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Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Onkologisk endokrinologi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Onkologisk endokrinologi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Onkologisk endokrinologi)
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2007 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, no 10, 2986-2991 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: A retrospective analysis of the toxicity and efficacy of temozolomide in advanced neuroendocrine tumors. Experimental Design: Thirty-six patients with advanced stages of neuroendocrine tumor (1 gastric, 7 thymic and 13 bronchial carcinoids, 12 pancreatic endocrine tumors, 1 paraganglioma, 1 neuroendocrine foregut, and 1 neuroendocrine cecal cancer) were treated with temozolomide (200 mg/m2) for 5 days every 4 weeks. Patients had previously received a mean of 2.4 antitumoral medical regimens. Tumor response was evaluated radiologically according to the Response Evaluation Criteria in Solid Tumors every 3 months on an intent-to-treat basis. The circulating tumor marker plasma chromogranin A was also assessed. The expression of 06-methylguanine DNA methyltransferase, an enzyme implicated in chemotherapy resistance, was studied by immunohistochemistry (n = 23) and compared with response to temozolomide. Results: Median overall time to progression was 7 months (95% confidence interval, 3-10). Radiologic response was seen in 14% of patients and stable disease in 53%. Side effects were mainly hematologic; 14% experienced grade 3 or 4 thrombocytopenia (National Cancer Institute toxicity criteria). Ten patients had tumors with 06-methylguanine DNA methyltransferase immunoreactivity in <10% of nuclei, whereas four patients showed radiologic responses. Conclusions: Temozolomide as monotherapy had acceptable toxicity and antitumoral effects in a small series of patients with advanced malignant neuroendocrine tumors and four of these showed radiologic responses.

Place, publisher, year, edition, pages
2007. Vol. 13, no 10, 2986-2991 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-12826DOI: 10.1158/1078-0432.CCR-06-2053ISI: 000246572600023PubMedID: 17505000OAI: oai:DiVA.org:uu-12826DiVA: diva2:40595
Available from: 2008-06-04 Created: 2008-06-04 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Pancreatic Endocrine Tumors and GIST - Clinical Markers, Epidemiology and Treatment
Open this publication in new window or tab >>Pancreatic Endocrine Tumors and GIST - Clinical Markers, Epidemiology and Treatment
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pancreatic endocrine tumors and gastrointestinal stromal tumors are rare. Evidence regarding prognostic factors, and in the former also treatment, is scarce.

We evaluated the survival and prognostic factors in a consecutive series of 324 patients with pancreatic endocrine tumors treated at a single institution. Radical surgery, WHO classification, TNM stage, age and Ki67 ≥2% emerged as independent prognostic factors. Having a non-functioning tumor was not an independent prognostic marker, and neither was hereditary tumor disease. We present the first evaluation of the newly proposed TNM staging system for these patients. A separate analysis of well-differentiated neuroendocrine carcinomas is reported, suggesting tumor size ≥5cm and Ki67 ≥2% as negative prognostic markers in this group.

The first 36 patients with advanced neuroendocrine tumors treated with temozolomide at our clinic were evaluated. The median time to progression was seven months. Fourteen percent showed partial regression and 53% stabilization of disease. Side effects were generally mild. Investigation of O6-methylguanine DNA methyltransferase revealed a low expression in a subset of tumors. Four out of five patients responding to treatment had tumors with low expression.

Concomitant expression of the orexigen ghrelin and its receptor in pancreatic endocrine tumors is demonstrated. No significant difference in mean plasma ghrelin between patients and controls were found, but elevated plasma ghrelin was seen in five patients.

We provide the first report of expression of ghrelin and its receptor in gastrointestinal stromal tumors. Concomitant expression was frequent, indicating the presence of an autocrine loop. The tumors also expressed the neuroendocrine marker synaptic vesicle protein 2. Together, these findings are suggestive of neuroendocrine features.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 64 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 267
Keyword
Medicine, Pancreatic endocrine tumor, Gastrointestinal stromal tumor, Neuroendocrine, Multiple endocrine neoplasia type 1, Prognostic factors, Temozolomide, TNM staging, O6-methylguanine DNA methyltransferase, Growth hormone secretagogue receptor, Ghrelin, Medicin
Identifiers
urn:nbn:se:uu:diva-7937 (URN)978-91-554-6921-4 (ISBN)
Public defence
2007-09-07, Enghoffsalen, ing. 50, b.v., Akademiska Sjukhuset, Uppsala, 09:15 (English)
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Available from: 2007-05-24 Created: 2007-05-24 Last updated: 2009-08-13Bibliographically approved

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Ekeblad, SaraSundin, AndersJanson, Eva TiensuuGranberg, DanKindmark, HenrikÖberg, KjellEriksson, BarbroSkogseid, Britt

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Ekeblad, SaraSundin, AndersJanson, Eva TiensuuGranberg, DanKindmark, HenrikÖberg, KjellEriksson, BarbroSkogseid, Britt
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