Identification of Areas for Improvement in the Management of Bone Metastases in Patients with Neuroendocrine Neoplasms

Abstract

Background: There is no global consensus on the optimal management of bone metastases (BMs) in neuroendocrine neoplasms (NENs). Objectives: To review current management and outcomes of patients with BMs in NENs, in order to identify areas for improvement. Methods: A retrospective study of all patients with NENs, except Grade 3 lung NENs (April 2002 to March 2018) was conducted. Baseline characteristics, nature of BMs, treatment received and overall survival (OS) were evaluated. Statistical analyses were performed using SPSS version 23.0/STATA v12. Results: Of 1,212 patients, 85 (7%) had BMs; median age 58 years. The majority had a gastro-entero-pancreatic primary (49%, n = 42) followed by lung (25%, n = 21), unknown primary (20%, n = 17), and "others" (6%, n = 5). Two-thirds (n = 57) had G1-2 neuroendocrine tumours, and 41% (n = 35) had functional tumours. Overall, 28% (n = 24) presented with synchronous BMs at first NEN diagnosis, and 55% (n = 47) developed BMs at the same time as other distant metastases. For the subpopulation of patients in whom BMs developed metachronously to other distant metastases (45%, n = 38), median time to development of BMs was 14.0 months. BMs were "widespread" in 61% (n = 52). Although only 22% (n = 19) reported symptoms at initial diagnosis of BMs, most (78%) developed symptoms at some time during the follow-up period (pain/hypercalcaemia 64%, skeletal-related events 20%). BMs were mainly managed with analgesia (44%, n = 37). Radiotherapy and bisphosphonates were used in 34% (n = 29) and 22% (n = 19) respectively. Surgery was rarely performed (2%, n = 2). Median OS from identification of BMs was 31.0, and 18.9 months from development of BMs-related symptoms. Conclusions: In this cohort study, most patients with BMs developed symptoms. The utility of radiotherapy and/or bisphosphonates should be prospectively and systematically explored further for its potential impact on patients' quality of life and survival outcomes.

Bone Metastases in Neuroendocrine Tumors: Molecular Pathogenesis and Implications in Clinical Practice

“…In a large retrospective analysis from a part of the US National Comprehensive Cancer Network database including 691 patients, significantly lower survival rates were observed in low-grade NETs arising from both pancreas and small bowel [9]. Similar findings have been reported by other studies performed in ENETS Centers of Excellence across Europe, confirming the negative prognostic impact of bone metastases on patients’ survival [7, 10, 45]. Nevertheless, in a study enrolling 312 consecutive patients with sporadic, grade 1/2, stage IV, nonfunctioning panNETs, the presence of bone lesions predicted a shorter PFS, in the absence of any impact on overall survival [52].…”

“…In this regard, an analysis of 85 patients with NETs metastatic to the skeleton showed that bone pain was reported by 28 and 14% of subjects at the initial diagnosis and during the follow-up, respectively [7]. On the other hand, fractures have been described as rare events, occurring in nearly 10–20% of cases, and even lower rates of spinal compression (5%) and hypercalcemia (1–4%) have been reported [7, 45]. Although no clear factor able to predict the development of NET bone metastases has been identified, a correlation with deteriorated performance status has been observed [10].…”

“…Nevertheless, in a study enrolling 312 consecutive patients with sporadic, grade 1/2, stage IV, nonfunctioning panNETs, the presence of bone lesions predicted a shorter PFS, in the absence of any impact on overall survival [52]. Overall, median survival time from bone metastases identification ranges from 20 to 60 months [7, 9, 10, 45, 49], a figure that highlights the negative impact of this specific metastatic pattern compared with patients with stage IV disease without skeletal colonization, where median survival rates are usually comprised between 80 and 100 months [7, 9, 53]. Consistently, poorer survival outcomes have been reported for NET patients diagnosed with synchronous bone metastases as compared with those presenting metachronous skeletal colonization [11, 13].…”

Bone metastases from neuroendocrine tumors: clinical and biological considerations

“…However, in our study, the NETs that caused skeletal complications are invariably G1 or G2 and this could suggest that bone metastases therapy should therefore be started early also in the less-aggressive types of NET. Preventing skeletal related-events should be one of the primary aims in the treatment process of these patients ( 16 ).…”

Neuroendocrine neoplasia and bone (Review)

“…In terms of skeleton health, patients with NENs may suffer from a multitude of factors, not only from direct malignant dissemination to the bone (47,48). For instance, secondary diabetes mellitus due to pancreatic and duodenal tumors such as somatostatinomas (with or without underlying neurofibromatosis type 1), or pheocromocytomas or due to paraneoplastic hypercortisolemia may cause a deterioration of bone quality like that reflected by TBS in addition to abnormal turnover that increase fracture risk (49)(50)(51).…”