Preclinical imagingImpact of pre- and early per-treatment FDG-PET based dose-escalation on local tumour control in fractionated irradiated FaDu xenograft tumours

ObjectiveTo investigate local tumour control after dose-escalation based on [18F]2-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) obtained before and early during fractionated irradiation.Materials and methods85 mice bearing FaDu xenografts underwent FDG-PET twice: first immediately prior to the first 2-Gy fraction of irradiation (PET1_0) and second after 18°Gy (PET2_18). After these 9 fractions, animals were randomly allocated to: (1) continuation of 2-Gy fractions (cumulative dose of 60°Gy; n = 31), (2) dose-escalation with 3-Gy fractions (cumulative EQD2-dose 86.25°Gy [α/β-value: 10]; n = 25), or (3) with 4-Gy fractions (cumulative EQD2-dose 116°Gy; n = 29). The effects of SUVmax0°Gy, SUVmax18°Gy, and dose on local tumour control were analysed in two ways. First, the Cox proportional hazards model was used with two covariates: continuous SUVmax values and dose. Second, the Kaplan-Meier method was used, with tumours classified according to SUVmax greater than or less than (1) median maximum standardized uptake value (SUVmax) at PET1_0 and PET2_18, or (2) the cut-off value 2.5.ResultsThe multivariate Cox analysis revealed a significant negative association between higher SUVmax determined before start of treatment and local control (HR = 1.59, [95% CI 1.04, 2.42], p = 0.031), whereas higher dose had a significant positive effect (HR = 0.95, [0.93, 0.98], p < 0.001). In contrast, FDG uptake at 18 Gy did not correlate with local control (HR = 1.14, [0.53, 2.45], p = 0.73). Neither FDG uptake prior to irradiation nor at 18 Gy correlated with local control irrespective of the delivered dose (log-rank test) when using the median SUVmax values for stratification (SUVmax0 Gy: 60 Gy: p = 0.25, 86.25 Gy: p = 0.47, 116 Gy: p = 0.88 and SUVmax18 Gy: 60 Gy: p = 0.42, 86.25 Gy: p = 0.34, 116 Gy: p = 0.99). By contrast, stratifying the animals by the cut-off 2.5 at PET1_0 reveals a significant difference in local control for the 60 Gy group (p = 0.034), but not for the other dose groups. At PET2_18, no significant effect for any dose group was detected.ConclusionsThe multivariate Cox analysis revealed a significantly higher hazard of recurrence for mice with higher SUVmax determined before start of treatment. These results support the hypothesis that patients with high pre-therapeutic FDG uptake should be considered at increased risk of local failure and therefore as possible candidates for dose escalation strategies.