Caroline Rousseau

Treatment of bone metastases of prostate cancer with strontium-89 chloride: efficacy in relation to the degree of bone involvement.

Abstract. This retrospective study evaluated the toxicity and efficacy of strontium-89 chloride (Metastron, Amersham) in 94 patients with painful bone metastases of prostate cancer (117 injections of 150xa0MBq) and compared the efficacy of treatment in patients with moderate and extensive bone involvement. The predictive value of flare response with regard to analgesic response was also studied. High-grade leukothrombopenias were observed after only 5% of injections. An improvement in quality of life was obtained in 65% of cases, a decrease in pain in 78% (31% complete response) and a reduction of analgesics in 60%. Efficacy was significantly better for pain decrease (P=0.005) and reduction of analgesics (P=0.018), and response was significantly longer (P<0.0035) in patients with moderate than in patients with extensive bone involvement. The flare response observed in 23% of cases was not predictive of pain response (P=0.919) or reduction of analgesics (P=0.353). A second dose prolonged analgesia in three-quarters of cases without any apparent increase in toxicity. These results confirm the benefit of 89Sr chloride for the treatment of metastatic bone pain and suggest that internal radiotherapy should be started earlier. A bone scan could be proposed at the time of hormonal escape resulting in bone pain, and internal radiotherapy could be initiated when several metastatic foci exist, even if only one is painful. In this way, pain-free follow-up could be prolonged, and the transition to other therapeutic approaches, particularly opioids, delayed.

Assessment of acquisition protocols for routine imaging of Y-90 using PET/CT

BackgroundDespite the early theoretical prediction of the 0+-0+ transition of 90Zr, 90Y-PET underwent only recently a growing interest for the development of imaging radioembolization of liver tumors. The aim of this work was to determine the minimum detectable activity (MDA) of 90Y by PET imaging and the impact of time-of-flight (TOF) reconstruction on detectability and quantitative accuracy according to the lesion size.MethodsThe study was conducted using a Siemens Biograph® mCT with a 22xa0cm large axial field of view. An IEC torso-shaped phantom containing five coplanar spheres was uniformly filled to achieve sphere-to-background ratios of 40:1. The phantom was imaged nine times in 14xa0days over 30xa0min. Sinograms were reconstructed with and without TOF information. A contrast-to-noise ratio (CNR) index was calculated using the Rose criterion, taking partial volume effects into account. The impact of reconstruction parameters on quantification accuracy, detectability, and spatial localization of the signal was investigated. Finally, six patients with hepatocellular carcinoma and four patients included in different 90Y-based radioimmunotherapy protocols were enrolled for the evaluation of the imaging parameters in a clinical situation.ResultsThe highest CNR was achieved with one iteration for both TOF and non-TOF reconstructions. The MDA, however, was found to be lower with TOF than with non-TOF reconstruction. There was no gain by adding TOF information in terms of CNR for concentrations higher than 2 to 3xa0MBqxa0mL−1, except for infra-centimetric lesions. Recovered activity was highly underestimated when a single iteration or non-TOF reconstruction was used (10% to 150% less depending on the lesion size). The MDA was estimated at 1xa0MBqxa0mL−1 for a TOF reconstruction and infra-centimetric lesions. Images from patients treated with microspheres were clinically relevant, unlike those of patients who received systemic injections of 90Y.ConclusionsOnly one iteration and TOF were necessary to achieve an MDA around 1xa0MBqxa0mL−1 and the most accurate localization of lesions. For precise quantification, at least three iterations gave the best performance, using TOF reconstruction and keeping an MDA of roughly 1xa0MBqxa0mL−1. One and three iterations were mandatory to prevent false positive results for quantitative analysis of clinical data.Trial registrationhttp://IDRCB2011-A00043-38P101103

FDG PET evaluation of early axillary lymph node response to neoadjuvant chemotherapy in stage II and III breast cancer patients

PurposeRegional axillary lymph node status has remained the single most independent variable to predict prognosis both in terms of disease recurrence and survival. This study aimed to prospectively assess sequential [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) findings as early predictors of axillary lymph node response to neoadjuvant chemotherapy in stage II and III breast cancer patients.MethodsImages were acquired with a PET/CT scanner in 52 patients after administration of FDG (5 MBq/kg) at baseline and after the first, second, third and sixth course of chemotherapy before surgery. Clinical examination and ultrasound (US) were used to assess the size of axillary nodes. Decrease in the standardized uptake value (SUV) with PET corrected or not for partial volume effects was compared to the pathological response.ResultsThe sensitivity, specificity and accuracy of axillary node staging was higher with PET (75, 87 and 80%) than with US (50, 83 and 65%), and even more so when PET images were corrected for partial volume effects (86, 83 and 84%). While FDG uptake did not vary much in non-responders, as confirmed by histopathological analysis, it markedly decreased to baseline levels in responders (pu2009<u200910−5). Fifty per cent of baseline SUV was considered the best cutoff value to distinguish responders from non-responders. The sensitivity, specificity, negative predictive value and accuracy of FDG PET after one course of chemotherapy were, respectively, 96, 75, 95 and 84%.ConclusionThe pathological status of regional axillary lymph nodes in stage II and III breast cancer patients could be accurately predicted after one course of neoadjuvant chemotherapy based on FDG PET images.

Three methods assessing red marrow dosimetry in lymphoma patients treated with radioimmunotherapy.

Maximum injected activity in radioimmunotherapy (RIT) is limited by bone marrow toxicity. Many dosimetric approaches have been proposed, leading to high variability in the results and elusive absorbed dose‐effect relations. This study presents the results of red marrow (RM) absorbed dose estimates performed with 3 methods.

A pretargeting system for tumor PET imaging and radioimmunotherapy

Labeled antibodies, as well as their fragments and antibody-derived recombinant constructs, have long been proposed as general vectors to target radionuclides to tumor lesions for imaging and therapy. They have indeed shown promise in both imaging and therapeutic applications, but they have not fulfilled the original expectations of achieving sufficient image contrast for tumor detection or sufficient radiation dose delivered to tumors for therapy. Pretargeting was originally developed for tumor immunoscintigraphy. It was assumed that directly-radiolabled antibodies could be replaced by an unlabeled immunoconjugate capable of binding both a tumor-specific antigen and a small molecular weight molecule. The small molecular weight molecule would carry the radioactive payload and would be injected after the bispecific immunoconjugate. It has been demonstrated that this approach does allow for both antibody-specific recognition and fast clearance of the radioactive molecule, thus resulting in improved tumor-to-normal tissue contrast ratios. It was subsequently shown that pretargeting also held promise for tumor therapy, translating improved tumor-to-normal tissue contrast ratios into more specific delivery of absorbed radiation doses. Many technical approaches have been proposed to implement pretargeting, and two have been extensively documented. One is based on the avidin-biotin system, and the other on bispecific antibodies binding a tumor-specific antigen and a hapten. Both have been studied in preclinical models, as well as in several clinical studies, and have shown improved targeting efficiency. This article reviews the historical and recent preclinical and clinical advances in the use of bispecific-antibody-based pretargeting for radioimmunodetection and radioimmunotherapy of cancer. The results of recent evaluation of pretargeting in PET imaging also are discussed.

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 (665u2009MBq) 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 28u2009kgu2009m(-2) suggesting that for the scanner, the nonlinear reconstruction algorithm used in this study and BMI < 28u2009kgu2009m(-2), NEC, or the number of true events linearly correlated with SNR(2).

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-CEAu2009×u2009anti-histamine-succinyl-glycine (HSG)-humanized trivalent bispecific antibody (TF2) and the IMP288 bivalent HSG peptide. Patients underwent a pretherapeutic imaging session S1 (44 or 88u2009nmol/m2 of TF2 followed by 4.4u2009nmol/m2, 185u2009MBq, of 111In-labeled IMP288) and, 1–2u2009weeks later, a therapy session S2 (240 or 480u2009nmol/m2 of TF2 followed by 24u2009nmol/m2, 1.1u2009GBq/m2, of 177Lu-labeled IMP288). The pretargeting delay was 24 or 48u2009h. 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 0.33u2009±u20090.03u2009L/h/m2. 111In- and 177Lu-IMP288 PK was also well represented by a two-compartment model. IMP288 PK was faster (clearance 1.4–3.3u2009L/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 (pu2009<u20090.002). 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).

Assessment of Lymph Nodes and Prostate Status Using Early Dynamic Curves with 18F-Choline PET/CT in Prostate Cancer

Introduction Dynamic image acquisition with 18F-Choline [fluorocholine (FCH)] PET/CT in prostate cancer is mostly used to overcome the bladder repletion, which could obstruct the loco-regional analysis. The aim of our study was to analyze early dynamic FCH acquisitions to define pelvic lymph node or prostate pathological status. Material and methods Retrospective analysis was performed on 39 patients for initial staging (nu2009=u200918), or after initial treatment (nu2009=u200921). Patients underwent 10-min dynamic acquisitions centered on the pelvis, after injection of 3–4u2009MBq/kg of FCH. Whole-body images were acquired about 1u2009h after injection using a PET/CT GE Discovery LS (GE-LS) or Siemens Biograph mCT (mCT). Maximum and mean SUV according to time were measured on nodal and prostatic lesions. SUVmean was corrected for partial volume effect (PVEC) with suitable recovery coefficients. The status of each lesion was based on histological results or patient follow-up (>6u2009months). A Mann–Whitney test and ANOVA were used to compare mean and receiver operating characteristic (ROC) curve analysis. Results The median PSA was 8.46u2009ng/mL and the median Gleason score was 3u2009+u20094. Ninety-two lesions (43 lymph nodes and 49 prostate lesions) were analyzed, including 63 malignant lesions. In early dynamic acquisitions, the maximum and mean SUV were significantly higher, respectively, on mCT and GE-LS, in malignant versus benign lesions (pu2009<u20090.001, pu2009<u20090.001). Mean SUV without PVEC, allowed better discrimination of benign from malignant lesions, in comparison with maximum and mean SUV (with PVEC), for both early and late acquisitions. For patients acquired on mCT, area under the ROC curve showed a trend to better sensitivity and specificity for early acquisitions, compared with late acquisitions (SUVmax AUC 0.92 versus 0.85, respectively). Conclusion Assessment of lymph nodes and prostate pathological status with early dynamic imaging using PET/CT FCH allowed prostate cancer detection in situations where proof of malignancy is difficult to obtain.

Clinical and Survival Impact of FDG PET in Patients with Suspicion of Recurrent Ovarian Cancer: A 6-Year Follow-Up

Background The aim of this retrospective study was to evaluate the contribution of fluorine-18-fluoro-deoxyglucose (FDG) positron emission tomography (PET) to the clinical management and survival outcome of patients (pts) suspected of recurrent ovarian carcinoma, with the hypothesis that early diagnosis of recurrent ovarian cancer may improve overall survival (OS). Methods Fifty-three FDG PET/CT scans were retrospectively analyzed for 42 pts. CT and PET/CT findings were confirmed by imaging and clinical follow-up, and/or pathology, which were considered as the gold standard diagnosis. The treatment plan based on CT staging was compared with that based on PET/CT findings. Medical records were reviewed for pts characteristics, progression-free survival (PFS), and OS. PFS and OS were analyzed using the Cox proportional hazards regression model. Results The final diagnosis of recurrence was established pathologically (nu2009=u200916), or by a median clinical follow-up of 6.5u2009years (range 0.5-7.5) after the PET/CT (nu2009=u200937). PET/CT provided a higher detection sensitivity (92.2%, 47/51) than CT (60.8%, 31/51) (pu2009<u20090.001). Globally, PET/CT modified the treatment plan in 56.6% (30/53) and in 65.2% (15/23) when the CT was negative prior to PET/CT. In 30 cases, those benefited from a modified treatment plan, these changes led to the intensification of a previous treatment procedure in 83.3% (25/30), and to a reduction in the previous treatment procedure in 16.6% of cases (5/30). The Cox regression multivariate analysis showed that the number of lesions visualized by CT and presence of lung lesions detected by PET/CT were significantly associated with PFS (pu2009=u20090.002 and pu2009=u20090.035, respectively). Conclusion On account of its impact on treatment planning, and especially in predicting patient outcome, FDG PET is a valuable diagnostic tool for cases of suspected ovarian cancer recurrence.

Quantitative Evaluation of Therapeutic Response by FDG-PET–CT in Metastatic Breast Cancer

Purpose To assess the therapeutic response for metastatic breast cancer with 18F-FDG position emission tomography (PET), this retrospective study aims to compare the performance of six different metabolic metrics with PERCIST, PERCIST with optimal thresholds, and an image-based parametric approach. Methods Thirty-six metastatic breast cancer patients underwent 128 PET scans and 123 lesions were identified. In a per-lesion and per-patient analysis, the performance of six metrics: maximum standardized uptake value (SUVmax), SUVpeak, standardized added metabolic activity (SAM), SUVmean, metabolic volume (MV), total lesion glycolysis (TLG), and a parametric approach (SULTAN) were determined and compared to the gold standard (defined by clinical assessment and biological and conventional imaging according RECIST 1.1). The evaluation was performed using PERCIST thresholds (for per-patient analysis only) and optimal thresholds (determined by the Youden criterion from the receiver operating characteristic curves). Results In the per-lesion analysis, 210 pairs of lesion evolutions were studied. Using the optimal thresholds, SUVmax, SUVpeak, SUVmean, SAM, and TLG were significantly correlated with the gold standard. SUVmax, SUVpeak, and SUVmean reached the best sensitivity (91, 88, and 83%, respectively), specificity (93, 95, and 97%, respectively), and negative predictive value (NPV, 90, 88, and 83%, respectively). For the per-patient analysis, 79 pairs of PET were studied. The optimal thresholds compared to the PERCIST threshold did not improve performance for SUVmax, SUVpeak, and SUVmean. Only SUVmax, SUVpeak, SUVmean, and TLG were correlated with the gold standard. SULTAN also performed equally: 83% sensitivity, 88% specificity, and NPV 86%. Conclusion This study showed that SUVmax and SUVpeak were the best parameters for PET evaluation of metastatic breast cancer lesions. Parametric imaging is helpful in evaluating serial studies.