defined using CTCAE 5.0 criteria. 99mTc99-MAG3 scintigraphy was used to assess potential renal tubular damage. Progression free survival (PFS) and Overall survival (OS) analysis was performed with the Kaplan-Meier-method. The median PFS after initial PRRT was 33 months (95% CI: 30–36). The mean cumulative dose for including salvage PRRT was 44 GBq (range 33.5–47). One pat. (2.9%) showed grade 3 hematotoxicity. Kidney dosimetry revealed a mean cumulative kidney dose after a median of 6 PRRT cycles of 23.8 Gy. No grade 3 / 4 nephrotoxicity or relevant decrease in renal function was observed. Follow-up imaging was available in 32 patients after salvage therapy. Best response according to RECIST 1.1. was PR in one patient (3.1%), SD in 26 patients (81.3%) and PD in 5 patients (15.6%). PFS after salvage therapy was 6 months (95% CI: 0–16; 8 patients censored). Mean OS after initial PRRT was 105 months (95% CI: 92–119) and 51 months (95% CI: 41–61) after start of salvage therapy. Median OS was not reached within a follow-up of 71 months after initial PRRT and 25 months after start of salvage PRRT, respectively. Salvage therapy with 177Lu-DOTATATE is safe and effective even in patients with extensive previous multimodal therapies during disease progression and represents a feasible and valuable therapy option for progressive NET.

Recent immunotherapeutic approaches have evolved as powerful treatment options with high anti-tumour responses involving the patient’s own immune system. Passive immunotherapy applies agents that enhance existing anti-tumour responses, such as antibodies against immune checkpoints. Active immunotherapy uses agents that direct the immune system to attack tumour cells by targeting tumour antigens. Active cellular-based therapies are on the rise, most notably chimeric antigen receptor T cell therapy, which redirects patient-derived T cells against tumour antigens. Approved treatments are available for a variety of solid malignancies including melanoma, lung cancer and haematologic diseases. These novel immune-related therapeutic approaches can be accompanied by new patterns of response and progression and immune-related side-effects that challenge established imaging-based response assessment criteria, such as Response Evaluation Criteria in Solid tumours (RECIST) 1.1. Hence, new criteria have been developed. Beyond morphological information of computed tomography (CT) and magnetic resonance imaging, positron emission tomography (PET) emerges as a comprehensive imaging modality by assessing (patho-)physiological processes such as glucose metabolism, which enables more comprehensive response assessment in oncological patients. We review the current concepts of response assessment to immunotherapy with particular emphasis on hybrid imaging with ¹⁸F-FDG-PET/CT and aims at describing future trends of immunotherapy and additional aspects of molecular imaging within the field of immunotherapy.

After focused high dose radiotherapy of brain metastases, differentiation between tumor recurrence and radiation-induced lesions by conventional MRI is challenging. This study investigates the usefulness of dynamic O-(2-18F-Fluoroethyl)-L-Tyrosine positron emission tomography (18F-FET PET) in patients with MRI-based suspicion of tumor recurrence after focused high dose radiotherapy of brain metastases. Twenty-two patients with 34 brain metastases (median age 61.9 years) were included. Due to follow-up scan evaluations after repeated treatment in a subset of patients, a total of 50 lesions with MRI-based suspicion of tumor recurrence after focused high dose radiotherapy could be evaluated. 18F-FET PET analysis included the assessment of maximum and mean tumor-to-background ratio (TBRmax and TBRmean) and analysis of time-activity-curves (TAC; increasing vs. decreasing) including minimal time-to-peak (TTPmin). PET parameters were correlated with histological findings and radiological-clinical follow-up evaluation. Tumor recurrence was found in 21/50 cases (15/21 verified by histology, 6/21 by radiological-clinical follow-up) and radiation-induced changes in 29/50 cases (5/29 verified by histology, 24/29 by radiological-clinical follow-up). Median clinical-radiological follow-up was 28.3 months (range 4.2–99.1 months). 18F-FET uptake was higher in tumor recurrence compared to radiation-induced changes (TBRmax 2.9 vs. 2.0, p < 0.001; TBRmean 2.2 vs. 1.7, p < 0.001). Receiver-operating-characteristic (ROC) curve analysis revealed optimal cut-off values of 2.15 for TBRmax and 1.95 for TBRmean (sensitivity 86 %, specificity 79 %). Increasing TACs and long TTPmin were associated with radiation-induced changes, decreasing TACs with tumor recurrence (p = 0.01). By combination of TBR and TACs, sensitivity and specificity could be increased to 93 and 84 %. In patients with MRI-suspected tumor recurrence after focused high dose radiotherapy, 18F-FET PET has a high sensitivity and specificity for the differentiation of vital tumor tissue and radiation-induced lesions.