Increased therapeutic effect on medullary thyroid cancer using a combination of radiation and tyrosine kinase inhibitors.

Since patients with medullary thyroid cancer (MTC) often have metastatic disease at the time of diagnosis, the development of efficient systemic treatment options for MTC is important. Vandetanib and cabozantinib are two tyrosine kinase inhibitors (TKIs) that were recently approved by FDA and EMA for systemic treatment of metastatic MTC. Additionally, since MTC is of a neuroendocrine tumour type, treatment with radiolabelled somatostatin analogues (e.g. 177Lu-octreotate) is a valid option for patients with MTC. The aim of this study was to investigate the potentially increased therapeutic effect of combining radiation therapy with these TKIs for treatment of MTC in a mouse model. Nude mice carrying patient-derived MTC tumours (GOT2) were treated with external beam radiotherapy (EBRT) and/or one of the two TKIs vandetanib or cabozantinib. The tumour volume was determined and compared with that of mock-treated controls. The treatment doses were chosen to give a moderate effect as monotherapy to be able to detect any increased therapeutic effect from the combination therapy. At the end of follow-up, tumours were processed for immunohistochemical (IHC) analyses. The animals in the combination therapy groups showed the largest reduction in tumour volume and the longest time to tumour progression. Two weeks after start of treatment, the tumour volume for these mice was reduced by about 70-75% compared with controls. Furthermore, also EBRT and TKI monotherapy resulted in a clear anti-tumour effect with a reduced tumour growth compared with controls. The results show that an increased therapeutic effect could be achieved when irradiation is combined with TKIs for treatment of MTC. Future studies should evaluate the potential of using 177Lu-octreotate therapy in combination with TKIs in patients.

Gemcitabine potentiates the anti-tumour effect of radiation on medullary thyroid cancer.

Patients with medullary thyroid cancer (MTC) are often diagnosed with spread tumour disease and the development of better systemic treatment options for these patients is important. Treatment with the radiolabelled somatostatin analogue 177Lu-octreotate is already a promising option but can be optimised. For example, combination treatment with another substance could increase the effect on tumour tissue. Gemcitabine is a nucleoside analogue that has been shown to sensitise tumour cells to radiation. The aim of this study was to investigate potentially additive or synergistic effects of combining radiation with gemcitabine for treatment of MTC. Nude mice transplanted with patient-derived MTC tumours (GOT2) were divided into groups and treated with radiation and/or gemcitabine. Radiation treatment was given as 177Lu-octreotate or external beam radiotherapy (EBRT). The volume of treated and untreated tumours was followed. The absorbed dose and amount of gemcitabine were chosen to give moderate tumour volume reduction when given as monotherapy to enable detection of increased effects from combination treatment. After follow-up, the mice were killed and tumours were immunohistochemically (IHC) analysed. Overall, the animals that received a combination of EBRT and gemcitabine showed the largest reduction in tumour volume. Monotherapy with EBRT or gemcitabine also resulted in a clear detrimental effect on tumour volume, while the animals that received 177Lu-octreotate monotherapy showed similar response as the untreated animals. The GOT2 tumour was confirmed in the IHC analyses by markers for MTC. The IHC analyses also revealed that the proliferative activity of tumour cells was similar in all tumours, but indicated that fibrotic tissue was more common after EBRT and/or gemcitabine treatment. The results indicate that an additive, or even synergistic, effect may be achieved by combining radiation with gemcitabine for treatment of MTC. Future studies should be performed to evaluate the full potential of combining 177Lu-octreotate with gemcitabine in patients.

Local treatment of liver metastases by administration of 177Lu-octreotate via isolated hepatic perfusion - A preclinical simulation of a novel treatment strategy.

INTRODUCTION: Systemic 177Lu-octreotate treatment for metastatic neuroendocrine tumours is restricted by organs at risk. By administering 177Lu-octreotate during isolated hepatic perfusion (IHP), the uptake in organs at risk might be strongly reduced. The aim of this study was to investigate the feasibility to use the combination of IHP and radionuclide therapy. METHODS: To simulate IHP, the liver of a pig was prepared for ex vivo perfusion. Blood containing 490 MBq 177Lu-octreotate was circulated through the liver for 60 min, after which the liver was rinsed. After IHP, the liver was examined by SPECT/CT. Lastly, an intraoperative gamma detector (IGD) was used to determine 177Lu activity concentration in the liver and results were compared with the activity concentration in corresponding liver biopsies. RESULTS: Detector measurements over the liver during the IHP showed a fast increase with a maximum after approximately 10-15 min. After IHP, about 75% of the 177Lu in the liver could be washed out. The SPECT/CT images revealed a relatively inhomogeneous distribution. Nevertheless, the IGD values of 177Lu activity concentration showed acceptable agreement with the biopsy values. CONCLUSIONS: Our results in pig show that it could be feasible to treat patients with liver metastases from NETs with 177Lu-octreotate via IHP 177. However, an inhomogeneous distribution of 177Lu-octreotate in normal liver tissue is expected, and in order to determine the activity concentration with satisfactory accuracy using an IGD, measurements need to be performed at several positions over the liver.

177Lu-octreotate therapy for neuroendocrine tumours is enhanced by Hsp90 inhibition.

177Lu-octreotate is an FDA-approved radionuclide therapy for patients with gastroenteropancreatic neuroendocrine tumours (NETs) expressing somatostatin receptors. The 177Lu-octreotate therapy has shown promising results in clinical trials by prolonging progression-free survival, but complete responses are still uncommon. The aim of this study was to improve the 177Lu-octreotate therapy by means of combination therapy. To identify radiosensitising inhibitors, two cell lines, GOT1 and P-STS, derived from small intestinal neuroendocrine tumours (SINETs), were screened with 1,224 inhibitors alone or in combination with external radiation. The screening revealed that inhibitors of Hsp90 can potentiate the tumour cell-killing effect of radiation in a synergistic fashion (GOT1; false discovery rate <3.2×10-11). The potential for Hsp90 inhibitor ganetespib to enhance the anti-tumour effect of 177Lu-octreotate in an in vivo setting was studied in the somatostatin receptor-expressing GOT1 xenograft model. The combination led to a larger decrease in tumour volume relative to monotherapies and the tumour-reducing effect was shown to be synergistic. Using patient-derived tumour cells from eight metastatic SINETs, we could show that ganetespib enhanced the effect of 177Lu-octreotate therapy for all investigated patient tumours. Levels of Hsp90 protein expression were evaluated in 767 SINETs from 379 patients. We found that Hsp90 expression was upregulated in tumour cells relative to tumour stroma in the vast majority of SINETs. We conclude that Hsp90 inhibitors enhance the tumour-killing effect of 177Lu-octreotate therapy synergistically in SINET tumour models and suggest that this potentially promising combination should be further evaluated.

Evaluation of two intraoperative gamma detectors for assessment of 177Lu activity concentration in vivo.

BACKGROUND: Patients with somatostatin receptor-expressing neuroendocrine tumours can be treated with intravenously administered 177Lu-octreotate. Few patients are cured with the present protocol due to the current dose limitation of normal organs at risk, such as the kidneys. By locally administering 177Lu-octreotate to the liver for the purpose of treating liver metastases, a substantially reduced absorbed dose to organs at risk could be achieved. The development of such a technique requires the capability of measuring the 177Lu activity concentration in tissues in vivo. The aim of this study was to evaluate different performance parameters of two commercially available intraoperative gamma detectors in order to investigate whether intraoperative gamma detector measurements could be used to determine 177Lu activity concentration in vivo. RESULTS: Measurements were made using different sources containing 177Lu. Response linearity, sensitivity, spatial resolution and its depth dependence, organ thickness dependence of the measured count rate and tumour detectability were assessed for two intraoperative gamma detectors. The two detectors (a scintillation and a semiconductor detector) showed differences in technical performance. For example, the sensitivity was higher for the scintillation detector, while the spatial resolution was better for the semiconductor detector. Regarding organ thickness dependence and tumour detectability, similar results were obtained for both detectors, and even relatively small simulated tumours of low tumour-to-background activity concentration ratios could be detected. CONCLUSIONS: Acceptable results were obtained for both detectors, although the semiconductor detector proved more advantageous for our purpose. The measurements demonstrated factors that must be corrected for, such as organ thickness or dead-time effects. Altogether, intraoperative gamma detector measurements could be used to determine 177Lu activity concentration in vivo.

OPTIMISATION OF OCCUPATIONAL RADIATION PROTECTION IN IMAGE-GUIDED INTERVENTIONS: EXPLORING VIDEO RECORDINGS AS A TOOL IN THE PROCESS.

The overall purpose of this work was to explore how video recordings can contribute to the process of optimising occupational radiation protection in image-guided interventions. Video-recorded material from two image-guided interventions was produced and used to investigate to what extent it is conceivable to observe and assess dose-affecting actions in video recordings. Using the recorded material, it was to some extent possible to connect the choice of imaging techniques to the medical events during the procedure and, to a less extent, to connect these technical and medical issues to the occupational exposure. It was possible to identify a relationship between occupational exposure level to staff and positioning and use of shielding. However, detailed values of the dose rates were not possible to observe on the recordings, and the change in occupational exposure level from adjustments of exposure settings was not possible to identify. In conclusion, the use of video recordings is a promising tool to identify dose-affecting instances, allowing for a deeper knowledge of the interdependency between the management of the medical procedure, the applied imaging technology and the occupational exposure level. However, for a full information about the dose-affecting actions, the equipment used and the recording settings have to be thoroughly planned.

Derivation and application of dose reduction factors for protective eyewear worn in interventional radiology and cardiology.

Doses to the eyes of interventional radiologists and cardiologists could exceed the annual limit of 20 mSv proposed by the International Commission on Radiological Protection. Lead glasses of various designs are available to provide protection, but standard eye dosemeters will not take account of the protection they provide. The aim of this study has been to derive dose reduction factors (DRFs) equal to the ratio of the dose with no eyewear, divided by that when lead glasses are worn. Thirty sets of protective eyewear have been tested in x-ray fields using anthropomorphic phantoms to simulate the patient and clinician in two centres. The experiments performed have determined DRFs from simulations of interventional procedures by measuring doses to the eyes of the phantom representing the clinician, using TLDs in Glasgow, Scotland and with an electronic dosemeter in Gothenburg, Sweden. During interventional procedures scattered x-rays arising from the patient will be incident on the head of the clinician from below and to the side. DRFs for x-rays incident on the front of lead glasses vary from 5.2 to 7.6, while values for orientations similar to those used in the majority of clinical practice are between 1.4 and 5.2. Specialised designs with lead glass side shields or of a wraparound style with angled lenses performed better than lead glasses based on the design of standard spectacles. Results suggest that application of a DRF of 2 would provide a conservative factor that could be applied to personal dosemeter measurements to account for the dose reduction provided by any type of lead glasses provided certain criteria relating to design and consistency of use are applied.