¹⁸F-FDG and ¹¹C-4DST PET/CT for evaluating response to platinum-based doublet chemotherapy in advanced non-small cell lung cancer: a prospective study

This prospective study was approved by the local institutional review board of our hospital, and written informed consent was obtained from all patients prior to enrollment. Between October 2011 and June 2016, patients with advanced-stage NSCLC were recruited into the study. Inclusion criteria were (1) pathologically diagnosed NSCLC; (2) inability to perform treatment using radiation therapy with Union for International Cancer Control (UICC) 7th clinical stage IIIB or IV, or recurrence after surgery; (3) at least one measurable target lesion; (4) age > 20 years; (5) Eastern Cooperative Oncology Group performance (ECOG) status of 0 or 1; (6) no history of receiving PT-DC or planning to change PT-DC regimen due to insufficient treatment response confirmed in first- or second-line therapy; (7) no history of surgical operation within 4 weeks; (8) no history of radiation therapy within 2 weeks; and (9) white blood cell count ≥ 3000 mm³, hemoglobin ≥ 9.0 g/dl, platelets ≥ 100,000/mm³, total bilirubin ≤ 1.5 mg/dl, AST ≤ 100 IU/l, ALT ≤ 100 IU/l, serum creatinine ≤ 1.2 mg/dl, and SpO₂ ≥ 90%. Exclusion criteria were (1) symptomatic brain metastasis; (2) double cancer; (3) symptomatic superior vena cava syndrome; (4) symptomatic pleural effusion, and/or ascites and/or cardiac effusion; (5) spinal compression by tumor; (6) uncontrolled hypertension or diabetes; (7) active interstitial pneumonia; (8) PT-DC allergy; (9) concurrent steroid therapy; or (10) pregnancy.

Two cycles of PT-DC were administered to all participants. Fifteen patients received PT-DC as first-line therapy, four patients as second-line therapy, and three patients as third-line therapy. Nine patients had received platinum plus tegafur/gimeracil/oteracil (TS-1), eight patients had received platinum plus pemetrexed, four patients had received platinum plus docetaxel, and one patient had received platinum plus gemcitabine. The median number of chemotherapy cycles was 4 (range, 2–5).

The presence of a recurrent lesion was determined clinically based on the results of repeated contrast-enhanced (CE) chest and abdominal CT and CE brain magnetic resonance imaging (MRI) every 2–3 months for the first year, then every 4–6 months.

CE CT, FDG PET/CT, and 4DST PET/CT scans were performed within 20 days before initiation of PT-DC therapy (baseline) and after completing 2 cycles of PT-DC (interim). Multidetector-row CT (SOMATOM Definition: SIEMENS Health Care, or Discovery Revolution: GE Healthcare, or Aquilion One: Toshiba Medical Systems) covering the thorax, abdomen, and pelvis was performed with intravenous contrast, and images were reconstructed using a slice thickness of 2.5 mm. An in-house cyclotron and automated synthesis system (F200; Sumitomo Heavy Industries) was used in accordance with the authorized procedure to synthesize FDG. The time between tracer injection and acquisition of data was 60 min for FDG, and 293 ± 60 MBq of FDG was administrated on average. Mean blood glucose level was 104 ± 18 mg/dl (range, 69–152 mg/dl) for baseline FDG PET/CT and 114 ± 16 mg/dl (range, 90–151 mg/dl) for interim FDG PET/CT. Synthesis of 4DST was performed as described previously [18]. The time between tracer injection and acquisition of data was 40 min for 4DST, and 358 ± 40 MBq of 4DST was administered on average. PET images were obtained using Discovery PET/CT 600 (GE Healthcare) or Biograph 16 (SIEMENS Health Care) after the patient had fasted for at least 6 h. Cross-calibration was performed between the two PET scanners, and the same PET/CT scanner was used for baseline and interim PET/CT scans for each patient. Low-dose CT was performed first and was used for attenuation correction and image fusion. Emission images were acquired in three-dimensional mode for 2.5 min/bed position. PET data were reconstructed using a Gaussian filter with an ordered subset expectation maximization algorithm (3 iterations and 16 subsets for Discovery PET/CT 600; and 3 iterations and 8 subsets for Biograph 16).

All CT studies were reviewed in consensus by at least two radiologists (≥ 10 years of experience), and RECIST uni-dimensional measurements were recorded prospectively by the same radiologists. All PET/CT studies were reviewed in consensus by at least two nuclear medicine physicians (≥ 5 years of experience), who were blinded to the clinical data and the results of other imaging studies. On baseline FDG PET/CT, we measured maximum standardized uptake value (SUV_max) for the lesion showing the most intense FDG uptake (highest SUV_max), sum of SUV_max for up to six lesions showing the highest SUV_max (sum of SUV_max), total metabolic tumor volume (MTV), and total lesion glycolysis (TLG). We defined positive 4DST uptake as visually higher than that of the surrounding background and referred to the CT portion of the PET/CT to identify the targeted lesions. On baseline 4DST PET/CT, we measured SUV_max of the lesion showing the most intense 4DST uptake (highest SUV_max), sum of SUV_max for up to six lesions showing the highest SUV_max (sum of SUV_max), and total MTV. For the 4DST PET/CT, total lesion proliferation (TLP) was defined as SUV_mean multiplied by MTV. Assessed lesions were regarded as “targeted lesions” on interim PET/CT. On the interim PET/CT, we measured highest SUV_max, sum of SUV_max for up to six lesions showing the most intense FDG or 4DST activity, the percentage decrease in SUV_max of targeted lesion between baseline and interim PET/CT (%Δ highest SUV_max), the percentage decrease in sum of SUV_max for the target lesions (%Δ sum of SUV_max), TLG, the percentage decrease in TLG between baseline and interim PET/CT (%ΔTLG), TLP and percentage decrease in TLP between baseline and interim PET/CT (%ΔTLP), MTV and the percentage decrease in MTV between baseline and interim PET/CT (%ΔMTV). SUV_max, TLG, TLP, and MTV of lesions were measured with the PETedge tool MIM encore version 6.6 software (MIM Software, Cleveland, OH), using a gradient-based tumor segmentation method that detects the steepest drop-off in SUV values to create the contour boundary automatically [24].

Response to chemotherapy using CECT as interim analysis was assessed based on RECIST 1.1. For the FDG PET/CT, assessment of metabolic response was conducted in accordance with the European Organization for Research and Treatment of Cancer (EORTC) [25] and PET Response Criteria in Solid Tumors (PERCIST) 1.0 guidelines [26].

Data are expressed as mean ± standard deviation. Differences in measurements of target lesions between baseline and interim scans with FDG PET/CT (SUV_max, sum of SUV_max, SUL [SUV normalized by lean body mass], MTV, TLG) and 4DST PET/CT parameters (SUV_max, sum of SUV_max, MTV, and TLP), differences in measurements of reference organs with FDG PET/CT (liver SUL and liver SUL standard deviation), and differences in measurements for sums of uni-dimensional measurements of target lesions were compared using the Wilcoxon signed-rank test in cases with patients receiving both baseline PET and interim PET. According to National Comprehensive Cancer Network (NCCN) guidelines, evaluation of tumor response for NSCLC is set after 4–6 cycles of doublet chemotherapy when deciding to proceed with subsequent therapy or continue maintenance therapy [1]. We thus evaluated differences in CT, FDG, and 4DST parameters between PFS > 4 months and ≤ 4 months, to estimate the status of disease progression after 4 cycles of PT-DC. Differences in FDG and 4DST PET parameters between PFS > 4 months and ≤ 4 months were compared using the Mann-Whitney U test. Receiver operating characteristic (ROC) analysis was performed to determine optimal cutoff values for uptake on baseline PET and uptake reduction from baseline to interim PET in predicting PFS > 4 months and ≤ 4 months. Positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated based on the optimal cutoff value determined by ROC analysis, and also according to RECIST 1.1, EORTC, and PERCIST 1.0. For RECIST 1.1, cases interpreted as showing stable disease (SD) or progressive disease (PD) were classified as non-responders to PT-DC, and studies interpreted as showing complete response (CR) or partial response (PR) were classified as responders to PT-DC. For EORTC criteria and PERCIST 1.0, studies interpreted as showing stable metabolic disease (SMD) or progressive metabolic disease (PMD) were classified as non-responders to PT-DC, and studies interpreted as showing complete metabolic response (CMR) or partial metabolic response (PMR) were classified as responders to PT-DC. PFS was calculated from the start of treatment until the date of disease progression or last follow-up. OS was calculated from the start of treatment until the date of death or last follow-up. Analyses of PFS and OS were performed using Kaplan-Meier estimates and log-rank tests for CT, FDG, and 4DST parameters. Times to progression and death served as endpoints. Analyses were performed using STATA version 14. Two-tailed values of p < 0.05 were considered significant.

Twenty-two consecutive patients (mean age, 69.8 ± 8.8 years; 5 females, 17 males) were enrolled in this study. Patient characteristics are shown in Table 1. All patients underwent baseline CT, 4DST, and FDG PET/CT. These patients were included in the analysis to assess relationships between baseline PET and both PFS and OS. Four patients could not receive interim PET/CT because of clinical deterioration resulting from chemotherapy. Consequently, 18 patients with baseline CT, 4DST, and FDG PET/CT and interim CT, 4DST, and FDG PET/CT were included in the analysis to assess relationships between baseline PET and prognosis.

The mean interval between baseline FDG and baseline 4DST, between baseline CT and baseline 4DST, and between baseline FDG and baseline CT was 6 days, 15 days, and 12 days, respectively. The mean interval between initiating chemotherapy and any baseline scan was 5 days. The mean interval between interim FDG and interim 4DST, between interim CT and interim 4DST, and between interim FDG and interim CT was 2 days, 4 days, and 3 days, respectively. The mean interval between baseline and interim FDG, 4DST, and CT was 54 days, 51 days, and 62 days, respectively. Median follow-up for progression-free patients was 118 days (range, 36–556 days). Twelve patients showed PFS ≤ 4 months (range, 36–122 days), and 10 patients showed PFS > 4 months (range, 126–556 days). Median follow-up for surviving patients was 429 days (range, 78–1455 days).

Results are shown in Table 2. No significant differences were confirmed between baseline and interim assessments. Liver SUL and SD at baseline FDG and interim PET/CT displayed no significant difference. The results for differences in PET/CT parameters with PFS > 4 months and ≤ 4 months are shown in Table 3. No significant difference was observed in CT or PET parameters between PFS > 4 months and ≤ 4 months. Table 4 shows the result of ROC analyses and PPV, NPV, and accuracy of each PET parameter and several response assessment criteria. For predicting PFS > 4 months and ≤ 4 months, MTV of baseline 4DST showed the highest AUC (0.73), PPV (80.0%), NPV (67.7%), and accuracy (72.7%) among baseline measurement data and metabolic responses from 4DST PET/CT, FDG PET/CT, and CT. Represented images are shown in Fig. 1.

Kaplan-Meier curves for PFS with MTV of baseline FDG (p = 0.048) and baseline 4DST (p = 0.018) revealed significant results. No significant result was obtained from changes in parameters between baseline and interim PET for Kaplan-Meier curves of PFS (Table 5). The Kaplan-Meier curves for OS with MTV of baseline FDG (p = 0.02) and baseline TLG (p = 0.04), and MTV of baseline 4DST (p = 0.007) revealed significant results (Table 5, Figs. 2 and 3).