Advances in Radionuclide Therapies for Patients with Neuro-endocrine Tumors.

PURPOSE OF REVIEW: To provide insights into the role of peptide receptor radionuclide therapy (PRRT) in patients with advanced neuroendocrine tumors (NET) and an overview of possible strategies to combine PRRT with locoregional and systemic anticancer treatments. RECENT FINDINGS: Research on combining PRRT with other treatments encompasses a wide variety or treatments, both local (transarterial radioembolization) and systemic therapies, chemotherapy (i.e., capecitabine and temozolomide), targeted therapies (i.e., olaparib, everolimus, and sunitinib), and immunotherapies (e.g., nivolumab and pembrolizumab). Furthermore, PRRT shows promising first results as a treatment prior to surgery. There is great demand to enhance the efficacy of PRRT through combination with other anticancer treatments. While research in this area is currently limited, the field is rapidly evolving with numerous ongoing clinical trials aiming to address this need and explore novel therapeutic combinations.

Heading toward radioactive seed localization in non-palpable breast cancer surgery? A meta-analysis.

Wire-guided localization is the most commonly used technique for intraoperative localization of non-palpable breast cancer. Radioactive seed localization (RSL) is becoming more popular and seems to be a reliable alternative for intraoperative lesion localization. The purpose of the present meta-analysis was to evaluate the use of RSL. Primary study outcomes were irradicality and re-excision rates. In total 3168 patients were included. The clinical adaptation shows growing confidence in RSL and further growth is expected.

Baseline and on Treatment Biodistribution Variability of 18 F-FLT Uptake in Patients With Advanced Melanoma: Brief Communication.

PURPOSE: This prospective study evaluates the biodistribution of 18 F-FLT PET in patients with advanced melanoma before and after treatment with BRAF/MEK inhibitors. PATIENTS AND METHODS: Eighteen BRAF-positive unresectable stage IIIc or IV melanoma patients referred for 18 F-FLT PET/CT before (BL) and during (D14) BRAF/MEK inhibition were included. 18 F-FLT accumulation in the liver, bone marrow, blood, and muscle was quantified. RESULTS: Baseline interpatient 18 F-FLT uptake had a coefficient-of-variation between 17.5% and 21.5%. During treatment, liver uptake increased (SUV meanBL = 4.86 ± 0.98, SUV meanD14 = 6.31 ± 1.36, P < 0.001) and bone marrow uptake decreased (SUV meanBL = 7.67 ± 1.65, SUV meanD14 = 6.78 ± 1.19, P < 0.025). Both changes were unrelated to baseline metabolic tumor volume or tumor response. CONCLUSIONS: To assess 18 F-FLT PET, both liver and bone marrow uptake may be used as normal tissue references at baseline, but 18 F-FLT biodistribution significantly changes in longitudinal response studies when treated with BRAF/MEK inhibitors.

The Predictive Value of FDG PET/CT for Determining Progression-Free Survival in Advanced Stage III-IV BRAF -Mutated Melanoma Patients Treated With Targeted Therapy-What Can Be Learned From Progression?

PURPOSE: The aims of this study were to investigate whether (early) PERCIST response monitoring with 18 F-FDG PET/CT is predictive for progression-free survival (PFS) in unresectable stage III or IV melanoma patients treated with BRAF/MEK inhibitor (MEKi) and to define dissemination patterns at progression with a lesion-based evaluation in direct comparison to baseline to improve our understanding of 18 F-FDG PET/CT during BRAF/MEKi. PATIENTS AND METHODS: This prospective multicenter single-arm study included 70 patients with unresectable stage III/IV BRAF -mutated melanoma who underwent contrast-enhanced CT and 18 F-FDG PET/CT at baseline and 2 and 7 weeks during treatment with vemurafenib plus cobimetinib and at progression if possible. Tumor response assessment was done with RECIST1.1 and PERCIST. Follow-up PET/CT scans were visually compared with baseline to assess dissemination patterns. RESULTS: Using RECIST1.1, PFS was not significantly different between the response groups ( P = 0.26). At 2 weeks, PERCIST median PFS was 15.7 months for patients with complete metabolic response (CMR) versus 8.3 months for non-CMR ( P = 0.035). The hazards ratio (HR) for progression/death in non-CMR versus CMR was 1.99 (95% confidence interval [CI], 1.03-3.84; P = 0.040) and 1.77 (95% CI, 0.91-3.43; P = 0.0935) when adjusting for lactate dehydrogenase (LDH). At 7 weeks, median PFS for PERCIST CMR was 16.7 months versus 8.5 months for non-CMR ( P = 0.0003). The HR for progression/death in the non-CMR group was significantly increased (HR, 2.94; 95% CI, 1.60-5.40; P = 0.0005), even when adjusting for LDH (HR, 2.65; 95% CI, 1.43-4.91; P = 0.0020). At week 7, 18 F-FDG PET/CT was false-positive in all 4 (6%) patients with new FDG-avid lesions but CMR of known metastases. When 18 F-FDG PET/CT was performed at progressive disease, 18/22 (82%) patients had progression of known metastases with or without new 18 F-FDG-avid lesions. CONCLUSIONS: This study shows that PERCIST response assessment at week 7 is predictive for PFS, regardless of LDH. At 2 weeks, patients with CMR have longer PFS than patients with non-CMR, but different PET parameters should be investigated to further evaluate the added value of early 18 F-FDG PET/CT. Disease progression on PET/CT is predominated by progression of known metastases, and new 18 F-FDG-avid lesions during BRAF/MEKi are not automatically a sign of recurrent disease.

Pre-hydration in cisplatin-based CCRT: Effects on tumour concentrations and treatment outcome.

AIMS: Pre-hydration is routinely applied to reduce nephrotoxicity in concurrent cisplatin-based chemo-radiotherapy (CCRT). However, pre-hydration may also have systemic effects, potentially leading to lower tumour cisplatin concentrations. We investigated the impact of pre-hydration on tumour cisplatin concentrations in mice, and on treatment outcomes in a clinical cohort study. MATERIALS AND METHODS: Four groups of 20 mice received either no pre-hydration prior to full-dose (6 mg/kg) or half-dose cisplatin, overnight dehydration prior to full-dose cisplatin (dehydration), or NaCl intraperitoneally prior to full-dose cisplatin (pre-hydration). Kidney function and tumour platinum concentration were measured. In patients, a retrospective study compared 2 historical NSCLC cohorts which received CCRT with daily cisplatin, with and without standard pre-hydration. Overall survival (OS) and progression free survival (PFS) were compared using Kaplan-Meier and cox-regression. RESULTS: Pre-hydration significantly decreased cisplatin tumour concentrations in mice, comparable to mice receiving half the dose. In 419 patients (211 without and 208 with pre-hydration) with median follow-up 22 months, there were no significant differences in PFS (18 vs. 15 months) or OS (23 vs. 23 months). CONCLUSION: Pre-hydration reduces cisplatin tumour concentrations in mice, but it does not compromise treatment outcomes in NSCLC patients treated with daily cisplatin and radiotherapy.

A Practical Guide for the Production and PET/CT Imaging of 68Ga-DOTATATE for Neuroendocrine Tumors in Daily Clinical Practice.

Neuroendocrine tumors are a rare form of cancer that arise from neuroendocrine cells and can be present at almost any location throughout the body. Although heterogeneous in presentation, a common denominator among these tumors is the overexpression of somatostatin receptors. 68Ga-DOTATATE is a somatostatin analog labeled with the positron emitter gallium-68 (68Ga). For well-differentiated neuroendocrine tumors, 68Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) imaging is used for diagnosis, determination of disease burden, and therapy selection. This protocol details the radiolabeling of 68Ga-DOTATATE, quality control, patient preparation, and subsequent PET/CT imaging. Radiolabeling of 68Ga-DOTATATE is performed with a fully automated labeling module coupled to a germanium-68 (68Ge)/68Ga generator. Quality control of the final product evaluates radiochemical purity with instant thin-layer chromatography and solid-phase chromatography, and pH prior to patient injection. Periodic quality control is performed to determine 68Ge breakthrough, sterility, and (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) content. Patient preparation includes patient instructions, a protocol for 68Ga-DOTATATE during treatment with somatostatin analogs, and intravenous administration of the radiopharmaceutical. For PET/CT imaging, the acquisition and reconstruction settings are described. For each step, radiation safety will be highlighted, as well as time constrictions due to the short half-life of 68Ga. Fully automated in-house production and quality control of 68Ga-DOTATATE leads to very high success rates (95%) and produces two to four patient dosages per batch, depending on the yield of the generator. In conclusion, 68Ga-DOTATATE PET/CT imaging is a noninvasive and fast method of providing information on the tumor burden of neuroendocrine tumors (NETs) while also assisting in diagnosis and therapy selection.

89Zr-labeled CEA-targeted IL-2 variant immunocytokine in patients with solid tumors: CEA-mediated tumor accumulation and role of IL-2 receptor-binding.

Cergutuzumab amunaleukin (CEA-IL2v) is an immunocytokine directed against carcinoembryonic antigen (CEA) containing an IL2v-moiety with abolished IL-2 receptor (IL-2R) α binding. We describe the biodistribution and tumor accumulation of 89Zr-labeled CEA-IL2v. Twenty-four patients with advanced solid CEA positive (CEA+) or negative (CEA-) tumors received CEA-IL2v 6 mg (4 CEA+; 3 CEA-), 20 mg (9 CEA+), or 30 mg (4 CEA+; 4 CEA-) biweekly. In cycle 1, 2 mg of the total dose comprised 89Zr-CEA-IL2v (50 MBq) and serial 89Zr-PET imaging was conducted. Four CEA+ patients with visually confirmed 89Zr-CEA-IL2v tumor accumulation at 20 mg had repeated 89Zr-PET imaging during cycle 4. 89Zr-CEA-IL2v immuno-PET demonstrated preferential drug accumulation in CEA+ tumors (%ID/mLpeak CEA- 3.6 × 10-3 vs. CEA+ 6.7 ×∙10-3). There was a non-significant trend towards dose-dependent tumor uptake, with higher uptake at doses ≥20 mg. Biodistribution was dose- and CEA-independent with major accumulation in lymphoid tissue compatible with IL-2R binding. Reduced exposure and reduced tumor accumulation (%ID/mLpeak 57% lower) on cycle 4 vs. cycle 1 was consistent with peripheral expansion of immune cells. The findings of this immune PET imaging study with 89Zr-CEA-IL2v support the therapeutic concept of CEA-IL2v, confirming selective and targeted tumor accumulation with this novel immunocytokine.

A New Portable Hybrid Camera for Fused Optical and Scintigraphic Imaging: First Clinical Experiences.

PURPOSE: Although portable gamma cameras (PGCs) have been helpful to depict sentinel nodes (SNs), sometimes nuclear physicians or surgeons have difficulties to interpret PGC images because of the lack of anatomical information. The aim of the present study was to develop and clinically test the prototype of a new portable hybrid camera (PHC), which adds optical to γ-imaging. METHODS: In 2 hospitals, the existing PGC (Sentinella S102; Oncovision) was upgraded with an optical module (BB2-08S2C-25; Point Grey Research) to build a PHC. Preoperative PHC overview images (positioned at 15 cm distance) and close-up image (position at <5 cm distance) were obtained from 25 patients (12 melanoma, 2 oral cavity, and 11 breast cancer) after conventional lymphoscintigraphy. Errors in the optical image coregistration were evaluated with a 5-mm accuracy for each patient. RESULTS: Conventional lymphoscintigraphy and the close-up PHC images depicted 55 SNs in total. In the PHC overview images, the optical module offered fused optical and γ-imaging indicating the image field of view and anatomical SN locations. Average optical image coregistration errors were 1.0 cm (range, 0-2.0 cm). CONCLUSIONS: Fused optical and γ-imaging with the prototype PHC is technically feasible and helpful for the image interpretation. The optical image visualizes the γ-image field of view, enabling SN localization in an anatomical context in a preoperative setting; however, for the operating room, the use of its optical component needs to be additionally adjusted.

Intraoperative 3D Navigation for Single or Multiple 125I-Seed Localization in Breast-Preserving Cancer Surgery.

BACKGROUND: Mammographic screening has led to the identification of more women with nonpalpable breast cancer, many of them to be treated with breast-preserving surgery. To accomplish radical tumor excision, adequate localization techniques such as radioactive seed localization (RSL) are required. For RSL, a radioactive I-seed is implanted central in the tumor to enable intraoperative localization using a γ-probe. In case of extensive tumor or multifocal carcinoma, multiple I-seeds can be used to delineate the involved area. Preoperative imaging is performed different from surgical positioning; therefore, exact I-seed depth remains unknown during surgery. PATIENTS AND METHODS: Twenty patients (mean age, 56.8 years) with 25 implanted I-seeds scheduled for RSL were included. Sixteen patients had 1 I-seed implanted in the primary lesion, 3 patients had 2 I-seeds, and 1 patient had 3 I-seeds. Freehand SPECT localized I-seeds by measuring γ-counts from different directions, all registered by an optical tracking system. A reconstruction and visualization algorithm enabled 3-dimensional (3D) navigation toward the I-seeds. RESULTS: Freehand SPECT visualized all I-seeds in primary tumors and provided preincision depth information. The deviation, mean (SD), between the freehand SPECT depth and the surgical depth estimation was 1.9 (2.1) mm (range, 0-7 mm). Three-dimensional freehand SPECT was especially useful identifying multiple implanted I-seeds because the conventional γ-probe has more difficulty discriminating I-seeds transcutaneous. CONCLUSIONS: Freehand SPECT with 3D navigation is a valuable tool in RSL for both single and multiple implanted I-seeds in breast-preserving cancer surgery. Freehand SPECT provides continuous updating 3D imaging with information about depth and location of the I-seeds contributing to adequate excision of nonpalpable breast cancer.

Improved Accuracy and Reproducibility Using a Training Protocol for Freehand-SPECT 3D Mapping in Radio-Guided Surgery.

PURPOSE: Freehand single-photon emission computed tomography (SPECT) (fh-SPECT) for optical tracked 3-dimensional radioactivity mapping raises popularity for sentinel node biopsy and other radio-guided procedures. However, the device seems to be complex, requiring both training and a standardized scan protocol. Therefore, the aim of this study was to compare handling reproducibility between novice and expert users; subsequently, using additional scans, we evaluated a standardized scan protocol to be tested in novice users after receiving training. MATERIALS AND METHODS: Three groups (untrained novices, experts, and trained novices), each one composed of 5 fh-SPECT users, were given the same short introduction and the assignment to perform 3 fh-SPECT scans with the same time per scan. For the scans, a reproducible phantom with an iodine-125 point source was used. Furthermore, we performed probe-trajectory evaluation including pattern, speed, and length of scans based on recorded videos and digital target tracking. RESULTS: The training period encompasses 30 minutes per novice user. The mean error in 3 directions based on 45 measurements was 7.4 mm for untrained novices and 3.2 mm for expert users. The trained novice group had a mean error of 2.9 mm (a significant 61% reduction), comparable to the expert group. The reproducibility values, expressed in SD, were 4.1 mm for the untrained novice group, 1.3 mm for the expert group, and 1.1 mm for the trained novices (73% improvement). The standardized scan protocol was demonstrated by means of trajectory evaluation, a scan path better systematized. CONCLUSION: Scanning with fh-SPECT for radio-guided surgery requires a specific training period to increase handling and reproducibility of 3-dimensional imaging, and to enhance its accuracy in the operating room.

Detecting near-the-injection-site sentinel nodes in head and neck melanomas with a high-resolution portable gamma camera.

BACKGROUND: In head/neck melanomas, near-the-injection-site sentinel nodes (NIS-SNs) may be missed on planar lymphoscintigraphy and/or SPECT/CT. The aim of the present study is to establish the performance of a portable gamma camera (PGC) to detect NIS-SNs in a simulation phantom set-up, and subsequently in head/neck melanoma patients scheduled for a SN procedure. METHODS: Five plastic Eppendorf tubes filled with technetium-99m-albumin nanocolloid were used to simulate 4 radiotracer deposit sites, as traditionally injected in melanoma patients, and 1 NIS-SN. A PGC was used with 2 pinhole collimators (2.5 and 4.0 mm). Image acquisition time was 1 minute with the camera positioned at various distances (range 1.5-15.5 cm). Results were compared with conventional lymphoscintigraphy and SPECT/CT acquired with a dual-head gamma camera as well with a gamma probe. Additionally, the same PGC setting was used in a case series of 3 patients with head/neck melanomas. RESULTS: The simulated NIS-SN was differentiated from the injection site at a distance of 3 mm with the 2.5-mm pinhole and at 5 mm with the 4-mm pinhole when the PGC was positioned at 1.5 cm distance. Planar lymphoscintigraphy, SPECT/CT, and the gamma probe depicted the NIS-SN separated from the injection site at distances of 7, 10, and 22 mm, respectively. In all 3 patients, 6 NIS-SNs were depicted with the PGC. CONCLUSION: A high-resolution PGC, positioned close to the skin, is able to detect SNs at distances of at least 3 mm from the injection site. A further clinical evaluation of this device to establish its added value in reducing false-negative procedures and potential recurrences is necessary.

Radio-guided seed localization for breast cancer excision: an ex-vivo specimen-based study to establish the accuracy of a freehand-SPECT device in predicting resection margins.

PURPOSE: Radioactive seed localization (RSL) uses an iodine-125 ((125)I) seed as a marker for tumour location. The (125)I seed is implanted into the tumour and enables intraoperative localization with a conventional gamma probe. However, specimen margins in relation to the (125)I seed are estimated on the basis of gamma-probe readings only. A novel device, freehand SPECT, is capable of measuring the distance from the resection plane to the (125)I seed. The aim of this feasibility study was to establish the accuracy of this device in predicting resection margins in ex-vivo tumour specimens excised with RSL guidance. PATIENTS AND METHODS: In this feasibility study 10 patients with nonpalpable breast cancer scheduled for wide local excision with RSL were included. After surgery, the specimens containing the breast tumour and the (125)I seed were scanned using freehand SPECT. Measurements from five directions were taken and compared with distances measured by means of an ex-vivo computed tomographic (CT) scan and related to the pathology report. RESULTS: The difference between freehand SPECT and CT measurements was 2.9±2.7 mm (mean±SD). One patient had a positive margin based on freehand SPECT. This specimen contained a focal irradical resection ventral of the tumour based on the pathology report. The smallest distance to the (125)I seed was 4 mm for the freehand SPECT and 5 mm for the CT scan. CONCLUSION: Accurate ex-vivo measurements of the tumour resection margins using (125)I seeds and freehand SPECT are feasible in patients undergoing breast-conserving surgery. Incorporation of the freehand-SPECT device in RSL protocols may enable a real-time estimation of resection margins, which may be useful for surgeons to adjust resection planes.

I-123-MIBG myocardial imaging in trastuzumab-based cardiotoxicity: the first experience.

INTRODUCTION: Cardiotoxicity related to trastuzumab anticancer treatment poses a diagnostic challenge at early stages. The aim of the present pilot study was to assess the value of iodine-123-metaiodobenzylguanidine (I-123-MIBG) scintigraphy in breast cancer patients treated with trastuzumab who showed a decrease in their cardiac function. MATERIALS AND METHODS: I-123-MIBG scintigraphy was performed in nine patients with decreased or significantly decreasing left ventricular ejection fraction (LVEF) during trastuzumab therapy. On the basis of planar images, 4 h heart-to-mediastinum (HMR) ratio and washout percentages (WR) were calculated. RESULTS: I-123-MIBG scintigraphy revealed abnormal 4 h HMR and increased WR in three patients. LVEF recovery was observed in none of these patients during 3, 6, and 13 months of follow-up. In two of five patients with normal 4 h HMR the washout rates were also normal, whereas in three patients slightly increased washout rates were found. All five patients demonstrated a recovery of their LVEF value during follow-up. One patient with a normal 4 h HMR and normal WR initially showed a significant decrease in LVEF, which decreased further during follow-up. However, the LVEF value remained at 53%, which was within normal limits, after trastuzumab administration. CONCLUSION: In this pilot study we have explored the role of I-123-MIBG scintigraphy in the assessment of trastuzumab-related cardiotoxicity and suggest that, in patients with a persistently decreasing LVEF, I-123-MIBG scintigraphy might indicate whether recovery will occur and, consequently, whether retreatment may be initiated.