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)
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
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
"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