Assessment of Clinical Response Following Atezolizumab and Bevacizumab Treatment in Patients With Neuroendocrine Tumors: A Nonrandomized Clinical Trial.

Importance: Therapies for patients with advanced well-differentiated neuroendocrine tumors (NETs) have expanded but remain inadequate, with patients dying of disease despite recent advances in NET therapy. While patients with other cancers have seen long-term disease control and tumor regression with the application of immunotherapies, initial prospective studies of single-agent programmed cell death 1 inhibitors in NET have been disappointing. Objective: To evaluate the response rate following treatment with the combination of the vascular endothelial growth factor inhibitor bevacizumab with the programmed cell death 1 ligand 1 inhibitor atezolizumab in patients with advanced NETs. Design, Setting, and Participants: This single-arm, open-label nonrandomized clinical study in patients with rare cancers included 40 patients with advanced, progressive grade 1 to 2 NETs (20 with pancreatic NETs [pNETs] and 20 with extrapancreatic NETs [epNETs]) treated at a tertiary care referral cancer center between March 31, 2017, and February 19, 2019. Data were analyzed from June to September 2021. Interventions: Patients received intravenous bevacizumab and atezolizumab at standard doses every 3 weeks until progression, death, or withdrawal. Main Outcomes and Measures: The primary end point was objective radiographic response using Response Evaluation Criteria in Solid Tumors, version 1.1, with progression-free survival (PFS) as a key secondary end point. Results: Following treatment of the 40 study patients with bevacizumab and atezolizumab, objective response was observed in 4 patients with pNETs (20%; 95% CI, 5.7%-43.7%) and 3 patients with epNETs (15%; 95% CI, 3.2%-37.9%). The PFS was 14.9 (95% CI, 4.4-32.0) months and 14.2 (95% CI, 10.2-19.6) months in these cohorts, respectively. Conclusions and Relevance: In this nonrandomized clinical trial, findings suggest that clinical responses in patients with NET may follow treatment with the combination of bevacizumab and atezolizumab, with a PFS consistent with effective therapies. Trial Registration: ClinicalTrials.gov Identifier: NCT03074513.

A Systematic Review of Economic and Quality-of-Life Research in Carcinoid Syndrome.

BACKGROUND: To date, the economic burden and patient-reported outcomes associated with carcinoid syndrome (CS) in patients with neuroendocrine tumor (NET) remain largely unknown. OBJECTIVES: The objective of this study was to perform a systematic review of economic and quality-of-life (QOL) studies related to the treatment of CS. METHODS: Articles included in the review were extracted from PubMed, Embase, and the Cochrane Library. Studies had to be in English and published between 1 January 2000 and 2 July 2020. Other study eligibility criteria included patients with NET with CS receiving treatment for CS, study outcomes of cost or QOL, and clinical trials or population-based studies using claims or other secondary databases. The interventions included somatostatin analogs, telotristat ethyl, or other treatment for CS. To evaluate the quality and bias of the included studies, the 24-item CHEERS and 10-item Gill and Feinstein checklists were used. We report a narrative synthesis of the findings from the selected studies. RESULTS: A total of 12 economic and 12 QOL studies met the inclusion criteria and were included for review. Patients with uncontrolled CS symptoms had 23-92% higher costs than those with controlled CS; mostly, ambulatory/outpatient services were the primary drivers of the costs. The use of telotristat ethyl may be cost effective if the societal willingness to pay is as high as $US150,000 per quality-adjusted life-year in the USA. Of the 12 QOL papers, only three case-control studies assessed QOL at baseline and more than two follow-up time points. Seven studies evaluated QOL at two or more time points but lacked a control group, obscuring direct intervention effects on patients' well-being. CONCLUSIONS: We observed wide variations in the reviewed studies evaluating the economic burden and patient-reported outcomes, in terms of cost and QOL, of patients with CS. Although QOL is consistently impaired and costs are consistently increased by CS, the numbers of both cost and QOL studies among this patient population remain sparse, and many of the existing studies indicated an important need for quality improvement.

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.

Racial Differences in the Incidence and Survival of Patients With Neuroendocrine Tumors.

OBJECTIVES: The incidence of neuroendocrine tumors (NETs) has been steadily increasing. Racial differences in the incidence and survival are mostly unknown. This study examines the racial differences and the underlying causes. METHODS: We conducted a retrospective, population-based study using datasets from Surveillance, Epidemiology, and End Results (SEER) cancer registry and SEER data linked with Medicare claims (SEER-Medicare). We examined the incidence rates and the effects of patient demographics, clinical characteristics, and socioeconomic factors on survival. RESULTS: Of the 15,786 and 1731 cases from SEER and SEER-Medicare, 1991 and 163 were blacks, respectively. We found that blacks had higher NET incidence for all stages, with the largest difference noted in the local stage (4.3 vs 2.6 per 100,000 in whites). We found worse survival for distant-stage black patients, although they more often had clinical factors typically associated with better prognosis in NETs. However, they were also found to have significant unfavorable differences in socioeconomic and sociodemographic factors. CONCLUSIONS: Blacks have higher incidence of NETs and worse survival compared with other races, especially whites. The influences of neighborhood socioeconomic, sociodemographic, and marital status suggest that social determinants, support mechanisms, and access to health care may be contributing factors.

Costs of Cancer Care for Elderly Patients with Neuroendocrine Tumors.

BACKGROUND: The incidence and prevalence of neuroendocrine tumors (NETs) have been steadily rising. NETs can arise in various parts of the body and have distinct pathogenesis, clinical manifestations, treatment, and survival compared to other neoplasms. The magnitude of the economic burden of NETs is largely unknown. This study aimed to estimate the cost of illness for NETs among elderly patients based on a large amount of observational data. METHODS: We estimated the direct medical costs by phase of care using the Surveillance, Epidemiology, and End Results-Medicare data, including claims from January 1, 2002 through to December 31, 2012. Patients' care was categorized into three phases: initial phase (first year after diagnosis), terminal phase (last year of life), and continuing phase (the period between). We estimated the cost of illness by calculating the difference in medical costs between NET patients and a matched sample from a non-cancer control group. RESULTS: Our study sample included 8409 elderly NET patients in the initial phase, 9218 patients in the continuing phase, and 7897 in the terminal phase. The mean cost of care for the initial phase was $46,462 in 2016 US dollars; mean cost of care for the terminal phase with a cancer-related death was $122,702; while the mean cost of care for the continuing phase was $10,457. The mean 5-year cost was $87,079. CONCLUSIONS: This population-based study showed that NET patients had substantial continuing phase costs and 5-year costs. Among elderly NET patients, those with pancreas as the primary cancer site had the highest costs.

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.

Octreotide long-acting repeatable use among elderly patients with carcinoid syndrome and survival outcomes: a population-based analysis.

BACKGROUND: Octreotide long-acting repeatable (LAR) is indicated for the treatment of carcinoid syndrome and diarrhea related to VIPoma, and may delay tumor growth in patients with neuroendocrine tumors (NETs). To the authors' knowledge, the pattern of octreotide LAR use in clinical practice and its impact on survival outcomes has not been well documented. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, the authors identified patients with NET aged ≥ 65 years who were diagnosed between July 1999 and December 2007. Patients with US Food and Drug Administration-approved indications for octreotide LAR were identified from Medicare claims. Multivariate logistic regression was performed to ascertain factors associated with octreotide LAR use, whereas the Cox proportional hazards model was used to evaluate the impact of octreotide LAR on survival. RESULTS: Among those with Food and Drug Administration-approved indications, 245 of 4848 patients with distant-stage disease (51%) and 81 of 807 patients with local/regional disease (10%) initiated treatment with octreotide LAR within 6 months of diagnosis. Multivariate logistic regression indicated that among those with distant-stage disease, older age (≥ 80 years vs 65-69 years) (odds ratio [OR], 0.43; 95% confidence interval [95% CI], 0.23-0.81), female sex (OR, 0.62; 95% CI, 0.40-0.97), and living in the South (vs Northeast) (OR, 0.36; 95% CI, 0.18-0.72) were associated with a lower likelihood of using octreotide LAR. The multivariate proportional hazards model showed that octreotide LAR provided a significant 5-year survival benefit for patients with distant-stage disease (hazards ratio, 0.61; P ≤ .001), whereas this survival benefit was not shown for the patients with local/regional stage (hazards ratio, 0.88; P = .563). CONCLUSIONS: The results of this retrospective study suggest a possible survival benefit for the use of octreotide LAR in elderly patients with distant-stage NET with carcinoid syndrome. The results of the current study also suggest that octreotide LAR is underused in this population despite recommended guidelines.

Clinical burden of illness in patients with neuroendocrine tumors.

OBJECTIVE: The objective of this study was to evaluate the incremental risk of morbidities affecting the cardiovascular, hepatic, gastrointestinal, skeletal, and neuropsychiatric systems in patients with neuroendocrine tumors (NETs) compared with a noncancer cohort. METHODS: In a retrospective, matched-control study using US claims databases, noncancer control subjects (n = 3524) were matched 2:1 with patients with newly diagnosed NET (n = 1762) on age, sex, region, hospital data availability, and index year. Rates of select morbidities were compared between patients with NET and control subjects. Incremental risks were analyzed using logistic regressions adjusting for baseline characteristics. RESULTS: In the first 3 years after diagnosis in patients with NET versus matched control subjects without cancer, (1) the adjusted risk of cardiovascular morbidities was higher (odds ratio [OR], 1.26; P = 0.0206); (2) the adjusted risk of hepatic or gastrointestinal morbidities was higher (OR, 1.95, P < 0.0001); (3) the adjusted risk of osteoporosis/osteopenia was higher among those 50 years or younger (OR, 3.24; P = 0.0081); and (4) the adjusted risk of anxiety/depression was higher among those 65 years or younger (OR, 1.48; P = 0.0210). CONCLUSIONS: Patients with NET have greater clinical burden of disease than matched control subjects with respect to conditions affecting the cardiovascular, hepatic, and gastrointestinal systems. Excess clinical burden of disease with respect to anxiety, depression, osteoporosis, and osteopenia was observed in patients with NET in the younger age groups.

Comparison of health-related quality of life in patients with neuroendocrine tumors with quality of life in the general US population.

OBJECTIVE: The objective of this study was to evaluate the health-related quality of life (HRQL) burden of patients with neuroendocrine tumor (NET) and associations with demographic and clinical factors. METHODS: Patients with NET were invited to participate in an online, anonymous survey consisting of 2 standardized HRQL measures, SF-36 and PROMIS-29, and a set of demographic and disease-related questions. General linear models were used to evaluate the associations between HRQL and demographic and clinical characteristics. RESULTS: A total of 663 patients participated. These patients with NET demonstrated worse HRQL scores compared to the general population and to a sample of mixed cancer patients and survivors. Patients with current NET (tumor not surgically removed or came back after surgery), carcinoid syndrome, or an increased number of bowel movements or flushing episodes experience worsened HRQL compared to patients with NET without those characteristics after adjustment for other clinical and demographic variables. CONCLUSIONS: Patients with NET reported worse HRQL scores compared to the general population. NET-related symptoms such as diarrhea and flushing were associated with reduced quality of life in this cross-sectional study. Optimal management of NET and carcinoid syndrome may significantly improve HRQL among patients with NETs.