Topotecan Demonstrates Significant Activity in Small-Cell Lung Cancer

Topotecan HCl, an investigational anticancer drug, has demonstratedsignificant antitumor activity in previously treated small-celllung cancer (SCLC) patients, according to European Organizationfor Research and Treatment of Cancer (EORTC) researchers, whopresented phase II trial data at the Eighth European Conferenceon Clinical Oncology, Cancer Research and Cancer Nursing (ECCO-8)in Paris.

Final data from a pan-European trial evaluating the effect oftopotecan as a second-line, single-agent treatment for refractorySCLC showed response rates of up to 39% in patients who relapsedafter completing primary treatment. Investigators also noted thatthe duration of response was more than twice that commonly reportedwith standard therapy.

"These data represent an important step forward in the managementof small-cell lung cancer--a tumor for which second-line treatmentoptions are painfully limited," said Andrea Ardizzoni, MD,from the National Institute for Cancer Research, Genova, Italy,and the study's principal investigator. "Response rates forcurrent second-line single agent SCLC therapies typically do notexceed 30%, with an average response duration of less than threemonths."

Topotecan is a novel anticancer agent that has demonstrated activityagainst a variety of tumors in both preclinical and clinical studies.The drug is an analog of camptothecin, a plant alkaloid derivedfrom the deciduous tree Camptothecaacuminata. Topotecancurrently is in the final stages of clinical development for SCLCand ovarian cancer.

New cases of SCLC--the most aggressive of all pulmonary tumors--occurat a rate of 40,000 per year in European countries. Only 10% ofpatients remain disease-free more than 2 years from the startof treatment.

"Because long-term survival rates are so low and the greatmajority of patients experience tumor recurrence, the improvementof second-line treatment options--especially those that lead tofirst-line advances--is a critical goal for cancer researcherstoday," said Dr. Ardizzoni.

Two groups of SCLC patients were enrolled in the open-label, multicenterstudy: patients refractory to first-line chemotherapy and patientssensitive to first-line chemotherapy who relapsed. Patients refractoryto first-line chemotherapy included those who never respondedto the initial treatment regimen and those who demonstrated progressivedisease less than 3 months after a previous chemotherapy regimen.Patients sensitive to first-line chemotherapy were defined aspatients who demonstrated progressive disease more than 3 monthsafter responding to the previous chemotherapy regimen.

In the phase II study, 49 refractory and 45 sensitive patientswere enrolled, for a total of 94 eligible patients. Each patientreceived 1.5 mg/m² of topotecan as a 30-minute intravenousinfusion. This dose was administered for 5 consecutive days every3 weeks until disease progressed or patients became intolerantof treatment-related side effects. Patients received an averageof three to five courses of topotecan.

Phase II Study Results

Of the 94 patients enrolled in the study, 87 were evaluable forresponse. Six of the 44 sensitive patients demonstrated a completeresponse--that is, disappearance of signs and symptoms of cancer--and11 patients experienced a partial response, or a decrease of measurabletumor by at least 50%. These results yielded an overall responserate of 39% among patients sensitive to first-line chemotherapy.Among the 43 patients refractory to first-line chemotherapy, onecomplete response and two partial responses occurred, for an overallresponse rate of 7%.

Median duration of response was 6 months in refractory patientsand 7.6 months in the sensitive group. "This is a remarkableincrease from the three or less months achieved with standardtherapies," he said.

The major dose-limiting side effect of topotecan was hematologictoxicity, specifically, leukopenia and neutropenia. Clinical trialsof topotecan indicate that hematologic toxicity appears to bepredictable, reversible, and noncumulative. Few cases of severenonhematologic toxicity--such as nausea, vomiting, and mucositis--wereobserved in this study, which is consistent with other clinicalfindings to date.

"Based on the results of this phase II trial, further studiesof 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 newclass of anticancer agents that selectively inhibit the nuclearenzyme 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 replicationproduces DNA damage that results in the death of proliferatingtumor cells.