Original articlePhase II trial of capecitabine combined with thalidomide in second-line treatment of advanced pancreatic cancer
Introduction
Pancreatic cancer is a common malignant tumor with poor prognosis, 5 years survival of 5%, owing to the difficulty from detecting at an early stage and high malignant potential [1]. Only 20% patients who does not have locally advanced or metastatic tumor are resectable [2]. Chemotherapy plays an important role in the treatment of pancreatic cancer. With the development of new drugs, the new chemotherapy for pancreatic cancer appears constantly. However, gemcitabine (GEM) has remained a backbone of new first-line chemotherapy regimen for advanced or metastatic pancreatic cancer and controlled disease-related symptoms [3]. In first-line treatment, GEM plus 5-flurouracil and folinic acid (FUFA) combination appeared to be well-tolerated and very active in patients. The median progression-free survival (PFS) was 9.75 months (95% CI 6.9–12.6) and the median overall survival (OS) was 13.10 months (95% CI 9.6–16.6) [4]. GEM combined with oxaliplatin was better than that of GEM alone in terms of clinical benefit, response rate, progression-free survival and a beneficial trend in survival of almost 2 months in first-line treatment [5]. Nowadays, several combination treatments of GEM plus targeted agents such as bevacizumab, cetuximab and erlotinib have been analyzed in advanced pancreatic cancer (APC). However, only erlotinib succeeded among these combinations. Therefore, in 2010, the National Comprehensive Cancer Network (NCCN) recommended that the treatment strategy for patients with advanced or metastatic pancreatic cancer is GEM or GEM-based regimen [6]. Yet, in first-line treatment, the period of relief was short. This situation suggested that the next objective is to find out what kind of further treatment after progression will improve the quality of life and prolong the survival time. An increasing number of patients maintained good clinical conditions after optimized first-line chemotherapy. These patients with a good functional performance status should be considered for clinical trial participation. Capecitabine (Xeloda) is an orally administered fluoropyrimidine and generally well tolerated in treating patients with APC. Treatment with capecitabine resulted in clinically significant beneficial effects on tumor-related symptoms and yielded objective response activity in patients with locally advanced or metastatic pancreatic cancer. Ten (24%) of 42 patients experienced a clinical benefit response (95% CI, 12.1–39.5%) as evidenced by improvement in analgesic consumption, pain intensity, and/or Karnofsky performance status [7]. In advanced pancreatic ductal adenocarcinoma, capecitabine has been shown single-agent activity, with 7% objective response rate (ORR), 24% positive clinical benefit response (CBR) and median survival of approximately 6 months. Capecitabine monotherapy has demonstrated clinically significant benefit on tumor-related symptoms and achieved partial objective responses in advanced or metastatic pancreatic cancer [8]. Thalidomide is a non-barbiturate sedative and hypnotic drug which has anti-angiogenic and immunomodulatory properties [9] and a novel anti-cytokine agent with secondary anti-angiogenesis activity. It has been widely utilized to control growth of advanced solid tumor in combination therapy and proved to be effective at attenuating weight loss in APC patients with cachexia [10]. It restricted tumor hyperplasia through the epoxy iodide enzyme 2 pathway rather than inhibiting angiogenesis and reducing capillaries density [11], [12]. Thalidomide has different mechanisms of action and activity in various malignant tumors [13]. It has been evaluated and has demostrated activity against solid tumors and has an anti-angiogenic and immunomodulatory effects, including the inhibition of vascular endothelial growth factor, basic fibroblast growth factor and tumor necrosis factor alpha [14]. This phase II trial was designed to evaluate the efficacy and safety of capecitabine combined with thalidomide in GEM-pretreated patients with locally advanced or metastatic pancreatic cancer.
Section snippets
Patients and methods
A total of 31 patients were recruited prospectively in Shandong Tumor Hospital from May 2007 to April 2009. Patients with locally advanced or metastatic pancreatic cancer confirmed by histology and cytology, received capecitabine combined with thalidomide as second-line treatment. The patient's selection criteria were 20–74 years old, the Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2,adequate hematological (white blood cell count ≥4.0 × 109/l, neutrophil count ≥ 1.5 × 109
Patient characteristics
Between May 2007 and April 2009, a total of 31 patients were enrolled in this trial. Fourteen (45.2%) patients were female and 17 (54.8%) were male, with a median age of 59.5 (range: 34–75 years). ECOG PS scores were 0, 1, 2 (15, 14 and 2 patients), respectively. One patient had locally advanced disease and 30 patients had metastatic disease. All 31 patients had previously progressed or followed GEM-based therapy (GEM alone: 17 patients, GEM plus Oxaliplatin: 14 patients). All patients received
Discussion
Pancreatic cancer is a malignant disease with poor prognosis. At present, there is no standard treatment for second-line therapy of patients with APC who progress after GEM-based therapy. The median survival with best supportive care in patients who have failed GEM therapy is approximately 2 months, and about half of patients with GEM-pretreated disease may be candidates for further treatment [15]. In second-line treatment, few randomized data existed for patients with APC. Capecitabine in
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