Combination Capecitabine/Temozolomide Appears Highly Effective in Patients With Treatment-Resistant Neuroendocrine Tumors
Interim results from an ongoing phase II clinical trial in patients with various types of advanced neuroendocrine tumors show that a new chemotherapy combination of capecitabine and temozolomide either stalled disease progression or shrank tumors in 95% of patients whose disease worsened after standard high-dose octreotide. The responses were long-lasting, with a median progression-free survival of 30 months, and most patients experienced only mild side effects. According to the authors, the combination may eventually replace all other second-line therapies for advanced neuroendocrine tumors because of its superior efficacy. The findings will be reported at the 2014 Gastrointestinal Cancers Symposium, held January 16 to 18 in San Francisco (Abstract 179).
“In this study we’re seeing patients who had been given 6 months to live that are still alive 8 years after starting [capecitabine/temozolomide]. The regimen was effective even in patients with tumors that hadn’t responded to any other standard treatment, including chemotherapy, high-dose octreotide, small molecule inhibitors, radiation, or surgery,” said lead study author Robert Fine, MD, an Associate Professor of Medicine at New York Presbyterian Hospital-Columbia University Medical Center in New York. In addition, the combination was associated with a low rate of serious side effects, and there were no hospitalizations or treatment-related deaths.
Study Details
A total of 28 patients with various subtypes of metastatic neuroendocrine tumors were treated as part of the study. All patients had so-called well or moderately differentiated tumors, which account for most cases of neuroendocrine tumors. All patients’ diseases had either progressed despite standard therapy with high-dose octreotide or they were ineligible for this treatment based on a negative octreotide scan.
Because neuroendocrine tumors grow slowly, they are frequently resistant to chemotherapy. In lab studies of neuroendocrine tumor cells researchers discovered that fluorouracil (5-FU) enhanced temozolomide’s anticancer activity threefold. With this insight, the researchers selected the doses and the order in which the two drugs are given to patients (capecitabine first, temozolomide second) to maximize the efficacy of the combination regimen. The prior oral 5-FU chemotherapy depleted thymidine stores, which improved the temozolomide antitumor effect two- to fourfold, according to Dr. Fine.
Outcomes
Nearly all patients experienced clinical benefit from capecitabine and temozolomide, and the combination caused tumor shrinkage in 43% of patients overall and stalled tumor growth in 54% of patients. High response rates were observed in carcinoid and pituitary tumors, two very difficult-to-treat neuroendocrine tumor subtypes. Among the 12 patients with carcinoid tumors, 41% had tumor shrinkage; this finding is particularly striking since the typical response rate to chemotherapy for these patients is 0% to 4%. And among the four patients with pituitary tumors resistant to radiation therapy, chemotherapy, and surgery, two had complete remissions with capecitabine/temozolomide, one had a 75% reduction in tumor size, and one has had stable disease for 5 years.
At the latest data analysis, the median progression-free survival was close to 30 months, and more than 4 years for 25% of patients. The median overall survival was greater than 25 months.
The investigators are working on ways to make combination capecitabine/temozolomide even more effective, such as combining it with drugs that block the platelet-derived growth factor pathway. Dr. Fine said that he would like to have the regimen tested in brain tumors and melanoma, as temozolomide is a major treatment option in those settings.
Dr. Fine reported receiving research funding from Merck.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
