Computing the Cost of Care per Patient per Day for Patients With Metastatic Neuroendocrine Neoplasms.

PURPOSE: Patients with well-differentiated, low-grade metastatic neuroendocrine neoplasms (NENs) usually have a long median survival and require complex, expensive care over many years at multidisciplinary centers. The cost burden for patients and institutions serves as a barrier to care. Understanding the drivers of these costs and whether intense monitoring adds value will help to optimize value-based care. METHODS: We adapted the cost of care per patient per day (CCPD) validated methodology to measure cost while accounting for varying follow-up duration. We queried the Stanford NEN Database, which aggregates data from the electronic health record and other electronic sources, to study patients with metastatic NENs receiving regular care at Stanford. Current Procedural Terminology codes for services incurred during the monitoring period for each patient were mapped to the corresponding cost conversion factor and date in the Medicare fee schedule. RESULTS: Two hundred two patients between 2010 and 2017 were studied with a mean CCPD of $119.11 in US dollars (USD); NEN-specific systemic therapy made up 55% of this cost. Somatostatin analogs were the costliest systemic therapy. Systemic therapy was the driver of cost differences among patients with various primary tumor types, stage of disease, tumor differentiation and grade, and functional hormone status. Patients in the most expensive CCPD group did not have a significant survival benefit (P = .66). CONCLUSION: The CCPD methodology was effective in studying cancer care value in NENs. Systemic therapy, specifically somatostatin analogs, was the primary driver of cost, and intense monitoring and higher-cost care did not improve survival outcomes.

Exploratory genomic analysis of high-grade neuroendocrine neoplasms across diverse primary sites.

High-grade (grade 3) neuroendocrine neoplasms (G3 NENs) have poor survival outcomes. From a clinical standpoint, G3 NENs are usually grouped regardless of primary site and treated similarly. Little is known regarding the underlying genomics of these rare tumors, especially when compared across different primary sites. We performed whole transcriptome (n = 46), whole exome (n = 40), and gene copy number (n = 43) sequencing on G3 NEN formalin-fixed, paraffin-embedded samples from diverse organs (in total, 17 were lung, 16 were gastroenteropancreatic, and 13 other). G3 NENs despite arising from diverse primary sites did not have gene expression profiles that were easily segregated by organ of origin. Across all G3 NENs, TP53, APC, RB1, and CDKN2A were significantly mutated. The CDK4/6 cell cycling pathway was mutated in 95% of cases, with upregulation of oncogenes within this pathway. G3 NENs had high tumor mutation burden (mean 7.09 mutations/MB), with 20% having >10 mutations/MB. Two somatic copy number alterations were significantly associated with worse prognosis across tissue types: focal deletion 22q13.31 (HR, 7.82; P = 0.034) and arm amplification 19q (HR, 4.82; P = 0.032). This study is among the most diverse genomic study of high-grade neuroendocrine neoplasms. We uncovered genomic features previously unrecognized for this rapidly fatal and rare cancer type that could have potential prognostic and therapeutic implications.

Rapid Progression After 177Lu-DOTATATE in Patients With Neuroendocrine Tumors.

ABSTRACT: Peptide receptor radionuclide therapy (PRRT) is a treatment option for somatostatin receptor-positive, unresectable or metastatic neuroendocrine tumors (NETs). Despite high disease control rates seen with PRRT, a subset of the NET population seems to have a short progression-free interval. We hypothesize that patients with NETs with rapid progression post-PRRT may have mixed low- and high-grade cell populations, and PRRT treats the lower-grade component, allowing the more aggressive high-grade component to progress.We report 7 patients with biopsy-proven NET who received PRRT with 177Lu-DOTATATE at the Stanford Cancer Center who had evidence of progressive disease (PD) on or within 6 months of therapy.All patients had primary pancreatic, metastatic, well-differentiated NET on diagnosis and were heavily pretreated before receiving PRRT. Two patients had PD while on PRRT; 5 had PD within 6 months of completing PRRT. The median time from the last cycle to PD was 3.2 months (range, 1.1-4.6 months). The median progression-free survival was 7.7 months (95% confidence interval, 5.7-9.8 months). Three patients had a repeat biopsy post-PRRT, 2 of which demonstrated higher disease grade compared with their initial pathology. Further evaluation in larger patient cohorts is warranted to elucidate predictive factors of PRRT response/nonresponse to enable better patient selection.

Temozolomide in Grade 3 Gastroenteropancreatic Neuroendocrine Neoplasms: A Multicenter Retrospective Review.

BACKGROUND: Grade 3 gastroenteropancreatic neuroendocrine neoplasms (G3 GEPNENs) are often aggressive, and the optimal treatment is unclear for this subgroup of neuroendocrine neoplasms (NENs). Temozolomide (TEM)-based regimens have been increasingly used to treat grade 1-2 NENs, but their efficacy in G3 NENs remains undetermined. We aimed to assess the clinical efficacy of TEM-containing regimens in advanced grade 3 GEPNENs. MATERIALS AND METHODS: A multicenter retrospective review (2008-2018) of patients with metastatic/unresectable G3 GEPNENs who received a TEM-containing regimen was undertaken within a North American partnership to pool data. The primary endpoint was time to treatment failure (TTF). Radiologic response was extracted from local reports. RESULTS: One hundred and thirty patients in six high-volume NEN centers were included (median age 55, 64% male, 18% functional, 67% pancreatic NEN). Forty-nine percent were well-differentiated, 35% poorly differentiated, and 15% unknown based on local pathology reports. The regimen used was capecitabine and temozolomide (CAPTEM) in 92% and TEM alone in 8%. Radiological response by local assessment was seen in 36% of patients. Median TTF was 3.6 months and median overall survival (OS) 19.2 months. Six percent of patients required discontinuation of therapy due to adverse events. TTF was longer in first-line treatment (7.8 months vs. 2.9 months; hazard ratio, 1.62; 95% confidence interval, 1.11-2.36; p = .015) and in patients with pancreatic NENs (panNENs) compared with gastrointestinal NENs (5.8 months vs 1.8 months; p = .04). The overall response rate was higher in the first-line setting (51% vs 29%; p = .02) and in panNEN (41% vs 23%; p = .04). CONCLUSION: This is the largest TEM treatment series in G3 NEN, involving collaboration of several major North American NEN centers as a partnership. Thirty-six percent of patients showed some degree of radiographic response, and treatment was generally well tolerated, although the median duration of response was short. Response rates and time to treatment failure were superior in the first-line setting. CAPTEM should be considered a viable treatment option in this setting. Further randomized trials are warranted. IMPLICATIONS FOR PRACTICE: Neuroendocrine neoplasms (NENs) are heterogeneous, and optimal treatment for aggressive grade 3 (G3) NENs remains undetermined. The capecitabine and temozolomide (CAPTEM) regimen has been used in low-grade pancreas NENs but there are few data for its safety and efficacy in the G3 setting. This article reports on the efficacy of temozolomide-containing regimens, particularly CAPTEM, in management of G3 NENs. The good tolerance and response rate show that CAPTEM should be considered a viable regimen in treatment of G3 NENs pending confirmatory prospective studies.

Examination of factors associated with lymph node metastases in lung carcinoids: Results from a single institution retrospective cohort study.

BACKGROUND: Well-differentiated lung neuroendocrine tumors (NETs), also known as typical and atypical carcinoids, have a decreased incidence of lymph node (LN) and distant metastases compared to poorly differentiated lung NETs. We aimed to (i) examine the clinicopathologic features associated with LN involvement in lung carcinoids and (ii) describe the postoperative management of patients with LN metastases. METHODS: We identified 98 patients who underwent surgical resection and lymph node sampling at Stanford University. We assessed the following and used AJCC staging version 7: clinical features (age, sex, race, prior malignancy, smoking history), tumor features (functional syndrome, histology, size, location, laterality), pre-operative workup performed (imaging and suspicion of LN metastases), surgery (nodes and stations sampled, margin status, surgical approach, and type of surgery), and recurrence outcome. These features were examined between patients with and without LN metastases using the Wilcoxon test (continuous variables) and Fisher's exact test (categorical variables). RESULTS: 87 patients (89%) had typical carcinoid and 11 patients (11%) had atypical carcinoid. 17 patients were found to have at least one positive lymph node, with 11 having N1 disease and 6 having N2 disease. In the univariable analysis, patients with lymph node disease were more likely to have recurrence of lung carcinoid (29% vs. 6%, p=0.01). In the multivariable logistic regression, there was a trend towards performance of preoperative SSTR imaging and lymph node involvement (OR = 3.06, p=0.07). No patients received adjuvant therapy. CONCLUSION: We found a trend for the performance of SSTR imaging and association of lymph node metastases in both univariable and multivariable analysis. A large proportion (41%) of patients with lymph node positive disease had < 2 cm tumors. This suggests the potential importance of incorporating SSTR imaging into routine practice and not restricting the use of this staging modality in patients with small tumors.

PAM staining intensity of primary neuroendocrine neoplasms is a potential prognostic biomarker.

Neuroendocrine neoplasms (NENs) are rare epithelial tumors with heterogeneous and frequently unpredictable clinical behavior. Available biomarkers are insufficient to guide individual patient prognosis or therapy selection. Peptidylglycine α-amidating monooxygenase (PAM) is an enzyme expressed by neuroendocrine cells that participates in hormone maturation. The objective of this study was to assess the distribution, clinical associations and survival implications of PAM immunoreactivity in primary NENs. Of 109 primary NENs, 7% were PAM-negative, 25% were PAM-low and 68% were PAM-high. Staining intensity was high in small bowel (p = 0.04) and low in stomach (p = 0.004) NENs. PAM staining was lower in higher grade tumors (p < 0.001) and patients who died (p < 0.001) but did not vary by tumor size or stage at surgery. In patients who died, time to death was shorter in patients with reduced PAM immunoreactivity: median times to death were 11.3 (PAM-negative), 29.4 (PAM-low) and 61.7 (PAM-high) months. Lower PAM staining was associated with increased risk of death after adjusting for disease stage [PAM negative, HR = 13.8 (CI: 4.2-45.5)]. PAM immunoreactivity in primary NENs is readily assessable and a potentially useful stage-independent predictor of survival.