Peptide Receptor Radiotherapy Research Articles

Safety and Efficacy of Para-Aminohippurate Coinfusion for Renal Protection During Peptide Receptor Radiotherapy in Patients with Neuroendocrine Tumors.

Para-aminohippurate, also known as p-aminohippuric acid (PAH), is used clinically to measure effective renal plasma flow. Preclinically, it was shown to reduce 177Lu-DOTATOC uptake in the kidneys while improving bioavailability compared with amino acid (AA) coinfusion. We report the safety and efficacy of PAH coinfusion during peptide receptor radiotherapy in patients with neuroendocrine tumors. Methods: Twelve patients with metastatic or unresectable gastroenteropancreatic neuroendocrine tumors received 177Lu-DOTATOC in 33 treatment cycles. Either 8 g of PAH or a mixture of 25 g of arginine and 25 g of lysine were coinfused. Safety was assessed by monitoring laboratory data, including hematologic and renal data, as well as electrolytes obtained before and 24 h after treatment. For radiation dosimetry, whole-body scans were performed at 1, 24, and 48 h and a SPECT/CT scan was performed at 48 h, along with blood sampling at 5 min and 0.5, 2, 4, 24, and 48 h after administration. Absorbed dose estimations for the kidneys and bone marrow were performed according to the MIRD concept. Results: In 15 treatment cycles, PAH was coinfused. No changes in mean creatinine level, glomerular filtration rate, and serum electrolytes were observed before or 24 h after treatment when using PAH protection (P ≥ 0.20), whereas serum chloride and serum phosphate increased significantly under AA (both P < 0.01). Kidney-absorbed dose coefficients were 0.60 ± 0.14 Gy/GBq with PAH and 0.53 ± 0.16 Gy/GBq with AA. Based on extrapolated cumulative kidney-absorbed doses for 4 cycles, 1 patient with PAH protection and 1 patient with AA protection in our patient group would exceed the 23-Gy conservative threshold. The bone marrow-absorbed dose coefficient was 0.012 ± 0.004 Gy/GBq with PAH and 0.012 ± 0.003 Gy/GBq with AA. Conclusion: PAH is a promising alternative to AA for renal protection during peptide receptor radiotherapy. Further research is required to systematically investigate the safety profile and radiation dosimetry at varying PAH plasma concentrations.

An audit of medullary thyroid carcinoma from a tertiary care hospital in northwest India.

Medullary thyroid carcinoma (MTC) is a rare thyroid malignancy originating from parafollicular C cells. It accounts for 5%-10% of all thyroid malignancies. An ambispective analysis of pathologically proven MTC presented in a tertiary care hospital in northwest India was performed after considering demography, clinical manifestation, RET mutation status, management, and outcome as denominators. Among 2,735 thyroid malignancy cases who presented to our institute in the last 10 years (2012-2022), 78 (3%) had MTC with a mean age of presentation of 43 ± 11 years; 60% of them were female. The median duration of symptoms was 23 months (IQR 12-36 months). The most common presenting complaint was goiter with lymphadenopathy (80.8%). Among the atypical presentations, one each had ectopic Cushing's syndrome, hypertensive crisis in pregnancy due to pheochromocytoma, synchronous chondrosarcoma, and Von Hippel-Lindau disease spectrum. Median calcitonin and carcinoembryonic antigen (CEA) levels at presentation were 1,274 pg/mL (n = 64) and 149 ng/mL (n = 39), respectively. Twenty-two patients were germline RET mutation-positive, and they presented at a younger age. Majority of the patients presented with stage IV disease. Surgery was the primary modality of therapy. Twenty-nine patients received radiotherapy and 25 patients received tyrosine kinase inhibitors (TKIs). Nine patients received peptide receptor radiotherapy (PRRT) with Lu-177 with neoadjuvant capecitabine. Median progression-free survival (PFS) was 60 months. Patients without structurally and biochemically residual disease and stable disease after the first modality of therapy (Log-rank 11.4; p = 0.004) had a better PFS. Female patients (Log-rank: 9.5; p = 0.002) had a better PFS than male patients. This study showed that MTC comprises 3% of thyroid malignancies with a female preponderance. RET mutation-positive patients had a younger age at presentation. Surgery was the first-line therapy. Radiotherapy, TKI, and PRRT were given as a part of second-line or third-line therapy due to persistent disease and/or disease recurrence. The median PFS was better in female patients and in patients who had no residual lesions and stable disease after the primary modality of therapy.

Peptide receptor radiotherapy (prrt) for well- differentiated metastatic paraganglioma and phaeochromocytomas (ppgl)

Peptide receptor radiotherapy (prrt) for well- differentiated metastatic paraganglioma and phaeochromocytomas (ppgl)

Aggressive pituitary adenoma and pituitary carcinoma

Anterior pituitary tumours, once considered benign neoplasms, may rarely have aggressive behaviour and can even metastasize. The current guideline of the European Society of Endocrinology defines aggressive pituitary adenomas as radiologically invasive tumours with an unusually rapid growth rate and frequent relapses despite the optimal use of standard therapies. Currently, there is not any single, well-defined pathological marker of malignancy. Pituitary carcinomas are thus clinically defined by the presence of craniospinal or distant metastases, typically developing several years after the first presentation. Histopathology may predict aggressive behaviour if the Ki67 index and mitotic rate are elevated and in case of positive p53 staining. These patients' short- and long-term therapy should be individualized and regularly discussed by a multidisciplinary pituitary team. Besides standard medical treatment administered in maximally tolerated doses, current recommendations suggest repeated surgery and radiotherapy. If this approach fails, the next choice of treatment is chemotherapy with temozolomide. After that, immune checkpoint inhibitors, bevacizumab, and peptide receptor radiotherapy are emerging therapies that should be used on a case-by-case basis. Orv Hetil. 2023; 164(30): 1167-1175.

Radiovirotherapy at twenty

Radiovirotherapy at twenty

Carcinoid Heart Disease Management: A Multi-Disciplinary Collaboration.

Carcinoid heart disease (CaHD) is an important complication among patients with metastatic neuroendocrine tumors and carcinoid syndrome (CS). CS patients (25%-65%) eventually develop CaHD; these patients face a significantly increased risk of morbidity and mortality. Guidance papers (eg, clinical practice guidelines, consensus guidelines, and expert statements) have been established by major organizations across the disciplines of cardiology and oncology; however, these recommendations are not routinely implemented. The aim of this article is to encourage the integration of current recommendations from national societies into clinical practice. Early screening upon recognition of CS and prior to the development of CaHD symptoms is paramount, as no existing therapies are approved to reverse the fibrotic damage to the heart once it occurs. Valvular replacement is the only definitive treatment for CaHD once it has developed. When patients are noted to have urinary 5-hydroxyindoleacetic acid (5-HIAA) levels ≥300 µmol/24 h and/or serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels >260 pg/mL, echocardiography is recommended. Systemic approaches to control tumor growth and hormonal secretion include somatostatin analogs (SSAs), followed by options including peptide receptor radiotherapy (PRRT), everolimus and liver embolization. Telotristat is the primary choice for control of diarrhea refractory to SSA. Diuretics are the mainstay of heart failure symptom management for patients who develop CaHD. Considerations for future research are discussed, including the ongoing TELEHEART (TELotristat Ethyl in a HEART biomarker study) trial involving telotristat and not yet activated CHARRT (Carcinoid Heart disease And peptide Receptor Radiotargetted Therapy) study involving PRRT with lutetium 177 (177Lu) dotatate.

Vaccinia virus and peptide-receptor radiotherapy synergize to improve treatment of peritoneal carcinomatosis

Tumor-specific overexpression of receptors enables a variety of targeted cancer therapies, exemplified by peptide-receptor radiotherapy (PRRT) for somatostatin receptor (SSTR)-positive neuroendocrine tumors. While effective, PRRT is restricted to tumors with SSTR overexpression. To overcome this limitation, we propose using oncolytic vaccinia virus (vvDD)-mediated receptor gene transfer to permit molecular imaging and PRRT in tumors without endogenous SSTR overexpression, a strategy termed radiovirotherapy. We hypothesized that vvDD-SSTR combined with a radiolabeled somatostatin analog could be deployed as radiovirotherapy in a colorectal cancer peritoneal carcinomatosis model, producing tumor-specific radiopeptide accumulation. Following vvDD-SSTR and 177Lu-DOTATOC treatment, viral replication and cytotoxicity, as well as biodistribution, tumor uptake, and survival, were evaluated. Radiovirotherapy did not alter virus replication or biodistribution, but synergistically improved vvDD-SSTR-induced cell killing in a receptor-dependent manner and significantly increased the tumor-specific accumulation and tumor-to-blood ratio of 177Lu-DOTATOC, making tumors imageable by microSPECT/CT and causing no significant toxicity. 177Lu-DOTATOC significantly improved survival over virus alone when combined with vvDD-SSTR but not control virus. We have therefore demonstrated that vvDD-SSTR can convert receptor-negative tumors into receptor-positive tumors and facilitate molecular imaging and PRRT using radiolabeled somatostatin analogs. Radiovirotherapy represents a promising treatment strategy with potential applications in a wide range of cancers.

Addition of Peptide Receptor Radiotherapy to Immune Checkpoint Inhibition Therapy Improves Outcomes in Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) are often diagnosed in advanced stages. Despite the advances in treatment approaches, including somatostatin analogs and peptide receptor radionuclide therapy (PRRT), these patients have no curative treatment option. Moreover, immunotherapy often yields modest results in NETs. We investigated whether combining PRRT using [177Lu]DOTATATE and immune checkpoint inhibition therapy improves treatment response in NETs. Methods: A gastroenteropancreatic NET model was generated by subcutaneous implantation of human QGP-1 cells in immune-reconstituted NOD.Cg-Prkdcscid Il2rgtm1Wjl /SzJ mice engrafted with human peripheral blood mononuclear cells (n = 96). Mice were randomly assigned to receive pembrolizumab (anti-PD1), [177Lu]DOTATATE (PRRT), simultaneous anti-PD1 and PRRT (S-PRRT), anti-PD1 on day 0 followed by PRRT on day 3 (delayed PRRT [D-PRRT]), PRRT on day 0 followed by anti-PD1 (early PRRT [E-PRRT]), or vehicle as control (n = 12/group). Human granzyme-B-specific [68Ga]NOTA-hGZP PET/MRI was performed before and 6 d after treatment initiation, as an indicator of T-cell activation. Response to treatment was based on tumor growth over 21 d and on histologic analyses of extracted tissues on flow cytometry for T cells, hematoxylin and eosin staining, and immunohistochemical staining. Results: [68Ga]NOTA-hGZP PET/MRI showed significantly increased uptake in tumors treated with E-PRRT, S-PRRT, and anti-PD1 on day 6 compared with baseline (SUVmax: 3.36 ± 0.42 vs. 0.73 ± 0.23; 2.36 ± 0.45 vs. 0.76 ± 0.30; 2.20 ± 0.20 vs. 0.72 ± 0.28, respectively; P < 0.001), whereas no significant change was seen in PET parameters in the D-PRRT, PRRT, or vehicle groups (P > 0.05). Ex vivo analyses confirmed the PET results showing the highest granzyme-B levels and T cells (specifically CD8-positive effector T cells) in the E-PRRT group, followed by the S-PRRT and anti-PD1 groups. Tumor growth follow-up showed the most significant tumor size reduction in the E-PRRT group (baseline to day 21, 205.00 ± 30.70 mm3 vs. 78.00 ± 11.75 mm3; P = 0.0074). Tumors showed less growth reduction in the PRRT, D-PRRT, and S-PRRT groups than in the E-PRRT group (P < 0.0001). The vehicle- and anti-PD-1-treated tumors showed continued growth. Conclusion: Combination of PRRT and anti-PD1 shows the most robust inflammatory response to NETs and a better overall outcome than immune checkpoint inhibition or PRRT alone. The most effective regimen is PRRT preceding anti-PD1 administration by several days.

Mechanisms of Resistance in Gastroenteropancreatic Neuroendocrine Tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), although curable when localized, frequently metastasize and require management with systemic therapies, including somatostatin analogues, peptide receptor radiotherapy, small-molecule targeted therapies, and chemotherapy. Although effective for disease control, these therapies eventually fail as a result of primary or secondary resistance. For small-molecule targeted therapies, the feedback activation of the targeted signaling pathways and activation of alternative pathways are prominent mechanisms, whereas the acquisition of additional genetic alterations only rarely occurs. For somatostatin receptor (SSTR)-targeted therapy, the heterogeneity of tumor SSTR expression and dedifferentiation with a downregulated expression of SSTR likely predominate. Hypoxia in the tumor microenvironment and stromal constituents contribute to resistance to all modalities. Current studies on mechanisms underlying therapeutic resistance and options for management in human GEP-NETs are scant; however, preclinical and early-phase human studies have suggested that combination therapy targeting multiple pathways or novel tyrosine kinase inhibitors with broader kinase inhibition may be promising.

Epigenetic potentiation of somatostatin-2 by guadecitabine in neuroendocrine neoplasias as a novel method to allow delivery of peptide receptor radiotherapy

BackgroundSomatostatin receptor-2 (SSTR2) is expressed on cell surface of neuroendocrine neoplasias; its presence is exploited for the delivery of peptide receptor radionuclide therapy (PRRT). Patients with no or low expression of SSTR2 are not candidates for PRRT. SSTR2 promotor undergoes epigenetic modification, known to regulate gene expression. We investigated whether the demethylation agent, guadecitabine, could enhance the expression of SSTR2 in NET models, using radioligand uptake/PET imaging as a biomarker of epigenetic modification. MethodsThe effects of guadecitabine on the transcriptional, translational, and functional regulation of SSTR2 both in vitro and in vivo using low (QGP-1) and high (BON-1) methylated neuroendocrine neoplasia models was characterised. Promotor region methylation profiling of clinical samples (n = 61) was undertaken. Safety of combination guadecitabine and PRRT was assessed in vivo. ResultsPyrosequencing of cell lines illustrated differential methylation indices – BON: 1 94%, QGP: 1 21%. Following guadecitabine treatment, a dose-dependent increase in SSTR2 in BON-1 at a transcriptional, translational, and functional levels using the SSTR2-directed radioligand, 18F-FET-βAG-TOCA ([18F]-FETO) (150% increase [18F]-FETO uptake, p < 0.05) was observed. In vivo, guadecitabine treatment resulted in a 70% increase in [18F]-FETO uptake in BON-1 tumour models compared models with low baseline percentage methylation (p < 0.05). No additive toxicity was observed with the combination treatment of PRRT and guadecitabine in vivo. Methylation index in clinical samples was 10.5% compared to 5.2% in controls (p = 0.03) and correlated with SSTR2 expression (Wilcoxon rank sign −3.75,p < 0.01). ConclusionGuadecitabine increases SSTR2 expression both in vitro and in vivo. The combination of demethylation agents with PRRT warrants further investigation.

Artisan trial protocol: A single center, open-label, phase II trial of the safety and efficacy of TheraSphere selective internal radiation therapy (SIRT) in the treatment of inoperable metastatic (liver) neuroendocrine neoplasia (NENs).

e16208 Background: Patients(pts) with NENs present with advanced, unresectable disease, with liver metastases. Liver metastases dictates prognosis. SIRT allows targeted high dose radiation directly to tumours, with relative sparing of the surrounding liver tissue. ArTisaN is a phase II study assessing efficacy and tolerability of SIRT using TheraSpheres for management of liver metastases secondary to NENs. Methods: Pts with liver dominant NENs will receive up to 2 TheraSphere treatments. Pts will be followed until disease progression for up to 2-years. Primary endpoints: objective response rate (ORR) within the treated liver volume, incidence of adverse events. Secondary endpoints: progression-free survival (PFS), overall (OS) and quality of life (EORTC QLQ-C30 and QLQ-GI.NET21). Assuming ORR 40%, sample size 24 patients-95% confidence interval will extend 20% in either direction. Results: 13 pts completed therapy: 69% female, primary site: 23% pancreatic, 31% small bowel. Grade: 54%-1, 46% - 2. 69% had previously received more than one line of systemic therapy including 7 who had previously received peptide receptor radiotherapy. 92% received bilobar treatment-average dose 2.49GBq administered. Hepatic ORR-69%. Grade 3 treatment related events occurred in 2 patients–1 ischaemic limb and 1 radiation induced hepatitis. Quality of life-maintained across all parameters. At the time of analysis, 5 pts had progressed, 3 had extrahepatic progression. Median PFS was 15.4 months (95%CI 11.5-19.4) and median OS was 18.5months (95%CI 7.4-29.6). Conclusions: Theraspheres is a safe and effective therapy for the management of patients with liver dominant disease from NENs. Clinical trial information: NCT04362436.

Survival According to Therapy Regimen for Small Intestinal Neuroendocrine Tumors

Introduction: Scarce data exist for therapy regimens other than somatostatin analogues (SSA) and peptide receptor radiotherapy (PRRT) for siNET. We analyzed real world data for differences in survival according to therapy. Patients and methods: Analysis of 145 patients, diagnosed between 1993 and 2018 at a single institution, divided in treatment groups. Group (gr.) 0: no treatment (n = 10), gr 1: TACE and/or PRRT (n = 26), gr. 2: SSA (n = 32), gr. 3: SSA/PRRT (n = 8), gr. 4: chemotherapy (n = 8), gr. 5: not metastasized (at diagnosis), surgery only (n = 53), gr. 6 = metastasized (at diagnosis), surgery only (n = 10). Results: 45.5% female, median age 60 years (range, 27–84). A total of 125/145 patients with a resection of the primary tumor. For all patients, 1-year OS (%) was 93.8 (95%-CI: 90–98), 3-year OS = 84.3 (CI: 78–90) and 5-year OS = 77.5 (CI: 70–85). For analysis of survival according to therapy, only stage IV patients (baseline) that received treatment were included. Compared with reference gr. 2 (SSA only), HR for OS was 1.49 (p = 0.47) for gr. 1, 0.72 (p = 0.69) for gr. 3, 2.34 (p = 0.19) for gr. 4. The 5 y OS rate of patients whose primary tumor was resected (n = 125) was 73.1%, and without PTR was 33.3% (HR: 4.31; p = 0.003). Individual patients are represented in swimmer plots. Conclusions: For stage IV patients in this analysis (limited by low patient numbers in co. 3/4), multimodal treatment did not significantly improve survival over SSA treatment alone. A resection of primary tumor significantly improves survival.

Evaluation of radiation safety of the newly established national New Zealand 177–Lutetium (177-Lu or Lutate) Peptide Receptor Radiation Therapy (PRRT) service, a palliative treatment for patients with metastatic neuroendocrine tumours

Following the initiation of a fortnightly interim National service in New Zealand for PRRT, for 6 months, radiation safety measurements over several hours during the treatment were recorded. This was to ensure that good medical practice and local regulations were being followed, also to ensure that the staffing groups involved, were not unnecessarily exposed to excessive levels of radiation while working regularly with an unsealed radiation source. Additionally, the external radiation doserate levels at discharge were assessed in order to assure radiation safety of family members and members of the general public.

Molecular Imaging and Theragnostics of Thyroid Cancers.

Simple SummaryAccording to the American Cancer Society, approximately 53,000 new cases of thyroid cancer were diagnosed and more than 2200 people died from the disease in 2020. New developments in molecular imaging are significantly improving thyroid cancer diagnostics and therapy. Continuous research in molecular imaging techniques additionally contributes to an understanding of a variety of diseases and enables more efficient care of thyroid cancer patients. Molecular imaging-based personalized therapy has been a fascinating concept for individualized therapeutic strategy, which is able to attain the highest efficacy and reduce adverse effects in certain patients. Theragnostics, which integrates diagnostic testing to detect molecular targets for particular therapeutic modalities, is one of the key technologies that contributes to the success of personalized medicine. This review details the inception of molecular imaging and theragnostic applications for thyroid cancer management.Molecular imaging plays an important role in the evaluation and management of different thyroid cancer histotypes. The existing risk stratification models can be refined, by incorporation of tumor-specific molecular markers that have theranostic power, to optimize patient-specific (individualized) treatment decisions. Molecular imaging with varying radioisotopes of iodine (i.e., 131I, 123I, 124I) is an indispensable component of dynamic and theragnostic risk stratification of differentiated carcinoma (DTC) while [18F]F-fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) helps in addressing disease aggressiveness, detects distant metastases, and risk-stratifies patients with radioiodine-refractory DTC, poorly differentiated and anaplastic thyroid cancers. For medullary thyroid cancer (MTC), a neuroendocrine tumor derived from thyroid C-cells, [18F]F-dihydroxyphenylalanine (6-[18F]FDOPA) PET/CT and/or [18F]FDG PET/CT can be used dependent on serum markers levels and kinetics. In addition to radioiodine therapy for DTC, some theragnostic approaches are promising for metastatic MTC as well. Moreover, new redifferentiation strategies are now available to restore uptake in radioiodine-refractory DTC while new theragnostic approaches showed promising preliminary results for advanced and aggressive forms of follicular-cell derived thyroid cancers (i.e., peptide receptor radiotherapy). In order to help clinicians put the role of molecular imaging into perspective, the appropriate role and emerging opportunities for molecular imaging and theragnostics in thyroid cancer are discussed in our present review.

Risk of myelodysplastic syndrome/acute leukemia with sequential capecitabine/temozolomide and 177Lu-dotatate.

513 Background: The treatment landscape for neuroendocrine tumors includes alkylating-agent chemotherapy and peptide receptor radiotherapy (PRRT) with 177Lu-Dotatate. The risk of MDS/AML associated with 177Lu-Dotatate is approximately 2-3%. Several small prior studies have suggested substantially higher rates of MDS/AML (approximately 10%) in patients who have also received alkylating agent chemotherapy with streptozocin or temozolomide, either combined with PRRT or sequentially. Methods: Retrospective study of all patients with advanced NENs treated at the Moffitt Cancer Center between 1/2008 and 9/2019 who received treatment with CAPTEM. Results: 462 patients received treatment with CAPTEM, among whom 49 received also received PRRT. Median follow-up was x months. 4 patients developed MDS/AML, all of whom had also received both CAPTEM and PRRT. None of the patients who received CAPTEM chemotherapy without PRRT developed a long-term hematological malignancy. Conclusions: 8% of patients who received both CAPTEM and PRRT developed MDS or AML, a risk that is higher than that associated with PRRT alone. This cumulative risk needs to be considered when sequencing treatments in NETs.

Targeted α-Emitter Therapy with 212Pb-DOTAMTATE for the Treatment of Metastatic SSTR-Expressing Neuroendocrine Tumors: First-in-Humans Dose-Escalation Clinical Trial.

Peptide receptor radiotherapy with somatostatin analogs has been successfully used for years as a treatment for somatostatin-overexpressing tumors. Treatment of neuroendocrine tumors (NETs) with the β-particle emitter 177Lu-DOTATATE is currently considered the standard of care for subjects with gastroenteropancreatic NETs. Despite the success of 177Lu-DOTATATE, there remains significant room for improvement in terms of both safety and efficacy. Targeted α-emitter therapy with isotopes such as 212Pb has the potential to improve both. Here, we present the preliminary results of the phase 1 first-in-humans dose-escalation trial evaluating 212Pb-DOTAMTATE (a bifunctional metal chelator [DOTAM] and the SSTR-targeting peptide [TATE]) in patients with somatostatin receptor-positive NETs. Methods: Twenty subjects with histologically confirmed NETs, prior positive somatostatin analog scans, and no prior history of 177Lu/90Y/111In peptide receptor radiotherapy, with different primary sites of the disease, were enrolled. Treatment began with single ascending doses of 212Pb-DOTAMTATE, with subsequent cohorts receiving an incremental 30% dose increase, which was continued until a tumor response or a dose-limiting toxicity was observed. This was followed by a multiple ascending dose regimen. The recommended phase 2 dose regimen consisted of 4 cycles of 2.50 MBq/kg (67.6 μCi/kg) of 212Pb-DOTAMTATE administered at 8-wk intervals, intravenously. Results: Ten subjects received the highest dose, 2.50 MBq/kg/cycle (67.6 μCi/kg/cycle). Treatment was well tolerated, with the most common treatment-emergent adverse events being nausea, fatigue, and alopecia. No serious treatment-emergent adverse events were related to the study drug, and no subjects required treatment delay or a dose reduction. An objective radiologic response of 80% was observed for the first 10 subjects treated at the recommended phase 2 dose. Conclusion: Targeted α-therapy with 212Pb-DOTAMTATE has been shown to be well tolerated. Preliminary efficacy results are highly promising. If these results are confirmed in a larger, multicenter clinical trial, 212Pb-DOTAMTATE would provide a substantial benefit over currently Food and Drug Administration-approved therapies for patients with metastatic or inoperable SSTR-expressing NETs regardless of the grade and location of the primary tumor.

Efficacy and Toxicity Analysis of Capecitabine and Temozolomide in Neuroendocrine Neoplasms.

The capecitabine/temozolomide (CAPTEM) regimen has significant activity in advanced neuroendocrine tumors (NETs). Questions exist regarding activity in pancreatic versus nonpancreatic NETs, risk of opportunistic infections, long-term myelotoxicity, and safety of prolonged treatment duration. Analysis of large patient cohorts is needed for the evaluation of rare toxicities and assessment of risk factors. We conducted a retrospective study of all patients with advanced NETs seen at Moffitt Cancer Center between January 2008 and June 2019 who received treatment with CAPTEM. A total of 462 patients were eligible. The objective radiographic response rate was 46%, and the disease control rate was 81%. Median progression-free survival (PFS) was 18 months (95% CI, 14.0-21.9 months) and median overall survival was 51 months (95% CI, 42.8-59.2 months): 62 months in well-differentiated NETs versus 14 months in poorly differentiated neuroendocrine carcinomas (P<.0001). Patients with primary pancreatic tumors had the highest partial response rates and longest median PFS. Incidences of grade 4 thrombocytopenia and neutropenia were 7% and 3%, respectively, and substantially higher in women than men (P=.02 and P=.004, respectively). Only 1 case (0.2%) of suspected Pneumocystis pneumonia (PCP) was observed in a patient receiving corticosteroids. Three patients developed myelodysplastic disease, all of whom had received prior peptide receptor radiotherapy (PRRT). There were no acute treatment-related deaths; 1 patient died 2 months after a thrombocytopenic bleed. The CAPTEM regimen is exceptionally safe. Efficacy is particularly robust in well-differentiated pancreatic NETs. Severe myelotoxicity is rare; the risk of grade 4 cytopenias is significantly increased in women, and therefore sex-based dosing should be considered. There were no cases of myelodysplastic syndromes, except among patients who had received PRRT, a known risk factor. The risk of PCP is negligible.

Clinical Features and Prognosis of Patients with Carcinoid Syndrome and Carcinoid Heart Disease: A Retrospective Multicentric Study of 276 Patients

Introduction: Carcinoid syndrome is the most frequent functional syndrome of neuroendocrine neoplasia. It is characterized by flushing, diarrhea, wheezing, hypotension, and exanthema and may cause carcinoid heart disease. Methods: We assessed clinical characteristics and prognosis of patients with carcinoid syndrome and carcinoid heart disease in 276 patients from 3 referral centers. Results: Carcinoid syndrome patients had a mean age of 57 years (range 21–84) and a normal BMI of 24.9 (SD 4.5; range 13.8–39.6). Most primaries were of small bowel or unknown primaries with distant metastasis in 94.6%. Flushing was the most frequent symptom in 74.3% of patients, followed by diarrhea in 68.8%, and wheezing in 40.9%. Pain was described by 45.3%, weakness by 23.5%, and weight loss of >10% in 6 months by 30.1% of patients. Carcinoid heart disease was diagnosed in 37.3% of patients (n = 104) by echocardiography and involved predominantly in the tricuspid valve. Combinations with other valve defects were common. Somatostatin analogs were taken by 80.4% of patients and 17% needed additional loperamide/opium tincture. Surgery and peptide receptor radiotherapy were most frequent treatments. The median survival of patients with carcinoid syndrome after diagnosis was 9 years. Prognosis was significantly impaired by male sex and diagnosis of carcinoid heart disease but surprisingly significantly increased by the presence of symptoms flushing and weakness. Discussion/Conclusion: Carcinoid syndrome is associated with extensive disease and primaries in small bowels or of unknown primary. Weight loss, weakness, and pain are frequent, and carcinoid heart disease is diagnosed in more than one-third of patients.

Advanced Pancreatic Neuroendocrine Neoplasms: Which Systemic Treatment Should I Start With?

Pancreatic neuroendocrine neoplasms (panNENs) often present as advanced disease and there is little data to guide treatment sequencing in the advance disease setting. Therefore, we aim to provide a comprehensive summary of the current evidence supporting the use of systemic treatment for patients with diagnosis of advanced and metastatic panNENs, as well as to provide strategies for treatment selection and address challenges for treatment selection and sequencing of therapy. Substantial advances have been made and many clinical trials have been performed over the past two decades expanding therapeutic options available for patients with advanced panNETs. Available systemic treatments for patients with well-differentiated pancreatic neuroendocrine tumors include somatostatin receptors ligands (SRLs), traditional cytotoxic chemotherapy regimens, peptide receptor radiotherapy (PRRT), and biologically targeted therapies, whereas patients with poorly differentiated neurodocrine carcinomas have more limited treatment options. Despite these advances, no clear guidelines exist to support the best sequence of treatments, not only the first-line, but also subsequent lines of therapy in patients with panNENs. Advances in molecular research and discovery of biomarkers for response allowing a more personalized approach to the multimodality therapy of panNENs are still limited. Understanding the impact of previous therapies on subsequent treatment efficacy and toxicity is also an ongoing research question. In the absence of definite predictive markers and paucity of comparative randomized trials, along with the heterogeneity of this patient population, systemic therapy selection in advanced non-resectable disease should be patient centered and often require evaluation within a multidisciplinary setting. The specific clinical context of the patient, with assessment of individual patient clinical and pathological features, somatostatin receptors imaging, and goals of treatment must all be considered when deciding on systemic therapy in the patient. Additional research is needed to address the gap in knowledge regarding optimal sequencing and timing of therapies and to provide individual care.

Targeted Therapies in the Management of Well-Differentiated Digestive and Lung Neuroendocrine Neoplasms

Ongoing advances in our understanding of neuroendocrine tumor (NET) biology, genetics, and immunology, will continue to expand the availability of targeted therapies, thus improving the outcomes of patients. Well-differentiated neuroendocrine tumors (NETs) are grouped into pancreatic and non-pancreatic NETs (includes GI and thoracic NETs) for treatment considerations (Fig.1). For panNETs, initial therapy is driven by the need of radiographic response, and targeted agents are typically reserved for second and third line based on the toxicity profile. Treatment options for non-pancreatic NETs are also expanding and while SSAs are the typical first-line option, everolimus and PRRT both remain approved therapies for future lines, and VEGF TKIs are showing promising results in research settings. Sequencing these agents and best time to incorporate peptide receptor radio therapy into the management algorithm remains an unmet need.