Efficacy of [177Lu]Lu-DOTATATE in metastatic neuroendocrine neoplasms of different locations: data from the SEPTRALU study.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) is one of the most promising therapeutic strategies in neuroendocrine neoplasms (NENs). Nevertheless, its role in certain tumor sites remains unclear. This study sought to elucidate the efficacy and safety of [177Lu]Lu-DOTATATE in NENs with different locations and evaluate the effect of the tumor origin, bearing in mind other prognostic variables. Advanced NENs overexpressing somatostatin receptors (SSTRs) on functional imaging, of any grade or location, treated at 24 centers were enrolled. The protocol consisted of four cycles of 177Lu-DOTATATE 7.4 GBq iv every 8 weeks (NCT04949282). RESULTS: The sample comprised 522 subjects with pancreatic (35%), midgut (28%), bronchopulmonary (11%), pheochromocytoma/ paraganglioma (PPGL) (6%), other gastroenteropancreatic (GEP) (11%), and other non-gastroenteropancreatic (NGEP) (9%) NENs. The best RECIST 1.1 responses were complete response, 0.7%; partial response, 33.2%; stable disease, 52.1%; and tumor progression, 14%, with activity conditioned by the tumor subtype, but with benefit in all strata. Median progression-free survival (PFS) was 31.3 months (95% CI, 25.7-not reached [NR]) in midgut, 30.6 months (14.4-NR) in PPGL, 24.3 months (18.0-NR) in other GEP, 20.5 months (11.8-NR) in other NGEP, 19.8 months (16.8-28.1) in pancreatic, and 17.6 months (14.4-33.1) in bronchopulmonary NENs. [177Lu]Lu-DOTATATE exhibited scant severe toxicity. CONCLUSION: This study confirms the efficacy and safety of [177Lu]Lu-DOTATATE in a wide range of SSTR-expressing NENs, regardless of location, with clinical benefit and superimposable survival outcomes between pNENs and other GEP and NGEP tumor subtypes different from midgut NENs.

Dependency of the remnant 131I-NaI biokinetics on the administered activity in patients with differentiated thyroid cancer.

PURPOSE: To study the dependency of the effective half-life on the administered activity and the correlation between the time-integrated activity and the remnant uptake at 2d and 7d in patients treated for DTC with 1.11 GBq, 3.7 GBq or 5.55 GBq of 131I-NaI. METHODS: Ninety-two patients undergoing total thyroidectomy and lymph node removal were included. If cancer had not spread to lymph nodes, patients received 1.11 GBq of 131I-NaI when the lesion maximal diameter was smaller than 4 cm, and 3.7 GBq for bigger sizes. If cancer had spread to lymph nodes patients received 5.55 GBq. There were 30, 49 and 13 patients respectively treated with 1.11 GBq(Group 1), 3.7 GBq(Group 2) and 5.55 GBq(Group 3). Two SPECT/CT scans were performed at 2d and 7d after radioiodine administration for each patient to determine the thyroid remnant activities and effective half-lives of the radioiodine. RESULTS: Statistical analysis showed significant differences (p < 0.05) in the effective half-life among patients treated with 1.11 GBq, 3.7 GBq and 5.55 GBq. A high positive correlation (ρ > 0.95) was found between the time-integrated activity and the remnant activity at 2d for the three groups of patients. CONCLUSIONS: There were significant differences in the effective half-life of the radioiodine in remnants of patients treated with activities of 1.11 GBq, 3.7 GBq or 5.55 GBq. The high positive linear correlation found between the time-integrated activity and the remnant activity at 2d for the three groups of patients indicate that the time-integrated activity could be estimated from one time-point.

A retrospective study on the potential of 99m Tc-HDP imaging before therapy for individualizing treatments with 223 Ra-Cl2 for metastatic castration resistant prostate cancer.

PURPOSE: Research on dose-effect correlation is necessary to move toward an individualization of treatments of metastatic castration resistant prostate cancer (mCRPC) with 223 Ra-Cl2 . We first looked for a possible correlation of 99m Tc-HDP lesion uptake in pretreatment whole-body scans (WBSs) with lesion absorbed dose. Moreover, we looked for a possible correlation of 99m Tc-HDP lesion uptake in pretreatment WBSs and of lesion absorbed dose with relative change in the 99m Tc-HDP lesion uptake obtained from pre- and post-treatment WBSs in patients treated for mCRPC with six cycles of 223 Ra-Cl2 . METHODS: Eleven patients received six cycles of 55 kBq/kg of 223 Ra-Cl2 separated by 4 weeks. In addition, one patient received concomitant treatment with abiraterone and two patients with enzalutamide. The 99m Tc-HDP WBSs were acquired before the first cycle and after the sixth cycle of the treatment. For the lesions with the higher 99m Tc-HDP uptake, the absorbed dose was calculated for the first cycle. Lesion volume was determined from 99m Tc-HDP SPECT/CT images before the first cycle and 223 Ra-Cl2 activity in the lesions was determined from 223 Ra-Cl2 planar images after the first cycle. The effect of the treatment was evaluated from the relative change of the mean and the maximum counts in the lesions, both estimated from the WBSs acquired before the first cycle and after the sixth cycle. RESULTS: The absorbed dose was calculated for 30 lesions, with values ranging between 0.4 and 3.8 Gy (mean 1.5 Gy). A significant (P < 0.05) high positive linear correlation was found between the lesion absorbed dose in the first treatment cycle and the mean and maximum counts in the lesions in the WBSs acquired before the first cycle (R = 0.75 and 0.76, respectively). The relative change of the mean and the maximum counts in the lesions in the 99m Tc-HDP WBSs showed a significant (P < 0.05) high positive logarithmic correlation with the 99m Tc-HDP mean and maximum counts in the lesions before the first cycle (R = 0.79 and 0.78, respectively). Lastly, a significant (P < 0.05) high positive logarithmic correlation was also found between the relative change of the mean and the maximum counts in the lesions in the 99m Tc-HDP WBSs and the lesion absorbed dose (R = 0.86 and 0.85, respectively). For this correlation the influence of the administered activity and of the concomitant treatments was not found to be significant (P > 0.05). CONCLUSIONS: The high correlations found for the 99m Tc-HDP lesion uptake before the first cycle lesion with the relative change in the 99m Tc-HDP lesion uptake after the six cycles of 223 Ra-Cl2 , and with the lesion absorbed dose in the first cycle show the potential of pretreatment 99m Tc-HDP imaging in order to personalize the performance of these treatments.

Microdosimetry-based determination of tumour control probability curves for treatments with 225Ac-PSMA of metastatic castration resistant prostate cancer.

We performed Monte Carlo simulations in order to determine, by means of microdosimetry calculations, tumour control probability (TCP) curves for treatments with 225Ac-PSMA of metastatic castration resistant prostate cancer (mCRPC). Realistic values of cell radiosensitivity, nucleus size and lesion size were used for calculations. As the cell radiosensitivity decreased, the nucleus size decreased and the lesion size increased, the absorbed dose to reach a given TCP increased. The widest variations occurred with regard to the cell radiosensitivity. For the Monte Carlo simulations, in order to address a non-uniform PSMA expression, different 225Ac-PSMA distributions were considered. The effect of these different PSMA distributions resulted in small variations in the TCP curves (maximum variation of 5%). Absorbed doses to reach a TCP of 0.9 for a uniform 225Ac-PSMA distribution, considering a relative biological effectiveness (RBE) of 5, ranged between 35.0 Gy and 116.5 Gy. The lesion absorbed doses per administered activity reported in a study on treatments with 225Ac-PSMA of mCRPC ranged between 1.3 Gy MBq-1 and 9.8 Gy MBq-1 for a RBE = 5. For a 70 kg-patient to whom 100 kBq kg-1 of 225Ac-PSMA are administered, the range of lesion absorbed doses would be between 9.1 Gy and 68.6 Gy. Thus, for a single cycle of 100 kBq kg-1, a number of lesions would not receive an absorbed dose high enough to reach a TCP of 0.9.

Feasibility and limitations of quantitative SPECT for 223Ra.

The aim of this paper is to investigate the feasibility and limitations of activity-concentration estimation for 223Ra using SPECT. Phantom measurements are performed using spheres (volumes 5.5 mL to 26.4 mL, concentrations 1.6 kBq mL-1 to 4.5 kBq mL-1). Furthermore, SPECT projections are simulated using the SIMIND Monte Carlo program for two geometries, one similar to the physical phantom and the other being an anthropomorphic phantom with added lesions (volumes 34 mL to 100 mL, concentrations 0.5 kBq mL-1 to 4 kBq mL-1). Medium-energy and high-energy collimators, 60 projections with 55 s per projection and a 20% energy window at 82 keV are employed. For the Monte Carlo simulated images, Poisson-distributed noise is added in ten noise realizations. Reconstruction is performed (OS-EM, 40 iterations, 6 subsets) employing compensation for attenuation, scatter, and collimator-detector response. The estimated concentrations in the anthropomorphic phantom are also corrected using recovery coefficients. Errors for the largest sphere in the physical phantom range from -25% to -34% for the medium-energy collimator and larger deviations for smaller spheres. Corresponding results for the high-energy collimator are -15% to -31%. The corresponding Monte Carlo simulations show standard deviations of a few percentage points. For the anthropomorphic phantom, before application of recovery coefficients the bias ranges from -16% to -46% (medium-energy collimator) and -10% to -28% (high-energy collimator), with standard deviations of 2% to 14% and 1% to 16%. After the application of recovery coefficients, the biases range from -3% to -35% (medium energy collimator) and from 0% to -18%. The errors decrease with increasing concentrations. Activity-concentration estimation of 223Ra with SPECT is feasible, but problems with repeatability need to be further studied.

Analysis of activity uptake, effective half-life and time-integrated activity for low- and high-risk papillary thyroid cancer patients treated with 1.11 GBq and 3.7 GBq of 131I-NaI respectively.

PURPOSE: To analyse the activity uptakes, effective half-lives and time-integrated activities, of relevance for remnant dosimetry, for patients treated for papillary thyroid cancer (PTC) with a different amount of activity of 131I-NaI. METHODS: Fifty patients were included. Of those, 18 patients had low-risk PTC and were treated with 1.11 GBq of 131I-NaI (Group 1), and 32 patients had high-risk PTC and were treated with 3.7 GBq (Group 2). Radioiodine was administered after total thyroidectomy and rhTSH stimulation. Two SPECT/CT scans were performed for each patient to determine the remnant activities and effective half-lives. RESULTS: Significantly higher values (p < 0.05) were obtained for Group 1 for the remnant activity at 7 d (medians 1.4 MBq vs 0.27 MBq), the remnant activity per administered activity at 2 d (0.35% vs 0.09%) and at 7 d (0.13% vs 0.007%), and the effective half-life (93 h vs 40 h). Likewise, the time-integrated activity coefficient was significantly higher for Group 1. The time-integrated activity did not differ significantly between the two groups (p > 0.05). CONCLUSIONS: We found a significant difference in the remnant activity per administered activity, the rate of washout from thyroid remnants, and the time-integrated activity coefficient between low-risk PTC patients treated with 1.11 GBq and high-risk PTC patients treated with 3.7 GBq. On the contrary, there was no such difference in the time-integrated activity. If remnant masses were also not statistically different (reasonable assumption for this monocentric study) no difference in time-integrated activity would imply no difference in remnant absorbed dose, of relevance for treatment efficacy and the risks of stochastic effects.

Outcomes after a first and/or second salvage treatment in patients with oligometastatic prostate cancer recurrence detected by (18-F) choline PET-CT.

OBJECTIVE: The primary objective of this study was to assess clinical outcomes in patients with oligometastatic prostate cancer recurrence after single or repeated salvage radiation treatment. METHODS: Forty-nine consecutive prostate cancer patients diagnosed with oligometastatic recurrence on Ch-PET have been prospectively treated. Seven (23%) patients had castrate-resistant disease. Clinical outcomes were assessed using the Kaplan-Meier method. Potential prognostic factors were examined using univariate proportional hazards regression. RESULTS: The treatments administered to the initial oligorecurrence sites were intensity-modulated radiotherapy (IMRT) ± ADT (26 patients; 53%) and stereotactic ablative radiotherapy (SABR) ± ADT (23 patients; 47%). With a median follow-up of 24 months (range 6-39), 24 patients developed a biochemical failure. Twenty out of the 24 relapsed patients underwent a second Ch-PET/CT. Seven patients presented poly-metastatic relapse and 10 oligometastatic diseases. Six of 10 patients with a second oligorecurrence were treated again with SABR. Overall, 102 lesions were treated. Local control was detected in 45 (91.8%) patients. No relevant (grade ≥ 2) toxicity was reported, and there was no grade 3 toxicity. On univariate analysis, none of the variables were significantly predicted for clinical disease-free survival. At last follow-up visit, 24 patients (40%) were free from biochemical failure and 37 (71%) patients were free from clinical disease. The 2-year OS and PCSS were 91.8% and 95.9% respectively. CONCLUSION: Salvage IMRT or SBRT of oligometastatic prostate cancer recurrence is associated with a prolonged cDFS. This may result in a longer time to develop castrate-resistant disease and a longer time without systemic therapies.

Comparison of microdosimetry-based absorbed doses to control tumours and clinically obtained tumour absorbed doses in treatments with 223Ra.

We performed Monte Carlo simulations in order to determine by means of microdosimetry calculations the average number of hits to the cell nucleus required to reach a tumour control probability (TCP) of 0.9, [Formula: see text], for the source geometry of a nucleus embedded in a homogeneous distribution of 223Ra atoms. From the results obtained and following the MIRD methodology, we determined the values of lesion absorbed doses needed to reach a TCP of 0.9, [Formula: see text], for different values of mass density, cell radiosensitivity, nucleus radius and lesion volume. The greatest variation of those absorbed doses occurred with cell radiosensitivity and no dependence was found on mass density. The source geometry used was chosen because we aimed to compare the values of [Formula: see text] with the lesion absorbed doses obtained from image-based macrodosimetry in treatments of metastatic castration-resistant prostate cancer with 223Ra which were obtained assuming a homogeneous distribution of 223Ra atoms within the lesion. In a comparison with a study including 29 lesions, results showed that even for the case of the most radiosensitive cells simulated, 45% of the lesions treated following a schedule of two cycles of 110 kBq kg-1 body mass would receive absorbed doses below the values of [Formula: see text] determined in this study.

Whole-remnant and maximum-voxel SPECT/CT dosimetry in 131I-NaI treatments of differentiated thyroid cancer.

PURPOSE: To investigate the possible differences between SPECT/CT based whole-remnant and maximum-voxel dosimetry in patients receiving radio-iodine ablation treatment of differentiated thyroid cancer (DTC). METHODS: Eighteen DTC patients were administered 1.11 GBq of 131I-NaI after near-total thyroidectomy and rhTSH stimulation. Two patients had two remnants, so in total dosimetry was performed for 20 sites. Three SPECT/CT scans were performed for each patient at 1, 2, and 3-7 days after administration. The activity, the remnant mass, and the maximum-voxel activity were determined from these images and from a recovery-coefficient curve derived from experimental phantom measurements. The cumulated activity was estimated using trapezoidal-exponential integration. Finally, the absorbed dose was calculated using S-values for unit-density spheres in whole-remnant dosimetry and S-values for voxels in maximum-voxel dosimetry. RESULTS: The mean absorbed dose obtained from whole-remnant dosimetry was 40 Gy (range 2-176 Gy) and from maximum-voxel dosimetry 34 Gy (range 2-145 Gy). For any given patient, the activity concentrations for each of the three time-points were approximately the same for the two methods. The effective half-lives varied (R = 0.865), mainly due to discrepancies in estimation of the longer effective half-lives. On average, absorbed doses obtained from whole-remnant dosimetry were 1.2 ± 0.2 (1 SD) higher than for maximum-voxel dosimetry, mainly due to differences in the S-values. The method-related differences were however small in comparison to the wide range of absorbed doses obtained in patients. CONCLUSIONS: Simple and consistent procedures for SPECT/CT based whole-volume and maximum-voxel dosimetry have been described, both based on experimentally determined recovery coefficients. Generally the results from the two approaches are consistent, although there is a small, systematic difference in the absorbed dose due to differences in the S-values, and some variability due to differences in the estimated effective half-lives, especially when the effective half-life is long. Irrespective of the method used, the patient absorbed doses obtained span over two orders of magnitude.

Whole-remnant and maximum-voxel SPECT/CT dosimetry in 131 I-NaI treatments of differentiated thyroid cancer.

PURPOSE: To investigate the possible differences between SPECT/CT based whole-remnant and maximum-voxel dosimetry in patients receiving radio-iodine ablation treatment of differentiated thyroid cancer (DTC). METHODS: Eighteen DTC patients were administered 1.11 GBq of 131 I-NaI after near-total thyroidectomy and rhTSH stimulation. Two patients had two remnants, so in total dosimetry was performed for 20 sites. Three SPECT/CT scans were performed for each patient at 1, 2, and 3-7 days after administration. The activity, the remnant mass, and the maximum-voxel activity were determined from these images and from a recovery-coefficient curve derived from experimental phantom measurements. The cumulated activity was estimated using trapezoidal-exponential integration. Finally, the absorbed dose was calculated using S-values for unit-density spheres in whole-remnant dosimetry and S-values for voxels in maximum-voxel dosimetry. RESULTS: The mean absorbed dose obtained from whole-remnant dosimetry was 40 Gy (range 2-176 Gy) and from maximum-voxel dosimetry 34 Gy (range 2-145 Gy). For any given patient, the activity concentrations for each of the three time-points were approximately the same for the two methods. The effective half-lives varied (R = 0.865), mainly due to discrepancies in estimation of the longer effective half-lives. On average, absorbed doses obtained from whole-remnant dosimetry were 1.2 ± 0.2 (1 SD) higher than for maximum-voxel dosimetry, mainly due to differences in theS-values. The method-related differences were however small in comparison to the wide range of absorbed doses obtained in patients. CONCLUSIONS: Simple and consistent procedures for SPECT/CT based whole-volume and maximum-voxel dosimetry have been described, both based on experimentally determined recovery coefficients. Generally the results from the two approaches are consistent, although there is a small, systematic difference in the absorbed dose due to differences in the S-values, and some variability due to differences in the estimated effective half-lives, especially when the effective half-life is long. Irrespective of the method used, the patient absorbed doses obtained span over two orders of magnitude.