Abstract
PurposeTo assess tumor cell proliferation and repopulation during fractionated radiotherapy and investigate the spatial concordance of cell proliferation and repopulation according to the uptake of 3′-[18F]fluoro-3′-deoxythymidine ([18F]FLT).ProceduresMice bearing A549 xenograft tumors were assigned to five irradiated groups, including 3 fraction (f)/6 days (d), 6f/12d, 9f/18d, 12f/24d, and 18f/36d with 2 Gy/f irradiations performed every other day and one non-irradiated group. Serial [18F]FLT positron emission tomography (PET) scans were performed at different time points as the groups finished the radiotherapy. The maximum of standard uptake values (SUVmax) were measured to confirm the likely time of tumor repopulation. A layer-by-layer comparison between SUVmax of PET images and Ki-67 LI of pathology images, including the thresholds at which maximum overlap occurred between FLT-segmented areas and cell proliferation areas were conducted to evaluate the spatial correlation.ResultsThe SUVmax decreased in the 3f/6d group (P = 0.000) compared to the non-irradiated group, increased in the 6f/12d group and then gradually reduced with prolonged treatment. Proliferation changes in 6f/12d group on pathology images were also confirmed. Significant correlations were found between the SUVmax and Ki-67 LI in each in vitro tumor of cell proliferation group and accelerated repopulation group (both of the P < 0.001). Furthermore, the mean overlap region rates (ORRs) were 56.21 % and 57.82 % in the proliferation group and repopulation group, respectively. The data represented the preferable registration.Conclusions[18F]FLT PET is a promising imaging surrogate of tumor proliferative response to fractionated radiotherapy and may help make an adaptive radiation oncology treatment plan to realize radiotherapy dose painting.
Highlights
The prognosis of patients with locally advanced non-small cell lung cancer (NSCLC) remains poor despite the use of new radiation techniques and addition of chemotherapy to radiotherapy [1,2,3]
SUVmax was significantly increased later in the 6f/12d group when compared to the 3f/6d group (2.3327, P = 0.000); this difference was not significant when comparing to the nonirradiated group (P = 0.056)
Ki-67 LI in the 6f/12d group was significantly increased from 3f/6d group (82.33 %, P = 0.006), it decreased with prolonged treatment time in both12f/24d and 18f/36d groups
Summary
The prognosis of patients with locally advanced non-small cell lung cancer (NSCLC) remains poor despite the use of new radiation techniques and addition of chemotherapy to radiotherapy [1,2,3]. Poor overall survival with chemoradiotherapy is related to sufficient local tumor control despite distant metastases. Increasing the radiation dose may improve local control, but the risk of complications will limit the possibility of dose escalation. A more sophisticated approach may be to selectively increase the dose to treatment-resistant areas while maintaining the dose to other parts of the target volume instead of escalating the dose to the whole tumor, which is called dose painting [4]. This requires an imaging biomarker to determine more treatment-resistant sub-volumes that should receive a higher dose. Functional imaging can complement anatomic imaging modalities and provide biologic tumor information relevant to radiotherapy dose planning by selecting the appropriate PET tracer [5]
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