Abbreviated dynamic total-body [¹⁸F]FDG PET/CT protocols for predicting response in locally advanced non-small cell lung cancer via Patlak-Ki analysis

Introduction

In the evolving field of locally advanced non-small cell lung cancer (LA-NSCLC), integrating immunotherapy with chemotherapy and radiotherapy represents a groundbreaking global approach (1). Advances in immunotherapy have led to the development of innovative therapeutic strategies, such as combining chemotherapy with immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) pathway (2,3). However, results from the PACIFIC and CheckMate 816 studies suggest that PD-L1 expression is not significantly associated with the effectiveness of combined immuno-chemotherapy (4,5). Conversely, imaging plays a crucial role in cancer management and has been notably impacted by ICIs (6,7). These impacts include changes in the criteria for evaluating solid tumor responses [Response Evaluation Criteria in Solid Tumors (RECIST)] and the increasing need to identify a broader range of immune-related adverse events (irAEs) through diagnostic imaging (7). Novel imaging strategies, such as immune-based RECIST (iRECIST), have been developed to assess ICI therapy (8). In this context, positron emission tomography (PET), particularly fluorodeoxyglucose (FDG) PET, has proven to be an essential diagnostic tool for evaluating oncologic response, predicting outcomes, and detecting irAEs early (9-11). As a metabolism-based imaging modality, [¹⁸F]FDG PET/computed tomography ([¹⁸F]FDG PET/CT) offers enhanced sensitivity for detecting tumor activity, viability, and irAEs by revealing functional changes within the tumor early in therapy (12,13).

Total body PET imaging offers a comprehensive and dynamic view of the entire body, enabling clinicians to monitor disease progression, assess therapeutic effectiveness, and make informed decisions regarding the management of non-small cell lung cancer (NSCLC) patients (14). Our previous research identified a correlation between the Patlak-Ki value, obtained through dynamic total body [¹⁸F]FDG PET/CT imaging with the uEXPLORER system, and the response to induction immuno-chemotherapy in LA-NSCLC (15). Higher Patlak-Ki values were linked to a more favorable response to induction treatment (15). Despite its established utility, dynamic PET imaging presents challenges for many patients and institutions. The standard imaging duration for dynamic total body [¹⁸F]FDG PET/CT is 1 hour (16-18), which may cause discomfort, especially for uncooperative patients or those with claustrophobia, potentially leading to motion artifacts. This lengthy acquisition time reduces the advantages of shorter scans made possible by modern digital scanners, potentially disrupting workflow in busy nuclear medicine departments. Traditionally, a time-activity curve spanning 60 minutes or longer has been used for this purpose (19-21). However, the uEXPLORER system, with its significantly increased sensitivity for whole-body scans, has dramatically reduced noise levels in reconstructed dynamic images (22). This reduction has improved the reliability of nonlinear estimation, allowing for greater flexibility in protocol design. Previous studies have shown that abbreviated dynamic imaging protocols for [¹⁸F]FDG PET/CT can maintain acceptable Ki quantification while also enabling standardized uptake value (SUV) measurement (18,23-25). These shorter protocols may prove more practical in clinical settings and offer valuable insights for future cancer management.

In this study, we employed a systematic clinical approach to evaluate abbreviated scan protocols using [¹⁸F]FDG PET/CT imaging data from LA-NSCLC patients imaged with the uEXPLORER. We hypothesized that a shortened dynamic [¹⁸F]FDG PET/CT scan protocol could improve the clinical feasibility and utility of parametric imaging data in predicting responses to immuno-chemotherapy. The study aimed to determine the acceptability of the abbreviated scan protocols and their effectiveness in quantifying Patlak-Ki values and predicting responses to induction immuno-chemotherapy in LA-NSCLC patients. Exploring abbreviated scan protocols may offer significant value in clinical decision-making and facilitate broader adoption of dynamic total body [¹⁸F]FDG PET/CT. We present this article in accordance with the TRIPOD reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-327/rc).

Methods

Patients and treatment

Patients diagnosed with stage III NSCLC at Sun Yat-sen University Cancer Center were included in the study. Eligibility criteria were as follows: (I) age between 18 and 75 years; (II) histologically or cytologically confirmed untreated NSCLC; (III) unresectable stage III disease according to the eighth edition of the American Joint Committee on Cancer (AJCC)’s Tumor Node Metastasis (TNM) staging system; (IV) presence of measurable lesions as defined by the RECIST criteria; (V) Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1; (VI) adequate bone marrow function (hemoglobin concentration ≥90 g/L, platelet count ≥100×10⁹/L, neutrophil count ≥1.5×10⁹/L), kidney function (serum creatinine clearance ≥50 mL/min), and liver function [aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 times the upper limit of normal (ULN); serum bilirubin ≤1.5 times the ULN]; and (VII) forced expiratory volume in 1 second (FEV₁) ≥0.8 L. Major exclusion criteria were: (I) contraindication to immune-chemotherapy; (II) histologically mixed small cell and NSCLC; (III) history of prior malignancies, excluding curable non-melanoma skin cancer or cervical carcinoma in situ; (IV) poorly controlled intercurrent illness; and (V) pregnant or breastfeeding females, or individuals deemed unsuitable for the study by the researchers. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Although this was a single-center study conducted at Sun Yat-sen University Cancer Center (No. B2025-109-01), ethical approval was also obtained from the Guangdong Association Study of Thoracic Oncology (GASTO) (No. 20201126/A2020-011) as the study was collaboratively initiated and managed under its scientific oversight. Written informed consent was obtained from all participants.

Two cycles of induction chemotherapy combined with immunotherapy were administered to all enrolled patients every 3 weeks. The chemotherapy regimen comprised docetaxel at a dose of 60 mg/m² and cisplatin at a dose of 75 mg/m². Intravenous infusions of nivolumab (360 mg), camrelizumab (200 mg), or tirelizumab (200 mg) were administered on day 1 of each chemotherapy cycle.

The enrolled patients with LA-NSCLC were divided into a testing group and a validation group. In the testing group, three different abbreviated dynamic total body [¹⁸F]FDG PET/CT scan protocols were developed and compared with the standard scan protocol to predict treatment response to induction immuno-chemotherapy. The most effective abbreviated scan protocol was selected based on predictive efficiency and scan duration. In the validation group, the selected abbreviated scan protocol was used to assess its predictive performance for response to induction immuno-chemotherapy.

Standard dynamic total body [¹⁸F]FDG PET/CT scan protocol (testing group)

Eligible patients in the testing group underwent a standard dynamic total body [¹⁸F]FDG PET/CT scan protocol using the uEXPLORER PET/CT scanner (United Imaging, Shanghai, China) prior to the induction immuno-chemotherapy. Following the injection of 3.0 MBq/kg of [¹⁸F]FDG, dynamic PET imaging was performed from head to toe within a 0–60 minute timeframe.

Prior to the total body [¹⁸F]FDG PET/CT scan, patients were instructed to avoid strenuous activities for 24 hours and to fast for 6 hours. Patients with blood glucose levels exceeding 9 mmol/L at the time of [¹⁸F]FDG injection, or those unwilling or unable to undergo the PET scan, were excluded from the study.

PET reconstructions and quantitative analysis of dynamic parameter Patlak-Ki

The raw dynamic [¹⁸F]FDG PET/CT data underwent scatter and attenuation correction, followed by reconstruction with a spatial resolution of 1.67 mm × 1.67 mm × 2.89 mm. The reconstruction process involved 92 frames, including 2 s × 30, 5 s × 12, 10 s × 6, 30 s × 4, 60 s × 25, and 120 s × 15. Images were reconstructed using the ordered subset expectation maximization (OSEM) algorithm with 4 iterations and 20 subsets, incorporating point spread function (PSF) recovery and time of flight (TOF) techniques. Patlak-Ki parameters were derived using the Patlak graphical analysis method based on the two-tissue compartment model. Following intravenous administration, [¹⁸F]FDG is phosphorylated by hexokinase to [¹⁸F]FDG-6-phosphate, which remains trapped intracellularly due to negligible glucose-6-phosphatase activity. The Patlak approach linearizes this irreversible metabolic trapping process and yields the net influx constant Ki, a quantitative index of tissue [¹⁸F]FDG uptake reflecting glucose metabolism.

The standard two-compartment model for [¹⁸F]FDG pharmacokinetics comprises two distinct tissue compartments: (I) free [¹⁸F]FDG compartment (C₁): represents unmetabolized tracer in the extracellular and intracellular spaces; (II) phosphorylated [¹⁸F]FDG-6-phosphate compartment (C₂): represents metabolically trapped tracer following phosphorylation. The model is characterized by three fundamental rate constants: K1: transport rate constant from plasma to tissue (mL/min/100 g); k2: transport rate constant from tissue back to plasma (min⁻¹); k3: phosphorylation rate constant (min⁻¹). The net influx constant Ki, calculated as Ki = (K1 × k3)/(k2 + k3) (Figure S1), represents the overall rate of [¹⁸F]FDG utilization and serves as the primary quantitative endpoint in our analysis.

The Patlak equation provides a linear representation of the compartmental kinetics:

CT(t)Cp(t)=Ki×∫0tCp(τ)dτCp(t)+V[1]

Where CT(t): tissue activity concentration at time t (kBq/mL or kBq/cc); CP(t): Plasma activity concentration at time t (kBq/mL); Ki: net influx constant (mL/min/100 g); V: apparent distribution volume of free [¹⁸F]FDG (mL/100 g); ∫0tCp(τ)dτ: cumulative plasma activity from time 0 to t (kBq·min/mL). The slope of the linear portion of the plot of CT(t)/CP(t) versus ∫0tCp(τ)dτ/CP(t) (typically from 20–60 minutes post-injection) yields the Ki value, while the y-intercept provides the distribution volume V.

Ki values were calculated using the Patlak graphical analysis implementation within the PXMOD toolkit (PMOD Technologies, Fällanden, Switzerland, version 4.2). For each imaging protocol, time-activity curves were generated from carefully delineated volumes of interest (VOIs) encompassing primary tumors. An experienced nuclear medicine doctor and a radiation oncologist, each with over 10 years of experience, manually contoured the VOI. The Evidance platform (Homology Medical Technologies Inc., Ningbo, China) was used to fuse the [¹⁸F]FDG PET and CT images, enabling precise VOI delineation. The input function was derived using either: (I) image-derived input function (IDIF) from the descending aorta for the standard 20–60-minute protocol; or (II) population-based input function-derived IDIF (PBIF-derived IDIF) for the abbreviated protocols (30–60-minute, 40–60-minute, and 50–60-minute). Linear regression analysis was performed on data points from the appropriate steady-state phase for each protocol duration, and the resulting regression slope provided the Ki value in standardized units of mL/min/100 g.

Calculation of Patlak-Ki values from 4 different dynamic total body [¹⁸F]FDG PET/CT scan protocols

In this study, four distinct imaging protocols for calculating Patlak-Ki were developed, including a standard dynamic scan protocol and three abbreviated dynamic scan protocols. The standard protocol utilized an IDIF and calculated Patlak-Ki using frames acquired between 20 and 60 minutes post-injection (26). The IDIF was extracted from the ascending aorta, as this region is less influenced by respiratory motion. The abbreviated protocols derived Patlak-Ki images from frames captured within intervals of 30–60-minute, 40–60-minute, and 50–60-minute post-injection, respectively. These protocols used a PBIF for calculations. The PBIF was generated from the IDIF obtained in this study, following the methodology described in a previous study (27). For each abbreviated protocol, the IDIF was derived from the PBIF using a method based on the area under the time-activity curve of the aorta. This approach facilitated a more efficient and optimized imaging procedure while maintaining the accuracy of Patlak-Ki calculations. The standard scan protocol was used as a reference for comparison with the abbreviated protocols. Patlak-Ki images from the four scan protocols were analyzed at the pixel level using the PXMOD toolkit from PMOD software (pmod.com), employing the IDIF or PBIF-derived IDIF and dynamic frames as specified. Figure 1 illustrates the standard total body dynamic [¹⁸F]FDG PET/CT scan protocol alongside the three abbreviated protocols. The agreement, correlation, and predictive ability of Patlak-Ki values from the four protocols were compared to identify the most effective abbreviated protocol.

Figure 1 Illustration depicting the three different abbreviated and the standard dynamic total-body [¹⁸F]FDG PET/CT scan protocols. [¹⁸F]FDG PET/CT, [¹⁸F]fluorodeoxyglucose positron emission tomography/computed tomography; CT, computed tomography.

The selected abbreviated dynamic total body [¹⁸F]FDG PET/CT scan protocol (validation group)

The patients in the validation group underwent a dynamic total-body [¹⁸F]FDG PET/CT scan using the abbreviated scan protocol selected before the induction of immuno-chemotherapy. The predictive ability of the Patlak-Ki value, derived from the abbreviated scan protocol in the validation group, was compared with that in the testing group.

Evaluation of therapeutic response following induction immuno‑chemotherapy

All eligible patients were evaluated for treatment response according to RECIST criteria after two cycles of induction immuno-chemotherapy (28), and categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD).

Statistical analysis

Statistical analyses were performed using IBM SPSS software (version 27, Chicago, IL, USA). Descriptive statistics were employed to analyze baseline characteristics. The agreement and correlation between the Patlak-Ki values from three different abbreviated scan protocols and the standard scan protocol were assessed using Bland-Altman analysis and Pearson’s correlation coefficient. Mean biases were calculated to evaluate the relative performance of the Patlak-Ki values across different scan protocols. A correlation coefficient greater than 0.7 was considered indicative of a ’strong’ correlation. The predictive ability of Patlak-Ki values for treatment response was evaluated using the area under the curve (AUC) from the receiver operating characteristic (ROC) curve. The validation group was used to assess the predictive performance of Patlak-Ki values obtained from the selected abbreviated scan protocol. Data between groups were compared using the t-test, with a P value less than 0.05 considered statistically significant.

Results

Clinical characteristics and treatment details

From September 2020 to August 2023, a total of 38 patients with LA-NSCLC in the testing group and 34 patients in the validation group were enrolled and analyzed (Figure 2). The median age at diagnosis was 58 years, with a range of 33 to 75 years. The majority of the patients were male (60 out of 72, 83.3%) and had a history of smoking (48 out of 72, 66.7%). Adenocarcinoma was the predominant histologic type, affecting 33 out of 72 patients (45.8%). Regarding disease stage, 15 patients (20.8%) were classified as stage IIIA, 32 patients (44.4%) as stage IIIB, and 25 patients (34.7%) as stage IIIC. All patients received two cycles of induction chemotherapy in conjunction with either nivolumab, camrelizumab, or tirelizumab, according to the protocol. Detailed patient characteristics are summarized in Table 1. Prior to induction immuno-chemotherapy, the 38 patients in the testing group underwent the standard dynamic total body [¹⁸F]FDG PET/CT scan protocol, while the 34 patients in the validation group received the abbreviated scan protocol.

Figure 2 Flow chart of study design. [¹⁸F]FDG PET/CT, [¹⁸F]fluorodeoxyglucose positron emission tomography/computed tomography; NSCLC, non-small cell lung cancer; PET, positron emission tomography.

Comparisons of Patlak-Ki values between the 3 different abbreviated scan protocols and the standard scan protocol in testing group

Comparisons of the Patlak-Ki values across different scan protocols are illustrated in Figure 3. The Bland-Altman analysis results reveal that, relative to the standard Patlak-Ki values, the 30–60-minute Patlak-Ki values exhibited a mean bias of -0.03 mL/min/100 g, with 95% limits of agreement ranging from −0.62 to 0.56 mL/min/100 g. The 40–60-minute Patlak-Ki values showed a mean bias of −0.02 mL/min/100 g, with 95% limits of agreement ranging from −0.73 to 0.69 mL/min/100 g. The 50–60-minute Patlak-Ki values demonstrated a mean bias of 0.04 mL/min/100 g, with 95% limits of agreement ranging from −1.09 to 1.18 mL/min/100 g. Among these, the mean bias between the 40–60-minute and standard Patlak-Ki values was closest to zero, indicating minimal error. Furthermore, the 30–60-minute, 40–60-minute, and standard Patlak-Ki values showed superior concordance compared to the 50–60-minute values, as evidenced by the tighter clustering of data points around the mean bias.

Figure 3 Bland-Altman plot for agreement analysis of Patlak-Ki values obtained from the 3 different abbreviated scan protocols [(A) 30–60-minute, (B) 40–60-minute, (C) 50–60-minute] compared with standard dynamic total-body [¹⁸F]FDG PET/CT scan protocol. [¹⁸F]FDG PET/CT, [¹⁸F]fluorodeoxyglucose positron emission tomography/computed tomography.

In the correlation analysis, the scatterplot clearly revealed strong correlations between the abbreviated and standard Patlak-Ki values. The Pearson correlation coefficients for the 30–60-minute, 40–60-minute, and 50–60-minute scan protocols were 0.98, 0.96, and 0.94, respectively (Figure 4). Our previous study divided patients into high FDG Ki and low FDG Ki groups based on their Patlak-Ki value (15). Figure 5 displays representative images of a high FDG Ki patient (Patlak-Ki >2.779 mL/min/100 g) and a low FDG Ki patient (Patlak-Ki ≤2.779 mL/min/100 g), selected from the three abbreviated protocols and the standard dynamic total body [¹⁸F]FDG PET/CT scans.

Figure 4 Correlation analysis of Patlak-Ki values obtained from the three different abbreviated dynamic total-body [¹⁸F]FDG PET/CT scan protocols [(A) 30–60-minute, (B) 40–60-minute, (C) 50–60-minute] and the standard scan protocol. [¹⁸F]FDG PET/CT, [¹⁸F]fluorodeoxyglucose positron emission tomography/computed tomography.

Figure 5 Ki images of a High-Ki (A) and Low-Ki (B) patients from the three different abbreviated and the standard dynamic total-body [¹⁸F]FDG PET/CT scan protocols. Red boxes indicate the target tumor on the Ki images. [¹⁸F]FDG PET/CT, [¹⁸F]fluorodeoxyglucose positron emission tomography/computed tomography.

The predictive efficiency of Patlak-Ki values from different abbreviated scan protocols in the testing group

After two cycles of induction immunochemotherapy, 26 out of 38 patients (68.4%) achieved a PR, while 12 patients (31.6%) exhibited SD in the testing group. ROC curve analysis for predicting treatment response indicated that the standard Patlak-Ki values had the highest AUC of 0.75 [95% confidence interval (CI): 0.52–0.97], followed by the 30–60-minute Patlak-Ki values with an AUC of 0.74 (95% CI: 0.52–0.96), the 40–60-minute Patlak-Ki values with an AUC of 0.73 (95% CI: 0.50–0.95), and the 50–60-minute Patlak-Ki values with an AUC of 0.71 (95% CI: 0.50–0.93) (Figure 6). Figure S2 showed the correlation between 50–60-minute Patlak-Ki values and 50–60-minute SUVmean/SUVmax. To a certain extent, there was a linear correlation between these two parameters. We further compared the performance of Patlak-Ki and 50–60-minute SUV in predicting tumor response, and the results were shown in Figure S3. Patlak-Ki had superior predicting performance compared to both SUVmean and SUVmax [AUC: 50–60-minute Patlak-Ki: 0.71 (95% CI: 0.50–0.93); 50–60-minute SUVmean: 0.68 (95% CI: 0.48–0.88); 50–60-minute SUVmax: 0.66 (95% CI: 0.46–0.87)]. The sensitivity and specificity of Patlak-Ki in differentiating responder from non-responder were compared across different scan protocols, using the cut-off value (Ki =2.779 mL/min/100 g) reported in our previous study (15). The results showed that 40–60-minute Patlak-Ki values exhibited identical sensitivity (80.8%) and specificity (75.0%) to standard Patlak-Ki values (Table S1). Besides, the sensitivity of 40–60-minute Patlak-Ki was superior to that of 30–60-minute and 50–60-minute Patlak-Ki (80.8% vs. 73.1% & 69.2%). Our results demonstrated that the 30–60-minute and 40–60-minute Patlak-Ki values produced similar ROC curves, indicating comparable discriminative performance in predicting induction treatment response. Given that the 40–60-minute Patlak-Ki values exhibited an excellent AUC, sensitivity and specificity, coupled with its moderate scanning duration, we selected this protocol for further evaluation. Collectively, these findings highlight the superior predictive capacity of the 40–60-minute Patlak-Ki values, combined with its efficient scanning time.

Figure 6 ROC curves of Patlak-Ki values obtained from three different abbreviated and the standard dynamic total-body [¹⁸F]FDG PET/CT scan protocols (green: standard; blue: 30–60-minute, pink: 40–60-minute, purple: 50–60-minute) on the prediction of induction immuno-chemotherapy response in the testing group. [¹⁸F]FDG PET/CT, [¹⁸F]fluorodeoxyglucose positron emission tomography/computed tomography; AUC, area under the curve; ROC, receiver operating characteristic.

The predictive efficiency of the Patlak-Ki value from the 40–60-minute abbreviated scan protocol in the validation group

A validation cohort of 34 patients with LA-NSCLC was enrolled to assess the predictive performance of the 40–60-minute Patlak-Ki value. All 34 patients underwent a 40–60-minute abbreviated dynamic total body [¹⁸F]FDG PET/CT scan prior to receiving induction immuno-chemotherapy. After two cycles of induction immuno-chemotherapy, 24 patients (70.6%) demonstrated PR, while 10 patients (29.4%) exhibited SD. The ROC curve analysis yielded an AUC of 0.78 (95% CI: 0.56–1.00) (Figure 7). The figures below illustrate SUV images of patients with high and low Ki values from the 40–60-minute abbreviated scan protocol, along with their respective tumor responses after two cycles of immuno-chemotherapy (Figure 8).

Figure 7 ROC curves of Patlak-Ki values obtained from the 40–60-minute abbreviated dynamic total-body [¹⁸F]FDG PET/CT scan protocol on the prediction of induction immuno-chemotherapy response in the validation group. [¹⁸F]FDG PET/CT, [¹⁸F]fluorodeoxyglucose positron emission tomography/computed tomography; AUC, area under the curve; ROC, receiver operating characteristic.

Figure 8 The SUV images from the 40–60-minute abbreviated dynamic total-body [¹⁸F]FDG PET/CT scan protocol of a High-Ki (A) and a Low-Ki (B) patients. The High-Ki patient achieved PR while the Low-Ki patient had SD after the induction immuno-chemotherapy. Red boxes and red contour areas delineate the target tumors on the SUV and CT images, respectively. [¹⁸F]FDG PET/CT, [¹⁸F]fluorodeoxyglucose positron emission tomography/computed tomography; PR, partial response; SD, stable disease; SUV, standardized uptake value.

Discussion

Over the last decade, advancements in detector technology and heightened clinical application demands have driven the development and recent introduction of long axial field of view (LAFOV) PET systems, such as the Vision Quadra PET/CT with a LAFOV of 106 cm, the PennPET Explorer with a LAFOV of 64 cm and the uEXPLORER with a LAFOV of 194 cm. LAFOV systems enable non-invasive whole body dynamic [¹⁸F]FDG Patlak imaging methods, employing an IDIF, which has been validated against the gold standard of arterial blood sampling. Although technological advancements in PET allow for whole body parametric imaging, they also facilitate the acquisition of whole-body static images at significantly shortened scan durations, thereby enhancing patient throughput. Consequently, evaluating non-invasive whole body [¹⁸F]FDG Patlak imaging using a PBIF for acquisition at reduced scan time intervals could be a beneficial and compatible method for these LAFOV PET systems.

In this study, we compared the Patlak-Ki values obtained from a standard 20–60-minute scan protocol with those from three abbreviated scan protocols of 30–60-minute, 40–60-minute, and 50–60-minute post-FDG injection, using the 194 cm LAFOV uEXPLORER. Our results showed that the mean bias between the 40–60-minute Patlak-Ki values and the standard Patlak-Ki values was closest to zero, signifying minimal error. Additionally, the concordance and discriminative performance of the 30–60-minute, 40–60-minute, and standard Patlak-Ki values were superior to those of the 50–60-minute values. The 20-minute scan duration in the 40–60-minute abbreviated scan protocol was better tolerated by most patients compared to the 20–60-minute and 30–60-minute protocols. In a validation cohort of 34 LA-NSCLC patients, the Ki derived from the 40–60-minute abbreviated scan protocol yielded an AUC of 0.78 (95% CI: 0.56–1.00) for predicting the response to immunotherapy. Therefore, the 40–60-minute abbreviated dynamic total body [¹⁸F]FDG PET/CT imaging protocol may be a suitable alternative to the standard 20–60-minute scan in LA-NSCLC patients undergoing induction immuno-chemotherapy.

Our previous study found that the Patlak-Ki values derived from dynamic total body [¹⁸F]FDG PET/CT scans were associated with tumor response to immuno-chemotherapy in LA-NSCLC (15). Patients were categorized into two groups based on their FDG Ki values: the high FDG Ki group (Ki >2.779 mL/min/100 g) and the low FDG Ki group (Ki ≤2.779 mL/min/100 g). The high FDG Ki group demonstrated a better response to the induction immuno-chemotherapy than the low FDG Ki group. Additionally, we found that Patlak-Ki values effectively predict progression-free survival and overall survival in LA-NSCLC patients undergoing immuno-chemotherapy and concurrent chemoradiation therapy (29). These results indicated that dynamic total body [¹⁸F]FDG PET/CT is a valuable tool for guiding combined treatment in clinical practice for inoperable LA-NSCLC.

Similarly, prior studies have reported the prognostic significance of Ki values derived from dynamic PET/CT in various cancers, including breast cancer and non-Hidgkin’s lymphoma (30,31). Despite these advantages, dynamic [¹⁸F]FDG PET/CT imaging has not achieved widespread clinical acceptance, partly due to the time-intensive nature of the procedure for both clinicians and patients. To reduce the duration of dynamic imaging, several studies have investigated abbreviated scan protocols. Joyce et al. found that a shorter scan interval of 40–60 minutes post-injection could be a reasonable trade-off between scan duration (60 minutes) and the quantitative accuracy of tumor Ki values, although it is associated with increased noise and slightly diminished image quality when using the 106 cm Vision Quadra PET/CT system with a sensitivity of 82.6 kcps/MBq at the center of the field of view (FOV) (32). Lan et al. demonstrated that the ultra-high sensitivity (UHS) mode with a 50–65-minute abbreviated scan protocol can provide Ki and DV values comparable to those from a full 65-minute dynamic scan using the Biograph Vision Quadra PET/CT scanner (33). Although both studies aimed to optimize abbreviated scan protocols using LAFOV PET, our study differs in several aspects: First, we investigated whether the higher sensitivity of the 194 cm LAFOV uEXPLORER PET/CT system, with a sensitivity of 174 kcps/MBq at the center of the FOV, allows for shortened Patlak imaging while maintaining sufficient image quality and quantitative performance. Second, while previous studies covered a range of cancer types, our study focuses specifically on NSCLC. Third, our study evaluates the effectiveness of predicting immunotherapy outcomes using Ki values obtained from different abbreviated scan protocols. We utilized the Patlak Input Function (PIF) and conducted a comparative analysis of FDG kinetic parameters across various imaging frame scales in LA-NSCLC patients undergoing dynamic PET scans with the uEXPLORER PET/CT scanner. The mean bias between the 40–60-minute and standard Patlak-Ki values was close to zero, indicating minimal error. The 30–60-minute, 40–60-minute, and standard Patlak-Ki values showed better concordance compared to the 50–60-minute values. Although reducing scan time from 30 minutes (30–60-minute abbreviated scan protocol) to 20 minutes (40–60-minute abbreviated scan protocol) may seem modest, it generally improves patient tolerance. Additionally, shorter acquisition times result in fewer data counts and smaller dataset sizes, facilitating faster data reconstruction and transmission. This enhancement makes it feasible to integrate dynamic [¹⁸F]FDG PET/CT imaging into clinical routines, providing valuable diagnostic and predictive insights.

Despite the significant sensitivity achieved by total body PET/CT, obtaining a full-length arterial IDIF requires an hour-long scan, which causes patient discomfort and places a strain on critical infrastructure, thereby limiting its use in routine clinical practice. To address the limitations of scan time, abbreviated scans provide only a partial IDIF but can be utilized for parametric imaging when combined with a PBIF (34). Wu et al. demonstrated that Ki images reconstructed with PBIF using 20-minute scan data offer diagnostic efficiency comparable to images reconstructed with IDIF from 40-minute dynamic data, with no significant difference between Ki images generated using IDIF or PBIF for the uEXPLORER scanner (27). Consequently, our study employed IDIF for the standard protocol and PBIF for the abbreviated protocols.

Patlak analysis may have limitations in cases where the phosphate pentose pathway is active, but it remains a widely used and clinically validated method for [¹⁸F]FDG PET quantification in many cancer types (35-38). Furthermore, our prior researches have substantiated the value of Patlak analysis in evaluating dynamic metabolic heterogeneity, as well as in predicting the response to immunotherapy and chemoradiotherapy among NSCLC (15,29,39). The simplicity and robustness of Patlak analysis make it particularly valuable for routine clinical evaluation in lung cancer patients. Logan analysis may offer advantages for specific cancer subtypes where [¹⁸F]FDG kinetics deviate from the irreversible trapping assumption. We plan to investigate the relationship between cancer subtypes and optimal kinetic modeling approaches (Patlak versus Logan graphical analysis) for the 0–60-minute data in subsequent studies.

Immunotherapy has emerged as a promising neoadjuvant treatment option for LA-NSCLC. The KEYNOTE-799 trial demonstrated the efficacy of immuno-chemotherapy followed by concurrent chemoradiotherapy in patients with LA-NSCLC (40). Recently, the CheckMate 816 trial confirmed that neoadjuvant nivolumab combined with chemotherapy significantly improved event-free survival and increased the pathological CR rate in operable NSCLC compared to chemotherapy alone (5). The combined regimen of nivolumab and chemotherapy has been approved in the United States as a neoadjuvant treatment option for NSCLC patients eligible for surgery. Given the importance of neoadjuvant immuno-chemotherapy, identifying markers that predict treatment efficacy is essential. Our previous study found that elevated [¹⁸F]FDG Patlak-Ki values were associated with increased immune cell infiltration in the tumor microenvironment (TME), indicating that immunotherapy may benefit a specific subgroup of patients (39). We subsequently classified LA-NSCLC patients into high FDG Patlak-Ki and low FDG Patlak-Ki groups and observed that high FDG Ki patients had a more favorable response to induction immuno-chemotherapy (15). In the present study, the ROC curves for the 40–60-minute Patlak-Ki values and standard Patlak-Ki values were similar, indicating comparable discriminative performance in predicting the induction treatment response. Additionally, the validation group demonstrated that Patlak-Ki values from the abbreviated 40–60-minute scan protocol also had strong predictive capabilities for induction immuno-chemotherapy response, making it a more convenient option in clinical practice.

Several limitations should be considered in this study. Firstly, it is retrospective in nature with a relatively small sample size. Future propective study with larger sample sizes and stage IV patients is needed to validate the results. Second, while the feasibility of the IDIF was demonstrated, it was not validated using arterial blood samples. Third, the current study did not apply motion correction to the dynamic frames, which may affect the precision of the Patlak-related parameters, particularly in tumors with small volumes and/or necrosis. Finally, we did not correlate dynamic imaging with delayed imaging in this study.

Conclusions

We demonstrated the feasibility of obtaining reliable Patlak-Ki values using 40–60-minute of post-injection [¹⁸F]FDG PET data in patients with LA-NSCLC by employing ultra-high sensitivity dynamic total-body [¹⁸F]FDG PET/CT. The Patlak-Ki values derived from the 40–60-minute dynamic scan protocol showed strong agreement with those obtained from the standard dynamic scan protocol for predicting the response to induction immuno-chemotherapy in LA-NSCLC patients. These findings suggest the potential for broader adoption of dynamic total-body [¹⁸F]FDG PET/CT. Considering the retrospective design and limited sample size, larger prospective studies are warranted to validate these results, including in stage IV patients receiving first-line immunochemotherapy.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-327/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-327/dss

Funding: This study was supported by the National Natural Science Foundation of China (No. 82073328).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-327/coif). Hui Liu (the fourth author) is currently an employee of United Imaging Healthcare, Shanghai, China. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Although this was a single-center study conducted at Sun Yat-sen University Cancer Center (No. B2025-109-01), ethical approval was also obtained from the Guangdong Association Study of Thoracic Oncology (GASTO) (No. 20201126/A2020-011) as the study was collaboratively initiated and managed under its scientific oversight. Written informed consent was obtained from all participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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