PK-PD modeling of individual lesion FDG-PET response to predict overall survival in patients with sunitinib-treated gastrointestinal stromal tumor.
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ABSTRACT:
SUBMITTER: Schindler E
PROVIDER: S-EPMC4846778 | biostudies-literature | 2016 Apr
REPOSITORIES: biostudies-literature
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PK-PD modeling of individual lesion FDG-PET response to predict overall survival in patients with sunitinib-treated gastrointestinal stromal tumor.
Schindler E E Amantea M A MA Karlsson M O MO Friberg L E LE
CPT: pharmacometrics & systems pharmacology 20160316 4
Pharmacometric models were developed to characterize the relationships between lesion-level tumor metabolic activity, as assessed by the maximum standardized uptake value (SUVmax) obtained on [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET), tumor size, and overall survival (OS) in 66 patients with gastrointestinal stromal tumor (GIST) treated with intermittent sunitinib. An indirect response model in which sunitinib stimulates tumor loss best described the typically rapid dec ...[more]
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Project description:BackgroundThis study aimed to evaluate the prognostic value of pretreatment 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in patients with localized primary gastrointestinal stromal tumors (GISTs) and to compare the predictive values of 18F-FDG PET/CT parameters with those of clinicopathological prognostic factors.MethodsSixty-two localized GIST patients who underwent staging with 18F-FDG PET/CT from January 2007 to December 2013 before surgery were retrospectively enrolled. A volume of interest with a standardized uptake value (SUV) threshold of 2.5 was used to determine the metabolic tumor volume (MTV) and total lesion glycolysis (TLG). These metabolic indices, along with the maximum SUV (SUVmax), were analyzed to evaluate recurrence-free survival (RFS). Other significant clinical and pathologic indices were also retrospectively reviewed for RFS analysis.ResultsPatients were followed up for a median of 42.0 months (range, 5.6-111.5). During the follow-up period, 13 patients (21.0%) experienced disease recurrence. In univariate analysis, tumor size (> 5 cm), mitotic count (> 5/high-power field), modified National Institutes of Health (NIH) consensus criteria, adjuvant imatinib treatment, SUVmax (≥ 7.04), MTV (≥ 50.76 cm3), and TLG (≥ 228.79 g) were significant prognostic factors affecting RFS (p < 0.05). In multivariate analysis, only MTV (hazard ratio, 17.69; 95% confidence interval [CI], 2.03-154.17, p = 0.009) and TLG (hazard ratio, 20.48; 95% CI, 2.19-191.16, p = 0.008) were independent prognostic factors for RFS. The 5-year RFS rates were 96.4% and 96.6% in patients with a low MTV and TLG and 27.3% and 23.6% in patients with a high MTV and TLG, respectively (p < 0.001).ConclusionMTV and TLG are independent prognostic factors for predicting recurrence in patients with localized primary GIST. Patients with a high MTV or TLG are at risk for poor prognosis and should be closely observed for disease recurrence.
| S-EPMC7844977 | biostudies-literature
Project description:Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. In advanced setting and after progression to imatinib, the multi-targeted receptor tyrosine kinase inhibitor sunitinib has clearly demonstrated a clinical benefit in terms of response rate and progression-free survival with an acceptable toxicity profile. The recommended schedule for sunitinib administration is 50 mg per day 4 weeks ON and 2 weeks OFF; however, potential alternative schedules are also reviewed in the present article. Several biomarkers have been explored to better select candidates for sunitinib therapy, such as the value of early changes in standardized uptake value assessed by positron emission tomography with 18F-fluorodeoxyglucose, circulating biomarkers, clinical biomarkers such as the appearance of arterial hypertension during treatment that correlates with better outcomes, and the GIST genotype. GISTs with KIT mutations at exon 9 and the so-called wild-type GISTs seem to better respond to sunitinib. Nonetheless, further investigation is required to confirm these findings as well as to understand the mechanisms of sunitinib resistance such as the development of new KIT mutations or conformational changes in KIT receptor.
| S-EPMC5171199 | biostudies-literature
Project description:PurposeThe starting dose of sunitinib in children with gastrointestinal stromal tumors (GIST) was extrapolated based on data in adults with GIST or solid tumors and children with solid tumors.MethodsIntegrated population pharmacokinetics (PK), PK/pharmacodynamics (PD), and exposure-response analyses using nonlinear mixed-effects modeling approaches were performed to extrapolate PK and PD of sunitinib in children with GIST at projected dose(s) with plasma drug exposures comparable to 50-mg/day in adults with GIST. The analysis datasets included PK/PD data in adults with GIST and adults and children with solid tumors. The effect of covariates on PK and safety/efficacy endpoints were explored.ResultsTwo-compartment models with lag time were successfully used to describe the PK of sunitinib and its active metabolite SU012662. PK/PD models were successfully built to describe key continuous safety and efficacy endpoints. The effect of age on sunitinib apparent clearance (CL/F) and body surface area on SU012662 CL/F was statistically significant (P ≤ 0.001): children who were younger or of smaller body size had lower CL/F; however, age and body size did not appear to negatively affect safety or efficacy response to plasma drug exposure.ConclusionBased on PK, safety, and efficacy trial simulations, a sunitinib starting dose of ~ 25 mg/m2/day was predicted to provide comparable plasma drug exposures in children with GIST as in adults with GIST treated with 50 mg/day. However, in the absence of a tumor type effect of sunitinib on CL/F in children, the projected equivalent dose for this population would be ~ 20 mg/m2/day.
| S-EPMC8026416 | biostudies-literature
Project description:IntroductionMetabolic brain network analysis based on graph theory using FDG PET imaging is potentially useful for investigating brain activity alternation due to metabolism changes in different stages of Alzheimer's disease (AD). Most studies on metabolic network construction have been based on group data. Here a novel approach in building an individual metabolic network was proposed to investigate individual metabolic network abnormalities.MethodFirst, a weighting matrix was calculated based on the interregional effect size difference of mean uptake between a single subject and average normal controls (NCs). Then the weighting matrix for a single subject was multiplied by a group-based connectivity matrix from an NC cohort. To study the performance of the proposed individual metabolic network, inter- and intra-hemispheric connectivity patterns in the groups of NC, sMCI (stable mild cognitive impairment), pMCI (progressive mild cognitive impairment), and AD using the proposed individual metabolic network were constructed and compared with those from the group-based results. The network parameters of global efficiency and clustering coefficient and the network density score (NDS) in the default-mode network (DMN) of generated individual metabolic networks were estimated and compared among the disease groups in AD.ResultsOur results show that the intra- and inter-hemispheric connectivity patterns estimated from our individual metabolic network are similar to those from the group-based method. In particular, the key patterns of occipital-parietal and occipital-temporal inter-regional connectivity deficits detected in the groupwise network study for differentiating different disease groups in AD were also found in the individual network. A reduction trend was observed for network parameters of global efficiency and clustering coefficient, and also for the NDS from NC, sMCI, pMCI, and AD. There was no significant difference between NC and sMCI for all network parameters.ConclusionWe proposed a novel method in constructing the individual metabolic network using a single-subject FDG PET image and a group-based NC connectivity matrix. The result has shown the effectiveness and feasibility of the proposed individual metabolic network in differentiating disease groups in AD. Future studies should include investigation of inter-individual variability and the correlation of individual network features to disease severities and clinical performance.
| S-EPMC7235322 | biostudies-literature
Project description:IntroductionMacrophagic myofasciitis (MMF) is an emerging condition with highly specific myopathological alterations. A peculiar spatial pattern of a cerebral glucose hypometabolism involving occipito-temporal cortex and cerebellum have been reported in patients with MMF; however, the full pattern is not systematically present in routine interpretation of scans, and with varying degrees of severity depending on the cognitive profile of patients. Aim was to generate and evaluate a support vector machine (SVM) procedure to classify patients between healthy or MMF 18F-FDG brain profiles.Methods18F-FDG PET brain images of 119 patients with MMF and 64 healthy subjects were retrospectively analyzed. The whole-population was divided into two groups; a training set (100 MMF, 44 healthy subjects) and a testing set (19 MMF, 20 healthy subjects). Dimensionality reduction was performed using a t-map from statistical parametric mapping (SPM) and a SVM with a linear kernel was trained on the training set. To evaluate the performance of the SVM classifier, values of sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV) and accuracy (Acc) were calculated.ResultsThe SPM12 analysis on the training set exhibited the already reported hypometabolism pattern involving occipito-temporal and fronto-parietal cortices, limbic system and cerebellum. The SVM procedure, based on the t-test mask generated from the training set, correctly classified MMF patients of the testing set with following Se, Sp, PPV, NPV and Acc: 89%, 85%, 85%, 89%, and 87%.ConclusionWe developed an original and individual approach including a SVM to classify patients between healthy or MMF metabolic brain profiles using 18F-FDG-PET. Machine learning algorithms are promising for computer-aided diagnosis but will need further validation in prospective cohorts.
| S-EPMC5509294 | biostudies-literature
Project description:The purpose of the study is to determine the efficacy of hepatic artery embolization (HAE) as a therapy for gastrointestinal stromal tumor (GIST) in patients who are refractory to imatinib and sunitinib.After institutional review board approval, a retrospective review revealed 11 patients with GIST metastatic to the liver who underwent 15 HAEs between February 2002 and May 2013. These patients were stratified into two groups according to the previous treatment: (a) those treated with HAE as second-line treatment after failing first-line imatinib (n?=?3) and (b) those treated with HAE as third-line therapy after failing first-line imatinib and second-line sunitinib (n?=?8). Initial therapeutic response, overall survival (OS), progression-free survival (PFS), and safety were evaluated.Initial therapeutic response rates at 3 months after HAE were 27.3 % (95 % confidence interval (CI), 6.0-61.0 %) by Response Evaluation Criteria in Solid Tumor (RECIST) version 1.0 and 45.5 % (95 % CI, 16.7-76.6 %) by modified RECIST (mRECIST). The median OS and PFS after HAE were 14.9 and 3.9 months in group A and 23.8 and 3.4 months in group B, respectively. No procedure-related mortality or major complication was observed.HAE is an effective and well-tolerated therapeutic option for GIST liver metastases. Although larger studies are necessary, HAE should be considered as an alternative or adjuvant to third-line or even second-line systemic treatment.
| S-EPMC5637522 | biostudies-literature
Project description:Positron emission tomography using 18F-Fluro-deoxy-glucose (18F-FDG) is a useful tool to detect regions of inflammation in patients. We utilized this imaging technique to investigate the kinetics of gastrointestinal recovery after radiation exposure and the role of bone marrow in the recovery process. Male Sprague-Dawley rats were either sham irradiated, irradiated with their upper half body shielded (UHBS) at a dose of 7.5 Gy, or whole body irradiated (WBI) with 4 or 7.5 Gy. Animals were imaged using 18F-FDG PET/CT at 5, 10 and 35 days post-radiation exposure. The gastrointestinal tract and bone marrow were analyzed for 18F-FDG uptake. Tissue was collected at all-time points for histological analysis. Following 7.5 Gy irradiation, there was a significant increase in inflammation in the gastrointestinal tract as indicated by the significantly higher 18F-FDG uptake compared to sham. UHBS animals had a significantly higher activity compared to 7.5 Gy WBI at 5 days post-exposure. Animals that received 4 Gy WBI did not show any significant increase in uptake compared to sham. Analysis of the bone marrow showed a significant decrease of uptake in the 7.5 Gy animals 5 days post-irradiation, albeit not observed in the 4 Gy group. Interestingly, as the metabolic activity of the gastrointestinal tract returned to sham levels in UHBS animals it was accompanied by an increase in metabolic activity in the bone marrow. At 35 days post-exposure both gastrointestinal tract and bone marrow 18F-FDG uptake returned to sham levels. 18F-FDG imaging is a tool that can be used to study the inflammatory response of the gastrointestinal tract and changes in bone marrow metabolism caused by radiation exposure. The recovery of the gastrointestinal tract coincides with an increase in bone marrow metabolism in partially shielded animals. These findings further demonstrate the relationship between the gastrointestinal syndrome and bone marrow recovery, and that this interaction can be studied using non-invasive imaging modalities.
| S-EPMC5214459 | biostudies-literature
Project description:PurposeMedical oncology needs early identification of patients that are not responding to systemic therapy. (18)F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) performed before and early during treatment has been proposed for this purpose. However, the best way to assess the change in FDG uptake between two scans has not been identified. We studied cutoff thresholds to identify responding tumours as a function of the method used to measure tumour uptake.MethodsThe study included 28 metastatic colorectal cancer (mCRC) patients who underwent 2 FDG PET/CT scans (baseline and at day 14 of the first course of polychemotherapy). For 78 tumour lesions, 4 standardized uptake value (SUV) indices were measured: maximum SUV (SUV(max)) and mean SUV in a region obtained using an isocontour (SUV(40 %)), with each of these SUV normalized either by the patient body weight (BW) or body surface area (BSA). The per cent change and absolute change in tumour uptake between the baseline and the early PET scans were measured based on these four indices. These changes were correlated to the RECIST 1.0-based response using contrast-enhanced CT at baseline and at 6-8 weeks on treatment.ResultsThe 78 tumours were classified as non-responding (NRL, n = 58) and responding lesions (RL, n = 20). Receiver-operating characteristic (ROC) curves characterizing the performance in NRL/RL classification using early FDG PET uptake had areas under the curve between 0.75 and 0.84, without significant difference between the indices. The cutoff threshold in FDG uptake per cent change to get a 95 % sensitivity of RL detection depended on the way uptake was measured: -14 % (specificity of 53 %) and -22 % (specificity of 64 %) for SUV(max) and SUV(40 %), respectively. Thresholds expressed as absolute SUV decrease instead of per cent change were less sensitive to the SUV definition: an SUV decline by 1.2 yielded a sensitivity of RL detection of 95 % for SUV(max) and SUV(40 %). For a given cutoff threshold, the sensitivity was the same whatever the normalization (by BSA or BW).ConclusionA 14 % drop of tumour FDG SUV(max), 22 % drop of SUV(40 %) or 1.2 drop of SUV(max) or SUV(mean) after one single course of polychemotherapy predicts objective response in mCRC lesions with a high sensitivity, potentially allowing the early identification of non-responding patients.
| S-EPMC3458195 | biostudies-literature
Project description:AimCombined therapy of EGFR TKI and VEGFR TKI may produce a greater therapeutic benefit and overcome EGFR TKI-induced resistance. However, a previous study shows that a combination of EGFR TKI erlotinib (ER) with VEGFR TKI sunitinib (SU) did not improve the overall survival in patients with non-small-cell lung cancer (NSCLC). In this study we examined the anticancer effect of ER, SU and their combination in the treatment of A549 human NSCLC xenograft mice, and conducted PK/PD modeling and simulations to optimize the dose regimen.MethodsER (20, 50 mg·kg(-1)·d(-1)) or SU (5, 10, 20 mg·kg(-1)·d(-1)) alone, or their combination were administered to BALB/c nude mice bearing A549 tumors for 22 days. The tumor size and body weight were recorded daily. The experimental data were used to develop PK/PD models describing the quantitative relationship between the plasma concentrations and tumor suppression in different dose regimens. The models were further evaluated and validated, and used to predict the efficacy of different combination regimens and to select the optimal regimen.ResultsThe in vivo anticancer efficacy of the combination groups was much stronger than that of either drug administered alone. A PK/PD model was developed with a combination index (?) of 4.4, revealing a strong synergistic effect between ER and SU. The model simulation predicted the tumor growth in different dosage regimens, and showed that the dose of SU played a decisive role in the combination treatment, and suggested that a lower dose of ER (?5 mg·kg(-1)·d(-1)) and adjusting the dose of SU might yield a better dosage regimen for clinical research.ConclusionThe experimental data and modeling confirm synergistic anticancer effect of ER and SU in the treatment of A549 xenograft mice. The optimal dosage regimen determined by the PK/PD modeling and simulation can be used in future preclinical study and provide a reference for clinical application.
| S-EPMC4933764 | biostudies-literature
Project description:Quantitative assessment of radio- and chemotherapy response with 18F-FDG whole-body PET has attracted increasing interest in recent years. In most published work, SUV has been used for this purpose. In the context of therapy response assessment, the reliability of lesion SUVs, notably their test-retest stability, thus becomes crucial. However, a recent study demonstrated substantial test-retest variability (TRV) in SUVs. The purpose of the present study was to investigate whether the tumor-to-blood SUV ratio (SUR) can improve TRV in tracer uptake. Methods: 73 patients with advanced non-small cell lung cancer from the prospective multicenter trials ACRIN 6678 (n = 34) and MK-0646-008 (n = 39) were included in this study. All patients underwent two 18F-FDG PET/CT investigations on two different days (time difference, 3.6 ± 2.1 d; range, 1-7 d) before therapy. For each patient, up to 7 tumor lesions were evaluated. For each lesion, SUVmax and SUVpeak were determined. Blood SUV was determined as the mean value of a 3-dimensional aortic region of interest that was delineated on the attenuation CT image and transferred to the PET image. SURs were computed as the ratio of tumor SUV to blood SUV and were uptake time-corrected to 75 min after injection. TRV was quantified as 1.96 multiplied by the root-mean-square deviation of the fractional paired differences in SUV and SUR. The combined effect of blood normalization and uptake time correction was inspected by considering RTRV (TRVSUR/TRVSUV), a ratio reflecting the reduction in the TRV in SUR relative to SUV. RTRV was correlated with the group-averaged-value difference (?) in CFmean (?CFmean) of the quantity ?CF = |CF - 1|, where CF is the numeric factor that converts individual ratios of paired SUVs into corresponding SURs. This correlation analysis was performed by successively increasing a threshold value ?CFmin and computing ?CFmean and RTRV for the remaining subgroup of patients/lesions with ?CF ? ?CFminResults: The group-averaged TRVSUV and TRVSUR were 32.1 and 29.0, respectively, which correspond to a reduction of variability in SUR by an RTRV factor of 0.9 in comparison to SUV. This rather marginal improvement can be understood to be a consequence of the atypically low intrasubject variability in blood SUV and uptake time and the accordingly small ?CF values in the investigated prospective study groups. In fact, subgroup analysis with increasing ?CFmin thresholds revealed a pronounced negative correlation (Spearman ? = -0.99, P < 0.001) between RTRV and ?CFmean, where RTRV ? 0.4 in the ?CFmin = 20% subgroup, corresponding to a more than 2-fold reduction of TRVSUR compared with TRVSUVConclusion: Variability in blood SUV and uptake time has been identified as a causal factor in the TRV in lesion SUV. Therefore, TRV in lesion uptake measurements can be reduced by replacing SUV with SUR as the uptake measure. The improvement becomes substantial for the level of variability in blood SUV and uptake time typically observed in the clinical context.
| S-EPMC5666644 | biostudies-literature