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.

Real-World Treatment Patterns and Clinical Outcomes in Advanced Gastrointestinal Neuroendocrine Tumors (GI NET): A Multicenter Retrospective Chart Review Study.

BACKGROUND: We assessed treatment patterns and outcomes of patients with advanced gastrointestinal (GI) neuroendocrine tumors (NET) at four large tertiary referral centers in the U.S. PATIENTS AND METHODS: We performed a retrospective chart review of patients aged ≥18 years at advanced GI NET diagnosis, treated between July 2011 and December 2014. Index date was the histologically confirmed diagnosis date of locally advanced/metastatic GI NET. Data included baseline characteristics, treatment patterns, progression, death, and GI NET-related health care resource utilization from index date through last contact or death. Time-to-event analyses, including treatment discontinuation, progression, and overall survival (OS), were performed using Kaplan-Meier analysis. RESULTS: We identified 273 patients; 156 (57%) had primary ileum NET, and 174 (64%) had functional NET. First-line treatments included somatostatin analog (SSA) alone (89%) or in combination (2%), liver-directed therapy (LDT; 8%), and cytotoxic chemotherapy or interferon (2%). One hundred fifty-five patients continued with second-line therapy, including SSA alone (17%) or in combination (75%, with 3% combined with peptide receptor radionuclide therapy), LDT (4%), and other treatments (3%). Median time (months) to first-line discontinuation was 154.0 for SSAs and 3.8 for cytotoxic chemotherapy. Overall median time to investigator-assessed progression following treatment initiation was 30.3 months. Median OS (months) following first-line initiation was 151.8 for all patients and 178.9 for first-line SSA. CONCLUSION: Our study illustrates the common use of SSAs in both first-line and subsequent treatment of patients with GI NETs, as well as the relatively long survival durations and multiple additional treatments received by patients with this condition. Treatment pattern assessment at later times, following approval of newer treatments, is warranted. IMPLICATIONS FOR PRACTICE: This study, assessing treatment patterns over a period of up to 30 years, showed that SSAs, LDT, cytotoxic chemotherapy, and interferon are common treatments for advanced GI NETs. SSAs alone or in combination with other treatments were the most frequent therapy in first and subsequent lines. Patients in this study remained on SSAs long-term, with median treatment duration of 12.8 years in first line. Treatment patterns should be assessed beyond this study's time period, given recent U.S. Food and Drug Administration approvals for additional treatments for GI NET, which will likely be incorporated in the continuum of care of patients.

Treatment Patterns and Clinical Outcomes in Advanced Lung Neuroendocrine Tumors in Real-World Settings: A Multicenter Retrospective Chart Review Study.

BACKGROUND: Using data from four tertiary referral centers in the U.S., we assessed real-world treatment patterns and clinical outcomes of patients with advanced lung neuroendocrine tumors (NETs). SUBJECTS, MATERIALS, AND METHODS: We performed a retrospective chart review of adult patients with locally advanced/metastatic (typical/atypical) lung NETs treated between July 2011 and December 2014. Index date was histologically confirmed typical/atypical carcinoid tumor diagnosis date. Data included baseline characteristics, treatment patterns, progression, death, and lung NET-related health care resource use from index date through last contact/death. Time to treatment discontinuation and first progression, time from first to second progression, and overall survival (OS) were estimated using Kaplan-Meier analysis. RESULTS: We identified 83 patients; 19 (23%) had functional NET. First-line treatments included somatostatin analogs (SSAs) alone (56%) or in combination with other therapies (6%), cytotoxic chemotherapy (20%), external beam radiation therapy (EBRT) (9%), liver-directed therapy (LDT) (4%), and everolimus/other (5%). Sixty patients had second-line therapy including SSA alone (18%) or in combination (40%), cytotoxic chemotherapy (17%), everolimus (12%), LDT (7%), EBRT (3%), and other treatments (3%). Median time (months) to first-line discontinuation were as follows: SSAs, 43.3; cytotoxic chemotherapy, 3.6. Overall median time (months) to investigator-assessed progression following treatment initiation was 12.4. Median OS (months) following treatment initiation was 66.4 for all patients and 81.5 for patients receiving SSAs. CONCLUSION: SSAs, alone and in combination, are common treatments for advanced lung NETs. Patients have additional treatment options and relatively long survival compared with patients with other advanced cancers. Treatment pattern assessment following approval of newer treatments is needed. IMPLICATIONS FOR PRACTICE: Somatostatin analogs (SSAs), cytotoxic chemotherapy, EBRT, liver-directed therapy, and targeted therapies are common treatments for locally advanced/metastatic (typical/atypical) lung neuroendocrine tumors (NETs). SSAs alone or in combination with other treatment modalities were the most common first- and second-line therapy, followed by cytotoxic chemotherapy. Patients continued treatment with SSAs long-term with median treatment duration of 43 months. Median overall survival was 66 months following initiation of first-line therapy for all patients. Treatment pattern assessment beyond the time period of this study is needed given recent U.S. Food and Drug Administration approvals for additional treatments for lung NETs that will likely be incorporated in the treatment landscape.

A Phase II Trial of Ziv-Aflibercept in Patients With Advanced Pancreatic Neuroendocrine Tumors.

OBJECTIVES: Therapies for patients with advanced well-differentiated pancreatic neuroendocrine tumors (pNETs) are insufficient, with patients succumbing to disease despite recent treatment advances. Ziv-aflibercept is a fusion protein of portions of the vascular endothelial growth factor (VEGF) receptors 1 and 2, fused to the Fc portion of immunoglobulin G1, forming a VEGF trap. Perfusion computed tomography (CT) has previously defined hyperperfused neuroendocrine tumors, potentially predicting antiangiogenic benefit. METHODS: We performed a single-arm open-label study, using the Simon optimal 2-stage design, of 6 mg/kg ziv-aflibercept in patients with advanced pNETs. The primary end point was objective radiographic response, with a hierarchically tested co-primary end point of response prediction by baseline hyperperfusion, defined as blood volume greater than 5.25 mL/100 g and permeability surface area product greater than 25 mL/min per 100 g. RESULTS: Between July 3, 2014, and September 28, 2016, 21 patients were treated. Two patients (9.5%; 95% confidence interval, 1.1%-30.4%) demonstrated objective response, satisfying criteria to open the second stage, but the study was terminated for accrual. Perfusion CT could not be confirmed to predict radiographic response. Toxicities include 1 grade 5 gastrointestinal hemorrhage and 5 incidents of proteinuria requiring treatment discontinuation. CONCLUSIONS: Responses with ziv-aflibercept were consistent with other VEGF inhibitors in pNET, but perfusion CT could not be confirmed to predict outcome.

Risk factors associated with neuroendocrine tumors: A U.S.-based case-control study.

Carcinoids are rare neuroendocrine tumors (NETs); however, their incidence has significantly increased in the United States over the past 30 years. Little is known about the epidemiology of these cancers and their associated risk factors. We evaluated the independent effects of multiple risk factors associated with NETs arising at 5 disease sites (small intestine, stomach, lung, pancreas and rectum). We conducted a retrospective, hospital-based, case-control study involving 740 patients with histologically confirmed NETs and 924 healthy controls. Information on different risk factors was collected, and unconditional logistic regression analysis was used to determine adjusted odds ratios (AORs) and 95% confidence interval (CI) by the maximum-likelihood method. Smoking and alcohol consumption were not associated with NETs development in either men or women. However, a family history of cancer was a significant risk factor for all NETs. A long-term history of diabetes mellitus was a significant risk factor for gastric NETs (AOR = 5.6; 95% CI, 2.1-14.5), particularly in women (AOR = 8.4; 95% CI, 1.9-38.1). Diabetes modified the risk among women with a positive family history of cancer for the development of gastric NETs (AOR = 52.2; 95% CI, 5.5-491.5). Our results suggest that the risk of NETs may mostly explained by genetic factors. The increased risk of gastric NETs in women with both diabetes and a positive family history of cancer suggest that women may have a greater genetic susceptibility to NETs than men.

Family history of cancer and associated risk of developing neuroendocrine tumors: a case-control study.

BACKGROUND: Carcinoids are rare neuroendocrine tumors (NET). Familial clusterings of NETs are rarely reported, except for a small proportion associated with multiple endocrine neoplasia syndrome type 1. We evaluated the effect of positive family history of NET as well as other cancers on the development of NETs arising at five different locations. METHODS: We conducted a retrospective, hospital-based, case-control study involving 740 patients with histologically confirmed NETs and 924 healthy controls. Information on family history of cancer was collected, and unconditional logistic regression analysis was used to determine adjusted odds ratios (AOR) and 95% confidence intervals (CI). RESULTS: The authors observed a significant relationship between first-degree relatives with cancers and the development of NETs arising at the small intestine, stomach, lung, and pancreas; AORs (95% CI) were 1.6 (1.1-2.4), 2.5 (1.1-6.3), 2.6 (1.5-4.5), and 1.8 (1.1-3.1), respectively. A first-degree family history of esophageal cancer was significantly associated with pancreatic NETs; AOR, 5.6 (95% CI, 1.1-29.6). There was a 70% and 130% increased risk of developing small intestinal NETs among subjects with family histories of colorectal cancer and prostate cancer, respectively. Moreover, individuals with a family history of lung cancer had a 2-fold increase in risk of developing pulmonary NETs. CONCLUSIONS: Having a first-degree relative with any cancer in general, and NET in particular, was a risk factor for NETs. The elevated risk of developing NETs extended to individuals with a family history of other cancers (not NETs) among first-degree relatives. These results suggested that risk of NETs may be partially explained by genetic factors.

Improving the success rate of gluteal intramuscular injections.

OBJECTIVES: This study aimed to improve the success rate of gluteal intramuscular (IM) injection. METHODS: The outcomes of 328 intended gluteal IM injections in 115 patients receiving depot octreotide were evaluated using computed tomography performed in routine clinical practice. Patient-, nursing-, and technique-dependent factors were correlated with successful delivery of medication. Techniques associated with successful injection were taught to center nurses. RESULTS: At baseline, 52% of injections were successfully delivered (66% men, 36% women; P = 0.001). Factors associated with successful delivery included nurses' frequency of injections (P = 0.008), landmarks use to select injection site (P < 0.001), quick needle insertion (P < 0.001), and use of nonsyringe hand to compress injection site (P < 0.001). Patient-related factors included male sex (P < 0.001), lower body mass index (P < 0.001), and lower skin-to-muscle depth at injection site (P < 0.001). Techniques associated with successful injections were then taught to center nurses. After instruction, the success rate increased from 52% to 75% (P = 0.001). Importantly, improvements were observed in both men (66%-75%; P = 0.43) and women (38%-75%; P < 0.001). Successful injection was associated with better control of flushing among those with carcinoid syndrome (P = 0.005). CONCLUSIONS: Intended gluteal IM injections often are given into the subcutaneous space. Education in techniques associated with successful injections improves IM delivery rates.