Impact of different standardized uptake value measures on PET-based quantification of treatment response.

UNLABELLED: PET-based treatment response studies typically measure the change in the standardized uptake value (SUV) to quantify response. The relative changes of different SUV measures, such as maximum, peak, mean, or total SUVs (SUV(max), SUV(peak), SUV(mean), or SUV(total), respectively), are used across the literature to classify patients into response categories, with quantitative thresholds separating the different categories. We investigated the impact of different SUV measures on the quantification and classification of PET-based treatment response. METHODS: Sixteen patients with solid malignancies were treated with a multitargeted receptor tyrosine kinase inhibitor, resulting in a variety of responses. Using the cellular proliferation marker 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT), we acquired whole-body PET/CT scans at baseline, during treatment, and after treatment. The highest (18)F-FLT uptake lesions (~2/patient) were segmented on PET images. Tumor PET response was assessed via the relative change in SUV(max), SUV(peak), SUV(mean), and SUV(total), thereby yielding 4 different responses for each tumor at mid- and posttreatment. For each SUV measure, a population average PET response was determined over all tumors. Standard deviation (SD) and range were used to quantify variation of PET response within individual tumors and population averages. RESULTS: Different SUV measures resulted in substantial variation of individual tumor PET response assessments (average SD, 20%; average range, 40%). The most extreme variation between 4 PET response measures was 90% in individual tumors. Classification of tumor PET response depended strongly on the SUV measure, because different SUV measures resulted in conflicting categorizations of PET response (ambiguous treatment response assessment) in more than 80% of tumors. Variation of the population average PET response was considerably smaller (average SD, 7%; average range, 16%), and this variation was not statistically significant. Differences in tumor PET response were greatest between SUV(mean) and SUV(total) and smallest between SUV(max) and SUV(peak). Variations of tumor PET response at midtreatment and posttreatment were similar. CONCLUSION: Quantification and classification of PET-based treatment response in individual patients were strongly affected by the SUV measure used to assess response. This substantial uncertainty in individual patient PET response was present despite the concurrent robustness of the population average PET response. Given the ambiguity of individual patient PET responses, selection of PET-based treatment response measures and their associated thresholds should be carefully optimized.

Impact of the definition of peak standardized uptake value on quantification of treatment response.

UNLABELLED: PET-based treatment response assessment typically measures the change in maximum standardized uptake value (SUV(max)), which is adversely affected by noise. Peak SUV (SUV(peak)) has been recommended as a more robust alternative, but its associated region of interest (ROI(peak)) is not uniquely defined. We investigated the impact of different ROI(peak) definitions on quantification of SUV(peak) and tumor response. METHODS: Seventeen patients with solid malignancies were treated with a multitargeted receptor tyrosine kinase inhibitor resulting in a variety of responses. Using the cellular proliferation marker 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT), whole-body PET/CT scans were acquired at baseline and during treatment. (18)F-FLT-avid lesions (∼2/patient) were segmented on PET images, and tumor response was assessed via the relative change in SUV(peak). For each tumor, 24 different SUV(peaks) were determined by changing ROI(peak) shape (circles vs. spheres), size (7.5-20 mm), and location (centered on SUV(max) vs. placed in highest-uptake region), encompassing different definitions from the literature. Within each tumor, variations in the 24 SUV(peaks) and tumor responses were measured using coefficient of variation (CV), standardized deviation (SD), and range. For each ROI(peak) definition, a population average SUV(peak) and tumor response were determined over all tumors. RESULTS: A substantial variation in both SUV(peak) and tumor response resulted from changing the ROI(peak) definition. The variable ROI(peak) definition led to an intratumor SUV(peak) variation ranging from 49% above to 46% below the mean (CV, 17%) and an intratumor SUV(peak) response variation ranging from 49% above to 35% below the mean (SD, 9%). The variable ROI(peak) definition led to a population average SUV(peak) variation ranging from 24% above to 28% below the mean (CV, 14%) and a population average SUV(peak) response variation ranging from only 3% above to 3% below the mean (SD, 2%). The size of ROI(peak) caused more variation in intratumor response than did the location or shape of ROI(peak). Population average tumor response was independent of size, shape, and location of ROI(peak). CONCLUSION: Quantification of individual tumor response using SUV(peak) is highly sensitive to the ROI(peak) definition, which can significantly affect the use of SUV(peak) for assessment of treatment response. Clinical trials are necessary to compare the efficacy of SUV(peak) and SUV(max) for quantification of response to therapy.

Pharmacodynamic study using FLT PET/CT in patients with renal cell cancer and other solid malignancies treated with sunitinib malate.

PURPOSE: To characterize proliferative changes in tumors during the sunitinib malate exposure/withdrawal using 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) positron emission tomography (PET)/computed tomography (CT) imaging. PATIENTS AND METHODS: Patients with advanced solid malignancies and no prior anti-VEGF exposure were enrolled. All patients had metastatic lesions amenable to FLT PET/CT imaging. Sunitinib was initiated at the standard dose of 50 mg p.o. daily either on a 4/2 or 2/1 schedule. FLT PET/CT scans were obtained at baseline, during sunitinib exposure, and after sunitinib withdrawal within cycle #1 of therapy. VEGF levels and sunitinib pharmacokinetic (PK) data were assessed at the same time points. RESULTS: Sixteen patients (8 patients on 4/2 schedule and 8 patients on 2/1 schedule) completed all three planned FLT PET/CT scans and were evaluable for pharmacodynamic imaging evaluation. During sunitinib withdrawal (change from scans 2 to 3), median FLT PET standardized uptake value (SUV(mean)) increased +15% (range: -14% to 277%; P = 0.047) for the 4/2 schedule and +19% (range: -5.3% to 200%; P = 0.047) for the 2/1 schedule. Sunitinib PK and VEGF ligand levels increased during sunitinib exposure and returned toward baseline during the treatment withdrawal. CONCLUSIONS: The increase of cellular proliferation during sunitinib withdrawal in patients with renal cell carcinoma and other solid malignancies is consistent with a VEGF receptor (VEGFR) tyrosine kinase inhibitor (TKI) withdrawal flare. Univariate and multivariate analysis suggest that plasma VEGF is associated with this flare, with an exploratory analysis implying that patients who experience less clinical benefit have a larger withdrawal flare. This might suggest that patients with a robust compensatory response to VEGFR TKI therapy experience early "angiogenic escape."

Early assessment of treatment response in patients with AML using [(18)F]FLT PET imaging.

Assessment of treatment response in acute leukemia is routinely performed after therapy via bone marrow biopsy. We investigated the use of positron emission tomography (PET) for early assessment of treatment response in patients with acute myeloid leukemia (AML), using the proliferation marker 3'-deoxy-3'-[(18)F]fluoro-l-thymidine (FLT). Eight adult AML patients receiving induction chemotherapy underwent whole-body FLT PET/CT scans acquired at different time points during therapy. Patients who entered complete remission (CR) exhibited significantly lower FLT uptake in bone marrow than those patients with resistant disease (RD). In bone marrow, mean and maximum standardized uptake values were 0.8, 3.6 for CR and 1.6, 11.4 for RD, p<0.001. FLT PET results for CR and RD patients were independent of assessment time point, suggesting that FLT PET scans acquired as early as 2 days after chemotherapy initiation may be predictive of clinical response. This pilot study suggests that FLT PET imaging during induction chemotherapy may serve as an early biomarker of treatment response in AML.

Assessment of GS-9219 in a pet dog model of non-Hodgkin's lymphoma.

PURPOSE: To assess, in dogs with naturally occurring non-Hodgkin's lymphoma, pharmacokinetics, safety, and activity of GS-9219, a prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyl) guanine (PMEG), which delivers PMEG and its phosphorylated metabolites to lymphoid cells with preferential cytotoxicity in cells with a high proliferation index such as lymphoid malignancies. EXPERIMENTAL DESIGN: To generate proof-of-concept, a phase I/II trial was conducted in pet dogs (n = 38) with naturally occurring non-Hodgkin's lymphoma using different dose schedules of GS-9219. A subset of dogs was further evaluated with 3'-deoxy-3'-(18)F-fluorothymidine positron emission tomography/computed tomography imaging before and after treatment. RESULTS: The prodrug had a short plasma half-life but yielded high and prolonged intracellular levels of the cytotoxic metabolite PMEG diphosphate in peripheral blood mononuclear cells in the absence of detectable plasma PMEG. Dose-limiting toxicities were generally manageable and reversible and included dermatopathy, neutropenia, and gastrointestinal signs. Antitumor responses were observed in 79% of dogs and occurred in previously untreated dogs and dogs with chemotherapy-refractory non-Hodgkin's lymphoma. The median remission durations observed compare favorably with other monotherapies in dogs with non-Hodgkin's lymphoma. High 3'-deoxy-3'-(18)F-fluorothymidine uptake noted in lymphoid tissues before treatment decreased significantly after treatment (P = 0.016). CONCLUSIONS: GS-9219 was generally well tolerated and showed significant activity against spontaneous non-Hodgkin's lymphoma as modeled in pet dogs and, as such, supports clinical evaluation in humans.