Heribert Hänscheid

In Vivo Formation of γ-H2AX and 53BP1 DNA Repair Foci in Blood Cells After Radioiodine Therapy of Differentiated Thyroid Cancer

DNA double-strand breaks (DSBs) are critical cellular lesions that can result from ionizing radiation exposure. A marker for DSB formation is the phosphorylated form of the histone H2 variant H2AX (γ-H2AX). DSBs also attract the damage sensor p53-binding protein 1 (53BP1) to the DSB-containing chromatin, because 53BP1 associates with the DSB-surrounding chromatin. We studied the induction, persistence, and disappearance of radiation-induced γ-H2AX and 53BP1 foci after the first 131I therapy of patients with differentiated thyroid carcinoma, a model for protracted, continuous, internal whole-body irradiation. Methods: Twenty-six patients (7 men, 19 women; mean age ± SD, 42 ± 13 y) underwent posttherapeutic blood dosimetry according to the standard operating procedure of the European Association of Nuclear Medicine, including peripheral blood sampling and external dose rate measurements at 2–144 h after administration of 131I for thyroid remnant ablation. The mean time curves of dose accumulation and dose rate to the blood were compared with the mean γ-H2AX and 53BP1 foci counts over the same period in samples of mononuclear peripheral blood leukocytes. Results: The mean absorbed dose to the blood in 24 patients evaluable for physical dosimetry was 0.31 ± 0.10 Gy (minimum, 0.17 Gy; maximum, 0.57 Gy). After 24 h, the mean daily dose increment was less than 0.05 Gy. The excess focus counts per nucleus—that is, nuclear foci in excess of the low background count—peaked at 2 h after radioiodine administration (median excess foci for γ-H2AX [n = 21 patients], 0.227, and for 53BP1 [n = 19 patients], 0.235) and progressively declined thereafter. Significantly elevated numbers of excess focus counts per nucleus (median excess foci for γ-H2AX [n = 8 patients], 0.054, and for 53BP1 [n = 6 patients], 0.046) still were present at 120–144 h after therapy. Because the rate of occurrence of radiation-induced focus counts per nucleus per absorbed dose varied considerably among patients, a dose–response relationship could not be established for this series as a whole. The number of excess radiation-induced focus counts per nucleus per absorbed dose rate increased with time, potentially indicating a slower rate of DNA repair or, alternatively, a higher de novo rate of focus formation. The values over time of both radiation-induced DSB markers correlated closely (r2 = 0.973). Conclusion: Radiation-induced γ-H2AX and 53BP1 nuclear foci are useful markers for detecting radiation exposure after radionuclide incorporation, even for absorbed doses to the blood below 20 mGy.

Long-Term Survival in Differentiated Thyroid Cancer Is Worse After Low-Activity Initial Post-Surgical 131I Therapy in Both High- and Low-Risk Patients

CONTEXT Recent trial results have revived interest in low-activity initial (131)I therapy (RIT) of differentiated thyroid cancer (DTC). OBJECTIVE This study sought to compare different initial (131)I activities for outcome. DESIGN AND SETTING A database study was performed in a University hospital. PATIENTS 1298 DTC patients were included (698 low risk, 434 high risk M0, and 136 M1), grouped according to ablation activity (I, ≤ 2000 MBq [54 mCi]; II, 2000-3000 MBq [54-81 mCi]; and III, >3000 MBq [81 mCi]), subdivided by age (<45 and ≥ 45 y at diagnosis). MAIN OUTCOME MEASURES Complete remission (CR, defined as thyroglobulin [Tg] below functional sensitivity combined with visually negative (131)I diagnostic whole-body scintigraphy), recurrence, DTC-specific mortality, and relative survival rates were studied. RESULTS Low-risk patients: In patients <45 years, a lower median cumulative activity was required to achieve CR in group III (3590 MBq) than in groups I (8050 MBq) and II (6300 MBq). In patients at least 45 years of age, DTC-specific mortality was significantly higher in group I than in groups II and III (15-y: 16.1 ± 7.7%, 0.8 ± 0.8%, and 7.2 ± 5.5%, respectively; P = .004). High-risk M0 patients: In patients at least 45 years of age, the recurrence rate (15-y: 44.4 ± 16.6%, 24.1 ± 7.6%, and 8.6 ± 3.9%; P = .001) and DTC-specific mortality (15-y: 51.8 ± 15.8%, 13.2 ± 4.4%, and 9.5 ± 3.7%; P = .004) were significantly higher in group I than in groups II and III. M1 patients: There were no significant differences in survival results between different activity groups in either age category. CONCLUSION Before adopting low initial activity RIT for, especially older, low-risk patients, results of long-term followup should be regarded critically. Low-activity RIT in older, high-risk patients is not to be recommended.

Radioiodine for remnant ablation and therapy of metastatic disease

Radioiodine is considered an effective and low-risk therapy modality of advanced differentiated thyroid cancer. For patients without lymph-node or distant metastases and low stages of the primary tumor, debate is ongoing about the necessity of thyroid remnant tissue ablation in an adjuvant setting. On the basis of evidence from retrospective studies, and until results of ongoing controlled prospective randomized trials become available, 131I ablation of remnant thyroid tissue in patients with primary tumors >1 cm is advisable. For thyroid remnant ablation, individual dosimetry is not obligatory. By contrast, the effectiveness of 131I therapy of locally advanced and/or metastatic disease can be improved by individual dosimetry. For practical reasons, an approach delivering the maximal possible radiation dose to the tumor without exceeding a critical blood dose of approximately 2 Gy seems advantageous. The availability of recombinant human TSH (rhTSH) has improved the quality of life of patients and reduces the radiation exposure of healthy nonthyroid tissue compared with TSH stimulation through levothyroxine withdrawal. In patients with distant metastases, rhTSH stimulation is possible only in off-label use, from which especially elderly and frail patients may benefit, as they most severely suffer from hypothyroidism caused by thyroid hormone withdrawal.

EANM Dosimetry Committee Series on Standard Operational Procedures for Pre-Therapeutic Dosimetry II. Dosimetry prior to radioiodine therapy of benign thyroid diseases

The EANM Dosimetry Committee Series “Standard Operational Procedures for Pre-Therapeutic Dosimetry” (SOP) provides advice to scientists and clinicians on how to perform patient-specific absorbed dose assessments. This particular SOP describes how to tailor the therapeutic activity to be administered for radioiodine therapy of benign thyroid diseases such as Graves’ disease or hyperthyroidism. Pretherapeutic dosimetry is based on the assessment of the individual 131I kinetics in the target tissue after the administration of a tracer activity. The present SOP makes proposals on the equipment to be used and guides the user through the measurements. Time schedules for the measurement of the fractional 131I uptake in the diseased tissue are recommended and it is shown how to calculate from these datasets the therapeutic activity necessary to administer a predefined target dose in the subsequent therapy. Potential sources of error are pointed out and the inherent uncertainties of the procedures depending on the number of measurements are discussed. The theoretical background and the derivation of the listed equations from compartment models of the iodine kinetics are explained in a supplementary file published online only.

Blood dosimetry from a single measurement of the whole body radioiodine retention in patients with differentiated thyroid carcinoma

A simple method is presented to estimate the radiation-absorbed dose to the blood after radioiodine administration from a single external measurement of the whole-body retention in patients suffering from differentiated thyroid cancer. The blood dose is calculated applying the formalism of the Medical International Radiation Dose Committee under the assumptions that whole-body activity decays exponentially and that 14% of the whole-body residence time can be attributed to the blood. Accuracy and applicability of the method were tested based on data from 29 assessments, 18 pre-therapeutic tracer studies, and 11 ablation therapies, with whole-body and blood-retention measurements over at least 4 days. The mean of the absolute deviations between estimates and actual blood doses was found to be 14%, if external whole-body counting was performed on day 1 or 2 after radioiodine administration. This simple formalism is: 1) applicable to pre-therapeutic dosimetry for remnant ablation or treatment of metastases in a blood dose-based treatment concept and 2) applicable to blood-dose estimates after radioiodine therapy to determine radiation exposure. When combined with a measurement of the whole body retention 1 or 2 days after radioiodine administration this single time-point method closely approximates the classic, yet much more labor intensive multi-day dosimetry that measures both blood and whole-body activities.

Molecular radiotherapy: The NUKFIT software for calculating the time-integrated activity coefficient

PURPOSE Calculation of the time-integrated activity coefficient (residence time) is a crucial step in dosimetry for molecular radiotherapy. However, available software is deficient in that it is either not tailored for the use in molecular radiotherapy and/or does not include all required estimation methods. The aim of this work was therefore the development and programming of an algorithm which allows for an objective and reproducible determination of the time-integrated activity coefficient and its standard error. METHODS The algorithm includes the selection of a set of fitting functions from predefined sums of exponentials and the choice of an error model for the used data. To estimate the values of the adjustable parameters an objective function, depending on the data, the parameters of the error model, the fitting function and (if required and available) Bayesian information, is minimized. To increase reproducibility and user-friendliness the starting values are automatically determined using a combination of curve stripping and random search. Visual inspection, the coefficient of determination, the standard error of the fitted parameters, and the correlation matrix are provided to evaluate the quality of the fit. The functions which are most supported by the data are determined using the corrected Akaike information criterion. The time-integrated activity coefficient is estimated by analytically integrating the fitted functions. Its standard error is determined assuming Gaussian error propagation. The software was implemented using MATLAB. RESULTS To validate the proper implementation of the objective function and the fit functions, the results of NUKFIT and SAAM numerical, a commercially available software tool, were compared. The automatic search for starting values was successfully tested for reproducibility. The quality criteria applied in conjunction with the Akaike information criterion allowed the selection of suitable functions. Function fit parameters and their standard error estimated by using SAAM numerical and NUKFIT showed differences of <1%. The differences for the time-integrated activity coefficients were also <1% (standard error between 0.4% and 3%). In general, the application of the software is user-friendly and the results are mathematically correct and reproducible. An application of NUKFIT is presented for three different clinical examples. CONCLUSIONS The software tool with its underlying methodology can be employed to objectively and reproducibly estimate the time integrated activity coefficient and its standard error for most time activity data in molecular radiotherapy.

First-in-Human Experience of CXCR4-Directed Endoradiotherapy with 177Lu- and 90Y-Labeled Pentixather in Advanced-Stage Multiple Myeloma with Extensive Intra- and Extramedullary Disease

Chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. Based on promising experiences with a radiolabeled CXCR4 ligand (68Ga-pentixafor) for diagnostic receptor targeting, 177Lu- and 90Y-pentixather were recently developed as endoradiotherapeutic vectors. Here, we summarize the first-in-human experience in 3 heavily pretreated patients with intramedullary and extensive extramedullary manifestations of multiple myeloma undergoing CXCR4-directed endoradiotherapy. Methods: CXCR4 target expression was demonstrated by baseline 68Ga-pentixafor PET. Each treatment was approved by the clinical ethics committee. Pretherapeutic 177Lu-pentixather dosimetry was performed before 177Lu-pentixather or 90Y-pentixather treatment. Subsequently, patients underwent additional chemotherapy and autologous stem cell transplantation for bone marrow rescue. Results: A remarkable therapeutic effect was visualized in 2 patients, who showed a significant reduction in 18F-FDG uptake. Conclusion: CXCR4-targeted radiotherapy with pentixather appears to be a promising novel treatment option in combination with cytotoxic chemotherapy and autologous stem cell transplantation, especially for patients with advanced multiple myeloma.

Combination of peptide receptor radionuclide therapy with fractionated external beam radiotherapy for treatment of advanced symptomatic meningioma

BackgroundExternal beam radiotherapy (EBRT) is the treatment of choice for irresectable meningioma. Due to the strong expression of somatostatin receptors, peptide receptor radionuclide therapy (PRRT) has been used in advanced cases. We assessed the feasibility and tolerability of a combination of both treatment modalities in advanced symptomatic meningioma.Methods10 patients with irresectable meningioma were treated with PRRT (177Lu-DOTA0,Tyr3 octreotate or - DOTA0,Tyr3 octreotide) followed by external beam radiotherapy (EBRT). EBRT performed after PRRT was continued over 5–6 weeks in IMRT technique (median dose: 53.0 Gy). All patients were assessed morphologically and by positron emission tomography (PET) before therapy and were restaged after 3–6 months. Side effects were evaluated according to CTCAE 4.0.ResultsMedian tumor dose achieved by PRRT was 7.2 Gy. During PRRT and EBRT, no side effects > CTCAE grade 2 were noted. All patients reported stabilization or improvement of tumor-associated symptoms, no morphologic tumor progression was observed in MR-imaging (median follow-up: 13.4 months). The median pre-therapeutic SUVmax in the meningiomas was 14.2 (range: 4.3–68.7). All patients with a second PET after combined PRRT + EBRT showed an increase in SUVmax (median: 37%; range: 15%–46%) to a median value of 23.7 (range: 8.0–119.0; 7 patients) while PET-estimated volume generally decreased to 81 ± 21% of the initial volume.ConclusionsThe combination of PRRT and EBRT is feasible and well tolerated. This approach represents an attractive strategy for the treatment of recurring or progressive symptomatic meningioma, which should be further evaluated.

Facing the Nuclear Threat: Thyroid Blocking Revisited

CONTEXT People being exposed to potentially harmful amounts of radioactive iodine need prophylaxis to prevent high radiation-absorbed doses to the thyroid. OBJECTIVE Parameters determining the individual protective effect of a pharmacological intervention were investigated. DESIGN AND PARTICIPANTS Biokinetics of (123)I was evaluated in 27 healthy volunteers (aged 22-46 yr, median 25 yr, in total 48 assessments) twice in a baseline measurement of the undisturbed kinetics and in an intervention assessment 48 h later. INTERVENTIONS Seven regimens using single doses of potassium iodide (KI) or sodium perchlorate (SP) at different times relative to exposure were compared: 100 mg KI (-24, 2, 8, 24 h), 100 mg SP (2 h), or 1 g SP (2, 8 h). MAIN OUTCOME MEASURES Different drugs and dosages and the influence of individual parameters of iodine kinetics should be tested. RESULTS Mean dose reductions for interventions at -24, 2, 8, and 24 h relative to the activity incorporation were 88.7, 59.7, 25.4, and 2.8%, respectively. One gram SP was equally effective as 100 mg KI; residual uptake was observed after 100 mg SP. The individual dose reduction decreased exponentially with the effective half-life of the activity in the blood. Kinetics in subjects older than 40 yr was as assumed in official guidelines for the prophylaxis after nuclear accidents but was faster in younger participants. CONCLUSIONS Data on the efficacy of thyroid blocking used in the guidelines are adequate for older people but not for young individuals with their typically faster kinetics. SP may be used for thyroid blocking as alternative for individuals with iodine hypersensitivity.

I-131 Activities as High as Safely Administrable (AHASA) for the Treatment of Children and Adolescents with Advanced Differentiated Thyroid Cancer

AIM Differentiated thyroid carcinoma (DTC) in children and young adults is rare, can be aggressive, and often presents at advanced stages. In a population of young Belarusian patients with advanced DTC after the nuclear reactor accident at Chernobyl, we determined the activities that are as high as safely administrable (AHASA). PATIENTS AND METHODS In 180 children and adolescents, we studied 133 courses of I-131 thyroid remnant ablation (median age at ablation, 14.3 yr) and 250 courses of I-131 therapy (median age at therapy, 15.7 yr). Remnant ablation was performed with weight-adapted I-131 activities of a median of 51.8 MBq/kg (range, 23.9-73.8 MBq/kg); and residual disease therapy was performed with a median activity of 98.0 MBq/kg (range, 56.7-164.7 MBq/kg). The radiation absorbed dose to the blood (BD) per unit of activity administered for each treatment was deduced from whole-body retention data measured twice daily using ceiling probes. The AHASA activity was calculated assuming an upper limit of 2 Gy BD. RESULTS For I-131 ablation, the median weight-adjusted AHASA activity leading to a BD of 2 Gy was 407 MBq/kg (range, 137-661 MBq/kg). In three patients with extensive diffuse pulmonary metastases, the AHASA was lower than 200 MBq/kg. For patients receiving additional I-131 treatments after ablation, a median body weight-adapted AHASA activity of 406 MBq/kg (range, 210-775 MBq/kg) was calculated. CONCLUSION Children and adolescents with advanced DTC can be treated with I-131 activities of at least 200 MBq/kg. For children with extensive pulmonary metastases, pretherapeutic dosimetry is needed to determine the AHASA.