3D dosimetry in patients with early breast cancer undergoing Intraoperative Avidination for Radionuclide Therapy (IART?) combined with external beam radiation therapy

Purpose

Intraoperative Avidination for Radionuclide Therapy (IART?) is a novel targeted radionuclide therapy recently used in patients with early breast cancer. It is a radionuclide approach with ⁹⁰Y-biotin combined with external beam radiotherapy (EBRT) to release a boost of radiation in the tumour bed. Two previous clinical trials using dosimetry based on the calculation of mean absorbed dose values with the hypothesis of uniform activity distribution (MIRD 16 method) assessed the feasibility and safety of IART?. In the present retrospective study, a voxel dosimetry analysis was performed to investigate heterogeneity in distribution of the absorbed dose. The aim of this work was to compare dosimetric and radiobiological evaluations derived from average absorbed dose vs. voxel absorbed dose approaches.

Methods

We evaluated 14 patients who were injected with avidin into the tumour bed after conservative surgery and 1?day later received an intravenous injection of 3.7?GBq of ⁹⁰Y-biotin (together with 185?MBq ¹¹¹In-biotin for imaging). Sequential images were used to estimate the absorbed dose in the target region according to the standard dosimetry method (SDM) and the voxel dosimetry method (VDM). The biologically effective dose (BED) distribution was also evaluated. Dose/volume and BED volume histograms were generated to derive equivalent uniform BED (EUBED) and equivalent uniform dose (EUD) values.

Results

No “cold spots” were highlighted by voxel dosimetry. The median absorbed-dose in the target region was 20?Gy (range 15–27?Gy) by SDM, and the median EUD was 20.4?Gy (range 16.5–29.4?Gy) by the VDM; SDM and VDM estimates differed by about 6?%. The EUD/mean voxel absorbed dose ratio was >0.9 in all patients, indicative of acceptable uniformity in the target. The median BED and EUBED values were 21.8?Gy (range 15.9–29.3?Gy) and 22.8?Gy (range 17.3–31.8?Gy), respectively.

Conclusion

VDM highlighted the absence of significant heterogeneity in absorbed dose in the target. The EUD/mean absorbed dose ratio indicated a biological efficacy comparable to that of uniform distribution of absorbed dose. The VDM is recommended for improving accuracy, taking into account actual activity distribution in the target region. The radiobiological model applied allowed us to compare the effects of IART? with those of EBRT and to match the two irradiation modalities.     

Personalized <Superscript>177</Superscript>Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: a simulation study

Purpose

Peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-octreotate is commonly administered at empiric, fixed amounts of injected radioactivity (IA). This results in highly variable absorbed doses to critical organs and suboptimal treatment of most patients. The primary aims of this study were to design a personalized PRRT (P-PRRT) protocol based on dosimetry, and to perform a simulation of this protocol in a retrospective cohort of patients with neuroendocrine tumours, in order to assess the potential of P-PRRT to safely increase the absorbed dose to the tumour during a four-cycle induction course.

Methods

Thirty-six patients underwent 122 fixed-IA ¹⁷⁷Lu-octreotate PRRT cycles with quantitative SPECT/CT-based dosimetry. Twenty-two patients completed a four-cycle induction course (29.6?±?2.4 GBq cumulative IA), with kidney, bone marrow and maximum tumour absorbed doses of 16.2?±?5.5, 1.3?±?0.8, and 114?±?66 Gy, respectively. We simulated a P-PRRT regime in which the renal absorbed dose per IA was predicted by the body surface area and glomerular filtration rate for the first cycle, and by renal dosimetry of the previous cycle(s) for the following cycles. Personalized IA was adjusted at each cycle in order to reach the prescribed renal absorbed dose of 23 Gy over four cycles (with a 25-50% reduction when renal or bone marrow function was impaired). Simulated IA and absorbed doses were based on actual patient characteristics, laboratory values and absorbed doses per IA delivered at each cycle.

Results

In the P-PRRT regime, cumulative IA could have been increased to 43.7?±?16.5 GBq over four induction cycles (10.9?±?5.0 GBq per cycle), yielding cumulative kidney, bone marrow and maximum tumour absorbed doses of 21.5?±?2.5, 1.63?±?0.61, and 163.4?±?85.9 Gy, respectively. This resulted in an average 1.48-fold increase in cumulative maximum tumour absorbed dose over empiric PRRT (range, 0.68–2.64-fold; P?=?0.0013).

Conclusion

By standardizing the renal absorbed dose delivered during the induction course, P-PRRT has the potential to significantly increase tumour absorbed dose, thus to augment the therapeutic benefit while limiting toxicity.

     

Patient-specific dosimetry for intracavitary 32P-chromic phosphate colloid therapy of cystic brain tumours

Purpose

³²P-chromic phosphate colloid treatments of astrocytoma and craniopharyngioma cystic brain tumours in paediatric patients are conventionally based on a sphere model under the assumption of uniform uptake. The aims of this study were to determine the distribution of the absorbed dose delivered by ³²P on a patient-specific basis and to evaluate the accuracy with which this can be predicted from a pretherapy administration of ^99mTc-Sn colloid.

Methods

Three patients were treated with ³²P-chromic phosphate colloid following ^99mTc-Sn colloid administrations. Convolution dosimetry was performed using pretherapy and posttherapy sequential SPECT imaging, and verified with EGSnrc Monte Carlo radiation transport simulations. Mean absorbed doses to the cyst wall and dose–volume histograms were also calculated and compared with those obtained by the sphere model approach.

Results

Highly nonuniform uptake distributions of both the ^99mTc and ³²P colloids were observed and characterized by dose–volume histograms to the cyst wall. Mean absorbed doses delivered to the cyst wall, obtained with the convolution method, were on average 21 % (SD 18 %) and 50 % (SD 30 %) lower than those predicted by the ^99mTc distribution and the uniform assumption of the sphere model, respectively.

Conclusion

Absorbed doses delivered to the cyst wall by ³²P are more accurately predicted from image-based patient-specific convolution dosimetry than from simple sphere models. These results indicate the necessity to perform personalized treatment planning and verification for intracavitary irradiation of cystic brain tumours treated with radiocolloids. Patient-specific dosimetry can be used to guide the frequency and levels of repeated administrations and would facilitate data collection and comparison to support the multicentre trials necessary to progress this therapy.     

99mTc-MAA overestimates the absorbed dose to the lungs in radioembolization: a quantitative evaluation in patients treated with 166Ho-microspheres

Purpose

Radiation pneumonitis is a rare but serious complication of radioembolic therapy of liver tumours. Estimation of the mean absorbed dose to the lungs based on pretreatment diagnostic ^99mTc-macroaggregated albumin (^99mTc-MAA) imaging should prevent this, with administered activities adjusted accordingly. The accuracy of ^99mTc-MAA-based lung absorbed dose estimates was evaluated and compared to absorbed dose estimates based on pretreatment diagnostic ¹⁶⁶Ho-microsphere imaging and to the actual lung absorbed doses after ¹⁶⁶Ho radioembolization.

Methods

This prospective clinical study included 14 patients with chemorefractory, unresectable liver metastases treated with ¹⁶⁶Ho radioembolization. ^99mTc-MAA-based and ¹⁶⁶Ho-microsphere-based estimation of lung absorbed doses was performed on pretreatment diagnostic planar scintigraphic and SPECT/CT images. The clinical analysis was preceded by an anthropomorphic torso phantom study with simulated lung shunt fractions of 0 to 30 % to determine the accuracy of the image-based lung absorbed dose estimates after ¹⁶⁶Ho radioembolization.

Results

In the phantom study, ¹⁶⁶Ho SPECT/CT-based lung absorbed dose estimates were more accurate (absolute error range 0.1 to ?4.4 Gy) than ¹⁶⁶Ho planar scintigraphy-based lung absorbed dose estimates (absolute error range 9.5 to 12.1 Gy). Clinically, the actual median lung absorbed dose was 0.02 Gy (range 0.0 to 0.7 Gy) based on posttreatment ¹⁶⁶Ho-microsphere SPECT/CT imaging. Lung absorbed doses estimated on the basis of pretreatment diagnostic ¹⁶⁶Ho-microsphere SPECT/CT imaging (median 0.02 Gy, range 0.0 to 0.4 Gy) were significantly better predictors of the actual lung absorbed doses than doses estimated on the basis of ¹⁶⁶Ho-microsphere planar scintigraphy (median 10.4 Gy, range 4.0 to 17.3 Gy; p?99mTc-MAA SPECT/CT imaging (median 2.5 Gy, range 1.2 to 12.3 Gy; p?99mTc-MAA planar scintigraphy (median 5.5 Gy, range 2.3 to 18.2 Gy; p?Conclusion In clinical practice, lung absorbed doses are significantly overestimated by pretreatment diagnostic ^99mTc-MAA imaging. Pretreatment diagnostic ¹⁶⁶Ho-microsphere SPECT/CT imaging accurately predicts lung absorbed doses after ¹⁶⁶Ho radioembolization.     

High-dose-rate interstitial brachytherapy in combination with androgen deprivation therapy for prostate cancer

Background and purpose

To evaluate the effectiveness of high-dose-rate interstitial brachytherapy (HDR-ISBT) as the only form of radiotherapy for high-risk prostate cancer patients.

Patients and methods

Between July 2003 and June 2008, we retrospectively evaluated the outcomes of 48 high-risk patients who had undergone HDR-ISBT at the National Hospital Organization Osaka National Hospital. Risk group classification was according to the criteria described in the National Comprehensive Cancer Network (NCCN) guidelines. Median follow-up was 73 months (range 12–109 months). Neoadjuvant androgen deprivation therapy (ADT) was administered to all 48 patients; 12 patients also received adjuvant ADT. Maximal androgen blockade was performed in 37 patients. Median total treatment duration was 8 months (range 3–45 months). The planned prescribed dose was 54 Gy in 9 fractions over 5 days for the first 13 patients and 49 Gy in 7 fractions over 4 days for 34 patients. Only one patient who was over 80 years old received 38 Gy in 4 fractions over 3 days. The clinical target volume (CTV) was calculated for the prostate gland and the medial side of the seminal vesicles. A 10-mm cranial margin was added to the CTV to create the planning target volume (PTV).

Results

The 5-year overall survival and biochemical control rates were 98 and 87?%, respectively. Grade 3 late genitourinary and gastrointestinal complications occurred in 2 patients (4?%) and 1 patient (2?%), respectively; grade 2 late genitourinary and gastrointestinal complications occurred in 5  patients (10?%) and 1 patient (2?%), respectively.

Conclusion

Even for high-risk patients, HDR-ISBT as the only form of radiotherapy combined with ADT achieved promising biochemical control results, with acceptable late genitourinary and gastrointestinal complication rates.     

Investigation of applicability of alanine and radiochromic detectors to dosimetry of proton clinical beams

Cancer therapy studies using proton accelarators are underway in several major medical centers in the U.S., Russia, Japan and elsewhere. To facilitate dosimetry intercomparisons between these laboratories, alanine-based detectors produced at the National Institute of Standards and Technology and Commercially available radiochromic films were studied for their possible use as passive transfer dosimeters for clinical proton beams. Evaluation of characteristics of these instruments, including the LET dependence of their response of proton energy, was carried out at the Institute of Theoretical and Experimental Physics. Results of absolute dose measurements were regarded as a preliminary step of dose intercomparison between ITEP and NIST. Measurements made in a number of experiments showed average agreement between the ITEP and NIST dosimetry standards to 2.5%.     

Phase I/II trials of <Superscript>186</Superscript>Re-HEDP in metastatic castration-resistant prostate cancer: post-hoc analysis of the impact of administered activity and dosimetry on survival

Purpose

To investigate the role of patient-specific dosimetry as a predictive marker of survival and as a potential tool for individualised molecular radiotherapy treatment planning of bone metastases from castration-resistant prostate cancer, and to assess whether higher administered levels of activity are associated with a survival benefit.

Methods

Clinical data from 57 patients who received 2.5–5.1 GBq of ¹⁸⁶Re-HEDP as part of NIH-funded phase I/II clinical trials were analysed. Whole-body and SPECT-based absorbed doses to the whole body and bone lesions were calculated for 22 patients receiving 5 GBq. The patient mean absorbed dose was defined as the mean of all bone lesion-absorbed doses in any given patient. Kaplan–Meier curves, log-rank tests, Cox’s proportional hazards model and Pearson’s correlation coefficients were used for overall survival (OS) and correlation analyses.

Results

A statistically significantly longer OS was associated with administered activities above 3.5 GBq in the 57 patients (20.1 vs 7.1 months, hazard ratio: 0.39, 95 % CI: 0.10–0.58, P?=?0.002). A total of 379 bone lesions were identified in 22 patients. The mean of the patient mean absorbed dose was 19 (±6) Gy and the mean of the whole-body absorbed dose was 0.33 (±0.11) Gy for the 22 patients. The patient mean absorbed dose (r?=?0.65, P?=?0.001) and the whole-body absorbed dose (r?=?0.63, P?=?0.002) showed a positive correlation with disease volume. Significant differences in OS were observed for the univariate group analyses according to disease volume as measured from SPECT imaging of ¹⁸⁶Re-HEDP (P?=?0.03) and patient mean absorbed dose (P?=?0.01), whilst only the disease volume remained significant in a multivariable analysis (P?=?0.004).

Conclusion

This study demonstrated that higher administered activities led to prolonged survival and that for a fixed administered activity, the whole-body and patient mean absorbed doses correlated with the extent of disease, which, in turn, correlated with survival. This study shows the importance of patient stratification to establish absorbed dose–response correlations and indicates the potential to individualise treatment of bone metastases with radiopharmaceuticals according to patient-specific imaging and dosimetry.

     

Biodosimetric quantification of short-term synchrotron microbeam versus broad-beam radiation damage to mouse skin using a dermatopathological scoring system

Objectives

Microbeam radiotherapy (MRT) with wafers of microscopically narrow, synchrotron generated X-rays is being used for pre-clinical cancer trials in animal models. It has been shown that high dose MRT can be effective at destroying tumours in animal models, while causing unexpectedly little damage to normal tissue. The aim of this study was to use a dermatopathological scoring system to quantify and compare the acute biological response of normal mouse skin with microplanar and broad-beam (BB) radiation as a basis for biological dosimetry.

Method

The skin flaps of three groups of mice were irradiated with high entrance doses (200 Gy, 400 Gy and 800 Gy) of MRT and BB and low dose BB (11 Gy, 22 Gy and 44 Gy). The mice were culled at different time-points post-irradiation. Skin sections were evaluated histologically using the following parameters: epidermal cell death, nuclear enlargement, spongiosis, hair follicle damage and dermal inflammation. The fields of irradiation were identified by γH2AX-positive immunostaining.

Results

The acute radiation damage in skin from high dose MRT was significantly lower than from high dose BB and, importantly, similar to low dose BB.

Conclusion

The integrated MRT dose was more relevant than the peak or valley dose when comparing with BB fields. In MRT-treated skin, the apoptotic cells of epidermis and hair follicles were not confined to the microbeam paths.Synchrotron microbeam radiotherapy (MRT) uses wafers of microscopically narrow, synchrotron-generated X-rays for pre-clinical cancer trials in animal models [1-6]. Previous studies have shown normal tissue to be extremely tolerant to MRT at doses in considerable excess of those that were therapeutically effective [7]. Further, MRT has been proven to have palliative and even curative effects on cerebral tumours implanted in rat brains [1,8]. The interpretation of the effects of MRT on biological tissue is complicated by difficulties in accurately measuring the absorbed dose deposited in tissue by MRT. Physical dosimetry associated with MRT is more complex than that for conventional broad-beam (BB) radiotherapy because there are different components to an MRT dose profile [9-12]. These components include the in-beam or “peak” dose, the valley dose (between adjacent microbeams) and the integrated dose. Dilmanian et al [13] defined the integrated dose as “the microbeam dose averaged over the entire irradiation area” and further “the integrated dose takes into account the volume of tissue in the low dose regions between the microbeams”. Zhong et al [7] stated that the “integrated microbeam doses, (which for low valley doses) can be approximated as the in-beam dose times the ratio of the beam width to beam spacing”. There exists a vast body of literature over several decades on the acute effects of radiation therapy on skin tissue (radiodermatitis), some of which have been documented in review articles [14,15] and text books [16-19]. McKee et al [20] state:

The histological features of acute radiation damage to skin involve both the epidermis and its adnexae, and the underlying dermis. The epithelium may be necrotic and accompanied by both spongiosis (inter-cellular oedema) and intra-cellular edema. The dermis is edematous and may show fibrin deposition. An inflammatory cell infiltrate consisting of macrophages, eosinophils, plasma cells and lymphocytes is present in the dermis.

Further, Lever and Schaumburg-Lever [21] state:

The cells of the hair follicles, sebaceous glands, and sweat glands also show degenerative changes. Some of the blood vessels are dilated, whereas others, especially large ones in the deep portions of the dermis show edema of their walls, endothelium and even thrombosis. The collagen bundles show edema. In cases with blisters, the degenerated epidermis is detached from the dermis, and, if ulceration is present, not only the epidermis but also the upper dermis has undergone necrosis. The area of necrosis is then surrounded by neutrophils.

The effects of synchrotron MRT on skin are less well documented [7,22] and to our knowledge a quantitative, histopathological comparison of MRT and BB has not been reported. The aim of this study was to use a histopathological skin scoring system to quantify the acute biological response of normal mouse skin to MRT and BB irradiations as a basis of biological dosimetry. We hypothesise high dose BB (hundreds of Gy) will cause more skin damage than high dose MRT for the same peak entrance dose. Further, low dose BB (tens of Gy) will cause equivalent levels of damage as high dose MRT.     

The Clatterbridge high-energy neutron facility: dosimetry intercomparisons

Dosimetry intercomparisons have been performed between the Clatterbridge high-energy neutron facility and the following institutions, all employing beams with similar neutron energies: Université Catholique de Louvain, Belgium; University of Washington, Seattle, USA; MD Anderson Hospital, Houston, USA; and Fermi National Accelerator Laboratory, Batavia, USA. The purpose of the intercomparison was to provide a basis for the exchange of dose-response data and to facilitate the involvement of Clatterbridge in collaborative clinical trials. Tissue-equivalent ionization chambers were used by the participants in each intercomparison to compare measurements of total (neutron plus gamma) absorbed dose in the host institution's neutron beam, following calibration of the chambers in a reference photon beam. The effects of differences in exposure standards, chamber responses in the neutron beams and protocol-dependent dosimetry factors were all investigated. It was concluded that the overall difference in the measurement of absorbed dose relative to that determined by the Clatterbridge group was less than 2%.     

EANM Dosimetry Committee guidelines for bone marrow and whole-body dosimetry

Introduction  

The level of administered activity in radionuclide therapy is often limited by haematological toxicity resulting from the absorbed dose delivered to the bone marrow. The purpose of these EANM guidelines is to provide advice to scientists and clinicians on data acquisition and data analysis related to bone-marrow and whole-body dosimetry.     

Improving the dose–myelotoxicity correlation in radiometabolic therapy of bone metastases with 153Sm-EDTMP

Purpose

¹⁵³Sm-ethylene diamine tetramethylene phosphonic acid (¹⁵³Sm-EDTMP) is widely used to palliate pain from bone metastases, and is being studied for combination therapy beyond palliation. Conceptually, red marrow (RM) dosimetry allows myelotoxicity to be predicted, but the correlation is poor due to dosimetric uncertainty, individual sensitivity and biological effects from previous treatments. According to EANM guidelines, basic dosimetric procedures have been studied to improve the correlation between dosimetry and myelotoxicity in ¹⁵³Sm-EDTMP therapy.

Methods

RM dosimetry for 33 treatments of bone metastases from breast, prostate and lung tumours was performed prospectively (with ^99mTc-MDP) and retrospectively, acquiring whole-body scans early and late after injection. The ¹⁵³Sm-EDTMP activity was calculated by prospective dosimetry based on measured skeletal uptake and full physical retention, with the RM absorbed dose not exceeding 3.8 Gy. Patient-specific RM mass was evaluated by scaling in terms of body weight (BW), lean body mass (LBM) and trabecular volume (TV) estimated from CT scans of the L2–L4 vertebrae. Correlations with toxicity were determined in a selected subgroup of 27 patients, in which a better correlation between dosimetry and myelotoxicity was expected.

Results

Skeletal uptakes of ^99mTc and ¹⁵³Sm (Tc_% and Sm_%) were well correlated. The median Sm_% was higher in prostate cancer (75.3 %) than in lung (60.5 %, p?=?0.005) or breast (60.8 %, p?=?0.008). PLT and WBC nadirs were not correlated with administered activity, but were weakly correlated with uncorrected RM absorbed doses, and the correlation improved after rescaling in terms of BW, LBM and TV. Most patients showed transient toxicity (grade 1–3), which completely and spontaneously recovered over a few days. Using TV, RM absorbed dose was in the range 2–5 Gy, with a median of 312 cGy for PLT in patients with toxicity and 247 cGy in those with no toxicity (p?=?0.019), and 312 cGy for WBC in those with toxicity and 232 cGy in those with no toxicity (p?=?0.019). ROC curves confirmed the correlations, yielding toxicity absorbed dose thresholds of 265 cGy for PLT and 232 cGy for WBC.

Conclusion

The best predictor of myelotoxicity and blood cells nadir was obtained scaling the RM absorbed dose in terms of the estimated TV. It seems clear that the increase in skeletal uptake due to the presence of bone metastases and the assumption of full physical retention cause an overestimation of the RM absorbed dose. Nevertheless, an improvement of the dose–toxicity correlation is easily achievable by simple methods, also leading to possible improvement in multifactorial analyses of myelotoxicity.     

Netherlands Radiobiological Society and the Radiotherapy Section of the Netherlands Radiological Society

Summary

Although the concept of absorbed dose is commonly used in radiation biology as a parameter for comparing the toxic effect of different levels of radiation on a system, there are situations where the absorbed dose by itself is inadequate, and additional dose distribution information is required to explain the observed biological effects. A good example is the irradiation of cells by alpha-particles. This paper reports the use of internal microdosimetry techniques to reinvestigate the dosimetry of two very similar experiments with apparently contradictory dose–response results.

Yields of dicentric chromosome aberrations induced in human blood lymphocytes following in vitro exposure to dissolved americium or plutonium at two separate laboratories produced linear dose–response functions, but the slopes of the best-fit straight lines differed by a factor of 12. Our microdosimetric analysis showed the results of one experiment to be inconsistent with a uniform distribution of activity. It also showed that the difference in slope could be attributed to differences in particulate size and spatial distribution as a result of dissimilarities in procedures used for preparing the actinide solutions.     

Individualized dosimetry in patients undergoing therapy with 177Lu-DOTA-D-Phe1-Tyr3-octreotate

Purpose

In recent years, targeted radionuclide therapy with [¹⁷⁷Lu-DOTA⁰, Tyr³]octreotate for neuroendocrine tumours has yielded promising results. This therapy may be further improved by using individualized dosimetry allowing optimization of the absorbed dose to the tumours and the normal organs. The aim of this study was to investigate the feasibility and reliability of individualized dosimetry based on SPECT in comparison to conventional planar imaging.

Methods

Attenuation-corrected SPECT data were analysed both by using organ-based volumes of interest (VOIs) to obtain the total radioactivity in the organ, and by using small VOIs to measure the tissue radioactivity concentration. During the first treatment session in 24 patients, imaging was performed 1, 24, 96 and 168 h after [¹⁷⁷Lu-DOTA⁰, Tyr³]octreotate infusion. Absorbed doses in non tumour-affected kidney, liver and spleen were calculated and compared for all three methods (planar imaging, SPECT organ VOIs, SPECT small VOIs).

Results

Planar and SPECT dosimetry were comparable in areas free of tumours, but due to overlap the planar dosimetry highly overestimated the absorbed dose in organs with tumours. Furthermore, SPECT dosimetry based on small VOIs proved to be more reliable than whole-organ dosimetry.

Conclusion

We conclude that SPECT dosimetry based on small VOIs is feasible and more accurate than conventional planar dosimetry, and thus may contribute towards optimising targeted radionuclide therapy.     

Prospective observational study of <Superscript>177</Superscript>Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity

Purpose

Peptide receptor radionuclide therapy in patients with neuroendocrine tumours has yielded promising results. This prospective study investigated the feasibility of dosimetry of the kidneys and bone marrow during therapy and its impact on efficacy and outcome.

Methods

The study group comprised 200 consecutive patients with metastasized somatostatin receptor-positive neuroendocrine tumours progressing on standard therapy or not suitable for other therapeutic options. A treatment cycle consisted of 7.4 GBq ¹⁷⁷Lu-DOTA-octreotate with co-infusion of a mixed amino acid solution, and cycles were repeated until the absorbed dose to the kidneys reached 23 Gy or there were other reasons for stopping therapy. The Ki-67 index was ≤2% in 47 patients (23.5%), 3–20% in 121 (60.5%) and >20% in 16 (8%).

Results

In 123 patients (61.5%) the absorbed dose to the kidneys reached 23 Gy with three to nine cycles during first-line therapy; in no patient was a dose to the bone marrow of 2 Gy reached. The best responses (according to RECIST 1.1) were a complete response (CR) in 1 patient (0.5%), a partial response (PR) in 47 (23.5%), stable disease (SD) in 135 (67.5%) and progressive disease (PD) in 7 (3.5%). Median progression-free survival was 27 months (95% CI 22–30 months) in all patients, 33 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 15 months in those in whom it did not. Median overall survival (OS) was 43 months (95% CI 39–53 months) in all patients, 54 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 25 months in those in whom it did not. Median OS was 60 months in patients with a best response of PR or CR, 42 months in those with SD and 16 months in those with PD. Three patients (1.5%) developed acute leukaemia, 1 patient (0.5%) chronic leukaemia (unconfirmed) and 30 patients (15%) grade 3 or 4 bone marrow toxicity. Eight patients (4%) developed grade 2 kidney toxicity and one patient (0.5%) grade 4 kidney toxicity.

Conclusions

Dosimetry-based therapy with ¹⁷⁷Lu-DOTA-octreotate is feasible. Patients in whom the absorbed dose to the kidneys reached 23 Gy had a longer OS than those in whom it did not. Patients with CR/PR had a longer OS than those with SD. Bone marrow dosimetry did not predict toxicity.

     

Validation of prospective whole-body bone marrow dosimetry by SPECT/CT multimodality imaging in 131I-anti-CD20 rituximab radioimmunotherapy of non-Hodgkin’s lymphoma

Purpose Radioimmunotherapy (RIT) for relapsed non-Hodgkins lymphoma is emerging as a promising treatment strategy. Myelosuppression is the dose-limiting toxicity and may be particularly problematic in patients heavily pretreated with chemotherapy. Reliable dosimetry is likely to minimise toxicity and improve treatment efficacy, and the aim of this study was to elucidate the complex problems of dosimetry of RIT by using an integrated SPECT/CT system.Methods As a part of a clinical trial of ¹³¹I-anti-CD20 rituximab RIT of non-Hodgkins lymphoma, we employed a patient-specific prospective dosimetry method utilising the whole-body effective half-life of antibody and the patients ideal weight to calculate the administered activity for RIT corresponding to a prescribed radiation absorbed dose of 0.75 Gy to the whole body. A novel technique of quantitation of bone marrow uptake with hybrid SPECT/CT imaging was developed to validate this methodology by using post-RIT extended imaging and data collection.Results A strong, statistically significant correlation (p=0.001) between whole-body effective half-life of antibody and effective marrow half-life was demonstrated. Furthermore, it was found that bone marrow activity concentration was proportional to administered activity per unit weight, height or body surface area (p<0.001).Conclusion The results of this study show the proposed whole-body dosimetry method to be valid and clinically applicable for safe, effective RIT.     

Accurate dosimetry in 131I radionuclide therapy using patient-specific, 3-dimensional methods for SPECT reconstruction and absorbed dose calculation.

(131)I radionuclide therapy studies have not shown a strong relationship between tumor absorbed dose and response, possibly due to inaccuracies in activity quantification and dose estimation. The goal of this work was to establish the accuracy of (131)I activity quantification and absorbed dose estimation when patient-specific, 3-dimensional (3D) methods are used for SPECT reconstruction and for absorbed dose calculation. METHODS: Clinically realistic voxel-phantom simulations were used in the evaluation of activity quantification and dosimetry. SPECT reconstruction was performed using an ordered-subsets expectation maximization (OSEM) algorithm with compensation for scatter, attenuation, and 3D detector response. Based on the SPECT image and a patient-specific density map derived from CT, 3D dosimetry was performed using a newly implemented Monte Carlo code. Dosimetry was evaluated by comparing mean absorbed dose estimates calculated directly from the defined phantom activity map with those calculated from the SPECT image of the phantom. Finally, the 3D methods were applied to a radioimmunotherapy patient, and the mean tumor absorbed dose from the new calculation was compared with that from conventional dosimetry obtained from conjugate-view imaging. RESULTS: Overall, the accuracy of the SPECT-based absorbed dose estimates in the phantom was >12% for targets down to 16 mL and up to 35% for the smallest 7-mL tumor. To improve accuracy in the smallest tumor, more OSEM iterations may be needed. The relative SD from multiple realizations was <3% for all targets except for the smallest tumor. For the patient, the mean tumor absorbed dose estimate from the new Monte Carlo calculation was 7% higher than that from conventional dosimetry. CONCLUSION: For target sizes down to 16 mL, highly accurate and precise dosimetry can be obtained with 3D methods for SPECT reconstruction and absorbed dose estimation. In the future, these methods can be applied to patients to potentially establish correlations between tumor regression and the absorbed dose statistics from 3D dosimetry.     

Assessment of the dicentric chromosome assay as a biodosimetry tool for more personalized medicine in a case of a high risk neuroblastoma 131I-mIBG treatment

Abstract

Purpose: The aims of this study were to estimate the whole - body absorbed - dose with the Dicentric Chromosome Assay (DCA) (biodosimetry) for ¹³¹I - metaiodobenzylguanidine (¹³¹I - mIBG) therapy for high - risk neuroblastoma, and to obtain an initial correlation with the physical dosimetry calculated as described by the Medical Internal Radiation Dosimetry formalism (MIRD). Together both objectives will aid the optimization of personalized targeted radionuclide therapies.

Material and methods: A 12 year-old child with relapsed high-risk neuroblastoma was treated with ¹³¹I-mIBG: a first administration with activity <444 MBq/kg was used as a tracer in order to calculate the activity needed in a second administration to achieve a whole body prescribed dose of ～4?Gy. Blood samples were obtained before and seven days after each administration to analyze the frequency of dicentrics. Moreover, consequent estimations of retained activity were done every few hours from equivalent dose rate measurements at a fixed position, two meters away from the patient, in order to apply the MIRD procedure. Blood samples were also drawn every 2- to -3 days to assess bone marrow toxicity.

Results: For a total activity of 22,867 MBq administered over two phases, both biological and physical dosimetries were performed. The former estimated a whole-body cumulated dose of 3.53 (2.58–4.41) Gy and the latter a total whole-body absorbed dose of 2.32?±?0.48?Gy. The patient developed thrombocytopenia grade 3 after both infusions and neutropenia grade 3 and grade 4 (based on CTCAE 4.0) during respective phases.

Conclusion: The results indicate a possible correlation between biodosimetry and standard physical dosimetry in ¹³¹I-mIBG treatment for high-risk neuroblastoma. A larger cohort and refinement of the DCA for internal irradiation are needed to define the role of biodosimetry in clinical situations.     

Pre-dosing with lilotomab prior to therapy with <Superscript>177</Superscript>Lu-lilotomab satetraxetan significantly increases the ratio of tumor to red marrow absorbed dose in non-Hodgkin lymphoma patients

Purpose

¹⁷⁷Lu-lilotomab satetraxetan is a novel anti-CD37 antibody radionuclide conjugate for the treatment of non-Hodgkin lymphoma (NHL). Four arms with different combinations of pre-dosing and pre-treatment have been investigated in a first-in-human phase 1/2a study for relapsed CD37+ indolent NHL. The aim of this work was to determine the tumor and normal tissue absorbed doses for all four arms, and investigate possible variations in the ratios of tumor to organs-at-risk absorbed doses.

Methods

Two of the phase 1 arms included cold lilotomab pre-dosing (arm 1 and 4; 40 mg fixed and 100 mg/m² BSA dosage, respectively) and two did not (arms 2 and 3). All patients were pre-treated with different regimens of rituximab. The patients received either 10, 15, or 20 MBq ¹⁷⁷Lu-lilotomab satetraxetan per kg body weight. Nineteen patients were included for dosimetry, and a total of 47 lesions were included. The absorbed doses were calculated from multiple SPECT/CT-images and normalized by administered activity for each patient. Two-sided Student’s t tests were used for all statistical analyses.

Results

Organs with distinct uptake of ¹⁷⁷Lu-lilotomab satetraxetan, in addition to tumors, were red marrow (RM), liver, spleen, and kidneys. The mean RM absorbed doses were 0.94, 1.55, 1.44, and 0.89 mGy/MBq for arms 1–4, respectively. For the patients not pre-dosed with lilotomab (arms 2 and 3 combined) the mean RM absorbed dose was 1.48 mGy/MBq, which was significantly higher than for both arm 1 (p?=?0.04) and arm 4 (p?=?0.02). Of the other organs, the highest uptake was found in the spleen, and there was a significantly lower spleen absorbed dose for arm-4 patients than for the patient group without lilotomab pre-dosing (1.13 vs. 3.20 mGy/MBq; p?<?0.01).Mean tumor absorbed doses were 2.15, 2.31, 1.33, and 2.67 mGy/MBq for arms 1–4, respectively. After averaging the tumor absorbed dose for each patient, the patient mean tumor absorbed dose to RM absorbed dose ratios were obtained, given mean values of 1.07 for the patient group not pre-dosed with lilotomab, of 2.16 for arm 1, and of 4.62 for arm 4. The ratios were significantly higher in both arms 1 and 4 compared to the group without pre-dosing (p?=?0.05 and p?=?0.02). No statistically significant difference between arms 1 and 4 was found.

Conclusions

RM is the primary dose-limiting organ for ¹⁷⁷Lu-lilotomab satetraxetan treatment, and pre-dosing with lilotomab has a mitigating effect on RM absorbed dose. Increasing the amount of lilotomab from 40 mg to 100 mg/m² was found to slightly decrease the RM absorbed dose and increase the ratio of tumor to RM absorbed dose. Still, both pre-dosing amounts resulted in significantly higher tumor to RM absorbed dose ratios. The findings encourage continued use of pre-dosing with lilotomab.