Thomas Carlier

Cancer radioimmunotherapy with alpha-emitting nuclides

In lymphoid malignancies and in certain solid cancers such as medullary thyroid carcinoma, somewhat mixed success has been achieved when applying radioimmunotherapy (RIT) with β-emitters for the treatment of refractory cases. The development of novel RIT with α-emitters has created new opportunities and theoretical advantages due to the high linear energy transfer (LET) and the short path length in biological tissue of α-particles. These physical properties offer the prospect of achieving selective tumoural cell killing. Thus, RIT with α-emitters appears particularly suited for the elimination of circulating single cells or cell clusters or for the treatment of micrometastases at an early stage. However, to avoid non-specific irradiation of healthy tissues, it is necessary to identify accessible tumoural targets easily and rapidly. For this purpose, a small number of α-emitters have been investigated, among which only a few have been used for in vivo preclinical studies. Another problem is the availability and cost of these radionuclides; for instance, the low cost and the development of a reliable actinium-225/bismuth-213 generator were probably determining elements in the choice of bismuth-213 in the only human trial of RIT with an α-emitter. This article reviews the literature concerning monoclonal antibodies radiolabelled with α-emitters that have been developed for possible RIT in cancer patients. The principal radio-immunoconjugates are considered, starting with physical and chemical properties of α-emitters, their mode of production, the possibilities and difficulties of labelling, in vitro studies and finally, when available, in vivo preclinical and clinical studies.

Thoracic Staging in Lung Cancer: Prospective Comparison of 18F-FDG PET/MR Imaging and 18F-FDG PET/CT

Therapeutic decisions in non–small cell lung cancer (NSCLC) patients depend on the tumor stage. PET/CT with 18F-FDG is widely accepted as the diagnostic standard of care. The purpose of this study was to compare a dedicated pulmonary 18F-FDG PET/MR imaging protocol with 18F-FDG PET/CT for primary and locoregional lymph node staging in NSCLC patients using histopathology as the reference. Methods: Twenty-two patients (12 men, 10 women; mean age ± SD, 65.1 ± 9.1 y) with histopathologically confirmed NSCLC underwent 18F-FDG PET/CT, followed by 18F-FDG PET/MR imaging, including a dedicated pulmonary MR imaging protocol. T and N staging according to the seventh edition of the American Joint Committee on Cancer staging manual was performed by 2 readers in separate sessions for 18F-FDG PET/CT and PET/MR imaging, respectively. Results from histopathology were used as the standard of reference. The mean and maximum standardized uptake value (SUVmean and SUVmax, respectively) and maximum diameter of the primary tumor was measured and compared in 18F-FDG PET/CT and PET/MR imaging. Results: PET/MR imaging and 18F-FDG PET/CT agreed on T stages in 16 of 16 of patients (100%). All patients were correctly staged by 18F-FDG PET/CT and PET/MR (100%), compared with histopathology. There was no statistically significant difference between 18F-FDG PET/CT and 18F-FDG PET/MR imaging for lymph node metastases detection (P = 0.48). For definition of thoracic N stages, PET/MR imaging and 18F-FDG PET/CT were concordant in 20 of 22 patients (91%). PET/MR imaging determined the N stage correctly in 20 of 22 patients (91%). 18F-FDG PET/CT determined the N stage correctly in 18 of 22 patients (82%). The mean differences for SUVmean and SUVmax of NSCLC in 18F-FDG PET/MR imaging and 18F-FDG PET/CT were 0.21 and −5.06. These differences were not statistically significant (P > 0.05). The SUVmean and SUVmax measurements derived from 18F-FDG PET/CT and 18F-FDG PET/MR imaging exhibited a high correlation (R = 0.74 and 0.86, respectively; P < 0.0001). Size measurements showed an excellent correlation between 18F-FDG PET/MR imaging and 18F-FDG PET/CT (R = 0.99; P < 0.0001). The lower and upper limits of agreement between 18F-FDG PET/CT and 18F-FDG PET/MR imaging using Bland–Altman analysis were −2.34 to 3.89 for SUVmean, −7.42 to 4.40 for SUVmax, and −0.59 to 0.83 for the tumor size, respectively. Conclusion: 18F-FDG PET/MR imaging using a dedicated pulmonary MR imaging protocol, compared with 18F-FDG PET/CT, does not provide advantages in thoracic staging in NSCLC patients.

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.

¹⁸F-FDG-PET/CT in initial staging and assessment of early response to chemotherapy of pediatric rhabdomyosarcomas.

PurposeThe objective of this retrospective study was to compare positron emission tomography/computed tomography using fluorine-18-fluorodeoxyglucose (18F-FDG-PET/CT) and conventional imaging modalities (CIM) in initial staging and early assessment of response to chemotherapy in children and young adults treated for rhabdomyosarcoma (RMS). Patients and methodsAt initial staging, 23 patients (9 months to 21 years) with histologically proven RMS underwent 18F-FDG-PET/CT in addition to CIM (MRI of the primary site, whole-body CT, and bone scintigraphy). After three courses of chemotherapy, 13 patients underwent 18F-FDG-PET/CT in addition to CIM. RECIST criteria and visual analysis of 18F-FDG uptake were used for assessment of response. The standard of reference was determined by an interdisciplinary tumor board on the basis of imaging material, histopathology, and follow-up data (median=5 years). Results18F-FDG-PET/CT sensitivity was superior to that of CIM for determination of lymph node involvement (100 vs. 75%) and detection of metastases (100 vs. 66%). 18F-FDG-PET/CT results changed therapeutic management in 13% of cases. After three courses of chemotherapy 18F-FDG-PET/CT was able to detect 92% of objective responses compared with 84% by CIM. The rate of complete response was 69% with 18F-FDG-PET/CT compared with 8% with CIM. ConclusionThis study confirms that 18F-FDG-PET/CT reveals important additional information at initial staging of pediatric RMS, which suggests a superior prognostic value of 18F-FDG-PET/CT in early response to chemotherapy assessment.

Tumor Immunotargeting Using Innovative Radionuclides

This paper reviews some aspects and recent developments in the use of antibodies to target radionuclides for tumor imaging and therapy. While radiolabeled antibodies have been considered for many years in this context, only a few have reached the level of routine clinical use. However, alternative radionuclides, with more appropriate physical properties, such as lutetium-177 or copper-67, as well as alpha-emitting radionuclides, including astatine-211, bismuth-213, actinium-225, and others are currently reviving hopes in cancer treatments, both in hematological diseases and solid tumors. At the same time, PET imaging, with short-lived radionuclides, such as gallium-68, fluorine-18 or copper-64, or long half-life ones, particularly iodine-124 and zirconium-89 now offers new perspectives in immuno-specific phenotype tumor imaging. New antibody analogues and pretargeting strategies have also considerably improved the performances of tumor immunotargeting and completely renewed the interest in these approaches for imaging and therapy by providing theranostics, companion diagnostics and news tools to make personalized medicine a reality.

90Y -PET imaging: Exploring limitations and accuracy under conditions of low counts and high random fraction

PURPOSE (90)Y -positron emission tomography (PET) imaging is becoming a recognized modality for postinfusion quantitative assessment following radioembolization therapy. However, the extremely low counts and high random fraction associated with (90)Y -PET may significantly impair both qualitative and quantitative results. The aim of this work was to study image quality and noise level in relation to the quantification and bias performance of two types of Siemens PET scanners when imaging (90)Y and to compare experimental results with clinical data from two types of commercially available (90)Y microspheres. METHODS Data were acquired on both Siemens Biograph TruePoint [non-time-of-flight (TOF)] and Biograph microcomputed tomography (mCT) (TOF) PET/CT scanners. The study was conducted in three phases. The first aimed to assess quantification and bias for different reconstruction methods according to random fraction and number of true counts in the scan. The NEMA 1994 PET phantom was filled with water with one cylindrical insert left empty (air) and the other filled with a solution of (90)Y . The phantom was scanned for 60 min in the PET/CT scanner every one or two days. The second phase used the NEMA 2001 PET phantom to derive noise and image quality metrics. The spheres and the background were filled with a (90)Y solution in an 8:1 contrast ratio and four 30 min acquisitions were performed over a one week period. Finally, 32 patient data (8 treated with Therasphere(®) and 24 with SIR-Spheres(®)) were retrospectively reconstructed and activity in the whole field of view and the liver was compared to theoretical injected activity. RESULTS The contribution of both bremsstrahlung and LSO trues was found to be negligible, allowing data to be decay corrected to obtain correct quantification. In general, the recovered activity for all reconstruction methods was stable over the range studied, with a small bias appearing at extremely high random fraction and low counts for iterative algorithms. Point spread function (PSF) correction and TOF reconstruction in general reduce background variability and noise and increase recovered concentration. Results for patient data indicated a good correlation between the expected and PET reconstructed activities. A linear relationship between the expected and the measured activities in the organ of interest was observed for all reconstruction method used: a linearity coefficient of 0.89 ± 0.05 for the Biograph mCT and 0.81 ± 0.05 for the Biograph TruePoint. CONCLUSIONS Due to the low counts and high random fraction, accurate image quantification of (90)Y during selective internal radionuclide therapy is affected by random coincidence estimation, scatter correction, and any positivity constraint of the algorithm. Nevertheless, phantom and patient studies showed that the impact of number of true and random coincidences on quantitative results was found to be limited as long as ordinary Poisson ordered subsets expectation maximization reconstruction algorithms with random smoothing are used. Adding PSF correction and TOF information to the reconstruction greatly improves the image quality in terms of bias, variability, noise reduction, and detectability. On the patient studies, the total activity in the field of view is in general accurately measured by Biograph mCT and slightly overestimated by the Biograph TruePoint.

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.

State-of-the-art and recent advances in quantification for therapeutic follow-up in oncology using PET

18F-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography (PET) is an important tool in oncology. Its use has greatly progressed from initial diagnosis to staging and patient monitoring. The information derived from 18F-FDG-PET allowed the development of a wide range of PET quantitative analysis techniques ranging from simple semi-quantitative methods like the standardized uptake value (SUV) to “high order metrics” that require a segmentation step and additional image processing. In this review, these methods are discussed, focusing particularly on the available methodologies that can be used in clinical trials as well as their current applications in international consensus for PET interpretation in lymphoma and solid tumors.

Differences in the Biologic Activity of 2 Novel MEK Inhibitors Revealed by 18F-FDG PET: Analysis of Imaging Data from 2 Phase I Trials

Two mitogen-activated protein kinase kinase (MAPK2, also known as MEK) inhibitors were assessed with 18F-FDG PET in separate phase I clinical studies, clearly illustrating the potential of metabolic imaging for dose, dosing regimen, and compound selection in early-phase trials and utility for predicting nonresponding patients. Methods: 18F-FDG PET data were collected during 2 independent, phase I, dose-escalation trials of 2 novel MEK inhibitors (RO5126766 and RO4987655). PET acquisition procedures were standardized between the 2 trials, and PET images were analyzed centrally. Imaging was performed at baseline; at cycle 1, day 15; and at cycle 3, day 1. A 10-mm-diameter region of interest was defined for up to 5 lesions, and peak standardized uptake values were determined for each lesion. The relationship between PET response and pharmacokinetic factors (dose and exposure), inhibition of extracellular-signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells, and anatomic tumor response as measured by Response Evaluation Criteria in Solid Tumors was investigated for both compounds. Results: Seventy-six patients underwent PET, and 205 individual PET scans were analyzed. Strong evidence of biologic activity was seen as early as cycle 1, day 15, for both compounds. 18F-FDG PET revealed striking differences between the 2 MEK inhibitors at their recommended dose for phase II investigation. The mean amplitude of the decrease in 18F-FDG from baseline to cycle 1, day 15, was greater for patients receiving RO4987655 than for those receiving RO5126766 (47% vs. 16%, respectively; P = 0.052). Furthermore, a more pronounced relationship was seen between the change in 18F-FDG uptake and dose or exposure and phosphorylated ERK inhibition in peripheral blood mononuclear cells in patients receiving RO4987655. For both investigational drugs, PET responses tended to be greatest in patients with melanoma tumors. 18F-FDG was able to identify early nonresponding patients with a 97% negative predictive value. Conclusion: These data exemplify the role of 18F-FDG PET for guiding the selection of novel investigational drugs, choosing dose in early-phase clinical development, and predicting nonresponding patients early in treatment.

Clinical NECR in 18F-FDG PET scans: optimization of injected activity and variable acquisition time. Relationship with SNR

The injected activity and the acquisition time per bed position for 18F-FDG PET scans are usually optimized by using metrics obtained from phantom experiments. However, optimal activity and time duration can significantly vary from a phantom set-up and from patient to patient. An approach using a patient-specific noise equivalent count rate (NECR) modelling has been previously proposed for optimizing clinical scanning protocols. We propose using the clinical NECR on a large population as a function of the body mass index (BMI) for deriving the optimal injected activity and acquisition duration per bed position. The relationship between the NEC and the signal-to-noise ratio (SNR) was assessed both in a phantom and in a clinical setting. 491 consecutive patients were retrospectively evaluated and divided into 4 BMI subgroups. Two criteria were used to optimize the injected activity and the time per bed position was adjusted using the NECR value while keeping the total acquisition time constant. Finally, the relationship between NEC and SNR was investigated using an anthropomorphic phantom and a population of 507 other patients. While the first dose regimen suggested a unique injected activity (665 MBq) regardless of the BMI, the second dose regimen proposed a variable activity and a total acquisition time according to the BMI. The NEC improvement was around 35% as compared with the local current injection rule. Variable time per bed position was derived according to BMI and anatomical region. NEC and number of true events were found to be highly correlated with SNR for the phantom set-up and partially confirmed in the patient study for the BMI subgroup under 28 kg m(-2) suggesting that for the scanner, the nonlinear reconstruction algorithm used in this study and BMI < 28 kg m(-2), NEC, or the number of true events linearly correlated with SNR(2).