Topotecan(Drug information on topotecan) HCl, an investigational anticancer drug, has demonstrated significant antitumor activity in previously treated small-cell lung cancer (SCLC) patients, according to European Organization for Research and Treatment of Cancer (EORTC) researchers, who presented phase II trial data at the Eighth European Conference on Clinical Oncology, Cancer Research and Cancer Nursing (ECCO-8) in Paris.
Final data from a pan-European trial evaluating the effect of topotecan as a second-line, single-agent treatment for refractory SCLC showed response rates of up to 39% in patients who relapsed after completing primary treatment. Investigators also noted that the duration of response was more than twice that commonly reported with standard therapy.
"These data represent an important step forward in the management of small-cell lung cancer--a tumor for which second-line treatment options are painfully limited," said Andrea Ardizzoni, MD, from the National Institute for Cancer Research, Genova, Italy, and the study's principal investigator. "Response rates for current second-line single agent SCLC therapies typically do not exceed 30%, with an average response duration of less than three months."
Topotecan is a novel anticancer agent that has demonstrated activity against a variety of tumors in both preclinical and clinical studies. The drug is an analog of camptothecin, a plant alkaloid derived from the deciduous tree Camptotheca acuminata. Topotecan currently is in the final stages of clinical development for SCLC and ovarian cancer.
New cases of SCLC--the most aggressive of all pulmonary tumors--occur at a rate of 40,000 per year in European countries. Only 10% of patients remain disease-free more than 2 years from the start of treatment.
"Because long-term survival rates are so low and the great majority of patients experience tumor recurrence, the improvement of second-line treatment options--especially those that lead to first-line advances--is a critical goal for cancer researchers today," said Dr. Ardizzoni.
Two groups of SCLC patients were enrolled in the open-label, multicenter study: patients refractory to first-line chemotherapy and patients sensitive to first-line chemotherapy who relapsed. Patients refractory to first-line chemotherapy included those who never responded to the initial treatment regimen and those who demonstrated progressive disease less than 3 months after a previous chemotherapy regimen. Patients sensitive to first-line chemotherapy were defined as patients who demonstrated progressive disease more than 3 months after responding to the previous chemotherapy regimen.
In the phase II study, 49 refractory and 45 sensitive patients were enrolled, for a total of 94 eligible patients. Each patient received 1.5 mg/m² of topotecan as a 30-minute intravenous infusion. This dose was administered for 5 consecutive days every 3 weeks until disease progressed or patients became intolerant of treatment-related side effects. Patients received an average of three to five courses of topotecan.
Phase II Study Results
Of the 94 patients enrolled in the study, 87 were evaluable for response. Six of the 44 sensitive patients demonstrated a complete response--that is, disappearance of signs and symptoms of cancer--and 11 patients experienced a partial response, or a decrease of measurable tumor by at least 50%. These results yielded an overall response rate of 39% among patients sensitive to first-line chemotherapy. Among the 43 patients refractory to first-line chemotherapy, one complete response and two partial responses occurred, for an overall response rate of 7%.
Median duration of response was 6 months in refractory patients and 7.6 months in the sensitive group. "This is a remarkable increase from the three or less months achieved with standard therapies," he said.
The major dose-limiting side effect of topotecan was hematologic toxicity, specifically, leukopenia and neutropenia. Clinical trials of topotecan indicate that hematologic toxicity appears to be predictable, reversible, and noncumulative. Few cases of severe nonhematologic toxicity--such as nausea, vomiting, and mucositis--were observed in this study, which is consistent with other clinical findings to date.
"Based on the results of this phase II trial, further studies of topotecan in combination with other agents for both first- and second-line treatment of small cell lung cancer are warranted," said Dr. Ardizzoni.
Mechanism of Action
A novel cytotoxic drug, topotecan belongs to an important new class of anticancer agents that selectively inhibit the nuclear enzyme topoisomerase I. Topoisomerase I is involved in cell proliferation, including DNA replication, DNA damage repair, and gene expression. Inhibition of topoisomerase I by topotecan during replication produces DNA damage that results in the death of proliferating tumor cells.