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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) Published
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: 2018-10-18Bibliographically 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
Strosberg, J., Wolin, E., Chasen, B., Kulke, M., Bushnell, D., Caplin, M., . . . Krenning, E. (2018). Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With Lu-177-Dotatate in the Phase III NETTER-1 Trial. Journal of Clinical Oncology, 36(25), 2578-2584
Open this publication in new window or tab >>Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With Lu-177-Dotatate in the Phase III NETTER-1 Trial
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2018 (English)In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 36, no 25, p. 2578-2584Article in journal (Refereed) Published
Abstract [en]

Purpose

Neuroendocrine tumor (NET) progression is associated with deterioration in quality of life (QoL). We assessed the impact of Lu-177-Dotatate treatment on time to deterioration in health-related QoL.

Methods

The NETTER-1 trial is an international phase III study in patients with midgut NETs. Patients were randomly assigned to treatment with Lu-177-Dotatate versus high-dose octreotide. European Organisation for Research and Treatment of Cancer quality-of-life questionnaires QLQ C-30 and G.I.NET-21 were assessed during the trial to determine the impact of treatment on health-related QoL. Patients completed the questionnaires at baseline and every 12 weeks until tumor progression. QoL scores were converted to a 100-point scale according to European Organisation for Research and Treatment of Cancer instructions, and individual changes from baseline scores were assessed. Time to QoL deterioration (TTD) was defined as the time from random assignment to the first QoL deterioration 10 points for each patient in the corresponding domain scale. All analyses were conducted on the intention-to-treat population. Patients with no deterioration were censored at the last QoL assessment date.

Results

TTD was significantly longer in the Lu-177-Dotatate arm (n = 117) versus the control arm (n = 114) for the following domains: global health status (hazard ratio [HR], 0.406), physical functioning (HR, 0.518), role functioning (HR, 0.580), fatigue (HR, 0.621), pain (HR, 0.566), diarrhea (HR, 0.473), disease-related worries (HR, 0.572), and body image (HR, 0.425). Differences in median TTD were clinically significant in several domains: 28.8 months versus 6.1 months for global health status, and 25.2 months versus 11.5 months for physical functioning.

Conclusion

This analysis from the NETTER-1 phase III study demonstrates that, in addition to improving progression-free survival, Lu-177-Dotatate provides a significant QoL benefit for patients with progressive midgut NETs compared with high-dose octreotide.

Place, publisher, year, edition, pages
AMER SOC CLINICAL ONCOLOGY, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-363624 (URN)10.1200/JCO.2018.78.5865 (DOI)000445669200003 ()29878866 (PubMedID)
Available from: 2018-10-25 Created: 2018-10-25 Last updated: 2018-10-25Bibliographically approved
Amoroso, V., Pavel, M., Claps, M., Roca, E., Ravanelli, M., Maroldi, R., . . . Berruti, A. (2018). IFN-alpha in advanced well-differentiated neuroendocrine tumors: the neglected drug?. Future Oncology, 14(10), 897-899
Open this publication in new window or tab >>IFN-alpha in advanced well-differentiated neuroendocrine tumors: the neglected drug?
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2018 (English)In: Future Oncology, ISSN 1479-6694, E-ISSN 1744-8301, Vol. 14, no 10, p. 897-899Article in journal, Editorial material (Other academic) Published
Keywords
bevacizumab, IFN-alpha, neuroendocrine tumors, randomized trials, targeted therapies
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-366629 (URN)10.2217/fon-2017-0667 (DOI)000437050000001 ()29528242 (PubMedID)
Available from: 2018-11-26 Created: 2018-11-26 Last updated: 2018-11-26Bibliographically 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
Waldum, H. L., Öberg, K., Sördal, Ö. F., Sandvik, A. K., Gustafsson, B. I., Mjönes, P. & Fossmark, R. (2018). Not only stem cells, but also mature cells, particularly neuroendocrine cells, may develop into tumours: time for a paradigm shift. Therapeutic Advances in Gastroenterology, 11, Article ID UNSP 1756284818775054.
Open this publication in new window or tab >>Not only stem cells, but also mature cells, particularly neuroendocrine cells, may develop into tumours: time for a paradigm shift
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2018 (English)In: Therapeutic Advances in Gastroenterology, ISSN 1756-283X, E-ISSN 1756-2848, Vol. 11, article id UNSP 1756284818775054Article, review/survey (Refereed) Published
Abstract [en]

Stem cells are considered the origin of neoplasms in general, and malignant tumours in particular, and the stage at which the stem cells stop their differentiation determines the degree of malignancy. However, there is increasing evidence supporting an alternative paradigm. Tumours may develop by dedifferentiation from mature cells able to proliferate. Studies of gastric carcinogenesis demonstrate that mature neuroendocrine (NE) cells upon long-term overstimulation may develop through stages of hyperplasia, dysplasia, and rather benign tumours, into highly malignant carcinomas. Dedifferentiation of cells may change the histological appearance and impede the identification of the cellular origin, as seen with gastric carcinomas, which in many cases are dedifferentiated neuroendocrine tumours. Finding the cell of origin is important to identify risk factors for cancer, prevent tumour development, and tailor treatment. In the present review, we focus not only on gastric tumours, but also evaluate the role of neuroendocrine cells in tumourigenesis in two other foregut-derived organs, the lungs and the pancreas, as well as in the midgut-derived small intestine.

Place, publisher, year, edition, pages
SAGE PUBLICATIONS LTD, 2018
Keywords
carcinogenesis, neuroendocrine, stem cells, tumour
National Category
Gastroenterology and Hepatology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-364740 (URN)10.1177/1756284818775054 (DOI)000443188600001 ()29872453 (PubMedID)
Available from: 2018-11-01 Created: 2018-11-01 Last updated: 2018-11-01Bibliographically 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
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-3432-1182

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