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(Drug information on doxorubicin) [Adriamycin], vincristine; cisplatin (or carboplatin(Drug information on carboplatin) [Paraplatin]) and the DNA topoisomerase II inhibitor etoposide(Drug information on etoposide); or the alternation of these two combinations (eg, CAV followed by cisplatin(Drug information on 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(Drug information on ifosfamide) [Ifex] or paclitaxel(Drug information on 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(Drug information on 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(Drug information on 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(Drug information on 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.
A 70-year-old man with a history of localized prostate cancer treated with whole-pelvis radiation therapy with a boost to the prostate, in conjunction with androgen deprivation therapy 7 years prior, presented with lower back pain. A bone scan revealed an area of activity in the sacrum. What is the most likely diagnosis?
