Tumour control probability derived from dose distribution in homogeneous and heterogeneous models: assuming similar pharmacokinetics, (125)Sn-(177)Lu is superior to (90)Y-(177)Lu in peptide receptor radiotherapy.

Clinical trials on (177)Lu-(90)Y therapy used empirical activity ratios. Radionuclides (RN) with larger beta maximal range could favourably replace (90)Y. Our aim is to provide RN dose-deposition kernels and to compare the tumour control probability (TCP) of RN combinations. Dose kernels were derived by integration of the mono-energetic beta-ray dose distributions (computed using Monte Carlo) weighted by their respective beta spectrum. Nine homogeneous spherical tumours (1-25 mm in diameter) and four spherical tumours including a lattice of cold, but alive, spheres (1, 3, 5, 7 mm in diameter) were modelled. The TCP for (93)Y, (90)Y and (125)Sn in combination with (177)Lu in variable proportions (that kept constant the renal cortex biological effective dose) were derived by 3D dose kernel convolution. For a mean tumour-absorbed dose of 180 Gy, 2 mm homogeneous tumours and tumours including 3 mm diameter cold alive spheres were both well controlled (TCP > 0.9) using a 75-25% combination of (177)Lu and (90)Y activity. However, (125)Sn-(177)Lu achieved a significantly better result by controlling 1 mm-homogeneous tumour simultaneously with tumours including 5 mm diameter cold alive spheres. Clinical trials using RN combinations should use RN proportions tuned to the patient dosimetry. (125)Sn production and its coupling to somatostatin analogue appear feasible. Assuming similar pharmacokinetics (125)Sn is the best RN for combination with (177)Lu in peptide receptor radiotherapy justifying pharmacokinetics studies in rodent of (125)Sn-labelled somatostatin analogues.

Hemoglobin level significantly impacts the tumor cell survival fraction in humans after internal radiotherapy.

BACKGROUND: Anemia is usually not taken into account in internal radiotherapy. We investigated whether the hemoglobin (Hb) level could have an impact on the tumor response, as observed in external beam radiotherapy (EBRT). METHODS: Absorbed doses of 25 hepatic metastatic sites in eight patients who underwent a liver selective internal radiotherapy (SIRT) were computed by a 3D convolution of a dose deposition kernel with the 90Y time-of-flight positron emission tomography (TOF-PET) images acquired following therapy. Early tumor response was assessed by comparing a follow-up FDG TOF-PET scan with a baseline scan. Hb level was measured on the day of the SIRT procedure. RESULTS: All patients displayed early tumor response increasing with the tumor-absorbed dose. Significant differences between patients were noted, the response slope correlating with the Hb level. After applying a global fit on all metastases using a tumor radiosensitivity modulated by a Hb enhancement factor (HEF) linearly dependent on the Hb level, a strong correlation (R = 0.96) was observed between the early response and the absorbed dose. Hb level had a major impact on tumor response by modulating HEF by a factor 6. CONCLUSIONS: These results prove the significant impact of Hb level on the tumor response and support the study of methods for correcting tumor hypoxia, such as intensively performed in EBRT. The quantitative analysis of the relationship between tumor doses and early response has the power to allow fast screening of such correction methods in limited patient series. Internal radiotherapy could be more efficient if performed earlier in the therapy line, when the disease- and treatment-related anemia remains limited.

Comparison of yttrium-90 quantitative imaging by TOF and non-TOF PET in a phantom of liver selective internal radiotherapy.

The aim of this study is to determine the feasibility of achieving quantitative measurement in (90)Y-microspheres liver selective internal radiotherapy (SIRT) by imaging (90)Y with a conventional non-time of flight (TOF) PET device. Instead of the bremsstrahlung x-rays of the ß-decay, the low branch of e(-)- e(+) pair production in the (90)Y-decay was used. The activity distribution in a phantom-simulated liver SIRT was obtained by direct (90)Y-PET imaging. We tested a LYSO TOF PET and two GSO and BGO non-TOF PET scanners using a 3.6-l cylindrical phantom filled with the (90)Y solution containing two sets of hot and cold spheres. The best hot contrast was obtained with the LYSO TOF. It was close to the expected value and remained constant, even for short acquisition times. The LYSO non-TOF was about 10% lower. The GSO performed similarly but degraded for shorter times whilst the BGO was the worst with 40% loss. For the cold spheres, the LYSO TOF and the GSO provided the best results, while the LYSO non-TOF and the BGO were the worst. (90)Y PET imaging in liver SIRT is achievable with LYSO TOF. Conventional LYSO and GSO show a loss of contrast and require longer acquisition times. BGO imaging is not feasible for dosimetry calculation.

Dosimetry of yttrium-labelled radiopharmaceuticals for internal therapy: 86Y or 90Y imaging?

This paper reviews issues concerning (86)Y positron emission tomography (PET), (90)Y PET and (90)Y bremsstrahlung imaging. Specific methods and corrections developed for quantitative imaging, for application in preclinical and clinical studies, and to assess (90)Y dosimetry are discussed. The potential imaging capabilities with the radioisotopes (87)Y and (88)Y are also considered. Additional studies required to assess specific unaddressed issues are also identified.

Effect of interferon-alpha treatment on [68Ga-DOTA,Tyr3,Thre8]octreotide uptake in CA20948 tumors: a small-animal PET study.

UNLABELLED: In peptide receptor radionuclide therapy of neuroendocrine tumors, improvements have been made by increasing the affinity for receptors and by protecting critical organs (e.g., kidneys). However, tumor parameters involved in radiopeptide uptake are still under investigation. Interferon-α (IFNα) is used as biotherapy for neuroendocrine tumors. Several mechanisms of action are described, but the potential effect of IFNα on tumor uptake of labeled peptide has not been studied in vivo yet. METHODS: Twenty-six male CA20948 tumor-bearing Lewis rats were imaged before and during IFNα treatment using quantitative small-animal PET with [(68)Ga-DOTA,Tyr(3),Thre(8)]octreotide. Imaging was performed at days 0, 3, and 7. Animals were divided into 3 groups according to the treatment: control (injected daily with saline), half (4 d of IFNα treatment from day 0 to day 3, then saline), and full (7 d of IFNα). A daily dose of IFNα (1.5 mIU) was administered subcutaneously. Quantitative PET results are expressed as percentage injected dose per cm(3) and normalized to baseline (day 0) values. Tumor size was monitored by PET and caliper measurements. RESULTS: Gross tumor uptake and tumor volumes increased in all groups over the 7-d period. On day 3, mean ± SD ratios to day 0 were 1.2 ± 0.2, 1.3 ± 0.5, and 1.2 ± 0.4, respectively, for control, half, and full groups. On day 7, respective values were 1.1 ± 0.2, 1.3 ± 0.6, and 1.5 ± 0.4. At day 3, a comparison among groups showed no statistically significant difference. At day 7, the full group showed a significantly higher ratio in activity concentration than the control group (P = 0.021). A good correlation was found between tumor volumes assessed by small-animal PET and caliper measurements (R = 0.89, P < 0.0001). CONCLUSION: As expected, over a period of 7 d, both tumor volumes and radiopeptide uptake increased in all animals. However, the activity concentration increased significantly more at day 7 in animals treated for 7 d with IFNα, compared with controls. This is the first, to our knowledge, in vivo indication that IFNα is able to increase tumor uptake of the labeled analog in a small-animal model of neuroendocrine tumors. The mechanisms underlying this effect (flow, vascular permeability, receptor upregulation) remain unknown and need to be further investigated.

Experimental facts supporting a red marrow uptake due to radiometal transchelation in 90Y-DOTATOC therapy and relationship to the decrease of platelet counts.

PURPOSE: The aim of this study was to retrospectively evaluate whether the red marrow (RM) takes up (111)In-diethylenetriaminepentaacetic acid (DTPA)-D-Phe(1)-octreotide and (86)Y-DOTATOC and to assess the correlation between the RM absorbed doses and platelet count reduction as a biological dose estimate. METHODS: Data from 12 patients who underwent at 24 h p.i. high statistics (111)In single photon emission computed tomography (SPECT) and (86)Y positron emission tomography (PET) acquisitions of the chest were analysed. Uptake was measured on >7 cm spine length and converted to total RM uptake using standard RM distribution in man. RM absorbed doses were calculated assuming specific RM uptake and using the plasma and remainder of the body models. RM doses were correlated with the platelet count reduction at 4 weeks. In vitro experiments explored the metabolism of (111)In-DTPA-D-Phe(1)-octreotide and (90)Y-DOTATOC in plasma. RESULTS: The correlation between the uptake of both tracers was excellent (R = 0.80), indicating that RM uptake of (86)Y-DOTATOC reflects a real physiological process and not reconstruction artefacts. The kinetics of (86)Y-DOTATOC RM activity was different than that in blood and tumours, with no activity at 4 h p.i. indicating that the uptake is not somatostatin receptor dependent. In vitro experiments showed a transchelation of both radiometals to free transferrin that could explain the RM uptake. In patients without chemotherapy and with a normal platelet count recovery, a good correlation (R = 0.96) was found between the RM doses and the platelet count reduction at the nadir. CONCLUSION: These experimental facts support the existence of a true RM uptake likely related to transchelation of the radiometal to transferrin. RM uptake correlates well with the observed acute RM toxicity.

Yttrium-90-labeled microsphere tracking during liver selective internal radiotherapy by bremsstrahlung pinhole SPECT: feasibility study and evaluation in an abdominal phantom.

BACKGROUND: The purpose of the study is to evaluate whether a pinhole collimator is better adapted to bremsstrahlung single photon emission computed tomography [SPECT] than parallel-hole collimators and in the affirmative, to evaluate whether pinhole bremsstrahlung SPECT, including a simple model of the scatter inside the patient, could provide a fast dosimetry assessment in liver selective internal radiotherapy [SIRT]. MATERIALS AND METHODS: Bremsstrahlung SPECT of an abdominal-shaped phantom including one cold and five hot spheres was performed using two long-bore parallel-hole collimators: a medium-energy general-purpose [MEGP] and a high-energy general-purpose [HEGP], and also using a medium-energy pinhole [MEPH] collimator. In addition, ten helical MEPH SPECTs (acquisition time 3.6 min) of a realistic liver-SIRT phantom were also acquired. RESULTS: Without scatter correction for SPECT, MEPH SPECT provided a significantly better contrast recovery coefficient [CRC] than MEGP and HEGP SPECTs. The CRCs obtained with MEPH SPECT were still improved with the scatter correction and became comparable to those obtained with positron-emission tomography [PET] for the 36-, 30- (cold), 28-, and 24-mm-diameter spheres: CRC = 1.09, 0.59, 0.91, and 0.69, respectively, for SPECT and CRC = 1.07, 0.56, 0.84, and 0.63, respectively, for PET. However, MEPH SPECT gave the best CRC for the 19-mm-diameter sphere: CRC = 0.56 for SPECT and CRC = 0.01 for PET. The 3.6-min helical MEPH SPECT provided accurate and reproducible activity estimation for the liver-SIRT phantom: relative deviation = 10 ± 1%. CONCLUSION: Bremsstrahlung SPECT using a pinhole collimator provided a better CRC than those obtained with parallel-hole collimators. The different designs and the better attenuating material used for the collimation (tungsten instead of lead) explain this result. Further, the addition of an analytical modeling of the scattering inside the phantom resulted in an almost fully recovered contrast. This fills the gap between the performance of90Y-PET and bremsstrahlung pinhole SPECT which is a more affordable technique and could even be used during the catheterization procedure in order to optimize the90Y activity to inject.

4-Step renal dosimetry dependent on cortex geometry applied to 90Y peptide receptor radiotherapy: evaluation using a fillable kidney phantom imaged by 90Y PET.

UNLABELLED: Accurate dosimetry in (90)Y peptide receptor radionuclide therapy (PRRT) helps to optimize the injected activity, to prevent kidney or red marrow toxicity, while giving the highest absorbed dose to tumors. The aim of this study was to evaluate whether direct (90)Y bismuth germanate or lutetium yttrium orthosilicate time-of-flight PET was accurate enough to provide dosimetry estimates suitable to (90)Y PRRT. METHOD: To overcome the statistical uncertainty arising from the low (90)Y positron counting rate, the computation of the cortex mean-absorbed dose was divided into 4 steps: delineation of the cortex volume of interest (VOI) on the CT scan, determination of the recovery coefficient from the cortex VOI using the point-spread function of the whole imaging process, determination of the mean cortex-absorbed dose per unit cumulated activity in the cortex (S(cortex←cortex) value) from the cortex VOI using a (90)Y voxel S value kernel, and determination of the number of decays in the cortex VOI from the PET reconstruction. Our 4-step method was evaluated using an anthropomorphic abdominal phantom containing a fillable kidney phantom based on the MIRD kidney model. Vertebrae with an attenuation similar to that of bone were also modeled. Two tumors were modeled by 7-mL hollow acrylic spheres and the spleen by a plastic bag. Activities corresponded to typical tissue uptake in a first (90)Y-DOTATOC cycle of 4.4 GBq, considered as free of significant renal toxicity. Eight successive 45-min scans were acquired on both systems. RESULTS: Both PET systems were successful in determining absorbed dose to modeled tumors but failed to provide accurate red marrow dosimetry. Renal cortex dosimetry was reproducible for both PET systems, with an accuracy of 3% for the bismuth germanate system but only 18% for the lutetium yttrium orthosilicate time-of-flight system, which was hindered by the natural radioactivity of the crystal, especially in the most attenuated area of the kidney. CONCLUSION: This study supports the use of direct (90)Y PET of the first PRRT cycle to assess the kidney-absorbed dose and optimize the injected activity of the following cycles.

Feasibility of 90Y TOF PET-based dosimetry in liver metastasis therapy using SIR-Spheres.

PURPOSE: (90)Y-labelled compounds used in targeted radiotherapy are usually imaged with SPECT by recording the bremsstrahlung X-rays of the beta decay. The continuous shape of the X-ray spectrum induces the presence of a significant fraction of scatter rays in the acquisition energy window, reducing the accuracy of biodistribution and of dosimetry assessments. METHODS: The aim of this paper is to use instead the low branch of e(-) e(+) pair production in the (90)Y decay. After administration of (90)Y-labelled SIR-Spheres by catheterization of both liver lobes, the activity distribution is obtained by (90)Y time-of-flight (TOF) PET imaging. The activity distribution is convolved with a dose irradiation kernel in order to derive the regional dosimetry distribution. RESULTS: Evaluation on an anatomical phantom showed that the method provided an accurate dosimetry assessment. Preliminary results on a patient demonstrated a high-resolution absorbed dose distribution with a clear correlation with tumour response. CONCLUSION: This supports the implementation of (90)Y PET in selective internal radiation therapy of the liver.

90Y-edotreotide for metastatic carcinoid refractory to octreotide.

PURPOSE: Metastatic carcinoid is an incurable malignancy whose symptoms, such as diarrhea and flushing, can be debilitating and occasionally life-threatening. Although symptom relief is available with octreotide, the disease eventually becomes refractory to octreotide, leaving no proven treatment options. The goal of this study was to evaluate the clinical effect of using (90)Y-edotreotide to treat symptomatic patients with carcinoid tumors. PATIENTS AND METHODS: Patients enrolled had metastatic carcinoid, at least one sign/symptom refractory to octreotide, and at least one measurable lesion. Study treatment consisted of three cycles of 4.4 GBq (120 mCi) (90)Y-edotreotide each, once every 6 weeks. RESULTS: Ninety patients were enrolled in the study. Using Southwest Oncology Group tumor response criteria, 67 (74.%) of 90 patients (95% CI, 65.4% to 83.4%) were objectively stable or responded. A statistically significant linear trend toward improvement was demonstrated across all 12 symptoms assessed. Median progression-free survival was significantly greater (P = .03) for the 38 patients who had durable diarrhea improvement than the 18 patients who did not (18.2 v 7.9 months, respectively). Adverse events (AEs) were reported in 96.7% (87 of 90) of patients. These AEs consisted primarily of reversible GI events (76 of 90), which could be caused in part by concomitant administration of amino acid solution given to reduce radiation exposure to the kidneys. There was one case each of grade 3 oliguria and grade 4 renal failure, each lasting 6 days. CONCLUSION: (90)Y-edotreotide treatment improved symptoms associated with malignant carcinoid among subjects with no treatment alternatives. Treatment was well-tolerated and had an acceptable expected AE profile.

Tumor uptake of 68Ga-DOTA-Tyr3-octreotate: animal PET studies of tumor flow and acute somatostatin receptor modulation in the CA20948 rat model.

INTRODUCTION: Factors determining the in vivo uptake of radiolabeled somatostatin analogs by neuroendocrine tumors are poorly known. The aim is to evaluate in vivo tumor perfusion and regulation of somatostatin receptors (sstr) following acute exposure to octreotide, in an animal model of neuroendocrine tumor. METHODS: H(2)(15)O flow studies were performed in 8 CA20948 tumor-bearing rats and another 36 rats underwent three [(68)Ga]-DOTA-Tyr(3)-octreotate imaging sessions at 24-h intervals. After baseline (Day 0) imaging, scanning was repeated on Day 1 after octreotide injection (175 microg/kg), with a variable delay: no injection (controls, n=7), coinjection (n=6), and octreotide injection 20 min (n=7), 2 h (n=8) and 4 h (n=8) before imaging. Repeat images without octreotide was performed at Day 2 followed by sacrifice and tumor counting. RESULTS: H(2)(15)O studies failed to measure quantitative tumor perfusion in this model. On Day 1, ratio of tumor uptake to Day 0 was 1.2+/-0.3 in controls; 0.6+/-0.2 in the coinjection group; 0.9+/-0.2, 1.1+/-0.1 and 1.2+/-0.2 in the other groups, respectively. Uptake in the coinjection group showed a statistically significant reduction of tumor uptake (P<.0001). All groups showed increased uptake on Day 2, without statistical differences between groups. In vivo tumor counts showed good correlation with ex vivo countings (R(2)=0.946). CONCLUSION: Acute exposure to unlabeled octreotide in this neuroendocrine tumor model results in a rapid recycling or resynthesis of sstr. Positron emission tomography (PET) allowed to reliably assess quantitative uptake of [(68)Ga]-DOTA-Tyr(3)-octreotate over time in the same animal, but failed in this model to measure tumor perfusion.

Single photon emission-computed tomography (SPECT) for functional investigation of the proximal tubule in conscious mice.

Noninvasive analysis of renal function in conscious mice is necessary to optimize the use of mouse models. In this study, we evaluated whether single photon emission-computed tomography (SPECT) using specific radionuclear tracers can be used to analyze changes in renal proximal tubule functions. The tracers included (99m)TC- dimercaptosuccinic acid ((99m)Tc-DMSA), which is used for cortex imaging; (99m)Tc-mercaptoacetyltriglycine ((99m)Tc-MAG3), used for dynamic renography; and (123)I-beta(2)-microglobulin, which monitors receptor-mediated endocytosis. (99m)Tc-DMSA SPECT imaging was shown to delineate the functional renal cortex with a approximately 1-mm spatial resolution and accumulated in the cortex reaching a plateau 5 h after injection. The cortical uptake of (99m)Tc-DMSA was abolished in Clcn5 knockout mice, a model of proximal tubule dysfunction. Dynamic renography with (99m)Tc-MAG3 in conscious mice demonstrated rapid extraction from blood, renal accumulation, and subsequent tubular secretion. Anesthesia induced a significant delay in the (99m)Tc-MAG3 clearance. The tubular reabsorption of (123)I-beta(2)-microglobulin was strongly impaired in the Clcn5 knockout mice, with defective tubular processing and loss of the native tracer in urine, reflecting proximal tubule dysfunction. Longitudinal studies in a model of cisplatin-induced acute tubular injury revealed a correlation between tubular recovery and (123)I-beta(2)-microglobulin uptake. These data show that SPECT imaging with well-validated radiotracers allows in vivo investigations of specific proximal tubule functions in conscious mice.

Therapy using labelled somatostatin analogues: comparison of the absorbed doses with 111In-DTPA-D-Phe1-octreotide and yttrium-labelled DOTA-D-Phe1-Tyr3-octreotide.

OBJECTIVE: We estimated the absorbed doses for (111)In-DTPA-D-Phe(1)-octreotide and (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide in the same patients in order to compare the potential effectiveness (tumour dose) and safety (kidney and red marrow dose) of these drugs for peptide-targeted radiotherapy of somatostatin receptor positive tumours. METHODS: Six patients with neuroendocrine tumours underwent quantitative (111)In-DTPA-D-Phe(1)-octreotide SPECT and (86)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide PET scan at intervals of 1 week. All studies were performed with a co-infusion of amino acids for renal protection. PET and SPECT were reconstructed using iterative algorithms, incorporating attenuation and scatter corrections. Tissue uptakes (IA%) were measured and used to calculate residence times. Absorbed doses to tissues were estimated and the maximal allowed activity, defined as either the activity delivering 23 Gy to the kidneys (MAA(K)) or 2 Gy to the red marrow (MAA(RM)), was calculated and the resulting tumour absorbed doses were computed. RESULTS: For the MAA(K) the mean absorbed dose to the red marrow was lower for (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide than for (111)In-DTPA-D-Phe(1)-octreotide (1.8+/-0.9 Gy vs. 6.4+/-1.6 Gy; P<0.001). The median absorbed dose to tumours for the MAA(K) was two-fold higher for (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide as compared to (111)In-DTPA-D-Phe(1)-octreotide (30.1 vs. 12.6 Gy; P<0.05). The median absorbed dose to tumours estimated for the MAA(RM) was 10-fold higher for (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide than for (111)In-DTPA-D-Phe(1)-octreotide (35.1 Gy vs. 3.9 Gy; P<0.05). CONCLUSIONS: This direct intra-patient comparison confirms that the use of (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide is more appropriate for therapy of somatostatin receptor bearing tumours. When using (111)In-DTPA-D-Phe(1)-octreotide, the red marrow represents the major critical organ; this can result in significant toxicity if high activities have to be administered to obtain efficient tumour irradiation.

Survival and response after peptide receptor radionuclide therapy with [90Y-DOTA0,Tyr3]octreotide in patients with advanced gastroenteropancreatic neuroendocrine tumors.

Because the role of chemotherapy, interferon, or somatostatin analogs as antiproliferative agents is uncertain, currently few treatment options exist for patients with metastatic or inoperable gastroenteropancreatic neuroendocrine tumors (GEP-NET). Fifty-eight patients with somatostatin receptor-positive GEP-NET were treated in a phase I dose-escalating study with cumulative doses of 47 mCi to 886 mCi of the radiolabeled somatostatin analog [(90)Y-DOTA(0),Tyr(3)]-octreotide. At baseline, 47 patients had progressive disease, and 36 were symptomatic. The extent of disease was: 4 patients without liver metastases and 52 patients with liver metastases, including 16 patients with very advanced disease, qualified as "end-stage," and 2 end-stage patients without liver metastases. The objective responses were 5 partial response (PR), 7 minor response (MR), 29 stable disease (SD), and 17 PD. Overall, 33 patients (57%) experienced some improvement in their disease status, including conversion from PD into SD and improvement from SD into MR. Accordingly, 21 of 36 patients (58%) had improvement in Karnofsky performance score or symptoms. The median overall survival (OS) was 36.7 months (95% confidence interval [CI] 19.4-54.1 months). The median progression-free survival in 41 patients who had at least stable disease at the end of the treatment period was 29.3 months (95% CI 19.3-39.3 months). Patients who had SD at baseline had a significantly better OS than patients who had PD at baseline. The extent of disease at baseline also was a significant predictive factor for OS. The OS after therapy with [(90)Y-DOTA(0),Tyr(3)]-octreotide was significantly better than in a historic control group of 32 comparable patients with GEP-NET who had been treated with another radiolabeled somatostatin analog, [(111)In-DTPA(0)]-octreotide (median OS 12.0 months, 95% CI 6.2-17.8 months). The difference in OS for both therapies remained highly significant in a multivariate Cox proportional hazard model including progression status and extent of disease at baseline as covariates. Although the objective response after therapy with [(90)Y-DOTA(0),Tyr(3)]-octreotide by standard criteria seems modest, the significantly longer OS compared with historic controls is most encouraging.