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

Cives, Mauro; Pellè, Eleonora; Rinzivillo, Maria; Prosperi, Daniela; Tucci, Marco; Silvestris, Franco; Panzuto, Francesco

doi:10.1159/000508633

Cited by 16 publications

(17 citation statements)

References 65 publications

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“…By multivariable analysis, only the hepatic tumor load independently predicted OS in the present study. Although bone metastases have been previously described as a negative prognostic factor in patients with NETs [21], in our series their presence did not significantly affect clinical outcomes, possibly a consequence of low numbers of patients with bone neoplastic involvement (n = 13).…”

Section: Discussioncontrasting

confidence: 72%

Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10%?

et al. 2020

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Background Long‐acting somatostatin analogs (SSAs) are the primary first‐line treatment of well‐differentiated advanced gastroenteropancreatic neuroendocrine tumors (NETs), but data about their efficacy in pancreatic NETs (panNETs) with Ki‐67 ≥10% are still limited. Materials and Methods To assess the clinical outcomes of advanced, nonfunctioning, well‐differentiated panNETs with Ki‐67 ≥10% receiving first‐line long‐acting SSAs in a real‐world setting, we carried out a retrospective, multicenter study including patients treated between 2014–2018 across 10 centers of the NET CONNECT Network. The primary endpoints were time to next treatment (TNT) and progression‐free survival (PFS), whereas overall survival (OS) and treatment safety were secondary endpoints. Results A total of 73 patients were included (68 grade [G]2, 5 G3), with liver metastases in 61 cases (84%). After a median follow‐up of 36.4 months (range, 6–173), the median TNT and PFS were 14.2 months (95% confidence interval [CI], 11.6–16.2) and 11.9 months (95% CI, 8.6–14.1) respectively. No statistically significant difference was observed according to the somatostatin analog used (octreotide vs. lanreotide), whereas increased tumor grade (hazard ratio [HR], 4.4; 95% CI, 1.2–16.6; p = .04) and hepatic tumor load (HR, 2; 95% CI, 1–4; p = .03) were independently associated with shortened PFS. The median OS recorded was 86 months (95% CI, 56.8–86 months), with poor outcomes observed when the hepatic tumor burden was >25% (HR, 3.4; 95% CI, 1.2–10; p = .01). Treatment‐related adverse events were reported in 14 patients, most frequently diarrhea. Conclusion SSAs exert antiproliferative activity in panNETs with Ki‐67 ≥10%, particularly in G2 tumors, as well as when hepatic tumor load is ≤25%. Implications for Practice The results of the study call into question the antiproliferative activity of somatostatin analogs (SSAs) in pancreatic neuroendocrine tumors with Ki‐67 ≥10%. Patients with grade 2 tumors and with hepatic tumor load ≤25% appear to derive higher benefit from SSAs. Prospective studies are needed to validate these results to optimize tailored therapeutic strategies for this specific patient population.

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Section: Discussioncontrasting

confidence: 72%

Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10%?

et al. 2020

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“…This study reported 11 patients (41 cycles) treated with 177 Lu-DOTATATE, demonstrating median PFS of 21 months 22 . There have been no specific studies that have looked at the impact of other systemic treatments, for example, chemotherapy or molecular targeted treatments on bone metastases 23 …”

Section: Discussionmentioning

confidence: 97%

Safety and Efficacy of 177Lu-DOTATATE in Neuroendocrine Tumor Patients With Extensive Bone Disease

Alsadik¹,

Gnanasegaran²,

Chen³

et al. 2023

Clin Nucl Med

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The aim of this study was to assess the efficacy and safety of 177 Lu-DOTATATE in patients with neuroendocrine tumors (NETs) and extensive bone metastases, that is, more than 50% of the skeleton involved. Method: A single-center retrospective analysis was performed in 30 patients (13 women and 17 men, mean age, 60 years; range, 35-77 years) undergoing 177 Lu-DOTATATE therapy. Patients had progressive metastatic NETs with extensive skeletal metastases (>50% skeletal involvement seen on baseline 68 Ga-DOTATATE PET/CT). The average administered activity was 7.308 (SD, 0.02) GBq per cycle with average treatment interval of 15 weeks. Survival analyses (progression-free survival [PFS], overall survival), radiological response assessment, toxicity assessment, and health-related quality of life (QoL) was performed. Results: Overall, 26 patients completed 4 cycles, and 4 patients had less than 4 cycles of 177 Lu-DOTATATE. One patient (3%) did not complete treatment because of hematological toxicity. The estimated median PFS and median overall survival were calculated at 27 and 35 months, respectively. End-of-treatment radiological assessment showed partial response in 5 patients (17%), stable disease in 20 patients (66%), and radiological progressive disease in 3 patients (10%). Clinical progression was seen in a further 2 patients (7%).The incidence of grade 3/4 bone marrow toxicity was 10%. No patient had grade 3/4 peptide receptor radionuclide therapy-related nephrotoxicity. There was overall improvement in global QoL score (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Gastrointestinal NET-21) ( P = 0.019) Conclusion: 177 Lu-DOTATATE seems to have satisfactory therapeutic outcome in patients with advanced metastatic NET with extensive bone disease, with reasonable PFS and significant improvement in the global health-related QoL. The bone marrow toxicity was within the accepted range. Increasing the interval between cycles does not seem to reduce efficacy and may reduce toxicity, ensuring the bone marrow has sufficient time to recover between cycles.

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“…In our series, confirming this, we find only 4% of patients with metastases exclusively in the bone. Nevertheless, bone metastases from NET are known as negative prognostic factors and determine a significant decrease in progression-free survival and overall survival ( 7 , 8 ). In our study, the death risk rate of patients with synchronous BM is approximately 2.59 times the one of patients with metachronous BM.…”

Section: Discussionmentioning

confidence: 99%

“…The primary sites most frequently involved were the small intestine and pancreas, followed at a distance by the lung and rectum ( 6 ). Bone metastases can have an important impact on the patient’s quality of life and are considered negative prognostic factors of NETs ( 7 , 8 ). The sites most frequently affected are the truncal skeleton, mostly in the vertebral region, followed by the pelvic region and ribs.…”

Section: Introductionmentioning

confidence: 99%

Bone metastases from neuroendocrine tumors: clinical and biological considerations

Scopel

Carlo

Bergamo

et al. 2022

Endocrine Connections

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We considered 351 patients affected by neuroendocrine tumors, followed at the University Hospital of Padua and at the Veneto Oncological Institute. Of these, 72 (20.5%) suffered from bone metastases. The sample was divided according to the timing of presentation of bone metastases into synchronous (within 6 months of diagnosis of primary tumor) and metachronous (after 6 months). We collected data on the type and grading of the primary tumor, and on the features of bone metastases. Our analysis shows that the group of synchronous metastases generally presents primary tumors with a higher degree of malignancy rather than the ones of the metachronous group. This is supported by the finding of a Ki-67 level in GEP-NETs, at the diagnosis of bone metastases, significantly higher in the synchronous group. Moreover, in low-grade NETs, Chromogranin A values are higher in the patients with synchronous metastases, indicating a more burden of disease. The parameters of phospho-calcium metabolism are within the normal range, and we do not find significant differences between the groups. Serious bone complications are not frequent and are not correlated with the site of origin of the primary tumor. From the analysis of the survival curves of the total sample, a cumulative survival rate of 33% at 10 years emerges. The average survival is 80 months, higher than what reported in the literature, while the median is 84 months. In our observation period, synchronous patients tend to have a worse prognosis than metachronous ones with 52-months survival rates of 58% and 86%.

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

Cited by 16 publications

References 65 publications

Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10%?

Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10%?

Safety and Efficacy of 177Lu-DOTATATE in Neuroendocrine Tumor Patients With Extensive Bone Disease

Bone metastases from neuroendocrine tumors: clinical and biological considerations

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