Early reduction in tumour [18F]fluorothymidine (FLT) uptake in patients with non-small cell lung cancer (NSCLC) treated with radiotherapy alone

Abstract

Purpose: Changes in tumour 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) uptake during concurrent chemo-radiotherapy in patients with non-small cell lung cancer (NSCLC) have been reported, at variable time points, in two pilot positron emission tomography (PET) studies. The aim of this study was to assess whether FLT changes occur early in response to radiotherapy (RT) without concurrent chemotherapy and whether such changes exceed test-retest variability.

Methods: Sixteen patients with NSCLC, scheduled to have radical RT, underwent FLT PET once/twice at baseline to assess reproducibility and/or after 5-11 RT fractions to evaluate response. Primary and nodal malignant lesions were manually delineated on CT and volume, mean and maximum standardized uptake values (SUV(mean) and SUV(max)) estimated. Analysis included descriptive statistics and parameter fitting to a mixed-effects model accounting for patients having different numbers of evaluable lesions.

Results: In all, 35 FLT PET scans from 7 patients with a total of 18 lesions and 12 patients with a total of 30 lesions were evaluated for reproducibility and response, respectively. SUV(mean) reproducibility in primary tumours (SD 8.9%) was better than SUV(max) reproducibility (SD 12.6%). In nodes, SUV(mean) and SUV(max) reproducibilities (SD 18.0 and 17.2%) were comparable but worse than for primary tumours. After 5-11 RT fractions, primary tumour SUV(mean) decreased significantly by 25% (p = 0.0001) in the absence of significant volumetric change, whereas metastatic nodes decreased in volume by 31% (p = 0.020) with a larger SUV(mean) decrease of 40% (p < 0.0001). Similar changes were found for SUV(max).

Conclusion: Across this group of NSCLC patients, RT induced an early, significant decrease in lesion FLT uptake exceeding test-retest variability. This effect is variable between patients, appears distinct between primary and metastatic nodal lesions, and in primary tumours is lower than previously reported for concurrent chemo-RT at a similar time point. These results confirm the potential for FLT PET to report early on radiation response and to enhance the clinical development of novel drug-radiation combinations by providing an interpretable, early pharmacodynamic end point.

Fig. 1

Representative CT (left) and PET (right, SUV 45–60 min) images of patient 11 acquired at baseline (top) and after delivery of 27.5 Gy (bottom). Primary tumour is manually delineated within green outline. Note sharply demarcated dramatic reduction in bone marrow uptake and modest reduction of tumour uptake after RT, as previously reported [21]

Fig. 2

Baseline (single/average) volume (top), SUV_mean (middle) and SUV_max (bottom) of primary tumours (squares) and metastatic nodal lesions (circles) of 16 patients

Fig. 3

a Lesion reproducibilities (%) plotted against mean baseline lesion values for volumes (top), SUV_mean (middle) and SUV_max (bottom). b RT-induced responses (%) plotted against baseline parameter values (second baseline scan if two baseline scans acquired). Dashed lines in SUV graphs set at mean test-retest difference ± RC = 1.96 × SD, where SD is standard deviation of respective parameter reproducibility. In volume graphs dashed lines not displayed as absolute volume reproducibility correlated with baseline average volume. Primary tumours represented by squares and metastatic nodes by circles. The second evaluable lesion of patient 7 (4R) was measured as 170 % larger post-RT. This outlier is not shown in b, to enhance visibility, nevertheless was included in the statistical analyses

Fig. 4

Lack of dose-response relationship between SUV_max response (expressed as ratio of SUV_max during RT to single/latest baseline value) and calendar days on RT. Primary tumours represented by squares and metastatic nodes by circles