Marnix G. E. H. Lam

EANM procedure guideline for treatment of refractory metastatic bone pain

IntroductionBone pain is a common symptom of metastatic disease in cancer, experienced with various intensities by about 30% of cancer patients, during the development of their disease, up to 60–90% in the latest phases.DiscussionIn addition to other therapies, such as analgesics, bisphosphonates, chemotherapy, hormonal therapy and external beam radiotherapy, bone-seeking radiopharmaceuticals are also used for the palliation of pain from bone metastases. Substantial advantages of bone palliation radionuclide therapy include the ability to simultaneously treat multiple sites of disease with a more probable therapeutic effect in earlier phases of metastatic disease, the ease of administration, the repeatability and the potential integration with the other treatments.ConclusionThe Therapy, Oncology and Dosimetry Committees have worked together to revise the EANM guidelines on the use of bone-seeking radiopharmaceuticals. The purpose of this guideline is to assist the nuclear medicine physician in treating and managing patients undergoing such treatment.

99mTc-Macroaggregated Albumin Poorly Predicts the Intrahepatic Distribution of 90Y Resin Microspheres in Hepatic Radioembolization

In hepatic 90Y radioembolization, pretreatment 99mTc-macroaggregated albumin (99mTc-MAA) nuclear imaging is used for lung shunt analysis, evaluation of extrahepatic deposition, and sometimes for treatment planning, using a partition model. A high level of agreement between pretreatment 99mTc-MAA distribution and final 90Y-microsphere distribution is assumed. The aim of this study was to investigate the value of pretreatment 99mTc-MAA SPECT to predict intrahepatic posttreatment 90Y-microsphere distribution. Methods: Volumes of interest (VOIs) were delineated on pretreatment contrast-enhanced CT or MR images according to Couinaud liver segmentation. All VOIs were registered to the 99mTc-MAA SPECT and 90Y SPECT images. The 99mTc-MAA SPECT and 90Y SPECT activity counts were normalized to the total administered activity of 90Y. For each VOI, this practice resulted in a predictive amount of 90Y (MBq/cm3) based on 99mTc-MAA SPECT in comparison with an actual amount of 90Y based on 90Y SPECT. Bland–Altman analysis was used to investigate the agreement of the activity distribution between 99mTc-MAA SPECT and 90Y SPECT. Results: A total of 39 procedures (225 VOIs) in 31 patients were included for analysis. The overall mean difference between pretreatment and posttreatment distribution of activity concentration for all segments was −0.022 MBq/cm3 with 95% limits of agreement of −0.581 to 0.537 MBq/cm3 (−28.9 to 26.7 Gy absorbed dose). A difference of >10%, >20%, and >30% of the mean activity per milliliter was found in, respectively, 153 (68%), 97 (43%), and 72 (32%) of the 225 segments. In every 99mTc-MAA procedure, at least 1 segment showed an under- or overestimation of >10%. The position of the catheter tip during administrations, as well as the tumor load of the liver segments, significantly influenced the disagreement. Conclusion: In current clinical practice, 99mTc-MAA distribution does not accurately predict final 90Y activity distribution. Awareness of the importance of catheter positioning and adherence to specific recommendations may lead to optimization of individualized treatment planning based on pretreatment imaging.

Quantitative Comparison of PET and Bremsstrahlung SPECT for Imaging the In Vivo Yttrium-90 Microsphere Distribution after Liver Radioembolization

Background After yttrium-90 (90Y) microsphere radioembolization (RE), evaluation of extrahepatic activity and liver dosimetry is typically performed on 90Y Bremsstrahlung SPECT images. Since these images demonstrate a low quantitative accuracy, 90Y PET has been suggested as an alternative. The aim of this study is to quantitatively compare SPECT and state-of-the-art PET on the ability to detect small accumulations of 90Y and on the accuracy of liver dosimetry. Methodology/Principal Findings SPECT/CT and PET/CT phantom data were acquired using several acquisition and reconstruction protocols, including resolution recovery and Time-Of-Flight (TOF) PET. Image contrast and noise were compared using a torso-shaped phantom containing six hot spheres of various sizes. The ability to detect extra- and intrahepatic accumulations of activity was tested by quantitative evaluation of the visibility and unique detectability of the phantom hot spheres. Image-based dose estimates of the phantom were compared to the true dose. For clinical illustration, the SPECT and PET-based estimated liver dose distributions of five RE patients were compared. At equal noise level, PET showed higher contrast recovery coefficients than SPECT. The highest contrast recovery coefficients were obtained with TOF PET reconstruction including resolution recovery. All six spheres were consistently visible on SPECT and PET images, but PET was able to uniquely detect smaller spheres than SPECT. TOF PET-based estimates of the dose in the phantom spheres were more accurate than SPECT-based dose estimates, with underestimations ranging from 45% (10-mm sphere) to 11% (37-mm sphere) for PET, and 75% to 58% for SPECT, respectively. The differences between TOF PET and SPECT dose-estimates were supported by the patient data. Conclusions/Significance In this study we quantitatively demonstrated that the image quality of state-of-the-art PET is superior over Bremsstrahlung SPECT for the assessment of the 90Y microsphere distribution after radioembolization.

Bone Seeking Radiopharmaceuticals for Palliation of Pain in Cancer Patients with Osseous Metastases

Many patients with cancer develop symptomatic skeletal metastases at an advanced stage of their disease. Skeletal metastases are often complicated by pain. They cause considerable morbidity and mortality. Besides analgesics, treatment options include external beam radiotherapy, bisphosphonates, chemotherapy, surgery and bone seeking radiopharmaceuticals. Pain palliation with bone seeking radiopharmaceuticals has proved to be an effective treatment modality in patients with metastatic bone pain. Radiopharmaceuticals bind to the bone matrix in areas of increased bone turnover, due to a metastatic response. Beta rays from the specific radionuclide, bound to its carrier ligand, result in the therapeutic effect. Various radiopharmaceuticals have been developed for this purpose. All have their own characteristics. The radiopharmaceuticals Samarium-153-ethylenediaminetetramethylenephosphonic acid ((153)Sm-EDTMP) and Strontium-89-Chloride, which are approved in the USA and Europe, as well as the not universally approved Rhenium-186-hydroxyethylidenediphosphonic acid ((186)Re-HEDP), will be discussed in greater detail. Depending on the half-life and radiation energy of the specific radionuclide, they exert a different effect and toxicity profile. In most cases, bone marrow toxicity is limited and reversible, which makes repetitive treatment relatively safe. Several studies have shown encouraging clinical results of palliative therapy using bone seeking radiopharmaceuticals, with an overall reported pain response rate in the order of +/- 70-80% of patients. This systemic form of radionuclide therapy is simple to administer and complements other treatment options. It has been associated with marked pain reduction, improved mobility in many patients, reduced dependence on analgesics, and improved performance status and quality of life. Additionally, new therapeutic strategies hold the promise of enhancement of the palliative and anticancer effects of this form of therapy.

Holmium-166 radioembolization for the treatment of patients with liver metastases : design of the phase I HEPAR trial

BackgroundIntra-arterial radioembolization with yttrium-90 microspheres ( 90Y-RE) is an increasingly used therapy for patients with unresectable liver malignancies. Over the last decade, radioactive holmium-166 poly(L-lactic acid) microspheres ( 166Ho-PLLA-MS) have been developed as a possible alternative to 90Y-RE. Next to high-energy beta-radiation, 166Ho also emits gamma-radiation, which allows for imaging by gamma scintigraphy. In addition, Ho is a highly paramagnetic element and can therefore be visualized by MRI. These imaging modalities are useful for assessment of the biodistribution, and allow dosimetry through quantitative analysis of the scintigraphic and MR images. Previous studies have demonstrated the safety of 166Ho-PLLA-MS radioembolization ( 166Ho-RE) in animals. The aim of this phase I trial is to assess the safety and toxicity profile of 166Ho-RE in patients with liver metastases.MethodsThe HEPAR study (Holmium Embolization Particles for Arterial Radiotherapy) is a non-randomized, open label, safety study. We aim to include 15 to 24 patients with liver metastases of any origin, who have chemotherapy-refractory disease and who are not amenable to surgical resection. Prior to treatment, in addition to the standard technetium-99m labelled macroaggregated albumin ( 99mTc-MAA) dose, a low radioactive safety dose of 60-mg 166Ho-PLLA-MS will be administered. Patients are treated in 4 cohorts of 3-6 patients, according to a standard dose escalation protocol (20 Gy, 40 Gy, 60 Gy, and 80 Gy, respectively). The primary objective will be to establish the maximum tolerated radiation dose of 166Ho-PLLA-MS. Secondary objectives are to assess tumour response, biodistribution, performance status, quality of life, and to compare the 166Ho-PLLA-MS safety dose and the 99mTc-MAA dose distributions with respect to the ability to accurately predict microsphere distribution.DiscussionThis will be the first clinical study on 166Ho-RE. Based on preclinical studies, it is expected that 166Ho-RE has a safety and toxicity profile comparable to that of 90Y-RE. The biochemical and radionuclide characteristics of 166Ho-PLLA-MS that enable accurate dosimetry calculations and biodistribution assessment may however improve the overall safety of the procedure.Trial registrationClinicalTrials.gov NCT01031784

Additional Heparin Preadministration Improves Cardiac Glucose Metabolism Suppression over Low-Carbohydrate Diet Alone in ¹⁸F-FDG PET Imaging.

Adequate suppression of cardiac glucose metabolism increases the interpretability and diagnostic reliability of 18F-FDG PET studies performed to detect cardiac inflammation and infection. There are no standardized guidelines, though prolonged fasting (>6 h), carbohydrate-restricted diets, fatty meals, and heparin loading all have been proposed. The aim of this study was to compare the 3 preparatory protocols used in our institution. Methods: 18F-FDG PET scans were selected and grouped according to 3 preparatory protocols (50 consecutive scans per group): 6-h fast (group 1), low-carbohydrate diet plus 12-h fast (group 2), and low-carbohydrate diet plus 12-h fast plus intravenous heparin preadministration (50 IU/kg) (group 3). Consecutive scans were retrospectively included from time frames during which the particular protocol was used. Group 1 included oncologic indications, and groups 2 and 3 infection or inflammation detection. Cardiac segments for which inflammation or infection foci had been confirmed on other imaging modalities were excluded from the analysis. 18F-FDG uptake in normal myocardium was scored according to a scale ranging from 0 (uptake less than that in left ventricle blood pool) to 4 (diffuse uptake greater than that in liver). Adequate suppression was defined as uptake less than that in liver and without any focus (scores 0–2). Results: Adequate suppression differed significantly between groups: 28% in group 1, 54% in group 2, and 88% in group 3 (P < 0.0001 for all comparisons). Conclusion: Single-dose heparin administration before 18F-FDG PET in addition to a low-carbohydrate diet significantly outperforms a low-carbohydrate diet alone in adequately suppressing cardiac glucose metabolism.

Quantitative Monte Carlo–Based 90Y SPECT Reconstruction

The evaluation of radiation absorbed doses in tumorous and healthy tissues is of increasing interest for 90Y microsphere radioembolization of liver malignancies. The objectives of this work were to introduce and validate a new reconstruction method for quantitative 90Y bremsstrahlung SPECT to improve posttreatment dosimetry. Methods: A fast Monte Carlo simulator was adapted for 90Y and incorporated into a statistical reconstruction algorithm (SPECT-MC). Photon scatter and attenuation for all photons sampled from the full 90Y energy spectrum were modeled during reconstruction by Monte Carlo simulations. The energy- and distance-dependent collimator–detector response was modeled with precalculated convolution kernels. The National Electrical Manufacturers Association 2007/International Electrotechnical Commission 2008 image quality phantom was used to quantitatively evaluate the performance of SPECT-MC in comparison with those of state-of-the-art clinical SPECT reconstruction and PET. The liver radiation absorbed doses estimated by SPECT, PET, and SPECT-MC were evaluated in 5 patients consecutively treated with radioembolization. Results: In comparison with state-of-the-art clinical 90Y SPECT reconstruction, SPECT-MC substantially improved image contrast (e.g., from 25% to 88% for the 37-mm sphere) and decreased the mean residual count error in the lung insert (from 73% to 15%) at the cost of higher image noise. Image noise and the mean count error were lower for SPECT-MC than for PET. Image contrast was higher in the larger spheres (diameter of ≥28 mm) but lower in the smaller spheres (≤22 mm) for SPECT-MC than for PET. In the clinical study, mean absorbed dose estimates in liver regions with high absorbed doses were consistently higher for SPECT-MC than for SPECT (P = 0.0625) and consistently higher for SPECT-MC than for PET (P = 0.0625). Conclusion: The quantitative accuracy of 90Y bremsstrahlung SPECT is substantially improved by Monte Carlo–based modeling of the image-degrading factors. Consequently, 90Y bremsstrahlung SPECT may be used as an alternative to 90Y PET.

Prognostic Utility of 90Y Radioembolization Dosimetry Based on Fusion 99mTc-Macroaggregated Albumin–99mTc-Sulfur Colloid SPECT

Planning hepatic 90Y radioembolization activity requires balancing toxicity with efficacy. We developed a dual-tracer SPECT fusion imaging protocol that merges data on radioactivity distribution with physiologic liver mapping. Methods: Twenty-five patients with colorectal carcinoma and bilobar liver metastases received whole-liver radioembolization with resin microspheres prescribed as per convention (mean administered activity, 1.69 GBq). As part of standard treatment planning, all patients underwent SPECT imaging after intraarterial injection of 37 MBq of 99mTc-macroaggregated albumin (99mTc-MAA) to simulate subsequent 90Y distribution. Immediately afterward, patients received 185 MBq of labeled sulfur colloid (99mTc-SC) intravenously as a biomarker for normal hepatic reticuloendothelial function and SPECT was repeated. The SPECT images were coregistered and fused. A region-based method was used to predict the 90Y radiation absorbed dose to functional liver tissue (DFL) by calculation of 99mTc-MAA activity in regions with 99mTc-SC uptake. Similarly, the absorbed dose to tumor (DT) was predicted by calculation of 99mTc-MAA activity in voxels without 99mTc-SC uptake. Laboratory data and radiographic response were measured for 3 mo, and the survival of patients was recorded. SPECT-based DT and DFL were correlated with parameters of toxicity and efficacy. Results: Toxicity, as measured by increase in serum liver enzymes, correlated significantly with SPECT-based calculation of DFL at all time points (P < 0.05) (mean DFL, 27.9 Gy). Broad biochemical toxicity (>50% increase in all liver enzymes) occurred at a DFL of 24.5 Gy and above. In addition, in uni- and multivariate analysis, SPECT-based calculation of DT (mean DT, 44.2 Gy) correlated with radiographic response (P < 0.001), decrease in serum carcinoembryonic antigen (P < 0.05), and overall survival (P < 0.01). The cutoff value of DT for prediction of 1-y survival was 55 Gy (area under the receiver-operating-characteristic curve = 0.86; P < 0.01). Patients who received a DT of more than 55 Gy had a median survival of 32.8 mo, compared with 7.2 mo in patients who received less (P < 0.05). Conclusion: Dual-tracer 99mTc-MAA–99mTc-SC fusion SPECT offers a physiology-based imaging tool with significant prognostic power that may lead to improved personalized activity planning.

186Re-HEDP for metastatic bone pain in breast cancer patients

Two-thirds of patients with metastatic cancer suffer from pain. Pain originating from skeletal metastases is the most common form of cancer-related pain. Bone pain, often exacerbated by pressure or movement, limits the patient’s autonomy and social life. Pain palliation with bone-seeking radiopharmaceuticals has proven to be an effective treatment modality in patients with metastatic bone pain. These bone-seeking radiopharmaceuticals are extremely powerful in treating scattered painful bone metastases, for which external beam radiotherapy is impossible because of the large field of irradiation. 186Re-hydroxyethylidene diphosphonate (HEDP) is a potentially useful radiopharmaceutical for this purpose, having numerous advantageous characteristics. Bone marrow toxicity is limited and reversible, which makes repetitive treatment safe. Studies have shown encouraging clinical results of palliative therapy using 186Re-HEDP, with an overall response rate of ca. 70% in painful bone metastases. It is effective for fast palliation of painful bone metastases from various tumours and the effect tends to last longer if patients are treated early in the course of their disease. 186Re-HEDP is at least as effective in breast cancer patients with painful bone metastases as in patients with metastatic prostate cancer. It is to be preferred to radiopharmaceuticals with a long physical half-life in this group of patients, who tend to have more extensive haematological toxicity since they have frequently been pretreated with bone marrow suppressive chemotherapy. This systemic form of radionuclide therapy is simple to administer and complements other treatment options. It has been associated with marked pain reduction, improved mobility in many patients, reduced dependence on analgesics, and improved performance status and quality of life.

The Efficacy of Hepatic 90Y Resin Radioembolization for Metastatic Neuroendocrine Tumors: A Meta-Analysis

90Y resin radioembolization is an emerging treatment in patients with liver-dominant metastatic neuroendocrine tumors (mNETs), despite the absence of level I data. The aim of this study was to evaluate the efficacy of this modality in a meta-analysis of the published literature. Methods: A comprehensive review protocol screened all reports in the literature. Strict selection criteria were applied to ensure consistency among the selected studies: human subjects, complete response data with time interval, resin microspheres, more than 5 patients, not a duplicate cohort, English language, and separate and complete data for resin-based 90Y treatment of mNET if the study included multiple tumor and microsphere types. Selected studies were critically appraised on 50 study criteria, in accordance with the research reporting standards for radioembolization. Response data (Response Evaluation Criteria in Solid Tumors) were extracted and analyzed using both fixed and random-effects meta-analyses. Results: One hundred fifty-six studies were screened; 12 were selected, totaling 435 procedures for response assessment. Funnel plots showed no evidence of publication bias (P = 0.841). Critical appraisal revealed a median of 75% of desired criteria included in selected studies. Very high between-study heterogeneity ruled out a fixed-effects model. The random-effects weighted average objective response rate (complete and partial responses, CR and PR, respectively) was 50% (95% confidence interval, 38%–62%), and weighted average disease control rate (CR, PR, and stable disease) was 86% (95% confidence interval, 78%–92%). The percentage of patients with pancreatic mNET was marginally associated with poorer response (P = 0.030), accounting for approximately 23% of the heterogeneity among studies. The percentage of CR and PR correlated with median survival (R = 0.85; P = 0.008). Conclusion: This meta-analysis confirms radioembolization to be an effective treatment option for patients with hepatic mNET. The pooled data demonstrated a high response rate and improved survival for patients responding to therapy.