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Irinotecan Therapy for Small-Cell Lung Cancer

Irinotecan Therapy for Small-Cell Lung Cancer

ABSTRACT: The DNA topoisomerase inhibitor irinotecan (CPT-11, Camptosar) is being evaluated as a novel chemotherapeutic agent that may complement other agents and treatment modalities for small-cell lung cancer (SCLC). Combination chemotherapy is the most effective means of improving the survival of patients with extensive disease, but until recently, no combination demonstrated superior efficacy. In a recent Japanese phase III study, irinotecan in combination with cisplatin significantly improved the survival of previously untreated patients with extensive SCLC compared to standard etoposide/cisplatin therapy (median progression-free survival: 6.9 vs 4.8 months, P = .003; median overall survival: 12.8 vs 9.4 months, I = .002). Two additional phase III trials have been planned in the United States to confirm these results, and to investigate how the administration schedule of irinotecan/cisplatin may be modified to improve its therapeutic index. The results of phase I/II studies have shown that other irinotecan-based combinations demonstrate promising activity in this disease as both first- and second-line therapy. This article reviews the rationale for the use of irinotecan in SCLC, examines key findings from recent clinical studies of irinotecan-based therapy, and discusses how the use of irinotecan in combination with new noncytotoxic anticancer agents can and will be further explored. [ONCOLOGY 16:419-438, 2002]

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.[4] 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.[1] 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.[5]

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).[7] 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
profile.[1]

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
maintenance therapy.[3,7,21-24]

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).[7] Among the most active to date has been the
topoisomerase I inhibitor irinotecan (CPT-11, Camptosar).[25] This review
focuses on first- and second-line treatment of extensive SCLC with
irinotecan-containing regimens.

Mechanism of Action and Preclinical Activity

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.[28] 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.[29]

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
radiosensitizing properties.[39]

Irinotecan in Second-Line Therapy

Single-Agent Irinotecan

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[46]; however, one study included some previously untreated
patients,[40] and the other study was conducted mostly in patients who were
considered sensitive relapses to first-line therapy.[41]

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.[43]
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).[47] Thus, when used alone in the second-line setting,
topoisomerase I inhibitors appear to have activity only in patients with
sensitive SCLC.

Irinotecan Combinations

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).[45] 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.[44]

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.[48] The overall response
rate was 71%, with 25% complete responses. Median survival was 8.2 months, and
the 1-year survival was 29%.[48] The median survival for patients with relapsed
SCLC receiving second-line chemotherapy was approximately 5 months—an
encouraging result.[49] It should be noted that at least 80% of patients in the
study were considered sensitive relapses, which may account for some of the
improved responsiveness.

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.[50] 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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