Surveillance and detection of recurrence in patients treated with SBRT for lung cancer is challenging due to fibrosis on CT scans33. Various strategies including CT based radiomic signatures, apparent diffusion coefficient maps from MRI, and PET have been tried to differentiate fibrosis from recurrence 14,16. FDG-PET measures glucose metabolism and is the most common PET tracer used across malignancies to evaluate recurrence. Due to non-specific uptake in inflammatory tissue, its use in post-treatment settings led to equivocal findings and the evaluation of other PET tracers 22,34. FLT-PET has emerged promising as it is specific for tumor proliferation and shows minimal uptake in inflammatory tissues 35,36. The present study evaluated FLT-PET in a cohort of lung cancer patients treated with SBRT. It showed that FLT-PET SUV max values were lower in the fibrosis cohort, and FLT-PET may help differentiate fibrosis from recurrence.
FLT-PET is explored for assessment of response following conventionally fractionated radiotherapy in lung cancer 37-39. Everitt et al. compared the response following radical chemoradiation in lung cancer patients between FDG versus FLT-PET 28. They found median SUV max values were lower with FLT than FDG post-therapy. Studies evaluating FLT-PET/CT after SBRT to lung assessing fibrosis or recurrence are scarce. Christensen et al. investigated FDG and FLT-PET/CT in 61 patients suspected of relapse following definitive radiotherapy for lung cancer 31. Twenty-eight patients (45%) received SBRT alone, and the FLT and FDG SUV max values were higher in those who relapsed. A pilot study by Hiniker et al. evaluated FLT-PET in 10 patients treated with SBRT/hyperfractionated radiotherapy to the lung with equivocal FDG-PET for assessment of recurrence 30. FLT-PET accurately differentiated inflammatory changes from recurrence in 7 of 8 patients (87.5%). The FLT parameters – high SUV max and the ratio of SUV max of the lesion to SUV max of the mediastinal pool more than two was indicative of recurrence. In the present study, four out of 5 patients in the recurrence cohort had SUV max greater than two and ratio of the lesion to mediastinal SUV max more than two.
The role of FLT-PET in the diagnosis of lung cancer has been studied, and it shows high specificity, but low sensitivity compared to FDG-PET, making it attractive to differentiate malignant from benign lung nodules 26. The uptake of FLT is low compared to FDG at diagnosis 40. The baseline FLT SUV max may carry a prognostic value. Saga et al. showed that in 20 lung cancer patients treated with carbon ion radiotherapy, patients who developed recurrence or died during follow up had high pretreatment FLT uptake and those with FLT SUV max less than 3.7 had better progression-free survival 41. In the present study, the SUV max values were lower with FLT than FDG PET in the pretreatment cohort. No local recurrences were identified, and the prognosis was not assessed in this cohort.
The FLT-PET parameters have varied among the studies, with use of SUV max, SUV mean or SUV peak to assess the response or for prognosis 36. To evaluate recurrence, while Hiniker et al. used SUV max and ratio of SUV max to the mediastinal pool, Christensen evaluated various parameters like SUV max, SUV peak, PTV 80% and 50% 30,31. In the present study, we used SUV max, SUV mean, SUV peak, SUV50 and SUV95, and all were lower in fibrosis than the recurrence cohort. The disparity in PET variables and values reported across studies for PET could be due to inconsistencies in procedures (isotope injection and imaging time, fasting duration, different scanners, blood glucose concentration)42. There is a need for standardization of reporting of SUV values across institutions and adherence to guidelines 43-45.
PET images are affected by partial volume effects which are intensified in lung due to respiratory movement 46. This effect is significant for FLT-PET, where the signal to background ratio is lower compared to FDG-PET. In a study comparing 4D and non-gated FDG-PET, 4D PET defined moving tumors better and reduced blurring 47. We did not find any statistically significant difference in our FLT-PET SUV variables between non-gated and 4D gated FLT-PET both phase-matched and helical-gated. This finding could be due to low average tumor motion of this cohort and absence of selection of moving tumor (>1 cm). Comparing 4D with non-gated could be more helpful in tumors with greater respiratory motion and will be evaluated in the future. Driscoll et al found motion blur to be significant for SUV mean, SUV max and SUV peak for motion >1 cm and 4DPET reconstructions significantly reduced the blur 48. The use of phase matched AC for respiratory gated PET significantly improved precision over helical CT for hypoxia PET imaging.
The study's strengths are that this is one of few studies evaluating FLT-PET in a homogenous cohort of patients treated with SBRT in early lung cancer. We have explored various FLT parameters and assessed the effect of breathing. The limitations of the study are the small sample size in the recurrence cohort. The absence of longitudinal information across the cohorts led to inability to compare pre- and post-SBRT FLT parameters. We did not attempt to generate threshold values for FLT-PET SUV parameters due to low patient numbers. Larger multi-institutional validation studies are needed to ascertain the utility of FLT-PET to confirm the findings of the present study.
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