Topoisomerase I Inhibitors in Small-Cell Lung Cancer

An estimated 75,000 new cases of lung cancer were diagnosed in Japan in 2002. Approximately 15% of these cases were diagnosed as small-cell lung cancer (SCLC), which is strongly associated with tobacco use, as is non-small-cell lung cancer (NSCLC). The clinical characteristics of SCLC tend to be more aggressive, but also more sensitive to chemotherapy and radiation therapy than those of NSCLC. Smallcell lung cancer is usually staged as either limited disease (LD) or extensive disease (ED).[1] Platinum-based chemotherapy remains the mainstay of treatment regimens for ED-SCLC. In a metaanalysis of 19 randomized trials comparing a cisplatin(Drug information on cisplatin)-based regimen with a non-cisplatin-based regimen, patients randomized to a regimen containing cisplatin had a significantly higher probability of response and survival, with no significant increase in toxicity.[2] Berghmans et al presented a detailed analysis of the roles of etoposide(Drug information on etoposide) and cisplatin in the treatment of SCLC.[3] Between 1980 and 1998, 36 eligible trials were performed. These trials concluded that the use of cisplatin and/or etoposide offered a significant survival advantage to patients with SCLC. Irinotecan(Drug information on irinotecan) (Camptosar) has been semisynthesized as a water-soluble derivative of camptothecin, an inhibitor of nuclear enzyme topoisomerase I, in an attempt to reduce its toxicity and to improve its therapeutic efficacy.[ 4-8] In a phase II trial of irinote can for SCLC, the response rate was 47%.[9,10] In preclinical studies, irinotecan and cisplatin exhibited synergistic activities. Their toxicity pro- files also showed a minimal overlap.[ 11-16] In a phase II trial of irinotecan and cisplatin, the response rate was 86%.[17] In these trials, the principal toxicities were neutropenia and diarrhea. Phase III Trial Comparing Irinotecan and Cisplatin With Cisplatin and Etoposide Based on the results of the phase II trial, the Japan Clinical Oncology Group (JCOG) conducted a multiinstitutional randomized phase III trial (JCOG-9511) comparing irinotecan and cisplatin (IP) with cisplatin and etoposide (EP) in patients with previously untreated ED-SCLC.[18] The patient characteristics in this trial included an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and age ≤ 70 years. Patients with symptomatic central nervous system metastases requiring radiation or corticosteroid treatment were excluded from the trial. The experimental arm consisted of irinotecan at 60 mg/m² administered on days 1, 8, and 15 of each 4-week cycle, along with cisplatin at 60 mg/m² administered on day 1 for a total of four 4-week cycles (IP). This treatment regimen was compared with a regimen of etoposide at 100 mg/m² administered on the first 3 days of each 3-week cycle along with cisplatin at 80 mg/m² administered on day 1 for a total of four 3-week cycles (EP). The principal end point was overall survival. The projected accrual for this trial was 230 patients (115 patients per arm). An interim analysis conducted after 77 patients had been accrued in each arm showed a significant survival advantage for the IP arm. Therefore, further enrollment in the trial was discontinued. The response rate was significantly higher in the IP arm than in the EP arm (84% vs 68%; P = .02). Additionally, the IP arm showed a statistically significant improvement in both progression-free survival (6.9 vs 4.8 months; P = .003) (Figure 1) and median overall survival (12.8 vs 9.4 months; P = .002) (Figure 2). The results of this trial were the most exciting to be seen in patients with previously untreated SCLC. The IP regimen is thus another platinumbased combination that should be considered for the treatment of ED-SCLC. Appropriately, the combination of cisplatin and irinotecan has become the new standard treatment for patients with ED-SCLC in Japan. However, several points must be examined before the IP regimen can be fully established as the new standard treatment for ED-SCLC. Three randomized controlled trials comparing the EP regimen with the IP regimen are presently under way in Europe and the United States. Phase II Trial of Cisplatin, Irinotecan, and Etoposide Administered Weekly or Every 4 Weeks JCOG 9511 showed that the IP regimen was significantly better than the EP regimen. However, because etoposide was still considered to be a key drug in the treatment of SCLC, a combination of these three drugs- irinotecan, cisplatin, and etoposide (IPE)-seemed to be a promising strategy for the treatment of EDSCLC. The recommended weekly doses (JCOG 9507) and the dosages for each 4-week cycle (JCOG 9512) for IPE were decided using dose-es calation trials. For these reasons, a phase II trial of irinotecan, cisplatin, and etoposide administered weekly or every 4 weeks for ED-SCLC (JCOG 9902-DI) was performed.[19] The purpose of this trial was to evaluate the toxicity and antitumor effect of the combination of irinotecan, cisplatin, and etoposide administered according to two schedules, weekly (arm A) and every 4 weeks (arm B), for the treatment of previously untreated ED-SCLC, and to select the appropriate arm for use in phase III trials. Patients were enrolled in this trial if they met the following criteria: (1) a histologic or cytological diagnosis of SCLC; (2) no prior treatment; (3) measurable disease; (4) extensive disease, defined as distant metastasis or contralateral hilar lymph node metastasis; (5) performance status of 0 to 2 on the ECOG scale; (6) a life expectancy of 3 months or longer; (7) age between 20 and 70 years; (8) adequate organ function; and (9) written informed consent. The treatment schedule is shown in Figure 3. In arm A, cisplatin at 25 mg/m² was administered intravenously (IV) over 60 minutes on day 1 and at 1-week intervals for 9 weeks; irinotecan at 90 mg/m² was administered IV over 90 minutes on day 1 on weeks 1, 3, 5, 7, and 9; and etoposide at 60 mg/m² was administered by IV over 60 minutes on days 1 to 3 of weeks 2, 4, 6, and 8. Granulocyte colony-stimulating factor (G-CSF) was administered prophylactically on the days when a cytotoxic drug was not given, unless the white blood cell (WBC) count exceeded 10.0 * 10⁹/L. In arm B, cisplatin at 60 mg/m² was administered by IV over 60 minutes on day 1; irinotecan at 60 mg/m² was administered by IV over 90 minutes on days 1, 8, and 15; and etoposide at 50 mg/m² was administered by IV over 60 minutes on days 1 to 3. G-CSF was injected subcutaneously from day 5 until the day when the WBC count exceeded 10.0 * 10⁹/L. This treatment was repeated every 4 weeks for a total of four cycles. Patient characteristics are listed in Table 1. Between August 1999 and October 2000, 30 patients were entered in each arm. The last follow-up examination was performed in February 2002. All enrolled patients were included in the toxicity, tumor response, and patient survival analyses. No differences in any of the listed characteristics were observed between the two arms. Treatment delivery is listed in Table 2. Of the 30 patients in each arm, 22 (73%) and 21 (70%) patients in arms A and B, respectively, received full cycles of chemotherapy (nine cycles in arm A and four cycles in arm B). Therapy was stopped because of toxicity in four (13%) patients in arm A and in six (20%) patients in arm B. Therapy was stopped because of tumor progression in three (10%) patients in each arm. The need for treatment delay in arm A and treatment skipping in arm B, however, was significant. Only eight (27%) patients in arm A completed the treatment without delay, and only seven (23%) patients in arm B received all the planned doses. A total of 105 chemotherapy cycles were administered to 30 patients in arm B, but eight (8%) doses of irinotecan on day 8, and 33 (31%) doses of irinotecan on day 15 were omitted because of toxicity, according to criteria in the protocol. The median total dosages of cisplatin and etoposide administered per patient were maintained at the planned dosage levels in both arms (Table 3). The median total dosage of irinotecan as a percentage of the scheduled dosage (the relative total dosage) was 100% in arm A, but only 78% in arm B, reflecting the doses of irinotecan that were skipped on days 8 and 15. Dose intensity was evaluated in 29 patients in arm A and 28 patients in arm B (Table 3). The median relative dosage intensity was well maintained at a level of 80% or higher, except that of irinotecan in arm B (77%). The median actual dosage intensity of etoposide was 70 mg/m²/wk in arm A and 37 mg/m²/wk in arm B. Toxicity was evaluated in all patients. The incidences of grade 3/4 neutropenia, anemia, thrombocytopenia, infection, and diarrhea in arm A were 57%, 43%, 27%, 7%, and 7%, respectively, and 87%, 47%, 10%, 13%, and 10%, respectively, in arm B. A treatment-related death occurred in one patient in arm A (Table 4). Two complete responses (CRs) and 23 partial responses (PRs) were obtained in arm A, resulting in an overall clinical response rate of 83%, whereas five CRs and 18 PRs were obtained in arm B, resulting in an overall response rate of 77% (Table 5). The median time to survival and 1-year survival rate in arm A were 8.9 months and 40%, respectively, and 12.9 months and 57%, respectively, in arm B (Figure 4). In this trial, the two IPE schedules were both effective against ED-SCLC and had an acceptable toxicity level. Arm B was adopted as the investigational arm in phase III trials. Conclusion The combination of cisplatin and irinotecan has become the new standard treatment for patients with EDSCLC in Japan. However, SCLC is rarely cured, although the response rate has been improved and the survival time extended through the use of chemotherapy. Based on the results of JCOG 9511 and JCOG 9902- DI, a randomized trial comparing IP with IPE administered every 3 weeks in patients with previously untreated ED-SCLC is now being performed in Japan.