Papillary thyroid cancer (PTC) and poorly differentiated thyroid cancer (PDTC) are treated with radioiodine to reduce recurrence and to treat the spread of disease. Adequate iodine accumulation in cancer tissue, iodine avidity, is important for treatment effect. This study investigated which clinical and histological tumour characteristics correlate with avidity. To quantify avidity in cancer tissue, tracer amounts of iodine-131 were given to 45 patients with cytologically confirmed thyroid cancer. At pathology grossing, representative samples of tumour and lymph nodes were taken and subjected to radioactivity quantification ex vivo to determine avidity. Afterwards, samples underwent extended pathology work-up and analysis. We found that tumoural Tg expression and Ki-67 index were correlated with avidity, whereas tumour size and pT stage were not. The histological variant of thyroid cancer was also correlated with iodine avidity. Variants associated with worse clinical prognoses displayed lower avidity than variants with better prognoses. This work provides new information on which tumours have low iodine avidity. Lower avidity in aggressive histological PTC variants may explain their overall poorer prognoses. Our findings also suggest that radioiodine dosage could be adapted to Tg expression, Ki-67 index or histological variant instead of pT stage, potentially improving the efficacy of radioiodine therapy.

BackgroundHalf the children with high-risk neuroblastoma die with widespread metastases. Molecular radiotherapy is an attractive systemic treatment for this relatively radiosensitive tumor. 131I-mIBG is the most widely used form in current use, but is not universally effective. Clinical trials of 177Lutetium DOTATATE have so far had disappointing results, possibly because the administered activity was too low, and the courses were spread over too long a period of time, for a rapidly proliferating tumor. We have devised an alternative administration schedule to overcome these limitations. This involves two high-activity administrations of single agent 177Lu-DOTATATE given 2 weeks apart, prescribed as a personalized whole body radiation absorbed dose, rather than a fixed administered activity. “A phase II trial of 177Lutetium-DOTATATE in children with primary refractory or relapsed high-risk neuroblastoma - LuDO-N” (EudraCT No: 2020-004445-36, ClinicalTrials.gov Identifier: NCT04903899) evaluates this new dosing schedule.MethodsThe LuDO-N trial is a phase II, open label, multi-center, single arm, two stage design clinical trial. Children aged 18 months to 18 years are eligible. The trial is conducted by the Nordic Society for Pediatric Hematology and Oncology (NOPHO) and it has been endorsed by SIOPEN (https://www.siopen.net). The Karolinska University Hospital, is the sponsor of the LuDO-N trial, which is conducted in collaboration with Advanced Accelerator Applications, a Novartis company. All Scandinavian countries, Lithuania and the Netherlands participate in the trial and the UK has voiced an interest in joining in 2022.ResultsThe pediatric use of the Investigational Medicinal Product (IMP) 177Lu-DOTATATE, as well as non-IMPs SomaKit TOC® (68Ga-DOTATOC) and LysaKare® amino acid solution for renal protection, have been approved for pediatric use, within the LuDO-N Trial by the European Medicines Agency (EMA). The trial is currently recruiting. Recruitment is estimated to be finalized within 3–5 years.DiscussionIn this paper we present the protocol of the LuDO-N Trial. The rationale and design of the trial are discussed in relation to other ongoing, or planned trials with similar objectives. Further, we discuss the rapid development of targeted radiopharmaceutical therapy and the future perspectives for developing novel therapies for high-risk neuroblastoma and other pediatric solid tumors.

Purpose To evaluate if satisfactory post-therapeutic image-based dosimetry can be achieved for Lu-177-DOTATATE treatments using a reduced number of image acquisitions to improve patient comfort and reduce economical costs. Methods 39 patients who underwent 147 treatment cycles of Lu-177-DOTATATE for neuroendocrine tumors were included in the study. A total of 291 and 284 absorbed doses were calculated to kidneys and tumors, respectively. Single-point dosimetry was performed using one SPECT/CT image acquired at 1 d or 7 d post-treatment using a fixed effective half-life (Teff) or using a patient-specific Teff determined for the initial cycle. Also, dose-per-activity values, (D/A)1, were determined from the first cycle and used to calculate doses for subsequent cycles. All absorbed doses were evaluated against “true” doses calculated using both the 1 d and 7 d images. The relation between tumor grade and absorbed doses was also investigated. All dosimetry was performed on SPECT images. Results Absorbed doses to kidneys were most accurate when single-point dosimetry was performed using 1 d images with median ratios in relation to “true” doses in total dose of 1.00 (IQR: 0.97–1.03) when using fixed Teff and 1.01 (IQR: 0.98–1.04) when using Teff from the initial cycle. Calculations based on the 7 d image were most accurate for tumors with corresponding ratios in total absorbed dose of 0.98 (IQR: 0.96–1.00) and 1.00 (IQR: 0.99–1.01) when using a fixed Teff or Teff from the first cycle, respectively. The (D/A)1 approach performed worse, as 2 of 77 total absorbed doses to the kidneys deviated with > 30%, and tumor-absorbed doses were increasingly overestimated with every cycle. Absorbed doses, Teff and 1 d uptake were higher for G1 tumors than G2 tumors. Conclusion Dosimetry can be performed with satisfactory accuracy when using single SPECT/CT images acquired at 1 d for kidneys or at 7 d for tumors.