Interstitial needles versus intracavitary applicators only for locally advanced cervical cancer: results from real-life dosimetric comparisons.

Background and purpose: Image-guided adapted brachytherapy (IGABT) is superior to other radiotherapy techniques in the treatment of locally advanced cervical cancer (LACC). We aimed to investigate the benefit of interstitial needles (IN) for a combined intracavitary/interstitial (IC/IS) approach using IGABT over the intracavitary approach (IC) alone in patients with LACC after concomitant external beam radiotherapy (EBRT) and chemotherapy. Materials and methods: We included consecutive patients with LACC who were treated with IC/IS IGABT after radiochemotherapy (RCT) in our retrospective, observational study. Dosimetric gain and sparing of organs at risk (OAR) were investigated by comparing the IC/IS IGABT plan with a simulated plan without needle use (IC IGABT plan) and the impact of other clinical factors on the benefit of IC/IS IGABT. Results: Ninety-nine patients were analyzed, with a mean EBRT dose of 45.5 ± 1.7 Gy; 97 patients received concurrent chemotherapy. A significant increase in median D90% High Risk Clinical target volume (HR-CTV) was found for IC/IS (82.8 Gy) vs IC (76.2 Gy) (p < 10-4). A significant decrease of the delivered dose for all OAR was found for IC/IS vs IC for median D2cc to the bladder (77.2 Gy), rectum (68 Gy), sigmoid (53.2 Gy), and small bowel (47 Gy) (all p < 10-4). Conclusion: HR-CTV coverage was higher with IC/IS IGABT than with IC IGABT, with lower doses to the OAR in patients managed for LACC after RCT. Interstitial brachytherapy in the management of LACC after radiotherapy provides better coverage of the target volumes, this could contribute to better local control and improved survival of patients.

In vivo gadolinium nanoparticle quantification with SPECT/CT.

BACKGROUND: Gadolinium nanoparticles (Gd-NP) combined with radiotherapy are investigated for radiation dose enhancement in radiotherapy treatment. Indeed, NPs concentrated in a tumor could enhance its radiosensitization. The noninvasive quantification of the NP concentration is a crucial task for radiotherapy treatment planning and post-treatment monitoring as it will determine the absorbed dose. In this work, we evaluate the achievable accuracy of in vivo SPECT-based Gd-NP organ concentration on rats. METHODS: Gd-NPs were labeled with 111In radionuclide. SPECT images have been acquired on phantom and rats, with various Gd-NP injections. Images have been calibrated and corrected for attenuation, scatter, and partial volume effect. Image-based estimations were compared to both inductively coupled plasma mass spectrometer (ICP-MS) for Gd concentration and ex vivo organ activity measured by gamma counter. RESULTS: The accuracy for the Gd mass measurements in organ was within 10% for activity above 2 MBq or concentrations above ∼ 3-4 MBq/mL. The Gd mass calculation is based on In-Gd coefficient which defines the Gd detection limit. It was found to be in a range from 2 mg/MBq to 2 µg/MBq depending on the proportions of initial injection preparations. Measurement was also impaired by free Gd and 111In formed during metabolic processes. CONCLUSIONS: Even if SPECT image quantification remains challenging mostly due to partial volume effect, this study shows that it has potential for the Gd mass measurements in organ. The main limitation of the method is its indirectness, and a special care should be taken if the organ of interest could be influenced by different clearance rate of free Gd and 111In formed by metabolic processes. We also discuss the practical aspects, potential, and limitations of Gd-NP in vivo image quantification with a SPECT.

A first-in-human study investigating biodistribution, safety and recommended dose of a new radiolabeled MAb targeting FZD10 in metastatic synovial sarcoma patients.

BACKGROUND: Synovial Sarcomas (SS) are rare tumors occurring predominantly in adolescent and young adults with a dismal prognosis in advanced phases. We report a first-in-human phase I of monoclonal antibody (OTSA-101) targeting FZD10, overexpressed in most SS but not present in normal tissues, labelled with radioisotopes and used as a molecular vehicle to specifically deliver radiation to FZD10 expressing SS lesions. METHODS: Patients with progressive advanced SS were included. In the first step of this trial, OTSA-101 in vivo bio-distribution and lesions uptake were evaluated by repeated whole body planar and SPECT-CT scintigraphies from H1 till H144 after IV injection of 187 MBq of 111In-OTSA-101. A 2D dosimetry study also evaluated the liver absorbed dose when using 90Y-OTSA-101. In the second step, those patients with significant tumor uptake were randomized between 370 MBq (Arm A) and 1110 MBq (Arm B) of 90Y-OTSA-101 for radionuclide therapy. RESULTS: From January 2012 to June 2015, 20 pts. (median age 43 years [21-67]) with advanced SS were enrolled. Even though 111In-OTSA-101 liver uptake appeared to be intense, estimated absorbed liver dose was less than 20 Gy for each patient. Tracer intensity was greater than mediastinum in 10 patients consistent with sufficient tumor uptake to proceed to treatment with 90Y-OTSA-101: 8 were randomized (Arm A: 3 patients and Arm B: 5 patients) and 2 were not randomized due to worsening PS. The most common Grade ≥ 3 AEs were reversible hematological disorders, which were more frequent in Arm B. No objective response was observed. Best response was stable disease in 3/8 patients lasting up to 21 weeks for 1 patient. CONCLUSIONS: Radioimmunotherapy targeting FZD10 is feasible in SS patients as all patients presented at least one lesion with 111In-OTSA-101 uptake. Tumor uptake was heterogeneous but sufficient to select 50% of pts. for 90Y-OTSA-101 treatment. The recommended activity for further clinical investigations is 1110 MBq of 90Y-OTSA-101. However, because of hematological toxicity, less energetic particle emitter radioisopotes such as Lutetium 177 may be a better option to wider the therapeutic index. TRIAL REGISTRATION: The study was registered on the NCT01469975 website with a registration code NCT01469975 on November the third, 2011.

Image-based SPECT calibration based on the evaluation of the Fraction of Activity in the Field of View.

BACKGROUND: SPECT quantification is important for dosimetry in targeted radionuclide therapy (TRT) and the calibration of SPECT images is a crucial stage for image quantification. The current standardized calibration protocol (MIRD 23) uses phantom acquisitions to derive a global calibration factor in specific conditions. It thus requires specific acquisitions for every clinical protocols. We proposed an alternative and complementary image-based calibration method that allows to determine a calibration factor adapted to each patient, radionuclide, and acquisition protocol and that may also be used as an additional independent calibration. RESULTS: The proposed method relies on a SPECT/CT acquisition of a given region of interest and an initial whole-body (WB) planar image. First, the conjugate view of WB planar images is computed after scatter and attenuation correction. 3D SPECT images are reconstructed with scatter, attenuation, and collimator-detector response (CDR) corrections and corrected from apparent dead-time. The field of view (FOV) of the SPECT image is then projected on the corrected WB planar image. The fraction of activity located in the area corresponding to the SPECT FOV is then calculated based on the counts on the corrected WB planar image. The Fraction of Activity in Field Of View (FAF) is then proposed to compute the calibration factor as the total number of counts in the SPECT image divided by this activity. Quantification accuracy was compared with the standard calibration method both with phantom experiments and on patient data. Both standard and image-based calibrations give good accuracy on large region of interest on phantom experiments (less than 7% of relative difference compared to ground truth). Apparent dead-time correction allows to reduce the uncertainty associated with standard calibration from 2.5 to 1%. The differences found between both methods were lower than the uncertainty range of the standard calibration (<3%). In patient data, although no ground truth was available, both methods give similar calibration factor (average difference 3.64%). CONCLUSIONS: A calibration factor may be computed directly from the acquired SPECT image providing that a WB planar image is also available and if both acquisitions are performed before biological elimination. This method does not require to perform phantom acquisition for every different acquisition conditions and may serve to double check the calibration with an independent factor.

Voxel-based multimodel fitting method for modeling time activity curves in SPECT images.

PURPOSE: Estimating the biodistribution and the pharmacokinetics from time-sequence SPECT images on a per-voxel basis is useful for studying activity nonuniformity or computing absorbed dose distributions by convolution of voxel kernels or Monte-Carlo radiation transport. Current approaches are either region-based, thus assuming uniform activity within the region, or voxel-based but using the same fitting model for all voxels. METHODS: We propose a voxel-based multimodel fitting method (VoMM) that estimates a fitting function for each voxel by automatically selecting the most appropriate model among a predetermined set with Akaike criteria. This approach can be used to compute the time integrated activity (TIA) for all voxels in the image. To control fitting optimization that may fail due to excessive image noise, an approximated version based on trapezoid integration, named restricted method, is also studied. From this comparison, the number of failed fittings within images was estimated and analyzed. Numerical experiments were used to quantify uncertainties and feasibility was demonstrated with real patient data. RESULTS: Regarding numerical experiments, root mean square errors of TIA obtained with VoMM were similar to those obtained with bi-exponential fitting functions, and were lower (< 5% vs.  > 10%) than with single model approaches that consider the same fitting function for all voxels. Failure rates were lower with VoMM and restricted approaches than with single-model methods. On real clinical data, VoMM was able to fit 90% of the voxels and led to less failed fits than single-model approaches. On regions of interest (ROI) analysis, the difference between ROI-based and voxel-based TIA estimations was low, less than 4%. However, the computation of the mean residence time exhibited larger differences, up to 25%. CONCLUSIONS: The proposed voxel-based multimodel fitting method, VoMM, is feasible on patient data. VoMM leads organ-based TIA estimations similar to conventional ROI-based method. However, for pharmacokinetics analysis, studies of spatial heterogeneity or voxel-based absorbed dose assessment, VoMM could be used preferentially as it prevents model overfitting.

3D absorbed dose distribution estimated by Monte Carlo simulation in radionuclide therapy with a monoclonal antibody targeting synovial sarcoma.

BACKROUND: Radiolabeled OTSA101, a monoclonal antibody targeting synovial sarcoma (SS) developed by OncoTherapy Science, was used to treat relapsing SS metastases following a theranostic procedure: in case of significant 111In-OTSA101 tumor uptake and favorable biodistribution, patient was randomly treated with 370/1110 MBq 90Y-OTSA101. Monte Carlo-based 3D dosimetry integrating time-activity curves in VOI was performed on 111In-OTSA101 repeated SPECT/CT. Estimated absorbed doses (AD) in normal tissues were compared to biological side effects and to the admitted maximal tolerated absorbed dose (MTD) in normal organs. Results in the tumors were also compared to disease evolution. RESULTS: Biodistribution and tracer quantification were analyzed on repeated SPECT/CT acquisitions performed after injection of 111In-OTSA101 in 19/20 included patients. SPECT images were warped to a common coordinates system with deformable registration. Volumes of interest (VOI) for various lesions and normal tissues were drawn on the first CT acquisition and reported to all the SPECT images. Tracer quantification and residence time of 111In-OTSA101 in VOI were used to evaluate the estimated absorbed doses per MBq of 90Y-OTSA101 by means of Monte Carlo simulations (GATE). A visual scale analysis was applied to assess tumor uptake (grades 0 to 4) and results were compared to the automated quantification. Results were then compared to biological side effects reported in the selected patients treated with 90Y-OTSA101 but also to disease response to treatment. After screening, 8/20 patients were treated with 370 or 1110 MBq 90Y-OTSA101. All demonstrated medullary toxicity, only one presented with transient grade 3 liver toxicity due to disease progression, and two patients presented with transient grade 1 renal toxicity. Median absorbed doses were the highest in the liver (median, 0.64 cGy/MBq; [0.27 -1.07]) being far lower than the 20 Gy liver MTD, and the lowest in bone marrow (median, 0.09 cGy/MBq; [0.02 -0.18]) being closer to the 2 Gy bone marrow MTD. Most of the patients demonstrated progressive disease on RECIST criteria during patient follow-up. 111In-OTSA101 tumors tracer uptake visually appeared highly heterogeneous in inter- and intra-patient analyses, independently of tumor sizes, with variable kinetics. The majority of visual grades corresponded to the automated computed ones. Estimated absorbed doses in the 95 supra-centimetric selected lesions ranged from 0.01 to 0.71 cGy per injected MBq (median, 0.22 cGy/MBq). The maximal tumor AD obtained was 11.5 Gy. CONCLUSIONS: 3D dosimetry results can explain the observed toxicity and tumors response. Despite an intense visual 111In-OTSA101 liver uptake, liver toxicity was not the dose limiting factor conversely to bone marrow toxicity. Even though tumors 111In-OTSA101 avidity was visually obvious for treated patients, the low estimated tumors AD obtained by 3D dosimetry explain the lack of tumor response.