Trends in nuclear medicine and the radiopharmaceutical sciences in oncology: workforce challenges and training in the age of theranostics.

Although the promise of radionuclides for the diagnosis and treatment of disease was recognised soon after the discovery of radioactivity in the late 19th century, the systematic use of radionuclides in medicine only gradually increased over the subsequent hundred years. The past two decades, however, has seen a remarkable surge in the clinical application of diagnostic and therapeutic radiopharmaceuticals, particularly in oncology. This development is an exciting time for the use of theranostics in oncology, but the rapid growth of this area of nuclear medicine has created challenges as well. In particular, the infrastructure for the manufacturing and distribution of radiopharmaceuticals remains in development, and regulatory bodies are still optimising guidelines for this new class of drug. One issue of paramount importance for achieving equitable access to theranostics is building a sufficiently trained workforce in high-income, middle-income, and low-income countries. Here, we discuss the key challenges and opportunities that face the field as it seeks to build its workforce for the 21st century.

Recent advances and impending challenges for the radiopharmaceutical sciences in oncology.

This paper is the first of a Series on theranostics that summarises the current landscape of the radiopharmaceutical sciences as they pertain to oncology. In this Series paper, we describe exciting developments in radiochemistry and the production of radionuclides, the development and translation of theranostics, and the application of artificial intelligence to our field. These developments are catalysing growth in the use of radiopharmaceuticals to the benefit of patients worldwide. We also highlight some of the key issues to be addressed in the coming years to realise the full potential of radiopharmaceuticals to treat cancer.

Production and regulatory issues for theranostics.

Theranostics has become a major area of innovation and progress in cancer care over the last decade. In view of the introduction of approved therapeutics in neuroendocrine tumours and prostate cancer in the last 10 years, the ability to provide access to these treatments has emerged as a key factor in ensuring global benefits from this cancer therapy approach. In this Series paper we explore the issues that affect access to and availability of theranostic radiopharmaceuticals, including supply and regulatory issues that might affect the availability of theranostic treatments for patients with cancer.

Six country vignettes: Strengthening radiotherapy and theranostics.

BACKGROUND: For cancer patient populations worldwide, the synchronous scale-up of diagnostics and treatments yields meaningful gains in survival and quality of life. Among advanced cancer therapies, radiotherapy (RT) and theranostics are key to achieving practical, high-quality, and personalized precision medicine - targeting disease manifestations of individual patients and broad populations, alike. Aiming to learn from one another across different world regions, the six country vignettes presented here depict both challenges and victories in de novo establishment or improvement of RT and theranostics infrastructure. METHODS: The International Atomic Energy Agency (IAEA) convened global RT and theranostics experts from diverse world regions and contexts to identify relevant challenges and report progress in their own six countries: Belgium, Brazil, Costa Rica, Jordan, Mongolia, and South Africa. These accounts are collated, compared, and contrasted herein. RESULTS: Common challenges persist which could be more strategically assessed and addressed. A quantifiable discrepancy entails personnel. The estimated radiation oncologists (ROs), nuclear medicine physicians (NMPs), and medical physicists (MPs for RT and nuclear medicine) per million inhabitants in the six collective countries respectively range between 2.69-38.00 ROs, 1.00-26.00 NMPs, and 0.30-3.45 MPs (Table 1), reflecting country-to-country inequities which largely match World Bank country-income stratifications. CONCLUSION: Established goals for RT and nuclear medicine advancement worldwide have proven elusive. The pace of progress could be hastened by enhanced approaches such as more sustainably phased implementation; better multinational networking to share lessons learned; routine quality and safety audits; as well as capacity building employing innovative, resource-sparing, cutting-edge technologic approaches. Bodies such as ministries of health, professional societies, and the IAEA shall serve critical roles in convening and coordinating more innovative RT and theranostics translational research, including expanding nuanced global database metrics to inform, reach, and potentiate milestones most meaningfully. POLICY SUMMARY: Aligned with WHO 25×25 NCDs target; WHA70.12 and WHA76.5 resolutions.

Guiding principles on the education and practice of theranostics.

PURPOSE: The recent development and approval of new diagnostic imaging and therapy approaches in the field of theranostics have revolutionised nuclear medicine practice. To ensure the provision of these new imaging and therapy approaches in a safe and high-quality manner, training of nuclear medicine physicians and qualified specialists is paramount. This is required for trainees who are learning theranostics practice, and for ensuring minimum standards for knowledge and competency in existing practising specialists. METHODS: To address the need for a training curriculum in theranostics that would be utilised at a global level, a Consultancy Meeting was held at the IAEA in May 2023, with participation by experts in radiopharmaceutical therapy and theranostics including representatives of major international organisations relevant to theranostics practice. RESULTS: Through extensive discussions and review of existing curriculum and guidelines, a harmonised training program for theranostics was developed, which aims to ensure safe and high quality theranostics practice in all countries. CONCLUSION: The guiding principles for theranostics training outlined in this paper have immediate relevance for the safe and effective practice of theranostics.

Clinical characteristics associated with idiopathic rapid gastric emptying in patients referred for gastric emptying studies.

OBJECTIVES: Rapid gastric emptying (RGE) is diagnosed using nuclear medicine gastric emptying scintigraphy (GES). The clinical symptoms are non-specific and its pathophysiology in the absence of gastric surgery is poorly understood. We aimed to evaluate the clinical characteristics associated with idiopathic RGE. METHODS: GES studies were reviewed from a database of 1958 4-hour solid-phase GES performed over an 8-year period. RGE was defined as <30% of the test meal remaining in the stomach at 1 hour. Patients who had had any gastric operation were excluded. A chart review was conducted to extract patients' baseline data and clinical characteristics. RESULTS: Of the 1958 GES studies reviewed, 156 (8.0%) patients had RGE, and 534 (27.3%) had delayed gastric emptying (>10% retained food at 4 h), respectively. Idiopathic RGE constituted 22.6% (156/690) of all abnormal GES studies. The patients' average age at diagnosis was 54.0 years and 53.8% of patients with RGE were female. Most (69.2%) of these studies were ordered with an initial clinical suspicion of gastroparesis, compared with only 12.2% with a suspicion of RGE. Among this idiopathic RGE cohort, 71.2% presented with symptoms of nausea, 42.9% with vomiting, 32.1% with abdominal pain, 21.2% with bloating and 17.9% with early satiety. Only 7.7% presented with diarrhea, 0.6% with palpitations and 0.6% with hypoglycemia. CONCLUSIONS: Idiopathic RGE is an important differential diagnosis in patients with symptoms classically associated with gastroparesis. Few have postprandial diarrhea or palpitations as their presenting symptom. Further studies of idiopathic RGE syndrome are warranted.

Very high coronary artery calcium score with normal myocardial perfusion SPECT imaging is associated with a moderate incidence of severe coronary artery disease.

PURPOSE: Myocardial perfusion imaging (MPI) has limitations in the presence of balanced multivessel disease (MVD) and left main (LM) coronary artery disease, occasionally resulting in false-normal results despite the high cardiovascular risk associated with this condition. The purpose of this study was to assess the incidence of severe coronary artery disease (CAD) in the presence of a very high Agatston coronary artery calcium (CAC) score (>1,000) in stable symptomatic patients without known CAD but with normal MPI results. METHODS: A total of 2,659 prospectively acquired consecutive patients were referred for MPI and evaluation of CAC score by CT. Of this patient population, 8 % (222/2,659) had ischemia without myocardial infarction (MI) on MPIand 11 % (298/2,659) had abnormal MPI (MI and/or ischemia). On presentation 1 % of the patients (26/2,659) were symptomatic, had a CAC score >1,000 and normal MPI results. The definition of normal MPI was strict and included a normal hemodynamic response without ischemic ECG changes and normal imaging, particularly absence of transient ischemic dilation. All of these 26 patients with a CAC score >1,000 and normal MPI findings underwent cardiac catheterization. RESULTS: Of these 26 patients, 58 % (15/26) had severe disease (≥70 % stenosis) leading to revascularization. Of this group, 47 % (7/15) underwent percutaneous intervention, and 53 % (8/15) underwent coronary artery bypass grafting. All of these 15 patients had either MVD (14/15) or LM coronary artery disease (1/15), and represented 0.6 % (15/2,659) of all referred patients (95 % CI 0.3 - 0.9 %). The majority, 90 % (8/9), had severe CAD with typical chest pain. CONCLUSION: A very high CAC score (>1,000) with normal MPI in a small subset of symptomatically stable patients was associated with a moderate incidence of severe CAD (95 % CI 37 - 77 %). Larger studies and/or a meta-analysis of small studies are needed to more precisely estimate the incidence of CAD in this population. This study also supports the concept that a normal MPI result in patients with severe CAD may be due to balanced MVD.

Added-value of SPECT/CT to lymphatic mapping and sentinel lymphadenectomy in gynaecological cancers.

Lymphatic mapping and sentinel lymphadenectomy (LM/SL) have been successfully used in pre-treatment nodal staging of gynaecological cancers. We hypothesised the added-value of LM/SL plus SPECT/CT in patients with early stage of cervical cancer and vulvar cancer. A prospective, single-center, diagnostic, open label, active control, non-randomized clinical trial has been conducted in 7 patients with FIGO IA-IB1 cervical cancer and 7 patients with FIGO stage I-II-IIIcN0 vulvar cancer. All patients underwent LM/SL plus SPECT/low-dose CT and complete lymph node dissection (CLND) according to the standard of care. In case of negative hematoxylin-eosin staining, serial sections of the SLNs were analysed by immunohistochemistry and high molecular weight cytokeratin. Primary outcome measures were the detection rate, the sensitivity (SV), the negative predictive value (NPV), the diagnostic accuracy (DA) for anatomic localisation of SLNs, and the impact on management of SPECT/CT guided LM/SL versus CLND. The secondary outcome measure was the patient tolerability and operating time of LM/SL guided SPECT/CT versus CLND. http://clinicaltrials.gov/show/NCT00773071 All 14 patients were enrolled into the 1-day research protocol with dual-tracer LM/SL and SPECT/CT. Additional SLNs were detected on SPECT/CT compared to conventional planar imaging. Hot and cold > 1cm SLNs were detected on SPECT/CT. Detection rate, SV, NPV, DA were 100% in both groups; false negative rate was 0%. Rate of SLN metastases was 28.5% in cervical cancer and 42.9% in vulvar cancer. Impact on treatment was 28.5% and 14.3% in cervical cancer and vulvar cancer patients, respectively. SPECT/CT was well tolerated by all patients and operating time for LM/SL was within 30 min. No adverse events were reported with a time frame of 1-to-3 years. In early stage of gynaecological cancers, SPECT/low-dose CT is technically feasible and of clinical added-value for LM/SL.

Clinical utility of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in the staging of patients with potentially resectable esophageal cancer.

INTRODUCTION: (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) may play an important role in staging patients with potentially resectable esophageal cancer but its impact on clinical management remains unclear. METHODS: In a multicenter prospective cohort study of patients with potentially resectable esophageal cancer, we compared stage of disease based on PET/CT with the stage based on conventional staging performed before PET/CT (American Joint Committee on Cancer, 6th edition). The primary outcome was the proportion of patients with a clinically important change in stage, based on PET/CT findings. We used health administrative databases to track health services use and mortality after the index PET/CT scan. RESULTS: Four hundred ninety-one patients who received a PET/CT scan for staging of potentially resectable esophageal cancer were included in the study cohort. PET/CT led to clinically important changes in stage for a total of 188 patients (24.0%): 107 patients (21.8%) were upstaged and 11 patients (2.2%) were downstaged. Results of PET/CT were associated with differences in actual management. At the 6-month follow-up, use of surgery was greater in patients with M0 disease (54.4%) compared with those with M1a (25.0%; p < 0.001) or M1b (7.3%; p < 0.001) disease based on PET/CT. The overall cohort had a median survival of 603 days, and higher stage of disease on PET/CT (i.e., M stage) was associated with shorter survival (p < 0.001). CONCLUSIONS: PET/CT identifies disease not otherwise detected on conventional staging and results in clinically important changes in stage for an appreciable number of patients with potentially resectable esophageal cancer and can make important contributions to the management of these patients.

SPECT/CT imaging of the lumbar spine in chronic low back pain: a case report.

Mechanical low back pain is a common indication for Nuclear Medicine imaging. Whole-body bone scan is a very sensitive but poorly specific study for the detection of metabolic bone abnormalities. The accurate localisation of metabolically active bone disease is often difficult in 2D imaging but single photon emission computed tomography/computed tomography (SPECT/CT) allows accurate diagnosis and anatomic localisation of osteoblastic and osteolytic lesions in 3D imaging. We present a clinical case of a patient referred for evaluation of chronic lower back pain with no history of trauma, spinal surgery, or cancer. Planar whole-body scan showed heterogeneous tracer uptake in the lumbar spine with intense localisation to the right lateral aspect of L3. Integrated SPECT/CT of the lumbar spine detected active bone metabolism in the right L3/L4 facet joint in the presence of minimal signs of degenerative osteoarthrosis on CT images, while a segment demonstrating more gross degenerative changes was more quiescent with only mild tracer uptake. The usefulness of integrated SPECT/CT for anatomical and functional assessment of back pain opens promising opportunities both for multi-disciplinary clinical assessment and treatment for manual therapists and for research into the effectiveness of manual therapies.

Intensity modulated radiotherapy of non-small-cell lung cancer incorporating SPECT ventilation imaging.

PURPOSE: The authors performed this retrospective study to investigate the impact of using ventilation scans obtained from single photon emission computed tomography (SPECT) in selecting beam directions in intensity modulated radiation therapy (IMRT) planning in lung cancer radiotherapy to spare dosimetrically well ventilated lung. METHODS: For ten consecutive stage III non-small-cell lung cancer patients, the authors obtained both ventilation/perfusion SPECT scans and four-dimensional CT scans for treatment planning purposes. Each ventilation scan was registered with the corresponding planning CT and ventilation volumes corresponding to either > or = 50% (vv50) or > or = 70% (vv70) of the maximum SPECT count were automatically segmented. For each patient, three IMRT plans were generated: One using nine equally spaced beams optimized according to nonfunctional lung based mean lung dose and lung v20; a second using nine equally spaced beams optimized to avoid vv50 and vv70; and a third plan using only three beams with gantry angles chosen based on minimum mean ventilated lung dose calculated for each conformal beam at every 10 degrees gantry angle avoiding vv50 and vv70. Resultant dose volume histogram indices were calculated for each plan and were compared with respect to calculated SPECT-based ventilation parameters in order to quantify the potential utility of ventilation SPECT in this setting. RESULTS: Two patient groups were identified based on (i) the overlap volume between PTV and vv50 and (ii) the average angular mean ventilated lung dose (AAMvLD). The first parameter quantifies the proximity of the PTV to well ventilated lung and the second parameter quantifies the degree of ventilation that surrounds the PTV. For group 1 patients, < or = 5% of the vv50 overlapped with the PTV. For group 2 patients, > 5% of the vv50 overlapped the PTV. Group 1 was further classified into subgroups 1A and 1B: For subgroup 1A, AAMvLD is >18 Gy, implying that the functional lung surrounds the PTV; for subgroup 1B, AAMvLD is <18 Gy, implying that the well ventilated lung does not completely surround PTV. For subgroup 1A, the plans generated using ventilated lung avoidance reduced dose to vv50 and vv70, with below tolerance dose to normal lung and acceptable coverage of the PTV. For subgroup 1B, the dose to the total lung and well ventilated lung are reduced with the beam direction optimization for the three-beam plan. For group 2, there was no significant dosimetric advantage of using SPECT-based ventilation information in IMRT plan optimization. CONCLUSIONS: In conclusion, it is feasible to use SPECT ventilation scans to optimize IMRT beam direction and, subsequently, to reduce dose to ventilated lung when overlap of the PTV and the ventilated lung is minimal and that the PTV is not surrounded by the ventilated lung. The potential benefit of ventilation SPECT scanning can be determined by preplanning assessment of overlap volumes and the AAMvLD.

Complementary roles of low-dose SPECT-CT and high-resolution volume CT for detection of coronary artery disease.

A 70-year-old woman with a high pretest likelihood of coronary artery disease (CAD) underwent a Tc-99m MIBI SPECT-CT study for myocardial perfusion imaging (MPI), which was complemented by a high-resolution volume CT (VCT) study. After attenuation correction, an MPI pattern of ischemia was detected in the lateral wall of the myocardium. The CT calcium score (CTCS) was above the 75th percentile. The CT angiography (CTA) demonstrated a 70% stenosis at the ostial part of the circumflex artery, and incidentally revealed a saccular aneurysm. In today's nuclear cardiology, low-dose SPECT-CT plus high-resolution VCT allows anatofunctional assessment of suspected CAD.

Role of nuclear medicine in the management of cutaneous malignant melanoma.

Malignant melanoma of the skin is one of the most lethal cancers. The disease may spread either locally or regionally and to distant sites through predictable or unpredictable metastatic pathways. Accurate staging and restaging of disease are required for appropriate treatment decision making. Routine protocols based on clinical examinations and traditional radiologic evaluations are not cost-effective for the detection of systemic disease. In the last decade, nuclear medicine techniques, such as lymphoscintigraphy-directed lymphatic mapping and sentinel lymphadenectomy and (18)F-FDG PET, have played key roles in nodal and distant staging of melanoma. More recently, anatomic-functional imaging has been improved with the development of integrated PET/CT devices or combined SPECT/CT systems. (18)F-FDG-sensitive intraoperative probes have been specifically designed to detect small nodal and visceral metastases from melanoma and may become important tools for the cancer surgeon. In this article, we review the role of nuclear medicine in the assessment of malignant melanoma.

Thyroid-stimulating hormone-stimulated fused positron emission tomography/computed tomography in the evaluation of recurrence in 131I-negative papillary thyroid carcinoma.

UNLABELLED: Fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) detects recurrence of papillary thyroid carcinoma (PTC) in thyroidectomized patients with elevated thyroglobulin (Tg) levels and negative (131)I-whole-body scans. This paper describes the utility of thyroid-stimulating hormone (TSH)-stimulated fused FDG-PET/computed tomography (CT) scanning on our first 15 patients of this population. METHODS: Patients were prepared for PET/CT imaging with thyroid hormone withdrawal (n = 7) or recombinant human TSH (n = 8). All other imaging before the PET/CT did not demonstrate evidence of recurrence. RESULTS: PET/CT scans revealed active foci in 9 patients, 4 prepared with hypothyroidism, and 5 with exogenous TSH. Positive results were demonstrated even in those with relatively low stimulated-TSH Tg values (13 and 14 microg/L). Six patients with positive PET/CT scans were treated surgically, yielding malignant tissue for 5 of those patients. CONCLUSION: PET/CT scans performed under TSH stimulation are an effective method of detecting of recurrence of PTC and direct surgical interventions, even in those with persistently elevated but relatively low Tg levels.