Olivier Couturier

Sequential Positron Emission Tomography Using [18F]Fluorodeoxyglucose for Monitoring Response to Chemotherapy in Metastatic Breast Cancer

Purpose: To evaluate the clinical value of positron emission tomography (PET) for monitoring chemotherapy in metastatic breast cancer. Experimental Design: Twenty patients with hormonorefractory or hormonoreceptor-negative multimetastatic breast cancer were prospectively included. PET studies were done at baseline, at day 21 after the first cycle and at day 21 after the third cycle of chemotherapy. Metabolic response was defined based on visual and various modes of standardized uptake value (SUV) analysis of sequential PET studies. Results: After one cycle, PET indicated a partial response in 12 patients, stable disease in 7 patients, and progressive disease in 1 patient, according to the visual analysis. After three cycles, PET showed a complete response in 5 patients, partial response in 11 patients, stable disease in 3 patients, and progressive disease in 1 patient. Seventy-five percent of the patients showing a metabolic response on visual analysis effectively responded to the treatment. The average SUV decreased on both the second and the third PET study, but only changes measured after three cycles of chemotherapy predicted the clinical response to chemotherapy and the overall survival. All methods for calculating the SUV (normalized for body weight, body surface area, or lean body mass) provided similar results. Conclusion: Semiquantitative analysis of [18F]fluorodeoxyglucose-PET studies done after three cycles of chemotherapy is useful for monitoring the response to chemotherapy in metastatic breast cancer.

Does 18fluoro‐fluorodeoxyglucose positron emission tomography improve recurrence detection in patients treated for head and neck squamous cell carcinoma with negative clinical follow‐up?

The aim of this study was to determine the benefits of 18fluoro‐fluorodeoxyglucose positron emission tomography (18F‐FDG PET) in the detection of head and neck squamous cell carcinoma (HNSCC) recurrence in patients with negative clinical follow‐up.

Gastric scintigraphy with a liquid-solid radiolabelled meal : performances of solid and liquid parameters

AimTo assess the clinical performance of parameters of liquid–solid gastric emptying (GE) scintigraphy. MethodsFifty-three controls and 476 patients underwent GE scintigraphy using a liquid–solid test meal (non-ulcer dyspepsia, n=180; gastro-oesophageal reflux disease, n=123; dyspepsia after anti-reflux surgery, n=29; diabetes mellitus, n=96; cystic fibrosis prior to heart–lung transplantation, n=48). Time–activity curves were fitted by a power exponential function and half-emptying times (T1/2) were computed. The lag phase (Tlag) and constant emptying (TRE) times of solid emptying were also calculated using a mathematical method (maximum slope tangent method). ResultsTRE and T1/2 of solids were higher in each subgroup of patients vs. controls (P=0.0001) and in cystic fibrosis patients vs. gastro-oesophageal reflux patients (P=0.0001). Tlag was significantly higher only in non-ulcer dyspepsia patients vs. controls (P=0.001). There was no significant difference for liquid parameters. Using the mean±1.96 SD of the solid and liquid T1/2 values obtained in controls, GE was normal (n=251; 53%), delayed (n=183; 38%), accelerated (n=33; 7%) or mixed (n=9; 2%). Delayed solid T1/2 was the most prominent alteration (n=189), and alterations of liquid GE alone were present in only 24 (5%) patients. A good correlation was found between solid T1/2 and TRE (r=0.88), but no correlation between Tlag and TRE, suggesting that these estimates represent independent phases of GE. In 26 patients, all GE parameters of solids and liquids were normal except Tlag (n=8) or TRE (n=18). The lack of significant differences between the different patient subgroups did not allow emptying profiles to be drawn according to patient pathology. ConclusionLiquid GE scintigraphy provided poor and unreliable information in terms of patient discrimination and the drawing of pathophysiological profiles of abnormal GE. Tlag and TRE may confirm GE alteration, especially when solid T1/2 values are at the superior limit of normality, and may improve the performance of GE scintigraphy, rather than using liquid parameters.

Limited screening with versus without (18)F-fluorodeoxyglucose PET/CT for occult malignancy in unprovoked venous thromboembolism: an open-label randomised controlled trial.

BACKGROUND Clear guidelines for the investigation of occult malignancy after unprovoked venous thromboembolism are not yet available. (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT could serve as a comprehensive screening strategy for occult malignancy in this context. We aimed to compare a screening strategy based on (18)F-FDG PET/CT with a limited screening strategy for detection of malignant disease in patients with unprovoked venous thromboembolism. METHODS In an open-label, multicentre, randomised study we enrolled patients from four French university hospitals. Patients aged 18 years or older, diagnosed with unprovoked venous thromboembolism (not provoked by a major inherited or acquired risk factor) were invited to participate. Patients were randomly assigned in a 1:1 ratio to a limited screening strategy (physical examination, usual laboratory tests, and basic radiographs) or a screening strategy consisting of the limited strategy plus an (18)F-FDG PET/CT scan. Randomisation was done with a dedicated central web-based randomisation system, in block sizes of six, stratified by centre, and concealed from the investigators. Patients and investigators were not masked to study group assignment. Patients were followed up for 2 years. The primary outcome was the proportion of patients with a cancer diagnosis in each group after the initial screening assessment. Analyses were conducted in modified intention-to-test and per-protocol populations. This trial is completed and registered with ClinicalTrials.gov, number NCT00964275. FINDINGS Between March 3, 2009, and Aug 18, 2012, we enrolled and randomly assigned 399 patients; five withdrew consent, leaving 197 in each group for the modified intention-to-test analysis. After initial screening assessment, cancer was diagnosed in 11 (5·6%) patients in the (18)F-FDG PET/CT group and four (2·0%) patients in the limited screening group (absolute risk difference 3·6%, 95% CI -0·4 to 7·9; p=0·07). At the initial screening assessment, seven (64%) of the 11 cancers diagnosed in the (18)F-FDG PET/CT group were early-stage compared with two of four cancers diagnosed in the limited screening group (p=1·00). One (0·5%) occult malignancy was detected in 186 patients who had negative initial screening in the (18)F-FDG PET/CT group, compared with nine (4·7%) in 193 patients in the limited screening group (absolute risk difference 4·1%, 95% CI 0·8 to 8·4, p=0·01). Overall, five (42%) of the 12 cancers diagnosed in the (18)F-FDG PET/CT group were advanced stage, compared with seven (54%) of the 13 cancers diagnosed in the limited screening group (p=0·70). 16 patients died during follow-up, eight (4·1%) in each group. Two (1·0%) patients in the (18)F-FDG PET/CT group and five (2·5%) in the limited screening group had cancer-related deaths. INTERPRETATION A strategy including limited screening and a (18)F-FDG PET/CT was not associated with a significantly higher rate of cancer diagnosis after unprovoked venous thromboembolism. The risk of subsequent cancer diagnosis was, however, lower in patients who had negative initial screening that included (18)F-FDG PET/CT than in patients who had negative initial limited screening. Whether or not (18)F-FDG PET/CT might be useful in a more selected population of patients with a high risk of cancer remains to be determined. FUNDING Programme Hospitalier de Recherche Clinique (French Department of Health).

Lipid nanocapsules loaded with rhenium-188 reduce tumor progression in a rat hepatocellular carcinoma model.

Background Due to their nanometric scale (50 nm) along with their biomimetic properties, lipid nanocapsules loaded with Rhenium-188 (LNC188Re-SSS) constitute a promising radiopharmaceutical carrier for hepatocellular carcinoma treatment as its size may improve tumor penetration in comparison with microspheres devices. This study was conducted to confirm the feasibility and to assess the efficacy of internal radiation with LNC188Re-SSS in a chemically induced hepatocellular carcinoma rat model. Methodology/Principal Findings Animals were treated with an injection of LNC188Re-SSS (80 MBq or 120 MBq). The treated animals (80 MBq, n = 12; 120 MBq, n = 11) were compared with sham (n = 12), blank LNC (n = 7) and 188Re-perrhenate (n = 4) animals. The evaluation criteria included rat survival, tumor volume assessment, and vascular endothelial growth factor quantification. Following treatment with LNC188Re-SSS (80 MBq) therapeutic efficiency was demonstrated by an increase in the median survival from 54 to 107% compared with control groups with up to 7 long-term survivors in the LNC188Re-SSS group. Decreased vascular endothelial growth factor expression in the treated rats could indicate alterations in the angiogenesis process. Conclusions/Significance Overall, these results demonstrate that internal radiation with LNC188Re-SSS is a promising new strategy for hepatocellular carcinoma treatment.

Immuno-PET Using Anticarcinoembryonic Antigen Bispecific Antibody and 68Ga-Labeled Peptide in Metastatic Medullary Thyroid Carcinoma: Clinical Optimization of the Pretargeting Parameters in a First-in-Human Trial

Earlier clinical studies reported a high sensitivity of pretargeted immunoscintigraphy using murine or chimeric anticarcinoembryonic antigen (CEA) bispecific antibody (BsMAb) and peptides labeled with 111In or 131I in medullary thyroid carcinoma (MTC). Preclinical studies showed that new-generation humanized recombinant anti-CEA × antihistamine-succinyl-glycine (HSG) trivalent BsMAb TF2 and radiolabeled HSG peptide (IMP288) present good features for PET. This study aimed at optimizing molar doses and pretargeting interval of TF2 and 68Ga-labeled IMP288 for immuno-PET in relapsed MTC patients with calcitonin serum levels greater than 150 pg/mL. Methods: Five cohorts (C1–C5) of 3 patients received variable molar doses of TF2 and approximately 150 MBq of 68Ga-IMP288 after different pretargeting time intervals (C1: 120 nmol TF2, 6 nmol IMP288, 24 h; C2: 120 nmol TF2, 6 nmol IMP288, 30 h; C3: 120 nmol TF2, 6 nmol IMP288, 42 h; C4: 120 nmol TF2, 3 nmol IMP288, 30 h; and C5: 60 nmol TF2, 3 nmol IMP288, 30 h). TF2 and 68Ga-IMP288 pharmacokinetics were monitored. Whole-body PET was recorded 60 and 120 min after 68Ga-IMP288 injection. Tumor maximal SUV (T-SUVmax) and T-SUVmax–to–mediastinum blood-pool (MBP) SUVmean ratios (T/MBP) were determined. Results: In C1, T-SUVmax and T/MBP ranged from 4.09 to 8.93 and 1.39 to 3.72 at 60 min and 5.14 to 11.25 and 2.73 to 5.38 at 120 min, respectively. Because of the high MBP, the delay was increased to 30 h in C2, increasing T-SUVmax and T/MBP. Further increasing the delay to 42 h in C3 decreased T-SUVmax and T/MBP, showing that 30 h was the most favorable delay. In C4, the TF2-to-peptide mole ratio was increased to 40 (delay 30 h), resulting in high T-SUVmax but with higher MBP than in C2. In C5, the molar dose of TF2 was reduced, resulting in lower imaging performance. Pharmacokinetics demonstrated a fast TF2 clearance and a clear relationship between blood activity clearance and the ratio between the molar amount of injected peptide to the molar amount of circulating TF2 at the time of peptide injection. Conclusion: High tumor uptake and contrast can be obtained with pretargeted anti-CEA immuno-PET in relapsed MTC patients, especially using optimized pretargeting parameters: a BsMAb-to-peptide mole ratio of 20 and 30 h pretargeting delay.

Calibration Test of PET Scanners in a Multi-Centre Clinical Trial on Breast Cancer Therapy Monitoring Using 18F-FLT

A multi-centre trial using PET requires the analysis of images acquired on different systems We designed a multi-centre trial to estimate the value of 18F-FLT-PET to predict response to neoadjuvant chemotherapy in patients with newly diagnosed breast cancer. A calibration check of each PET-CT and of its peripheral devices was performed to evaluate the reliability of the results. Material and Methods 11 centres were investigated. Dose calibrators were assessed by repeated measurements of a 68Ge certified source. The differences between the clocks associated with the dose calibrators and inherent to the PET systems were registered. The calibration of PET-CT was assessed with an homogeneous cylindrical phantom by comparing the activities per unit of volume calculated from the dose calibrator measurements with that measured on 15 Regions of Interest (ROIs) drawn on 15 consecutive slices of reconstructed filtered back-projection (FBP) images. Both repeatability of activity concentration based upon the 15 ROIs (ANOVA-test) and its accuracy were evaluated. Results There was no significant difference for dose calibrator measurements (median of difference −0.04%; min = −4.65%; max = +5.63%). Mismatches between the clocks were less than 2 min in all sites and thus did not require any correction, regarding the half life of 18F. For all the PET systems, ANOVA revealed no significant difference between the activity concentrations estimated from the 15 ROIs (median of difference −0.69%; min = −9.97%; max = +9.60%). Conclusion No major difference between the 11 centres with respect to calibration and cross-calibration was observed. The reliability of our 18F-FLT multi-centre clinical trial was therefore confirmed from the physical point of view. This type of procedure may be useful for any clinical trial involving different PET systems.

Unusual uptake of 18FDG by a hepatic adenoma.

Hepatic adenoma is a rare, benign tumor (with potential for malignant degeneration) and its diagnosis is difficult because its presentation is highly variable in medical imaging, particularly with MRI. In such cases, the use of a hepatic biopsy is usually recommended. (18)FDG-PET/CT provides a very significant predictive value for malignant hepatic lesions. In addition, the occurrence of an (18)FDG-avid benign tumor is a rare event. We hereby present the case of a patient with advanced breast cancer for whom an (18)FDG-PET/CT showed a focal hepatic uptake. A subsequent biopsy provided a diagnosis of a hepatic adenoma.

Pharmacokinetics and Dosimetry Studies for Optimization of Pretargeted Radioimmunotherapy in CEA-Expressing Advanced Lung Cancer Patients

Objectives A phase I pretargeted radioimmunotherapy trial (EudractCT 200800603096) was designed in patients with metastatic lung cancer expressing carcinoembryonic antigen (CEA) to optimize bispecific antibody and labeled peptide doses, as well as the delay between their injections. Methods Three cohorts of three patients received the anti-CEA × anti-histamine-succinyl-glycine (HSG)-humanized trivalent bispecific antibody (TF2) and the IMP288 bivalent HSG peptide. Patients underwent a pretherapeutic imaging session S1 (44 or 88 nmol/m2 of TF2 followed by 4.4 nmol/m2, 185 MBq, of 111In-labeled IMP288) and, 1–2 weeks later, a therapy session S2 (240 or 480 nmol/m2 of TF2 followed by 24 nmol/m2, 1.1 GBq/m2, of 177Lu-labeled IMP288). The pretargeting delay was 24 or 48 h. The dose schedule was defined based on preclinical TF2 pharmacokinetic (PK) studies, on our previous clinical data using the previous anti-CEA-pretargeting system, and on clinical results observed in the first patients injected using the same system in Netherlands. Results TF2 PK was represented by a two-compartment model in which the central compartment volume (Vc) was linearly dependent on the patient’s surface area. PK was remarkably similar, with a clearance of 0.33 ± 0.03 L/h/m2. 111In- and 177Lu-IMP288 PK was also well represented by a two-compartment model. IMP288 PK was faster (clearance 1.4–3.3 L/h). The Vc was proportional to body surface area, and IMP288 clearance depended on the molar ratio of injected IMP288 to circulating TF2 at the time of IMP288 injection. Modeling of image quantification confirmed the dependence of IMP288 kinetics on circulating TF2, but tumor activity PK was variable. Organ-absorbed doses were not significantly different in the three cohorts, but the tumor dose was significantly higher with the higher molar doses of TF2 (p < 0.002). S1 imaging predicted absorbed doses calculated in S2. Conclusion The best dosing parameters corresponded to the shorter pretargeting delay and to the highest TF2 molar doses. S1 imaging session accurately predicted PK as well as absorbed doses of S2, thus potentially allowing for patient selection and dose optimization. Trial Registration ClinicalTrials.gov NCT01221675 (EudractCT 200800603096).

Comparison of gastric emptying scintigraphy based on the geometric mean of the gastric proportion of the abdominal radioactivity or on the geometric mean of the intragastric radioactivity

PurposeUsing gastric emptying scintigraphy the gastric retention rate is commonly calculated within a gastric region of interest (intragastric method). This technique may have significant limitations when left oblique anterior views are acquired, due in part to attenuation resulting from intragastric redistribution. To minimize these drawbacks, it was proposed to express the intragastric content as a percentage of the abdominal radioactivity (abdominal method). Our goal was to compare these two methods when anterior–posterior scanning is used. MethodsAntero-posterior scintigraphic data of 272 consecutive patients were analysed by both methods. Retention rates were obtained by both observation and calculation by power exponential fit. Gastric emptying parameters (half-emptying time of solids (T50,S) and liquids (T50,L), lag phase (Tlag) time and real emptying time (TRE)), and quality of fit were also computed and compared. ResultsFor solids, the intragastric method resulted in weakly higher experimental retention rates, whereas retention rates were quite similar for liquids. Differences between experimental and calculated retention rates were smaller for abdominal method, for both liquids and solids. As a result, values for the quality of fit were higher for the abdominal method. Significant differences were observed only for calculated T50,S (122±46 min vs. 124±48 min, mean difference 2±2 min, P<0.00001) and TRE (163±64 min vs. 168±68 min, mean difference 4.5±3.8 min, P<0.05), respectively, for the abdominal and the intragastric methods. However, the Bland–Altman statistical method revealed good agreements (<5% outliers). ConclusionIntragastric and abdominal methods can be used indifferently to treat antero-posterior data of gastric scintigraphy.