Peptide Receptor Radionuclide Therapy - Prospects for Personalised Treatment.

Peptide receptor radionuclide therapy is a type of molecular radiotherapy that has been used in the treatment of patients with neuroendocrine tumours for over two decades. It is not until recently, however, that it has achieved regulatory approval. The currently approved treatment regimen is a one-size-fits-all scheme, i.e. all patients receive a fixed activity of the radiopharmaceutical (177Lu-DOTATATE) and a fixed number of treatment cycles. Several research groups around the world have studied different approaches of further improving on the results of peptide receptor radionuclide therapy, with many promising retrospective and prospective clinical studies having been published over the years. In this overview, we summarise some of the most promising strategies identified so far.

Dosimetry in patients with B-cell lymphoma treated with [(90)Y]ibritumomab tiuxetan or [(131)I]tositumomab.

Radioimmunotherapy involves the use of radiolabeled monoclonal antibodies (MAbs) to treat malignancy. The therapeutic effect is determined by the radiopharmaceutical, the radiation absorbed dose and previous treatments. There are currently two approved radiopharmaceuticals for the treatment of B-cell lymphoma - the (90)Y-labeled ibritumomab and the (131)I-labeled tositumomab. Both are directed against CD20, albeit not against the same epitope. This paper summarizes current results of dose-responses for normal tissues and tumours of [(131)I]tositumomab and [(90)Y]ibritumomab tiuxetan, discusses them in the context of dosimetry methods used and highlights the assumptions being made in the different dosimetry methodologies. Moreover, we wish to point at the possibility of performing low-cost therapy bremsstrahlung imaging for [(90)Y]ibritumomab tiuxetan to confirm biodistribution, and possibly also for dosimetric calculations.

Registration of serial SPECT/CT images for three-dimensional dosimetry in radionuclide therapy.

For radionuclide therapy, individual patient pharmacokinetics can be measured in three dimensions by sequential SPECT imaging. Accurate registration of the time series of images is central for voxel-based calculations of the residence time and absorbed dose. In this work, rigid and non-rigid methods are evaluated for registration of 6-7 SPECT/CT images acquired over a week, in anatomical regions from the head-and-neck region down to the pelvis. A method for calculation of the absorbed dose, including a voxel mass determination from the CT images, is also described. Registration of the SPECT/CT images is based on a CT-derived spatial transformation. Evaluation is focused on the CT registration accuracy, and on its impact on values of residence time and absorbed dose. According to the CT evaluation, the non-rigid method produces a more accurate registration than the rigid one. For images of the residence time and absorbed dose, registration produces a sharpening of the images. For volumes-of-interest, the differences between rigid and non-rigid results are generally small. However, the non-rigid method is more consistent for regions where non-rigid patient movements are likely, such as in the head-neck-shoulder region.

Evaluation of quantitative (90)Y SPECT based on experimental phantom studies.

In SPECT imaging of pure beta emitters, such as (90)Y, the acquired spectrum is very complex, which increases the demands on the imaging protocol and the reconstruction. In this work, we have evaluated the quantitative accuracy of bremsstrahlung SPECT with focus on the reconstruction algorithm including model-based attenuation, scatter and collimator-detector response (CDR) compensations. The scatter and CDR compensation methods require pre-calculated point-spread functions, which were generated with the SIMIND MC program. The SIMIND program is dedicated for simulation of scintillation camera imaging and only handles photons. The aim of this work was therefore twofold. The first aim was to implement simulation of bremsstrahlung imaging into the SIMIND code and to validate simulations against experimental measurements. The second was to investigate the quality of bremsstrahlung SPECT imaging and to evaluate the possibility of quantifying the activity in differently shaped sources. In addition, a feasibility test was performed on a patient that underwent treatment with (90)Y-Ibritumomab tiuxetan (Zevalin). The MCNPX MC program was used to generate bremsstrahlung photon spectra which were used as source input in the SIMIND program. The obtained bremsstrahlung spectra were separately validated by experimental measurement using a HPGe detector. Validation of the SIMIND generated images was done by a comparison to gamma camera measurements of a syringe containing (90)Y. Results showed a slight deviation between simulations and measurements in image regions outside the source, but the agreement was sufficient for the purpose of generating scatter and CDR kernels. For the bremsstrahlung SPECT experiment, the RSD torso phantom with (90)Y in the liver insert was measured with and without background activities. Projection data were obtained using a GE VH/Hawkeye system. Image reconstruction was performed by using the OSEM algorithm with and without different combinations of model-based attenuation, scatter and CDR compensations. The reconstructed images were then evaluated in terms of the accuracy of the total activity estimate in the liver insert. It was found that the activity in a large source such as the liver was estimated with a bias of around -70%, when no compensations were included in the reconstruction, whereas when compensations were included the bias obtained was between -10 and 16%. It is concluded that although the (90)Y bremsstrahlung spectrum is continuous with no pronounced peak and the count rate is low, it is possible to achieve reasonably accurate activity estimates from bremsstrahlung SPECT images if proper compensations are applied in the reconstruction. This conclusion was also confirmed by the patient study.