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Irinotecan Plus Cisplatin in Small-Cell Lung Cancer

Irinotecan Plus Cisplatin in Small-Cell Lung Cancer

ABSTRACT: The DNA topoisomerase inhibitor irinotecan (CPT-11, Camptosar) is being evaluated as a novel chemotherapeutic agent for small-cell lung cancer that may complement other agents and treatment modalities. Combination chemotherapy is recognized as the most effective means of improving survival in patients with extensive-stage small-cell lung cancer, but until recently, no one combination had emerged as superior. In a recent Japanese phase III study, irinotecan in combination with cisplatin significantly improved survival of previously untreated patients with extensive small-cell lung cancer compared with standard etoposide/cisplatin therapy (median progression-free survival: 6.9 vs 4.8 months, P < .001; median overall survival: 12.8 vs 9.4 months, P = .0021). Two additional phase III trials are planned to confirm these results in the United States, and to investigate how the irinotecan/cisplatin administration schedule may be modified to improve therapeutic index. This article will review the use of irinotecan in combination with cisplatin in patients with small-cell lung cancer. [ONCOLOGY 16(Suppl 9):39-44, 2002]

Small-cell lung cancer accounts for approximately 20% to 25% of all cases of
lung cancer and has an especially poor prognosis, resulting in about 25% of all
lung cancer deaths.[1-3] Small-cell lung cancer is characterized by an
aggressive clinical course with early dissemination of regional and distant
metastases. Tumors are initially chemosensitive but acquire drug resistance
during disease progression.[4] About 30% to 40% of small-cell lung cancer
patients present with limited-stage disease that is 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 extensive-stage disease. The 5-year survival rate for
small-cell lung cancer is only about 5% overall, and is negligible for patients
with extensive-stage disease.[1]

Combination chemotherapy is the most effective treatment modality for
small-cell lung cancer. For patients with extensive-stage small-cell lung
cancer, chemotherapy can increase median survival from approximately 1.5 months
to 7 to 11 months, with 2-year survival uncommon.[1,5] Standard chemotherapy
regimens for small-cell lung cancer include cyclophosphamide (Cytoxan, Neosar),
doxorubicin (Adriamycin), and vincristine (CAV); cisplatin or carboplatin (Paraplatin)
plus the DNA topoisomerase II inhibitor etoposide; or alternating these two
combinations (eg, CAV followed by cisplatin/etoposide).[6] Cisplatin/etoposide
is the most widely used first-line regimen for patients with extensive-stage
small-cell lung cancer, and results in survival comparable to that obtained with
CAV or other early combinations (median overall survival: 7 to 11 months), but
with a more favorable toxicity profile.[1]

Several new agents, including paclitaxel, topotecan (Hycamtin), gemcitabine (Gemzar),
and irinotecan (CPT-11, Camptosar), have exhibited significant activity as
single agents against small-cell lung cancer (Table
1
).[6] This review will
focus on the treatment of extensive-stage small-cell lung cancer with the
topoisomerase I inhibitor irinotecan when used alone and in combination with
cisplatin.

Irinotecan Mechanism of Action and Preclinical Activity

Irinotecan hydrochloride, a semisynthetic derivative of the plant alkaloid
camptothecin, inhibits topoisomerase I activity. During DNA replication, the
enzyme topoisomerase I relieves torsional strain by inducing reversible
single-strand breaks.[7,8] Irinotecan, and to a much greater extent its active
metabolite SN-38, prevents religation of those breaks by binding to the
topoisomerase I/DNA complex.[9] Irinotecan-induced cytotoxic death may occur
through interaction of replication enzymes with this ternary molecular complex,
possibly by arresting DNA replication and leading to lethal double-strand DNA
breaks.[10]

Antitumor activity of irinotecan has been demonstrated in preclinical studies
with a variety of mouse tumors and human tumor xenografts, including
drug-resistant tumors, when administered either intravenously or orally.[11,12]
Irinotecan also complements the antitumor activity of agents that act through
other effects on DNA replication (eg, cisplatin or gemcitabine) or interfere
with other vital cell functions (eg, the taxanes), either additively or
synergistically.[13,14]

Single-Agent Irinotecan

Single-agent irinotecan has demonstrated antitumor activity as second-line
therapy in several phase II studies of patients with extensive-stage small-cell
lung cancer, achieving overall response rates of 13.6% to 47% with doses of 100
to 125 mg/m² weekly and 350 mg/m² every 3 weeks (Table
2
).[15-17]

In a recent U.S. phase II study involving previously treated small-cell lung
cancer patients, 45 patients received irinotecan at 125 mg/m² weekly for 4
weeks, followed by a 2-week rest; the majority of patients received only one
treatment course.[18] The response rate was 14% overall, but 29% among 17
patients with sensitive-relapse disease (ie, relapse more than 90 days after
completing chemotherapy). Similarly, topotecan, another camptothecin analog,
achieved a 38% response rate among chemosensitive patients, but only 6% of
refractory patients responded (ie, patients not initially responding to
chemotherapy, or those with relapse less than 90 days after completing
chemotherapy).[19]

Irinotecan With Cisplatin

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