Extensive-stage Disease Small Cell Lung Cancer Research Articles

Phase II trial of pemetrexed (P) and carboplatin (C) in previously untreated extensive stage disease small cell lung cancer (ED-SCLC): A NCCTG Study

8066 Background: The primary endpoint of this trial was to evaluate the response rate (RR) of PC in untreated patients with ED- SCLC and obtain preliminary estimates in older patients (≥ 70 years).Toxicity was a secondary endpoint. Methods: Multi-center phase II trial of primary treatment with P (500mg/M2) and C (AUC=5) on day 1 every 21 days for a maximum of 6 cycles. Patients were pretreated with folic acid and B12. Standard pretreatment blood counts and chemistries were mandated and creatinine clearance of ≥ 45 ml/min was required. Toxicity was assesses according to CTCv3. Design was a single stage sample size of 70 with 46 in younger age group (<70) and 24 in the older cohort. The primary endpoint of success was a 60% response rate (RR) with acceptable toxicity.(Ho RR 40% and Ha RR of 60%) Results: 48 eligible patients were enrolled and received treatment (17 ≥ 70 years). The mean age was 65 with 54% males and 85% PS 0 or 1. 46 patients were evaluable for response and 30 of 46 have progressed. 33 of 4...

A Phase I and Pharmacologic Study of Belotecan in Combination with Cisplatin in Patients with Previously Untreated Extensive-Stage Disease Small Cell Lung Cancer

Belotecan (Camtobell, CKD602) is a novel camptothecin derivative. This study was designed to determine the maximum tolerated dose (MTD), toxicity profile, and dose-limiting toxicity of belotecan in combination with cisplatin in patients with previously untreated extensive-stage disease small cell lung cancer (SCLC). Furthermore, pharmacokinetics and preliminary antitumor activity against SCLC were evaluated. Belotecan was administered i.v. as intermittent 30-min infusions on days 1 to 4, starting dose of 0.40 mg/m2/d with increment of 0.05 mg/m2/d. Intrapatient dose escalation was not allowed. Cisplatin (60 mg/m2) was given on day 1. The treatments were repeated every 3 weeks. Pharmacokinetics was determined during the first cycle using noncompartmental pharmacokinetic analysis. Seventeen chemotherapy-naive patients with extensive-stage disease SCLC were treated. The MTD of belotecan was 0.50 mg/m2/d with the dose-limiting toxicity of grade 4 neutropenia with fever. A partial response was seen in 13 of 17 patients (76.5%). The most common toxicity was neutropenia but nonhematologic toxicity was very favorable. Pharmacokinetic analysis revealed that, at the dose of 0.50 mg/m2/d, plasma clearance of belotecan was 5.78 +/- 1.32 L/h and terminal half-life was 8.55 +/- 2.12 h. Fraction of excreted amount in urine was 37.36 +/- 5.55%. Pharmacokinetics of belotecan was not altered by administration of cisplatin compared with historical control. The MTD and recommended dose of belotecan for phase II studies was 0.50 mg/m2/d on days 1 to 4 in combination with 60 mg/m2 cisplatin on day 1 every 3 weeks.

A phase II study of biweekly irinotecan and cisplatin for patients with extensive stage disease small cell lung cancer

An irinotecan and cisplatin (IP) combination is one of active regimen used in treatment of extensive stage disease (ED) small cell lung cancer (SCLC). However, a 4-week cycle of irinotecan treatment can result in significant myelosuppression and diarrhea. Therefore, the present study was conducted to evaluate the efficacy and safety of biweekly IP in patients with ED SCLC. Patients with previously untreated ED SCLC received intravenous irinotecan at a dose of 60mg/m(2) and cisplatin at a dose of 30mg/m(2) on days 1 and 15 every 4 weeks. Thirty-five patients were enrolled in this study. Three complete responses and 23 partial responses were confirmed, giving an overall response rate of 74.3%. After a median follow-up of 15.1 months, the median time to progression and overall survival were 7.7 months and 12.2 months, respectively. Grade 3/4 neutropenia occurred in seven patients and grade 3 febrile neutropenia was observed in one patient. Grade 3 diarrhea occurred in two patients. The combination chemotherapy of biweekly IP was found to be well tolerated and effective in patients with ED SCLC. Further evaluation of the combination of IP at the dose and schedule in this study is warranted in ED SCLC patients.

P1-220: A phase I and pharmacologic study of Belotecan in combination with Cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer

P1-220: A phase I and pharmacologic study of Belotecan in combination with Cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer

A phase I and pharmacologic study of belotecan in combination with cisplatin in patients with previously untreated extensive-stage disease small cell lung cancer

18053 Background: Belotecan (CKD602) is a novel camptothecin derivative antitumor agent. This phase I study was designed to determine the maximum-tolerated dose (MTD), toxicity profile, and dose-limiting toxicity (DLT) of belotecan in combination with cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer (ED SCLC). Furthermore, pharmacokinetics (PK) and preliminary antitumor activity of belotecan against SCLC were evaluated. Methods: Patients with ED SCLC, age 18–70, ECOG PS 0–2, no prior chemotherapy and adequate organ function were eligible. Cisplatin with fixed dose of 60 mg/m2 was administered intravenously (i.v.) over 2 hours on day 1. Belotecan was administered iv as intermittent 30-minute infusions on days 1 to 4, starting dose of 0.40 mg/m2/day with increment of 0.05 mg/m2/day. Modified Fibonacci escalation was used (3 to 6 patients per cohort) and intra-patient dose escalation was not allowed. PK of belotecan was determined during the first treatment using non-compartmental pharmacokinetic analysis. Results: Seventeen patients were treated at 4 dose levels (0.40 to 0.55 mg/m2/day). At 0.55 mg/m2/day of belotecan, the DLT of grade 4 neutropenia with fever occurred in 2 of 5 patients, and therefore the MTD was 0.50 mg/m2/day. Interestingly, out of 17 patients, there were 14 partial responses (82.4%; 95% CI, 63.4% to 100.0%). PK analysis revealed that at 0.50 mg/m2/day, plasma clearance of belotecan was 5.78 ± 1.32 L/hr and terminal half-life was 8.55 ± 2.12 hr. Fraction of excreted amount in urine was 37.36 ± 5.55 %. PK of belotecan were not altered by administration of cisplatin, as compared with historical control. Conclusions: The MTD of belotecan was 0.50 mg/m2/day for intermittent 30-min i.v. infusion for 4 days in combination with cisplatin 60 mg/m2 on day 1 every 3 weeks. Furthermore, very promising antitumor activity against SCLC was observed. The phase II study is being conducted now. No significant financial relationships to disclose.

Fractionated Administration of Irinotecan and Cisplatin in Japanese Patients With Extensive-Stage–Disease Small-Cell Lung Cancer

TO THE EDITOR: We read with great interest the recent article by Hanna et al, in which they reported irinotecan and cisplatin (IP) regimen was not superior to the etoposide and cisplatin (EP) regimen for extensive-stage–disease (ED) small-cell lung cancer (SCLC), even though Noda et al clearly showed the superiority of IP regimen over EP regimen. We previously fractionated the schedule of IP to obtain the synergistic effect of the two drugs and to reduce toxicities. The recommended doses of irinotecan and cisplatin on days 1 and 8 were determined to be 50 mg/m and 60 mg/m, respectively. However, the phase II study for ED SCLC was stopped early because of poor outcomes in the interim analysis. Despite the small number of patients in our study, the median survival time and 1-year survival rates were similar to those reported in the study by Hanna et al (Table 1). The delivered doses of irinotecan and cisplatin in their study were 1.8 times and 0.7 times as much as those of our study, respectively (Table 1). In comparison to the study by Noda et al, we should have modified fractionated administration by escalating the dose of irinotecan and reducing that of cisplatin to improve the outcomes. However, both irinotecan and cisplatin in the Hanna et al study showed more dose intensity than that reported in the Noda et al study. Hanna et al suggested that IP might therefore be a better regimen for Japanese patients. We considered fractionated administrations of IP to be inferior to the original schedules of IP (cisplatin on day 1 and irinotecan on days 1, 8, and 15) for not only American but also Japanese patients with ED SCLC based on the findings of our study. Another explanation for the negative results of the Hanna et al study might be due to salvage chemotherapy. More patients on the IP arm received subsequent treatment with etoposide (47.2% v 22.6%) whereas more patients on the EP arm received subsequent treatment with topoisomerase I inhibitors including irinotecan or topotecan (33% v 24.1%). Noda et al did not describe the use of salvage chemotherapy, which might have affected the survival difference in both arms. Because chemotherapy with fluorouracil, leucovorin, and irinotecan (FOLFIRI), followed by fluorouracil, leucovorin, and oxaliplatin (FOLFOX), had almost the same efficacy as that with FOLFOX followed by FOLFIRI in the treatment of advanced colorectal cancer, IP followed by EP might therefore have had the same efficacy as EP followed by IP in the treatment of ED SCLC. To achieve a prolonged survival, the administration of all three active cytotoxic drugs (cisplatin, irinotecan, and etoposide) during the treatment course may thus be necessary.

Treatment of small cell lung cancer

The incidence of small cell lung cancer (SCLC) is declining in the United States (US). SCLC is nearly universally smoking-related and is very sensitive to both chemotherapy and radiation therapy. In contrast to non-small cell lung cancer (NSCLC), SCLC is staged as either limited-stage disease (LD) or extensive-stage disease (ED). Chemotherapy remains the essential component for treatment of all patients with SCLC, regardless of stage or performance status. In LD, the addition of radiation therapy improves survival over chemotherapy alone. However, the dose, timing and schedule of radiation are not well defined. Prophylactic cranial irradiation (PCI) reduces brain relapse rates, and modestly improves survival in patients in a clinical remission. Many chemotherapy agents and combinations result in high response rates in ED SCLC; however, median survival time remains 8–10 months. Cisplatin (or carboplatin) and etoposide is the standard doublet used in the United States. One study has shown cisplatin plus irinotecan to have a survival benefit over cisplatin plus etoposide, but confirmatory studies are needed. Patients with ED frequently relapse, and relapsed/refractory SCLC has a poor prognosis. The challenge remains to identify novel therapies and molecular targets to improve survival in SCLC.