Small-cell lung cancer (SCLC) accounts for
approximately 20% to 25% of all lung cancer cases and is associated with an
especially poor prognosis, resulting in about 25% of all lung cancer
deaths.[1-3] The disease is characterized by an aggressive clinical course with
early dissemination of regional and distant metastasis. Tumors are initially
chemosensitive but become drug-resistant during treatment. About 30% to 40%
of SCLC patients present with limited-stage disease confined to one hemithorax
and regional lymph nodes without pericardial or pleural effusion. The
majority of patients are initially diagnosed with more advanced and less
treatment-sensitive disease. The 5-year survival for limited-stage SCLC is about
20% to 25% and is negligible for patients with extensive disease.
Combination chemotherapy is the most effective treatment modality for SCLC.
For patients with extensive-stage SCLC, chemotherapy can increase the median
survival from about 1.5 months to 7 to 11 months, with 2-year survival
uncommon.[1,6] Standard chemotherapy regimens for SCLC include CAV
(cyclophosphamide [Cytoxan, Neosar], doxorubicin [Adriamycin], vincristine;
cisplatin (or carboplatin [Paraplatin]) and the DNA topoisomerase II inhibitor
etoposide; or the alternation of these two combinations (eg, CAV followed by
cisplatin/etoposide). For patients with extensive SCLC, etoposide/cisplatin
is most commonly used as first-line treatment. Survival with this regimen is
comparable to that achieved with CAV and other early combinations (median
overall survival: 7 to 11 months), but with a more favorable toxicity
Over the past 2 decades, randomized clinical trials have established some of
the limits of combination chemotherapy for SCLC in terms of a survival benefit
for patients with extensive disease (Table 1).[8-20] These limits include the
following observations: (1) Improvements have been modest, and no combination
regimen has emerged as consistently superior, either in pre-1990 trials or in
trials of new agents over the past decade; (2) neither high-dose chemotherapy,
increased dose intensity, nor the addition of a third agent (ie, ifosfamide
[Ifex] or paclitaxel) have improved survival; (3) chemotherapy for up to six
treatment cycles is as effective as longer-term treatment or the addition of
Several new agents, including carboplatin, ifosfamide, and the taxanes, have
been shown to be active against SCLC but have not produced an improvement in
overall survival (Table 1). Among the most active to date has been the
topoisomerase I inhibitor irinotecan (CPT-11, Camptosar). This review
focuses on first- and second-line treatment of extensive SCLC with
Irinotecan hydrochloride is a semisynthetic derivative of the plant alkaloid
camptothecin that inhibits topoisomerase I activity. During DNA replication,
topoisomerase I relieves torsional strain by inducing reversible single-strand
breaks.[26,27] Irinotecan, and to a much greater extent its active metabolite
SN-38, prevent relegation of these breaks by binding to the topoisomerase I-DNA
complex. Irinotecan-induced cytotoxic death may occur through the
interaction of replication enzymes with this ternary molecular complex, possibly
by arresting DNA replication and leading to lethal double-strand DNA breaks.
When administered either intravenously or orally, irinotecan has demonstrated
antitumor activity in preclinical studies in a variety of mouse tumors and human
tumor xenografts, including drug-resistant tumors.[30-32] Irinotecan also
complements the antitumor activity of agents that act through other effects on
DNA replication (eg, cisplatin or gemcitabine [Gemzar]) or interfere with other
vital cell functions (eg, the taxanes), either additively or
synergistically.[33-38] In addition, irinotecan is being evaluated for its
In several phase II studies, single-agent irinotecan has shown antitumor
activity as second-line therapy in patients with extensive SCLC. Overall
response rates in these trials have ranged from 13.6% to 47%, with doses of
100 to 125 mg/m² weekly and 350 mg/m² every 3 weeks (Table 2).[40-45] In
two of these studies, response rates were substantially higher than the
approximately 20% response rate typically achieved with single-agent
etoposide; however, one study included some previously untreated
patients, and the other study was conducted mostly in patients who were
considered sensitive relapses to first-line therapy.
In a recent US phase II study involving previously treated SCLC patients, 45
patients received irinotecan at 125 mg/m²/wk for 4 weeks, followed by 2 weeks of
rest. The majority of patients received only a single course of treatment.
The overall response rate was 14%, but 29% among 17 patients with
sensitive-relapse disease (ie, relapse > 90 days after completing
chemotherapy). Similarly, another camptothecin analog, topotecan (Hycamtin),
produced a response rate of 38% among chemosensitive patients but of only 6%
among refractory patients (ie, patients not initially responding to
chemotherapy, or those who relapsed less than 90 days after completing
chemotherapy). Thus, when used alone in the second-line setting,
topoisomerase I inhibitors appear to have activity only in patients with
The combination of irinotecan and cisplatin has been studied in patients with
previously treated SCLC. In a phase II trial in such patients, Nakanishi et al
established significant activity with irinotecan, 60 mg/m², administered on days
1, 8, and 15 of each 4-week cycle, together with either 30 or 60 mg/m² of
cisplatin every 28 days (Table 2). In an earlier investigation that used the
higher dose of cisplatin, unspecified reductions in the dose of irinotecan were
required due to the occurrence of leukopenia.
Masuda and colleagues reported a phase II trial of the combination of
irinotecan and etoposide that included 17 eligible patients with previously
treated SCLC. Treatment consisted of irinotecan, 70 mg/m², on days 1, 8, and 15
of each 28-day cycle, plus etoposide, 80 mg/m², on days 1 to 3, with granulocyte
colony-stimulating factor (G-CSF, Neupogen) support. The overall response
rate was 71%, with 25% complete responses. Median survival was 8.2 months, and
the 1-year survival was 29%. The median survival for patients with relapsed
SCLC receiving second-line chemotherapy was approximately 5 monthsan
encouraging result. It should be noted that at least 80% of patients in the
study were considered sensitive relapses, which may account for some of the
A phase I study in patients with extensive SCLC evaluated second-line
irinotecan/paclitaxel following induction therapy with, or relapse from,
cisplatin/etoposide. A weekly regimen of irinotecan, 60 mg/m², plus
dose-escalated paclitaxel, 15 to 60 mg/m², for 3 weeks achieved responses in 5
of 7 patients, including 3 complete remissions. Based on these results, a
phase II study is currently under way, with paclitaxel being administered
at 50 mg/m² in previously untreated patients.
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