A prospective randomised phase-II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: A study of the CESAR Central European Society for Anticancer Drug Research–EWIV

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Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease. To improve the standard therapy with gemcitabine, we initiated a prospective randomised phase-II trial with gemcitabine (GEM) versus gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. The rational of adding sunitinib was its putative antiangiogenic mechanism of action.

Methods

A total of 106 eligible patients with locally advanced, unresectable or metastatic PDAC without previous system therapy were randomised to receive GEM at a dosage of 1.000 mg/m2 d1, 8, 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000 mg/m2 d1 + 8 and sunitinib 50 mg p.o. d1–14, q21d. The primary end-point was progression free survival (PFS), secondary end-points were overall survival (OS), toxicity and overall response rate (ORR).

Results

The confirmatory analysis of PFS was based on the intend-to-treat (ITT) population (N = 106). The median PFS was 13.3 weeks (95% confidence interval (95%-CI): 10.4–18.1 weeks) for GEM and 11.6 weeks for SUNGEM (95%-CI: 7.0–18.0 weeks; p = 0.78 one-sided log-rank). The ORR was 6.1% (95%-CI: 0.7–20.2%) for GEM and for 7.1% (95%-CI: 0.9–23.5%) for SUNGEM (p = 0.87). The median time to progression (TTP) was 14.0 weeks (95%-CI: 12.4–22.3 weeks) for GEM and 18.0 weeks (95%-CI: 11.3–19.3 weeks) for SUNGEM (p = 0.60; two-sided log-rank). The median OS was 36.7 weeks (95%-CI: 20.6–49.0 weeks) for the GEM arm and 30.4 weeks (95%-CI: 18.1–37.6 weeks) for the SUNGEM (p = 0.78, one-sided log-rank). In regard to toxicities, suspected SAEs were reported in 53.7% in the GEM arm and 71.2% in the SUNGEM arm. Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1% versus 27.8% in the GEM arm (p = 0.045, two sided log-rank).

Conclusions

The combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading causes of cancer deaths worldwide [1]. The median age at diagnose is 70 years for men and 76 years for women with a lifetime risk of 1.5% for both genders [1]. Only 10–20% of pancreatic cancer patients can be resected with curative intention at the time of diagnosis [2]. Most patients with pancreatic cancer are diagnosed with locally advanced stage or metastatic disease. Approximately 50% of new pancreatic cancer cases are diagnosed with metastatic disease. Despite some progress in systemic therapies, the outcome in advanced stages is rather poor with a 5-year survival of about 5–10% only. The main back bone agent is still gemcitabine, but meanwhile the combination FOLFIRINOX demonstrated some superiority to gemcitabine alone [4]. Additionally, the combination of gemcitabine with nab-paclitaxel improved overall survival (OS) from 6.7 to 8.5 months [3]. However, there is still a medical need for new therapeutic options.

Pancreatic cancer is a result of multiple genetic alterations for example activation of the K-Ras or BRAF oncogenes, as well as inactivation of the tumour-suppressor genes DPC4, CDKN2A and TP53 [5]. Additionally, down-regulation of STAT3 signalling has been shown to induce apoptosis but also to promote anti-apoptotic gene expression in human pancreatic cancer cells [6], [7], [8]. Moreover, an increased activation of the PI3K/AKT-pathway has been detected in about half of pancreatic cancers [9], [10]. Recently, Georgiadou et al. [11] could demonstrate that vascular endothelial growth factor (VEGF) and Id-1 overexpression in PDAC were found to be associated with high microvessel density and was associated with a worse outcome in terms of patient survival. Additionally, curcumin has been shown to inhibit the growth of PDAC cell lines in vitro and in a mouse model by inhibiting various intracellular pathways including nuclear factor kappa B (NFkB), which is involved in angiogenesis [12], [13]. Therefore, the potential of anti-angiogenic active VEGF directed multi tyrosine-kinase-inhibitors (TKI) such as the receptor TKI sunitinib should be assessed for improving the outcome in PDAC. Sunitinib is well established in the treatment of metastatic renal cell cancer and gastrointestinal stromal tumours (GIST) [14], [15].

Based on the phase-I data of phase-I trials [16], [17] regarding the combination of gemcitabine and sunitinib in advanced solid tumours, we initiated a prospective randomised phase-II trial comparing gemcitabine and sunitinib (SUNGEM) with gemcitabine (GEM) alone in locally advanced or metastatic PDAC.

Section snippets

Inclusion and exclusion criteria

Eligible patients were at least 18 year old with a histologically or cytologically confirmed metastatic or locally advanced pancreatic adenocarcinoma.

Additional eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate haematologic, hepatic and renal function, a normal electrocardiogram (ECG) without QT prolongation (corrected QT (QTc) < 450 ms) as well as a measurable disease with at least one uni-dimensionally measurable target lesion by

Patient characteristics

In this multicenter study a total of 118 patients were recruited by 12 institutions starting on April 16, 2008 (1st patient in), and February 6, 2012 (last patient out). Of in total 118 screened patients, 113 patients were randomised (95.8%) and five patients had screening failures (4.2%). Seven (6.2%) of the 113 randomised patients did not receive any study medication (GEM: 3; SUNGEM: 4) while 106 patients (93.8%) received the study medication at least once and according to the study protocol

Discussion

Locally advanced or metastatic PDAC is still associated with a poor prognosis and in recent years only limited progress has been made to improve its outcome [3], [4]. The discovery of co-expression of VEGF and PDGF as a potential therapeutic target for pancreatic carcinoma has raised hope for new treatment options [20], [21], [22], [23]. Inhibition of VEGF or VEGFR has shown to inhibit pancreatic tumour cell growth in vitro and in mouse models [21], [22], [23] and therapeutic concepts including

Conflict of interest statement

None declared.

Acknowledgement

The study was supported with a grant from Pfizer Pharma, Berlin, Germany.

References (36)

  • G. Feldmann et al.

    Molecular genetics of pancreatic intraepithelial neoplasia

    J Hepatobiliary Pancreat Surg

    (2007)
  • W. Glienke et al.

    Targeting STAT3 signaling in pancreatic cancer promotes antiapoptotic gene expression

    Pancreas

    (2011)
  • W. Glienke et al.

    Downregulation of STAT3 signaling induces apoptosis but also promotes anti-apoptotic gene expression in human pancreatic cancer cell lines

    Tumour Biol

    (2011)
  • G.G. Mackenzie et al.

    Targeting mitochondrial STAT3 with the novel phospho-valproic acid (MDC-1112) inhibits pancreatic cancer growth in mice

    PLoS One

    (2013)
  • C. Delbaldo et al.

    Predictive biomarkers for the activity of mammalian target of rapamycin (mTOR) inhibitors

    Rev Targ Oncol

    (2011)
  • T. Asano

    The PI3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factor NF-kappaB and c-Myc in pancreatic cancer cells

    Oncogene

    (2004)
  • W. Glienke et al.

    Curcumin inhibits constitutive STAT3 phosphorylation in human pancreatic cancer cell lines and downregulation of survivin/BIRC5 gene expression

    Cancer Invest

    (2010)
  • S. Bimonte et al.

    Curcumin inhibits tumor growth and angiogenesis in an orthotopic mouse model of human pancreatic cancer

    Biomed Res Int

    (2013)
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