Relationship Between Absorbed Dose and Response in Neuroendocrine Tumors Treated with [Lu]Lu-DOTATATE.

Peptide receptor radionuclide therapy presents the possibility of tracing and quantifying the uptake of the drug in the body and performing dosimetry, potentially allowing individualization of treatment schemes. However, the details of how neuroendocrine tumors (NETs) respond to different absorbed doses are insufficiently known. Here, we investigated the relationship between tumor-absorbed dose and tumor response in a cohort of patients with NETs treated with [Lu]Lu-DOTATATE.

Phase II trial demonstrates the efficacy and safety of individualized, dosimetry-based Lu-DOTATATE treatment of NET patients.

Purpose: Radionuclide therapy with Lu-DOTATATE is well established for patients with advanced somatostatin receptor-positive neuroendocrine tumors with a standard schedule of 7.4 GBq at four occasions. However, this approach does not consider individual variability affecting the tumor radiation dose or dose to organs at risk.

Increased risk of Graves´ophthalmopathy in patients with increasing TRAb after radioiodine treatment and the impact of CTLA4 on TRAb titres.

Introduction: Treatment of Graves´ disease (GD) with radioiodine increases the risk of developing Graves´ ophthalmopathy (GO), and the link between thyroid and orbital tissue may be the presence of TSH-receptors. Radioiodine increases the titers of TRAb and the aim was to investigate the relationship between GO and TRAb titers after treatment with radioiodine and to define the impact of risk genes.

Methods: GD patients without ophthalmopathy or previous treatment with radioiodine were prospectively included at treatment with radioiodine for hyperthyroidism.

Dosimetric Quantities in Neuroendocrine Tumors over Treatment Cycles with Lu-DOTATATE.

Tumor dosimetry was performed for Lu-DOTATATE with the aims of better understanding the range and variation of the tumor-absorbed doses (ADs), how different dosimetric quantities evolve over the treatment cycles, and whether this evolution differs depending on the tumor grade. Such information is important for radiobiologic interpretation and may inform the design of alternative administration schemes. The data came from 41 patients with neuroendocrine tumors (NETs) of grade 1 ( = 23) or 2 ( = 18) who had received between 2 and 9 treatment cycles.

Pituitary Function after High-Dose 177Lu-DOTATATE Therapy and Long-Term Follow-Up.

Introduction: The pituitary gland has a high expression of somatostatin receptors and is therefore a potential organ at risk for radiation-induced toxicity after 177Lu-DOTATATE treatment.

Objective: To study changes in pituitary function in patients with neuroendocrine tumors (NETs) treated with dosimetry-based 177Lu-DOTATATE to detect possible late toxicity.

Methods: 68 patients from a phase II clinical trial of dosimetry-based, individualized 177Lu-DOTATATE therapy were included in this analysis.

Substantial intrinsic variability in chemoradiosensitivity of newly established anaplastic thyroid cancer cell-lines.

Well characterized human cell lines are needed for preclinical treatment studies of anaplastic thyroid cancer (ATC). The aim was to establish, verify and characterize a panel of ATC cell lines. Cell lines were established from ATC fine-needle aspiration biopsies and characterized genetically and functionally regarding treatment sensitivities.

The Effect of Radioiodine Treatment on TRAb, Anti-TPO, and Anti-TG in Graves' Disease.

Background: In Graves' disease (GD), immunocompetent cells infiltrate thyroid tissue with release of TSH-receptor antibodies (TRAb), and radioiodine treatment is known to elicit an immune response with an increase in TRAb.

Objectives: The aim was to study if all patients treated with radioiodine respond with a release of TRAb, anti-thyroperoxidase (anti-TPO), and anti-thyroglobulin (anti-TG).

Methods: This is a prospective observational study.

Feasibility of simplifying renal dosimetry in Lu peptide receptor radionuclide therapy.

Background: Recently, Lu-dotatate therapy for neuroendocrine tumours has received regulatory approval. Dosimetry can be used to optimize treatment on an individual basis, but there is no international consensus as to how it should be done. The aim of this study is to determine a feasible and accurate dosimetry method to guide individualized peptide receptor radionuclide therapy (PRRT) for patients with neuroendocrine tumours.

Individualised Lu-DOTATATE treatment of neuroendocrine tumours based on kidney dosimetry.

Purpose: To present data from an interim analysis of a Phase II trial designed to determine the feasibility, safety, and efficacy of individualising treatment based on renal dosimetry, by giving as many cycles as possible within a maximum renal biologically effective dose (BED).

Method: Treatment was given with repeated cycles of 7.4 GBq Lu-DOTATATE at 8-12-week intervals.

Evaluation of immune cell markers in tumor tissue treated with radioimmunotherapy in an immunocompetent rat colon carcinoma model.

Background: Immune cells within the tumor can act either to promote growth or rejection of tumor cells. The aim of the present study was to evaluate immune cell markers (number and localization) within the tumor before and during rejection due to radioimmunotherapy, to determine whether there is a change in markers related to rejection and/or tolerance of the tumor cells.

Methods: Thirty immunocompetent rats were inoculated with syngeneic rat colon carcinoma cells and 13-14 days later 21 of these rats were treated with 400 MBq/kg of (177)Lu-DOTA-BR96 monoclonal antibodies.

Long-Term Retention of 177Lu/177mLu-DOTATATE in Patients Investigated by γ-Spectrometry and γ-Camera Imaging.

Unlabelled: Dosimetry in peptide receptor radionuclide therapy using (177)Lu-DOTATATE is based on patient imaging during the first week after administration and determination of the activity retention as a function of time for different tissues. For calculation of the absorbed dose, it is generally assumed that the long-term activity retention follows the pattern determined from the first week. This work aimed to investigate the validity of this assumption by performing additional patient measurements between 5 and 10 wk after administration.

Role of CD8-positive cells in radioimmunotherapy utilizing (177)Lu-mAbs in an immunocompetent rat colon carcinoma model.

Background: CD8-positive cells might play a crucial role in the therapeutic response to radiation, which has however not been investigated in radioimmunotherapy (RIT). The aim of this study was to evaluate whether cytotoxic T cells affect the response of established tumors and, above all, if they delay or prevent the development of distant metastases after RIT, using an immunocompetent syngeneic rat colon carcinoma model.

Methods: The cytotoxic T cells were depleted in 15 rats by anti-CD8 before the injection of the radioimmunoconjugate (400 MBq/kg body weight (177)Lu-BR96, which binds to the tumor-associated antigen Lewis Y).

Sequential radioimmunotherapy with 177Lu- and 211At-labeled monoclonal antibody BR96 in a syngeneic rat colon carcinoma model.

Unlabelled: Alpha-particle emitters, such as astatine-211 (211At), are generally considered suitable for the treatment of small cell clusters due to their short path length, while beta-particle emitters, for example, Lutetium-177 (177Lu), have a longer path length and are considered better for small, established tumors. A combination of such radionuclides may be successful in regimens of radioimmunotherapy. In this study, rats were treated by sequential administration of first a 177Lu-labeled antibody, followed by a 211At-labeled antibody 25 days later.

Change in cell death markers during (177)Lu-mAb radioimmunotherapy-induced rejection of syngeneic rat colon carcinoma.

Purpose: To monitor cell death in tumors during the rejection process after treatment with an antibody radiolabeled with a β-emitter.

Methods: Tumors during rejection after treatment with (177)Lu-labeled antibody BR96 and after administration of unlabeled BR96 were compared with untreated tumors from the same immunocompetent syngeneic rat tumor model. Cell death was monitored with the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and immunohistochemical staining of activated caspase-3 and γH2AX.

The intratumoral distribution of radiolabeled 177Lu-BR96 monoclonal antibodies changes in relation to tumor histology over time in a syngeneic rat colon carcinoma model.

Unlabelled: The therapeutic effect of radioimmunotherapy depends on the distribution of the absorbed dose in relation to viable cancer cells within the tumor, which in turn is a function of the activity distribution. The aim of this study was to investigate the distribution of (177)Lu-DOTA-BR96 monoclonal antibodies targeting the Lewis Y antigen over 7 d using a syngeneic rat model of colon carcinoma.

Methods: Thirty-eight tumor-bearing rats were intravenously given 25 or 50 MBq of (177)Lu-DOTA-BR96 per kilogram of body weight and were sacrificed 2, 8, 24, 48, 72, 96, 120, or 168 h after injection, with activity measured in blood and tumor samples.

Successful radioimmunotherapy of established syngeneic rat colon carcinoma with 211At-mAb.

Background: Most carcinomas are prone to metastasize despite successful treatment of the primary tumor. One way to address this clinical challenge may be targeted therapy with α-emitting radionuclides such as astatine-211 (211At). Radioimmunotherapy utilizing α-particle emitting radionuclides is considered especially suitable for the treatment of small cell clusters and single cells, although lesions of different sizes may also be present in the patient.

Pattern of antigen expression in metastases after radioimmunotherapy of a syngeneic rat colon carcinoma utilizing the BR96 antibody.

Background: Repeated administration of antibody-based therapies such as radioimmunotherapy depends on preserved antigen expression in tumor lesions. The purpose of this study was to evaluate whether the antigen expression in metastases observed after radioimmunotherapy differs from that of untreated primary tumors.

Findings: 30 of the 35 Brown Norway rats with syngeneic colon carcinoma treated with 400 MBq/kg 177Lu-DOTA-BR96 exhibited consistent complete response of the primary tumor.

Two-year survival follow-up of the randomized, double-blind, placebo-controlled phase II study of radium-223 chloride in patients with castration-resistant prostate cancer and bone metastases.

Background: This phase II randomized, placebo-controlled study was conducted to evaluate efficacy and safety of radium-223 in patients with castration-resistant prostate cancer (CRPC) and painful bone metastases. Twelve- and 18-month survival results were reported previously. Here we report 24-month overall survival (OS) and safety data from the period 12 to 24 months after the first injection of study medication.

Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial.

Background: No effective standard treatment exists for patients with radioiodine-refractory, advanced differentiated thyroid carcinoma. We aimed to assess efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signalling, in this setting.

Methods: In this randomised, double-blind, phase 2 trial, we enrolled adults (aged ≥18 years) with locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated) at 16 European medical centres.

Use of Monte Carlo simulations with a realistic rat phantom for examining the correlation between hematopoietic system response and red marrow absorbed dose in Brown Norway rats undergoing radionuclide therapy with (177)Lu- and (90)Y-BR96 mAbs.

Purpose: Biokinetic and dosimetry studies in laboratory animals often precede clinical radionuclide therapies in humans. A reliable evaluation of therapeutic efficacy is essential and should be based on accurate dosimetry data from a realistic dosimetry model. The aim of this study was to develop an anatomically realistic dosimetry model for Brown Norway rats to calculate S factors for use in evaluating correlations between absorbed dose and biological effects in a preclinical therapy study.

Treatment with unlabeled mAb BR96 after radioimmunotherapy with 177Lu-DOTA-BR96 in a syngeneic rat colon carcinoma model.

Metastatic disease after successful treatment of the primary tumor continues to be a therapeutic challenge. Enhancement of therapeutic effects by the administration of unlabeled monoclonal antibodies (mAbs) after radioimmunotherapy (RIT) may provide a means of preventing or delaying the development of metastatic disease. In the present study, Brown Norway rats with syngeneic grafted colon carcinomas were administered the minimal effective therapeutic dose of 400 MBq/kg lutetium-177 ((177)Lu)-DOTA-BR96.

Repeated radioimmunotherapy with 177Lu-DOTA-BR96 in a syngeneic rat colon carcinoma model.

Aim: Fractionation is generally used as a mean to improve radioimmunotherapy (RIT). Since RIT is considered suitable for small-volume disease, the aim of the current study was to investigate whether repeated administration of (177)Lu-labeled mAb BR96 was tolerated and could delay or prevent metastatic disease after complete remission of the tumor obtained by the first administration.

Methods: Immunocompetent rats bearing a syngeneic colon carcinoma were first treated with 400 MBq/kg (177)Lu-DOTA-BR96, an activity resulting in complete response in 29 of 30 animals.