Treatment Of Neuroendocrine Tumors Research Articles

Real-world analysis of peptide receptor radionuclide therapy (PRRT) in the treatment of neuroendocrine tumors.

e16701 Background: PRRT received FDA approval in 2018 for treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEPNETs) based on NETTER-1 trial data that included only small bowel grade 1 and 2 neuroendocrine tumors. We present real-world data of PRRT outcomes and implementation from a large tertiary treatment center following approval. Methods: Patients treated with PRRT at University of Iowa between Jan 2018 - July 2019 were included in this retrospective study. Patient and tumor characteristics, cumulative dose and cycles of Lu 177 PRRT administered, treatment course, treatment-related toxicity and responses were reviewed, and 1-year progression-free and overall survival rates were calculated. Results: 67 patients received PRRT, of which 61 completed at least 2 doses. Primary tumor sites included small bowel (64.1%), pancreas (20.3%), and lung (9.4%). 43 (64%) had grade 2 NET; 5 had grade 3 (7.4%). 44 (65.6%) completed 4 cycles of PRRT per FDA approval while 10 received 3 cycles (14.9%). Median duration of follow up was 11.7 months. 53 patients received at least 2 doses and at least one imaging procedure post-PRRT. No complete responses were noted. 9 patients were found to have disease progression at last follow up. 1-year progression-free survival was 78% (95% CI 64-88%). 1-year overall survival was 88% (95% CI 75-94%). Of 23 patients who received fewer than 4 cycles, PRRT was discontinued in 4 (5.9%) due to myelosuppression, specifically thrombocytopenia grade 2 and above. 9 patients discontinued therapy due to change in clinical status or progression per treating physician, 2 experienced carcinoid crisis and 2 had renal function deterioration (preexisting renal disease). 5 patients had previously received PRRT with either Y90 or Lu 177 prior to FDA approval and were retreated in our cohort. 5 patients had preexisting renal disease, including one patient on peritoneal dialysis. Conclusions: We noted a higher rate of treatment discontinuation after 3 cycles, possibly due to heavy pretreatment or treatment of patients with advanced disease, not uncommon after a new therapy is approved and implemented into practice. Discontinuation due to myelosuppression or renal dysfunction was minimal, consistent with NETTER-1 data. Our cohort is unique as it included patients who had received prior PRRT as well as others with preexisting renal dysfunction. Despite this, treatment-related toxicity in our cohort was not significantly higher.

Survey of challenges in access to diagnostics and treatment for neuroendocrine tumor (NET) patients (SCAN): Awareness of specialized techniques and latest interventions.

e16708 Background: SCAN measured global readiness to provide diagnostics and treatments for NET patients in terms of awareness, availability, quality and affordability. This analysis focused on patient and healthcare professional (HCP) awareness of NET diagnostics and treatments. Methods: During Sept-Nov 2019, NET patients and HCPs completed an online survey (available in 14 languages). Results: There were 2795 respondents from 68 countries across 6 continents (2359 patients/carers; 436 HCPs). Primary NETs were most often gastroenteropancreatic NETs (GEP NET; 71% [1408/1983]), particularly small intestinal (35% [690/1983]) or pancreatic (20% [402/1983]). Biopsy was the most well-known diagnostic option in the overall NET patient group (82% [1917/2325]), the GEP NET patient subgroup (83% [1156/1395]) and HCPs (94% [411/435]), followed by CT (all patients: 81% [1874/2325]; GEP NET: 80% [1118/1395]; HCPs: 86% [376/435]). More HCPs were aware of specialized diagnostics, such as 68Ga-DOTA PET CT (HCP 81% [353/435]) and chromogranin A (CgA; 79% [344/435]), than patients (all: 68% [1574/2325] & 62% [1451/2325], respectively; GEP NET: 69% [962/1395] & 67% [936/1395]). The vast majority of all patients (87% [1983/2275]), GEP NET patients (89% [1215/1363]) and HCPs (91% [392/431]) knew surgery was a treatment option. Somastatin analogues were recognised as a treatment option by 90% of HCPs (387/431), but only 75% of GEP NET patients (1019/1363) and 70% of all NET patients (1599/2275). Nearly a quarter of HCPs (22% [95/431]) and one-third of patients (all: 33% [755/2275]; GEP NET: 30% [409/1363]) had not heard of peptide receptor radionuclide therapy (PRRT). The majority of patients (all: 88% [2007/2273]; GEP NET: 89% [1213/1370]) and HCPs (93% [396/425]) were aware of conventional imaging, such as CT/MRI/ultrasound, being used for ongoing monitoring of NETs. Approximately a third of all NET patients and a quarter of HCPs were unware CgA (patients: 32% [723/2273]; HCPs: 22% [94/425]) or 68Ga-DOTA PET CT (patients: 29% [670/2273]; HCPs: 24% [102/425]) were ongoing monitoring tools. Similarly, CgA and 68Ga-DOTA PET CT were not recognized by 27% of GEP NET patients (364/1370 & 371/1370, respectively). Conclusions: Increased awareness of NET diagnostics and treatments, particularly newer, more specialized tools, amongst both HCPs and patients is required to ensure continued advancements and improvements in the global standard of care for NETs.

SUN-LB26 Radioligand Theranostics of Endocrine-Related Cancers; A New, Revolutionary Approach

The successful clinical development of octreotide targeting somatostatin receptors (SSRs) revolutionized treatment of Neuro Endocrine Tumors (NETs)and pituitary adenomas. Recently, clinical applications of peptide bioconjugates including octreotide have taken a giant leap forward into a new diagnostic and therapeutic arena of additional endocrine-related cancers including prostate, breast, and small cell lung cancers. Molecularly targeted radionuclide therapy (RT) opens new horizons for otherwise resistant or widely dispersed malignancies and has far-reaching implications as a personalized therapeutic approach. Cancer-type specific, radiolabeled diagnostic imaging agents have been developed to select patients who then receive precise radioligand therapy targeting the identified cancer cells. This RT using alpha or beta radiation is cytotoxic to targeted cancer cells, while nearby healthy cells are unharmed—minimizing side effects and improving patient quality of life. Thus, theranostics represent a groundbreaking approach to bring radionuclide endocrine cancer therapy to patients via a multidisciplinary team consisting of endocrinologists, surgeons, oncologists and nuclear medicine physicians. In recognition of this exploding new field, the US FDA approved 68Ga-DOTATOC and -DOTATATE for use in PET/CT and 177Lu-DOTATATE for the treatment of SSR-positive NETs. Clinical trials with new theranostic compounds are ongoing for prostate cancer (PSMA), breast cancer (bombesin receptor), and small cell lung cancer (cytokine receptor CXCR4). Exciting future developments will undoubtedly involve development of radionuclide agents targeting additional cell surface receptors, enzymatic pathways, and clonal variations as well as combinations of alpha- and beta-emitters. Health care facilities worldwideare in the process of adding RT to their armamentarium for cancer patients; this requires a multidisciplinary team approach to optimize access to and delivery of care. To advance the science and enable translation of theranostics worldwide, the Gordon Research Conferences (GRC) organization [www.grc.org] has selected the authors to organize a 5-day inaugural meeting on Radionuclide Theranostics for the Management of Cancer in June 2020 [https://www.grc.org/radionuclide-theranostics-for-the-management-of-cancer-conference/2020/]that brings together cancer biologists, radiation physicists, receptor pharmacologists, nuclear medicine physicians, and industry representatives to 1) Identify new molecular targets and targeting vectors for specific malignancies; 2) Explore development of novel radionuclides and molecularly targeted radiopharmaceuticals; and 3) Optimize therapeutic benefits based on an understanding of radionuclide risks to normal tissues. This presentation will review the key topics discussed during this GRC meeting2496 characters (without spaces): limit 2500.

SUN-118 Somatostatin Agonist Conjugated to the Evans Blue Moiety Is a Superior Analog in the Diagnosis and Treatment of Tumors Characterized by High Somatostatin Receptor Expression

Background: Radiolabeled somatostatin (SST) analogs have been proven to be effective in the diagnosis and treatment of neuroendocrine tumors (NETs), which are characterized by high somatostatin receptor (SSTR2) expression. At present, there are several SST analogs available that differ from each other in the affinity for SSTR2 and tumor retention time. To date, only a single SST agonist -DOTA-TATE- has been approved by the FDA for imaging and treatment of NETs. Recent studies have shown that addition of Evans blue (EB) moiety to an SST agonist results in superior uptake and increased retention time within the tumors. The goal of our study was to compare the diagnostic and therapeutic efficacy of three different radiolabeled SST analogs in a tumor mice model: EB-TATE - a novel modified agonist; DOTA-TATE - an agonist and JR11 - an antagonist. Methods: A rat pancreatic cell line (AR42J), characterized by high SSTR2 expression, was used to create a subcutaneous xenograft mice model. The AR42J cells formed sizable tumors within two weeks post-injection. The 86Y-EB-TATE, 68Ga-DOTA-TATE, and 68Ga-DOTA-JR11 were used to determine standard uptake values by positron emission tomography (PET) imaging. For treatment purposes, the SST analogs were labeled with 177Lu to generate 177Lu-EB-TATE, 177Lu-DOTA-TATE and 177Lu-DOTA-JR11. The mice were assigned to treatment groups based on comparable tumor volume at baseline and received two doses (0.5mCi) of the 177Lu-labeled analogs one week apart. Tumor measurements were performed twice per week and the mice were euthanized if their tumor burden exceeded 2 cm at any point in the study or after 6 weeks - landmark of the end of the study. Results: Among the three analogs tested, the novel SST analog 86Y-EB-TATE was characterized by 4.3- and 3.7- fold higher tumor uptake in comparison to 68Ga-DOTA-TATE (p<0.001) and 68Ga-DOTA-JR11 (p<0.001), respectively. There was no significant difference between the uptake of 68Ga-DOTA-TATE and 68Ga-DOTA-JR11 (p=0.9). Consistently with higher tumor uptake on imaging, 177Lu-EB-TATE-treated mice responded to the treatment with an overall 86.5±13.2% reduction in the tumor volume after two weeks post-therapy. On the contrary, despite therapy with 177Lu-DOTA-TATE and 177Lu-DOTA-JR11, the mice treated with these agents presented with tumor progression exceeding 2 cm and were euthanized. Consequently, the progression-free survival (PFS) was significantly longer in 177Lu-EB-TATE group (24±0 days) compared with 177Lu-DOTA-TATE (7.7±2.6 days, p<0.001) and 177Lu-DOTA-JR11 (6.3±3 days, p<0.001). There was no difference in PFS between 177Lu-DOTA-TATE and 177Lu-DOTA-JR11-treated mice (p=0.3). Conclusion: EB-TATE is characterized by superior diagnostic and therapeutic efficacy in comparison to DOTA-TATE and DOTA-JR11. EB-TATE might be used as imaging and therapeutic agent in tumors characterized by high SSTR2 expression.

MON-214 Biochemical Abnormalities in Endocrine Function Associated with Lutetium 177-DOTATATE Therapy in Metastatic Pheochromocytoma and Paraganglioma

Background: Lutetium-177 (177Lu) DOTATATE (Lutathera ®) is a form of peptide receptor radionuclide therapy (PRRT) that has shown efficacy in the treatment of neuroendocrine tumors through its action on somatostatin receptor 2. The effects of Lutathera on endocrine function in metastatic pheochromocytoma and paraganglioma (PPGL) has not been evaluated. Methods: We performed a prospective analysis on 21 patients (10 female, 11 male) with metastatic PPGL receiving 177Lu DOTATATE (NCT03206060) at our center from July 2017 to August 2019. Hormonal evaluation was obtained 24 and 48 hours after each 177Lu DOTATATE administration and 4 weeks ± 1 week after each cycle to assess for biochemical endocrine abnormalities (BEAs). Blood samples were obtained after 30 minutes of resting with an in-dwelling intravenous catheter. We excluded BEAs that were present either prior to the initiation of 177Lu DOTATATE or due to a pre-existing endocrine disorder. Results: We observed BEAs in 18 of 21 (85.7%, 7 female, 11 male) patients. BEAs most commonly involved the pituitary-adrenal axis [ACTH (N: 5-46 pg/mL): 6/21 (28.5%, 5 high, 1 low); serum cortisol (N: 5-25 mcg/dL): 5/21 (23.8%, 2 high, 3 low)], followed by pituitary-thyroid axis [TSH (N: 0.27-4.2 IU/mL): 6/21 (28.5%, 4 high, 2 low); free thyroxine (N: 0.9-1.7 ng/dL): 2/21 (9%, 0 high, 2 low)], pituitary-gonadal axis [FSH (N: 1-11 U/L): 2/21 (9%, 1 high, 1 low); LH (1-8 U/L): 1/21 (5%, 0 high, 1 low); total testosterone (N: 262-1593 ng/dL): 4/21 (19%, 0 high, 4 low)]; and growth hormone [3/21 (N: 0 - 3 ng/mL): (14.3%, 3 high, 0 low)]. Of the 28 observed BEAs, 17/28 (61%) were initially noted during cycle 1, 7/28 (25%) during cycle 2, and 4/28 (14%) during cycle 3, and 16/28 (57%) were noted within 48 hours of 177Lu DOTATATE injection. There was no significant association between the standardized uptake values of adrenals (p=0.28), pituitary (p=0.75), and thyroid gland (p=0.61) on the baseline diagnostic 68Ga DOTATATE scan and their respective BEAs. One patient developed overt hypothyroidism and was started on levothyroxine, and another patient developed central adrenal insufficiency likely from immunotherapy started after 177Lu DOTATATE therapy. In all other patients, BEAs were transient and spontaneously resolved. Limitations included the observational nature of the study, lack of data on levels of IGF-1, parathyroid hormone, or hemoglobin A1C. Conclusion:177Lu DOTATATE therapy for metastatic PPGL is associated with biochemical abnormalities in endocrine function. Although mostly transient, there is a potential risk for BEAs to be permanent and to manifest clinically. Therefore, serial monitoring of abnormal hormonal values is necessary and treatment should be considered when appropriate. Studies on larger populations with long-term follow-up are necessary to further investigate the incidence of endocrine abnormalities with 177Lu DOTATATE therapy.

SAT-305 Veldoreotide (COR005) Mechanisms of Action Studies: Comparison to Octreotide and Pasireotide

Stable somatostatin analogs (SSAs) are the first choice for medical treatment of pituitary adenomas and other neuroendocrine tumors. The somatostatin analogs octreotide, pasireotide, and veldoreotide primarily have been characterized according to their binding profiles. However, their ability to activate individual somatostatin receptor subtypes (SSTs) has not been directly assessed so far. In this study, we assessed G-protein signaling in human embryonic kidney (HEK293) cells stably expressing G protein-coupled inwardly rectifying potassium (GIRK) channels and SSTs using a novel fluorescence-based membrane potential assay. Dose-response curves obtained for veldoreotide revealed high potency and efficacy in cells expressing SST2, SST4, and SST5. Veldoreotide also inhibited proliferation and chromogranin A secretion in SST4-transfected BON-1 cells. In addition, we assessed G-protein signaling in primary pituitary cultures from SST2 and SST5 knockout mice. Our results show that octreotide mediates its effects selectively via the SST2 receptor. Conversely, pasireotide mediates its effects selectively via the SST5 receptor. In contrast, veldoreotide can activate both SST2 and SST5 receptors under otherwise identical conditions. Thus, veldoreotide is a unique SSA with full agonistic activity at the SST2, SST4, and SST5 receptors.

SUN-914 Peptide Receptor Radionuclide Therapy for an Inoperable Small Cell Neuroendocrine Tumor in the Philippines

Background: Peptide Receptor Radionuclide Therapy treatment for neuroendocrine tumors is a well-tolerated treatment option for patients not amenable to receiving chemotherapy and radiotherapy. Clinical Case: A 42-year-old female was evaluated by a cardiologist for complaints of new onset recurrent throat discomfort, chest pain and palpitations. Two-Dimensional echo showed a large extra-cardiac mass compressing the main pulmonary artery. Chest CT with contrast reveal a 5.8 x 6.0 x 7.2 cm enhancing lobulated anterior mediastinal mass. Attempts to excise the mass failed due to the proximity to major blood vessels. Biopsy revealed a Carcinoid Tumor that was Chromogranin A positive but was asymptomatic for carcinoid syndrome. Everolimus treatment was given but was halted due to stomatitis. The patient remained fully functional. Re-evaluation of the mass with FDG PET show an increase in tumor size. Biopsy tissue re-testing showed small cell neuroendocrine carcinoma. Urine 5-hydroxyindoleacetic acid, plasma 5-hydroxyindoleacetic acid, and serum Chromogranin A were normal. A 68Ga-DOTATATE PET/CT scan reveal a slight increase in the mass that was intensely DOTATATE-avid. Two sessions of Peptide Receptor Radionuclide Therapy (PRRT) Lutetium-177 DOTATATE given at an 8-month interval were given. SPECT/CT re-evaluation showed good response and no evidence of metastases. A 68Ga-DOTA-octreotate PET-CT scan was done and showed good response to treatment. According to treatment guidelines, small cell neuroendocrine carcinoma that are non-resectable are treated with radiotherapy plus chemotherapy. But since the patient is fully functional and has minimal symptoms, other means of treatment such as PRRT may be well suited due to good tolerability and good treatment outcomes. Conclusion: PRRT is a promising treatment for NETs that is well tolerated giving better functionality and quality of life for patients opting not to undergo chemotherapy and radiotherapy. Reference: Cadiot, G. (2019). French and European Neuroendocrine Tumor Society consensus guidelines. Annales d’Endocrinologie, 80(3), p.174.

Toxicity of a combined therapy using the mTOR-inhibitor everolimus and PRRT with [177Lu]Lu-DOTA-TATE in Lewis rats

PurposePeptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA0,TYR3-octreotate ([177Lu]Lu-DOTA-TATE) and the mechanistic target of rapamycin (mTOR) inhibitor everolimus are both approved for the treatment of neuroendocrine tumours (NET). However, tumour progression is still frequent, and treatment strategies need further improvement. One possible approach could be to combine different therapy options. In this study, we investigated the toxicity of a combined treatment with everolimus and [177Lu]Lu-DOTA-TATE in female Lewis rats.MethodsAnimals received 200 MBq of [177Lu]Lu-DOTA-TATE once and/or 5 mg/kg body weight everolimus or placebo weekly for 16 weeks and were divided into four groups (group 1, placebo; group 2, everolimus; group 3, placebo + [177Lu]Lu-DOTA-TATE; group 4, everolimus + [177Lu]Lu-DOTA-TATE). Blood levels of creatinine and blood urea nitrogen (BUN) were assessed weekly to monitor nephrotoxicity, and a full blood count was performed at the time of euthanasia to monitor myelotoxicity. Additionally, renal function was analysed by sequential [99mTc]Tc-mercaptoacetyltriglycine ([99mTc]Tc-MAG3) scintigraphies. Histopathological examination was performed in all the kidneys using a standardized renal damage score (RDS).ResultsRats receiving everolimus showed a significantly lower increase in creatinine levels than those receiving placebo. Everolimus therapy reduced white blood count significantly, which was not observed for [177Lu]Lu-DOTA-TATE. Functional renal scintigraphies using [99mTc]Tc-MAG3 showed a compromised initial tracer uptake after PRRT and slower but still preserved excretion after everolimus. Histology showed no significant RDS differences between groups.ConclusionRenal scintigraphy is a highly sensitive tool for the detection of renal function impairment after a combination of everolimus and PRRT. Additional treatment with everolimus does not increase renal and haematological toxicity of PRRT with [177Lu]Lu-DOTA-TATE.

The Altered Metabolic Molecular Signatures Contribute to the RAD001 Resistance in Gastric Neuroendocrine Tumor.

Although the inhibition of mTOR is a promising treatment for neuroendocrine tumors, several questions are still open for cell specificity and resistance. With the newly characterized gastric neuroendocrine tumor mouse model (CEA424-SV40 T antigen transgenic mice), the anti-tumor efficiency of RAD001 (Everolimus) was tested both in vitro and in vivo. Tumor samples were analyzed for the expression of RNA by cDNA microarrays and also signaling pathways to get more details on the local surviving or selected cells. RAD001 treatment dramatically slowed down tumor growth and prolonged the animals' survival. This inhibitory effect has a preference for tumor cells since gastrointestinal hormone and neuroendocrine tumor specific markers were more reduced than the epithelial ones. While phosphorylation of p70S6K was almost completely blocked both in vitro and in vivo, the phosphorylation of 4EBP1 was only partially inhibited in vitro and unaffected in vivo. RAD001 treatment induced feedback activation of metabolism related pathways like PI(3)K–Akt–mTOR and MEK/ERK signalings. An induction of senescence as well as differential expression of genes responsible for metabolism was also observed, which highlighted the contribution of metabolic molecular signatures to the escape of the tumor cells from the treatment. Together, our data revealed efficient anti-tumor ability of RAD001 in a new gastric neuroendocrine tumor mouse model system and offered new insights into the clinical aspects of the incomplete elimination of tumor cells in patients treated.

Peptide Receptor Radionuclide Therapy for the Treatment of Pancreatic Neuroendocrine Tumors: Recent Insights.

Peptide receptor radionuclide therapy (PRRT) is a paradigm shifting approach to the treatment of neuroendocrine tumors. Although there are no prospective randomized trials directly studying PRRT in pancreatic neuroendocrine tumors (panNETs), there are data to suggest benefit in this patient population. Collectively, the data, consisting of two prospective and six retrospective studies, show a median PFS ranging from 20 to 39 months and a median OS ranging from 37 to 79 months. There are ongoing (and upcoming) prospective, randomized trials of PRRT in panNETs, which will provide further evidence to support this approach.

Risk factors for short recurrence-free survival after resection of pancreatic neuroendocrine tumor (PanNET) liver metastases: which patients should undergo resection?

Background: In the treatment of metastatic pancreatic neuroendocrine tumors (PanNETs), surgical resection is the first choice if curative resection is expected. However, most patients develop recurrence after resection of liver metastasis. Because one of the benefits of resection is to gain a tumor-free period for the patients, it is important to identify which patients achieve longer recurrence-free survival (RFS) by resection. In this study, the clinicopathological factors associated with RFS after resection of metastatic PanNETs in the liver were evaluated to identify the patient group that is suitable for resection.Methods: Consecutively diagnosed patients with PanNET liver metastasis with resection at our hospital from January 2000 to July 2019 were evaluated. A total of 26 metastatic PanNET patients with primary liver resections were evaluated. The median follow-up time was 48.3 months.Results: There were 18 NET recurrences of the total 26 resections, with a median RFS of 17.9 months. Independent risk factors for short RFS were a high Ki67 index (p = .009) and the number of resected tumors (p = .045). When the cut-off value for the Ki67 index was 5.0% and that for the number of resected tumors was 6, Ki67 > 5.0% tumors had shorter RFS (4.9 months vs. 38.2 months p = .006), and patients with tumors > = 7 tumors had shorter RFS (4.7 months vs. 27.5 months p = .001).Conclusions: These findings indicate that good candidates for resection of metastatic tumors of PanNETs could be patients with low Ki67 tumors and a small number of metastatic tumors.

Neuroendocrine tumors of the lung: clinicopathological and molecular features.

In 1970, neuroendocrine tumors of the lung were classified into three categories: typical carcinoid (TC), atypical carcinoid (AC), and small cell lung carcinoma (SCLC). The third edition of the World Health Organization (WHO) classification in 1999 defined large cell neuroendocrine carcinoma (LCNEC) as a variant of large cell carcinomas, whereas the fourth edition of the WHO classification redefined LCNEC as a neuroendocrine tumor. Currently, neuroendocrine tumors of the lung are classified into four main categories: TC, AC, LCNEC, and SCLC. Although the treatments for TC, AC, and SCLC have not changed remarkably, the treatment strategy for LCNEC is not yet established because of its reclassification from a variant of "large cell carcinoma" to a new category of "neuroendocrine tumor". In this review article, we discuss the pathological findings, biological behavior, and treatment of neuroendocrine tumors of the lung.

EANM Dosimetry Committee series on standard operational procedures for internal dosimetry for 131I mIBG treatment of neuroendocrine tumours

The purpose of the EANM Dosimetry Committee Series on “Standard Operational Procedures for Dosimetry” (SOP) is to provide advice to scientists and clinicians on how to perform patient-specific absorbed dose assessments. This SOP describes image and data acquisition parameters and dosimetry calculations to determine the absorbed doses delivered to whole-body, tumour and normal organs following a therapeutic administration of 131I mIBG for the treatment of neuroblastoma or adult neuroendocrine tumours. Recommendations are based on evidence in recent literature where available and on expert opinion within the community. This SOP is intended to promote standardisation of practice within the community and as such is based on the facilities and expertise that should be available to any centre able to perform specialised treatments with radiopharmaceuticals and patient-specific dosimetry. A clinical example is given to demonstrate the application of the absorbed dose calculations.

Genomic Profiles and Current Therapeutic Agents in Neuroendocrine Neoplasms.

Neuroendocrine neoplasms (NENs) are rare tumors that mainly occur in the gastroenteropancreatic (GEP) tract and lungs. According to the current World Health Organization classification for GEP-NENs and lung NENs, treatment strategies differ for well-differentiated and poorly differentiated subtypes. For well-differentiated GEP-NENs, somatostatin analogues (SSA), peptide receptor radionuclide therapy, and molecular-targeted agents are approved as the standards of care based on phase III clinical trial data. Promising data regarding the use of everolimus and the novel SSA pasireotide for lung NENs are emerging, though additional studies are required to confirm these effects. For poorly differentiated tumors from the GEP tract and lung, a platinum-based cytotoxic regimen is widely used. Genomic analysis has recently revealed a diverse pattern of primary organ-dependent mutations, and the use of traditional treatment strategies versus organ-specific strategies is currently under discussion. In addition, clinical trials for several molecular-targeted agents and immune checkpoint inhibitors for the treatment of NENs are currently underway. Accumulating genomic information is expected to contribute to the development of novel therapies for other organ-derived NENs or poorly differentiated neuroendocrine carcinomas (NECs). Here, we provide an updated overview of the current knowledge regarding genomic profiles and representative agents for NENs and highlight the prospects for future investigations.

Response and relapse rates after treatment with long-acting somatostatin analogs in multifocal or recurrent type-1 gastric carcinoids: A systematic review and meta-analysis.

Type-1 gastric neuroendocrine tumors represent a recurring disease and long-acting somatostatin analogs can inhibit both gastrin release and endocrine cell proliferation. The efficacy and timing of this treatment are still unclear. We performed a systematic review of the literature to clarify the role of somatostatin analog treatment in type-1 gastric neuroendocrine tumors. A computerized literature search was performed using relevant keywords to identify all the pertinent articles published in the last 15 years. Eight studies were included in this systematic review on somatostatin analogs in type-1 gastric neuroendocrine tumors. A complete response rate ranged from 25-100%. When only the six prospective studies were considered, no significant heterogeneity was observed, and the pooled cumulative complete response rate was 84.5% (confidence interval 73.8-92.8). Three studies evaluated the type-1 gastric neuroendocrine tumor recurrence, with a cumulative relapse rate of 30.2% (confidence interval 13.1-50.6) after 34 months. Somatostatin analogs, namely lanreotide and octreotide, have an excellent response rate, with a good safety profile in selected type-1 gastric neuroendocrine tumors, which cannot be safely managed by endoscopic follow-up or resection due to multiple or frequently recurring disease. After therapy discontinuation, the cumulative relapse rate observed after a median 34-month follow-up was relatively high (30.2%).

Somatostatin Analogs in Clinical Practice: A Review

Somatostatin analogs are an invaluable therapeutic option in the diagnosis and treatment of somatotropinomas, thyrotropinomas, and functioning and non-functioning gastroenteropancreatic neuroendocrine tumors. They should also be considered an effective and safe therapeutic alternative to corticotropinomas, gonadotropinomas, and prolactinomas resistant to dopamine agonists. Somatostatin analogs have also shown to be useful in the treatment of other endocrine diseases (congenital hyperinsulinism, Graves’ orbitopathy, diabetic retinopathy, diabetic macular edema), non-endocrine tumors (breast, colon, prostate, lung, and hepatocellular), and digestive diseases (chronic refractory diarrhea, hepatorenal polycystosis, gastrointestinal hemorrhage, dumping syndrome, and intestinal fistula).

Influence of pretreatment with everolimus or sunitinib on the subacute hematotoxicity of 177Lu-DOTATATE PRRT

Background: Peptide receptor radionuclide therapy (PRRT) is a validated treatment for somatostatin receptor overexpressing neuroendocrine tumors (NETs). The NETTER-1 trial demonstrated a pronounced positive effect on progression-free-survival compared to high dose somatostatin analogs (SSAs), with a strong tendency toward overall survival benefit. Our aim was to investigate the influence of pretreatment with everolimus and/or sunitinib on subacute hematotoxicity of PRRT. To assess the influence of prior treatment with everolimus/sunitinib might be of clinical relevance due to the link between short-term hematotoxicity and increased incidence of late hematotoxicity.Material and methods: Our single-center retrospective study enrolled all patients treated with 177Lu-DOTATATE PRRT (1–4 cycles of 7.4 GBq), between November 2013 and July 2018. Patients were assigned to two groups according to their pretreatment: no targeted agents (N = 41), or targeted agents (everolimus, sunitinib or both; N = 41). The end point was subacute hematotoxicity, defined as the nadir value between the first administration until 3 months after the last administration, using the CTCAE 4.03 classification. The impact of splenectomy was also explored.Results: Eighty percent of patients had a primary gastroenteropancreatic NET. No statistically significant differences in severe subacute hematotoxicity were seen in the pretreated group vs. the naive group for hemoglobin (grade 3/4: 12% vs. 22%), neither for leucocytes (grade 3/4: 10% vs. 7%), neutrophils (grade 3/4: 5% vs. 7%), lymphocytes (grade 3/4: 49% vs. 37%) and platelets (grade 3/4: 15% vs. 15%). Furthermore, we observed significantly lower toxicity for total white blood cells, lymphocytes and platelets in the subgroup that had splenectomy (N = 12). Limitations of this study include the potential bias in lack of use of targeted agents in patients more susceptible to toxicity, and the limited number of patients and events.Conclusions: In a patient cohort with NET pretreated with everolimus and/or sunitinib, we could not demonstrate a significant effect of prior/pretreatment with everolimus and/or sunitinib on the subacute hematotoxicity of 177Lu-DOTATATE PRRT.

Efficacy and safety of modified endoscopic mucosal resection forrectal neuroendocrine tumors: a meta-analysis.

Rectal neuroendocrine tumors are rare with good prognosis. Several endoscopic methods such as endoscopic polypectomy, endoscopic submucosal dissection (ESD), endoscopic mucosal resection (EMR), and modified endoscopic mucosal resection (m-EMR) are used in the treatment of rectal neuroendocrine tumors. Although m-EMR is derived from traditional EMR, it has not been widely used in clinical practice. In this study, we compared the efficacy and safety of EMR and m-EMR in the treatment of rectal neuroendocrine tumors by performing a meta-analysis. We searched PubMed, Web of Science, and EMBASE index up to the end of January 2017 for all published literature about EMR and m-EMR in the treatment of rectal neuroendocrine tumors. A total of 11 studies involving 811 patients were included. The pooled data suggested that there was a significantly higher rate of histologic complete resection and endoscopic complete resection among patients treated with m-EMR than those treated with EMR (histologic complete resection: OR = 0.23, 95 % CI = 0.10-0.51, p < 0.01; endoscopic complete resection: OR = 0.13, 95 % CI = 0.02-0.74, p = 0.02). The procedure time of EMR was longer than m-EMR (MD = 2.40, 95 % CI = 0.33-4.46, p = 0.02). There was a significantly higher rate of vertical margin involvement among patients treated with EMR than those treated with m-EMR; whereas, there was no significant difference of lateral margin involvement between the m-EMR and EMR groups (vertical margin involvement: OR = 5.00, 95 % CI = 2.67-9.33, p < 0.01; lateral margin involvement: OR = 1.44, 95 % CI = 0.48-4.37, p = 0.52). There was no significant difference in mean tumor size among patients treated with m-EMR versus those treated with EMR (MD = -0.30, 95 % CI = -0.75-0.14, p = 0.18); further, there was no significant difference in endoscopic mean sizes of the tumor and pathological mean sizes of the tumor between the m-EMR and EMR groups (endoscopic mean sizes of the tumor: MD = 0.20, 95 % CI = -0.44-0.84, p = 0.43; pathological mean sizes of the tumor: MD = 0.62, 95 % CI = -0.68-1.92, p = 0.05). No significant differences were detected among the treatment groups with regard to complications (bleeding: OR = 0.87, 95 % CI = 0.39-1.95, p = 0.73; complications (bleeding and perforation): OR = 0.87, 95 % CI = 0.40-1.88, p = 0.73). The efficacy of m-EMR are better than EMR among patients undergoing endoscopic treatment of rectal neuroendocrine tumors, and the safety of m-EMR is equivalent to EMR treatment.

Phase I dose-escalation trial of trifluridine/tipiracil (TAS-102) and temozolomide in the treatment of advanced neuroendocrine tumors.

615 Background: Systemic chemotherapy plays a role in treating neuroendocrine tumors. Trifluridine/tipiracil (FTD/TPI), known as TAS-102, is an antineoplastic agent that is non-cross resistant with 5-fluorouracil and capecitabine and that has a different toxicity profile. We are presenting results from a phase 1 portion of the study evaluating safety of FTD/TPI in combination with TMZ in patients in neuroendocrine tumors. Methods: Phase 1 portion to the study utilized “3+3” design to determine maximum tolerated doses (MTD) of FTD/TPI and TMZ when administered in combination. Patients with advanced NETs of any grade were eligible for participation. FTD/TPI was taken twice a day on days 1-5 and 8-12 and TMZ was taken daily on days 8-12 of a 28 day cycle. 3 dose levels (Lv) were evaluated. FTD/TPI was started at a goal dose of 35 mg/m2 twice daily. Three doses of TMZ were studied: 100, 150 and 200 mg/m2. Growth factor support was required during DLT evaluation period for all patients starting with the fourth subject on study. Results: Sixteen evaluable subjects (6 females, median age 64) enrolled in the phase 1 portion of the study (4 on Lv1, 6 on Lv2, 6 on Lv3). 3/16 had high-grade tumors, 8/16 had non-GI or unknown primary. No DLTs were observed on Lv1. One DLT was observed on Lv2 (grade 3 fatigue and inability to resume treatment) and 1 DLT on Lv3 (grade 4 thrombocytopenia). Overall the treatment was well tolerated. 7 subjects had grade ≥3 AEs at least possibly related to treatment, with neutropenia and lymphopenia being the most common. 4 subjects required dose reductions. 7 subjects remain on active treatment. 4 subjects discontinued treatment due to AEs and 1 due to clinical disease progression. Efficacy data is being collected and will be presented at the meeting. Conclusions: This study established MTD of FTD/TPI (35mg/m2 twice daily) and TMZ (200 mg/m2). This regimen is well tolerated. Enrollment into expansion cohort for patients with advanced Grade 1-2 pancreatic NETs is ongoing (NCT02943733). Clinical trial information: NCT02943733.

Long-term safety and efficacy of lanreotide treatment in Japanese patients with neuroendocrine tumors: Final analysis of a phase II open-label extension study.

621 Background: Lanreotide autogel 120mg (lanreotide) was approved in Japan in July 2017 for the treatment of gastroenteropancreatic neuroendocrine tumors (NETs) based on the results from an international phase III study (CLARINET study) and a Japanese single-arm phase II study. The CLARINET extension study demonstrated long-term efficacy and safety of lanreotide treatment; however, no Japanese patients were included in the study. To describe the safety and efficacy of long-term lanreotide treatment for NETs in Japanese patients, the final analysis of the Japanese phase II study and its extension study was performed. Methods: This open-label extension study (Study 002, JapicCTI-142698) enrolled patients who completed 48 weeks of treatment with 4-weekly subcutaneous lanreotide in an open-label phase II study in Japanese patients with NETs (Study 001, JapicCTI-132375). Study 002 had the same design as Study 001. Results: Of the 32 patients who started treatment with lanreotide, 17 completed Study 001 and enrolled in Study 002. In the safety analysis set (n = 17), 16 patients (94.1%) developed adverse events (AEs) that were considered drug-related (adverse drug reactions; ADRs), most commonly faeces pale (n = 5; 29.4%), injection site induration (n = 4; 23.5%), flatulence and diabetes mellitus (both n = 3; 17.6% each). No patient permanently discontinued lanreotide or died as a result of an AE. Four patients had a total of eight serious AEs; of these, two events of bile duct stones were considered to be ADRs. In the efficacy analysis set (n = 28), the median lanreotide exposure over Studies 001 and 002 was 52.7 weeks (range: 12–181 weeks). The best overall response was partial response in 2 patients (7.1%; reached at 60 and 108 weeks), stable disease in 20 patients (71.4%) and progressive disease in 6 patients (21.4%). Conclusions: No unexpected serious AEs developed during prolonged use of lanreotide. Lanreotide was effective over long-term treatment in Japanese patients with NETs. Clinical trial information: JapicCTI-132375, JapicCTI-142698.