Background and Aim Chemotherapy with streptozocin (STZ) in combination with 5-FU

Background and Aim Chemotherapy with streptozocin (STZ) in combination with 5-FU or doxorubicin (Dox) represents a standard of care for patients with metastatic pancreatic neuroendocrine neoplasms (pNEN). with a median OS (mOS) of 28 months. Objective response rate (ORR) and disease control rate (DCR) were 34% and 72%, respectively. Biochemical response and positive octreotide scintigraphy predicted objective response. Univariate analysis revealed Ki-67 > 10% and the absence of biochemical or objective response by imaging as impartial risk factors for shorter PFS. Additionally, overall performance status (PS) and resection of the primary tumor were observed to influence mOS. Treatment was well tolerated with less than 10% grade 3 and 4 toxicities. Conclusions STZ-based chemotherapy is an effective and well-tolerated treatment option in patients with well differentiated neuroendocrine neoplasms. Positive octreotide scintigraphy and biochemical response predict objective response. Introduction Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms with increasing incidence [1] originating from endocrine cells in different anatomic locations. Pancreatic NETs differ AR-42 from intestinal NETs in many aspects including clinical presentation with unique hormone syndromes, genetic findings (e.g. mutations in the Menin gene [2]), a more aggressive course of disease resulting in worse prognosis [1], and responsiveness to treatment modalities such as molecular targeted brokers and chemotherapy. While the results of chemotherapy in patients with intestinal NETs are disappointing resulting in objective response rates of less than 20% in most trials, pancreatic NETs were shown to be chemosensitive. The combination of streptozocin (STZ) and fluorouracil (5-FU) is recommended as standard treatment for metastatic pancreatic AR-42 NETs in European guidelines [3, 4]. STZ is available since the early 80ies and approved for the treatment of pancreatic NETs in several countries. The early prospective randomized trials by Moertel reported high response rates (RR) of STZ-based combinations exceeding 60% [5, 6]. However, two subsequent retrospective series failed to confirm these results, which was attributed the definition of response [7, 8]. More recently, larger retrospective studies using standardized radiological response criteria repeatedly reported RRs ranging between 30 and 40% for STZ-based combination treatments [9C11]. A variety of prognostic factors has been described for patients with NETs including age, performance status, stage according to ENETS [12, 13] and AJCC [14], tumor load, levels of chromogranin A (CgA) [15], presence of circulating tumor cells [16] and grading based on the proliferation marker Ki-67. The latest WHO classification [17] of NETs is based on Ki-67 values and the prognostic relevance of this grading system has been validated in several studies [12, 18C20]. In contrast, the predictive value of Ki-67 is usually less clear. To date, no established predictive markers are available to facilitate treatment decisions. The ESMO guideline recommends the use of STZ-based chemotherapy in patients with pancreatic NETs and a proliferation rate between 5 and 20% [4]. However, this represents an expert opinion which is not evidence-based, since most chemotherapy trials in pNEN published so far did not assess the role of Ki-67 as predictive marker. Only in one study by OToole and co-workers an association between Ki-67 levels >5% and lack of response to systemic chemotherapy was reported [21]. It was thus the aim of our study to identify prognostic and predictive markers for pNEN-patients treated with STZ-based chemotherapy at our center. Patients and Methods Patients 77 consecutive patients with histologically confirmed pancreatic neuroendocrine tumors who received STZ-based chemotherapy between 1995 and 2013 were retrospectively recognized from a database at Rabbit Polyclonal to HBP1 the comprehensive cancer center at the University or college Hospital of Marburg. This study was conducted in accordance with the Declaration of Helsinki. Collection, storage, and evaluation of patient-related information in our NEN database were performed with the approval of the local ethics committee at the University or college of Marburg and after obtaining the patients informed consent. The initial statement of the local ethics committee was that a formal approval and written informed consent for collection and analysis of data arising from the routine clinical evaluation within the own hospital was not required. Therefore, patients who experienced their last visit/ died before 2004 only were asked for verbal consent (with approval of the ethics committee of this consent process). In 2004 the German NET registry was built up and for transmission of pseudonymized data a written AR-42 approval of the ethics committee was obtained. Since then all patients additionally gave a written consent for data collection and analysis. Protocol treatment and toxicity assessment All patients received STZ-containing chemotherapy in combination with Doxorubicin (Dox) or 5-FU. For patients who in the beginning received chemotherapy with STZ/Dox, Dox was replaced by 5-FU before the cumulative cardiotoxic dose of 550mg/m2 Dox AR-42 was reached. The chemotherapeutic STZ/Dox regimen included STZ at a dose of 500 mg/m2 on day 1C5 and Dox at a dose of 50 mg/m2 on day 1 and 22. The regimen was repeated.

Comments are closed.