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Grimaldi, F., Fazio, N., Attanasio, R., Frasoldati, A., Papini, E., Cremonini, N., . . . Öberg, K. (2018). Assessment of Response to Treatment and Follow-Up in Gastroenteropancreatic Neuroendocrine Neoplasms. Endocrine, Metabolic & Immune Disorders - Drug Targets, 18
Open this publication in new window or tab >>Assessment of Response to Treatment and Follow-Up in Gastroenteropancreatic Neuroendocrine Neoplasms
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2018 (English)In: Endocrine, Metabolic & Immune Disorders - Drug Targets, ISSN 1871-5303, E-ISSN 2212-3873, Vol. 18Article in journal (Refereed) Epub ahead of print
Abstract [en]

Well-established criteria for evaluating the response to treatment and the appropriate follow-up of individual patients are critical in clinical oncology. The current evidence-based data on these issues in terms of the management of gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are unfortunately limited. This document by the Italian Association of Clinical Endocrinologists (AME) on the criteria for the follow-up of GEP-NEN patients is aimed at providing comprehensive recommendations for everyday clinical practice based on both the best available evidence and the combined opinion of an interdisciplinary panel of experts. The initial risk stratification of patients with NENs should be performed according to the grading, staging and functional status of the neoplasm and the presence of an inherited syndrome. The evaluation of response to the initial treatment, and to the subsequent therapies for disease progression or recurrence, should be based on a cost-effective, risk-effective and timely use of the appropriate diagnostic resources. A multidisciplinary evaluation of the response to the treatment is strongly recommended and, at every step in the follow-up, it is mandatory to assess the disease state and the patient performance status, comorbidities, and recent clinical evolution. Local expertise, available technical resources and the patient preferences should always be evaluated while planning the individual clinical management of GEP-NENs.

Keywords
NEN, NET follow-up, Neuroendocrine tumors, carcinoid syndrome, criteria of response, gastrinoma, imaging, insulinoma, markers, non-functioning NET
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-342312 (URN)10.2174/1871530318666171213145803 (DOI)29237387 (PubMedID)
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-03-16Bibliographically approved
Daskalakis, K., Karakatsanis, A., Hessman, O., Stuart, H. C., Welin, S., Tiensuu Janson, E., . . . Stålberg, P. (2018). Association of a Prophylactic surgical approach to Stage IV Small Intestinal Neuroendocrine Tumors with Survival.. JAMA Oncology, 4(2), 183-189
Open this publication in new window or tab >>Association of a Prophylactic surgical approach to Stage IV Small Intestinal Neuroendocrine Tumors with Survival.
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2018 (English)In: JAMA Oncology, ISSN 2374-2437, E-ISSN 2374-2445, Vol. 4, no 2, p. 183-189Article in journal (Refereed) Published
Abstract [en]

Importance: Primary tumor resection and mesenteric lymph node dissection in asymptomatic patients with stage IV Small Intestinal Neuroendocrine Tumors (SI-NETs) is controversial.

Objective:  To determine whether locoregional surgery performed at diagnosis in asymptomatic SI-NETs patients with distant metastases affects overall survival (OS), morbidity and mortality, length of hospital stay (LOS) and re-operation rates.

Design: This investigation was a cohort study of asymptomatic patients with stage IV SI-NET, diagnosed between 1985 and 2015, using the prospective Uppsala database of SI-NETs and the Swedish National Patient Register. Patients included were followed until May 2016 and divided to a first group, which underwent Prophylactic Upfront Surgery within six months from diagnosis Combined with Oncological treatment (PUSCO group) and a second group, which was either treated non-surgically or operated later (Delayed Surgery As Needed Combined with Oncological treatment [DSANCO group]).

Setting: A tertiary referral center with follow-up data from the Swedish National Patient Register.

Participants: We included 363 stage IV SI-NET patients without any abdominal symptoms within 6 months from diagnosis, treated either with PUSCO (n=161) or DSANCO (n=202).

Exposure: PUSCO vs DSANCO.

Main Outcomes and Measures: Overall survival (OS), length of hospital stay (LOS), postoperative morbidity and mortality and re-operation rates measured from baseline. Propensity score match was performed between the two groups.

Results: Two isonumerical groups (n=91) occurred after propensity score matching. There was no difference between groups in OS (PUSCO median 7.9 vs DSANCO 7.6 years; [hazard ratio] HR, 0.98; [95% CI, 0.70-1.37]; log-rank P=.93) and cancer-specific survival (median 7.7 vs 7.6 years, HR, 0.99; [95%CI, 0.71-1.40]; log-rank P=.99). There was no difference in 30-day mortality (0% in both matched groups) or postoperative morbidity (2% vs 1%; P>.99), LOS (median 73 vs 76 days; P=.64), LOS due to local tumor-related symptoms (median 7 vs 11.5 days; P=.81) or incisional hernia repairs (4% in both groups; P>.99).  Patients from the PUSCO group underwent more re-operative procedures (14%) compared to the DSANCO group (3%) due to intestinal obstruction (P< .001).

Conclusion: Prophylactic upfront locoregional surgery confers no survival advantage in asymptomatic stage IV SI-NET patients. Delayed surgery as needed seems to be comparable in all examined outcomes, whilst offering the advantage of less re-operations for intestinal obstruction.  The value of a priori locoregional surgery in the presence of distant metastases is challenged and needs to be elucidated in a randomized controlled study.

 

Keywords
Small Intestinal NETs, prophylactic loco-regional surgery, stage IV
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-330702 (URN)10.1001/jamaoncol.2017.3326 (DOI)000424778600010 ()29049611 (PubMedID)
Funder
Göran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Cancer Society
Available from: 2017-10-21 Created: 2017-10-03 Last updated: 2018-04-16Bibliographically approved
Weickert, M. O., Kaltsas, G., Hörsch, D., Lapuerta, P., Pavel, M., Valle, J. W., . . . Kulke, M. H. (2018). Changes in Weight Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome. Clinical Therapeutics, 40(6), 952-962
Open this publication in new window or tab >>Changes in Weight Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome
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2018 (English)In: Clinical Therapeutics, ISSN 0149-2918, E-ISSN 1879-114X, Vol. 40, no 6, p. 952-962Article in journal (Refereed) Published
Abstract [en]

Purpose: In the placebo-controlled Phase III TELE-STAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome) trial, the oral tryptophan hydroxylase inhibitor telotristat ethyl significantly reduced bowel movement (BM) frequency during a 12-week, double-blind treatment period in 135 patients with metastatic neuroendocrine tumors with carcinoid syndrome and >= 4 BMs per day. Patients (mean [SD] age, 63.5 [8.9] years; mean [SD] body mass index, 24.9 [4.9] kg/m(2)) received placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg 3 times per day (TID) in addition to somatostatin analogue therapy. Weight loss is associated with uncontrolled carcinoid syndrome and may be associated with reduced survival.

Methods: Assessment of the occurrence of weight change >= 3% at week 12 was prespecified in the statistical analysis plan.

Findings: In 120 patients with weight data available, weight gain >= 3% was observed in 2 of 39 patients (5.1%) taking placebo [1.1), 7 of 41 (17.1%) taking telotristat ethyl 250 mg TID, and 13 of 40 (32.5%) taking telotristat ethyl 500 mg TID (P = 0.0017) at week 12. Weight loss >= 3% was observed in 5 of 39 patients (12.8%) taking placebo TID, 4 of 41 (9.8%) taking telotristat ethyl 250 mg TID, and 6 of 40 (15.0%) taking telotristat ethyl 500 mg TID (P = 0.77). Biochemical and metabolic parameters of serum albumin and cholesterol significantly increased (P = 0.02 and P = 0.001, respectively) in patients gaining weight and decreased in patients who lost weight, suggesting an improvement in overall nutritional status.

Place, publisher, year, edition, pages
ELSEVIER, 2018
Keywords
carcinoid syndrome, carcinoid syndrome diarrhea, malnutrition, neuroendocrine tumor, telotristat ethyl, weight
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-360481 (URN)10.1016/j.clinthera.2018.04.006 (DOI)000437389200017 ()29724499 (PubMedID)
Available from: 2018-09-17 Created: 2018-09-17 Last updated: 2018-09-17Bibliographically approved
Hörsch, D., Kulke, M. H., Caplin, M. E., Anthony, L. B., Bergsland, E., Öberg, K., . . . Pavel, M. (2018). Efficacy and Safety of Telotristat Ethyl in Patients With Carcinoid Syndrome Inadequately Controlled by Somatostatin Analogs: Analysis of the Completed TELESTAR Extension Period. Paper presented at The 10th Annual Meeting of the North American Neuroendocrine Tumor Society, October 19–21, 2017, Philadelphia, Pennsylvania.. Pancreas, 47(3), 341-342
Open this publication in new window or tab >>Efficacy and Safety of Telotristat Ethyl in Patients With Carcinoid Syndrome Inadequately Controlled by Somatostatin Analogs: Analysis of the Completed TELESTAR Extension Period
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2018 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 47, no 3, p. 341-342Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-351593 (URN)10.1097/MPA.0000000000000997 (DOI)000426086300052 ()
Conference
The 10th Annual Meeting of the North American Neuroendocrine Tumor Society, October 19–21, 2017, Philadelphia, Pennsylvania.
Available from: 2018-05-29 Created: 2018-05-29 Last updated: 2018-05-29Bibliographically approved
Van Leeuwaarde, R., Spada, F., Cheung, W., Gonzalez-Clavijo, A., Pracht, M., Emelianova, G., . . . Öberg, K. (2018). Is the EORTC QLQ-QNET21 Optimal for Patients with Neuroendocrine Tumors?. Paper presented at 15th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 07-09, 2018, Barcelona, SPAIN. Neuroendocrinology, 106(Supplement: 1), 122-122
Open this publication in new window or tab >>Is the EORTC QLQ-QNET21 Optimal for Patients with Neuroendocrine Tumors?
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2018 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, no Supplement: 1, p. 122-122Article in journal, Meeting abstract (Other academic) Published
Keywords
quality of life, gep-net, eortc qlq-ginet21
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-355839 (URN)10.1159/000487699 (DOI)000427285300120 ()
Conference
15th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 07-09, 2018, Barcelona, SPAIN
Note

Meeting Abstract: D65

Available from: 2018-07-13 Created: 2018-07-13 Last updated: 2018-07-13Bibliographically approved
Öberg, K. (2018). Management of functional neuroendocrine tumors of the pancreas. Gland surgery, 7(1), 20-27
Open this publication in new window or tab >>Management of functional neuroendocrine tumors of the pancreas
2018 (English)In: Gland surgery, ISSN 2227-684X, E-ISSN 2227-8575, Vol. 7, no 1, p. 20-27Article, review/survey (Refereed) Published
Abstract [en]

Pancreatic neuroendocrine tumors (pNETs) constitute a heterogenous group of malignancies with varying clinical presentation, tumor biology and prognosis. The incidence of pNETs has steadily increased during the last decades with an estimated incidence 2012 of 4.8/100,000. Recent whole genome sequencing of pNETs has demonstrated mutations in the DNA repair genes MUTYH and point mutations and gene fusions in four main pathways from chromatin remodeling, DNA damage repair, activation of mechanistic target of rapamycin (mTOR) signaling and the telomere maintenance. This new information will be the foundation for new therapies in the near future for malignant pNETs. The functioning pNETs constitute about 30-40% of all pNETs displaying nine different clinical syndromes: insulinoma, Zollinger-Ellison, Verner-Morrison, glucagonoma, somatostatinomas, ectopic adrenocorticotropic hormone (ACTH) and parathyroid hormone related peptide (PTH-rP) syndromes. Single patients might also present carcinoid syndrome. The diagnostic work-up include histopathology with the new WHO 2017 Classification, biomarkers (CgA, NSE), radiology and molecular imaging including CT-scan, magnetic resonance imaging (MRI), ultrasound and PET-scan. A cornerstone in the treatment of pNETs is surgery which is rarely curative but can reduce the clinical symptoms by debulking which also include radiofrequency ablation, embolization of liver metastases. Medical treatment includes chemotherapy and the targeted agents such as everolimus, sunitinib and peptide receptor radiotherapy (PRRT). Somatostatin analogs has for the last decades been the main stay for management for clinical symptoms related to functioning pNETs and is often combined with new targeted agents as well as chemotherapy. Long-term management of functioning pNETs need a combination of different procedures, surgery, local ablation, targeted agents and somatostatin analogs. Future therapies might be based on the recent advances in molecular genetics and tumor biology.

Place, publisher, year, edition, pages
AME PUBL CO, 2018
Keywords
Functioning pancreatic neuroendocrine tumors (FpNETs), positron emission tomography scan (PET scan), chemotherapy, targeted agents, everolimus, sunitinib, peptide receptor radiotherapy (PRRT), surgery
National Category
Endocrinology and Diabetes Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-350109 (URN)10.21037/gs.2017.10.08 (DOI)000423441800003 ()29629316 (PubMedID)
Available from: 2018-05-07 Created: 2018-05-07 Last updated: 2018-05-07Bibliographically approved
Strosberg, J., Wolin, E., Chasen, B., Kulke, M., Bushnell, D., Caplin, M., . . . Krenning, E. (2018). QOL Improvements in NETTER-1 Phase III Trial in Patients With Progressive Midgut Neuroendocrine Tumors. Paper presented at The 10th Annual Meeting of the North American Neuroendocrine Tumor Society, October 19–21, 2017, Philadelphia, Pennsylvania.. Pancreas, 47(3), 355-355
Open this publication in new window or tab >>QOL Improvements in NETTER-1 Phase III Trial in Patients With Progressive Midgut Neuroendocrine Tumors
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2018 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 47, no 3, p. 355-355Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-351594 (URN)10.1097/MPA.0000000000000997 (DOI)000426086300102 ()
Conference
The 10th Annual Meeting of the North American Neuroendocrine Tumor Society, October 19–21, 2017, Philadelphia, Pennsylvania.
Available from: 2018-05-29 Created: 2018-05-29 Last updated: 2018-05-29Bibliographically approved
Strosberg, J., Wolin, E., Chasen, B., Kulke, M., Bushnell, D., Caplin, M., . . . Krenning, E. (2018). Selected For Oral Presentation: Overall Survival, Progression-Free Survival, and Quality of Life Updates from the NETTER-1 Study: 177Lu-Dotatate Vs. High Dose Octreotide In Progressive Midgut Neuroendocrine Tumors. Paper presented at 15th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 07-09, 2018, Barcelona, SPAIN. Neuroendocrinology, 106(Supplement: 1), 260-260
Open this publication in new window or tab >>Selected For Oral Presentation: Overall Survival, Progression-Free Survival, and Quality of Life Updates from the NETTER-1 Study: 177Lu-Dotatate Vs. High Dose Octreotide In Progressive Midgut Neuroendocrine Tumors
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2018 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, no Supplement: 1, p. 260-260Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
KARGER, 2018
Keywords
177lu-dotatate, prrt, net, quality of life
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-354381 (URN)10.1159/000487699 (DOI)000427285300258 ()
Conference
15th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 07-09, 2018, Barcelona, SPAIN
Note

Meeting Abstract: K22

WoS title: Overall Survival, Progression-Free Survival, and Quality of Life Updates from the NETTER-1 Study: 177Lu-Dotatate vs. High Dose Octreotide in Progressive Midgut Neuroendocrine Tumors

Available from: 2018-06-29 Created: 2018-06-29 Last updated: 2018-06-29Bibliographically approved
Weickert, M. O., Kaltsas, G., Hörsch, D., Lapuerta, P., Pavel, M., Valle, J. W., . . . Kulke, M. H. (2018). Weight Change Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome. Paper presented at The 10th Annual Meeting of the North American Neuroendocrine Tumor Society, October 19–21, 2017, Philadelphia, Pennsylvania.. Pancreas, 47(3), 357-358
Open this publication in new window or tab >>Weight Change Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome
Show others...
2018 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 47, no 3, p. 357-358Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-351595 (URN)10.1097/MPA.0000000000000997 (DOI)000426086300110 ()
Conference
The 10th Annual Meeting of the North American Neuroendocrine Tumor Society, October 19–21, 2017, Philadelphia, Pennsylvania.
Available from: 2018-05-29 Created: 2018-05-29 Last updated: 2018-05-29Bibliographically approved
Ferolla, P., Brizzi, M. P., Meyer, T., Mansoor, W., Mazieres, J., Do Cao, C., . . . Baudin, E. (2017). Efficacy and safety of long-acting pasireotide or everolimus alone or in combination in patients with advanced carcinoids of the lung and thymus (LUNA): an open-label, multicentre, randomised, phase 2 trial. The Lancet Oncology, 18(12), 1652-1664
Open this publication in new window or tab >>Efficacy and safety of long-acting pasireotide or everolimus alone or in combination in patients with advanced carcinoids of the lung and thymus (LUNA): an open-label, multicentre, randomised, phase 2 trial
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2017 (English)In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 18, no 12, p. 1652-1664Article in journal (Refereed) Published
Abstract [en]

Background

There are no data from prospective studies focused exclusively on patients with advanced lung and thymic carcinoids. We aimed to assess the efficacy and safety of long-acting pasireotide and everolimus, administered alone or in combination, in patients with advanced carcinoids of the lung or thymus.

Methods

LUNA was a prospective, multicentre, randomised, open-label, phase 2 trial of adult patients (aged >18 years) with advanced (unresectable or metastatic), well differentiated carcinoid tumours of the lung or thymus, with radiological progression within 12 months before randomisation, and a WHO performance status of 0–2. At each centre, the investigator or their designee registered each patient using an interactive voice recognition system into one of the three treatment groups. The randomisation allocation sequence was generated by an external company; patients were randomly assigned (1:1:1) to receive treatment with long-acting pasireotide (60 mg intramuscularly every 28 days), everolimus (10 mg orally once daily), or both in combination, for the core 12-month treatment period. Patients were stratified by carcinoid type (typical vs atypical) and line of study treatment (first line vs others). The primary endpoint was the proportion of patients progression-free at month 9, defined as the proportion of patients with overall lesion assessment at month 9 showing a complete response, partial response, or stable disease according to local Response Evaluation Criteria in Solid Tumors, version 1.1, assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment. The trial is registered with ClinicalTrials.gov, number NCT01563354. The extension phase of the study is ongoing.

Findings

Between Aug 16, 2013, and Sept 30, 2014, 124 patients were enrolled from 36 centres in nine countries: 41 were allocated to the long-acting pasireotide group, 42 to the everolimus group, and 41 to the combination group. At month 9, the proportion of patients with an overall lesion assessment of complete response, partial response, or stable disease was 16 of 41 patients (39·0%, 95% CI 24·2–55·5) in the long-acting pasireotide group, 14 of 42 patients (33·3%, 19·6–49·5) in the everolimus group, and 24 of 41 patients (58·5%, 42·1–73·7) in the combination group. The most common grade 1–2 adverse events with a suspected association with long-acting pasireotide monotherapy were diarrhoea (15 [37%] of 41), hyperglycaemia (17 [41%]), and weight loss (8 [20%]); those with a suspected association with everolimus monotherapy were stomatitis (26 [62%] of 42) and diarrhoea (16 [38%]); and those suspected to be associated with combination treatment were hyperglycaemia (27 [66%] of 41]), diarrhoea (19 [46%]), and asthenia (8 [20%]). The most common grade 3–4 adverse events with a suspected association with long-acting pasireotide monotherapy were γ-glutamyltransferase increased (four [10%] of 41 patients), diarrhoea (three [7%]), and hyperglycaemia (three [7%]); those for everolimus were hyperglycaemia (seven [17%] of 42 patients), stomatitis (four [10%]), and diarrhoea (three [7%]); those for combination treatment were hyperglycaemia (nine [22%] of 41 patients) and diarrhoea (four [10%]). 11 patients died during the core 12-month treatment phase or up to 56 days after the last study treatment exposure date: two (5%) of 41 in the long-acting pasireotide group, six (14%) of 42 in the everolimus group, and three (7%) of 41 in the combination group. No deaths were suspected to be related to long-acting pasireotide treatment. One death in the everolimus group (acute kidney injury associated with diarrhoea), and two deaths in the combination group (diarrhoea and urinary sepsis in one patient, and acute renal failure and respiratory failure in one patient) were suspected to be related to everolimus treatment. In the latter patient, acute renal failure was not suspected to be related to everolimus treatment, but respiratory failure was suspected to be related.

Interpretation

The study met the primary endpoint in all three treatment groups. Safety profiles were consistent with the known safety profiles of these agents. Further studies are needed to confirm the antitumour efficacy of the combination of a somatostatin analogue with everolimus in lung and thymic carcinoids.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-344203 (URN)10.1016/S1470-2045(17)30681-2 (DOI)000417001900043 ()29074099 (PubMedID)
Available from: 2018-03-06 Created: 2018-03-06 Last updated: 2018-03-08Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-3432-1182

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