Diagnostic performance of [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the spine, and whole-body diagnostic CT and MRI in the detection of spinal bone metastases associated with pheochromocytoma and paraganglioma.

OBJECTIVE: To compare the diagnostic performance of [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the spine, and whole-body CT and MRI for the detection of pheochromocytoma/paraganglioma (PPGL)-related spinal bone metastases. MATERIALS AND METHODS: Between 2014 and 2020, PPGL participants with spinal bone metastases prospectively underwent [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the cervical-thoracolumbar spine (MRIspine), contrast-enhanced MRI of the neck and thoraco-abdominopelvic regions (MRIWB), and contrast-enhanced CT of the neck and thoraco-abdominopelvic regions (CTWB). Per-patient and per-lesion detection rates were calculated. Counting of spinal bone metastases was limited to a maximum of one lesion per vertebrae. A composite of all functional and anatomic imaging served as an imaging comparator. The McNemar test compared detection rates between the scans. Two-sided p values were reported. RESULTS: Forty-three consecutive participants (mean age, 41.7 ± 15.7 years; females, 22) with MRIspine were included who also underwent [68Ga]DOTATATE PET/CT (n = 43), [18F]FDG PET/CT (n = 43), MRIWB (n = 24), and CTWB (n = 33). Forty-one of 43 participants were positive for spinal bone metastases, with 382 lesions on the imaging comparator. [68Ga]DOTATATE PET/CT demonstrated a per-lesion detection rate of 377/382 (98.7%) which was superior compared to [18F]FDG (72.0%, 275/382, p < 0.001), MRIspine (80.6%, 308/382, p < 0.001), MRIWB (55.3%, 136/246, p < 0.001), and CTWB (44.8%, 132/295, p < 0.001). The per-patient detection rate of [68Ga]DOTATATE PET/CT was 41/41 (100%) which was higher compared to [18F]FDG PET/CT (90.2%, 37/41, p = 0.13), MRIspine (97.6%, 40/41, p = 1.00), MRIWB (95.7%, 22/23, p = 1.00), and CTWB (81.8%, 27/33, p = 0.03). CONCLUSIONS: [68Ga]DOTATATE PET/CT should be the modality of choice in PPGL-related spinal bone metastases due to its superior detection rate. CLINICAL RELEVANCE STATEMENT: In a prospective study of 43 pheochromocytoma/paraganglioma participants with spinal bone metastases, [68Ga]DOTATATE PET/CT had a superior per-lesion detection rate of 98.7% (377/382), compared to [18F]FDG PET/CT (p < 0.001), MRI of the spine (p < 0.001), whole-body CT (p < 0.001), and whole-body MRI (p < 0.001). KEY POINTS: • Data regarding head-to-head comparison between functional and anatomic imaging modalities to detect spinal bone metastases in pheochromocytoma/paraganglioma are limited. • [68Ga]DOTATATE PET/CT had a superior per-lesion detection rate of 98.7% in the detection of spinal bone metastases associated with pheochromocytoma/paraganglioma compared to other imaging modalities: [18]F-FDG PET/CT, MRI of the spine, whole-body CT, and whole-body MRI. • [68Ga]DOTATATE PET/CT should be the modality of choice in the evaluation of spinal bone metastases associated with pheochromocytoma/paraganglioma.

Case report of adrenocortical carcinoma associated with double germline mutations in MSH2 and RET.

Adrenocortical carcinoma (ACC) is a rare aggressive malignancy that originates in the outer layer of the adrenal gland. Most ACCs are sporadic, but a small percentage of cases are due to hereditary cancer syndromes such as Li-Fraumeni syndrome (LFS), Lynch syndrome (LS), and familial adenomatous polyposis (FAP). Multiple endocrine neoplasia type 2A (MEN2A) is an inherited disorder that predisposes to medullary thyroid cancer, pheochromocytoma, and parathyroid hyperplasia. We present here a case of ACC with both LS and MEN2A; the family and medical history were consistent with Lynch. This is, to our knowledge, the first report of a patient with ACC associated with germline mutations in RET and MSH2, and no phenotypical characteristics of MEN2A.

Comprehensive guidance on the diagnosis and management of primary mesenchymal tumours of the thyroid gland.

Most primary thyroid tumours are of epithelial origin. Primary thyroid mesenchymal tumours are rare but are being increasingly detected. A vast majority of thyroid mesenchymal tumours occur between the fourth and seventh decades of life, presenting as progressively enlarging thyroid nodules that often yield non-diagnostic results or spindle cells on fine needle aspiration biopsy. Surgery is the preferred mode of treatment, with adjuvant chemoradiotherapy used for malignant thyroid mesenchymal tumours. Benign thyroid mesenchymal tumours have excellent prognosis, whereas the outcome of malignant thyroid mesenchymal tumours is variable. Each thyroid mesenchymal tumour is characterised by its unique histopathology and immunohistochemistry. Because of the rarity and aggressive nature of malignant thyroid mesenchymal tumours, a multidisciplinary team-based approach should ideally be used in the management of these tumours. Comprehensive guidelines on the management of thyroid mesenchymal tumours are currently lacking. In this Review, we provide a detailed description of thyroid mesenchymal tumours, their clinical characteristics and tumour behaviour, and provide recommendations for the optimal management of these tumours.

Endocrine-Related Adverse Events Related to Immune Checkpoint Inhibitors: Proposed Algorithms for Management.

Immune checkpoint inhibitors have proven to be effective for various advanced neoplasia. Immune-related adverse events (irAEs) as a result of increased T cell activation are unique and potentially life-threating toxicities associated with the use of immune checkpoint inhibitors. Multiple endocrine irAEs, including primary hyperthyroidism and hypothyroidism, thyroiditis, primary adrenal insufficiency, type 1 diabetes mellitus, and hypophysitis, have been reported with the use of various immune checkpoint inhibitors. In some cases, these irAEs can lead to discontinuation of treatment. Here we propose for the general oncologist algorithms for managing endocrine irAEs to aid in the clinical care of patients receiving immunotherapy. KEY POINTS: There is a relative high risk of endocrine immune-related adverse events (irAEs) during therapy with checkpoint inhibitors, particularly when combination therapy is implemented. Patients treated with anti-CTLA-4 antibodies have an increased risk of hypophysitis, whereas patients treated with anti-PD-1/PD-L1 antibodies have a higher risk of primary thyroid dysfunction. Rarely, patients develop T1DM and central diabetes insipidus, and hypoparathyroidism is a rare occurrence. A growing clinical understanding of endocrine irAEs has led to effective treatment strategies with hormone replacement.

Update on the Treatment of Medullary Thyroid Carcinoma in Patients with Multiple Endocrine Neoplasia Type 2.

Medullary Thyroid Carcinoma (MTC) is a rare neuroendocrine cancer that accounts for 1-2% of thyroid cancers in the United States (U.S.). While most cases are sporadic, 25% of MTC cases are hereditary. These hereditary cases occur in the setting of Multiple Endocrine Neoplasia Type 2A (MEN2A) or 2B (MEN2B) driven by mutations in the Rearranged during Transfection RET proto-oncogene. This article discusses hereditary MTC in the setting of MEN2 and the treatment options available for it. The first line treatment for this disease is typically a total thyroidectomy and tyrosine kinase inhibitors. Two tyrosine kinase inhibitors, vandetanib and cabozantinib, have been approved for treatment of advanced MTC, but options beyond those are limited. However, several promising treatments are being studied, which are discussed in this review.

Emerging Treatments for Advanced/Metastatic Pheochromocytoma and Paraganglioma.

OPINION STATEMENT: The incidence of metastatic pheochromocytoma (PHEO) and paraganglioma (PGL) may occur in as many as 35% of patients particularly with PGL and even more frequently in those with specific mutations. Biochemical, morphological, and molecular markers have been investigated for use in the distinction of benign from malignant PHEO/PGL. PHEO/PGL metastasizes via hematogenous or lymphatic routes and shows differences based on mutational status. The most common sites of involvement in patients that have an SDHB mutation are the bone (78%), lungs (45%), lymph nodes (36%), and liver (35%). In patients with sporadic PHEO/PGL, the most common sites of metastasis are the bones (64%), lungs (47%), lymph nodes (36%), and liver (32%). Metastases may be present at presentation or may occur later. Metastases to the liver and lungs are associated with a shorter survival. Overall, the estimated 5-year survival rates are between 34 and 74%. Currently, treatments for metastatic PHEO/PGL are essentially palliative. Surgery is potentially curative; however, tumor dissemination limits the chance for a curative resection. When surgical intervention is not amenable, the therapeutic options include radiolabeled MIBG (Azedra®-iobenguane 131 was recently FDA-approved for patients > 12 years and older with iobenguane scan positive) or systemic chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD) with an overall objective response rate (ORR) of less than 40%; however, it is not clear if the administration of CVD impacts overall survival, as nearly all patients develop progressive and ultimately fatal disease. Other treatment modalities under investigation include cytoreductive techniques, novel radiopharmaceuticals, chemotherapy, radiotherapy, immunotherapy, and experimental therapies. Here we are discussing emerging treatment for advanced/metastatic PHEO/PGL.

Phase I/II Trial of Vandetanib and Bortezomib in Adults with Locally Advanced or Metastatic Medullary Thyroid Cancer.

LESSONS LEARNED: Vandetanib at a dose of 300 mg orally every day plus bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8, and 11 could be administered safely.Assessing outcomes in 17 patients with medullary thyroid cancer, investigators considered the combination to be more difficult to administer than single-agent vandetanib and that achieving better outcomes was unlikely. Consequently, a planned phase II study was terminated early. BACKGROUND: The proto-oncogene RET (REarranged during Transfection) has a critical role in the pathogenesis of medullary thyroid cancer (MTC). Vandetanib (V), a multitargeted tyrosine kinase inhibitor approved for the treatment of MTC, is thought to inhibit RET in MTC. Supported by preclinical studies demonstrating that bortezomib (B) administration lowered RET mRNA and protein levels, we conducted a phase I study in advanced solid tumors of vandetanib in combination with bortezomib. The goal was to establish an RP2D (recommended phase II dose) for the combination of vandetanib plus bortezomib, a regimen envisioned as a dual strategy for targeting RET in MTC. METHODS: Patients with advanced solid tumors were treated with escalating doses of bortezomib or vandetanib to assess the safety and tolerability of daily oral vandetanib and intravenous (IV) bortezomib administered on days 1, 4, 8, and 11 of a 28-day cycle. Intrapatient dose escalation was allowed. RESULTS: Twenty-two patients were enrolled and received escalating mg/m2 bortezomib and mg vandetanib (number of patients) at initial doses of 1 and 100 (3), 1.3 and 100 (6), 1.3 and 200 (6), and 1.3 and 300 (7), respectively. Patients received a median of four cycles of bortezomib/vandetanib (range: 1-10), with 13 patients escalating to 1.3/200 and 10 to 1.3/300. G3 toxicities occurring in more than one patient included hypertension (24%), fatigue (19%), thrombocytopenia (10%), diarrhea (10%), and arthralgia (10%). There were no drug-related G4/5 toxicities. There was one dose-limiting toxicity, G3 thrombocytopenia, at bortezomib/vandetanib doses of 1.3/200 in cycle 2 that resolved without intervention. Four patients with a diagnosis of MTC (27%) had a partial response (PR). CONCLUSION: The MTD of the combination was established as bortezomib, 1.3 mg/m2 IV days 1, 4, 8, and 11 with vandetanib 300 mg p.o. daily. RECIST responses were observed in patients with a diagnosis of MTC.

PARP Inhibitors: The Cornerstone of DNA Repair-Targeted Therapies.

The activity and therapeutic licensing of poly(ADP-ribose) polymerase (PARP) inhibitors is the culmination of 50 years of research. However, the biology, mechanisms of action, adequate treatment combinations, and targeted populations for these agents need to be explored further. PARP activity is essential for the repair of single-strand DNA breaks via the base excision repair pathway. This pathway is the default repair pathway in cells with deficient high-fidelity double-strand break homologous recombination (HR) repair, such as occurs with loss of BRCA1 or BRCA2 function. Therefore, inhibition of PARP function results in cell death in HR-deficient tumors, and sensitizes tumor cells to cytotoxic agents that induce DNA damage. Applications of PARP inhibition are now being expanded beyond tumors with HR deficiency-to HR-competent tumors in which HR has been synthetically impaired through use of other agents given in combination with PARP inhibitors, or resulting from PARP inhibition in the setting of BRCA1 or BRCA2 loss.

The size of the primary tumor and age at initial diagnosis are independent predictors of the metastatic behavior and survival of patients with SDHB-related pheochromocytoma and paraganglioma: a retrospective cohort study.

BACKGROUND: Succinate dehydrogenase subunit B (SDHB) mutations are associated with aggressive pheochromocytoma (PHEO)/paraganglioma (PGL) behavior, often resulting in metastatic disease and fatal outcomes. These tumors are often larger, extra-adrenal, and contain lower catecholamine concentrations than other hereditary PHEOs/PGLs. This study evaluated the size and age at diagnosis of primary SDHB-related PHEOs/PGLs as independent predictors of their metastatic behavior and outcome (survival). METHODS: One hundred six patients with SDHB mutation-related PHEO/PGL were included in this retrospective study. The recorded largest diameters, locations, and patient ages at initial diagnosis of SDHB-related primary tumors were analyzed in the context of time to metastasis and patient survival. RESULTS: First, the development of metastatic disease in patients with primary tumors ≥4.5 cm was significantly earlier than in patients with smaller tumors (P = 0.003). Second, patients with primary tumors larger than 5.5 cm also had worse overall survival than patients with smaller tumors (P = 0.008). Third, age at initial diagnosis was found to be an independent predictor of patient survival (PHEOs: P = 0.041; PGLs: P < 0.001). Fourth, we did not observe a significant difference in survival based on the specific SDHB mutations or patient sex. CONCLUSION: Receiver operating characteristic curves established 4.5 cm as the best value to dichotomize the primary SDHB-related PHEO/PGL in order to evaluate the development of metastatic disease and 5.5 cm as the best value for survival prediction. Subsequently, the size of the primary tumor was found as an age-independent predictor of patient survival and metastases development in PGL. In both PHEO and PGL, age at diagnosis was found to be a size-independent predictor of patient survival. No significant difference was found in metastases development or patient survival between males and females or among specific SDHB mutations. This data further extends and supports previous recommendations that carriers with SDHB mutations must undergo early and regular evaluations to detect PHEO/PGL in order to achieve the best clinical outcome.

Managing Catecholamine Release Syndrome During and Following Lu-177-DOTATATE in High-Risk Pheochromocytoma Patients.

Pheochromocytomas and paragangliomas (PPGLs) are rare catecholamine-producing tumors that express somatostatin receptors (SSTR) that can be treated with lutetium-177 DOTATATE (Lu-177-TRT); however, treatment can be associated with life-threatening cardiovascular events. A patient case with management strategies for high-risk PPGL patients receiving Lu-177-TRT is described. The 78-year-old patient with metastatic paraganglioma was enrolled and treated under NCT03206060. Deemed to be at high risk, the patient was preemptively admitted to the intensive care unit (ICU) with central line access placed. Due to comorbidities, a reduced dose of 100 mCi x 4 cycles was used for this patient. Vital signs, blood work, and serum catecholamine levels were obtained at various time points. Despite reduced dosing, the patient still developed a severe hypertensive reaction with systolic blood pressure of 240 mmHg within minutes of Lu-177-TRT infusion, which was controlled with an intravenous nicardipine drip. The patient remained in the ICU for 24 hours post Lu-177-TRT before moving to an inpatient ward for an additional 24 hours. All subsequent infusions were performed using reduced doses with elective ICU admissions and were well-tolerated. Despite the increased risk, metastatic PPGL patients can be safely treated with proper staff training, monitoring, and preparation for intravenous medications, especially nicardipine.

Pulmonary Metastasectomy for Adrenocortical Carcinoma-Not If, but When.

BACKGROUND: Adrenocortical carcinoma (ACC) commonly metastasizes to the lungs, and pulmonary metastasectomy (PM) is utilized due to limited systemic options. METHODS: All ACC patients with initially only lung metastases (LM) from a single institution constituted this observational case series. Kaplan-Meier and Cox proportional hazard analyses evaluated the association with potential prognostic factors and outcomes. Overall survival (OS) was calculated from the date of the PM or, in those patients who did not undergo surgery, from the development of LM. RESULTS: A total of 75 ACC patients over a 45-year period met the criteria; 52 underwent PM, and 23 did not. The patients undergoing PM had a median OS of 3.1 years (95% CI: 2.4, 4.7 years) with the 5- and 10-year OS being 35.5% and 32.8%, respectively. The total resected LM did not impact the OS nor the DFS. The patients who developed LM after 11 months from the initial ACC resection had an improved OS (4.2 years; 95% CI: 3.2, NR; p = 0.0096) compared to those developing metastases earlier (2.4 years; 95% CI: 1.6, 2.8). Patients who underwent PM within 11 months of adrenalectomy demonstrated a reduced OS (2.2 years; 95% CI: 1.0, 2.7) compared to those after 11 months (3.6 years, 95% CI: 2.6, NR; p = 0.0045). PM may provide benefit to those patients with LM at presentation (HR: 0.5; p = 0.2827), with the time to first PM as a time-varying covariate. CONCLUSIONS: PM appears to have a role in ACC patients. The number of nodules should not be an exclusion factor. Patients developing LM within a year of primary tumor resection may benefit from waiting before further surgeries, which may provide additional insight into who may benefit from PM.

Activity of the Ubiquitin-activating Enzyme Inhibitor TAK-243 in Adrenocortical Carcinoma Cell Lines, Patient-derived Organoids, and Murine Xenografts.

Current treatment options for metastatic adrenocortical carcinoma (ACC) have limited efficacy, despite the common use of mitotane and cytotoxic agents. This study aimed to identify novel therapeutic options for ACC. An extensive drug screen was conducted to identify compounds with potential activity against ACC cell lines. We further investigated the mechanism of action of the identified compound, TAK-243, its synergistic effects with current ACC therapeutics, and its efficacy in ACC models including patient-derived organoids and mouse xenografts. TAK-243, a clinical ubiquitin-activating enzyme (UAE) inhibitor, showed potent activity in ACC cell lines. TAK-243 inhibited protein ubiquitination in ACC cells, leading to the accumulation of free ubiquitin, activation of the unfolded protein response, and induction of apoptosis. TAK-243 was found to be effluxed out of cells by MDR1, a drug efflux pump, and did not require Schlafen 11 (SLFN11) expression for its activity. Combination of TAK-243 with current ACC therapies (e.g., mitotane, etoposide, cisplatin) produced synergistic or additive effects. In addition, TAK-243 was highly synergistic with BCL2 inhibitors (Navitoclax and Venetoclax) in preclinical ACC models including patient-derived organoids. The tumor suppressive effects of TAK-243 and its synergistic effects with Venetoclax were further confirmed in a mouse xenograft model. These findings provide preclinical evidence to support the initiation of a clinical trial of TAK-243 in patients with advanced-stage ACC. TAK-243 is a promising potential treatment option for ACC, either as monotherapy or in combination with existing therapies or BCL2 inhibitors. SIGNIFICANCE: ACC is a rare endocrine cancer with poor prognosis and limited therapeutic options. We report that TAK-243 is active alone and in combination with currently used therapies and with BCL2 and mTOR inhibitors in ACC preclinical models. Our results suggest implementation of TAK-243 in clinical trials for patients with advanced and metastatic ACC.

International consensus on mitotane treatment in pediatric patients with adrenal cortical tumors: indications, therapy, and management of adverse effects.

OBJECTIVE: Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects. METHODS: A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements. RESULTS: We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stages III and IV and with incomplete resection/tumor spillage. For stage II patients, mitotane is not generally indicated. The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14 and 20 mg/L. Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2-4 weeks), along with evaluation and assessment of laboratory values, are required. CONCLUSIONS: The Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.

Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement.

Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.

Grade Progression and Intrapatient Tumor Heterogeneity as Potential Contributors to Resistance in Gastroenteropancreatic Neuroendocrine Tumors.

Gastroenteropancreatic neuroendocrine neoplasms (NENs) are a heterogenous group of tumors that are incurable when metastatic, regardless of grade. The aim of this article is to understand tumor heterogeneity and grade progression as possible contributors to drug resistance in gastroentropancreatic neuroendocrine tumors (GEP-NETs). Heterogeneity has been observed in the genetic, pathological, and imaging features of these tumors at baseline. Diagnostic challenges related to tumor sampling and the potential for changes in grade over time further confound our ability to optimize therapy for patients. A better understanding of NEN biology and tumor heterogeneity at baseline and over time could lead to the development of new therapeutic avenues.

Practical considerations when providing palliative care to patients with neuroendocrine tumors in the context of routine disease management or hospice care.

This serves as a white paper by the North American Neuroendocrine Tumor Society (NANETS) on the practical considerations when providing palliative care to patients with neuroendocrine tumors in the context of routine disease management or hospice care. The authors involved in the development of this manuscript represent a multidisciplinary team of patient advocacy, palliative care, and hospice care practitioners, endocrinologist, and oncologists who performed a literature review and provided expert opinion on a series of questions often asked by our patients and patient caregivers affected by this disease. We hope this document serves as a starting point for oncologists, palliative care teams, hospice medical teams, insurers, drug manufacturers, caregivers, and patients to have a frank, well-informed discussion of what a patient needs to maximize the quality of life during a routine, disease-directed care as well as at the end-of-life.

Pulmonary large cell neuroendocrine carcinoma (LCNEC): a population-based study addressing recent molecular-genetic advances and emerging therapeutic approaches.

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) of the lung is a rare, aggressive cancer most commonly found in the lungs but not exclusively, with a worse prognosis than non-small cell lung carcinomas. Currently, LCNEC patients are treated using small cell and non-small cell protocols. This study aims to use the SEER database to identify demographic, clinical, pathological, and therapeutic factors affecting the prognosis and survival of patients with LCNEC of the lung. METHODS: Demographic, clinical, and management data of patients with lung LCNEC were extracted from the SEER database for the period 2000-2018. RESULTS: In the USA, LCNEC has a higher incidence in elderly white men: M:F ratio = 1.2:1, Caucasian: 83.3%, mean age: 67 ± 10.2 years. The most common treatment modality was chemotherapy only: 29.2%, followed by surgery: 21.5% (but in this group the statuses of chemotherapy were unknown), and combination surgery/chemotherapy: 8.8%. The overall and cause-specific 5-year survival was 17.5% (95% CI 16.3-18.8) and 21.9% (95% CI 20.5-23.4), respectively. By treatment, the best 5-year survival was for surgery alone (48%), followed by multimodality therapy (chemo + surgery + radiation) at 35% (95% CI 27-43). Age > 60 years, male gender, size > 7 cm, and nodal and liver metastasis were independent risk factors associated with increased mortality. CONCLUSION: Lung LCNEC is an aggressive neoplasm most common in older white males that presents at an advanced stage despite small primary tumors. Most patients die within 2 years. The best predictor of survival is surgery with chemotherapy. Given its dismal prognosis, new treatment guidelines are needed for this aggressive cancer.