Shifting Paradigms in the Pathophysiology and Treatment of Carcinoid Crisis.

Carcinoid crisis is a potentially fatal condition characterized by various symptoms, including hemodynamic instability, flushing, and diarrhea. The incidence of carcinoid crisis is unknown, in part due to inconsistency in definitions across studies. Triggers of carcinoid crisis include general anesthesia and surgical procedures, but drug-induced and spontaneous cases have also been reported. Patients with neuroendocrine tumors (NETs) and carcinoid syndrome are at risk for carcinoid crisis. The pathophysiology of carcinoid crisis has been attributed to secretion of bioactive substances, such as serotonin, histamine, bradykinin, and kallikrein by NETs. The somatostatin analog octreotide has been considered the standard of care for carcinoid crisis due to its inhibitory effect on hormone release and relatively fast resolution of carcinoid crisis symptoms in several case studies. However, octreotide's efficacy in the treatment of carcinoid crisis has been questioned. This is due to a lack of a common definition for carcinoid crisis, the heterogeneity in clinical presentation, the paucity of prospective studies assessing octreotide efficacy in carcinoid crisis, and the lack of understanding of the pathophysiology of carcinoid crisis. These issues challenge the classical physiologic model of carcinoid crisis and its common etiology with carcinoid syndrome and raise questions regarding the utility of somatostatin analogs in its treatment. As surgical procedures and invasive liver-directed therapies remain important treatment modalities in patients with NETs, the pathophysiology of carcinoid crisis, potential benefits of octreotide, and efficacy of alternative treatment modalities must be studied prospectively to develop an effective evidence-based treatment strategy for carcinoid crisis.

High-Contrast Detection of Somatostatin Receptor Subtype-2 for Fluorescence-Guided Surgery.

Dye design can influence the ability of fluorescently labeled imaging agents to generate tumor contrast and has become an area of significant interest in the field of fluorescence-guided surgery (FGS). Here, we show that the charge-balanced near-infrared fluorescent (NIRF) dye FNIR-Tag enhances the imaging properties of a fluorescently labeled somatostatin analogue. In vitro studies showed that the optimized fluorescent conjugate MMC(FNIR-Tag)-TOC bound primarily via somatostatin receptor subtype-2 (SSTR2), whereas its negatively charged counterpart with IRDye 800CW had higher off-target binding. NIRF imaging in cell line- and patient-derived xenograft models revealed markedly higher tumor contrast with MMC(FNIR-Tag)-TOC, which was attributed to increased tumor specificity. Ex vivo staining of surgical biospecimens from primary and metastatic tumors, as well as involved lymph nodes, demonstrated binding to human tumors. Finally, in an orthotopic tumor model, a simulated clinical workflow highlighted our unique ability to use standard preoperative nuclear imaging for selecting patients likely to benefit from SSTR2-targeted FGS. Our findings demonstrate the translational potential of MMC(FNIR-Tag)-TOC for intraoperative imaging and suggest broad utility for using FNIR-Tag in fluorescent probe development.

Fluorouracil, Doxorubicin with Streptozocin and Subsequent Therapies in Pancreatic Neuroendocrine Tumors.

We evaluated outcomes of treatment with 5-fluorouracil (5-FU), doxorubicin, and streptozocin (FAS) in well-differentiated pancreatic neuroendocrine tumors (PanNETs) and its impact on subsequent therapy (everolimus or temozolomide). Advanced PanNET patients treated at our center from 1992 to 2013 were retrospectively reviewed. Patients received bolus 5-FU (400 mg/m2), streptozocin (400 mg/m2) (both IV, days 1-5), and doxorubicin (40 mg/m2 IV, day 1) every 28 days. Overall response rate (ORR) was assessed using RECIST version 1.1. Of 243 eligible patients, 220 were evaluable for ORR, progression-free survival (PFS), and toxicity. Most (≥90%) had metastatic, nonfunctional PanNETs; 14% had prior therapy. ORR to FAS was 41% (95% confidence interval [CI]: 36-48%). Median follow-up was 61 months. Median PFS was 20 (95% CI: 15-23) months; median overall survival (OS) was 63 (95% CI: 60-71) months. Cox regression analyses suggested improvement with first-line versus subsequent lines of FAS therapy. Main adverse events ≥ grade 3 were neutropenia (10%) and nausea/vomiting (5.5%). Dose reductions were required in 32% of patients. Post-FAS everolimus (n = 108; 68% second line) had a median PFS of 10 (95% CI: 8-14) months. Post-FAS temozolomide (n = 60; 53% ≥ fourth line) had an ORR of 13% and median PFS of 5.2 (95% CI: 4-12) months. In this largest reported cohort of PanNETs treated with chemotherapy, FAS demonstrated activity without significant safety concerns. FAS did not appear to affect subsequent PFS with everolimus; this sequence is being evaluated prospectively. Responses were noted with subsequent temozolomide-based regimens although PFS was possibly limited by line of therapy.

Development of the Functional Assessment of Cancer Therapy-Carcinoid Syndrome Symptom Index.

OBJECTIVE: To develop a symptom-focused index to evaluate representative symptoms, treatment side effects, and emotional and functional well-being of patients with carcinoid syndrome (CS). METHODS: The development of the Functional Assessment of Cancer Therapy-Carcinoid Syndrome Symptom Index (FACT-CSI) followed US Food and Drug Administration guidelines for the development of patient-reported outcome (PRO) measures and involved the following: (a) literature review; (b) interviews with 14 CS patients; (c) interviews with 9 clinicians; and (d) instrument development involving input from a range of PRO measure development and CS experts. The resulting draft instrument underwent cognitive interviews with 7 CS patients. RESULTS: Forty-six CS sources were reviewed. Analysis of patient interviews produced 23 patient-reported symptoms. The most frequently endorsed physical symptoms were flushing, diarrhea, abdominal pain, fatigue, and food sensitivity/triggers. Seven priority CS emotional and functional themes were also identified by patients. Expert interviews revealed 12 unique priority symptoms - the most common being diarrhea, flushing, wheezing, edema, abdominal pain/cramping, fatigue, and 8 emotional and functional concerns. Through an iterative process of team and clinical collaborator meetings, data review, item reduction and measure revision, 24 items were selected for the draft symptom index representing symptoms, emotional concerns, global assessment of treatment side effects, and functional well-being. Cognitive interview results demonstrated strong content validity, including positive endorsement of item clarity (>86% across items), symptom relevance (>70% for most items), and overall measure content (86%). CONCLUSIONS: The FACT-CSI is a content-relevant, symptom-focused index reflecting the highest priority and clinically relevant symptoms and concerns of people with CS.

Incidence of Lymph Node Metastases and Impact of Radical Surgery for Duodenal Neuroendocrine Tumors.

BACKGROUND: Despite the high frequency of regional lymph node (LN) metastases associated with duodenal neuroendocrine tumors (D-NETs), the impact of these metastases on survival and the ideal extent of LN dissection are unknown. We used the National Cancer Database (NCDB) to investigate factors associated with survival, including LN metastases and types of surgery, in patients with D-NETs. METHODS: All patients with D-NETs recorded in the NCDB between 2004 and 2016 were included in the study. We applied a multivariate Cox regression model to assess the relationship between the clinicopathological characteristics and overall survival (OS). RESULTS: We identified 7613 patients, among whom 4886 local excisions and 233 radical surgeries had been performed. Among patients with at least 1 LN pathologically examined, the overall incidence of LN metastasis was 41.2%. For all patients, the median OS was 10.6 years. Univariate analyses showed equivalent OS in N0 and N1 groups (HR,0.83; 95% CI,0.64-1.09) and diminished OS in those who had undergone radical surgery compared with those who had undergone local resection (HR,1.35; 95% CI,1.02-1.8). In multivariable analyses, tumor size >50 mm and having more than 9 positive LNs were associated with diminished OS (HR,1.64 and 5.2; 95% CI,1.25-2.16 and 1.91-14.18), whereas the type of surgery did not remain in the model. CONCLUSION: Our study revealed that the presence of regional LN metastases and extent of surgery did not affect OS among patients with D-NETs. Radical resection to clear occult LN metastases for nonfunctioning, sporadic D-NETs was not supported by the current study.

Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials.

BACKGROUND: Metastatic high-grade neuroendocrine neoplasms (G3NENs) have limited treatment options after progression on platinum-based therapy. We addressed the role of Pembrolizumab in patients with previously treated metastatic G3NENs. METHODS: Two open-label, phase 2 studies enrolled patients with G3NEN (Ki-67 > 20%) to receive Pembrolizumab at 200 mg I.V. every 3 weeks. Radiographic evaluation was conducted every 9 weeks with overall response rate as the primary endpoint. RESULTS: Between November 2016 and May 2018, 29 patients (13 males/16 females) with G3NENs were enrolled. One patient (3.4%) had an objective response and an additional six patients (20.7%) had stable disease, resulting in a disease control rate of 24.1%. Disease control rate (DCR) at 18 weeks was 10.3% (3/29). There was no difference in the DCR, PFS or OS between the PD-L1-negative and -positive groups (p 0.56, 0.88 and 0.55, respectively). Pembrolizumab was well tolerated with only 9 grade 3, and no grade 4 events considered drug-related. CONCLUSIONS: Pembrolizumab can be safely administered to patients with G3NENs but has limited activity as a single agent. Successful completion of our trials suggest studies in G3NENs are feasible and present an unmet need. Further research to identify active combination therapies should be considered. CLINICAL TRIAL REGISTRATION NUMBER: NCT02939651 (10/20/2016).

Assessment of change in quality of life, carcinoid syndrome symptoms and healthcare resource utilization in patients with carcinoid syndrome.

BACKGROUND: There is limited information on changes over time in carcinoid syndrome (CS) symptoms and quality of life (QoL). This study assessed change in CS symptoms and QoL in patients treated with somatostatin analogs (SSAs) using the Functional Assessment of Cancer Therapy-General (FACT-G) and Patient-Reported Outcomes Measurement Information System (PROMIS)-29 instruments. METHODS: Patients ≥18 years old with CS symptoms and treated with SSA or non-SSA agents in the United States were recruited through a patient advocacy group to complete a two-part, anonymous online survey. Time point (T) 1 survey was fielded from July-October 2016, and T2 survey followed 6 months later. Clinical characteristics and SSA treatment duration were assessed at T1. FACT-G and PROMIS-29 QoL surveys were administered and CS symptoms were assessed at T1 and T2; proportions of patients not experiencing symptoms were compared by McNemar's test. Healthcare resource utilization (HRU) was assessed for the T1-T2 interval, and mean difference in QoL score from T1 to T2 by SSA duration was calculated. RESULTS: Of 117 participants at T1, 89 (76%) completed the T2 survey and served as the study sample; 11 (13%) were treated with SSAs for > 0-2 years, 37 (42%) for > 2-5 years, and 39 (45%) for > 5 years. A higher proportion of patients at T2 vs. T1 reported the following symptoms as not applicable: diarrhea (16% vs. 7%, p < 0.05), flushing (28% vs. 18%, p < 0.05), wheezing (78% vs 66%, p = 0.008). Most patients (89%) had a physical exam and a mean of 7.2 healthcare provider visits between T1 and T2. Patients treated with SSAs for ≤2 years had a mean positive change of 3.7 in their FACT-G total score between surveys, and 6.0 in an additional set of CS-specific questions. Patients receiving SSAs for > 2 years did not appear to associate with a clinically meaningful improvement in QoL score as assessed by FACT-G between T1 and T2; patients also had no clinically meaningful improvement as assessed by PROMIS-29. CONCLUSIONS: There may be clinically important improvement in QoL as measured by FACT-G in patients in earlier years of receiving SSA, which may not appear in later years of SSA treatment.

Discrepancies in endpoints between clinical trial protocols and clinical trial registration in randomized trials in oncology.

BACKGROUND: Clinical trials are an essential part of evidence-based medicine. Hence, to ensure transparency and accountability in these clinical trials, policies for registration have been framed with emphasis on mandatory submission of trial elements, specifically outcome measures. As these efforts evolve further, we sought to evaluate the current status of endpoint reporting in clinical trial registries. METHODS: We reviewed 71 oncology related randomized controlled trials published in three high impact journals. We compared primary (PEP) and non-primary endpoints (NPEP) between the clinical trial protocols of these trials and their corresponding registration in one of the 14 primary global clinical trial registries. A discrepancy was defined as the non-reporting or absence of an endpoint in either the protocol or registry. The primary endpoint was the rate of discrepancy between secondary endpoints in clinical trial protocols and clinical trial registries. RESULTS: Of the 71 clinical trials, a discrepancy in PEP was found in only 4 trials (6%). Secondary endpoint (SEP) differences were found in 45 (63%) trials. Among these 45 trials, 36 (80%) had SEPs that were planned in the protocol but not reported in the registry and 19 (42%) had SEPs with endpoints in the registry that were not found in the protocol. The total number of SEPs that were absent from the corresponding registry and protocol were 84 and 29, respectively. Of these endpoints, 48 (57%) and 9 (31%) were included in the published report of these trials. CONCLUSION: Although recent regulations and enhanced procedures have improved the number and quality of clinical trial registrations, inconsistencies regarding endpoint reporting still exist. Though further guidelines for the registration of clinical trials will help, greater efforts to provide a correct, easily accessible, and complete representation of planned endpoints are needed.

Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis: a population-based study.

BACKGROUND: Neuroendocrine tumours (NETs) can secrete bioactive amines into the bloodstream, causing carcinoid syndrome, with symptoms including flushing and diarrhoea. However, carcinoid syndrome frequency in the NET population has never been rigorously assessed, nor has its relationship to presenting clinicopathological characteristics. This analysis assessed the proportion of patients with NETs and carcinoid syndrome in the USA and associated clinical factors. METHODS: We identified patients (≥65 years of age) from the Surveillance, Epidemiology, and End Results-Medicare database, excluding those with pancreatic tumours or small-cell or large-cell lung cancer, as well as those without complete data. We assessed the incidence of patients with at least two insurance claims of flushing, diarrhoea, or carcinoid syndrome during the 3 months before and after NET diagnosis. We compared demographic and clinical characteristics between patients with and without carcinoid syndrome using χ2 tests. We used the Cochran-Armitage trend test to identify trends in carcinoid syndrome incidence and Cox regression to assess the relationship between carcinoid syndrome and survival. FINDINGS: Between April 1, 2000, and Dec 31, 2011, 9512 eligible patients were diagnosed with NETs, of whom 1786 (19%) had carcinoid syndrome. The number of patients with NETs and carcinoid syndrome increased from 50 (11%) of 465 patients in 2000 to 160 (19%) of 854 in 2011 (p<0·0001). The proportion of patients with carcinoid syndrome compared with those without did not differ significantly with respect to age at diagnosis (p=0·65), geographical region (p=0·054), or urban versus rural status (p=0·53). Patients with carcinoid syndrome were more frequently female than male (p=0·0003). Race was associated with a significant difference in the reported incidence of carcinoid syndrome (p<0·0001), as was tumour grade, stage, and primary tumour site (all p<0·0001). Patients with carcinoid syndrome had a shorter overall survival (median 5 years [95% CI 4·5-5·4]) than did those without carcinoid syndrome (5·6 years [5·4-5·9]; hazard ratio 1·102 [1·016-1·194]; p=0·019). Use of octreotide (p<0·0001) and chemotherapy (p=0·003) were more common in patients with carcinoid syndrome than in those without it, whereas surgery was used more frequently in patients without carcinoid syndrome (p=0·009); use of radiotherapy was not significantly associated with the presence of carcinoid syndrome at diagnosis (p=0·07). INTERPRETATION: This population-based analysis reveals that carcinoid syndrome is significantly associated with tumour grade, stage, and primary tumour site, and leads to shorter survival compared with those patients without carcinoid syndrome. An improved understanding of the heterogeneity of presenting symptoms among patients with NETs might permit more tailored assessment and management than at present and enable future research into the effect of carcinoid syndrome control on patient survival. FUNDING: Ipsen.

A tale of two tumors: treating pancreatic and extrapancreatic neuroendocrine tumors.

Despite their perceived rarity, gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rising in incidence and prevalence. The biology, natural history, and therapeutic options for GEP-NETs are heterogeneous: NETs arising in the pancreas can be distinguished from those arising elsewhere in the gastrointestinal tract, and therapy is dichotomized between these two groups. Somatostatin analogues are the mainstay of oncologic management of bowel NETs; everolimus, streptozocin, and sunitinib are approved to treat pancreatic NETs. There are significant differences in molecular genetics between pancreatic and extrapancreatic NETs, and studies are evaluating whether additional NET patients may benefit from targeted agents. We discuss the distinguishing features of these two groups of tumors, as well as the therapeutic implications of the distinction. We also examine the evolving therapeutic landscape and discuss the likelihood that treatment will be developed independently for pancreatic and extrapancreatic gastrointestinal NETs, with novel therapeutics effective for newly identified pathologically or molecularly defined subgroups.

Carcinoid Syndrome and Costs of Care During the First Year After Diagnosis of Neuroendocrine Tumors Among Elderly Patients.

BACKGROUND: Neuroendocrine tumors (NETs) can secrete hormonal peptides that lead to additional symptom burdens. However, it is largely unknown whether and to what extent the additional symptom burdens translate into higher costs of care. This study aimed to examine the cost pattern of elderly NET patients during the first year of diagnosis, taking into account of the carcinoid syndrome status. METHODS: We used Surveillance, Epidemiology, and End Results Medicare data to identify elderly NET patients diagnosed between January 2003 and December 2011. Patients who had at least two claims indicative of carcinoid syndrome during the 3 months before and after the NET diagnosis were considered to have carcinoid syndrome. We adopted a payer's perspective and quantified economic outcomes using the following three measures: (a) total Medicare reimbursement amount, (b) inpatient amount, and (c) outpatient amount. We used a generalized linear model (GLM) to examine the association between syndrome and costs. RESULTS: Our study cohort included 6,749 elderly NET well-differentiated and moderately differentiated patients. Of these patients, 5,633 (83%) were alive 1 year after diagnosis with continuous enrollment, and 1,116 (17%) died within 1 year. The multivariable GLM showed significant association between the syndrome and higher total, inpatient, and outpatient costs among the group who survived the whole year; the association was insignificant among the group who died within the first year of diagnosis. CONCLUSION: This population-based study showed that NET patients with carcinoid syndrome incurred higher costs of care especially among those who survived the first year of diagnosis. IMPLICATIONS FOR PRACTICE: This is the first population-based study that examines the health care costs associated with carcinoid syndrome among neuroendocrine tumor patients. Among patients alive throughout the first year, the unadjusted analyses showed that total median monthly costs were above $1,000 higher ($3,801 vs. $2,481) for patients with carcinoid syndrome compared with patients without. A significant association was found between carcinoid syndrome and higher total inpatient and outpatient costs among the group that survived the whole year even after controlling for clinical factors, treatment received, and demographics and neighborhood socioeconomic status; the association was insignificant among the group that died within the first year of diagnosis.

Is estrogen exposure a protective factor for pancreatic neuroendocrine tumours in female patients with multiple endocrine neoplasia syndrome type 1?

OBJECTIVE: Pancreatic neuroendocrine tumours (PNETs) are the most common cause of death in patients with multiple endocrine neoplasia type 1 (MEN1). Women have been shown to have improved survival, which may suggest a possible protective effect of female sex hormones. The aim of this study was to evaluate the relationship between estrogen exposure and PNET tumourigenesis, tumour growth and survival in female MEN1 patients with these tumours. DESIGN: We performed a retrospective chart review of the existing MEN1 database in our institution. Detailed information about female patients' menstrual and reproductive history, and PNET clinicopathologic characteristics was collected. Questionnaires regarding estrogen exposure were used to collect information that was missing in the database. PATIENTS: Of 293 confirmed MEN1 cases, 141 women met the inclusion criteria. MEASUREMENTS: We used measures of cumulative estrogen exposure time (CEET), parity, live birth pregnancies and bilateral oophorectomy to estimate estrogen exposure. RESULTS: There was no significant association between CEET and time to PNET diagnosis (hazard ratio = 0·966, P = 0·380). For the correlation between estrogen exposure and PNET type, size, numbers, distant metastasis, lymph node metastasis, lymphovascular invasion, AJCC (American Joint Committee on Cancer) stage and overall survival, only CEET was significantly correlated with PNET size (P = 0·043). CONCLUSIONS: In female patients with MEN1, estrogen exposure may inhibit PNET growth. A demonstrable protective effect against PNET tumourigenesis, tumour growth and survival of patients with these tumours may require a larger cohort.

[177Lu-DOTA0,Tyr3]-octreotate in the treatment of midgut neuroendocrine tumors.

Midgut neuroendocrine tumors (NETs) are relatively rare and remarkably heterogeneous. Although recent developments for pancreatic NETs have brought multiple new therapies to patients who need them, there has been little observed efficacy against midgut NETs. Peptide receptor radionuclide therapy utilizes somatostatin analogs conjugated to radioactive isotopes in order to deliver high doses of radiation directly to tumor cells, which express somatostatin receptors. Peptide receptor radionuclide therapy with [(177)Lu-DOTA(0),Tyr(3)]-octreotate (DOTATATE) has been reported and investigated for more than a decade, and the randomized controlled NETTER-1 study of this agent has recently been reported to show promising results. In this article, we will summarize and evaluate the rationale and existing clinical data for the activity of DOTATATE in midgut NETs, to give context for the interpretation of NETTER-1 results when they are fully available.

Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study.

BACKGROUND: Treatment options for advanced, well-differentiated neuroendocrine tumours (NETs) remain scarce. Pazopanib is an orally bioavailable, small molecule, multitargeted kinase inhibitor that inhibits VEGF receptors 1, 2, and 3. We did a study of the efficacy of pazopanib with depot octreotide in patients with advanced NETs. METHODS: We did a parallel cohort study of patients with metastatic or locally advanced grade 1-2 carcinoid tumours or pancreatic NETs, by use of a single-group, two-stage design. Patients received pazopanib 800 mg orally once per day and octreotide at their preprotocol dosage. The primary endpoint was the proportion of patients achieving an objective response, as assessed by investigators, by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00454363, and was completed in March, 2014. FINDINGS: Between April 12, 2007, and July 2, 2009, we enrolled 52 patients, including 32 individuals with pancreatic NETs and 20 individuals with carcinoid tumours. Seven (21·9%, 95% CI 11·0-38·8) of 32 patients with pancreatic NETs achieved an objective response. We detected no responses in the first stage of the cohort with carcinoid tumours, and we terminated accrual at 20 patients. Toxic effects included one patient with grade 4 hypertriglyceridaemia and one with grade 4 thrombosis, with the most common grade three events being aminotransferase increases and neutropenia, each of which happened in 3 patients. In all 52 patients, the most frequently observed toxic effects were fatigue (39 [75%]), nausea (33 [63%]), diarrhoea (33 [63%]), and hypertension (28 [54%]). INTERPRETATION: Treatment with pazopanib is associated with tumour response for patients with pancreatic NETs, but not for carcinoid tumours; a randomised controlled phase 3 study to assess pazopanib in advanced pancreatic NETs is warranted. FUNDING: US National Cancer Institute of the National Institutes of Health.

A phase I study of imatinib, dacarbazine, and capecitabine in advanced endocrine cancers.

BACKGROUND: Patients with advanced endocrine cancers, such as adrenocortical carcinoma and medullary thyroid carcinoma, have few well-validated therapeutic options. Pre-clinical studies have suggested potential activity of imatinib in these tumors. We therefore sought to establish a safe, novel treatment regimen combining imatinib with cytotoxic chemotherapy for future study in endocrine cancers. METHODS: A standard 3 + 3 dose-escalation design was used with a 21-day cycle, including imatinib on days 1-21, dacarbazine on days 1-3, and capecitabine on days 1-14. RESULTS: Twenty patients were treated. The most frequent toxicities were edema and fatigue, with dose-limiting fatigue and dyspnea. The recommended phase II regimen is dacarbazine 250 mg/m2 daily on day 1-3, capecitabine 500 mg/m2 twice daily on days 1-14, and imatinib 300 mg daily on days 1-21 of a 21-day cycle. Interestingly, responses were seen in patients with adrenocortical carcinoma, with 1 of 6 patients experiencing a partial response and a second experiencing a minor response, with progression-free survival of 8.8 and 6.4 months, respectively. CONCLUSIONS: The regimen of imatinib, dacarbazine, and capecitabine is well-tolerated. It may have some activity in adrenocortical carcinoma, and further study of this combination or its components may be beneficial for this disease with limited treatment options. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00354523, registered July 18, 2006.

Resectable, borderline resectable, and locally advanced pancreatic cancer: what does it matter?

Pancreatic adenocarcinoma represents a significant cause of morbidity and mortality in the modern era. Despite advances in the management of unresectable and advanced disease, the only potential avenue for cure at this time is resection. As our radiographic and surgical techniques have improved, we are better able to select patients who are the best candidates for a margin-negative resection, with or without the use of preoperative therapy. There is an emerging consensus on the definition of borderline resectable pancreatic cancer, but much work still needs to be done given the heterogeneous patient population, intervention, and outcome metrics used in previous retrospective and prospective studies. When designing future prospective trials of novel preoperative approaches, standardization of the stage of disease for the study population is essential to allow for accurate interpretation of study results. Ultimately, to make significant progress in localized pancreatic cancer, we urgently need effective novel therapeutic agents used in an optimal sequence with surgery.

Transformation of G1-G2 neuroendocrine tumors to neuroendocrine carcinomas following peptide receptor radionuclide therapy.

We observed that some patients with well-differentiated neuroendocrine tumors (NET) who received peptide receptor radionuclide therapy (PRRT) with Lutetium-177 (177Lu) DOTATATE developed rapid disease progression with biopsy-proven histologic transformation to neuroendocrine carcinoma (NEC), an outcome that has not been previously described. Therefore, we conducted a retrospective review of all patients with well-differentiated G1-G2 NET who received at least one cycle of PRRT with (177Lu) DOTATATE at our center from January 2019 to December 2020. Among 152 patients, we identified 7 patients whose NET transformed to NEC. Median time from start of PRRT to transformation was 8.2 months (range: 2.6-14.4 months). All patients whose tumors underwent transformation had pancreatic tail as the primary site and had prior chemotherapy with temozolomide. No differences in the incidence of transformation were observed according to gender, race, original tumor grade, or number of prior therapies. Six patients received treatment with platinum and etoposide after transformation with two patients having partial response as best response. All patients with transformation died from progressive disease with median overall survival (OS) after transformation of 3.3 months (95% CI 2.1-4.4). Molecular testing of transformed NEC identified mutation(s) in TP53 and/or ATM in all cases. Transformation of NET to NEC following PRRT is associated with aggressive course and dismal prognosis. Patients with pancreatic tail as the primary site who had prior therapy with temozolomide may be at a higher risk. Further investigation is necessary to determine the best treatment sequence in this patient population.

Somatostatin Receptor Subtype-2 Targeting System for Specific Delivery of Temozolomide.

Temozolomide (TMZ) is a DNA alkylating agent that produces objective responses in patients with neuroendocrine tumors (NETs) when the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is inactivated. At high doses, TMZ therapy exhausts MGMT activity but also produces dose-limiting toxicities. To reduce off-target effects, we converted the clinically approved radiotracer 68Ga-DOTA-TOC into a peptide-drug conjugate (PDC) for targeted delivery of TMZ to somatostatin receptor subtype-2 (SSTR2)-positive tumor cells. We used an integrated radiolabeling strategy for direct quantitative assessment of receptor binding, pharmacokinetics, and tissue biodistribution. In vitro studies revealed selective binding to SSTR2-positive cells with high affinity (5.98 ± 0.96 nmol/L), internalization, receptor-dependent DNA damage, cytotoxicity, and MGMT depletion. Imaging and biodistribution analysis showed preferential accumulation of the PDC in receptor-positive tumors and high renal clearance. This study identified a trackable SSTR2-targeting system for TMZ delivery and utilizes a modular design that could be broadly applied in PDC development.

Efficacy and Safety of Atezolizumab and Bevacizumab in Appendiceal Adenocarcinoma.

PURPOSE: Appendiceal adenocarcinoma (AA) remains an orphan disease with limited treatment options for patients unable to undergo surgical resection. Evidence supporting the efficacy of combined VEGF and PD-1 inhibition in other tumor types provided a compelling rationale for investigating this combination in AA, where immune checkpoint inhibitors have not been explored previously. EXPERIMENTAL DESIGN: We conducted a prospective, single-arm phase II study evaluating efficacy and safety of atezolizumab in conjunction with bevacizumab (Atezo+Bev) in advanced, unresectable AA. RESULTS: Patients treated with the Atezo+Bev combination had 100% disease control rate (1 partial response, 15 stable disease) with progression-free survival (PFS) of 18.3 months and overall survival not-yet-reached with median duration of follow-up of 40 months. These survival intervals were significantly longer relative to a clinically and molecularly matched synthetic control cohort treated with cytotoxic chemotherapy designed for colorectal cancer (PFS of 4.4 months, P = 0.041). CONCLUSIONS: In light of recent data demonstrating a lack of efficacy of 5-fluorouracil-based chemotherapy, Atezo+Bev is a promising treatment option for patients with low-grade unresectable AA; further study is warranted. SIGNIFICANCE: AA remains an orphan disease with limited systemic therapy options for patients who are not candidates for surgical resection. These data suggest activity from combined VEGF and PD-L1 inhibition that warrants further study.