Frederic Courbon

Pilot Study of Neoadjuvant Treatment with Erlotinib in Nonmetastatic Head and Neck Squamous Cell Carcinoma

Purpose: To determine the safety and efficacy of erlotinib given as neoadjuvant treatment in patients with head and neck squamous cell carcinoma (HNSCC). Further objectives were to identify markers of response to erlotinib and to assess the pharmacodynamic effects of erlotinib in tumor cells. Experimental Design: Patients with locally advanced nonmetastatic HNSCC were treated with erlotinib 150 mg daily pending surgical management. Tumor samples were collected before and after erlotinib treatment and were analyzed using immunohistochemistry. Epidermal growth factor receptor copy number was determined in tumors using CISH analysis. Results: Between November 2003 and December 2005, 35 patients were included in the study. Neoadjuvant treatment with erlotinib in HNSCC patients was well tolerated and did not necessitate modification to routine surgical procedures. Among 31 evaluable patients, erlotinib was given for a median of 20 days. At the time of surgery, tumor shrinkage was observed in nine patients (29%). Immunohistochemistry analyses were done for 31 patients and showed a decrease in phosphorylated tyrosine residues and phosphorylated erk immunostaining after erlotinib treatment. In a retrospective analysis, baseline p21waf expression in the basal-like cell layer was statistically positively correlated with clinical response to treatment. Epidermal growth factor receptor copy number did not correlate with response to erlotinib. Conclusion: Neoadjuvant treatment of HNSCC with erlotinib was well tolerated. Baseline p21waf expression was associated with response to erlotinib and so might be useful as a tool to select patients for erlotinib therapy in this setting.

Importance of cholesterol and oxysterols metabolism in the pharmacology of tamoxifen and other AEBS ligands

Tamoxifen is one of the major drugs used for the hormonotherapy of estrogen receptor positive breast cancers. However, its therapeutic efficacy can be limited by acquired resistance and tumor recurrence can occur after several years of treatment. Tamoxifen is known as the prototypical modulator of estrogen receptors, but other targets have been identified that could account for its pharmacology. In particular, tamoxifen binds with high affinity to the microsomal antiestrogen binding site (AEBS) and inhibits cholesterol esterification at therapeutic doses. We have recently shown that the AEBS was a hetero-oligomeric complex composed of 3β-hydroxysterol-Δ(8)-Δ(7)-isomerase and 3β-hydroxysterol-Δ(7)-reductase, that binds different structural classes of ligands, including selective estrogen receptor modulators, several sigma receptor ligands, poly-unsaturated fatty acids and ring B oxysterols. We established a link between the modulation of cholesterol metabolism by tamoxifen and other AEBS ligands and their capacity to induce breast cancer cell differentiation, apoptosis and autophagy. Moreover, we showed that the AEBS carries out cholesterol-5,6-epoxide hydrolase activity and established that cholesterol-5,6-epoxide hydrolase is a new target for tamoxifen and other AEBS ligands. Finally in this review, we report on recent data from the literature showing how the modulation of cholesterol and oxysterol metabolism can be linked to the antitumor and chemopreventive properties of tamoxifen, and give new perspectives to improve the clinical outcome of the hormonotherapy of breast cancers.

Coregistration of prechemotherapy PET-CT for planning pediatric Hodgkin's disease radiotherapy significantly diminishes interobserver variability of clinical target volume definition.

PURPOSE To assess the interobserver variability in clinical target volume (CTV) definitions when using registered (18)F-labeled deoxyglucose positron emission tomography (FDG-PET-CT) versus side-by-side image sets in pediatric Hodgkins disease (HD). METHODS AND MATERIALS Prechemotherapy FDG-PET-CT scans performed in the treatment position were acquired from 20 children (median age, 14 years old) with HD (stages 2A to 4B) and registered with postchemotherapy planning CT scans. The patients had a median age of 14 years and stages of disease ranging between 2A and 4B. Image sets were coregistered using a semiautomatic coregistration system. The biological target volume was defined on all the coregistered images as a guide to defining the initial site of involvement and to avoid false-positive or negative results. Five radiation oncologists independently defined the CTV for all 20 patients: once using separate FDG-PET-CT images as a guide (not registered) to define CTVa and once using the registered FDG-PET-CT data to define CTVb. The total volumes were compared, as well as their coefficients of variation (COV). To assess the interobserver variability, the percentages of intersection between contours drawn by all observers for each patient were calculated for CTVa and for CTVb. RESULTS The registration of a prechemotherapy FDG-PET-CT scan caused a change in the CTV for all patients. Comparing CTVa with CTVb showed that the mean CTVb increased in 14 patients (range, 0.61%-101.96%) and decreased in 6 patients (range, 2.97%-37.26%). The COV for CTVb significantly decreased for each patient; the mean COVs for CTVa and CTVb were 45% (21%-65%) and 32% (13%-57%), respectively (p = 0.0004). The percentage of intersection among all CTVbs for the five observers increased significantly by 89.77% (1.99%-256.41%) compared to that of CTVa (p = 0.0001). CONCLUSIONS High observer variability can occur during CT-based definition of CTVs for children diagnosed with HD. Registration of FDG-PET and planning CT images resulted in significantly greater consistency of tumor volume definition.

Preclinical and Clinical Evidence that Deoxy-2-[18F]fluoro-D-glucose Positron Emission Tomography with Computed Tomography Is a Reliable Tool for the Detection of Early Molecular Responses to Erlotinib in Head and Neck Cancer

Purpose: There is a clinical need to identify predictive markers of the responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). Deoxy-2-[18F]fluoro-d-glucose positron emission tomography with computed tomography (18FDG-PET/CT) could be a tool of choice for monitoring the early effects of this class of agent on tumor activity. Experimental Design: Using models of human head and neck carcinoma (CAL33 and CAL166 cell lines), we first tested in vitro and in vivo whether the in vivo changes in 18FDG-PET/CT uptake were associated with the molecular and cellular effects of the EGFR-TKI erlotinib. Then, the pathologic and morphologic changes and the 18FDG-PET/CT uptake before and after erlotinib exposure in patients were analyzed. Results: Erlotinib strongly inhibited extracellular signal-regulated kinase-1/2 (ERK-1/2) phosphorylation both in the preclinical models and in patients. Western blotting, immunofluorescence, and immunohistochemistry showed that erlotinib did not modify Glut-1 expression at the protein level either in cell line models or in tumor tissue from mouse xenografts or in patients. Phospho-ERK-1/2 inhibition was associated with a reduction in 18FDG uptake in animal and human tumors. The biological volume was more accurate than the standardized uptake value for the evaluation of the molecular responses. Conclusion: These results show that the 18FDG-PET/CT response is a reliable surrogate marker of the effects of erlotinib in head and neck carcinoma. Clin Cancer Res; 16(17); 4434–45. ©2010 AACR.

A new respiratory gating device to improve 4D PET/CT

PURPOSE Respiratory motion creates artifacts in positon emission tomography with computed tomography (PET/CT) images especially for lung tumors, and can alter diagnosis. To account for motion effects, respiratory gating techniques have been developed. However, the lack of measures strongly correlated with tumor motion limits their accuracy. The authors developed a real-time pneumotachograph device (SPI) allowing to sort PET and CT images depending on lung volumes. METHODS The performance of this innovative respiratory tracking system was characterized and compared to a standard system. Our experimental setup consisted in a movable platform and a thorax phantom with six fillable spheres simulating lung tumors. The accuracy of SPI to detect inhalation peaks was also determined on volunteers. A comparison with the real-time position management (RPM) device, that relies on abdominal height measurement, was then investigated. RESULTS Experiments showed a high accuracy of the measured signal compared to the input signal (R = 0.88 to 0.99), and of the detection of the inhalation peaks (error of 0.1 +/- 5.8 ms) necessary for prospective binning mode. Activity recovery coefficient was improved (until +39%) and the smearing effect was reduced (until 2.74 times lower) with SPI compared to ungated PET/CT acquisition. The spatial distribution of activity in spheres was similar for 4D PET gated with SPI and RPM. Significant improvement of the binning stability and matching between PET and CT were highlighted for irregular breathing patterns with SPI. CONCLUSIONS SPI is an innovative device that provides better binning performance than the current gating device on phantom experiments. Future works will focus on patients where the authors expect a significant improvement of specificity and sensitivity of PET/CT examinations.

Oncocytic Adenoma of Thyroid Incidentally Detected by 18F-Fluorocholine PET/CT

A 58-old-man underwent 18F-fluorocholine PET/CT for restaging of prostate cancer because of a rising level of prostate-specific antigen.18F-fluorocholine showed no significant tracer uptake at the site of the prostatectomy or the pelvic lymph nodes. Incidental high tracer uptake was observed in a 26 × 23 mm left thyroid nodule. A benign tumor of the thyroid (oncocytic adenoma of thyroid) was diagnosed after left loboisthmectomy.

Quality controls and delineation protocol of PET/CT gated acquisition in function of the movement amplitude, size of spheres and signal over background ratio

This study presents quality controls and segmentation tools for gated acquisition imaging of moving tumors. We study the effect of different amplitudes in a bin in function of sizes of spheres and signal to background ratios. Simple rules are then derived to establish which bins are appropriate to quantify tumor activity and to delineate volume. Finally the threshold technics for gated acquisition exams are discussed in function of the different parameters. Our experimental setup consisted of a movable platform, a thorax phantom with 6 fillable spheres and a real time position management device allowing to synchronize the PET/CT image with movement. The spheres were filled with F-Fluoro-2-deoxy-glucose and the activity in the tank was adjusted to obtain signal to background ratios from 3.5 to 20 (228 combinations of experimental parameters were studied). Maximal activity, optimal threshold and elongation of the sphere images between static and moving tumors were then compared with our own matlab program. Significant changes had appearing for movement superior to 7.5 mm in a bin leading to an activity decrease, an increase of the optimal threshold and an elongation in the movement direction. These effects were accentuated for low SBR and a sphere diameter inferior to 20 mm. The optimal threshold value was around 35% for large spheres and high SBR. This value increase when the sphere size and the SBR decrease. We then deduce from our measurements the relevant parameters for the delineation procedure. In conclusion, the effect of movement were successfully quantified in function of the sphere size, SBR and movement in a bin. Calibration threshold curves are now available in a clinical routine used for gated acquisitions.

ACCURATE PET-PET REGISTRATION TO ASSESS LUNG TUMOR EVOLUTION

Monitoring lung tumors necessitates precise registration of PET images acquired at different stages of a therapy. Existing direct registration methods try to match images leading to distorting the tumor. Inaccurate medical decisions would follow. This paper contributes to solving this problem. The proposed method consists of an indirect registration that takes three different stages. First, multimodal registration of pairs of CT and PET images is performed. Second, CT images are registered to estimate anatomical deformations. Third, the obtained transformation serves for the reconstruction of the PET moving image. The result is a pair of comparable PET images that can be analyzed to assess the actual evolution of the disease. The method has been validated using two types of experiments: phantoms and simulated tumors with synthetic deformations. The paper shows results of these experiments. They prove the validity of the approach and the accuracy of the reconstruction.

18F-Fluorine-18-l-dihydroxyphenylalanine (18F-DOPA) positive isolated peritoneal carcinomatosis from a MENII-related medullary thyroid carcinoma. About an atypical metastatic site and utility of 18F-FDOPA

A patient, operated for a medullary thyroid carcinoma (MTC) with a positive RET mutation, showed several peritoneal nodes on a computed tomography (CT), with increased Thyrocalcitonine. A 18F‐Fluorine‐18‐l‐dihydroxyphenylalanine (18‐F‐FDOPA) positron emission tomography (PET/CT) showed isolated tracer uptake on the nodes. A biopsy confirmed that it was from the MTC, with the same RET mutation as in blood.

Comparison of an alternative and existing binning methods to reduce the acquisition duration of 4D PET/CT.

PURPOSE Respiratory motion is a source of artifacts that reduce image quality in PET. Four dimensional (4D) PET/CT is one approach to overcome this problem. Existing techniques to limiting the effects of respiratory motions are based on prospective phase binning which requires a long acquisition duration (15-25 min). This time is uncomfortable for the patients and limits the clinical exploitation of 4D PET/CT. In this work, the authors evaluated an existing method and an alternative retrospective binning method to reduce the acquisition duration of 4D PET/CT. METHODS The authors studied an existing mixed-amplitude binning (MAB) method and an alternative binning method by mixed-phases (MPhB). Before implementing MPhB, they analyzed the regularity of the breathing patterns in patients. They studied the breathing signal drift and missing CT slices that could be challenging for implementing MAB. They compared the performance of MAB and MPhB with current binning methods to measure the maximum uptake, internal volume, and maximal range of tumor motion. RESULTS MPhB can be implemented depending on an optimal phase (in average, the exhalation peak phase -4.1% of the entire breathing cycle duration). Signal drift of patients was in average 35% relative to the breathing amplitude. Even after correcting this drift, MAB was feasible in 4D CT for only 64% of patients. No significant differences appeared between the different binning methods to measure the maximum uptake, internal volume, and maximal range of tumor motion. The authors also determined the inaccuracies of MAB and MPhB to measure the maximum amplitude of tumor motion with three bins (less than 3 mm for movement inferior to 12 mm, up to 6.4 mm for a 21 mm movement). CONCLUSIONS The authors proposed an alternative binning method by mixed-phase binning that halves the acquisition duration of 4D PET/CT. Mixed-amplitude binning was challenging because of signal drift and missing CT slices. They showed that more than three bins were necessary for a more accurate measurement of the maximum amplitude of the tumor motion. However, the current 4D-CT technology limits the increase of the number of bins in 4D PET/CT because of missing CT slices. One can reconstruct 4D PET images with more bins but without attenuation/scatter correction.