First-Line Chemotherapy With Capecitabine and Temozolomide in Patients With Metastatic Pancreatic Endocrine Carcinomas

Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
Cancer (Impact Factor: 4.89). 01/2011; 117(2):268-75. DOI: 10.1002/cncr.25425
Source: PubMed


Temozolomide is an active agent in metastatic pancreatic endocrine carcinomas. In vitro data indicate that the combination of capecitabine and temozolomide is synergistic for induction of apoptosis in neuroendocrine tumor cell lines. The authors retrospectively evaluated the efficacy of capecitabine and temozolomide in 30 patients with metastatic pancreatic endocrine carcinomas to assess response rate, progression free survival (PFS), and overall survival (OS).
Patients with metastatic, well, or moderately differentiated pancreatic endocrine carcinomas who had not received prior systemic chemotherapy were treated with capecitabine (750 mg/m² twice daily, days 1-14) and temozolomide (200 mg/m² once daily, days 10-14) every 28 days.
Among 30 patients treated, 21 (70%) patients achieved an objective radiographic response. Median progression-free survival was 18 months. The rate of survival at two years was 92%. Only 4 patients (12%) experienced grade 3 or 4 adverse events.
The combination of capecitabine and temozolomide is associated with an exceptionally high and durable response rate in metastatic endocrine carcinomas of the pancreas. Clinical endpoints, including response rate, survival, and toxicity, are superior to those observed with streptozocin-based regimens.

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Available from: Larry Kvols, Sep 17, 2014
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    • "Temozolomide may be used as first-line treatment for advanced p-NET. retrospective data showed a response rate of 70% and pfS of 18 months of the convenient, oral combination of temozolomide and capecitabine [33]. in a retrospective analysis of patients with p-NET receiving various temozolomide-based treatments, 34% experienced partial response with a median pfS of 13.6 months. by contrast, only 2% of non-p-NET patients had an objective response with a pfS of 9.6 months [34]. "
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    ABSTRACT: Background: The diagnostic work-up and treatment of patients with neuroendocrine neoplasms (NENs) has undergone major recent advances and new methods are currently introduced into the clinic. An update of the WHO classification has resulted in a new nomenclature dividing NENs into neuroendocrine tumours (NETs) including G1 (Ki67 index ≤ 2%) and G2 (Ki67 index 3-20%) tumours and neuroendocrine carcinomas (NECs) with Ki67 index > 20%, G3. Aim. These Nordic guidelines summarise the Nordic Neuroendocrine Tumour Group's current view on how to diagnose and treat NEN-patients and are meant to be useful in the daily practice for clinicians handling these patients.
    Acta Oncologica 09/2014; 53(10). DOI:10.3109/0284186X.2014.941999 · 3.00 Impact Factor
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    • "Recent prospective and retrospective studies have suggested that temozolomide-based regimens may be comparable in efficacy and more tolerable than streptozocin-based regimens. In retrospective series, temozolomide-based therapy has been associated with overall response rates of 8 %–70 % in patients with advanced pancreatic NET [62–64]. "
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    ABSTRACT: Opinion statement Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies characterized by variable but most often indolent biologic behavior. Well-differentiated NETs can be broadly classified as either carcinoid or pancreatic NET. Although they have similar characteristics on routine histologic evaluation, the 2 tumor subtypes have different biology and respond differently to treatment, with most therapeutic agents demonstrating higher response rates in pancreatic NETs compared with carcinoid. Until recently, systemic treatment options for patients with advanced NETs were limited. However, improvements in our understanding of signaling pathways involved in the pathogenesis, growth, and spread of NETs have translated into an expansion of treatment options. Aberrant signaling through the mechanistic pathway of rapamycin (mTOR) pathway has been implicated in neuroendocrine tumorigenesis. Additionally, altered expression of mTOR pathway components has been observed in NETs and has been associated with clinical outcomes. Targeting the mTOR pathway has emerged as an effective treatment strategy in the management of advanced NETs. In a randomized, placebo-controlled study of patients with advanced pancreatic NET, treatment with the mTOR inhibitor everolimus was associated with improved progression-free survival (PFS). Largely based upon these data, everolimus has been approved in the United States and Europe for the treatment of patients with advanced pancreatic NET. The activity of everolimus remains under investigation in patients with carcinoid tumors. In a randomized study of patients with advanced carcinoid tumors associated with carcinoid syndrome, the addition of everolimus to octreotide was associated with improved PFS compared with octreotide. However, the results did not meet the prespecified level of statistical significance based on central review of radiographic imaging. Results from a randomized study examining the efficacy of everolimus in patients with nonfunctional gastrointestinal and lung NETs are awaited. In addition, further investigation is needed to determine whether primary tumor site or other clinical and molecular factors can impact response to mTOR inhibition. Although everolimus can slow tumor progression, significant tumor reduction is rarely obtained. Targeting multiple signaling pathways is a treatment strategy that may provide better tumor control and overcome resistance mechanisms involved with targeting a single pathway. Results of ongoing and future studies will provide important information regarding the added benefit of combining mTOR inhibitors with other targeted agents, such as VEGF pathway inhibitors, and cytotoxic chemotherapy in the treatment of advanced NETs.
    Current Treatment Options in Oncology 08/2014; 15(3). DOI:10.1007/s11864-014-0294-4 · 3.24 Impact Factor
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    • "In addition, combining LuTate with other concomitant chemotherapy agents to further increase efficacy should also be considered. Recent studies have shown that capecitabine and temozolomide are highly active and well tolerated in well-differentiated metastatic pancreatic NET [29, 30]. A recent study combining this regimen with LuTate has shown promising results [31], and therefore may be considered in patients with metastatic grade 2 NET or grade 3 neuroendocrine carcinoma of the pancreas. "
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    ABSTRACT: Purpose To review the response and outcomes of 177Lu-DOTA-octreotate chemoradionuclide therapy (LuTate PRCRT) in patients with neuroendocrine tumour (NET) expressing high levels of somatostatin receptors with uncontrolled symptoms or disease progression. Methods A total of 68 patients (39 men; 17 – 76 years of age) who had completed an induction course of at least three cycles of LuTate PRCRT between January 2006 and June 2010 were reviewed. Ten patients were treated for uncontrolled symptoms and 58 had disease progression despite conventional treatment. The majority had four induction LuTate cycles (median treatment duration 5 months and cumulative activity 31 GBq), and 63 patients had concomitant 5-FU radiosensitizing infusional chemotherapy. Factors predicting overall survival were assessed using the log-rank test and Cox proportional hazards regression. Results Of those treated for uncontrolled symptoms, 70 % received benefit maintained for at least 6 months after treatment. Among patients with progressive disease 68 % showed stabilization or regression on CT, 67 % on molecular imaging and 56 % biochemically up to 12 months after treatment; 32 patients died. Overall survival rates at 2 and 5 year were 72.1 % and 52.1 %, respectively. Median overall survival was not estimable at a median follow-up of 60 months (range 5 – 86 months). Nonpancreatic primary sites, dominant liver metastases, lesion size 5 cm) appeared to have lower objective response rates and may need a more aggressive treatment approach.
    European journal of nuclear medicine and molecular imaging 05/2014; 41(10). DOI:10.1007/s00259-014-2788-5 · 5.38 Impact Factor
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