Risk of treatment-altering haematological toxicity and its dependence on bone marrow doses in peptide receptor radionuclide therapy.

BACKGROUND: Peptide receptor radionuclide therapy is effective in treating neuroendocrine tumours, but treatment may be limited by kidney and bone marrow toxicity. In this work, the absorbed dose burden to the bone marrow was estimated using image-based dosimetry and its potential use for predicting treatment-altering toxicity was studied. Peripheral blood samples taken before and after 229 treatments with 177Lu-DOTATATE in 59 patients were studied. In connection to the treatments, a total of 940 blood sample occasions provided data on white blood cell, neutrophil granulocyte, platelet, erythrocyte and haemoglobin concentrations. SPECT/CT image data were collected at two or three time points after each treatment. Absorbed doses to bone marrow were calculated from the activity concentration in a metastasis-free lumbar vertebra. The rate of delayed and aborted treatments was analysed based on medical records. RESULTS: The average absorbed dose to the bone marrow was 0.42 Gy (median 0.33 Gy, SD 0.27 Gy) per treatment. Dose-response relationships between white blood cells, neutrophil granulocytes and haemoglobin concentrations were observed, most prominently at 31-45 days after each treatment. The correlations were stronger in patients with skeletal metastases. The rates of haematological toxicity-related delays and aborted treatments were 6% and 12%, respectively. None of the studied bone marrow dosimetric parameters could clearly predict treatment-related toxicity. However, patients with skeletal metastases had higher risk of treatment-altering toxicity (odds ratio = 6.0). CONCLUSIONS: Treatment-altering haematological toxicity in peptide receptor radionuclide therapy is relatively rare and appears difficult to fully predict from post-therapeutic image-based dosimetry. However, for patients with skeletal metastases, the haematological dose-response relationships are stronger. Future studies may focus on this patient group, to further investigate the usefulness of dosimetry in predicting decreases in blood values.

Comparative in vivo biodistribution of cells labelled with [89Zr]Zr-(oxinate)4 or [89Zr]Zr-DFO-NCS using PET.

BACKGROUND: In vivo monitoring of cell biodistribution using positron emission tomography (PET) provides a quantitative non-invasive method to further optimize cell therapies and related new developments in the field. Our group has earlier optimized and evaluated the in vitro properties of two radiotracers,[89Zr]Zr-(oxinate)4 and [89Zr]Zr-DFO-NCS, for the radiolabelling of different cell types. Here, we performed a microPET study to assess the in vivo biodistribution of cells in rats using these two radiotracers. Human decidual stromal cells (hDSC) and rat macrophages (rMac) were radiolabelled with [89Zr]Zr-(oxinate)4 or [89Zr]Zr-DFO-NCS. Rats were intravenously injected with radiolabelled cells, and the in vivo biodistribution was monitored with microPET/CT imaging for up to day 7. Organ uptake was evaluated and presented as a percentage of injected activity per gram tissue (%IA/g) and total absorbed organ doses (mSv/MBq). RESULTS: The biodistribution in vivo showed an immediate uptake in the lungs. Thereafter, [89Zr]Zr-(oxinate)4 labelled cells migrated to the liver, while the signal from [89Zr]Zr-DFO-NCS labelled cells lingered in the lungs. The differences in the in vivo behaviour for the same cell type appeared related to the radiotracer labelling. After 24 h, [89Zr]Zr-(oxinate)4 labelled cells had over 70% higher liver uptake for both hDSC and rMac compared to [89Zr]Zr-DFO-NCS labelled cells, whereas [89Zr]Zr-DFO-NCS labelled cells showed over 60% higher uptake in the lungs compared to [89Zr]Zr-(oxinate)4 labelled cells. This difference in both lung and liver uptake continued until day 7. Dosimetry calculations showed a higher effective dose (mSv/MBq) for [89Zr]Zr-DFO-NCS compared to [89Zr]Zr-(oxinate)4, for both cell types. Although the bone uptake was higher for [89Zr]Zr-(oxinate)4 labelled cells, the prolonged uptake in the lungs contributed to a significant crossfire to bone marrow resulting in a higher bone dose. CONCLUSION: The [89Zr]Zr-DFO-NCS labelled cells suggest a prolonged accumulation in the lungs, while [89Zr]Zr-(oxinate)4 suggests quicker clearance of the lungs followed by accumulation in the liver. Accumulation of radiolabelled cells in the liver corresponds to other cell-tracking methods. Further studies are required to determine the actual location of the [89Zr]Zr-DFO-NCS labelled cell.

Dosimetric dependencies on target geometry and size in radioiodine therapy for differentiated thyroid cancer.

Purpose Radioiodine therapy is used in most disease stages for differentiated thyroid cancer. Its success depends on several factors, such as lesion size, completeness of surgery, extent of metastasis and tumoural iodine avidity. We aimed to investigate the importance of non-spherical geometries and size of metastases and thyroid remnants for the absorbed dose delivered. Methods Absorbed doses and energy depositions from homogeneously distributed iodine-131 in clinically relevant geometries and sizes were calculated using Monte Carlo simulations with MCNP6. A total of 162 volumes with different sizes and geometries corresponding to spheres, and prolate or oblate spheroids were simulated. Results Oblate and prolate spheroids had worse radiation coverage compared to spheres for equal masses, up to a difference of 38% for the most eccentric oblate spheroids and smallest masses simulated (a micrometastasis of mass 0.005 g). The differences in coverage could be explained by different volume - to - surface - area ratios of the spheroids. The impact of size alone caused up to 71% lower absorbed doses per decay in a spherical target mass of 0.005 g compared to 50 g. Conclusions While the iodine avidity, and therefore the total amount of decays, is the predominant contributing factor to absorbed dose in radioiodine therapy, eccentric spheroids and small target sizes can receive substantially lower absorbed doses from the same administration of radioiodine.

Simplified dosimetry for kidneys and tumors in 177Lu-labeled peptide receptor radionuclide therapy.

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.

Radioiodine treatment outcome by dosimetric parameters and renal function in hyperthyroidism.

BACKGROUND: Hyperthyroidism has been treated with radioiodine therapy for eight decades, with known benefits and side-effects. No consensus exists on which activity dosage and pre-therapeutic measurements are required for optimal treatment, balancing risk of incomplete response, therapy-induced hypothyroidism and radiation exposure. A retrospective analysis was performed to assess these questions. METHODS: Data was collected on radioiodine treatment outcomes for 904 patients treated for Graves' disease or toxic nodular goitres at our institution during 2016-2020. The prescribed absorbed doses were 120 Gy (Graves' disease), 200 Gy (toxic multinodular goitre) and 300 Gy (solitary toxic adenoma). Univariate analysis and multivariate regression modelling were used to find factors linked to treatment outcome. RESULTS: The cure rate of hyperthyroidism after one administration of radioiodine was 79% for Graves' disease, 94% for toxic multinodular goitre and 98% for solitary toxic adenoma. Thyroid mass, uptake and effective half-life were all significantly associated with cure in Graves' disease, but not in toxic multinodular goitre. The rates of therapy-induced hypothyroidism were 20% and 29% for toxic multinodular goitre and solitary toxic adenoma. Neither the cure rate nor the hypothyroidism rate was found to be superior among patients with individualised effective half-life measurements in toxic nodular goitres. Poor renal function was associated with dubious iodine uptake measurements but was not found to correlate with worse outcome. CONCLUSIONS: Multiple measurements of individual iodine uptake for kinetics estimation may be unnecessary, and a population-based value can be used instead. Patients with renal impairment had similar outcome as other patients, but with a higher risk of dubious uptake measurements.

Cancer risk after breast proton therapy considering physiological and radiobiological uncertainties.

BACKGROUND: The reduced normal tissue dose burden from protons can reduce the risk of second cancer for breast cancer patients. Breathing motion and the impact of variable relative biological effectiveness (RBE) are however concerns for proton dose distributions. This study aimed to quantify the impact of these factors on risk predictions from proton and photon therapy. MATERIALS AND METHODS: Twelve patients were planned in free breathing with protons and photons to deliver 50 Gy (RBE) in 25 fractions (assuming RBE = 1.1 for protons) to the left breast. Second cancer risk was evaluated with several models for the lungs, contralateral breast, heart and esophagus as organs at risk (OARs). Plans were recalculated on CT-datasets acquired in extreme phases to account for breathing motion. Proton plans were also recalculated assuming variable RBE for a range of radiobiological parameters. RESULTS: The OARs received substantially lower doses from protons compared to photons. The highest risks were for the lungs (average second cancer risks of 0.31% and 0.12% from photon and proton plans, respectively). The reduced risk with protons was maintained, even when breathing and/or RBE variation were taken into account. Furthermore, while the total risks from the photon plans were seen to increase with the integral dose, no such correlation was observed for the proton plans. CONCLUSIONS: Protons have an advantage over the photons with respect to the induction of cancer. Uncertainties in physiological movements and radiobiological parameters affected the absolute risk estimates, but not the general trend of lower risk associated with proton therapy.

Out-of-field doses from secondary radiation produced in proton therapy and the associated risk of radiation-induced cancer from a brain tumor treatment.

PURPOSE: To determine out-of-field doses produced in proton pencil beam scanning (PBS) therapy using Monte Carlo simulations and to estimate the associated risk of radiation-induced second cancer from a brain tumor treatment. METHODS: Simulations of out-of-field absorbed doses were performed with MCNP6 and benchmarked against measurements with tissue-equivalent proportional counters (TEPC) for three irradiation setups: two irradiations of a water phantom using proton energies of 78-147 MeV and 177-223 MeV, and one brain tumor irradiation of a whole-body phantom. Out-of-field absorbed and equivalent doses to organs in a whole-body phantom following a brain tumor treatment were subsequently simulated and used to estimate the risk of radiation-induced cancer. Additionally, the contribution of absorbed dose originating from radiation produced in the nozzle was calculated from simulations. RESULTS: Out-of-field absorbed doses to the TEPC ranged from 0.4 to 135 µGy/Gy. The average deviation between simulations and measurements of the water phantom irradiations was about 17%. The absorbed dose contribution from radiation produced in the nozzle ranged between 0 and 70% of the total dose; the contribution was however small in absolute terms. The absorbed and equivalent doses to the organs ranged between 0.2 and 60 µGy/Gy and 0.5-151 µSv/Gy. The estimated lifetime risk of radiation-induced second cancer was approximately 0.01%. CONCLUSIONS: The agreement of out-of-field absorbed doses between measurements and simulations was good given the sources of uncertainties. Calculations of out-of-field organ doses following a brain tumor treatment indicated that proton PBS therapy of brain tumors is associated with a low risk of radiation-induced cancer.

Organ doses from a proton gantry-mounted cone-beam computed tomography system characterized with MCNP6 and GATE.

PURPOSE: To determine organ doses from a proton gantry-mounted cone-beam computed tomography (CBCT) system using two Monte Carlo codes and to study the influence on organ doses from different acquisition modes and repeated imaging. METHODS: The CBCT system was characterized with MCNP6 and GATE using measurements of depth doses in water and spatial profiles in air. The beam models were validated against absolute dose measurements and used to simulate organ doses from CBCT imaging with head, thorax and pelvis protocols. Anterior and posterior 190° scans were simulated and the resulting organ doses per mAs were compared to those from 360° scans. The influence on organ doses from repeated imaging with different imaging schedules was also investigated. RESULTS: The agreement between MCNP6, GATE and measurements with regard to depth doses and beam profiles was within 4% for all protocols and the corresponding average agreement in absolute dose validation was 4%. Absorbed doses for in-field organs from 360° scans ranged between 6 and 8 mGy, 15-17 mGy and 24-54 mGy for the head, thorax and pelvis protocols, respectively. Cumulative organ doses from repeated CBCT imaging ranged between 0.04 and 0.32 Gy for weekly imaging and 0.2-1.6 Gy for daily imaging. The anterior scans resulted in an average increase in dose per mAs of 24% to the organs of interest relative to the 360° scan, while the posterior scan showed a 37% decrease. CONCLUSIONS: A proton gantry-mounted CBCT system was accurately characterized with MCNP6 and GATE. Organ doses varied greatly depending on acquisition mode, favoring posterior scans.

Impact of irradiation setup in proton spot scanning brain therapy on organ doses from secondary radiation.

A Monte Carlo model of a proton spot scanning pencil beam was used to simulate organ doses from secondary radiation produced from brain tumour treatments delivered with either a lateral field or a vertex field to one adult and one paediatric patient. Absorbed doses from secondary neutrons, photons and protons and neutron equivalent doses were higher for the vertex field in both patients, but the differences were low in absolute terms. Absorbed doses ranged between 0.1 and 43 µGy.Gy-1 in both patients with the paediatric patient receiving higher doses. The neutron equivalent doses to the organs ranged between 0.5 and 141 µSv.Gy-1 for the paediatric patient and between 0.2 and 134 µSv.Gy-1 for the adult. The highest neutron equivalent dose from the entire treatment was 7 mSv regardless of field setup and patient size. The results indicate that different field setups do not introduce large absolute variations in out-of-field doses produced in patients undergoing proton pencil beam scanning of centrally located brain tumours.

MONTE CARLO SIMULATIONS OF SPATIAL LET DISTRIBUTIONS IN CLINICAL PROTON BEAMS.

The linear energy transfer (LET) is commonly used as a parameter which describes the quality of the radiation applied in radiation therapy with fast ions. In particular in proton therapy, most models which predict the radiobiological properties of the applied beam, are fitted to the dose-averaged LET, LETd. The related parameter called the fluence- or track-averaged LET, LETt, is less frequently used. Both LETt and in particular LETd depends profoundly on the encountered secondary particle spectrum. For proton beams including all secondary particles, LETd may reach more than 3 keV/um in the entry channel of the proton field. However, typically the charged particle spectrum is only averaged over the primary and secondary protons, which is in the order of 0.5 keV/um for the same region. This is equal to assuming that the secondary particle spectrum from heavier ions is irrelevant for the resulting radiobiology, which is an assertion in the need of closer investigation. Models which rely on LETd should also be clear on what type of LETd is used, which is not always the case. Within this work, we have extended the Monte Carlo particle transport code SHIELD-HIT12A to provide dose- and track-average LET-maps for ion radiation therapy treatment plans.

Reduced acquisition times in whole body bone scintigraphy using a noise-reducing Pixon®-algorithm-a qualitative evaluation study.

BACKGROUND: Reducing scan-time while maintaining sufficient image quality is a common issue in nuclear medicine diagnostics. This matter can be addressed by different post-processing methods such as Pixon® image processing. The aim of the present study was to evaluate if a commercially available noise-reducing Pixon-algorithm applied on whole body bone scintigraphy acquired with half the standard scan-time could provide the same clinical information as full scan-time non-processed images. METHODS: Twenty patients were administered with 500 MBq (99m)Tc-diphosphonate and scanned on a Siemens Symbia T16 system. Each patient was first imaged using a standard clinical protocol and subsequently imaged using a protocol with half the standard scan-time. Half-time images were processed using a commercially available software package, Enhanced Planar Processing, from Siemens. All images were anonymized and visually evaluated with regard to clinically relevant lesion detectability by three experienced nuclear medicine physicians. The result of this evaluation was grouped into four BMI intervals to investigate the performance of the algorithm with regard to different patient size. Also, a comparison study was performed where the physicians compared the standard image and the processed half-time image corresponding to the same patient with regard to lesion detectability, image noise, and artifacts. RESULTS: The results showed that 93 % of the processed half-time images and 98 % of the standard images were rated as sufficient or good with regard to lesion detectability. The processed half-time images were predominately considered sufficient (65 %), whereas the majority of the standard images were graded as good (83 %). The performance of the algorithm was unaffected by patient size as the average grading of all half-time processed images was constant independent of patient BMI. The comparison study showed that the standard images were rated superior with regard to lesion detectability, image noise, and artifacts, in 32, 65, and 23 % of the evaluations, respectively. CONCLUSIONS: The results indicate that the Pixon Enhanced Planar Processing does not fully compensate for the loss of counts associated with reducing the scan-time in half for whole body bone scintigraphies. The findings showed that implementing the Pixon-algorithm on images acquired with half the acquisition time in overall provide sufficient clinical information regardless of patient size. The half-time processed images were predominantly graded lower in comparison to images acquired with full time protocols, and a less aggressive reduction in scan-time is therefore recommended.

Are IMRT treatments in the head and neck region increasing the risk of secondary cancers?

BACKGROUND: Intensity-modulated radiation therapy (IMRT) has been increasingly employed for treating head and neck (H&N) tumours due to its ability to produce isodoses suitable for the complex anatomy of the region. The aim of this study was to assess possible differences between IMRT and conformal radiation therapy (CRT) with regard to risk of radiation-induced secondary malignancies for H&N tumours. MATERIAL AND METHODS: IMRT and CRT plans were made for 10 H&N adult patients and the resulting treatment planning data were used to calculate the risk of radiation-induced malignancies in four different tissues. Three risk models with biologically relevant parameters were used for calculations. The influence of scatter radiation and repeated imaging sessions has also been investigated. RESULTS: The results showed that the total lifetime risks of developing radiation-induced secondary malignancies from the two treatment techniques, CRT and IMRT, were comparable and in the interval 0.9-2.5%. The risk contributions from the primary beam and scatter radiation were comparable, whereas the contribution from repeated diagnostic imaging was considerably smaller. CONCLUSION: The results indicated that the redistribution of the dose characteristic to IMRT leads to a redistribution of the risks in individual tissues. However, the total levels of risk were similar between the two irradiation techniques considered.