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Background Although an increasing number of treatments have become available for patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP‐NETs), there remains little consensus on treatment sequence and its impact on health care resource use (HRU). We sought to describe treatment patterns and HRU, in a cohort of patients with metastatic GEP‐NETs treated at a tertiary referral center in the U.S. Materials and Methods We identified patients with a well‐differentiated, metastatic GEP‐NET evaluated at Dana‐Farber Cancer Institute between July 2003 and May 2015. For these patients, we describe the sequence of treatment regimens received for their disease, together with associated HRU. Results We identified 682 patients with advanced GEP‐NETs. Of these patients, 597 (87.0%) initiated ≥1 treatment over the follow‐up period. The mean age at diagnosis was 58.5 years, 50.2% were men, and 94.0% were white. A total of 83.1% initiated a somatostatin analog (SSA) as their first‐line treatment, with 55% and 31% of patients continuing with second‐ and third‐line therapies. A total of 31.2% of patients with SSAs underwent dose escalation to above standard dose. In this setting, patients with pancreatic neuroendocrine tumors were more commonly treated with cytotoxic regimens than other NET tumor types and also had higher HRU. Conclusion Our study suggests that, at a tertiary referral center, patients with advanced NETs commonly received multiple courses of treatments. Our data suggest a clear preference for use of SSAs as a first‐line treatment for patients with advanced NETs, with SSAs commonly escalated and continued throughout the course of treatment in combination with other regimens. Implications for Practice The current study demonstrates the common use of somatostatin analog as a first‐line therapy for patients with advanced gastroenteropancreatic neuroendocrine tumors as well as the incorporation of multiple different treatment regimens in the treatment course of patients with this disease., This article focuses on treatment of gastroenteropancreatic neuroendocrine tumors (GEP‐NETs) and health resource use among patients with advanced GEP‐NETs treated at a tertiary referral center in the United States.

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.

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.

Background Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome. Subjects, materials, and methods Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long-term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated. Results Mean (median; range) duration of exposure and follow-up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient-years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4. Conclusion Based on long-term safety data, telotristat ethyl is well tolerated and has a favorable long-term safety profile in patients with carcinoid syndrome. Implications for practice Carcinoid syndrome can cause persistent diarrhea, even in patients treated with somatostatin analogs. Across five clinical trials in patients with carcinoid syndrome, telotristat ethyl has been well tolerated and efficacious, providing clinicians with a new approach to help control carcinoid syndrome diarrhea, in addition to somatostatin analog therapy. By reducing the stool frequency in patients with carcinoid syndrome whose diarrhea is refractory to anticholinergics, such as loperamide and atropine/diphenoxylate, and somatostatin analog dose escalation, improvement in quality of life becomes an achievable goal.

Background. Octreotide LAR is used in patients for control of carcinoid syndrome (CS) and other symptoms of hormone hypersecretion. The aim of this study was to examine reasons for octreotide LAR dose escalation and observe CS symptom improvement in patients with neuroendocrine tumors (NETs) who underwent octreotide LAR dose escalation at three cancer referral centers. Methods. Medical records for patients with diagnosis of carcinoid or pancreatic NET who had received one dose or more of octreotide LAR above 30 mg every 4 weeks from 2000 to 2012 were reviewed. Reasons for dose escalation and symptomatic outcomes were abstracted for each patient 3 months prior to and up to 12 months following the dose escalation. Results. Of the evaluated 239 NET patients, 53% were male, mean age at first dose escalation was 60 years (standard deviation [SD]: 11 years), and mean time from octreotide LAR initiation to first dose escalation was 1.7 years (SD: 2.0 years). The primary reasons reported for dose escalation were carcinoid or hormonal syndrome (62%) or radiographic progression (28%). The most common dose changes at the first dose escalation were 40 mg every 4 weeks (71%) and 60 mg every 4 weeks (18%). Of 90 patients in whom flushing was reported prior to first dose escalation, 73 (81%) were reported to have experienced improvement or resolution of their symptoms following the dose escalation. Of 107 patients who were reported to have experienced diarrhea before the first dose escalation, 85 (79%) were reported to have experienced improvement or resolution after first dose escalation. Conclusion. The goal of improved symptom control is a common reason for dose escalation of octreotide LAR. This study suggests that escalation to above the standard dose of octreotide LAR of 30 mg every 4 weeks may result in improved CS symptom control.

In the past 3 years, we have witnessed the completion of four randomized phase III studies in neuroendocrine tumors and the approval of two new drugs, everolimus and sunitinib, for the treatment of patients with well-differentiated pancreatic neuroendocrine tumors. These studies demonstrate a shift from case series and single-arm studies toward prospective, randomized controlled clinical trials and evidence-based therapy in the neuroendocrine tumor field. However, the clinical development of these agents also highlights the potential challenges awaiting other new drugs in this area. Herein, we discuss the strengths and weaknesses of the most recent phase II and phase III neuroendocrine tumor studies and discuss how limitations inherent in current trial design can lead to potential pitfalls. We also discuss how trial design can be improved, with the hope of increasing the number of drugs successfully developed to treat patients with neuroendocrine tumors.

Treatments for advanced neuroendocrine tumors were, until recently, rather limited. Salvage surgery and liver-directed therapy both have relatively limited impact, and systemic cytotoxic chemotherapy has minimal efficacy. In the absence of other effective treatments, somatostatin analogs have been used for years to control disease and neuroendocrine symptoms, without cytotoxic intent. Advances in targeted therapy for neuroendocrine tumors have opened several potentially new treatment paradigms in the management of these otherwise relatively drug-resistant neoplasms. Promising results have emerged from studies evaluating radiolabeled somatostatin analogs and inhibitors of the vascular endothelial growth factor and mammalian target of rapamycin pathways. This article reviews several of the more encouraging developments in this field.

The close relationship between poorly differentiated NETs (PDNETs) and well or intermediately differentiated neuroendocrine tumors (NETs) is evidenced by the World Health Organization criteria for distinguishing these groups and by recognition by the National Comprehensive Cancer Network that octreotide therapy should be considered in some PDNETs. Based on the possible derivation from similar normal cells and the somewhat arbitrary World Health Organization distinction, particularly between intermediate and poorly differentiated NETs, it seems reasonable that future studies of targeted agents in the treatment of NETs should evaluate patients with PDNETs as well.

Purpose Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and are approved for the treatment of patients with KRAS wild-type metastatic colorectal cancer. There are no data that describe the activity of panitumumab in patients with progressive disease on cetuximab. We performed a single-arm phase II trial of panitumumab in patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab. Patients and Methods We used a two-stage study design to treat patients with panitumumab at 6 mg/kg every 14 days (cycle length = 28 days). Treatment was continued until disease progression, death, inability to tolerate panitumumab, or study withdrawal. The primary endpoint was response rate; secondary endpoints included progression-free survival and overall survival. Twenty patients were treated in the first stage, with plans to treat an additional twelve pa tients if there was at least one objective response. We collected blood samples at baseline and prior to cycles 2 and 3 to evaluate for the presence of anti-cetuximab and anti-panitumumab antibodies. Results We treated twenty patients for a median of two cycles (range 1–4). No patients responded, and 45% had a best response of stable disease (no progression for at least two cycles). Median progression-free survival was 1.7 months and median overall survival was 5.2 months. Panitumumab was well tolerated. Thirteen patients (65%) had grade 1–2 dry skin or rash, and three patients had treatment-related grade 3 toxicities (one each with hyperglycemia, hyperbilirubinemia, and hypokalemia). No patients had detectable anti-cetuximab antibodies at any time point; one patient developed anti-panitumumab antibodies. Conclusions Panitumumab has minimal benefit in patients with KRAS wild-type metastatic colorectal cancer that has progressed on prior cetuximab. Discussion Both cetuximab and panitumumab competitively inhibit ligand binding to EGFR, thereby promoting receptor internalization and blocking receptor-mediated signaling. Although the two agents have never been compared directly in a randomized clinical trial, they produce similar response rates when used alone as well as in combination with cytotoxic agents. Cetuximab is a chimeric antibody with approximately 30% murine protein, while panitumumab is a fully human monoclonal antibody. Correspondingly, rates of severe hypersensitivity reactions are somewhat increased with cetuximab (3%) compared to panitumumab (1%). However, the potential efficacy of panitumumab in patients who have developed disease progression on cetuximab has been an open question. Metges et al. (PANERB trial) prospectively treated 32 KRAS wild-type metastatic colorectal cancer patients with cetuximab and irinotecan followed by panitumumab monotherapy after progression. Remarkably, the authors reported an objective response rate of 22% to panitumumab, including a disease control rate (objective response plus stable disease) of 73% in 11 patients who had previously responded to cetuximab and irinotecan. In contrast, we found no responders and a stable disease rate of 45% with a median duration of only 1.7 months in our trial of 20 patients. Moreover, no patients had detectable anticetuximab antibodies at baseline. It is not clear to what extent the PANERB trial included patients without objective disease progression on cetuximab or for whom cetuximab-containing regimens may have been ceased due to toxicity in the absence of disease progression. In both circumstances, retreatment with panitumumab may be expected to demonstrate some degree of clinical activity. In our study, disease progression after at least 4 weeks of cetuximab documented radiographically or by increased carcinoembryonic antigen (CEA) levels was required for inclusion in order to ensure that the study population demonstrated unequivocal evidence of progression on cetuximab. While it remains possible that a small subset of patients may benefit from panitumumab after progression on cetuximab, our results suggest that this approach should not be adopted until predictive biomarkers for panitumumab response in this setting have been discovered and validated. Until then, patients who develop progression on cetuximab should be enrolled in trials of novel agents.

Background. The median survival time for patients with unresectable hepatocellular carcinoma (HCC) is Methods. Nineteen patients with measurable, unresectable, or metastatic HCC were enrolled. All patients were required to have adequate major organ function and performance status. The treatment consisted of weekly epirubicin at a dose of 20 mg/m2 administered i.v. and daily thalidomide at a dose of 200 mg orally given as a 3-weeks-on/1-week-off schedule. Intrapatient dose escalation of thalidomide was allowed every 2 weeks up to 800 mg daily as long as tolerated. Physical examinations, toxicity assessments, and serum chemistry analyses were performed weekly, and tumor measurements were conducted every 8 weeks. Results. All 19 patients enrolled into the study were evaluable for toxicity assessment and 17 patients were evaluable for response assessment. A total of 71 cycles of chemotherapy was administered, with a median of two cycles administered to each patient (range 1–14). No complete or partial responses were observed. Seven patients (41%) had stable disease, with a median duration of 6 months (range 5–14). The median survival time for all 19 patients was 196 days (95% confidence interval 93–302). The treatment was generally well tolerated. Treatment-related toxicities included constipation (grade 3, 5%; grade 2, 37%; grade 1, 21%), fatigue (grade 3, 5%; grade 2, 42%), and sensory neuropathy (grade 2, 5%; grade 1, 32%). Four patients required dose reductions of thalidomide due to treatment-related toxicities, and the median tolerated dose of thalidomide was 200 mg daily. Conclusions. The combination of epirubicin and thalidomide was well tolerated when administered in the schedule used in this study. This regimen has limited activity in HCC, with some patients achieving stable disease and clinical benefit. There is a need for defining more effective systemic therapies for HCC.