A phase II study of sunitinib as a second-line treatment in advanced biliary tract carcinoma: A multicentre, multinational study

https://doi.org/10.1016/j.ejca.2011.11.017Get rights and content

Abstract

Background

Biliary tract carcinoma (BTC) is rare in the West, but not uncommon in Asia and is a highly fatal malignancy. VEGF expression is related with poor outcome in patients with BTC. Therefore, we conducted a phase II study to evaluate the efficacy and safety of sunitinib as second-line treatment.

Methods

This was a prospective, single-arm, multicentre, multinational study. Patients with unresectable, metastatic BTC who progressed after first-line chemotherapy were eligible. Sunitinib was administered at 37.5mg once daily continuously with 4-week cycle. The primary end point was the time to progression (TTP).

Results

Between May 2009 and October 2010, a total of 56 patients were enrolled from three countries. The median age was 55 years (range 38–75) and male to female ratio was 37:19. Median TTP was 1.7 months (95% confidence interval (CI) 1.0–2.4). The objective response rate was 8.9% (5 partial response) and disease control rate was 50.0%. (23 stable disease) Grade 3–4 toxicities were observed in 46.4% of the patients with neutropenia and thrombocytopenia being the most frequent (21.4%).

Conclusions

This phase II study suggests that sunitinib monotherapy demonstrated marginal efficacy in metastatic BTC patients although toxicity should be concerned in Asian population.

Introduction

Biliary tract cancers (BTCs) encompass adenocarcinomas arising in the intra or extrahepatic biliary tree and in the gall bladder. BTC is a relatively uncommon malignancy in Western countries,1 but has a high incidence in Asia and Latin America.2, 3 Surgery is the only curative treatment option for BTCs; however, only 25% of the cases are resectable at presentation and the relapse rate is high after surgery.4 Palliative chemotherapy is usually considered for patients with unresectable or advanced BTCs. While a combination of gemcitabine and platinum agents seems to be a reasonable treatment option as first-line treatment,5, 6, 7, 8 no standard therapy has yet been established following occurrence of gemcitabine refractoriness.9

Several studies have reported that vascular endothelial growth factor (VEGF) is overexpressed in BTCs and that the VEGF expression is associated with more advanced stage and worse prognosis.10, 11, 12 This suggests the possibility that VEGF may represent a potential therapeutic target. Indeed, Zhu et al. have demonstrated that anti-VEGF treatment with bevacizumab, combined with gemcitabine plus cisplatin, showed antitumour activity and resulted in median overall survival (OS) of 12.7 months and progression free survival (PFS) of 7.0 months in patients with advanced BTCs.13 In a study by Lubner et al., anti-VEGF treatment with bevacizumab, along with erlotinib, resulted in meaningful clinical outcomes, with over 50% of patients with advanced BTCs showing documented stable disease.14

Sunitinib is an orally administered inhibitor of multiple receptor tyrosine kinases that are involved in tumour proliferation and angiogenesis; specifically, platelet-derived growth factor receptor (PDGFR), VEGF receptor, stem cell factor receptor (KIT), Fms-like tyrosine kinase (Flt-3) and rearranged during transfection (RET). This agent has shown efficacy against many solid cancers, including metastatic clear cell renal cell carcinoma,15 imatinib-refractory gastrointestinal stromal tumour16 and pancreatic neuroendocrine tumour.17 In addition, an objective response has been observed in phase 2 trials in patients with breast cancer,18 non-small cell lung cancer,19 colorectal cancer20 and prostate cancer.21 In the present study, we conducted a phase II, multinational, multicentre trial to analyse the efficacy and toxicity of sunitinib in patients with advanced biliary tract cancer following failure of first-line treatment. This study has been registered at www.clinicaltrials.gov as # NCT01082809.

Section snippets

Study design

This was an open label, phase II, single arm, multicentre, multinational study conducted at Samsung Medical Center, Seoul; Korea, Rajiv Gandhi Cancer Institute & Research Centre, New Delhi, India and ChiangMai University, ChiangMai, Thailand. The protocol was approved by the institutional review board of each institute and the trial was conducted in accordance with the Declaration of Helsinki. All patients were required to give written informed consent before enrolment. Pfizer provided

Patient characteristics

Between May 2009 and October 2010, a total of 56 patients were enrolled in this study, consisting of 37 patients from South Korea, 17 patients from Thailand and two patients from India. The median age was 55 years (range 38–75) and male to female ratio was 37:19 (66.1%:33.9%). In total, 35 patients (62.5%) had intrahepatic duct cancer, 6 (10.7%) had extrahepatic duct cancer and 15 (26.8%) had gall bladder cancer. Histological examination revealed that, the cohort had 53 (94.6%) cases of

Discussion

Our study showed the following: (1) Second-line sunitinib demonstrated a median TTP of 1.7 months (95% CI 1.0–2.4), objective response rate of 8.9% (95% CI 3.0–19.6) and a disease control rate of 50.0% (95% CI 36.3–63.7) in 54 Asian patients with advanced BTCs who had shown progressive disease after first-line cytotoxic chemotherapy; (2) 46.4% of patients had experienced grade 3 or 4 adverse events, which resulted in frequent dose reductions and treatment delays.

Owing to the rarity of BTCs and the

Conflict of interest statement

None declared.

References (30)

  • Furuse.J. OT et al.

    A randomized study of gemcitabine/cisplatin versus single-agent gemcitabine in patients with biliary cancer

    J Clin Oncol

    (2009)
  • A. Sharma et al.

    Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study

    J Clin Oncol

    (2010)
  • J. Lee et al.

    Phase II trial of gemcitabine combined with cisplatin in patients with inoperable biliary tract carcinomas

    Cancer Chemother Pharmacol

    (2008)
  • Y. Hida et al.

    Vascular endothelial growth factor expression is an independent negative predictor in extrahepatic biliary tract carcinomas

    Anticancer Res

    (1999)
  • T. Nakashima et al.

    Vascular endothelial growth factor-C expression in human gallbladder cancer and its relationship to lymph node metastasis

    Int J Mol Med

    (2003)
  • Cited by (107)

    • Continuum of care for advanced biliary tract cancers

      2020, Clinics and Research in Hepatology and Gastroenterology
      Citation Excerpt :

      Likewise, randomized phase II trials with cediranib [56], sorafenib [57], and vandetanib [58] were also negative. In L2, sunitinib provided a marginal median time to progression of 1.7 months in a single-arm phase II study [59]. On another hand, antiangiogenics may be of interest in patients with iCCA.

    • Targeted Therapy: Molecular Pathology and Targets of Gallbladder Cancer

      2023, Gallbladder Cancer: Current Treatment Options
    View all citing articles on Scopus
    View full text