Nicolas Christian

Assessment by a deformable registration method of the volumetric and positional changes of target volumes and organs at risk in pharyngo-laryngeal tumors treated with concomitant chemo-radiation

PURPOSE Anatomic changes occur during radiation therapy (RT) for head and neck (H&N) tumors. This study aims at quantifying the volumetric and positional changes of gross tumor volumes (GTV), clinical target volumes (CTV), and organs at risk (OAR). Anatomic (CT) and functional (FDG-PET) imaging were used for the delineation of the GTVs. MATERIALS AND METHODS Ten patients with H&N tumors treated by chemo-RT were used. Contrast-enhanced CT and FDG-PET were acquired prior and during RT following delivery of mean doses of 14.2, 24.5, 35.0, and 44.9 Gy. CT-based GTVs were manually delineated, and PET-based GTVs were segmented using a gradient-based segmentation method. Pre-treatment prophylactic dose CTVs were manually delineated on the pre-treatment CT using consistent and reproducible guidelines. Per-treatment prophylactic CTVs were obtained with an automatic re-contouring method based on deformable registration. For the therapeutic dose CTVs, a 5 mm margin was applied around the corresponding GTVs. OARs such as the parotid glands and the submandibular glands were manually delineated on the pre-treatment CT. OARs on the per-treatment CT were automatically delineated using the method used for prophylactic CTVs. The mean slopes of the relative change in volume over time and the mean displacements of the center of mass after 44.9 Gy were calculated for each volume. RESULTS Regarding volumetric changes, CT-based and PET-based primary tumor GTVs decreased at a mean rate of 3.2% and 3.9%/treatment day (td), respectively; nodal GTVs decreased at a mean rate of 2.2%/td. This led to a corresponding decrease of the CT-based and PET-based therapeutic CTVs by 2.4% and 2.5%/td, respectively. CT- and PET-based prophylactic tumor CTVs decreased by an average of 0.7% and 0.5%/td, respectively. No difference in volume shrinkage was observed between CT- and PET-based volumes. The ipsilateral and contralateral parotid glands showed a mean decrease of 0.9% and 1.0%/td, respectively. The ipsilateral and contralateral submandibular glands shrank at a mean rate of 1.5% and 1.3%/td, respectively. Regarding positional changes, CT-based GTVs showed a lateral shift of 1.3 mm, PET-based GTVs a posterior shift of 3.4mm and the nodal GTVs a medial shift of 1.0 mm, translating into parallel shifts of the therapeutic CTVs. The ipsilateral prophylactic nodal CTV shifted medially by 1.8 mm. The ipsilateral parotid gland shifted medially by 3.4 mm. The ipsilateral submandibular gland showed a medial shift of 1.7 mm and a superior shift of 2.7 mm. The contralateral submandibular gland only showed a superior shift of 1.7 mm. CONCLUSIONS Volumetric and positional changes in TVs and OARs were observed during concomitant chemo-RT suggesting that adaptive strategies, where patients are re-imaged and possibly re-planned during treatment, are worth evaluating.

The limitation of PET imaging for biological adaptive-IMRT assessed in animal models

PURPOSE Biological image-guided radiotherapy aims at specifically irradiating biologically relevant sub-volumes within the tumor, as determined for instance by PET imaging. This approach requires that PET imaging be sensitive and specific enough to image various biological pathways of interest, e.g. tumor metabolism, proliferation and hypoxia. In this framework, a validation of PET imaging used for adaptive radiotherapy was undertaken in animal models by comparing small-animal PET images (2.7mm resolution) with autoradiography (AR) (100mum resolution) in various tumors under various physiological situations. METHODS A specific template for tumor-bearing mouse imaging has been designed (Christian, R&O, 2008). It allows for the registration between MRI images (Biospec, Bruker), FDG-PET images (Mosaic, Philips) and AR (FLA-5100, Fujifilm). After registration, the tumors on the PET and AR images were segmented using a threshold-based method. The thresholds were selected to obtain absolute equal volumes in the PET and AR images. Matching indexes were then calculated between the various volumes. The entire imaging process was performed for FSAII tumors (n=5), SCCVII (n=5) and irradiated (35Gy) FSAII tumors (n=5). RESULTS In regions with high FDG activity delineated using high value thresholds, low matching values of 39%+/-11% (mean+/-SD) were observed between the volumes delineated on the PET images and those delineated on AR. The matching values progressively increased when considering larger volumes obtained with lower thresholds. These findings were independent of tumor type, tumor metabolism or tumor size. The relationship between the matching values and the percentage of overall tumor volume was fitted through a power regression (r=0.93). As shown by simulations, the matching improved with higher PET resolution. The results can be extrapolated to human tumors imaged with a whole-body PET system. CONCLUSION Discrepancies were found between the PET images and the underlying microscopic reality represented by AR images. These differences, attributed to the finite resolution of PET, were important when considering small and highly active regions of the tumors. Dose painting based on PET images should therefore be carefully considered and should take these limitations into account.

Is 18F-FDG a surrogate tracer to measure tumor hypoxia? Comparison with the hypoxic tracer 14C-EF3 in animal tumor models

INTRODUCTION Fluorodeoxyglucose (FDG) has been reported as a surrogate tracer to measure tumor hypoxia with positron emission tomography (PET). The hypothesis is that there is an increased uptake of FDG under hypoxic conditions secondary to enhanced glycolysis, compensating the hypoxia-induced loss of cellular energy production. Several studies have already addressed this issue, some with conflicting results. This study aimed to compare the tracers (14)C-EF3 and (18)F-FDG to detect hypoxia in mouse tumor models. MATERIALS AND METHODS C3H, tumor-bearing mice (FSAII and SCCVII tumors) were injected iv with (14)C-EF3, and 1h later with (18)F-FDG. Using a specifically designed immobilization device with fiducial markers, PET (Mosaic®, Philips) images were acquired 1h after the FDG injection. After imaging, the device containing mouse was frozen, transversally sliced and imaged with autoradiography (AR) (FLA-5100, Fujifilm) to obtain high resolution images of the (18)F-FDG distribution within the tumor area. After a 48-h delay allowing for (18)F decay a second AR was performed to image (14)C-EF3 distribution. AR images were aligned to reconstruct the full 3D tumor volume, and were compared with the PET images. Image segmentation with threshold-based methods was applied on both AR and PET images to derive various tracer activity volumes. The matching index DSI (dice similarity index) was then computed. The comparison was performed under normoxic (ambient air, FSAII: n=4, SCCVII, n=5) and under hypoxic conditions (10% O(2) breathing, SCCVII: n=4). RESULTS On AR, under both ambient air and hypoxic conditions, there was a decreasing similarity between (14)C-EF3 and FDG with higher activity sub-volumes. Under normoxic conditions, when comparing the 10% of tumor voxels with the highest (18)F-FDG or (14)C-EF3 activity, a DSI of 0.24 and 0.20 was found for FSAII and SCCVII, respectively. Under hypoxic conditions, a DSI of 0.36 was observed for SCCVII tumors. When comparing the (14)C-EF3 distribution in AR with the corresponding (18)F-FDG-PET images, the DSI reached values of 0.26, 0.22 and 0.21 for FSAII and SCCVII under normoxia and SCCVII under hypoxia, respectively. CONCLUSION This study showed that FDG is not a good surrogate tracer for tumor hypoxia under either ambient or hypoxic conditions. Only specific hypoxia tracers should be used to measure tumor hypoxia.

Thyroid Status is a Key Modulator of Tumor Oxygenation: Implication for Radiation Therapy

Abstract Jordan, B. F., Christian, N., Crokart, N., Grégoire, V., Feron, O. and Gallez, B. Thyroid Status is a Key Modulator of Tumor Oxygenation: Implication for Radiation Therapy. Radiat. Res. 168, 428–432 (2007). In normal tissues, thyroid hormones play a major role in the metabolic activity and oxygen consumption of cells. Because the rate of oxygen consumption is a key factor in the response of tumors to radiation, we hypothesized that thyroid hormones may affect the metabolic activity of tumor cells and hence modulate the response to cytotoxic treatments. We measured the influence of thyroid status on the tumor microenvironment in experimental tumors. Hypothyroidism and hyperthyroidism were generated in mice by chronic treatment with propyl thiouracil and l-thyroxine. Thyroid status significantly modified tumor pO2 as measured with EPR oximetry. Mechanistically, this was the result of the profound changes in oxygen consumption rates. Thyroid status was associated with a significant change in tumor radiosensitivity since the regrowth delay was increased in hypothyroid mice compared to euthyroid mice, an effect that was abolished when temporarily clamped tumors were irradiated. This study provides unique insights into the impact of modulating tumor oxygen consumption and could have implications in the management of cancer patients with thyroid disorders.

Immobilization device for in vivo and in vitro multimodality image registration of rodent tumors

Biological image-guided radiotherapy requires that PET accurately identifies biologically relevant sub-volumes within a tumor. In this framework, an immobilization device was developed to study multi-imaging (CT, micro-MRI, micro-PET, and autoradiography) registration of mouse tumors. The registration accuracy assessed by calculating the average minimal distance between two skew lines was in the order of 0.2-0.3 mm.

Alginate moulding: an empirical method for magnetic resonance imaging/positron emission tomography co-registration in a tumor rat model

BACKGROUND AND PURPOSE In the experimental field of animal models, co-registration between positron emission tomography (PET) and magnetic resonance imaging (MRI) data still relies on non-automated post-processing using sophisticated algorithms and software developments. We assessed the value of an empirical method using alginate moulding for PET-MR co-registration in a tumor rat model. METHODS Male WAG/RijHsd rats bearing grafted syngenic rhabdomyosarcoma were examined under general anesthesia by MRI using a clinical whole-body 3-T system equipped with a sensitivity-encoding four-channel wrist coil and by a small animal PET system using labelled [(18)F]-fluorocholine as tracer. An alginate mould including a system of external fiducials was manufactured for each animal, allowing strict immobilization and similar positioning for both modalities. Fourteen rats (27 tumors) had only one MR/PET imaging session. Five rats (9 tumors) had a similar MR/PET session before and 3 days after external radiation therapy (13 Gy in one fraction) using the same mould. Co-registration was performed using the Pmod release 2.75 software (PMOD Technologies, Ltd., Adliswil, Switzerland) with mutual information algorithm. RESULTS The manufacture of the alginate moulds was easy and innocuous. Imaging sessions were well tolerated. PET-MR co-registration based on mutual information was perfect at visual examination, which was confirmed by the superimposition of external fiducials on fused images. Reuse of the same mould for the post-therapeutic session was feasible 3 days after the pre-therapeutic one in spite of tumor growth. CONCLUSION The empirical method using alginate moulding with external fiducials for PET-MR co-registration in a rodent tumor model was feasible and accurate.

Do refined consensus guidelines improve the uniformity of clinical target volume delineation for rectal cancer? Results of a national review project

In a previous national central review project, 74% of the rectal cancer clinical target volumes (CTVs) needed a modification. In a follow-up initiative, we evaluated whether the use of refined international consensus guidelines improves the uniformity of CTV delineation in clinical practice.