Many studies have suggested a prognostic value of one or several positron emission tomography (PET) parameters in patients with small cell lung cancer (SCLC). However, studies are often small, and there is a considerable interstudy disagreement about which PET parameters have a prognostic value. The objective of this study was to perform a review and meta-analysis to identify the most promising PET parameter for prognostication. PubMed^®, Cochrane, and Embase^® were searched for papers addressing the prognostic value of any PET parameter at any treatment phase with any endpoint in patients with SCLC. Pooled hazard ratios (HRs) were calculated by a random effects model for the prognostic value of the baseline maximum standardized uptake value (SUV_max) and metabolic tumor volume (MTV). The qualitative analysis included 38 studies, of these, 19 studies were included in the meta-analyses. The pooled results showed that high baseline MTV was prognostic for overall survival (OS) (HR: 2.83 (95% confidence interval [CI]: 2.00–4.01) and progression-free survival (PFS) (HR: 3.11 (95% CI: 1.99–4.90)). The prognostic value of SUV_max was less pronounced (OS: HR: 1.50 (95% CI: 1.17–1.91); PFS: HR: 1.24 (95% CI: 0.94–1.63)). Baseline MTV is a strong prognosticator for OS and PFS in patients with SCLC. MTV has a prognostic value superior to those of other PET parameters, but whether MTV is superior to other prognosticators of tumor burden needs further investigation.

PET/CT with the tracer 2-[¹⁸F]fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) has improved diagnostic imaging in cancer and is routinely used for diagnosing, staging and treatment planning in lung cancer patients. However, pitfalls of [¹⁸F]FDG-PET/CT limit the use in specific settings. Additionally, lung cancer is still the leading cause of cancer associated death and has high risk of recurrence after curative treatment. These circumstances have led to the continuous search for more sensitive and specific PET tracers to optimize lung cancer diagnosis, staging, treatment planning and evaluation. The objective of this review is to present and discuss current knowledge and perspectives of new PET tracers for use in lung cancer. A literature search was performed on PubMed and clinicaltrials.gov, limited to the past decade, excluding case reports, preclinical studies and studies on established tracers such as [¹⁸F]FDG and DOTATE. The most relevant papers from the search were evaluated. Several tracers have been developed targeting specific tumor characteristics and hallmarks of cancer. A small number of tracers have been studied extensively and evaluated head-to-head with [¹⁸F]FDG-PET/CT, whereas others need further investigation and validation in larger clinical trials. At this moment, none of the tracers can replace [¹⁸F]FDG-PET/CT. However, they might serve as supplementary imaging methods to provide more knowledge about biological tumor characteristics and visualize intra- and inter-tumoral heterogeneity.

Diagnosing relapse after radiotherapy for lung cancer is challenging. The specificity of both CT and ¹⁸F-FDG PET/CT is low because of radiation-induced changes. 3′-deoxy-3′-¹⁸F-fluorothymidine (¹⁸F-FLT) PET has previously demonstrated higher specificity for malignancy than ¹⁸F-FDG PET. We investigated the value of ¹⁸F-FLT PET/CT for diagnosing relapse in irradiated lung cancer. Methods: Patients suspected of relapse of lung cancer after definitive radiotherapy (conventional fractionated radiotherapy [cRT] or stereotactic body radiotherapy [SBRT]) were included. Sensitivity and specificity were analyzed both within the irradiated high-dose volume (HDV) and on a patient basis. Marginal differences and interobserver agreement were assessed. Results: Sixty-three patients who had received radiotherapy in 70 HDVs (34 cRT; 36 SBRT) were included. The specificity of ¹⁸F-FLT PET/CT was higher than that of ¹⁸F-FDG PET/CT (HDV, 96% [95% CI, 87–100] vs. 71% [95% CI, 57–83] [P = 0.0039]; patient-based, 90% [95% CI, 73–98] vs. 55% [95% CI, 36–74] [P = 0.0020]). The difference in specificity between ¹⁸F-FLT PET/CT and ¹⁸F-FDG PET/CT was higher after cRT than after SBRT. The sensitivity of ¹⁸F-FLT PET/CT was lower than that of ¹⁸F-FDG PET/CT (HDV, 69% [95% CI, 41–89] vs. 94% [95% CI, 70–100] [P = 0.1250]; patient-based, 70% [95% CI, 51–84] vs. 94% [95% CI, 80–99] [P = 0.0078]). Adding ¹⁸F-FLT PET/CT when ¹⁸F-FDG PET/CT was positive or inconclusive improved the diagnostic value compared with ¹⁸F-FDG PET/CT alone. In cRT HDVs, the probability of malignancy increased from 67% for ¹⁸F-FDG PET/CT alone to 100% when both tracers were positive. Conclusion:¹⁸F-FLT PET/CT adds diagnostic value to ¹⁸F-FDG PET/CT in patients with suspected relapse. The diagnostic impact of ¹⁸F-FLT PET/CT was highest after cRT. We suggest adding ¹⁸F-FLT PET/CT when ¹⁸F-FDG PET/CT is inconclusive or positive within the previously irradiated volume to improve diagnostic value in patients for whom histologic confirmation is not easily obtained.

Radiation-induced changes may cause a non-malignant high 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG)-uptake. The 3′-deoxy-3′-[¹⁸F]fluorothymidine (FLT)-PET/CT performs better in the differential diagnosis of inflammatory changes and lung lesions with a higher specificity than FDG-PET/CT. We investigated the association between post-radiotherapy FDG-PET-parameters, FLT-PET-parameters, and outcome. Sixty-one patients suspected for having a relapse after definitive radiotherapy for lung cancer were included. All the patients had FDG-PET/CT and FLT-PET/CT. FDG-PET- and FLT-PET-parameters were collected from within the irradiated high-dose volume (HDV) and from recurrent pulmonary lesions. For associations between PET-parameters and relapse status, respectively, the overall survival was analyzed. Thirty patients had a relapse, of these, 16 patients had a relapse within the HDV. FDG-SUV_max and FLT-SUV_max were higher in relapsed HDVs compared with non-relapsed HDVs (median FDG-SUV_max: 12.8 vs. 4.2; p < 0.001; median FLT-SUV_max 3.9 vs. 2.2; p < 0.001). A relapse within HDV had higher FDG-SUV_peak (median FDG-SUV_peak: 7.1 vs. 3.5; p = 0.014) and was larger (median metabolic tumor volume (MTV_50%): 2.5 vs. 0.7; 0.014) than the relapsed lesions outside of HDV. The proliferative tumor volume (PTV_50%) was prognostic for the overall survival (hazard ratio: 1.07 pr cm³ [1.01–1.13]; p = 0.014) in the univariate analysis, but not in the multivariate analysis. FDG-SUV_max and FLT-SUV_max may be helpful tools for differentiating the relapse from radiation-induced changes, however, they should not be used definitively for relapse detection.

Background: Small cell lung cancer (SCLC) is an aggressive cancer often presenting in an advanced stage and prognosis is poor. Early response evaluation may have impact on the treatment strategy. Aim: We evaluated ¹⁸F-fluorothymidine-(FLT)-PET/diffusion-weighted-(DW)-MRI early after treatment start to describe biological changes during therapy, the potential of early response evaluation, and the added value of FLT-PET/DW-MRI. Methods: Patients with SCLC referred for standard chemotherapy were eligible. FLT-PET/DW-MRI of the chest and brain was acquired within 14 days after treatment start. FLT-PET/DW-MRI was compared with pretreatment FDG-PET/CT. Standardized uptake value (SUV), apparent diffusion coefficient (ADC), and functional tumor volumes were measured. FDG-SUV_peak, FLT-SUV_peak, and ADC_median; spatial distribution of aggressive areas; and voxel-by-voxel analyses were evaluated to compare the biological information derived from the three functional imaging modalities. FDG-SUV_peak, FLT-SUV_peak, and ADC_median were also analyzed for ability to predict final treatment response. Results: Twelve patients with SCLC completed FLT-PET/MRI 1–9 days after treatment start. In nine patients, pretreatment FDG-PET/CT was available for comparison. A total of 16 T-sites and 12 N-sites were identified. No brain metastases were detected. FDG-SUV_peak was 2.0–22.7 in T-sites and 5.5–17.3 in N-sites. FLT-SUV_peak was 0.6–11.5 in T-sites and 1.2–2.4 in N-sites. ADC_median was 0.76–1.74 × 10^− 3 mm²/s in T-sites and 0.88–2.09 × 10⁻³ mm²/s in N-sites. FLT-SUV_peak correlated with FDG-SUV_peak, and voxel-by-voxel correlation was positive, though the hottest regions were dissimilarly distributed in FLT-PET compared to FDG-PET. FLT-SUV_peak was not correlated with ADC_median, and voxel-by-voxel analyses and spatial distribution of aggressive areas varied with no systematic relation. LT-SUV_peak was significantly lower in responding lesions than non-responding lesions (mean FLT-SUV_peak in T-sites: 1.5 vs. 5.7; p = 0.007, mean FLT-SUV_peak in N-sites: 1.6 vs. 2.2; p = 0.013). Conclusions: FLT-PET and DW-MRI performed early after treatment start may add biological information in patients with SCLC. Proliferation early after treatment start measured by FLT-PET is a promising predictor for final treatment response that warrants further investigation. Trial registration: Clinicaltrials.gov, NCT02995902. Registered 11 December 2014 - Retrospectively registered.

Background/Objectives: Identifying treatment failure at earlier time points to could spare cancer patients from ineffective treatment and side effects. In this study, circulating tumor DNA (ctDNA) and [¹⁸F]FDG-PET/CT were investigated during the first cycle of anticancer therapy in patients with advanced non-small cell lung cancer (NSCLC) to explore their potential for early response evaluation. Methods: Patients with advanced NSCLC receiving first-line therapy with immune checkpoint inhibitors and/or chemotherapy were included. CtDNA and [¹⁸F]FDG-PET/CT assessments were conducted before treatment and at weeks 1 and 3 during the first cycle of therapy. ctDNA quantification was performed using a targeted next-generation sequencing (NGS) panel, and the least favorable change in any mutated allele frequency at a given time was used for analysis. [¹⁸F]FDG-PET/CT was quantified using sumSUL_peak and metabolic tumor volume (MTV_4.0). Early changes in ctDNA levels and [¹⁸F]FDG-PET parameters were compared with final treatment response, measured by RECIST after 12 weeks, as well as progression-free survival and overall survival. Results: Of the sixteen included patients, eight were non-responders. ctDNA mutations were detected in baseline blood samples in eight patients. Changes in ctDNA level, MTV_4.0, and sumSUL_peak at week 3 indicated response in 7 out of 8 patients, 13 out of 15 patients, and 9 out of 15 patients, respectively. At week 3, no false increases were seen with ctDNA and MTV_4.0. Conclusions: These results suggest that early changes in ctDNA and [¹⁸F]FDG-PET/CT at 3 weeks of treatment could be used to early assess treatment response. Increased levels of ctDNA and MTV_4.0 at week 3 were only observed in patients with treatment failure.