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Objective: To retrospectively analyze toxicity, progression-free survival (PFS), overall survival (OS), and their determinants in patients with advanced pancreatic neuroendocrine tumors (PanNETs), previously pretreated with chemothe-r-apy, undergoing peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE., Methods: A total of 102 patients with advanced PanNETs, previously pretreated with one (67%) or several (33%) lines of chemotherapy, were included, of whom 90% had progressive disease and the majority (74.5%) had grade 2 tumors. 177Lu-DOTATATE, 7.4 GBq per cycle, was administered with 6- to 8-week intervals in 88% of patients utilizing a dosimetry-guided protocol until an absorbed dose of 23 Gy to the kidneys was reached., Results: A mean dose of 32 ± 10.9 GBq per patient was administered in 1-10 cycles starting a median of 36 months after PanNET diagnosis. The median follow-up was 34 months, the median PFS was 24 months, and the median OS was 42 months from start of PRRT. Independent risk factors for both progression and death were liver tumor burden >50%, more than one line of previous chemotherapy, and elevated alkaline phosphatase. Resection of the primary tumor was linked to longer survival. Bone marrow toxicity grade 3-4 occurred in 10.8%. One patient (1.0%) developed acute myeloid leukemia. Bone marrow toxicity was unrelated to type and length of previous chemotherapy, amount of administered activity, and absorbed dose to the bone marrow., Conclusion: 177Lu-DOTATATE therapy was feasible, highly effective, and safe in patients with advanced PanNETs heavily pretreated with chemotherapy. More than one line of chemotherapy was a therapy-related independent risk factor for shorter PFS and OS., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Introduction: Little is known about how pancreatic neuroendocrine tumors (PanNETs) evolve over time and if changes toward a more aggressive biology correlate with prognosis. The purpose of this study was to characterize changes in PanNET differentiation and proliferation over time and to correlate findings to overall survival (OS)., Patients and Methods: In this retrospective cohort study, we screened 475 PanNET patients treated at Uppsala University Hospital, Sweden. Sporadic patients with baseline and follow-up tumor samples were included. Pathology reports and available tissue sections were reevaluated with regard to tumor histopathology and Ki-67 index., Results: Forty-six patients with 106 tumor samples (56 available for pathology reevaluation) were included. Median Ki-67 index at diagnosis was 7% (range 1-38%), grade 1 n = 8, grade 2 n = 36, and grade 3 n = 2. The median change in Ki-67 index (absolute value; follow-up - baseline) was +14% (range -11 to +80%). Increase in tumor grade occurred in 28 patients (63.6%), the majority from grade 1/2 to grade 3 (n = 24, 54.5%). The patients with a high-grade progression had a median OS of 50.2 months compared to 115.1 months in patients without such progression (hazard ratio 3.89, 95% CI 1.91-7.94, p < 0.001)., Conclusions: A longitudinal increase in Ki-67 index and increase in tumor grade were observed in a majority of PanNETs included in this study. We propose that increase in Ki-67 index and high-grade progression should be investigated further as important biomarkers in PanNET., (© 2019 S. Karger AG, Basel.)

Background: In our center, the combination of streptozocin (STZ) and 5-fluorouracil (5-FU) has been used as the first-line treatment in the majority of patients with pancreatic neuroendocrine tumors (pNETs) over the past few decades. The objective of the current study was to assess the efficacy, prognostic factors and safety of the combination of STZ and 5-FU., Patients and Methods: Medical records and radiological reports of 133 patients with pNETs who received the combination of STZ and 5-FU during the period 1981-2014 were retrospectively evaluated., Results: The median survival from the start of treatment was 51.9 months in the whole group. In the radiologically evaluable patients (n = 100), progression-free survival was 23 months. Complete response was reached in 3 patients (3%), partial response in 25 patients (25%), 64 patients (64%) had stable disease, and 8 patients (8%) had progressive disease. In a multivariate analysis, surgery of the primary tumor and having a G3 tumor were significant positive and negative prognostic factors of survival from the start of treatment, respectively. Having either a G3 tumor or a stage IV tumor were significant prognostic factors for a shorter progression-free survival. Chemotherapy had to be discontinued in 29 patients due to side effects, of which kidney toxicity (mainly grades 1-2) was the most frequent., Conclusion: As shown in recent reports, the combination of STZ and 5-FU is effective in the treatment of pNETs in terms of survival and radiological response and has an acceptable toxicity profile., (© 2015 S. Karger AG, Basel.)

Introduction: Metastatic bronchial carcinoids are rare neoplasms, where efforts of medical treatment so far have been disappointing. A previous study from our center indicated that temozolomide might be of value., Materials and Methods: All patients with progressive metastatic bronchial carcinoid treated with temozolomide as monotherapy at our center between 2004 and 2010 (n = 31) were included in this retrospective study. 14 tumors were classified as typical and 15 as atypical carcinoids, whereas 2 tumors could not be classified. Temozolomide was given on 5 consecutive days every 4 weeks. Toxicity was evaluable in 28 of 31 patients, and 22 patients were evaluable by RECIST 1.1., Results: There were no complete responses. A partial response was seen in 3 patients (14%), stable disease in 11 (52%) and progressive disease in 7 patients (33%). Median progression-free survival was 5.3 months and median overall survival was 23.2 months from the start of temozolomide. Toxicities grade 3-4 were noted in 4 patients, thrombocytopenia (n = 3) and leukopenia (n = 1)., Conclusion: Temozolomide as monotherapy shows activity in metastatic bronchial carcinoids. Regimens combining temozolomide with other agents (e.g. capecitabine and/or bevacizumab, everolimus, radiolabeled somatostatin analogues) should be further studied in these patients., (Copyright © 2013 S. Karger AG, Basel.)

Background: Patients with malignant midgut carcinoids are occasionally diagnosed with limited tumor spread, and surgery with radical intention is performed. Despite curative intent, recurrences occur frequently, motivating long-term biochemical and radiological follow-up. This study aimed to compare the usefulness of various methods in detecting such recurrences., Methods: This retrospective study included 56 patients with radically operated midgut carcinoids referred to our University Hospital for evaluation and follow-up between 1985 and 2004. Patients were monitored 1-3 times per year using plasma-chromogranin A (P-CgA), urinary 5-hydroxyindoleacetic acid (U-5HIAA) concentrations as well as radiological examinations, including ultrasonography, computerized tomography or magnetic resonance investigation. In a subset of cases, somatostatin receptor scintigraphy and/or positron emission tomography with 5-hydroxytryptophan was performed. Time from operation until established recurrence was recorded., Results: Tumor recurrence was established in 33 of 56 patients after a median of 32 months (range 6-217). Elevated P-CgA was the first marker to become pathologically elevated in 28 of these 33 patients (85%). In 3 of these 28 patients, radiology was simultaneously positive for a recurrence., Conclusion: P-CgA was the first marker to indicate tumor recurrence in the majority of radically operated midgut carcinoid patients. To avoid unnecessary and costly examinations in asymptomatic patients, we suggest that follow-up should comprise measurements of P-CgA twice a year and annual ultrasonography until P-CgA is elevated or clinical symptoms occur, at which time all efforts should be made to identify recurrent tumor lesions in order to give the patient the best possible treatment which, if possible, should be surgical removal of the recurrence.

Unlabelled: Treatment with combined streptozotocin and liposomal doxorubicin is safe and efficient in patients with endocrine pancreatic tumors (EPTs). No cardiac toxicity was reported., Background: The combination of streptozotocin and doxorubicin has been shown to be superior to streptozotocin and fluorouracil in the treatment of metastatic EPTs. However, the risk of cardiac toxicity from anthracyclins hampers the usefulness of the drug combination. Liposomal doxorubicin has a lower frequency of cardiac adverse events compared to doxorubicin. We wanted to assess the efficacy and safety of combined streptozotocin and liposomal doxorubicin in patients with metastatic EPTs., Methods: Thirty patients with metastatic EPTs were recruited from three medical centers in Norway and Sweden during a time period of 3 years. All patients had histopathologically confirmed diagnoses and bidimensionally measurable lesions. 30 mg/m(2) of liposomal doxorubicin was administered on day 1 of each cycle. During the first course, 1 g of streptozotocin was given on 5 consecutive days. Thereafter, 2 g of streptozotocin was given on day 1 only. Treatment was repeated every 3 weeks., Results: Twelve of 30 patients (40%) achieved an objective radiological response with a median duration of 9 months. Stabilization of disease was achieved in 17 of 30 patients (57%) for a median duration of 11 months. Only one patient had progressive disease as best response. The 2-year progression-free survival was 18% and the 2-year overall survival was 72%. The treatment was well tolerated. None of the patients experienced cardiac toxicity., Conclusion: We conclude that combined streptozotocin and liposomal doxorubicin is a safe and efficient treatment for EPTs. The efficacy seems to be comparable to that of combined streptozotocin and doxorubicin, whereas the cardiac toxicity clearly favors using the liposomal drug combination., (2008 S. Karger AG, Basel.)

Background: The expression of certain tyrosine kinase receptors (TKR) has been shown to have a prognostic value in many tumor entities. In recent years, inhibitors and monoclonal antibodies directed towards these receptors have been developed. Several have shown antitumoral effects and have been tested in clinical trials. We wanted to investigate whether midgut carcinoid tumors express TKR and therefore would be suitable for clinical trials with TKR inhibitors (TKRI) or monoclonal antibodies., Material and Methods: Tumor tissue from 36 patients (24 women and 12 men) with a malignant midgut carcinoid tumor was obtained. The tissues were examined with immunohistochemistry, using polyclonal antibodies against platelet-derived growth factor receptor-alpha (PDGFRalpha), platelet-derived growth factor receptor-beta (PDGFRbeta), epidermal growth factor receptor (EGFR) and c-kit. Human BON1 cells were cultivated and stimulated with PDGF-BB. We also present a case report of a patient with a malignant midgut carcinoid tumor who had stabilization of tumor growth during treatment with imatinib., Results: Immunohistochemical staining for PDGFRalpha in tumor cells showed immunoreaction for the receptor in 13/34 (38%) for PDGFRbeta in 29/33 (88%), and 24/33 (73%) were immunoreactive for EGFR. No tumor tissue showed immunoreaction for c-kit. In tumor stroma PDGFRalpha was expressed in 35%, PDGFRbeta in 94% and EGFR in 9%. We show that human neuroendocrine tumor cells respond to PDGF, indicating that these tumors express functional PDGF receptors., Conclusion: Malignant midgut carcinoid tumors may express three of the four TKR tested in this investigation. Therefore, these tumors might be susceptible for treatment with TKRI or monoclonal antibodies and this should be further explored in clinical trials., (Copyright 2006 S. Karger AG, Basel.)

This 6-month, open, non-controlled, multicenter, dose-titration study evaluated the efficacy and safety of 28-day prolonged-release (PR) lanreotide in the treatment of carcinoid syndrome. Eligible patients had a carcinoid tumor with > or =3 stools/day and/or > or =1 moderate/severe flushing episodes/day. Six treatments of 28-day PR lanreotide were administered by deep subcutaneous injection. The dose for the first two injections was 90 mg. Subsequent doses could be titrated (60, 90, 120 mg) according to symptom response. Seventy-one patients were treated. Flushing decreased from a mean of 3.0 at baseline to 2.3 on day 1, and 2.0 on day 2, with a daily mean of 2.1 for the first week post-treatment (p < 0.05). Diarrhea decreased from a mean of 5.0 at baseline to 4.3 on day 1 (p < 0.05), and 4.5 on day 2, with a daily mean of 4.4 for the first week post-treatment (p < 0.001). Symptom frequency decreased further after the second and third injections, and reached a plateau after the fourth injection. By month 6, flushing and diarrhea had significantly decreased from baseline by a mean of 1.3 and 1.1 episodes/day, respectively (both p < or = 0.001); 65% of patients with flushing as the target symptom and 18% of diarrhea-target patients achieved > or =50% reduction from baseline. Median urinary 5-hydroxyindoleacetic acid and chromogranin A levels decreased by 24 and 38%, respectively. Treatment was well tolerated. 28-day PR lanreotide was effective in reducing the symptoms and biochemical markers associated with carcinoid syndrome.